Insulin resistance and steatosis in chronic hepatitis C

array:23 ["pii" => "S1665268119318290" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)31829-0" "estado" => "S300" "fechaPublicacion" => "2009-01-01" "aid" => "71491" "copyright" => "Fundación Clínica Médica Sur, A.C." "copyrightAnyo" => "2009" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2009;8 Supl 1:S67-75" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 63 "formatos" => array:3 [ "EPUB" => 11 "HTML" => 25 "PDF" => 27 ] ] "itemAnterior" => array:19 [ "pii" => "S1665268119318289" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)31828-9" "estado" => "S300" "fechaPublicacion" => "2009-01-01" "aid" => "71490" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2009;8 Supl 1:S60-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 62 "formatos" => array:3 [ "EPUB" => 11 "HTML" => 21 "PDF" => 30 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Is exercise an effective treatment for NASH? Knowns and unknowns" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "S60" "paginaFinal" => "S66" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1." "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 604 "Ancho" => 1504 "Tamanyo" => 96052 ] ] "descripcion" => array:1 [ "en" => "Potential mechanisms (mediators) of the therapeutic effect of exercise on NAFL/NASH." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Stephen Caldwell, Mariana Lazo" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Stephen" "apellidos" => "Caldwell" ] 1 => array:2 [ "nombre" => "Mariana" "apellidos" => "Lazo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119318289?idApp=UINPBA00004N" "url" => "/16652681/00000008000000S1/v1_201906260858/S1665268119318289/v1_201906260858/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "titulo" => "Insulin resistance and steatosis in chronic hepatitis C" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "S67" "paginaFinal" => "S75" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Mariana V. Machado, Helena Cortez-Pinto" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Mariana V." "apellidos" => "Machado" "email" => array:1 [ 0 => "hlcortezpinto@netcabo.pt" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] 1 => array:2 [ "nombre" => "Helena" "apellidos" => "Cortez-Pinto" ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Serviço de Gastrenterologia, Hospital de Santa Maria. Unidade de Nutrigao e Metabolismo, Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal." "etiqueta" => "1" "identificador" => "aff1" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Address for correspondence:" ] ] ] ] "textoCompleto" => "IntroductionChronic hepatitis C closely relates to hepatic steatosis and insulin resistance (IR)/ increased risk of type 2 diabetes mellitus (DM). Although this association may be a consequence of metabolic factors, hepatitis C virus (HCV) itself has the ability to directly promote steatosis and IR. This association is extremely important as it not only is very frequent, but it has a harmful influence in the prognosis and anti-viral treatment.This article aims to be an in depth review of the epidemiological data of IR/DM and steatosis in chronic hepatitis C, its mechanisms, and how it influences the response to anti-viral treatment and prognosis.EpidemiologyInsulin resistance/diabetes mellitusThe prevalence of DM in chronic hepatitis C patients is higher than the expected, having in consideration data from the general population. In patients with hepatic cirrhosis it is estimated to be 24-50%.<a class="elsevierStyleCrossRefs" href="#bib0005">1</a>-<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Hepatic cirrhosis is itself diabetogenic, however, the risk of DM in HCV related hepatic cirrhosis is 3 to 5 times greater than in other etiologies of hepatic cirrhosis, including hepatitis B virus (HBV) related.<a class="elsevierStyleCrossRefs" href="#bib0010">2</a>-<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The prevalence of DM in a non cirrhotic population with chronic hepatitis C is 7.6-21%, representing a 2 to 4 fold increased risk when compared to other forms of chronic hepatitis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>,<a class="elsevierStyleCrossRefs" href="#bib0030">6</a>-<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Only 4 studies failed to demonstrate a positive association between DM and HCV infection.<a class="elsevierStyleCrossRefs" href="#bib0080">16</a>-<a class="elsevierStyleCrossRef" href="#bib0095">19</a> A recent meta-analyses on 34 studies found an adjusted odds ratio of 1.67 (95% CI [1.28-2.06] relatively to non infected subjects.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> A follow up population study, a subset of ARIC - Atherosclerosis Risk in Communities Study, re-evaluated, at the end of 9 years, 1,084 patients without DM, and found that the subgroup of patients chronically infected by HCV had a 2 fold increased risk of developing DM, and that risk increased to 11 fold in high risk patients taking in consideration age and body mass index (BMI).<a class="elsevierStyleCrossRef" href="#bib0100">20</a> The opposite is also true, that is, patients with DM have a higher risk of being infected with HCV, as compared with the general population, being the prevalence of HCV seropositivity in patients with DM 4.2-10.5% in different studies.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> This can be explained by the induction of DM by HCV, but also by a greater susceptibility of patients with DM to be infected with HCV. In fact, a recent study in patients suffering from chronic renal failure in hemodialysis showed that patients with DM had a 10 fold increased risk of HCV infection, with a higher annual seroconversion rate (11 versus 7%) and in a smaller time period of hemodialysis (30 versus 50 months).<a class="elsevierStyleCrossRef" href="#bib0105">21</a>One explanation to the higher prevalence of DM could be a β-pancreatic cell dysfunction, as suggested by the fact that these patients present a blunted acute response of insulin secretion to hyperglycemia,<a class="elsevierStyleCrossRef" href="#bib0015">3</a> and also by the presence of HCV RNA in pancreatic tissue<a class="elsevierStyleCrossRef" href="#bib0110">22</a>,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> which may translate a direct cytopathic effect. However, it is now more consensual to accept the development of DM as a consequence of induction of IR.In fact, chronically HCV infected subjects present a 3 fold increased risk of IR and glucose metabolism impairment,<a class="elsevierStyleCrossRef" href="#bib0120">24</a>,<a class="elsevierStyleCrossRef" href="#bib0125">25</a> with IR occurring in very early stages of hepatic lesion (fibrosis stage 0 or 1),<a class="elsevierStyleCrossRef" href="#bib0130">26</a> with a worsening tendency as hepatic fibrosis progress.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>,<a class="elsevierStyleCrossRef" href="#bib0060">12</a>,<a class="elsevierStyleCrossRefs" href="#bib0130">26</a>-<a class="elsevierStyleCrossRef" href="#bib0145">29</a> IR severity can be genotype specific, although the different studies are not consensual in that regard: some authors found a greater IR severity in genotype 1 and 4 as compared to genotype 3,<a class="elsevierStyleCrossRef" href="#bib0035">7</a>,<a class="elsevierStyleCrossRef" href="#bib0130">26</a> others in genotype 2a as compared to genotype 1,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> and others failed to found an association with genotype.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>,<a class="elsevierStyleCrossRef" href="#bib0150">30</a> Two levels of evidence suggest a causal relation between HCV infection and DM: an association between IR severity and DM with higher viral load,<a class="elsevierStyleCrossRef" href="#bib0035">7</a>,<a class="elsevierStyleCrossRef" href="#bib0150">30</a>,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> and an improvement in IR after a sustained viral response (SVR) to anti-viral treatment as opposite to an unchanged IR in non responders, despite a decrease in BMI.<a class="elsevierStyleCrossRefs" href="#bib0160">32</a>-<a class="elsevierStyleCrossRef" href="#bib0170">34</a>SteatosisAlthough the estimated prevalence of hepatic steatosis in the general population is 20%, in patients with chronic hepatitis C it may vary from 40-80%, depending on alcohol consumption, obesity, diabetes and other risk factors to fatty liver.<a class="elsevierStyleCrossRefs" href="#bib0175">35</a>-<a class="elsevierStyleCrossRef" href="#bib0215">43</a> If all steatogenic co-factors are excluded, the prevalence of steatosis remains 50% (although present in less than 30% of the hepatocytes in about two thirds of the patients),<a class="elsevierStyleCrossRef" href="#bib0190">38</a>,<a class="elsevierStyleCrossRef" href="#bib0200">40</a> resulting in a 2.5 fold increased prevalence as compared with the general population and other forms of chronic liver disease,<a class="elsevierStyleCrossRefs" href="#bib0220">44</a>-<a class="elsevierStyleCrossRef" href="#bib0230">46</a> particularly HBV infection, in which the prevalence of steatosis is 18%.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> In chronic hepatitis C, although hepatic steatosis can be related to metabolic factors like obesity, dyslipidaemia and DM,<a class="elsevierStyleCrossRefs" href="#bib0190">38</a>-<a class="elsevierStyleCrossRefs" href="#bib0210">42</a>,<a class="elsevierStyleCrossRef" href="#bib0240">48</a>,<a class="elsevierStyleCrossRef" href="#bib0245">49</a> as much as one third of the patients with steatosis do not have any metabolic impairment.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> Also, steatosis is more frequent in HCV as compared to HBV infected subjects, even after adjustment to BMI. As shown in <a class="elsevierStyleCrossRef" href="#t0005">Table I</a>.<a class="elsevierStyleCrossRef" href="#bib0185">37</a><elsevierMultimedia ident="t0005"></elsevierMultimedia>Several lines of evidence suggest that steatosis can be attributed to HCV infection. Steatosis is more frequent in association to genotype 3a as compared to other genotypes (74 versus 50%),<a class="elsevierStyleCrossRef" href="#bib0130">26</a>,<a class="elsevierStyleCrossRef" href="#bib0195">39</a>,<a class="elsevierStyleCrossRef" href="#bib0215">43</a>,<a class="elsevierStyleCrossRef" href="#bib0240">48</a>,<a class="elsevierStyleCrossRefs" href="#bib0250">50</a>-<a class="elsevierStyleCrossRef" href="#bib0270">54</a> which suggests that some sequences of viral genome may be involved in the intracellular lipid accumulation. On the other hand, in genotype 3 infection, steatosis correlates to viral load<a class="elsevierStyleCrossRef" href="#bib0195">39</a>,<a class="elsevierStyleCrossRef" href="#bib0200">40</a>,<a class="elsevierStyleCrossRef" href="#bib0215">43</a>,<a class="elsevierStyleCrossRef" href="#bib0270">54</a> and can revert after effective treatment but reoccurs in re-infection,<a class="elsevierStyleCrossRef" href="#bib0200">40</a>,<a class="elsevierStyleCrossRef" href="#bib0275">55</a>,<a class="elsevierStyleCrossRef" href="#bib0280">56</a> the same having not been verified in the other genotypes.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>,<a class="elsevierStyleCrossRef" href="#bib0200">40</a>,<a class="elsevierStyleCrossRef" href="#bib0215">43</a> Also, the localization of steatosis, particularly in genotype 3 infected patients, is predominantly in periportal zone (acinar 1) and not in centrilobular zone (acinar 3) more typical of metabolic associated steatohepatitis.<a class="elsevierStyleCrossRef" href="#bib0285">57</a>It is now accepted that in chronic hepatitis C, there can occur two types of steatosis, a “metabolic” steatosis, that is consequence of metabolic factors like alcohol consumption and risk factors of non alcoholic fatty liver (the most important ones being obesity, visceral fat and IR); and a viral steatosis that may result from a direct viral cytopathic effect. The former associates to genotype 1, 2 and 4<a class="elsevierStyleCrossRef" href="#bib0195">39</a>,<a class="elsevierStyleCrossRef" href="#bib0240">48</a>,<a class="elsevierStyleCrossRef" href="#bib0290">58</a>,<a class="elsevierStyleCrossRef" href="#bib0295">59</a> and do not revert after anti-viral treatment.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> The latter associates to genotype 3 and does not relate to BMI or IR.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> However, even the “metabolic” steatosis can be partially an indirect consequence of viral infection, since HCV induces a metabolic deregulation with IR.PathogenesisIR occurs very early in HCV infection, in parallel with an elevation in TNF-α levels.<a class="elsevierStyleCrossRefs" href="#bib0300">60</a>-<a class="elsevierStyleCrossRef" href="#bib0315">63</a> TNF-α induces IR through the inhibition of insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation,<a class="elsevierStyleCrossRef" href="#bib0305">61</a>,<a class="elsevierStyleCrossRef" href="#bib0320">64</a> impairing the signaling pathway which would lead to the translocation of GLUT4 to the cell surface membrane, diminishing the cellular glucose uptake.HCV also directly promotes IR through the proteasomal degradation of IRS-1.<a class="elsevierStyleCrossRef" href="#bib0325">65</a>,<a class="elsevierStyleCrossRef" href="#bib0330">66</a> The molecular mechanism that leads to IRS-1 degradation varies according to genotype.<a class="elsevierStyleCrossRef" href="#bib0335">67</a> Genotype 1 promotes the expression of SOCS-3 (suppressor of cytokine signaling 3), a negative regulator of insulin signaling, which acts through the IRS-1 ubiquitination, targeting it to proteasomes where it is destroyed. Genotype 1b also diminishes IRS-1 levels, trough the activation of mTOR (mammalian target of rapamycin) which induces serine/threonine phosphorylation, redistribution and proteasomal degradation of IRS-1.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> Genotype 3 promotes SOCS 7 expression,<a class="elsevierStyleCrossRef" href="#bib0345">69</a> with a mechanism of IRS-1 degradation similar to that induced by SOCS 3; it also inhibits PPAR-γ, further worsening IR.<a class="elsevierStyleCrossRef" href="#bib0335">67</a>Lastly, HCV induces protein phosphatase 2A expression, through an endoplasmic reticulum stress response pathway, which dephosphorylates PkB/Akt (a main enzyme in the insulin signaling pathway), and thereby lowers its kinase activity.<a class="elsevierStyleCrossRef" href="#bib0350">70</a>HCV infection can indirectly promote the development of hepatic steatosis, but it is itself steatogenic. All genotypes are steatogenic, however genotype 3 is three times more potent.<a class="elsevierStyleCrossRef" href="#bib0355">71</a> In fact, animal models with transgenic mice showed that the core protein can induce the appearance of lipid droplets.<a class="elsevierStyleCrossRef" href="#bib0360">72</a> More recently, in vitro and in vivo studies showed a topological relation, with the core protein being localized in the membrane of those lipidic vesicles.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> We already know what sequences in core protein are essential to that preferential localization.<a class="elsevierStyleCrossRef" href="#bib0370">74</a>,<a class="elsevierStyleCrossRef" href="#bib0375">75</a> One possible molecular explanation to a greater steatogenic property of genotype 3, could be a phenylalanine residue at position 164 in core protein domain II, instead of tyrosine like in other genotypes, what translates in a higher affinity to lipids.<a class="elsevierStyleCrossRef" href="#bib0380">76</a>Steatosis can be induced in 3 ways: decreasing the lipids export by hepatocytes, decreasing fatty acids consumption (that is its oxidation) or increasing de novo synthesis.Decreased hepatocyte lipid export is a consequence of a decreased assembly of triglycerides in VLDL (very low density lipoproteins) particles and its secretion. Animal models and studies in humans, demonstrated that core protein inhibits microsomal triglyceride transfer protein (MTP) activity,<a class="elsevierStyleCrossRef" href="#bib0385">77</a> an enzyme that transfers lipids to endo-plasmic reticulum, allowing its association to B apolipo-protein and triglycerides rich VLDL assembly. That inhibition occurs in all genotypes, however it is more potent with genotype 3;<a class="elsevierStyleCrossRef" href="#bib0390">78</a> in genotype 1 and 2 infected patients, the decreased MTP activity seems to be a consequence of a reduced transcription induced by IR and hyperinsulinism. In fact, insulin inhibits MTP expression through a MAP-Kerk (mitogen-activated extracellular signal-regulated protein kinase) pathway.<a class="elsevierStyleCrossRef" href="#bib0395">79</a>,<a class="elsevierStyleCrossRef" href="#bib0400">80</a> In accordance to MTP dysfunction, HCV infected patients with severe steatosis present decreased cholesterol and apo B plasma levels.<a class="elsevierStyleCrossRef" href="#bib0405">81</a>,<a class="elsevierStyleCrossRef" href="#bib0410">82</a>Other animal models propose an inhibition of VLDL secretion by a different mechanism, oxidative stress dependent. Oxygen reactive species are a consequence of mitochondrial respiratory chain impairment, when a small proportion of electron efflux interacts with oxygen molecules before reaching the cytochrome oxidase complex.<a class="elsevierStyleCrossRef" href="#bib0415">83</a> Core protein may accumulate in mitochondria, impairing electron transport and thus increasing the production of oxygen reactive species.<a class="elsevierStyleCrossRef" href="#bib0420">84</a> Oxidative stress leads to cellular damage through lipids and structural proteins peroxidation, disturbing the cellular traffic apparatus and VLDL secretion.<a class="elsevierStyleCrossRef" href="#bib0425">85</a> Recently a study suggested that HCV can impair the lipid cellular metabolism, through a modification in the response to VLDL and LDL. In fact, Napolitano et al. demonstrated an impaired metabolic response to VLDL and LDL isolated from patients infected with HCV, with a slower VLDL catabolism, which can result in a higher VLDL-LDL switch in circulation. They also showed a higher LDL catabolism with subsequent intracellular lipid accumulation leading to steatosis. The mechanism of response modulation to VLDL/LDL still needs to be explained, but it can be a consequence of a direct binding between HCV and lipoproteins or a modification in their molecular composition.<a class="elsevierStyleCrossRef" href="#bib0430">86</a>A second steatogenic pathway is decreased fatty acids consumption, through mitochondrial beta-oxidation inhibition. In fact, core protein may induce structural changes in mitochondria membranes, with subsequent derangement of lipid β-oxidation, promoting steatosis.<a class="elsevierStyleCrossRef" href="#bib0435">87</a> More recently, it has also been demonstrated a diminished PPARα (peroxisome proliferators-activated receptor α expression induced by core protein<a class="elsevierStyleCrossRefs" href="#bib0440">88</a>-<a class="elsevierStyleCrossRef" href="#bib0455">91</a> which is more potent with genotype 3 as compared to genotype 1.<a class="elsevierStyleCrossRef" href="#bib0455">91</a> PPAR-α is a nuclear receptor that regulates the transcription of several major genes in the lipids metabolism, for instance CPT1A (mitochondrial carnitine palmitoyl acyl-CoA transferase 1), which is a rate limiting enzyme in the mitochondrial β-oxidation mediating the entry of fatty acids in the mitochondria; ACOX (acyl-CoA oxidase), the main enzyme in mitochondrial β-oxidation; and Mdr2, a transport protein in canalicula membranes which controls biliary phospholipids secretion. Several experimental models showed a diminished PPAR-α expression and transcriptional activity, with a decreased CPT1A and ACOX expression with decreased fatty acids oxidation, as well as a decreased Mdr2 expression with a potential decrease in phospholipids associated fatty acids biliary excretion.<a class="elsevierStyleCrossRefs" href="#bib0440">88</a>-<a class="elsevierStyleCrossRef" href="#bib0455">91</a>A third steatogenic mechanism is the promotion of de novo fatty acids synthesis. A chimpanzee animal model showed an early SREBP-lc (sterol regulatory element binding protein signaling pathway) expression induction after HCV infection.<a class="elsevierStyleCrossRef" href="#bib0460">92</a> SREBP-lc is a transcriptional factor that regulates several genes in lipid metabolism, namely fatty acids syntethase, acetyl-CoA carboxylase and stearoyl-CoA desaturase, key lipogenic enzymes which are also overexpressed in HCV infection.<a class="elsevierStyleCrossRefs" href="#bib0465">93</a>-<a class="elsevierStyleCrossRef" href="#bib0475">95</a> Additionally, core protein also binds to DNA-binding domain of RXRα (retinoid X receptor α - a nuclear receptor that regulates several genes involved in cellular lipids synthesis), increasing its transcriptional activity.<a class="elsevierStyleCrossRef" href="#bib0480">96</a>Interestingly, hepatic steatosis may promote viral replication. HCV may associate to LDL in lipo-viral particles that circulate in blood stream.<a class="elsevierStyleCrossRef" href="#bib0485">97</a> Therefore, LDL receptors allow HCV cellular intake,<a class="elsevierStyleCrossRefs" href="#bib0490">98</a>-<a class="elsevierStyleCrossRef" href="#bib0500">100</a> and VLDL/LDL plasma levels may regulate HCV binding to its target by competitive inhibition. So, when HCV promotes lower VLDL plasma levels, it enhances its cellular dissemination.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>Consequences in the prognosis of chronic hepatitis CIR favors fibrosis progression in chronic hepatitis C.<a class="elsevierStyleCrossRef" href="#bib0130">101</a>,<a class="elsevierStyleCrossRef" href="#bib0510">102</a> Hyperinsulinism, IR related, directly activates stellate cells<a class="elsevierStyleCrossRef" href="#bib0515">103</a> and, in association to hyperglycemia, it increases connective tissue growth factor (CTGF),<a class="elsevierStyleCrossRef" href="#bib0520">104</a> a key cytokine in hepatic fibrogenesis.<a class="elsevierStyleCrossRef" href="#bib0525">105</a>, <a class="elsevierStyleCrossRef" href="#bib0530">106</a> Steatosis also relates to more advanced fibrosis<a class="elsevierStyleCrossRef" href="#bib0175">35</a>,<a class="elsevierStyleCrossRef" href="#bib0190">38</a>,<a class="elsevierStyleCrossRef" href="#bib0240">48</a>,<a class="elsevierStyleCrossRef" href="#bib0290">58</a> and to accelerated fibrosis progression,<a class="elsevierStyleCrossRef" href="#bib0195">39</a>, <a class="elsevierStyleCrossRef" href="#bib0535">107</a>, <a class="elsevierStyleCrossRef" href="#bib0540">108</a> in such a way that some authors suggest treating HCV infected patients with evidence of hepatic steatosis, even if they only present mild inflammatory activity. Steatosis may sensitize the liver to inflammation<a class="elsevierStyleCrossRef" href="#bib0175">35</a> and apoptosis, and subsequently enhance fibrosis.<a class="elsevierStyleCrossRef" href="#bib0545">109</a> In fact, a recent study showed that hepatic steatosis associates to higher programmed cell death by apoptosis with stellate cells activation.<a class="elsevierStyleCrossRef" href="#bib0545">109</a>DM associates to a decreased life expectancy in cirrhotic patients,<a class="elsevierStyleCrossRef" href="#bib0550">110</a> as well as an earlier progression to more severe hepatic encephalopathy.<a class="elsevierStyleCrossRef" href="#bib0555">111</a> The mechanism that favors encephalopathy is still not known, but it may be dependent on diabetes-related autonomic neuropathy and subsequent constipation and/or impairment in ammonia metabolism.<a class="elsevierStyleCrossRef" href="#bib0560">112</a> A recent study also demonstrated IR as a risk factor to portal hypertension and the development of esophageal varices.<a class="elsevierStyleCrossRef" href="#bib0565">113</a> In fact, the authors found that HOMA-IR index higher than 3.5 was a good predictor of esophageal varices presence, with an AUC 0.80.DM is a risk factor for the development of hepatocellular carcinoma.<a class="elsevierStyleCrossRef" href="#bib0570">114</a> Regarding a possible association between hepatic steatosis and hepatic carcinogenesis, different studies show opposite results.<a class="elsevierStyleCrossRefs" href="#bib0575">115</a>-<a class="elsevierStyleCrossRef" href="#bib0585">117</a>Treatment implicationsObesity and steatosis decrease anti-viral treatment response.<a class="elsevierStyleCrossRef" href="#bib0200">40</a>,<a class="elsevierStyleCrossRef" href="#bib0270">54</a>,<a class="elsevierStyleCrossRefs" href="#bib0590">118</a>-<a class="elsevierStyleCrossRef" href="#bib0610">122</a> However, that negative influence seems to be limited to metabolic steatosis and not to viral one, since genotype 3 associated steatosis does not seem to change the response to anti-viral treatment.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Patients with BMI higher than 30 kg/m2 have a 4 fold lower chance of sustained viral response.<a class="elsevierStyleCrossRef" href="#bib0590">118</a> A pilot study showed that weight loss, even if mild, associates to an improvement not only in steatosis, but also in fibrosis, in patients with chronic hepatitis C, after as little as 3 months.<a class="elsevierStyleCrossRef" href="#bib0615">123</a>,<a class="elsevierStyleCrossRef" href="#bib0620">124</a>There are 3 mechanisms which may explain why obesity compromises anti-viral treatment response. First, obesity may interfere with interferon bio-availability. In fact, subcutaneous administration of pegylated interferon in obese patients may decrease its absorption as a consequence of defective subcutaneous lymph drainage, leading to lower plasma levels.<a class="elsevierStyleCrossRef" href="#bib0625">125</a>Another proposed mechanism is obesity as a pro-inflammatory state<a class="elsevierStyleCrossRef" href="#bib0630">126</a> with a negative influence in immune response to therapy. Several adipokines may have a major role in that immune deregulation. Leptine is an adipocyte secreted cytokine that is increased in obesity. However, in obesity, despite there is hyperleptinemia, there is also resistance to leptin actions.<a class="elsevierStyleCrossRef" href="#bib0635">127</a> Leptine has a pro-inflammatory action promoting Th1 immune response, which is believed to be essential in achieving a sustained response to interferon. Therefore, leptin resistance may have a negative influence in anti-viral treatment.<a class="elsevierStyleCrossRef" href="#bib0640">128</a> Another important cytokine is adiponectin, which has an anti-inflammatory activity antagonizing TNF-α,<a class="elsevierStyleCrossRef" href="#bib0645">129</a> being decreased in obesity and HCV infection.<a class="elsevierStyleCrossRef" href="#bib0650">130</a>,<a class="elsevierStyleCrossRef" href="#bib0655">131</a> On the contrary, TNF-α not only has a pro-inflammatory activity, as directly promotes IR, and inversely correlates to anti-viral treatment response.<a class="elsevierStyleCrossRef" href="#bib0660">132</a>Lastly, obesity promotes IR, which is known to associate to a negative influence in anti-viral treatment response.<a class="elsevierStyleCrossRefs" href="#bib0665">133</a>-<a class="elsevierStyleCrossRef" href="#bib0675">135</a> In fact, Romero-Gomez et al. showed 33% sustained viral response rate in genotype 1 in patients with IR, as opposed to 66% in patients without IR.<a class="elsevierStyleCrossRef" href="#bib0680">136</a> Also, Poustchi et al. found a 6.5 times lower sustained viral response in patients with IR.<a class="elsevierStyleCrossRef" href="#bib0675">135</a> The association between IR and no response to anti-viral treatment may be a due to a SOCS-3 activation, which not only promotes IR, but also inhibits STAT-1 (signal transducer and activator of transcription).<a class="elsevierStyleCrossRef" href="#bib0685">137</a> After α interferon binds to its receptor, it activates tyrosine kinases that phosphorylate STAT-1, promoting its migration to the nucleus, where it regulates several anti-viral genes transcription. SOCS-3 protein inhibits that tyrosine phosphorylation, thus inhibiting α interferon action.<a class="elsevierStyleCrossRef" href="#bib0690">138</a>We still do not know whether treating IR actually translates in a better response to a interferon. At the moment, patients should be advised to change to healthier life styles that promote less IR, as weight loss and physical exercise; however medication with insulin sensitizer agents in this context still do not have an evidence based fundament,<a class="elsevierStyleCrossRef" href="#bib0695">139</a> although a small retrospective study suggests that a better glycemic control may improve survival in these patients.<a class="elsevierStyleCrossRef" href="#bib0700">140</a> However, a pilot study in previously non responders to standard anti-viral therapy with IR, showed no benefit of a triple therapy with pioglita-zone.<a class="elsevierStyleCrossRef" href="#bib0705">141</a>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres1212009" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0010" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1128079" "titulo" => "Key words" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Epidemiology" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Insulin resistance/diabetes mellitus" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Steatosis" ] ] ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Pathogenesis" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Consequences in the prognosis of chronic hepatitis C" ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Treatment implications" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2008-12-21" "fechaAceptado" => "2008-12-21" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key words" "identificador" => "xpalclavsec1128079" "palabras" => array:4 [ 0 => "Steatosis" 1 => "insulin resistance" 2 => "diabetes mellitus" 3 => "chronic hepatitis C" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "In chronic hepatitis C, insulin resistance (IR) and type 2 diabetes mellitus (DM) are more prevalent than in healthy controls or in chronic hepatitis B patients. HCV infection promotes IR mainly through increased TNF-α and cytokine suppressor (SOCS-3) production. Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. Hepatic steatosis is also 2.5 fold more frequent in hepatitis C virus (HCV) infected patients as compared to the general population. Metabolic factors play a crucial role in the etiology of hepatic steatosis genotype non-3 related, which are also the genotypes with a greater association to IR. However, genotype 3, and particularly 3a, has a greater direct steatogenic capacity, and consequently, in those patients, the association with metabolic factors is weaker. Instead, in genotype 3, steatosis associates with viral factors like viral load. Those metabolic factors influence not only the natural history of HCV infection, as well as associate to an accelerated hepatic fibrosis progression, to a worse prognosis when hepatic cirrhosis is present, namely an increased risk of hepatocellular carcinoma, and to a lower sustained viral response rate. On the other hand, in patients who achieve viral eradication, IR and hepatic steatosis may regress, and return if viral infection recurs, which once again indicates an intrinsic steatosis and IR promoter action by HCV." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table I" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "NA = not available, BMI = body mass index, DM = diabetes mellitus." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " rowspan="3" align="left" valign="top" scope="col">Reference</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " rowspan="3" align="left" valign="top" scope="col">Number of patients</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " rowspan="3" align="left" valign="top" scope="col">Steatosis (% of patients)</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="6" align="left" valign="top" scope="col">Association to Steatosis</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="left" valign="top" scope="col">Host factors</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="left" valign="top" scope="col">Viral factors</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">BMI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Alcohol \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">DM \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Genotype \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Viral load \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Fibrosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Leandro 20 06<a class="elsevierStyleCrossRef" href="#bib0175">35</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">3,068 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Rubbia-Brandt 2004<a class="elsevierStyleCrossRef" href="#bib0290">58</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">755 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Patton 2004<a class="elsevierStyleCrossRef" href="#bib0270">54</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">574 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Poynard 2003<a class="elsevierStyleCrossRef" href="#bib0200">40</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">1,428 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Asselah 2003<a class="elsevierStyleCrossRef" href="#bib0710">142</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">290 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Castera 2003<a class="elsevierStyleCrossRef" href="#bib0715">143</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Monto 2002<a class="elsevierStyleCrossRef" href="#bib0240">48</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">297 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Serfaty 2002<a class="elsevierStyleCrossRef" href="#bib0720">144</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">142 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Hui 2002<a class="elsevierStyleCrossRef" href="#bib0260">52</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">124 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Westin 2002<a class="elsevierStyleCrossRef" href="#bib0725">145</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">98 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Ong 2001<a class="elsevierStyleCrossRef" href="#bib0730">146</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">170 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Hwang 2001<a class="elsevierStyleCrossRef" href="#bib0210">42</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">106 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Adinolfi 2001<a class="elsevierStyleCrossRef" href="#bib0195">39</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">180 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Rubbia-Brandt 2000<a class="elsevierStyleCrossRef" href="#bib0255">51</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">101 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Hourigan 1999<a class="elsevierStyleCrossRef" href="#bib0190">38</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">148 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Giannini 1999<a class="elsevierStyleCrossRef" href="#bib0735">147</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">172 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Czaja 1998<a class="elsevierStyleCrossRef" href="#bib0185">37</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Mihm 1997<a class="elsevierStyleCrossRef" href="#bib0250">50</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes, 3a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Wong 1996<a class="elsevierStyleCrossRef" href="#bib0740">148</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Fiore 1996<a class="elsevierStyleCrossRef" href="#bib0205">41</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="right" valign="middle">121 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">no \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">yes \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2069130.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Factors associated to hepatic steatosis in chronic hepatitis C." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:148 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance and hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v12.i44.7075" "Revista" => array:6 [ "tituloSerie" => "World J Gastroenterol" "fecha" => "2006" "volumen" => "12" "paginaInicial" => "7075" "paginaFinal" => "7080" "link" => array:1 [ …1] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of diabetes mellitus in Japanese patients infected chronically with hepatitis C virus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s005350300063" "Revista" => array:6 [ "tituloSerie" => "J Gastroenterol" "fecha" => "2003" "volumen" => "38" "paginaInicial" => "355" "paginaFinal" => "360" "link" => array:1 [ …1] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510300416" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1999" "volumen" => "30" "paginaInicial" => "1059" "paginaFinal" => "1063" "link" => array:1 [ …1] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "1994" "volumen" => "21" "paginaInicial" => "1135" "paginaFinal" => "1139" "link" => array:1 [ …1] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2000" "volumen" => "32" "paginaInicial" => "209" "paginaFinal" => "217" "link" => array:1 [ …1] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C infection and risk of diabetes: A systematic review and meta-analysis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2008.08.006" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2008" "volumen" => "49" "paginaInicial" => "831" "paginaFinal" => "844" "link" => array:1 [ …1] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2007.11.010" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2008" "volumen" => "134" "paginaInicial" => "416" "paginaFinal" => "423" "link" => array:1 [ …1] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of diabetes mellitus and chronic hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510290235" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1999" "volumen" => "29" "paginaInicial" => "328" "paginaFinal" => "333" "link" => array:1 [ …1] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Community-based study of hepatitis C virus infection and type 2 diabetes: an association affected by age and hepatitis severity status" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/aje/kwg259" "Revista" => array:6 [ "tituloSerie" => "Am J Epidemiol" "fecha" => "2003" "volumen" => "158" "paginaInicial" => "1154" "paginaFinal" => "1160" "link" => array:1 [ …1] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7326/0003-4819-133-8-200010170-00009" "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "2000" "volumen" => "133" "paginaInicial" => "592" "paginaFinal" => "599" "link" => array:1 [ …1] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High prevalence of diabetes mellitus among adult beta-thalassaemic patients with chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Gastroenterol Hepatol" "fecha" => "1999" "volumen" => "11" "paginaInicial" => "1033" "paginaFinal" => "1036" "link" => array:1 [ …1] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2005.40429.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2005" "volumen" => "100" "paginaInicial" => "48" "paginaFinal" => "55" "link" => array:1 [ …1] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes mellitus is associated with chronic hepatitis C but not chronic hepatitis B infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Isr J Med Sci" "fecha" => "1996" "volumen" => "32" "paginaInicial" => "526" "paginaFinal" => "530" "link" => array:1 [ …1] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High prevalence of hepatitis C virus infection in diabetic patients" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.19.9.998" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "1996" "volumen" => "19" "paginaInicial" => "998" "paginaFinal" => "1000" "link" => array:1 [ …1] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of chronic hepatitis C infection and diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Trop Gastroenterol" "fecha" => "1998" "volumen" => "19" "paginaInicial" => "141" "paginaFinal" => "144" "link" => array:1 [ …1] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glycemic homeostasis in chronic viral hepatitis and liver cirrhosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Metab" "fecha" => "2001" "volumen" => "27" "paginaInicial" => "476" "paginaFinal" => "481" "link" => array:1 [ …1] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2893.2005.00677.x" "Revista" => array:7 [ "tituloSerie" => "J Viral Hepat" "fecha" => "2006" "volumen" => "13" "paginaInicial" => "303" "paginaFinal" => "310" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver cirrhosis and diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Hepatol" "fecha" => "1996" "volumen" => "24" "paginaInicial" => "645" "link" => array:1 [ …1] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HCV and diabetes mellitus: evidence for a negative association" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.1998.00688.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "1998" "volumen" => "93" "paginaInicial" => "2363" "paginaFinal" => "2367" "link" => array:1 [ …1] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus infection and incident type 2 diabetes" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2003.50291" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2003" "volumen" => "38" "paginaInicial" => "50" "paginaFinal" => "56" "link" => array:1 [ …1] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The susceptibility of patients with type-2 diabetes to hepatitis C virus infection during long-term haemodialysis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "2003/45/smw-10402" "Revista" => array:6 [ "tituloSerie" => "Swiss Med Wkly" "fecha" => "2003" "volumen" => "133" "paginaInicial" => "611" "paginaFinal" => "618" "link" => array:1 [ …1] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Distribution of markers of hepatitis C virus infection throughout the body" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "2000" "volumen" => "20" "paginaInicial" => "85" "paginaFinal" => "102" "link" => array:1 [ …1] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome: specific detection of negative-strand viral RNA in various tissues" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510280531" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1998" "volumen" => "28" "paginaInicial" => "1398" "paginaFinal" => "1401" "link" => array:1 [ …1] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.27.5.1171" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2004" "volumen" => "27" "paginaInicial" => "1171" "paginaFinal" => "1175" "link" => array:1 [ …1] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chronic hepatitis C virus infection without cirrhosis induces insulin resistance in patients with alpha-thalassaemia major" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Gastroenterol Hepatol" "fecha" => "2001" "volumen" => "13" "paginaInicial" => "1195" "paginaFinal" => "1199" "link" => array:1 [ …1] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2003" "volumen" => "125" "paginaInicial" => "1695" "paginaFinal" => "1704" "link" => array:1 [ …1] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C." "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2001" "volumen" => "35" "paginaInicial" => "279" "paginaFinal" => "283" "link" => array:1 [ …1] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2006.00835.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2006" "volumen" => "101" "paginaInicial" => "2752" "paginaFinal" => "2759" "link" => array:1 [ …1] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severity of HCV-induced liver damage alters glucose homeostasis in noncirrhotic patients with chronic HCV infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000007778" "Revista" => array:6 [ "tituloSerie" => "Digestion" "fecha" => "2000" "volumen" => "62" "paginaInicial" => "52" "paginaFinal" => "59" "link" => array:1 [ …1] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C viremia increases the association with type 2 diabetes mellitus in a hepatitis B and C endemic area: an epidemiological link with virological implication" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2007.01181.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2007" "volumen" => "102" "paginaInicial" => "1237" "paginaFinal" => "1243" "link" => array:1 [ …1] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1478-3231.2007.01626.x" "Revista" => array:6 [ "tituloSerie" => "Liver Int" "fecha" => "2008" "volumen" => "28" "paginaInicial" => "271" "paginaFinal" => "277" "link" => array:1 [ …1] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2006.01038.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2007" "volumen" => "102" "paginaInicial" => "570" "paginaFinal" => "576" "link" => array:1 [ …1] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interferon-alpha reduces insulin resistance and beta-cell secretion in responders among patients with chronic hepatitis B and C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Endocrinol" "fecha" => "2003" "volumen" => "178" "paginaInicial" => "457" "paginaFinal" => "465" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc06-0456" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2006" "volumen" => "29" "paginaInicial" => "2462" "paginaFinal" => "2466" "link" => array:1 [ …1] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2006.03.014" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2006" "volumen" => "130" "paginaInicial" => "1636" "paginaFinal" => "1642" "link" => array:1 [ …1] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis in chronic hepatitis C: why does it really matter?" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.2005.069757" "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "2006" "volumen" => "55" "paginaInicial" => "123" "paginaFinal" => "130" "link" => array:1 [ …1] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Host-and disease-specific factors affecting steatosis in chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "1998" "volumen" => "29" "paginaInicial" => "198" "paginaFinal" => "206" "link" => array:1 [ …1] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510290401" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1999" "volumen" => "29" "paginaInicial" => "1215" "paginaFinal" => "1219" "link" => array:1 [ …1] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2001.24432" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2001" "volumen" => "33" "paginaInicial" => "1358" "paginaFinal" => "1364" "link" => array:1 [ …1] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2003.50267" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2003" "volumen" => "38" "paginaInicial" => "75" "paginaFinal" => "85" "link" => array:1 [ …1] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver steatosis and chronic hepatitis C: a spurious association?" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Gastroenterol Hepatol" "fecha" => "1996" "volumen" => "8" "paginaInicial" => "125" "paginaFinal" => "129" "link" => array:1 [ …1] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Gastroenterol Hepatol" "fecha" => "2001" "volumen" => "16" "paginaInicial" => "190" "paginaFinal" => "195" "link" => array:1 [ …1] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22392" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2008" "volumen" => "48" "paginaInicial" => "723" "paginaFinal" => "731" "link" => array:1 [ …1] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2004" "volumen" => "126" "paginaInicial" => "586" "paginaFinal" => "597" "link" => array:1 [ …1] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1993" "volumen" => "104" "paginaInicial" => "595" "paginaFinal" => "603" "link" => array:1 [ …1] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C and steatosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arcmed.2006.09.001" "Revista" => array:6 [ "tituloSerie" => "Arch Med Res" "fecha" => "2007" "volumen" => "38" "paginaInicial" => "621" "paginaFinal" => "627" "link" => array:1 [ …1] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Gastroenterol Hepatol" "fecha" => "2006" "volumen" => "18" "paginaInicial" => "233" "paginaFinal" => "237" "link" => array:1 [ …1] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.35064" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2002" "volumen" => "36" "paginaInicial" => "729" "paginaFinal" => "736" "link" => array:1 [ …1] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2001" "volumen" => "34" "paginaInicial" => "314" "paginaFinal" => "320" "link" => array:1 [ …1] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of histo-pathological manifestations of chronic hepatitis C virus infection with respect to virus genotype" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510250340" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1997" "volumen" => "25" "paginaInicial" => "735" "paginaFinal" => "739" "link" => array:1 [ …1] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2000" "volumen" => "33" "paginaInicial" => "106" "paginaFinal" => "115" "link" => array:1 [ …1] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Gastroenterol Hepatol" "fecha" => "2002" "volumen" => "17" "paginaInicial" => "873" "paginaFinal" => "881" "link" => array:1 [ …1] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.21711" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2007" "volumen" => "46" "paginaInicial" => "380" "paginaFinal" => "387" "link" => array:1 [ …1] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2003.11.004" "Revista" => array:6 [ "tituloSerie" => "J Hepatol" "fecha" => "2004" "volumen" => "40" "paginaInicial" => "484" "paginaFinal" => "490" "link" => array:1 [ …1] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus genotype 3 is cytopathic to hepatocytes: Reversal of hepatic steatosis after sustained therapeutic response" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.36370" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2002" "volumen" => "36" "paginaInicial" => "1266" "paginaFinal" => "1272" "link" => array:1 [ …1] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0280" "etiqueta" => "56." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.2002.009936" "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "2004" "volumen" => "53" "paginaInicial" => "420" "paginaFinal" => "424" "link" => array:1 [ …1] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0285" "etiqueta" => "57." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jcp.54.6.461" "Revista" => array:6 [ "tituloSerie" => "J Clin Pathol" "fecha" => "2001" "volumen" => "54" "paginaInicial" => "461" "paginaFinal" => "465" "link" => array:1 [ …1] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0290" "etiqueta" => "58." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis affects chronic hepatitis C progression in a genotype specific way" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.2003.018770" "Revista" => array:7 [ "tituloSerie" => "Gut" "fecha" => "2004" "volumen" => "53" "paginaInicial" => "406" "paginaFinal" => "412" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0295" "etiqueta" => "59." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2006.01025.x" "Revista" => array:6 [ "tituloSerie" => "Am J Gastroenterol" "fecha" => "2007" "volumen" => "102" "paginaInicial" => "634" "paginaFinal" => "641" "link" => array:1 [ …1] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0300" "etiqueta" => "60." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2004" "volumen" => "126" "paginaInicial" => "840" "paginaFinal" => "848" "link" => array:1 [ …1] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0305" "etiqueta" => "61." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "TNF-{alpha}, chronic hepatitis C and diabetes: a novel triad" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/qjmed/hci001" "Revista" => array:6 [ "tituloSerie" => "Qjm" "fecha" => "2005" "volumen" => "98" "paginaInicial" => "1" "paginaFinal" => "6" "link" => array:1 [ …1] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0310" "etiqueta" => "62." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Gastroenterol Hepatol" …5 ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0315" "etiqueta" => "63." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diacare.2951096" "Revista" => array:6 [ …6] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0320" "etiqueta" => "64." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of TNFalpha and TNF receptors in obesity and insulin resistance" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0325" "etiqueta" => "65." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0002-9440(10)63408-6" "Revista" => array:6 [ …6] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0330" "etiqueta" => "66." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.hep.2003.09.012" "Revista" => array:6 [ …6] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0335" "etiqueta" => "67." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms." "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.21634" "Revista" => array:6 [ …6] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0340" "etiqueta" => "68." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/mend.14.6.0446" "Revista" => array:6 [ …6] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.C200444200" "Revista" => array:6 [ …6] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2008.04.007" "Revista" => array:6 [ …6] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2004.12.034" "Revista" => array:6 [ …6] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus core protein induces hepatic steatosis in transgenic mice" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1099/0022-1317-78-7-1527" "Revista" => array:7 [ …7] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0365" "etiqueta" => "73." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Topological and evolutional relationships between HCV core protein and hepatic lipid vesicles: studies in vitro and in conditionally transgenic mice" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v13.i25.3472" "Revista" => array:6 [ …6] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0370" "etiqueta" => "74." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1099/0022-1317-81-8-1913" "Revista" => array:6 [ …6] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0375" "etiqueta" => "75." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structural determinants that target the hepatitis C virus core protein to lipid droplets" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.M601031200" "Revista" => array:6 [ …6] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0380" "etiqueta" => "76." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.2006.108647" "Revista" => array:6 [ …6] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0385" "etiqueta" => "77." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1096/fj.01-0396com" "Revista" => array:6 [ …6] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0390" "etiqueta" => "78." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2006.02.035" "Revista" => array:6 [ …6] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0395" "etiqueta" => "79." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0400" "etiqueta" => "80." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/diabetes.52.5.1073" "Revista" => array:7 [ …7] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0405" "etiqueta" => "81." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2003.07402.x" "Revista" => array:6 [ …6] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0410" "etiqueta" => "82." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ …7] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0415" "etiqueta" => "83." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative stress: role of mitochondria and protection by glutathione" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0420" "etiqueta" => "84." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0425" "etiqueta" => "85." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms and significance of liver steatosis in hepatitis C virus infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v12.i42.6756" "Revista" => array:6 [ …6] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0430" "etiqueta" => "86." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Very low density lipoprotein and low density lipoprotein isolated from patients with hepatitis C infection induce altered cellular lipid metabolism" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jmv.20793" "Revista" => array:6 [ …6] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib0435" "etiqueta" => "87." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/2053" "Revista" => array:6 [ …6] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib0440" "etiqueta" => "88." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 88 => array:3 [ "identificador" => "bib0445" "etiqueta" => "89." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Desreumaux P. Hepatitis C virus infection down-regulates the expression of peroxisome proliferator-activated receptor alpha and carnitine palmitoyl acyl-CoA transferase 1A" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v11.i48.7591" "Revista" => array:6 [ …6] ] ] ] ] ] 89 => array:3 [ "identificador" => "bib0450" "etiqueta" => "90." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 90 => array:3 [ "identificador" => "bib0455" "etiqueta" => "91." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Peroxi-some proliferator-activated receptor-alpha and-gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2036.2006.02729.x" "Revista" => array:6 [ …6] ] ] ] ] ] 91 => array:3 [ "identificador" => "bib0460" "etiqueta" => "92." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genomic analysis of the host response to hepatitis C virus infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.202608199" "Revista" => array:6 [ …6] ] ] ] ] ] 92 => array:3 [ "identificador" => "bib0465" "etiqueta" => "93." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbrc.2007.02.044" "Revista" => array:6 [ …6] ] ] ] ] ] 93 => array:3 [ "identificador" => "bib0470" "etiqueta" => "94." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enhancement of de novo fatty acid biosynthesis in hepatic cell line Huh7 expressing hepatitis C virus core protein" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 94 => array:3 [ "identificador" => "bib0475" "etiqueta" => "95." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2006.10.019" "Revista" => array:6 [ …6] ] ] ] ] ] 95 => array:3 [ "identificador" => "bib0480" "etiqueta" => "96." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2002.32470" "Revista" => array:6 [ …6] ] ] ] ] ] 96 => array:3 [ "identificador" => "bib0485" "etiqueta" => "97." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characterization of low-and very-low-density hepatitis C virus RNA-containing particles" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/jvi.76.14.6919-6928.2002" "Revista" => array:7 [ …7] ] ] ] ] ] 97 => array:3 [ "identificador" => "bib0490" "etiqueta" => "98." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low density lipoprotein receptor as a candidate receptor for hepatitis C virus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 98 => array:3 [ "identificador" => "bib0495" "etiqueta" => "99." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus and other flaviviridae viruses enter cells via low density lipo-protein receptor" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.96.22.12766" "Revista" => array:6 [ …6] ] ] ] ] ] 99 => array:3 [ "identificador" => "bib0500" "etiqueta" => "100." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cell surface expression of LDL receptor in chronic hepatitis C: correlation with viral load" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/ajpendo.00091.2007" "Revista" => array:6 [ …6] ] ] ] ] ] 100 => array:3 [ "identificador" => "bib0505" "etiqueta" => "101." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2008.01813.x" "Revista" => array:6 [ …6] ] ] ] ] ] 101 => array:3 [ "identificador" => "bib0510" "etiqueta" => "102." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 102 => array:3 [ "identificador" => "bib0515" "etiqueta" => "103." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510290632" "Revista" => array:7 [ …7] ] ] ] ] ] 103 => array:3 [ "identificador" => "bib0520" "etiqueta" => "104." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2001.28055" "Revista" => array:6 [ …6] ] ] ] ] ] 104 => array:3 [ "identificador" => "bib0525" "etiqueta" => "105." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of connective tissue growth factor in experimental rat and human liver fibrosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510300425" "Revista" => array:7 [ …7] ] ] ] ] ] 105 => array:3 [ "identificador" => "bib0530" "etiqueta" => "106." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Connective tissue growth factor in human liver cirrhosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 106 => array:3 [ "identificador" => "bib0535" "etiqueta" => "107." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of steatosis on progression of fibrosis in patients with mild hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.20519" "Revista" => array:6 [ …6] ] ] ] ] ] 107 => array:3 [ "identificador" => "bib0540" "etiqueta" => "108." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The presence of steatosis and elevation of alanine aminotrans-ferase levels are associated with fibrosis progression in chronic hepatitis C with non-response to interferon therapy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2007.12.025" "Revista" => array:6 [ …6] ] ] ] ] ] 108 => array:3 [ "identificador" => "bib0545" "etiqueta" => "109." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis and liver cell apoptosis in chronic hepatitis C: a mechanism for increased liver injury" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.20179" "Revista" => array:6 [ …6] ] ] ] ] ] 109 => array:3 [ "identificador" => "bib0550" "etiqueta" => "110." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2005.00307.x" "Revista" => array:6 [ …6] ] ] ] ] ] 110 => array:3 [ "identificador" => "bib0555" "etiqueta" => "111." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2006.00649.x" "Revista" => array:6 [ …6] ] ] ] ] ] 111 => array:3 [ "identificador" => "bib0560" "etiqueta" => "112." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Higher prevalence and severity of hepatic encephalopathy in patients with HCV cirrhosis and diabetes mellitus: is presence of autonomic neuropathy the missing part of the puzzle?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2006.00800.x" "Revista" => array:6 [ …6] ] ] ] ] ] 112 => array:3 [ "identificador" => "bib0565" "etiqueta" => "113." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510240222" "Revista" => array:3 [ …3] ] ] ] ] ] 113 => array:3 [ "identificador" => "bib0570" "etiqueta" => "114." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 114 => array:3 [ "identificador" => "bib0575" "etiqueta" => "115." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1440-1746.2005.04007.x" "Revista" => array:6 [ …6] ] ] ] ] ] 115 => array:3 [ "identificador" => "bib0580" "etiqueta" => "116." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.11427" "Revista" => array:6 [ …6] ] ] ] ] ] 116 => array:3 [ "identificador" => "bib0585" "etiqueta" => "117." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v13.i39.5180" "Revista" => array:6 [ …6] ] ] ] ] ] 117 => array:3 [ "identificador" => "bib0590" "etiqueta" => "118." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2003.50350" "Revista" => array:6 [ …6] ] ] ] ] ] 118 => array:3 [ "identificador" => "bib0595" "etiqueta" => "119." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Obesity and its nurturing effect on hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2003.50413" "Revista" => array:6 [ …6] ] ] ] ] ] 119 => array:3 [ "identificador" => "bib0600" "etiqueta" => "120." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 120 => array:3 [ "identificador" => "bib0605" "etiqueta" => "121." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1478-3231.2006.01347.x" "Revista" => array:6 [ …6] ] ] ] ] ] 121 => array:3 [ "identificador" => "bib0610" "etiqueta" => "122." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Weight affect relapse rates in latinos with genotype 2/3 chronic hepatitis C (CHC) treated with peg IFN alfa-2a (Pegasys) 180 mcg/week and 800 mg daily of ribavirin for 24 weeks" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jmv.21253" "Revista" => array:7 [ …7] ] ] ] ] ] 122 => array:3 [ "identificador" => "bib0615" "etiqueta" => "123." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.51.1.89" "Revista" => array:6 [ …6] ] ] ] ] ] 123 => array:3 [ "identificador" => "bib0620" "etiqueta" => "124." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Does a lower insulin resistance affect antiviral therapy response in patients suffering from HCV related chronic hepatitis?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ …5] ] ] ] ] ] 124 => array:3 [ "identificador" => "bib0625" "etiqueta" => "125." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of obesity on treatment of chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.21239" "Revista" => array:6 [ …6] ] ] ] ] ] 125 => array:3 [ "identificador" => "bib0630" "etiqueta" => "126." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22311" "Revista" => array:7 [ …7] ] ] ] ] ] 126 => array:3 [ "identificador" => "bib0635" "etiqueta" => "127." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Leptin, obesity and cardiovascular disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 127 => array:3 [ "identificador" => "bib0640" "etiqueta" => "128." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 128 => array:3 [ "identificador" => "bib0645" "etiqueta" => "129." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Beyond insulin resistance in NASH: TNF-alpha or adiponectin?" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.20280" "Revista" => array:6 [ …6] ] ] ] ] ] 129 => array:3 [ "identificador" => "bib0650" "etiqueta" => "130." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glucose intolerance and hypoadiponectinemia are already present in lean patients with chronic hepatitis C infected with genotype non-3 viruses" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MEG.0b013e3281532b9a" "Revista" => array:6 [ …6] ] ] ] ] ] 130 => array:3 [ "identificador" => "bib0655" "etiqueta" => "131." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2005.00311.x" "Revista" => array:6 [ …6] ] ] ] ] ] 131 => array:3 [ "identificador" => "bib0660" "etiqueta" => "132." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510230203" "Revista" => array:6 [ …6] ] ] ] ] ] 132 => array:3 [ "identificador" => "bib0665" "etiqueta" => "133." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2005.41403.x" "Revista" => array:6 [ …6] ] ] ] ] ] 133 => array:3 [ "identificador" => "bib0670" "etiqueta" => "134." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance is a major determinant of sustained virological response in genotype 1 chronic hepatitis c patients receiving peginterferon Alpha-2b plus ribavirin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/apt.13365" "Revista" => array:3 [ …3] ] ] ] ] ] 134 => array:3 [ "identificador" => "bib0675" "etiqueta" => "135." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2007.07.026" "Revista" => array:6 [ …6] ] ] ] ] ] 135 => array:3 [ "identificador" => "bib0680" "etiqueta" => "136." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 136 => array:3 [ "identificador" => "bib0685" "etiqueta" => "137." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.2005.069674" "Revista" => array:6 [ …6] ] ] ] ] ] 137 => array:3 [ "identificador" => "bib0690" "etiqueta" => "138." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.273.52.35056" "Revista" => array:6 [ …6] ] ] ] ] ] 138 => array:3 [ "identificador" => "bib0695" "etiqueta" => "139." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Loria P. HCV and diabetes. A two-question-based reappraisal" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.dld.2007.05.005" "Revista" => array:6 [ …6] ] ] ] ] ] 139 => array:3 [ "identificador" => "bib0700" "etiqueta" => "140." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prognostic significance of glycaemic control in patients with HBV and HCV-related cirrhosis and diabetes mellitus" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1464-5491.2005.01687.x" "Revista" => array:6 [ …6] ] ] ] ] ] 140 => array:3 [ "identificador" => "bib0705" "etiqueta" => "141." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pioglitazone in chronic hepatitis C not responding to pegylated interferon-alpha and ribavirin" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jhep.2008.03.033" "Revista" => array:6 [ …6] ] ] ] ] ] 141 => array:3 [ "identificador" => "bib0710" "etiqueta" => "142." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.52.11.1638" "Revista" => array:7 [ …7] ] ] ] ] ] 142 => array:3 [ "identificador" => "bib0715" "etiqueta" => "143." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.52.2.288" "Revista" => array:6 [ …6] ] ] ] ] ] 143 => array:3 [ "identificador" => "bib0720" "etiqueta" => "144." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of the interaction between steatosis and alcohol intake on liver fibrosis progression in chronic hepatitis C" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1572-0241.2002.05793.x" "Revista" => array:6 [ …6] ] ] ] ] ] 144 => array:3 [ "identificador" => "bib0725" "etiqueta" => "145." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wejstal R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 145 => array:3 [ "identificador" => "bib0730" "etiqueta" => "146." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chronic hepatitis C and superimposed nonalcoholic fatty liver disease" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 146 => array:3 [ "identificador" => "bib0735" "etiqueta" => "147." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Steatosis and bile duct damage in chronic hepatitis C: distribution and relationships in a group of Northern Italian patients." "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ …6] ] ] ] ] ] 147 => array:3 [ "identificador" => "bib0740" "etiqueta" => "148." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrosis and other histological features in chronic hepatitis C virus infection: a statistical model" "autores" => array:1 [ …1] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/jcp.49.6.465" "Revista" => array:6 [ …6] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/16652681/00000008000000S1/v1_201906260858/S1665268119318290/v1_201906260858/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/16652681/00000008000000S1/v1_201906260858/S1665268119318290/v1_201906260858/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119318290?idApp=UINPBA00004N"]

Statistics

Mariana V. Machado

Corresponding author

hlcortezpinto@netcabo.pt

Address for correspondence:

, Helena Cortez-Pinto

1 Serviço de Gastrenterologia, Hospital de Santa Maria. Unidade de Nutrigao e Metabolismo, Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal.

Read

1209

Times
was read the article

313

Total PDF

896

Total HTML

Share statistics

 array:23 [
  "pii" => "S1665268119318290"
  "issn" => "16652681"
  "doi" => "10.1016/S1665-2681(19)31829-0"
  "estado" => "S300"
  "fechaPublicacion" => "2009-01-01"
  "aid" => "71491"
  "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
  "copyrightAnyo" => "2009"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
  "subdocumento" => "fla"
  "cita" => "Ann Hepatol. 2009;8 Supl 1:S67-75"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 63
    "formatos" => array:3 [
      "EPUB" => 11
      "HTML" => 25
      "PDF" => 27
    ]
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1665268119318289"
    "issn" => "16652681"
    "doi" => "10.1016/S1665-2681(19)31828-9"
    "estado" => "S300"
    "fechaPublicacion" => "2009-01-01"
    "aid" => "71490"
    "copyright" => "Fundaci&#243;n Cl&#237;nica M&#233;dica Sur&#44; A&#46;C&#46;"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/"
    "subdocumento" => "fla"
    "cita" => "Ann Hepatol. 2009;8 Supl 1:S60-6"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 62
      "formatos" => array:3 [
        "EPUB" => 11
        "HTML" => 21
        "PDF" => 30
      ]
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "titulo" => "Is exercise an effective treatment for NASH&#63; Knowns and unknowns"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "S60"
          "paginaFinal" => "S66"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "f0005"
          "etiqueta" => "<span class="elsevierStyleItalic"><span class="elsevierStyleBold">Figure 1&#46;</span></span>"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr1.jpeg"
              "Alto" => 604
              "Ancho" => 1504
              "Tamanyo" => 96052
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Potential mechanisms &#40;mediators&#41; of the therapeutic effect of exercise on NAFL&#47;NASH&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Stephen Caldwell, Mariana Lazo"
          "autores" => array:2 [
            0 => array:2 [
              "nombre" => "Stephen"
              "apellidos" => "Caldwell"
            ]
            1 => array:2 [
              "nombre" => "Mariana"
              "apellidos" => "Lazo"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119318289?idApp=UINPBA00004N"
    "url" => "/16652681/00000008000000S1/v1_201906260858/S1665268119318289/v1_201906260858/en/main.assets"
  ]
  "en" => array:16 [
    "idiomaDefecto" => true
    "titulo" => "Insulin resistance and steatosis in chronic hepatitis C"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "S67"
        "paginaFinal" => "S75"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Mariana V&#46; Machado, Helena Cortez-Pinto"
        "autores" => array:2 [
          0 => array:4 [
            "nombre" => "Mariana V&#46;"
            "apellidos" => "Machado"
            "email" => array:1 [
              0 => "hlcortezpinto@netcabo.pt"
            ]
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor1"
              ]
            ]
          ]
          1 => array:2 [
            "nombre" => "Helena"
            "apellidos" => "Cortez-Pinto"
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:3 [
            "entidad" => "Servi&#231;o de Gastrenterologia&#44; Hospital de Santa Maria&#46; Unidade de Nutrigao e Metabolismo&#44; Instituto de Medicina Molecular &#40;IMM&#41;&#44; Faculdade de Medicina da Universidade de Lisboa&#44; Portugal&#46;"
            "etiqueta" => "1"
            "identificador" => "aff1"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor1"
            "etiqueta" => "&#42;"
            "correspondencia" => "Address for correspondence&#58;"
          ]
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Chronic hepatitis C closely relates to hepatic steatosis and insulin resistance &#40;IR&#41;&#47; increased risk of type 2 diabetes mellitus &#40;DM&#41;&#46; Although this association may be a consequence of metabolic factors&#44; hepatitis C virus &#40;HCV&#41; itself has the ability to directly promote steatosis and IR&#46; This association is extremely important as it not only is very frequent&#44; but it has a harmful influence in the prognosis and anti-viral treatment&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">This article aims to be an in depth review of the epidemiological data of IR&#47;DM and steatosis in chronic hepatitis C&#44; its mechanisms&#44; and how it influences the response to anti-viral treatment and prognosis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Epidemiology</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Insulin resistance&#47;diabetes mellitus</span><p id="p0015" class="elsevierStylePara elsevierViewall">The prevalence of DM in chronic hepatitis C patients is higher than the expected&#44; having in consideration data from the general population&#46; In patients with hepatic cirrhosis it is estimated to be 24-50&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Hepatic cirrhosis is itself diabetogenic&#44; however&#44; the risk of DM in HCV related hepatic cirrhosis is 3 to 5 times greater than in other etiologies of hepatic cirrhosis&#44; including hepatitis B virus &#40;HBV&#41; related&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The prevalence of DM in a non cirrhotic population with chronic hepatitis C is 7&#46;6-21&#37;&#44; representing a 2 to 4 fold increased risk when compared to other forms of chronic hepatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Only 4 studies failed to demonstrate a positive association between DM and HCV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> A recent meta-analyses on 34 studies found an adjusted odds ratio of 1&#46;67 &#40;95&#37; CI &#91;1&#46;28-2&#46;06&#93; relatively to non infected subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> A follow up population study&#44; a subset of ARIC - <span class="elsevierStyleItalic">Atherosclerosis Risk in Communities Study&#44;</span> re-evaluated&#44; at the end of 9 years&#44; 1&#44;084 patients without DM&#44; and found that the subgroup of patients chronically infected by HCV had a 2 fold increased risk of developing DM&#44; and that risk increased to 11 fold in high risk patients taking in consideration age and body mass index &#40;BMI&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The opposite is also true&#44; that is&#44; patients with DM have a higher risk of being infected with HCV&#44; as compared with the general population&#44; being the prevalence of HCV seropositivity in patients with DM 4&#46;2-10&#46;5&#37; in different studies&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> This can be explained by the induction of DM by HCV&#44; but also by a greater susceptibility of patients with DM to be infected with HCV&#46; In fact&#44; a recent study in patients suffering from chronic renal failure in hemodialysis showed that patients with DM had a 10 fold increased risk of HCV infection&#44; with a higher annual seroconversion rate &#40;11 <span class="elsevierStyleItalic">versus</span> 7&#37;&#41; and in a smaller time period of hemodialysis &#40;30 <span class="elsevierStyleItalic">versus</span> 50 months&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">One explanation to the higher prevalence of DM could be a &#946;-pancreatic cell dysfunction&#44; as suggested by the fact that these patients present a blunted acute response of insulin secretion to hyperglycemia&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and also by the presence of HCV RNA in pancreatic tissue<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> which may translate a direct cytopathic effect&#46; However&#44; it is now more consensual to accept the development of DM as a consequence of induction of IR&#46;</p><p id="p0025" class="elsevierStylePara elsevierViewall">In fact&#44; chronically HCV infected subjects present a 3 fold increased risk of IR and glucose metabolism impairment&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> with IR occurring in very early stages of hepatic lesion &#40;fibrosis stage 0 or 1&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> with a worsening tendency as hepatic fibrosis progress&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> IR severity can be genotype specific&#44; although the different studies are not consensual in that regard&#58; some authors found a greater IR severity in genotype 1 and 4 as compared to genotype 3&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> others in genotype 2a as compared to genotype 1&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and others failed to found an association with genotype&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Two levels of evidence suggest a causal relation between HCV infection and DM&#58; an association between IR severity and DM with higher viral load&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and an improvement in IR after a sustained viral response &#40;SVR&#41; to anti-viral treatment as opposite to an unchanged IR in non responders&#44; despite a decrease in BMI&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Steatosis</span><p id="p0030" class="elsevierStylePara elsevierViewall">Although the estimated prevalence of hepatic steatosis in the general population is 20&#37;&#44; in patients with chronic hepatitis C it may vary from 40-80&#37;&#44; depending on alcohol consumption&#44; obesity&#44; diabetes and other risk factors to fatty liver&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> If all steatogenic co-factors are excluded&#44; the prevalence of steatosis remains 50&#37; &#40;although present in less than 30&#37; of the hepatocytes in about two thirds of the patients&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> resulting in a 2&#46;5 fold increased prevalence as compared with the general population and other forms of chronic liver disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> particularly HBV infection&#44; in which the prevalence of steatosis is 18&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> In chronic hepatitis C&#44; although hepatic steatosis can be related to metabolic factors like obesity&#44; dyslipidaemia and DM&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> as much as one third of the patients with steatosis do not have any metabolic impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Also&#44; steatosis is more frequent in HCV as compared to HBV infected subjects&#44; even after adjustment to BMI&#46; As shown in <a class="elsevierStyleCrossRef" href="#t0005">Table I</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0035" class="elsevierStylePara elsevierViewall">Several lines of evidence suggest that steatosis can be attributed to HCV infection&#46; Steatosis is more frequent in association to genotype 3a as compared to other genotypes &#40;74 <span class="elsevierStyleItalic">versus</span> 50&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> which suggests that some sequences of viral genome may be involved in the intracellular lipid accumulation&#46; On the other hand&#44; in genotype 3 infection&#44; steatosis correlates to viral load<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> and can revert after effective treatment but reoccurs in re-infection&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> the same having not been verified in the other genotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Also&#44; the localization of steatosis&#44; particularly in genotype 3 infected patients&#44; is predominantly in periportal zone &#40;acinar 1&#41; and not in centrilobular zone &#40;acinar 3&#41; more typical of metabolic associated steatohepatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">It is now accepted that in chronic hepatitis C&#44; there can occur two types of steatosis&#44; a &#8220;metabolic&#8221; steatosis&#44; that is consequence of metabolic factors like alcohol consumption and risk factors of non alcoholic fatty liver &#40;the most important ones being obesity&#44; visceral fat and IR&#41;&#59; and a viral steatosis that may result from a direct viral cytopathic effect&#46; The former associates to genotype 1&#44; 2 and 4<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> and do not revert after anti-viral treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> The latter associates to genotype 3 and does not relate to BMI or IR&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> However&#44; even the &#8220;metabolic&#8221; steatosis can be partially an indirect consequence of viral infection&#44; since HCV induces a metabolic deregulation with IR&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis</span><p id="p0045" class="elsevierStylePara elsevierViewall">IR occurs very early in HCV infection&#44; in parallel with an elevation in TNF-<span class="elsevierStyleItalic">&#945;</span> levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> TNF-<span class="elsevierStyleItalic">&#945;</span> induces IR through the inhibition of insulin receptor and IRS-1 &#40;insulin receptor substrate&#41; tyrosine phosphorylation&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> impairing the signaling pathway which would lead to the translocation of GLUT4 to the cell surface membrane&#44; diminishing the cellular glucose uptake&#46;</p><p id="p0050" class="elsevierStylePara elsevierViewall">HCV also directly promotes IR through the proteasomal degradation of IRS-1&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> The molecular mechanism that leads to IRS-1 degradation varies according to genotype&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> Genotype 1 promotes the expression of SOCS-3 &#40;suppressor of cytokine signaling 3&#41;&#44; a negative regulator of insulin signaling&#44; which acts through the IRS-1 ubiquitination&#44; targeting it to proteasomes where it is destroyed&#46; Genotype 1b also diminishes IRS-1 levels&#44; trough the activation of mTOR &#40;mammalian target of rapamycin&#41; which induces serine&#47;threonine phosphorylation&#44; redistribution and proteasomal degradation of IRS-1&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> Genotype 3 promotes SOCS 7 expression&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> with a mechanism of IRS-1 degradation similar to that induced by SOCS 3&#59; it also inhibits PPAR-&#947;&#44; further worsening IR&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a></p><p id="p0055" class="elsevierStylePara elsevierViewall">Lastly&#44; HCV induces protein phosphatase 2A expression&#44; through an endoplasmic reticulum stress response pathway&#44; which dephosphorylates PkB&#47;Akt &#40;a main enzyme in the insulin signaling pathway&#41;&#44; and thereby lowers its kinase activity&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">HCV infection can indirectly promote the development of hepatic steatosis&#44; but it is itself steatogenic&#46; All genotypes are steatogenic&#44; however genotype 3 is three times more potent&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> In fact&#44; animal models with transgenic mice showed that the core protein can induce the appearance of lipid droplets&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> More recently&#44; <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> studies showed a topological relation&#44; with the core protein being localized in the membrane of those lipidic vesicles&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> We already know what sequences in core protein are essential to that preferential localization&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> One possible molecular explanation to a greater steatogenic property of genotype 3&#44; could be a phenylalanine residue at position 164 in core protein domain II&#44; instead of tyrosine like in other genotypes&#44; what translates in a higher affinity to lipids&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">Steatosis can be induced in 3 ways&#58; decreasing the lipids export by hepatocytes&#44; decreasing fatty acids consumption &#40;that is its oxidation&#41; or increasing de novo synthesis&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Decreased hepatocyte lipid export</span> is a consequence of a decreased assembly of triglycerides in VLDL &#40;very low density lipoproteins&#41; particles and its secretion&#46; Animal models and studies in humans&#44; demonstrated that core protein inhibits microsomal triglyceride transfer protein &#40;MTP&#41; activity&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> an enzyme that transfers lipids to endo-plasmic reticulum&#44; allowing its association to B apolipo-protein and triglycerides rich VLDL assembly&#46; That inhibition occurs in all genotypes&#44; however it is more potent with genotype 3&#59;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> in genotype 1 and 2 infected patients&#44; the decreased MTP activity seems to be a consequence of a reduced transcription induced by IR and hyperinsulinism&#46; In fact&#44; insulin inhibits MTP expression through a MAP-Kerk &#40;mitogen-activated extracellular signal-regulated protein kinase&#41; pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> In accordance to MTP dysfunction&#44; HCV infected patients with severe steatosis present decreased cholesterol and apo B plasma levels&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Other animal models propose an inhibition of VLDL secretion by a different mechanism&#44; oxidative stress dependent&#46; Oxygen reactive species are a consequence of mitochondrial respiratory chain impairment&#44; when a small proportion of electron efflux interacts with oxygen molecules before reaching the cytochrome oxidase complex&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> Core protein may accumulate in mitochondria&#44; impairing electron transport and thus increasing the production of oxygen reactive species&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Oxidative stress leads to cellular damage through lipids and structural proteins peroxidation&#44; disturbing the cellular traffic apparatus and VLDL secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> Recently a study suggested that HCV can impair the lipid cellular metabolism&#44; through a modification in the response to VLDL and LDL&#46; In fact&#44; Napolitano et al&#46; demonstrated an impaired metabolic response to VLDL and LDL isolated from patients infected with HCV&#44; with a slower VLDL catabolism&#44; which can result in a higher VLDL-LDL switch in circulation&#46; They also showed a higher LDL catabolism with subsequent intracellular lipid accumulation leading to steatosis&#46; The mechanism of response modulation to VLDL&#47;LDL still needs to be explained&#44; but it can be a consequence of a direct binding between HCV and lipoproteins or a modification in their molecular composition&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">A second steatogenic pathway is <span class="elsevierStyleBold">decreased fatty acids consumption&#44;</span> through mitochondrial beta-oxidation inhibition&#46; In fact&#44; core protein may induce structural changes in mitochondria membranes&#44; with subsequent derangement of lipid &#946;-oxidation&#44; promoting steatosis&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> More recently&#44; it has also been demonstrated a diminished PPAR<span class="elsevierStyleItalic">&#945;</span> &#40;peroxisome proliferators-activated receptor <span class="elsevierStyleItalic">&#945;</span> expression induced by core protein<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">88</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> which is more potent with genotype 3 as compared to genotype 1&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> PPAR-<span class="elsevierStyleItalic">&#945;</span> is a nuclear receptor that regulates the transcription of several major genes in the lipids metabolism&#44; for instance CPT1A &#40;mitochondrial carnitine palmitoyl acyl-CoA transferase 1&#41;&#44; which is a rate limiting enzyme in the mitochondrial &#946;-oxidation mediating the entry of fatty acids in the mitochondria&#59; ACOX &#40;acyl-CoA oxidase&#41;&#44; the main enzyme in mitochondrial &#946;-oxidation&#59; and Mdr2&#44; a transport protein in canalicula membranes which controls biliary phospholipids secretion&#46; Several experimental models showed a diminished PPAR-<span class="elsevierStyleItalic">&#945;</span> expression and transcriptional activity&#44; with a decreased CPT1A and ACOX expression with decreased fatty acids oxidation&#44; as well as a decreased Mdr2 expression with a potential decrease in phospholipids associated fatty acids biliary excretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">88</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">A third steatogenic mechanism is the promotion of de novo fatty acids synthesis&#46; A chimpanzee animal model showed an early SREBP-lc &#40;sterol regulatory element binding protein signaling pathway&#41; expression induction after HCV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> SREBP-lc is a transcriptional factor that regulates several genes in lipid metabolism&#44; namely fatty acids syntethase&#44; acetyl-CoA carboxylase and stearoyl-CoA desaturase&#44; key lipogenic enzymes which are also overexpressed in HCV infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">93</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> Additionally&#44; core protein also binds to DNA-binding domain of RXR<span class="elsevierStyleItalic">&#945;</span> &#40;retinoid X receptor <span class="elsevierStyleItalic">&#945;</span> - a nuclear receptor that regulates several genes involved in cellular lipids synthesis&#41;&#44; increasing its transcriptional activity&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a></p><p id="p0090" class="elsevierStylePara elsevierViewall">Interestingly&#44; hepatic steatosis may promote viral replication&#46; HCV may associate to LDL in lipo-viral particles that circulate in blood stream&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> Therefore&#44; LDL receptors allow HCV cellular intake&#44;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">98</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> and VLDL&#47;LDL plasma levels may regulate HCV binding to its target by competitive inhibition&#46; So&#44; when HCV promotes lower VLDL plasma levels&#44; it enhances its cellular dissemination&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Consequences in the prognosis of chronic hepatitis C</span><p id="p0095" class="elsevierStylePara elsevierViewall">IR favors fibrosis progression in chronic hepatitis C&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">101</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> Hyperinsulinism&#44; IR related&#44; directly activates stellate cells<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a> and&#44; in association to hyperglycemia&#44; it increases connective tissue growth factor &#40;CTGF&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> a key cytokine in hepatic fibrogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> Steatosis also relates to more advanced fibrosis<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> and to accelerated fibrosis progression&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a> in such a way that some authors suggest treating HCV infected patients with evidence of hepatic steatosis&#44; even if they only present mild inflammatory activity&#46; Steatosis may sensitize the liver to inflammation<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and apoptosis&#44; and subsequently enhance fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> In fact&#44; a recent study showed that hepatic steatosis associates to higher programmed cell death by apoptosis with stellate cells activation&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a></p><p id="p0100" class="elsevierStylePara elsevierViewall">DM associates to a decreased life expectancy in cirrhotic patients&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> as well as an earlier progression to more severe hepatic encephalopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">111</span></a> The mechanism that favors encephalopathy is still not known&#44; but it may be dependent on diabetes-related autonomic neuropathy and subsequent constipation and&#47;or impairment in ammonia metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> A recent study also demonstrated IR as a risk factor to portal hypertension and the development of esophageal varices&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">113</span></a> In fact&#44; the authors found that HOMA-IR index higher than 3&#46;5 was a good predictor of esophageal varices presence&#44; with an AUC 0&#46;80&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">DM is a risk factor for the development of hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a> Regarding a possible association between hepatic steatosis and hepatic carcinogenesis&#44; different studies show opposite results&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">115</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment implications</span><p id="p0110" class="elsevierStylePara elsevierViewall">Obesity and steatosis decrease anti-viral treatment response&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">118</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">122</span></a> However&#44; that negative influence seems to be limited to metabolic steatosis and not to viral one&#44; since genotype 3 associated steatosis does not seem to change the response to anti-viral treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Patients with BMI higher than 30 kg&#47;m<span class="elsevierStyleSup">2</span> have a 4 fold lower chance of sustained viral response&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> A pilot study showed that weight loss&#44; even if mild&#44; associates to an improvement not only in steatosis&#44; but also in fibrosis&#44; in patients with chronic hepatitis C&#44; after as little as 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">There are 3 mechanisms which may explain why obesity compromises anti-viral treatment response&#46; First&#44; obesity may interfere with interferon bio-availability&#46; In fact&#44; subcutaneous administration of pegylated interferon in obese patients may decrease its absorption as a consequence of defective subcutaneous lymph drainage&#44; leading to lower plasma levels&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">Another proposed mechanism is obesity as a pro-inflammatory state<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">126</span></a> with a negative influence in immune response to therapy&#46; Several adipokines may have a major role in that immune deregulation&#46; Leptine is an adipocyte secreted cytokine that is increased in obesity&#46; However&#44; in obesity&#44; despite there is hyperleptinemia&#44; there is also resistance to leptin actions&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> Leptine has a pro-inflammatory action promoting Th1 immune response&#44; which is believed to be essential in achieving a sustained response to interferon&#46; Therefore&#44; leptin resistance may have a negative influence in anti-viral treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a> Another important cytokine is adiponectin&#44; which has an anti-inflammatory activity antagonizing TNF-<span class="elsevierStyleItalic">&#945;</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a> being decreased in obesity and HCV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">130</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">131</span></a> On the contrary&#44; TNF-<span class="elsevierStyleItalic">&#945;</span> not only has a pro-inflammatory activity&#44; as directly promotes IR&#44; and inversely correlates to anti-viral treatment response&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">132</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">Lastly&#44; obesity promotes IR&#44; which is known to associate to a negative influence in anti-viral treatment response&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">133</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">135</span></a> In fact&#44; Romero-Gomez et al&#46; showed 33&#37; sustained viral response rate in genotype 1 in patients with IR&#44; as opposed to 66&#37; in patients without IR&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">136</span></a> Also&#44; Poustchi et al&#46; found a 6&#46;5 times lower sustained viral response in patients with IR&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">135</span></a> The association between IR and no response to anti-viral treatment may be a due to a SOCS-3 activation&#44; which not only promotes IR&#44; but also inhibits STAT-1 &#40;signal transducer and activator of transcription&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a> After <span class="elsevierStyleItalic">&#945;</span> interferon binds to its receptor&#44; it activates tyrosine kinases that phosphorylate STAT-1&#44; promoting its migration to the nucleus&#44; where it regulates several anti-viral genes transcription&#46; SOCS-3 protein inhibits that tyrosine phosphorylation&#44; thus inhibiting <span class="elsevierStyleItalic">&#945;</span> interferon action&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a></p><p id="p0130" class="elsevierStylePara elsevierViewall">We still do not know whether treating IR actually translates in a better response to <span class="elsevierStyleItalic">a</span> interferon&#46; At the moment&#44; patients should be advised to change to healthier life styles that promote less IR&#44; as weight loss and physical exercise&#59; however medication with insulin sensitizer agents in this context still do not have an evidence based fundament&#44;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">139</span></a> although a small retrospective study suggests that a better glycemic control may improve survival in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">140</span></a> However&#44; a pilot study in previously non responders to standard anti-viral therapy with IR&#44; showed no benefit of a triple therapy with pioglita-zone&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">141</span></a></p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:8 [
        0 => array:3 [
          "identificador" => "xres1212009"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abs0010"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1128079"
          "titulo" => "Key words"
        ]
        2 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        3 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Epidemiology"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Insulin resistance&#47;diabetes mellitus"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Steatosis"
            ]
          ]
        ]
        4 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Pathogenesis"
        ]
        5 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Consequences in the prognosis of chronic hepatitis C"
        ]
        6 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Treatment implications"
        ]
        7 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2008-12-21"
    "fechaAceptado" => "2008-12-21"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Key words"
          "identificador" => "xpalclavsec1128079"
          "palabras" => array:4 [
            0 => "Steatosis"
            1 => "insulin resistance"
            2 => "diabetes mellitus"
            3 => "chronic hepatitis C"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="asp0005" class="elsevierStyleSimplePara elsevierViewall">In chronic hepatitis C&#44; insulin resistance &#40;IR&#41; and type 2 diabetes mellitus &#40;DM&#41; are more prevalent than in healthy controls or in chronic hepatitis B patients&#46; HCV infection promotes IR mainly through increased TNF-<span class="elsevierStyleItalic">&#945;</span> and cytokine suppressor &#40;SOCS-3&#41; production&#46; Both events inhibit insulin receptor and IRS-1 &#40;insulin receptor substrate&#41; tyrosine phosphorylation&#46; Hepatic steatosis is also 2&#46;5 fold more frequent in hepatitis C virus &#40;HCV&#41; infected patients as compared to the general population&#46; Metabolic factors play a crucial role in the etiology of hepatic steatosis genotype non-3 related&#44; which are also the genotypes with a greater association to IR&#46; However&#44; genotype 3&#44; and particularly 3a&#44; has a greater direct steatogenic capacity&#44; and consequently&#44; in those patients&#44; the association with metabolic factors is weaker&#46; Instead&#44; in genotype 3&#44; steatosis associates with viral factors like viral load&#46; Those metabolic factors influence not only the natural history of HCV infection&#44; as well as associate to an accelerated hepatic fibrosis progression&#44; to a worse prognosis when hepatic cirrhosis is present&#44; namely an increased risk of hepatocellular carcinoma&#44; and to a lower sustained viral response rate&#46; On the other hand&#44; in patients who achieve viral eradication&#44; IR and hepatic steatosis may regress&#44; and return if viral infection recurs&#44; which once again indicates an intrinsic steatosis and IR promoter action by HCV&#46;</p></span>"
      ]
    ]
    "multimedia" => array:1 [
      0 => array:7 [
        "identificador" => "t0005"
        "etiqueta" => "Table I"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="np0005" class="elsevierStyleSimplePara elsevierViewall">NA &#61; not available&#44; BMI &#61; body mass index&#44; DM &#61; diabetes mellitus&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="3" align="left" valign="top" scope="col">Reference</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="3" align="left" valign="top" scope="col">Number of patients</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="3" align="left" valign="top" scope="col">Steatosis &#40;&#37; of patients&#41;</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="6" align="left" valign="top" scope="col">Association to Steatosis</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="left" valign="top" scope="col">Host factors</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="left" valign="top" scope="col">Viral factors</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col">BMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col">Alcohol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col">DM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col">Genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col">Viral load&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col">Fibrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Leandro 20 06<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">3&#44;068&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Rubbia-Brandt 2004<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">755&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Patton 2004<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">574&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Poynard 2003<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">1&#44;428&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Asselah 2003<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">142</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">290&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Castera 2003<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">143</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Monto 2002<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">297&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Serfaty 2002<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">144</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">142&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Hui 2002<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">124&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Westin 2002<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">145</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Ong 2001<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">146</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">170&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Hwang 2001<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">106&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Adinolfi 2001<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">180&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Rubbia-Brandt 2000<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">101&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Hourigan 1999<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">148&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Giannini 1999<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">147</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">172&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Czaja 1998<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Mihm 1997<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&#44; 3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Wong 1996<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">148</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Fiore 1996<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="right" valign="middle">121&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">no&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2069130.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Factors associated to hepatic steatosis in chronic hepatitis C&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bs0005"
          "bibliografiaReferencia" => array:148 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance and hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v12.i44.7075"
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Gastroenterol"
                        "fecha" => "2006"
                        "volumen" => "12"
                        "paginaInicial" => "7075"
                        "paginaFinal" => "7080"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of diabetes mellitus in Japanese patients infected chronically with hepatitis C virus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s005350300063"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gastroenterol"
                        "fecha" => "2003"
                        "volumen" => "38"
                        "paginaInicial" => "355"
                        "paginaFinal" => "360"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510300416"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1999"
                        "volumen" => "30"
                        "paginaInicial" => "1059"
                        "paginaFinal" => "1063"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1994"
                        "volumen" => "21"
                        "paginaInicial" => "1135"
                        "paginaFinal" => "1139"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C&#44; alcohol&#44; or cholestatic disease"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2000"
                        "volumen" => "32"
                        "paginaInicial" => "209"
                        "paginaFinal" => "217"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C infection and risk of diabetes&#58; A systematic review and meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2008.08.006"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2008"
                        "volumen" => "49"
                        "paginaInicial" => "831"
                        "paginaFinal" => "844"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance in chronic hepatitis C&#58; association with genotypes 1 and 4&#44; serum HCV RNA level&#44; and liver fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2007.11.010"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2008"
                        "volumen" => "134"
                        "paginaInicial" => "416"
                        "paginaFinal" => "423"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of diabetes mellitus and chronic hepatitis C virus infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510290235"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1999"
                        "volumen" => "29"
                        "paginaInicial" => "328"
                        "paginaFinal" => "333"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Community-based study of hepatitis C virus infection and type 2 diabetes&#58; an association affected by age and hepatitis severity status"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/aje/kwg259"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Epidemiol"
                        "fecha" => "2003"
                        "volumen" => "158"
                        "paginaInicial" => "1154"
                        "paginaFinal" => "1160"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.7326/0003-4819-133-8-200010170-00009"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "2000"
                        "volumen" => "133"
                        "paginaInicial" => "592"
                        "paginaFinal" => "599"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High prevalence of diabetes mellitus among adult beta-thalassaemic patients with chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Gastroenterol Hepatol"
                        "fecha" => "1999"
                        "volumen" => "11"
                        "paginaInicial" => "1033"
                        "paginaFinal" => "1036"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chronic hepatitis C and type II diabetes mellitus&#58; a prospective cross-sectional study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2005.40429.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "2005"
                        "volumen" => "100"
                        "paginaInicial" => "48"
                        "paginaFinal" => "55"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes mellitus is associated with chronic hepatitis C but not chronic hepatitis B infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Isr J Med Sci"
                        "fecha" => "1996"
                        "volumen" => "32"
                        "paginaInicial" => "526"
                        "paginaFinal" => "530"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High prevalence of hepatitis C virus infection in diabetic patients"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.19.9.998"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "1996"
                        "volumen" => "19"
                        "paginaInicial" => "998"
                        "paginaFinal" => "1000"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association of chronic hepatitis C infection and diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Trop Gastroenterol"
                        "fecha" => "1998"
                        "volumen" => "19"
                        "paginaInicial" => "141"
                        "paginaFinal" => "144"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glycemic homeostasis in chronic viral hepatitis and liver cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Metab"
                        "fecha" => "2001"
                        "volumen" => "27"
                        "paginaInicial" => "476"
                        "paginaFinal" => "481"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes mellitus in chronic hepatitis B and C&#58; prevalence and potential association with the extent of liver fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2893.2005.00677.x"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Viral Hepat"
                        "fecha" => "2006"
                        "volumen" => "13"
                        "paginaInicial" => "303"
                        "paginaFinal" => "310"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver cirrhosis and diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1996"
                        "volumen" => "24"
                        "paginaInicial" => "645"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HCV and diabetes mellitus&#58; evidence for a negative association"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.1998.00688.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "1998"
                        "volumen" => "93"
                        "paginaInicial" => "2363"
                        "paginaFinal" => "2367"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus infection and incident type 2 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2003.50291"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2003"
                        "volumen" => "38"
                        "paginaInicial" => "50"
                        "paginaFinal" => "56"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The susceptibility of patients with type-2 diabetes to hepatitis C virus infection during long-term haemodialysis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "2003/45/smw-10402"
                      "Revista" => array:6 [
                        "tituloSerie" => "Swiss Med Wkly"
                        "fecha" => "2003"
                        "volumen" => "133"
                        "paginaInicial" => "611"
                        "paginaFinal" => "618"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Distribution of markers of hepatitis C virus infection throughout the body"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Semin Liver Dis"
                        "fecha" => "2000"
                        "volumen" => "20"
                        "paginaInicial" => "85"
                        "paginaFinal" => "102"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome&#58; specific detection of negative-strand viral RNA in various tissues"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510280531"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1998"
                        "volumen" => "28"
                        "paginaInicial" => "1398"
                        "paginaFinal" => "1401"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High prevalence of glucose abnormalities in patients with hepatitis C virus infection&#58; a multivariate analysis considering the liver injury"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.27.5.1171"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2004"
                        "volumen" => "27"
                        "paginaInicial" => "1171"
                        "paginaFinal" => "1175"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chronic hepatitis C virus infection without cirrhosis induces insulin resistance in patients with alpha-thalassaemia major"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Gastroenterol Hepatol"
                        "fecha" => "2001"
                        "volumen" => "13"
                        "paginaInicial" => "1195"
                        "paginaFinal" => "1199"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression &#91;corrected&#93;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2003"
                        "volumen" => "125"
                        "paginaInicial" => "1695"
                        "paginaFinal" => "1704"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C&#46;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2001"
                        "volumen" => "35"
                        "paginaInicial" => "279"
                        "paginaFinal" => "283"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2006.00835.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "2006"
                        "volumen" => "101"
                        "paginaInicial" => "2752"
                        "paginaFinal" => "2759"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severity of HCV-induced liver damage alters glucose homeostasis in noncirrhotic patients with chronic HCV infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000007778"
                      "Revista" => array:6 [
                        "tituloSerie" => "Digestion"
                        "fecha" => "2000"
                        "volumen" => "62"
                        "paginaInicial" => "52"
                        "paginaFinal" => "59"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C viremia increases the association with type 2 diabetes mellitus in a hepatitis B and C endemic area&#58; an epidemiological link with virological implication"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2007.01181.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "2007"
                        "volumen" => "102"
                        "paginaInicial" => "1237"
                        "paginaFinal" => "1243"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1478-3231.2007.01626.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Liver Int"
                        "fecha" => "2008"
                        "volumen" => "28"
                        "paginaInicial" => "271"
                        "paginaFinal" => "277"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clearance of HCV improves insulin resistance&#44; beta-cell function&#44; and hepatic expression of insulin receptor substrate 1 and 2"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2006.01038.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "2007"
                        "volumen" => "102"
                        "paginaInicial" => "570"
                        "paginaFinal" => "576"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interferon-alpha reduces insulin resistance and beta-cell secretion in responders among patients with chronic hepatitis B and C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Endocrinol"
                        "fecha" => "2003"
                        "volumen" => "178"
                        "paginaInicial" => "457"
                        "paginaFinal" => "465"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc06-0456"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2006"
                        "volumen" => "29"
                        "paginaInicial" => "2462"
                        "paginaFinal" => "2466"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Relationship between steatosis&#44; inflammation&#44; and fibrosis in chronic hepatitis C&#58; a meta-analysis of individual patient data"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2006.03.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2006"
                        "volumen" => "130"
                        "paginaInicial" => "1636"
                        "paginaFinal" => "1642"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis in chronic hepatitis C&#58; why does it really matter&#63;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.2005.069757"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gut"
                        "fecha" => "2006"
                        "volumen" => "55"
                        "paginaInicial" => "123"
                        "paginaFinal" => "130"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Host-and disease-specific factors affecting steatosis in chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1998"
                        "volumen" => "29"
                        "paginaInicial" => "198"
                        "paginaFinal" => "206"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510290401"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1999"
                        "volumen" => "29"
                        "paginaInicial" => "1215"
                        "paginaFinal" => "1219"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2001.24432"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2001"
                        "volumen" => "33"
                        "paginaInicial" => "1358"
                        "paginaFinal" => "1364"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2003.50267"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2003"
                        "volumen" => "38"
                        "paginaInicial" => "75"
                        "paginaFinal" => "85"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "41&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver steatosis and chronic hepatitis C&#58; a spurious association&#63;"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Gastroenterol Hepatol"
                        "fecha" => "1996"
                        "volumen" => "8"
                        "paginaInicial" => "125"
                        "paginaFinal" => "129"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "42&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic steatosis in chronic hepatitis C virus infection&#58; prevalence and clinical correlation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gastroenterol Hepatol"
                        "fecha" => "2001"
                        "volumen" => "16"
                        "paginaInicial" => "190"
                        "paginaFinal" => "195"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "43&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genotype-specific interactions of insulin resistance&#44; steatosis&#44; and fibrosis in chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22392"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "48"
                        "paginaInicial" => "723"
                        "paginaFinal" => "731"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis and hepatitis C virus&#58; mechanisms and significance for hepatic and extrahepatic disease"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2004"
                        "volumen" => "126"
                        "paginaInicial" => "586"
                        "paginaFinal" => "597"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "45&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathological diagnosis of chronic hepatitis C&#58; a multicenter comparative study with chronic hepatitis B&#46; The Hepatitis Interventional Therapy Group"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "1993"
                        "volumen" => "104"
                        "paginaInicial" => "595"
                        "paginaFinal" => "603"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "46&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C and steatosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arcmed.2006.09.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Med Res"
                        "fecha" => "2007"
                        "volumen" => "38"
                        "paginaInicial" => "621"
                        "paginaFinal" => "627"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "47&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of liver steatosis in patients with chronic hepatitis B&#58; a study of associated factors and of relationship with fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Gastroenterol Hepatol"
                        "fecha" => "2006"
                        "volumen" => "18"
                        "paginaInicial" => "233"
                        "paginaFinal" => "237"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis in chronic hepatitis C&#58; relative contributions of obesity&#44; diabetes mellitus&#44; and alcohol"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.35064"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2002"
                        "volumen" => "36"
                        "paginaInicial" => "729"
                        "paginaFinal" => "736"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "49&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis and chronic hepatitis C&#58; analysis of fibrosis and stellate cell activation"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2001"
                        "volumen" => "34"
                        "paginaInicial" => "314"
                        "paginaFinal" => "320"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "50&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of histo-pathological manifestations of chronic hepatitis C virus infection with respect to virus genotype"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510250340"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1997"
                        "volumen" => "25"
                        "paginaInicial" => "735"
                        "paginaFinal" => "739"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "51&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2000"
                        "volumen" => "33"
                        "paginaInicial" => "106"
                        "paginaFinal" => "115"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "52&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gastroenterol Hepatol"
                        "fecha" => "2002"
                        "volumen" => "17"
                        "paginaInicial" => "873"
                        "paginaFinal" => "881"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "53&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence for a role of nonalcoholic steatohepatitis in hepatitis C&#58; a prospective study"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.21711"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2007"
                        "volumen" => "46"
                        "paginaInicial" => "380"
                        "paginaFinal" => "387"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "54&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2003.11.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2004"
                        "volumen" => "40"
                        "paginaInicial" => "484"
                        "paginaFinal" => "490"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "55&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus genotype 3 is cytopathic to hepatocytes&#58; Reversal of hepatic steatosis after sustained therapeutic response"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.36370"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2002"
                        "volumen" => "36"
                        "paginaInicial" => "1266"
                        "paginaFinal" => "1272"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "56&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C&#58; indirect evidence of a role of hepatitis C virus genotype 3 in steatosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.2002.009936"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gut"
                        "fecha" => "2004"
                        "volumen" => "53"
                        "paginaInicial" => "420"
                        "paginaFinal" => "424"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "57&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jcp.54.6.461"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Pathol"
                        "fecha" => "2001"
                        "volumen" => "54"
                        "paginaInicial" => "461"
                        "paginaFinal" => "465"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "58&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis affects chronic hepatitis C progression in a genotype specific way"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.2003.018770"
                      "Revista" => array:7 [
                        "tituloSerie" => "Gut"
                        "fecha" => "2004"
                        "volumen" => "53"
                        "paginaInicial" => "406"
                        "paginaFinal" => "412"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "59&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2006.01025.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Gastroenterol"
                        "fecha" => "2007"
                        "volumen" => "102"
                        "paginaInicial" => "634"
                        "paginaFinal" => "641"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "60&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus infection and diabetes&#58; direct involvement of the virus in the development of insulin resistance"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2004"
                        "volumen" => "126"
                        "paginaInicial" => "840"
                        "paginaFinal" => "848"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "61&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "TNF-&#123;alpha&#125;&#44; chronic hepatitis C and diabetes&#58; a novel triad"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/qjmed/hci001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Qjm"
                        "fecha" => "2005"
                        "volumen" => "98"
                        "paginaInicial" => "1"
                        "paginaFinal" => "6"
                        "link" => array:1 [ …1]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "62&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gastroenterol Hepatol"
                         …5
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "63&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Proinflammatory cytokines&#44; insulin resistance&#44; and insulin secretion in chronic hepatitis C patients&#58; A case-control study"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diacare.2951096"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "64&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of TNFalpha and TNF receptors in obesity and insulin resistance"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "65&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0002-9440(10)63408-6"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "66&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impaired IRS-1&#47;PI3-kinase signaling in patients with HCV&#58; a mechanism for increased prevalence of type 2 diabetes"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.hep.2003.09.012"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "67&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms&#46;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.21634"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "68&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/mend.14.6.0446"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "69&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.C200444200"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "70&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2008.04.007"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "71&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An <span class="elsevierStyleItalic">in vitro</span> model of hepatitis C virus genotype 3a-associated triglycerides accumulation"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2004.12.034"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "72&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus core protein induces hepatic steatosis in transgenic mice"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1099/0022-1317-78-7-1527"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "73&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Topological and evolutional relationships between HCV core protein and hepatic lipid vesicles&#58; studies in vitro and in conditionally transgenic mice"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v13.i25.3472"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "74&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1099/0022-1317-81-8-1913"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "75&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Structural determinants that target the hepatitis C virus core protein to lipid droplets"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.M601031200"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "76&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an <span class="elsevierStyleItalic">in vitro</span> cellular model"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.2006.108647"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "77&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion&#58; a model of viral-related steatosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1096/fj.01-0396com"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "78&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2006.02.035"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib0395"
              "etiqueta" => "79&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Microsomal triglyceride transfer protein &#40;MTP&#41; regulation in HepG2 cells&#58; insulin negatively regulates MTP gene expression"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "80&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells&#58; roles of MAPKerk and MAPKp38"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/diabetes.52.5.1073"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib0405"
              "etiqueta" => "81&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load&#44; steatosis&#44; and liver fibrosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2003.07402.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "82&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus induced hypobetalipoproteinemia&#58; a possible mechanism for steatosis in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "83&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oxidative stress&#58; role of mitochondria and protection by glutathione"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "84&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mitochondrial injury&#44; oxidative stress&#44; and antioxidant gene expression are induced by hepatitis C virus core protein"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "85&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms and significance of liver steatosis in hepatitis C virus infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v12.i42.6756"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "86&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Very low density lipoprotein and low density lipoprotein isolated from patients with hepatitis C infection induce altered cellular lipid metabolism"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jmv.20793"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib0435"
              "etiqueta" => "87&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/2053"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            87 => array:3 [
              "identificador" => "bib0440"
              "etiqueta" => "88&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            88 => array:3 [
              "identificador" => "bib0445"
              "etiqueta" => "89&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Desreumaux P&#46; Hepatitis C virus infection down-regulates the expression of peroxisome proliferator-activated receptor alpha and carnitine palmitoyl acyl-CoA transferase 1A"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v11.i48.7591"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            89 => array:3 [
              "identificador" => "bib0450"
              "etiqueta" => "90&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            90 => array:3 [
              "identificador" => "bib0455"
              "etiqueta" => "91&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Peroxi-some proliferator-activated receptor-alpha and-gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2036.2006.02729.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            91 => array:3 [
              "identificador" => "bib0460"
              "etiqueta" => "92&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genomic analysis of the host response to hepatitis C virus infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.202608199"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            92 => array:3 [
              "identificador" => "bib0465"
              "etiqueta" => "93&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2007.02.044"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            93 => array:3 [
              "identificador" => "bib0470"
              "etiqueta" => "94&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enhancement of de novo fatty acid biosynthesis in hepatic cell line Huh7 expressing hepatitis C virus core protein"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            94 => array:3 [
              "identificador" => "bib0475"
              "etiqueta" => "95&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein&#58; genotype-3a core has a stronger effect than genotype-1b core"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2006.10.019"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            95 => array:3 [
              "identificador" => "bib0480"
              "etiqueta" => "96&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2002.32470"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            96 => array:3 [
              "identificador" => "bib0485"
              "etiqueta" => "97&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of low-and very-low-density hepatitis C virus RNA-containing particles"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/jvi.76.14.6919-6928.2002"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            97 => array:3 [
              "identificador" => "bib0490"
              "etiqueta" => "98&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Low density lipoprotein receptor as a candidate receptor for hepatitis C virus"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            98 => array:3 [
              "identificador" => "bib0495"
              "etiqueta" => "99&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis C virus and other flaviviridae viruses enter cells via low density lipo-protein receptor"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.96.22.12766"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            99 => array:3 [
              "identificador" => "bib0500"
              "etiqueta" => "100&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cell surface expression of LDL receptor in chronic hepatitis C&#58; correlation with viral load"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/ajpendo.00091.2007"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            100 => array:3 [
              "identificador" => "bib0505"
              "etiqueta" => "101&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2008.01813.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            101 => array:3 [
              "identificador" => "bib0510"
              "etiqueta" => "102&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            102 => array:3 [
              "identificador" => "bib0515"
              "etiqueta" => "103&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells&#58; differential effects on signal transduction pathways"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510290632"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            103 => array:3 [
              "identificador" => "bib0520"
              "etiqueta" => "104&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High glucose and hyperinsulinemia stimulate connective tissue growth factor expression&#58; a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2001.28055"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            104 => array:3 [
              "identificador" => "bib0525"
              "etiqueta" => "105&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of connective tissue growth factor in experimental rat and human liver fibrosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510300425"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            105 => array:3 [
              "identificador" => "bib0530"
              "etiqueta" => "106&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Connective tissue growth factor in human liver cirrhosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            106 => array:3 [
              "identificador" => "bib0535"
              "etiqueta" => "107&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of steatosis on progression of fibrosis in patients with mild hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.20519"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            107 => array:3 [
              "identificador" => "bib0540"
              "etiqueta" => "108&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The presence of steatosis and elevation of alanine aminotrans-ferase levels are associated with fibrosis progression in chronic hepatitis C with non-response to interferon therapy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2007.12.025"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            108 => array:3 [
              "identificador" => "bib0545"
              "etiqueta" => "109&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis and liver cell apoptosis in chronic hepatitis C&#58; a mechanism for increased liver injury"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.20179"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            109 => array:3 [
              "identificador" => "bib0550"
              "etiqueta" => "110&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2005.00307.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            110 => array:3 [
              "identificador" => "bib0555"
              "etiqueta" => "111&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2006.00649.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            111 => array:3 [
              "identificador" => "bib0560"
              "etiqueta" => "112&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Higher prevalence and severity of hepatic encephalopathy in patients with HCV cirrhosis and diabetes mellitus&#58; is presence of autonomic neuropathy the missing part of the puzzle&#63;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2006.00800.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            112 => array:3 [
              "identificador" => "bib0565"
              "etiqueta" => "113&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510240222"
                      "Revista" => array:3 [ …3]
                    ]
                  ]
                ]
              ]
            ]
            113 => array:3 [
              "identificador" => "bib0570"
              "etiqueta" => "114&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            114 => array:3 [
              "identificador" => "bib0575"
              "etiqueta" => "115&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1440-1746.2005.04007.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            115 => array:3 [
              "identificador" => "bib0580"
              "etiqueta" => "116&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/cncr.11427"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            116 => array:3 [
              "identificador" => "bib0585"
              "etiqueta" => "117&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v13.i39.5180"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            117 => array:3 [
              "identificador" => "bib0590"
              "etiqueta" => "118&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2003.50350"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            118 => array:3 [
              "identificador" => "bib0595"
              "etiqueta" => "119&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Obesity and its nurturing effect on hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2003.50413"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            119 => array:3 [
              "identificador" => "bib0600"
              "etiqueta" => "120&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            120 => array:3 [
              "identificador" => "bib0605"
              "etiqueta" => "121&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1478-3231.2006.01347.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            121 => array:3 [
              "identificador" => "bib0610"
              "etiqueta" => "122&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Weight affect relapse rates in latinos with genotype 2&#47;3 chronic hepatitis C &#40;CHC&#41; treated with peg IFN alfa-2a &#40;Pegasys&#41; 180 mcg&#47;week and 800 mg daily of ribavirin for 24 weeks"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jmv.21253"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            122 => array:3 [
              "identificador" => "bib0615"
              "etiqueta" => "123&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.51.1.89"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            123 => array:3 [
              "identificador" => "bib0620"
              "etiqueta" => "124&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Does a lower insulin resistance affect antiviral therapy response in patients suffering from HCV related chronic hepatitis&#63;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [ …5]
                    ]
                  ]
                ]
              ]
            ]
            124 => array:3 [
              "identificador" => "bib0625"
              "etiqueta" => "125&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of obesity on treatment of chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.21239"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            125 => array:3 [
              "identificador" => "bib0630"
              "etiqueta" => "126&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22311"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            126 => array:3 [
              "identificador" => "bib0635"
              "etiqueta" => "127&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Leptin&#44; obesity and cardiovascular disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            127 => array:3 [
              "identificador" => "bib0640"
              "etiqueta" => "128&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            128 => array:3 [
              "identificador" => "bib0645"
              "etiqueta" => "129&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Beyond insulin resistance in NASH&#58; TNF-alpha or adiponectin&#63;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.20280"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            129 => array:3 [
              "identificador" => "bib0650"
              "etiqueta" => "130&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glucose intolerance and hypoadiponectinemia are already present in lean patients with chronic hepatitis C infected with genotype non-3 viruses"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/MEG.0b013e3281532b9a"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            130 => array:3 [
              "identificador" => "bib0655"
              "etiqueta" => "131&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3&#44; but not genotype 1 infection"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2005.00311.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            131 => array:3 [
              "identificador" => "bib0660"
              "etiqueta" => "132&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.510230203"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            132 => array:3 [
              "identificador" => "bib0665"
              "etiqueta" => "133&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2005.41403.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            133 => array:3 [
              "identificador" => "bib0670"
              "etiqueta" => "134&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance is a major determinant of sustained virological response in genotype 1 chronic hepatitis c patients receiving peginterferon Alpha-2b plus ribavirin"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/apt.13365"
                      "Revista" => array:3 [ …3]
                    ]
                  ]
                ]
              ]
            ]
            134 => array:3 [
              "identificador" => "bib0675"
              "etiqueta" => "135&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2007.07.026"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            135 => array:3 [
              "identificador" => "bib0680"
              "etiqueta" => "136&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            136 => array:3 [
              "identificador" => "bib0685"
              "etiqueta" => "137&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 &#40;SOCS-3&#41; in patients with chronic hepatitis C&#44; viral genotype 1"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.2005.069674"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            137 => array:3 [
              "identificador" => "bib0690"
              "etiqueta" => "138&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The suppressor of cytokine signaling &#40;SOCS&#41; 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.273.52.35056"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            138 => array:3 [
              "identificador" => "bib0695"
              "etiqueta" => "139&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Loria P&#46; HCV and diabetes&#46; A two-question-based reappraisal"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.dld.2007.05.005"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            139 => array:3 [
              "identificador" => "bib0700"
              "etiqueta" => "140&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognostic significance of glycaemic control in patients with HBV and HCV-related cirrhosis and diabetes mellitus"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1464-5491.2005.01687.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            140 => array:3 [
              "identificador" => "bib0705"
              "etiqueta" => "141&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pioglitazone in chronic hepatitis C not responding to pegylated interferon-alpha and ribavirin"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2008.03.033"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            141 => array:3 [
              "identificador" => "bib0710"
              "etiqueta" => "142&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver fibrosis is not associated with steatosis but with necroinflammation in French patients with chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.52.11.1638"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
            ]
            142 => array:3 [
              "identificador" => "bib0715"
              "etiqueta" => "143&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/gut.52.2.288"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            143 => array:3 [
              "identificador" => "bib0720"
              "etiqueta" => "144&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of the interaction between steatosis and alcohol intake on liver fibrosis progression in chronic hepatitis C"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1572-0241.2002.05793.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            144 => array:3 [
              "identificador" => "bib0725"
              "etiqueta" => "145&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Wejstal R&#46; Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            145 => array:3 [
              "identificador" => "bib0730"
              "etiqueta" => "146&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chronic hepatitis C and superimposed nonalcoholic fatty liver disease"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            146 => array:3 [
              "identificador" => "bib0735"
              "etiqueta" => "147&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Steatosis and bile duct damage in chronic hepatitis C&#58; distribution and relationships in a group of Northern Italian patients&#46;"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            147 => array:3 [
              "identificador" => "bib0740"
              "etiqueta" => "148&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibrosis and other histological features in chronic hepatitis C virus infection&#58; a statistical model"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/jcp.49.6.465"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/16652681/00000008000000S1/v1_201906260858/S1665268119318290/v1_201906260858/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/16652681/00000008000000S1/v1_201906260858/S1665268119318290/v1_201906260858/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119318290?idApp=UINPBA00004N"
]

Article information

ISSN: 16652681
Original language: English

DOI:10.1016/S1665-2681(19)31829-0

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	0	4
2024 October	18	0	18
2024 September	20	2	22
2024 August	33	6	39
2024 July	15	6	21
2024 June	27	3	30
2024 May	18	1	19
2024 April	32	6	38
2024 March	56	8	64
2024 February	35	4	39
2024 January	34	8	42
2023 December	28	4	32
2023 November	26	6	32
2023 October	13	5	18
2023 September	15	4	19
2023 August	17	2	19
2023 July	14	2	16
2023 June	18	3	21
2023 May	42	2	44
2023 April	42	4	46
2023 March	36	2	38
2023 February	19	6	25
2023 January	20	6	26
2022 December	30	4	34
2022 November	10	5	15
2022 October	9	8	17
2022 September	9	7	16
2022 August	8	11	19
2022 July	16	7	23
2022 June	9	5	14
2022 May	15	5	20
2022 April	14	6	20
2022 March	5	7	12
2022 February	6	5	11
2022 January	7	5	12
2021 December	8	16	24
2021 November	9	8	17
2021 October	5	6	11
2021 September	8	9	17
2021 August	6	5	11
2021 July	7	5	12
2021 June	4	8	12
2021 May	11	7	18
2021 April	34	11	45
2021 March	13	8	21
2021 February	5	4	9
2021 January	5	8	13
2020 December	4	2	6
2020 November	3	2	5
2020 October	4	2	6
2020 September	3	5	8
2020 August	4	2	6
2020 July	3	1	4
2020 June	4	2	6
2020 May	4	3	7
2020 April	1	1	2
2020 March	3	4	7
2020 February	5	4	9
2020 January	8	7	15
2019 December	6	6	12
2019 November	1	0	1
2019 October	2	1	3
2019 September	1	2	3
2019 August	1	1	2
2019 July	2	2	4
2019 June	2	6	8

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter