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Clinical Practice Guideline
Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH)
Juan P. Araba,b, Juan P. Robleroc, Jose Altamiranod,e, Fernando Bessonef, Roberta Chaves Araujog, Fatima Higuera-De la Tijerah, Juan Carlos Restrepoi,j, Aldo Torrek, Alvaro Urzual, Douglas A. Simonettob, Juan G. Abraldesm, Nahum Méndez-Sánchezn, Fernando Contreraso, Michael R. Luceyp, Vijay H. Shahb, Helena Cortez-Pintoq, Ramon Batallerr,
Corresponding author
Bataller@pitt.edu

Corresponding author at: Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, W1144 Biomedical Sciences Tower, 200 Lothrop St, Pittsburgh, PA 1526, USA.
a Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
b Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
c Instituto Chileno Japonés de Enfermedades Digestivas, Facultad de Medicina, Universidad de Chile, Hospital Clínico San Borja Arriarán, Santiago, Chile
d Liver Unit-Internal Medicine Department, Hospital Universitario Valle Hebron, Barcelona, Spain
e Internal Medicine Department, Hospital Quiron Salud Barcelona, Barcelona, Spain
f Servicio de Gastroenterología y Hepatología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
g Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil
h Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico City, Mexico
i Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
j Unidad de Hepatología y Trasplante Hepático, Hospital Pablo Tobón Uribe, Medellin, Colombia
k Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico City, Mexico
l Departamento de Medicina Interna, Sección de Gastroenterología, Hospital Clínico Universidad de Chile, Santiago, Chile
m Cirrhosis Care Clinic Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
n Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
o Universidad Pedro Henriquez Urena, Santo Domingo, Dominican Republic
p Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
q Departmento de Gastrenterologia e Hepatologia, Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Portugal
r Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Liver Research Center, Pittsburgh, PA, USA
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Alcohol-related liver disease &#40;ALD&#41; is a major cause of chronic liver disease in Latin-America <a class="elsevierStyleCrossRef" href="#bib0830">&#91;1&#93;</a>&#46; Although data on prevalence in Latin-America is scarce&#44; alcohol is reported to have been the main cause of cirrhosis in Argentina&#44; Brazil&#44; Chile&#44; Mexico and Peru <a class="elsevierStyleCrossRefs" href="#bib0835">&#91;2&#8211;4&#93;</a>&#46; According to the WHO Global Status Report on Alcohol and Health of 2018&#44; individuals above 15 years of age drink 8 liters of pure alcohol per year in the WHO Region of the Americas and over 6&#46;4<span class="elsevierStyleHsp" style=""></span>l globally <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a>&#46; Researchers have largely neglected this disease&#44; and as a result the treatment has remained unaltered for many years <a class="elsevierStyleCrossRef" href="#bib0855">&#91;6&#93;</a>&#46; Recently&#44; there has been a renewed interest in understanding the pathophysiology and natural history of ALD&#44; which has yielded the discovery of novel targets&#46; The current concepts and recent advances in ALD have been summarized in clinical practice guidelines &#40;CPG&#41; from important international scientific societies <a class="elsevierStyleCrossRefs" href="#bib0860">&#91;7&#8211;9&#93;</a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The current CPG are the result of the effort of the Latin-American Special Interest Group for the Study of Alcohol-related Liver Disease &#40;ALEH-GLEHA&#41;&#44; under the sponsorship of the Latin-American Association for the Study of the Liver &#40;ALEH&#41; &#40;<a href="http://alehlatam.org/">http&#58;&#47;&#47;alehlatam&#46;org&#47;</a>&#41;&#46; The aims of these CPG are to provide physicians with evidence-based clinical recommendations&#44; tailored to Latin-American patients&#44; identifying areas of improvement&#44; collaboration&#44; and research&#46; The evidence and the expert panel recommendations were graded according to the Grading Assessment Development and Evaluation &#40;GRADE&#41; system <a class="elsevierStyleCrossRef" href="#bib0875">&#91;10&#93;</a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The strength of recommendations reflects the quality of underlying evidence&#46; The quality of the evidence in these CPGs has been classified into one of four levels&#58; high&#44; moderate&#44; low or very low&#44; considering the confidence in the effect estimate based on current literature&#46; The GRADE system offers two grades of recommendation&#58; strong or weak &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; These CPG thus consider the quality of evidence&#58; the higher the quality of evidence&#44; the more likely a strong recommendation is warranted&#59; the greater the variability in values and preferences&#44; or the greater the uncertainty&#44; the more likely a weaker recommendation is warranted&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0020">Definition and natural history</span><p id="par0020" class="elsevierStylePara elsevierViewall">Alcohol-related liver disease comprises of a clinical-pathological spectrum&#44; which ranges from steatosis&#44; alcohol-related steatohepatitis &#40;ASH&#41; and progressive fibrosis&#46; Patients with advanced forms&#44; which are associated with liver failure and complications of portal hypertension&#44; include alcoholic hepatitis &#40;AH&#41;&#44; alcohol-related cirrhosis and hepatocellular carcinoma &#40;HCC&#41; <a class="elsevierStyleCrossRef" href="#bib0880">&#91;11&#93;</a>&#46; Most heavy drinkers &#40;almost 90&#37;&#41; develop steatosis&#44; which is the earliest histopathological liver manifestation of alcohol ingestion&#46; Steatosis can develop as soon as 3&#8211;7 days after heavy alcohol consumption&#46; Steatosis is mostly asymptomatic and may be associated with mild elevations of gamma-glutamyltransferase &#40;GGT&#41;&#46; It is histologically characterized by macrovesicular fat accumulation&#44; typically located in centrilobular areas&#46; Isolated steatosis should not be considered a benign condition since it can evolve to more severe forms&#46; Continuous and excessive alcohol drinking may lead&#44; in 10&#8211;35&#37;&#44; to the development of ASH&#44; which is characterized by steatosis&#44; hepatocellular damage &#40;i&#46;e&#46; ballooning&#44; Mallory-Denk bodies &#8211; MDB&#41;&#44; inflammatory infiltrates &#8211; mainly neutrophils&#8211;&#44; and different stages of fibrosis that present with a pericellular pattern <a class="elsevierStyleCrossRef" href="#bib0880">&#91;11&#93;</a>&#46; Approximately 20&#8211;40&#37; of patients with ASH will develop progressive fibrosis&#44; of which 8&#8211;20&#37; will develop cirrhosis&#46; Some patients may present AH&#44; which usually occurs in the context of ASH with advanced fibrosis or in patients with established cirrhosis&#46; Currently&#44; AH is considered a form of acute-on-chronic liver failure &#40;ACLF&#41;&#44; which is characterized by hepatocellular damage&#44; severe fibrosis &#40;mainly cirrhosis&#41;&#44; an intense systemic inflammatory response&#44; multiorgan failure and high short-term mortality &#40;18&#8211;50&#37; at 3 months&#41; <a class="elsevierStyleCrossRefs" href="#bib0885">&#91;12&#44;13&#93;</a>&#46; Unfortunately&#44; most patients with ALD are diagnosed at an advanced stage&#44; when they develop jaundice or other complications of cirrhosis <a class="elsevierStyleCrossRef" href="#bib0895">&#91;14&#93;</a>&#46; An Argentinean study reported a 32&#46;2&#37; incidence of AH by clinical plus histology criteria in patients with ALD <a class="elsevierStyleCrossRef" href="#bib0900">&#91;15&#93;</a>&#44; but its incidence in Latin-America is unknown&#46; In the region&#44; the aforementioned study from Argentina reported a short-term mortality of 40&#37;&#46; Studies from Mexico show a mortality of 63&#37; and 89&#37; at 30 and 90 days&#44; respectively <a class="elsevierStyleCrossRefs" href="#bib0900">&#91;15&#44;16&#93;</a>&#46; This highlights the importance of characterizing this disease in Latin-America&#44; since mortality seems to be higher than in other regions&#46; Latin-Americans may also have higher percentages of cirrhosis in patients who are hospitalized with AH <a class="elsevierStyleCrossRef" href="#bib0905">&#91;16&#93;</a>&#46; A large observational study to characterize AH is this region in underway&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">ALD is the main cause of cirrhosis in Latin-America&#46; Excessive alcohol consumption should be actively sought as a cause of cirrhosis &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">1&#46;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Natural history studies assessing characteristics of the disease in the region&#44; ideally including multiple centers and countries&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">2&#46;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Studies evaluating the natural history of the disease&#44; with a special emphasis on early stages of ALD and AH&#44; due to a higher mortality observed in Latin-American populations&#46;</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0025">Risk factors</span><p id="par0050" class="elsevierStylePara elsevierViewall">The amount of alcohol intake is the most important risk factor for developing ALD <a class="elsevierStyleCrossRef" href="#bib0910">&#91;17&#93;</a>&#46; However&#44; extensive individual variability exists as only 10&#8211;20&#37; of heavy alcohol drinkers develop cirrhosis&#46; Other disease modifiers that influence the development and progression of ALD include alcohol-related factors &#40;i&#46;e&#46; pattern of drinking&#44; predominant type of alcoholic beverage consumed&#41;&#44; environmental factors &#40;presence of undernutrition&#47;obesity&#44; co-existence of chronic hepatitis B or C&#44; and cigarette smoking&#41;&#44; and genetic&#47;epigenetic factors&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">There has been large controversy in the definition of a standard drink&#44; regarding the grams of alcohol&#44; varying from 8 to 16<span class="elsevierStyleHsp" style=""></span>g&#46; According to the Dietary guidelines for Americans&#44; one standard drink of &#8220;pure&#8221; alcohol is defined as 14<span class="elsevierStyleHsp" style=""></span>g <a class="elsevierStyleCrossRef" href="#bib0915">&#91;18&#93;</a>&#44; which is equivalent to approximately 350<span class="elsevierStyleHsp" style=""></span>mL of beer &#40;5&#37; weight&#47;volume&#41;&#44; 150<span class="elsevierStyleHsp" style=""></span>mL of wine &#40;12&#8211;13&#37; weight&#47;volume&#41;&#44; or 45&#8211;50<span class="elsevierStyleHsp" style=""></span>mL of liquor &#40;40&#8211;45&#37; weight&#47;volume&#41; <a class="elsevierStyleCrossRef" href="#bib0920">&#91;19&#93;</a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Alcohol-use disorder &#40;AUD&#41; is defined as consumption of more than 3 standard drinks per day in men&#44; and more than 2 drinks per day in women&#44; or binge drinking &#40;defined as more than 5 standard drinks in men and more than 4 in women over a 2<span class="elsevierStyleHsp" style=""></span>h period&#41; <a class="elsevierStyleCrossRef" href="#bib0870">&#91;9&#93;</a>&#46; It implies a greater risk of developing health problems associated with alcohol&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The pattern of drinking&#44; especially heavy episodic drinking&#47;binge drinking&#44; is another factor that has been proposed to favor ALD&#46; However&#44; a clear role in humans has not been proven&#44; and new studies are required <a class="elsevierStyleCrossRef" href="#bib0925">&#91;20&#93;</a>&#46; The role of type of alcohol drink consumed &#40;i&#46;e&#46; liquor&#44; beer or wine&#41; on the development of severe forms of ALD is not well known <a class="elsevierStyleCrossRef" href="#bib0930">&#91;21&#93;</a>&#46; Women are more sensitive to alcohol-mediated hepatotoxicity&#46; They are prone to develop severe ALD at lower doses and with shorter duration of alcohol consumption than men <a class="elsevierStyleCrossRef" href="#bib0935">&#91;22&#93;</a>&#46; This could be explained by their higher body fat composition and lower gastric alcohol dehydrogenase activity <a class="elsevierStyleCrossRef" href="#bib0940">&#91;23&#93;</a>&#46; Overweight and obesity have also been associated with increased ALD risk&#46; The combination of both&#44; heavy alcohol drinking and obesity&#47;overweight &#40;especially BMI<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30&#41;&#44; synergistically induce liver disease <a class="elsevierStyleCrossRefs" href="#bib0945">&#91;24&#44;25&#93;</a>&#46; For that reason&#44; it is recommended to reduce cut-off levels of hazardous drinking in obese subjects &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Large epidemiological studies have found that light-to-moderate alcohol consumption&#44; even in obese patients&#44; may reduce the risk of non-alcoholic fatty liver disease &#40;NAFLD&#41; <a class="elsevierStyleCrossRef" href="#bib0955">&#91;26&#93;</a>&#46; Furthermore&#44; it has been observed that in patients with NAFLD&#44; the severity of inflammation and fibrosis could decrease with low alcohol consumption <a class="elsevierStyleCrossRefs" href="#bib0960">&#91;27&#44;28&#93;</a>&#46; A large recent study&#44; however&#44; showed that even one single drink per day increases all-cause mortality&#44; probably related to cancer <a class="elsevierStyleCrossRef" href="#bib0970">&#91;29&#93;</a>&#46; In the clinical setting&#44; patients with obesity-related liver disease are recommended to limit the amount of alcohol consumption&#46; In addition&#44; we should consider other risk factors&#44; such as type of drink and genetic factors <a class="elsevierStyleCrossRef" href="#bib0975">&#91;30&#93;</a>&#46; The presence of protein calorie malnutrition has an important role in determining the outcome of patients with ALD&#46; Mortality increases in direct proportion to the extent of malnutrition&#44; approaching 80&#37; in patients with severe malnutrition &#40;i&#46;e&#46;&#44; &#60;50&#37; of normal body weight&#41; <a class="elsevierStyleCrossRef" href="#bib0980">&#91;31&#93;</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Excessive alcohol consumption has also shown to increase the risk of advanced liver disease and HCC in patients with chronic hepatitis B and C virus infection <a class="elsevierStyleCrossRefs" href="#bib0985">&#91;32&#44;33&#93;</a>&#46; Additionally&#44; alcohol has a synergistic hepatotoxic effect with NAFLD&#44; iron overload and other metabolic disorders <a class="elsevierStyleCrossRef" href="#bib0880">&#91;11&#93;</a>&#46; Interestingly&#44; coffee seems to have a protective effect against liver injury in people who drink alcohol&#44; however&#44; current available data is controversial <a class="elsevierStyleCrossRef" href="#bib0995">&#91;34&#93;</a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Genetic factors are involved in the onset&#44; progression&#44; and clinical outcome of ALD&#46; Epidemiological studies conducted among family members and between twins strongly support a genetic component <a class="elsevierStyleCrossRefs" href="#bib1000">&#91;35&#8211;37&#93;</a>&#46; Moreover&#44; ethnicity influences the susceptibility to ALD&#44; and Latin-America is very heterogeneous&#46; Studies conducted in Mexico&#44; have identified genetic polymorphisms among Amerindian populations that would increase the predisposition and severity of ALD <a class="elsevierStyleCrossRefs" href="#bib1015">&#91;38&#44;39&#93;</a>&#46; Similarly&#44; studies conducted in United States of America have shown that Individuals with Hispanic ancestry have a higher incidence and a more aggressive pattern of liver disease than individuals of other ethnic groups <a class="elsevierStyleCrossRefs" href="#bib1025">&#91;40&#44;41&#93;</a>&#46; In recent years&#44; the polymorphisms of the gene coding for Patatin-like phospholipase domain-containing 3 &#40;PNPLA3&#41; have generated great interest&#44; which would play a key role in the development of alcohol-related cirrhosis&#46; The PNPLA3 I148M genetic variant&#44; which functionally involves the loss of protein function with a consequent increase in intrahepatic fat and progression of liver disease&#44; was found primarily in patients with NAFLD <a class="elsevierStyleCrossRef" href="#bib1020">&#91;39&#93;</a>&#46; Studies conducted in the region&#44; in South America and also in Mexico&#44; have shown that this polymorphism is significantly more frequent in individuals with Native American ancestry and it is a risk factor for the development of advanced liver disease <a class="elsevierStyleCrossRefs" href="#bib1035">&#91;42&#8211;44&#93;</a>&#46; Subsequently&#44; it has been demonstrated that individuals carrying this polymorphism constitute a genetic subpopulation with an increased risk of ALD and progression to cirrhosis and HCC <a class="elsevierStyleCrossRefs" href="#bib1050">&#91;45&#44;46&#93;</a>&#46; A meta-analysis showed that GG genotype had approximately a four-fold risk of having alcohol-related cirrhosis when compared with the CC genotype <a class="elsevierStyleCrossRef" href="#bib1060">&#91;47&#93;</a>&#46; The fact that PNPLA3 variant is more frequent in people with indigenous ancestry explains in part the high prevalence of liver cirrhosis in Latin-America <a class="elsevierStyleCrossRef" href="#bib1065">&#91;48&#93;</a>&#46; In a recent genome-wide association study &#40;GWAS&#41;&#44; PNPLA3 has been confirmed as the main risk locus for alcohol-related cirrhosis&#46; Variations in two other genes &#40;i&#46;e&#46; TM6SF2 and MBOAT7&#41; also confer risk for severe ALD&#46; These two genes&#44; along with PNPLA3&#44; are related to lipid metabolic processes <a class="elsevierStyleCrossRefs" href="#bib1070">&#91;49&#44;50&#93;</a>&#46; The TM6SF2 and PNPLA3 polymorphism variants apparently have a role on the modulation of hepatic fat accumulation&#44; fibrosis and HCC development&#46; The MBOAT7 polymorphism has been associated mainly with fibrosis <a class="elsevierStyleCrossRefs" href="#bib1080">&#91;51&#8211;53&#93;</a>&#46; Recently&#44; it has been also described the a splice variant in HSD17B13&#44; encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 17&#44; which appeared to protect against alcohol-associated and non-alcohol associated steatohepatitis&#44; cirrhosis and hepatocellular carcinoma <a class="elsevierStyleCrossRef" href="#bib1095">&#91;54&#93;</a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">2&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">The amount of alcohol consumed is the most important risk factor for the development of ALD &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">3&#46;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Subjects consuming more than 3 standard drinks per day in men&#44; and more than 2 drinks per day in women&#44; or repeated binge drinking &#40;defined as more than 5 drinks in men and more than 4 in women over a 2<span class="elsevierStyleHsp" style=""></span>h period&#41; are at risk of developing liver disease and should receive counseling &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">4&#46;</span><p id="par0090" class="elsevierStylePara elsevierViewall">The impact of the type of alcoholic drink consumed &#40;i&#46;e&#46; liquor&#44; beer or wine&#41; and the pattern of drinking on the risk of developing ALD is not well known &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">5&#46;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patients with any chronic liver disease and protein calorie malnutrition should be advised to avoid regular alcohol consumption &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li></ul></p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">3&#46;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Studies assessing the impact of the type of alcohol consumed in ALD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">4&#46;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Large genome wide association studies&#44; in different ethnicities of Latin-America&#44; to identify the genetic determinants implicated in individual susceptibility to ALD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">5&#46;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Studies assessing the role of environmental factors influencing the susceptibility to develop severe ALD&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology and burden of the disease</span><p id="par0120" class="elsevierStylePara elsevierViewall">Alcohol is one of the five main factors responsible for disease&#44; death and disability worldwide&#46; In 2016&#44; 3 million people died due to alcohol-related causes&#44; which represents 5&#46;3&#37; of all deaths <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a>&#46; ALD is one of the most important consequences of chronic alcohol drinking and represents the main cause of cirrhosis worldwide&#46; Globally&#44; alcohol-attributable fraction &#40;AAF&#41; of liver cirrhosis is up to 50&#37;&#46; In Latin-America&#44; excessive alcohol consumption and its consequences represent a major public health problem&#46; Even though studies from the region are scarce&#44; and there is great variability among Latin-American countries&#44; the magnitude of the problem can be assessed through the WHO Global Alcohol database <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a>&#46; Latin-America consists of 20 countries comprising 58&#37; of the population of the Region of the Americas&#46; In terms of alcohol consumption&#44; the Region of the Americas ranks second following the European Region&#46; The total per capita pure alcohol consumption per year in 2016 in the Region of the Americas was 8&#46;0<span class="elsevierStyleHsp" style=""></span>l compared to 6&#46;2<span class="elsevierStyleHsp" style=""></span>l worldwide&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">About 43&#37; of adults in the world are current drinkers&#44; defined as those people who have consumed alcohol within the last 12 months&#46; Among Latin American countries such as Argentina&#44; Chile&#44; Paraguay&#44; Peru and Colombia current drinkers are more than 80&#37;&#44; and in Argentina&#44; Chile and Peru more than 60&#37; are current drinkers&#44; in both cases considering men and women&#46; In Argentina&#44; Chile and Uruguay the average of standard drinks per day are 2&#8211;3 in women&#46; Meanwhile&#44; men from Paraguay&#44; Ecuador&#44; Colombia&#44; Venezuela and Mexico are 3&#8211;4 standard drinks daily <a class="elsevierStyleCrossRef" href="#bib1100">&#91;55&#93;</a>&#46; The countries in Latin-America with highest alcohol consumption &#40;L&#47;per capita&#41; are Uruguay&#44; Argentina and Chile and the countries with lower consumption are Guatemala&#44; El Salvador and Honduras &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Of note&#44; the consumption of homemade alcoholic beverages&#44; very typical in rural areas in Latin America&#44; is unknown and may account for an important and unrecorded proportion of alcohol intake&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">AAFs for all-cause disability adjusted life years &#40;DALYs&#41; and for all-cause deaths in 2016 in Latin-America were 6&#46;7&#37; and 5&#46;5&#37;&#44; respectively <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a>&#46; The cirrhosis burden&#44; which is caused mainly by alcohol in our region&#44; is particularly alarming in Latin-America&#46; In 2012&#44; liver cirrhosis was responsible for 60&#44;600 deaths and 1&#44;787&#44;000 DALYs <a class="elsevierStyleCrossRef" href="#bib1105">&#91;56&#93;</a>&#46; In Latin America&#44; and especially in the Central region of Latin America&#44; cirrhosis causes high mortality&#46; It is responsible of about 2&#46;7&#37; of all deaths&#44; one of the highest rates in the world&#44; being only greater in countries from the Middle East and North Africa <a class="elsevierStyleCrossRef" href="#bib1100">&#91;55&#93;</a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">In some countries of Latin-America consumption has increased&#44; and this trend is expected to continue over the next 25 years&#44; unless drastic public health measures are taken to reduce consumption <a class="elsevierStyleCrossRefs" href="#bib1110">&#91;57&#44;58&#93;</a>&#46; The prevalence of AUD&#44; alcohol dependence and harmful use of alcohol constitutes a major problem in the region&#46; Peru is the country with the highest prevalence of AUD &#40;8&#46;9&#37;&#41;&#46; It is worthwhile to note that this percentage is higher only in some countries of Europe&#46; In addition&#44; Latin-America has one of the highest prevalence of AUD in the world among women&#44; being especially high in Colombia&#44; Haiti&#44; Peru and Venezuela <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Regarding consumption patterns&#44; America also has a high prevalence of heavy episodic drinking&#47;binge drinking&#46; There is a prevalence of 21&#46;3&#37; in the overall population &#40;15 or more years of age&#41; and 40&#46;5&#37; among drinkers&#46; Peru is the country with the highest prevalence of heavy drinking&#47;binge drinking&#44; being 26&#46;4&#37; among the general population <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Regarding the type of beverage consumed&#44; the regions of South America&#44; Chile&#44; Argentina&#44; and Uruguay are high consumers of wine&#46; Other Latin-American countries&#44; for example&#44; Guatemala&#44; Nicaragua&#44; Costa Rica&#44; and Peru mostly consume spirits&#44; followed by beer&#46; Overall&#44; beer is the most frequently consumed beverage in Central and South America&#44; constituting about 50&#37; of the total recorded alcohol consumed <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In Latin-America&#44; we urge to strengthen public policies to reduce excessive alcohol consumption&#46; This is especially important in the countries of the region where laws have not been developed yet to address this issue&#46; In fact&#44; at present&#44; only eight of the twenty Latin-American countries have written national policies on alcohol <a class="elsevierStyleCrossRef" href="#bib0850">&#91;5&#93;</a>&#46; Public policies such as increased taxation have proved to be effective in other countries&#46; Also&#44; the taxation proportional to the percentage of alcohol&#44; for example&#44; introducing the Minimum Unit Pricing&#44; have shown to reduce alcohol-related diseases <a class="elsevierStyleCrossRef" href="#bib1120">&#91;59&#93;</a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">6&#46;</span><p id="par0155" class="elsevierStylePara elsevierViewall">Latin-America is one of the regions with high prevalence of excessive alcohol consumption and the resulting health consequences represent a major public health concern&#46; Implementation of public health policies aimed at reducing the burden of alcohol-related cirrhosis are urgently needed &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li></ul></p><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">6&#46;</span><p id="par0165" class="elsevierStylePara elsevierViewall">Epidemiological studies assessing the prevalence of ALD in Latin-America&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">7&#46;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Studies evaluating cost-effectiveness of public policies and measures to reduce alcohol consumption and the burden of ALD&#46;</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">5</span><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis of alcohol-use disorder and alcohol-related liver disease</span><p id="par0175" class="elsevierStylePara elsevierViewall">The existence of AUD should be assessed in all patients presenting with abnormal liver function tests or with liver-related complications&#46; It is important to keep in mind that hazardous drinking refers to the drinking pattern of alcohol that increases the risk of physical harm or psychological problems&#46; AUD refers to the harmful use of alcohol and alcohol dependence&#46; The harmful use of alcohol corresponds to the pattern of intake that has potential to cause physical or mental harm&#46; Alcohol dependence is defined by the WHO as a cluster of behavioral&#44; cognitive&#44; and physiological phenomena that develop after alcohol use&#46; It typically includes a strong desire to consume alcohol&#44; difficulty in controlling its use&#44; persistent use despite harmful consequences&#44; a higher priority given to alcohol use than to other activities&#44; increased tolerance&#44; and sometimes a physiological withdrawal state <a class="elsevierStyleCrossRef" href="#bib1125">&#91;60&#93;</a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Some questionnaires can help us to distinguish patients with alcohol abuse&#46; The <span class="elsevierStyleItalic">Alcohol Use Disorders Identification Test</span> &#40;AUDIT&#41; comprises ten questions with a specific scoring system <a class="elsevierStyleCrossRef" href="#bib1130">&#91;61&#93;</a>&#46; An AUDIT score &#62;8 is considered a positive screening test result&#44; which indicates the presence of AUD&#46; A score of &#62;20 implies the presence of alcohol dependence <a class="elsevierStyleCrossRef" href="#bib1135">&#91;62&#93;</a>&#46; The AUDIT-C is a shorter version of AUDIT &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; that consists of three questions with a specific scoring system that ranges from 0 to 12&#46; A positive screening result is a score of 3 or more for women and 4 or more for men&#46; A score between 7 and 10 has been associated with an increased risk of alcohol dependence&#46; The AUDIT-C has 73&#37; sensitivity and 91&#37; specificity for AUD and 85&#37; sensitivity and 89&#37; specificity for detecting alcohol dependence <a class="elsevierStyleCrossRef" href="#bib1140">&#91;63&#93;</a>&#46; The CAGE questionnaire is also a useful and an easily applied tool &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Two or more out of the four possible &#8220;yes&#8221; responses indicate that the possibility of AUD should be investigated further <a class="elsevierStyleCrossRef" href="#bib1145">&#91;64&#93;</a>&#46; A meta-analysis that evaluated the CAGE questionnaire using a cutoff of more than two positive responses&#44; found an overall sensitivity of 71&#37; and specificity of 90&#37; <a class="elsevierStyleCrossRef" href="#bib1150">&#91;65&#93;</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">The diagnosis of ALD relies on a history of significant alcohol intake&#44; clinical features&#44; laboratory abnormalities and on excluding other causes of liver disease&#46; Aminotransferases can be slightly or moderately elevated&#44; but usually serum values are less than 300&#8211;400<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#46; The ratio of aspartate aminotransferase &#40;AST&#41; to alanine aminotransferase &#40;ALT&#41; level is generally greater than 2&#46; This ratio is due to reduced hepatic ALT activity&#44; alcohol-induced depletion of hepatic pyridoxal 5&#8217;-phosphate and an increased hepatic mitochondrial aspartate aminotransferase <a class="elsevierStyleCrossRef" href="#bib1150">&#91;65&#93;</a>&#46; Other typical laboratory abnormalities are elevation of GGT and of mean corpuscular volume&#46; Imaging studies&#44; such as ultrasound&#44; computed tomography scan&#44; and magnetic resonance imaging &#40;MRI&#41; are non-specific for diagnosis of ALD&#46; However&#44; they are useful to search for characteristic findings of fatty liver&#44; cirrhosis&#44; hepatocellular carcinoma&#44; and also for differential diagnosis with biliary tract diseases&#46; The differential diagnosis between ALD and NAFLD in patients with both risk factors is challenging&#46; A cross-sectional cohort study performed at the Mayo Clinic identified the mean corpuscular volume&#44; AST&#47;ALT ratio&#44; body mass index&#44; and gender as the most important variables that differentiate patients with ALD from those with NAFLD&#46; These variables were used to generate the ALD&#47;NAFLD Index &#40;ANI&#41; <a class="elsevierStyleCrossRef" href="#bib1155">&#91;66&#93;</a>&#46; In many patients&#44; however&#44; ALD and NAFLD coexist&#46; A new nomenclature defining the combined etiology should be developed&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Although the diagnosis of ALD is clinico-pathological&#44; a liver biopsy helps to establish the diagnosis and to exclude coexisting conditions&#46; However&#44; in clinical practice the diagnosis is often made without recourse to a biopsy&#46; The histological features of ALD can vary&#44; depending on the extent and stage of injury and are not pathognomonic for ALD&#46; Macrovesicular steatosis is the earliest and most commonly seen pattern&#46; Cirrhosis may occur after a median of 10&#46;5 years in 10&#37; of patients with steatosis&#46; In patients with ASH&#44; the main findings are steatosis&#44; hepatocellular injury characterized by ballooned hepatocytes that often contain amorphous eosinophilic inclusions called MDB surrounded by neutrophils&#44; intra-sinusoidal fibrosis&#44; also perivenular and&#47;or periportal fibrosis&#44; and cirrhosis&#46; In addition to these features&#44; AH is characterized by intraparenchymal cholestasis or bilirubinostasis <a class="elsevierStyleCrossRef" href="#bib1120">&#91;59&#93;</a>&#46; Other histologic findings associated with AH may include megamitochondria&#44; foamy degeneration of hepatocytes and acute sclerosing hyaline necrosis <a class="elsevierStyleCrossRefs" href="#bib1140">&#91;63&#44;67&#93;</a>&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Fibrosis is one of the main prognostic factors&#44; and in the absence of a biopsy&#44; non-invasive methods to assess fibrosis in ALD have been developed <a class="elsevierStyleCrossRef" href="#bib1165">&#91;68&#93;</a>&#46; Some alternatives are commercially available serum biomarkers&#44; such as Fibrotest<span class="elsevierStyleSup">&#174;</span>&#44; Fibrometer<span class="elsevierStyleSup">&#174;</span>&#44; and Hepascore<span class="elsevierStyleSup">&#174;</span>&#46; The diagnostic accuracy of these tests is greater than other biomarkers developed for viral hepatitis &#40;i&#46;e&#46; APRI&#44; Forn&#39;s Index&#44; FIB4&#41; <a class="elsevierStyleCrossRef" href="#bib1120">&#91;59&#93;</a>&#46; A combination of any of these tests was not useful in improving diagnostic performance <a class="elsevierStyleCrossRef" href="#bib1170">&#91;69&#93;</a>&#46; Another noninvasive approach is the use of transient elastography&#44; which assesses liver stiffness&#46; Liver stiffness measurement &#40;LSM&#41; closely correlates with the degree of fibrosis and is excellent to exclude significant fibrosis or cirrhosis in patients first assessed for ALD <a class="elsevierStyleCrossRefs" href="#bib1175">&#91;70&#44;71&#93;</a>&#46; The cutoff values for F3 and F4 were considerably higher when compared to patients with viral hepatitis&#46; Confounding factors that can interfere with LSM include AST<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>UI&#47;L <a class="elsevierStyleCrossRef" href="#bib1185">&#91;72&#93;</a>&#44; recent alcohol intake&#44; no compliance with fasting recommendation before the assessment and the presence of cholestasis <a class="elsevierStyleCrossRef" href="#bib1190">&#91;73&#93;</a>&#46; Recently&#44; Magnetic Resonance Elastography &#40;MRE&#41; has been shown to be an excellent tool to evaluate the elasticity of the liver tissue&#44; with&#44; according to recent studies&#44; an accuracy equal to or superior to TE for the diagnosis of advanced fibrosis and cirrhosis&#44; regardless of the etiology&#46; It has the advantage that it carries out an evaluation of all the liver tissue and that it can be done in a two-dimensional and even three-dimensional way <a class="elsevierStyleCrossRef" href="#bib1195">&#91;74&#93;</a>&#46; However&#44; it is a high cost test&#44; which is a problem for use in Latin American countries&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">7&#46;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Alcohol use disorder should be assessed in all patients presenting with newly recognized liver disfunction&#44; by application of specific questionnaires &#40;i&#46;e&#46; AUDIT or CAGE&#41; that can be easily applied in daily clinical practice &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">8&#46;</span><p id="par0210" class="elsevierStylePara elsevierViewall">In patients with AUD&#44; clinical&#44; biochemical and radiological evaluation is mandatory for early detection of underlying ALD &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">9&#46;</span><p id="par0215" class="elsevierStylePara elsevierViewall">A liver biopsy may be considered when the ALD diagnosis is unclear due to the existence of other potential etiological factors &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; weak&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">10&#46;</span><p id="par0220" class="elsevierStylePara elsevierViewall">In patients with excessive alcohol use and obesity-related metabolic syndrome&#44; the Alcoholic liver disease&#47;Nonalcoholic Fatty Liver Disease Index &#40;ANI&#41; could be helpful in differentiating ALD and NAFLD &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">11&#46;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Liver stiffness measurement or patented serum biomarkers may be useful for assessing liver fibrosis in patients with ALD&#44; however&#44; certain conditions&#44; such as the presence of ASH&#44; cholestasis&#44; and active alcohol intake can overestimate the degree of fibrosis &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li></ul></p><p id="par0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">8&#46;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Studies to identify reliable noninvasive biomarkers to differentiate between steatosis&#44; steatohepatitis and fibrosis in the setting of ALD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">9&#46;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Population based studies to assess the prevalence of AUD and ALD in Latin-America&#46;</p></li></ul></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">6</span><span class="elsevierStyleSectionTitle" id="sect0040">Alcoholic hepatitis&#58; diagnosis and prognosis</span><p id="par0245" class="elsevierStylePara elsevierViewall">Alcoholic hepatitis &#40;AH&#41; is a clinical entity characterized by abrupt onset of jaundice&#44; and liver-related decompensation in patients with excessive and prolonged alcohol consumption&#46; It should not be confused with early ASH that is detectable through histology in patients with silent disease&#46; AH manifests with rapid onset of progressive jaundice&#44; leukocytosis and right upper quadrant abdominal discomfort&#46; This may transition to a more severe hepatic injury&#44; including acute-on-chronic liver failure &#40;ACLF&#41; and multi-organ failure&#44; which carry a mortality risk of 18&#8211;50&#37; in 1 month depending on the number of comprised extra-hepatic organs <a class="elsevierStyleCrossRef" href="#bib0880">&#91;11&#93;</a>&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Regarding laboratory tests&#44; AST levels are typically elevated &#40;2&#8211;6 times ULN&#41; with AST&#47;ALT ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2&#46; Hyperbilirubinemia and leukocytosis are also frequently observed&#46; In severe cases&#44; serum albumin may be decreased&#44; and the INR elevated&#46; Patients with severe forms of AH are prone to develop bacterial infections and acute renal injury <a class="elsevierStyleCrossRef" href="#bib1160">&#91;67&#93;</a>&#46; An NIH-sponsored consensus meeting of investigators recently proposed the following criteria for clinical diagnosis&#58; &#40;1&#41; heavy alcohol use for &#62;6 months &#40;typically<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5 years&#41;&#44; &#40;2&#41; active alcohol use until &#60;60 days prior to presentation&#44; &#40;3&#41; sudden onset or worsening of jaundice&#44; &#40;4&#41; AST&#47;ALT ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5&#58;1 with levels<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>400<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#44; and &#40;5&#41; absence of other causes of liver disease <a class="elsevierStyleCrossRef" href="#bib1200">&#91;75&#93;</a>&#46; Histologically&#44; AH is associated with ballooned hepatocytes&#44; MDB&#44; lobular polymorphonuclear neutrophils and pericellular&#44; bilirrubinostasis and sinusoidal fibrosis &#40;&#8220;chicken wire&#8221; appearance&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The lesions defining ASH do not differ in essence from those described in non-alcoholic steatohepatitis <a class="elsevierStyleCrossRef" href="#bib0860">&#91;7&#93;</a>&#46; In patients with suspected AH&#44; a transjugular liver biopsy is recommended when the clinical diagnosis is confounded by another liver disease etiology&#44; in the presence of confounding factors or when the alcohol consumption history is uncertain&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0255" class="elsevierStylePara elsevierViewall">Multiple scoring systems have been developed to predict short-term prognosis in patients with AH&#46; One of the first and most validated is the Maddrey Discriminant Function &#40;MDF&#41;&#44; which includes prothrombin time &#40;PT&#41; and total bilirubin&#44; and where severe AH is defined by a score &#8805;32 <a class="elsevierStyleCrossRef" href="#bib1205">&#91;76&#93;</a>&#46; This score was used in the original trial assessing corticosteroids treatment of AH&#46; A MDF score &#8805;32 predicts a 30-day mortality rate of approximately 20&#8211;50&#37; <a class="elsevierStyleCrossRef" href="#bib1210">&#91;77&#93;</a>&#46; Many other scoring systems have also been validated&#46; These include the Model for End-Stage Liver Disease &#40;MELD&#41; score&#44; the Glasgow Alcoholic Hepatitis Score &#40;GAHS&#41; and the Age&#44; serum Bilirubin&#44; INR&#44; and serum Creatinine &#40;ABIC&#41; <a class="elsevierStyleCrossRef" href="#bib1210">&#91;77&#93;</a>&#46; The MELD score is being increasingly used to assess severity of AH given its better accuracy&#44; worldwide use in organ allocation and use of INR as standard in reporting prothrombin time&#46; It also incorporates renal function&#47;serum creatinine&#44; which is a major determinant of outcomes in AH patients&#46; A MELD score &#62;20 has been proposed as defining severe AH <a class="elsevierStyleCrossRef" href="#bib1215">&#91;78&#93;</a>&#46; The ABIC score classifies patients according to low&#44; intermediate and high risk for death <a class="elsevierStyleCrossRef" href="#bib1220">&#91;79&#93;</a>&#46; Another relevant prognostic tool is the Lille score&#44; which is a continuous score with a scale from 0 to 1&#44; assessed at 4&#8211;7 days of corticosteroid therapy&#46; A Lille score &#60;0&#46;45 predicts a favorable response to corticosteroids and continuation of prednisolone for a total of 4 weeks is recommended <a class="elsevierStyleCrossRef" href="#bib1225">&#91;80&#93;</a>&#46; The vast majority of these scores have been shown to predict prognosis accurately at 30 days but have failed in predicting survival beyond 90 days&#46; The strongest predictor of survival after 90 days is the ability to maintain abstinence from alcohol <a class="elsevierStyleCrossRef" href="#bib1230">&#91;81&#93;</a>&#46; A very interesting recent study showed that a combining the MELD score at baseline and the Lille score at day 7 performs best for prognostication of 2-month and 6-month mortality <a class="elsevierStyleCrossRef" href="#bib1235">&#91;82&#93;</a>&#46; Another recent study showed that MELD&#44; ABIC and GAHS are superior to the DF in AH&#46; Furthermore&#44; in combination with the Lille score&#44; this allows for a reduction in the number of patients treated unnecessarily with corticosteroids&#44; leading to an improvement in survival at 90 days <a class="elsevierStyleCrossRef" href="#bib1240">&#91;83&#93;</a>&#46; Multiple other criteria and biomarkers have been recently proposed and need further validation&#44; including serum lipopolysaccharide levels&#44; SIRS criteria&#44; and procalcitonin <a class="elsevierStyleCrossRef" href="#bib1245">&#91;84&#93;</a>&#46; Further studies should evaluate the performance of the existing prognostic scoring systems in Latin America&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">12&#46;</span><p id="par0265" class="elsevierStylePara elsevierViewall">AH is clinically defined as abrupt onset of progressive jaundice and liver-related complications with hyperbilirubinemia &#40;&#62;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; AST&#47;ALT ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5 with levels of AST<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5 times the upper limit of normal but &#60;400<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#59; and heavy alcohol drinking until 60 days before onset of symptoms and absence of other causes of liver disease &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">13&#46;</span><p id="par0270" class="elsevierStylePara elsevierViewall">Liver biopsy to diagnose AH is recommended in patients with suspected AH&#44; but who do not meet the abovementioned criteria&#44; in the presence of confounding factors or when other etiology is also suspected &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li></ul></p><p id="par0275" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">10&#46;</span><p id="par0280" class="elsevierStylePara elsevierViewall">Studies assessing the clinical features&#44; mortality and usefulness of existing scoring systems in Latin-America&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">11&#46;</span><p id="par0285" class="elsevierStylePara elsevierViewall">Studies assessing noninvasive biomarkers useful to diagnose AH and to predict survival and response to therapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">12&#46;</span><p id="par0290" class="elsevierStylePara elsevierViewall">Studies assessing the prevalence and predictors of alcohol relapse and its impact on long-term outcome in patients surviving an episode of AH&#46;</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">7</span><span class="elsevierStyleSectionTitle" id="sect0045">Cirrhosis and hepatocellular carcinoma</span><p id="par0295" class="elsevierStylePara elsevierViewall">Alcohol is the main etiology of cirrhosis worldwide including Latin-America <a class="elsevierStyleCrossRef" href="#bib0830">&#91;1&#93;</a>&#46; Cirrhosis is the most important risk factor for HCC development&#46; A multicenter prospective study&#44; from Latin-America&#44; reported that 85&#37; of HCC patients had underlying cirrhosis <a class="elsevierStyleCrossRef" href="#bib1250">&#91;85&#93;</a>&#46; HCC association with cirrhosis secondary to chronic hepatitis B and C infections&#44; and hemochromatosis is stronger than with cirrhosis related to ALD&#44; where the association is less intense <a class="elsevierStyleCrossRef" href="#bib1255">&#91;86&#93;</a>&#46; The population-attributable fractions are greatest for metabolic disorders &#40;32&#37;&#41;&#44; followed by hepatitis C virus &#40;HCV&#41; &#40;20&#46;5&#37;&#41;&#44; and alcohol &#40;13&#46;4&#37;&#41; <a class="elsevierStyleCrossRef" href="#bib1260">&#91;87&#93;</a>&#46; Multiple studies have shown cumulative risk of HCC higher than 1&#46;5&#37; per year&#44; which represents the threshold proposed for HCC surveillance&#44; so HCC screening is recommended in all patients with alcohol-related cirrhosis <a class="elsevierStyleCrossRefs" href="#bib1265">&#91;88&#44;89&#93;</a>&#46; To date&#44; no Latin-American studies aimed at assessing this issue have been published&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">The amount of alcohol ingestion has been shown to affect&#44; although not in a linear fashion&#44; the development of cirrhosis and HCC&#46; Higher intake confers higher risk of HCC&#44; but there is no established threshold <a class="elsevierStyleCrossRef" href="#bib1275">&#91;90&#93;</a>&#46; There are no data on the role of the duration or pattern of drinking &#40;continuous versus binge&#41; on HCC development&#46; Regarding other risk factors&#44; women have higher incidence of cirrhosis and HCC with lower levels of alcohol ingestion <a class="elsevierStyleCrossRef" href="#bib1275">&#91;90&#93;</a>&#46; Genetic polymorphisms also affect the predisposition to HCC in ALD&#46; The <span class="elsevierStyleItalic">PNPLA3</span> gene polymorphism &#40;C&#62;G&#41; increases the risk of HCC with an OR of 2&#46;20 &#40;1&#46;80&#8211;2&#46;67&#41; for G allele <a class="elsevierStyleCrossRef" href="#bib1280">&#91;91&#93;</a>&#46; These results might have a great impact in Latin-America&#44; where GG polymorphism is frequently seen <a class="elsevierStyleCrossRef" href="#bib1285">&#91;92&#93;</a>&#46; Finally&#44; cigarette smoking significantly increases the risk of developing HCC <a class="elsevierStyleCrossRef" href="#bib1290">&#91;93&#93;</a>&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Multiple studies have shown that chronic hepatitis B and C infections act synergistically with alcohol in the progression&#44; risk and incidence of HCC <a class="elsevierStyleCrossRef" href="#bib1295">&#91;94&#93;</a>&#46; In Latin-America&#44; HBsAg prevalence is lower than other developing regions and it has recently dropped probably due to vaccination programs&#46; Nevertheless&#44; there are still some regions of the Amazonia with high prevalence &#40;&#62;8&#37;&#41;&#46; Meanwhile&#44; chronic hepatitis C prevalence in the region is similar to Europe or the United States <a class="elsevierStyleCrossRef" href="#bib1300">&#91;95&#93;</a>&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Surveillance for HCC should not be different in ALD related cirrhosis in Latin-America compared to other etiologies&#46; ALEH guidelines recommend liver ultrasonography every 6 months and to consider serum alpha-fetoprotein &#40;AFP&#41; as a biomarker <a class="elsevierStyleCrossRef" href="#bib1305">&#91;96&#93;</a>&#46; Patients with ALD are less frequently screened and have less adherence&#46; As a consequence&#44; HCC is diagnosed at advanced stages in this patient population and carry lower survival rates&#46; However&#44; after adjusting for disease stage&#44; the natural history and survival are similar to other causes of HCC <a class="elsevierStyleCrossRef" href="#bib1310">&#91;97&#93;</a>&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">14&#46;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Alcohol-related cirrhosis is one of the main causes of HCC in Latin-America &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">15&#46;</span><p id="par0325" class="elsevierStylePara elsevierViewall">The risk of HCC in ALD-related cirrhosis is similar to other etiologies and surveillance should be performed by ultrasonography every 6 months with or without serum alpha-fetoprotein levels &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li></ul></p><p id="par0330" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">13&#46;</span><p id="par0335" class="elsevierStylePara elsevierViewall">Epidemiological studies focusing on the risk factors of hepatocellular carcinoma and their impact on its development in Latin-America&#44; with a special emphasis on ALD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">14&#46;</span><p id="par0340" class="elsevierStylePara elsevierViewall">Studies assessing the role of genetic&#47;epigenetics on the predisposition to development of HCC in alcohol-related cirrhosis&#46;</p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8</span><span class="elsevierStyleSectionTitle" id="sect0050">Management of alcohol-related liver disease</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0055">Management of long-term complications of alcohol-related liver disease</span><p id="par0345" class="elsevierStylePara elsevierViewall">The first step in management of ALD should be directed to an early recognition of excessive alcohol intake by both the patient and the physician&#46; Patients often underreport alcohol intake and a motivational and empathetic relationship with the provider is highly advised&#46; It is recommended that physicians taking care of these patients also get some training in motivational interviewing and addiction medicine&#46; In fact&#44; a proportion of alcohol abusers many times also consume other drugs <a class="elsevierStyleCrossRef" href="#bib1315">&#91;98&#93;</a>&#46; The current long-term management of alcohol-related cirrhosis should focus on&#58; alcohol abstinence&#44; aggressive nutritional therapy rich in calories and proteins&#44; and prevention&#47;early therapy of cirrhosis complications &#40;i&#46;e&#46; variceal bleeding and HCC&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a> summarizes an algorithm for diagnosis and management of ALD and AUD&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0060">Alcohol abstinence</span><p id="par0350" class="elsevierStylePara elsevierViewall">Achieving prolonged alcohol abstinence is the main therapeutic goal in all patients with ALD regardless of the stage&#46; Abstinence decreases morbidity and mortality from alcohol both in patients with early and advanced ALD <a class="elsevierStyleCrossRefs" href="#bib1230">&#91;81&#44;99&#93;</a>&#46; A remarkable aspect of heavy alcohol consumption is the tendency for relapse after both long and short periods of abstinence&#46; Of patients that survive an episode of AH&#44; more than 60&#37; patients relapse&#46; In many cases&#44; alcohol relapse occurs years after the index episode of an AH&#46; After surviving the acute inflammatory syndrome of AH&#44; the intermediate and long-term prognosis is governed by abstinence or relapse <a class="elsevierStyleCrossRef" href="#bib1230">&#91;81&#93;</a>&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;1&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0065">Psychosocial therapy and behavioral treatment</span><p id="par0355" class="elsevierStylePara elsevierViewall">Brief motivational interventions lasting no more than 5&#8211;10<span class="elsevierStyleHsp" style=""></span>min are useful and recommended in all patients with ALD and active drinking&#46; The main goals of these interventions are to educate the patient about the impact of alcohol and to stimulate their desire to discontinue alcohol intake&#46; Although these interventions alone are not sufficient to impact alcohol dependence in heavy drinkers&#44; they might reinforce compliance to medication <a class="elsevierStyleCrossRef" href="#bib1325">&#91;100&#93;</a>&#46; Specific psychological and behavioral therapies should be kept in mind as important tools to identify triggers resulting in relapse and for modifying maladaptive behavior&#46; This includes facilitating 12 steps&#44; such as cognitive behavioral therapy &#40;CBT&#41; and motivational enhancement therapy &#40;MET&#41;&#46; This twelve-step facilitation intervention is abstinence-based and involves participation of the patient in alcoholic anonymous &#40;AA&#41; meetings&#46; MET is intended to find a framework for modifying alcohol intake and to help these patients work on developing resistance and to change alcoholic habits&#46; CBT focuses on identifying triggers that compulsively lead to resuming alcohol intake&#46; This approach tends to replace old alcoholism promoting behaviors that lead the patient to consume alcohol and replace them with alcohol-free behaviors&#46; Since none of the psychosocial interventions alone have proved to be efficient in maintaining abstinence&#44; the combination of the two approaches &#40;i&#46;e&#46; CBT and MET&#41; is useful to increase abstinence rates <a class="elsevierStyleCrossRef" href="#bib1325">&#91;100&#93;</a>&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;1&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0070">Pharmacological therapy</span><p id="par0360" class="elsevierStylePara elsevierViewall">Pharmacological treatment is useful to prevent relapse in patients with AUD&#46; However&#44; few studies have assessed the efficacy and safety of anti-craving drugs in patients with ALD <a class="elsevierStyleCrossRef" href="#bib1275">&#91;90&#93;</a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; In particular&#44; naltrexone and acamprosate&#44; two FDA-approved drugs for AUD&#44; have not specifically been tested in ALD patients&#46; Moreover&#44; other commonly used drugs such as disulfiram can cause severe hepatotoxicity and are contraindicated in patients with ALD&#46; Drugs such as topiramate&#44; gabapentin&#44; ondansetron&#44; and varenicline can be useful as anti-craving drugs in patients with AUD and are probably safe in patients with ALD&#44; although further studies are warranted before they can be recommended to ALD patients&#46; Baclofen&#44; a GABA receptor agonist&#44; is the only anti-craving drug tested in a controlled trial in patients with severe ALD <a class="elsevierStyleCrossRef" href="#bib1330">&#91;101&#93;</a>&#46; In a placebo-controlled trial&#44; baclofen was useful and safe to prevent relapse in alcohol-related cirrhotics&#46; Therefore&#44; although further studies are needed&#44; this medication has shown to be useful for therapy in patients with severe ALD&#46; Robust clinical trials testing the role of drugs in ALD and exploring combinations of pharmacologic and behavioral treatment in AUD in the setting of ALD are lacking <a class="elsevierStyleCrossRef" href="#bib1335">&#91;102&#93;</a>&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0075">Nutritional support</span><p id="par0365" class="elsevierStylePara elsevierViewall">Malnutrition with and without sarcopenia is common among patients with ALD <a class="elsevierStyleCrossRef" href="#bib1340">&#91;103&#93;</a>&#46; Although alcohol is a high-calorie power beverage&#44; alcohol intake provides empty calories&#46; More than 50&#37; of patients with alcohol-related cirrhosis have some degree of protein-calorie malnutrition&#46; Complications of portal hypertension &#40;i&#46;e&#46; variceal bleeding&#44; encephalopathy and ascites&#41; and sepsis are also more commonly observed in malnourished cirrhotic patients <a class="elsevierStyleCrossRef" href="#bib1340">&#91;103&#93;</a>&#46; Increased catabolism&#44; decreased food intake due to alcoholic gastritis and esophagitis&#44; diarrhea induced by malabsorption&#44; pancreatic insufficiency&#44; and complications of cirrhosis&#44; such as encephalopathy&#44; contribute to malnutrition in ALD&#46; Most studies aimed at assessing a beneficial effect of parenteral nutritional supplementation in ALD have shown disappointing results&#46; A limited number of patients and a short period of treatment were the main causes of failure for these trials <a class="elsevierStyleCrossRef" href="#bib1345">&#91;104&#93;</a>&#46; However&#44; enteral nutritional support increases survival when nutritional status was assessed through several reliable tools in clinical practice&#44; such as nitrogen balance&#44; and anthropometric variables <a class="elsevierStyleCrossRef" href="#bib1345">&#91;104&#93;</a>&#46; Most of the current guidelines recommend a protein intake of 1&#46;2&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>g of protein per kg of body weight and a calorie intake of 30&#8211;35<span class="elsevierStyleHsp" style=""></span>kcal per kg of body weight&#44; including late-evening snack&#46; During cirrhosis decompensations&#44; a maximum protein intake &#40;i&#46;e&#46;&#44; 1&#46;5<span class="elsevierStyleHsp" style=""></span>g per kg of body weight&#41; and 40<span class="elsevierStyleHsp" style=""></span>kcal per kg of body weight should be indicated&#44; since it has been shown to improve caloric malnutrition <a class="elsevierStyleCrossRef" href="#bib1350">&#91;105&#93;</a>&#46; Finally&#44; it is important to note that patients with ALD usually have vitamins and micronutrients deficiency&#46; Vitamins &#40;i&#46;e&#46; thiamine&#44; folate&#44; pyridoxine and cyanocobalamin&#41; and minerals &#40;i&#46;e&#46; potassium&#44; phosphate&#44; magnesium and zinc&#41; should be measured and&#47;or supplemented as needed &#40;<a class="elsevierStyleCrossRefs" href="#tbl0030">Tables 6 and 7</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0080">Prophylaxis of variceal bleeding</span><p id="par0370" class="elsevierStylePara elsevierViewall">Recommendations for screening for varices should follow Baveno guidelines&#46; If elastography is available&#44; a liver stiffness<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>kPa together with a platelet count<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>150 in a compensated patient indicates a very low risk of varices needed treatment&#44; and endoscopy can be avoided <a class="elsevierStyleCrossRef" href="#bib1355">&#91;106&#93;</a>&#46; In compensated patients with <span class="elsevierStyleItalic">no varices</span> at screening endoscopy&#44; and with ongoing liver injury &#40;i&#46;e&#46; active drinking&#41;&#44; surveillance endoscopy should be repeated at 2-year intervals&#46; In compensated patients with small varices and with ongoing liver injury &#40;i&#46;e&#46; active drinking&#41;&#44; surveillance endoscopy should be repeated at 1-year intervals&#46; In compensated patients with <span class="elsevierStyleItalic">no varices</span> at screening endoscopy in whom the etiological factor has been removed &#40;i&#46;e&#46; long-lasting abstinence&#41; and who have no co-factors &#40;i&#46;e&#46; obesity&#41;&#44; surveillance endoscopy should be repeated at 3-year intervals&#46; In compensated patients with <span class="elsevierStyleItalic">small varices</span> at screening endoscopy in whom the etiological factor has been removed &#40;i&#46;e&#46; long-lasting abstinence&#41; and who have no co-factors &#40;i&#46;e&#46; obesity&#41;&#44; surveillance endoscopy should be repeated at 2-year intervals <a class="elsevierStyleCrossRef" href="#bib1360">&#91;107&#93;</a>&#46; Primary prophylaxis of esophageal bleeding should be performed in all patients with alcohol-related cirrhosis with either beta-blockers or variceal ligation&#46; Secondary prophylaxis should be performed similarly to that in other etiologies of cirrhosis &#40;with banding and betablockers&#44; if tolerated&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;1&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0085">Pharmacological treatment for fibrosis&#47;cirrhosis</span><p id="par0375" class="elsevierStylePara elsevierViewall">The most effective therapy to treat liver fibrosis associated with ALD is permanent alcohol abstinence <a class="elsevierStyleCrossRef" href="#bib1165">&#91;68&#93;</a>&#46; None of the antifibrotic drugs investigated in patients with ALD&#44; including <span class="elsevierStyleItalic">S</span>-adenosyl-<span class="elsevierStyleSmallCaps">l</span>-methionine&#44; propylthiouracil&#44; colchicine&#44; and sylimarin have been validated enough to be recommended for clinical use&#46; Current clinical trials to treat liver fibrosis include drugs aimed at&#58; &#40;1&#41; eliminating or attenuating the underlying liver disease&#44; &#40;2&#41; antagonizing receptor-ligand interactions and intracellular signaling&#44; &#40;3&#41; inhibiting fibrogenesis&#44; and &#40;4&#41; promoting fibrosis resolution&#46; Currently&#44; more than 500 trials relating to anti-fibrotic strategies are registered&#44; and recently reviewed in detail elsewhere <a class="elsevierStyleCrossRef" href="#bib1365">&#91;108&#93;</a>&#46;</p><p id="par0380" class="elsevierStylePara elsevierViewall">One of the critical issues in the development of drugs to treat alcohol liver-related disease is the &#8220;dogma&#8221; that abstinence is a <span class="elsevierStyleItalic">sine qua non</span> for treating patients&#46; It is probably time to accept that patients have to be treated&#44; even if consumption is kept&#44; in parallel with other diseases where treatments are accepted&#44; although patients do not comply with a change of lifestyle or losing weight&#44; as in nonalcoholic fatty liver disease&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">16&#46;</span><p id="par0390" class="elsevierStylePara elsevierViewall">Complete abstinence is the major therapeutic approach that decreases mortality and liver-related complications in patients with ALD &#40;Grade of evidence&#58; high quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">17&#46;</span><p id="par0395" class="elsevierStylePara elsevierViewall">In patients with severe ALD&#44; baclofen has been proven to be effective and safe in preventing alcohol relapse &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">18&#46;</span><p id="par0400" class="elsevierStylePara elsevierViewall">Protein-calorie malnutrition is common in patients with ALD&#46; Adequate food intake with proper protein and caloric content should be considered &#40;Grade of evidence&#58; high quality&#59; grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">19&#46;</span><p id="par0405" class="elsevierStylePara elsevierViewall">Medical treatment of ALD should be performed by multidisciplinary teams&#44; including alcohol addiction specialists &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">20&#46;</span><p id="par0410" class="elsevierStylePara elsevierViewall">General recommendations for screening and management of cirrhosis complications should be applied to patients with alcohol-related cirrhosis &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">21&#46;</span><p id="par0415" class="elsevierStylePara elsevierViewall">No specific pharmacological therapy for alcohol-related fibrosis has demonstrated consistent benefits and should only be used in the context of clinical trials &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li></ul></p><p id="par0420" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">15&#46;</span><p id="par0425" class="elsevierStylePara elsevierViewall">Studies analyzing effectiveness and potential risk of hepatotoxicity of different anti-craving medications in patients with ALD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">16&#46;</span><p id="par0430" class="elsevierStylePara elsevierViewall">Studies aimed to identify factors that predict alcohol relapse in ALD patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">17&#46;</span><p id="par0435" class="elsevierStylePara elsevierViewall">Clinical trials aimed at testing new drugs and combination therapies to treat liver fibrosis in patients with compensated ALD&#46;</p></li></ul></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0090">Management of alcoholic hepatitis</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0095">General and supportive measures</span><p id="par0440" class="elsevierStylePara elsevierViewall">Patients with severe AH should be admitted to the hospital for management&#46; Nutritional support includes providing adequate calorie and protein intake&#44; as well as vitamins &#40;i&#46;e&#46; thiamine&#44; folate&#44; and pyridoxine&#41; and minerals &#40;i&#46;e&#46; potassium&#44; phosphate&#44; magnesium&#41; repletion&#46; Vitamin B1 supplementation is recommended due to a high risk of Wernicke encephalopathy &#40;before any carbohydrate&#44; 200<span class="elsevierStyleHsp" style=""></span>mg three times per day&#44; preferably intravenously for 3&#8211;5 days if Wernicke is suspected&#44; and 100<span class="elsevierStyleHsp" style=""></span>mg daily by mouth for long-term supplementation&#41;&#46; Also assess or supplement magnesium sulfate as they may be unresponsive to parenteral thiamine in the presence of hypomagnesemia&#46; Oral intake should be started as soon as possible and a daily intake of 1&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;kg of ideal body weight of protein should be assured&#46; Intensive care unit admission is generally recommended in critically-ill patients &#40;patients with septic shock&#44; grade III&#8211;IV encephalopathy&#44; acute variceal bleeding or severe withdrawal syndrome&#41; <a class="elsevierStyleCrossRef" href="#bib0965">&#91;28&#93;</a>&#46; Airway protection with orotracheal intubation may be necessary in patients with high grade hepatic encephalopathy or severe withdrawal syndrome&#46; Finally&#44; although benzodiazepines are not recommended in patients with decompensated cirrhosis&#44; their use may be necessary to treat severe alcohol withdrawal&#46; Short acting benzodiazepines &#40;i&#46;e&#46; lorazepam&#41; should be used&#46;</p><p id="par0445" class="elsevierStylePara elsevierViewall">Patients with AH are prone to develop cirrhosis complications that should be managed according to current guidelines <a class="elsevierStyleCrossRefs" href="#bib1370">&#91;109&#8211;113&#93;</a>&#46; Bacterial infections are frequent among patients with AH and predispose them to multiple organ failure and death <a class="elsevierStyleCrossRef" href="#bib1245">&#91;84&#93;</a>&#46; Since infection is a major prognostic factor for short and long-term mortality in patients with AH <a class="elsevierStyleCrossRef" href="#bib1395">&#91;114&#93;</a>&#44; a complete infectious disease work-up is mandatory at admission&#46; Diagnostic paracentesis&#44; blood cultures&#44; urine and sputum cultures should be obtained&#46; In patients with high suspicion of infection&#44; empirical broad-spectrum antibiotics should be initiated&#46; A recent study showed that the risk of developing an infection was lower in patients with AH receiving antibiotics after gastrointestinal bleeding <a class="elsevierStyleCrossRef" href="#bib1400">&#91;115&#93;</a>&#46; Clinical trials evaluating the specific role of antibiotic prophylaxis in patients with AH are underway&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0100">Specific therapies</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2&#46;2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0105">Corticosteroids</span><p id="par0450" class="elsevierStylePara elsevierViewall">The rationale behind using corticosteroids in AH is due to their immunomodulatory and anti-inflammatory effects&#46; Despite conflicting data <a class="elsevierStyleCrossRefs" href="#bib1405">&#91;116&#8211;121&#93;</a>&#44; corticosteroids are the first-line treatment in severe AH &#40;DF<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>32 points or MELD<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>20&#41; <a class="elsevierStyleCrossRefs" href="#bib0860">&#91;7&#44;122&#93;</a>&#46; Data from a recent network meta-analysis&#44; including 22 randomized controlled trials&#44; support the use of corticosteroids either alone or in combination with N-acetyl-cysteine &#40;NAC&#41;&#44; to reduce short-term mortality in patients with AH <a class="elsevierStyleCrossRef" href="#bib1440">&#91;123&#93;</a>&#46; A large double-blinded multicentric trial &#40;<span class="elsevierStyleItalic">STOPAH</span> trial&#41;&#44; reported an OR for mortality at 28 days for prednisolone of 0&#46;72 &#40;95&#37; CI&#44; 0&#46;52&#8211;1&#46;01&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06&#41;&#46; After adjustment for baseline severity and prognostic factors&#44; the OR in the prednisolone treated group was 0&#46;61 &#40;95&#37; CI&#44; 0&#46;41&#8211;0&#46;91&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41;&#46; Importantly&#44; prednisolone was not associated with a reduction in mortality beyond 28 days <a class="elsevierStyleCrossRef" href="#bib1445">&#91;124&#93;</a>&#46; The contraindications for the use of corticosteroids include the presence of sepsis which is common among patients with severe AH&#46; It is important to keep in mind that steroids increase the risk of both bacterial and fungal infections&#46; Other relative contraindications include active gastrointestinal bleeding&#44; acute pancreatitis&#44; active tuberculosis&#44; uncontrolled diabetes and psychosis&#46; In summary&#44; corticosteroids can be used in selected patients and response&#47;complications should be assessed during treatment&#44; for example&#44; with Lille score&#46;</p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">8&#46;2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0110">Other therapies</span><p id="par0455" class="elsevierStylePara elsevierViewall">Pentoxifylline is a phosphodiesterase inhibitor with anti-tumor necrosis factor-&#945; &#40;TNF-&#945;&#41; activity&#46; An initial study with pentoxifylline therapy in AH showed a 25&#37; improvement in mortality rate associated with hepatorenal syndrome reduction <a class="elsevierStyleCrossRef" href="#bib1450">&#91;125&#93;</a>&#46; However&#44; data from the STOPAH trial did not confirm a survival benefit with pentoxifylline <a class="elsevierStyleCrossRef" href="#bib1445">&#91;124&#93;</a>&#46; A combination of pentoxifylline with corticosteroids has also been evaluated with no evidence of survival improvement at 6-months <a class="elsevierStyleCrossRef" href="#bib1455">&#91;126&#93;</a>&#46; Finally&#44; rescue treatment by switching to pentoxifylline in patients not responding to corticosteroids at 7 days did not show benefit in 2-month survival <a class="elsevierStyleCrossRef" href="#bib1460">&#91;127&#93;</a>&#46;</p><p id="par0460" class="elsevierStylePara elsevierViewall">Combination therapy with prednisolone plus NAC&#44; a powerful antioxidant&#44; has shown to improve 1-month survival and to reduce the rate of infections&#46; However&#44; when analyzing survival at 6 months&#44; no differences were found &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;07&#41; <a class="elsevierStyleCrossRef" href="#bib1465">&#91;128&#93;</a>&#46; Additional confirmatory studies using this strategy are warranted&#46;</p><p id="par0465" class="elsevierStylePara elsevierViewall">Both infliximab &#40;a chimeric mouse-human anti-TNF antibody&#41; and etanercept &#40;a competitive inhibitor of TNF-&#945; to its cell surface receptors&#41; have been tested in AH patients&#46; Both molecules increased mortality due to an increased rate of severe infections&#46; In consequence&#44; biological anti-TNF-&#945; therapies do not have a current role in AH treatment <a class="elsevierStyleCrossRefs" href="#bib1470">&#91;129&#44;130&#93;</a>&#46;</p><p id="par0470" class="elsevierStylePara elsevierViewall">Ineffective liver regeneration has been postulated as one of the potential causes for progressive liver failure in AH <a class="elsevierStyleCrossRef" href="#bib1480">&#91;131&#93;</a>&#46; Recently a pilot&#44; open-label&#44; randomized trial comparing granulocyte colony-stimulating factors &#40;G-CSF&#41; plus standard medical therapy vs&#46; standard medical therapy alone in patients with severe AH showed a significant increase in circulating CD34<span class="elsevierStyleSup">&#43;</span> stem cells after G-CSF therapy accompanying a marked decrease in the MELD score and Maddrey&#39;s DF at 1&#44; 2&#44; and 3 months of follow-up in the G-CSF group&#46; At 3 months&#44; an improvement in survival was found in the G-CSF compared with standard medical therapy group &#40;78 vs&#46; 30&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Additionally&#44; the development of bacterial infections was less frequent <a class="elsevierStyleCrossRef" href="#bib1485">&#91;132&#93;</a>&#46; Oxandrolone &#40;an anabolic-androgenic steroid&#41;&#44; propylthiouracil&#44; metadoxine &#40;a drug with antioxidant properties&#41; and other antioxidants such as vitamin E and silymarin have not shown any survival benefit in patients with AH <a class="elsevierStyleCrossRefs" href="#bib1490">&#91;133&#8211;137&#93;</a>&#46;</p><p id="par0475" class="elsevierStylePara elsevierViewall">Malnutrition due to impaired caloric intake and increased catabolism is frequent in patients with AH <a class="elsevierStyleCrossRef" href="#bib1515">&#91;138&#93;</a>&#46; Two recent&#44; randomized controlled trials evaluating the effect of intensive enteral nutrition have not shown any difference in short-term mortality of patients with severe AH <a class="elsevierStyleCrossRefs" href="#bib1520">&#91;139&#44;140&#93;</a>&#46; However&#44; patients with low calorie intake &#40;less than 21&#46;5<span class="elsevierStyleHsp" style=""></span>kcal&#47;kg&#47;day&#41; had significantly lower survival at 6 months compared to those with higher calorie intake <a class="elsevierStyleCrossRef" href="#bib1525">&#91;140&#93;</a>&#46; Further studies are needed to explore the benefits of nutritional support in this life-threatening condition&#46;</p><p id="par0480" class="elsevierStylePara elsevierViewall">Recently&#44; studies have been carried out evaluating the role of gut microbiota modification in patients with AH&#46; Probiotics have shown to decrease inflammation&#44; improve liver function and decrease re-hospitalizations <a class="elsevierStyleCrossRefs" href="#bib1530">&#91;141&#44;142&#93;</a>&#46; In another recent pilot study&#44; fecal microbiota transplant &#40;FMT&#41; was associated with lower mortality &#40;as compared with historical controls&#41; in patients with severe AH <a class="elsevierStyleCrossRef" href="#bib1540">&#91;143&#93;</a>&#46; There are clinical trials underway examining the role of probiotics&#44; rifaximin and FMT in AH patients&#46;</p><p id="par0485" class="elsevierStylePara elsevierViewall">Artificial and bio-artificial Liver Support Systems&#44; such as the molecular adsorbent recirculating system &#40;MARS&#41; and Prometheus devices&#44; have been tested in patients with ACLF &#40;some of them triggered by superimposed AH&#41;&#46; The MARS device&#44; but not the Prometheus device&#44; showed a significant attenuation of hyperdynamic circulation in ACLF&#44; presumably by a difference in the removal rate of certain vasoactive substances <a class="elsevierStyleCrossRef" href="#bib1545">&#91;144&#93;</a>&#46; In addition&#44; treatment with MARS also produces an acute reduction on portal pressure and improves encephalopathy in patients with AH <a class="elsevierStyleCrossRefs" href="#bib1550">&#91;145&#44;146&#93;</a>&#46; However&#44; the effect on relevant clinical outcomes is unknown&#46;</p><p id="par0490" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a> summarizes a proposed algorithm for the diagnosis and management of AH&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0495" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">22&#46;</span><p id="par0500" class="elsevierStylePara elsevierViewall">Corticosteroids are the first-line therapy in patients with severe AH &#40;Grade of evidence&#58; high quality&#59; Grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">23&#46;</span><p id="par0505" class="elsevierStylePara elsevierViewall">Pentoxifylline treatment has limited impact improving short and long-term survival of patients with severe AH and is not currently recommended &#40;Grade of evidence&#58; high quality&#59; Grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">24&#46;</span><p id="par0510" class="elsevierStylePara elsevierViewall">The use of biological anti- TNF-&#945; drugs has no role in the treatment of severe AH&#46; Their use is not recommended because of their deleterious effects on increasing the rate of severe infections and death in these patients &#40;Grade of evidence&#58; high quality&#59; Grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">25&#46;</span><p id="par0515" class="elsevierStylePara elsevierViewall">Antioxidants&#44; such as metadoxine and NAC&#44; may be useful for improving short-term mortality of patients with severe AH receiving corticosteroids &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; weak&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">26&#46;</span><p id="par0520" class="elsevierStylePara elsevierViewall">Artificial liver supportive systems do not improve short and long-term survival rates in patients with severe AH &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; strong&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">27&#46;</span><p id="par0525" class="elsevierStylePara elsevierViewall">G-CSF should not be used outside of clinical studies until further supportive evidence is available &#40;Grade of evidence&#58; low quality&#59; Grade of recommendation&#58; weak&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">28&#46;</span><p id="par0530" class="elsevierStylePara elsevierViewall">Intensive enteral nutrition in patients with AH has showed no benefit on short-term survival when added to corticosteroid treatment&#46; However&#44; patients with higher calorie intake do have a better survival at 6 months &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; weak&#41;&#46;</p></li></ul></p><p id="par0535" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">18&#46;</span><p id="par0540" class="elsevierStylePara elsevierViewall">Large clinical trials analyzing the potential benefit of antioxidants in combination with prednisolone on the short and long-term survival of patients with AH&#46;</p></li><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">19&#46;</span><p id="par0545" class="elsevierStylePara elsevierViewall">Clinical trials aimed at testing and validating the efficacy of liver regeneration through G-CSF therapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">20&#46;</span><p id="par0550" class="elsevierStylePara elsevierViewall">The potential effect of antibiotic prophylaxis on patient&#39;s survival and complication rate should be delineated in future studies&#46;</p></li></ul></p></span></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">9</span><span class="elsevierStyleSectionTitle" id="sect0115">Liver transplantation</span><p id="par0555" class="elsevierStylePara elsevierViewall">ALD represents the second most frequent indication for liver transplantation in the United States and Europe&#46; Post-transplant survival of ALD patients is comparable or even higher than that of non-ALD patients <a class="elsevierStyleCrossRefs" href="#bib1560">&#91;147&#8211;149&#93;</a>&#46; There is little information available from Latin-America&#59; however&#44; prospective databases are underway&#46; Studies conducted in some countries of the region show that ALD is among the three leading causes of liver transplant <a class="elsevierStyleCrossRefs" href="#bib1575">&#91;150&#8211;153&#93;</a>&#46;</p><p id="par0560" class="elsevierStylePara elsevierViewall">When hepatic function does not improve after sustained alcohol abstinence or when the disease severity does not allow for a prolonged period of abstinence&#44; liver transplant represents a potential curative treatment for patients with life-threatening liver disease related to alcohol <a class="elsevierStyleCrossRef" href="#bib1595">&#91;154&#93;</a>&#46; Selection criteria and the minimal duration of abstinence prior to transplantation are a matter of intense debate&#46; In most centers&#44; patients with ALD are required to have a period of abstinence of at least 6 months&#46; This measure is being increasingly questioned especially in patients who do not have other addictions <a class="elsevierStyleCrossRefs" href="#bib1600">&#91;155&#44;156&#93;</a>&#46; There are no well-conducted studies that support the 6-month abstinence rule as predictor of a lower likelihood of alcohol relapse <a class="elsevierStyleCrossRef" href="#bib1605">&#91;156&#93;</a>&#46; Beyond the duration of abstinence&#44; psychosocial factors are likely to be more important as predictors of abstinence after transplantation&#46; Positive predictive factors include self-awareness by the patient of the alcohol problem&#44; the presence of good social support and the attendance to addiction therapy&#46; Negative prognostic factors include the presence of other psychiatric disorders and additional drug abuse&#44; failed previous alcohol therapies and poor family support <a class="elsevierStyleCrossRefs" href="#bib1610">&#91;157&#44;158&#93;</a>&#46; In a Latin-American study&#44; 16&#46;7&#37; of patients transplanted for ALD had relapse and only 5&#46;6&#37; severe recurrence that led to liver graft dysfunction <a class="elsevierStyleCrossRef" href="#bib1590">&#91;153&#93;</a>&#46;</p><p id="par0565" class="elsevierStylePara elsevierViewall">In selected patients with severe AH non-responders to medical therapy&#44; recent studies have shown that early liver transplantation &#40;not requiring a minimum period of abstinence&#41; markedly improves survival <a class="elsevierStyleCrossRefs" href="#bib1620">&#91;159&#8211;162&#93;</a>&#46; In these preliminary studies&#44; patients are required to have reasonable family support and absence of other serious psychiatric disorders <a class="elsevierStyleCrossRef" href="#bib1640">&#91;163&#93;</a>&#46; Further studies are required to better delineate the indications&#44; patient selection and applicability of early transplant in these patients&#46;</p><p id="par0570" class="elsevierStylePara elsevierViewall">Due to the aforementioned reasons&#44; a comprehensive psychosocial assessment is mandatory in these patients prior to transplantation&#46; In addition&#44; it is important to evaluate other alcohol-induced organ damage including heart failure&#44; chronic pancreatitis&#44; and any involvement of the central and peripheral nervous system <a class="elsevierStyleCrossRef" href="#bib1615">&#91;158&#93;</a>&#46; Importantly&#44; since these patients frequently smoke cigarettes and this has been linked to post-transplant cancer and cardiovascular complications&#44; it is highly recommended that patients stop smoking before LT&#46; Attendance to smoking-cessation programs is therefore recommended in this patient population <a class="elsevierStyleCrossRefs" href="#bib1565">&#91;148&#44;149&#93;</a>&#46;</p><p id="par0575" class="elsevierStylePara elsevierViewall">Transplanted patients for ALD have a reduced incidence of acute and chronic rejection compared to patients with nonalcoholic liver disease <a class="elsevierStyleCrossRef" href="#bib1645">&#91;164&#93;</a>&#46; In patients transplanted for ALD&#44; the main causes of death are malignancies&#44; infections&#44; and cardiovascular events&#44; mainly related to environmental factors &#8211; tobacco&#44; obesity&#44; and alcohol relapse &#8211; as well as chronic immunosuppression&#46; Abstinence from cigarette smoking is strongly recommended&#46; As a result&#44; there are current efforts to tailor immunosuppression in patients with ALD by minimizing the exposure to calcineurin inhibitors&#46; Although some recent retrospective studies support this strategy in patients with ALD <a class="elsevierStyleCrossRef" href="#bib1650">&#91;165&#93;</a>&#44; further studies are needed to define the optimal immunosuppressive regimes in LT recipients due to ALD&#46;</p><p id="par0580" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Recommendations&#47;key concepts</span><ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">29&#46;</span><p id="par0585" class="elsevierStylePara elsevierViewall">Liver transplantation should be considered in the management of patients with end-stage ALD &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">30&#46;</span><p id="par0590" class="elsevierStylePara elsevierViewall">In patients with end-stage ALD&#44; candidacy for transplantation criteria should be comprehensive and not only based on the 6-month rule of abstinence&#44; since this may not be feasible in patients with severe AH or severe decompensated ALD where survival is limited &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; weak&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0255"><span class="elsevierStyleLabel">31&#46;</span><p id="par0595" class="elsevierStylePara elsevierViewall">Patients undergoing liver transplantation evaluation for ALD should be assessed by multidisciplinary teams&#44; including addiction specialists&#44; and should be screened for use of alcohol and other substances &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0260"><span class="elsevierStyleLabel">32&#46;</span><p id="par0600" class="elsevierStylePara elsevierViewall">Immunosuppression should be prescribed at the lowest possible dose and smoking cessation should be advised and assisted to reduce the risk of cancer in this group of patients&#46; Also&#44; a complete cardiovascular evaluation is advised &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;</p></li></ul></p><p id="par0605" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Suggestions for future studies in Latin-America</span><ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0265"><span class="elsevierStyleLabel">21&#46;</span><p id="par0610" class="elsevierStylePara elsevierViewall">Epidemiological studies evaluating liver transplantation outcomes for ALD in Latin-America&#46;</p></li><li class="elsevierStyleListItem" id="lsti0270"><span class="elsevierStyleLabel">22&#46;</span><p id="par0615" class="elsevierStylePara elsevierViewall">Studies evaluating criteria and outcomes of patients transplanted for severe AH&#46;</p></li><li class="elsevierStyleListItem" id="lsti0275"><span class="elsevierStyleLabel">23&#46;</span><p id="par0620" class="elsevierStylePara elsevierViewall">Studies on immunosuppression in patients transplanted for ALD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0280"><span class="elsevierStyleLabel">24&#46;</span><p id="par0625" class="elsevierStylePara elsevierViewall">Protocols for cancer and cardiovascular screening in transplanted patients for ALD&#46;</p></li></ul></p><p id="par0630" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0120"><span class="elsevierStyleBold">Abbreviations</span></span><span class="elsevierStyleDefTerm">AAF</span><span class="elsevierStyleDefDescription"><p id="par0635" class="elsevierStylePara elsevierViewall">alcohol-attributable fraction</p></span><span class="elsevierStyleDefTerm">ABIC</span><span class="elsevierStyleDefDescription"><p id="par0640" class="elsevierStylePara elsevierViewall">age&#44; serum bilirubin&#44; INR&#44; and serum creatinine</p></span><span class="elsevierStyleDefTerm">ACLF</span><span class="elsevierStyleDefDescription"><p id="par0645" class="elsevierStylePara elsevierViewall">acute-on-chronic liver failure</p></span><span class="elsevierStyleDefTerm">AFP</span><span class="elsevierStyleDefDescription"><p id="par0650" class="elsevierStylePara elsevierViewall">alpha-fetoprotein</p></span><span class="elsevierStyleDefTerm">AH</span><span class="elsevierStyleDefDescription"><p id="par0655" class="elsevierStylePara elsevierViewall">alcoholic hepatitis</p></span><span class="elsevierStyleDefTerm">ALD</span><span class="elsevierStyleDefDescription"><p id="par0660" class="elsevierStylePara elsevierViewall">alcohol-related liver disease</p></span><span class="elsevierStyleDefTerm">ALEH</span><span class="elsevierStyleDefDescription"><p id="par0665" class="elsevierStylePara elsevierViewall">Latin-American Association for the Study of the Liver</p></span><span class="elsevierStyleDefTerm">ALT</span><span class="elsevierStyleDefDescription"><p id="par0670" class="elsevierStylePara elsevierViewall">alanine aminotransferase</p></span><span class="elsevierStyleDefTerm">ANI</span><span class="elsevierStyleDefDescription"><p id="par0675" class="elsevierStylePara elsevierViewall">ALD&#47;NAFLD Index</p></span><span class="elsevierStyleDefTerm">ASDR</span><span class="elsevierStyleDefDescription"><p id="par0680" class="elsevierStylePara elsevierViewall">age-standardized death rates</p></span><span class="elsevierStyleDefTerm">ASH</span><span class="elsevierStyleDefDescription"><p id="par0685" class="elsevierStylePara elsevierViewall">alcohol-related steatohepatitis</p></span><span class="elsevierStyleDefTerm">AST</span><span class="elsevierStyleDefDescription"><p id="par0690" class="elsevierStylePara elsevierViewall">aspartate aminotransferase</p></span><span class="elsevierStyleDefTerm">AUD</span><span class="elsevierStyleDefDescription"><p id="par0695" class="elsevierStylePara elsevierViewall">alcohol-use disorder</p></span><span class="elsevierStyleDefTerm">AUDIT</span><span class="elsevierStyleDefDescription"><p id="par0700" class="elsevierStylePara elsevierViewall">Alcohol Use Disorders Identification Test</p></span><span class="elsevierStyleDefTerm">BMI</span><span class="elsevierStyleDefDescription"><p id="par0705" class="elsevierStylePara elsevierViewall">body mass index</p></span><span class="elsevierStyleDefTerm">CBT</span><span class="elsevierStyleDefDescription"><p id="par0710" class="elsevierStylePara elsevierViewall">cognitive behavioral therapy</p></span><span class="elsevierStyleDefTerm">CPG</span><span class="elsevierStyleDefDescription"><p id="par0715" class="elsevierStylePara elsevierViewall">clinical practical guidelines</p></span><span class="elsevierStyleDefTerm">DALYs</span><span class="elsevierStyleDefDescription"><p id="par0720" class="elsevierStylePara elsevierViewall">disability adjusted life years</p></span><span class="elsevierStyleDefTerm">FMT</span><span class="elsevierStyleDefDescription"><p id="par0725" class="elsevierStylePara elsevierViewall">fecal microbiota transplant</p></span><span class="elsevierStyleDefTerm">GAHS</span><span class="elsevierStyleDefDescription"><p id="par0730" class="elsevierStylePara elsevierViewall">Glasgow Alcoholic Hepatitis Score</p></span><span class="elsevierStyleDefTerm">G-CSF</span><span class="elsevierStyleDefDescription"><p id="par0735" class="elsevierStylePara elsevierViewall">granulocyte colony-stimulating factors</p></span><span class="elsevierStyleDefTerm">GGT</span><span class="elsevierStyleDefDescription"><p id="par0740" class="elsevierStylePara elsevierViewall">gamma-glutamyltransferase</p></span><span class="elsevierStyleDefTerm">GRADE</span><span class="elsevierStyleDefDescription"><p id="par0745" class="elsevierStylePara elsevierViewall">grading assessment development and Jo&#235;l evaluation</p></span><span class="elsevierStyleDefTerm">GWAS</span><span class="elsevierStyleDefDescription"><p id="par0750" class="elsevierStylePara elsevierViewall">genome-wide association studies</p></span><span class="elsevierStyleDefTerm">HCC</span><span class="elsevierStyleDefDescription"><p id="par0755" class="elsevierStylePara elsevierViewall">hepatocellular carcinoma</p></span><span class="elsevierStyleDefTerm">HCV</span><span class="elsevierStyleDefDescription"><p id="par0760" class="elsevierStylePara elsevierViewall">hepatitis C virus</p></span><span class="elsevierStyleDefTerm">HED</span><span class="elsevierStyleDefDescription"><p id="par0765" class="elsevierStylePara elsevierViewall">heavy episodic drinking</p></span><span class="elsevierStyleDefTerm">MARS</span><span class="elsevierStyleDefDescription"><p id="par0770" class="elsevierStylePara elsevierViewall">molecular adsorbent recirculating system</p></span><span class="elsevierStyleDefTerm">MDB</span><span class="elsevierStyleDefDescription"><p id="par0775" class="elsevierStylePara elsevierViewall">Mallory-Denk bodies</p></span><span class="elsevierStyleDefTerm">MDF</span><span class="elsevierStyleDefDescription"><p id="par0780" class="elsevierStylePara elsevierViewall">Maddrey Discriminant Function</p></span><span class="elsevierStyleDefTerm">MELD</span><span class="elsevierStyleDefDescription"><p id="par0785" class="elsevierStylePara elsevierViewall">model for end-stage liver disease</p></span><span class="elsevierStyleDefTerm">MET</span><span class="elsevierStyleDefDescription"><p id="par0790" class="elsevierStylePara elsevierViewall">motivational enhancement therapy</p></span><span class="elsevierStyleDefTerm">MRI</span><span class="elsevierStyleDefDescription"><p id="par0795" class="elsevierStylePara elsevierViewall">magnetic resonance imaging</p></span><span class="elsevierStyleDefTerm">NAC</span><span class="elsevierStyleDefDescription"><p id="par0800" class="elsevierStylePara elsevierViewall">N-acetyl-cysteine</p></span><span class="elsevierStyleDefTerm">NAFLD</span><span class="elsevierStyleDefDescription"><p id="par0805" class="elsevierStylePara elsevierViewall">non-alcoholic fatty liver disease</p></span><span class="elsevierStyleDefTerm">LSM</span><span class="elsevierStyleDefDescription"><p id="par0810" class="elsevierStylePara elsevierViewall">liver stiffness measurement</p></span><span class="elsevierStyleDefTerm">PNPLA3</span><span class="elsevierStyleDefDescription"><p id="par0815" class="elsevierStylePara elsevierViewall">patatin-like phospholipase domain protein 3</p></span><span class="elsevierStyleDefTerm">PT</span><span class="elsevierStyleDefDescription"><p id="par0820" class="elsevierStylePara elsevierViewall">prothrombin time</p></span><span class="elsevierStyleDefTerm"><span class="elsevierStyleItalic">TNF-</span>&#945;</span><span class="elsevierStyleDefDescription"><p id="par0825" class="elsevierStylePara elsevierViewall">tumor necrosis factor-&#945;</p></span><span class="elsevierStyleDefTerm">WHO</span><span class="elsevierStyleDefDescription"><p id="par0830" class="elsevierStylePara elsevierViewall">World Health Organization</p></span></span></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0835" class="elsevierStylePara elsevierViewall">The authors have nothing to disclose&#46;</p></span></span>"
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          "titulo" => "Diagnosis of alcohol-use disorder and alcohol-related liver disease"
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          "titulo" => "Alcoholic hepatitis&#58; diagnosis and prognosis"
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          "titulo" => "Cirrhosis and hepatocellular carcinoma"
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          "titulo" => "Management of alcohol-related liver disease"
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              "titulo" => "Management of long-term complications of alcohol-related liver disease"
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                  "titulo" => "Alcohol abstinence"
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            2 => "Corticosteroids"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Alcohol-related liver disease &#40;ALD&#41; is a major cause of advanced chronic liver disease in Latin-America&#44; although data on prevalence is limited&#46; Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented&#46; ALD comprises a clinical-pathological spectrum that ranges from steatosis&#44; steatohepatitis to advanced forms such as alcoholic hepatitis &#40;AH&#41;&#44; cirrhosis and hepatocellular carcinoma&#46; Besides genetic factors&#44; the amount of alcohol consumption is the most important risk factor for the development of ALD&#46; Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease&#46; The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets&#46; Early forms of ALD are often missed and most clinical attention is focused on AH&#44; which is defined as an abrupt onset of jaundice and liver-related complications&#46; In patients with potential confounding factors&#44; a transjugular biopsy is recommended&#46; The standard therapy for AH &#40;i&#46;e&#46; prednisolone&#41; has not evolved in the last decades yet promising new therapies &#40;i&#46;e&#46; G-CSF&#44; N-acetylcysteine&#41; have been recently proposed&#46; In both patients with early and severe ALD&#44; prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality&#46; A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD&#46; Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence&#46; In selected cases&#44; increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy&#46;</p></span>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Grading of evidence</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High quality&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Further research is very unlikely to change our confidence in the estimate of effect&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate quality&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low quality&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Very low quality&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any estimate of effect is very uncertain&#46;&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Grading of recommendation</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Strong recommendation&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Factors influencing the strength of the recommendation included the quality of the evidence&#44; presumed patient-important outcomes&#44; and cost&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weak recommendation&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variability in preferences and values&#44; or more uncertainty&#58; more likely a weak recommendation is warranted&#46;Recommendation is made with less certainty&#59; higher cost or resource consumption&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Countries&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Alcohol consumption &#40;L&#47;per capita&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>Total &#40;male&#47;female&#41;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Alcoholic beverages &#40;&#37;&#41;Wine&#47;beer&#47;spirits&#47;other&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HED &#40;&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AAF &#40;&#37;&#41; liver cirrhosis male&#47;female<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AUD &#40;&#37;&#41;Total &#40;male&#47;female&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Argentina&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;8 &#40;16&#46;1&#47;4&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#47;40&#47;10&#47;10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;9&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;3&#47;54&#46;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;8 &#40;10&#46;8&#47;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bolivia&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;8 &#40;8&#47;1&#46;6&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;73&#47;21&#47;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#46;5&#47;34&#46;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;7 &#40;9&#46;8&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brazil&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;8 &#40;13&#46;4&#47;2&#46;4&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;62&#47;34&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;4&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&#46;5&#47;42&#46;6&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;2 &#40;6&#46;9&#47;1&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chile&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;3 &#40;15&#47;3&#46;7&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#47;36&#47;31&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;6&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#47;53&#46;6&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;10&#46;3&#47;1&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colombia&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;8 &#40;10&#46;1&#47;1&#46;8&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;72&#47;27&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#46;9&#47;34&#46;5&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;10&#46;4&#47;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Costa Rica&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;8 &#40;8&#46;1&#47;1&#46;4&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#47;64&#47;28&#47;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;9&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#46;7&#47;32&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;9 &#40;10&#46;4&#47;3&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cuba&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;1 &#40;10&#46;2&#47;1&#46;9&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;37&#47;58&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#46;3&#47;37&#46;7&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;6 &#40;9&#46;6&#47;3&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dominican R&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;9 &#40;11&#46;6&#47;2&#46;2&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;52&#47;42&#47;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;8&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;9&#47;39&#46;5&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;8 &#40;9&#46;9&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ecuador&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;4 &#40;7&#46;4&#47;1&#46;5&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;80&#47;18&#47;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#46;2&#47;31&#46;9&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;7 &#40;9&#46;7&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">El Salvador&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;7 &#40;6&#46;9&#47;1&#46;1&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;48&#47;51&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#46;2&#47;27&#46;8&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;2 &#40;9&#46;3&#47;3&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Guatemala&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;4 &#40;4&#46;3&#47;0&#46;7&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;56&#47;42&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#46;5&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;2&#47;23&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;4 &#40;9&#46;5&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haiti&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;8 &#40;10&#47;1&#46;8&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#47;2&#47;98&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;5&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;8&#47;35&#46;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;9 &#40;10&#46;3&#47;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Honduras&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;6&#46;9&#47;1&#46;2&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;47&#47;52&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#46;5&#47;27&#46;9&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;7 &#40;9&#46;7&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mexico&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;5 &#40;11&#46;1&#47;2&#46;1&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;77&#47;20&#47;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#46;4&#47;38&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;3 &#40;4&#46;3&#47;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nicaragua&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;2 &#40;9&#46;1&#47;1&#46;5&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;40&#47;59&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;6&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&#47;33&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;6 &#40;9&#46;7&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Panama&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;9 &#40;13&#46;2&#47;2&#46;6&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#47;77&#47;19&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">67&#47;41&#46;5&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;8 &#40;9&#46;9&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Paraguay&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;2 &#40;12&#46;2&#47;2&#46;1&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#47;54&#47;27&#47;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#46;3&#47;39&#46;4&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7 &#40;10&#46;2&#47;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peru&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;3 &#40;10&#46;4&#47;2&#46;2&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#47;60&#47;32&#47;&#60;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&#46;4&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;1&#47;40&#46;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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;9 &#40;14&#47;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Uruguay&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;8 &#40;17&#46;8&#47;4&#46;5&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#47;35&#47;21&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#46;6&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&#46;4&#47;57&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;4 &#40;9&#46;6&#47;3&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Venezuela&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;6 &#40;9&#46;7&#47;1&#46;7&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#47;69&#47;29&#47;2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#46;5&#47;34&#46;5&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;9 &#40;10&#47;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2047876.png"
              ]
            ]
          ]
          "notaPie" => array:4 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Alcohol per capita consumption&#44; in liters of pure alcohol&#44; 2016&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Prevalence of heavy episodic drinking &#40;HED&#41;&#47;Binge drinking&#44; &#40;&#37;&#41;&#44; 2016&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Alcohol-attributable fractions &#40;AAF&#41;&#44; cirrhosis males&#47;females&#44; &#40;&#37;&#41;&#44; 2016&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Alcohol use disorder &#40;AUD&#41;&#44; &#40;&#37;&#41;&#44; 2016&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Epidemiological data for Latin-American&#46;</p>"
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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          ]
        ]
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The AUDIT-c questionnaire is scored on a scale of 0&#8211;12&#46; In men&#44; a score of 4 or more is considered positive&#44; optimal for identifying hazardous drinking or active alcohol use disorders&#46; In women&#44; a score of 3 or more is considered positive&#46; However&#44; when the points are all from Question &#35;1 alone &#40;and &#35;2 and &#35;3 are zero&#41;&#44; it can be assumed that the patient is drinking below recommended limit s and it is suggested that the physician review the patient&#39;s alcohol intake over the past few years to confirm accuracy&#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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Questions&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">0&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">4&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46; How often did you have a drink containing alcohol in the past year&#63;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Never&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monthly or less&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#8211;4 times a month&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#8211;3 times a week&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 or more times a week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46; How many drinks containing alcohol did you have on a typical day when you were drinking in the past year&#63;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 or 2&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 or 4&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 or 6&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#8211;9&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; How often did you have 6 or more drinks on one occasion in the past year&#63;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Never&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Less than monthly&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monthly&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weekly&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Daily or almost daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2047873.png"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">AUDIT-c Questionnaire <a class="elsevierStyleCrossRefs" href="#bib1130">&#91;61&#44;63&#93;</a>&#46;</p>"
        ]
      ]
      9 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Scoring&#58; Each response is scored as 0 or 1&#44; with a higher score indicative of alcohol-related problems&#44; and a total of &#8805;2 clinically significant&#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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46; Have you ever felt you should cut down on your drinking&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46; Have people annoyed you by criticizing your drinking&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; Have you ever felt bad or guilty about your drinking&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46; Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover &#40;eye-opener&#41;&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2047872.png"
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            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">The CAGE Questionnaire <a class="elsevierStyleCrossRef" href="#bib1145">&#91;64&#93;</a>&#46;</p>"
        ]
      ]
      10 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Table "
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          ]
        ]
        "tabla" => array:1 [
          "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Proven to be safe and efficient in ALD</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baclofen &#40;10<span class="elsevierStyleHsp" style=""></span>mg TID&#59; 80<span class="elsevierStyleHsp" style=""></span>mg QD max&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Probably safe but not proven in ALD patients</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acamprosate &#40;666<span class="elsevierStyleHsp" style=""></span>mg TID&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Naltrexone &#40;PO&#58; 50<span class="elsevierStyleHsp" style=""></span>mg QD IM&#58; 380<span class="elsevierStyleHsp" style=""></span>mg monthly&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nalmefene &#40;Max daily dose&#58; 1 tablet 18<span class="elsevierStyleHsp" style=""></span>mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Topiramate &#40;300<span class="elsevierStyleHsp" style=""></span>mg QD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gabapentin &#40;900&#8211;1800<span class="elsevierStyleHsp" style=""></span>mg QD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Varenicline &#40;2<span class="elsevierStyleHsp" style=""></span>mg QD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ondansetron &#40;1&#8211;16<span class="elsevierStyleHsp" style=""></span>mcg&#47;kg BID&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Contraindicated medications in cirrhosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disulfiram&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab2047878.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Proposed medications to treat alcohol use disorders in cirrhotic patients&#46;</p>"
        ]
      ]
      11 => array:8 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at6"
            "detalle" => "Table "
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        "tabla" => array:1 [
          "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALD is the main cause of cirrhosis in Latin-America&#46; Excessive alcohol consumption should be actively sought as a cause of cirrhosis &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The amount of alcohol consumed is the most important risk factor for the development of ALD &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subjects consuming more than 3 standard drinks per day in men&#44; and more than 2 drinks per day in women&#44; or repeated binge drinking &#40;defined as more than 5 drinks in men and more than 4 in women over a 2<span class="elsevierStyleHsp" style=""></span>h period&#41; are at risk of developing liver disease and should receive counseling &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The impact of the type of alcoholic drink consumed &#40;i&#46;e&#46; liquor&#44; beer or wine&#41; and the pattern of drinking on the risk of developing ALD is not well known &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with any chronic liver disease and protein calorie malnutrition should be advised to avoid alcohol consumption &#40;Grade of evidence&#58; very low quality&#59; grade of recommendation&#58; weak&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Latin-America is one of the regions with high prevalence of excessive alcohol consumption and the resulting health consequences represent a major public health concern&#46; Implementation of public health policies aimed at reducing the burden of alcohol-related cirrhosis is urgently needed &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcohol use disorder should be assessed in all patients presenting with newly recognized liver disfunction&#44; by application of specific questionnaires &#40;i&#46;e&#46; AUDIT or CAGE&#41; that can be easily applied in daily clinical practice &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with AUD&#44; clinical&#44; biochemical and radiological evaluation is mandatory for early detection of underlying ALD &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A liver biopsy may be considered when the ALD diagnosis is unclear due to the existence of other potential etiological factors &#40;Grade of evidence&#58; low quality&#59; grade of recommendation&#58; weak&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with excessive alcohol use and obesity-related metabolic syndrome&#44; the Alcoholic liver disease&#47;Nonalcoholic Fatty Liver Disease Index &#40;ANI&#41; could be helpful in differentiating ALD and NAFLD &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liver stiffness measurement or patented serum biomarkers may be useful for assess liver fibrosis in patients with ALD&#44; however&#44; certain conditions&#44; such as the presence of ASH&#44; cholestasis&#44; and active alcohol intake can overestimate the degree of fibrosis &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AH is clinically defined as abrupt onset of progressive jaundice and liver-related complications with hyperbilirubinemia &#40;&#62;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; AST&#47;ALT ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5 with levels of AST<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5 times the upper limit of normal but &#60;400<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#59; and heavy alcohol drinking until 60 days before onset of symptoms and absence of other causes of liver disease &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liver biopsy to diagnose AH is recommended in patients with suspected AH&#44; but who do not meet the abovementioned criteria&#44; in the presence of confounding factors or when other etiology is also suspected &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcohol-related cirrhosis is one of the main causes of HCC in Latin-America&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The risk of HCC in ALD-related cirrhosis is similar to other etiologies and surveillance should be performed by ultrasonography every 6 months with or without serum alpha-fetoprotein levels &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete abstinence is the major therapeutic approach that decreases mortality and liver-related complications in patients with ALD &#40;Grade of evidence&#58; high quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with severe ALD&#44; only baclofen has been proven to be effective and safe in preventing alcohol relapse &#40;Grade of evidence&#58; moderate quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Protein-calorie malnutrition is common in patients with ALD&#46; Adequate food intake with proper protein and caloric content should be considered &#40;Grade of evidence&#58; high quality&#59; grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Medical treatment of ALD should be performed by multidisciplinary teams&#44; including alcohol addiction specialists &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">General recommendations for screening and management of cirrhosis complications should be applied to patients with alcohol-related cirrhosis &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No specific pharmacological therapy for alcohol-related fibrosis has demonstrated consistent benefit and should only be used in the context of clinical trials &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Corticosteroids are the first-line therapy in patients with severe AH &#40;Grade of evidence&#58; high quality&#59; Grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pentoxifylline treatment has limited impact improving short and long-term survival of patients with severe AH and are not currently recommended &#40;Grade of evidence&#58; high quality&#59; Grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The use of biological anti- TNF-&#945; drugs has no role in the treatment of severe AH&#46; Their use is not recommended because of their deleterious effects on increasing the rate of severe infections and death in these patients &#40;Grade of evidence&#58; high quality&#59; Grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antioxidants&#44; such as metadoxine and NAC&#44; may be useful improving short-term mortality of patients with severe AH receiving corticosteroids &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; weak&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The artificial liver supportive systems in the treatment of severe AH do not help to improve short and long-term survival rates &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; strong&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G-CSF should not be used outside of clinical studies until further supportive evidence is available &#40;Grade of evidence&#58; low quality&#59; Grade of recommendation&#58; weak&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intensive enteral nutrition in patients with AH has showed no benefit on short-term survival when added to corticosteroid treatment&#46; However&#44; patients with higher calorie intake do have a better survival at 6 months &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; weak&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liver transplantation can be considered in the management of patients with end-stage ALD &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In patients with end-stage ALD&#44; candidacy for transplantation criteria should be comprehensive and not only based on the 6-month rule of abstinence&#44; since this may not be feasible in patients with severe AH or severe decompensated ALD where survival is limited &#40;Grade of evidence&#58; moderate quality&#59; Grade of recommendation&#58; weak&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients undergoing liver transplantation evaluation for ALD should be assessed by multidisciplinary teams&#44; including addiction specialists&#44; and should be screened for use of alcohol and other substances &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immunosuppression should be prescribed at the lowest possible dose and smoking cessation should be advised and assisted to reduce the risk of cancer in this group of patients&#46; Also&#44; a complete cardiovascular evaluation is advised &#40;Key concept&#47;Expert&#39;s opinion&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Recommendations and key concepts on the management of alcohol-related liver disease&#46;</p>"
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      12 => array:8 [
        "identificador" => "tbl0035"
        "etiqueta" => "Table 7"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at7"
            "detalle" => "Table "
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        "tabla" => array:1 [
          "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Natural history studies assessing characteristics of the disease in the region&#44; ideally including multiple centers and countries&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Studies evaluating the natural history of the disease&#44; with a special emphasis on early stages of ALD and AH&#44; due to a higher mortality observed in Latin-American populations&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Studies assessing the impact of the type of alcohol consumed in ALD&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Large genome wide association studies&#44; in different ethnicities of Latin-America&#44; to identify the genetic determinants implicated in individual susceptibility to ALD&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Studies assessing the role of environmental factors influencing the susceptibility to develop severe ALD&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epidemiological studies assessing the prevalence of ALD in Latin-America&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Studies to identify reliable noninvasive biomarkers to differentiate between steatosis&#44; steatohepatitis and fibrosis in the setting of ALD&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Population based studies to assess the prevalence of AUD and ALD in Latin-America&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Studies assessing the clinical features&#44; mortality and usefulness of existing scoring systems in Latin-America&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Studies assessing noninvasive biomarkers useful to diagnose AH and to predict survival and response to therapy&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Large clinical trials analyzing the potential benefit of antioxidants in combination with prednisolone on the short and long-term survival of patients with AH&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Clinical trials aimed at testing and validating the efficacy of liver regeneration through G-CSF therapy&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">The potential effect of antibiotic prophylaxis on patient&#39;s survival and complication rate should be delineated in future studies&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Epidemiological studies evaluating liver transplantation outcomes for ALD in Latin-America&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Studies evaluating criteria and outcomes of patients transplanted for severe AH&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Studies on immunosuppression in patients transplanted for ALD&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Protocols for cancer and cardiovascular screening in transplanted patients for ALD&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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ISSN: 16652681
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos