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Early warning of liver disease in diabetics
Juan Pablo Arab, Carolina Ramírez, Marco Arrese
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marrese@med.puc.cl

Correspondence and reprint request:
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Comment</span><p id="p0005" class="elsevierStylePara elsevierViewall">The coexistence of diabetes mellitus &#40;DM&#41; and chronic liver disease &#40;CLD&#41; is commonly seen in daily clinical practice and indeed these two conditions are associated with each other more frequently than expected by chance&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The intricacies of this association are multiple and their relationship is of bidirectional nature&#46; Thus&#44; while cirrhosis itself and some etiologic agents of cirrhosis&#44; such as the hepatitis C virus&#44; can contribute to development of DM through a myriad of mechanisms&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> DM may also be considered a metabolic pathway leading to CLD via the development of non-alcoholic fatty liver disease &#91;NAFLD&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">Non-alcoholic fatty liver disease &#40;NAFLD&#41; is a cli-nico-pathological entity defined by the presence of hepatic histological changes that are similar to those observed in heavy-drinkers but detected in patients that deny significant alcohol consumption and do not have other known causes of chronic liver disease&#44; such as viral hepatitis or drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The histo-logical hallmark of NAFLD is the accumulation of fat in the liver &#40;conventionally set as more than 5&#37; by weight&#41; which may or may not be accompanied by the presence of necro-inflammatory changes and&#47; or hepatic fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> When the latter features are present the term non-alcoholic steatohepatitis &#91;NASH&#93; is used&#46; The subgroup of patients with NASH are deemed to have a more aggressive form of the disease that poses the risk of developing cirrhosis and hepatocellular carcinoma &#91;HCC&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">NAFLD is now recognized as one the most common liver diseases worldwide and is emerging as a relevant cause of liver-related mortality&#46; Epidemiolo-gical studies have shown that NAFLD affects a substantial proportion of the general population of several countries&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Current estimates from different sources indicate that up to 30&#37; of the general population is affected by NAFLD&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> This high fre-quency is mainly due to the close relationship between this type of fatty liver and obesity&#44; a condition that have now reached epidemic proportions in the world&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In fact&#44; the prevalence of NAFLD in morbidly obese population can reach up to 75&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Another group with high prevalence of NAFLD is that of patients with type 2 DM&#46; In fact&#44; NAFLD prevalence among these patients ranges from 49&#37; to 62&#37;&#46; Moreover&#44; patients with type 2 DM are more likely to have the histologically more aggressive form of NAFLD &#40;i&#46;e&#46; NASH&#41;&#44; with a prevalence of 12&#46;2&#37; among those with diabetes compared to 4&#46;7&#37; among non-diabetics&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">From the above-mentioned figures one can conclude that NAFLD is a very common disorder in type 2 DM and that those patients with DM are indeed at risk of developing CLD&#46; However&#44; in spite of this data and in contrast with the known risk of re-tinopathy&#44; chronic kidney disease and atherosclerosis&#44; clinicians are frequently unaware that patients with DM are uniquely prone to develop NAFLD and particularly its more aggressive form NASH&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> An example of this lack of awareness is the fact that potential risk of CLD is not mentioned in the currently used guidelines for DM management&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Obviously&#44; data is needed to precisely define at which extent liver cirrhosis may be an under-recognized complication in patients with DM&#46; The recent paper by<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleItalic">et al&#46;</span> makes a significant contribution in this regard&#46; In their study&#44; the authors used administrative health databases for the province of Ontario from 1994 to 2006 to identify 438&#44;069 adults with newly diagnosed diabetes and matched them in a 5&#58;1 ratio by birth year&#44; sex&#44; and local health region with a group of 2&#44;059&#44;708 individuals without known diabetes&#46; The main study endpoint was incident serious liver disease&#44; defined as cirrhosis&#44; liver failure and its complications&#44; or receipt of a liver transplant&#44; over a median of 6&#46;4 years of follow-up&#46; Results showed that adults with newly diagnosed diabetes had a significantly greater risk of liver disease &#40;unadjusted hazard ratio was 1&#46;92 &#40;95&#37; confidence interval &#91;CI&#93; 1&#46;83-2&#46;01&#41; compared with controls&#46; The association remained significant &#40;hazard ratio was 1&#46;77 &#40;95&#37; CI 1&#46;68-1&#46;86&#41; after adjustment&#41; after adjusting for other demographical variables that may influence the risk for liver disease such as age&#44; gender&#44; urban versus rural residence&#44; and income level&#46; Moreover&#44; diabetes&#44; with or without pre-existing hypertension&#44; dyslipidemia or obesity&#44; conferred a higher risk of serious liver disease than any of the three other conditions in isolation&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">The study by Porepa et al&#46; has some important limitations that the authors delineate in their re-port&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Among them&#44; misclassification of persons with diabetes&#44; inability to distinguish between newly diagnosed type 1 and type 2 DM and lack of ethnicity data deserve to be mentioned&#46; However&#44; the most important point is that causality cannot be demonstrated in an association study&#46; The possibility exists that some patients with DM already had subclinical cirrhosis at the moment of study entry and that DM may be a consequence of CLD rather than its cau-se&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> This however&#44; is unlikely for most of patients since hepatogenous diabetes is often seen in advanced &#40;and clinically apparent&#41; cirrhosis&#46; Although definitive proof is lacking&#44; currently available basic and clinical data<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> on NAFLD and its risk of progression to CLD is highly suggestive of a causal relationship of NAFLD and the risk of serious liver disease in DM&#46;</p><p id="p0030" class="elsevierStylePara elsevierViewall">The fact that diagnosis of DM is a risk factor for serious liver disease&#44; likely via NAFLD&#44; has important clinical implications&#46; The silent nature of the NAFLD and NASH poses a diagnostic problem&#46; Although detection of steatosis is relatively simple through the use of simple techniques such as abdominal ultrasound &#40;with 93&#37; sensitivity and 89&#37; specificity&#41;&#44; discrimination of patients with NASH or advanced fibrosis is difficult&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Of note&#44; declining mortality rates in people with DM make plausible that an unknown proportion of older diabetics may already have unrecognized cirrhosis being at risk of cirrhotic complications and HCC&#46; To rely on normal levels of aminotransferases to exclude liver disease in patients with DM may not be an adequate strategy since severe fibrosis may be presence in this set-ting&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> To date liver biopsy is considered the gold standard for the definitive diagnosis of NAFLD<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> but this procedure&#44; in virtue of its invasive nature&#44; is not easily accepted by patients and doctors&#46; In light of lack of guidelines&#44; the pros and cons of liver biopsy in the individual patients should be adequately balanced ideally with the involvement of a hepato-logist&#46; Non invasive strategies for assessment of ongoing liver injury or hepatic fibrogenesis in NA-FLD are being developed and assessed in clinical studies&#46; Among them&#44; plasma biomarkers of apoptosis such as cytokeratin-18 fragments<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> or new imaging studies such as transient elastography<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> or magnetic resonance elastography<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> hold promise and their entrance to clinical practice is eagerly awaited&#46; In the meantime&#44; the first task is to increase the awareness on the risk or the presence of serious liver disease in patients with DM among physicians caring these patients&#46; The hepatological community should develop active educational strategies in this regard&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Acknowledgement</span><p id="p0035" class="elsevierStylePara elsevierViewall">This work was partially funded by Grants from the Fondo Nacional De Ciencia y Tecnologia de Chile &#40;Fondecyt &#35; 1080170 to MA&#41;&#46;</p></span></span>"
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        "resumen" => "<span id="abs0005" class="elsevierStyleSection elsevierViewall"><p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Porepa L&#44; Ray JG&#44; Sanchez-Romeu MP&#44; Booth GL&#46; Newly diagnosed diabetes mellitus as a risk factor for serious liver disease&#46; <span class="elsevierStyleItalic">CMAJ</span> 2010&#59; DOI&#58;10&#46;1503&#47;cmaj&#46;092144&#46;</p></span> <span id="abs0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Original Abstract</span><p id="sp0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Background&#46;</span> The negative impact of diabetes mellitus is well recognized&#44; yet little is known about the effect of this disease on the liver&#44; an organ susceptible to nonalcoholic fatty liver disease related to insulin resistance&#46; We evaluated whether adults with newly diagnosed diabetes were at increased risk of serious liver disease&#46;</p><p id="sp2010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Methods&#46;</span> We used administrative health databases for the province of Ontario &#40;1994-2006&#41; to perform a population based matched retrospective cohort study&#46; The exposed group comprised 438 069 adults with newly diagnosed diabetes&#46; The unexposed comparison group-those without known diabetes-consisted of 2 059 708 individuals&#44; matched 5&#58;1 to exposed persons&#44; by birth year&#44; sex and local health region&#46; We excluded individuals with preexisting liver or alcohol-related disease&#46; The primary study outcome was the subsequent development of serious liver disease&#44; namely&#44; liver cirrhosis&#44; liver failure and its sequelae&#44; or receipt of a liver transplant&#46;</p><p id="sp3010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Results&#46;</span> The incidence rate of serious liver disease was 8&#46;19 per 10 000 person-years among those with newly diagnosed diabetes and 4&#46;17 per 10 000 person-years among those without diabetes&#46; The unadjusted hazard ratio was 1&#46;92 &#40;95&#37; confidence interval &#91;CI&#93; 1&#46;83-2&#46;01&#41;&#46; After adjustment for age&#44; income&#44; urban residence&#44; health care utilization and pre-existing hypertension&#44; dysli-pidemia&#44; obesity and cardiovascular disease&#44; the hazard ratio was 1&#46;77 &#40;95&#37; CI 1&#46;68-1&#46;86&#41;&#46;</p><p id="sp6010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Interpretation&#46;</span>Adults with newly diagnosed diabetes appeared to be at higher risk of advanced liver disease&#44; also known as diabetic hepatopathy&#46; Whether this reflects nonalcoholic fatty liver disease or direct glycemic injury of the liver remains to be de-termined&#46;</p></span>"
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Article information
ISSN: 16652681
Original language: English
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