Not routine screening, but vigilance for chronic liver disease in patients with type 2 diabetes
Authors: Vincent Wai-Sun Wong, Naga Chalasani
Journal: Journal of Hepatology (2016)

Type 2 diabetes and risk of hospital admission or death for chronic liver diseasesJournal of HepatologyVol. 64Issue 6PreviewThe impact of type 2 diabetes (T2DM) on hospital admissions and deaths due to common chronic liver diseases (CLDs) is uncertain. Our aim was to investigate associations between T2DM and CLDs in a national retrospective cohort study and to investigate the role of sex and socio-economic status (SES). Full-Text PDF The link between type 2 diabetes and the liver is multidimensional. Non-alcoholic fatty liver disease (NAFLD), often considered the hepatic manifestation of metabolic syndrome, is strongly associated with diabetes and insulin resistance. Diabetes is a strong predictor of cirrhosis among NAFLD patients [[1]Kwok R. Choi K.C. Wong G.L. Zhang Y. Chan H.L. Luk A.O. et al.Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.Gut. 2015; ([Epub ahead of print])https://doi.org/10.1136/gutjnl-2015-309265Crossref Scopus (290) Google Scholar]. Beyond NAFLD, diabetic patients with other liver diseases such as viral hepatitis also have a higher risk of hepatocellular carcinoma (HCC) than those without diabetes [[2]Veldt B.J. Chen W. Heathcote E.J. Wedemeyer H. Reichen J. Hofmann W.P. et al.Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.Hepatology. 2008; 47: 1856-1862Crossref PubMed Scopus (249) Google Scholar]. Based on population-attributable fraction analysis in the United States, eliminating diabetes and obesity may have an even greater impact on the incidence of HCC than eliminating viral hepatitis [[3]Welzel T.M. Graubard B.I. Quraishi S. Zeuzem S. Davila J.A. El-Serag H.B. et al.Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States.Am J Gastroenterol. 2013; 108: 1314-1321Crossref PubMed Scopus (220) Google Scholar]. Besides, the liver is an important organ for glucose metabolism. Severe insulin resistance and diabetes are common in patients with advanced liver disease [[4]Zein N.N. Abdulkarim A.S. Wiesner R.H. Egan K.S. Persing D.H. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease.J Hepatol. 2000; 32: 209-217Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar]. In this issue of the Journal, Wild et al., make a strong case for paying attention to the livers of diabetic patients [[5]Wild S.H. Morling J.R. McAllister D.A. Kerssens J. Fischbacher C. Parkes J. et al.Type 2 diabetes and risk of hospital admission or death for chronic liver diseases.J Hepatol. 2016; 64: 1358-1364Abstract Full Text Full Text PDF Scopus (43) Google Scholar]. They first identified patients with type 2 diabetes using the Scottish diabetes register which records glucose and glycosylated haemoglobin results from primary and secondary care settings. The national hospital, cancer and death data from 2004 to 2013 were then used to capture hospitalizations of patients with the diagnostic codes of different chronic liver diseases and HCC. Because the registries cover the majority of patients in Scotland, the analysis provides a reasonable estimate on the population incidence of hospitalizations related to chronic liver diseases in people with and without diabetes. During the study period, there were 40,291 first records of chronic liver diseases or HCC, among which 6667 occurred in patients with type 2 diabetes. Type 2 diabetes increased the incidence of hospitalizations with alcoholic liver disease, NAFLD, autoimmune liver disease, haemochromatosis and HCC by around 1.4–3.4-fold in men and 1.3–5.1-fold in women, after adjusting for age and socioeconomic status. The association was not apparent for viral hepatitis. As expected, the association was strongest for NAFLD, and diabetes was also associated with a more than 3-fold increase in hospitalizations with HCC. How should we interpret the results? Like many registry studies, the Scottish cohort has a large sample size and reflects phenomena at a population level. The authors also carefully considered and addressed potential confounders and interactions. The purest conclusion of this study would be that diabetic patients are more likely to be hospitalized with a chronic liver disease than non-diabetic individuals. One may also be tempted to conclude that diabetic patients have a higher incidence of chronic liver diseases or liver-related complications. Nevertheless, it is important to understand the study design. The definition of chronic liver disease events in this study is based on diagnostic codes during hospitalization. Since most cases of chronic liver diseases are diagnosed and managed at the out-patient setting, the current data do not represent the incidence of liver diseases. What about liver-related complications? While liver-related complications definitely contributed to some of the hospitalizations, diabetic patients with chronic liver diseases could be hospitalized for other reasons. Even in pure NAFLD cohorts, more patients die from cardiovascular causes than liver-related complications [[6]Ekstedt M. Hagstrom H. Nasr P. Fredrikson M. Stal P. Kechagias S. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1305) Google Scholar]. Since diabetic patients are more likely to be hospitalized for cardiovascular diseases and other complications unrelated to the liver, it comes as no surprise that the rate of hospitalization was higher in diabetic patients with chronic liver disease than non-diabetic patients with chronic liver disease. Unfortunately, the reasons of hospital admissions were not captured. On the other hand, HCC was the most robust event in this study. Most patients with HCC would be hospitalized at some time point, and malignancies are usually coded more reliably. The association between diabetes and HCC is therefore likely to be genuine and is consistent with previous studies [[7]El-Serag H.B. Tran T. Everhart J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.Gastroenterology. 2004; 126: 460-468Abstract Full Text Full Text PDF PubMed Scopus (1007) Google Scholar]. There are several explanations for this observation. First, NAFLD is associated with diabetes and can progress to HCC. According to the Surveillance, Epidemiology and End Results registries, NAFLD became the third leading cause of HCC in the United States in 2009 [[8]Younossi Z.M. Otgonsuren M. Henry L. Venkatesan C. Mishra A. Erario M. et al.Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.Hepatology. 2015; 62: 1723-1730Crossref PubMed Scopus (491) Google Scholar]. Although NAFLD remains an uncommon cause of HCC in Asia, diabetes is again one of the major risk factors of HCC in this population [[9]Kawamura Y. Arase Y. Ikeda K. Seko Y. Imai N. Hosaka T. et al.Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma.Am J Gastroenterol. 2012; 107: 253-261Crossref PubMed Scopus (202) Google Scholar]. Second, the pathogenic pathways of insulin resistance, hepatic steatosis and HCC overlap at multiple sites. For instance, fatty acid synthase has recently been shown to contribute to AKT-driven hepatocarcinogenesis [[10]Li L. Pilo G.M. Li X. Cigliano A. Latte G. Che L. et al.Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans.J Hepatol. 2016; 64: 333-341Abstract Full Text Full Text PDF Scopus (92) Google Scholar]. Third, diabetes is associated with cirrhosis not only in NAFLD patients but also in those with viral hepatitis [[11]Wong G.L. Wong V.W. Choi P.C. Chan A.W. Chim A.M. Yiu K.K. et al.Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B.Gut. 2009; 58: 111-117Crossref PubMed Scopus (191) Google Scholar]. While this may partly be explained by the direct effect of cirrhosis on insulin resistance, a reverse relationship is possible. For example, in chronic hepatitis B patients treated with tenofovir, a history of diabetes is one of the strongest factors associated with failure of cirrhosis regression [[12]Marcellin P. Gane E. Buti M. Afdhal N. Sievert W. Jacobson I.M. et al.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.Lancet. 2013; 381: 468-475Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar]. How do we apply these clinical observations into practice? In our opinion, there is already sufficient evidence to support metabolic management of patients with chronic liver diseases. Animal studies have demonstrated mechanistic links between regular exercise and HCC prevention [[13]Saran U. Humar B. Kolly P. Dufour J.F. Hepatocellular carcinoma and lifestyles.J Hepatol. 2016; 64: 203-214Abstract Full Text Full Text PDF Scopus (77) Google Scholar]. The use of metformin and statins, both central in the management of type 2 diabetes, is associated with a lower incidence of not only HCC but also HCC recurrence after liver resection [14Hsiang J.C. Wong G.L. Tse Y.K. Wong V.W. Yip T.C. Chan H.L. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: a propensity score landmark analysis.J Hepatol. 2015; 63: 1190-1197Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 15Wu C.Y. Chen Y.J. Ho H.J. Hsu Y.C. Kuo K.N. Wu M.S. et al.Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection.JAMA. 2012; 308: 1906-1914Crossref PubMed Scopus (677) Google Scholar]. These drugs are time-honored and have been shown to be safe in patients with compensated liver disease. The more controversial question is whether we should screen diabetic patients for chronic liver diseases. One also needs to define what conditions we are screening for. Theoretically, we may screen for liver diseases, advanced liver diseases (e.g. advanced fibrosis or early cirrhosis), or HCC in patients at risk. Let's focus on liver diseases as the role of HCC screening has been extensively discussed. Readers are referred to the Wilson and Junger classic screening criteria (Table 1) [[16]Wilson J.M.G. Jungner G. Principles and practice of screening for disease. World Health Organization, 1968Google Scholar]. Undoubtedly, chronic liver diseases are important causes of morbidity and mortality, and the natural history of many chronic liver diseases is relatively well defined. Before liver decompensation and HCC develop, liver diseases are largely asymptomatic and latent. Though new drugs are under development, many chronic liver diseases have recognized treatments and defined criteria for treatment. At least for viral hepatitis, treatment has been shown to reduce HCC, cirrhotic complications and liver-related mortality by good observational studies [[17]Wong G.L. Chan H.L. Mak C.W. Lee S.K. Ip Z.M. Lam A.T. et al.Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis.Hepatology. 2013; 58: 1537-1547Crossref PubMed Scopus (361) Google Scholar].Table 1Wilson and Jungner classic screening criteria [16]Wilson J.M.G. Jungner G. Principles and practice of screening for disease. World Health Organization, 1968Google Scholar. Open table in a new tab The choice of screening test is more debatable. During history taking, health care providers should ask about heavy alcohol consumption, but this should apply to patients with and without diabetes anyway. Screening for hepatitis B and C should follow the recommendations of current guidelines, and the study by Wild et al., does not suggest that viral hepatitis is more common in diabetic patients [[5]Wild S.H. Morling J.R. McAllister D.A. Kerssens J. Fischbacher C. Parkes J. et al.Type 2 diabetes and risk of hospital admission or death for chronic liver diseases.J Hepatol. 2016; 64: 1358-1364Abstract Full Text Full Text PDF Scopus (43) Google Scholar]. The current American guidelines do not support screening for NAFLD in both average risk and high risk individuals because of uncertainties surrounding the screening tests and whether screening improves clinical outcomes [[18]Chalasani N. Younossi Z. Lavine J.E. Diehl A.M. Brunt E.M. Cusi K. et al.The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association.Hepatology. 2012; 55: 2005-2023Crossref PubMed Scopus (2531) Google Scholar]. Nonetheless, a study in Hong Kong showed that 73% of the diabetic patients at primary care and hospital clinics had fatty liver, and 18% had increased liver stiffness by transient elastography suggestive of advanced fibrosis [[1]Kwok R. Choi K.C. Wong G.L. Zhang Y. Chan H.L. Luk A.O. et al.Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.Gut. 2015; ([Epub ahead of print])https://doi.org/10.1136/gutjnl-2015-309265Crossref Scopus (290) Google Scholar]. That said, it is unlikely that complicated assessments can be implemented widely, particularly at the primary care setting. Unfortunately, in another study by the Scottish group, different serum tests of fibrosis agree poorly with each other when applied to the diabetic population [[19]Morling J.R. Fallowfield J.A. Guha I.N. Nee L.D. Glancy S. Williamson R.M. et al.Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study.J Hepatol. 2014; 60: 384-391Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. More work is needed to develop tests that can be applied widely and can detect patients with significant liver diseases at risk of HCC and liver-related complications. In a recent cost-effectiveness analysis, Corey et al., constructed a Markov model to compare two management strategies to screen for non-alcoholic steatohepatitis (NASH) in middle aged diabetics. In the no screening strategy, patients do not undergo screening, although NASH may be clinically diagnosed subsequently. In the screening strategy, all patients receive one-time liver ultrasound and those with fatty liver are biopsied to identify individuals with NASH for subsequent medical treatment. Although the screening strategy led to 12.9% reduction in incident cirrhosis and 11.9% decrease in liver-related deaths, it was associated with 0.02 fewer quality-adjusted life years because of disutility associated with treatment. Notwithstanding the many shortcomings of this analysis, the authors concluded that screening for NASH in diabetics may improve liver-related outcomes, but it is not cost-effective until better tolerated and more effective treatments become available [[20]Corey K.E. Klebanoff M.J. Tramontano A.C. Chung R.T. Hur C. Screening for nonalcoholic steatohepatitis in individuals with type 2 diabetes: a cost-effectiveness analysis.Dig Dis Sci. 2016; ([Epub ahead of print])https://doi.org/10.1007/s10620-016-4044-2Crossref Scopus (50) Google Scholar]. In summary, the study by Wild and colleagues provides new information on the link between diabetes and the natural history of chronic liver diseases. Based on this paper and other recent studies it is tempting to consider screening type 2 diabetics for chronic liver diseases, especially NAFLD. However, currently available diagnostic tools and treatment options do not lend support for systematic screening for chronic liver diseases (especially for NAFLD) at this time. We encourage health care providers taking care of diabetic patients to be vigilant for any signs and symptoms of chronic liver disease and refer the patients for further assessment and management. Dr. Chalasani serves as a consultant to many pharmaceutical companies for NASH and drug hepatotoxicity. Dr. Wong has served as an advisory board member for Gilead and Janssen, and received paid lecture fees from AbbVie, Echosens and Gilead. None of these represent significant and direct conflict with this editorial.