Hepatogenous Diabetes in Cirrhosis: Academic Sport or a Neglected Disease?

To the Editor

Impaired glucose tolerance and overt diabetes mellitus (DM) are both frequently prevalent in cirrhosis [1] [2] [3] [4]. In most cases, diabetes seems to follow cirrhosis and is therefore called hepato­genous diabetes (HD). Furthermore, a possible normalization of diabetic condition was observed after orthotopic liver transplantation [3]. It is not possible to distinguish between HD and type 2 diabetes mellitus clinically or by assessing laboratory parameters. However, HD represents a different entity than type 2 diabetes mellitus and is characterized by certain characteristics including lack of family history of diabetic condition and very rare microangiopathic complications [1] [2] [3] [4]. According to literature, more than 20% of all cirrhotic patients are affected by diabetic condition while the prevalence of impaired glucose tolerance (IGT) occurs in up to 96% [2].

Compared to type 2 diabetes, diabetic microvascular complications seem to occur less frequently in cirrhotic diabetics [4]. However, overall prognosis, prevalence and mortality rate of typical complications of cirrhosis are significantly increased in diabetic patients compared to non-diabetic cirrhotics which represents the major indication for adequate treatment of diabetic condition [5]. Diabetics with cirrhosis have more severe hepatic encephalopathy (HE) at earlier stages of biochemical decompensation and portal hypertension compared with nondiabetic patients [6]. In a randomized, prospective and placebo-controlled trial, hypoglycemic agent acarbose significantly improved HE symptoms while a significant decrease in fasting and postprandial glucose level, glycated hemoglobin values and postprandial C peptide could be observed compared with placebo [7]. Additionally, infections including spontaneous bacterial peritonitis are more prevalent among diabetic cirrhotics [8]. In patients with cirrhosis and refractory ascites, diabetes was an independent predictive factor of poor survival while abstinence was an independent predictive factor of good survival [9]. Furthermore, the risk of hepatocellular carcinoma (HCC) is significantly increased in the coexistence of cirrhosis and diabetes probably due to insulin resistance which plays a role in hepatocarcinogenesis while diabetic patients are at a cumulative increased risk for postoperative hepatic decompensation after resection of HCC compared to cirrhotics without diabetes [10] [11]. Interestingly, improved disease control in diabetes seems to represent measures of cancer prevention since treatment with metformin may reduce significantly the risk of HCC [12] [13] [14].

Although control of diabetic condition is of particular importance in cirrhotic patients, there is insufficient clarity about the practicability of anti-diabetic therapy and the most efficacious therapy. Furthermore, compared with common complications of cirrhosis such as bleeding esophageal varices or ascites, the prevalence and impact of disturbances of glucose metabolism is often underestimated in daily clinical routine.

To evaluate the awareness of gastroenterologists and hepatologists for diabetic condition in cirrhosis, we devised and piloted a questionnaire and sent it to all 576 members of the Bavarian Society of Gastroenterology. The state of Bavaria possesses an excellent supply concerning chronic liver disease (CLD). In 2008 there were more than 24 000 internal beds available in Bavarian hospitals of those ca. 10% belonged to gastroenterological and hepatological units while 752 doctors worked as ambulant gastroenterologists and hepatologists in Bavaria [15] [16] [17]. Therefore, the Bavarian Society of Gastroenterology represented a very good collective to analyse the awareness for this frequent complication of cirrhosis. Furthermore, the questionnaire contained several questions dealing with different aspects of malnutrition in cirrhosis as it is described elsewhere [18].

We asked for the estimated prevalence of IGT and HD in patients with cirrhosis [“How many of your patients with Child B or Child C stage cirrhosis are affected from impaired glucose tolerance and hepatogenous diabetes?”]. No open questions were included in our survey since possible answers including the correct answer could be chosen by multiple choice system. The questionnaires were returned anonymously and were analysed with descriptive statistics. 253 questionnaires (44%) were returned; of those 239 were fully completed and suitable for further analysis. Only 23 (9.1%) could name the correct prevalence of IGT in advanced cirrhosis (>stage B, according to Child-classification) according to recent literature while 230 (90.9%) underestimated this problem ([Fig. 1]). 145 (57.3%) of respondents could name the correct estimated prevalence of diabetes in advanced cirrhosis according to published literature while 60 (23.7%) underestimated and 39 (15.4%) overestimated this problem ([Fig. 2]).

Fig. 1 Cumulative frequency concerning question: “How many of your patients with Child B or Child C stage cirrhosis are affected from impaired glucose tolerance [IGT [1]] and hepatogenous diabetes [2]?”.

Fig. 2 Cumulative frequency concerning question: “How many of your patients with Child B or Child C stage cirrhosis are affected from impaired glucose tolerance [IGT [1]] and hepatogenous diabetes [2]?”.

Despite of its very high incidence and despite growing scientific information our survey showed that a substantial proportion of the medical community even in a sample of highly specialised experts might take insufficient notice of frequent diabetic condition in cirrhosis.

HD which develops as a complication of cirrhosis is not recognized by the American Diabetes Association and the World Health Organization as a specific independent entity [19]. Since all of the oral antidiabetic drugs but also long acting insulins may cause potential hepatotoxic effects and hypoglycemia, the safest and most efficacious therapy for diabetic condition in cirrhosis is still not defined. Since disturbances of glucose metabolism in patients with cirrhosis affect prognosis, complication- and mortality rate, guidelines or guideline-like recommendations are necessary for medical practitioners, especially gastroenterologists and hepatologists treating patients with chronic liver diseases.

There is strong evidence from observational studies, that treatment of HD improves the prognosis of cirrhosis. However, prospective studies evaluating the impact of diabetes therapy in cirrhosis are rare. Therefore, prospective intervention studies are needed to confirm the benefit of diabetes control in cirrhotic patients while analyzing the safety profile of antidiabetic medication in chronic liver disease.

• References

• 1 Naunyn B. Glykosurie und Diabetes durch experimentelle Insulte und Krankheiten der Leber. In: Naunyn B. ed. Der Diabetes mellitus: Vienna, Austria: A. Holder; 1898: 38-49
• 2 García-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ et al. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol 2012; 11: 240-248
• 3 Shetty A, Wilson S, Kuo P et al. Liver transplantation improves cirrhosis-associated impaired oral glucose tolerance. Transplantation 2000; 69: 2451-2454
• 4 Holstein A, Hinze S, Thiessen E et al. Clinical implications of hepatogenous diabetes in liver cirrhosis. J Gastroenterol Hepatol 2002; 17: 677-681
• 5 Nishida T, Tsuji S, Tsujii M et al. Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. Am J Gastroenterol 2006; 101: 70-75
• 6 Sigal SH, Stanca CM, Kontorinis N et al. Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis. Am J Gastroenterol 2006; 101: 1490-1496
• 7 Gentile S, Guarino G, Romano M et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005; 3: 184-191
• 8 Diaz J, Monge E, Roman R et al. Diabetes as a risk factor for infections in cirrhosis. Am J Gastroenterol 2008; 103: 248
• 9 Moreau R, Delègue P, Pessione F et al. Clinical characteristics and outcome of patients with cirrhosis and refractory ascites. Liver Int 2004; 24: 457-464
• 10 Ha NB, Ha NB, Ahmed A et al. Risk factors for hepatocellular carcinoma in patients with chronic liver disease: a case-control study. Cancer Causes Control 2012; 23: 455-462
• 11 Huo TI, Lui WY, Huang YH et al. Diabetes mellitus is a risk factor for hepatic decompensation in patients with hepatocellular carcinoma undergoing resection: a longitudinal study. Am J Gastroenterol 2003; 98: 2293-2298
• 12 Nkontchou G, Cosson E, Aout M et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011; 96: 2601-2608
• 13 Donadon V, Balbi M, Mas MD et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int 2010; 30: 750-758
• 14 Lai SW, Chen PC, Liao KF et al. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol 2012; 107: 46-52
• 15 www. arbeitsministerium.bayern.de/krankenhaus/plan/2007
• 16 www.statistik.bayern.de
• 17 www.blaek.de
• 18 Gundling F, Seidl H, Pehl C et al. How close do gastroenterologists follow specific guidelines for enteral nutrition in liver cirrhosis. Eur J Gastroenterol Hepatol 2009; 21: 756-761
• 19 American Diabetes Association . Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2012; 35 (Suppl. 01) S64-S71