The Prognosis of Glycoregulation Disturbances and Insulin Secretion in Alcoholic and C Virus Liver Cirrhosis

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1 The Prognosis of Glycoregulation Disturbances and Insulin Secretion in Alcoholic and C Virus Liver Cirrhosis D. SÂMPELEAN 1, BIANCA HĂNESCU 1, ANCA HAN 2, M. ADAM 1, F. CASOINIC 1 ¹ IVth Medical Clinic, Cluj-Napoca ² Infectious Disease Clinic, Cluj-Napoca We studied 49 alcoholic and viral C liver cirrhosis, over a period of 5 years, we evaluated OGTT, HOMA-IR, HOMA-β, Child Score, diabetes mellitus and liver cirrhosis complications and survival. Both insulin resistance and lower insulin secretion in liver cirrhosis are important determinants of the degree of oral glucose tolerance. There is a correlation between the bad prognosis in patients with cirrhosis and glycoregulation disturbances, especially in those with alcoholic etiology. Key words: liver cirrhosis, oral glucose tolerance test (OGTT), diabetes mellitus, prognosis. The significance and prognostic value of oral glucose tolerance test (OGTT) and insulin secretion in (liver cirrhosis) LC is a matter of debate. Currently, it is a matter for debate whether type 2 diabetes mellitus (DM), in the absence of other risk factors contributing to metabolic syndrome (obesity and hypertriglyceridaemia) could be a risk factor for the development and progression of liver disease [1][2]. Fasting serum glucose levels may be normal in compensated LC and in these cases it is necessary to perform an OGTT to detect an impairment of glucose metabolism [3]. Also we need to perform at the same time HOMA-beta to detect early impairment in insulin secretion and decrease of beta cell reserve because insulin resistance could be a primary event complicating cirrhosis, but additional b-cell secretory defects were crucial for development of diabetes [4]. The etiology of liver disease is important for the incidence and pathogenesis of DM, since nonalcoholic fatty liver disease (NAFDL), alcohol, hepatitis C virus (HCV) and hemocromatosis are frequently associated with DM [1][2][5][6]. The aim of our study was to evaluate the prognostic role of oral glucose tolerance test (OGTT) and HOMA-beta in alcoholic and viral C cirrhosis patients. MATERIAL AND METHODS DM was diagnosed on the basis of the current WHO criteria and the oral glucose tolerance test (OGTT) and followed LC. LC was evaluated as previously described [7]. We assessed insulin resistance with HOMA-IR formula = I G/405, I = basal insulin in plasma (µu/ml) using plasma immunoreactive insulinaemia (IRI-Kit RK, 400M Isotope) and G = basal blood glucose (mg/dl); where normal value was < 2 and a pathological value 2 and also the insulin secretion through HOMA β (%) = I 360 / G 63 ( 80% indicating pathological value), the Child-Pugh score, the evaluation and the complications of the liver disease and DM, as well as the survival during 5 years. We used statistical methods: ANOVA. RESULTS 1. Sex repartition More than ¾ patients with LC were males (Fig. 1) (39 of 49 cases) 2. LC etiology There is an alcoholic and mixed (with C virus) predominance (72% of cases) (Fig. 2) 3. OGTT 2/3 of LC presented altered oral glucose tolerance of which was newly diagnosed by OGTT; 35% were diabetics (Fig. 3). 4. OGTT and etiology DM and IGT was more frequent in alcoholic and mixed (with C virus) etiology and in Child B and C class (Figs. 4,5). ROM. J. INTERN. MED., 2009, 47, 4,

2 388 D. Sâmpelean et al. 2 Sex repartition 10 Fig. 1. Sex Repartition % women men Liver cirrhosis etiology 28% 44% Fig. 2. LC etiology. 29% alcoholic viral C alcoholic+viral C Glucose intolerance after OGTT 35% 45% normal test (NT) impaired glucose tolerance (IGT) DM Fig. 3. OGTT in LC. 5. HOMA-IR, HOMA-beta and LC (Tables I, II) Insulinoresistance was more frequent and pronounced in DM (90% of cases >2) Diminished beta cell reserve (<80%) was recorded in 24% of DM 6. DM and LC survival (Table III) 13/18 of LC who deceased during 5 years had DM&IGT, more frequently of double etiology (C virus and alcohol) (11/13 cases).

3 3 Glycoregulation disturbances and insulin secretion in cirrhosis % 50% 40% 30% glicoregulation disturbances Liver cirrhosis etiology of patients with glycoregulation disturbances 50% 42% 40% 30% 18% 10% 0% IGT DM alcoholic viral C alcoholic+viral C Fig. 4. OGTT and etiology of LC Child-Pugh Score % A B C NGT IGT DM Fig. 5. Child-Pugh Score. Table I HOMA IR HOMA IR Normal test Impaired glucose test DM < 2 52% 40% 10% > 2 48% 60% 90% Table II HOMA β HOMA β Normal test Impaired glucose test DM < 80 % 24% > 80 % 37% 17% 22%

4 390 D. Sâmpelean et al. 4 Table III LC survival Deceased: 18 cases Etiology of liver cirrhosis Alcoholic Alcoholic + Viral C Viral C (No. cases) Glycoregulation disturbances Normoglycemic Impaired glucose tolerance DM (No. cases) Causes of death Cardio-Vascular Cirrhosis complications Other causes (No. cases) Cardiovascular and hepatic complications were almost equally frequent (8 vs 7) responsible for death. DISCUSSION Male sex predominance in our patients (75%) could be explained by the higher alcoholic etiology incidence in our group of liver cirrhosis (72%). The incidence of glucose intolerance in our group of alcoholic and C virus cirrhosis was 55% with 35% diabetes mellitus which was more frequent in alcoholics and Child B and C class. The reported incidence of glucose intolerance varies from 60% to 80% depending on the etiology, degree of liver damage and diagnostic criteria [2][3][8][9]. Up to 96% of patients with cirrhosis may be glucose intolerant and 30% may be clinically diabetic [5]. Cirrhosis alone does not always induce diabetes, and the cause of liver disease and environmental factors may play a role. Zein et al. [10] found that the prevalence of diabetes was increased in HCV cirrhosis (25%) and alcoholic liver disease (19%) but not in cholestatic liver disease (1.3%). Patients with alcoholic liver disease have a high relative risk of suffering diabetes [10], risk directly related to the amount of ingested alcohol [11]. Excessive alcohol intake may have a direct effect on the development of type 2 diabetes by decreasing insulin-mediated glucose uptake in the acute situation and by damaging pancreatic islet cells with chronic use [5]. Also development of diabetes. The specific mechanisms responsible for the development of diabetes in HCV-infected patients are not fully understood, but it seems that an increase of insulin resistance associated with either body iron stores, hepatpersistent HCV infection is associated with the subsequent hepatic steatosis, or tumor necrosis factor- could play an important role [6]. Altered oral glucose tolerance was detected by OGTT in of LC confirming once again the subclinical impairment of glucose metabolism in LC and the importance of OGTT [3][12]. Using HOMA-IR and HOMA beta we discovered insulinoresistance in almost all cirrhotics with diabetes but in one of four (24%) beta cell reserve began to decrease. This fact may be partially explained by the frequently associated chronic pancreatic damage and injury of pancreatic islet beta cells in chronic alcoholism resulting in lower insulinemia and DM [5][7][13] when acting on a chronic insulinoresistance state. It has also been speculated that genetic and environmental factors and some etiologic agents in liver disease such as HCV, alcohol, and iron infiltration impair insulin secretion activity of beta-cells of the pancreas [14]. Perseghin et al. [4] found that liver transplantation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic-diabetic patients; nevertheless, 33% were still diabetics because of the persistence of a reduced b-cell function. It seems that glucose intolerance in LC may result from two abnormalities that occur simultaneously: insulin resistance of muscle and an inadequate response of betacells to appropriately secrete insulin to overcome the defect in insulin action [15]. DM develops as the result of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycemia and a diabetic glucose profile [16]. We registered during 5 years follow-up significantly more deaths in cirrhotics with diabetes and among them cardiovascular complications were equally encountered with hepatic complications. Nishida

5 5 Glycoregulation disturbances and insulin secretion in cirrhosis 391 et al. [3] also found that the survival rates of cirrhotic patients with type 2 diabetes were significantly lower than those with normal glucose tolerance. In contrast with type 2 DM, hepatogenous diabetes is considered to be less frequently associated with microangiopathy, so that patients with cirrhosis and diabetes suffer more frequently from complications of cirrhosis, which can cause death [1][3]. The increased incidence of cardiovascular complications in our group of alcoholic and C virus LC could be explained by atherosclerotic lipidic profile and hepatic steatosis of chronic alcoholism and chronic C virus infection acting like metabolic syndrome components to increase cardiovascular risk in LC. So, alcoholic liver cirrhosis followed by diabetes mellitus has a similar evolution and complications as hepatogenous diabetes of non alcoholic liver cirrhosis with metabolic syndrome. CONCLUSION 1. Both insulin resistance and lower insulin secretion in liver cirrhosis followed by diabetes are important determinants of the degree of oral glucose tolerance. 2. There is a correlation between the bad prognosis and OGTT in patients with liver cirrhosis which explained the higher risk of death. 3. Death prevalence by vascular complications is higher in alcoholic liver cirrhosis with diabetes mellitus. S-au studiat 49 ciroze hepatice alcoolice şi virale C, timp de 5 ani, prin TTGO, HOMA-IR, HOMA-β, clasa Child, complicaţiile diabetului şi ale cirozei precum şi supravieţuirea la 5 ani. S-a constatat că, atât insulinorezistenţa, cât şi scăderea secreţiei de insulină sunt determinante importante ale gradului de alterare a toleranţei la glucoză în ciroza hepatică. Există o corelaţie negativă în ceea ce priveşte prognosticul, la pacienţii cu ciroză hepatică şi tulburări de glicoreglare, în special la cei cu etiologie alcoolică. Corresponding author: Bianca Hănescu MD C.F. Hospital, Cluj-Napoca, Str. Republicii nr bianca_hanescu@yahoo.com REFERENCES 1. EL-SERAG H.B., TRAN T., EVERHART J.E., Diabetes Increases the Risk of Chronic Liver Disease and Hepatocellular Carcinoma, Gastroenterology, 2004; 126: TOLMAN K. G., FONSECA VIVIAN, DALPIAZ A., TAN M. H., Spectrum of Liver Disease in Type 2 Diabetes and Management of Patients with Diabetes and Liver Disease. Diabetes Care, 30, 3, March 2007, NISHIDA T., TSUJI S., TSUJII M. et al., Oral Glucose Tolerance Test Predicts Prognosis of Patients with Liver Cirrhosis, Am. J. Gastroenterol., 2006; 101: PERSEGHIN G., MAZZAFERRO V., PICENI SERENI LUCIA et al., Contribution of Reduced Insulin Sensitivity and Secretion to the Pathogenesis of Hepatogenous Diabetes: Effect of Liver Transplantation. Hepatology, 31, 3: , HICKMAN INGRID J., MACDONALD G.A., Impact of Diabetes on the Severity of Liver Disease. The American Journal of Medicine (2007), 120, LECUBE A., HERN ANDEZ CRISTINA, GENESC A. JOAN et al., High Prevalence of Glucose Abnormalities in Patients with Hepatitis C Virus Infection A multivariate analysis considering the liver injury. Diabetes Care, 27: , SAMPELEAN D., MOTOCU M., Low insulin secretion in decompensated liver cirrhosis with diabetes mellitus. Rev. Roum. Med. Int. 34, 4: , HOLSTEIN A., HINZE S., THIEßEN E. et al., HEPATOGENOUS DIABETES IN LIVER CIRRHOSIS Clinical implications of hepatogenous diabetes in liver cirrhosis. Journal of Gastroenterology and Hepatology, 2002; 17, MERLI MANUELA, LEONETTI FRIDA, RIGGIO O. et al., Glucose Intolerance and Insulin Resistance in Cirrhosis Are Normalized After Liver Transplantation, Hepatology, 1999; 30: ZEIN N.N., ABDULKARIM A.S., WIESNER R.H. et al., Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. Journal of Hepatology, 2000; 32:

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