NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN MEN WITH TYPE 2 DIABETES

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1 NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN MEN WITH TYPE 2 DIABETES D. Bakalov 1, M. Boyanov 1, G. Sheinkova 1, L. Vezenkova 1, G. Prodanova 2, V. Christov 1 1 Endocrinology Clinic 2 Sonography unit Central Consultation Policlinic, Alexandrovska University Hospital, Department Internal Medicine, Medical University Sofia Key words: metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease Contact details: D. Bakalov, Endocrinology Clinic, Alexandrovska UMHAT, 1 Sv. G. Sofiiski Blvd.,Sofia 1431, fax: , dbakalov@abv.bg Abstract: The non-alcoholic fatty liver disease (NAFLD) is implicated in the pathogenesis of insulin resistance, of the metabolic syndrome (MS) and type 2 diabetes mellitus (DM 2). The objective was to study the prevalence of NAFLD in men with diabetes type 2. Materials and methods: This is a retrospective, cross-sectional, observational study. We analyzed data from hospitalized patients: 80 men with diabetes type 2 (mean age 59.0 ± 10.7 years). Body weight, height, BMI, waist circumference, systolic and diastolic blood pressure were analyzed, as well as laboratory parameters such as fasting plasma glucose (FPG), glycated hemoglobin A1c, serum lipids, liver enzymes (AST, ALT, GGT). The liver shape, size and sonographic pattern were documented by abdominal ultrasonography. Results: 11.2% of type 2 diabetic men had ALA > 40 IU/L and 35.0% - GGT >35 IU/L. 40% of the men with DM 2 had liver steatosis. Between the subgroups (with/without NAFLD) the differences were significant only for BMI (р=0.027), diastolic blood pressure (р=0.031), and GGT (р=0.044). If a diagnostic threshold for NAFLD is set on 30 UI/L, the sensitivity of ALT is around 29% and that of GGT around 33%. Discussion: This study revealed a high prevalence of sonographic signs for liver steatosis in men with diabetes type 2 and emphasized on the need for sonography screening in such patients for the diagnosing of NAFLD. Original Article Introduction In Bulgaria, non-alcoholic fatty liver disease (NAFLD) is often referred to as the non-alcoholic steatohepatitis syndrome (NASH-syndrome). The NAFLD is assumed to be the hepatic manifestation of the metabolic syndrome. 1,2 Numerous studies have confirmed a bilateral relationship - NAFLD prevalence is higher among people with type 2 diabetes and metabolic syndrome 3,4 and vice versa - the prevalence of diabetes among people with this liver pathology is higher. 5,6,7 NAFLD is associated with increased risk for cardiovascular diseases, hepatocellular carcinoma and total mortality. 8,9,10,11,12 Different therapeutic approaches for treatment of NAFLD are explored from lifestyle changes to drugs influencing elements of the insulin resistance and the metabolic syndrome. 13 The prevalence of the NAFLD in the general population is high - about 15-30% and even higher among people with type 2 diabetes or metabolic syndrome. 4,14,15,16 The prevalence of diabetes and pre-diabetic conditions among people with known non-alcoholic fatty liver disease has been the predominant subject of research in our country in the last decade. 5,17 The objective of this study is to determine the 31

2 NAFLD in Men with Type 2 Diabetes prevalence of the non-alcoholic fatty liver disease by abdominal ultrasound and the associated clinical and laboratory parameters among men with type 2 diabetes mellitus. Materials and methods The presented study is a retrospective, cross-sectional and observational one. We analyzed data from 80 hospitalized men with diabetes type 2, admitted between 2006 and 2008, with mean age 59.0 ± 10.7 (from 36 to 85) The Diabetes mellitus in the study participants had a mean duration of 10 years (minimum 1 year, maximum 30 years) and was primarily treated with metformin (70% of men), sulfonylureas (40%), insulin (60%), and other oral agents (40%). 70% of the men with type 2 diabetes met the IDF 18 criteria of the metabolic syndrome - an increased waist circumference (> 94 cm) plus fasting glycaemia 5.6 mmol/l, or dyslipidemia (triglycerides 1.7 mmol/l, HDL - cholesterol <1.1 mmol/l), or arterial hypertension (blood pressure above 130/85 mm Hg). After taking the patient s history (including previous liver diseases and alcohol intake), physical examination was performed and the following anthropometric variables were included in the analysis - height, weight, body mass index, waist circumference. They are summarized in Table 1. The main inclusion criterion for the data analysis was the presence of abdominal ultrasonography with documented assessment of the shape, size and echogeneicity of the liver. The latter examination was conducted at random, but only with a small percentage of the hospitalized patients diagnosed with diabetes mellitus. The abdominal ultrasonography was carried out by the same experienced specialist, using a Versa Pro apparatus (Siemens, Germany) and a convex 3.0 and 5.0 MHz transducer. We kept to the internationally adopted criteria and scale for echogenicity of the liver parenchyma, the visibility of the diaphragm and the intrahepatic vessels, allowing the diagnosis diffuse increased echogenicity - probable fatty liver. The diagnosis probable NAFLD was suggested in the absence of a history or evidence of hepatitis, other significant hepatobiliary disease, medications that affect the liver or regular alcohol intake (daily> 30 g of concentrate). If there was a positive history of a liver noxious factor, the patient data were not included in the analysis (30 people failed this criterion). Laboratory tests included morning fasting plasma glucose, glycated hemoglobin A1c, serum lipids, liver enzymes (AST, ALT, GGT) - as part of the routine biochemical panels in the Central Clinical Laboratory of UMHAT Alexandrovska - Sofia. All these parameters were measured after at least 12 hours of fasting. Reference values for AST and ALT were 5 to 40 IU/l, and for GGT - <35 IU/L. Blood pressure was determined by an aneroid sphygmomanometer on the dominant arm as mean of two consecutive measurements. The statistical analysis was performed on SPSS 13.0 software program (SPSS Institute, Chicago, IL) and included descriptive statistics, analysis of frequency distribution, cross tables and ANOVA. The level of significance was accepted as p Results The summarized results from the biochemical panel of the participants with diabetes mellitus are presented in table 2. The mean systolic blood pressure was ± 14.2 mm Hg, while the mean diastolic ± 9.7 mm Hg. 11.2% of type 2 diabetic men had ALT > 40 IU/L and 35.0% - GGT> 35 IU/L. The mean index AST/ALT was 0.83 ± 0.31 (minimum 0.45, maximum ) and ratio over 1.0 had 10.0%. 40% of the diabetics had liver steatosis. Subgroup differences (with/without NAFLD) were significant only for the BMI (р=0.027), the diastolic blood pressure (р=0.031), and the GGT-values (р=0.044). The relation between the increasing metabolic parameters and the prevalence of the liver steatosis is presented in table 3. If the diagnostic threshold for NAFLD is 30 UI/L, the sensitivity of ALT is around 29% and that of GGT around 33%. The increase of the threshold lowers the 32

3 sensitivity. Thus, if the threshold for both enzymes is > 60 IU/L, the sensitivity decreases to 5% for ALT and 8% for GGT. Discussion The Non-alcoholic fatty liver disease (NAFLD, NASH) affects a significant proportion of the general population and is associated with a variety of features of the metabolic syndrome. Its role in the progression of atherosclerosis and carcinogenesis has been also demonstrated. Worldwide, more epidemiological data are collected on the prevalence of this type of liver pathology. The reported prevalence among healthy persons is around 16%, 23%, 27%, 32.6% 6,9,19, while among type 2 diabetics - much higher: 49.0% to 69.4% 1,20. S. Jimba et al. established increase in prevalence of NAFLD with the impairment of glucose homeostasis - from 27% in healthy persons to 43% in impaired fasting glycaemia and 62% in newly diagnosed with diabetes type Thus, our data on the prevalence of hepatic steatosis, being 40% in manifested diabetes type 2, are lower than most literature data. So far, the NAFLD prevalence data has been scarce in Bulgaria. Mateva L. et al. found that if non-alcoholic fatty liver is present, the prevalence of metabolic syndrome is between 52% and 76% depending on the used definition, while in the manifested diabetes type %. 3,17 In our study, we paid special attention to the liver enzymes levels. A. Dassanayake et al. reported that the double increase of ALT above the upper normal limit is associated with increased risk of NAFLD. 21 Elevations of ALT, however, are associated with an extensive differential diagnosis, which was reported in detail by C.-H. Chen et al. 22 Despite the fact we used an extremely low threshold criteria - lower than the upper reference limit, our data revealed relatively low sensitivity of increased ALT and GGT for detecting NAFLD - about 20-30%. With the increase of the threshold, sensitivity decreased significantly. A threshold at 1½ times the upper reference limit of both enzymes leads to a decrease in sensitivity below 10%. In a study of S. Zelber-Sagi et al., the sensitivity of the increased ALT is 33

4 NAFLD in Men with Type 2 Diabetes of the same magnitude, compared to the abdominal ultrasonography - 8.2%. 23 From these results it appears obvious that the increase of ALT and GGT is a neither sufficiently sensitive, nor a sufficiently specific criterion for the diagnosis of NAFLD. We were unable to confirm significant differences between subgroups with and without steatosis on the basis of the examined clinical and laboratory parameters - only in terms of BMI, diastolic blood pressure and values of GGT. The literature also does not present convincing evidence of a direct quantitative relationship between NAFLD, obesity, insulin resistance, dyslipidemia and hyperglycemia in both sexes. 4,6,16 Our study poses the question about the use of the abdominal ultrasonography in the diagnosis of NAFLD. Histological examination of liver bioptate remains the gold standard for defining simple steatosis from steatohepatitis with a potential for significant fibrosis or cirrhosis. 19 Fatty infiltration of the liver, however, can be demonstrated with ultrasonography - although not the most accurate, but the most widely available method with sufficiently good specificity. 20 Histological evaluation of liver tissue is indicated primarily in cases of concurrent elevations of AST and at least doubled ALT-values. 24 Among our participants, there were none with a significant increase in all transaminases, thereby no such evaluation was required. When analyzing our data the limitations of our study should be kept in mind. It was conducted with a relatively modest number of participants, selected among hospitalized patients. The exclusion of alcohol or viral genesis of the liver pathology was based mainly on previous history and the available medical records. Conclusions Non-alcoholic fatty liver disease (NAFLD) is associated with increased mortality, cardiovascular morbidity, hepatocellular carcinogenesis and involvement in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus. It is worth focusing research efforts in the direction of NAFLD because of the potentials for treating that liver disease and the scarce available data in Bulgaria. Acknowledgements The authors would like to thank Svetla Kecheva - a nurse at the Endocrinology Clinic, for assistance in data collection. 34

5 Bibliography: 1. El-Zayadi, A.-R. Hepatic steatosis: A benign disease or a silent killer. World J Gastroenterol. 2008; 14(26): Raman M., J. Allard. Nonalcoholic fatty liver disease: A clinical approach and review. Can. J Gastroenterol. 2006; 20(5): Dimitrova, V., A. Alexiev, L. Mateva. Elevated liver enzymes, fatty liver and signs of metabolic syndrome in healthy volunteers. Bulgarian hepatogastroenterology. 2008; 10(2): Leite, N. C., G.F. Salles, A.L.E. Araujo, et al. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver International. 2009; 20(1): Mateva L. Insulin resistance and diabetes in chronic liver disease. Dissertation, Medical University Sofia, Riquelme, A., M. Arrese, A. Soza, et al. Non-alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C-reactive protein in Hispanics. Liver International. 2009; 20(1): Wong, V., A. Hui, S. Tsang, et al. Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics. 2006; 24(8): Ivanova, R., D. Stanchev, A. Alexiev, et al. Cardiovascular risk in non-alcoholic fatty liver disease (NAFLD). Comparative assessment of the risk of IHD according to Framingham risk score in healthy subjects and NAFLD. Bulgarian hepatogastroenterology. 2008; 10(2): Choi, S.-Y., D. Kim, H. Kim, et al. The relation between non-alcoholic fatty liver disease and the risk of coronary heart disease in Koreans. American Journal of Gastroenterology. 2009; 104(8): Donato, F., U. Gelatti, R. Limina, et al. Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence. Oncogene. 2006; 25(27): Targher, G. Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens. Diabetic Medicine. 2007; 24(1): Targher, G., L.Bertolini, R. Padovani, et al. Increased prevalence of cardiovascular disease in Type 2 diabetic patients with nonalcoholic fatty liver disease. Diabetic Medicine. 2006; 23(4): Lingvay, I., P. Raskin, L.S. Szczepaniak. Effect of Insulin and Metformin Combination on Hepatic Steatosis. in Type 2 Diabetes. J Diabetes Complications. 2007; 21(3): Gupte, P., D. Amarapurkar, A. Deepak, et al. Nonalcoholic steatohepatitis in type 2 diabetes mellitus. Journal of Gastroenterology & Hepatology. 2004; 19(8): Jimba, S., T. Nakagami, M. Takahashi, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabetic Medicine. 2005; 22(9): Park, S. H., W.K. Jeon, S.H. KIM, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. Journal of Gastroenterology & Hepatology. 2006; 21(1): Mateva, L., V. Dimitrova, A. Alexiev, C de Mey. Are the healthy clinical research volunteers really healthy? I. Ultrasonography signs of steatosis and metabolic syndrome in healthy volunteers. JCM. 2009; 1: Alberti, K.G., P. Zimmet, J. Shaw. The metabolic syndrome a new worldwide definition. Lancet. 2005, 366(9491), Hubscher, S. Role of liver biopsy in the assessment of non-alcoholic fatty liver disease. European Journal of Gastroenterology & Hepatology. 2004, 16(11): Joy, D., V. Thava, B. Scott. Diagnosis of fatty liver disease: is biopsy necessary? European Journal of Gastroenterology & Hepatology. 2003; 15(5): Dassanayake, A. S., A. Kasturiratne, S. Rajindrajith, et al. Prevalence and risk factors for non-alcoholic fatty liver disease among adults in an urban Sri Lankan population. Journal of Gastroenterology & Hepatology. 2009; 24(7): Chen, C.H.,, M.H. Huang, J.C. Yang, et al. Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan. Journal of Gastroenterology & Hepatology. 2007; 22(9): Zelber-Sagi, S., D. Nitzan-Kaluski, Z. Halpern, et al. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver International. 2006; 26(7): de Ledinghen, V., M. Combes, H. Trouette, et al. Should a liver biopsy be done in patients with subclinical chronically elevated transaminases? European Journal of Gastroenterology & Hepatology. 2004; 16(9):