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1S u zan n a N dr ah a, 2M ar d i S an tos o, 3F en dr a Wician 1 Gastroenterology and Hepatology consultant, Department of Internal Medicine Faculty of Medicine Ukrida Jakarta 2 Metabolic endocrine and Diabetes consultant, Department of Internal Medicine Faculty of Medicine Ukrida Jakarta 3 Department of Internal Medicine Faculty of Medicine Ukrida Jakarta

ABSTRACT Introduction: Approximately 30% of patients with liver cirrhosis also had diabetes mellitus, known as Hepatogenous Diabetes (HD). Insulin resistance and hyperinsulinemia was thought that they have a role in the pathophysiology. The purpose of this study was to evaluate the glucose metabolic disorders in patients with liver cirrhosis in Koja Hospital, and to see the effect of insulin resistance in hepatogenous diabetes. Method: Research that conducted in February-July 2013 was divided into 2 phases. The first phase used an observational design. The inclusion criteria was all liver cirrhosis patients and the exclusion criteria was patients who suffering acute complications. We recorded their nutritional status, child pugh criteria and the results of oral glucose tolerance. Patients who met the DM criteria continued to the second phase, with type 2 diabetes mellitus (T2DM) patients as a control. In the next step, we assessed the difference in average of postprandial plasma glucose (PP2h) / Fasting plasma glucose (FPG) and fasting insulin levels HD with T2DM. Result: We Obtained 24 patients with liver cirrhosis. The majority had normal nutritional status (62.5%), the rest had mild malnutrition (37.5%). The Child Pugh B was largely found (66.7%), the rest was Child Pugh C (25%). Normal glucose tolerance test results was found in 29%, impaired glucose tolerance (IGT) was 25% and hepatogenous diabetes was 46%. From analytic study in the second phase, we obtained the ratio of PP2h/ FPG in patients with HD were 20,5 and T2DM patients were 1,50,4 (p=0,01). Average fasting insulin levels in patients with HD were 10,84,2 IU/mL and T2DM patients were 9,35,3 IU/mL (p=0,5). These results indicated the proportion of HD was higher than previous studies. The ratio of PP2h / FPG was higher in hepatogenous diabetes, and statistically significant. Conclusion: As many as 71% of patients with liver cirrhosis had glucose metabolic disorders, IGT 25% and HD 46%. Effect of insulin resistance and hyperinsulinemia appeared to play a role in hepatogenous diabetes.

Keywords: Hepatogenous diabetes, Type 2 Diabetes Mellitus, The ratio of postprandial plasma glucose / Fasting plasma glucose

PREFACE Approximately 30% of patients with liver cirrhosis (LC) also had diabetes mellitus (DM). DM as a complication of liver cirrhosis known as 'hepatogenous diabetes'.1,2 Insulin resistance in muscle and fat tissue and hyperinsulinemia was thought have a role in the pathophysiology. Disruption of pancreatic beta cell function and hepatic insulin resistance also play a role. 'Hepatogenous diabetes' is a disease that is clinically different from type 2 diabetes mellitus (T2DM), because macroangiopatic complications are rarely seen and patients experienced cirrhosiss chronic complications more frequently. DM increases liver cirrhosis mortality. Treatment is become more complex because it must consider the damage of the liver and its oral hypoglycemic drug hepatotoxicity (OHD). On the other hand, there is a assumption that spread in the community that liver disease requires a high sugar intake. This makes patients with chronic liver disorders will increase his/her sugar intake. Eventhough these patients have been known that they suffer diabetes, they still choose high glucose intake for their liver disease improvement efforts. It is often missed by medical practioners, and may be another factor that complicates the management of DM in liver disease. Not many researchers wrote about the HD. In the early 80s, Budisantoso2 get the DM population in 1981, 25% had impaired glucose tolerance, and 32% had diabetes mellitus. In 1985 Budisantoso3, 4 got that 34.7% had impaired glucose tolerance, and 48.6% had HD. However, subsequent publications on hepatogenous diabetes were difficult to obtain. American Diabetes Association (ADA) 20055 classified DM in 4 groups, there are [1] Type 1 Diabetes Mellitus or Insulin Dependent Diabetes Mellitus / IDDM, [2] Type 2 Diabetes Mellitus or Non-Insulin Dependent Diabetes Mellitus / NIDDM [3] Other Types of Diabetes Mellitus and [4] Gestational Diabetes Mellitus. Other types of Diabetes Mellitus which intended in the classification of ADA 2005 are a genetic defect cell function, genetic defects of insulins work, pancreatic exocrine gland disease, endocrinopatic, drugs or chemicals, infections, uncommon forms of immune-mediated diabetes and other genetic syndromes associated with diabetes. In this classification, there is no longer hepatogenous diabetes (Table 1). The question arises, how the presence of hepatogenous diabetes in the classification of diabetes mellitus today. Table 1. Classification of diabetes mellitus according to ADA 20055
Etiologic Characteristics of Diabetes Mellitus I. Type 1 diabetes ( -cell destruction, usually leading to absolute insulin deficiency) a. Immune mediated b. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. Other specific types A. Genetic defects of -cell function a. Chromosome 12, HNF-1(MODY3) b. Chromosome 7, glucokinase (MODY2) c. Chromosome 20, HNF-4(MODY1)








d. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) e. Chromosome 17, HNF-1 (MODY5) f. Chromosome 2,NeuroD1(MODY6) g. Mitochondrial DNA h. Others Genetic defects in insulin action a. Type A insulin resistance b. Leprechaunism c. Rabson-Mendenhall syndrome d. Lipoatrophic diabetes e. Others Diseases of the exocrine pancreas a. Pancreatitis b. Trauma/pancreatectomy c. Neoplasia d. Cystic fibrosis e. Hemochromatosis f. Fibrocalculous pancreatopathy g. Others Endocrinopathies a. Acromegaly b. Cushings syndrome c. Glucagonoma d. Pheochromocytoma e. Hyperthyroidism f. Somatostatinoma g. Aldosteronoma h. Others Drug- or chemical-induced a. Vacor b. Pentamidine c. Nicotinic acid d. Glucocorticoids e. Thyroid hormone f. Diazoxide g. -adrenergic agonists h. Thiazides i. Dilantin j. -Interferon k. Others Infections a. Congenital rubella b. Cytomegalovirus c. Others Uncommon forms of immune-mediated diabetes a. Stiff-man syndrome b. Antiinsulin receptor antibodies c. Others Other genetic syndromes sometimes associated with diabetes a. Down s syndrome b. Klinefelters syndrome c. Turners syndrome d. Wolframs syndrome e. Friedreichs ataxia f. Huntingtons chorea g. Laurence-Moon-Biedl syndrome


h. Myotonic dystrophy i. Porphyria j. Prader-Willi syndrome k. Others Gestational diabetes mellitus (GDM)

'Hepatogenous diabetes' is a disease that is clinically different from type 2 diabetes mellitus (T2DM). A study comparing HD with T2DM. Obtained the ratio of postprandial plasma glucose / fasting plasma glucose = 2.27 in HD, and 1.69 in T2DM. Fasting insulin in HD 23.2 IU / mL, and 11.6 IU / mL in T2DM. HOMA Insulin Resistance index on cirrhosis type DM 8.38, and 3.52 at DMT2.6 METHOD The study was conducted in Koja Hospital during the period, February 2013 - June 2013. This research was divided into two phases, the first phase used an observational design, and the second phase used analytic. Affordable population was all liver cirrhosis patients who went to Internal Medicine Unit or treated in Koja Hospital. Which made the inclusion of first phase was all liver cirrhosis patients, for second phase was all hepatogenous diabetes patients. Patients were excluded if there was an acute complication, refused to be included, or already suffering hepatoma. All patients who passed the inclusion phase, we recorded their identity, checked their nutritional status (body mass index and mid-arm muscle circumference), recorded their subjective global assessment (SGA), checked their albumin, bilirubin, prothrombin time, oral glucose tolerance tests (OGTT) and fasting insulin in laboratory . Nine people got OGTT results appropriate with hepatogenous diabetes, so the nine subjects were included for second phase studies. At the end of this stage, the patientss nutritional status, child-pugh criteria, and sugar metabolism status (normal, impaired glucose tolerance or hepatohenous diabetes) were concluded. (Subjects were stated hepatogenous diabetes when the result of Postprandial plasma glucose (PP2h) was aboved 200 mg / dl). In second stage, 9 patients was taken from first stage who met the criteria for hepatogenous diabetes and for the control group, 9 T2DM patients were taken with the same sex, and the age range was not more than 5 years difference from hepatogenous diabetes group. Inclusion criteria for the control group was uncontrolled diabetes that was not using oral hypoglycemic drugs or insulin for more than 1 week. In the group of hepatogenous diabetes and type 2 DM, fasting insulin, fasting plasma glucose, post-prandial plasma glucose were examined, and then the ratio of PP2h / FPG was calculated. For univariate analysis, all categories data were presented in n (%) and normally distributed numerical data are presented as mean (SD). Unpaired mean test was used for bivariate analysis to determine differences in the average ratio of PP2h / FPG and fasting insulin levels between groups of hepatogenous diabetes and type 2 DM. The data were processed using a computer with SPSS 20.

RESULT During 5 months period, in February 2013 - June 2013, we got 24 liver cirrhosis patients who met the inclusion criteria. Data characteristics of patients can be seen in Table 2.

Table 2. Characteristis of 24 liver cirrhosis patients in Koja Hospital

Characteristics Sex a. Male b. Female Age a. <40 b. 40-60 c. >60 Clinical findings a. Icteric b. Ascites c. Splenomegaly d. Palmar erithyma e. Caput medusa f. Melena g. Hematemesis h. Encephalohepatic Albumin a. >3.5 mg/dL b. 2.8-3.5mg/dL c. <2.8 mg/dL Bilirubin a. <2 mg/dL b. 2-3 mg/dL c. >3 mg/dL Prothombin time a. <4 s b. 4-6 s c. >6 s BMI a. Under b. Normo c. Overweight d. obese MAMC a. <5 b. 5-15 c. >15 SGA a. SGA A b. SGA B c. SGA C Child Pugh Classification a. A b. B c. C Frequency (n) 15 9 5 11 8 6 20 4 2 1 11 13 2 6 12 6 17 2 5 22 4 6 3 18 2 1 0 9 15 8 8 8 2 16 6 Percentage(%) 62,5 37,5 20,8 45,8 33,4 25 83,3 16,7 8,3 4,2 45,8 54,2 8,3 25 50 25 70,9 8,3 20,8 58,3 16,7 25 12,5 75 8,3 4,2 0 37,5 62,5 33,4 33,3 33,3 8,3 66,7 25

From the 24 patients which were examined, we found that 17 (71%) of patients with liver cirrhosis suffered sugar metabolic disorders, and 7 subjects (29%) had a normal glucose tolerance. From the 17 people, 6 subjects (25% of the total subjects, 35% of 17 subjects) met the criteria for impaired glucose tolerance (IGT) and 11 people (46% of the total subjects, 65% of 17 subjects) were hepatogenous diabetes. Figure 1 showed the proportion of hepatogenous diabetes to all patients with liver cirrhosis.
6 Hepatogenous diabetes (46%) 7 11 IGT (25%) Normal (29%)

Figure 1. Distribution of patients with liver cirrhosis according to the results of oral glucose tolerance test (n = 24) From the 11 subjects who met the criteria of hepatogenous diabetes, we took 9 people to continue into second phase. In second phase, 9 hepatogenous diabetes subjects were compared with 9 T2DM patients, which had the same sex and age range was not more than 5 years. In both groups, we took the data of fasting plasma glucose (FPG), postprandial plasma glucose and fasting insulin. Presence of insulin resistance was assessed by the ratio PP2h / FPG and fasting insulin levels. Figure 2 shows the ratio PP2h / FPG, while Figure 3 shows fasting insulin levels in both groups.
the ratio of PP2h /FPG, 2 1.5 1 0.5 0 HD T2DM 2 1.5 fasting insulin levels (IU/mL) 11 10.5 10 10.8 9.5 9 8.5 HD T2DM 9.3

Figure 2: Average of the ratio PP2h / FPG (p=0,01)

Figure 3: Average of insulin fasting levels in both groups (p=0,5)

From the results of the examination, we obtained the ratio PP2h / FPG in patients with hepatogenous diabetes was 20,5 and T2DM patients was 1,50,4 (p=0,01). Average fasting insulin levels in patients with hepatogenous diabetes was 10,84,2 IU/mL and T2DM was 9,35,3 IU/mL (p=0,5). DISCUSSION In this study, we found that liver cirrhosis was more common in male patients (62.5%), most aged 40-60 years (45.8%), most clinical findings were ascites (83.3%), hematemesis (54.2%), and melena (45.8%). This is consistent with the findings that have been obtained before.7, 8.9 Nutritional status assessment in this study was based on 3 different types of parameters, using BMI, MAMC, and SGA. Based on BMI, we obtained 75% of subjects had an adequate nutrition, malnutrition was 12.5%, and 8.3% was over nutrition. Based on MAMC, 62.5% was obtained had no malnutrition (normal), and 37.5% suffered mildly malnourished. Based on SGA, we obtained 33.3% was manultrition. From these 3 nutrient parameters, we found that nutritional status, which was based on MAMC measurement did not vary much with SGA (37.5% and 33.3%), but when we used the BMI, the results of malnutrition was much lower (12.5%). This difference was due to the bias which were caused by edema and ascites when using BMI, so that MAMC and SGA were preferred over IMT.9, 10,11 Hepatogenous diabetes is generally subclinical, and has a normal fasting glucose level, so the oral glucose tolerance test is necessary to be done to detect a diagnosis.6 From the oral glucose tolerance test results, we obtained 46% of liver cirrhosis patients in Koja Hospital also had diabetes, 25% had impaired glucose tolerance test and only 29% had no other metabolic abnormalities of glucose. Compean6 argued, in liver cirrhosis, he obtained an impaired glucose tolerance up to 96%, and 30% of them were hepatogenous diabetes. On our data, we obtained impaired glucose tolerance as much as 71%, and 65% of them were hepatogenous diabetes. Compared to the Compean data, we had a lower rating for impaired glucose tolerance in overall (71% vs. 96%), but who met the criteria for diabetes were higher (46% of the total subjects, or 65% of total impaired glucose tolerance). Liver plays an important role in the metabolism of carbohydrates, particularly through the process of glycogenogenesis and glycogenolysis. The presence of chronic liver disease, glucose metabolism becomes impaired, there was insulin resistance, glucose intolerance and hepatogenous diabetes. Insulin resistance and hyperinsulinemia are thought as a basic pathophysiology of hepatogenous diabetes. Management of hepatogenous diabetes is slightly different from type 2 DM because in hepatogenous diabetes, rarely found microangiopatic complications, and the importance to anticipate the hepatotoxic effects of oral hypoglycemic drugs. However, in the classification of diabetes according to the ADA 2005, "hepatogenous diabetes" was not explicitly stated as one of others type of DM.5, 6 To determine the existence of hyperinsulinemia, then the insulin levels fasting was examined in all 24 patients. We obtained 17 (70.8%) patients had fasting insulin levels within normal values (2.6 IU/mL-24, 9IU/mL), 4 (16.7%) had low levels (<2.6 IU / mL) and 3 (12.5%) had high fasting insulin levels (> 24.9 IU / mL). Kawaguchi12 recorded as many as 57% of patients with liver cirrhosis showed an increase in insulin resistance. Levels of insulin in patients with hepatogenous diabetes were higher than type 2 DM. Hyperinsulinemia in liver cirrhosis could be due to damage to the liver parenchymal cells, so that the process of degradation of insulin was impaired. In our subjects, hyperinsulinemia was obtained only at 12.5%. In the second phase, mean

of fasting insulin levels mean in hepatogenous diabetes group was compared to the group of type 2 diabetes. We obtained that an average fasting insulin levels in hepatogenous diabetes patients were 10,84,2 IU/mL and in T2DM patients were 9,35,3 IU/mL (p=0,5). These data indicated a relative hyperinsulinemia in hepatogenous diabetes group to the T2DM (10,84,2 IU/mL vs 9,35,3 IU/mL), but apparently this difference was not statistically significant. This was likely due to the lack of large samples, an inappropriate technique of blood sampling, or bad processing techniques of material. Furthermore, the ratio postprandial plasma glucose / fasting plasma glucose was assessed in both groups. The higher ratio PP2h / FPG indicated a failure of insulin to enter glucose into the cells, so that the higher the ratio, the higher the resistance to insulin. In Hepatogenous diabetes, we obtained that ratio PP2h / FPG was 20,5 and 1,50,4 in T2DM (p=0,01). The ratio PP2h / FPG was higher in hepatogenous diabetes, and statistically significant. These data support the existence of a higher insulin resistance in hepatogenous diabetes compared with type 2 DM.

CONCLUSION As many as 71% of liver cirrhosis patients had a glucose metabolism impairment, 65% of them met the hepatogenous diabetes criteria. The influence of insulin resistance and hyperinsulinemia are thought that they have a role in hepatogenous diabetes. PREFERANCE 1. Compean DG, Quintana JOJ, -Gonzalez JAG, -Garza HM. Liver cirrhosis and diabetes: Risk factors, pathophysiology, clinical implications and management. World J Gastroenterol2009 January 21; 15(3): 280-288 2. Boedisantoso AR. Intoleransi glukosa dan gangguan sekresi insulin pada penderita sirosis hepatis post nekrotikum. Dalam: Naskah lengkap symposium diabetes mellitus. Jakarta.1981.hlm.101-111 3. Boedisantoso AR. Fungsi sel beta pancreas pada diabetes mellitus tipe sirosis hati. Tesis. Jakarta 1985. 4. Boedisantoso AR. Penatalaksanaan Diabetes Melitus tipe sirosis hepatis. Seminar Diabetes Melitus. Diea Natalis UI ke 37, Jakarta 1985, in Press. 5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011;34:s62-9. 6. Compean DG, Quintana JOJ, Garza HM. Hepatogenous diabetes. Current views of an ancient problem. Annals of Hepatology 2009; 8(1):13-20 7. Nurdjanah S. Sirosis hati. Dalam : Sudoyo AW, Bambang S, Idrus A, Marcellus S, Siti S. Buku ajar Ilmu Penyakit Dalam Jilid 1. Jakarta: Pusat penerbitan departemen IPD FKUI; 2006 . hlm : 443-6. 8. Kusumobroto HO. Sirosis hati. Dalam: Sulaiman HA, Akbar HN, Lesmana LA, Noer HMS. Buku ajar ilmu penyakit hati. Edisi pertama. Jakarta:Jayabadi; 2007.hlm. 335-45 9. Ndraha S, Simadibrata M. Child Pugh and male gender were related to nutritional status of liver cirrhosis patients in Koja hospital. The Indonesian Journal of Gastroenterology, Hepatology, and Digestive Endoscopy 2009;10(3):110-112

10. Henkel AS, Buchman AL. Nutritional support in patients with chronic liver disease. Nature Clinical Practice Gastroenterology & Hepatology 2006;3:202-9 11. Kalaitzakis E, Olsson R, Henfridsson P, Hugosson I, Bengtsson M, Jalan R. Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis. Liver International 2007;27:1194-201 12. Kawaguchi T, Taniguchi E, Itou M, Sakata M, Sumie S, Sata M. Insulin resistance and chronic liver disease. World J Hepatol 2011; 3(5): 99-107

Name: Suzanna Ndraha Institution: Faculty of Medicine, University of Krida Wacana Jakarta Mailing address: Tebet Timur Dalam Vlll-X no 22 Jakarta selatan Phone/Facs Number: 021-8313072, 02197103012, 085883311441 e-mail: