8. BRIEF RESUME OF THE INTENDED STUDY
8.1 INTRODUCTION
Nonalcoholic fatty liver disease is a chronic liver condition characterized by insulin resistance and hepatic fat accumulation, in the absence of other identifiable causes of fat accumulation, such as Alcohol abuse, Viral hepatitis, Autoimmune hepatitis, Alpha-1 antitrypsin deficiency, medications like corticosteroids and estrogens, and other conditions.
Hepatic steatosis may range from a 'benign' indolent deposition of fat to severe lipo toxicity-induced steatohepatitis with necroinflammation [known as nonalcoholic steatohepatitis (NASH)].NASH is an overlooked complication of Type 2 diabetes mellitus (T2DM) that if missed may carry serious long-term consequences. NASH is frequently associated with fibrosis and approximately 10% of patients develop cirrhosis. The risk of hepatocellular carcinoma is also increased in patients with T2DM and NASH.
Diabetes, Dyslipidemia, Hypertension, and Cardiovascular disease (CVD) occur more frequently in individuals with NAFLD.NAFLD may also be associated with a greater risk of renal disease in patients with T2DM.Health care costs have been long suspected to be higher in NASH patients.
Fatty liver or hepatic steatosis is characterized by diffuse accumulation of fat in hepatocytes. Fatty liver occurring in individuals without a history of significant alcohol intake is termed as non-alcoholic fatty liver disease (NAFLD).The natural history of NAFLD ranges from pure steatosis to steatohepatitis to cirrhosis and in some patients to hepatocellular carcinoma. NAFLD is strongly associated with obesity, Type-2 diabetes mellitus and hyperlipidema. Numerous studies show that it is hepatic component of metabolic syndrome whose central features are peripheral insulin resistance, obesity, hyperinsulinemia, hypertriglyceridemia and hypertension.
It has been reported that fatty liver influences the severity of hepatic insulin resistance in Type-2 diabetes mellitus. the hepatic fat content predicts the amount of daily insulin needed to maintain adequate glycemic control. NAFLD is a type of chronic liver disorder which is gaining significant importance worldwide. It is now recognized as the most common liver disorder in the United States with an estimated prevalence of 30% in the general population.
8.2 NEED FOR THE STUDY
Though the prevalence of liver enzyme abnormalities in patient with Type 2 Diabetes Mellitus ranges from 7.8% to 22.9 %,1 the prevalence of NASH in these patients largely remains unknown, as it is generally an asymptomatic disorder, with liver biopsy being the only means of its detection which would not be routinely done unless indicated. We propose to conduct a prospective study to find out the prevalence of NAFLD and in particular NASH in patients with Type 2 DM and find the risk factors for predicting the same.
8.3 REVIEW OF LITERATURE
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterized histologically by macro vesicular hepatic steatosis and occurs in those who do not consume alcohol in amounts generally considered to be harmful to the liver.NAFLD includes both nonalcoholic fatty liver, and non-alcoholic steatohepatitis (NASH), with or without varying degrees of fibrosis and cirrhosis. Cross-sectional studies in patients with NASH have shown that 30-40% of patients have advanced liver fibrosis at the time of presentation, whereas 10-15% have established cirrhosis.2
Progression of liver fibrosis has been demonstrated in a third of patients with NASH, with a proportion of patients progressing to end stage liver disease and hepatocellular carcinoma.3 The incidence of Type 2 DM is increasing throughout the world, reaching levels of a pandemic in countries like India and China.4 Only recently has liver disease been recognized as a major complication of type 2 DM with standard mortality rates for cirrhosis greater than that for cardiovascular disease. Insulin resistance (IR) plays the central pathogenesis role in both type 2 DM and NAFLD with the latter being considered as the hepatic manifestation of the metabolic syndrome.
Only recently has liver disease been recognized as a major complication of Type 2 DM with standard mortality rates for Cirrhosis greater than that for cardiovascular disease.5 Insulin resistance (IR) plays the central pathogenesis role in both Type 2 DM and NAFLD with the latter being considered as the hepatic manifestation of the metabolic syndrome.6
8.4 AIM AND OBJECTIVES OF THE STUDY
AIM: Main aim of the study is to know the risk factors for Nonalcoholic fatty liver disease and Nonalcoholic steatohepatitis in patients of Type 2 Diabetes Mellitus.
OBJECTIVE: To determine the Prevalence of Nonalcoholic fatty liver disease and Nonalcoholic steatohepatitis in patients with Type 2 Diabetes Mellitus.
9. MATERIALS AND METHODS.
9.1 SOURCES OF COLLECTION OF DATA
The cases for the study were selected from all patients with Type 2 diabetes mellitus diagnosed by standard criteria above the age of 40 years who attended the M.S.Ramaiah Hospital. The study shall be PROSEPECTIVE OBSERVATIONAL STUDY, where continuous data will be enumerated who fulfills the inclusion criteria. This study will be conducted between October 2010-October 2012.
Patients satisfying the inclusive criteria will be enrolled in this study, after providing written informed consent, a thorough medical history and physical examination will be performed for each individual, which included measurements of weight and height.BMI was calculated as a measure of obesity, whereas waist/hip ratio was measured as an index of splanchnic fat accumulation. After an over-night fast, serum samples were obtained from all subjects for liver function tests (aspartateamino-transferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase), serum lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol [HDL-C] and low-density lipoprotein cholesterol [LDL-C]), fasting blood glucose (FBS) serum insulin level and hemoglobin A1c (HbA1c).
Overweight was defined as a body mass index (BMI) between 23 and 25 kg/m2, and obesity as BMI equal or above 25 kg/ m2.7 Patients were considered centrally obese if the waist circumference was greater than 80 cm in females and 90 cm in males.15 Patients with one of the criteria: LDL-C 100 mg/dL, total cholesterol 200 mg/ dL, triglycerides 150 mg/dL, or HDL-C < 40 mg/dL in males and <50 mg/dL in females were considered to have dyslipidemia.8
Homeostasis Model Assistant–Insulin Resistance (HOMA-IR) and Quantitative Insulin Sensitivity check Index (QUICKI) were calculated as measures of insulin resistance and sensitivity using following formula:
HOMA-IR= [fasting insulin (µU/ml) ×fasting glucose (mmol/l)]/22.5
QUICKI=1/ [log (fasting insulin (µU/ml)) ± log (glucose (mg/dl))]
All subjects underwent abdominal ultrasonography by the radiologist for evidence of fatty liver disease. Based on ultrasonographic findings (diffuse increase in echogenicity as compared to that of the spleen or renal cortex).
9.2 STATISTICAL ANALYSIS AND RESULTS
Sample size was estimated using nMaster software to access the single proportion (proportion of NAFLD and NASH among Type 2 Diabetes mellitus) where
Expected proportion - 0.44(44%) 9
Relative proportion - 20 % 9
Confident interval - 95% (alpha=5%) 9
From the above sample size was estimated to be 122.
9.3 INCLUSION CRITERIA
1. Patients of age above 40 years with Type 2 diabetes mellitus on oral hypoglycemic drugs.
9.4 EXCLUSION CRITERIA
1. Any quantity of alcohol consumption based on careful history.
2. Usage of drugs known to cause steatosis is including Amiodarone, Corticosteroids, Tamoxifen, Methotrexate and high dose Estrogen.
3. Significant co-morbidities precluding a liver biopsy
4. History of jejunoileal bypass or extensive small bowel resection.
5. Patients with Type 2 diabetes mellitus on insulin therapy.
9.5 FOLLOWING INVESTIGATIONS WILL BE REQUIRED
1. Careful History
2. Anthropometric Measurements
3. Fasting Blood Sugar & Post Lunch Blood Sugar
4. HBA1C
5. Fasting Lipid Profile
6. Fasting insulin level
7. HBsAg, antiHCV & TSH
8. Liver Function Test
9. Ultrasonography Scan of Abdomen
9.6 DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS?
Yes, as given in 9.5. All these investigations are routinely done and the cost will be borne by the patient himself. Informed consent will be taken. No animal study required.
9.7 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION.
Yes (Copies enclosed)
10. LIST OF REFERENCES:
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2) Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease.
Gastroenterology 2002; 123:1705-25.
3) Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural histor y of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004; 40:820-26.
4) Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-53.
5) Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123:1705-25.
6) Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N: Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50:1844-50.
7) C h a m u k u t t a n S n e h a l a t h a , V i j a y V i s w a n a t h a n , A m b a d y Ramachandran,: Cutoff values for normal anthropometric variables in Asian Indian adults. Diabetes Care 2003; 26: 1380-4.
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9) Merat S, Yadahmadi S, Tahaghoghi S, Alizadeh Z, Sedighi N, Mansournia N, Ghorbani A, Malekzaden R. Prevalence of Fatty liver disease among Type 2 Diabetes Mellitus patients and its relation to insulin resistence;Middle East J of Digestive disease.2009; 1(2):74-79.
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11) Singh SP. Non alcoholic fatty liver disease. The unfolding monster? editorial. J Gastroenterol Hepatol 2006; 21: 199 – 201.
12) Maheshwari A, Thuluvath PJ. Cryptogenic cirrhosis and NAFLD: are they related. Am J Gastroenterol 2006; 101: 664 – 68.
13) Harrison SA, Torgerson S, Hayashi PH. The natural history of non-alcoholic fatty liver disease a clinicohistopathological study. Am J Gastroenterol 2003;98:2042– 47.
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