Prevalence of Non Alcoholic Fatty Liver Disease (NAFLD) in obese and non-obese Hypothyroid subjects Prof. Sandeep Garg Department of Medicine Maulana Azad Medical College New Delhi INDIA

INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) - most common cause of chronic liver disease in developed countries (prevalence of 20–30% in the adult population). NAFLD in children related to the increasing rates of childhood obesity worldwide 1 Non alcoholic steatohepatitis (NASH) is currently the third leading indication for liver transplantation (LT) in the United States 2 Advanced age, diabetes type 2, impaired glucose tolerance, and obesity, are risk factors for NAFLD. It is anticipated that cirrhosis due to these conditions may surpass other causes of cirrhosis in a near future. 1. Dunn W, Schwimmer JB. The obesity epidemic and nonalcoholic fatty liver disease in children. Curr Gastroenterol Rep. 2008; 10:67– Wong R, Cheung R, Ahmed A. Nonalcoholic Steatohepatitis Is the Most Rapidly Growing Indication for Liver Transplantation in Patients With Hepatocellular Carcinoma in the U.S. Hepatology.2014.;59(6):

Pathogenesis of NAFLD : Excess of lipid accumulation within the liver and equilibrium between synthesis and utilisation gets deranged. A three-hit hypothesis has been proposed. - The first hit involves the accumulation of lipid in liver. - The second hit-initiation of an inflammatory response and the cell death.- hallmark - The third hit is a defective repair and regenerative response. Diagnosis of NAFLD - evidence of hepatic steatosis on imaging or histology, and other causes of liver disease or steatosis have been excluded.

Ultrasonography detects fatty liver if more than 33% steatosis is there which appears as a diffuse increase in hepatic echogenicity, or “bright liver”., USG offers a fairly accurate diagnosis of moderate-to-severe hepatic steatosis, with reported sensitivity ranging from 81.8% to 100.0% and specificity as high as 98%. * Liver biopsy still remains the ‘golden standard’ for confirming or excluding the diagnosis of NASH * Lee SS, Park SH, Kim HJ, Kim SY, Kim MY, Kim DY, Suh DJ, Kim KM, Bae MH, Lee JY, Lee SG, Yu ES. Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations. J Hepatol. 2010; 52:

NAFLD - >5% of hepatocytes are steatotic in patients who do not consume excessive alcohol consumption (<20 g/day for women and <30 g/day for men) - simple steatosis (fat without hepatic inflammation or hepatocellular injury- seen in 70-90%) - steatohepatitis (fat with hepatocellular injury and inflammation 10-30%- NASH) - NASH  (25-40%) Hepatic fibrosis  Cirrhosis of Liver (20-30%)* * Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–74.

The thyroid gland is significantly involved in energy homeostasis, lipid and carbohydrate metabolism, regulation of body weight and adipogenesis. In a clinical setting, subclinical hypothyroidism has been associated with metabolic syndrome, cardiovascular mortality and disturbance of lipid metabolism * Hypothyroidism is a treatable condition and if it is a risk factor factor for NAFLD this can be useful in preventing the progression to NASH and subsequently to CLD. * Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA.2010; 304:

The present presentation is the part of the study where prevalence of NAFLD was seen in non obese, non diabetic hypothyroid patient. We want to see that whether some other mechanism, other than insulin resistance are the cause of the NASH and finally NAFLD in the hypothyroid patients

Aim: To find out the prevalence of NAFLD in Obese and Non obese hypothyroid patients. Type of study: Prospective analytical study Study Area: Department of Medicine in Maulana Azad Medical College associated with LokNayak Hospital. Study population: Patients were selected from Endocrinology clinic from Dec 2014 to May A total of 41 patients were selected.

Inclusion criteria: All diagnosed hypothyroid patient for more than 2 years with a serum TSH>5.5mIU/L with or without treatment. Exclusion Criteria: Diabetic patients( as per ADA criteria) Patients with hypertension BP >130/80mm Hg Alcohol consumption of > 20 gm/ day for men and > 10gm / day for women. Past history of jaundice On going pregnancy and post-partum female Patients on drugs causing dyslipidemia Patients on steatohepatic drug intake (tamoxifen, glucorticoids, isoniazid, amiodarone, methotrexate)

MATERIALS AND METHODS 41 subjects were chosen who were diagnosed as a case of hypothyroidism TSH > 5.5 mIU/L. A written and informed consent was taken from each patients. They were divided into two groups based on their BMI. The non obese group included subjects with BMI < 28.5kg/m 2 and the obese were the pateints with BMI of > 28.5 kg/m 2. Both the groups were subjected to the blood tests including complete hemogram, KFT’s, LFT’s, complete lipid profile total serum protein and albumin, serum electrolytes and ultrasonography for the diagnosis of NAFLD.

Patients were asked to come early morning fasting for blood investigations and abdominal ultrasonography. The ultrasonographer was unaware of the patient’s medical history and the study group in which they were enrolled. A positive case was diagnosed with diffusely increased echogenicity (“bright”) in liver greater than kidney, with vascular blurring, and deep attenuation of ultrasound signal. Data collected was tabulated and a detailed descriptive analysis was done. - Statistical analysis was performed using SPSS 22.0 version. - A p values of <0.05 was considered significant. - Person correlation co-efficient was used to correlate the variables

RESULTS Out of 41 patients these there were 20 obese and 21 non obese subjects. The results are shown in table no.1 The prevalence of NAFLD in these 41 subjects was 56.09%. The prevalence of NAFLD in non-obese hypothyroid subjects was 47.6% as compared to 65% in the obese subjects.

Table no. 1 Baseline characteristics and prevalence of NAFLD Non Obese (21)Obese(20) Age yr36.14± ±2.21 Gender, female n(%)17(80.9)16(80) BMI(kg/m 2 )24.90± ±0.47 ALT (IU/L)36.19±4.5847±3.08 AST(IU/L)38.04± ±3.08 Total Cholesterol(mg/dl)171± ±9.45 HDL(mg/dl)40.9± ±0.73 LDL(mg/dl)129± ±7.883 Triglyceride (mg/dl)152± ±9.89 S TSH (mIU/L)15.68± ±3.15 NAFLD, n(%)10 (47.6)13(65)

Hypothyroidism and NAFLD The prevalence of NAFLD in these 41 subjects was 56.09%. The prevalence in non-obese and obese was 47.6% and 65% respectively. The USG grading for NALFD were positively correlated with increasing S TSH values in both obese as well as non obese subjects r(18)=0.64 and r (19)= 0.733, p<0.05 respectively. The USG grading for NAFLD correlated positively with increasing BMI in the obese hypothyroid subjects r(18)= with p<0.05. However no correlation to BMI and USG grading was found in non-obese group

LFT’s and Hypothroidism The prevalence of abnormal ALT> 40 IU/L was 14.28% in non-obese and 55% in obese. Increasing ALT levels were significantly correlated with increasing S TSH ( r= 0.604, p=0.04) and BMI (r=0.719, p=0.01) in obese subjects. Among the subjects with ultrasonographically diagnosed NAFLD the prevalence of abnormal ALT was 30% in the non obese and 76.9% in the obese subjects.

Lipid profile and Hypothyroidism The mean Total cholesterol, LDL and triglycerides levels were higher in obese as compared to non-obese subjects (table no. 1). The triglyceride and the total cholesterol showed a significant positive correlation with increasing BMI amongst the obese subjects Table no. 2 : Correlation r( 18 ) values OF lipid profile in hypothyroid obese subjects with BMI. ( r /p values) BMI kg/m 2 LDL0.64(p<0.05) T cholesterol0.52(p<0.05) Triglyceride0.44 (p<0.05)

The deranged LDL showed a positive significant correlation with increasing S. TSH in hypothyroid obese subjects. There was positive correlation TG as well as total cholesterol levels with increasing TSH. However it was not significant. Table no. 3 : Correlation r( 18 ) values OF lipid profile in hypothyroid obese subjects with Serum TSH. TSH LDL r(18)= 0.7 (p=.001) T cholesterol r(18)= 0.39 (p=.08) Triglyceride ( r(18) =0.50 (p=.07)

Conclusion and Summary Our study showed that there is a high prevalence of NAFLD in hypothyroid subjects more so in obese hypothyroid subjects. Hypothyroidism leads to obesity which further increases the risk of NAFLD. The findings of fatty liver on USG were positively correlating with the increasing serum TSH levels. Our study results were in consensus with the study done by A. Eshraghian et al 34 where it was shown that elevated serum ALT levels was an independent predictors of NAFLD in hypothyroid patients.

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Possible mechanisms of liver dysfunction in Hypothyroidism Hypothyroidism leads to an increased risk of hyperlipidemia 38 which leads to increased fatty acid oxidation and hepatic output of triglycerides leading to altered lipid peroxidation 39 which further leads to liver cell damage. Decreased thyroid function is also associated with insulin resistance, which is a hallmark of hepatic steatosis, as well a as feature of the metabolic syndrome

limitations The sample size was small to find more correlation between USG findings and dyslipidemia. Our diagnosis of NAFLD was based on USG findings however liver biopsy is need for confirmation therefore the prevalence might even be higher as USG cannot detect steatosis below 30%.

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World J Gastroenterol Jul 7; 20(25): 8102–8109. Published online 2014 Jul 7. doi: