1. Nonalcoholic fatty liver disease in Patients of Primary Hypothyroidism Dr Madhukar Mittal MD, DM Asst. Professor Endocrine Unit, Department of Medicine King George Medical University (earlier CSMMU) Lucknow, India

2. Background Several endocrine disorders are known to have increased risk for Nonalcoholic fatty liver diseae (NAFLD) –Diabetes mellitus –Hypothyroidism –Adrenal insufficiency –GH deficiency –PCOS

3. NAFLD spectrum Simple steatosis Inflammatory steatohepatitis (NASH) Fibro-fatty Liver (Increasing levels of fibrosis) Cirrhosis

4. NAFLD Prevalence NAFLD –20% and 30% in Western adults 1,2 –90% in the morbidly obese 3 NASH (the more advanced form of NAFLD) –2–3% in the general population 4 –16 and 37% in the morbidly obese 3 1 Browning JD et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387 2 Bedogni G et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005;42:44 3 Machado M et al. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 2006;45:600–6 4 Neuschwander-Tetri BA et al. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003;37:1202

5. Aims and Objectives Study to see for prevalence of NAFLD in patients of primary hypothyroidism To evaluate metabolic parameters in this group of patients with NAFLD

6. Material and Methods Consecutive primary hypothyroid patients Tested for antibodies against thyroid peroxidase (TPO) and thyroglobulin (TG) Insulin resistance assessed –Fasting insulin –Homeostasis model assessment of insulin resistance (HOMA-IR) –Quantitative insulin-sensitivity check index (QUICKI)

7. USG grading USG abdomen done by two radiologists to grade fatty liver Jain KA et al. Spectrum of CT and sonographic appearance of fatty infiltration of the liver. Clin Imaging 1993;17:162 Saadeh S et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745 Tchelepi H et al. Sonography of diffuse liver disease. J Ultrasound Med 2002; 21: 1023 Zwiebel WJ. Sonographic diagnosis of diffuse liver disease. Semin Ultrasound CT MR 1995;16:8 Feature at USGScore Liver echogenicity exceeds that of renal cortex and spleen1 Attenuation of the ultrasound wave1 Loss of definition of the diaphragm1 Poor delineation of the intrahepatic architecture1 Total Maximum Score4

8. NAFLD diagnosis NAFLD defined as –USG score >2 –Fatty liver not resulting from Excessive alcohol consumption (>20 grams/day) Drugs/Toxins (tamoxifen, methotrexate, amiodarone etc) Infectious diseases (viral hepatitis etc) Any other identifiable exogenous causes (Wilson disease, Hemochromatosis, α-1 antitrypsin deficiency etc)

9. Statistical Analysis Data presented as mean + SD, median (interquartile range) or N (%) Distribution of continuous data tested for normality –Kolmogorov- Smirnov test Comparing between groups for continuous variable –Student T test –Mann Whitney test for non-uniformly distributed data Comparing categorical data –Chi square test or Fisher exact test A two tailed p value <0.05 regarded as significant Statistical software SPSS15.0 (SPSS, Chicago, IL)

10. Results

11. Baseline Characteristics ParametersValues N71 Females, n (%)64 (90.1) Age (yr)37.7 + 13.2 Age at diagnosis (yr)35.4 + 13.1 BMI (Kg/m 2 )26.6 + 6.1 TPO/TG positive, n (%)60 (84.5) TPO and TG, n (%)39 (54.9)

12. Comaparison of thyroid antibody postive vs. antibody negative patients ParametersTPO/TG +ve (N=60) TPO/TG –ve (N=11) P value Age (yr)36.2+13.046.0+14.10.024 Age at diagnosis (yr)32.1+12.544.0+13.70.021 Fasting Insulin (μIU/ml)12.47+7.116.27+2.920.014 HOMA-IR2.90+1.721.30+0.770.010 QUICKI0.345+0.0450.393+0.0770.033 BMI (Kg/m 2 )26.1+5.425.4+6.40.738 FBS (mg/dl)92.1+19.180.0+15.90.126 PPBS (mg/dl)129.7+23.5123.4+17.50.510 TG (mg/dl)149.9+55.1153.9+60.00.867 VLDL (mg/dl)27.9+9.529.6+12.30.694 HDL (mg/dl)40.9+12.248.3+12.30.154

13. NAFLD characteristics ParametersN% No of patients3245.1 Females32100 Grade 11753.1 Grade 21443.8 Grade 313.1

14. NAFLD positive vs. NAFLD negative patients ParametersNAFLD Present (N=32) NAFLD Absent (N=39) P value BMI (Kg/m 2 )27.6+4.424.6+5.60.046 SBP (mm of Hg)131.3+14.5124.7+10.40.038 DBP (mm of Hg)77.3+10.578.1+12.80.778 SGOT/AST (U/L)42.2+15.836.2+13.30.104 SGPT/ALT (U/L)41.0+17.337.4+17.00.629 TG (mg/dl)174.5+74.4146.4+79.50.146 VLDL (mg/dl)30.6+10.725.9+7.90.043 HDL (mg/dl)38.8+10.546.0+11.80.012 FBS (mg/dl)98.2+26.687.2+16.40.041 PPBS (mg/dl)147.4+58.1124.7+20.20.029 Fasting Insulin (μIU/ml)12.4+6.210.1+7.50.272 HOMA-IR2.99+1.652.18+1.670.103 QUICKI0.339+0.0360.369+0.0670.102 TPO or TG +ve, n (%)28320.743

15. Discussion

16. NAFLD Non-alcoholic fatty liver disease affects all ethnic groups Prevalence higher in Hispanic and European Americans compared with African-Americans

17. NAFLD prevalence in India SettingN (M/F)AgeCriteriaPrevalenceRisk Factors Amarapurkar D et al. Annals of Hepatology 2007 Population730 (341/389) >20yrUSG18.9% (M/F 24.6%/13.6%) Age>40 Male Central Obesity BMI>25 Increased FBS Uchil D et al. JAPI 2009 Hospital1003 (565/438) 18-60yrUSG22.6% (M/F 29%/13.9%) waist circumference TG, Low HDL- c, Blood pressure, FBS Singh SP et al. Trop Gastroenterol 2004 Population159USG24.5% (M/F 26.9%/13.8%) BMI NAFLD was seen in around half of hypothyroid patients

18. Chung GE et al. 2324 cases of hypothyroidism (overt and subclinical) NAFLD based on USG 62% female NAFLD prevalence 30.2% Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol. 2012 Jul;57(1):150-6

19. Thyroid antibody positivity Thyroid antibody positivity correlated with higher markers of insulin resistance ParametersTPO/TG +ve (N=60) TPO/TG –ve (N=11) P value Age (yr)36.2+13.046.0+14.10.024 Age at diagnosis (yr)32.1+12.544.0+13.70.021 Fasting Insulin12.47+7.116.27+2.920.014 HOMA-IR2.90+1.721.30+0.770.010 QUICKI0.345+0.0450.393+0.0770.033 Low normal FT4 levels were significantly associated with increased insulin resistance Roos A et al. J Clin Endocrinol Metab 2007;92(2):491

20. NAFLD in hypothyroidism and metabolic characteristics Patients who had NAFLD had higher systolic blood pressure and deranged metabolic parameters (higher BMI, FBS, PPBS, VLDL and low HDL) ParametersNAFLD Present (N=32) NAFLD Absent (N=39) P value BMI (Kg/m 2 )27.6+4.424.6+5.60.046 SBP (mm of Hg)131.3+14.5124.7+10.40.038 VLDL30.6+10.725.9+7.90.043 HDL38.8+10.546.0+11.80.012 FBS98.2+26.687.2+16.40.041 PPBS147.4+58.1124.7+20.20.029 Fasting Insulin12.4+6.210.1+7.50.272 HOMA-IR2.99+1.652.18+1.670.103 QUICKI0.339+0.0360.369+0.0670.102

21. Health ABC study. Waring CA et al. Clin Endocrinol 2012;76(6):911 2119 patients 684 initially identified with metabolic syndrome Higher TSH levels and subclinical hypothyroidism with TSH>10 mIU/L significantly associated with prevalent metabolic syndrome Each unit increase in TSH associated with 3% increase in odds of prevalent metabolic syndrome Thyroid function and prevalent and incident metabolic syndrome in older adults: the health, ageing and body composition (Health ABC) study. Warin CA et al. Clin Endocrinol 2012;76(6):911

22. Conclusion NAFLD seen in nearly half of primary hypothyroid patients Insulin resistance higher in thyroid antibody positive patients NAFLD associated with increased clustering of parameters of metabolic syndrome

23. Limitations Histopathology (Liver Biopsy) not done –USG cannot differentiate between Simple Steatosis and NASH Larger sample size needed

24. Future Course Ongoing study Currently 142 patients included Noninvasive markers for liver cirrhosis –AST to platelet ratio index (APRI) –AST/ALT ratio (AAR) –BARD score

25. Acknowledgement Dr Neha Jain Dr Anit Parihar Dr Vivek Kumar Dr Ravi Misra Dr AK Vaish

26. Thank You King George Medical University, Lucknow

28. S No Female (n=64)Male (n=7)P value Age of patient 37.18+12.9342.14+15.52.352 Age at diagnosis34.64+12.8141.57+15.16.191 BMI27.23+6.0421.75+4.28.020 height152.54+7.45162+8.87.001 weight63.48+15.0357.85+12.28.346 Systolic BP128.92+14.07125.14+13.26.502 Dystolic BP78.21+10.8881.71+24.21.498 Initial TSH33.66+48.0622.03+20.98.532 TPO807.06+890.20275.02+509.44.163 TG202.44+316.3466.64+82.92.060 S. bilirubin1.06+2.001.01 +0.45.945 SGOT44.50+29.5933.00+6.24.313 SGPT47.78+44.1632.14+6.25.357 SALP194.17+101.14190.85+58.94.933 CHO189.77+46.58178.42+61.75.563 TG155.69+55.87179.57+107.79.353 LDL108.69+42.30103.50+22.48.770 HDL42.13+11.6942.28+10.09.970 VLDL28.77+9.5827.29+9.50.702 Fasting insulin12.78+7.938.37+3.13.153 Fasting blood sugar90.28+18.3691.42+15.93.876 Post prandial sugar127.86+20.75134.42+23.03.441 Platelet count1.66+0.681.58+0.75.803 MCV85.15+8.5888.84+11.29 MCH27.78+3.6830.57+4.04 MCHC31.79+2.2133.71+2.14 MMSE27.02+2.0028.00+1.15.211 HAMD14.64+6.0713.00+5.48.499 SGOT/SGPT=AAR1.11+0.391.05+0.24.719 BARD2.21+0.872.00+1.00.555 AST/platelet=APRI1.85+1.461.31+0.72.335 HOMA2.75+1.831.97+0.96.278 33.QUICKI1.52+0.321.40+0.16.348

29. NASH was first coined by Ludwig et al. in 1980 the prevalence of NAFLD has risen rapidly in parallel with the dramatic rise in population levels of obesity and diabetes, resulting in NAFLD now representing the most common cause of liver disease in the Western world