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

Background

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

NAFLD spectrum

• Simple steatosis• Inflammatory steatohepatitis (NASH)• Fibro-fatty Liver (Increasing levels of fibrosis)• Cirrhosis

NAFLD Prevalence

• NAFLD– 20% and 30% in Western adults1,2

– 90% in the morbidly obese3

• NASH (the more advanced form of NAFLD)– 2–3% in the general population4

– 16 and 37% in the morbidly obese3

1Browning JD et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:13872Bedogni G et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005;42:443Machado M et al. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 2006;45:600–64Neuschwander-Tetri BA et al. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003;37:1202

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

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)

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;17:162Saadeh 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: 1023Zwiebel WJ. Sonographic diagnosis of diffuse liver disease. Semin Ultrasound CT MR 1995;16:8

Feature at USG Score

Liver echogenicity exceeds that of renal cortex and spleen 1

Attenuation of the ultrasound wave 1

Loss of definition of the diaphragm 1

Poor delineation of the intrahepatic architecture 1

Total Maximum Score 4

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)

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)

Results

Baseline Characteristics

Parameters ValuesN 71

Females, n (%) 64 (90.1)

Age (yr) 37.7 + 13.2

Age at diagnosis (yr) 35.4 + 13.1

BMI (Kg/m2) 26.6 + 6.1

TPO/TG positive, n (%) 60 (84.5)

TPO and TG, n (%) 39 (54.9)

Comaparison of thyroid antibody postive vs. antibody negative patients

Parameters TPO/TG +ve(N=60)

TPO/TG –ve(N=11)

P value

Age (yr) 36.2+13.0 46.0+14.1 0.024

Age at diagnosis (yr) 32.1+12.5 44.0+13.7 0.021

Fasting Insulin (μIU/ml) 12.47+7.11 6.27+2.92 0.014

HOMA-IR 2.90+1.72 1.30+0.77 0.010

QUICKI 0.345+0.045 0.393+0.077 0.033

BMI (Kg/m2) 26.1+5.4 25.4+6.4 0.738

FBS (mg/dl) 92.1+19.1 80.0+15.9 0.126

PPBS (mg/dl) 129.7+23.5 123.4+17.5 0.510

TG (mg/dl) 149.9+55.1 153.9+60.0 0.867

VLDL (mg/dl) 27.9+9.5 29.6+12.3 0.694

HDL (mg/dl) 40.9+12.2 48.3+12.3 0.154

NAFLD characteristics

Parameters N %No of patients 32 45.1

Females 32 100

Grade 1 17 53.1

Grade 2 14 43.8

Grade 3 1 3.1

NAFLD positive vs. NAFLD negative patientsParameters NAFLD Present

(N=32)NAFLD Absent

(N=39)P value

BMI (Kg/m2) 27.6+4.4 24.6+5.6 0.046

SBP (mm of Hg) 131.3+14.5 124.7+10.4 0.038

DBP (mm of Hg) 77.3+10.5 78.1+12.8 0.778

SGOT/AST (U/L) 42.2+15.8 36.2+13.3 0.104

SGPT/ALT (U/L) 41.0+17.3 37.4+17.0 0.629

TG (mg/dl) 174.5+74.4 146.4+79.5 0.146

VLDL (mg/dl) 30.6+10.7 25.9+7.9 0.043

HDL (mg/dl) 38.8+10.5 46.0+11.8 0.012

FBS (mg/dl) 98.2+26.6 87.2+16.4 0.041

PPBS (mg/dl) 147.4+58.1 124.7+20.2 0.029

Fasting Insulin (μIU/ml) 12.4+6.2 10.1+7.5 0.272

HOMA-IR 2.99+1.65 2.18+1.67 0.103

QUICKI 0.339+0.036 0.369+0.067 0.102

TPO or TG +ve, n (%) 28 32 0.743

Discussion

NAFLD

• Non-alcoholic fatty liver disease affects all ethnic groups

• Prevalence higher in Hispanic and European Americans compared with African-Americans

NAFLD prevalence in India

Setting N (M/F) Age Criteria Prevalence Risk Factors

Amarapurkar D et al. Annals of Hepatology 2007

Population 730 (341/389)

>20yr USG 18.9%(M/F 24.6%/13.6%)

Age>40MaleCentral ObesityBMI>25Increased FBS

Uchil D et al. JAPI 2009

Hospital 1003 (565/438)

18-60yr USG 22.6%(M/F 29%/13.9%)

waist circumference TG, Low HDL-c, Blood pressure, FBS

Singh SP et al. Trop Gastroenterol 2004

Population 159 USG 24.5% (M/F 26.9%/13.8%)

BMI

NAFLD was seen in around half of hypothyroid patients

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

Thyroid antibody positivity

Thyroid antibody positivity correlated with higher markers of insulin resistance

Parameters TPO/TG +ve(N=60)

TPO/TG –ve(N=11)

P value

Age (yr) 36.2+13.0 46.0+14.1 0.024

Age at diagnosis (yr) 32.1+12.5 44.0+13.7 0.021

Fasting Insulin 12.47+7.11 6.27+2.92 0.014

HOMA-IR 2.90+1.72 1.30+0.77 0.010

QUICKI 0.345+0.045 0.393+0.077 0.033

• Low normal FT4 levels were significantly

associated with increased insulin resistance

Roos A et al. J Clin Endocrinol Metab

2007;92(2):491

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)

Parameters NAFLD Present(N=32)

NAFLD Absent (N=39)

P value

BMI (Kg/m2) 27.6+4.4 24.6+5.6 0.046

SBP (mm of Hg) 131.3+14.5 124.7+10.4 0.038

VLDL 30.6+10.7 25.9+7.9 0.043

HDL 38.8+10.5 46.0+11.8 0.012

FBS 98.2+26.6 87.2+16.4 0.041

PPBS 147.4+58.1 124.7+20.2 0.029

Fasting Insulin 12.4+6.2 10.1+7.5 0.272

HOMA-IR 2.99+1.65 2.18+1.67 0.103

QUICKI 0.339+0.036 0.369+0.067 0.102

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

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

Limitations

• Histopathology (Liver Biopsy) not done– USG cannot differentiate between Simple Steatosis

and NASH

• Larger sample size needed

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

Acknowledgement

• Dr Neha Jain• Dr Anit Parihar• Dr Vivek Kumar• Dr Ravi Misra• Dr AK Vaish

Thank You

King George Medical University, Lucknow

S No Female (n=64) Male (n=7) P value

Age of patient 37.18+12.93 42.14+15.52 .352

Age at diagnosis 34.64+12.81 41.57+15.16 .191

BMI 27.23+6.04 21.75+4.28 .020

height 152.54+7.45 162+8.87 .001

weight 63.48+15.03 57.85+12.28 .346

Systolic BP 128.92+14.07 125.14+13.26 .502

Dystolic BP 78.21+10.88 81.71+24.21 .498

Initial TSH 33.66+48.06 22.03+20.98 .532

TPO 807.06+890.20 275.02+509.44 .163

TG 202.44+316.34 66.64+82.92 .060

S. bilirubin 1.06+2.00 1.01 +0.45 .945

SGOT 44.50+29.59 33.00+6.24 .313

SGPT 47.78+44.16 32.14+6.25 .357

SALP 194.17+101.14 190.85+58.94 .933

CHO 189.77+46.58 178.42+61.75 .563

TG 155.69+55.87 179.57+107.79 .353

LDL 108.69+42.30 103.50+22.48 .770

HDL 42.13+11.69 42.28+10.09 .970

VLDL 28.77+9.58 27.29+9.50 .702

Fasting insulin 12.78+7.93 8.37+3.13 .153

Fasting blood sugar 90.28+18.36 91.42+15.93 .876

Post prandial sugar 127.86+20.75 134.42+23.03 .441

Platelet count 1.66+0.68 1.58+0.75 .803

MCV 85.15+8.58 88.84+11.29

MCH 27.78+3.68 30.57+4.04

MCHC 31.79+2.21 33.71+2.14

MMSE 27.02+2.00 28.00+1.15 .211

HAMD 14.64+6.07 13.00+5.48 .499

SGOT/SGPT=AAR 1.11+0.39 1.05+0.24 .719

BARD 2.21+0.87 2.00+1.00 .555

AST/platelet=APRI 1.85+1.46 1.31+0.72 .335

HOMA 2.75+1.83 1.97+0.96 .278

33. QUICKI 1.52+0.32 1.40+0.16 .348

• 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