Effects of 4-month Therapy of Levothyroxine on Non-Alcoholic Fatty Liver Disease (NAFLD) and Diabetes Control in Diabetic Patients

Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by lipid accumulation in hepatocytes. These conditions range from fat accumulation in the liver (hepatosteatosis) to non-alcoholic steatohepatitis (NASH), which in turn, increases the risk for cirrhosis and hepatocellular cancer. NAFLD occurs in 25-35 % of the general United States population, and its prevalence is estimated to be 60 %-80 % for patients with type II diabetes mellitus (DM). Its co-occurrence with type II DM significantly increases the risks for renal and cardiovascular disease. The prevalence of NAFLD in Singapore is not known. However, given that the estimated percentage of adults with type II DM or obesity are approaching 10 % and rapidly rising, a significant proportion of the Singaporean population is likely at risk for NAFLD. Although there are drug therapies for diabetes; currently, there is no effective treatment for NAFLD.

Although NAFLD may cause inflammation, lipotoxicity, and scarring within the liver, it also can have profound metabolic effects as it induces hepatic insulin resistance. Defects in β-oxidation of fatty acids are thought to play an important role in the pathogenesis of NAFLD, which then leads to further insulin resistance and worsened glycemic control in diabetic patients. Since thyroid hormones (THs: T3, T4) promote the oxidation of fatty acids within the liver, it is possible that ineffective TH action in the liver may contribute to NAFLD.

It has been shown recently that the incidence of hypothyroidism is doubled in patients with NAFLD as approximately 15% patients are affected. Additionally, several TH and TH analogues are able to ameliorate NAFLD in rodents fed with high fat chow diets. At the genomic level, many of the genes that have altered expression in NAFLD are regulated by TH further supporting the notion that defects in TH signalling may promote hepatosteatosis and hepatic damage. Two recent studies also have shown thyroid hypo-function in both young and elderly adults with NAFLD.

In this study, we seek to examine whether short-term low dose levothyroxine can decrease hepatic fat deposition and improve glucose control in diabetic patients with NAFLD.

Accordingly, we plan to treat 50 male patients with stable Type II DM and NAFLD with low dose LT4, and assess fat content in the liver by MRI and glucose control by measuring serum fasting glucose, HbA1c, and degree of insulin resistance as determined by the homeostatic model assessment (HOMA-IR). The potential benefit for the patient will be reduction of hepatic fat content and/or improvement in glucose control. The potential major side effects are atrial arrhythmias and osteoporosis. The risk for the latter side effects will be minimized by treating subjects that do not have any known heart disease or osteoporosis with low dose levothyroxine. It is expected that thyroid hormone levels will be in the high normal range. Patient will undergo hepatic MRI at beginning of study and at 16 weeks and phlebotomy at beginning of study, at 8 weeks, and at 16 weeks. The study will be conducted in compliance with the protocol, Singapore Guideline for Good Clinical Practice (SGGCP), site's respective Institutional Review Board (IRB), and Health Science Authority (HSA) requirements.