How do thyroid dysfunction and liver disease affect each other in patients with pre-existing thyroid or liver conditions?

Bidirectional Thyroid-Liver Interactions in Clinical Practice

How Liver Disease Affects Thyroid Function

Liver disease directly impairs thyroid hormone metabolism and can cause abnormal thyroid function tests even in euthyroid patients, while chronic hepatitis C infection significantly increases the risk of autoimmune thyroid disease and thyroid cancer. 1, 2

Hepatic Effects on Thyroid Hormone Metabolism

• The liver metabolizes thyroid hormones and regulates their systemic endocrine effects, with hepatic dysfunction reducing thyroid hormone concentrations and their effects on peripheral tissues 2, 3
• Liver disease frequently causes elevation of thyroxine-binding globulin (TBG) and total thyroxine (T4), which can create diagnostic confusion, though free T4 (FT4) and TSH typically remain normal in euthyroid patients with liver disease 1
• Chronic hepatitis and cirrhosis increase the prevalence of disturbed glucose homeostasis and insulin resistance, which can indirectly affect thyroid function 4

HCV-Specific Thyroid Complications

• Autoimmune thyroid diseases are among the most frequent endocrine disorders in HCV-infected patients, with thyroid dysfunction (mainly hypothyroidism) present in approximately 30% of patients 4
• The prevalence of anti-thyroglobulin antibody (AbTG), anti-thyroid peroxidase antibody (AbTPO), and hypothyroidism are significantly higher in HCV-positive patients compared to controls 4
• HCV-infected patients have a higher prevalence of papillary thyroid cancer, particularly those with autoimmune thyroid diseases, with anti-HCV seropositivity associated with increased hazard ratio for thyroid cancer 4
• Patients with HCV-associated mixed cryoglobulinemia show even higher prevalence of thyroid dysfunction than HCV patients without cryoglobulinemia 4

Clinical Monitoring Algorithm for Liver Disease Patients

• Measure FT4 and TSH (which remain normal in euthyroid patients with liver disease) to rule out coexistent thyroid dysfunction in any patient with unexplained liver biochemical test abnormalities 1
• Monitor patients with autoimmune liver disease for development of thyroid dysfunction, as these conditions frequently coexist (e.g., primary biliary cirrhosis and hypothyroidism) 1
• In HCV-positive patients, perform baseline determination of FT4, TSH, AbTg, and AbTPO with thyroid ultrasonography, then repeat approximately every year 4
• Perform fine-needle aspiration of thyroid nodules if larger than 1 cm or if malignancy is suspected 4

How Thyroid Dysfunction Affects the Liver

Thyroid hormones regulate hepatic carbohydrate and fat metabolism to control circulating glucose, cholesterol, and triglyceride levels, with both hypothyroidism and hyperthyroidism causing distinct patterns of liver injury and metabolic dysfunction. 2, 5

Hypothyroidism and Hepatic Metabolism

• Hypothyroidism and "intrahepatic" hypothyroidism contribute to development of hypercholesterolemia and metabolic dysfunction-associated steatotic liver disease (MASLD) 2, 5
• Dysregulation of thyroid hormone levels in hypothyroidism is associated with dyslipidemia, hepatic lipotoxicity, inflammation, and fibrosis 5, 6
• Reductions in circulating and intrahepatic thyroid hormone concentrations increase MASLD risk by inducing lipotoxicity, inflammation and fibrosis 6
• Hypothyroidism may cause elevation of aspartate aminotransferase (AST) 1

Hyperthyroidism and Hepatic Effects

• Hyperthyroidism may cause elevation of alanine aminotransferase (ALT) and alkaline phosphatase (mainly of bone origin) 1
• Thyroid hormones regulate the basal metabolic rate of all cells including hepatocytes, thereby modulating hepatic function 3
• Both hypo- and hyperthyroidism influence hepatic carbohydrate and fat metabolism 2

Thyroid Hormone Receptor Actions in Liver

• Thyroid hormone action is mediated by thyroid hormone receptor (THR) isoforms, with THRβ being the main isoform expressed in the liver 5
• Thyroid hormones regulate hepatic metabolic pathways including cholesterol metabolism, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism 5, 6

Treatment-Related Bidirectional Effects

Interferon Therapy Complications

• IFN-α therapy is a well-known risk for development of autoimmune thyroid diseases and thyroid dysfunctions, with thyroid disease developing in up to 25-30% of HCV patients during Peg-IFN/RBV treatment 4
• Approximately half of patients who develop thyroid disease during IFN therapy require thyroid treatment 4
• Most patients with IFN-α-induced hyperthyroidism present with Hashimoto disease and transitory hyperthyroidism, while a minority develop Graves' disease 4
• Assessment of TSH and thyroid autoantibodies at baseline and close monitoring of thyroid function during Peg-IFN/RBV therapy are necessary for early detection and management 4
• Monitor patients receiving IFN therapy for development of thyroid dysfunction 1

Antithyroid Drug Hepatotoxicity

• Antithyroid drug therapy may result in hepatitis, cholestasis, or transient subclinical hepatotoxicity 1
• Monitor patients receiving antithyroid therapy for development of hepatic injuries 1

Drug-Drug Interactions

• Strict follow-up of main liver function tests (LFTs) and accurate evaluation of possible drug-drug interactions between direct-acting antivirals (DAAs) and non-etiologic drugs (e.g., cyclosporine) should be performed in HCV-positive patients 4
• Possible interactions of levothyroxine (L-T4) with DAAs suggest accurate tailoring of treatment schedules 4

Emerging Therapeutic Implications

• Resmetirom, a liver and THRβ-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH) 6
• Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred development of thyromimetics that target THRβ and/or the liver itself 6
• Early identification and treatment of insulin resistance or type 2 diabetes in HCV patients reduce liver disease progression, incidence of hepatocellular carcinoma, transplant-related morbidity and mortality 4

Critical Clinical Pitfalls to Avoid

• Do not interpret elevated total T4 in liver disease as hyperthyroidism without checking FT4 and TSH, as TBG elevation is common in liver disease 1
• Do not overlook thyroid dysfunction as a cause of unexplained liver biochemical test abnormalities 1
• Do not neglect thyroid monitoring in HCV patients, particularly those with autoimmune features or receiving interferon therapy 4
• Recognize that thyroid-liver associations may cause diagnostic confusion and errors in patient care if not properly considered 1