Thyroid and Liver: Key Functions and Their Interplay

The thyroid and liver work together to regulate metabolism, energy balance, and overall health. The thyroid produces hormones that influence physiological processes, while the liver processes these hormones to ensure proper function. Disruptions in either organ can significantly affect metabolism.

Understanding their interaction helps explain conditions like hypothyroidism, hyperthyroidism, and liver disease. Their relationship extends beyond hormone regulation, impacting metabolic pathways essential for maintaining homeostasis.

Hormone Processing By The Liver

The liver regulates thyroid hormone activity by converting, metabolizing, and clearing these hormones from circulation. Thyroxine (T4), the thyroid’s primary hormone, is largely inactive until converted into triiodothyronine (T3), its biologically active form. This conversion occurs mainly in the liver through iodothyronine deiodinases, particularly deiodinase type 1 (D1), which ensures adequate T3 levels for metabolic regulation. Impaired hepatic enzyme activity can disrupt thyroid hormone balance, contributing to low T3 syndrome, commonly seen in liver disease patients.

The liver also synthesizes transport proteins such as thyroxine-binding globulin (TBG), transthyretin, and albumin, which influence hormone bioavailability. Only unbound hormones exert physiological effects. Liver dysfunction, as seen in cirrhosis, can alter protein synthesis, leading to abnormal thyroid function tests despite normal thyroid activity.

Thyroid hormone metabolism and excretion depend on hepatic conjugation pathways. The liver conjugates T4 and T3 with glucuronic acid or sulfate to facilitate excretion. Enzymes like UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) regulate hormone half-life. Liver disease can reduce conjugation capacity, prolonging hormone circulation and exacerbating metabolic imbalances. Certain medications, including glucocorticoids and antiepileptic drugs, can induce hepatic enzymes that accelerate thyroid hormone metabolism, sometimes leading to subclinical hypothyroidism.

Impact On Lipid And Glucose Metabolism

Thyroid hormones significantly influence lipid and glucose metabolism, with the liver as a key regulatory site. T3 modulates hepatic lipid turnover by regulating genes involved in cholesterol synthesis, fatty acid oxidation, and lipoprotein metabolism. When T3 levels fluctuate, these pathways are disrupted, contributing to dyslipidemia and nonalcoholic fatty liver disease (NAFLD). Hypothyroidism is linked to elevated cholesterol and low-density lipoprotein (LDL) levels due to reduced LDL receptor expression, impairing cholesterol clearance. Conversely, hyperthyroidism accelerates cholesterol degradation, often resulting in hypocholesterolemia.

Thyroid hormones also regulate hepatic triglyceride metabolism by modulating sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs). T3 promotes fatty acid oxidation while suppressing triglyceride accumulation. In hypothyroidism, reduced β-oxidation leads to hepatic lipid deposition, increasing the risk of steatosis. Clinical studies show that untreated hypothyroidism can lead to increased liver fat content and more severe liver dysfunction. Hyperthyroidism, on the other hand, enhances fatty acid oxidation and lipoprotein catabolism, sometimes causing excessive lipid depletion and muscle wasting.

Glucose homeostasis is also tightly regulated by thyroid hormones. The liver maintains blood sugar levels through gluconeogenesis and glycogenolysis. T3 enhances glucose production by upregulating enzymes like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase. In hyperthyroidism, excessive glucose output contributes to insulin resistance and impaired glucose tolerance. Studies link hyperthyroidism to a higher prevalence of diabetes, with increased fasting glucose levels and reduced insulin sensitivity. Hypothyroidism, in contrast, is associated with diminished hepatic glucose production, potentially leading to hypoglycemia. Reduced insulin clearance in hypothyroid individuals can prolong insulin activity, further complicating glucose regulation.

Effects On Bile Secretion

Bile production and secretion, critical for lipid digestion and waste excretion, are influenced by thyroid hormones. The liver synthesizes bile acids from cholesterol, a process regulated by cholesterol 7α-hydroxylase (CYP7A1). Thyroid hormone receptors control CYP7A1 expression, dictating bile acid synthesis. Low thyroid hormone levels reduce CYP7A1 activity, decreasing bile acid production and potentially disrupting fat absorption. Excess thyroid hormone increases bile acid production, altering biliary secretion composition.

Changes in bile composition affect gallbladder function and gallstone risk. Hypothyroidism impairs gallbladder motility, leading to bile stasis and cholesterol crystallization. Studies show a higher prevalence of gallstones in hypothyroid individuals due to decreased bile acid secretion and reduced gallbladder contractility. Hyperthyroidism accelerates bile turnover, which may lower gallstone risk but contribute to bile acid malabsorption. This imbalance can lead to diarrhea and reduced absorption of fat-soluble vitamins A, D, E, and K.

Thyromimetics And Hepatic Function

Thyromimetics, synthetic compounds that mimic thyroid hormone activity, are being explored for their potential to enhance liver metabolism without the systemic effects of excess thyroid hormones. These compounds selectively target thyroid hormone receptors (THRs), particularly the beta subtype (THR-β), which is highly expressed in hepatic tissue. By activating THR-β while sparing THR-α, which is found in the heart and bones, thyromimetics aim to deliver metabolic benefits without adverse cardiovascular effects like tachycardia or osteoporosis. This specificity makes them promising for treating metabolic liver disorders such as nonalcoholic steatohepatitis (NASH) and dyslipidemia.

Resmetirom (MGL-3196), a well-studied thyromimetic, has shown promise in reducing hepatic fat accumulation and improving lipid profiles. By upregulating genes involved in fatty acid oxidation and cholesterol clearance, Resmetirom enhances hepatic energy expenditure and reduces triglyceride storage. Clinical trials have reported significant reductions in liver fat content, with some patients showing histological improvements in fibrosis, a key factor in disease progression. These findings highlight the potential of thyromimetics to modify liver disease at a cellular level rather than merely managing symptoms.