Hepatic Dysfunction in Hyperthyroidism

Hyperthyroidism can affect multiple organ systems, including the cardiovascular, nervous, gastrointestinal, and hepatic systems. The interaction between the thyroid and liver is critical for maintaining homeostasis in both sites. Thyroid hormones are glucuronidated and sulfated within the liver and subsequently excreted into bile; in addition, these hormones maintain the metabolism of bilirubin by playing a role in the enzymatic activity of glucuronyltransferase and by regulating the level of ligandin, a major organic anion-binding protein.¹ Therefore, it is not surprising that hepatic dysfunction is commonly observed in patients with thyroid disease. In 1874, Habershon described a patient with exophthalmic goiter, heart disease, and jaundice who died.² Many subsequent case reports and series have highlighted the prevalence of liver test abnormalities (ranging from 15% to 76%) in the setting of hyperthyroidism.^3,4 There are several mechanisms of liver dysfunction in the setting of hyperthyroidism, including liver abnormalities due to hyperthyroidism alone, liver damage related to heart failure and hyperthyroidism, and concomitant liver disease in the setting of hyperthyroidism.

In our hyperthyroidism and liver dysfunction case series, patients were categorized into 3 groups: patients without heart failure, patients with heart failure, and patients without heart failure who had concomitant liver disease.³ In patients without heart failure, liver dysfunction ranged from mild liver test abnormalities to deep jaundice. This range of liver dysfunction is consistent with other cases reported in the literature.^4–7 However, no studies have demonstrated a correlation between abnormal liver biochemical tests and thyroid hormone levels. Studies monitoring treatment of hyperthyroidism have noted that improvement in a patient's thyroid function is accompanied by normalization of the liver panel. The mechanism of liver injury in pure hyperthyroid states is not well understood. Recently, Upadhyay and colleagues used in vivo and in vitro models to show that excess T3 induces apoptosis of hepatocytes and causes liver dysfunction through activation of the mitochondrial-dependent pathway.⁸ In most cases of hyperthyroidism and liver dysfunction without heart failure, liver histology demonstrates some degree of fatty infiltration, cytoplasmic vacuolization, nuclear irregularity, and hyperchromatism in hepatocytes.⁸ Functional changes in mitochondria (such as enlargement) and formation of megamitochondria have been reported in the livers of hyperthyroid patients and in a rat model of hyperthyroidism.^9,10

Hyperthyroid patients with heart failure in our series were more likely to manifest more severe liver dysfunction with respect to deep jaundice (mean, 5.3 mg/dL; highest, 24 mg/dL), coagulopathy, hepatomegaly, and even ascites, compared to patients without heart failure.³ Heart failure resulting in hepatic congestion—even in the absence of hyperthyroidism—is often associated with protean liver test abnormalities, including acute hepatocellular injury, hyperbilirubinemia, and coagulopathy.¹¹ In particular, right-sided heart failure can result in passive congestion of the liver usually referred to as “congestive hepatopathy.” Decreased cardiac output may also result in decreased hepatic blood flow and arterial oxygen saturation. These processes are intertwined, and clear distinctions may not be possible.¹² The liver is often enlarged and pulsatile in patients with congestive hepatopathy. Ascites is common due to enlargement of sinusoidal fenestrae secondary to sinusoidal congestion and exudation of protein-rich fluid into the space of Disse, which subsequently overwhelms the lymphatic vessels.¹³ Myers and colleagues assessed the clinical, hemodynamic, and histologic data of 83 patients with congestive hepatopathy; mild abnormalities in liver enzymes and bilirubin levels were noted in most patients.¹¹ However, aminotransferase levels may be higher than 2,000 IU/L in the setting of acute cardiac dysfunction, and patients may have profound jaundice along with coagulopathy.¹¹

Hyperthyroidism, particularly Graves disease, can also be associated with other liver conditions. Up to 10% of patients with Graves disease have a coexisting autoimmune disorder.¹⁴ The association between Graves disease and primary biliary cirrhosis (PBC) or autoimmune hepatitis is well described in the literature. Conversely, Graves disease is a common concurrent autoimmune condition associated with various chronic liver diseases.¹⁵

The case reported by Venkat and colleagues—which describes a patient with Graves disease, heart failure, jaundice, and positive autoimmune markers—illustrates the challenges of discerning the cause of liver dysfunction in this setting.¹⁶ The clinical presentation of this patient was very similar to that of our own patients. However, this case study is the first reported case of Graves disease coexisting with autoimmune cholangiopathy (AIC). Originally referred to as “immunocholangitis” by Brunner and Klinge, AIC is an antimitochondrial antibody (AMA)-negative and antinuclear antibody (ANA)-positive condition; otherwise, AIC shares the typical clinical and histologic features of PBC.¹⁷ Mitochondrial antigen has been shown to be expressed on the apical membranes of biliary epithelial cells from AMA-negative as well as AMA-positive PBC patients, suggesting that the pathogenesis of both conditions is very similar.¹⁸ Michieletti and associates compared 17 AIC patients with 17 PBC patients and found that both conditions had a predilection for women and an association with hypothyroidism.¹⁹ Liver tests were characterized by high alkaline phosphatase levels (mean, 500 U/L). In the patient treated by Venkat and coworkers, histopathologic findings were consistent with AIC, although the alkaline phosphatase level was not as elevated as in a typical AIC patient.¹⁶ The presence of a high ANA value and a negative AMA titer is also consistent with AIC. The interpretation of autoimmune markers in Graves disease should take into consideration the high prevalence of nonthyroid autoantibodies, particularly ANA.^20–22

In conclusion, it is apparent that the thyroid and liver are intertwined in many ways. A vigilant effort should be undertaken to diagnose the liver condition of patients who present with hyperthyroidism and liver dysfunction—as in the case report by Venkat and associates—so that appropriate therapy can be promptly initiated.