Congestive hepatopathy secondary to graves’ disease: a case report

INTRODUCTION

Graves’ disease is a common cause of hyperthyroidism in iodine-sufficient parts of the world, with prevalence ranging from 0.2% to 1.3%.¹ In Indonesia, the reported prevalence of hyperthyroidism is 6.9%.² Excessive thyroid hormone is known to have multiple effects on various organs, including liver. Hepatic dysfunction in patients with thyroid disease is a common condition. Possible causes of hepatic dysfunction in Graves’ disease includes effect of thyroid hormone excess, anti-thyroid drug related hepatic injury, and presence of concomitant liver disease.^3,4

CASE REPORT

A 49-year old Indonesian male presented with worsening jaundice, abdominal pain, and distension since 1 week. He also complained of dyspnea, nausea, tremor, and palpitation since past 2 months. His history of disease was Graves’ disease since 5 years ago, but he hadn’t visited the hospital since 2-years ago because of the COVID-19 pandemic. He previously had visited the outpatient clinic for the same symptoms, and had started his anti-thyroid medication again since then.

On physical examination, his blood pressure was 120/80 mmHg, heart was rate 107 bpm (irregular), respiratory rate was 22 times per minute, temperature was 37.3°C, oxygen saturation in room air was 98%. Ophthalmic examination showed bilateral exophthalmos and jaundice on the sclera. Thyroid gland was diffusely enlarged. Cardiac auscultation revealed pansystolic murmur on tricuspid valve. Abdominal examination shows normal bowel sounds, with positive shifting dullness and hepatomegaly. Patient also had pitting edema on both legs. Hepatojugular reflux was also present on this patient.

Laboratory findings were: Haemoglobin 8.9 g/dl, white blood cell 4.000/μl, thrombocyte 223.000/μl. ALT 17 U/l, AST 44 U/l, total bilirubin 4.56 mg/dl, direct bilirubin 3,8 mg/dl, and indirect bilirubin 0,76 mg/dl. Patient has normal blood sugar and kidney function. Thyroid function test showed hyperthyroidism: thyroid-stimulating-hormone (TSH) 0.16 mIU/l (0.35-5.10), free thyroxine (FT4) 3.6 ng/dl (0.5-1.4). HBsAg and anti-HCV test was negative. Postero-anterior chest X-ray showed cardiomegaly with minimal right pleural effusion. Electrocardiography (ECG) showed atrial fibrillation with normal ventricular response, while his ECG from 2 years ago showed no atrial fibrillation (sinus tachycardia). Abdominal ultrasonography suggested that he had congestive liver, with suspected cardiac cirrhosis (dilatation of the hepatic vein with normal portal vein and portal velocity), ascites, and splenomegaly. No dilatatation of intrahepatic and extrahepatic bile duct was found. Echocardiography examination revealed dilated left atrium, right atrium, and right ventricle, moderate tricuspid and mitral regurgitation, normal left ventricle ejection fraction/LVEF (61%), and normal right ventricle systolic function 9 [Tricuspid anullar plane systolic excursion (TAPSE) 29 mm].

Patient was treated with methimazole 10 mg BID, spironolactone 50 mg QID, bisoprolol 2.5 mg QD, clopidogrel 75 mg QD, candesartan 8 mg QD, and intravenous furosemide 20 mg BID. Patient was also given 2 units of packed red cell. After 5 days of treatment, his ascites was resolved, along with normalization of bilirubin. Patient was discharged after the 6 days of treatment with stable condition.

DISCUSSION

Liver is one of the affected organs in patients with hyperthyroidism, with 15% to 79% patients with untreated hyperthyroidism suffering from severe liver damage and impaired synthetic function. There are multiple interactions of thyroid hormones and the liver in maintaining homeostasis. About 80% T3 is formed by 51-deiodination of T4 in extrathyroidal tissue, such the kidney and liver. The liver also produced serum proteins (thyroxine-binding globulin/TBG, transthyretin, albumin, and lipoproteins) required by thyroid hormones to maintain serum free thyroid and availability to the tissues. Thyroid hormones are needed by the liver to perform its metabolic functions, by regulating the levels of ligandin that affects the enzymatic activity of glucoronyltransferase. Liver dysfunction in patients with hyperthyroidism can be caused by multiple mechanisms: (1) direct liver toxicity from exposure of excess thyroid hormones; (2) liver cell degeneration from accelerated decomposition of liver glycogen and protein; (3) congestive hepatopathy from thyrotoxic heart failure; (4) previous underlying liver disease; (5) toxicity and injury by antithyroid medications; (6) autoimmune-related liver injury.^5,6 Retrospective studies also reported that the risk factors of liver dysfunction were age, course of Graves’ disesase, heart rate, weight of the thyroid gland, FT4 level, TR-antibodies, and TPO-antibodies.⁷

Congestive hepatopathy is described as manifestations of chronic, passive congestion of the liver in the setting of heart failure or other cardiac defects that result in elevation of central venous pressure.^6,8 Circulatory system disorders may cause hepatic dysfunction due to several mechanisms. First, right ventricular dysfunction increases preload or central venous pressure that can cause direct liver damage. From the right heart chamber, the pressure is then transmitted to the hepatic vein and sinusoids, which leads to intrahepatic edema, decreased perfusion, oxygen diffusion, hemorrhagic injury, and modification of the hepatic architecture and atrophy, which appear as elevation of hepatic enzymes. If the left side of the heart is also affected, perfusion and tissue hypoxia occurs, causing elevation of hepatic enzymes, LDH, and prolongation of coagulation status. These process caused the clinical manifestation of cardiac cirrhosis, such as shortness of breath, leg swelling, paroxysmal nocturnal dyspnea, and orthopnea, combined with symptoms due to liver dysfunction: abdominal pain, nausea, vomiting, jaundice, hepatomegaly, abdominal distention, and ascites. Hepatocytes, bile ducts, and biliary epithelium are sensitive to increase of lobular pressure, causing elevated bilirubin suggesting cholestasis. Thyrotoxicosis may also cause congestive heart failure secondary to atrial fibrillation and sinus tachycardia.⁹ Ascites is caused by the 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.¹⁰ Hepatojugular reflux can be demonstrated by sustained abdominal pressure, causing increase in venous return, shown by paradoxical rise in jugular venous pressure (JVP), usually correlated with right heart failure.¹¹

Chest radiographs findings in congestive hepatopathy are not specific, but pericardial calcification may suggest constrictive pericarditis. Abdominal ultrasonography shows dilated inferior vena cava and dilated hepatic veins. Abdominal CT scan findings are hepatomegaly, dilatation of inferior vena cava and hepatic veins, hepatic vein-to-hepatic vein shunts, and abnormal enhancement of the liver parenchyma with contrast CT scan.¹²

Graves’ disease is treated with anti-thyroid medications such as propylthiouracil (PTU) and thiamazole. These drugs, especially PTU, was associated with liver damage and failure.³ Methimazole has also been associated with transient asymptomatic elevations of serum aminotransferase, especially during first 3 months after starting the high dose therapy. Methimazole is also reported to cause liver injury with cholestatic or mixed pattern, but fatalities are rare.¹³ Studies have reported normalization liver enzymes (ALT, AST, GGT) in patients with liver function abnormalities after starting anti-thyroid medications.¹⁴ The American thyroid association (ATA) recommends checking baseline liver enzyme and reconsider the initiation of anti-thyroid medication if baseline liver enzymes are above 5×ULN.¹⁵ Treatment modalities for Graves’ disease with liver injury also includes radioactive iodine (RAI) and surgery. Radioactive iodine-131 (¹³¹I) treatment usually does not cause radiation damage to the liver, and was reported to return hepatic function indices after 6 months.¹⁶

In our case, this patient had stable course of Grave’s disease for 5 years, until he stopped taking anti-thyroid medication for the last 2 years. This patient didn’t have history of heart and liver failure, and the development of atrial fibrillation was presumed to occur after stopping the anti-thyroid medication. Patient manifested with exophthalmos, jaundice, ascites, pitting edema, and positive hepatojugular reflux, suggesting congestive hepatopathy. He has normal ALT and AST, with hyperbilirubinemia and jaundice. Normal or mildly elevated liver enzymes can be found in liver dysfunction due to congestive hepatopathy, even though acute congestion may lead to marked increases in levels of aminotransferases and bilirubin as high as viral and toxic hepatitis. Drug-induced liver dysfunction associated with anti-thyroid medication may be excluded because the patient has stopped taking drugs for the last 2 years. Other causes of liver dysfunction in patients with thyrotoxicosis cannot be ruled out yet, because of the many mechanisms of thyroid hormones interacting with liver function. Liver dysfunction in patients with thyrotoxicosis is commonly found in daily practice. However, establishing the cause of hepatic dysfunction can be a challenge. Managing thyrotoxicosis in patients with hepatic dysfunction is also a difficult decision, considering both PTU and thiamazole may cause hepatic complications.

CONCLUSION

Graves’ disease is a common cause of hyperthyroidism in iodine-sufficient parts of the world, with prevalence ranging from 0.2% to 1.3%, and 6.9% patients in Indonesia is diagnosed with hyperthyroidism. Congestive hepatopathy is on of the causes of liver dysfunction in patients with Graves’ disease. However, management of hyperthyroidism itself such as methimazole and PTU can sometimes cause further hepatotoxicity. Thyroid dysfunction should also be assessed in patients with unexplained liver dysfunction, especially in patients with history of previous thyroid disease.

ACKNOWLEDGEMENTS

Author would like to thank Ketut Suryana as chairman of internal medicine department, Wangaya general hospital, Denpasar, Bali, Indonesia for reviewing our work and general support.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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