Hepatopathy in Graves Thyrotoxicosis

A 46-year-old female patient attended our outpatient clinic for further evaluation and treatment after diagnosis of overt hyperthyroidism by her general practitioner. The laboratory tests revealed an autoimmune thyrotoxicosis due to Graves disease, with positive thyroid-stimulating hormone receptor antibodies (free triiodothyronine [fT3]: 12.4 pg/mL, norm: 2-4.4; free tetraiodothyronine [fT4]: 43.2 ng/L, norm: 9.3-17; thyroid-stimulating hormone [TSH]: <0.01 µIU/mL, norm: 0.27-4.2; thyroid-receptor hormone-stimulating antibodies [TSH-R-Ab]: 15.60 IU/L, norm: 0-1.75). Ultrasound of the thyroid revealed a marked hypoechogenicity and hypervascularization (Figure 1A). Because therapy with thionamides was planned, and hepatotoxicity is a frequent side effect of thionamide treatment, an extended blood test was performed. The results revealed mixed hepatotoxic and cholestatic liver damage with elevated serum aminotransferase activities (aspartate-aminotransferase [AST]: 127 U/L, norm: 10-35; alanine-aminotransferase [ALT]: 249 U/L, norm: 10-35; alkaline phosphatase: 207 U/L, norm: 35-104; gamma glutamyltransferase: 400 U/L, norm: 6-42). The patient had no prior history of liver disease, alcohol abuse, or hepatotoxic medication. We decided to start symptomatic therapy with a beta-blocker (propranolol 160 mg/d, due to the inhibition of peripheral conversion of T4 to T3) and perform an extended hepatopathy screening prior to initiation of the specific antithyroid therapy. Liver sonography was normal, with no detectable signs of steatosis, gallbladder disease, abnormalities of the biliary excretion, or disturbed perfusion (Figure 1B). Chronic and acute viral and nonviral liver diseases were excluded. After the exclusion of primary liver conditions, we concluded that the laboratory findings were caused by the thyrotoxicosis and initiated treatment with thionamides. We favored carbimazole over propylthiouracil based on the slightly better safety profile. We achieved peripheral euthyroid status after 4 weeks of moderate dosage (20 mg/d). As suspected, liver tests improved over the treatment period and were within normal ranges 6 weeks after therapy initiation. Previously, data had shown an association between Graves disease and abnormal liver enzymes, with the prevalence of liver involvement in the thyrotoxic phase of Graves ranging between 37% and 78%.1Hsieh A Adelstein S McLennan SV Williams PF Chua EL Twigg SM Liver enzyme profile and progression in association with thyroid autoimmunity in Graves' disease.Endocrinol Diabetes Metab. 2019; 2: e00086Crossref PubMed Google Scholar In most cases, the elevation of liver enzymes is mild.2Zhang R Tian X Qin L Wei X Wang J Shen J Factors predicting abnormal liver function tests induced by Graves' disease alone: a retrospective cohort study.Medicine (Baltimore). 2015; 94: e839Crossref PubMed Scopus (14) Google Scholar There is no obvious autoimmune mechanism for the observed liver participation. The authors of a recent review hypothesized that alterations in the microcirculation and perfusion on the cell level and increased apoptosis might be potential mechanisms.3Yorke E Hyperthyroidism and liver dysfunction: a review of a common comorbidity.Clin Med Insights Endocrinol Diabetes. 2022; 1511795514221074672Crossref PubMed Scopus (11) Google Scholar Because carbimazole and thiamazole are known to induce cholestatic liver injury, and propylthiouracil is known to cause hepatotoxic damage,4Yu W Wu N Li L Wang J OuYang H Shen H Side effects of PTU and MMI in the treatment of hyperthyroidism: a systematic review and meta-analysis.Endocr Pract. 2020; 26: 207-217Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar it is crucial to differentiate primary hepatic damage from thyrotoxicosis-induced hepatopathy when deciding on the appropriate therapy. According to the current guidelines, drug-induced hepatotoxicity or deterioration of pre-existing liver disease are indications for radical treatment (thyroidectomy or radioiodine therapy).5Kahaly GJ Bartalena L Hegedus L Leenhardt L Poppe K Pearce SH 2018 European Thyroid Association guideline for the management of graves' hyperthyroidism.Eur Thyroid J. 2018; 7: 167-186Crossref PubMed Scopus (445) Google Scholar Therefore, raised liver enzymes may lead to hesitancy to commence first-line pharmacotherapy and thus, result in avoidable radical treatment. We conclude, that given the complexity and uncertainty of disease progression, cautious monitoring is required to avoid a false diagnosis and overtreatment.