Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). https://doi.org/10.1177/11795514221074672 Clinical Medicine Insights: Endocrinology and Diabetes Volume 15: 1–3 © The Author(s) 2022 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/11795514221074672 Introduction Hyperthyroidism impacts multiple systems of the body such the nervous, cardiovascular and gastrointestinal systems, with the liver being an important organ affected in the latter.1 Hyperthyroidism disproportionately affects women rather than men (5:1) and appears to be common among smokers.2,3 The overall incidence of hyperthyroidism is estimated to be about 0.05% to 1.3 % with a predominant number being subclinical, this figure rises to between 4% and 5 % among older women.3 Aside other abnormalities,4 liver biochemical dysfunctions are found in between 15% and 79% of untreated hyperthyroid- ism patients with some suffering from severe liver damage of failure and impaired synthetic function.5,6 In a recently pub- lished systematic review and meta-analysis by Scappaticcio et al,7 between 55% and 60% of patients with untreated hyper- thyroidism had at least one abnormal liver function test. The prevalence of abnormal liver function tests with respect to ala- nine transaminase (ALT), aspartate transaminase (AST), alka- line phosphatase (ALP), total bilirubin (BIL), and γ-glutamyltransferase (GGT) among the hyperthyroid patients were 33%, 23%, 44%, 12%, and 24% respectively. The liver and thyroid hormones interact at multiple levels to maintain homeostasis. The two biologically active thyroid hor- mones: thyroxine (T4) and 3,5,31 triiodothyronine (T3) are synthesized solely in the thyroid gland in the case of the former and both thyroid gland and other tissues in the latter.8,9 Approximately 80% of T3 is formed by 51-deiodination of T4 in extrathyroidal tissue: commonly the liver and kidney and rapidly degraded by deiodination at a rate of approximately 75% per day.8,9 The production rate of T4 is 80 to 100 mcg per day, all of which is produced in the thyroid gland and is degraded at a rate of 10% per day. Approximately 80% is deiodinated: 40% to form T3 and 40% to form reverse T3 (rT3). The remaining 20% is conjugated with glucoronide and sulfate, deaminated and decarboxylated to form tetraiodothy- roacetic acid (tetrac) in the liver.8,9 Over 99% of T4 and T3 in serum are bound to serum pro- teins, thyroxine-binding globulin (TBG), transthyretin, albu- min and lipoproteins which are mainly produced in the liver. These aids to maintain the serum free thyroid hormones within narrow limits yet ensure immediate and continuous availability to tissues. It is the serum-free T4 and T3 concentrations that determine the hormones biological activity.8,9 The liver requires adequate amounts of thyroid hormones to execute its metabolic functions optimally. Thyroid hormones, through regulating the levels of ligandin, an anion-binding protein, affect the enzymatic activity of glucuronyltransferase which helps in maintaining the metabolism of bilirubin.10 Among patients with preexisting liver disease, the liver dys- function may be as a result the underlying liver disease alone or a combination of the effects of thyrotoxicosis and the liver disease. The review focused on a literature search from the period January 2000 to June 2021 in the English language using MEDLINE via Ovid and EMBASE databases. Four random and relevant literature published before 2000 were included. Key search terms included hyperthyroidism, thyro- toxicosis, liver dysfunction, hepatitis and liver enzymes. Putative Mechanisms for Liver Dysfunction in Hyperthyroidism Several direct and indirect mechanisms have been suggested as the cause of liver dysfunction in hyperthyroidism. Summarily, these include direct liver toxicity from prolonged exposure to excessive thyroid hormones and hepatocyte anxoxia with Hyperthyroidism and Liver Dysfunction: A Review of a Common Comorbidity Ernest Yorke Department of Medicine & Therapeutics, University of Ghana Medical School, Accra, Ghana. ABSTRACT: Deranged liver enzymes due to hyperthyroidism rather than intrinsic liver pathology are not uncommon. The reported prevalence of liver biochemical abnormalities in patients with untreated thyrotoxicosis varies widely ranging from 15% to 76%. The suggested causes of liver dysfunction include direct hepatocyte injury, co-morbid heart failure, associated autoimmune conditions (especially in the setting of Graves’ Disease), preexisting liver disease and drugs including antithyroid medications. Although, some patients may have a pattern of mild liver injury, about 1% to 2% can have fulminant hepatitis. Liver enzymes can return to normalcy in as many as 77% to 83% of patients once the initiations of thionamides are started in a timely fashion, which can help forestall complications and prevent or minimize multi-organ dysfunction. Clinicians should maintain a high index of suspicion for underlying hyperthyroidism in patients presenting with unexplained liver dysfunction or unexplained jaundice. KeywoRDS: Hyperthyroidism, liver dysfunction, liver enzymes ReCeIVeD: October 4, 2021. ACCePTeD: December 22, 2021. TyPe: Review Article FunDIng: The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by the author. DeCLARATIon oF ConFLICTIng InTeReSTS: The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. CoRReSPonDIng AuTHoR: Ernest Yorke, Department of Medicine & Therapeutics, College of Health Sciences, University of Ghana Medical School, Accra, Ghana. P.O. Boc KB796, Korle-Bu, Accra. Emails: pavlovium@yahoo.com; eyorke@ug.edu.gh 1074672 END0010.1177/11795514221074672Clinical Medicine Insights: Endocrinology and DiabetesYorke review-article2022 https://uk.sagepub.com/en-gb/journals-permissions mailto:pavlovium@yahoo.com mailto:eyorke@ug.edu.gh http://crossmark.crossref.org/dialog/?doi=10.1177%2F11795514221074672&domain=pdf&date_stamp=2022-02-07 2 Clinical Medicine Insights: Endocrinology and Diabetes free-radical damage as a result of the hypermetabolic state, liver cell degeneration from accelerated liver glycogen and protein decomposition, autoimmune-related liver injury, congestive hepatopathy (necrosis) from concomitant thyrotoxic heart fail- ure, previous underlying liver disease and antithyroid medica- tion-related liver toxicity and injury,1,11-14 refer Figure 1. The pattern of liver dysfunction associated with hyperthy- roidism vary. In situations without heart failure and underlying autoimmune causes, elevated aspartate amino transferase, and alanine aminotransferase (transaminitis) results from tissue ischemia and infarction of the hepatocytes. This is as a result of the increase in metabolic activity which increases oxygen demand by the liver.1,15-17 T3 causes apoptosis through a mitochondrion- dependent pathway. Typical histological findings include fatty infiltration of the hepatocytes, nuclear irregularity, hyperchro- matism in hepatocytes and vacuolization of the cytoplasm. Cholestatic pattern is commoner than synthetic liver dysfunc- tion,18 and some may present with severe jaundice as the main presentation. Rises in ALP and GGT are seen about 64% and up to 62% of thyrotoxicosis cases respectively.19,20 In one series, elevations in serum ALP were followed in frequency by increases in levels of GGT, bilirubin, and aminotransferases.18 Elevation in ALP is due to increased osteoblastic activity and driven mainly by bone isoenzyme.21 Congestive heart failure may occur as a complication of hyper- thyroidism (thyrotoxic heart failure) or as a preexisting condition. Whilst sinus tachycardia, atrial fibrillations are common manifes- tations, frank heart failure is uncommon without underlying pre- existing heart condition. In the series by Wafa et al22 only two patients with severe hepatic dysfunction had global heart failure. Heart failure usually results in mild abnormalities in liver dys- function, however, acute congestion may lead to marked increases in aminotransferases and bilirubin similar to values associated with viral and toxic hepatitis.16,23 In a recent publication involving 2 patients with Graves’ disease, we found out that the liver dys- function was a predominantly cholestatic pattern rather than transaminitis in the patient with thyrotoxic heart failure, whilst the second patient without heart failure had equivalent derange- ments in cholestasis and transaminitis.6 Generally, it is observed that patients with hyperthyroidism and heart failure exhibit more severe liver dysfunction (deep jaundice), hepatomegaly, ascites and coagulopathy than those without heart failure.15,16 Graves’ disease can occur concurrently with other autoim- mune conditions in about 10 % of cases24; common among these are primary biliary cirrhosis (PBC), autoimmune cholan- giopathy (AIC) or autoimmune hepatitis. These autoimmune conditions usually have positive antinuclear antibody (ANA) and high ALP; AIC and some PBC cases are negative for anti- mitochondrial antibody (AMA). It is often difficult to decide if the cause of hepatic dysfunction is due to antithyroid medications (thionamides) particularly if liver functions tests (LFTs) were not assessed before commence- ment of medications. It is estimated that the incidence of antithy- roid associated hepatic dysfunction is between 0.1% and 0.2%25; and risk factors for hepatic injury include older age and higher doses of antithyroid medications. In severe cases of liver dysfunc- tion, the offending drugs should be withdrawn and consideration given to the use cholestyramine to improve cholestatic symptoms, whilst the underlying hyperthyroidism is definitively treated with radioiodine therapy or surgery.26,27 Predictors of Liver Dysfunction and Recovery So far, studies have not demonstrated a correlation between abnormal liver biochemical tests and thyroid hormone levels. Generally, there is normalization of liver dysfunction as thyroid hormone improves.6,22 Li et al28 found out that among Graves’ disease patients, higher thyroid hormone of free thyroxine (FT4) >70.5 pmol/L with the heart rate above 90 beats per minute, the risk of hepatic function injury increases. Another study also found that hepatic abnormalities were greater in a cohort of 19 patients with hyperthyroidism and chronic heart failure (CHF).16 One study however showed a negative correla- tion between ALT and left ventricular ejection fraction (LVEF) among patients with thyrotoxicosis and heart failure.22 Timely initiation of antithyroid medications lead to improvement in liver dysfunction6,22; particularly when bio- chemical euthyroidism is attained. In a recent systematic review and meta-analysis, following the initiation of antithyroid med- ications and attainment of euthyroidism, there was normaliza- tion abnormalities in ALT, AST, ALP, BIL, and GGT in 83%, 87%, 53%, 50%, and 70% respectively. Conclusion Hepatic dysfunction associated with thyrotoxicosis is common finding in clinical practice. Whilst the exact mechanisms are unknown, both direct and indirect causes are involved. The Liver Dysfunc�on Direct Liver toxicity from excess thyroid hormones Previous Underlying liver disease Liver cell degenra�on Autoimmune liver injury Drug-related liver injury Conges�ve Hepatopathy and necrosis Figure 1. Mechanisms for liver dysfunction in hyperthyroidism. Yorke 3 challenge is sometimes to establish the definitive factor causing liver injury in a particular patient. Examination of liver func- tion in the setting of hyperthyroidism is important to identify any abnormalities; timely initiation of antithyroid medication generally results in improvement. Author Contributions EY conceived the study and its design, data search, analysis, drafted and produced the final manuscript. ORCID iD Ernest Yorke https://orcid.org/0000-0003-4257-7492 Data Accessibility/Availability The data used to support the findings of this study are available from the corresponding author upon request. RefeRenCes 1. Mansourian AR. Liver functional behavior during thyrotoxicosis: a review. 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