📖Hyperthyroidism and Liver Dysfunction: A Review of a Common Comorbidity

Abstract  抽象

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.
由于甲状腺功能亢进症而不是内在肝脏病变引起的肝酶紊乱并不少见。据报道，未经治疗的甲状腺毒症患者肝脏生化异常的患病率差异很大，从 15% 到 76% 不等。肝功能障碍的拟议原因包括直接肝细胞损伤、合并心力衰竭、相关的自身免疫性疾病（尤其是在 Graves 病的情况下）、先前存在的肝病和包括抗甲状腺药物在内的药物。虽然一些患者可能有轻度肝损伤，但约 1% 至 2% 的患者可能患有暴发性肝炎。一旦及时开始使用硫脲类药物，多达 77% 至 83% 的患者的肝酶可以恢复正常，这有助于预防并发症并预防或尽量减少多器官功能障碍。对于表现为不明原因肝功能障碍或不明原因黄疸的患者，临床医生应保持对潜在甲状腺功能亢进症的高度怀疑。

Keywords: Hyperthyroidism, liver dysfunction, liver enzymes
关键字： 甲状腺功能亢进、肝功能障碍、肝酶

Introduction  介绍

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
甲状腺功能亢进症会影响身体的多个系统，如神经、心血管和胃肠道系统，其中肝脏是后者的重要器官。 ¹ 甲状腺功能亢进症不成比例地影响女性而不是男性 （5：1），并且似乎在吸烟者中很常见。^2,3 甲状腺功能亢进症的总发病率估计约为 0.05% 至 1.3%，其中主要是亚临床，这一数字在老年女性中上升到 4% 至 5% 之间。 ³

Aside other abnormalities, ⁴ liver biochemical dysfunctions are found in between 15% and 79% of untreated hyperthyroidism patients with some suffering from severe liver damage of failure and impaired synthetic function.^5,6 In a recently published systematic review and meta-analysis by Scappaticcio et al, ⁷ between 55% and 60% of patients with untreated hyperthyroidism had at least one abnormal liver function test. The prevalence of abnormal liver function tests with respect to alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (BIL), and γ-glutamyltransferase (GGT) among the hyperthyroid patients were 33%, 23%, 44%, 12%, and 24% respectively.
除了其他异常外，在 4% 至 15% 未经治疗的甲状腺功能亢进患者中发现了 ⁷⁹ 种肝脏生化功能障碍，其中一些患者患有严重的肝损伤或衰竭和合成功能受损。^5,6 在 Scappaticcio 等人最近发表的系统评价和荟萃分析中，⁷ 55% 至 60% 未经治疗的甲状腺功能亢进症患者至少有一次肝功能检查异常。甲亢功能亢进患者丙氨酸转氨酶 （ALT） 、天冬氨酸转氨酶 （AST） 、碱性磷酸酶 （ALP） 、总胆红素 （BIL） 和 γ-谷氨酰转移酶 （GGT） 肝功能检查异常的患病率分别为 33% 、 23% 、 44% 、 12% 和 24%。

The liver and thyroid hormones interact at multiple levels to maintain homeostasis. The two biologically active thyroid hormones: 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 tetraiodothyroacetic acid (tetrac) in the liver.^8,9
肝脏和甲状腺激素在多个层面相互作用以维持体内平衡。两种生物活性甲状腺激素：甲状腺素 （T4） 和 3,5,3¹ 三碘甲状腺原氨酸 （T3） 仅在前者中合成，后者在甲状腺和其他组织中合成。^8,9 大约 80% 的 T3 是由甲状腺外组织中 T4 的 5¹-脱碘形成的：通常是肝脏和肾脏，并以每天约 75% 的速率通过脱碘迅速降解。^8,9T4 的产生速率为每天 80 至 100 微克，所有这些都在甲状腺中产生，并以每天 10% 的速度降解。大约 80% 被脱碘：40% 形成 T3,40% 形成反向 T3 （rT3）。剩余的 20% 与葡糖苷和硫酸盐结合，脱氨和脱羧，在肝脏中形成四碘甲状腺乙酸 （tetrac）。^8,9

Over 99% of T4 and T3 in serum are bound to serum proteins, thyroxine-binding globulin (TBG), transthyretin, albumin 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
血清中超过 99% 的 T4 和 T3 与主要在肝脏中产生的血清蛋白、甲状腺素结合球蛋白 （TBG）、转甲状腺素蛋白、白蛋白和脂蛋白结合。这些有助于将无血清甲状腺激素维持在狭窄的范围内，同时确保组织立即和持续可用。无血清 T4 和 T3 浓度决定了激素的生物活性。^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
肝脏需要足量的甲状腺激素才能最佳地执行其代谢功能。甲状腺激素通过调节配体素（一种阴离子结合蛋白）的水平，影响葡萄糖醛酸转移酶的酶活性，这有助于维持胆红素的代谢。 ¹⁰

Among patients with preexisting liver disease, the liver dysfunction 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, thyrotoxicosis, liver dysfunction, hepatitis and liver enzymes.
在已有肝病的患者中，肝功能障碍可能是潜在的肝脏疾病单独或甲状腺毒症和肝病的综合作用的结果。本综述的重点是通过 Ovid 和 EMBASE 数据库使用 MEDLINE 检索 2000 年 1 月至 2021 年 6 月期间的英语文献。纳入了 2000 年之前发表的 4 篇随机和相关文献。主要检索词包括甲状腺功能亢进症、甲状腺毒症、肝功能障碍、肝炎和肝酶。

Putative Mechanisms for Liver Dysfunction in Hyperthyroidism
甲状腺功能亢进症肝功能障碍的推定机制

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 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 failure, previous underlying liver disease and antithyroid medication-related liver toxicity and injury,^1,11-14 refer Figure 1.
有几种直接和间接机制被认为是甲状腺功能亢进症肝功能障碍的原因。总而言之，这些包括长期暴露于过量甲状腺激素和肝细胞焦虑症引起的直接肝毒性，由于代谢亢进状态导致自由基损伤，肝细胞变性加速肝糖原和蛋白质分解，自身免疫相关肝损伤，伴随甲状腺毒性心力衰竭引起的充血性肝病（坏死），既往基础肝病和抗甲状腺药物相关的肝毒性和损伤，^1,11-14 参见 Figure 1 .

The pattern of liver dysfunction associated with hyperthyroidism 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, hyperchromatism in hepatocytes and vacuolization of the cytoplasm. Cholestatic pattern is commoner than synthetic liver dysfunction, 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
与甲状腺功能亢进症相关的肝功能障碍模式各不相同。在没有心力衰竭和潜在自身免疫性原因的情况下，天冬氨酸氨基转移酶和丙氨酸氨基转移酶升高（转氨酶）是由肝细胞组织缺血和梗死引起的。这是由于代谢活动增加的结果，这增加了肝脏的需氧量。^1,15-17T3 通过线粒体依赖性途径引起细胞凋亡。典型的组织学发现包括肝细胞脂肪浸润、核不规则、肝细胞重染性和细胞质空泡化。胆汁淤积模式比合成肝功能障碍更常见，¹⁸ 并且有些可能以严重黄疸为主要表现。ALP 和 GGT 升高分别见于甲状腺毒症病例的 64% 和高达 62%。^19,20 元在一项系列研究中，血清 ALP 升高后 GGT、胆红素和转氨酶水平升高的频率更高。 ¹⁸ ALP 升高是由于成骨细胞活性增加，主要由骨同工酶驱动。 ²¹

Congestive heart failure may occur as a complication of hyperthyroidism (thyrotoxic heart failure) or as a preexisting condition. Whilst sinus tachycardia, atrial fibrillations are common manifestations, frank heart failure is uncommon without underlying preexisting heart condition. In the series by Wafa et al ²² only two patients with severe hepatic dysfunction had global heart failure. Heart failure usually results in mild abnormalities in liver dysfunction, 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 dysfunction was a predominantly cholestatic pattern rather than transaminitis in the patient with thyrotoxic heart failure, whilst the second patient without heart failure had equivalent derangements 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
充血性心力衰竭可能是甲状腺功能亢进症（甲状腺毒性心力衰竭）的并发症，也可能是先前存在的疾病。虽然窦性心动过速、心房颤动是常见表现，但如果没有潜在的先前存在的心脏病，明显的心力衰竭并不常见。在 Wafa 等人 ²² 的系列研究中，只有两名严重肝功能障碍患者患有整体心力衰竭。心力衰竭通常会导致肝功能障碍的轻度异常，然而，急性充血可能导致转氨酶和胆红素的显着增加，类似于与病毒性和中毒性肝炎相关的值。^16,23 元在最近一篇涉及 2 名 Graves 病患者的出版物中，我们发现甲状腺毒性心力衰竭患者的肝功能障碍主要是胆汁淤积模式，而不是转氨酶炎，而第二名没有心力衰竭的患者在胆汁淤积和转氨酶炎方面有等效的紊乱。 ⁶ 一般来说，据观察，甲状腺功能亢进症和心力衰竭患者比没有心力衰竭的患者表现出更严重的肝功能障碍（深部黄疸）、肝肿大、腹水和凝血病。^15,16 元

Graves’ disease can occur concurrently with other autoimmune conditions in about 10 % of cases ²⁴ ; common among these are primary biliary cirrhosis (PBC), autoimmune cholangiopathy (AIC) or autoimmune hepatitis. These autoimmune conditions usually have positive antinuclear antibody (ANA) and high ALP; AIC and some PBC cases are negative for antimitochondrial antibody (AMA).
格雷夫斯病可与其他自身免疫性疾病同时发生，约 10% 的病例 ²⁴ ;其中常见的是原发性胆汁性肝硬化 （PBC）、自身免疫性胆管病 （AIC） 或自身免疫性肝炎。这些自身免疫性疾病通常具有抗核抗体 （ANA） 阳性和高 ALP;AIC 和一些 PBC 病例的抗线粒体抗体 （AMA） 呈阴性。

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 commencement of medications. It is estimated that the incidence of antithyroid 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 dysfunction, 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
通常很难确定肝功能障碍的原因是否是由于抗甲状腺药物（硫脲类药物）引起的，尤其是在开始用药前未评估肝功能检查 （LFT） 的情况下。据估计，抗甲状腺相关肝功能障碍的发生率在 0.1% 至 0.2% ^{之间 25} ;肝损伤的危险因素包括高龄和较高剂量的抗甲状腺药物。在严重的肝功能障碍病例中，应停用致病药物，并考虑使用考来烯胺改善胆汁淤积症状，同时通过放射性碘治疗或手术确定性治疗潜在的甲状腺功能亢进症。^26,27 元

Predictors of Liver Dysfunction and Recovery
肝功能障碍和恢复的预测因子

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 al ²⁸ 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 correlation between ALT and left ventricular ejection fraction (LVEF) among patients with thyrotoxicosis and heart failure. ²²
到目前为止，研究尚未证明异常的肝脏生化检查与甲状腺激素水平之间存在相关性。一般来说，随着甲状腺激素的改善，肝功能障碍会恢复正常。^6,22Li et al ²⁸ 发现，在 Graves 病患者中，游离甲状腺素 （FT4） 的甲状腺激素 >70.5 pmol/L 较高，心率高于每分钟 90 次，肝功能损伤的风险增加。另一项研究还发现，在 19 名甲状腺功能亢进症和慢性心力衰竭 （CHF） 患者中，肝脏异常更严重。 ¹⁶ 然而，一项研究表明，在甲状腺毒症和心力衰竭患者中，ALT 与左心室射血分数 （LVEF） 呈负相关。 ²²

Timely initiation of antithyroid medications lead to improvement in liver dysfunction^6,22; particularly when biochemical euthyroidism is attained. In a recent systematic review and meta-analysis, following the initiation of antithyroid medications and attainment of euthyroidism, there was normalization abnormalities in ALT, AST, ALP, BIL, and GGT in 83%, 87%, 53%, 50%, and 70% respectively.
及时开始使用抗甲状腺药物可改善肝功能障碍 ^6,22;特别是当达到生化甲状腺功能正常时。在最近的一项系统评价和荟萃分析中，在开始抗甲状腺药物和达到甲状腺功能正常后，ALT、AST、ALP、BIL 和 GGT 正常化异常分别为 83%、87%、53%、50% 和 70%。

Conclusion  结论

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 challenge is sometimes to establish the definitive factor causing liver injury in a particular patient. Examination of liver function in the setting of hyperthyroidism is important to identify any abnormalities; timely initiation of antithyroid medication generally results in improvement.
与甲状腺毒症相关的肝功能障碍是临床实践中的常见发现。虽然确切的机制尚不清楚，但涉及直接和间接原因。有时挑战在于确定导致特定患者肝损伤的决定性因素。在甲状腺功能亢进的情况下，肝功能检查对于识别任何异常很重要;及时开始使用抗甲状腺药物通常会导致改善。