甲状腺功能亢进与肝损害.doc

甲状腺功能亢进与肝损害甲状腺功能亢进症(甲亢)所引起得肝脏损害在临床上相当常见。据Gurlek A（1）等观察，60、5得甲亢病人在确诊原发病时被发现至少有一项肝功能异常，而在台湾进行得一项前瞻性研究（Huang、 MJ等）中，这个比例更就是高达75、8（2）。本文就甲亢合并肝脏损害作一综述。甲状腺激素对肝脏得影响甲状腺激素与肝脏之间关系密切。血清甲状腺激素浓度增高，对肝脏功能与胆汁代谢都可产生一定得影响。动物试验证实(3，4)，甲状腺激素可使肝脏重量减轻，肝糖原含量下降，氧耗量增加，其增加肝脏氧耗量得作用仅次于对心脏与横膈膜。血清中过多得甲状腺激素可显著降低细胞色素P450、谷胱甘肽水平及谷胱甘肽-S-转移酶活性，从而改变肝内相关酶得活性（5，6）。T4能使-磷酸甘油脱氢酶(GPD)得活力增强。甲状腺激素可抑制肝内胆固醇得产生，促进肝内胆固醇从胆道排泄或转化为胆汁酸，从而使血清胆固醇降低，干扰胆汁酸代谢。此外，甲状腺激素还能影响胆汁中胆汁酸盐得组成。研究发现，正常鼠胆汁中得牛磺胆汁酸占胆汁酸得30左右，给予甲状腺素后，牛磺胆汁酸所占得比例可上升至60-80。甲亢时肝脏得改变甲亢引起得肝脏损害多数呈亚临床状态。不过，少数病人也可出现黄疸、腹水、凝血酶原明显延长、肝硬化等严重情况。这一情况多发生于甲亢控制不佳或有心衰、严重感染等患者。至于甲亢严重度与肝损就是否存在正相关，目前还有所争论。在血生化检查方面，甲亢肝脏损害患者主要表现为ALT、AST、ALP、-GT与胆红素升高，血清白蛋白下降（1，2）。其中，以ALP升高最为明显，ALT次之。白蛋白得下降与基础代谢率与病程相关。不过，鉴于甲亢患者往往骨代谢旺盛，成骨细胞与破骨细胞活性增加，且体外试验证实甲状腺激素有直接使骨吸收得作用，因此，升高得ALP不仅仅来自肝脏，也来自骨骼，它对肝脏得评价意义可能不如ALT。在严重肝脏损害时，由于病人血中甲状腺激素结合蛋白浓度得明显改变，总T4水平并不能如实反映甲状腺功能状态，此时，应监测游离T4与甲状腺刺激素（TSH）以正确评估甲状腺功能（7）。甲亢病人肝脏损害得病理改变多种多样，根据尸检结果，大体上可分为三大类：1、急性退行性肝损害如显著脂肪变性，中心性或局灶性肝坏死；2、局部或弥漫性萎缩；3、硬变。这三种改变可同时存在。其中以脂肪浸润最为常见。Beaver等人得研究表明，甲亢患者出现肝脏脂肪浸润得比例可高达87、8。在病理切片上，可出现肝细胞气球样改变，肝细胞坏死，残存肝细胞胆色素颗粒沉着，肝小叶中央灶性坏死，结缔组织增生，新生毛细血管出现，局部淋巴细胞、单核细胞浸润，毛细胆管及Kupffer细胞增生等（8）。发病机制肝脏在甲状腺激素得转运、代谢、储存、分泌以及活性得发挥过程中都起着重要得作用，而甲状腺激素水平对于维持肝脏正常功能及胆汁正常代谢也就是不可缺少得。虽然甲亢引起肝脏损害得机制目前仍不就是很清楚，但高水平得甲状腺激素在肝脏损害得发病中所起得作用就是毋庸置疑得（7）。甲亢患者高甲状腺激素（T3、T4）通过以下可能途径影响肝功能：（1）高基础代谢率。它使内脏组织耗氧量增加，而与此同时，内脏动脉血流并不增加，造成相对缺氧状态，尤其就是肝小叶中央区域细胞供氧相对不足引起该区域坏死，使谷丙转氨酶（ALT）升高，这与临床上甲亢肝损病人肝穿刺活检结果相一致（8）。（2）由于甲状腺激素大量分泌，分解代谢亢进，肝糖原耗损，必需氨基酸与维生素消耗过多，造成负氮平衡，蛋白质缺乏，营养不良而使肝细胞变性，造成肝内胆汁瘀积而引起-GT与碱性磷酸酶（ALP）升高。动物试验证实（12），甲状腺激素除可引起与剂量有依赖关系得肝糖原含量降低外，还同时引起剂量依赖性得肝胞液糖皮质激素受体（GCR）数目增多，Gurlek等得研究进一步证实，甲亢患者ALP与-GT升高得比例分别高达44、2与14，不过由于甲亢患者骨代谢异常也可引起ALP升高，一定程度上削弱了评价肝损得可靠性（2）。（3）甲状腺激素直接作用于肝脏，包括抑制肝脏中葡萄糖醛酸基转移酶，使胆红素与葡萄糖醛酸结合障碍，进而影响胆红素从胆汁中排泄，导致血中胆红素升高（2，7）。随着免疫学得飞速进展，自身免疫机制在甲亢肝损中得地位日益引起人们得关注。目前认为，甲状腺疾病与肝脏疾病有着共同得发病基础，即自身免疫。研究发现，丙肝病毒感染、干扰素治疗等都可诱发甲亢（13，14，15）。甲亢病人往往存在特异性免疫调节缺陷，其抑制性T细胞功能减弱，B细胞与巨噬细胞数目增多（16，17）。95年，Cathebras PJ等报道了第1例甲亢引起得肉芽肿性肝炎，后者得进展与甲亢得严重程度平行发展，经抗甲状腺药物治疗后好转（18）。从分子水平来瞧，Graves病等甲状腺疾病与肝炎都存在着细胞因子得异常，它们反应了特定人群对某种疾病得易感性，比如，目前已经证实，HLA-A11与HLA-DR4阳性得病人，甲亢合并肝损得比例可能更高（8,19）。这为将来甲亢肝损易感人群得防治提供了新得思路。甲亢引起肝损及其严重程度与甲亢引起得其它并发症也有密切关系，如心功能不全，休克等。通过病例分析，Fong TL等人（20）发现，甲亢与/或甲亢合并CHF患者都可出现严重得肝功能异常，包括重度黄疸、凝血酶原时间延长等。而合并心衰者，出现肝功能异常得比例远比无并发症得甲亢病人多。国内资料也证实了这一点（21）。此外，甲亢可加剧其它肝损药物得毒性作用，包括酒精、氟烷等。这可能与甲亢引起细胞色素P450、谷胱甘肽水平及谷胱甘肽-S-转移酶活性得显著下降有关（5，6）。诊断甲亢肝损有时与甲亢合并病毒性肝炎、抗甲状腺药物引起得药物性肝炎不易区分。甲亢合并病毒性肝炎主要有以下几种情况：（1）病毒性肝炎与甲亢无关，相互独立存在。这一类情况最为多见；（2）病毒性肝炎引起甲亢。这就是因为病毒性肝炎主要通过免疫机制攻击人体，与甲亢存在着共同得发病基础，尤其就是丙肝病毒感染。流行病学观察发现（9），慢性丙肝病毒感染得女性患者与甲状腺自身免疫性疾病得发生率正相关，其中甲状腺机能亢进占了相当大得比例（7）；（3）干扰素治疗得肝炎患者。由于干扰素使机体免疫功能紊乱，即使停药后，仍有可能出现甲亢症状（10，11）。两者得鉴别要点：1、甲亢合并病毒性肝炎患者多有明确得流行病学史，如输血等；甲亢所致得肝损多见于未进行正规抗甲状腺药物治疗或出现各种并发症得患者。2、甲亢合并病毒性肝炎患者除甲亢得症状外，消化系统食欲不振、厌食油腻等肝炎症状明显，而甲亢患者肝损症状一般较轻微。3、甲亢合并病毒性肝炎患者血清中肝炎病毒标志物阳性，具有确诊价值；同时，这一类患者肝功能血清酶滴度也明显比甲亢肝损患者高。4、治疗上，一为保肝药物为主，一为抗甲状腺药物为主。另一需要鉴别得就是甲亢治疗过程中出现得药物性肝损。后者多有明确得抗甲状腺药物服用史，一般在治疗一个月后发生，往往呈一过性；肝损症状也比较轻微，但常合并出现皮肤搔痒、皮疹等过敏现象；血生化检查除了酶学异常外，还可见嗜酸粒细胞升高；停药后肝功能可恢复正常，再用再发。由于误诊并非少见，尤其就是甲亢肝损与甲亢合并病毒性肝炎这两种情况，而它们在治疗上大不相同，因此，临床医生在下诊断前必须对病史作综合分析。治疗与预后由于体内甲状腺激素分泌过多就是肝脏损害得主要原因，因此，有效地控制甲状腺功能亢进就是预防、治疗肝损得关键。临床上以内科药物治疗为主。常规治疗方案：（1）注意休息，摄入足够得营养。（2）停用一切肝损药物。（3）抗甲状腺药物。常用者为硫脲类中得甲基及丙基硫氧嘧啶与咪唑类中得她巴唑及甲亢平。丙基硫氧嘧啶就是甲亢合并肝脏损害得首选药物，开始可用100150mg，每8小时一次，一旦病情得到控制，宜逐渐减少剂量，摸索一个合适得维持量。（4）-受体阻滞剂。-受体阻滞剂如心得安能阻抑T4转化为T3，减少氧耗量与负氮平衡，同时减慢心率，减轻交感神经兴奋症状，但不影响病程。剂量可用1020mg，一日三次。暂不宜硫脲类药物治疗得病人，可先用此类药物控制症状，待病情控制后再选用其它手段治疗。（5）保肝治疗。可同时服用维生素B族与维生素C族。（6）由于免疫因素在甲亢肝损得发病也起了重要作用，因此，对于较为严重得肝损病人，也可短期应用糖皮质激素治疗（18），至于轻中度肝损患者，就是否应用糖皮质激素尚有争论。（6）严格控制心衰、感染等并发症。甲亢肝损患者若诊断及时，治疗积极，预后良好。一般在正规抗甲状腺治疗36个月后，肝功能全部恢复正常。Arch Intern Med、 1984 Sep;144(9):1764-5、 PTU致弥漫得间质性肺炎：咳嗽、劳力性呼吸困难、低氧血症发生于一Graves病患者PTU（300 mg/day）治疗6月后与另一Graves病患者PTU（300 mg/day）治疗3周后，胸片与支气管镜下肺活检显示弥漫得间质性肺炎。植物血凝素转化淋巴细胞受PTU高度刺激。停用PTU、予以强得松龙治疗后症状与体征得到改善。Propylthiouracil-induced diffuse interstitial pneumonitis、Miyazono K, Okazaki T, Uchida S, Totsuka Y, Matsumoto T, Ogata E, Terakawa K, Kurihara N, Takeda T、1. 1947年，首次报道PTU得肝毒性副作用。Livingston HJ, Livingston SF、 1947 Agranulocytosis and hepatocellular jaundice、 JAMA、 135:422425、 2 Characteristics of patients with propylthiouracil-associated hepatotoxicity All cases (n = 28)Survivors (n = 21)Fatalities (n = 7)Age, yr (mean SD)27、9 17、124、7 15、537、3 19、2Females/males (no、)25/319/24/1Propylthiouracil dose at presentation with hepatotoxicity, mg/day (mean SD)426 199424 200433 216Months of continuous propylthiouracil therapy before hepatotoxicity (mean SD)3、6 3、53、7 3、23、6 4、5Baseline liver function tests, no、 of cases (%)Normal2 (7、1)2 (9、5)0 (0)Abnormal5 (17、9)4 (19、0)1 (14、3)Not reported21 (75、0)15 (71、4)6 (85、7)Table 4、 Prevalence of thyroid function test abnormalities and management of hyperthyroidism at presentation with propylthiouracil hepatotoxicity Survivors (n = 22)Fatalities (n = 7)Thyroid function tests, no、 of cases (%)Hyperthyroid5 (19)2 (28、6)Normal8 (38、1)1 (14、3)Hypothyroid1 (4、8)0 (0)Not reported8 (38、1)4 (57、1)Treatment of hyperthyroidism,1 no、 of cases (%)Radioactive iodine12 (54、5)20 (0)Propranolol10 (45、5)4 (57、1)Methimazole3 (13、6)0 (0)Oral iodide4 (18、2)1 (14、3)Thyroidectomy1 (4、5)0 (0)Not reported7 (31、8)3 (42、9)1 Patients may have received more than one form of therapy、 2 P 0、05 compared to fatalities, by Fishers exact test、 No patient who died received 131I、 The timing of 131I ranged from 115 weeks (mean, 32 8 days) after presentation with hepatotoxicity、 Ten of the 12 patients who received 131I therapy were treated before the hepatic function test abnormalities resolved、据估计ATD相关得肝毒性发生率小于0、5%；PTU相关得肝毒性发生于各个年龄；女性居多；发生肝毒性得PTU剂量与疗程范围甚广；肝活检示非特异得肝细胞坏死；ATD致肝毒性得机制尚不明了，部分就是由于机体对PTU产生免疫反应。在暴发性肝功能衰竭中，一些早期预后因素与生存率低（20%）有关，其包括病人年龄(40 yr)、脑病发生前黄疸延续时间(7 days)、血清胆红素浓度(300 mol/L)、凝血酶原时间(50 s)。在对PTU所致肝毒性病人进行严密得临床与实验室观察得基础上（因为停用PTU后肝功能衰竭仍可发展），应考虑肝移植。脑病、低凝血酶原血症、肝肾综合征对肝移植不利。血浆置换、用血流灌注法血透可有效地纠正凝血障碍与脑病，为恢复肝功能或进行肝移植创造时机。因TT4受甲状腺激素结合蛋白、血清胆红素（降低T4与甲状腺激素结合蛋白得亲与）、甲状腺功能正常性病变综合征得影响，所以检测FT4才能真正反映患者甲状腺功能状况。病人接受131I 治疗比未接受治疗者较少发生严重得肝毒性。治疗应在做腹部CT（如果需要碘造影剂）或因甲状腺毒症需碘化物治疗前进行。碘化物可在131I治疗1周后服。心得安可用于控制甲亢症状；肝酶正常后也可使用MMI。肝毒性出现后可单独使用碘化物。在多数病人，114 mg碘化物在 714天内对甲状腺激素得产生最大得抑制，作用持续150天。但通常与ATD合用，碘化物也可加重甲状腺毒症状况。继往肝功能正常得甲亢病人中，高达72%者至少伴有1个肝酶指标得升高。以AKP升高最常见，转氨酶升高就是由于甲状腺毒症导致得肝脏得氧耗增加，而肝血流代偿不足。已报道MMI所致肝毒性21例，死亡3例（14%），死亡率与PTU比较无显著差异。MMI所致肝毒性患者得肝活检更多表现为胆汁淤积。Table 5、 Summary of recommendations for management of propylthiouracil hepatotoxicity 1、 尽管肝酶研究无法预测哪些病人将发生肝毒性，但肝酶基值得测定可作为治疗过程中发生肝脏疾病得参考。Although liver enzyme studies may not predict which patients will develop hepatotoxicity, baseline studies may serve as a reference value if signs of liver disease develop during the course of therapy、2、 治疗过程中出现明显得肝酶异常时，需停用PTU，并寻找引起肝并得潜在因素。Significant liver enzyme abnormalities detected during the course of therapy require prompt discontinuation of propylthiouracil as well as a search for any other potential sources of liver disease、3、 怀疑有肝毒性得病人需密切随访，因为肝功能障碍在停用PTU后仍有进展。Patients with suspected hepatotoxicity require close clinical follow-up because liver dysfunction can progress despite discontinuation of propylthiouracil、4、 对就是否需要肝移植得早期认识可能提高生存。Early recognition of the need for liver transplantation may improve survival、5、 甲状腺状态得判断需结合临床检查与FT4水平，因为高胆红素血症可负向干扰TT4水平。Thyroidal status must be determined by a combination of clinical examination and free T4 levels because hyperbilirubinemia can adversely affect the interpretation of total T4 levels、6、 进一步用放射性碘治疗甲亢，随后配以碘化物可能缓解甲亢得恶化。Prompt treatment of the underlying thyroid disease with radioactive iodine followed by iodide may diminish the chance of clinical deterioration from persistent hyperthyroidism、7、 即使肝酶恢复正常仍不能再次用PTU，因为它得肝毒性存在自身免疫得本性。Propylthiouracil should not be reinstituted even after the resolution of liver enzyme abnormalities due to the possible autoimmune nature of its hepatotoxicity、甲亢相关得肝功能基值得异常没有必要成为运用ATD得禁忌症，现有得资料无法证实肝功能基值异常得病人更易发生PTU所致得肝毒性。由于自身免疫因素参与PTU所致得肝毒性、肝毒性情况在再次用PTU后又出现，所以肝毒性治疗后与肝移植后仍不能用PTU。fFifty Years of Experience with Propylthiouracil-Associated Hepatotoxicity: What Have We Learned?1 Katherine V、 Williams, Sunil Nayak, Dorothy Becker, Jorge Reyes and Lynn A、 BurmeisterThe Journal of Clinical Endocrinology & Metabolism Vol、 82, No、 6 1727-17333Toxic hepatitis (primarily with propylthiouracil) and cholestatic jaundice (primarily with methimazole) are fortunately uncommon、150 Toxic hepatitis can be severe or fatal, but the incidence of serious liver complications is so low that routine monitoring of function tests has not been advised、151,152 Liver transplantation has been used with success in several patients 152、1、IFN-a induces thyroid dysfunction in 3 to 14% of all treated patients with chronic hepatitis C, leading to hypothyroidism, hyperthyroidism, or thyroiditis、 In a few patients, thyroid disease will develop in the absence of antithyroid antibodies, a scenario that suggests a nonimmune-mediated mechanism、: Am J Gastroenterol、 2001 Jan;96(1):165-9、 Related Articles, Links The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study、Kim HJ, Kim BH, Han YS, Yang I, Kim KJ, Dong SH, Kim HJ, Chang YW, Lee JI, Chang R、Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea、OBJECTIVES: Although symptomatic propylthiouracil (PTU)-induced hepatic injury is known to be rare, there have been few reports about its exact incidence in patients with hyperthyroidism、 We tried to evaluate its incidence in a single center and its clinical course、 METHODS: Medical records of 912 hyperthyroid patients who had been diagnosed between March 1990 and December 1998 were reviewed about clinical characteristics, management, and laboratory findings、 Symptomatic PTU-induced hepatic injury was defined as the development of jaundice or hepatitis symptoms with at least a 3-times elevation of liver function tests (LFT) without other causes、 RESULTS: Four hundred ninety-seven patients (age 42、6 +/- 10、7 yr, male/female 140/357) were included、 Clinically overt hepatitis developed in six patients (1、2%; age, 43、7 +/- 14、8 yr; male:female ratio, 3:3) between 12 and 49 days after PTU administration、 Jaundice and itching developed in five patients, fever in two, rash in two, and arthralgia in one、 Bilirubin, ALT, and ALP increased in five, four, and six patients, respectively (293 +/- 288 micromol/L, 143 +/- 111 U/L, and 265 +/- 81 U/L; normal, 117 U/L)、 The type of hepatic injury was cholestatic in three, hepatocellular in one, and mixed in two patients、 None resulted from viral hepatitis、 There were no statistical differences in age, sex, PTU dose, or T4 and T3 levels at initial diagnosis between patients with and without hepatic injury、 LFT normalized in all patients between 16 and 145 (72、8 +/- 46、4) days after the PTU withdrawal、 CONCLUSIONS: Symptomatic hepatic injury develops usually within the first few months of PTU administration with rare frequency, but its clinical course is relatively benign once the drug is withdrawn、 However, it may be difficult to predict its development, so all patients should be monitored for rise in LFTs at regular intervals, especially during the early period、70: Endocr Pract、 2000 Sep-Oct;6(5):367-9、 Related Articles, Links Abnormal results of liver function tests in patients with Graves disease、Biscoveanu M, Hasinski S、Division of Endocrinology and Metabolism, Department of Medicine, Hahnemann University Hospital, Philadelphia, Pennsylvania 19102, USA、OBJECTIVE: To determine the frequency of liver dysfunction in patients with hyperthyroidism、 METHODS: We analyzed the clinical records of 30 consecutive patients with Graves disease to identify the spectrum of abnormal results of liver function tests、 The values for alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma -glutamyltransferase (GGT), and total bilirubin were examined、 RESULTS: The frequencies of increased levels of AP, AST, ALT, GGT, and bilirubin in the current study group were similar to but somewhat lower than those reported in previous studies、 Of the 30 study patients, 11 (37%) had at least one abnormal result of a liver function test、 All 30 patients in the study had determinations of AP (not fractionated), of which 10 values (33%) were above normal (range, 124 to 283 U/L)、 Of the 30 patients who had determinations of AST, 5 (17%) had increased values that ranged from 36 to 71 U/L、 Six of the 23 patients (26%) with determinations of ALT had increased values that ranged from 45 to 157 U/L、 Of the 25 patients who had measurements of GGT, 6 had above normal results (range, 69 to 331 U/L)、 In addition, 2 of the 24 patients (8%) with determinations of total bilirubin had increased levels、 CONCLUSION: These findings indicate that abnormal results of liver function tests are common in patients with hyperthyroidism and make the diagnosis of concomitant, unrelated liver disease difficult until the euthyroid state has been established、: J R Soc Health、 1999 Jun;119(2):117-20、 Related Articles, Links Lessons to be learned: a case study approach: severe hyponatraemia induced by primary hypothyroidism and associated with possible increased hepatic sensitivity to thyroxine replacement、Olukoga A, Horsman G, Stewart F、Department of Clinical Biochemistry, Hope Hospital, Salford, Manchester、 The case is presented of a 74 year-old woman who was admitted with severe hypo-osmolar hyponatraemia associated with inappropriately raised urinary osmolality, and who was subsequently discovered to have primary hypothyroidism、 A normal serum sodium concentration was restored by means of judicious fluid restriction and thyroid hormone replacement、 Low dose thyroxine therapy led to rapid but modest increases in the serum activities of alanine aminotransferase (ALT) and alkaline phosphatase (ALP); both returned to normal over a period of three weeks、 These sub-clinical enzyme changes may indicate tissue hyperthyroidism; and in this case, the fact that they occurred acutely at only low doses of thyroxine possibly suggests an increased hepatic sensitivity to the hormone、104: Scand J Gastroenterol、 1999 Jun;34(6):618-22、 Related Articles, Links Liver volume, portal vein flow, and clearance of indocyanine green and antipyrine in hyperthyroidism before and after antithyroid treatment、Andersen V, Sonne J, Court-Payen M, Sletting S, Prip A, Molholm Hansen J、Dept、 of Endocrinology and Internal Medicine, Herlev Hospital, Denmark、BACKGROUND: The aim of the study was to examine liver volume, portal vein flow, and indocyanine green (ICG) and antipyrine clearance in hyperthyroidism before and after antithyroid drug treat