1、1甲状腺功能亢进与肝损害甲状腺功能亢进症(甲亢) 所引起的肝脏损害在临床上相当常见。据 Gurlek A（1） 等观察，60.5的甲亢病人在确诊原发病时被发现至少有一项肝功能异常，而在台湾进行的一项前瞻性研究（Huang. MJ 等）中，这个比例更是高达75.8 （2） 。本文就甲亢合并肝脏损害作一综述。甲状腺激素对肝脏的影响甲状腺激素和肝脏之间关系密切。血清甲状腺激素浓度增高，对肝脏功能和胆汁代谢都可产生一定的影响。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，其增加肝脏氧耗量的作用仅次于对心脏和横膈膜。血清中过多的甲状腺激素可显著降低细胞色素 P450
2、、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的活性 （5，6） 。T4 能使 -磷酸甘油脱氢酶(GPD)的活力增强。甲状腺激素可抑制肝内胆固醇的产生，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的组成。研究发现，正常鼠胆汁中的牛磺胆汁酸占胆汁酸的 30左右，给予甲状腺素后，牛磺胆汁酸所占的比例可上升至 60-80。甲亢时肝脏的改变甲亢引起的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
3、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 和胆红素升高，血清白蛋白下降 （1，2） 。其中，以 ALP 升高最为明显，ALT次之。白蛋白的下降与基础代谢率和病程相关。不过，鉴于甲亢患者往往骨代谢旺盛，成骨细胞和破骨细胞活性增加，且体外试验证实甲状腺激素有直接使骨吸收的作用，因此，升高的 ALP 不仅仅来自肝脏，也来自骨骼，它对肝脏的评价意义可能不如 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的明显改变，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 和甲状腺刺激素（TSH）以正确评估甲状
4、腺功能 （7） 。甲亢病人肝脏损害的病理改变多种多样，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 等人的研究表明，甲亢患者出现肝脏脂肪浸润的比例可高达 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2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的转运、代谢、储存、分泌以及活性的发挥过程中都起着重要的作用，而甲
5、状腺激素水平对于维持肝脏正常功能及胆汁正常代谢也是不可缺少的。虽然甲亢引起肝脏损害的机制目前仍不是很清楚，但高水平的甲状腺激素在肝脏损害的发病中所起的作用是毋庸置疑的 （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，必需氨基酸和维生素消耗过多，造成负氮平衡，蛋白质缺乏，营养不良而使肝细
6、胞变性，造成肝内胆汁瘀积而引起 -GT 和碱性磷酸酶（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的肝糖原含量降低外，还同时引起剂量依赖性的肝胞液糖皮质激素受体（GCR）数目增多，Gurlek 等的研究进一步证实，甲亢患者 ALP 和 -GT 升高的比例分别高达 44.2和 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的可靠性 （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，使胆红素和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） 。随着免疫学的飞速进展，自身免疫机制在
7、甲亢肝损中的地位日益引起人们的关注。目前认为，甲状腺疾病与肝脏疾病有着共同的发病基础，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 细胞和巨噬细胞数目增多 （16，17） 。95 年，Cathebras PJ 等报道了第 1 例甲亢引起的肉芽肿性肝炎，后者的进展与甲亢的严重程度平行发展，经抗甲状腺药物治疗后好转 （18） 。从分子水平来看，Graves 病等甲状腺疾病和肝炎都存在着细胞因子的异常，它们反应了特定人群对某种疾病的易感性，比如，目前已经证实，HLA-A11 和HLA-DR4
8、 阳性的病人，甲亢合并肝损的比例可能更高 （8,19） 。这为将来甲亢肝损易感人群的防治提供了新的思路。甲亢引起肝损及其严重程度与甲亢引起的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，甲亢和/ 或甲亢合并 CHF 患者都可出现严重的肝功能异常，包括重度黄疸、凝血酶原时间延长等。3而合并心衰者，出现肝功能异常的比例远比无并发症的甲亢病人多。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的毒性作用，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-转移酶活性的显著下降有关 （5，6） 。诊断甲
9、亢肝损有时与甲亢合并病毒性肝炎、抗甲状腺药物引起的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）病毒性肝炎和甲亢无关，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，与甲亢存在着共同的发病基础，尤其是丙肝病毒感染。流行病学观察发现 （9） ，慢性丙肝病毒感染的女性患者与甲状腺自身免疫性疾病的发生率正相关，其中甲状腺机能亢进占了相当大的比例（7） ；（3）干扰素治疗的肝炎患者。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） 。两者的鉴别要点：1、甲亢合并病毒性肝炎患者多有明确的流行病学史，如
10、输血等；甲亢所致的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的患者。2、甲亢合并病毒性肝炎患者除甲亢的症状外，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。另一需要鉴别的是甲亢治疗过程中出现的药物性肝损。后者多有明确的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
11、功能可恢复正常，再用再发。由于误诊并非少见，尤其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是肝脏损害的主要原因，因此，有效地控制甲状腺功能亢进是预防、治疗肝损的关键。临床上以内科药物治疗为主。常规治疗方案：（1）注意休息，摄入足够的营养。 （2）停用一切肝损药物。 （3）抗甲状腺药物。常用者为硫脲类中的甲基及丙基硫氧嘧啶和咪唑类中的他巴唑及甲亢平。丙基硫氧嘧啶是甲亢合并肝脏损害的首选药物，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4合适的维持量。
12、 （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的病人，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 族和维生素 C 族。 （6）由于免疫因素在甲亢肝损的发病也起了重要作用，因此，对于较为严重的肝损病人，也可短期应用糖皮质激素治疗（18） ，至于轻中度肝损患者，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
13、后，肝功能全部恢复正常。Arch Intern Med. 1984 Sep;144(9):1764-5. PTU 致弥漫的间质性肺炎：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 月后和另一 Graves病患者 PTU（300 mg/day）治疗3 周后，胸片和支气管镜下肺活检显示弥漫的间质性肺炎。植物血凝素转化淋巴细胞受 PTU 高度刺激。停用 PTU、予以强的松龙治疗后症状和体征得到改善。Propylthiouracil-induced diffuse interstitial pneumonitis.Miyazono K, Okaza
14、ki T, Uchida S, Totsuka Y, Matsumoto T, Ogata E, Terakawa K, Kurihara N, Takeda T.1. 1947 年，首次报道 PTU 的肝毒性副作用。Livingston HJ, Livingston SF. 1947 Agranulocytosis and hepatocellular jaundice. JAMA. 135:422425. 2 Characteristics of patients with propylthiouracil-associated hepatotoxicity All cases (n =
15、28)Survivors (n = 21)Fatalities (n = 7)Age, yr (mean SD) 27.9 17.1 24.7 15.5 37.3 19.2Females/males (no.) 25/3 19/2 4/1Propylthiouracil dose at presentation with hepatotoxicity, mg/day (mean SD)426 199 424 200 433 216Months of continuous propylthiouracil therapy before hepatotoxicity (mean SD)3.6 3.
16、5 3.7 3.2 3.6 4.5Baseline liver function tests, no. of cases (%)Normal 2 (7.1) 2 (9.5) 0 (0)Abnormal 5 (17.9) 4 (19.0) 1 (14.3)Not reported 21 (75.0) 15 (71.4) 6 (85.7)5Table 4. Prevalence of thyroid function test abnormalities and management of hyperthyroidism at presentation with propylthiouracil
17、hepatotoxicity Survivors (n = 22) Fatalities (n = 7)Thyroid function tests, no. of cases (%)Hyperthyroid 5 (19) 2 (28.6)Normal 8 (38.1) 1 (14.3)Hypothyroid 1 (4.8) 0 (0)Not reported 8 (38.1) 4 (57.1)Treatment of hyperthyroidism,1 no. of cases (%)Radioactive iodine 12 (54.5)2 0 (0)Propranolol 10 (45.
18、5) 4 (57.1)Methimazole 3 (13.6) 0 (0)Oral iodide 4 (18.2) 1 (14.3)Thyroidectomy 1 (4.5) 0 (0)Not reported 7 (31.8) 3 (42.9)1 Patients may have received more than one form of therapy. 2 P 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的临床和实验室观察的基础上（因为停用 PTU 后肝功能衰竭仍可发展），应
19、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和脑病，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的亲和）、甲状腺功能正常性病变综合征的影响，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的肝毒性。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。6肝毒性出现后可单独使用碘化物。在多数病人，114 m
20、g 碘化物在 714 天内对甲状腺激素的产生最大的抑制，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。继往肝功能正常的甲亢病人中，高达 72%者至少伴有 1 个肝酶指标的升高。以 AKP 升高最常见，转氨酶升高是由于甲状腺毒症导致的肝脏的氧耗增加，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 所致肝毒性患者的肝活检更多表现为胆汁淤积。Table 5. Summary of recommendations for management of propylthiouracil hepatoto
21、xicity 1. 尽管肝酶研究无法预测哪些病人将发生肝毒性，但肝酶基值的测定可作为治疗过程中发生肝脏疾病的参考。 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的肝酶异常时，需停用 PTU，并寻找引起肝并的潜在因素。S
22、ignificant 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. 怀疑有肝毒性的病人需密切随访，因为肝功能障碍在停用 PTU 后仍有进展。Patients with suspected hepatotoxicity require close clinical fol
23、low-up because liver dysfunction can progress despite discontinuation of propylthiouracil.4. 对是否需要肝移植的早期认识可能提高生存。 Early recognition of the need for liver transplantation may improve survival.5. 甲状腺状态的判断需结合临床检查和 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 clini
24、cal 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的恶化。Prompt treatment of the underlying thyroid disease with radioactive iodine followed by iodide may diminish the chance of clinical deterioration fr
25、om persistent hyperthyroidism.7. 即使肝酶恢复正常仍不能再次用 PTU，因为它的肝毒性存在自身免疫的本性。Propylthiouracil should not be reinstituted even after the resolution of liver enzyme abnormalities due to the possible autoimmune nature of its hepatotoxicity.甲亢相关的肝功能基值的异常没有必要成为运用 ATD 的禁忌症，现有的资料无法证实肝功能基值异常的病人更易发生 PTU 所致的肝毒性。由于自身免
26、疫因素参与 PTU 所致的肝毒性、肝毒性情况在再次用 PTU 后又出现，所以肝毒性治疗后和肝移植后仍不能用 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. Burmeister7The Journal of Clinical Endocrinology 96(1):165-9. Relat
27、ed 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 Medicin
28、e, 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
29、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 jaund
30、ice or hepatitis symptoms with at least a 3-8times 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; m
31、ale: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
32、 +/- 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 wi
33、thout 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
34、 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 pa
35、tients 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
36、 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
37、 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
38、 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 AL
39、T 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 abnor
40、mal 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.9: J R Soc Health. 1999 Jun;119(2):117-20. Related Articles, Links Lessons to be learned: a case stu
41、dy 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. AOThe case is presented of a 74 year-old wo
42、man 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 repl
43、acement. 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 cas
44、e, 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 hype
45、rthyroidism 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 (IC
46、G) and antipyrine clearance in hyperthyroidism before and after antithyroid drug treatment. METHODS: Liver volume and blood flow in the portal vein were investigated in nine fasting patients with hyperthyroidism by means of computed tomography scan and Doppler ultrasound, respectively. ICG clearance
47、 was estimated by bolus injection of ICG (0.5 mg/kg body weight) and antipyrine clearance with a one-sample technique. All patients were investigated before and after 3 months of antithyroid treatment, when euthyroidism had been achieved. The Wilcoxon matched-pairs test was used for statistical anal
48、ysis. RESULTS: The median liver volume increased by 238 (155-289) ml (median, 95% confidence interval), corresponding to 19%, and the weight by 5.0 (0.0-8.0) kg (8%), and the antipyrine clearance decreased by 8 (3.1-34.4) ml/min (16%). These changes were all significant (P 0.05). The relation betwee
49、n liver 10volume and body weight increased from 19.9 (16.5-23.7) ml/kg to 21.4 (17.1-21.9) ml/kg (P = 0.11). The liver blood flow as estimated by ICG clearance and Doppler ultrasound was not altered significantly after the treatment period (P = 0.07 and 0.77, respectively). CONCLUSIONS: The liver volume increased by 19% in nine hyperthyroid patients during treatment with antithyroids. Antipyrine clearance was reduced by 16%, whereas liver blood flow, as estimated by ICG clearance and Doppler ultrasound examination of portal vein
