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   复旦学报(医学版)  2021, Vol. 48 Issue (3): 418-422      DOI: 10.3969/j.issn.1672-8467.2021.03.022
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人工肝支持系统联合131I成功救治Grave's病所致重度黄疸1例并文献复习
闫丹丹1 , 于浩泳1 , 俞岗2 , 罗全勇3 , 包玉倩1 , 李连喜1 , 吴松华1 , 刘芳1     
1. 上海交通大学附属第六人民医院内分泌代谢科-上海市糖尿病临床医学中心-上海市代谢性疾病临床医学中心-上海市糖尿病重点实验室 上海 200233;
2. 上海交通大学附属第六人民医院肾内科 上海 200233;
3. 上海交通大学附属第六人民医院核医学科 上海 200233
摘要:甲亢所致重度黄疸在甲亢性肝损伤中少见且危重,临床治疗棘手。本例患者为23岁男性,1年半前确诊甲亢,口服抗甲状腺药物后出现肝损伤,停药保肝治疗后肝功能恢复正常。予甲状腺局部注射环磷酰胺+地塞米松治疗8个月后甲亢好转,未继续治疗。4个月前甲亢复发,肝功能再次出现异常,予多种保肝药物及静脉应用糖皮质激素,胆红素仍持续进行性升高。入院后明确为甲亢所致肝损伤,但患者存在重度黄疸,手术及131I治疗甲亢均存在较大风险,故在稳定心率、保肝退黄及小剂量糖皮质激素治疗基础上利用人工肝支持系统进行治疗。治疗后,黄疸及高代谢症状均较前明显减轻,血胆红素、甲状腺素、甲状腺自身抗体水平明显降低。之后予131I治疗,目前肝功能已恢复正常,甲亢明显改善。
关键词Grave's病    重度黄疸    人工肝支持系统    
Artificial liver support system combined with 131I for severe jaundice caused by Grave's disease: a case report and literature review
YAN Dan-dan1 , YU Hao-yong1 , YU Gang2 , LUO Quan-yong3 , BAO Yu-qian1 , LI Lian-xi1 , WU Song-hua1 , LIU Fang1     
1. Department of Endocrinology and Metabolism-Shanghai Clinical Center for Diabetes-Shanghai Key Clinical Center for Metabolic Disease-Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China;
2. Department of Nephrology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China;
3. Department of Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China
Abstract: Severe jaundice is a rare and severe liver injury caused by hyperthyroidism, which is troublesome in clinical practice.A 23-year-old male was admitted with hyperthyroidism and severe jaundice.One and a half years ago, he got liver damage after oral antithyroid drugs, liver function returned to normal via antithyroid drugs withdrawal and liver protection treatment.Then he accepted injection of cyclophosphamide and dexamethasone in thyroid gland for 8 months, and discontinued when the serum thyroxine returned to normal.However, hyperthyroidism recurred 4 months ago, and abnormal liver function appeared again. His serum bilirubin kept rising in spite of various liver protection drugs and intravenous glucocorticoids treatment.After admission, hyperthyroidism was confirmed as the cause of liver injury.However, in the case of severe jaundice, both surgery and 131I treatment for hyperthyroidism are of high risk.Therefore, based on the treatment of heart rate control, liver protection and low-dose glucocorticoid, artificial liver support system was added, then his jaundice and hypermetabolism symptoms were both relieved, serum bilirubin, thyroxine, thyroid autoantibody levels were significantly reduced.Thereafter, he accepted 131I treatment, and then hyperthyroidism has been significantly relieved and the liver function has returned to normal range.
Key words: Grave's disease    severe jaundice    artificial liver support system    

Grave’s病是甲状腺功能亢进症(以下简称:甲亢)最常见的病因,也是一种自身免疫性疾病,可引起心血管系统、消化系统等全身多系统损害,其中肝功能损害为常见的损害之一[1-2]。甲亢导致的肝损伤临床表现多样,以转氨酶升高多见,个别甲亢患者出现胆红素升高并引起重度黄疸,此类情况临床少见,治疗难度大,病死率高。人工肝支持系统的应用显著提高了甲亢合并重度黄疸的治愈率。

病例资料  患者男性,23岁,因“手抖1年半,心慌、怕热、多汗4个月,伴皮肤黄染半个月”收入上海交通大学附属第六人民医院。于2017年5月出现手抖,当时无其他高代谢症状,当地医院诊断为“甲亢”,予赛治10 mg/qd治疗1周,手抖症状无改善,复查肝功能示转氨酶升高(具体不详),遂停用赛治并保肝治疗2周,复查肝功能正常。2017年6月就诊于上海市某医院,予地塞米松、环磷酰胺甲状腺局部注射,每周1次,共计8个月,期间间断补钾保肝治疗。2018年1月复查甲功及肝功能均在正常范围,手抖症状明显好转。2018年7月出现心慌手抖、怕热多汗,汗液色黄伴臭味,前胸后背散发皮疹,当时无皮肤或巩膜黄染,无胸闷、乏力,未就诊,症状进行性加重。2018年10月于外院复查提示甲亢复发,肝功能示:丙氨酸氨基转移酶(alanine aminotransferase,ALT)176 U/L(参考值9~50 U/L),血清总胆红素52.3 μmol/L(参考值3.4~17.1 μmol/L),直接胆红素31.5 μmol/L(参考值0~3.4 μmol/L)。随后在该院内分泌科住院,予保肝(水飞蓟宾葡甲胺、双环醇、去氧胆酸胶囊等)、稳定心率(琥珀酸美托洛尔)治疗,复查ALT逐渐下降至62 U/L,但血清总胆红素进行性升高至149.7 μmol/L,直接胆红素升至94.7 μmol/L,心慌无缓解,并出现全身皮肤黄染伴皮肤瘙痒及巩膜黄染;转入该院感染科,第二天起予静脉应用甲强龙治疗9天(80 mg/qd×3天,60 mg/qd×3天,40 mg/qd×3天),复查胆红素仍持续升高(总胆红素452 μmol/L,直接胆红素247.9 μmol/L),皮肤及巩膜黄染进行性加重,并出现纳差、乏力。于2018年11月转入我院内分泌代谢科。发病以来,大便2~3次/天,成形,睡眠差。近1个月体重减轻约7 kg。既往体健,无肝炎病史。

查体:体温36.8 ℃,血压140/80 mmHg,神清,体型消瘦,全身皮肤黏膜黄染,前胸后背及上腹部可见散在丘疹,色暗红,双侧眼球略突出,巩膜黄染,有瞬目减少(如图5A~B),无复视。Joffory征阴性,Graefe征阴性,辐辏反射正常,伸舌震颤阳性,双侧甲状腺Ⅱ度肿大、质软、无压痛,未闻及血管杂音。心率110次/min,律齐,第一心音亢进,未闻及杂音。胸廓外形正常,肺部呼吸音清。腹部凹陷,无压痛反跳痛,肝脾肋缘下未触及,Murphy征阴性,肝肾区无叩痛,肠鸣音5次/min。有双手水平细颤,无胫前黏液性水肿。

诊疗过程   患者入院前于外院治疗1月余,经多种保肝药物及静脉糖皮质激素治疗,胆红素仍持续进行性升高(图 1)。入我院后行自免肝全套、肝炎病毒全套、肝脏超声、上腹部磁共振胰胆管成像等检查,均无异常。结合患者病史及相关辅助检查,考虑为甲亢导致的肝损伤。但考虑到患者存在重度高胆红素血症,高代谢症状明显,既往口服抗甲状腺药物后出现肝损伤,抗甲状腺药物治疗存在禁忌,在甲亢未控制情况下进行手术及131I治疗可能诱发甲亢危象,故在原有内科保守的保肝治疗基础上,于肾内科进行人工肝透析治疗。患者经透析后胆红素呈波动式下降(图 2A),游离三碘甲状腺原氨酸(free triiodothyronine,FT3)、游离甲状腺素(free thyroxine,FT4)及促甲状腺素受体抗体(thyrotrophin receptor antibody,TRAb)均逐渐降低(表 1),高代谢症状明显好转,考虑肝功能等改善。于2018年11月行同位素(131I)病因治疗,共9 mCi。治疗后1周,复查血胆红素较前又升高,再次行人工肝透析治疗2次,胆红素继续下降(图 2B)。于2018年12月行超声引导下肝脏穿刺活检,明确肝脏病理学改变(图 3),提示肝细胞重度淤胆,毛细胆管内胆栓形成,肝小叶内见点灶坏死伴肝细胞再生性改变,未发现自身免疫性肝炎的证据[3]。经人工肝支持系统治疗后,患者黄疸及高代谢症状均明显减轻(图 4C~D),肝功能恢复正常。出院后定期查甲功,提示FT3、FT4降低,但TSH始终< 0.005(参考值0.27~4.20 IU/L)。于2019年3月予第2次131I治疗(10 mCi),并口服复方碘溶液(5滴/次,每天3次,共2周),2个月后复查甲功提示“甲减”,予优甲乐每日50 μg口服替代,院外监测肝功能始终正常。目前患者继续在我科门诊随访。

TBIL: Total bilirubin; ALT: Glutamic-pyruvic transaminase. 图 1 患者入院前肝功能变化情况 Fig 1 Liver function of the patient before admission
A: Before 131I treatment; B: After 131I treatment.There were 3 test results of liver function on 2018-11-10 in the morning and in the afternoon just before and after artifical liver support system treatment respectively.There were 2 test results of liver function on 2018-11-13 in the morning and in the afternoon just before artifical liver support system treatment.Arrow points to the day of artificial liver dialysis.TBIL: Total bilirubin; ALT: Glutamic-pyruvic transaminase. 图 2 131I治疗前后患者肝功能变化情况 Fig 2 Liver function of the patient before and after 131I treatment
表 1 患者病程中甲功及甲状腺自身抗体变化情况 Tab 1 Thyroid function and auto-antibodies changes of the patient during the course of disease
Reference and date FT3 (pmol/L) FT4 (pmol/L) TSH (IU/L) TRAb (IU/L) TGAb (kIU/L) TPOAb (kIU/L)
Reference 3.1-6.8 12-22 0.27-4.20 0-1.58 0-115 0-35
Another hospital
  2018-04-06 33.7 89.5 0.010 - - -
  2018-10-25 43.5 100.0 0.010 29.1 601.3 147.3
Our hospital before 131I therapy
  2018-11-09 23.3 88.8 0.010 24.6 466.2 111.3
  2018-11-28 6.9 20.2 0.010 4.1 90.8 31.0
After the first 131I therapy
  2018-12-06 10.5 40.4 0.010 4.8 51.5 37.2
  2019-01-16 10.4 24.9 < 0.005 4.7 - -
  2019-02-20 16.5 33.2 < 0.005 37.1 - -
After the second 131I therapy
  2019-06-06 5.5 23.7 0.770 - - -
The patient received 131I at 9 mCi on Nov 28th, 2018, and131I at 10 mCi on Mar 1st, 2019, then he took Lugol's solution for 2 wk.FT3:Free triiodothyronine; FT4:Free thyroxine; TSH: Thyroid stimulating hormone; TRAb: Thyrotrophin receptor antibody; TGAb: Antithyroglobulin antibody; TPOAb: Anti-thyroid peroxidase antibody.
The hepatocytes in the lobules were swollen and denatured, and some showed feather denaturation.Punctate necrosis was occasionally seen.There was no enlargement of the portal area, and the inflammation was slight. 图 3 患者超声引导下肝脏穿刺病理结果(HE染色,×200) Fig 3 Biopsy of the liver via ultrasound-guided liver puncture (HE staining, ×200)
A and C: Manifestation of eye and skin on the second day after admission on Nov 9th, 2018;B and D: Manifestation of eye and skin on the discharge day on Dec 28th, 2018. 图 4 患者人工肝治疗前后体征对比 Fig 4 Appearance change of the patient before and after treatment

讨论  甲亢导致的肝损伤临床表现多样,从无症状的转氨酶升高,到严重肝功能异常、胆汁淤积性黄疸,甚至肝衰竭均可发生[4-5]。主要发病机制[6]包括:(1)高代谢状态可引起肝脏相对缺氧和供能障碍;(2)甲状腺激素(thyroid hormones,TH)对肝细胞的直接损失;(3)TH可影响肝内各种代谢酶活性;(4)免疫介导途径损伤肝细胞;(5)抗甲状腺药物本身可能引起肝损伤。此外,甲亢合并肝功能异常需排除肝脏及胆道系统本身病变。临床中发现甲亢合并轻度肝功能异常时,在明确为甲亢导致的肝损伤后,通常可在保肝治疗的基础上行药物、手术或131I治疗,控制甲亢后多预后良好。但在重度黄疸状态下,药物、手术、131I治疗均存在禁忌[7],高水平TH及胆红素持续作用于肝细胞,肝功能损害持续加重,最终导致肝衰竭,往往预后较差,病死率高。

本例患者初期甲状腺局部注射有效,病情缓解,但停止治疗半年后甲亢加重,且出现肝功能异常,排除其他原因后考虑为甲亢本身所致肝损伤。在多种保肝药积极治疗情况下,患者肝损伤进行性加重,且出现胆酶分离现象,能否及时有效降低血清胆红素水平、纠正黄疸,成为逆转结局的关键[8]

人工肝支持系统可通过在体外进行血浆置换、血浆吸附或血液滤过等方法,对血液中包括胆红素在内的多种有害物质进行清除,改善机体内环境,有利于肝细胞及毛细胆管的修复,为肝细胞再生及疾病治疗创造了条件[9]。人工肝支持系统起源于20世纪70年代,基于血浆置换或分子吸附再循环系统来治疗严重的病毒性肝炎,目前已广泛应用于急慢性肝衰竭伴肝肾综合征、肝性脑病、电解质紊乱等疾病的治疗[10-12],是临床治疗各种原因所致肝衰竭的一种安全有效的方法。利用人工肝支持系统治疗甲亢合并肝衰竭,可迅速控制甲亢症状并改善肝功能,为后续治疗创造条件[13-15]。国内多项临床回顾性研究显示,与传统内科治疗相比,人工肝支持系统可显著改善甲亢合并各种类型肝损伤患者的临床预后[16-19]。而目前国外仅有相关病例的个案报道,尚无系统性研究。

本例患者所应用的人工肝支持系统是在血液透析系统的基础上,加入具有特异性吸附胆红素功能的灌流器进行胆红素吸附,可有效降低血清胆红素水平,改善肝功能。同时该系统还可以通过吸附作用有效降低血清TH及包括TRAb在内的免疫复合物水平,从而改善机体高代谢状态,降低TH及相关免疫复合物对肝脏的损伤。本例患者入院诊断为Graves病合并重度黄疸,经临床排查及肝脏病理证实,排除溶血性黄疸、胆道梗阻、病毒性肝炎、自身免疫性肝炎等可能引起肝功能异常的原因[20],明确肝损伤为甲亢所致。患者早期透析后胆红素明显降低,但次日回升,后期胆红素的波动相对较小,可能与其早期高水平TH、相关免疫复合物及胆红素等毒物持续作用于肝脏有关。因此,患者利用人工肝支持系统有效降低血清胆红素水平、机体黄疸及高代谢状态明显改善后,及时进行131I治疗以消除病因,人工肝支持系统为后续131I治疗创造了机会。另外,患者治疗过程中辅以小剂量糖皮质激素[21],通过抗炎、抗毒、非特异性抑制免疫、调节机体应激等作用,减轻免疫因素对肝细胞的损伤,从而降低了甲亢危象的发生概率。

该例患者成功救治的经验总结如下:(1)甲亢出现肝功能异常病因不明时,需行肝脏穿刺活检明确诊断;(2)甲亢合并黄疸临床进展快,内科治疗效果差时,可介入人工肝支持系统;(3)当胆红素有效降低并稳定时,131I治疗需及时跟进。

作者贡献声明   闫丹丹  数据收集和整合,论文撰写。于浩泳,李连喜,刘芳  论文构思和修改,数据解释。俞岗,罗全勇  诊疗协助,论文指导。包玉倩,吴松华  论文审定。

利益冲突声明  所有作者均声明不存在利益冲突。

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文章信息

闫丹丹, 于浩泳, 俞岗, 罗全勇, 包玉倩, 李连喜, 吴松华, 刘芳
YAN Dan-dan, YU Hao-yong, YU Gang, LUO Quan-yong, BAO Yu-qian, LI Lian-xi, WU Song-hua, LIU Fang
人工肝支持系统联合131I成功救治Grave's病所致重度黄疸1例并文献复习
Artificial liver support system combined with 131I for severe jaundice caused by Grave's disease: a case report and literature review
复旦学报医学版, 2021, 48(3): 418-422.
Fudan University Journal of Medical Sciences, 2021, 48(3): 418-422.
通信作者
LIU Fang, E-mail: f-liu@sjtu.edu.cn.
基金项目
国家自然科学基金(81770802)
Foundation item
This work was supported by the National Natural Science Foundation of China (81770802)

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