4例不同类型胆管损伤型药物性肝损伤的临床病理特点分析

张天鹏; 叶立红; 高红霞; 董金红; 王翀奎

doi:10.3969/j.issn.1001-5256.2023.07.021

4例不同类型胆管损伤型药物性肝损伤的临床病理特点分析

DOI: 10.3969/j.issn.1001-5256.2023.07.021

张天鹏¹,
叶立红^2a,
高红霞^2b,
董金红^2c,
王翀奎^3, , ,

1.
石家庄市中医院肛肠科，石家庄 050011
2a.
石家庄市第五医院病理科，石家庄 050021
2b.
石家庄市第五医院内镜室，石家庄 050021
2c.
石家庄市第五医院肿瘤科，石家庄 050021
3.
河北中医学院实验中心，石家庄 050200

基金项目:

河北省医学科学研究课题计划项目 (20221688)

伦理学声明：本研究于2021年6月经石家庄市第五医院伦理委员会审批，批号：SJZWY2022015。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：张天鹏负责文章撰写；叶立红负责统计及表格设计；高红霞负责资料收集；董金红负责文献检索；王翀奎负责文章指导及最终审阅。

详细信息

通信作者:
王翀奎，sjzwck@163.com (ORCID：0000-0002-3040-8600)

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出版历程
- 收稿日期: 2022-10-24
- 录用日期: 2022-11-30
- 出版日期: 2023-07-20

Clinical and pathological features of drug-induced liver injury with different types of bile duct injury: An analysis of four cases

1.
Department of Coloproctology, Shijiazhuang Hospital of Traditional Chinese Medicine, Shijiazhuang 050011, China
2a.
Department of Pathology, Shijiazhuang Fifth Hospital, Shijiazhuang 050021, China
2b.
Endoscopy Room, Shijiazhuang Fifth Hospital, Shijiazhuang 050021, China
2c.
Department of Oncology, Shijiazhuang Fifth Hospital, Shijiazhuang 050021, China
3.
Experiment Center, Hebei University of Chinese Medicine, Shijiazhuang 050200, China

Research funding:

Medical Science Research Project of Hebei Province (20221688)

More Information

Corresponding author: WANG Chongkui, sjzwck@163.com (ORCID: 0000-0002-3040-8600)

摘要

摘要: 目的对比观察不同类型胆管损伤型药物性肝损伤(DILI)患者的临床、生化、病理、病程及预后特点。方法选取石家庄市第五医院2015年3月-2020年10月经肝穿刺组织病理明确诊断为胆管损伤型DILI 4例患者。收集患者的临床资料、历次实验室检查、影像学检查及预后情况, 并对肝脏病理形态进行半定量评分, 对比分析4例患者各指标之间的差异。结果胆管损伤型DILI女性患者多见, 多数预后较好。胆管损伤的部位、级别、范围及再生修复不同, 其相应的临床症状、肝生化指标及预后亦不同。结论肝穿刺组织病理仍然是胆管损伤型DILI明确诊断、了解病变损伤情况及判断预后的金标准。
- 化学性与药物性肝损伤 /
- 胆汁淤积 /
- 病理状态, 体征和症状
Abstract: Objective To investigate the clinical, biochemical, pathological, disease course, and prognostic features of drug-induced liver injury (DILI) patients with different types of bile duct injury. Methods Four patients who were diagnosed with bile duct injury-type DILI by liver biopsy in Shijiazhuang Fifth Hospital, from March 2015 to October 2010 were selected, and related data were collected, including clinical data, laboratory examinations, radiological examination, and prognosis.The semi-quantitative score was determined for liver pathological morphology, and each indicator was compared between the four patients. Results Bile duct injury-type DILI was more common in female patients, and most patients tended to have a good prognosis.Clinical symptoms, liver biochemical parameters, and prognosis varied with the site, grade, scope, regeneration, and repair of bile duct injury. Conclusion Liver biopsy is still the gold standard for making a definite diagnosis of bile duct injury-type DILI, understanding the condition of lesions, and judging the prognosis of this disease.
- Chemical and Drug Induced Liver Injury /
- Cholestasis /
- Pathological Conditions, Signs and Symptoms

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图 1 病例1发病期间肝生化变化趋势

Figure 1. Variation trend of liver biochemical of case 1 during the onset

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图 2 病例2发病期间肝生化变化趋势

Figure 2. Variation trend of liver biochemical of case 2 during the onset

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图 3 病例3发病期间肝生化变化趋势

Figure 3. Variation trend of liver biochemical of case 3 during the onset

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图 4 病例4发病期间肝生化变化趋势

Figure 4. Variation trend of liver biochemical of case 4 during the onset

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表 1 患者一般情况

Table 1. General data of patients

病例	性别	年龄 (岁)	既往史	用药史	病理诊断	病程	预后
1	女	59	无	因关节痛口服10付中药(含红花，土鳖等)	单纯胆汁淤积	2.5个月肝功能恢复	好
2	女	70	无	服“生发”中药(均含何首乌)治疗4个月	淤胆性肝炎	3个月肝功能恢复	好
3	女	23	无	因面部座疮口服“土霉素片”2个月	急性VBDS	1年肝功能基本恢复	较好
4	男	47	饮酒史20年	反复服用“阿莫西林” 3年	胆汁性肝硬化	3年7个月进展为肝衰竭	差
注：VBDS，胆管消失综合征。

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表 2 患者临床症状及体征情况

Table 2. Clinical symptoms and signs of patients

症状	单纯淤胆 (病例1)	淤胆性肝炎 (病例2)	急性VBDS (病例3)	胆汁性肝硬化 (病例4)
乏力	-	+	-	+
食欲不振	-	+	-	+
呕吐	-	-	-	-
恶心	-	-	-	-
发热	-	一过性	-	-
瘙痒	++	++	-	++
皮肤巩膜黄染	++	++	+	+++
厌油腻	-	+	-	+
茶色尿	+	+	-	+
大便发白	+	-	-	-
蜘蛛痣/肝掌	-	-	-	-/+
腹痛/腹泻	-	-	-	-/+
呕血/黑便	-	-	-	-
食管胃底静脉曲张	-	-	-	+
肝大	-	肋下2 cm	+	剑突下8 cm
脾大	-	肋下7 cm	+	巨脾
皮疹	-	-	-	偶有
注：+ 轻度；++ 中度；+++ 重度。

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表 3 患者肝生化指标高峰值及自身抗体情况

Table 3. The peak value of liver biochemical indexes and autoantibodies of patients

病例	ALT (U/L)	AST (U/L)	ALP (U/L)	GGT (U/L)	TBil (μmol/L)	DBil (μmol/L)	Alb (g/L)	GLB (g/L)	TBA (μmol/L)	ChE (U/L)	TC (U/L)	TG (U/L)	自身抗体
1	88	83	344	114	195	151	39	34	231	4 297	6.8	/	-
2	1 427	1 506	295	196	266	193	28	53	129	3 916	7.5	3.4	ANA 1∶640
3	356	258	745	826	54	38	35	46	135	3 824	10.9	2.9	-
4	150	193	711	514	585	447	26	33	389	1 189	4.7	1.6	-
注：肝功能各项指标均为病程中最高值(Alb为最低值)。GLB，球蛋白；ChE，胆碱酯酶；ANA，抗核抗体。/，未检测，-，阴性。

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表 4 患者影像学及病理检查

Table 4. Imaging and pathological examination of the patient

病例	胆囊壁厚 (mm)	脾长/厚 (cm)	肝最大斜径 (cm)	损伤靶点	病理描述
1	2	10.7/2.4	10.8	单纯毛细胆管损伤DILI临床分类淤胆型	肝小叶2带、3带肝细胞胆汁淤积及毛细胆管胆栓形成，吞噬细胞吞噬毛细胆管胆栓致肝窦轻度扩张，肝板排列较规整。汇管区内无明显炎症浸润。病理诊断：单纯性胆汁淤积
2	6	6.7/3.6	13.6	毛细胆管+肝细胞损伤DILI临床分类混合型	中央静脉周围可见融合性坏死，并见羽毛样变性及毛细胆管胆栓，坏死带内肝细胞脱失、网架塌陷，周围肝板呈双排(提示肝细胞再生)；汇管区内中度混合性炎细胞浸润。汇管区周边少数细胆管增生，部分小胆管上皮排列不整。病理诊断：淤胆性肝炎，早期再生修复
3	3	12.5/4.1	11.8	小叶间胆管损伤(VBDS)	汇管区间质内轻度单个核细胞浸润，并见蜡质样细胞沉积，其中5个汇管区均未见小叶间胆管；小叶内局部肝板断离及肝窦扩张，周围可见增宽的肝板(提示肝细胞再生)。病理诊断：VBDS
4	4	18.4/5.6	12.4	小叶间胆管及隔胆管以上较大胆管损伤(VBDS +胆汁性肝硬化)	第一次肝穿刺: 肝实质被纤维化扩大的汇管区及纤维间隔分隔成七巧板样结节，大部汇管区内未见小动脉伴行小胆管，可见较多增生细胆管，周边带肝细胞部分肿大呈胆盐淤积，毛细胆管内见粗大胆栓。病理诊断：胆汁性肝硬化第二次肝穿刺: 汇管区纤维化扩大程度较第一次肝穿刺加重，肝实质被破坏，仅见小团肝细胞残留。扩大汇管区及间隔内中度单个核细胞浸润，周边带细胆管增生较明显。被分隔肝实质内毛细胆管胆栓较第一次肝穿刺明显增多。病理诊断：胆汁性肝硬化，肝内慢性淤胆，药物性胆管损伤(VBDS)可能性大

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表 5 患者病理形态学特点及评分情况

Table 5. Pathological morphological characteristics and scores of patients

项目	单纯淤胆 (病例1)	淤胆性肝炎 (病例2)	急性VBDS (病例3)	胆汁性肝硬化 (病例4)
发病-肝穿刺时间	28天	42天	60天	3年5个月
肝穿刺长(cm)/汇管区(个)	1.0/7	1.2/10	1.2/6	1.3
坏死(分)	0	2	2	1
凋亡(分)	0	1	0	0
羽毛样变性(分)	1	2	0	1
毛细胆管胆栓(分)	2	1	0	3
胆色素(分)	2	2	0	0
吞噬细胞(分)	2	2	0	0
肝细胞再生(分)	0	3	2	0
汇管区扩大(分)	0	2	1	4
汇管区炎症(分)	1	3	1	2
炎细胞成分	单个核细胞	混合性炎细胞EOS+、P++	单个核细胞	混合性炎细胞
界面炎(分)	0	2	1	3
边缘胆管	轻度扩张、增生	轻度扩张、增生	无	中度扩张、增生
细胆管增生Ⅱ型(分)	0	1	0	3
纤维化分期	0	1	0	4
小叶间胆管损伤特点	胆管上皮变性、排列不整	胆管上皮空泡变、嗜酸性变性，排列不整	5/7汇管区缺乏小叶间胆管; 另2个汇管区内小叶间胆管变性、排列不整	汇管区内绝大部分小叶间胆管消失
注：EOS，嗜酸性粒细胞；P，浆细胞；各形态评分参照王泰龄教授DILI评分标准^[5]。

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