Gilbert综合征29例临床病理及基因分析

Gilbert syndrome:clinicopathological and genetic analyses of 29 cases

目的分析Gilbert综合征(GS)的临床特征、组织病理、超微病理及基因变化特点,探讨GS的综合精准诊断要点。方法收集2015-01—2017-03间广州金域医学检验中心2270例肝穿刺活检病理资料,其中29例诊断为GS。采用HE染色、铁染色、铜染色、网染、Masson染色等组织化学染色及超微病理观察,并结合临床表现、诱发因素、基因检查等资料进行分析总结。结果 29例GS约占总肝穿病例的1.3%,男女之比为2.6∶1,年龄5~62岁,多在20~50岁发病。临床主要表现为反复发生的眼黄、尿黄、皮肤黄染(100%),其次为乏力、纳差、上腹部不适(17.2%),脾大(13.7%),肝大(6.8%)。实验室检查常有胆红素升高(75%),以间接胆红素升高为主;22例(91.7%)ALT、AST、GGT正常,9例(29.2%)ALP轻度升高,2例叠加药物性肝损伤者以上4项均明显升高。组织病理:肝小叶结构基本完整,肝细胞正常或轻微水肿,胞质内仅见少量棕黄色细小脂褐素样色素颗粒,以中央静脉周围肝细胞为明显,偶见脂肪变性,Kupffer细胞内无吞噬色素颗粒现象;汇管区无炎症反应或仅见少量淋巴细胞散在分布,无界面炎及纤维化,仅1例见小叶间短的纤维间隔。超微病理:肝细胞内淤胆性色素颗粒沿毛细胆管周围分布,颗粒中透亮区大于电子致密区,毛细胆管轻度扩张,管腔空虚。基因检测:6例GS均显示UGT1A1基因突变。结论 GS在青中年多发,临床表现及实验室检查有一定特点,但缺乏特异性,肝穿刺病理病变轻微,常无慢性肝病表现,而超微病理具有特征性改变。因此,肝穿刺组织病理、超微病理并结合基因检测是诊断GS的可靠方法。

Objective To comprehensively analyze the clinical features,histopathological,ultrastructural pathological and genetic changes of Gilbert syndrome（ GS）,and to investigate the value of combined approaches for presicion diagnosis of GS. Methods The study was based on data of 2270 cases of liver biopsy pathological analyses from January 2015 to March 2017 in Guangzhou Kingmed Center for Clinical Laboratory. Among these,29 cases were diagnosed as GS,by using the conventional HE staining,iron,copper,dye,Masson histochemical staining and ultrastructural observation,combined with the clinical manifestation,inducing factors,such as laboratory data analysis. Results 29 cases of GS accounted for1. 3% of the total cases,the ratio of male to female was 2. 6∶ 1,age ranging 5 ~ 62 years old,mostly at 20 ~ 50 years old.The main clinical manifestations were recurrent yellow eyes,yellow urine and yellow skin（ 100%）,followed by fatigue,anorexia,abdominal discomfort（ 17. 2%）,splenomegaly（ 13. 7%）,hepatomegaly（ 6. 8%）. Laboratory examination of ten cases had elevated bilirubin（ 75%）,mainly with elevated indirect bilirubin,22 cases（ 91. 7%） had normal ALT,AST and GGT,and 9 cases（ 29. 2%） had mild elevated ALP,the above 4 items were obviously elevated in 2 cases with superimposed drug-induced liver injury. Histopathologically,the structure of hepatic lobules was basically intact,liver cells were normal or slight edema,only a few small brown lipofuscin like pigment granules were seen in liver cells,especially around the central vein; fatty degeneration of liver cells was found occasionally; there was no phenomenon of phagocytosis in Kupffer cells. The portal area had no inflammation or only a few scattered lymphocytes,no interfacial inflammation or fibrosis in this zone,short interlobular fibrous septa were seen in only 1 cases. Ultrastructurally,cholestatic pigment granules in hepatocytes were distributed around the capillary bile duct,the transparency region in the granules was larger than the electron dense region,the capillary bile duct dilated slightly and the lumen was emptiness. Genetic analysis showed that 6 cases of GS showed mutation in the UGT1 A1 gene. Conclusions GS is more frequently found in young and middle-aged patients,the clinical manifestation and laboratory examination have some characteristics, but lack specificity. The pathological changes of liver biopsy are mild,and chronic liver injury is absent,and the ultrastructure displays some characteristic changes. Therefore,histopathology and ultrastructural pathology of liver biopsy combined with gene detection are reliable methods for diagnosis of GS.