Sun Lei, Li Man, Zhang Liang, Teng Xiaoying, Chen Xiangmei, Zhou Xingang, Ma Zhiyuan, Qi Liming, Wang Peng
Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, People's Republic of China.
Medicine (Baltimore). 2017 Nov;96(45):e8620. doi: 10.1097/MD.0000000000008620.
Diagnosis of Crigler-Najjar syndrome type II (CNS-II) and Gilbert syndrome (GS) based on the serum bilirubin concentration is difficult, because this parameter can fluctuate under certain conditions. The aim of this study was to explore differences in UGT1A1 gene mutations, which cause both CNS and GS, and pathological changes between CNS-II and GS.Ninety-five Chinese patients with hereditary unconjugated hyperbilirubinemia were enrolled in this study. Peripheral blood samples obtained from patients were used to evaluate bilirubin levels and for UGT1A1 gene testing. Percutaneous needle biopsy of the liver and staining of tissue samples with hematoxylin and eosin, Masson trichrome, reticulin, and Perl Prussian blue were performed for 59 patients. The Ishak scoring system was used to assess inflammatory activity and the extent of fibrosis.One hundred ninety-two UGT1A1 mutations at 6 sites were detected in the 95 patients; the most common mutation in GS was c.-3279T>G in the phenobarbital response enhancing motif of the UGT1A1 promoter, whereas the most common mutation in CNS-II was p.G71R. The frequency of heterozygous p.G71R mutations in CNS-II was significantly higher than that in GS (P = .001); however, the frequency of homozygous c.-3279T>G mutations in CNS-II was markedly lower than that in GS (P = .032). Among all patients with multiple mutations, the frequency of p.Y486D was significantly higher in CNS-II than in GS (P = .007). The frequency of compound c.-3279T>G, A(TA)7TAA, and p.G71R mutations in CNS-II was significantly higher than that in GS (P = .001). Among the 59 patients who underwent percutaneous needle biopsy, 20 had iron deposition in the liver. The frequency of hepatic iron deposition in CNS-II was significantly higher than that in GS (P = .002).The linked polymorphic mutations, A(TA)7TAA and c.-3279T>G in UGT1A1, were most strongly associated with GS, whereas mutations in the coding region, especially p.G71R and p.Y486D, were more strongly associated with CNS-II. Iron deposition was more common in liver biopsies from patients with CNS-II than in those with GS.
基于血清胆红素浓度来诊断Ⅱ型克里格勒 - 纳贾尔综合征（CNS - II）和吉尔伯特综合征（GS）是困难的，因为该参数在某些情况下会波动。本研究的目的是探讨导致CNS和GS的尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1）基因突变以及CNS - II和GS之间的病理变化差异。
本研究纳入了95例中国遗传性非结合性高胆红素血症患者。采集患者的外周血样本用于评估胆红素水平和进行UGT1A1基因检测。对59例患者进行了肝脏经皮穿刺活检，并对组织样本进行苏木精 - 伊红、马松三色、网状纤维和普鲁士蓝染色。采用伊沙克评分系统评估炎症活动和纤维化程度。
在95例患者中检测到6个位点的192个UGT1A1突变；GS中最常见的突变是UGT1A1启动子苯巴比妥反应增强基序中的c.-3279T>G，而CNS - II中最常见的突变是p.G71R。CNS - II中杂合子p.G71R突变的频率显著高于GS（P = 0.001）；然而，CNS - II中纯合子c.-3279T>G突变的频率明显低于GS（P = 0.032）。在所有有多个突变的患者中，CNS - II中p.Y486D的频率显著高于GS（P = 0.007）。CNS - II中复合c.-3279T>G、A(TA)7TAA和p.G71R突变的频率显著高于GS（P = 0.001）。在接受经皮穿刺活检的59例患者中，20例肝脏有铁沉积。CNS - II中肝脏铁沉积的频率显著高于GS（P = 0.002）。
UGT1A中的连锁多态性突变A(TA)7TAA和c.-3279T>G与GS关联最为密切，而编码区的突变，尤其是p.G71R和p.Y486D，与CNS - II关联更为密切。CNS - II患者肝脏活检中的铁沉积比GS患者更为常见。
