Differences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome type II.

Lei Sun,Xingang Zhou,Zhiyuan Ma,Xiangmei Chen,Peng Wang,Liang Zhang,Liming Qi,Man Li,Xiaoying Teng

doi:10.1097/md.0000000000008620

Abstract

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.

Highlights

Bilirubin is a water-insoluble breakdown product of hemoglobin that is transported to the liver, where it is conjugated with glucuronic acid by the uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) enzyme, and excreted into the bile.[1]
Among the 95 patients with unconjugated hyperbilirubinemia enrolled in this study, there were 59 cases with Gilbert syndrome (GS) (62.1%), 36 cases with Crigler-Najjar syndrome type II (CNS-II) (37.9%), and none with Crigler-Najjar syndrome (CNS)-I
The Ishak scores for inflammation and fibrosis were not significantly different between patients with CNS-II and GS in our study; we found that the frequency of hepatic iron deposition was significantly higher in CNS-II than in GS, which may be associated with elevated serum bilirubin concentrations,[26] as these can promote iron loading by decreasing oxidative stress and inhibiting hepcidin signaling as a result of reduced inflammatory activity

Summary

Introduction

Bilirubin is a water-insoluble breakdown product of hemoglobin that is transported to the liver, where it is conjugated with glucuronic acid by the uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) enzyme, and excreted into the bile.[1]. Crigler-Najjar syndrome is classified into 2 types, depending on serum total bilirubin (TBIL) concentration: the more severe (CNS-I) is characterized by high levels of TBIL (342–684 mmol/ L), whereas the milder form (CNS-II) is characterized by TBIL values ranging from 103 to 342 mmol/L.[8] In CNS-I, the most severe UGT1A1-associated hereditary disorder, described in 1952 by Crigler and Najjar, there is complete, or almost complete, absence of UGT1A1 enzyme activity, with severe jaundice, resulting in life-threatening hyperbilirubinemia and a lack of response to phenobarbital. CNS-II, described by Arias in 1962, is characterized by partial loss of UGT1A1 activity, leading to a moderate degree of jaundice, and a moderate response to phenobarbital, indicated by an approximately 30% decrease in serum bilirubin.[2]

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