UGT1A1 gene polymorphisms in patients with Gilbert syndrome and Crigler-Najjar syndrome type Ⅱ / 临床肝胆病杂志

Objective To investigate the differences in UGT1A1 gene mutation sites, haplotypes, and diplotypes between patients with Gilbert syndrome (GS) and those with Crigler-Najjar syndrome type Ⅱ (CN-2). Methods A retrospective analysis was performed for the clinical data of 138 patients with GS or CN-2 who attended Beijing YouAn Hospital, Capital Medical University, from January 1, 2010 to December 31, 2019, with 109 patients in the GS group and 29 patients in the CN-2 group, and the differences in mutation sites were analyzed between the two phenotypes. The Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. SNPStats software was used to perform linkage disequilibrium (LD) and haplotype analyses of mutation sites. Strong LD was defined as both | D ′| and r 2 > 0.8, and moderate LD was defined as | D ′| > 0.8 and r 2 > 0.4. Results UGT1A1 gene detection was performed for all patients, and mutations mainly included -3279T > G mutation (104 patients, 75.36%) and -3152G > A mutation (82 patients, 59.42%) in the upstream promoter PBREM region, a promoter TATA box TA insertion mutation (88 patients, 63.77%), and c.211G > A mutation in Exon 1 of the coding region (66 patients, 47.83%). Compared with the CN-2 group, the GS group had a significantly higher proportion of PBREM region -3279T > G mutation (82.57% vs 48.28%, χ 2 =14.508, P A mutation (68.81% vs 24.14%, χ 2 =18.955, P (TA) 7 mutation (72.48% vs 31.03%, χ 2 =17.027, P 0.8, r 2 > 0.8) between (TA) 6 > (TA) 7 and -3152G > A and moderate LD (| D ′| > 0.8, r 2 > 0.4) between (TA) 6 > (TA) 7 and -3279T > G, between -3152G > A and -3279T > G, between (TA) 6 > (TA) 7 and c.211G > A, and between -3279T > G and c.211G > A. Haplotype frequency analysis showed that compared with the CN-2 group, the GS group had a significantly higher frequency of haplotype -3279G—-3152A—(TA) 7 (45.72% vs 17.24%, χ 2 =7.833, P =0.005) and significantly lower frequencies of c.1456G (4.10% vs 16.48%, χ 2 =4.873, P =0.027) and c.211A—c.1456G (1.86% vs 24.90%, χ 2 =15.210, P < 0.001). The diplotype analysis showed that diplotypes consisting of haplotype c.1456G or c.211A—c.1456G were associated with a higher level of total bilirubin (TBil). Conclusion There are differences in common mutation sites and major haplotypes of the UGT1A1 gene between patients with GS and those with CN-2, and the common diplotypes of CN-2 correspond to a higher level of TBil.

Value of common clinical indices and noninvasive liver fibrosis scores in the diagnosis of advanced liver fibrosis in hepatic-type Wilson’s disease in China / 临床肝胆病杂志

ObjectiveTo investigate the association of common clinical indices and noninvasive liver fibrosis scores with hepatic-type Wilson’s disease (WD) in Chinese patients and their ability to identify advanced liver fibrosis. MethodsA retrospective analysis was performed for the clinical data of 236 Chinese patients with WD who were diagnosed and treated in Beijing YouAn Hospital and China-Japan Friendship Hospital from May 1996 to April 2020. A total of 26 patients with hepatic-type WD who underwent liver pathological examination and had complete clinical data were enrolled; the METAVIR score was used to determine liver fibrosis stage, and the patients were divided into advanced liver fibrosis (F3 and F4 stages) group and non-advanced liver fibrosis (F0, F1, and F2 stages) groups. Three noninvasive liver fibrosis scores ［Sheth index, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) index］ were calculated for both groups, and the above indices and related clinical indices were compared between the two groups. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the Fisher’s exact test was used for comparison of categorical data between two groups. The Spearman rank correlation test was used for further analysis of indices with statistical significance, and the clinical indices and scoring criteria correlated with liver fibrosis degree were screened out; the receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated. ResultsMost of the patients in this study developed the disease in childhood and adolescence, and among these patients, 10 (38.5%) had positive K-F ring and 17 (65%) were in the stage of advanced liver fibrosis. There were significant differences between the advanced liver fibrosis group and the non-advanced liver fibrosis group in white blood cell count (WBC) (Z=-2.102, P=0.036), hemoglobin (Hb) (t=-2.860, P=0009), platelet count (PLT) (t=-4.053, P＜0.001), direct bilirubin (DBil) (Z=-2.130, P=0.033), albumin (Alb) (t=-2.875, P=0.008), and Sheth index (Z=-3.369, P=0.001). WBC, Hb, PLT, and Alb were negatively correlated with liver fibrosis degree in WD patients (r=-0.587, -0.610, -0.656, and -0.411, all P＜0.05), and DBil and Sheth index were positively correlated with liver fibrosis degree (r=0.486 and 0.711, both P＜0.05). The ROC curve analysis showed that WBC, DBil, Sheth index, Hb, PLT, and Alb had an AUC of ＞0.7, among which Sheth index had the largest AUC of 0.908, with a sensitivity of 70.6%, a specificity of 100.0%, a positive predictive value of 100.0%, and a negative predictive value of 64.3%. ConclusionSheth index has a better diagnostic efficiency than the other clinical indices alone and can well identify advanced liver fibrosis in Chinese patients with hepatic-type WD.