Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature.

Introduction: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Methods: In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature. We performed whole-exome sequencing and then confirmed it with Sanger sequencing. In addition, as a result of in silico analyses and cDNA analysis, we showed that the USP53 protein in our patient was shortened. Results: We report a novel splice variant (NM_019050.2:c.238-1G>C) in the USP53 gene via whole-exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by Sanger sequencing and was a result of family segregation analysis; it was found to be in a heterozygous state in the parents and the other healthy elder brother of our patient. According to in silico analyses, the change in the splice region resulted in an increase in the length of exon 2, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1,073 amino acids, has been reduced to a small protein of 82 amino acids. Conclusion: We propose a model for the tertiary structure of USP53 for the first time, and together with all these data, we support the association of biallelic variants of the USP53 gene with cholestasis phenotype. We also present a comparison of previously reported patients with USP53-associated cholestasis phenotype to contribute to the literature.

Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria.

AIMS: Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey. METHODS AND RESULTS: The resection specimens of 59 cases diagnosed as 'hepatocellular adenoma' collected from 15 institutions were reviewed to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, ß-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. We identified 24 (50%) hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) ß-catenin-activated HCAs, three (6%) ß-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34 years and a median tumour diameter of 60 mm. In the ß-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the ß-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The original diagnosis of HCA was changed to well-differentiated hepatocellular carcinoma in nine cases and to focal nodular hyperplasia in two cases. CONCLUSION: In our series, the major HCA subtype was HNF1α-inactivated HCA. We found a low incidence of inflammatory-type HCA. Our data also showed that ß-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings are in contrast to those of most other studies of HCA subtypes.

Diagnostic accuracy of different noninvasive scores for detecting advanced fibrosis in chronic hepatitis B.

OBJECTIVES: The liver biopsy is the gold standard for determining the level of fibrosis in chronic hepatitis B infection (CHBI). Nonetheless, it is possible to predict liver fibrosis through some noninvasive methods such as noninvasive scoring (NIS) of some serum biomarkers obtained from routine blood tests. We aimed to evaluate the diagnostic accuracy of nine NIS for detecting advanced fibrosis in CHBI. PATIENTS AND METHODS: We reviewed the hospital records of CHBI cases with liver biopsy between January 2011 and December 2016 retrospectively. Using Ishak scoring method, we classified fibrosis stage 1-2 as mild and 3-6 as advanced fibrosis. We calculated the NIS by considering the age, platelet count, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, platelet, and international normalized ratio values at the time of the biopsy. RESULTS: The mean age of 202 patients was 37.69± 11.33 years. In cases with advanced fibrosis, the age, gammaglutamyltransferase, and international normalized ratio values were higher and platelet count was lower (P < 0.05). Mean platelet volume was not different between the two groups (P = 0.499). The median values of γ-glutamyl peptidase-platelet ratio (GPR), FibroQ, Goteborg University Cirrhosis Index, fibrosis-4 (FIB-4), aspartate aminotransferase-platelet ratio index, age-platelet index, and King scoring were significantly higher in the advanced fibrosis group. The highest area under the curve value was in GPR [AUC = 0.731 (0.639-0.788); P = 0.000] in the receiver operating characteristic curve analysis. Cirrhosis Discriminant Score and Aspartate aminotransferase-to-alanine aminotransferase ratio tests were not valuable in detecting advanced fibrosis. FIB-4 had the highest (0.678) diagnostic accuracy rate. CONCLUSION: We found that the calculation of NIS before liver biopsy, especially GPR and FIB-4, may be useful for predicting advanced fibrosis in cases with CHBI.