APPSPGHAN 2022

Jian-She Wang

Director, Center for Pediatric Liver Diseases, Children's Hospital of Fudan University

China

Dr. Jian-she Wang received his PhD degree in pediatrics and has been working on pediatric hepatitis B and inherited liver diseases since he started his PhD study. For hepatitis B, he provided important evidence for HBV-markers mother-to-babies transmission and the risk factors for mother-to-baby transmission of the virus. He is the pioneer in inherited liver diseases in China. He first diagnosed many inherited liver diseases in that population, such as Alagille syndrome, PFIC1-3, CTX, CBAS etc. As principal investigator, his group worldwidely first reported that MYO5B associated familiar intrahepatic cholestasis, ZFYVE19 associated high GGT cholestasis, ATP8B1 deficiency associated hypothyroidism, etc. He has been funded by The National Key Research and Development Program of China, and the Sino-Canada health cooperation project, and 6 regular projects from the Natural Science Foundation of China.

Inherited Intrahepatic cholestasis: molecular and clinical aspects

Liver Symposium : Neonatal cholestasis

13 October 2022 (1100-1300) @ Sipadan Hall 2

Familiar intrahepatic cholestasis (FIC) is a group of autosomal recessive disorders with genetical and clinical heterogeneity. Three well known types of FICs, namely type I-III, are caused by mutation in genes ATP8B1, ABCB11 and ABCB4 accordingly. ATP8B1 and ABCB11 are linked with low/normal gamma-glutamyltransferase (GGT) cholestasis. ABCB4 is a cause of high GGT cholestasis. Along with the application of next generation sequencing, mutations in TJP2, NR1H4, MYO5B and USP53 are identified as the new cause of low-GGT cholestasis, while KIF12 and ZFYVE19 high-GGT cholestasis in recently years.

Low GGT FICs usually manifest as a spectrum with various severity. The most severe form is progressive familiar intrahepatic cholestasis (PFIC), while mild forms are benign recurrent intrahepatic cholestasis (BRIC) or transit neonatal cholestasis (TNC). Some PFICs may have extrahepatic manifestations, such as hearing loss in ATP8B1-, TJP2-, USP53- PFICs; hypothyroidism in ATP8B1-PFIC; diarrhea in ATP8B1- and MYO5B- PFICs. ABCB11- and TJP2- PFICs may develop hepatocellular carcinoma. The liver severity of ABCB11-, TJP2-, and MYO5B- PFICs are associated with the predicted consequence of mutations in corresponding genes, while lack of a correlation between the phenotype and genotype of ATP8B1-PFIC.

Mutation in MYO5B (encoding myosin-VB) was original associated with microvillus inclusion disease (MVID). In 2016, we identified MYO5B bi-allelic mutation is also associated with low-GGT cholestasis without obvious diarrhea. MVID usually occurs in patients with bi-allelic null mutations, while MYO5B-associated FICs occur in patients with at least one non-null (missense or non-canonical splicing) mutation. The missense mutation may gain-of-toxicity for the transportation of bile salt export pump (BSEP). A clear phenotype-genotype correlation in MYO5B-FICs was further demonstrated in 2021 by our group.

We demonstrated bi-allelic pathogenic variants in USP53 are associated with low-GGT cholestasis in 2020. Most of the pathogenic variants are null variants. The presenting symptoms and histologic & ultrastructure abnormality are some like TJP2-associated low-GGT cholestasis. However, most of the patients experienced a much milder liver manifestation - transit neonatal cholestasis, though liver transplantation has been reported in a case.

In 2019, we demonstrated bi-allelic mutations in ZFYVE19 are associated with high GGT cholestasis. Some of cases presented as neonatal cholestasis and resolved. Most of them presented as consequences of portal hypertension. Liver histological changes resemble congenital hepatic fibrosis and sclerosing cholangiopathy. Up to now, all the reported pathogenic variants were predicted or proved leading to null effects. ZFYVE19 is known involved in cell division. Cilia abnormality was observed in patients and cell lines.
In conclusion, inherited intrahepatic cholestasis is caused by mutations in variety of genes. Most FICs have a spectrum of disease with different severity. Clear genotype-phenotype correlation has been observed in most of them, that may facility the precision management of patients.

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