Hepatitis, Fulminant Viral, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to fulminant viral hepatitis (FVH) is conferred by homozygous mutation in the IL18BP gene (604113) on chromosome 11q13. One such patient has been reported.

Clinical Features

Belkaya et al. (2019) reported an 11-year-old girl, born of consanguineous Algerian parents, who developed fatal fulminant hepatitis upon acute infection with hepatitis A. The patient presented with fatigue, nausea, hepatomegaly, jaundice, decreased appetite, incoherent speech, and gingival bleeding, which rapidly progressed to coma, icterus, and liver failure. Liver enzymes were significantly increased, and she underwent liver transplantation, but died a day later of multiorgan failure. She had no previous chronic or acute liver disease, and her 2 brothers experienced benign hepatitis A infections. However, she had a history of autoimmune disease, including insulin-dependent diabetes mellitus with anti-islet cell and anti-insulin antibodies, Hashimoto thyroiditis with antithyroperoxidase antibodies, and antithyroglobulin antibodies. She was also seropositive for CMV and EBV. She had no other features of an immunodeficiency.

Inheritance

The transmission pattern of FVH in the family reported by Belkaya et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an 11-year-old girl, born of consanguineous Algerian parents, with FVH, Belkaya et al. (2019) identified a homozygous 40-bp deletion in the IL18BP gene (604113.0001), resulting in splicing abnormalities and complete IL18BP deficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the abnormal transcripts resulting from the mutation were unable to block any IL18 activity compared to wildtype or missense variants. Patient liver tissue showed high IL18 levels, barely detectable IL18BP, and high levels of inflammatory cells. Additional in vitro cellular studies showed that in the wildtype state, IL18-activated NK cells killed both infected and uninfected hepatocytes, and that this cytotoxicity was reversed by the addition of IL18BP. The findings indicated that absence of IL18BP in the patient with fulminant viral hepatitis due to hepatitis A led to uncontrolled IL18-mediated cytotoxic activity and an activated host response against hepatocytes.