A drug used to treat acetaminophen hepatotoxicity may give hope to an effective treatment for FVH caused by liver-impairing viruses, including hepatitis A.
Fulminant viral hepatitis (FVH) is a form of acute liver failure caused by a virus and characterized by severe impairment of liver function. Primarily, children and young adults are affected, and the condition is usually fatal unless liver transplantation is implemented early enough. FVH tends to occur in people who are healthy and without any history of previous liver disease and progresses rapidly leading to encephalopathy and death. Given the treatment challenges and lack of a full understanding of how FVH develops, a group of scientists from Rockefeller University in New York analyzed the DNA of an 11-year-old girl who died from FVH. An autosomal recessive mutation of the IL-18 binding protein gene (IL-18BP) was identified via whole exome sequencing and gene expression analysis. The gene encodes for a protein that binds IL-18, normally limiting the ability of IL-18 to activate natural killer (NK) and other immune cells. The mutation causes a loss of IL-18BP function that leads to excess IL-18 available for NK cell activation. Examination of liver sections from the patient with the IL-18BP mutation revealed a profound decrease in the number of liver cells and an increase in NK cells, macrophages, and other immune cells. Other in vitro study results showed that the addition of human IL-18BP to hepatic cell cultures inhibited IL-18−induced interferon-gamma production by co-cultured NK cells.
Additional in vitro experiments were conducted involving co-culture of hepatocytes and NK cells, then infection with hepatitis A virus. When hepatitis A was added to the co-culture, the IL-18–activated NK cells killed infected and uninfected hepatocytes; however, this effect was halted by the addition of IL-18BP. These results suggest that the IL-18BP mutation in the 11-year-old patient led to FVH.
The IL-18BP mutation removes the liver-protective IL-18 binding ability, resulting in excess IL-18 available to activate NK cells that destroy liver cells, even those that are not infected with the virus. A drug already approved for use in treating acetaminophen hepatotoxicity is a recombinant human IL-18PB. This drug may represent a possible effective treatment for FVH caused by hepatitis A and other liver-impairing viruses.
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Resource: Genetic cause for fatal response to Hepatitis A. (2019). ScienceDaily. Retrieved 19 August 2019, from https://www.sciencedaily.com/releases/2019/06/190618094427.htm