Published online May 26, 2021. doi: 10.12998/wjcc.v9.i15.3631
Peer-review started: October 17, 2020
First decision: November 3, 2020
Revised: December 16, 2020
Accepted: February 24, 2021
Article in press: February 24, 2021
Published online: May 26, 2021
Functioning farnesoid X receptor (FXR; encoded by NR1H4) is key to normal bile acid homeostasis. Biallelic mutations in NR1H4 are reported in a few children with intrahepatic cholestasis. We describe a boy with progressive familial intrahepatic cholestasis and homozygous mutation in NR1H4.
A boy had severe neonatal cholestasis with moderate hypercholanemia and persistently elevated alpha-fetoprotein. Despite medical treatment, coagulopathy was uncontrollable, prompting liver transplantation at age 8 mo with incidental splenectomy. The patient experienced catch-up growth with good liver function and did not develop allograft steatosis. However, 1 year after transplant, he died from an acute infection, considered secondary to immunosuppression and asplenia. A homozygous protein-truncating mutation, c.547C > T, p.(Arg183Ter), was subsequently identified in NR1H4, and both parents were shown to be heterozygous carriers. Absence of FXR and of bile salt export pump expression was confirmed by immunostaining of explanted liver.
Severe cholestasis with persistently high alpha-fetoprotein and modest elevation of serum bile acid levels may suggest FXR deficiency. Some patients with FXR deficiency may not develop allograft steatosis and may respond well to liver transplantation.
Core Tip: Despite the central role farnesoid X receptor (FXR) plays in bile acid metabolism, only a few children with cholestasis and biallelic FXR deficiency have been reported, and that only recently. Using banked DNA from patients without previous successful genetic diagnosis, we have identified a child with a homozygous mutation predicted to truncate FXR prematurely. We describe his disease course before and after liver transplantation, accompanied by immunohistochemical studies. This report adds meaningfully to the available information regarding disease course and outcomes in patients with severe FXR deficiency. It highlights biochemical findings that may be characteristic of FXR deficiency.