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Abstract
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.
Highlights
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis
Progressive familial intrahepatic cholestasis (PFIC) types 1, 2 and 3 are a group of cholestatic conditions caused by mutations in ATP8B1, ABCB11 and ABCB4 respectively, and defects in TJP2, encoding tight junction protein 2, can cause severe cholestatic liver disease[12]
Patients with PFIC1 or PFIC2 and patients with TJP2 mutations characteristically present with low-to-normal serum gamma-glutamyl transferase (GGT) activity[12,15]
Summary
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Elevated bile acid levels activate FXR to induce a program that represses hepatocyte bile acid biosynthesis and uptake while increasing export[1,2] This suppression of bile acid production makes FXR a therapeutic target for cholestatic liver disease, and clinical trials of FXR agonists in primary biliary cirrhosis are promising[3,4,5]. Patients with PFIC1 or PFIC2 and patients with TJP2 mutations characteristically present with low-to-normal serum gamma-glutamyl transferase (GGT) activity[12,15] Both ABCB11, which encodes the bile salt export pump (BSEP) and is deficient in PFIC2, and ABCB4, which encodes multidrug resistance protein 3, MDR3, and is deficient in PFIC3, are direct targets of FXR. We describe four patients from two families with homozygous loss of NR1H4 function and severe neonatal cholestasis
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