Date Published: June 22, 2020
Publisher: Wolters Kluwer
Author(s): Eric Arthur Lorio, David Valadez, Naim Alkhouri, Nicole Loo.
Benign recurrent intrahepatic cholestasis represents a rare class of autosomal recessive chronic cholestasis disorders, usually presenting with recurrent episodes of intense pruritus and jaundice. We report a 27-year-old woman presenting with benign recurrent intrahepatic cholestasis type 2 due to heterozygosity in ABCB11. Interestingly, she was also found to be heterozygous in cystic fibrosis transmembrane conductance regulator, NPHP4, and A1ATD (SERPINA1), which may explain the severe nature of her disease expression because heterozygosity in each of these genes has been associated with cholestasis. Finally, she exhibited a response to steroids that may have implications for future treatment of bile salt export pump-related diseases.
Benign recurrent intrahepatic cholestasis (BRIC) represents a class of autosomal recessive disorders characterized by intermittent bouts of cholestasis.1 BRIC type 1 results from mutations in ATP8B1, whereas BRIC type 2 is caused by heterozygous mutations in the ABCB11 gene (2q24) encoding the ATP-dependent bile salt export pump (BSEP) protein in intrahepatic biliary ducts. Recurrent cholestasis and jaundice are hallmarks of the disease. By definition, BRIC does not progress to advanced liver disease, although repeat episodes can contribute to a marked reduction in quality of life, and any BSEP deficiency increases the risk of hepatobiliary malignancy (estimated 15% lifetime risk).2 One of the diagnostic challenges of BRIC is that aminotransferase activity can be normal during cholestatic attacks, and liver biopsies often show nonspecific hepatocanalicular cholestasis. BRIC diagnosis requires a high degree of clinical suspicion and can only be confirmed with genetic testing for corresponding mutations in ATP8B1 and ABCB11. We present a patient with multiple hospitalizations for debilitating fatigue, weakness, and pruritus, and we demonstrate a BRIC-2 response to corticosteroids that may represent a novel therapy for treatment-refractory disease.
A 27-year-old Hispanic woman presented with jaundice, pruritus, and weakness for 4 weeks. This marked her third similar admission, having first presented with similar symptoms 3 years earlier when she was pregnant with her first child. At that time, she had a total bilirubin (TB) level of 13.2 and was diagnosed at 22 weeks with intrahepatic cholestasis of pregnancy (ICP). Hepatitis A, B, C, antinuclear antibody, antismooth muscle antibody, anti-liver/kidney microsome-1 antibody, antimitochondrial antibody, ceruloplasmin, ferritin, iron saturation, α-1 antitrypsin, right upper quadrant ultrasound, and magnetic resonance cholangiopancreatography were all negative, and signs and symptoms resolved after an uncomplicated preterm cesarean section.
We present a diagnosis of BRIC that remained elusive through multiple hospitalizations. Liver biopsy revealed hepatocyte pericentral and perisinusoidal fibrosis, which is more suggestive of PFIC, a progressive, fibrotic liver disease due to a homozygous ABCB11 mutation resulting in at least a 70% reduction in bile acid secretion.3 Although BRIC rarely progresses to PFIC, these disorders may not be entirely distinct, and evidence increasingly suggests they may represent a continuum of disease.4
Author contributions: All authors contributed equally to this manuscript. E. Lorio is the article guarantor.