Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum

Abstract

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease, characterised by intermittent attacks of cholestasis, which can start at any age and last for several weeks to months. Characteristically serum GGT activity is low and normal liver structure is preserved. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease, characterised by severe cholestasis, starting almost invariably before 6 months of age. All patients progress to cirrhosis, liver failure and death, unless a liver transplantation is performed. We now identified four patients who presented in childhood with recurrent attacks of cholestasis, while in the course of the disease the cholestasis gradually became permanent. Although liver biopsies performed in the early stages of the disease showed normal liver architecture, late stage biopsies revealed evident fibrosis with porto-portal septa formation. In conclusion, the disease of these patients started with the clinical and histopathological characteristics of BRIC but progressed to PFIC.

Introduction

BRIC, an autosomal recessively inherited liver disease, is characterised by intermittent attacks of cholestasis. It was first described in 1959 by Summerskill and Walshe [1]. The bouts of cholestasis in benign recurrent intrahepatic cholestasis (BRIC) can start at any age (usually before the second decade) and attacks can last for several weeks to months [2], [3], [4], [5]. During an attack serum bile salt concentrations and bilirubin values are elevated but gamma glutamyl transpeptidase (GGT) and cholesterol values remain in the normal range. During symptom-free intervals, lasting several months to years, serum biochemistry is normal. Liver biopsies are characterised histologically by intrahepatic cholestasis with preservation of normal liver structure. There is no progression to liver cirrhosis. Mutations in a single gene, FIC1 (recently renamed ATP8B1) were found to be responsible for this disease in most families described to date [6], [7], [8], although genetic heterogeneity is present [9], [10].

PFIC is another autosomal recessive liver disease, which is characterised by unremitting cholestasis that starts almost invariably before the age of 1 year and progresses to cirrhosis and liver failure [11]. Two clinically indistinguishable subtypes with a normal serum GGT activity are recognised: PFIC1, which is caused by mutations in the ATP8B1 gene [6], [8], [12], and PFIC2, which is caused by mutations in the ABCB11 gene (formerly called BSEP) [13]. In both subtypes cholestasis starts early and patients suffer from severe pruritis and, due to conjugated hyperbilirubinaemia, from jaundice [14], [15], [16], [17]. Liver biopsies show severe cholestasis with fibrosis and eventually cirrhosis [18], [19], [20], [21]. Death due to hepatic failure occurs in the first or second decade unless a liver transplantation is performed [15], [22], [23], [24].

In contrast to these two PFIC subtypes, MDR3 deficiency, sometimes referred to as PFIC3, is characterised by a markedly elevated serum GGT activity [25].

It is customary to see low GGT, PFIC and BRIC as sharply delineated entities (progressive versus remitting). However, some patients from the original Byler kindred, which we now know to have mutations in the ATP8B1 gene, had intermittent cholestasis in the first few years of life, before they developed progressive liver disease. Here we report four patients with classical BRIC (attacks of cholestasis and no liver damage) in the first decades of life, who developed permanent liver damage subsequently.