Progressive familial intrahepatic cholestasis : Clinical, biochemical, genetic and histopathological aspects

Abstract: In the early 1980 s, most cases of neonatal cholestasis (often referred to as neonatal hepatitis) remained unexplained. By today, many of these diseases have been characterized in detail. Progressive familial intrahepatic cholestasis (PFIC) is one of these cholestatic entities with early onset, where new techniques in genetics and molecular biology have contributed substantially to our understanding. The aims of this thesis were to further extend the knowledge of PFIC in terms of disease genetics, the effects of surgical diversion of bile, and the distribution of bile flows during cholestatic episodes and in remission. We studied a total of 18 patients. Genetic linkage analysis excluded involvement of the known disease locus at 18q21-22, and suggested that PFIC is a genetically heterogeneous disease. After the identification of the gene ABCB11, which causes PFIC type 2, genetic characterization showed a homozygous missense mutation (c.890A>G) causing an amino acid shift (p.E297G) in a majority of the Swedish children studied. One compound heterozygous child carried a microdeletion that had not previously been reported, and two children were negative for mutations in the coding sequence of ABCB11. A majority of the children studied presented with signs of coagulopathy, ranging in severity from bruises or nose bleeds to bleeding in the lung or brain, as a consequence of vitamin K malabsorption due to hampered hepatobiliary bile excretion. Complete relief of pruritus was observed in 7 of the 13 operated children within one month after partial external biliary diversion (PEBD). Six of the children were treated for increased stomal bile losses during the first 2-6 weeks after surgery. One patient underwent liver transplantation two months after PEBD due to end-stage liver disease, and one patient died of hepatocellular carcinoma 14 months after PEBD. At early follow-up after 11 to 21 months the children showed improved growth, and the biochemical markers of cholestasis were significantly reduced. All operated children suffered one or more cholestatic episode(s) of varying duration during the total follow-up period of 5 to 12 years. The total duration of these episodes correlated positively with the stage of liver fibrosis at the most recent follow-up liver biopsy (r=0.62, p<0.05). A statistically significant regress in histologic cholestasis was noted 3 years and 5 years after PEBD, and in fibrosis 5 years and more than 10 years after PEBD. A total of 13 scintigraphic examinations were performed on 9 operated children during episodes of cholestasis (n=5) and in remission (n=8). When we compared the fractions of isotopic activity lost through the stoma, in urine and remaining in the body during cholestasis and remission, we found a significantly larger fraction lost through the stoma (median 90% vs. 22%, p<0.05), and a smaller fraction into the urine (median 2.5% vs. 15%, p<0.05) in remission, than during cholestasis. We conclude that PFIC encompasses not one, but several cholestatic diseases, all caused by different defects in the formation of bile. Most children with PFIC caused by mutations in ABCB11 who undergo PEBD have a favorable long-term prognosis including histological improvement and long-term survival without the need for liver transplantation.