Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.

Cash WJ, Knisely AS, Waterhouse C, Iqbal M, Stokes V, Byrne B, McCormick PA. Successful pregnancy after liver transplantation in progressive familial intrahepatic cholestasis, type 1. Pediatr Transplantation 2011: 15: E174–E176. © 2010 John Wiley & Sons A/S.



Abstract:  A woman who had undergone liver transplantation for genetically documented ATP8B1 disease/progressive familial intrahepatic cholestasis, type 1, successfully conceived, carried, and was delivered of a healthy child. The pregnancy and its management are described; implications are discussed.

Successful pregnancy after liver transplantation in progressive familial intrahepatic cholestasis, type 1.

Progressive familial intrahepatic cholestasis (PFIC), as a diagnosis, was for years an omnium-gatherum. The qualifiers of cholestasis in PFIC mean that the liver disease of PFIC does not resolve, but instead persists, and progresses to fibrosis or cirrhosis; that within a family siblings are at risk of developing the same disease as does a proband (although, of course, this in actuality may never occur); and that the intrahepatic biliary tract is not abnormal, an inference —not necessarily correct—from demonstration that the extrahepatic biliary tract is not frankly obstructed. One can see that a misdiagnosed tyrosinemia, for example, lies within these bounds. Clinical data must be reviewed to ensure that usual causes for pediatric liver disease have been adequately assessed before PFIC is invoked, and care must be taken that PFIC is not used too loosely, as a “wastebasket” diagnosis.

Hepatocellular and Familial Cholestasis

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 18q2122, 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 followup 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.

https://openarchive.ki.se/xmlui/bitstream/handle/10616/39099/thesis.pdf;sequence=1

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

INTRODUCTION Progressive familial intrahepatic cholestasis (PFIC), originally described as “Byler disease” in an Amish kindred, had been distinguished from other forms of cholestatic liver disease in childhood by clinical findings, clinical-laboratory observations, and morphologic studies in biopsy, hepatectomy, and autopsy specimens. At the time of the publication of the original review article in Pediatric and Developmental Pathology (2000;3:113–125) correlation with genetic analyses permitted both more precise definition of PFIC and distinctions within PFIC. Two types of PFIC were recognized: PFIC-1, resulting from mutations in a gene called FIC1 (familial intrahepatic cholestasis, type 1), and PFIC-2, resulting from mutations in a gene called BSEP (bile salt export pump). We predicted that other forms of PFIC would be identified and that the roles of FIC1 and BSEP in the secretion of bile acids into bile and in the post-secretory modification of bile were under study. The description of other cholestatic disorders as the background against which PFIC must be considered and the historical sketch of how the concept of PFIC evolved to describe a category of disease, the summary of current knowledge on PFIC, and the contribution to analyses of cholestatic liver disease made by work among the Amish and their descendants remain substantially valid. Following is an update on these issues.

Progressive Familial Intrahepatic Cholestasis: An Update

Allograft steatosis is a feature of progressive familial intrahepatic cholestasis, type 1 (FIC1 disease), treated by orthotopic liver transplantation (OLTX).

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Allograft steatosis is a feature of progressive familial intrahepatic cholestasis, type 1 (FIC1 disease), treated by orthotopic liver transplantation (OLTX).