Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review

Abstract

Background and Aims Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant‐free survival, extrahepatic manifestations may cause relevant morbidity. Methods We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. Results Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver‐associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. Conclusion The spectrum of extrahepatic manifestations in PFIC highlights essential, non‐redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health‐related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.

Childhood Cholestatic Liver Diseases that Persist Into Adulthood

“…PFIC-1 is unique because of its propensity to develop extrahepatic complications because of the multiorgan tissue expression of ATP8B1. Extrahepatic symptoms may include diarrhea, pancreatitis, hearing loss, delayed puberty, and short stature 75,76 . Of the 3, PFIC-2 has the most aggressive liver phenotype, with a significant risk for early liver failure and hepatobiliary malignancy (up to 15% with hepatocellular carcinoma or cholangiocarcinoma).…”

“…Extrahepatic symptoms may include diarrhea, pancreatitis, hearing loss, delayed puberty, and short stature. 75,76 Of the 3, PFIC-2 has the most aggressive liver phenotype, with a significant risk for early liver failure and hepatobiliary malignancy (up to 15% with hepatocellular carcinoma or cholangiocarcinoma). Biochemically, they all have elevated serum bile acid levels; but PFIC-3 is differentiated from PFIC-1 and PFIC-2 by persistently high GGT levels, a consequence of biliary epithelium injury from the detergent effects of bile salts in the absence of biliary phospholipids.…”

Impaired transitioning of the FXR ligand binding domain to an active state underlies a PFIC5 phenotype

“…NR1H4 variants associated with PFIC (subtype 5) were characterized by coagulopathy and a rapid progression toward end-stage liver disease (5)(6)(7). While most patients carried bi-allelic protein-truncating variants (5)(6)(7)(8), only two NR1H4-associated PFIC patients carrying homozygous missense variants have been identified (7,9). While one patient died on the transplant waiting list due to end-stage liver disease at the age of 9 months (c.557G>A) (7), the other patient was successfully transplanted at the age of 8 months (c.887C>T, p.(Thr296Ile), referred to as T296I in the following) and is currently 10 years old (9).…”

“…While most patients carried bi-allelic protein-truncating variants (5)(6)(7)(8), only two NR1H4-associated PFIC patients carrying homozygous missense variants have been identified (7,9). While one patient died on the transplant waiting list due to end-stage liver disease at the age of 9 months (c.557G>A) (7), the other patient was successfully transplanted at the age of 8 months (c.887C>T, p.(Thr296Ile), referred to as T296I in the following) and is currently 10 years old (9). FXR and BSEP staining was found negative in the liver tissue of PFIC patients with protein-truncating NR1H4 variants (5,8).…”

A common variant in the hepatobiliary phospholipid transporter ABCB4 modulates liver injury in PBC but not in PSC: prospective analysis in 867 patients

“…Phospholipids inside bile canaliculi combine with cholesterol and bile salts to create mixed micelles which attenuate the toxic effects of bile on the epithelial cells of bile ducts [ 10 ]. Dysfunction of ABCB4 can lead to a range of clinical phenotypes ranging from slightly increased liver function tests, to gallstone disease, intrahepatic cholestasis of pregnancy (ICP), progressive familial intrahepatic cholestasis type 3 (PFIC-3), and biliary cirrhosis [ 11 – 13 ]. Among common ABCB4 variants, c.711A > T (p.I237I, rs2109505) has previously been associated with the risk of developing ICP [ 14 , 15 ].…”