Presentation of Progressive Familial Intrahepatic Cholestasis Type 3 Mimicking Wilson Disease: Molecular Genetic Diagnosis and Response to Treatment

Abstract

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disorder of cholestasis of hepatocellular origin, typically seen in infancy or childhood caused by a defect in the ABCB4 located on chromosome 7. Here we report on an older patient, aged 15, who presented with biochemical testing that led to an initial consideration of a diagnosis of Wilson disease (WD) resulting in a delayed diagnosis of PFIC3. Diagnosis of PFIC3 was later confirmed by molecular studies that identified novel mutations in the ABCB4 gene. Cholestasis due to PFIC3 can cause elevated hepatic copper and increased urine copper excretion that overlap with current diagnostic criteria for WD. Molecular diagnostics are very useful for establishing the diagnosis of PFIC3. Ursodeoxycholic acid ameliorates cholestasis in PFIC3, and may help mediate a reduction in hepatic copper content in response to treatment.

Keywords: Cholestasis; Ursodeoxycholic acid; Wilson disease; progressive familial intrahepatic.

Fig. 1. (A) Low magnification of the original biopsy which was extensively fragmentated and showed areas of bridging fibrosis (H&E, ×40). (B) Higher magnification showing ductular reaction, mild chronic inflammation and neutrophilic pericholangitis (H&E, ×200).

Fig. 2. (A) Low magnification of the follow-up biopsy showing cirrhosis (H&E, ×100). (B) Pale staining of periseptal hepatocyte suggestive of cholate stasis was subtle and focal (H&E, ×200). (C) Higher magnifcation showing ducutular reaction, chronic inflammation and neutrophilic pericholangitis. Brownish granular pigment representing copper can also be seen (H&E ×400). (D) Copper accumulation in the periseptal hepatocytes highlighted as red granules (rhodanine stain, ×400).

Fig. 3. Immunostaining for class III multidrug resistance shows normal canalicular staining (×200).