One Family with Cholestasis: The Twisted Road to the Diagnosis of Pfic 3-Three Case Reports

Abstract

Background and Clinical Significance: Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders consisting of mutations of hepatocyte transporting-system genes involved in bile formation. The exact prevalence remains unknown but is estimated at 1 in 500.000 for PFIC 3, caused by mutations in the ABCB4 gene. We report three cases of PFIC 3 from the patient's sister, brother, and cousin, diagnosed in our Pediatric Department in 2022-2023. Case Presentation: Case 1: A 10-year-old girl was admitted for jaundice and abdominal pain. She was diagnosed with severely advanced hepatic cirrhosis and massive cholestasis. Genetic testing showed ABCB4 homozygous mutation. She rapidly developed fulminant liver failure, and a living donor liver transplant was performed. Case 2: A 6-year-old brother was previously diagnosed with cholestatic hepatitis of unknown cause back in 2018 and presented with similar features (generalized jaundice, severe pruritus with generalized scratching lesions); symptoms had progressively developed from the first year of life. He also exhibited particular facial features (big forehead, twisted ear lobe, straight nose). He received cadaveric liver transplantation. Case 3: Nephew of first two children, a 3-year-5-month-old boy, was admitted for failure to thrive and a one-year history of jaundice, pruritus, and splenomegaly. He was tested positive for homozygous ABCB4 mutation. He is currently under medical treatment with stable liver function. Conclusions: The clinical significance of this particular homozygous variant identified in ABCB4 in our series of cases (c.2534G>T (p.Gly845Val)) was uncertain up to this case report. The present data provide convincing evidence as to the correlation between this mutation and the clinical phenotype of PFIC 3.

Keywords: chronic cholestasis; genetics; jaundice; metabolic liver disease; pruritus; transplantation.

Figure 1

Histology of the PFIC liver. (1) Histology images of PFIC 1–3 from the literature [1]. (1a) PFIC 1—moderate lobular and portal fibrosis. (1b) PFIC 2—hepatocyte necrosis, giant cells, cirrhosis. (1c1) PFIC 3—biliary cirrhosis, plugged bile ducts. (1c2) PFIC 3—ductular proliferation. (2–4) PFIC 3 liver in case 2. (2) Macroscopic appearance of extracted liver in case 2. (3) Liver cirrhosis in case 2. (3a) Low power view depicting micronodular cirrhosis with thin fibrous septa with bile ductular proliferation and mild chronic inflammation, HE, 50×. (3b) Masson trichrome stain highlights the fibrous septa delineating micronodules in liver cirrhosis, 50×. (4) Intrahepatic cholestasis in case 2. (4a) Hepatocytes showing cholestasis with pseudo-acinar changes and bile thrombi, HE, 200×. (4b): Small portal tract with bile plugs in small canaliculi, ductular reaction, and chronic inflammatory infiltrate, HE, 200×.

Figure 2

Imagistic findings in case 1. (a) Abdominal US—cirrhotic liver nodules. (b) Abdominal US—thick-walled gallbladder. (c) Abdominal MRI—enlarged liver and spleen.

Figure 3

Dynamics of bilirubin levels (mg/dL) in case 1 prior to transplantation.

Figure 4

Imagistic findings in case 2. (a) Abdominal US—liver nodules. (b) Abdominal US—thick-walled, double-layered gallbladder. (c) Abdominal US—enlarged spleen. (d) Abdominal MRI—enlarged liver and spleen. (e) Abdominal MRI—thick-walled, double-layered gallbladder.

Figure 5

Imaging findings in case 3. (a) Abdominal US—hepatosplenomegaly. (b) Abdominal MRI—hepatosplenomegaly.

Figure 6

Mechanism of action in PFIC 1, PFIC 2, and PFIC 3.

Figure 7

Structure of ABCB4 novel pathogenic variant [6].

Figure 8

Similar phenotypes with particular facial features. (a) Case 1—large forehead, deep-set eyes. (b) Case 2—triangle-shaped face, large forehead, deep-set eyes, straight nose. (c) Case 3—big forehead, straight nose, twisted ear lobe.