Immunohistochemistry in Progressive Familial Intrahepatic Cholestasis (PFIC): Bridging Gap Between Morphology and Genetics

Abstract

Background/aims: A heterogeneous group of disorders caused by bile secretion and transport defects is progressive familial intrahepatic cholestasis (PFIC). PFIC has various subtypes with different presentations, laboratory findings, treatments, progression, and prognosis. Genetic analysis is the gold standard for diagnosis but is costly, time-consuming, and not readily available. In this study, immunohistochemistry (IHC) was evaluated as a tool for identifying subtypes of PFIC and differentiating them from other causes of pediatric cholestasis.

Methods: The study included genetically confirmed PFIC (n = 40) and non-PFIC group (n = 20). Clinical history and laboratory investigations were recorded from the hospital information system. PFIC subtypes 1,2,3,4,5, and 6 showed the genetic mutation in ATP8B1, ABCB11, ABCB4, tight junction protein 2 (TJP2), NR1H4, and MYO5B, respectively. IHC has been applied for bile salt export pump (BSEP), multidrug resistance protein 3 (MDR3), TJP2, Claudin 1, farnesoid X receptor (FXR), and MYO5B.

Results: IHC staining for BSEP, MDR3, TJP2, and MYO5B was positive in 100% of PFIC 1 and negative in 90.9%, 84.6%, 100%, and 100%, respectively, of the PFIC subtypes 2, 3, 4, and 6. Significant differences were noted between PFIC and non-PFIC patients for BSEP (P = 0.044), MDR3 (P = 0.022), and TJP2 (P < 0.001). In comparison with the non-PFIC patients, BSEP's sensitivity and specificity for diagnosing PFIC 2 was 90.9% and 95%, MDR3's for diagnosing PFIC 3 was 84.6% and 95%, TJP2 for PFIC 4 was 100% and 95%, and MYO5B''s for PFIC 6.

Conclusion: Immunostaining for the markers BSEP, MDR3, TJP2, and MYO5B can differentiate various PFIC subtypes and distinguish between PFIC and non-PFIC patients.

Keywords: cholestasis; fibrosis; gamma-glutamyl transferase; immunohistochemistry; progressive familial intrahepatic cholestasis.