Newer variants of progressive familial intrahepatic cholestasis
Vignesh Vinayagamoorthy1, Anshu Srivastava2, Moinak Sen Sarma1
1Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India.
Insights
Progressive familial intrahepatic cholestasis (PFIC) encompasses genetic disorders affecting bile secretion. Newer variants like PFIC 4, 5, and MYO5B-related disease present unique challenges requiring genetic analysis for diagnosis and management.
Area of Science:
- Hepatology
- Genetics
- Pediatric Gastroenterology
Background:
- Progressive familial intrahepatic cholestasis (PFIC) comprises heterogeneous genetic disorders impacting bile secretion, presenting in infancy or childhood.
- Common types include PFIC 1 (ATP8B1 mutation), PFIC 2 (ABCB11 mutation), and PFIC 3 (ABCB4 mutation).
- Emerging variants, PFIC 4 (TJP2 mutation), PFIC 5 (NR1H4 mutation), and MYO5B-related disease (PFIC 6), expand the PFIC spectrum.
Purpose of the Study:
- To delineate the clinical presentations and diagnostic considerations for newly identified PFIC variants.
- To highlight the importance of genetic analysis and immunohistochemistry in differentiating PFIC subtypes.
- To inform management strategies for progressive liver disease and associated complications in pediatric cholestasis.
Main Methods:
- Review of clinical data and genetic analyses of patients with cholestasis of unknown etiology.
- Comparative analysis of phenotypic features across different PFIC variants.
- Discussion of diagnostic modalities including immunohistochemistry and genetic testing.
Main Results:
- PFIC 4 (TJP2 deficiency) shows variable disease progression, necessitating hepatocellular carcinoma surveillance.
- PFIC 5 (Farnesoid X receptor deficiency) presents with rapid liver disease, coagulopathy, and elevated alpha-fetoprotein, often requiring transplantation.
- MYO5B-related disease can manifest as isolated cholestasis or cholestasis with intractable diarrhea (MVID), with specific transplant considerations.
Conclusions:
- Accurate diagnosis of PFIC variants relies on a combination of clinical presentation, immunohistochemistry, and definitive genetic analysis.
- Management strategies must be tailored to the specific PFIC subtype to address progressive liver disease and associated risks.
- Early identification and genetic characterization are crucial for optimizing outcomes in children with rare cholestatic disorders.
Abstract:
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defects in bile secretion and presentation with intrahepatic cholestasis in infancy or childhood. The most common types include PFIC 1 (deficiency of FIC1 protein, ATP8B1 gene mutation), PFIC 2 (bile salt export pump deficiency, ABCB11 gene mutation), and PFIC 3 (multidrug resistance protein-3 deficiency, ABCB4 gene mutation). Mutational analysis of subjects with normal gamma-glutamyl transferase cholestasis of unknown etiology has led to the identification of newer variants of PFIC, known as PFIC 4, 5, and MYO5B related (sometimes known as PFIC 6). PFIC 4 is caused by the loss of function of tight junction protein 2 (TJP2) and PFIC 5 is due to NR1H4 mutation causing Farnesoid X receptor deficiency. MYO5B gene mutation causes microvillous inclusion disease (MVID) and is also associated with isolated cholestasis. Children with TJP2 related cholestasis (PFIC-4) have a variable spectrum of presentation. Some have a self-limiting disease, while others have progressive liver disease with an increased risk of hepatocellular carcinoma. Hence, frequent surveillance for hepatocellular carcinoma is recommended from infancy. PFIC-5 patients usually have rapidly progressive liver disease with early onset coagulopathy, high alpha-fetoprotein and ultimately require a liver transplant. Subjects with MYO5 B-related disease can present with isolated cholestasis or cholestasis with intractable diarrhea (MVID). These children are at risk of worsening cholestasis post intestinal transplant (IT) for MVID, hence combined intestinal and liver transplant or IT with biliary diversion is preferred. Immunohistochemistry can differentiate most of the variants of PFIC but confirmation requires genetic analysis.
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