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Newer variants of progressive familial intrahepatic cholestasis.

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.

SUBMITTER: Vinayagamoorthy V

PROVIDER: S-EPMC8727216 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProgressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance.MethodsDatabases including MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.ResultsThree systematic reviews and twenty-two studies were eligible for inclusion for the epidemiology of PFIC including a total of 2603 patients. Study periods ranged from 3 to 33 years. Local population prevalence of PFIC was reported in three studies, ranging from 9.0 to 12.0% of children admitted with cholestasis, acute liver failure, or splenomegaly. The most detailed data come from the NAPPED study where native liver survival of >15 years is predicted in PFIC2 patients with a serum bile acid concentration below 102 µmol/L following bile diversion surgery. Burden of disease was mainly reported through health-related quality of life (HRQL), rates of surgery and survival. Rates of biliary diversion and liver transplant varied widely depending on study period, sample size and PFIC type, with many patients have multiple surgeries and progressing to liver transplant. This renders data unsuitable for comparison.ConclusionUsing robust and transparent methods, this systematic review summarises our current knowledge of PFIC. The epidemiological overview is highly mixed and dependent on presentation and PFIC subtype. Only two studies reported HRQL and mortality results were variable across different subtypes. Lack of data and extensive heterogeneity severely limit understanding across this disease area, particularly variation around and within subtypes.

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Newer variants of progressive familial intrahepatic cholestasis.

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