Molecular overview of progressive familial intrahepatic cholestasis

Cholestasis is a clinical condition resulting from the imapairment of bile flow.This condition could be caused by defects of the hepatocytes,which are responsible for the complex process of bile formation and secretion,and/or caused by defects in the secretory machinery of cholangiocytes.Several mutations and pathways that lead to cholestasis have been described.Progressive familial intrahepatic cholestasis(PFIC)is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes.PFIC 1,also known as Byler’s disease,is caused by mutations of the ATP8B1 gene,which encodes the familial intrahepatic cholestasis 1 protein.PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump(BSEP)expression via variations in the ABCB11 gene.Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein,leading to the third type of PFIC.Newer variations of this disease have been described.Loss of function of the tight junction protein 2 protein results in PFIC 4,while mutations of the NR1H4 gene,which encodes farnesoid X receptor,an important transcription factor for bile formation,cause PFIC 5.A recently described type of PFIC is associated with a mutation in the MYO5B gene,important for the trafficking of BSEP and hepatocyte membrane polarization.In this review,we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

New tight junction protein 2 variant causing progressive familial intrahepatic cholestasis type 4 in adults: A case report

BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.

Progressive familial intrahepatic cholestasis—farnesoid X receptor deficiency due to NR1H4 mutation:A case report

BACKGROUND Functioning farnesoid X receptor(FXR;encoded by NR1H4)is key to normal bile acid homeostasis.Biallelic mutations in NR1H4 are reported in a few children with intrahepatic cholestasis.We describe a boy with progressive familial intrahepatic cholestasis and homozygous mutation in NR1H4.CASE SUMMARY A boy had severe neonatal cholestasis with moderate hypercholanemia and persistently elevated alpha-fetoprotein.Despite medical treatment,coagulopathy was uncontrollable,prompting liver transplantation at age 8 mo with incidental splenectomy.The patient experienced catch-up growth with good liver function and did not develop allograft steatosis.However,1 year after transplant,he died from an acute infection,considered secondary to immunosuppression and asplenia.A homozygous protein-truncating mutation,c.547C>T,p.(Arg183Ter),was subsequently identified in NR1H4,and both parents were shown to be heterozygous carriers.Absence of FXR and of bile salt export pump expression was confirmed by immunostaining of explanted liver.CONCLUSION Severe cholestasis with persistently high alpha-fetoprotein and modest elevation of serum bile acid levels may suggest FXR deficiency.Some patients with FXR deficiency may not develop allograft steatosis and may respond well to liver transplantation.

Newer variants of progressive familial intrahepatic cholestasis

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.

Novel ABCB4 mutations in an infertile female with progressive familial intrahepatic cholestasis type 3:A case report

BACKGROUND Mutations that occur in the ABCB4 gene,which encodes multidrug-resistant protein 3,underlie the occurrence of progressive familial intrahepatic cholestasis type 3(PFIC3).Clinical signs of intrahepatic cholestasis due to gene mutations typically first appear during infancy or childhood.Reports of PFIC3 occurring in adults are rare.CASE SUMMARY This is a case study of a 32-year-old infertile female Chinese patient with a 15-year history of recurrent abnormal liver function.Her primary clinical signs were elevated levels of alkaline phosphatase andγ-glutamyl transpeptidase.Other possible reasons for liver dysfunction were eliminated in this patient,resulting in a diagnosis of PFIC3.The diagnosis was confirmed using gene detection and histological analyses.Assessments using genetic sequencing analysis indicated the presence of two novel heterozygous mutations in the ABCB4 gene,namely,a 2950C>T;p.A984V mutation(exon 24)and a 667A>G;p.I223V mutation(exon 7).After receiving ursodeoxycholic acid(UDCA)treatment,the patient's liver function indices improved,and she successfully became pregnant by in vitro fertilization.However,the patient developed intrahepatic cholestasis of pregnancy in the first trimester.Fortunately,treatment with UDCA was safe and effective.CONCLUSION These novel ABCB4 heterozygous mutations have a variety of clinical phenotypes.Continued follow-up is essential for a comprehensive understanding of PFIC3.

ABCB4 gene mutation-associated cirrhosis with systemic amyloidosis:A case report

BACKGROUND Gene mutations in ATP-binding cassette,subfamily B(ABCB4)lead to autosomal recessive disorders.Primary light amyloidosis is a rare and incurable disease.Here,we report a rare case of liver cirrhosis caused by ABCB4 gene mutation combined with primary light amyloidosis.CASE SUMMARY We report a case of a 25-year-old female who was hospitalized due to recurrent abdominal pain caused by calculous cholecystitis and underwent cholecystectomy.Pathological examination of the liver tissue suggested liver cirrhosis with bile duct injury.Exon analyses of the whole genome from the patient’s peripheral blood revealed the presence of a heterozygous mutation in the ABCB4 gene.Bone marrow biopsy tissues,renal puncture examination,and liver mass spectrometry confirmed the diagnosis of a rare progressive familial intrahepatic cholestasis type 3 with systemic light chain type κ amyloidosis,which resulted in cirrhosis.Ursodeoxycholic acid and the cluster of differentiation 38 monoclonal antibody daretozumab were administered for treatment.Following treatment,the patient demonstrated significant improvement.Urinary protein became negative,peripheral blood-free light chain and urine-free light chain levels returned to normal,and the electrocardiogram showed no abnormalities.Additionally,the patient’s lower limb numbness resolved,and her condition remained stable.CONCLUSION This report presents the diagnosis and treatment of liver cirrhosis,a rare disease that is easily misdiagnosed or missed.