| Objective Progressive familial intrahepatic cholestasis type 1(PFIC1)is an autosomal recessive disease caused by biallelic mutations of the ATP8B1 gene,with progressive cholestasis being the main clinical manifestation.In this paper,the clinical and genetic features of 2 children with PFIC1 were reported and the relevant literatures were systematically reviewed,so as to provide references for the diagnosis and treatment of PFIC1.Methods Genetic analysis of 2 patients with cholestasis and their family members was performed through high-throughput sequencing,and then the results were confirmed by Sanger sequencing.A variety of bioinformatic tools such as comparative alignment of the homologous peptides,PROVEAN,Mutation Taster and Poly Phen-2were used to predict the pathogenicity of the novel variants according to the American College of Medical Genetics and Genomics(ACMG)standards and guidelines.The clinical data of the 2 PFIC1 patients above were retrospectively collected and analyzed,while CNKI,VIP Database,Wanfang,Pub Med,Web of Science and other medical reference databases were retrieved for relevant references and the molecular and clinical information of the PFIC1 patients was systematically reviewed.Results The 2 PFIC1 patients both showed jaundice and hepatomegaly within 6months after birth.Blood biochemistry analysis showed raised transaminases,direct bilirubin(DBIL),total bile acids(TBA)and other liver function indices while normal gamma-glutamyl transpeptidase(GGT)levels.Due to the poor response to oral ursodeoxycholic acid,vitamin AD and other internal medical treatment,patient 1underwent cholecystocolostomy and liver biopsy when aged 10 months and 24 days,and liver cirrhosis was revealed on pathological analysis.The jaundice gradually subsided and the pruritus disappeared thereafter,but recurred at the age of 1 year and8 months when the patient displayed enlarged liver and elevated transaminases,TBA and DBIL.Patient 2 responded well to oral ursodeoxycholic acid and vitamin AD,and jaundice and pruritus were negative on a follow up when aged 1 year and 3 months,with generally normal biochemistry indices.On genetic analysis,patient 1 was a compound heterozygote of the ATP8B1 variants c.2081T>A(p.Ile694Asn)and c.2787C>G(p.Phe929Leu),while patient 2,a compound heterozygote of c.2663C>T(p.Thr888Met)and c.614 dup A(p.Asn205 Lysfs Ter2).According to the in silico prediction results and ACMG standards,c.2787C>G(p.Phe929Leu)and c.2787C>G(p.Phe929Leu)were both diagnosed as likely pathogenic variants.A total of 27 literatures closely related to PFIC1 were found in the reference databases,involving 53 PFIC1 patients with detailed clinical data,and 43.4%(23/53)of them were females and 53.6%(30/53),males.The onset ages within 3 months,6 months and 1 year after birth were observed in 60.6%(20/33),87.9%(29/33)and 97%(32/33)of the PFIC1 cases,respectively.The commonest initial clinical manifestation was jaundice 63.9%(23/36),which was followed by pruritus 19.4%(7/36).Major clinical manifestations included jaundice 86.8%(46/53),pruritus 77.4%(41/53),hepatomegaly41.5%(22/53),splenomegaly 20.8%(11/53),acholic stool 15.1%(8/53),coagulopathy13.2%(7/53),and rickets 5.7%(3/53),along with such extrahepatic presentations as growth retardation 60.4%(32/53),diarrhea 22.6%(12/53),deafness 3.8%(2/53),mossy skin 5.7%(3/53),and swelling of the hands and feet 1.9%(1/53).In terms of laboratory changes,all patients 100%(49/49)showed normal GGT levels while elevated TBil,DBil,ALT,AST and TBA were found in 95%(38/40),94.7%(36/38),78.4%(29/37),88.2%(30/34)and 92%(25/27)of the cases,respectively,with most patients 62.3%(33/53)meeting the diagnosis of cholestasis.Liver biopsy results included hepatocellular and canalicular cholestasis as well as portal inflammation and fibrosis.Hepatocellular and canalicular cholestasis was positive in 96%(24/25)of patients as the main hepatopathologic feature.In response to oral ursodeoxycholic acid,pruritus and cholestasis was alleviated just in 26.7%(8/30)of the patients,and63.3%(19/30)of them had no satisfactory response.Fifteen patients underwent liver transplantation at the average age of 3.5 years(1 to 10 years),with the postoperational complications of fatty liver 85.7%(12/14),diarrhea 78.5%(11/14),liver dysfunction42.9%(6/14)and repeated bile tract infections 7.1%(1/14).Three of the transplanted patients 20%(3/15)underwent retransplantation due to liver failure.Four patients have died,and among them,2 refused liver transplantation and died of liver encephalopathy at the ages of 4 and 23 years,respectively,1 died of liver failure when aged 16 years after retransplantation,and the rest 1 died at the age 4.5 years after being treated with internal medicine,with unknown cause of death.Totally,33ATP8B1 variants were detected in the 53 patients.Missense variants were on top of the list,accounting for 45.5%(15/33),followed by frameshift 21.2%(7/33),splice-site18.2%(6/33),nonsense 9%(3/33),exon deletion 3%(1/33),and synonymous variants3%(1/33).Conclusions In this study,two PFIC1 patients were diagnosed definitely through clinical and genetic studies,and two novel ATP8B1 variants c.2787C>G(p.Phe929Leu)and c.2663C>T(p.Thr888Met)were identified.The literature review revealed that PFIC1 usually demonstrated onset within 1 year of age,presenting with jaundice,pruritus,hepatosplenomegaly as the main manifestations along with the extrahepatic presentations such as growth retardation,diarrhea and deafness.Biochemical analysis showed cholestatic changes with normal GGT levels.Oral ursodeoxycholic acid was just effective in a small proportion of patients.Liver transplantation was one of the options for liver failure;however,postoperational fatty liver,diarrhea and impaired liver function were common complications,and in some cases,a second transplantation was required due to liver failure.This study enriched the variant spectrum of ATP8B1 gene and deepened the scientific understanding of the clinical,laboratory characteristics of PFIC1 patients,with reference value for the diagnosis and management of such patients. |
PDF Full Text Request