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Selim N, Omair H, El-Karaksy H, Fathy M, Mahmoud E, Baroudy S, Fathy M, Yassin N. A study of exons 14, 15, and 24 of the ABCB11 gene in Egyptian children with normal GGT cholestasis. Arab J Gastroenterol 2022; 23:15-19. [PMID: 35153175 DOI: 10.1016/j.ajg.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/27/2021] [Accepted: 11/01/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND AND STUDY AIMS Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare inherited disorder caused by mutation in the ATP-binding cassette subfamily B member 11 gene (ABCB11) that encodes the bile salt export pump (BSEP), which is the main transporter of bile acids from hepatocytes to the canalicular lumen. Defects in BSEP synthesis and/or function lead to reduced bile salt secretion followed by accumulation of bile salts in hepatocytes and hepatocellular damage. This study aimed to detect variations in exons 14, 15, and 24 of the ABCB11 gene in patients with suspected PFIC2 among a group of Egyptian infants and children with normal gamma-glutamyl transpeptidase (GGT) cholestasis. PATIENTS AND METHODS This observational case-control study was conducted on 13 children with suspected PFIC2 and 13 healthy subjects as controls. Genotyping of the ABCB11 gene was performed via DNA extraction followed by PCR amplification, purification, and then sequencing analysis of exons 14, 15, and 24 of the ABCB11 gene. RESULTS The study detected two single nucleotide variations, c.1638+ 32T > C (rs2241340) in exon 14 and c.3084A > G (p.Ala1028 = ) (rs497692) in exon 24 of the ABCB11 gene. No variations were identified in exon 15. CONCLUSION The study revealed two benign variants involving exons 14 and 24 of the ABCB11 gene. Exons 14, 15, and 24 are not hot spots for common mutations in Egyptian PFIC2 patients. Further study of other exons of the ABCB11 gene is necessary to confirm the diagnosis of PFIC2.
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Affiliation(s)
- Nora Selim
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Heba Omair
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hanaa El-Karaksy
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Marianne Fathy
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Enas Mahmoud
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sherif Baroudy
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mona Fathy
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha Yassin
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Lee SJ, Kim JE, Choe BH, Seo AN, Bae HI, Hwang SK. Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing. Pediatr Gastroenterol Hepatol Nutr 2017; 20:114-123. [PMID: 28730136 PMCID: PMC5517378 DOI: 10.5223/pghn.2017.20.2.114] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 10/21/2016] [Indexed: 01/27/2023] Open
Abstract
PURPOSE The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. METHODS Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. RESULTS Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. CONCLUSION ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.
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Affiliation(s)
- Su Jeong Lee
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jung Eun Kim
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - An Na Seo
- Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Han-Ik Bae
- Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Su-Kyeong Hwang
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
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Sonthalia N, Jain SS, Pawar VB, Zanwar VG, Surude RG, Rathi PM, Munde KK, Bavdekar S. A Child with Debilitating Pruritus. Clin Pract 2016; 6:865. [PMID: 28028430 PMCID: PMC5136740 DOI: 10.4081/cp.2016.865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/28/2016] [Accepted: 09/22/2016] [Indexed: 11/23/2022] Open
Abstract
We describe a case of two-year-old boy presenting with debilitating pruritus, patchy alopecia and jaundice since the age of 6 months. On evaluation he had intrahepatic cholestasis with persistently raised serum alkaline phosphatase, normal Gamma glutamyl transferase and raised serum bile acid levels. His liver biopsy showed bland cholestasis and electron microscopy showed granular bile suggestive of progressive familial intrahepatic cholestasis type I. Medical therapy with ursodeoxycholic acid, cholestyramine, rifampicin with nutritional modification was successful in alleviating the symptoms and correcting the nutritional status. To our knowledge this is only the sixth case of progressive familial intrahepatic cholestasis type I reported from India. Herein we discuss the diagnostic and therapeutic hurdles that one encounters in managing progressive familial intrahepatic cholestasis and also review the literature regarding this rare disorder.
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Affiliation(s)
- Nikhil Sonthalia
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Samit S Jain
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Vinay B Pawar
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Vinay G Zanwar
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Ravindra G Surude
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Pravin M Rathi
- Department of Gastroenterology; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Kshitij K Munde
- Department of Pediatric Medicine; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
| | - Sandeep Bavdekar
- Department of Pediatric Medicine; Topiwala National Medical College and BYL Nair Ch Hospital , Mumbai, Maharashtra, India
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Park JS, Ko JS, Seo JK, Moon JS, Park SS. Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis. World J Gastroenterol 2016; 22:4901-4907. [PMID: 27239116 PMCID: PMC4873882 DOI: 10.3748/wjg.v22.i20.4901] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/29/2016] [Accepted: 03/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others.
METHODS: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal γ-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood.
RESULTS: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space.
CONCLUSION: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 11
- ATP-Binding Cassette Transporters/genetics
- Asian People/genetics
- Biopsy
- Carcinoma, Hepatocellular/diagnostic imaging
- Carcinoma, Hepatocellular/ethnology
- Carcinoma, Hepatocellular/genetics
- Cholestasis, Intrahepatic/diagnostic imaging
- Cholestasis, Intrahepatic/ethnology
- Cholestasis, Intrahepatic/genetics
- Cholestasis, Intrahepatic/surgery
- DNA Mutational Analysis
- Disease Progression
- Female
- Gallstones/diagnostic imaging
- Gallstones/ethnology
- Gallstones/genetics
- Genetic Association Studies
- Genetic Predisposition to Disease
- Heterozygote
- Humans
- Infant
- Infant, Newborn
- Liver Transplantation/methods
- Living Donors
- Male
- Microscopy, Electron
- Mutation, Missense
- Phenotype
- Prognosis
- Republic of Korea
- Retrospective Studies
- Tomography, X-Ray Computed
- Ultrasonography
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Hu G, He P, Liu Z, Chen Q, Zheng B, Zhang Q. Diagnosis of ABCB11 gene mutations in children with intrahepatic cholestasis using high resolution melting analysis and direct sequencing. Mol Med Rep 2014; 10:1264-74. [PMID: 24969679 PMCID: PMC4121405 DOI: 10.3892/mmr.2014.2349] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 04/28/2014] [Indexed: 12/17/2022] Open
Abstract
Intrahepatic cholestasis represents a heterogeneous group of disorders that begin during childhood, most commonly manifesting as neonatal cholestasis, and lead to ongoing liver dysfunction in children and adults. For children, inherited pathogenic factors of cholestasis have gained increasing attention owing to the rapid development of molecular biology technology. However, these methods have their advantages and disadvantages in terms of simplicity, sensitivity, specificity, time required and expense. In the present study, an effective, sensitive and economical method is recommended, termed high-resolution melting (HRM) analysis and direct sequencing, based on general polymerase chain reaction, to detect mutations in disease-causing genes. As one type of inherited intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by pathogenic mutations in the ABCB11 gene, HRM was used to detect mutations in the ABCB11 gene in the present study, and the diagnosis for PFIC2 was made by comprehensive analysis of genetic findings and clinical features. Furthermore, the characteristics of mutations and single nucleotide polymorphisms (SNPs) in the ABCB11 gene were elucidated. A total of 14 types of mutations/polymorphisms were identified in 20 patients from mainland China, including six missense mutations (p.Y337H, p.Y472C, p.R696W, p.Q931P, p.D1131V and p.H1198R), one nonsense mutation (p.R928X) and seven SNPs (p.D36D/rs3815675, p.F90F/rs4148777, p.Y269Y/rs2287616, p.I416I/rs183390670, p.V444A/rs2287622, p.A865V/rs118109635 and p.A1028A/rs497692). Five mutations were novel. The majority of the mutations were different from those detected in other population groups. A total of 4/20 patients (1/5) were diagnosed to be PFIC2 by combining genetic findings with the clinical features. Polymorphisms V444A and A1028A, with an allele frequency of 74.5 and 67.2%, respectively, were highly prevalent in the mainland Chinese subjects. No differences were found between the patients with cholestasis and the control subjects. Efficient genetic screening facilitates the clinical diagnosis of genetic disorders. The present study demonstrated that HRM analysis was efficient and effective in detecting mutations and expanded the known spectrum of ABCB11 gene mutations.
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Affiliation(s)
- Guorui Hu
- Medical College of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Ping He
- Medical College of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Zhifeng Liu
- Medical College of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Qian Chen
- Department of Digestive Disease, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Bixia Zheng
- Department of Digestive Disease, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Qihua Zhang
- Department of Digestive Disease, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
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Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol 2014; 4:25-36. [PMID: 25755532 PMCID: PMC4017198 DOI: 10.1016/j.jceh.2013.10.005] [Citation(s) in RCA: 179] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 10/31/2013] [Indexed: 12/12/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.
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Key Words
- ABC, ATP binding cassette
- ASBT, apical sodium bile salt transporter
- ATP, adenosine triphosphate
- ATPase, adenosine triphosphatase
- BRIC, benign recurrent intrahepatic cholestasis
- BSEP, bile salt exporter protein
- CFTR, cystic fibrosis transmembrane conductance regulator
- CYP, cytochrome P
- DNA, deoxyribonucleic acid
- ERAD, endoplasmic reticulum associated degradation
- ESLD, end stage liver disease
- FIC1, familial intrahepatic cholestasis protein 1
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- IB, ileal bypass
- ICP, intrahepatic cholestasis of pregnancy
- LT, liver transplant
- MARS, Molecular Adsorbent Recirculating System
- MDR, multidrug resistance protein
- MRCP, magnetic resonance cholangiopancreaticography
- PBD, partial biliary drainage
- PEBD, partial external biliary drainage
- PFIC, progressive familial intrahepatic cholestasis
- PIBD, partial internal biliary drainage
- PPAR, peroxisome proliferator activator receptor
- UDCA, ursodeoxycholic acid
- bile secretion
- children
- cholestasis
- familial
- mRNA, messenger ribonucleic acid
- pGp, p-glycoprotein
- pruritus
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Affiliation(s)
- Anshu Srivastava
- Address for correspondence: Anshu Srivastava, Associate Professor, Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. Tel.: +91 522 2495212, +91 9935219497 (mobile); fax: +91 522 2668017.
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Romero R, Yoon BH, Chaemsaithong P, Cortez J, Park CW, Gonzalez R, Behnke E, Hassan SS, Chaiworapongsa T, Yeo L. Bacteria and endotoxin in meconium-stained amniotic fluid at term: could intra-amniotic infection cause meconium passage? J Matern Fetal Neonatal Med 2013; 27:775-88. [PMID: 24028637 DOI: 10.3109/14767058.2013.844124] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Meconium-stained amniotic fluid (MSAF) is a common occurrence among women in spontaneous labor at term, and has been associated with adverse outcomes in both mother and neonate. MSAF is a risk factor for microbial invasion of the amniotic cavity (MIAC) and preterm birth among women with preterm labor and intact membranes. We now report the frequency of MIAC and the presence of bacterial endotoxin in the amniotic fluid of patients with MSAF at term. MATERIALS AND METHODS We conducted a cross-sectional study including women in presumed preterm labor because of uncertain dates who underwent amniocentesis, and were later determined to be at term (n = 108). Patients were allocated into two groups: (1) MSAF (n = 66) and (2) clear amniotic fluid (n = 42). The presence of bacteria was determined by microbiologic techniques, and endotoxin was detected using the Limulus amebocyte lysate (LAL) gel clot assay. Statistical analyses were performed to test for normality and bivariate comparisons. RESULTS Bacteria were more frequently present in patients with MSAF compared to those with clear amniotic fluid [19.6% (13/66) versus 4.7% (2/42); p < 0.05]. The microorganisms were Gram-negative rods (n = 7), Ureaplasma urealyticum (n = 4), Gram-positive rods (n = 2) and Mycoplasma hominis (n = 1). The LAL gel clot assay was positive in 46.9% (31/66) of patients with MSAF, and in 4.7% (2/42) of those with clear amniotic fluid (p < 0.001). After heat treatment, the frequency of a positive LAL gel clot assay remained higher in the MSAF group [18.1% (12/66) versus 2.3% (1/42), p < 0.05]. Median amniotic fluid IL-6 concentration (ng/mL) was higher [1.3 (0.7-1.9) versus 0.6 (0.3-1.2), p = 0.04], and median amniotic fluid glucose concentration (mg/dL) was lower [6 (0-8.9) versus 9 (7.4-12.6), p < 0.001] in the MSAF group, than in those with clear amniotic fluid. CONCLUSION MSAF at term was associated with an increased incidence of MIAC. The index of suspicion for an infection-related process in postpartum women and their neonates should be increased in the presence of MSAF.
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Affiliation(s)
- Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS , Bethesda, MD and Detroit, MI , USA
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Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol 2011; 35:687-96. [PMID: 21490445 DOI: 10.1097/pas.0b013e318212ec87] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellular cholestasis; most had canalicular bile plugs. At least 1 specimen from every patient had centrizonal/sinusoidal fibrosis, often with periportal fibrosis. Neonatal hepatitis-like features (inflammation, giant cells, necrosis) varied. In 2 of the 5 patients with paired specimens obtained >6 months apart, lobular and portal fibrosis worsened. Transmission electron microscopy (EM) in all 9 patients studied showed canalicular dilatation, microvilli loss, abnormal mitochondrial internal structure, and varying intracanalicular accumulation of finely granular bile. Canalicular staining for BSEP was absent in 10 patients and present in 2 patients, 1 of whom had intermittent symptoms. ABCB11 sequencing of all patients identified 6 novel and 10 previously described mutations, with nonsense, missense, and/or noncoding mutations in the 10 patients without immunohistochemically demonstrable BSEP. Missense and/or noncoding mutations were identified in the 2 patients with demonstrable BSEP, whose clinical course was more indolent. Mutations ending ABCB11 transcription appear linked, through hepatocellular necrosis and fibrosis, to worse outcome. In conclusion, light microscopy and electron microscopy findings in clinical PFIC2 can support diagnosis, but are variable and nonspecific. Therefore, no correlation between specific mutations and histopathology is yet possible.
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Deng YN, Wang LL, Tang Q, Chen XQ, Chen P, Shan QW, Lian SJ, Yun X. Association between BSEP V444A polymorphism and risk of idiopathic neonatal hepatitis/cholestasis. Shijie Huaren Xiaohua Zazhi 2011; 19:38-43. [DOI: 10.11569/wcjd.v19.i1.38] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the association between the V444A polymorphism in the bile salt export pump (BSEP) gene and the risk of idiopathic neonatal hepatitis/cholestasis.
METHODS: Eighty-one infants with idiopathic hepatitis/cholestasis (case group) and 48 healthy infants without intrahepatic cholestasis (control group) were included in this study. The V444A polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS: There are three V444A genotypes: AA homozygote, GA heterozygote, and GG homozygote. The frequencies of AA and AG and GG genotypes were 0.6%, 4.9% and 44.4% in the case group and 14.6%, 62.5% and 22.9% in the control group, respectively, with a significant difference between the two groups (P = 0.019). The distribution of GG genotype was significantly different between the two groups (P < 0.05, OR = 2.691, 95%CI: 1.205-6.008). The risk of suffering from idiopathic intrahepatic cholestasis in G allele carriers was 1.951 times higher than that in A allele carriers (OR = 1.951, 95%CI: 1.56-3.291).
CONCLUSION: The G allele of the BSEP V444A G polymorphism may be a risk factor for idiopathic intrahepatic cholestasis in infants.
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Chen HL, Liu YJ, Su YN, Wang NY, Wu SH, Ni YH, Hsu HY, Wu TC, Chang MH. Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography. J Pediatr 2008; 153:825-32. [PMID: 18692205 DOI: 10.1016/j.jpeds.2008.06.034] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2007] [Revised: 04/28/2008] [Accepted: 06/17/2008] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To determine if specific mutations were present in Asian patients with progressive familial intrahepatic cholestasis (PFIC) type 2 caused by defects in bile salt export pump (BSEP), encoded by ABCB11. STUDY DESIGN A combination of denaturing high-performance liquid chromatography (DHPLC) and direct sequencing was used to screen ABCB11 mutations in 18 Taiwanese patients with low gamma-glutamyltransferase PFIC or benign recurrent intrahepatic cholestasis (BRIC). Polymorphisms were also analyzed in patients with PFIC (n = 21), neonatal cholestasis (n = 23), and control subjects (n = 88). RESULTS Seven mutations in 4 of 16 patients with PFIC from different families were detected by DHPLC, including M183V, V284L, R303K, R487H, W493X, G1004D, and 1145delC. G1004D was found in a patient with BRIC. L827I was found in another patient with neonatal cholestasis. Absent or defective BSEP staining was found in the liver of patients with mutations. Polymorphisms V444A and A865V, with an allele frequencies 75.6% and 0.6%, respectively, were found in our population. No differences were found between patients with cholestasis and control subjects. CONCLUSIONS One-fourth of Taiwanese patients with PFIC/BRIC had compound heterozygous or single heterozygous ABCB11 mutations without hot spots. All of the mutations were different from those detected in Western countries.
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Affiliation(s)
- Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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