RESUMO
Hereditary bilirubin metabolic disorder is an important cause for jaundice. For its diverse types and similar clinical manifestations, it has been difficult to make a clear etiological diagnosis. The application of next generation sequencing in recent years has delineated the more and more genetic etiologies for jaundice. This article has reviewed the clinical manifestations and genetic etiology of bilirubin metabolic disorder jaundice, with an aim to enhance the understanding of such diseases and facilitate their clinical diagnosis and treatment, which will provide a reference for genetic counseling and/or prenatal diagnosis for the affected individuals and families.
Assuntos
Icterícia , Doenças Metabólicas , Feminino , Gravidez , Humanos , Doenças Metabólicas/genética , Icterícia/genética , Bilirrubina , Aconselhamento Genético , FenótipoRESUMO
Dual-hereditary jaundice (Dubin-Johnson syndrome (DJS) and Gilbert's syndrome (GS)) is a rare clinical entity resulting from defects of the ATP binding cassette subfamily C member 2 (ABCC2) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genes with autosomal recessive inheritance. In this study, we aimed to investigate the mutation profiles and characterize the phenotypes in a Han Chinese family with DJS and GS. Genetic screening for variants in the ABCC2 and UGT1A1, immunohistochemistry for expression of ABCC2, and histopathological examination were carried out. The proband and his brother had unconjugated and conjugated hyperbilirubinemia after birth. The proband's sister had only conjugated hyperbilirubinemia after birth. The proband developed into pleural effusions and ascites, pericardial thickening, intrahepatic and extrahepatic biliary duct dilatation, and enlarged gallbladder at age 50. Hepatocellular carcinoma occurred in the proband's brother at age 46. Seven compound defects of the ABCC2 gene [c.2414delG, p.(Ile1489Gly), p.(Thr1490Pro), and p.(Ile1491Gln)] and the UGT1A1 gene (c.-3279T>G, p.(Gly71Arg), and p.(Pro451Leu)) were identified in family members. Accumulation of pigment in hepatocytes characteristic of that in DJS was present in the proband and his brother. Expression of ABCC2 protein was markedly diminished in the patient's liver. Our results show a different genetic profile of DJS and GS in a Han Chinese family, indicating a more complex pattern of dual-hereditary jaundice among different populations. The present study illuminates the underpinnings of DJS and GS and extends the mutation profiles and phenotypes of these two syndromes in dual-hereditary jaundice.
Assuntos
Doença de Gilbert , Icterícia Idiopática Crônica , Icterícia , Humanos , Masculino , População do Leste Asiático , Doença de Gilbert/diagnóstico , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Hiperbilirrubinemia , Icterícia/genética , Icterícia Idiopática Crônica/genética , Icterícia Idiopática Crônica/patologia , Proteína 2 Associada à Farmacorresistência Múltipla , MutaçãoRESUMO
Dizygotic twin males, born at 34 weeks gestation, had prolonged jaundice, microcytic, hypochromic anemia, FABarts hemoglobin, elevated end-tidal CO, and blood films consistent with hereditary pyropoikilocytosis. DNA sequencing revealed both had a heterozygous alpha spectrin (SPTA1) mutation (c.460_462dup) inherited from their asymptomatic mother, plus a 3-base pair duplication in alpha globin (HBA2) (c.364_366dupGTG) inherited from their asymptomatic father.
Assuntos
Anemia Hemolítica/complicações , Anemia Hipocrômica/complicações , Eliptocitose Hereditária/complicações , Icterícia/complicações , Anemia Hemolítica/sangue , Anemia Hemolítica/genética , Anemia Hipocrômica/sangue , Anemia Hipocrômica/genética , Eliptocitose Hereditária/sangue , Eliptocitose Hereditária/genética , Humanos , Recém-Nascido , Icterícia/sangue , Icterícia/genética , Masculino , Mutação Puntual , Espectrina/genética , Gêmeos Dizigóticos/genéticaRESUMO
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder that manifests with bone marrow failure, thrombosis and hemolysis. We present a 28-year-old male who presented with weakness, jaundice and transfusion dependence. On initial investigation, he was found to have anemia with jaundice with hemoglobin (Hb) capillary zone electrophoresis suggestive of Hb E (HBB: c.79G>A) trait. The same anomaly was also found in his mother. However, transfusion requirement was an unusual feature in the patient. As his corrected reticulocyte count was raised along with lactate dehydrogenase (LDH), which was suggestive of a hemolytic process, he was worked-up for the same. However, the direct Coombs test was negative. A bone marrow aspiration and biopsy was done to rule out hypersplenism but it revealed erythroid hyperplasia with reduced iron stores despite normal ferritin and iron studies. This was unusual as the patient had anemia requiring transfusions. He had no history of hemoglobinuria but a PNH by flowcytomety revealed a large clone of 81.2% in granulocytes and 88.5% in monocytes. The patient was started on Danazol and steroids for anemia which improved. He was counseled for matched sibling stem cell transplant. He had a full match with his brother. At the time of this study he awaits his transplant.
Assuntos
Anemia/complicações , Hemoglobina E/genética , Hemoglobinúria Paroxística/complicações , Icterícia/complicações , Adulto , Anemia/genética , Anemia/terapia , Transfusão de Sangue , Danazol/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/terapia , Humanos , Icterícia/genética , Icterícia/terapia , Masculino , Esteroides/uso terapêuticoRESUMO
BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the most common inherent causes of cholestatic jaundice in Asian infants. Mutations in the SLC25A13 gene, which encodes citrin protein expressed in the liver, have been identified as the genetic cause for NICCD. CASE PRESENTATION: Here, we report a 4-month-old female with clinical features including jaundice, hyperbilirubinemia, hyperlactacidemia, and abnormal liver function. The patient was diagnosed with NICCD by differential diagnosis using genetic analysis. Mutations in 60 jaundice-related genes were tested by using amplicon sequencing, which was performed on an Ion S5XL genetic analyzer. A compound heterozygous mutation in the SLC25A13 gene was identified, consisting of a known deletion SLC25A13:c.852_855delTATG and a novel splicing mutation SLC25A13:c.1841 + 3_1841 + 4delAA. Sanger sequencing for the proband and her parents was performed to validate the result and reveal the source of mutations. CONCLUSION: A compound heterozygous mutation in the SLC25A13 gene was identified in a 4-month-old female patient with NICCD. Our data suggest that amplicon sequencing is a helpful tool for the differential diagnosis of inherited diseases with similar symptoms. Further studies of the mutation spectrum of neonatal jaundice in China are warranted.
Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Icterícia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação/genética , Transportadores de Ânions Orgânicos/deficiência , Diagnóstico Diferencial , Feminino , Heterozigoto , Humanos , Lactente , LinhagemRESUMO
Unstable hemoglobin (Hb) variants are a rare etiology of congenital jaundice caused by hemolytic anemia. For infant patients with jaundice this disorder is often under diagnosed or the last consideration. We report a 14-month-old boy, who presented with a long-standing jaundice. His diagnosis of Hb Sabine [ß91(F7)LeuâPro; HBB: c.275T > C] was not revealed until gene sequencing of the ß-globin gene was performed.
Assuntos
Predisposição Genética para Doença , Variação Genética , Hemoglobinas/genética , Icterícia/genética , Icterícia/metabolismo , Alelos , Substituição de Aminoácidos , Biomarcadores , Análise Mutacional de DNA , Índices de Eritrócitos , Estudos de Associação Genética , Hemoglobinas/metabolismo , Hemoglobinas Anormais/genética , Humanos , Lactente , Icterícia/diagnóstico , Masculino , Mutação , Estabilidade Proteica , Globinas beta/genéticaRESUMO
RATIONALE: Neonatal cholestasis is one of the most serious diseases in infancy. Progressive familial intrahepatic cholestasis (PFIC) is a disease that leads to intrahepatic cholestasis. It is one of the common causes of neonatal cholestasis in addition to biliary atresia (BA). The differential diagnosis of neonatal cholestasis is clinically challenging for pediatricians. PATIENT CONCERNS: A 4-month-old female presented with severe jaundice, pruritus, and pale stool for 20 days. Abnormally strong echoes near the portal area, an abnormally small gallbladder with an irregularly stiff wall, and splenomegaly were identified on abdominal ultrasound. Blood tests showed elevated alanine aminotransferase, total bilirubin, conjugated bilirubin, gamma-glutamyltranspeptidase, and total bile acid levels. DIAGNOSIS: Intraoperative cholangiography showed BA. ABCB4 gene mutation IVS13+6G>A/G was confirmed by genetic testing. The patient was diagnosed with BA combined with PFIC3. INTERVENTIONS: Kasai portoenterostomy and ursodeoxycholic acid were used for treatment. OUTCOMES: Her clinical symptoms and blood tests improved gradually. No recurrence was noted during 1 year of follow-up. LESSONS: Additional examinations, such as genetic testing, should be considered in patients with BA who had refractory jaundice after Kasai portoenterostomy in order to exclude intrahepatic cholestasis.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Atresia Biliar/complicações , Atresia Biliar/diagnóstico , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/diagnóstico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Atresia Biliar/genética , Atresia Biliar/terapia , Biomarcadores/sangue , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/terapia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Icterícia/diagnóstico , Icterícia/etiologia , Icterícia/genética , Icterícia/terapiaRESUMO
BACKGROUND/AIMS: Spontaneous viral clearance observed in some patients is one of the variants of the hepatitis C virus (HCV) infection natural history. We aimed to look at the complexity of factors affecting the spontaneous clearance of HCV (SC HCV). MATERIALS AND METHODS: A total of 357 anti-HCV positive patients (309 with chronic hepatitis C and 48 patients with SC HCV) were included into the study. We studied the effects of the interleukin-28B (IL-28B) gene polymorphism, gender, age, the routes of virus transmission, past hepatitis C with jaundice, HCV genotype, and hepatitis B virus (HBV) and HIV co-infection on the outcome of HCV infection. RESULTS: Based on the study results, the SC HCV was found in 48 individuals (13.4%). The most significant positive factors affecting the SC HCV included IL-28B single nucleotide polymorphism (SNP) rs12979860 (CC) and SNP rs8099917 (TT) (OR 4.03, p<0.001) and (OR 3.14, p<0.002), female gender (OR 2.72, p<0.001), young age (OR 2.30, p<0.008), and past history of jaundice (OR 5.12, p<0.001). The markers of a past HBV infection were found significantly more often in SC. CONCLUSION: Positive predictors of the SC HCV include favorable IL-28B genotype, female gender, young age, a history of jaundice, markers of a past HBV infection, the absence of HIV infection, but not the viral genotype.
Assuntos
Infecções por HIV/genética , Hepacivirus/genética , Hepatite B/genética , Hepatite C Crônica/genética , Interferons/genética , Adulto , Fatores Etários , Coinfecção/genética , Coinfecção/virologia , Feminino , Genótipo , HIV , Infecções por HIV/virologia , Hepatite B/virologia , Vírus da Hepatite B , Hepatite C Crônica/virologia , Humanos , Icterícia/genética , Icterícia/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Remissão Espontânea , Fatores Sexuais , Adulto JovemRESUMO
Approximately 10-20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3'UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10-7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10-8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.
Assuntos
Catepsina Z/genética , Icterícia/patologia , Cirrose Hepática Biliar/complicações , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Transcrição/genética , Progressão da Doença , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão/epidemiologia , Icterícia/epidemiologia , Icterícia/genética , Desequilíbrio de Ligação , Cirrose Hepática Biliar/epidemiologia , Cirrose Hepática Biliar/genética , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Progressive familial intrahepatic cholestasis is a common cause for jaundice and hepatic dysfunction in infancy. Recent studies have provided novel insights into the etiology and pathogenesis of this childhood disease. Japanese scholars have proposed that mutation in the gene encoding the tight junction protein 2 (TJP2) may result in progressive familial intrahepatic cholestasis type 4. Gaining a detailed understanding of the pathogenesis of this disease form, and of its molecular underpinnings, will promote the development of new and more effective diagnostic tools for infantile progressive familial intrahepatic cholestasis.
Assuntos
Colestase Intra-Hepática/genética , Colestase/genética , Mutação , Erros Inatos do Metabolismo de Esteroides/genética , Proteína da Zônula de Oclusão-2/genética , Criança , Humanos , Lactente , Icterícia/genéticaRESUMO
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
Assuntos
Sulfato de Atazanavir/efeitos adversos , Glucuronosiltransferase/antagonistas & inibidores , Inibidores da Protease de HIV/efeitos adversos , Hiperbilirrubinemia/induzido quimicamente , Icterícia/induzido quimicamente , Fígado/efeitos dos fármacos , Farmacogenética/normas , Predisposição Genética para Doença , Genótipo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Hiperbilirrubinemia/enzimologia , Hiperbilirrubinemia/genética , Icterícia/enzimologia , Icterícia/genética , Fígado/enzimologia , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
We report our experience with a preterm infant with severe hemolytic jaundice who required exchange transfusion just after birth. The patient was negative for alloimmune hemolysis as a result of maternal-fetal blood type incompatibility, and tests for inherited defects in erythrocyte metabolism, membrane function, and hemoglobin synthesis were normal. We also performed a bone marrow examination, but could not identify the cause of hemolysis. The patient had several other complications, including porencephaly, epilepsy, elevated serum levels of creatine kinase, and persistent microscopic hematuria. Later, we detected a genetic mutation in COL4A1, which was recently found to be associated with hemolytic anemia. We therefore believe that all of the patient's clinical features, including hemolytic anemia, were due to the mutation in COL4A1. Genetic testing for COL4A1 mutations is recommended in neonates who exhibit hemolytic disease of unknown etiology, especially when other complications compatible with COL4A1-related disorders are present.
Assuntos
Colágeno Tipo IV/genética , Icterícia/diagnóstico , Icterícia/genética , Mutação/genética , Incompatibilidade de Grupos Sanguíneos , Humanos , Recém-Nascido , Icterícia/complicações , MasculinoRESUMO
Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.
Assuntos
Terapia Genética , Icterícia/genética , Icterícia/terapia , Animais , Síndrome de Crigler-Najjar , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Doença de Gilbert , Humanos , Hiperbilirrubinemia Hereditária/diagnóstico , Hiperbilirrubinemia Hereditária/genética , Hiperbilirrubinemia Hereditária/terapia , Icterícia Idiopática Crônica/diagnóstico , Icterícia Idiopática Crônica/genética , Icterícia Idiopática Crônica/terapia , Fígado/metabolismo , Fígado/patologiaRESUMO
Variations of the ABCB4 and ABCB11 genes affect the composition of bile and are associated with cholestasis and cholelithiasis. However, their roles in the formation of primary intrahepatic stones (PIS) remains to be elucidated. The aim of the present study was to determine whether there is an association between PIS and variations in these genes. Exon sequencing was performed in order to analyze the ABCB4 and ABCB11 genes of 176 patients with PIS and 178 healthy subjects. One mutation in ABCB4 (no. 69233, G>A) and two other mutations in ABCB11, reference single nucleotide polymorphism (rs)118109635 and rs497692, were identified in association with PIS (P<0.001, P=0.04 and P=0.02, respectively). A synonymous mutation at no. 69233 G>A was detected in exon 26 of ABCB4 in 23 heterozygous patients with PIS. This mutation was not detected in healthy individuals or in the Single Nucleotide Polymorphism Database. No. 69233 G>A in ABCB4 was not associated with altered protein expression but with a reduced rate of PIS recurrence (P=0.01). The missense mutation rs118109635 was located on exon 21 of ABCB11 and was associated with the increased expression of ABCB11 protein (P=0.032) as well as altered bile salt export pump function. Another synonymous mutation, rs497692 in exon 24 was reported to decrease ABCB11 protein expression (P=0.001). In addition, the mutations of ABCB11 were associated with preoperative jaundice (P<0.001 and P=0.03, respectively). Consistently decreased levels of ABCB11 protein were associated with recurrent episodes of cholangitis (P=0.006) and preoperative jaundice (P=0.015). By contrast, ABCB4 expression was not found to be associated with clinical manifestations of PIS.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Ductos Biliares Intra-Hepáticos/patologia , Cálculos Biliares/genética , Cálculos Biliares/patologia , Estudos de Associação Genética , Variação Genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alelos , Substituição de Aminoácidos , Estudos de Casos e Controles , Colangite/etiologia , Cálculos Biliares/metabolismo , Cálculos Biliares/cirurgia , Genótipo , Humanos , Icterícia/genética , Mutação , Razão de Chances , Polimorfismo de Nucleotídeo Único , RecidivaRESUMO
BACKGROUND: To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes. METHODS: We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls. RESULTS: The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40-0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05-9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36-47.54, and P = 0.006, OR 7.84, 95 % CI 1.39-44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation. CONCLUSIONS: The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.
Assuntos
Predisposição Genética para Doença/genética , Icterícia/genética , Cirrose Hepática Biliar/genética , Transportador 1 de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Genótipo , Humanos , Japão , Icterícia/etiologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in bilirubin metabolism, and its genetic variant may modulate hyperbilirubinemia risk in neonates. The aim of the present study was to assess the association between heme oxygenase-1 gene variants and hyperbilirubinemia risk in Indian newborns. In a prospective case-control study, we analyzed (GT)n repeats and g.-413A>T variant of HO-1 gene and UGT1A1 gene variants in 100 case newborns with total serum bilirubin (TSB) levels exceeding 95th percentile and 100 control newborns with TSB levels below 75th percentile on the hour-specific bilirubin nomogram of the American Academy of Pediatrics. Study population consisted of term (37-41 weeks) and late preterm (34-36 weeks) newborns during the first 2 weeks of age. In our analysis, the (GT)n allele was highly polymorphic, ranging in number from 15 to 40. The incidence of short (GT)n allele (≤ 20) was significantly higher in neonates with hyperbilirubinemia than in controls. Although g.-413A>T variant was widely prevalent in the study population, no difference was noted in its prevalence between cases and controls. Short (GT)n repeats of HO-1 gene, c.211G>A variant of UGT1A1 gene, and excessive weight loss were independent risk factors for neonatal hyperbilirubinemia. In the presence of two or more risk factors, the odds of developing neonatal hyperbilirubinemia were high. Shorter (GT)n genotype in the promoter region of HO-1 gene is significantly associated with hyperbilirubinemia risk in Indian newborns. This genotype may interact with other genetic and clinical risk factors to further potentiate hyperbilirubinemia risk in newborns.
Assuntos
Bilirrubina/análise , Frequência do Gene , Glucuronosiltransferase/genética , Heme Oxigenase-1/genética , Hiperbilirrubinemia Neonatal/genética , Polimorfismo Genético , Análise de Variância , Estudos de Casos e Controles , Feminino , Humanos , Índia , Recém-Nascido , Icterícia/genética , Masculino , Análise Multivariada , Razão de Chances , Reação em Cadeia da Polimerase , Estudos Prospectivos , Fatores de RiscoRESUMO
Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and in ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Adenosina Trifosfatases/genética , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/genética , Mutação , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Biomarcadores/sangue , Colagogos e Coleréticos/uso terapêutico , Colestase/genética , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/epidemiologia , Colestase Intra-Hepática/terapia , Progressão da Doença , França/epidemiologia , Genótipo , Humanos , Icterícia/genética , Prevalência , Prognóstico , Prurido/genética , Resultado do Tratamento , Ácido Ursodesoxicólico/uso terapêutico , gama-Glutamiltransferase/sangueRESUMO
A 15 years old Muslim female presented with moderate anaemia, mild jaundice and hepatosplenomegaly with no history of blood transfusion in the past. Routine examination was suggestive of haemolytic jaundice. High pressure liquid chromatography (HPLC) electrophoresis of the patient's blood showed haemoglobin (Hb) SD disease. As it is a double heterozygous disease, family screening was done. It showed that the father was sickle cell trait. Mother was Hb D trait. Both the brothers were sickle cell trait and the only sister was normal. Hb SD disease is a very rare variety of haemoglobinopathy and the case is presented here due to its rarity.
Assuntos
Anemia Falciforme/diagnóstico , Países em Desenvolvimento , Hemoglobina Falciforme , Hemoglobinopatias/diagnóstico , Hemoglobinas Anormais , Traço Falciforme/diagnóstico , Adolescente , Anemia Falciforme/genética , Aberrações Cromossômicas , Feminino , Genes Dominantes/genética , Triagem de Portadores Genéticos , Testes Genéticos , Hemoglobinometria , Hemoglobinopatias/genética , Homozigoto , Humanos , Icterícia/diagnóstico , Icterícia/genética , Testes de Função Hepática , Traço Falciforme/sangue , Traço Falciforme/genéticaRESUMO
BACKGROUND AND AIMS: Post-operative hyperbilirubinaemia in patients undergoing liver resections is associated with high morbidity and mortality. Apart from different known factors responsible for the development of post-operative jaundice, little is known about the role of hepatobiliary transport systems in the pathogenesis of post-operative jaundice in humans after liver resection. METHODS: Two liver tissue samples were taken from 14 patients undergoing liver resection before and after Pringle manoeuvre. Patients were retrospectively divided into two groups according to post-operative bilirubin serum levels. The two groups were analysed comparing the results of hepatobiliary transporter [Na-taurocholate cotransporter (NTCP); multidrug resistance gene/phospholipid export pump(MDR3); bile salt export pump (BSEP); canalicular bile salt export pump (MRP2)], heat shock protein 70 (HSP70) expression as well as the results of routinely taken post-operative liver chemistry tests. RESULTS: Patients with low post-operative bilirubin had lower levels of NTCP, MDR3 and BSEP mRNA compared to those with high bilirubin after Pringle manoeuvre. HSP70 levels were significantly higher after ischaemia-reperfusion (IR) injury in both groups resulting in 4.5-fold median increase. Baseline median mRNA expression of all four transporters prior to Pringle manoeuvre tended to be lower in the low bilirubin group whereas expression of HSP70 was higher in the low bilirubin group compared to the high bilirubin group. DISCUSSION: Higher mRNA levels of HSP70 in the low bilirubin group could indicate a possible protective effect of high HSP70 levels against IR injury. Although the exact role of hepatobiliary transport systems in the development of post-operative hyper bilirubinemia is not yet completely understood, this study provides new insights into the molecular aspects of post-operative jaundice after liver surgery.
Assuntos
Proteínas de Transporte/metabolismo , Hepatectomia , Icterícia/metabolismo , Neoplasias Hepáticas/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Idoso , Bilirrubina/sangue , Proteínas de Transporte/genética , Feminino , Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Icterícia/genética , Icterícia/patologia , Testes de Função Hepática , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Complicações Pós-Operatórias , Estudos Retrospectivos , Simportadores/genética , Simportadores/metabolismoRESUMO
Patients with co-existing hereditary spherocytosis (HS) and UDP-glucuronosyltransferase 1A1 (UGT1A1) deficiency as Gilbert's syndrome (GS) have been reported, and previous studies have demonstrated an increased risk for developing gallstones in patients with co-inheritance of GS and HS. We experienced an interesting case of HS showing persistent jaundice after splenectomy, and upon further evaluation, the 25-year-old female patient was found to have HS combined with UGT1A1 deficiency. Sequence analysis of the UGT1A1 gene revealed that she was a compound heterozygote with p.[G71R; Y486D] + [Y486D] mutations, which suggests Crigler-Najjar syndrome type II rather than GS. Careful evaluation of inappropriately elevated bilirubin level compared with the degree of hemolysis is important, reflecting the therapeutic implication of splenectomy and cholecystectomy.