Gilbert's syndrome and jaundice in glucose-6-phosphate dehydrogenase deficient neonates.
(1/76)
BACKGROUND AND OBJECTIVE: The pathogenesis of the hyperbilirubinemia present in approximately 30% of neonates affected by glucose-6-phosphate dehydrogenase deficiency is an unsolved problem. We evaluated the effect of Gilbert's syndrome, the most common defect of bilirubin conjugation, on the hyperbilirubinemia of these neonates. DESIGN AND METHODS: One hundred and two neonates affected by glucose-6-phosphate dehydrogenase deficiency were enrolled in this study: 56 had hyperbilirubinemia and 46 had normal bilirubin levels. The analysis of the A(TA)nTAA motif in the promoter region of the UGT1A gene was performed by means of PCR, followed by separation on 6% denaturing polycrylamide gel. RESULTS: The frequency of the three different genotypes of the A(TA)nTAA motif was similar in the study and control groups. Our results demonstrated no difference in the percentage of homozygotes for the UGT1A (TA)7 variant associated with Gilbert's syndrome. INTERPRETATION AND CONCLUSIONS: These findings indicate that Gilbert's syndrome does not account for the hyperbilirubinemia occurring in some neonates with glucose-6-phosphate dehydrogenase deficiency. Furthermore our results suggest that hemolysis is not the major event in the pathogenesis of hyperbilirubinemia in these patients. (+info)
Co-inherited Gilbert's syndrome: a factor determining hyperbilirubinemia in homozygous beta-thalassemia.
(2/76)
BACKGROUND AND OBJECTIVE: Patients with thalassemia major and intermedia show a marked variability of serum indirect bilirubin levels. In this paper we tested the hypothesis related to the variability of the glucuronidation bilirubin rate which depends on the configuration of the A(TA)nTAA motif of the UGT1*1 glucuronosyltransferase gene promoter. DESIGN AND METHODS: We studied the configuration of the A(TA)nTAA motif in 26 patients with thalassemia major and 34 with thalassemia intermedia. RESULTS: In patients with thalassemia major and in those with thalassemia intermedia significantly higher bilirubin levels were found in patients with the (TA)7/(TA)7 genotype, than in those with the (TA)7/(TA)6 or (TA)6/(TA)6 genotype. INTERPRETATION AND CONCLUSIONS: These results indicate that the (TA)7/(TA)7 genotype, the configuration found in patients with Gilbert's syndrome, is capable of modifying the clinical phenotype of homozygous beta-thalassemia. This is an example of the role played by co-inherited modifying gene(s) on the extent of clinical heterogeneity of monogenic disorders. (+info)
(TA)8 allele in the UGT1A1 gene promoter of a Caucasian with Gilbert's syndrome.
(3/76)
BACKGROUND AND OBJECTIVE: Gilbert's syndrome, a chronic non-hemolytic unconjugated hyperbilirubinemia, is caused by a reduction in the activity of hepatic bilirubin UDP-glucuronosyltransferase (UGT1A1). This reduction has been shown to be due to a polymorphism in the promoter region of the UGT1A1 gene. The presence of seven thymine adenine (TA) repeats reduces the efficiency of transcription of the UGT1A1 gene. To elucidate the genetic background of a patient affected by Gilbert's syndrome, we collected blood samples from family members for the analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene. DESIGN AND METHODS: Analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene was performed by PCR. Estimation of UGT1A1 promoter containing the variable (TA) repeats was performed by using a luciferase reporter system. RESULTS: Three different genotypes were identified due to the presence of (TA)6, (TA)7 and (TA)8 repeats. The production of luciferase decreases in inverse relation to the number of repeats. INTERPRETATION AND CONCLUSIONS: The (TA)7 polymorphism, associated with Gilbert syndrome, is the only allele found up to now in white populations, while two other variants (TA)5 and (TA)8 have been identified in black populations. We describe here the first case of a subject affected by Gilbert's syndrome who is heterozygous for the (TA)8 allele in the promoter region of the UGT1A1 gene. This polymorphism, as well as the (TA)7 one, is associated with an increased level of bilirubin and a significant reduction of transcription activity of the UGT1A1 gene. (+info)
Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes.
(4/76)
BACKGROUND AND OBJECTIVE: Crigler-Najjar syndromes type I and II and Gilbert's syndrome are familial unconjugated hyperbilirubinemias caused by genetic lesions involving a single complex locus encoding for bilirubin-UDP-glucuronosyltransferase which is involved in the detoxification of bilirubin by conjugation with glucuronic acid. Over the last few years a number of different mutations affecting this gene have been characterized. The aim of this work is to review the molecular pathology of Crigler-Najjar and Gilbert's syndromes, to discuss its impact on the clinical and genetic classification of these conditions, and on the diagnostic evaluation of clinical pictures associated with unconjugated hyperbilirubinemia. EVIDENCE AND INFORMATION SOURCES: The authors of the present review are involved in the clinical management of patients with familial unconjugated hyperbilirubinemia as well as in the characterization of its molecular bases. Evidence from journal articles covered by the Science Citation Index and Medline has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERSPECTIVES: It has been known for many years that mild to severe deficiency of bilirubin UDP-glucuronosyltransferase in the liver is the cause of two types of familial unconjugated hyperbilirubinemia, Crigler-Najjar syndromes I and II, and Gilbert's syndrome. Since the characterization of the gene encoding for bilirubin UDP-glucuronosyltransferase, a number of mutations affecting the expression of this gene have been identified. These mutations can be classified into three groups: mutations which result in a reduced production of a normal enzyme; mutations which give rise to the synthesis of a structurally abnormal and dysfunctional enzyme; mutations which completely abolish the expression of the affected allele. The combination of mutations affecting the coding region of the gene and of promoter mutations which reduce the expression of the gene accounts for the wide clinical spectrum of familial unconjugated hyperbilirubinemias, ranging from the clinically negligible Gilbert's syndrome to the severe and often fatal Crigler-Najjar type I syndrome. A better understanding of the genetics of these conditions and the availability of molecular diagnosis will improve the diagnostic efficiency and afford better informed genetic counseling, not only for Crigler-Najjar and Gilbert's syndromes, but also for several acquired conditions characterized by unconjugated hyperbilirubinemia. (+info)
Role of bilirubin overproduction in revealing Gilbert's syndrome: is dyserythropoiesis an important factor?
(5/76)
Gilbert's syndrome was diagnosed in 37 patients with unconjugated hyperbilirubinaemia without overt haemolysis or structural liver abnormality, who had a marked reduction in hepatic bilirubin UDP-glucuronosyltransferase activity (B-GTA) (as compared with that of 23 normal subjects). No significant correlation existed in these patients between serum bilirubin level and the values of B-GTA, thus suggesting that factors other than a low B-GTA must influence the degree of hyperbilirubinaemia in Gilbert's syndrome. Studies of 51Cr erythrocyte survival and 59Fe kinetics in 10 unselected patients demonstrated slight haemolysis in eight, whereas mild ineffective erythropoiesis was suggested in all from a low 24-hour incorporation of radioactive iron into circulating red cells. This overproduction of bilirubin resulting from mild haemolysis and perhaps dyserythropoiesis might reflect only an extreme degree of the normal situation. It certainly contributes to the hyperbilirubinaemia of Gilbert's syndrome and may play a major role in the manifestation of this condition. (+info)
Jaundice with hypertrophic pyloric stenosis as an early manifestation of Gilbert syndrome.
(6/76)
Jaundice associated with hypertrophic pyloric stenosis was recognised in three patients; previous reports have suggested that this is a possible early manifestation of Gilbert syndrome. Most patients with Gilbert syndrome are homozygous for a (TA)(7)TAA polymorphism in the gene promoter coding for bilirubin glucuronosyltransferase. Two of the reported patients were homozygous for the (TA)(7)TAA polymorphism whereas the third was heterozygous for the same polymorphism. Furthermore, no other factors contributing to jaundice in the three patients were found. These results suggest that jaundice associated with hypertrophic pyloric stenosis is due to molecular defects within the gene promoter. (+info)
Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis.
(7/76)
The precocious formation of bilirubinate gallstones is the most common complication of hereditary spherocytosis (HS), and the prevention of this problem represents a major impetus for splenectomy in many patients with compensated hemolysis. Because Gilbert syndrome has been considered a risk factor for gallstone formation, there are reasons for postulating that the association of this common inherited disorder of hepatic bilirubin metabolism with HS could increase cholelithiasis. To test this hypothesis, 103 children with mild to moderate HS who, from age 1, have undergone a liver and biliary tree ultrasonography every year, were retrospectively examined. The 2-bp (TA) insertion within the promoter of the uridine diphosphate-glucuronosyltransferase gene (UGT1A1), associated with Gilbert syndrome, was screened. The risk of developing gallstones was statistically different among the 3 groups of patients: homozygotes for the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele with the TA insertion. Fitting a Cox regression model, in fact, a statistically significant hazard ratio of 2.19 (95% confidence interval: 1.31 to 3.66) was estimated from one to the next of these genetic classes. The individual proneness to form gallstones from TA insertion in the TATA-box of the UGT1A1 promoter should be considered during the follow-up of patients with HS. Although patients with HS were the only ones studied, extrapolating these data to patients who have different forms of inherited (eg, thalassemia, intraerythrocytic enzymatic deficiency) or acquired (eg, autoimmune hemolytic anemia, hemolysis from mechanical heart valve replacement) chronic hemolysis can be warranted. (+info)
Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics.
(8/76)
PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 mg/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one study and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2). At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU-resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing. (+info)