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Gilbert disease was diagnosed in a 15-year-old boy on the basis of the clinical pattern and the changing drug-metabolizing capacity of the liver-enzyme apparatus, which was drug-induced.
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Gilbert syndrome (GS), characterized by mild, chronic and isolated unconjugated hyperbilirubinemia is due to a partial deficiency of bilirubin-UDP-glucuronosyltransferase (UGT1A1). Recently, the genetic basis of GS has been identified in caucasian populations : it is related to the insertion of a dinucleotide (TA) in the promoter region of the UGT1A1 gene. In Asian populations, GS is due to missense mutations (either homozygous or heterozygous) in the coding sequence. The aim of this study was to develop a simple and rapid method to detect both genetic polymorphisms and mutations. This technique was performed (1) to explore unrelated unconjugated hyperbilirubinemia; (2) to evaluate the frequency of GS in a population of 97 healthy caucasian volunteers: 17% of them were homozygous for the TA7/TA7 polymorphism; (3) to determine the incidence of this syndrome in a population of 105 neonates with unconjugated hyperbilirubinemia. The incidence of GS (15%) was not significantly higher than it was in the control group. A correlation between GS genotype and neonatal jaundice was not established; (4) to seek a relationship between GS and preeclampsia with or without Hellp syndrome. The incidence in the Hellp syndrome group (n = 19) was 26%, two fold higher than in preeclampsia group (n = 22) and control group (n = 50) with only 14% and 13% respectively, (5) to start a study regarding the toxicity of irinotecan treatment in a population of homozygous children for the UGT1A1 polymorphism.
BACKGROUND: Gilbert syndrome and the Crigler-Najjar syndromes Type I and II are disorders of bilirubin conjugation with consecutive indirect hyperbilirubinemia of different severity. Morbus Gilbert is a mild hyperbilirubinemia, which is only of significance in case of drug therapy or differential diagnosis. Crigler-Najjar syndrome II leads to a more serious kind of hyperbilirubinemia. In case of Crigler-Najjar syndrome I patients are suffering from a very severe hyperbilirubinemia, which often causes death during the first months of life. MOLECULAR GENETICS: The molecular defects of these three syndromes have been characterized during the last decade. They are caused by mutations in the UGT1A1 gene locus. This locus codes for the enzyme bilirubin uridine 5'-diphosphate-(UDP-) glucuronosyltransferase (UGT1A1). In the case of Gilbert syndrome two bases are inserted into the promoter of the gene. In Crigler-Najjar syndrome type I and II mutations lead to the exchange of amino acids, changes of the reading frame or to stop codons. CONCLUSION: All three forms of indirect hyperbilirubinemia are caused by mutations in the UGT1A1 gene locus, which codes for the enzyme UDP-glucuronosyltransferase.
INTRODUCTION: Because of the potential hepatotoxicity of retinoids, prescription of isotretinoin is always very carefully made in healthy subjects, and prohibited in case of concomitant hepatopathy. Gilbert's syndrome consists of chronic, mild, unconjugated hyperbilirubinemia. In this syndrome, isotretinoin has been reported twice to be perfectly tolerated, and once even beneficial. We report here a new case of good tolerance and even improvement of a Gilbert's syndrome during isotretinoin therapy. CASE REPORT: A 17-year-old man with Gilbert's syndrome presented with a nodulocystic acne. Topical agents had been inefficient, and cyclines bad tolerated. Thus isotretinoin has been gradually introduced, with a regular monitoring of the liver function. We observed a steady decrease of the bilirubinemia during the course of isotretinoin, and then a reappearance of hyperbilirubinemia as soon as posology was diminished and particularly after completion of isotretinoin therapy. DISCUSSION: A review of the literature finds only very few cases of hepatic injuries caused by isotretinoin, contrary to etretinate. Safety of isotretinoin in Gilbert's syndrome was first observed in 1984, but its beneficial effects have only recently been described by Wang et al., and we report here a similar case. Pharmacological mechanisms remain hypothetic. However, considering the prevalence of Gilbert's syndrome and its usual first expression during postpubertal period, it seems to us interesting for therapeutic practice to know that isotretinoin is not less safe in these patients.
BACKGROUND: Gilbert's syndrome (GS) is a hereditary deficiency of bilirubin UDP-glucuronosyltransferase (UGT). The aim of this study was to analyze changes in the metabolism of paracetamol, which is primarily eliminated by liver glucuronidation, through urine concentrations of its four principal hepatic metabolites, in persons with GS. MATERIAL AND METHODS: Thirty-two healthy volunteers and 18 persons with GS were studied. Subjects were given 1.5 g of oral paracetamol. Elimination of free paracetamol, as well as derivatives of its conjugation (glucuronide, sulfate) and of its oxidation (cysteine, mercapturic acid), was determined in 24-hour urine by high performance liquid chromatography (HPLC). Results were expressed as a percentage of the total quantity of paracetamol eliminated. Patients with GS were divided in two subgroups (GS-I and GS-II) according to whether glucuronidation was greater than or less than 50%. RESULTS: Patients with GS showed no significant differences in the urinary elimination of metabolites compared with controls. However, the subgroup GS-II showed decreased glucuronidation (p = 0.0012) and increased oxidation (p = 0.0051) compared with the other two groups. Moreover, there was an inverse correlation between the glucuronide conjugate and oxidation derivatives (r = 0.08718; p < 0.005). CONCLUSIONS: Persons with GS form a heterogeneous group as far as paracetamol metabolism is concerned. In one subgroup metabolism was normal and in the other glucuronication was clearly decreased and oxidation was increased. These alterations could make these subjects more susceptible to liver damage after paracetamol overdose.
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An extensive review of Gilbert's disease (unconjugated, non-hemolytic hyperbilirubinemia) is made with incidence not exactly determined, but it is a disease linked to hereditary factors. Two types of the disease, together with the controversy existing as to their pathogenesis are discussed. The clinical picture and all laboratory studies carried out to reach a diagnosis are reviewed. Also, the histopathology and treatment are briefly described. Two cases of this disease in the same family are presented.
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Twenty-six patients with Gilbert's disease (congenital, non-haemolytic unconjugated hyperbilirubinaemia) were analysed regarding their clinical presentation, age at onset of symptoms, sex, frequency of symptoms, family history, race and religion. Seventy-three per cent were men, the mean age at onset of symptoms was 21 years, and frequency of symptoms ranged from 4 times a year to once every 5 years. The symptoms, which were extremely vague, included the following: recurrent asymptomatic jaundice in 74%, malaise in 66%, asthenia in 65%, and vague abdominal distension in 52% of patients. Eight per cent of patients were totally asymptomatic. There did not appear to be any particular race or religious group with a higher incidence of the disorder. No abnormal clinical features apart from mild jaundice were detected. The entirely benign nature of the syndrome is stressed, and a normal life expectancy is the rule. The avoidance of prolonged fasting is the best therapeutic measure, although enzyme induction by phenobarbitone therapy may have some place in the management of symptoms.
Gilbert's syndrome is characterized by mild unconjugated hyperbilirubinemia. The molecular basis of this syndrome usually concerns an additional dinucleotide insertion (TA) in the A(TA)(n)TAA configuration residing in the promoter region of the UGT1 A1 gene. This configuration may vary in length; the "n" represents the different number of TA repeats. The homozygosity A(TA)(7)TAA/A(TA)(7)TAA is involved in Gilbert's syndrome. In many cases of patients with thalassemia intermedia and sickle cell disease considerable variation in bilirubin levels is observed. In this study we investigated the contribution of the A(TA)(7)TAA/A(TA)(7)TAA genotype in the variable unconjugated serum bilirubin levels in 31 Greek patients with thalassemia intermedia and 27 Greek compound heterozygotes for beta thalassemia and sickle cell anemia. Analysis of the A(TA)(n)TAA configuration in the promoter region of the latter patients showed that those who were carrying the homozygosity A(TA)(7)TAA/A(TA)(7)TAA had higher levels of unconjugated bilirubin. These findings suggest that the coexistence of Gilbert's syndrome in patients with thalassemia intermedia and sickle cell disease may be the cause of the elevated values of unconjugated bilirubin, reducing the possibility of excessive hemolysis in these patients.
AIM: To research the behaviour of one biliary acid (glyco-cholic) i.v. injected in patients with Gilbert's disease and in healthy controls, so that contribute to the knowledge of the pathophysiological correlate between bilirubin and biliary acids. PATIENTS AND METHODS: We include 15 patients with Gilbert's disease and 7 healthy voluntary ones. We injected i.v. glycocholic acid and obtained the clearance curve (CG-RIA Abbot method). We evaluated the possible biostatistically significant differences between the obtained values of both groups though the non-parametric method of Mann-Whitney. RESULTS: The clearance curve of both groups had a similar profile; biostatisticaly there are not significant differences between the serum values of glyco-cholic acid in both groups. CONCLUSIONS: The clearance of the glyco-cholic acid in patients with Gilbert's disease had a similar behaviour as in healthy controls, without biostatisticaly significant differences between both groups.
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172 adolescent and adult patients with low grade nonhemolytic unconjugated hyperbilirubinaemia (n.u.h) were examined. Authors have come to the conclusion of the absence of an acquired (posthepatic) form of n.u.h., i.e of the existence of a single --constitutional--form (Gilbert's disease). Viral hepatitis is not likely to play the role of an etiological factor of n.u.h. but of a factor which manifests a congenital defect of bilirubin metabolism. The study of the glucuronidisation found out that its decrease is an important factor in the pathogenesis of the low grade n.u.h. that therefore cannot opposed to the n.u.h. with glucuronyl transferase deficiency group II according to Arias et al. In 61% of patients a moderately shortened erythrocyte life span has been revealed. However the increased bile pigment production in these cases does not speak against Gilbert's disease. The results of biochemical assays have shown that in n.u.h not only the intrahepatic bilirubin metabolism is disturbed but other functions of the liver cell as well. The morphological study of hepatocytes has revealed certain signs of their dystrophy. Based on their investigation the authors propose to single out a group of hereditary pigment hepatoses which include besides Gilbert's disease the syndromes of Crigler-Najjar, Dubin-Johnson and Rotor.
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