Genetic interactions in the pathogenesis of neonatal hyperbilirubinemia: Gilbert's Syndrome and glucose-6-phosphate dehydrogenase deficiency.
«Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a common condition with a worldwide distribution that has the potential for causing severe hyperbilirubinemia with bilirubin encephalopathy. Hemolysis resulting from identifiable triggers may be the cause of the jaundice in some cases, but in many, jaundice continues to occur despite avoidance of contact with known hemolytic triggers. In some G-6-PD-deficient population groups, carboxyhemoglobin studies have indicated exaggerated hemolysis; but in others, increasedhemolysis has not correlated with serum total bilirubin values. As hyperbilirubinemia results from an imbalance between bilirubin production and bilirubin elimination, diminishedbilirubin conjugation was suspected to contribute to the pathogenesis of hyperbilirubinemia. Serum-conjugated bilirubin fractions, reflecting intrahepatocytic bilirubin conjugation, were low in G-6-PD-deficient neonates who developed hyperbilirubinemia. This conjugated bilirubin profile was similar to that seen in adults with Gilbert's Syndrome, a condition associated with promoter polymorphism for the gene encoding the bilirubin-conjugating enzyme, UGT glucuronosyltransferase 1A1 (UGT). Whereas G-6-PD deficiency or Gilbert's Syndrome, alone, did not predispose to hyperbilirubinemia, G-6-PD-deficient neonates who also were heterozygotes or homozygotes for the variant UGT gene promoter did have significantlyincreased incidences of hyperbilirubinemia. Additional conditions which predispose to neonatal jaundice in the presence of Gilbert's Syndrome, include Coombs' negative ABO blood group heterospecificity, hereditary spherocytosis, and prolonged breastfeeding.Gilbert's Syndrome and G-6-PD deficiency are both common, inherited conditions. Individually, and in the absence of additional genetic or environmental factors, both are benign, and should result in minimal health disturbance or interference with the quality of life of affected individuals. However, in combination, or following exposure to environmental or other genetic factors, these benign conditions may have severe manifestations, with potentially dangerous and possibly life-threatening consequences. This review highlights the major clinical features of both Gilbert's Syndrome and G-6-PD deficiency, and surveys a series of studies related to neonatal jaundice in G-6-PD-deficient neonates culminating in the documentation of an interaction between the two conditions that is crucial to the pathogenesis of hyperbilirubinemia.»
Biological risks for neurological abnormalities associated with hyperbilirubinemia.
«Unconjugated bilirubin (UCB) injury to glial cells lead to the secretion of glutamate and elicits a typical inflammatory response. Release of pro-inflammatory cytokines may influence gliogenesis and neurogenesis, and lead to deficits in learning and memory. Glutamate metabolism dysregulation and overexpression of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta are consistent with schizophrenia neuropathology. Recently, an increased prevalence of schizophrenia was reported in individuals with Gilbert's syndrome and among those who have had elevated levels of UCB in the neonatal life. In this review, we explore the reactivity of astrocytes, neurons and microglia to UCB, the cascade of events implicated in the immunostimulant effects of UCB, as well as the role of each nerve cell type and maturation state in the neuropathology of UCB. Identification of the signaling events promoted by UCB will be relevant for developing novel therapies that might reduce the risk of brain injury and disabilities.»
Study of a family in the province of Matera presenting with glucose-6-phosphate dehydrogenase deficiency and Gilbert's syndrome.
«Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a recessive X-linked trait, is the most common enzyme deficiency in the world. The most devastating clinical consequence of this deficit is severe neonatal jaundice, which results in sensorineural deficit, and severe haemolytic anemia. However, patients may be asymptomatic. The most common clinical sign is hyperbilirubinemia (h↑), that is also related to Gilbert's syndrome, a condition associated with the promoter polymorphism of the UDP-glucuronosyltransferase 1 (UGT1A1) gene. The aim of this study was to underline (as is usually done by DNA molecular analysis) to detect and to clarify the genetic deficiency that is the reason of the disorder in question. In this study, different techniques were applied to analyse a family of four individuals presenting with hyperbilirubinemia: bilirubinic dosage, electrophoresis and enzymatic activity dosage of G6PD; molecular analysis of the UGT1A promoter to detect a thymine-adenine (TA) insertion, that causes the [A(TA)7TAA] mutation. The results showed that in certain cases, the presence of hyperbilirubinemia is not only associated with G6PD deficiency, but may be caused by the co-presence of a mutation in the UGTA1 promoter related to Gilbert's syndrome. As being affected by these two conditions predisposes to adverse effects towards certain drug treatments, it is advisable to study the UGTA1 gene before prescribing drugs for specific antineoplastic or retroviral treatment. We emphasize that investigating both the UGT1A gene and G6PD activity is the most reliable way to make a correct differential diagnosis.»
Intractable neonatal jaundice due to hereditary spherocytosis and Gilbert's syndrome.
«In this article the authors present a case of pathological neonatal jaundice resistant to phototherapy in a baby with a family history of Gilbert's syndrome and hereditary spherocytosis. Her presentation was ultimately explained with a diagnosis of both conditions, and required treatment with phenobarbitone. The authors discuss the mechanism by which Gilbert's syndrome results in hyperbilirubinaemia and its similarities with Crigler-Najjar syndrome. The presentation of hereditary spherocystosis in the neonatal period is also explored, as is the mechanism of exaggerated hyperbilirubinaemia when the two conditions co-exist.»
Vitamin B12 deficiency associated with hyperbilirubinemia and cholestasis in infants.
«RESULTS: About 48.8 percent of cases had vitamin B12 deficiency. Nosignificant differences were found when those cases with vitamin B12 deficiency and those without vitamin B12 deficiency were compared in terms of total, direct, or indirect bilirubin levels. Only two cases (0.9 percent) had cholestasis.»
SIGNIFICANT REDUCTION IN BILIRUBIN LEVELS IN A PATIENT WITH GILBERT SYNDROME UNDER ISOTRETINOIN TREATMENT FOR ACNE VULGARIS: A NEW AREA OF USE FOR ...
«Gilbert's syndrome is a hereditary and benign disorder characterized by intermittent nonconjugated hyperbilirubinemia. A twenty-three- year-old patient with Gilbert syndrome and moderate acne vulgaris was started on isotretinoin at a dose of 20 mg/day. One month later, serum bilirubin levels were found to be significantlylower than that of the baseline levels. Recent studies in the literature also support that bilirubin levels tend to decrease in patients with Gilbert syndrome under oral isotretinoin therapy. This article is protected by copyright. All rights reserved.»