Gilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidation

Ehmer, Ursula; Kalthoff, Sandra; Fakundiny, B; Pabst, Brigitte; Freiberg, N.; Naumann, Ronald; Manns, Michael P.; Strassburg, Christian P.

doi:10.1002/hep.25561

Cited by 49 publications

(41 citation statements)

References 32 publications

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“…32 Although this was a small study, it raises the possibility of survival bias in case-control studies of alleles influencing bilirubin levels and CVD. Further replication in large cohorts with a young recruitment age, extended followup, careful recording of CVD-related drug prescriptions, and inclusion of variants influencing bilirubin levels in addition to UGT1A1*28 2,33 is required to clarify the relationship between alleles causing hyperbilirubinemia and CVD risk.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

2012

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Background-Serum bilirubin is an endogenous antioxidant that is routinely measured before a statin is prescribed primarily to assess liver function, but the association with cardiovascular disease (CVD) in this population has not been explored. Method and Results-We identified patients from a United Kingdom primary care database (The Health Improvement Network) with measurements of serum total bilirubin levels recorded 3 months before the first statin treatment between January 1, 2000, and December 31, 2010, and no history of liver disease or CVD. In total, 130 052 patients met the inclusion criteria, and after a median follow-up of 43 months, there were 7850 CVD events. In men, the incidence of CVD in the lowest decile category of bilirubin (1-6 mol/L [0.06 -0.35 mg/dL]) was 215 per 10 000 person-years compared with 163 per 10 000 person-years in the highest decile (19 -40 mol/L [1.1-2.3 mg/dL]). Similar differences were seen for women. After conventional CVD risk factors were accounted for, the associations with bilirubin were nonlinear (L shaped), and the models predicted that, compared with patients with a bilirubin level of 10 mol/L (0.6 mg/dL), those with a similar CVD risk profile but a bilirubin level of 5 mol/L (0.3 mg/dL) had an 18% (95% confidence interval, 9 -27) higher risk of any CVD event, a 34% (95% confidence interval, 13-56) higher risk of myocardial infarction, and a 33% (95% confidence interval, 21-46) higher risk of death resulting from any cause. Conclusions-Serum bilirubin level measured before a statin prescription to assess liver function is an independent risk factor for CVD and death in both men and women. (Circulation. 2012;126:2556-2564.)

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Section: Discussionmentioning

confidence: 99%

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

2012

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“…Due to the phenomenon of linkage disequilibrium, most UGT1A1*28 homozygotes also have deficiencies in other UGT1A isoforms encoded just downstream of UGT1A1 [35]. All UGT1A isoforms are drug metabolising enzymes and a number of pharmacogenetic studies and investigations in patients with Gilbert's syndrome suggest altered glucuronidation capacity toward a range of common agents including 13 aspirin, paracetamol and statins [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…All UGT1A isoforms are drug metabolising enzymes and a number of pharmacogenetic studies and investigations in patients with Gilbert's syndrome suggest altered glucuronidation capacity toward a range of common agents including 13 aspirin, paracetamol and statins [35][36][37]. Given the high prevalence of the genetic variation underlying Gilbert's syndrome and the high burden of adverse reactions to these agents, further research into drug response is warranted.…”

Section: Discussionmentioning

confidence: 99%

Gilbert's syndrome and the risk of death: A population‐based cohort study

Horsfall

Nazareth

Pereira

et al. 2013

J of Gastro and Hepatol

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Background and Aims Gilbert's syndrome is a common familial hyperbilirubinemia that may reduce the risk of various age‐related diseases because of the antioxidant properties of bilirubin. We conducted a large cohort study using The Health Improvement Network primary care database and compared all‐cause mortality rates in those with and without Gilbert's syndrome. Methods Mortality rates in patients with a diagnosis of Gilbert's syndrome and raised bilirubin level (n = 4266) were compared with those of patients with similar characteristics but with normal bilirubin levels (n = 21 968). Multivariate Poisson regression was also used to estimate adjusted mortality rate ratios. Results During the 350 000 PYs of follow up across the Gilbert's and comparison cohorts, there were 1174 deaths. Mortality rates were 24/10 000 PYs in the Gilbert's cohort versus 50/10 000 PYs in the comparison cohort. Mortality rates were around half in patients with Gilbert's syndrome after accounting for sociodemographics and general health indicators (adjusted mortality rate ratio: 0.5 [95% confidence interval; 0.4–0.7; P < 0.001]). Conclusions Mortality rates observed for people with Gilbert's syndrome in the general population are almost half those of people without evidence of Gilbert's syndrome.

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“…In particular, the common UGT1A1 allele 28 polymorphism (UGT1A1*28), which is necessary, but not sufficient, for the clinical expression of Gilbert's syndrome (8), was more frequent in acromegalics with hepatotoxicity, thus representing, together with male gender, a predictor of LFT abnormalities (7). Other studies pointed out a role of diabetes mellitus, with significant odds ratios (OR) (from 2 to 5) for the association with PEG-V hepatotoxicity (9,10).…”

Section: Introductionmentioning

confidence: 99%

Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients

Filopanti

Barbieri

Mantovani

et al. 2014

European Journal of Endocrinology

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Context: Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome. Objective: To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment. Design and setting: Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy. Patients: A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled. Interventions: Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping. Results: No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratioZ1.25; PZ0.04) and the number of concomitant medications, other than SSTa (BZ3.9; PZ0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found. Conclusions: UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.

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Gilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidation

Cited by 49 publications

References 32 publications

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

Gilbert's syndrome and the risk of death: A population‐based cohort study

Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients

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