Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity?

Observational epidemiological studies showed that mild hyperbilirubinemia has beneficial effects on the prevention of cardiovascular disease, type 2 diabetes mellitus, and metabolic syndrome. In mammals, bilirubin plays a major role as a potent antioxidant. Uridine 5'-diphospho-glucuronosyl transferase (UGT)1A1 variants coding for bilirubin UDP-glucuronosyl transferase resulting in mild hyperbilirubinemia (as in Gilbert syndrome (GS)) may confer a strong genetic advantage. Strategies to boost bioavailability of bilirubin or to mimic GS represent an attractive approach to prevent many oxidative stress and inflammation-mediated diseases. Even a tiny, micromolar increase in serum bilirubin concentrations substantially decreases the risk of oxidative stress-mediated diseases. There are several possible ways to achieve this, including lifestyle changes, changes in dietary patterns, regular physical activities, or use of chemical drug or of specific plant products either in the form of regular food items or nutraceuticals. Further basic and experimental research is required to fully uncover this promising therapeutic field.

Genetic lesions in the UGT1A1 genes among Gilbert's syndrome patients from India.

The present study was undertaken to investigate genetic variations present in the coding regions of the UGT1A1 gene among the Gilbert's syndrome patients. Analysis of genetic variations was performed by direct DNA sequencing among the patients that do not have any polymorphic variations in the promoter regions of the UGT1A1 gene. We identified seven different sequence variations among Gilbert's Syndrome patients, of which four were novel. Out of seven variants, six missense and one silent single nucleotide substitutions were present in the UGT1A1 gene. In addition, molecular modeling of UGT1A1 (H55R, P152S and N212H) variants suggested a reduced activity of the enzyme. This study demonstrates that different variations present in the UGT1A1 gene and specifically, the H55R variation had a significant effect on bilirubin levels and could be genetic risk factors for hyperbilirubinemia.

Mortality outcomes after busulfan-containing conditioning treatment and haemopoietic cell transplantation in patients with Gilbert's syndrome: a retrospective cohort study.

BACKGROUND: Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative conditioning and haemopoietic cell transplantation would have different mortality outcomes depending on whether or not they had laboratory evidence of Gilbert's syndrome. METHODS: In this retrospective cohort study, we used clinical and laboratory data of patients who had haemopoietic cell transplantation from Jan 1, 1991, to Dec 31, 2011. Patients were included if they had received high-dose conditioning regimens of cyclophosphamide plus total body irradiation (CY/TBI), busulfan plus cyclophosphamide (BU/CY), busulfan plus melphalan plus thioTEPA (BUMELTT), or melphalan before transplant. Patients were excluded if their original consent forms to report transplant outcomes were not signed, if consent was withdrawn, or if they were a prisoner. Patients with Gilbert's syndrome were defined as having laboratory values before the start of conditioning therapy for unconjugated serum bilirubin concentrations of at least 17·1 µmol/L (≥1 mg/dL), normal conjugated serum bilirubin, and no evidence of hepatitis, cholestasis, or haemolysis. We assessed the association of Gilbert's syndrome with overall mortality and non-relapse mortality using adjusted Cox regression models at day 200 after transplantation. FINDINGS: Our study cohort was 3379 patients-1855 (55%) allograft and 1524 (45%) autograft recipients. 211 (6%) patients had Gilbert's syndrome and 3168 (94%) did not have this condition. Most patients were adults (median age 45·8 years [IQR 33·2-55·5]) with haematological malignancies. For overall mortality 664 (20%) patients had died by day 200 after transplant (47 [22%] of 211 who had Gilbert's syndrome vs 617 [19%] of 3168 who did not have Gilbert's syndrome), and for non-relapse mortality 499 (92%) patients had died before relapse was recorded (38 [18%] who had Gilbert's syndrome vs 461 [15%] who did not have Gilbert's syndrome). The effect of Gilbert's syndrome on the risk of overall mortality and non-relapse mortality by transplant day 200 varied between the conditioning regimens and donor groups. In patients conditioned with a myeloablative regimen that contained busulfan (n=1131), those with Gilbert's syndrome (n=60) were at a significantly increased risk of death and non-relapse mortality by day 200 compared with those without Gilbert's syndrome (n=1071; hazard ratio [HR] 2·30, 95% CI 1·47-3·61, p=0·00030; and 2·77, 1·71-4·49, p<0·0001). In patients who received CY/TBI or melphalan conditioning regimens, those with Gilbert's syndrome had similar outcomes to those without Gilbert's syndrome (overall mortality at day 200 HR 0·90, 95% CI 0·60-1·34, p=0·60; non-relapse mortality at day 200: 0·90, 0·56-1·45, p=0·65). Analyses of causes of death and busulfan disposition provided no mechanistic explanation for the differences in mortality. INTERPRETATION: Overall mortality and non-relapse mortality at day 200 after transplant were significantly worse in patients with Gilbert's syndrome who received busulfan-containing myeloablative conditioning regimens, compared with non-Gilbert's syndrome patients. Patients with Gilbert's syndrome should receive busulfan-containing myeloablative conditioning regimens with caution. FUNDING: US National Institutes of Health.

Oxidative stress and endothelial dysfunction: clinical evidence and therapeutic implications.

An imbalance of nitric oxide (NO) and reactive oxygen species (ROS), so-called "oxidative stress," may promote endothelial dysfunction, leading to cardiovascular complications. Activation of nicotinamide-adenine dinucleotide phosphate oxidase, xanthine oxidase, cyclooxygenase, and mitochondrial electron transport, inactivation of the antioxidant system, and uncoupling of endothelial NO synthase lead to oxidative stress along with an increase in ROS production and decrease in ROS degradation. Although experimental studies, both in vitro and in vivo, have shown a critical role of oxidative stress in endothelial dysfunction under the condition of excessive oxidative stress, there is little information on whether oxidative stress is really involved in endothelial function in humans. In a clinical setting, we showed an association between oxidative stress and endothelial function, especially in patients with renovascular hypertension as a model of increased oxidative stress and in patients with Gilbert syndrome as a model of decreased oxidative stress, through an increase in the antioxidant property of unconjugated bilirubin.

The evaluation of relationship between adiponectin levels and epicardial adipose tissue thickness with low cardiac risk in Gilbert`s syndrome: an observational study.

OBJECTIVE: Atherosclerotic heart diseases are less frequently seen in patients with Gilbert's syndrome (GS). We aimed to investigate whether serum adiponectin (APN) and epicardial adipose tissue (EAT) thickness have an effect beside the antioxidant effect of bilirubin in lowering the incidence of the atherosclerotic process. METHODS: Sixty-eight patients diagnosed with GS (39 females and 29 males) who had applied at the internal medicine clinic of the hospital were included in this cross-sectional, observational study. The control group included 63 healthy people (39 females and 24 males). EAT thickness was measured by echocardiography. The serum APN levels were also checked. Statistical analysis was performed by using independent sample t-test, Pearson correlation and linear regression analyses. RESULTS: The mean age of the GS group was 28 ± 9 years, and the average EAT thickness was found to be 2.5 ± 0.1 mm. The mean age of the control group was 26 ± 6 years, and the average EAT thickness was found to be 4.2 ± 0.5 mm. When comparing the two groups, the EAT thickness of the GS group was found to be significantly lower (p<0.001) than that of the control group. In the GS group the APN was 14.9 ± 4.2 mg/L, and in the control group the APN was 12.6 ± 4.5 mg/L (p<0.022). We found that total bilirubin (ß=-1,607, p<0,001) and indirect bilirubin (ß=1,086, p<0,001) have an independent association with decreased EAT thickness. CONCLUSION: EAT thickness is associated with coronary atherosclerosis. Low EAT thickness may be related with low release of proinflammatory cytokine. High levels of APN may be related high anti-inflammatory effect. Therefore, low EAT thickness and high levels of APN may demonstrate protective effect on atherosclerotic heart diseases in GS patients.

The effect of Gilbert's syndrome on the dispersions of QT interval and P-wave: an observational study.

OBJECTIVE: Gilbert's syndrome (GS) decreases the incidence of atherosclerotic heart disease. The aim of the study was to evaluate whether the arrhythmia risk markers such as P-wave dispersion (Pd), QT dispersion (QTd) are reduced in patients with GS compared with healthy subjects. METHODS: Sixty-one patients diagnosed with GS (31 females, 30 males) who had applied to the internal medicine outpatient clinic in the hospital were included in this cross-sectional, observational study. A control group of 61 healthy persons (31 females, 30 males), who were non-smokers and drinkers, were included. Both groups were between 16-45 years old. Results of anthropometric measurements, laboratory assays and electrocardiographic findings were recorded for each participant. Independent sample t-test and nested ANOVA were used for data analysis. RESULTS: In the GS group were Pd value 36±16.7 msec, QTd 48.7±10.7 msec and heart rate (HR) 74±8 beat/min. In the control group were Pd 51±28 msec, QTd 53±12 msec and HR 78±10 beat/min. The Pd of patients group (p<0.001), QTd (p=0.038) and HR (p=0.021) were significantly lower than the control group. CONCLUSION: According to our study's results, in these patients, increased bilirubin levels are associated with decrease in HR, Pd and QTd, which consequently might decrease the incidence of cardiac arrhythmias and coronary artery disease. Further studies are needed to clarify the protective role of bilirubin in risk of arrhythmias in this category of patients.

Investigation of the aortic pulse wave velocity in patients with Gilbert's syndrome.

Arterial stiffness is currently the "gold standard" measure of aortic (carotid-femoral) pulse wave velocity (PWV), which is an important independent predictor of risk of developing a cardiovascular event. Gilbert's syndrome is a congenital disorder characterized by intermittent and non-hemolytic elevation of indirect bilirubin levels due to the deficiency of the enzyme UDP-glucuronyl transferase in the liver and many prospective studies found an inverse relationship between bilirubin levels and cardiovascular events in these patients. We aimed to investigate serum bilirubin levels and arterial stiffness parameters in patients with Gilbert's syndrome in this study. A total of 53 cases, consisting of 26 patients with a diagnosis of Gilbert's syndrome and 27 healthy control subjects, were included in the study. Serum bilirubin levels, other routine blood chemistry, and arterial stiffness measurements were recorded. The mean ages of Gilbert's syndrome and the control group were 31.5 ± 9.7 and 36.8 ± 11.1 years, respectively. PWV measurements were significantly lower in Gilbert syndrome patients (6.68 and 7.3 m/s in patients and controls; respectively) (P < .05). In correlation analysis in Gilbert's syndrome patients, PWV had a significant correlation with total and indirect bilirubin levels (r = -0.370, P = .009/r = -0.495, P = .003, respectively). Gilbert's syndrome patients have lower PWV measurements compared to healthy subjects, and the total and indirect bilirubin levels are also associated with PWV measurements. These findings may indicate the decreased atherosclerotic disease incidence in Gilbert's syndrome patients.

Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome.

BACKGROUND: Patients with Gilbert syndrome have mild unconjugated hyperbilirubinemia. It has been shown that bilirubin is an endogenous antioxidant. We evaluated the role of oxidative stress in endothelial function in patients with Gilbert syndrome under normal conditions without cardiovascular risk factors. METHODS AND RESULTS: A total of 108 young men with Gilbert syndrome without cardiovascular risk factors and 108 age-matched healthy men (normal controls) were enrolled in this study. Serum concentrations of bilirubin were higher in patients with Gilbert syndrome than in control subjects (29.2±11.6 versus 9.4±2.7 µmol/L; P<0.001). Serum concentrations of malondialdehyde-modified low-density lipoprotein and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG), as indices of oxidative stress, were lower in patients with Gilbert syndrome than in control subjects (61.8±24.5 versus 72.5±21.8 U/L, P=0.034; 7.8±2.4 versus 10.4±3.2 ng/mg creatinine, P=0.001, respectively). Flow-mediated vasodilation was greater in patients with Gilbert syndrome than in normal control subjects (7.2±2.2% versus 5.9±1.7%; P<0.001). Vascular responses to nitroglycerine were not significantly different between the 2 groups. Flow-mediated vasodilation correlated with serum concentration of bilirubin (r=0.44, P<0.001), malondialdehyde-modified low-density lipoprotein (r=-0.25, P=0.01), and urinary excretion of 8-OHdG (r=-0.27, P=0.004) in patients with Gilbert syndrome but not in control subjects. In addition, serum concentration of bilirubin correlated with malondialdehyde-modified low-density lipoprotein (r=-0.20, P=0.04) and 8-OHdG (r=-0.21, P=0.02) in patients with Gilbert syndrome but not in control subjects. CONCLUSIONS: Patients with Gilbert syndrome had low levels of oxidative stress associated with hyperbilirubinemia and enhancement of endothelium-dependent vasodilation. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp. Unique identifier: UMIN000003409.

Decreased small dense LDL levels in Gilbert's syndrome.

OBJECTIVE: To investigate the role of small dense low density lipoprotein cholesterol (sd-LDL-C) in the mechanism of decreased incidence of cardiovascular disease in Gilbert's syndrome (GS). DESIGN AND METHODS: sd-LDL-C, ox-LDL, and high sensitive C reactive protein (hs-CRP) levels were investigated in subjects with GS (n=42) and compared to healthy controls (n=52). RESULTS: Age, gender and body mass index (BMI) distributions were similar between the two groups. sd-LDL-C, ox-LDL and hs-CRP levels were lower in GS than the healthy controls (p<0.001, p<0.001 and p=0.001, respectively). Unconjugated bilirubin was negatively correlated with sd-LDL-C, ox-LDL and hs-CRP (r=-0.594, p<0.001; r=-0.249, p=0.016 and r=-0.373, p<0.001 respectively). In addition, sd-LDL-C was positively correlated with ox-LDL (r=0.307, p=0.003). CONCLUSIONS: The findings of this preliminary study suggest that reduced sd-LDL-C, ox-LDL and hs-CRP levels may have a role in preventing atherosclerosis in subjects with GS.

Abnormalities in MRI signal intensity in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia.

OBJECTIVE: The purpose of the present study was to examine whether patients with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome; GS) have specific changes in signal intensity on magnetic resonance imaging (MRI). METHODS: Axial 5 mm-thick T1-weighted and T2-weighted MRI was acquired from schizophrenia patients with GS (n = 24) and schizophrenia patients without GS (n = 60). All patients were diagnosed according to DSM-IV criteria and were compared with age- and sex-matched healthy controls without GS (n=60) and controls with GS (n=36). Signal intensity in the hippocampus, amygdala, caudate, putamen, globus pallidus, thalamus, anterior cingulate gyrus, posterior cingulate gyrus, insular cortex, and cerebellum was measured in relation to the signal intensities of the vitreous body. RESULTS: Compared to both schizophrenia patients without GS and the control subjects without or with GS, the schizophrenia patients with GS had significantly decreased signal intensity in almost all the regions measured on T1-weighted MRI. On T2-weighted MRI, the schizophrenia patients with GS had significantly increased signal intensity in almost all the regions measured compared to both schizophrenia patients without GS and the control subjects without or with GS. CONCLUSION: Patients with schizophrenia-associated GS have specific changes in signal intensity on T1- and T2-weighted MRI, suggesting that schizophrenia with GS produces changes specifically in the frontotemporal cortex, limbic system, and basal ganglia.

[The prevalence of hyperbilirubinaemia and the diagnostics of Gilbert-syndrome in our work fitness examinations]. / A hyperbilirubinaemia gyakorisága és a Gilbert-szindróma diagnosztikája munkaköri alkalmassági vizsgálataink során.

The Gilbert-syndrome is a mild metabolism anomaly, which is spread all over the world. Every twentieth person is affected in the general population. We examined 1307 people in MH EVI at expedient operated specialist' workplaces, where we investigate work capacity evaluation in the first three months of 2006. Estimating the laboratory results, the frequent increases of total bilirubin plasma levels were remarkable, which we observed in 117 cases. Our control examinations pointed out that in 57 cases of the 117 the increase was caused by the accumulation of indirect unconjugated bilirubin. In theses cases, aimed examinations indicated neither hepatic disease nor any disease with increased hemolysis. Therefore, lack of other diagnostic sign, the abnormal value led to the diagnosis of Gilbert-syndrome. In respect of physical loading capacity, there is no united stand in the judging of Gilbert-syndrome. Therefore we made a comparison between the results of 57 patients with Gilbert-syndrome and of 57 healthy controls with the same age and gender. We made this examination in our institute, at the department which investigates the fitness for physical activity. We didn't notice any difference between the two groups' loading capacity. In consequence of our study and of other observations till now, we should re-interpret the question of restriction in the field of work. Our observations refer to a representative group. We hope this study will help in diagnostic considerations and in the correct general estimation of the importance of this metabolic anomaly.

''Iatrogenic Gilbert syndrome''--a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin.

The catabolism of heme, generating biliverdin, carbon monoxide, and free iron, is mediated by heme oxygenase (HO). One form of this of this enzyme, heme oxygenase-1, is inducible by numerous agents which promote oxidative stress, and is now known to provide important antioxidant protection, as demonstrated in many rodent models of free radical-mediated pathogenesis, and suggested by epidemiology observing favorable health outcomes in individuals carrying high-expression alleles of the HO-1 gene. The antioxidant impact of HO-1 appears to be mediated by bilirubin, generated rapidly from biliverdin by ubiquitously expressed biliverdin reductase. Bilirubin efficiently scavenges a wide range of physiological oxidants by electron donation. In the process, it is often reconverted to biliverdin, but biliverdin reductase quickly regenerates bilirubin, thereby greatly boosting its antioxidant potential. There is also suggestive evidence that bilirubin inhibits the activity or activation of NADPH oxidase. Increased serum bilirubin is associated with reduced risk for atherogenic disease in epidemiological studies, and more limited data show an inverse correlation between serum bilirubin and cancer risk. Gilbert syndrome, a genetic variant characterized by moderate hyperbilirubinemia attributable to reduced hepatic expression of the UDP-glucuronosyltransferase which conjugates bilirubin, has been associated with a greatly reduced risk for ischemic heart disease and hypertension in a recent study. Feasible strategies for boosting serum bilirubin levels may include administration of HO-1 inducers, supplementation with bilirubin or biliverdin, and administration of drugs which decrease the efficiency of hepatic bilirubin conjugation. The well-tolerated uricosuric drug probenecid achieves non-competitive inhibition of hepatic glucuronidation reactions by inhibiting the transport of UDP-glucuronic acid into endoplasmic reticulum; probenecid therapy is included in the differential diagnosis of hyperbilirubinemia, and presumably could be used to induce an ''iatrogenic Gilbert syndrome''. Other drugs, such as rifampin, can raise serum bilirubin through competitive inhibition of hepatocyte bilirubin uptake--although unfortunately rifampin is not as safe as probenecid. Measures which can safely achieve moderate serum elevations of bilirubin may prove to have value in the prevention and/or treatment of a wide range of disorders in which oxidants play a prominent pathogenic role, including many vascular diseases, cancer, and inflammatory syndromes. Phycobilins, algal biliverdin metabolites that are good substrates for biliverdin reductase, may prove to have clinical antioxidant potential comparable to that of bilirubin.

Gilbert's syndrome: an overview for clinical biochemists.

Gilbert's syndrome (GS) is a benign and inherited state characterized by mild, lifelong, unconjugated hyperbilirubinaemia in the absence of haemolysis or evidence of liver disease. Its molecular basis, mutations in the TATA box upstream of the uridine diphosphoglucose glucuronyltransferase gene, leads to impaired bilirubin glucuronidation. This synopsis outlines the pathophysiology and investigation appropriate for this innocent anomaly.

Un deportista de élite con Síndrome de Gilbert / An elite sportman with Gilbert´s syndrome

Presentamos el caso de un deportista de 24 años de edad perteneciente a la Selección Española Absoluta de Piragüismo, con hiperbilirrubinemia en presencia de antecedentes familiares de Síndrome de Gilbert. El objetivo de este estudio es intentar relacionar los niveles de bilirrubina total con la sensación de apatía que presenta tras la acumulación de cargas en los entrenamiento de resistencia

We analyzed the case of a 24 year old canoest from the Spanish National Team. He suffers from hiperbilirubinemia and some members of his family have been diagnosed with Gilbert´s syndrome. The goal of this estudy is to relate the levels of bilirubine with the feeling of apathy this athlete goes through after high intensity training sessions

A case report of Gilbert Syndrome.

Gilbert syndrome is benign, often familial condition characterized by recurrent but asymptomatic mild unconjugated hyperbilirubinemia in the absence of haemolysis or underlying liver disease. If, it becomes apparent, it is not until adolescence and then usually in association with stress such as intercurrent illness, fasting or strenuous exercise. Virtually all patients have decreased level of UDP-Glucuronosyltransferase, but there also is evidence for a defect in hepatic uptake of bilirubin as well. This case is reported due to its rarity. The prevalence of Gilbert syndrome in U.S is 3-7% of the population.

[Gilbert's syndrome: pathogenesis and diagnosis]. / Sindrom Zhil'bera: patogenez i diagnostika.

Pharmacological tests, dynamic hepatoscintigraphy, spectrophotometric evaluation of serum and bile content of bilirubin fractions were performed in examination of 136 patients with Gilbert syndrome (group 1), chronic hepatitis, steatosis or hepatic cirrhosis (group 2) and 23 patients free of hepatic pathology (control group). It was established that androgenic steroids have effect on bilirubin-glucuronidation. Hyperbilirubinemia in Gilbert syndrome can be caused not only inhibition of bilirubin-glucuronidation in the liver but also defective uptake of bilirubin by hepatocytes.