Dependence of blood biochemical parameters on various genotypes of the UGT1A1 gene associated with gilbert's syndrome.

Diagnosis of Gilbert's syndrome is based on the detection of homozygous carriage of an additional TA-repeat in the promoter of the UGT1A1 gene, leading to a decrease in the activity of the UGT enzyme. No large studies have been done in the Russian Federation on the prevalence of carriage of Gilbert's syndrome, as well as the biochemical and molecular profile of such patients. The aim of the study is to evaluate biochemical and molecular genetic parameters in patients with Gilbert's syndrome in Russia. The study included 124 healthy volunteers (group 1) and 5650 patients with suspected Gilbert's syndrome (group 2). The number of TA-repeats of the promoter region of the UGT1A1 gene was determined by the method of fragment analysis for all participants. The following biochemical parameters were analyzed for 299 patients from group 2: the level of bilirubin and its fractions, AST, ALT, cholesterol and LDL. In group 1 the prevalence of genotype (TA)6/(TA)6 was 39,52%, (TA)6/(TA)7 - 53,23%, (TA)7/(TA)7 - 7,26%, no rare forms were found. In group 2 the prevalence of genotype (TA)6/(TA)6 was 6,04%, (TA)6/(TA)7 - 20,05%, (TA)7/(TA)7 - 73,7%, rare alleles - 0,2%. Rare alleles included (TA)5/(TA)6, (TA)5/(TA)7, (TA)6/(TA)8 and (TA)7/(TA)8, as well as a new genotype not described in the literature previously - (TA)7/(TA)9. When assessing the level of total bilirubin and its fractions, a difference was revealed between the genotype of Gilbert's syndrome (TA)7/(TA)7 and the reference genotype (TA)6/(TA)6, and between genotypes (TA)7/(TA)7 and (TA)6/(TA)7. A significant increase in total bilirubin was demonstrated in carriers of a larger number of TA-repeats. There was no significant difference in the concentration of ALT, AST, cholesterol or LDL between different genotypes.The number of TA-repeats of the UGT1A1 gene affects the increase of total bilirubin and its indirect fraction, including the cases of rare allelic variants (TA≤5, TA≥8), but not the activity of ALT and AST and the lipid profile.

Bilirubin as a metabolic hormone: the physiological relevance of low levels.

Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.

Influence of UGT1A1 promoter polymorphism, α-thalassemia and ßs haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort.

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and ßS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and ßS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with ßS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.

Serum Bilirubin in the Czech Population　- Relationship to the Risk of Myocardial Infarction in Males.

BACKGROUND: The potential antiatherogenic role of bilirubin is generally acknowledged, so the aim of this study was to determine serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in the Czech general population with particular reference to its relationship to the risk of myocardial infarction (MI).Methods and Results:Biochemical markers were analyzed in 2 independent Czech post-MONICA studies (in total, n=3,311), and in 741 male MI patients. TheUGT1A1promoter gene variant (rs81753472) was analyzed in these MI patients and in the first control population cohort (n=717). Medians of serum bilirubin concentrations in the 2 Czech general population cohorts were 9.6 and 9.8 µmol/L (10.7 and 11.3 µmol/L in males, and 8.3 and 8.8 µmol/L in females; P<0.01). The prevalence of GS was 8.9%, twice as high in males compared with females (11.6 vs. 6.1%; P<0.01). TheUGT1A1(TA)7/7promoter repeats significantly influenced serum bilirubin concentrations in the controls, but not in the MI patients. Serum bilirubin concentrations were significantly lower in MI patients (7.7 vs. 10.7 µmol/L; P<0.01), with almost 5-fold lower prevalence of GS. CONCLUSIONS: Serum bilirubin concentrations and the prevalence of GS were determined in the Czech general population. Significantly lower serum bilirubin concentrations were observed in male MI patients.

Diagnostic criteria and contributors to Gilbert's syndrome.

Hyperbilirubinemia is a well-known condition in the clinical setting; however, the causes of elevated serum bilirubin are diverse, as are the clinical ramifications of this condition. For example, diagnoses of individuals vary depending on whether they exhibit an unconjugated or conjugated hyperbilirubinemia. Diagnoses can include conditions of disordered bilirubin metabolism (Gilbert's, Crigler-Najjar, Rotor, or Dubin-Johnson syndromes) or an acquired disease, including alcoholic/non-alcoholic fatty liver disease, hepatotropic hepatitis, cirrhosis, or hepato-biliary malignancy. Assessment of bilirubin concentrations is typically conducted as part of routine liver function testing. Mildly elevated total bilirubin with normal serum activities of liver transaminases, biliary damage markers, and red blood cell counts, however, may indicate the presence of Gilbert's syndrome (GS), a benign condition that is present in ∼5-10% of the population. In this case, mildly elevated unconjugated bilirubin in GS is strongly associated with "reduced" prevalence of chronic diseases, particularly cardiovascular diseases (CVD) and type 2 diabetes mellitus (and associated risk factors), as well as CVD-related and all-cause mortality. These reports challenge the dogma that bilirubin is simply a potentially neurotoxic by-product of heme catabolism and emphasize the importance of understanding its potential beneficial physiologic and detrimental pathophysiologic effects, in order to appropriately consider bilirubin test results within the clinical laboratory setting. With this information, we hope to improve the understanding of disorders of bilirubin metabolism, emphasize the diagnostic importance of these conditions, and outline the potential impact GS may have on resistance to disease.

Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome.

BACKGROUND AND AIMS: Hereditary unconjugated hyperbilirubinemias, Crigler-Najjar syndrome type I, Crigler-Najjar syndrome type II (CN-2), and Gilbert syndrome (GS) all result from mutations of the bilirubin uridine 5'-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1). Often, to distinguish between CN-2 and GS is difficult because the borderline of the two syndromes is unclear. We analyzed the genotypes and phenotypes of 163 Japanese patients with CN-2 or GS. METHODS: Japanese patients (99 males and 64 females) with unconjugated hyperbilirubinemia were analyzed. Their serum bilirubin concentrations varied from 1.2 to 22.2 mg/dL (20 to 379 µM). Genetic analysis of UGT1A1 was performed by PCR-amplified direct sequencing. Association between serum bilirubin concentrations and genotypes group (typical CN-2, intermediate group, and typical GS) was studied. RESULTS: Most patients had biallelic mutations of UGT1A1. Moreover, many of them (78.5%) had multiple mutations. The mutation in typical CN-2 was a homozygous double missense mutation of p.[G71R:Y486D]. In typical GS group, four prevalent genotypes were detected: homozygous UGT1A1*28, UGT1A1*6/UGT1A1*28, and homozygous UGT1A1*6, and UGT1A1*27/UGT1A1*28. In the intermediate group, three genotypes, p.[G71R:Y486D]/UGT1A1*7, p.[G71R:Y486D]/UGT1A1*6, and homozygous UGT1A1*7, were detected. Serum bilirubin concentrations of typical CN-2, intermediate group, and typical GS are respectively 12.9 ± 5.1, 5.2 ± 2.2, and 2.8 ± 1.1 mg/dL. Serum bilirubin concentration among the three groups is statistically different (P < 0.0001). CONCLUSIONS: The serum bilirubin concentration varied continuously from GS to CN-2 depending on genotypes. Because of the combination of the mutations and polymorphisms, many patients showed intermediate serum bilirubin concentration between two syndromes. Clinically, it is difficult to distinguish clearly between the two syndromes.

Unusual presentation of Gilbert disease with high levels of unconjugated bilirubin. Report of two cases.

Gilbert's syndrome is a benign condition characterized by asymptomatic sporadic episodes of jaundice, due to a mild unconjugated hyperbilirubinemia caused by a deficiency in bilirubin glucoronidation. Under certain physiologic or pathologic events bilirubin level rises but according to literature it does not reach out more than 3 mg/dl. We report 2 cases of Gilbert's syndrome, genetically tested, which presented with bilirubin levels above 6 mg/dl without any trigger or coexisting condition. In conclusion, bilirubin levels higher than 6 mg/dL in Gilbert syndrome are rare, hemolytic and other metabolism diseases must be ruled out, and genetic testing may be necessary in some cases.

[VISCOELASTISITY AND ELECTRICAL PARAMETERS OF ERYTHROCYTES IN GILBERT SYNDROME].

Results of viscoelastic and electrical properties of erythrocytes study in patients with genetically confirmed Gilbert's syndrome (n = 81) are presented. Dielectrophoresis of erythrocytes in a nonuniform an alterning electric field was performed in81 patients with Gilbert's syndrome and in 20 persons of the comparison group without of the pathology identified by thelaboratory and instrumental examination. The significant differences in viscoelasticity properties of erythrocytes in Gilbert'ssyndrome were obtained. The amplitude of the deformation, the speed of movement to the electrodes and the polarizability on electric field's of all frequencies were significantly lower, but generalized rigidity index, viscosity, index of aggregationand degradation on electric field's of all frequencies were higher than in the comparison group. A number of electricalparameters (conductivity, the capacity of the cells and the relative polarizability) were also higher than in the comparisongroup. Some differences in the parameters of erythrocytes were obtained from homozygous and heterozygous carriers of A(TA), TAA of gene UGT1A1 promotor.

Perfluorocarbons and Gilbert syndrome (phenotype) in the C8 Health Study Population.

BACKGROUND: Gilbert syndrome (GS) is an inherited defect of bilirubin conjugation, most commonly caused by a gene mutation for the enzyme UGT1A. GS is known to affect the metabolism and excretion of drugs and xenobiotics. Perfluorocarbon compounds (PFCs) are bio-persistent environmental contaminants that affect metabolic regulation. In this study, we examined the associations of GS phenotype and serum PFCs in the C8 Health Study Population. MATERIALS AND METHODS: Using 2005-2006 data from a large PFC-exposure population survey, we compared serum PFCs concentrations between GS and non GS clinical phenotypes, in a cross sectional design, adjusting for standard risk factors, including age, BMI, smoking status, socioeconomic status and gender. RESULTS: Among 10 PFC compounds considered, only perfluorohexanoic acid (PFHxA) was seen at a significantly higher concentration in GS men and women. CONCLUSION: PFHxA exposure may be associated with GS. Our findings do not support increased exposure in GS for other PFCs.

[Effect of anti-helicobacter therapy on the hepatic glucuronyl transferase system of adolescents with Gilbert's syndrome].

UNLABELLED: Bilirubin biotransformation occurs with the participation of the glucuronyl transferase (GTF) system of the liver and hepatocyte membranes. Disturbances in these systems may result in a rise of blood bilirubin levels and disbalance between direct and indirect bilirubin leading to jaundice. Gilbert's syndrome (GS) is a genetic disorder associated with the enhanced level of indirect bilirubin due to GTF insufficiency. MATERIALS AND METHODS: The study included adolescents aged 13.4 ± 0.42 yr divided into 2 groups depending on anti-Helicobacter therapy (AHBT). We measured levels of direct and indirect bilirubins, their ratio, and direct bilirubin content as percentage of total bilirubin at admission to and discharge from the hospital. The daily incremental growth of both bilirubin fractions was calculated RESULTS: Detailed analysis revealed negative effect of AHBT on the GTF system attributable to its impaired stability in patients with abnormal genotype. CONCLUSION: Prescription of AHBT to children with Gilbert's syndrome requires the thorough choice of medications and monitoring of their potential effect on the GFT system.

Analysis of UGT1A1 genotype-phenotype correlation in Chinese patients with gilbert and crigler-Najjar II syndrome.

The spectrum of UDP-glucuronosyltransferase (UGT1A1) variants, which are associated with Gilbert syndrome (GS) and Crigler-Najjar syndrome (CNS-II), has been reported in Chinese and western countries. However, the genotype-phenotype correlation of the individual UGT1A1 variants in GS and CNS-II remains to be clarified. To explore the UGT1A1 variant pattern and genotype-phenotype correlations, we enrolled 310 Chinese patients, including 232 patients with GS and 78 with CNS-II. Peripheral blood samples were collected for screening variants in the gene UGT1A1 by a polymerase chain reaction and Sanger sequencing. The correlation between different UGT1A1 variants and clinical phenotypes was analyzed. A total of 21 UGT1A1 variants were identified, including nine novel variants, and constituted 42 UGT1A1 genotypes in the GS and CNS-II patients. The most common UGT1A1 variants were A (TA)7TAA, p.G71R, p.Y486D, p.P364L, and p.P229Q, which were different from western countries. The p.Y486D variant had higher minor allele frequency in CNS-II than in GS whereas the A (TA)7TAA variant had higher minor allele frequency in GS than in CNS-II. The serum total bilirubin and triglyceride had significant differences among 14 recurrent genotypes of UGT1A1, in which the serum total bilirubin in patients with compound p.Y486D (homozygous)/p.G71R variant was significantly higher compared with homozygous A (TA)7TAA, homozygous p.G71R, compound heterozygous A (TA)7TAA/p.G71R and A (TA)7TAA/p.P364L, and combined heterozygous A (TA)7TAA/p.G71R/p.P229Q, while the serum triglyceride in patients with combined A (TA)7TAA (homozygous)/p.P229Q variant was significantly higher compared with compound heterozygous A (TA)7TAA/p.G71R, single heterozygous A (TA)7TAA, single heterozygous p.G71R, and homozygous A (TA)7TAA. The spectrum of UGT1A1 genotypes in Chinese patients was distinct from western countries. There were differential levels of serum total bilirubin and triglyceride in patients with recurrent genotypes of UGT1A1.

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.

Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome.

BACKGROUND: Moderately elevated unconjugated bilirubin concentrations protect against inflammatory diseases and are present in individuals with Gilbert's syndrome. This study examined the relationship between circulating haem oxygenase catabolites, unconjugated bilirubin, carboxy haemoglobin, iron and inflammatory parameters. MATERIALS AND METHODS: Seventy-six matched individuals were allocated to Gilbert's syndrome (GS) or control group (unconjugated bilirubin ≥ or < 17.1 µM). Iron, carboxy haemoglobin and high-sensitivity C-reactive protein were analysed using routine diagnostic tests. Unconjugated bilirubin and haem were analysed using high-performance liquid chromatography. The cytokines IL-1ß, TNF-α and IL-6 were assessed using high-sensitivity enzyme-linked immunosorbent assays. RESULTS: Gilbert's syndrome subjects had significantly greater levels of unconjugated bilirubin (P < 0.05), carboxy haemoglobin (P < 0.05), iron (P < 0.05), IL-1ß (P < 0.05), a significantly lower body mass index (P < 0.05) and IL-6 concentrations (P < 0.05) vs. controls. Regression analysis revealed that unconjugated bilirubin mainly explained IL-1ß results (16%), and body mass index+IL-6 predicted 26% of the variance in C-reactive protein concentrations. CONCLUSIONS: A positive relationship between unconjugated bilirubin and free plasma haem, iron and carboxy haemoglobin indicated a positive feedback loop of haem oxygenase induction possibly mediated by unconjugated bilirubin. Furthermore, reduced body mass index in Gilbert's syndrome individuals was linked to reduced inflammation status, which could be influenced by circulating haem oxygenase catabolites and contribute to reduced risk of noncommunicable diseases in this population.

Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome.

Recent epidemiological and clinical data show protection from CVD (cardiovascular disease), all-cause mortality and cancer in subjects with GS (Gilbert's syndrome), which is characterized by a mildly elevated blood bilirubin concentration. The established antioxidant effect of bilirubin, however, contributes only in part to this protection. Therefore we investigated whether mildly elevated circulating UCB (unconjugated bilirubin) is associated with altered lipid metabolism. The study was performed on GS and age- and gender-matched healthy subjects (n=59 per group). Full lipoprotein profile, TAG (triacylglycerols), Apo (apolipoprotein)-A1, Apo-B, lipoprotein(a), the subfractions of LDL (low-density lipoprotein) and selected pro-inflammatory mediators were analysed. A hyperbilirubinaemic rodent model (Gunn rats, n=40) was investigated to further support the presented human data. GS subjects had significantly (P<0.05) improved lipid profile with reduced total cholesterol, LDL-C (LDL-cholesterol), TAG, low- and pro-atherogenic LDL subfractions (LDL-1+LDL-2), Apo-B, Apo-B/Apo-A1 ratio and lower IL-6 (interleukin 6) and SAA (serum amyloid A) concentrations (P=0.094). When the control and GS groups were subdivided into younger and older cohorts, older GS subjects demonstrated reduced lipid variables (total cholesterol and LDL-C, TAG and LDL-C subfractions, Apo-B/Apo-A1 ratio; P<0.05; Apo-B: P<0.1) compared with controls. These data were supported by lipid analyses in the rodent model showing that Gunn rat serum had lower total cholesterol (2.29±0.38 compared with 1.27±0.72 mM; P<0.001) and TAG (1.66±0.67 compared with 0.99±0.52 mM; P<0.001) concentrations compared with controls. These findings indicate that the altered lipid profile and the reduced pro-inflammatory status in hyperbilirubinaemic subjects, particularly in the older individuals, probably contribute additionally to the commonly accepted beneficial antioxidant effects of bilirubin in humans.

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.

Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects.

The Gilbert syndrome is a benign form of unconjugated hyperbilirubinemia, mainly associated with alterations in UGT1A1 gene. This work investigated the effect of UGT1A1 variants on total bilirubin levels in Gilbert patients (n=45) and healthy controls (n=161). Total bilirubin levels were determined using a colorimetric method; molecular analysis of exons 1-5 and two UGT1A1 promoter regions were performed by direct sequencing and automatic analysis of fragments. Five in silico methods predicted the effect of new identified variants. A significant different allelic distribution, in Gilbert patients and in controls, was found for two promoter polymorphisms. Among patients, 82.2% were homozygous and 17.8% heterozygous for the c.-41_-40dupTA allele; in control group, 9.9% were homozygous and 43.5% heterozygous for this promoter variant, while 46.6% (n=75) presented the [A(TA)6TAA]. For the T>G transition at c.-3279 promoter region, in patients, 86.7% were homozygous and 13.3% heterozygous; in control group, 33.5% were homozygous for the wild type allele, 44.1% were heterozygous and 22.4% homozygous for the mutated allele. The two polymorphisms were in Hardy-Weinberg equilibrium in both groups. Sequencing of UGT1A1 coding region identified nine novel variants, five in patients and four in controls. In silico analysis of these amino acids replacements predicted four of them as benign and three as damaging. In conclusion, we demonstrated that total bilirubin levels are mainly determined by the TA duplication in the TATA-box promoter and by the c.-3279T>G variant. Alterations in the UGT1A1 coding region seem to be associated with increased bilirubin levels, and, therefore, with Gilbert syndrome.

Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilbert's syndrome measured with the micronucleus cytome assay.

Circulating unconjugated bilirubin (UCB) has been reported to protect against lung and colorectal cancer. The present study aimed to explore, for the first time, whether mildly elevated circulating UCB, as found in Gilbert`s syndrome (GS), is associated with changes of DNA damage. A random 76 individuals, matched for age and gender, were recruited from the general population and allocated into the GS group (UCB ≥ 17.1 µM; n = 38) or control group (UCB <17.1 µM; n = 38). Chromosomal and cytological changes were determined in lymphocytes and buccal cells using the cytokinesis-block micronucleus cytome assay (CBMN) and buccal micronucleus cytome assay (BMcyt). No significant differences were found between GS subjects and the control group in the CBMN and BMcyt determined endpoints. Subsequently, when age dependency of effects were analysed, lower formation of buccal micronucleated cells (by 73.3%) and buccal nuclear buds (by 70.9%) in the GS subgroup ≥ 30 years were found, compared to the GS subgroup <30 years. These findings suggest DNA protection in epithelial tissue of older individuals with GS.

Acetaminophen administration in a patient with Gilbert's syndrome.

The patient was an 8-year-old Japanese girl with Gilbert's syndrome (GS). Based on the DNA analysis, she was homozygous for a T-to-G transversion at nucleotide position 1456 in the UGT1A1 gene, leading to the substitution of aspartate for tyrosine at position 486 of the UGT1A1 enzyme. Because this mutation is located in an exon common to UGT1A genes, all the UGT1A enzymes may be affected. It is well-known that UGT1A1, UGT1A6 and UGT1A9 enzymes glucuronidate acetaminophen. To evaluate acetaminophen tolerance in the patient, serum acetaminophen levels were determined after oral administration of acetaminophen (15 mg/kg). The maximum serum acetaminophen level reached (12.8 µg/mL) was far below the toxic level. The finding suggested that the usual therapeutic dose of acetaminophen is safe for the GS patient. The combination of mutation analysis in UGT1A1 and acetaminophen loading test may be useful to avoid adverse effect in GS patients.