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Background: Congenital dyserythropoietic anemia Ⅱ (CDA Ⅱ) is a rare inherited disorder of defective erythropoiesis caused by SEC23B gene mutation. CDA Ⅱ is often misdiagnosed as a more common type of clinically related anemia, or it remains undiagnosed due to phenotypic variability caused by the coexistence of inherited liver diseases, including Gilbert's syndrome (GS) and hereditary hemochromatosis., Methods: We describe the case of a boy with genetically undetermined severe hemolytic anemia, hepatosplenomegaly, and gallstones whose diagnosis was achieved by targeted next generation sequencing., Results: Molecular analysis revealed a maternally inherited novel intronic variant and a paternally inherited missense variant, c.[994-3C > T];[1831C > T] in the SEC23B gene, confirming diagnosis of CDA Ⅱ. cDNA analysis verified that the splice acceptor site variant results in two mutant transcripts, one with an exon 9 skip and one in which exons 9 and 10 are deleted. SEC23B mRNA levels in the patient were lower than those in healthy controls. The patient was also homozygous for the UGT1A1 *6 allele, consistent with GS., Conclusion: Identification of the novel splice variant in this study further expands the spectrum of known SEC23B gene mutations. Molecular genetic approaches can lead to accurate diagnosis and management of CDA Ⅱ patients, particularly for those with GS coexisting.

Introduction: Neonatal jaundice and prematurity pose significant barriers to breastfeeding in the first days of life. There is limited literature exploring the relationship between prolonged jaundice in breastfed infants and Gilbert's (Meulengraght) syndrome. This case study describes the diagnostic and therapeutic challenges associated with Gilbert's syndrome in a late preterm breastfed infant born in Germany., Main Issue: In this case report, an infant born to a primipara woman presented at 3 weeks postpartum to an International Board Certified Lactation Consultant. The initial assessment revealed a late preterm infant with inadequate weight gain and jaundice. The dyad received breastfeeding support and eventually achieved adequate weight gain; however, the infant's jaundice persisted., Management: The consulting midwife suggested that the persistent jaundice was "breastmilk jaundice" and recommended temporarily interrupting breastfeeding. Due to a suspected family history of Gilbert's Syndrome, the dyad was referred, instead, to a pediatric gastroenterologist. Pathologic liver disease was excluded, and genetic testing confirmed Gilbert's Syndrome. At 6 months of age, the dyad was successfully breastfeeding and beginning complementary feeding., Conclusion: Genetic testing for Gilbert's Syndrome should be considered for infants with prolonged jaundice and positive family history. Interruption or cessation of breastfeeding are not evidence-based recommendations, and current guidelines do not support these practices. Lactation professionals play a critical role in the management of breastfeeding for preterm infants with prolonged jaundice and should refer to specialists to rule out pathologic etiologies., Competing Interests: Disclosures and Conflicts of InterestThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MT has previously received consultancy fees from the United Nations Children’s Fund (UNICEF), the World Health Organization (WHO), the Ludwig-Maximilians-University (LMU) Munich, the German Society for Paediatric and Adolescent Medicine (Deutsche Gesellschaft für Kinder- und Jugendmedizin e.V. (DGKJ). She has received travel fees from the Austrian Society of Paediatric and Adolescent Medicine (Österreichische Gesellschaft für Kinder und Jugendheilkunde).

BACKGROUND In the absence of liver transplantation, the natural history of acetaminophen-induced liver failure is characterized by a progressive increase of liver function tests, including bilirubin mainly as its conjugated form. The presence of high levels of unconjugated bilirubin is more unusual; its etiology is unclear and its prognostic factor has been poorly investigated. CASE REPORT A 52-year-old man with a history of chronic analgesics, alcohol, and illicit drug abuse developed acute liver failure in relationship with the ingestion of largely supra-therapeutic doses of acetaminophen over the days preceding admission. The patient received the classical N-acetylcysteine treatment regimen for acetaminophen overdose. Clinical course was characterized by a progressive worsening of the neurological condition, evolving to grade IV encephalopathy. Coagulation disorders persisted, with factor V level <10%. He fulfilled the criteria for liver transplantation, but this option was rejected after a careful psychiatric evaluation. Laboratory investigations revealed a progressive increase in serum unconjugated bilirubin until his death. As evidence for hemolysis was lacking, acquired deficit in bilirubin glucuronidation appeared likely and diagnosis of Gilbert's syndrome was excluded. CONCLUSIONS After the exclusion of other causes of high unconjugated bilirubin levels, the progressive increase in unconjugated bilirubin can reflect a persistent defect in bilirubin conjugation in relationship with liver centrilobular injury, but the relationship with acetaminophen-glucuronidation is not known and there are insufficient data to affirm that the ratio unconjugated/conjugated bilirubin could be used as a prognostic factor.

Background and Aims: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1*28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival., Methods: UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations., Results: In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL (P<0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3-1.7], P=0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin (P=0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia., Conclusions: In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Dual-hereditary jaundice (Dubin-Johnson syndrome (DJS) and Gilbert's syndrome (GS)) is a rare clinical entity resulting from defects of the ATP binding cassette subfamily C member 2 (ABCC2) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genes with autosomal recessive inheritance. In this study, we aimed to investigate the mutation profiles and characterize the phenotypes in a Han Chinese family with DJS and GS. Genetic screening for variants in the ABCC2 and UGT1A1, immunohistochemistry for expression of ABCC2, and histopathological examination were carried out. The proband and his brother had unconjugated and conjugated hyperbilirubinemia after birth. The proband's sister had only conjugated hyperbilirubinemia after birth. The proband developed into pleural effusions and ascites, pericardial thickening, intrahepatic and extrahepatic biliary duct dilatation, and enlarged gallbladder at age 50. Hepatocellular carcinoma occurred in the proband's brother at age 46. Seven compound defects of the ABCC2 gene [c.2414delG, p.(Ile1489Gly), p.(Thr1490Pro), and p.(Ile1491Gln)] and the UGT1A1 gene (c.-3279T>G, p.(Gly71Arg), and p.(Pro451Leu)) were identified in family members. Accumulation of pigment in hepatocytes characteristic of that in DJS was present in the proband and his brother. Expression of ABCC2 protein was markedly diminished in the patient's liver. Our results show a different genetic profile of DJS and GS in a Han Chinese family, indicating a more complex pattern of dual-hereditary jaundice among different populations. The present study illuminates the underpinnings of DJS and GS and extends the mutation profiles and phenotypes of these two syndromes in dual-hereditary jaundice., (© 2022. The Author(s).)

Most patients with hereditary spherocytosis (HS) have a family history of disease, while those without such a history are difficult to diagnose. We herein report a case of HS with no family history harboring a novel heterozygous mutation of SPTA1, c.2161G>A (p.E721K), and a homozygous polymorphism of UGT1A1*6. In silico analyses suggested that the mutation might contribute to the pathogenesis of HS. The coexistence of HS and Gilbert's syndrome increases the risk of gallstones. Therefore, splenectomy, alone or in combination with cholecystectomy, is recommended. The determination of genetic diathesis provides useful information for the management of hemolytic anemia.

Gilbert's syndrome is mainly diagnosed through genetic analysis and is primarily detected through a mutation in the promoter region of the UGT1A1 gene. However, most of the research has been conducted on Caucasian populations. In this study, we studied the Han population in Taiwan to investigate the possibility of other mutations that could cause Gilbert's syndrome. This study comprised a test group of 45 Taiwanese individuals with Gilbert's syndrome and 180 healthy Taiwanese individuals as a control group. We extracted DNA from the blood samples and then used Axiom Genome-Wide TWB 2.0 array plates for genotyping. Out of 302,771 single nucleotide polymorphisms (SNPs) from 225 subjects, we detected 57 SNPs with the most significant shift in allele frequency; 27 SNPs among them were located in the UGT1A region. Most of the detected SNPs highly correlated with each other and are located near the first exon of UGT1A1, UGT1A3, UGT1A6 , and UGT1A7 . We used these SNPs as an input for the machine learning algorithms and developed prediction models. Our study reveals a good association between the 27 SNPs detected and Gilbert's syndrome. Hence, this study provides a reference for diagnosing Gilbert's syndrome in the Taiwanese population in the future.

Background: Genetic testing of UGT1A1 was used to facilitate the diagnosis of Gilbert syndrome, and analyze the distribution features of pathogenic variants in the Chinese population., Methods: DNA was extracted from whole blood samples of patients with unconjugated hyperbilirubinemia, and sequencing of the UGT1A1 gene was performed after PCR amplification. After alignment with reference sequences, the known pathogenic variants were identified, the variant spectrum was analyzed, and the pathogenicity of novel variants was predicted using online mutation prediction tools., Results: A total of 117 patients were confirmed with Gilbert syndrome by UGT1A1 genetic diagnosis, where the most common pathogenic variants included promoter A(TA) 7 TAA insertion and p.Gly71Arg missense variant. Following novel variants were also identified: p.Ala61Gly, p.Tyr67Phe, p.Leu166Alafs*16, p.Arg240Lys, p.Ser306Phe, p.Arg341Gln, and p.Glu424* variants., Conclusions: Genetic testing of UGT1A1 in clinical practices could facilitate confirming Gilbert syndrome and performing differential diagnosis. The pathogenic variant spectrum in the Chinese population was similar to other Asian populations. The novel pathogenic variants identified in this study require further investigation., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation., Case Presentation: Two Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu. In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped., Conclusion: UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin. Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II., (© 2022. The Author(s).)

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., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the diagnosis method of Gilbert syndrome (GS) and the relationship between UGT1A1 gene polymorphism distribution with serum bilirubin. Methods: Clinical data of 115 GS cases diagnosed in our hospital from January 2013 to November 2018 were retrospectively analyzed. Chi-square test, Fisher's exact probability method, t-test, and non-parametric test were used for data analysis. Results: 115 cases with GS had an average age of (36.89 ± 12.77) years and an average serum total bilirubin level of (44.01 ± 18.78) μmol/L.UGT1A1*28/*28 (21, 18.3%), UGT1A1*1/*28 (17, 14.8%), and UGT1A1*1/*6 (17, 14.8%) were the most common single-site mutations. UGT1A1*1/*28 + *1/*6 (26, 22.6%), UGT1A1*28/*28 + *1/*27 (5, 4.3%) and UGT1A1*1/*28 + *1/*6 + *1/* 27 (5, 4.3%) were the most common multiple-site mutations. Among 110 cases with Gilbert syndrome combined with non-hemolytic diseases, pairwise comparisons showed that the total bilirubin levels of patients with UGT1A1*28/*28 mutations were significantly higher than UGT1A1*6/*6 and UGT1A1*1/*28 + *1/*6 mutation ( P < 0.05). Additionally, with the increase of UGT1A1*28 distribution, the serum total bilirubin level had gradually increased ( P = 0.028), but UGT1A1*6 was opposite ( P = 0.021). There were no significant differences in gene distribution and bilirubin level between GS group (67 cases) and GS combined with viral hepatitis group (32 cases) ( P > 0.05). Conclusion: UGT1A1 gene sequencing detection is a simple, safe, specific and sensitive effective method to assist GS diagnosis. It can reduce the misdiagnosis and mistreatment of clinical jaundice, thus reducing the patients' psychological burden and saving the limited medical resources. It is worthy of clinical application.

Variations at the six nucleotides -3279 (T > G), -53 (A[TA] 6 TAA > A[TA] 7 TAA), 211 (G > A), 686 (C > A), 1091 (C > T), and 1456 (T > G) in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene were determined in 178 Taiwanese patients with Gilbert's syndrome and in 200 healthy adults. Every subject was classified as a genotype depending on variation status of the six nucleotides in the UGT1A1 gene. The UGT1A1 activity for each genotype was calculated and then those genotypes were divided into 10 subgroups (Q1~Q10) according to their UGT1A1 activities, by using 10% as an interval. There were 24 genotypes observed, with UGT1A1 activity ranged 9%~100% of normal. There were two and six subjects with Gilbert's syndrome and none of healthy controls carrying genotypes in the Q1 and Q2 subgroups, respectively. The odds of developing Gilbert's syndrome were significantly higher for subjects carrying genotypes in the Q3, Q4, and Q5 subgroups than for those with genotype in the Q10 subgroup (odds ratios: 240.22, 59.80, and 14.67, respectively, P < .001 for each). Among the 178 patients of Gilbert's syndrome, serum bilirubin value was inversely correlated with UGT1A1 activity (r = -.306, P < .001). The sensitivity was 72.0% and the specificity was 90.5% by using UGT1A1 activity ≦40% of normal as the cut-off point to distinguish between healthy subjects and patients of Gilbert's syndrome. Our results demonstrate that UGT1A1 activity is certainly a determinate for serum bilirubin value and UGT1A1 activity ≦40% of normal is a proper risk factor for the development of Gilbert's syndrome., (© 2019 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

We report a series of seven patients with Gilbert's syndrome undergoing cardiac surgery. Early and transient increase of total, direct, and indirect bilirubin without other complications was observed. Although this is a benign process, we believe that this disease should be routinely included in the differential diagnosis of postoperative jaundice after cardiopulmonary bypass.

Competing Interests: Competing interests: None declared.

Crigler-Najjar syndrome type II is caused by mutations in the UGT1A1 gene resulting in severely reduced hepatic activity of UDP-glucoronyltransferase - an enzyme required to convert bilirubin into a more soluble form that can then be removed from the body. Absence or severe deficiency of this enzyme can lead to bilirubin accumulation in the body resulting in yellow skin and eyes (jaundice). The earliest signs of this disease can be apparent in the neonatal period. Patients with Crigglar-Najjar syndrome type II respond to phenobarbital therapy which decreases their chances of getting bilirubinemia by 60-70% in 3 weeks. A 17 years old boy presented with the complaint of gastroenteritis. On examination, he was jaundiced and his parents reported that it has been present since birth. He was admitted in the hospital with the differential diagnosis of Gilbert syndrome, but later it was found that the unconjugated bilirubin levels were higher than those required for Gilbert's criteria. We report, herein, an extremely rare case of Crigler-Najjar syndrome type II and how the patient responded to phenobarbital therapy. Periods of fasting, stress and any kind of illness can worsen unconjugated hyperbilirubinemia leading to complications like kernicterus, so higher levels of unconjugated bilirubin should be addressed immediately and the patient along with his/her family should be educated about this disease.

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.

Background and Aims: Mild endogenous elevation of unconjugated bilirubin (UCB) as seen in Gilbert's syndrome (GS), might mitigate cardiovascular disease (CVD) risk factors including overweight/obesity. This study aimed to determine whether hyperbilirubinaemia is linked to improved anthropometric data and lipid profile., Methods: Our study considered GS and age-/gender-matched healthy controls (n = 248). Additionally, obese female type 2 diabetic patients (DM2) (n = 26) were included as a "disease control group"., Results: BMI, hip circumference (HC), and lipid profile were significantly lower in GS. UCB was inversely correlated with BMI (p <0 .001), HC as well as with fat mass (FM) and lipid variables (p < 0.05). Moreover, DM2 patients had significantly lower UCB compared to GS and healthy controls. Older GS subjects (≥35 years) had significantly reduced anthropometric data and improved lipid profile., Conclusions: Our results propose that the health promoting potential of mild hyperbilirubinaemia may extend to protection from age-related weight gain and dyslipidaemia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Gilbert's syndrome (GS) is associated with a mild unconjugated hyperbilirubinemia, increased circulating antioxidant capacity, and reduced cardiovascular disease (CVD) risk. The current study investigated whether mildly elevated circulating unconjugated bilirubin (UCB) is negatively associated with multiple thrombotic risk factors including platelet activity, hemostatic function, and inflammation in individuals with GS. Blood samples were collected from matched GS and control subjects (14 per group). Activation-dependent platelet surface marker expression of PAC-1 (binds to GPIIb/IIIa surface receptors on activated platelets) and CD62P (marker for P-selectin released from activated degranulated platelets) was assessed in adenosine diphosphate (ADP)-stimulated platelets using flow cytometry. Exogenous agonists, ADP, collagen, and arachidonic acid (AA), were used to stimulate platelet aggregation. A statistically significant decrease in the expression of P-selectin (P = 0.030) on activated platelets was observed in GS subjects. Collagen and AA-induced platelet aggregation were significantly (P = 0.018; P = 0.032 for respective agonists) reduced in GS versus control group. Elevated UCB (P = 0.001) and high density lipoprotein (P = 0.033) in addition to reduced low density lipoprotein (P = 0.024) and high sensitive C-reactive protein (P = 0.043) were also observed in GS when compared to the control group. Reduced P-selectin expression suggests decreased platelet activation-dependent degranulation, while reduced platelet aggregation by AA and collagen indicates a quantitative decrease in platelet aggregation consequently targeting the cyclooxygenase-1 and GP VI pathways, respectively. These findings are the first to demonstrate that the activation of platelets is mildly inhibited in individuals with GS, an effect that might contribute to protection from platelet hyperactivation-induced thrombosis and thus cardiovascular mortality in individuals with benign hyperbilirubinemia.

Genetic causes of liver disease lead to a wide range of presentations, from mildly abnormal liver tests to acute liver failure. This article discusses the indications for testing and what to test for hereditary hemochromatosis, progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, lysosomal acid lipase deficiency, Gilbert syndrome, alpha-1 antitrypsin deficiency, and Wilson disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Mild but chronically elevated circulating unconjugated bilirubin is associated with reduced total and low-density lipoprotein cholesterol concentration, which is associated with reduced cardiovascular disease risk. We aimed to investigate whether unconjugated bilirubin influences macrophage cholesterol efflux, as a potential mechanism for the altered circulating lipoprotein concentrations observed in hyperbilirubinemic individuals., Methods and Results: Cholesterol efflux from THP-1 macrophages was assessed using plasma obtained from normo- and hyperbilirubinemic (Gilbert syndrome) humans (n=60 per group) or (heterozygote/homozygote Gunn) rats (n=20 per group) as an acceptor. Hyperbilirubinemic plasma from patients with Gilbert syndrome and Gunn rats induced significantly reduced cholesterol efflux compared with normobilirubinemic plasma. Unconjugated bilirubin (3-17.1 μmol/L) exogenously added to plasma- or apolipoprotein A1-supplemented media also decreased macrophage cholesterol efflux in a concentration- and time-dependent manner. We also showed reduced protein expression of the ATP-binding cassette transporter A1 (ABCA1), a transmembrane cholesterol transporter involved in apolipoprotein A1-mediated cholesterol efflux, in THP-1 macrophages treated with unconjugated bilirubin and in peripheral blood mononuclear cells obtained from hyperbilirubinemic individuals. Furthermore, we demonstrated that bilirubin accelerates the degradation rate of the ABCA1 protein in THP-1 macrophages., Conclusions: Cholesterol efflux from THP-1 macrophages is decreased in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression. These data improve our knowledge concerning bilirubin's impact on cholesterol transport and represent an important advancement in our understanding of bilirubin's role in cardiovascular disease., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders.

Dual hereditary jaundice, a combination of Dubin-Johnson and Gilbert's syndromes, is a rare clinical entity resulting from the compound defects of bilirubin conjugation and transport. We aimed to study the hereditary jaundice in 56 members from seven seemingly unrelated Roma families, to find the causal genetic defect and to estimate its origin in Roma population. On the basis of biochemical results of total and conjugated serum bilirubin and clinical observations, ABCC2 gene, TATA box and phenobarbital enhancer (PBREM) of UGT1A1 gene were analyzed by sequencing, RFLP and fragment analysis. We found a novel variant c.1013&#95;1014delTG in the eighth exon of ABCC2 gene in 17 individuals in homozygous state. Dual defect NG&#95;011798.1:c.[1013&#95;1014delTG]; NG&#95;002601.2:g.[175492&#95;175493insTA] in homozygous state was found in four subjects. Biochemical analyses of porphyrins and coproporphyrin isomers in urine performed by HPLC showed inverted ratio of excreted coproporphyrin, with the predominance of coproporphyrin I (up to 100%), typical for patients with Dubin-Johnson syndrome. Pursuant cultural and social specifics of the population led us to suspect a founder effect; therefore, we performed a haplotype study using genotyping data from Affymetrix Genome-Wide Human SNP Array 6.0. As a result, we detected a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families, and estimated the age of the ancestral variant to 178-185 years. In this study, we found a novel deletion in ABCC2 gene, described genetic and biochemical features of dual hereditary jaundice and confirmed the existence of founder effect and common haplotype among seven Roma families.

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.

Background & Aims: Gilbert's syndrome causes pharmacological variation in drug glucuronidation and unexpected toxicity from therapeutic agents. The two common genotypes of Gilbert's syndrome are a dinucleotide polymorphism (TA)7 in TATA-Box as well as the 211G>A mutation in the coding exon 1, particularly in Asians, of human UGT1A1 gene. In this study, we aimed to establish an effective method to detect the 211G>A mutation., Methods: The coding exon 1 sequence of human UGT1A1 gene was analysed by Vector NTI software. The 211G>A mutation in the coding exon 1 of UGT1A1 gene was determined by restriction fragment length polymorphism (RFLP) method. Serum total bilirubin level was measured as well., Results: A newly identified BsmBI site was located in the coding exon 1 of UGT1A1 gene. The 211G>A mutation in the coding exon 1 of UGT1A1 gene was determined by DNA RFLP. Furthermore, we reported our present work on genetic analysis of mutations of UGT1A1 gene, and the correlation of UGT1A1 mutations with serum total bilirubin levels in Taiwanese population. The results showed that 15 subjects carried 211G>A mutation in 23 subjects related with Gilbert's syndrome. The homozygous 211G>A mutant as well as simultaneously heterozygous mutants both in TATA-Box and 211G>A significantly increased the risk of Gilbert's syndrome similar to subjects carrying homozygous TATA-Box mutant., Conclusions: BsmBI RFLP is an effective method to detect 211G>A mutation in the coding exon 1 of UGT1A1 gene. The common 211G>A mutation is one of the causes of Gilbert's syndrome in Taiwanese population., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present a case about a 25-year-old male patient suffering from a rare genetic disorder called Mizuho haemoglobin. He was admitted to the Intensive Care Unit with acute liver and renal failure. During admission he also developed a cardiac tamponade twice. Finally he received a liver transplantation. Hereafter the patient stabilised and his liver and renal functions improved. His symptoms could not be explained solely by his known disease. After searching the literature, similarities between his symptoms and a rare complication of sickle cell disease were found. Molecular diagnostics showed that the patient also suffered from Gilbert's syndrome. Due to his chronic haemolysis, symptoms of this other disease were masked. This stresses the importance of always looking for other causes if symptoms or changes cannot be explained by a known rare disorder.

A 35-year-old man was diagnosed with tuberculous lymphadenitis and multibacillary borderline tuberculoid leprosy. On investigation, isolated unconjugated hyperbilirubinaemia was detected and evaluation led us to conclude that the probable cause was Gilbert's syndrome. He was successfully managed by administration of chemotherapy for the treatment of both the mycobacterial infections, with no adverse effects on liver function tests., (2014 BMJ Publishing Group Ltd.)

Gilbert's syndrome and hereditary hemochromatosis predominantly affect Caucasians with a low incidence in Asians. Here we report the case of a 16-year-old Chinese boy, who was admitted with hepatalgia, jaundice, hyperpigmentation, and splenomegaly to our hospital. After excluding chronic hepatitis, autoimmune disorders, and alcohol or drug injury, genetic analyses of the patient and his parents revealed simultaneous manifestations of Gilbert's syndrome and hereditary hemochromatosis, though his parents did not develop related symptoms. The presented case indicates that diagnoses of Gilbert's syndrome and hereditary hemochromatosis should be taken into consideration when chronic hepatitis is suspected without a clear etiology.

Objective: The etiology of jaundice in otherwise healthy breastfed newborns that can present as early-onset exaggerated physiologic jaundice, or late breast milk jaundice (BMJ), is not yet entirely understood. This study tested the hypothesis that molecular marker for Gilbert's syndrome (GS), UGT1A1 TATA-box polymorphism, is associated with this disorders., Methods: We have investigated the UGT1A1 polymorphism frequency and its relation to severity of hyperbilirubinemia and jaundice duration among 220 exclusively breastfed term newborns; 57 of them with non-physiologic hyperbilirubinemia (NH), and 163 with BMJ, and in 187 healthy controls., Results: Significant differences in TA7/7 genotype frequency were established. The highest frequency was observed among the newborns with BMJ (42.0%), intermediate in the NH group (24.6%), while the controls had the lowest TA7/7 frequency (12.8%). Linear increase in TA7/7 frequency was observed depending on the duration of jaundice, peaking at 42.4% in newborns with the longest jaundice duration. Positive correlation between the serum bilirubin levels and the TATA-box length was established in all groups., Conclusion: This study provides evidence that UGT1A1 TATA-box polymorphism is an important risk factor for developing jaundice in term breastfed newborns, presented as either early non-physiologic hyperbilirubinemia or breast milk jaundice. These results further support the original Odell's idea of neonatal jaundice as an early presentation of GS.

Gilbert's syndrome is suspected in patients with unconjugated hyperbilirubinemia caused by decreased activity of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene in the absence of abnormal liver function and hemolysis. The major genetic variants underlying Gilbert's syndrome are TATA-box repeats of the promoter region and exon 1 G211A of the coding region, particularly in Asians. The efficacy of DNA melting curve analysis, however, has not been established for the G211A mutation. For rapid and accurate molecular diagnosis of Gilbert's syndrome, DNA melting curve analysis was evaluated for its genotyping capability not only for TATA-box repeats of the UGT1A1 promoter, but also for G211A of UGT1A1 exon 1. TA repeats within the TATA-box sequence and the exon 1 G211A mutation of the UGT1A1 gene were analyzed by DNA melting curve analysis. To evaluate the assay reliability, direct sequencing or polyacrylamide gel electrophoresis was used as a comparative method. All homozygous and heterozygous polymorphisms of A(TA)7TAA within the TATA-box allele and of exon 1 G211A mutants of the UGT1A1 gene were successfully identified with DNA melting curve analysis. DNA melting curve analysis is, therefore, an effective molecular method for the rapid diagnosis of Gilbert's syndrome, as it detects not only TATA-box polymorphisms but also the exon 1 G211A mutation located within the UGT1A1 gene.

Two inherited unconjugated hyperbilirubinemias, Crigler-Najjar syndrome and Gilbert syndrome, arise due to deficiency of UGT1A1 enzyme activity. Crigler-Najjar syndrome type 1 (CN1) lies at the extreme severe end of the spectrum of UGT1A1 activity characterized by complete absence, followed by the less severe Crigler-Najjar syndrome type 2 (CN2). Gilbert syndrome is the mild form having only partial loss of UGT1A1 activity. The present study aimed to identify molecular genetic defects underlying unconjugated hyperbilirubinemias in children from six consanguineous Pakistani families. The patients were clinically diagnosed by exclusion of other unconjugated hyperbilirubinemias. Differential diagnosis of CN1 and CN2 was made on the basis of patient's response to phenobarbitone. The promoter region, coding exons, and adjacent splice sites of the UGT1A1 gene were PCR amplified from genomic DNA of all patients and their families, and were sequenced. DNA sequence analysis identified five different homozygous mutations: two novel missense mutations p.Y230C (proband A) and p.D36N (proband B), a 4-bp insertion c.622-625dupCAGC/p.Q208QfsX50 (probands C and E), a nonsense mutation p.R341X (proband D), and a TA insertion A(TA)7TAA in the promoter region (proband F). The present study extends the spectrum of UGT1A1 gene mutations and may be helpful in the diagnosis of Crigler-Najjar syndrome and Gilbert syndrome., (© 2013 John Wiley & Sons Ltd/University College London.)

Aim: Safety of moderate hyperbilirubinemia in healthy term neonates is still a matter of discussion. The purpose of this study was to compare developmental status of 18-month-old children with and without history of neonatal indirect nonhemolytic hyperbilirubinemia., Methods: In a case-control study, the developmental status of 18-month-old children referred to Azadshar primary health care center in Yazd, Iran, between December 2007 and June 2009 was evaluated via the Persian version of Ages and Stages Questionnaires (ASQ). Children in the case group were healthy term neonates with total serum bilirubin level of 20-25 mg/dl, birth weight of 2500-4000 g and no birth asphyxia who were admitted to hospital and had undergone phototherapy. The control group consisted of children who were healthy term neonates without history of neonatal hyperbilirubinemia., Results: 112 children (56 in each group) were evaluated. Four children in the case group and one in the control group had delay in communication skills. Three in the case group and three in the control group had fine motor delay. Only one child in the case group showed delay in problem solving. Statistically significant differences were not seen in the frequency of developmental delay as well as in the mean scores of all developmental domains in both groups., Conclusion: Based on the results of the present study by ASQ, the developmental status at the age of 18 months of healthy term neonates with moderate unconjugated hyperbilirubinemia was not different from the control group.

A 38-year-old housewife presented with a 3-month history of gradually progressive fatigue and deepening jaundice as well as a history of mild fluctuating jaundice since childhood. General examination revealed an obvious icterus. Systemic examination was normal. Laboratory tests confirmed unconjugated hyperbilirubinaemia. Further evaluation yielded a diagnosis of vitamin B12 deficiency on a background of Gilbert's syndrome.

Background: Gilbert's syndrome is a common metabolic dysfunction characterized by elevated levels of unconjugated bilirubin in the bloodstream. This condition is usually caused by additional (TA) insertions in a promoter region of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene, which instead of the sequence А(TА)6TАА contains А(TА)7TАА. While the condition itself is benign, it presents elevated risk for patients treated with irinotecan, a common chemotherapy drug., Methods: The technique is based on hybridization analysis of a pre-amplified segment of the UGT1A1 gene promoter performed on a microarray. Specific probes containing locked nucleic acids (LNA) were designed and immobilized on the microarray to provide accurate identification., Results: A microarray has been developed to identify both common and rare variants of UGT1A1(TA)n polymorphisms. In total, 108 individuals were genotyped. Out of these, 47 (43.5%) had homozygous wild-type genotypes (TA)6/(TA)6; 41(38%) were heterozygotes (TA)6/(TA)7; and 18 (16.7%)--homozygotes (TA)7/(TA)7. In two cases (1.8%), rare genotypes (TA)5/(TA)7 and (TA)5/(TA)6 were found. The results were in full agreement with the sequencing. In addition, synthetic fragments corresponding to all human allelic variants [(TA)5, (TA)6, (TA)7, (TA)8] were successfully tested., Conclusions: The developed microarray-based approach for identification of polymorphic variants of the UGT1A1 gene is a promising and reliable diagnostic tool that can be successfully implemented in clinical practice.

We recently encountered a case of hereditary spherocytosis coexisting with Gilbert's syndrome. Patient was initially diagnosed with Gilbert's syndrome and observed, but other findings suggestive of concurrent hemolysis, such as splenomegaly and gallstones were noted during the follow-up period. Therefore, further evaluations, including a peripheral blood smear, osmotic fragility test, autohemolysis test, and red blood cell membrane protein test were performed, and coexisting hereditary spherocytosis was diagnosed. Genotyping of the conjugation enzyme uridine diphosphate-glucuronosyltransferase was used to confirm Gilbert's syndrome. Because of the high prevalence rates and similar symptoms of these 2 diseases, hereditary spherocytosis can be masked in patients with Gilbert's syndrome. In review of a case and other article, the possibility of the coexistence of these 2 diseases should be considered, especially in patients with unconjugated hyperbilirubinemia who also have splenomegaly and gallstones.

Background: Uridine diphosphate-glucuronosyltransferase (UGT) gene family is involved in the detoxification of biomaterials and drugs in the liver. Among the UGT gene family members, only UGT1A1 is involved in bilirubin conjugation. As a result, deficient UGT1A1 activity causes jaundice. One disease that is characterized by reduced UGT1A1 activity is Gilbert's syndrome. Two prevalent UGT1A1 polymorphisms responsible for Gilbert's syndrome have been identified: G71R in exon 1 and A(TA)7TAA in the TATA box of the promoter region. Recently, the G71R polymorphism has been associated with breastfeeding jaundice and neonatal hyperbilirubinemia in term infants. However, its association with jaundice in very low birth weight infants (VLBWIs) has never been reported., Case Presentation: The patient was a female born at 28 weeks, 4 days gestation with a birth weight of 1172 g. On day 21, intense yellowing of the skin and eyes was noted, and the patient's total bilirubin level was 23.7 mg/dL (her direct bilirubin level was 2.1 mg/dL). Therefore, an exchange transfusion was conducted. She had neither blood type incompatibility nor a family history of constitutional jaundice. Metabolic screens for amino and organic acids were negative. No elevation of any of the examined antibody titers was noted, and no evidence of an inflammatory reaction was observed. In addition, no hematological abnormalities were detected. The direct/indirect Coombs test, irregular antibody test and red blood cell antibody dissociation test were all negative, and her thyroid function was normal. We performed sequence analysis of the UGT1A1 gene after the patient's parents provided written informed consent. Exon 1 of the UGT1 gene on chromosome 2 was analyzed by direct sequencing. A heterozygous substitution from G to A (211G→A: G71R) in base 211 was noted., Conclusion: We speculated that this preterm infant with carrying the G71R polymorphism reduced UGT1A1 activity and developed severe jaundice that was likely triggered by factors such as breast feeding and medications. The polymorphism appears at some frequency among VLBWIs, which would necessitate adequate care of severe jaundice even after the acute phase.

Gilbert's syndrome (GS) is a common cause of inherited benign unconjugated hyperbilirubinemia that occurs in the absence of overt hemolysis, other liver function test abnormalities, and structural liver disease. GS may not affect a patient's selection for living-donor liver transplantation (LDLT). Between February 2005 and April 2011, 446 LDLT procedures were performed at our institution. Two of the 446 living liver donors were diagnosed with GS. Both donors underwent extended right hepatectomies, and donors and recipients experienced no problem in the postoperative period. Their serum bilirubin levels returned to the normal range within 1-2 weeks postoperatively. In our opinion, extended right hepatectomy can be performed safely in living liver donors with GS if appropriate conditions are met and remnant volume is >30%. Livers with GS can be used successfully as grafts in LDLT recipients., (Copyright © 2012 Elsevier Inc. All rights reserved.)