Materiały źródłowe

• #1 Gilbert Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470200/

  Gilbert syndrome is a common genetic disorder affecting bilirubin metabolism in the liver. This autosomal recessive condition leads to mild to moderate unconjugated hyperbilirubinemia, often presenting as recurrent episodes of jaundice. […] Gilbert syndrome is inherited in an autosomal recessive manner. In the White population, Gilbert syndrome is most commonly associated with the homozygous polymorphism A(TA)7TAA in the promoter region of UGT1A1 (uridine diphosphoglucoronate-glucuronosyltransferase 1A1), which leads to a significant reduction in the glucuronidation of bilirubin. Homozygosity for a defect in the TATA box within the promoter region of UGT1A1 leads to a mutation of UGT1A1 called UGT1A1*28. The molecular defect inserts an additional dinucleotide sequence (TA) into the transcription initiation sequence: A(TA)6TAA to A(TA)7TAA.

• #2 Gilbert Syndrome – PubMed

  https://pubmed.ncbi.nlm.nih.gov/29262099/

  Gilbert syndrome is a common genetic disorder affecting bilirubin metabolism in the liver. This condition, described in the early 1900s by Gilbert, Castaigne, and Lereboulette, is an autosomal recessive disorder that is a frequent cause of mild-to-moderate isolated unconjugated hyperbilirubinemia. Reduced glucuronidation of bilirubin leads to unconjugated hyperbilirubinemia and recurrent episodes of jaundice. […] Disorders of hepatic uptake, storage, conjugation, and excretion can cause unconjugated and conjugated hyperbilirubinemia. […] Careful clinical assessment, targeted laboratory evaluation, and exclusion of other differential diagnoses associated with unconjugated hyperbilirubinemia, including other acute and chronic liver diseases, should be performed before diagnosing Gilbert syndrome. After diagnosing Gilbert syndrome, treatment is conservative with observation alone. The prognosis of patients with Gilbert syndrome is excellent.

• #3 Gilbert’s syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Gilbert%27s_syndrome

  Gilbert syndrome is due to a genetic variant in the UGT1A1 gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme. […] People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function, which contributes to a lower rate of glucuronidation of unconjugated bilirubin. This substance then accumulates in the body, causing mild hyperbilirubinemia. […] Gilbert syndrome is characterized by a 70-80% reduction in the glucuronidation activity of the enzyme (UGT1A1). […] Mutations in the UGT1A1 gene lead to Gilbert Syndrome. […] The theorized mechanism for the increased risk of breast cancer is elevated estrogen from its decreased metabolism by UDP-glucuronosyltransferase in those with Gilbert syndrome.

• #4 Gilbert syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/gilbert-syndrome/

  Gilbert syndrome is a relatively mild condition characterized by periods of elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). […] Changes in the UGT1A1 gene cause Gilbert syndrome. This gene provides instructions for making the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which is found primarily in liver cells and is necessary for the removal of bilirubin from the body. […] The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. During this reaction, the enzyme transfers a compound called glucuronic acid to unconjugated bilirubin, converting it to conjugated bilirubin. […] People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function. As a result, unconjugated bilirubin is not glucuronidated quickly enough. This toxic substance then builds up in the body, causing mild hyperbilirubinemia. […] Not everyone with the genetic changes that cause Gilbert syndrome develops hyperbilirubinemia, indicating that additional factors, such as conditions that further hinder the glucuronidation process, may be necessary for development of the condition.

• #5 Unconjugated Hyperbilirubinemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/178841-overview

  Gilbert syndrome is believed to affect approximately 3-10% of the adult population. […] Gilbert syndrome is a benign, familial disorder inherited in an autosomal recessive pattern characterized by intermittent jaundice in the absence of hemolysis or an underlying liver disease. The condition is recognized to arise from a mutation in the promoter region of the UGT1A1 gene, which results in reduced UGT production. […] Hepatic bilirubin UGT activity is consistently decreased to approximately 30% of normal in individuals with Gilbert syndrome. Decreased bilirubin-UGT activity has been attributed to an expansion of thymine-adenine (TA) repeats in the promoter region of the UGT-1TA gene. […] In Gilbert syndrome, the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and protease inhibitor side effects.

• #6 Gilbert syndrome – UpToDate

  https://www.uptodate.com/contents/gilbert-syndrome

  Gilbert syndrome (Meulengracht disease, constitutional hepatic dysfunction, and familial nonhemolytic jaundice) is a benign condition characterized by recurrent episodes of jaundice. […] The hyperbilirubinemia in patients with Gilbert syndrome is unconjugated. […] The genetic defect in patients with Gilbert syndrome involves the promotor region of uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene. Uridine diphosphoglucuronate-glucuronosyltransferases (UGTs) are a family of enzymes that mediate glucuronidation of various endogenous and exogenous compounds. The UGT1A gene that encodes the enzyme UGT1A1 is responsible for the conjugation of bilirubin with glucuronic acid, converting the bilirubin into a water-soluble form that is readily excreted in bile. […] Gilbert syndrome is an autosomal recessive disorder and manifests in people who are homozygous for the variant promoter. However, heterozygotes for the Gilbert genotype have higher average plasma bilirubin concentrations compared with those with two wild-type alleles.

• #7 Gilbert syndrome – UpToDate

  https://www.uptodate.com/contents/gilbert-syndrome/print

  Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation, with an estimated prevalence of 6 to 14 percent. […] The genetic defect in patients with Gilbert syndrome involves the promotor region of uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene. Uridine diphosphoglucuronate-glucuronosyltransferases (UGTs) are a family of enzymes that mediate glucuronidation of various endogenous and exogenous compounds. The UGT1A gene that encodes the enzyme UGT1A1 is responsible for the conjugation of bilirubin with glucuronic acid, converting the bilirubin into a water-soluble form that is readily excreted in bile. […] Gilbert syndrome is an autosomal recessive disorder and manifests in people who are homozygous for the variant promoter. However, heterozygotes for the Gilbert genotype have higher average plasma bilirubin concentrations compared with those with two wild-type alleles.

• #8

  https://omim.org/entry/143500

  A number sign (#) is used with this entry because Gilbert syndrome is caused by homozygous, compound heterozygous, or heterozygous mutation in the UDP-glucuronosyltransferase gene (UGT1A1; 191740) on chromosome 2q37. […] Detailed studies show that patients with Gilbert syndrome have reduced activity of bilirubin glucuronosyltransferase (Bosma et al., 1995, Koiwai et al., 1995). […] Billing et al. (1964) presented indirect evidence of a defect of uptake of bilirubin into the liver cell. Black and Billing (1969) found hepatic bilirubin UDP-transferase to be about 25% of normal in 11 patients with Gilbert syndrome. […] Hsieh et al. (2007) showed that mutant TA7 TATA-box-like sequence has reduced protein binding affinity compared to wildtype, and that binding affinity progressively decreases as the number of TA repeats in the UGT1A1 TATA-box-like sequence increases. The authors stated that this decrease in binding affinity underlies the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome.

• #9

  https://journals.lww.com/jpharmacogenetics/fulltext/2007/04000/Molecular_pathogenesis_of_Gilbert_s_syndrome_.1.aspx?generateEpub=Article%7Cjpharmacogenetics:2007:04000:00001%7C10.1097/fpc.0b013e328012d0da%7C

  Gilbert’s syndrome is a congenital, nonhemolytic, unconjugated hyperbilirubinemia. The most common genotype of Gilbert’s syndrome is the homozygous polymorphism, A(TA)7TAA, in the promoter of the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1), with a thymine adenine insertion in the TATA-box-like sequence, which results in a decrease in UGT1A1 activity. […] The mechanism responsible for this decrease in UGT1A1 activity, however, has not been elucidated. […] A competitive electrophoretic mobility shift assay showed a decrease in nuclear protein complex binding affinity and TATA-binding protein binding affinity of the mutant TATA-box-like sequence A(TA)7TAA. […] TA insertion in the TATA-box-like sequence of the UGT1A1 promoter affected its binding affinity for TATA-binding protein, causing a decrease in its activity. This explains the pathogenesis of Gilbert’s syndrome.

• #10 Gilbert Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470200/

  Gilbert syndrome represents a spectrum of disease activity, as represented by impaired UGT1A1 activity. More than 100 mutations have been associated with Gilbert Syndrome, with different frequencies noted in different ethnic groups. This is also why genetic testing should not be used to diagnose Gilbert syndrome definitively.

• #11 Gilbert or Crigler–Najjar syndrome? Neonatal severe unconjugated hyperbilirubinemia with P364L UGT1A1 homozygosity | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-022-01251-4

  Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. […] The UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. […] 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. […] The UGT1A1 mutations associated with Gilbert syndrome appear to be considerably different among ethnic groups. […] The mutation was at first identified in a heterozygous GS patient, but then it was associated both with prolonged unconjugated hyperbilirubinemia and with CNS II.

• #12 Unconjugated Hyperbilirubinemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/178841-overview

  Investigators have discovered that Gilbert syndrome may coexist with other liver diseases, such as nonalcoholic steatohepatitis. Therefore, unconjugated hyperbilirubinemia in patients with these other conditions may be due to Gilbert syndrome and should not always be attributed to the underlying liver disorder.

• #13 Gilbert’s syndrome coexisting with hereditary spherocytosis might not be rare: Six case reports

  https://www.wjgnet.com/2307-8960/full/v8/i10/2001.htm

  Gilberts syndrome (GS) and hereditary spherocytosis (HS) are hereditary disorders of similar etiology, the presence of isolated unconjugated hyperbilirubinemia. The pathogenesis of GS has been linked to a mutation in the gene that encodes UGT1A1, the enzyme that conjugates bilirubin in hepatocytes. Thus, in GS, the ability of hepatocytes to transport and conjugate serum bilirubin is impaired. Conversely, HS is a hemolytic disease that is secondary to an erythrocyte (RBC) membrane abnormality due to genetic mutations, most commonly for ANK1 and Band 3 (SLC4A1). […] Although the distinct pathogenesis of these two diseases make differential diagnosis between them straightforward when each is present alone, hemolytic disease comorbidity and compensatory mechanisms can obscure their diagnoses, leading to missed and delayed diagnosis.

• #14

  https://childshealth.zaslavsky.com.ua/index.php/journal/article/view/931

  The aim of the review was the analysis of the literature about the prevalence, etiology, genetics and pathogenesis of Gilberts syndrome (GS). […] GS is a predominantly hereditary unconjugated hyperbilirubinemia associated with the reduced activity of uridine diphosphate glucuronosyltransferase (UGT-1A) in liver, which is encrypted in external resources as ICD-10 E80.4; OMIM 143500; DiseasesDB 5218; MedlinePlus 000301; eMedicinemed 870; MeSHD 005878. […] The patients with GS have signs of disorders in all phases of metabolism of bilirubin from its production to excretion: the lack of bilitranslocase which is responsible for the capture of bilirubin from the blood and its transport to hepatocytes, the deficit of Y- and Z-protein ligand (glutathione-S-transferase enzyme), responsible for transport of bilirubin to microsomes, the deficiency of UGT-1A, which provides the transfer of glucuronic acid to bilirubin.

• #15 DOAJ Logotype

  https://doaj.org/article/3797990c62604c22b99c0bf5688fd30b

  The aim of the review was the analysis of the literature about the prevalence, etiology, genetics and pathogenesis of Gilberts syndrome (GS). […] GS is a predominantly hereditary unconjugated hyperbilirubinemia associated with the reduced activity of uridine diphosphate glucuronosyltransferase (UGT-1A) in liver, which is encrypted in external resources as ICD-10 E80.4; OMIM 143500; DiseasesDB 5218; MedlinePlus 000301; eMedicinemed 870; MeSHD 005878. The patients with GS have signs of disorders in all phases of metabolism of bilirubin from its production to excretion: the lack of bilitranslocase which is responsible for the capture of bilirubin from the blood and its transport to hepatocytes, the deficit of Y- and Z-protein ligand (glutathione-S-transferase enzyme), responsible for transport of bilirubin to microsomes, the deficiency of UGT-1A, which provides the transfer of glucuronic acid to bilirubin.

• #16 Gilbert’s syndrome: The good, the bad and the ugly

  https://www.wjgnet.com/1948-5182/full/v17/i2/98503.htm

  Gilberts syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism. […] More recent research has delved into the genetic mechanisms underlying the reduced expression of bilirubin UDP-glucuronosyltransferase, significantly enhancing our understanding of the pathogenesis of GS. […] A key feature of GS is a minimum 50% decrease in hepatic bilirubin UGT activity, leading to impaired bilirubin conjugation. […] The underlying genetic basis for this reduction involves mutations or polymorphisms in the UGT family 1 member A1 (UGT1A1) gene, with homozygosity for the (TA)7TAA variant in the promoter region being particularly prevalent in white populations. […] Abnormalities in hepatic uptake of bilirubin and potential defects in hepatocellular transport also contribute to the pathogenesis of hyperbilirubinemia in GS.

• #17 Inborn Metabolic Disorders Causing Hyperbilirubinemia – Hepatic and Biliary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/approach-to-the-patient-with-liver-disease/inborn-metabolic-disorders-causing-hyperbilirubinemia

  Gilbert syndrome is a presumably lifelong disorder in which the only significant abnormality is asymptomatic, mild, unconjugated hyperbilirubinemia. […] Pathogenesis may involve complex defects in the livers uptake of bilirubin. Glucuronyl transferase activity is low, though not as low as in Crigler-Najjar syndrome type II. […] In many patients, red blood cell destruction is also slightly accelerated, but this acceleration does not cause anemia or hyperbilirubinemia.

• #18 Gilbert syndrome: a case series | Pediatric Oncall Journal

  https://www.pediatriconcall.com/pediatric-journal/view-article/1072

  Gilbert Syndrome (GS) is a disorder of ineffective conjugation of glucuronic acid to bilirubin leading to an increase in unconjugated bilirubin levels in the blood. It is due to a deficiency or decreased activity of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1). […] Gilbert syndrome (GS) is the most common hereditary bilirubin mechanism disorder due to decreased activity of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) and is associated with unconjugated hyperbilirubinemia in the absence of liver disease or haemolysis. […] It is diagnosed around puberty due to an increase in bilirubin production under the influence of steroid hormones. […] The syndrome is usually asymptomatic and is only seen as jaundice during periods of stress such as fasting, dehydration, fatigue, menstruation etc.

• #19 PATHOGENESIS OF GILBERTS SYNDROME

  https://lirias.kuleuven.be/61817

  Chronic unconjugated hyperbilirubinaemia is a frequent finding. […] Our recent investigations in rats indicate that this might be due to inhibition of bilirubin conjugation by testosterone whereas progestogens combined with oestrogens produce a stimulation; if this holds for man, it could also explain why Gilbert’s syndrome is usually not apparent before puberty.

• #20

  https://childshealth.zaslavsky.com.ua/index.php/journal/article/view/931

  The main reason of the lack of the enzyme is mutation of the gene encoding UGT1A1, however, the other factors are also responsible for the development of the syndrome and manifestation of its symptoms (male gender, additional gene mutations: c.993 (p.Q331H); *6 (c.211G A); (nt-211, nt-686, nt-1,091 and nt-1456). […] The histological and ultrastructural features of GS include normal hepatic lobules and deposition of bile pigment granules in hepatocytes. Signs of the hepatosis are seen at later terms and serve as evidence of the evolution of the disease.

• #21 DOAJ Logotype

  https://doaj.org/article/3797990c62604c22b99c0bf5688fd30b

  The main reason of the lack of the enzyme is mutation of the gene encoding UGT1A1, however, the other factors are also responsible for the development of the syndrome and manifestation of its symptoms (male gender, additional gene mutations: c.993 (p.Q331H); *6 (c.211G A); (nt-211, nt-686, nt-1,091 and nt-1456). The specific polymorphism in candidate genes was identified (SLCO1B3 ABCC2 and NUP153). The histological and ultrastructural features of GS include normal hepatic lobules and deposition of bile pigment granules in hepatocytes. Signs of the hepatosis are seen at later terms and serve as evidence of the evolution of the disease.

• #22 Genetic interactions in the pathogenesis of neonatal hyperbilirubinemia: Gilbert’s Syndrome and glucose-6-phosphate dehydrogenase deficiency | Health & Environmental Research Online (HERO) | US EPA

  https://hero.epa.gov/hero/index.cfm/reference/details/reference_id/8650093

  Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a common condition with a worldwide distribution that has the potential for causing severe hyperbilirubinemia with bilirubin encephalopathy. […] As hyperbilirubinemia results from an imbalance between bilirubin production and bilirubin elimination, diminished bilirubin conjugation was suspected to contribute to the pathogenesis of hyperbilirubinemia. […] This conjugated bilirubin profile was similar to that seen in adults with Gilbert’s Syndrome, a condition associated with promoter polymorphism for the gene encoding the bilirubin-conjugating enzyme, UGT glucuronosyltransferase 1A1 (UGT). […] However, in combination, or following exposure to environmental or other genetic factors, these benign conditions may have severe manifestations, with potentially dangerous and possibly life-threatening consequences.

• #23 Investigation of Gilbert’s Syndrome

  http://www.teveritt.co.uk/clinical_chemistry/guidelines/gilberts.htm

  Gilberts syndrome is a common (occurring in ~5% of population) and benign condition characterized by recurrent episodes of mild jaundice, the total bilirubin concentration being less than 100 umol/L. […] The mechanism of jaundice is unclear but decreased bilirubin uptake by the liver is commonly present and decreased conjugation is demonstrable in some individuals. […] The conjugated bilirubin fraction accounts for 20% of the total bilirubin level i.e. increased total bilirubin in Gilberts syndrome should be due largely (80%) to unconjugated bilirubin. […] If further confirmation of Gilberts is required the response to fasting can be studied. Following a 24-hour fast (or 48 hours of a low caloric diet) there is a 2 to 3 fold increase in unconjugated bilirubin in subjects with Gilberts syndrome.

• #24

  https://journals.lww.com/hep/abstract/1981/03000/effects_of_corticosteroids_on_bilirubin_metabolism.12.aspx

  To elucidate the mechanism whereby corticosteroids decrease the serum bilirubin concentration, changes in bilirubin metabolism were studied in patients with Gilberts syndrome using a bilirubin load test and/or nicotinic acid test before and after corticosteroid treatment. […] Steroid administration increased hepatic clearance and uptake of bilirubin; the transfer rate for biliary excretion was unaffected. […] These results suggest that the main effect was enhancement of hepatic uptake or storage of bilirubin, which may be an important mechanism whereby corticosteroids reduce serum bilirubin concentrations in various liver disorders.

• #25 Features of an altered AMPK metabolic pathway in Gilbert’s Syndrome, and its role in metabolic health | Scientific Reports

  https://www.nature.com/articles/srep30051

  Energy metabolism, involving the ATP-dependent AMPK-PgC-Ppar pathway impacts metabolic health immensely, in that its impairment can lead to obesity, giving rise to disease. […] specific inter-group differences in the AMPK pathway regulation were explored. […] In GS individuals, rates of phospho-AMPK 1/2, -Ppar / and of PgC 1 were significantly higher, attesting to a boosted fasting response in this condition. […] In reflection of an apparently improved health status, GS individuals had significantly lower BMI, glucose, insulin, C-peptide and triglyceride levels. […] Herewith, we propose a new theory to explain why individuals having GS are leaner and healthier, and are therefore less likely to contract metabolic diseases or die prematurely thereof. […] This imposed the assumption that crucial energetic switches such as AMPK (heterotrimeric AMP-activated ser/thr kinase), are likely positively affected in the condition of GS.

• #26 Features of an altered AMPK metabolic pathway in Gilbert’s Syndrome, and its role in metabolic health | Scientific Reports

  https://www.nature.com/articles/srep30051

  The core regulatory unit studied, AMPK, is a member of a metabolite sensing protein kinase family, that is present in all eukaryotes, and retained in all cell types for regulating energy turnover. […] Active AMPK subsequently inactivates enzymes responsible for cholesterol-, fatty acid synthesis and gluconeogenesis. […] Another important effect of AMPK activation includes the post-translational phosphorylation of PgC 1, which is a positive regulator of energy consuming events such as oxidative processes (including mitogenesis and browning of adipose tissue), and adaptive thermogenesis. […] Ppars are considered as crucial networkers of energy- and nutrient-catabolism, which is why they are strongly implicated in the development and treatment of the metabolic syndrome. […] To further explore particularities of metabolic regulation in GS, a molecular approach was used focusing on the AMPK pathway.

• #27 Oxidative Stress and Related Biomarkers in Gilbert’s Syndrome: A Secondary Analysis of Two Case-Control Studies

  https://www.mdpi.com/2076-3921/10/9/1474

  Bilirubin is an important antioxidant and a modulator of biological functions. […] The aim of this case-control study was to investigate whether subjects with Gilbert’s syndrome (GS) experience different levels of lipid and protein oxidation (as well as differences in oxidative stress related markers) compared to healthy controls. […] Although not all markers related to oxidative stress were different between the groups (e.g., malondialdehyde, homocysteine, oxLDL, and myeloperoxidase; p > 0.05), the observed differences contribute to the explanation of why GS serves as an important protector in the pathogenesis of metabolic, oxidative stress related diseases. […] Mild hyperbilirubinemia, also known as Gilbert’s syndrome (GS), is prevalent in 5–10% of the general population, up to 20% in some areas such as the Middle East.

• #28

  https://apcz.umk.pl/JEHS/article/view/48507

  Gilberts syndrome is the most common inherited jaundice worldwide. It is caused by a mutation of the UGT1A1 gene, which results in impaired bilirubin metabolism. […] The result of the work is to present Gilberts syndrome as a disease that carries medical problems directly related to the mutation, but also, in some cases, has a protective effect on affected individuals. […] Mildly elevated bilirubin levels have an antioxidant and anti-inflammatory effect, which prevents the development of lifestyle diseases and cancer. […] Ongoing clinical trials suggest that this could be a great step toward new treatments for diseases affecting the entire human population. […] Gilberts syndrome carries not only the consequences associated with the mutation, but also has many benefits that patients may not be fully aware of.

• #29 Gilbert’s syndrome: protective effect on endothelial dysfunction

  https://www.degruyterbrill.com/document/doi/10.1515/tjb-2016-0150/html?srsltid=AfmBOoqHBTAXrsHMaXG5zHPeEW8b3XKlm4ptIIIJLI9lj_HaCNDjyYnH

  Gilberts syndrome (GS), is a benign condition characterized by unconjugated hyperbilirubinemia related to a decreased hepatic glucuronidating activity without symptoms and signs of liver disease or overt hemolysis. […] The present study showed for the first time that decreased levels of ADMA, PTX-3 and hs-CRP may prove the protective effects of hyperbilirubinemia on the endothelial dysfunction. […] Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis, leading to cardiovascular complications. […] Since endothelial dysfunction is a complex, multi-step mechanism where reduced NO levels have been reported as a marker, majority of these studies have typically focused on the potent endogenous antioxidant effect of bilirubin and accordingly beneficial effects on inhibition of the development of atherosclerosis.

• #30 Gilbert’s syndrome: protective effect on endothelial dysfunction

  https://www.degruyter.com/document/doi/10.1515/tjb-2016-0150/html?lang=en

  Gilberts syndrome (GS), is a benign condition characterized by unconjugated hyperbilirubinemia related to a decreased hepatic glucuronidating activity without symptoms and signs of liver disease or overt hemolysis. […] The present study showed for the first time that decreased levels of ADMA, PTX-3 and hs-CRP may prove the protective effects of hyperbilirubinemia on the endothelial dysfunction. […] Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis, leading to cardiovascular complications. […] Since endothelial dysfunction is a complex, multi-step mechanism where reduced NO levels have been reported as a marker, majority of these studies have typically focused on the potent endogenous antioxidant effect of bilirubin and accordingly beneficial effects on inhibition of the development of atherosclerosis.

• #31 Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert’s Syndrome | Scientific Reports

  https://www.nature.com/articles/srep22300

  Bilirubin (BR) is a natural endogenous compound with a potent bioactivity. Gilberts Syndrome (GS) is a benign hereditary condition of increased unconjugated bilirubin (UCB) in serum and serves as a convenient model for studying the effects of BR in humans. […] In the present study we have observed a relationship between mildly increased serum UCB and telomere length. […] An occurrence of longer telomeres was observed in male individuals chronically exposed to increased UCB, as well as in Gunn rats, an animal model of unconjugated hyperbilirubinaemia. […] Previously identified differences in immunomodulation and redox parameters in individuals with GS, such as IL-6, IL-1 and ferric reducing ability of plasma, were confirmed and proposed as possible contributors to the occurrence of longer telomeres in GS.

• #32 Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert’s Syndrome | Scientific Reports

  https://www.nature.com/articles/srep22300

  Our findings reveal a novel characteristic of Gilberts Syndrome, potentially related to a chronic exposure to moderately increased unconjugated serum bilirubin. We show that individuals with a GS phenotype have on average longer telomeres compared to age- and gender-matched controls. This difference appears to be more pronounced with age, suggesting a reduced or slower telomere attrition in GS. […] The most plausible hypothesis explaining slower telomere shortening in GS, is that UCB via its immune-modulatory activity leads to slower cell turnover and hence, a slower exhaustion of hematopoietic stem cells. […] A strong direct relationship between serum UCB and TL could not be established, likely due to the transient nature of measurable UCB concentrations, which are subject to day-to-day fluctuations. On the other hand, changes in TL are steady and can be only observed on a long-term basis. […] In conclusion, we could observe a further link between Gilberts Syndrome, and possibly unconjugated bilirubin, and longevity, with emphasis on healthy aging.

• #33 Gilbert’s Syndrome after Ritualistic Prolonged Fasting of Chhath Puja in Bihar, India: A Case Report and Literature Review

  https://www.ijmb.in/abstractArticleContentBrowse/IJMB/17731/JPJ/fullText

  Gilbert syndrome (GS), most common hereditary cause of unconjugated hyperbilirubinemia due to polymorphisms in uridine diphosphate glucuronosyltransferase (UGT) enzyme, was first described by Augustin Nicolas Gilbert and Pierre Lereboullet in 1901. […] Gilberts syndrome has an excellent prognosis and does not require any treatment. But recent studies have shown that patients with GS are more susceptible to enhanced toxicity of several drugs using UGT enzyme in their metabolism. […] In 1995, Bosma et al. proposed that the genetic basis of reduced hepatic bilirubin glucuronidation in GS is due to a variant TATAA element (which contains two extra nucleotides, TA) in upstream promoter region of the gene for bilirubin UGT located on chromosome 2. […] Although reduced expression of bilirubin UGTA1G1 is essential for the syndrome, usually it is not sufficient for the complete manifestation of the phenotype.

• #34 Gilberts Syndrome

  https://naturalhealthmedicine.com.au/gilberts-syndrome/

  Gilberts syndrome is a genetic condition in which the body is unable to effectively clear bilirubin from the body (unconjugated hyperbilirubinemia) which results in impaired detoxification. […] The mechanism which clears bilirubin from the body is called glucuronidation, a phase II liver detoxification pathway. In Gilberts Syndrome, this glucuronidation pathway is compromised, leading to high bilirubin levels and the overwhelm of this pathway reducing its other vital functions, such as the breakdown of common medications such as paracetamol. […] In Gilberts syndrome, the liver enzyme- bilirubin UDP-glucuronosyltransferase (UGT) that performs this reaction is impaired, leaving the liver unable to keep up with the demands of this conversion. […] Gilberts Syndrome can implicate the detoxification of exogenous compounds which also rely on glucuronidation; including hormones such as estrogen. This suggests that Gilbert Syndrome may contribute to conditions in which high estrogen is implicated. […] Treatment that supports phase II detoxification has the potential to counteract the disruption caused by unconjugated bilirubin.

• #35 Effect of bilirubin and Gilbert syndrome on health: cohort analysis of observational, genetic, and Mendelian randomisation associations | BMJ Medicine

  https://bmjmedicine.bmj.com/content/2/1/e000467

  In this study, we aimed to estimate the causal association between bilirubin and health outcomes using the Gilbert syndrome genotype as an instrumental variable and compare results with observational, measured analyses in a large UK volunteer cohort. […] In contrast to the observational data, patients with the Gilbert syndrome genotype had few associations with any healthcare outcomes; although we did identify increased associations with gallbladder pathology, which presumably relates to a direct increase in pigmented biliary stone formation secondary to increased unconjugated bilirubin. […] The other association we identified is, to the best of our knowledge, a previously unreported association with the skin condition pityriasis rosea. […] Despite a large sample size, no protective associations were identified. Previously reported associations in observational (and in some cases genetic) data are highly likely to be confounded to some extent. However, the novel association with pityriasis rosea deserves further investigation, and clinicians should be aware of the higher rates of biliary disease in people with Gilbert syndrome. […] However, we did identify a clear association between people who carry the Gilbert syndrome genotype and higher rates of biliary disease, which clinicians should be aware of, and a novel association with pityriasis rosea, which deserves further investigation.

• #36 SciELO Brazil – Associations between Gilbert’s syndrome and personality characteristics Associations between Gilbert’s syndrome and personality characteristics

  https://www.scielo.br/j/trends/a/psDv3FWGShGRM3sV8cfF4xP/

  The relationship between bilirubin levels and psychopathology has been investigated in a limited number of studies. […] Cloninger hypothesized that neurotransmitters were related with behavioral manifestations, such as, for example, serotonin with harm avoidance (behavioral inhibition); norepinephrine with reward dependence (behavioral maintenance); dopamine with novelty seeking (behavioral activation), and glutamine with persistence (behavioral perseverance). In this context, as an inherited disorder, GS may be associated with altered glucuronidation rates of these metabolites. […] This study can be considered an initial exploration of the personality structure of GS patients. However, we believe that clinicians should be cautious about interpreting the findings, in view of the studys confounding factors and limitations.

• #37 SciELO Brazil – Associations between Gilbert’s syndrome and personality characteristics Associations between Gilbert’s syndrome and personality characteristics

  https://www.scielo.br/j/trends/a/psDv3FWGShGRM3sV8cfF4xP/

  Gilberts syndrome (GS) is a benign genetic disorder that is characterized as intermittent mild jaundice, in which the liver doesnt process bilirubin properly. The mechanism of GS is linked to reduced uridine diphosphate-glucuronyl-transferase (UGT) 1A1 activity, resulting in unconjugated hyperbilirubinemia. […] Cloninger hypothesized that neurotransmitters were related to behavioral manifestations. In this context, as an inherited disorder, GS could be associated with altered glucuronidation rates of these metabolites and, consequently, with behavioral manifestations. […] Our current study showed that GS patients have a characteristic personality profile with higher scores for disorderliness, sentimentality, and fatigability and lower scores for empathy and transpersonal identification than healthy individuals.

• #38 SciELO Brazil – Associations between Gilbert’s syndrome and personality characteristics Associations between Gilbert’s syndrome and personality characteristics

  https://www.scielo.br/j/trends/a/psDv3FWGShGRM3sV8cfF4xP/

  In conclusion, our findings demonstrate significant differences in personality features (TCI 240) between GS patients and healthy individuals. There might be a relationship between GS and personality characteristics and therefore patients personality features might merit attention when evaluating patients with GS.

• #39 Gilbert’s syndrome: protective effect on endothelial dysfunction

  https://www.degruyter.com/document/doi/10.1515/tjb-2016-0150/html?lang=en

  We found that serum ADMA levels were decreased in our patient group compared to controls accompanied by a negative correlation between UCB and serum ADMA levels. […] We believe this decreased serum ADMA levels was caused by reduction in dimethylarginine dimethylaminohydrolase activity as indicated many times in previous studies on CVD. […] PTX-3 is a protein produced locally by the endothelium and other cells in the area of inflammation and has a close relation with endothelium cell functions. […] In the present study, there are significant differences in serum levels of PTX-3 between patients with GS and controls, suggesting that inflammation is decreased in patients with GS. […] In addition, UCB was found to be negatively correlated with hs-CRP in correlation analysis. Eventually, we think that lower levels of hs-CRP may contribute in reducing systematic inflammation and this may be another explanation of decreased CAD prevalence in GS. […] The findings of this study show that circulating levels of ADMA, PTX-3 and hs-CRP are decreased in GS. The results also indicate that UCB plays a complex role in preventing endothelial dysfunction and inflammation in GS.

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