Gilbert syndrome (GS) is a syndrome in which theliver of affected individuals processesbilirubin more slowly than the majority resulting in higher levels in the blood.[1] Many people never have symptoms.[1] Occasionallyjaundice (a yellowing of the skin or whites of the eyes) may occur.[1]
Typically no treatment is needed.[1]If jaundice is significant,phenobarbital may be used, which aids in the conjugation of bilirubin.[1] Gilbert syndrome is associated with decreased cardiovascular health risks but increased risks of some cancers and gallstones.[4][5] Gilbert syndrome affects about 5% of people in the United States.[3] Males are more often diagnosed than females.[1] It is often not noticed until late childhood to early adulthood.[2] The condition was first described in 1901 byAugustin Nicolas Gilbert.[6][2][7]
Gilbert syndrome produces an elevated level of unconjugated bilirubin in thebloodstream, but normally has no consequences. Mildjaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.[8][9] Severe cases are seen by yellowing of the skin tone and yellowing of the conjunctiva in the eye.[10]
Gilbert syndrome has been reported to contribute to an accelerated onset ofneonatal jaundice. The syndrome cannot cause severe indirect hyperbilirubinemia in neonates by itself, but it may have a summative effect on rising bilirubin when combined with other factors,[11] for example in the presence of increasedred blood cell destruction due to diseases such asG6PD deficiency.[12][13] This situation can be especially dangerous if not quickly treated, as thehigh serum bilirubin can cause irreversible neurological disability in the form ofkernicterus.[14][15][16]
Whileparacetamol (acetaminophen) is not metabolized by UGT1A1,[18] it is metabolized by one of the other enzymes also deficient in some people with GS.[19][20] A subset of people with GS may have an increased risk of paracetamol toxicity.[20][21]
Another drug that has increased adverse side-effects in individuals with Gilbert Syndrome isatazanavir.[22]Atazanavir is aprotease inhibitor for the treatment of HIV.[22]Atazanavir can lead to jaundice in individuals with Gilbert Syndrome because it further inhibits the UGT enzymes that are already exhibit decreased activity in Gilbert Syndome.[22]
The mild increase in unconjugated bilirubin due to Gilbert syndrome is closely related to the reduction in the prevalence of chronic diseases, especially cardiovascular disease and type 2 diabetes, related risk factors, and all-cause mortality.[23] Observational studies emphasize that the antioxidant effects of unconjugated bilirubin may bring survival benefits to patients.[24]
Specifically, people with mildly elevated levels of bilirubin (1.1 mg/dl to 2.7 mg/dl) were at lower risk for CAD and at lower risk for future heart disease.[27] These researchers went on to perform ameta-analysis of data available up to 2002, and confirmed the incidence ofatherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin.[25] This beneficial effect was attributed to bilirubin IXα which is recognized as a potent antioxidant, rather thanconfounding factors such ashigh-density lipoprotein levels.[27]
This association was also seen in long-term data from theFramingham Heart Study.[28][4][non-primary source needed] Moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype were associated with one-third the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA)6/(TA)6 genotype (i.e. a normal, nonmutated gene locus).
Platelet counts andMPV (mean platelet volume) are decreased in patients with Gilbert's syndrome. The elevated levels of bilirubin and decreasing levels of MPV andCRP in Gilbert's syndrome patients may have an effect on the slowing down of theatherosclerotic process.[29]
Symptoms, whether connected or not to GS, have been reported in a subset of those affected:fatigue (feeling tired all the time), difficulty maintaining concentration, unusual patterns ofanxiety, loss ofappetite,nausea, abdominal pain, loss of weight, itching (with no rash), and others,[30] such as humor change ordepression. But scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults. However, other substances glucuronidized by the affected enzymes in those with Gilbert's syndrome could theoretically, at their toxic levels, cause these symptoms.[31][32] Consequently, debate exists about whether GS should be classified as a disease.[31][33]
Gilbert syndrome has been linked to an increased risk ofgallstones,schizophrenia, breast cancer, and colorectal cancer.[30][34][5] The theorized mechanism for the increased risk of breast cancer is elevated estrogen from its decreased metabolism byUDP-glucuronosyltransferase in those with Gilbert syndrome.[5] The cause for the increased risk of schizophrenia is not yet fully understood and is the object of further research.[5]
Mutations in theUGT1A1 gene lead to Gilbert Syndrome.[35] The gene provides instructions for making thebilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which can be found in the liver cells and is responsible for preparing bilirubin for removal from the body.[36]
The bilirubin-UGT enzyme performs a chemical reaction calledglucuronidation.Glucuronic acid is transferred to unconjugated bilirubin, which is a yellowish pigment made when your body breaks down old red blood cells,[37] and then being converted to conjugated bilirubin during the reaction. Conjugated bilirubin passes from the liver into the intestines with bile. It's then excreted in stool.
People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function, which contributes to a lower rate ofglucuronidation of unconjugated bilirubin. This substance then accumulates in the body, causing mildhyperbilirubinemia.[36]
Gilbert syndrome is aphenotypic effect, mostly associated with increased blood bilirubin levels, but also sometimes characterized by mild jaundice due to increasedunconjugated bilirubin, that arises from several differentgenotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.[5]
Gilbert's syndrome is characterized by a 70–80% reduction in theglucuronidation activity of the enzyme (UGT1A1). TheUGT1A1 gene is located onhuman chromosome 2.[38]
More than 100polymorphisms of theUGT1A1 gene are known, designated asUGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of itspromoter region.UGT1A1is associated with aTATA box promoter region; this region most commonly contains the genetic sequence A(TA)6TAA; this variant accounts for about 50% ofalleles in many populations. However, several allelicpolymorphic variants of this region occur, the most common of which results from adding anotherdinucleotide repeat TA to the promoter region, resulting in A(TA)7TAA, which is calledUGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, around 3% of alleles, in Southeast and East Asian people and Pacific Islanders.[citation needed]
However, Gilbert syndrome can arise withoutTATA box promoter polymorphic variants; in some populations, particularly healthy Southeast and East Asians, Gilbert's syndrome is more often a consequence ofheterozygotemissense mutations (such as Gly71Arg also known asUGT1A1*6, Tyr486Asp also known asUGT1A1*7, Pro364Leu also known asUGT1A1*73) in the actual gene coding region,[21] which may be associated with significantly higher bilirubin levels.[21]
Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minorinborn error of metabolism.[citation needed]
Gilbert syndrome is typically diagnosed based on clinical findings and laboratory results, emphasizing the exclusion of other potential causes of elevated bilirubin levels. The key criteria include:
Mild, Unconjugated Hyperbilirubinemia:
Total serum bilirubin levels are mildly elevated, typically remaining below 6 mg/dL (102 µmol/L), with a predominance of the unconjugated (indirect) fraction.[42]
Normal Liver Function Tests:
Liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are within normal ranges, indicating no underlying liver disease.[43]
Absence of Hemolysis:
No evidence of increased red blood cell breakdown, as indicated by normal hemoglobin levels and reticulocyte counts.[43]
Intermittent Nature of Symptoms:
Episodes of jaundice that may be triggered by factors such as fasting, illness, stress, or exertion, with no other associated symptoms.[44] The level of total bilirubin is often further increased if the blood sample is taken afterfasting for two days,[45] and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose ofphenobarbital:[46] the bilirubin will decrease substantially.
Exclusion of Other Liver Disorders:
No clinical or laboratory evidence of other liver diseases; imaging studies and serologic tests for hepatitis are negative.[43]
Genetic Testing:
Identification of mutations in the UGT1A1 gene can confirm the diagnosis of Gilbert syndrome. While not routinely required, genetic testing may be considered in cases where the diagnosis is uncertain or to provide reassurance to patients.[47]
While Gilbert syndrome is considered harmless, it is clinically important because it may give rise to a concern about a blood or liver condition, which could be more dangerous. However, these conditions have additional indicators:
In GS, unless another disease of the liver is also present, the liver enzymesALT/SGPT andAST/SGOT, as well asalbumin, are within normal ranges.[43]
Crigler–Najjar syndrome (types I and II), a different glucuronyl transferase disorder, is much more severe, with 0–10% UGT1A1 activity,[48] with affected individuals at risk of brain damage in infancy (type I) and teenage years (type II).[48]
Hemolysis of any cause can be excluded by a full blood count, haptoglobin,lactate dehydrogenase levels, and the absence of reticulocytosis (elevated reticulocytes in the blood would usually be observed in haemolytic anaemia).[49]
Viral hepatitis associated with increase of conjugated bilirubin can be excluded by negative blood samples for antigens specific to the different hepatitis viruses.
Gilbert's syndrome is a benign condition that typically requires no medical treatment.[52] The primary approach involves patient education and reassurance about the harmless nature of the syndrome.[52] Episodes of jaundice, when they occur, are usually mild and resolve on their own without intervention.[52] To minimize the frequency of these episodes, individuals are advised to avoid known triggers such as fasting, dehydration, stress, and strenuous physical exertion.[52] Maintaining a healthy lifestyle, including regular meals and adequate hydration, can help manage the condition effectively.[52] If jaundice is significantphenobarbital may be used.[1]
Studies conducted so far suggest that subjects with GS may have lower levels of vitamin D and folic acid than control subjects, having these levels inversely correlated with bilirubin levels. It may be that GS may impair the metabolism or absorption of these vitamins, or that these vitamins may affect the expression or activity of the UGT1A1 enzyme that is responsible for bilirubin conjugation. However, these studies had limitations, such as the small sample size, the lack of a standardized definition of GS, the possible confounding factors of diet, lifestyle, and medication use, and the cross-sectional and observational design that does not allow for causal inference.[53]
Ongoing studies suggest that mild hyperbilirubinemia in GS may have beneficial effects, probably due to the antioxidant and anti-inflammatory properties of bilirubin. Hyperbilirubinemia in GS may protect against oxidative stress and inflammation-related diseases, such as cardiovascular diseases, cancers, diabetes, and neurodegenerative disorders. However, the mechanisms and pathways of bilirubin protection are not fully elucidated, and the optimal level and range of bilirubin are unknown. The genetic and environmental factors that influence UGT1A1 expression and activity are also poorly characterized and may affect the variability and penetrance of GS.[54] Despite the fact that hyperbilirubinemia in GS is associated with reduced incidence of cardiovascular diseases,[55] diabetes, and metabolic syndrome,[56] the clinical significance and implications of these GS research findings are unclear, and can not yet be translated into preventive or therapeutic strategies.[54]
^abcde"Gilbert Syndrome".NORD (National Organization for Rare Disorders). 2015.Archived from the original on 20 February 2017. Retrieved2 July 2017.
^abcdef"Gilbert syndrome".Genetics Home Reference. 27 June 2017.Archived from the original on 27 June 2017. Retrieved2 July 2017.
^abBulmer, A. C.; Verkade, H. J.; Wagner, K.-H. (April 2013). "Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection".Progress in Lipid Research.52 (2):193–205.doi:10.1016/j.plipres.2012.11.001.hdl:10072/54228.ISSN1873-2194.PMID23201182.
^abcdeBeutler K, Lewandowski J. Gilbert’s syndrome - bright and dark sides of the disease - literature review. Journal of Education, Health and Sport. 2024;63:146-154. doi:10.12775/JEHS.2024.63.011
^abGilbert A, Lereboullet P (1901). "La cholémie simple familiale".La Semaine Médicale.21:241–3.
^Bancroft JD, Kreamer B, Gourley GR (1998). "Gilbert syndrome accelerates development of neonatal jaundice".Journal of Pediatrics.132 (4):656–60.doi:10.1016/S0022-3476(98)70356-7.PMID9580766.
^Rauchschwalbe S, Zuhlsdorf M, Wensing G, Kuhlmann J (2004). "Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype".Int J Clin Pharmacol Ther.42 (2):73–7.doi:10.5414/cpp42073.PMID15180166.
^Kohle C, Mohrle B, Munzel PA, Schwab M, Wernet D, Badary OA, Bock KW (2003). "Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians".Biochem Pharmacol.65 (9):1521–7.doi:10.1016/S0006-2952(03)00074-1.PMID12732365.
^abEsteban A, Pérez-Mateo M (1999). "Heterogeneity of paracetamol metabolism in Gilbert's syndrome".European Journal of Drug Metabolism and Pharmacokinetics.24 (1):9–13.doi:10.1007/BF03190005.PMID10412886.S2CID27543027.
^abLadislav Novotnýc; Libor Vítek (2003). "Inverse Relationship Between Serum Bilirubin and Atherosclerosis in Men: A Meta-Analysis of Published Studies".Experimental Biology and Medicine.228 (5):568–571.doi:10.1177/15353702-0322805-29.PMID12709588.S2CID43486067.
^abVítek L; Jirsa M; Brodanová M; et al. (2002). "Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels".Atherosclerosis.160 (2):449–56.doi:10.1016/S0021-9150(01)00601-3.PMID11849670.
^Kundur, Avinash R.; Singh, Indu; Bulmer, Andrew C. (March 2015). "Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert's syndrome?".Atherosclerosis.239 (1):73–84.doi:10.1016/j.atherosclerosis.2014.12.042.ISSN1879-1484.PMID25576848.
^abOlsson R, Bliding A, Jagenburg R, Lapidus L, Larsson B, Svärdsudd K, Wittboldt S (1988). "Gilbert's syndrome—does it exist? A study of the prevalence of symptoms in Gilbert syndrome".Acta Medica Scandinavica.224 (5):485–490.doi:10.1111/j.0954-6820.1988.tb19615.x.PMID3264448.
^Larissa K. F. Temple; Robin S. McLeod; Steven Gallinger; James G. Wright (2001). "Defining Disease in the Genomics Era".Science Magazine.293 (5531):807–808.doi:10.1126/science.1062938.PMID11486074.S2CID6520035.
^Raijmakers MT, Jansen PL, Steegers EA, Peters WH (2000). "Association of human liver bilirubin UDP-glucuronyltransferase activity, most commonly due to a polymorphism in the promoter region of the UGT1A1 gene".Journal of Hepatology.33 (3):348–351.doi:10.1016/S0168-8278(00)80268-8.PMID11019988.
^Monaghan G, Ryan M, Seddon R, Hume R, Burchell B (1996). "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome".Lancet.347 (9001):578–81.doi:10.1016/S0140-6736(96)91273-8.PMID8596320.S2CID24943762.
^Grant, Lafaine M.; Faust, Thomas W.; Thoguluva Chandrasekar, Viveksandeep; John, Savio (2025),"Gilbert Syndrome",StatPearls, Treasure Island (FL): StatPearls Publishing,PMID29262099, retrieved2025-03-26
^abSingh, A.; Koritala, J.; Jialal, I. (20 May 2023). "Unconjugated Hyperbilirubinemia".StatPearls. Treasure Island, Florida: StatPearls Publishing.PMID31747203.Archived from the original on 18 November 2023. Retrieved21 December 2023.
^Gorbunova O, Chernysheva E (November 2019). "A New Look at Gilbert Syndrome (Literature Review)".Georgian Med News (in Russian) (296):75–81.PMID31889709.
