Gilbert's syndrome#Notable cases

Gilbert syndrome produces an elevated level of unconjugated bilirubin in the bloodstream, but normally has no consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.Kasper et al., Harrison's Principles of Internal Medicine, 16th edition, McGraw-Hill 2005Boon et al., Davidson's Principles & Practice of Medicine, 20th edition, Churchill Livingstone 2006 Severe cases are seen by yellowing of the skin tone and yellowing of the conjunctiva in the eye.{{cite web|last=Philadelphia|first=The Children's Hospital of|date=2014-08-23|title=Hyperbilirubinemia and Jaundice|url=https://www.chop.edu/conditions-diseases/hyperbilirubinemia-and-jaundice|access-date=2022-02-17|website=www.chop.edu|language=en|archive-date=2022-02-17|archive-url=https://web.archive.org/web/20220217090215/https://www.chop.edu/conditions-diseases/hyperbilirubinemia-and-jaundice|url-status=live}}

Gilbert syndrome has been reported to contribute to an accelerated onset of neonatal 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,{{cite journal |pmid = 21403409|year = 2011|last1 = Saki|first1 = F.|last2 = Hemmati|first2 = F.|last3 = Haghighat|first3 = M.|title = Prevalence of Gilbert syndrome in parents of neonates with pathologic indirect hyperbilirubinemia|journal = Annals of Saudi Medicine|volume = 31|issue = 2|pages = 140–4|doi = 10.4103/0256-4947.77498|pmc = 3102472 | doi-access=free }} for example in the presence of increased red blood cell destruction due to diseases such as G6PD deficiency.{{cite journal |vauthors=Bancroft JD, Kreamer B, Gourley GR |title=Gilbert syndrome accelerates development of neonatal jaundice |journal=Journal of Pediatrics | volume=132 |issue=4 |pages=656–60 |year=1998 |pmid=9580766 |doi=10.1016/S0022-3476(98)70356-7}}{{cite journal |vauthors=Cappellini MD, Di Montemuros FM, Sampietro M, Tavazzi D, Fiorelli G |title=The interaction between Gilbert's syndrome and G6PD deficiency influences bilirubin levels |journal=British Journal of Haematology | volume=104 |issue=4 |pages=928–9 |year=1999 |pmid=10192462 |doi=10.1111/j.1365-2141.1999.1331a.x|s2cid=40300539 |doi-access=free }} This situation can be especially dangerous if not quickly treated, as the high serum bilirubin can cause irreversible neurological disability in the form of kernicterus.{{cite journal|url=https://www.dovepress.com/acute-bilirubin-encephalopathy-and-its-progression-to-kernicterus-curr-peer-reviewed-article-RRN|title=Acute bilirubin encephalopathy and its progression to kernicterus: current perspectives|year=2018|doi=10.2147/RRN.S125758|last1=Usman|first1=Fatima|last2=Diala|first2=Udochukwu|last3=Shapiro|first3=Steven|last4=Le Pichon|first4=Jean-Baptiste|last5=Slusher|first5=Tina|journal=Research and Reports in Neonatology|volume=8|pages=33–44|doi-access=free|access-date=2020-07-15|archive-date=2020-08-13|archive-url=https://web.archive.org/web/20200813152457/https://www.dovepress.com/acute-bilirubin-encephalopathy-and-its-progression-to-kernicterus-curr-peer-reviewed-article-RRN|url-status=live}}{{cite journal|url=https://fn.bmj.com/content/104/2/F202|title=Learning from claims: hyperbilirubinaemia and kernicterus|year=2019|doi=10.1136/archdischild-2017-314622|last1=Rennie|first1=Janet M.|last2=Beer|first2=Jeanette|last3=Upton|first3=Michele|journal=Archives of Disease in Childhood - Fetal and Neonatal Edition|volume=104|issue=2|pages=F202–F204|pmid=29802103|pmc=6580733|access-date=2020-07-15|archive-date=2020-07-15|archive-url=https://web.archive.org/web/20200715192936/https://fn.bmj.com/content/104/2/F202|url-status=live}}{{cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK559120/ |title=Kernicterus |year=2021 |publisher=StatPearls |pmid=32644546 |last1=Reddy |first1=D. K. |last2=Pandey |first2=S. |access-date=2020-07-15 |archive-date=2021-08-28 |archive-url=https://web.archive.org/web/20210828093238/https://www.ncbi.nlm.nih.gov/books/NBK559120/ |url-status=live }}

The enzymes that are defective in GS – UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) – are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1.{{cite journal |vauthors=Marcuello E, Altés A, Menoyo A, Del Rio E, Gómez-Pardo M, Baiget M | title=UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer | journal=Br J Cancer | volume=91 | issue=4 | pages=678–82 | year=2004 | pmid=15280927 | doi=10.1038/sj.bjc.6602042 | pmc=2364770}}

While paracetamol (acetaminophen) is not metabolized by UGT1A1,{{cite journal |vauthors=Rauchschwalbe S, Zuhlsdorf M, Wensing G, Kuhlmann J | title=Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype | journal=Int J Clin Pharmacol Ther | volume=42 | issue=2 | pages=73–7 | year=2004 | pmid=15180166 | doi=10.5414/cpp42073}} it is metabolized by one of the other enzymes also deficient in some people with GS.{{cite journal |vauthors=Kohle C, Mohrle B, Munzel PA, Schwab M, Wernet D, Badary OA, Bock KW | title=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 | journal=Biochem Pharmacol | volume=65 | issue=9 | pages=1521–7 | year=2003 | pmid=12732365 | doi=10.1016/S0006-2952(03)00074-1}}{{cite journal |vauthors=Esteban A, Pérez-Mateo M |s2cid=27543027 |title=Heterogeneity of paracetamol metabolism in Gilbert's syndrome |journal=European Journal of Drug Metabolism and Pharmacokinetics |volume=24 |issue=1 |pages=9–13 |year=1999 |pmid=10412886 |doi=10.1007/BF03190005}} A subset of people with GS may have an increased risk of paracetamol toxicity.

Another drug that has increased adverse side-effects in individuals with Gilbert Syndrome is atazanavir.Strassburg, C. P. (2008). Pharmacogenetics of gilbert's syndrome. Pharmacogenomics, 9(6), 703-15. doi:https://doi.org/10.2217/14622416.9.6.703 Atazanavir is a protease inhibitor for the treatment of HIV. 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.

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.{{cite journal |pmid=29390925|year=2018|last1=Wagner|first1=K. H.|last2=Shiels|first2=R. G.|last3=Lang|first3=C. A.|last4=Seyed Khoei|first4=N.|last5=Bulmer|first5=A. C.|title=Diagnostic criteria and contributors to Gilbert's syndrome|journal=Critical Reviews in Clinical Laboratory Sciences|volume=55|issue=2|pages=129–139|doi=10.1080/10408363.2018.1428526|s2cid=46870015|doi-access=free|hdl=10072/381018|hdl-access=free}} Observational studies emphasize that the antioxidant effects of unconjugated bilirubin may bring survival benefits to patients.{{cite journal|url=https://pubmed.ncbi.nlm.nih.gov/30709860|pmid=30709860|year=2019|last1=King|first1=D.|last2=Armstrong|first2=M. J.|title=Overview of Gilbert's syndrome|journal=Drug and Therapeutics Bulletin|volume=57|issue=2|pages=27–31|doi=10.1136/dtb.2018.000028|s2cid=73447592|access-date=2021-02-17|archive-date=2021-05-23|archive-url=https://web.archive.org/web/20210523221721/https://pubmed.ncbi.nlm.nih.gov/30709860/|url-status=live}}

Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS.{{cite journal |author1=Ladislav Novotnýc |author2=Libor Vítek |s2cid=43486067 |title=Inverse Relationship Between Serum Bilirubin and Atherosclerosis in Men: A Meta-Analysis of Published Studies |journal=Experimental Biology and Medicine |issue= 5|pages=568–571 |year=2003 |pmid=12709588 |volume=228 |doi=10.1177/15353702-0322805-29}}{{cite journal |author1=Schwertner Harvey A |author2=Vítek Libor |title=Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin |journal=Atherosclerosis |volume=198 |issue=1 |pages=1–11 |date=May 2008 |pmid=18343383 |doi=10.1016/j.atherosclerosis.2008.01.001 |url=https://zenodo.org/record/1258770 |type=Review |access-date=2018-09-01 |archive-date=2018-09-04 |archive-url=https://web.archive.org/web/20180904052440/https://zenodo.org/record/1258770 |url-status=live }}

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.{{cite journal |author=Vítek L |title=Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels |journal=Atherosclerosis |volume=160 |issue=2 |pages=449–56 |year=2002|pmid=11849670 |doi=10.1016/S0021-9150(01)00601-3 |author2= Jirsa M |author3= Brodanová M |display-authors=etal }} These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin. This beneficial effect was attributed to bilirubin IXα which is recognized as a potent antioxidant, rather than confounding factors such as high-density lipoprotein levels.

This association was also seen in long-term data from the Framingham Heart Study.{{cite journal | author=Lin JP | title=Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study | journal=Circulation | volume=114 | pages=1476–81 | year=2006 | pmid=17000907 | doi=10.1161/CIRCULATIONAHA.106.633206 | issue=14| author2= O'Donnell CJ | author3= Schwaiger JP | display-authors=etal | doi-access=free }}{{Cite journal|last1=Bulmer|first1=A. C.|last2=Verkade|first2=H. J.|last3=Wagner|first3=K.-H.|date=April 2013|title=Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection|journal=Progress in Lipid Research|volume=52|issue=2|pages=193–205|doi=10.1016/j.plipres.2012.11.001|issn=1873-2194|pmid=23201182|hdl=10072/54228|hdl-access=free}}{{primary source inline|date=September 2018}} 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 and MPV (mean platelet volume) are decreased in patients with Gilbert's syndrome. The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process.{{Cite journal|last1=Kundur|first1=Avinash R.|last2=Singh|first2=Indu|last3=Bulmer|first3=Andrew C.|date=March 2015|title=Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert's syndrome?|journal=Atherosclerosis|volume=239|issue=1|pages=73–84|doi=10.1016/j.atherosclerosis.2014.12.042|issn=1879-1484|pmid=25576848}}

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 of anxiety, loss of appetite, nausea, abdominal pain, loss of weight, itching (with no rash), and others,[http://www.gilbertssyndrome.com/ GilbertsSyndrome.com] {{webarchive|url=https://web.archive.org/web/20060810065536/http://www.gilbertssyndrome.com/ |date=2006-08-10 }} such as humor change or depression. 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.{{cite journal |vauthors=Olsson R, Bliding A, Jagenburg R, Lapidus L, Larsson B, Svärdsudd K, Wittboldt S | title=Gilbert's syndrome—does it exist? A study of the prevalence of symptoms in Gilbert syndrome | journal= Acta Medica Scandinavica | volume=224 | issue=5 | pages=485–490 | year=1988 | pmid=3264448 | doi=10.1111/j.0954-6820.1988.tb19615.x}}{{cite journal |vauthors=Bailey A, Robinson D, Dawson AM | s2cid=41989158 | title=Does Gilbert's disease exist? | journal=Lancet | volume=1 | pages=931–3 | year=1977 | pmid=67389 | doi=10.1016/S0140-6736(77)92226-7 | issue=8018}} Consequently, debate exists about whether GS should be classified as a disease.{{cite journal |author1=Larissa K. F. Temple |author2=Robin S. McLeod |author3=Steven Gallinger |author4=James G. Wright | title=Defining Disease in the Genomics Era | journal= Science Magazine | volume=293 | issue=5531 | pages=807–808 | year=2001 | doi=10.1126/science.1062938 | pmid=11486074|s2cid=6520035 | doi-access= }}

Gilbert syndrome has been linked to an increased risk of gallstones, schizophrenia, breast cancer, and colorectal cancer.{{cite journal |vauthors=del Giudice EM, Perrotta S, Nobili B, Specchia C, d'Urzo G, Iolascon A |date=October 1999 |title=Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis |url=http://bloodjournal.hematologylibrary.org/cgi/pmidlookup?view=long&pmid=10498597 |url-status=dead |journal=Blood |volume=94 |issue=7 |pages=2259–62 |doi=10.1182/blood.V94.7.2259.419k42_2259_2262 |pmid=10498597 |s2cid=40558696 |archive-url=https://archive.today/20130414231815/http://bloodjournal.hematologylibrary.org/cgi/pmidlookup?view=long&pmid=10498597 |archive-date=2013-04-14|url-access=subscription }} 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. The cause for the increased risk of schizophrenia is not yet fully understood and is the object of further research.

Mutations in the UGT1A1 gene lead to Gilbert Syndrome.{{cite web |title=Gilbert Syndrome |url=https://rarediseases.org/rare-diseases/gilbert-syndrome/ |access-date=2022-03-24 |website=NORD (National Organization for Rare Disorders) |language=en-US |archive-date=2017-02-20 |archive-url=https://web.archive.org/web/20170220165114/https://rarediseases.org/rare-diseases/gilbert-syndrome/ |url-status=live }} The gene provides instructions for making the bilirubin 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.{{cite web |title=Gilbert syndrome: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/gilbert-syndrome/ |access-date=2022-03-24 |website=medlineplus.gov |language=en |archive-date=2019-04-08 |archive-url=https://web.archive.org/web/20190408003455/https://ghr.nlm.nih.gov/condition/gilbert-syndrome |url-status=live }}

The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. Glucuronic acid is transferred to unconjugated bilirubin, which is a yellowish pigment made when your body breaks down old red blood cells,{{cite web |title=Gilbert's syndrome - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/gilberts-syndrome/symptoms-causes/syc-20372811 |access-date=2022-03-24 |website=Mayo Clinic |language=en |archive-date=2017-11-08 |archive-url=https://web.archive.org/web/20171108164024/https://www.mayoclinic.org/diseases-conditions/gilberts-syndrome/basics/definition/con-20024904 |url-status=live }} 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 of glucuronidation of unconjugated bilirubin. This substance then accumulates in the body, causing mild hyperbilirubinemia.

Gilbert syndrome is a phenotypic effect, mostly associated with increased blood bilirubin levels, but also sometimes characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.Beutler 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

Gilbert's syndrome is characterized by a 70–80% reduction in the glucuronidation activity of the enzyme (UGT1A1). The UGT1A1 gene is located on human chromosome 2.{{cite web|title=Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54658|url-status=live|archive-url=https://web.archive.org/web/20101205081110/http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene|archive-date=2010-12-05}}

More than 100 polymorphisms of the UGT1A1 gene are known, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. UGT1A1 is associated with a TATA box promoter region; this region most commonly contains the genetic sequence A(TA)₆TAA; this variant accounts for about 50% of alleles in many populations. However, several allelic polymorphic variants of this region occur, the most common of which results from adding another dinucleotide repeat TA to the promoter region, resulting in A(TA)₇TAA, which is called UGT1A1*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.{{cn|date=March 2025}}

In most populations, Gilbert syndrome is most commonly associated with homozygous A(TA)₇TAA alleles.{{cite journal|vauthors=Raijmakers MT, Jansen PL, Steegers EA, Peters WH |title=Association of human liver bilirubin UDP-glucuronyltransferase activity, most commonly due to a polymorphism in the promoter region of the UGT1A1 gene|journal=Journal of Hepatology|year=2000|volume=33|issue=3|pages=348–351|pmid=11019988|doi=10.1016/S0168-8278(00)80268-8}}{{cite journal | author=Bosma PJ | title=The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome |journal=New England Journal of Medicine| volume=333 | issue=18 | pages=1171–5 | year=1995 | pmid=7565971 |doi=10.1056/NEJM199511023331802| author2= Chowdhury JR | author3= Bakker C | author4= Gantla S | author5= de Boer A | author6= Oostra BA | author7= Lindhout D | author8= Tytgat GN | author9= Jansen PL | author10= Oude Elferink RP | display-authors=etal | doi-access=free }}{{cite journal |vauthors=Monaghan G, Ryan M, Seddon R, Hume R, Burchell B | s2cid=24943762 | title=Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome | journal=Lancet | volume=347 | issue=9001 | pages=578–81 | year=1996 | pmid=8596320 | doi=10.1016/S0140-6736(96)91273-8}} In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.{{cn|date=March 2025}}

However, Gilbert syndrome can arise without TATA box promoter polymorphic variants; in some populations, particularly healthy Southeast and East Asians, Gilbert's syndrome is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6, Tyr486Asp also known as UGT1A1*7, Pro364Leu also known as UGT1A1*73) in the actual gene coding region,{{EMedicine|article|176822|Gilbert Syndrome}} which may be associated with significantly higher bilirubin levels.

Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism.{{cn|date=March 2025}}

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:

1. Mild, Unconjugated Hyperbilirubinemia:
2. * Total serum bilirubin levels are mildly elevated, typically remaining below 6 mg/dL (102 μmol/L), with a predominance of the unconjugated (indirect) fraction.{{Cite web |title=Gilbert syndrome - Symptoms, diagnosis and treatment {{!}} BMJ Best Practice US |url=https://bestpractice.bmj.com/topics/en-gb/346 |access-date=2025-03-26 |website=bestpractice.bmj.com}}
3. Normal Liver Function Tests:
4. * Liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are within normal ranges, indicating no underlying liver disease.{{Cite journal |last=Vítek |first=Libor |last2=Tiribelli |first2=Claudio |date=2023-10-01 |title=Gilbert's syndrome revisited |url=https://www.journal-of-hepatology.eu/article/S0168-8278(23)00421-X/fulltext?utm |journal=Journal of Hepatology |language=English |volume=79 |issue=4 |pages=1049–1055 |doi=10.1016/j.jhep.2023.06.004 |issn=0168-8278 |pmid=37390966}}
5. Absence of Hemolysis:
6. * No evidence of increased red blood cell breakdown, as indicated by normal hemoglobin levels and reticulocyte counts.
7. Intermittent Nature of Symptoms:
8. * Episodes of jaundice that may be triggered by factors such as fasting, illness, stress, or exertion, with no other associated symptoms.{{Cite web |title=Gilbert syndrome-Gilbert syndrome - Symptoms & causes |url=https://www.mayoclinic.org/diseases-conditions/gilberts-syndrome/symptoms-causes/syc-20372811?utm |access-date=2025-03-26 |website=Mayo Clinic |language=en}} The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days,{{cite journal |author1=J L Gollan |author2=C Bateman |author3=B H Billing |year=1976 |title=Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome |journal=Gut |volume=17 |issue=5 |pages=335–340 |doi=10.1136/gut.17.5.335 |pmc=1411132 |pmid=1278716}} and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital:{{cite journal |author1=N Carulli |author2=M Ponz de Leon |author3=E Mauro |author4=F Manenti |author5=A Ferrari |year=1976 |title=Alteration of drug metabolism in Gilbert's syndrome |journal=Gut |volume=17 |issue=8 |pages=581–587 |doi=10.1136/gut.17.8.581 |pmc=1411334 |pmid=976795}} the bilirubin will decrease substantially.
9. Exclusion of Other Liver Disorders:
10. * No clinical or laboratory evidence of other liver diseases; imaging studies and serologic tests for hepatitis are negative.
11. Genetic Testing:
12. * 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.{{Citation |last=Grant |first=Lafaine M. |title=Gilbert Syndrome |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK470200/?utm |access-date=2025-03-26 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29262099 |last2=Faust |first2=Thomas W. |last3=Thoguluva Chandrasekar |first3=Viveksandeep |last4=John |first4=Savio}}

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 Gilbert syndrome, unless another disease of the liver is also present, the liver enzymes ALT/SGPT and AST/SGOT, as well as albumin, are within normal ranges.
• Crigler–Najjar syndrome (types I and II), a different glucuronyl transferase disorder, is much more severe, with 0–10% UGT1A1 activity,{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK549796/|author1=Singh, A.|author2=Koritala, J.|author3=Jialal, I.|chapter=Unconjugated Hyperbilirubinemia|date=20 May 2023|access-date=21 December 2023|title=StatPearls|publisher=StatPearls Publishing|location=Treasure Island, Florida|pmid=31747203|archive-date=18 November 2023|archive-url=https://web.archive.org/web/20231118165105/http://www.ncbi.nlm.nih.gov/books/NBK549796/|url-status=live}} with affected individuals at risk of brain damage in infancy (type I) and teenage years (type II).
• 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).{{Cite web |title=Hemolytic Anemia Workup: Approach Considerations, Complete Blood Cell Count, Peripheral Blood Smear |url=https://emedicine.medscape.com/article/201066-workup?form=fpf |access-date=2025-03-26 |website=emedicine.medscape.com |language=en}}
• Dubin–Johnson syndrome and Rotor syndrome are rarer autosomal recessive disorders characterized by an increase of conjugated bilirubin.
• Viral hepatitis associated with increase of conjugated bilirubin can be excluded by negative blood samples for antigens specific to the different hepatitis viruses.
• Cholestasis can be excluded by normal levels of bile acids in plasma, the absence of lactate dehydrogenase, low levels of conjugated bilirubin, and ultrasound scan of the bile ducts.{{Citation |last=Shah |first=Rushikesh |title=Cholestatic Jaundice |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK482279/ |access-date=2025-03-26 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29489239 |last2=Grant |first2=Lafaine M. |last3=John |first3=Savio}}
• Vitamin B12 deficiency - elevated bilirubin levels (and MCV counts above 90–92) can be associated with a vitamin B12 deficiency.{{Cite journal |last=Erdol |first=Sahin |last2=Ozgur |first2=Taner |date=2018 |title=Vitamin B12 deficiency associated with hyperbilirubinemia and cholestasis in infants |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC6041549/ |journal=Pakistan Journal of Medical Sciences |volume=34 |issue=3 |pages=714–718 |doi=10.12669/pjms.343.14564 |issn=1682-024X |pmc=6041549 |pmid=30034445}}

Gilbert's syndrome is a benign condition that typically requires no medical treatment.{{Cite web |title=Gilbert's Syndrome: Symptoms, Causes, Tests & Treatment |url=https://my.clevelandclinic.org/health/diseases/17661-gilberts-syndrome |archive-url=http://web.archive.org/web/20250314051710/https://my.clevelandclinic.org/health/diseases/17661-gilberts-syndrome |archive-date=2025-03-14 |access-date=2025-03-26 |website=Cleveland Clinic |language=en}} The primary approach involves patient education and reassurance about the harmless nature of the syndrome. Episodes of jaundice, when they occur, are usually mild and resolve on their own without intervention. To minimize the frequency of these episodes, individuals are advised to avoid known triggers such as fasting, dehydration, stress, and strenuous physical exertion. Maintaining a healthy lifestyle, including regular meals and adequate hydration, can help manage the condition effectively. If jaundice is significant phenobarbital may be used.

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.{{cite journal |vauthors=Kamal S, Abdelhakam S, Ghoraba D, Massoud Y, Aziz KA, Hassan H, Hafez T, Abdel Sallam A |title=The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study |journal=BMC Gastroenterol |volume=19 |issue=1 |pages=22 |date=February 2019 |pmid=30717703 |pmc=6360704 |doi=10.1186/s12876-019-0931-2 |url= |doi-access=free }}

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. Despite the fact that hyperbilirubinemia in GS is associated with reduced incidence of cardiovascular diseases,{{cite journal |vauthors=Gorbunova O, Chernysheva E |title=A New Look at Gilbert Syndrome (Literature Review) |language=Russian |journal=Georgian Med News |volume= |issue=296 |pages=75–81 |date=November 2019 |pmid=31889709 |doi= |url=}} diabetes, and metabolic syndrome,{{cite journal |vauthors=Adin CA |title=Bilirubin as a Therapeutic Molecule: Challenges and Opportunities |journal=Antioxidants |volume=10 |issue=10 |date=September 2021 |page=1536 |pmid=34679671 |pmc=8532879 |doi=10.3390/antiox10101536 |url= |doi-access=free }} the clinical significance and implications of these GS research findings are unclear, and can not yet be translated into preventive or therapeutic strategies.{{cite journal |vauthors=Vítek L, Tiribelli C |title=Gilbert's syndrome revisited |journal=J Hepatol |volume=79 |issue=4 |pages=1049–1055 |date=October 2023 |pmid=37390966 |doi=10.1016/j.jhep.2023.06.004 |s2cid=259303433 |url=|doi-access=free }}

Gilbert syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.{{cite journal |vauthors=Gilbert A, Lereboullet P |title=La cholémie simple familiale |journal=La Semaine Médicale|volume=21 |pages=241–3 |year=1901 }} In German literature, it is commonly associated with Jens Einar Meulengracht.{{WhoNamedIt|doctor|2449|Jens Einar Meulengracht}}

Alternative, less common names for this disorder include:

• Familial benign unconjugated hyperbilirubinaemia
• Constitutional liver dysfunction
• Familial non-hemolytic non-obstructive jaundice
• Icterus intermittens juvenilis
• Low-grade chronic hyperbilirubinemia
• Unconjugated benign bilirubinemia

• Napoleon{{cite journal |author1=Foulk, WT |author2=Butt, HR |author3=Owen, CA Jr |author4=Whitcomb, FF Jr |author5=Mason, HL | title=Constitutional hepatic dysfunction (Gilbert's disease): its natural history and related syndromes | journal=Medicine (Baltimore) | volume=38 | year=1959 | pmid=13632313 | pages=25–46 | issue=1|doi=10.1097/00005792-195902000-00002 |s2cid=8265932 |doi-access=free }}
• Arthur Kornberg, Nobel laureate in Physiology or Medicine, 1959{{cite book|last=Shmaefsky|first=Brian|title=Biotechnology 101|publisher=Greenwood Publishing Group|year=2006|pages=[https://archive.org/details/biotechnology1010000shma/page/175 175]|chapter=5|isbn=978-0-313-33528-0|chapter-url=https://books.google.com/books?id=E4KhutqTYNAC&q=%22Arthur%20Kornberg%22%20gilbert&pg=PA175|url=https://archive.org/details/biotechnology1010000shma/page/175}}
• Nicky Wire, Manic Street Preachers bassist{{cite news|title=Wire preaches delights of three cliffs|date=2007-04-27|work=South Wales Evening Post|page=3}}
• Alexandr Dolgopolov (tennis player){{cite news |author=David Cox. |title=A Tennis Player Learns to Be Aggressive for Health's Sake |newspaper=New York Times |date=19 April 2014 |url=https://www.nytimes.com/2014/04/20/sports/tennis/tennis-roundup.html |location=Monte Carlo |url-status=live |archive-url=https://web.archive.org/web/20161014010306/http://www.nytimes.com/2014/04/20/sports/tennis/tennis-roundup.html |archive-date=14 October 2016 }}
• Jonas Folger, MotoGP rider.{{cite web |url=https://www.autosport.com/motogp/news/132907/illness-that-hut-down-folger-diagnosed |title=Illness that 'shut down' Tech3 MotoGP rookie Jonas Folger diagnosed |last=Khorounzhiy |first=Valentin |date=2017-11-09 |website=Autosport.com |publisher=Motorsport Network |access-date=2017-11-09 |quote=After visiting specialists in his native Germany, Folger has been diagnosed with Gilbert's syndrome – a genetic ailment that precludes the liver from correctly processing bilirubin. |archive-date=2017-11-10 |archive-url=https://web.archive.org/web/20171110114518/https://www.autosport.com/motogp/news/132907/illness-that-hut-down-folger-diagnosed |url-status=live }}

{{reflist|colwidth=30em}}

• [https://gilbertssyndrome.org.uk Understanding Gilbert's Syndrome and living better with Gilbert's Syndrome symptoms]
• {{RareDiseases|6507|Gilbert's syndrome }}
• [http://bestpractice.bmj.com/best-practice/monograph/346.html Gilbert's Syndrome] {{Webarchive|url=https://web.archive.org/web/20160518044745/http://bestpractice.bmj.com/best-practice/monograph/346.html |date=2016-05-18 }} BMJ Best Practices monograph

{{Heme metabolism disorders}}

{{Medical resources

| DiseasesDB = 5218

| ICD10 = {{ICD10|E|80|4|e|70}}

| ICD9 = {{ICD9|277.4}}

| ICDO =

| OMIM = 143500

| MedlinePlus = 000301

| eMedicineSubj = med

| eMedicineTopic = 870

| MeshID = D005878

| SNOMED CT = 27503000

}}

{{Authority control}}

{{DEFAULTSORT:Gilbert's Syndrome}}

Category:Accessory digestive gland disorders

Category:Hepatology

Category:Heme metabolism disorders

Category:Genetic syndromes

Category:Pediatrics

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