|Classification and external resources|
|Patient UK||Gilbert's syndrome|
Gilbert's syndrome (// zheel-BAIR), often shortened to GS, also called Gilbert–Meulengracht syndrome, is a genetic liver disorder and the most common hereditary cause of increased bilirubin and is found in up to 5% of the population (though some gastroenterologists maintain that it is closer to 10% in Caucasian people). A major characteristic is jaundice, caused by elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia).
The cause of this hyperbilirubinemia is the reduced activity of the enzyme glucuronyltransferase, which conjugates bilirubin and a few other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum.
Signs and symptoms
Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally has no serious consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic. Severe cases are seen by yellowing of the skin tone and yellowing of the sclera in the eye.
It has been reported that GS may contribute to an accelerated onset of neonatal jaundice, especially in the presence of increased hemolysis due to diseases like G6PD deficiency. This situation can be especially dangerous if not quickly treated as the high bilirubin causes irreversible neurological disability in the form of kernicterus.
Detoxification of certain drugs
The enzymes that are defective in GS (UGT1A1) are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert's syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1.
While paracetamol (acetaminophen or brand names Panadol, Tylenol) is not metabolized by UGT1A1, it is metabolized by one of the other enzymes also deficient in some people with GS. A subset of people with GS may have an increased risk of paracetamol toxicity.
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. These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed that 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 recognised as a potent antioxidant, rather than confounding factors such as high-density lipoprotein (HDL) levels.
This association was also seen in long-term data from the Framingham Heart Study. Moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype was associated with 1/3 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, non-mutated gene locus).
Signs and symptoms
Symptoms, whether connected or not to GS, have been reported in a subset of those affected: feeling tired all the time (fatigue), difficulty maintaining concentration, loss of appetite, abdominal pain, loss of weight, itching (with no rash), and others, but scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults. However, it is entirely possible that other substances glucuronidized by the affected enzymes in Gilbert's syndrome sufferers could theoretically, at their toxic levels, cause these symptoms.  (see below). There is consequently debate about whether GS should be classified as a disease. Gilbert's syndrome has, however, been linked to an increased risk of gallstones.
Gilbert's syndrome is a phenotypic effect, 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.
Gilbert's syndrome is characterized by a 70–80% reduction in the glucuronidation activity of the enzyme, uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDP-glucuronosyltransferase 1A1, or UGT1A1). The UGT1A1 gene is located on human chromosome 2.
There are more than 100 variants of the UGT1A1 gene, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. The UGT1A1 gene is associated with a TATA box promoter region ; this region most commonly contains the genetic sequence A(TA6)TAA; this variant accounts for about 50% of alleles in many populations. There are, however, several allelic polymorphic variants of this region, the most common of which results from adding another dinucleotide repeat TA to the promoter region, resulting in A(TA7)TAA, which is called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, approximately 3% of alleles, in southeast and east Asian people and Pacific Islanders.
In most populations, Gilbert's syndrome is most commonly associated with homozygous A(TA7)TAA alleles. In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.
However, Gilbert's syndrome can arise without TATA box promoter polymorphic mutations; 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, 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.
People with GS predominantly have elevated unconjugated bilirubin, while conjugated bilirubin is usually within the normal range and is less than 20% of the total. Levels of bilirubin in GS patients are reported to be from 20 μM to 90 μM (1.2 to 5.3 mg/dL) compared to the normal amount of < 20 μM. GS patients will have a ratio of unconjugated/conjugated (indirect/direct) bilirubin that is commensurately higher than those without GS.
The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days, 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: the bilirubin will decrease substantially.
There are also tests that detect DNA mutations of UGT1A1 by polymerase chain reaction or DNA fragment sequencing.
While Gilbert's 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:
- Hemolysis 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).
- Viral hepatitis can be excluded by negative blood samples for antigens specific to the different hepatitis viruses.
- Cholestasis can be excluded by the absence of lactate dehydrogenase, low levels of conjugated bilirubin and ultrasound scan of the bile ducts.
- More severe types of glucuronyl transferase disorders like Crigler–Najjar syndrome (types I and II). These are much more severe, with 0–10% UGT1A1 activity, with sufferers at risk of brain damage in infancy (type I) and teenage years (type II).
- Dubin–Johnson syndrome and Rotor syndrome, which are rarer autosomal recessive disorders that are characterized by an increase of conjugated bilirubin.
- In GS, 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.
Gilbert's syndrome usually does not need any treatment.
Gilbert's syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901. In German literature, it is commonly associated with 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 I of France
- Arthur Kornberg, Nobel laureate in Physiology or Medicine, 1959
- Nicky Wire, Manic Street Preachers bassist.
- Henry Wilfred "Bunny" Austin (tennis player) 
- Dugdale, David C. (2013-05-13). "Gilbert's disease". MedlinePlus. U.S. National Library of Medicine. Retrieved 10 February 2014.
- "Gilbert's syndrome". Gilbert's (zheel-BAYRZ) syndrome typically is harmless and doesn't require treatment.
- Kasper et al., Harrison's Principles of Internal Medicine, 16th edition, McGraw-Hill 2005
- Boon et al., Davidson's Principles & Practice of Medicine, 20th edition, Churchill Livingstone 2006
- 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. PMID 9580766.
- Cappellini MD, Di Montemuros FM, Sampietro M, Tavazzi D, Fiorelli G (1999). "The interaction between Gilbert's syndrome and G6PD deficiency influences bilirubin levels". British journal of haematology 104 (4): 928–9. doi:10.1111/j.1365-2141.1999.1331a.x. PMID 10192462.
- Marcuello E, Altés A, Menoyo A, Del Rio E, Gómez-Pardo M, Baiget M (2004). "UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer". Br J Cancer 91 (4): 678–82. doi:10.1038/sj.bjc.6602042. PMC 2364770. PMID 15280927.
- 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. PMID 15180166.
- 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. PMID 12732365.
- Esteban 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. PMID 10412886.
- Gilbert Syndrome at eMedicine
- Ladislav Novotnýc and 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. PMID 12709588.
- Schwertner Harvey A; Vítek Libor (2008). "Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin". Atherosclerosis 198 (1): 1–11. doi:10.1016/j.atherosclerosis.2008.01.001. PMID 18343383.
- Vítek 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. PMID 11849670.
- Lin JP, O’Donnell CJ, Schwaiger JP et al. (2006). "Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study". Circulation 114 (14): 1476–81. doi:10.1161/CIRCULATIONAHA.106.633206. PMID 17000907.
- Olsson 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's syndrome". Acta Med Scandinavia 224 (5): 485–490. doi:10.1111/j.0954-6820.1988.tb19615.x. PMID 3264448.
- Bailey A, Robinson D, Dawson AM. (1977). "Does Gilbert's disease exist?". Lancet 1 (8018): 931–3. doi:10.1016/S0140-6736(77)92226-7. PMID 67389.
- 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. PMID 11486074.
- del Giudice EM, Perrotta S, Nobili B, Specchia C, d'Urzo G, Iolascon A (October 1999). "Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis". Blood 94 (7): 2259–62. PMID 10498597.
- "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1".
- 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. PMID 11019988.
- Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP et al. (1995). "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome". New England Journal of Medicine 333 (18): 1171–5. doi:10.1056/NEJM199511023331802. PMID 7565971.
- 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. PMID 8596320.
- J L Gollan, C Bateman, B H Billing (1976). "Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome". Gut 17 (5): 335–340. doi:10.1136/gut.17.5.335. PMC 1411132. PMID 1278716.
- N Carulli, M Ponz de Leon, E Mauro, F Manenti, A Ferrari (1976). "Alteration of drug metabolism in Gilbert's syndrome". Gut 17 (8): 581–587. doi:10.1136/gut.17.8.581. PMC 1411334. PMID 976795.
- Gilbert's syndrome at Who Named It?
- Gilbert A, Lereboullet P (1901). "La cholemie simple familiale". Sem Med 21: 241–3.
- Jens Einar Meulengracht at Who Named It?
- Foulk, WT; Butt, HR; Owen, CA, Jr; Whitcomb, FF, Jr; Mason, HL (1959). "Constitutional hepatic dysfunction (Gilbert's disease): its natural history and related syndromes". Medicine (Baltimore) 38 (1): 25–46. PMID 13632313.
- Shmaefsky, Brian (2006). "5". Biotechnology 101. Greenwood Publishing Group. p. 175. ISBN 978-0-313-33528-0.
- "Wire preaches delights of three cliffs". South Wales Evening Post. 2007-04-27. p. 3.
- Thornton, M. (3 July 2009). "How our last Final hero, Henry 'Bunny' Austin, became an outcast for 40 years". Daily Mail (London).
- GilbertsSyndrome.com — collection of information on Gilbert's Syndrome, including symptom survey
- Gilbert's Syndrome Fact Sheet at AllRefer Health
- Children's Liver Disease Foundation
- Gilbert's syndrome at NIH's Office of Rare Diseases
- Gilbert's Syndrome BMJ Best Practices monograph
- Gilbert's Syndrome Support Forum — support for sufferers of Gilbert's Syndrome