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| | __NOTOC__ |
| '''For patient information click [[Gilbert's syndrome (patient information)|here]]''' | | '''For patient information click [[Gilbert's syndrome (patient information)|here]]''' |
| {{Infobox_Disease | | | {{Infobox_Disease | |
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| Image = Bilirubin.png | | | Image = Bilirubin.png | |
| Caption = [[Bilirubin]] | | | Caption = [[Bilirubin]] | |
| DiseasesDB = 5218 |
| | }} |
| ICD10 = {{ICD10|E|80|4|e|70}} |
| | {{Gilbert's syndrome}} |
| ICD9 = {{ICD9|277.4}} |
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| ICDO = |
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| OMIM = 143500|
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| MedlinePlus = |
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| eMedicineSubj = |
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| eMedicineTopic = |
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| MeshID = D005878 |
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| }} | |
| {{SI}} | |
| {{CMG}} | | {{CMG}} |
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| ==Overview==
| | {{SK}} Familial benign unconjugated hyperbilirubinaemia; Constitutional liver dysfunction; Familial non-hemolytic non-obstructive jaundice; Icterus intermittens juvenilis; Low-grade chronic hyperbilirubinemia; Unconjugated benign bilirubinemia; Morbus Meulengracht |
| '''Gilbert's syndrome''' (pr. Zhil-bear), often shortened to the acronym '''GS''', is the most common [[hereditary]] cause of increased [[bilirubin]], and is found in up to 5% of the population. The main symptom is otherwise harmless [[jaundice]] which does not require treatment, caused by elevated levels of unconjugated bilirubin in the bloodstream ([[hyperbilirubinemia]]).
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| The source of this hyperbilirubinemia is reduced activity of the [[enzyme]] [[glucuronyltransferase]] which [[Conjugated system|conjugates]] bilirubin and some other lipophilic molecules. Conjugation renders the bilirubin water-soluble and suitable for excretion via the [[kidneys]].
| | ==[[Gilbert's syndrome overview|Overview]]== |
| | ==[[Gilbert's syndrome historical perspective|Historical Perspective]]== |
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| ==Eponym== | | ==[[Gilbert's syndrome pathophysiology|Pathophysiology]]== |
| Gilbert's syndrome was first described by French [[gastroenterologist]] [[Augustin Nicolas Gilbert]] and co-workers in 1901.<ref>{{WhoNamedIt|synd|2877|Gilbert's syndrome}}</ref><ref>Gilbert A, Lereboullet P. La cholemie simple familiale. ''Sem Med'' 1901;21:241-3.</ref> | |
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| In German literature, it is commonly associated with Jens Einar Meulengracht.<ref>{{WhoNamedIt|doctor|2449}}</ref>
| | ==[[Gilbert's syndrome causes|Causes]]== |
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| ==Pathogenesis== | | ==[[Gilbert's syndrome differential diagnosis|Differentiating Gilbert's Syndrome from other Diseases]]== |
| | ==[[Gilbert's syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
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| Gilbert's syndrome is caused by approximately 30%-50% reduced [[glucuronidation]] activity of the enzyme [[glucuronosyltransferase|Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UGT1A1)]].<ref>{{cite journal|author=Raijmakers MT, Jansen PL, Steegers EA, Peters WH|title=Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene|journal=Journal of Hepatology|year=2000|volume=33|issue=3|pages=348-351|id=PMID 11019988}}</ref><ref>{{cite journal | author=Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Oude Elferink RP, et al. | 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 | id=PMID 7565971}}</ref> The gene which encodes UGT1A1 normally has a [[promoter region]] [[TATA box]] containing the [[allele]] A(TA<sub>6</sub>)TAA. Gilbert's syndrome is associated with [[homozygous]] A(TA<sub>7</sub>)TAA alleles.<ref>{{cite journal | author=Monaghan G, Ryan M, Seddon R, Hume R, Burchell B | title=Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. | journal=Lancet | volume=347 | issue=9001 | pages=578-81 | year=1996 | id=PMID 8596320}}</ref> The allele polymorphism is referred to as UGT1A1*28.
| | ==[[Gilbert's syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Signs and symptoms==
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| ===Jaundice===
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| Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the [[blood]]stream but normally this has no serious consequence. Mild [[jaundice]] may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.
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| <ref>Kasper et al, ''Harrison's Principles of Internal Medicine'', 16th edition, McGraw-Hill 2005</ref><ref>Boon et al, ''Davidson's Principles & Practice of Medicine'', 20th edition, Churchill Livingstone 2006</ref>
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| It has been reported that GS may contribute to an accelerated onset of neonatal jaundice<ref>{{cite journal |author=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}}</ref>.
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| Some patients report experiencing unpleasant physical symptoms during episodes of high bilirubin levels. They may report meal-related [[Fatigue (physical)|fatigue]], tremors, nausea, and abdominal pain, with jaundice.<ref >{{cite web|url=http://www.gilbertssyndrome.org.uk/What%20is%20Gilbert's%20Syndrome.html|title=What is Gilbert's Syndrome?|publisher=Action on Gilbert's Syndrome}}</ref> Because patients may be unaware of their condition but conscious of apparent jaundice, they may present these symptoms at urgent-care facilities needlessly.
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| ===Detoxification of certain drugs===
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| The enzymes that are defective in GS (UGT1A1) are also responsible for some of the [[liver]]'s ability to [[detoxification|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.<ref>{{cite journal | author=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}}</ref>
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| While [[paracetamol]] (acetaminophen) is not metabolized by UGT1A1,<ref>{{cite journal | author=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}}</ref> it is metabolized by one of the other enzymes also deficient in some people with GS.<ref>{{cite journal | author=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}}</ref><ref name=esteban>{{cite journal |author=Esteban A, Pérez-Mateo M |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=}}</ref> A subset of people with GS may have an increased risk of paracetamol toxicity.<ref name=esteban/><ref>Mukherjee S. Gilbert Syndrome. eMedicine.com. URL: [http://www.emedicine.com/med/topic870.htm http://www.emedicine.com/med/topic870.htm]. Accessed: October 7, 2007.</ref>
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| ===Debated signs and symptoms===
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| ====Reduced risk of ischemic heart disease====
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| One research group in the Czech Republic has found a reduced incidence of [[Atherosclerosis|atherosclerotic disease]] in subjects with GS<ref>{{cite journal |author=Ladislav Novotnýc and Libor Vítek |title=Inverse Relationship Between Serum Bilirubin and Atherosclerosis in Men: A Meta-Analysis of Published Studies |journal=Experimental Biology and Medicine |issue=228 |pages=568–571 |year=2003 |pmid=12709588}}</ref>. This is supposed to be due to bilirubin IXα being recognised as a potent antioxidant <ref>{{cite journal |author=Vítek L, Jirsa M, Brodanová M, ''et al'' |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 |url=http://linkinghub.elsevier.com/retrieve/pii/S0021915001006013}}</ref>.
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| ====Diffuse symptoms====
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| Many people report diffuse symptoms related to GS - feeling tired all the time (fatigue), difficulty maintaining concentration, loss of appetite, abdominal pain, loss of weight and others - <ref>[http://www.gilbertssyndrome.com/ GilbertsSyndrome.com]</ref>, but no clear adverse symptoms related to elevated levels of unconjugated bilirubin have been found in adults during scientific studies.<ref>{{cite journal | author=Gitlin N. | title=The clinical presentation of Gilbert's disease in 26 patients | journal= South Africa Medical Journal | volume=52 | issue=1 | pages=19–20 | year=1977 | pmid=888039}}</ref><ref name=dispute>{{cite journal | author=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's syndrome | journal= Acta Med Scandinavia | volume=224 | issue=5 | pages=485–490 | year=1988 | pmid=3264448}}</ref>. This has led some to dispute whether GS should classify as a disease.<ref name=dispute/><ref>{{cite journal | author=Larissa K. F. Temple, Robin S. McLeod, Steven Gallinger, 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}}</ref>
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| ==Diagnosis== | | ==Diagnosis== |
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| ===Exclusion of other conditions===
| | [[Gilbert's syndrome history and symptoms|History and Symptoms]] | [[Gilbert's syndrome physical examination|Physical Examination]] | [[Gilbert's syndrome laboratory findings|Laboratory Findings]] | [[Gilbert's syndrome echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Gilbert's syndrome other imaging findings|Other Imaging Findings]] | [[Gilbert's syndrome other diagnostic studies|Other Diagnostic Studies]] |
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| While this syndrome is considered harmless, it is clinically important because it may be confused with much more dangerous liver conditions. However, these will show other indicators of liver dysfunction:
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| *[[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).
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| *[[Hepatitis]] can be excluded by negative blood samples for antigens specific to the different hepatitis vira.
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| *[[Cholestasis]] can be excluded by the absence of [[lactate dehydrogenase]], low levels of conjugated bilirubin and [[ultrasound]] scan of the bile ducts.
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| *More severe types of glucoronyl 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).
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| *Other diseases of the liver can be exluded by the liver-enzymes [[ALT]], [[AST]] and [[albumin]] being within normal ranges.
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| Normal levels of total bilirubin (conjugated and unconjugated) are under 20 mmol/dL. Patients with GS show predominantly elevated unconjugated bilirubin, while conjugated is usually in normal ranges and form less than 20% of the total. Levels of bilirubin in GS patients should be between 20 mmol/dl and 80 mmol/dl (or, divided by 17.1 to express these numbers in mg/dL, between 1.17 and 4.68 mg/dL). GS patients will have a ratio of unconjugated/conjugated (indirect/direct) bilirubin that is commensurately higher than those without GS. Other liver enzymes are expected to be similar between patients with and without GS. Complete liver enzyme tests are ordered in order to assure the correct diagnosis.
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| The level of total bilirubin is often increased if the blood sample is taken while [[fasting]].
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| More severe types of glucoronyl transferase disorders like GS are [[Crigler-Najjar syndrome]] (types I and II). These are much more severe and cause brain damage in infancy (type I) and teenage years (type II).
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| ===Findings specific to Gilbert's syndrome=== | | ==Treatment== |
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| Patients with GS show predominantly elevated unconjugated bilirubin, while conjugated is usually within normal ranges and form less than 20% of the total. Levels of bilirubin in GS patients is reported to be from 20 μmol/dl to 90 μmol/dl (1.2 to 5.3 mg/dL)<ref>{{cite journal |author=Piter J. Bosma, Ph.D., Jayanta Roy Chowdhury, M.D., Conny Bakker, Shailaja Gantla, Ph.D., Anita de Boer, Ben A. Oostra, Ph.D., Dick Lindhout, Ph.D., Guido N.J. Tytgat, M.D., Peter L.M. Jansen, M.D., Ph.D., Ronald P.J. Oude Elferink, Ph.D., and Namita Roy Chowdhury, Ph.D. |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 |pages=1171–1175 |year=1995 | pmid=7565971 |doi=10.1056/NEJM199511023331802}}</ref> compared to the normal amount of < 20 μmol/dL. GS patients will have a ratio of unconjugated/conjugated (indirect/direct) bilirubin that is commensurately higher than those without GS.
| | [[Gilbert's syndrome medical therapy|Medical Therapy]] | [[Gilbert's syndrome prevention|Prevention]] | [[Gilbert's syndrome cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Gilbert's syndrome future or investigational therapies|Future or Investigational Therapies]] |
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| The level of total bilirubin is often increased if the blood sample is taken after [[fasting]] for two days<ref>{{cite journal |author=J L Gollan, C Bateman, B H Billing |title=Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome |journal=Gut |issue=17 |pages=335–340 |year=1976 |doi=10.1136/gut.17.5.335 |volume=17 |pmid=1278716}}</ref>, and a fast can therefore be useful diagnostically. If the total bilirubin does in fact increase while fasting, the patient can then be given low doses of phenobarbital<ref>{{cite journal |author=N Carulli, M Ponz de Leon, E Mauro, F Manenti, A Ferrari |title=Alteration of drug metabolism in Gilbert's syndrome |journal=Gut |issue=17 |pages=581–587 |year=1976 |doi=10.1136/gut.17.8.581 |volume=17 |pmid=976795}}</ref> when fasting has ended, and following samples should show a decrease in total bilirubin toward normal levels.
| | ==Case Studies== |
| | [[Gilbert's syndrome case study one|Case #1]] |
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| ==Synonyms== | | ==Related Chapters== |
| Alternative, less common names for this disorder are as follows:
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| * Familial benign unconjugated hyperbilirubinaemia
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| * Constitutional liver dysfunction
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| * Familial non-hemolytic non-obstructive jaundice
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| * Icterus intermittens juvenilis
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| * Low-grade chronic hyperbilirubinemia
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| * Unconjugated benign bilirubinemia
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| * Morbus Meulengracht
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| ==See also==
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| *[[Crigler-Najjar syndrome]] | | *[[Crigler-Najjar syndrome]] |
| *[[Dubin-Johnson syndrome]] | | *[[Dubin-Johnson syndrome]] |
| *[[Rotor syndrome]] | | *[[Rotor syndrome]] |
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| ==References==
| | {{Endocrine, nutritional and metabolic pathology}} |
| {{Reflist|2}} | |
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| {{Endocrine, nutritional and metabolic pathology}}
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| [[de:Morbus Meulengracht]] | | [[de:Morbus Meulengracht]] |
| [[es:Síndrome de Gilbert]] | | [[es:Síndrome de Gilbert]] |
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| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Syndromes]] | | [[Category:Syndromes]] |
| [[Category:Mature chapter]]
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| [[Category:Disease]] | | [[Category:Disease]] |
| [[Category:Metabolic disorders]] | | [[Category:Metabolic disorders]] |
