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Gilbert's syndrome

Gilbert's syndrome
Classification and external resources
ICD-10 E80.4
ICD-9-CM 277.4
OMIM 143500
DiseasesDB 5218
MedlinePlus 000301
eMedicine med/870
MeSH D005878

Gilbert's syndrome ( ),[1] often shortened to GS, also called Gilbert–Meulengracht syndrome, is a common genetic liver disorder found in 3-12% of the population.[1][2][3][4][5][1]

It produces elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia), but this normally has no serious consequences, although mild jaundice may appear under conditions of exertion or stress.

The cause of this hyperbilirubinemia is the reduced activity of the enzyme glucuronyltransferase,[6][7] 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. There are a number of variants of the gene for the enzyme, so the genetic basis of the condition is complex.

Contents

  • Signs and symptoms 1
    • Jaundice 1.1
    • Detoxification of certain drugs 1.2
    • Cardiovascular effects 1.3
    • Signs and symptoms 1.4
  • Genetics 2
  • Diagnosis 3
    • Differential diagnosis 3.1
  • Treatment 4
  • History 5
  • Notable cases 6
  • References 7
  • External links 8

Signs and symptoms

Jaundice

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.[8][9] Severe cases are seen by yellowing of the skin tone and yellowing of the sclera in the eye.

GS has been reported to possibly contribute to an accelerated onset of neonatal jaundice, especially in the presence of increased red blood cell destruction due to diseases such as G6PD deficiency.[10][11] 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 - UDP glucuronosyltransferase 1 family, polypeptide A1 (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.[12]

While paracetamol (acetaminophen) is not metabolized by UGT1A1,[13] it is metabolized by one of the other enzymes also deficient in some people with GS.[14][15] A subset of people with GS may have an increased risk of paracetamol toxicity.[15][16]

Cardiovascular effects

Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS.[17][18]

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.[19] 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.[17] This beneficial effect was attributed to bilirubin IXα which is recognised as a potent antioxidant, rather than confounding factors such as high-density lipoprotein levels.[19]

This association was also seen in long-term data from the Framingham Heart Study.[20] 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 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. [21]

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, unusual patterns of anxiety, loss of appetite, nausea, abdominal pain, loss of weight, itching (with no rash), and others,[22] 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 Gilbert's syndrome sufferers could theoretically, at their toxic levels, cause these symptoms.[23][24] (see below). Consequently, debate exists about whether GS should be classified as a disease.[23][25] However, Gilbert's syndrome has been linked to an increased risk of gallstones.[22][26]

Genetics

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, (UGT1A1). The UGT1A1 gene is located on human chromosome 2.[27]

More than 100 variants 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(TA6)TAA; 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(TA7)TAA, 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.

In most populations, Gilbert's syndrome is most commonly associated with homozygous A(TA7)TAA alleles.[28][29][30] 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,[16] which may be associated with significantly higher bilirubin levels.[16]

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.

Diagnosis

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)[29] compared to the normal amount of < 20 μM. GS patients have a ratio of unconjugated/conjugated (indirect/direct) bilirubin 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,[31] 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:[32] the bilirubin will decrease substantially.

Tests can also detect DNA mutations of UGT1A1 by polymerase chain reaction or DNA fragment sequencing.

Differential diagnosis

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 such as Crigler–Najjar syndrome (types I and II) 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 are rarer autosomal recessive disorders 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.

Treatment

Where jaundice is an issue, enzyme inductors such as Carbamazepine and Phenobarbital can reduce unconjugated bilirubin levels and may relieve other associated symptoms of Gilbert's Syndrome. Furthermore, it can be minimized by slightly modifying the person's diet. Recently a case was published in which Gilbert's was successfully treated with the paleolithic ketogenic diet [33]

History

Gilbert's syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.[34][35] In German literature, it is commonly associated with Jens Einar Meulengracht.[36]

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

Notable cases

References

  1. ^ a b c http://www.mayoclinic.org/diseases-conditions/gilberts-syndrome/basics/definition/con-20024904
  2. ^ Dugdale, David C. (2013-05-13). "Gilbert's disease". MedlinePlus. U.S. National Library of Medicine. Retrieved 10 February 2014. 
  3. ^ http://www.liverfoundation.org/abouttheliver/info/gilbertsyndrome/
  4. ^ http://www.nhs.uk/conditions/gilbertssyndrome/Pages/Introduction.aspx
  5. ^ http://ghr.nlm.nih.gov/condition/gilbert-syndrome
  6. ^ Bosma, PJ; Chowdhury, JR; Bakker, C; Gantla, S; de Boer, A; Oostra, BA; Lindhout, D; Tytgat, GN; Jansen, PL; Oude Elferink, RP (2 November 1995). "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome.". The New England Journal of Medicine 333 (18): 1171–5.  
  7. ^ Koiwai, O; Nishizawa, M; Hasada, K; Aono, S; Adachi, Y; Mamiya, N; Sato, H (July 1995). "Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase.". Human Molecular Genetics 4 (7): 1183–6.  
  8. ^ Kasper et al., Harrison's Principles of Internal Medicine, 16th edition, McGraw-Hill 2005
  9. ^ Boon et al., Davidson's Principles & Practice of Medicine, 20th edition, Churchill Livingstone 2006
  10. ^ Bancroft JD, Kreamer B, Gourley GR (1998). "Gilbert syndrome accelerates development of neonatal jaundice". Journal of Pediatrics 132 (4): 656–60.  
  11. ^ 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.  
  12. ^ 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.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ a b 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.  
  16. ^ a b c Gilbert Syndrome at eMedicine
  17. ^ a b 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.  
  18. ^ 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.  
  19. ^ a b 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.  
  20. ^ 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.  
  21. ^ Blood Coagul Fibrinolysis. 2013 Jul;24(5):484-8. doi: 10.1097/MBC.0b013e32835e4230. The effects of Gilbert's syndrome on the mean platelet volume and other hematological parameters. Cure MC1, Cure E, Kirbas A, Cicek AC, Yuce S.
  22. ^ a b GilbertsSyndrome.com
  23. ^ a b 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.  
  24. ^ Bailey A, Robinson D, Dawson AM. (1977). "Does Gilbert's disease exist?". Lancet 1 (8018): 931–3.  
  25. ^ 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.  
  26. ^ 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.  
  27. ^ "Entrez Gene: UGT1A1 UDP glucuronosyltransferase 1 family, polypeptide A1". 
  28. ^ 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.  
  29. ^ a b 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.  
  30. ^ 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.  
  31. ^ 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.  
  32. ^ 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.  
  33. ^ Tóth, Csaba, and Zsófia Clemens. Gilbert’s Syndrome Successfully Treated with the Paleolithic Ketogenic Diet. American Journal of Medical Case Reports 3.4 (2015): 117-120.
  34. ^ Gilbert's syndrome at Who Named It?
  35. ^ Gilbert A, Lereboullet P (1901). "La cholemie simple familiale". Sem Med 21: 241–3. 
  36. ^ Jens Einar Meulengracht at Who Named It?
  37. ^ 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.  
  38. ^ Shmaefsky, Brian (2006). "5". Biotechnology 101. Greenwood Publishing Group. p. 175.  
  39. ^ "Wire preaches delights of three cliffs".  
  40. ^ Thornton, M. (3 July 2009). "How our last Final hero, Henry 'Bunny' Austin, became an outcast for 40 years". Daily Mail (London). 
  41. ^ David Cox. (19 April 2014). "A Tennis Player Learns to Be Aggressive for Health’s Sake". New York Times (Monte Carlo). 

External links

  • Datagenno - Gilbert's syndrome
  • 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
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