Gilbert's syndrome

From Wikipedia, the free encyclopedia

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

Gilbert's syndrome, 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 (though some Gastroenterologists maintain that it is closer to 10%). The main symptom is otherwise harmless jaundice which does not require treatment, caused by elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia).

The source of this hyperbilirubinemia is reduced activity of the enzyme glucuronyltransferase which conjugates bilirubin and some other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum.

Contents

[edit] Pathogenesis

Gilbert's syndrome is caused by approximately 30%-50% reduced glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UGT1A1).[1][2] The gene which encodes UGT1A1 normally has a promoter region TATA box containing the allele A(TA6)TAA. Gilbert's syndrome is associated with homozygous A(TA7)TAA alleles.[3] The allele polymorphism is referred to as UGT1A1*28.

[edit] Signs and symptoms

[edit] Jaundice

Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally has no serious consequence. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise asymptomatic. [4][5]

It has been reported that GS may contribute to an accelerated onset of neonatal jaundice[6].

[edit] Detoxification of certain drugs

The enzymes that are defective in GS (UGT1A1) are also responible 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.[7]

While paracetamol (acetaminophen) is not metabolized by UGT1A1,[8] it is metabolized by one of the other enzymes also deficient in some people with GS.[9][10] A subset of people with GS may have an increased risk of paracetamol toxicity.[10][11]

[edit] Debated signs and symptoms

[edit] Reduced risk of ischemic heart disease

One research group in the Czech Republic has found a reduced incidence of atherosclerotic disease in subjects with GS[12]. This is supposed to be due to bilirubin IXα being recognised as a potent antioxidant [13].

[edit] Diffuse symptoms

Some people report diffuse symptoms related to GS[14], but no clear adverse symptoms related to GS in adults have been found in scientific studies.[15][16]. This has led some to dispute whether GS should classify as a disease.[16][17]

[edit] Diagnosis

[edit] Exclusion of other conditions

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:

  • 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).
  • Hepatitis can be excluded by negative blood samples for antigens specific to the different hepatitis vira.
  • Cholestasis can be excluded by the abscence of lactate dehydrogenase, low levels of conjugated bilirubin and ultrasound scan of the bile ducts.
  • More severe types of glucoronyl transferase disorders like 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).
  • Other diseases of the liver can be exluded by the liver-enzymes ALAT, ASAT and albumin being within normal ranges.

[edit] Findings specific to Gilbert's syndrome

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)[18] 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.

The level of total bilirubin is often increased if the blood sample is taken after fasting for two days[19], 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[20] when fasting has ended, and following samples should show a decrease in total bilirubin toward normal levels.

[edit] Eponym and synonyms

Gilbert's syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.[21][22] In German literature, it is commonly associated with Jens Einar Meulengracht.[23]

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
  • Morbus

[edit] See also

[edit] References

  1. ^ Raijmakers MT, Jansen PL, Steegers EA, Peters WH (2000). "Association of human liver bilirubin UDP-glucuronyltransferase activity with 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ Kasper et al, Harrison's Principles of Internal Medicine, 16th edition, McGraw-Hill 2005
  5. ^ Boon et al, Davidson's Principles & Practice of Medicine, 20th edition, Churchill Livingstone 2006
  6. ^ Bancroft JD, Kreamer B, Gourley GR (1998). "Gilbert syndrome accelerates development of neonatal jaundice.". Journal of Pediatrics 132 (4): 656-60. PMID 9580766. 
  7. ^ 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. PMID 15280927. 
  8. ^ 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. PMID 15180166. 
  9. ^ 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. 
  10. ^ 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. PMID 10412886. 
  11. ^ Mukherjee S. Gilbert Syndrome. eMedicine.com. URL: http://www.emedicine.com/med/topic870.htm. Accessed: October 7, 2007.
  12. ^ 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): 568-571. PMID 12709588. 
  13. ^ Libor Vítek, Milan Jirsa, Marie Brodanováb, Milan Kalább, Vilém Danzigb, Ladislav Novotnýc and Petr Kotal (2000). "Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels". Atherosclerosis 160 (2): 449-456. doi:10.1016/S0021-9150(01)00601-3. 
  14. ^ GilbertsSyndrome.com
  15. ^ Gitlin N. (1977). "The clinical presentation of Gilbert's disease in 26 patients.". South Africa Medical Journal 52 (1): 19-20. PMID 888039. 
  16. ^ 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. PMID 3264448. 
  17. ^ 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. 
  18. ^ 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. (1995). "The Genetic Basis of the Reduced Expression of Bilirubin UDP-Glucuronosyltransferase 1 in Gilbert's Syndrome". New England Journal of Medicine 333: 1171-1175. PMID 7565971. 
  19. ^ J L Gollan, C Bateman, B H Billing (1976). "Effect of dietary composition on the unconjugated hyperbilirubinaemia of Gilbert's syndrome". Gut (17): 335-340. doi:10.1136/gut.17.5.335. 
  20. ^ N Carulli, M Ponz de Leon, E Mauro, F Manenti, A Ferrari (1976). "Alteration of drug metabolism in Gilbert's syndrome". Gut (17): 581-587. doi:10.1136/gut.17.8.581. 
  21. ^ Gilbert's syndrome at Who Named It
  22. ^ Gilbert A, Lereboullet P. La cholemie simple familiale. Sem Med 1901;21:241-3.
  23. ^ doctor/2449 at Who Named It

[edit] External links

v • d • e
Heme metabolism disorders (E80, 277.1, 277.4)
Porphyrin
Hereditary hyperbilirubinemia