Classification & external resources
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. 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.
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.
Gilbert's syndrome is caused by approximately 30%-50% reduced glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UGT1A1). 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. The allele polymorphism is referred to as UGT1A1*28.
Signs and symptoms
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.
Gilbert's syndrome also reduces 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) 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.
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, and lactate dehydrogenase levels. Liver biopsy is rarely necessary. The onset of GS is often in childhood or early adulthood.
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.
The level of total bilirubin is often increased if the blood sample is taken while fasting.
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).
Alternative, less common names for this disorder are as follows:
- 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 at Who Named It
- ^ Gilbert A, Lereboullet P. La cholemie simple familiale. Sem Med 1901;21:241-3.
- ^ doctor/2449 at Who Named It
- ^ 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. 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. 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. PMID 8596320.
- ^ 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
- ^ 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.
- ^ 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.
- ^ 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. PMID 12732365.
- ^ 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.
- ^ Mukherjee S. Gilbert Syndrome. eMedicine.com. URL: http://www.emedicine.com/med/topic870.htm. Accessed: October 7, 2007.
|Metabolic pathology / Inborn error of metabolism (E70-90, 270-279)|
|Amino acid||Aromatic (Phenylketonuria, Alkaptonuria, Ochronosis, Tyrosinemia, Albinism, Histidinemia) - Organic acidemias (Maple syrup urine disease, Propionic acidemia, Methylmalonic acidemia, Isovaleric acidemia, 3-Methylcrotonyl-CoA carboxylase deficiency) - Transport (Cystinuria, Cystinosis, Hartnup disease, Fanconi syndrome, Oculocerebrorenal syndrome) - Sulfur (Homocystinuria, Cystathioninuria) - Urea cycle disorder (N-Acetylglutamate synthase deficiency, Carbamoyl phosphate synthetase I deficiency, Ornithine transcarbamylase deficiency, Citrullinemia, Argininosuccinic aciduria, Hyperammonemia) - Glutaric acidemia type 1 - Hyperprolinemia - Sarcosinemia|
|Carbohydrate||Lactose intolerance - Glycogen storage disease (type I, type II, type III, type IV, type V, type VI, type VII) - fructose metabolism (Fructose intolerance, Fructose bisphosphatase deficiency, Essential fructosuria) - galactose metabolism (Galactosemia, Galactose-1-phosphate uridylyltransferase galactosemia, Galactokinase deficiency) - other intestinal carbohydrate absorption (Glucose-galactose malabsorption, Sucrose intolerance) - pyruvate metabolism and gluconeogenesis (PCD, PDHA) -
Pentosuria - Renal glycosuria|
|Lipid storage||Sphingolipidoses/Gangliosidoses: GM2 gangliosidoses (Sandhoff disease, Tay-Sachs disease) - GM1 gangliosidoses - Mucolipidosis type IV - Gaucher's disease - Niemann-Pick disease - Farber disease - Fabry's disease - Metachromatic leukodystrophy - Krabbe disease|
Neuronal ceroid lipofuscinosis (Batten disease) - Cerebrotendineous xanthomatosis - Cholesteryl ester storage disease (Wolman disease)
|Fatty acid metabolism||Lipoprotein/lipidemias: Hyperlipidemia - Hypercholesterolemia - Familial hypercholesterolemia - Xanthoma - Combined hyperlipidemia - Lecithin cholesterol acyltransferase deficiency - Tangier disease - Abetalipoproteinemia |
Fatty acid: Adrenoleukodystrophy - Acyl-coA dehydrogenase (Short-chain, Medium-chain, Long-chain 3-hydroxy, Very long-chain) - Carnitine (Primary, I, II)
|Mineral||Cu Wilson's disease/Menkes disease - Fe Haemochromatosis - Zn Acrodermatitis enteropathica - PO43�' Hypophosphatemia/Hypophosphatasia - Mg2+ Hypermagnesemia/Hypomagnesemia - Ca2+ Hypercalcaemia/Hypocalcaemia/Disorders of calcium metabolism|
and acid-base balance
|Electrolyte disturbance - Na+ Hypernatremia/Hyponatremia - Acidosis (Metabolic, Respiratory, Lactic) - Alkalosis (Metabolic, Respiratory) - Mixed disorder of acid-base balance - H2O Dehydration/Hypervolemia - K+ Hypokalemia/Hyperkalemia - Cl�' Hyperchloremia/Hypochloremia|
|Purine and pyrimidine||Hyperuricemia - Lesch-Nyhan syndrome - Xanthinuria|
|Porphyrin||Acute intermittent, Gunther's, Cutanea tarda, Erythropoietic, Hepatoerythropoietic, Hereditary copro-, Variegate|
|Bilirubin||Unconjugated (Lucey-Driscoll syndrome, Gilbert's syndrome, Crigler-Najjar syndrome) - Conjugated (Dubin-Johnson syndrome, Rotor syndrome)|
|Glycosaminoglycan||Mucopolysaccharidosis - 1:Hurler/Hunter - 3:Sanfilippo - 4:Morquio - 6:Maroteaux-Lamy - 7:Sly|
|Glycoprotein||Mucolipidosis - I-cell disease - Pseudo-Hurler polydystrophy - Aspartylglucosaminuria - Fucosidosis - Alpha-mannosidosis - Sialidosis|
|Other||Alpha 1-antitrypsin deficiency - Cystic fibrosis - Amyloidosis (Familial Mediterranean fever) - Acatalasia|