Meulengracht's disease

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Classification according to ICD-10
E80.4 Gilbert Meulengracht Syndrome
ICD-10 online (WHO version 2019)

(Gilbert) Meulengracht disease , Meulengracht disease , Gilbert (Meulengracht) syndrome or icterus intermittens juvenilis is a hereditary transport and metabolic disorder . It is characterized by a significant increase in indirect bilirubin in the blood ( hyperbilirubinemia ), which occurs without increased hemolysis or underlying liver disease and has no disease value of its own. There are other familial hyperbilirubinemia syndromes .

frequency

Meulengracht's disease is widespread. The prevalence (frequency of occurrence) is more than eight percent of the population, with men being affected more often than women with reported ratios of 1.5: 1 to over 7: 1.

root cause

The cause of the metabolic disorder can be found in the process of hemoglobin breakdown: the blood cells are renewed after about 120 days. The red blood pigment, hemoglobin , is broken down in several steps in the bone marrow , the spleen and the liver and converted into a water-soluble form.

  1. Step: The red blood pigment, the hemoglobin is by means of heme oxygenase on α-Hydroxihämin to biliverdin degraded.
  2. Step: Biliverdin is reduced to unconjugated bilirubin (water-insoluble = "indirect" bilirubin) using biliverdin reductase . This water-insoluble bilirubin is then bound to albumin and transported to the liver.
  3. Step: The unconjugated bilirubin is converted into conjugated bilirubin (water-soluble = “direct” bilirubin) in the liver by microsomal UDP-glucuronosyltransferase (UDP-GT) with glucuronic acid .
  4. Step: The conjugated bilirubin is released into the intestine with the bile .
  5. Step: In the intestine, bilirubin is reduced to urobilinogen; 80 percent are excreted in the stool, about 20 percent reach the liver via the enterohepatic circulation after reabsorption , and a small part is excreted via the kidneys.

In Meulengracht's disease patients, the activity of UDP-glucuronyltransferase is reduced to about 30 percent of a healthy person, making the formation of conjugated bilirubin more difficult. The result is an increased bilirubin serum level ("indirect" serum level). If there is a more pronounced decrease in enzyme activity (to 0 to 10%), one speaks of Crigler-Najjar syndrome .

genetics

Meulengracht's disease is triggered by a 70 to 75 percent reduction in the activity of the enzyme UDP-glucuronosyltransferase (UDP-GT1-A1). The gene for UDP-GT1-A1 encoding ( UGT1A1 ), has usually a promoter - TATA box , the alleles A (TA 6 contains) TAA. The disease is mostly associated with the homozygous A (TA 7 ) TAA alleles. The polymorphism of the alleles is named UGT1A1 * 28. In 94 percent of cases, other enzymes from the glucuronosyltransferase family are also affected, such as UDP-GT1-A6 (around 50% inactivity) and UDP-GT1-A7 (around 83% inactivity). Because of the effects on the breakdown of drugs and bilirubin on the one hand and heredity on the other, Meulengracht's disease can be regarded as a congenital metabolic disease.

Gilbert's syndrome is an autosomal - recessive inherited.

Clinical manifestations

Patients are generally asymptomatic. Uncharacteristic symptoms such as fatigue do not correlate with bilirubin levels. The blood count is normal. The bilirubin continues to rise during fasting, which can lead to slightly yellowish colored eyes, more precisely to yellowish sclera .

The glucuronidation of foreign substances appears to be normal in Meulengracht's disease. The main exception is the intolerance of the chemotherapeutic agent Irinotecan. Some studies also assume that some medications, such as paracetamol , are processed differently . Other studies question this and assume that Meulengracht's disease does not lead to clinical complications when using these drugs. The use of the HIV drugs indinavir and atazanavir in association with Meulengracht's disease can lead to increased bilirubin levels because they block the UGT1A1 gene.

Diagnostics and consequences

Meulengracht's disease can be clearly identified by nicotinic acid or fasting tests. A liver biopsy is now no longer necessary. Another safer way of diagnosis is a molecular genetic examination.

When examining healthy people, bilirubin values ​​are usually also recorded (urine and blood). In Meulengracht's disease, values ​​are found that are about twice as high as the limit value.

Recent work speculates that the chronically elevated bilirubin could possibly protect against arteriosclerosis . This may also apply to colorectal cancer . A study from 2011 came to comparable results and found a reduction in lung diseases and an overall reduced death rate in people with slightly elevated bilirubin.

therapy

There is no indication for therapy. Avoiding paracetamol for pain management is recommended. The clinical manifestations are of no disease value, but the first time they appear they can be worrying for those affected. Therefore, detailed information is also important therapeutically.

history

Meulengracht's disease is named after the Danish doctor Einar Meulengracht , who played a key role in his research. Another namesake is the French doctor Augustin Nicolas Gilbert (1858–1927), who researched the disease together with Pierre Lereboullet (1874–1944) as early as 1900 .

Other familial hyperbilirubinemia syndromes

Web links

Individual evidence

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  4. Maarten Raijmakers, Peter Jansen, Eric Steegers, Wilbert Peters: Association of human liver bilirubin UDP-glucuronyltransferase activity, most commonly due to a polymorphism in the promoter region of the UGT1A1 gene . In: Journal of Hepatology . tape 33 , no. 3 , 2000, pp. 348-351 , doi : 10.1016 / S0168-8278 (00) 80268-8 .
  5. Piter J. Bosma et al. a .: The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome . In: New England Journal of Medicine . tape 333 , no. 18 , 1995, p. 1171–1175 , doi : 10.1056 / NEJM199511023331802 .
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  8. Harvey A. Schwertner: Bilirubin concentration, UGT1A1 * 28 polymorphism, and coronary artery disease . In: Clinical Chemistry . tape 49 , no. 7 , 2003, p. 1039-1040 , PMID 12816897 .
  9. L. Vítek et al. a .: Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels . In: Atherosclerosis . tape 160 , 2002, ISSN  0021-9150 , OCLC 121255719 , p. 449-456 , PMID 11849670 .
  10. SD Zucker, P. S. Horn, K. E. Sherman: Serum bilirubin levels in the US population: gender effect and inverse correlation with colorectal cancer . In: Hepatology . tape 40 , no. 4 , 2004, p. 827-835 , PMID 15382174 .
  11. JAMA 2011; 305 (7): 691-697 , quoted in Deutsches Ärzteblatt from February 17, 2011 ( memento of the original from December 1, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . @1@ 2Template: Webachiv / IABot / www.aerzteblatt.de
  12. Herold, Gerd: Internal Medicine - A lecture-oriented presentation. Herold Verlag, Cologne 2013, p. 518.