Background
The human organism has several mechanisms to metabolize endogenous and foreign substances. One of these mechanisms is glucuronidation, which occurs primarily in the liver. In this process, enzymes from the superfamily of UDP-glucuronosyltransferases (UGT) transfer a molecule of glucuronic acid from UDP-glucuronic acid to the substrate. Using acetaminophen as an example, alcohols, phenols, carboxylic acids, amines and thiols are accepted as substrates for the reaction. In addition to endogenous substrates such as bilirubin, bile acids, thyroxine, steroids and vitamins, many pharmaceutical agents are also glucuronidated. The purpose of this metabolic reaction is to inactivate the substrates and make them water-soluble so that they can be better excreted by the liver and kidney.
Symptoms
Meulengracht disease (synonym: Gilbert syndrome) is a mild unconjugated hyperbilirubinemia occurring in 3% to 10% of the population. It manifests as elevated blood bilirubin levels and can lead to jaundice with yellowing of the skin and eyes, which can greatly alarm affected individuals and family members prior to diagnosis. Unlike Crigler-Najjar syndrome, which is severe, Meulengracht disease is described in most publications as benign, asymptomatic and without complications. However, the syndrome is also attributed with numerous non-specific complaints such as fatigue, mood disorders, digestive disorders, headache and lower abdominal pain, which may affect the quality of life of affected individuals. It may therefore not be as harmless in individual cases as is generally assumed. We do not know how well the relationship between these symptoms and the disease has been scientifically established.
Causes
The cause of Gilbert syndrome is decreased enzyme activity of the UDP-glucuronosyltransferase UGT1A1. This leads to inadequate glucuronidation of the heme degradation product bilirubin and reduced excretion via the bile. The result is increased bilirubin concentrations in the blood and, in some cases, jaundice. In this case, unconjugated (so-called indirect) bilirubin increases. UGT1A1 is the only isoenzyme that conjugates bilirubin. Bilirubin concentrations may be elevated during fasting, physical activity, stress, illness, and menstruation, thus increasing jaundice. Bilirubin is a breakdown product of heme, mainly produced during the breakdown of red blood cells. Myoglobin in muscle and some enzymes also contain heme. The deeper cause of the syndrome is variants of the gene . The best known is the variant , in which two additional nucleotides TA are inserted in the promoter . This leads to a reduction of transcription by 70%. In addition, other genetic or acquired factors may also play a role.
Differential Diagnosis
The most important diagnostic criterion is elevated serum bilirubin, which is often discovered incidentally during a blood test. Many liver diseases can cause jaundice and must be excluded at diagnosis.
Pharmaceutical significance
Because pharmaceutical agents are also conjugated and inactivated via UGT1A1, increased plasma concentrations can be expected if degradation is inhibited. If this is an important metabolic pathway, adverse effects may result. However, the phenomenon has not been adequately studied. Substrates of UGT1A1 include, for example, atorvastatin, buprenorphine, estradiol, ethinylestradiol, gemfibrozil, ibuprofen, indinavir, a metabolite of irinotecan, ketoprofen, and simvastatin. Paracetamol is contraindicated in Gilbert’s syndrome, according to the drug information, because the liver-toxic metabolite NAPQI could be formed more frequently due to insufficient glucuronidation. However, the clinical relevance is controversial. On the other hand, it is relatively undisputed that the toxicity of the cytostatic and prodrug irinotecan is increased in patients with Gilbert syndrome because the main metabolite SN-38 is glucuronidated to atoxic metabolites. The dose must be reduced and blood counts monitored. Irinotecan is approved for the treatment of metastatic colon cancer. Agents that are activated rather than inactivated by glucuronidation are rare. In such a case, an attenuation of the effect is theoretically to be expected, since the active metabolite is not sufficiently formed.Since mutagenic xenobiotics are also detoxified by glucuronidation, there is a possibility that the organism may be more exposed to them. Finally, it has been shown that agents that inhibit UGT1A1 activity, such as the HIV protease inhibitors atazanavir and indinavir, can exacerbate or even induce hyperbilirubinemia.
Drug treatment
Usually, no therapy is prescribed because the condition is considered benign. The triggers mentioned (fasting, exercise, stress) can be partially influenced. Enzyme inducers may be considered for drug treatment. A regularly taken dose of phenobarbital reduces hyperbilirubinemia (daily dose 50-150 mg, off-label). Rifampicin may also be suitable and has been used successfully in a small study in two patients. However, adverse effects must be expected with both agents and they are rarely prescribed. Both are effective only as long as they are taken. In our view, these agents have too many adverse effects to be considered for treatment. The flavonoid chrysin (5,7-dihydroxyflavone) can induce UGT1A1 in vitro, but its relevance in vivo is controversial. Chrysin is reported to be found in passionflower herb, among others, and is sold as a food supplement in some countries. In principle, it should be possible to selectively induce UGT1A1 with a synthetic agent or a natural product and thus reduce hyperbilirubinemia with few adverse effects. Such a drug is not yet commercially available in this indication.
Trivia
Gilbert and Lereboullet described the phenomenon in 1901 and Meulengracht again in 1939. It is often referred to as Meulengracht’s disease in the German literature, but as Gilbert’s syndrome in English-speaking countries.