Bilirubin – the molecule responsible for jaundice

7 min


Bilirubin – we often see this term. Each general blood test determines the amount of bilirubin. Why is it important to know its quantity and what does it affect? Under the cut, we will analyze this question in detail, as well as the question of why bilirubin is an endogenous antioxidant.

Bile pigment bilirubin is the main end product of heme breakdown in the liver. Hem is a component of hemoglobin that gives it a red color. Bilirubin is excreted in the bile and urine. The yellow color of the pigment is responsible for the appearance of people with jaundice.

Determination of the concentration of bilirubin in the blood is the main test for the diagnosis of hepatobiliary disease, with violations of the heart or liver, etc.

History

In 1847, the German scientist Rudolf Virchow and his colleagues separated crystals of bilirubin from blood taken from a hematoma. More than a century later, Irving M. London and staff at Columbia University demonstrated that heme is indeed its source.

Jaundice is especially common in newborns and is not always destructive. The first mention of it probably dates back to the early 18th century. German pathologist Johannes Orth published his results in 1875 after opening a child who died of jaundice. The question was how to make the right diagnosis, based not only on skin color.

At the beginning of the 20th century, while working on a dissertation, gynecologist and obstetrician Gustav Hazlhurst discovered a method for detecting bile dye in urine and blood. Blood serum was mixed with alcohol and centrifuged, as a result of which the protein settled. An indicator containing a diazo group was added to the turbid supernatant (RC = N+= N) In the presence of bile dye, the liquid turned purple. After this step, alcohol was added in a certain amount and fatty acids dissolved, the liquid became transparent, if the violet color was more saturated than that of the reference sample, this meant that the level of bilirubin was above normal. In this case, adding alcohol gradually, it was possible to determine how much bilirubin in the serum exceeded the norm.

What is bilirubin?

Bilirubin – yellow-orange fat-soluble substance that has a cytotoxic effect at high concentrations. Experimental studies have shown that bilirubin has antioxidant properties such as absorption of reactive oxygen species (ROS) and inhibition of the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This leads to a decrease in oxidative stress and protects the body from atherosclerosis.

The central structure of the heme is a porphyrin ring. Bilirubin has an open-ring porphyrin structure: chains of substituted pyrrole and 1,3-dihydro-2H-pyrrol-2-one rings.

The basics of biochemistry of bilirubin

Red blood cells live for 3-4 months, after which, mainly, they undergo subsequent transformations in Kupffer cells of the liver and, to a lesser extent, in macrophages of the spleen and bone marrow. These cells are called cells of the reticuloendothelial system (RES). Hem, the breakdown product of erythrocyte hemoglobin in RES cells, is oxidized by oxygen, as a result of decomposition substances such as iron and biliverdin are released. Iron further binds to either transferrin or ferritin, and biliverdin is enzymatically converted to bilirubin.

From RES cells, bilirubin enters the bloodstream, where it is mainly associated with albumin, which performs a transport function. Such complexes limit the excretion of bilirubin in the urine. The complex of bilirubin with albumin is called free or indirect bilirubin.

From the vascular bed, bilirubin enters hepatocytes, which make up 60 to 80% of liver cells. Next, bilirubin is transported to the endoplasmic reticulum, where it binds to uridine diphosphate glucuronic (UDP) glucuronic acid, forming mono- and digluoronides, and bilirubin can also bind to sulfates, phosphates and glucosides there. Bilirubin-glucuronide is a bound or direct bilirubin. Then, getting into the bile ducts, and then into the intestines, bilirubin is enzymatically converted into free bilirubin. Part of the bilirubin from the bile enters the bloodstream again. Thus, free bilirubin (about 80%) and bound bilirubin (the remaining 20%) coexist in the blood.

In the intestines, bilirubin is converted to mesobilirubin and urobilinogen. Part of urobilinogen enters the liver, with healthy liver function, mesobilirubin and urobilinogen do not enter the bloodstream, but are retained in hepatocytes. Metabolites remaining in the intestine turn into stercobilinogen. Derivatives of bilirubin and he himself are pigments, staining the products of excretion, and also with liver pathologies, the resulting jaundice is associated with impaired bilirubin metabolism.

Bilirubin Metabolism

The main factors affecting the metabolism of bilirubin

The conversion of bilirubin precursors is carried out by enzymes such as hemoxygenase, biliverdin reductase,

Hepatic UDP-glucuronosyltransferase-1 UGT1A1, a polypeptide transporting organic anions and multidrug resistance proteins, regulates serum bilirubin levels by binding and transporting bilirubin. Intestinal bacteria also control bilirubin levels.

Important properties of bilirubin

  • High bilirubin levels correlate with reduced risks of cardiovascular and metabolic diseases. At high bilirubin concentrations, an improvement in endothelial function and a decrease in oxidative stress markers are observed. Bilirubin inhibits the progression of atherosclerosis, participating in the regulation of vascular inflammation. Based on this, it is suggested that bilirubin may be a potential target for the treatment of cardiovascular disease. For example, you can artificially increase its concentration using UGT1A1 inhibitors [1].
  • People with elevated bilirubin may experience overweight and obesity. This can be explained by the effect of bilirubin on the PPARα receptor, which is a transcription factor in the liver, kidneys, adipose tissue, heart, and muscles [2].
  • Nitric oxide is a gas in the body released by endothelial cells, is a vasoactive agent, that is, it affects the tone and diameter of the lumen of blood vessels. With endothelial insufficiency, the bioavailability of nitric oxide decreases, the number of reactive oxygen species increases. Bilirubin in turn deactivates reactive oxygen species. Bilirubin also inhibits the activity of NADPH oxidase. Thus, the antioxidant properties of bilirubin are explained. [1].
  • It is important to note that bilirubin levels are inversely related to the risk of type 2 diabetes. [3]

[3]

Bilirubin in the laboratory

In laboratory practice, use such markers as total bilirubin – free and direct, as well as direct bilirubin.

Norms – 3.4 -17.1 μmol / L. Of these, direct up to 3.4 μmol / L. And indirect – up to 13.7 μmol / l. Jaundice appears when the total bilirubin is above 27-34 μmol / L. The price of the test is about 500 rubles + 200 rubles for taking blood from a vein. The same price for direct bilirubin analysis.

When is the study scheduled?

  • With symptoms of blood diseases, as well as blood vessels
  • When it is necessary to evaluate the functional state of the liver
  • With jaundice
  • When evaluating biliary tract function

Additionally

“Hepatoprotectors” – substances capable of fulfilling or facilitating the function of detoxification are used for liver and other insufficiencies, as well as in cases of poisoning. This list is not a panacea, but, according to the author, when taken together with many drugs unpleasant for the liver (for example, with non-steroidal anti-inflammatory drugs) it can minimize the negative consequences for the body.

  • Ursodeoxycholic acid is the epimer of chenodeoxycholic acid. Non-toxic component of bile, facilitates the digestion process. Ursosan enhances lipase activity, has a hypolglycemic effect, enhances gastric and pancreatic secretion. It has an immunomodulatory effect. Lowers cholesterol in bile. Helps maintain the normal state of people, for example, with Gilbert syndrome, hereditary liver pathology (familial non-hemolytic jaundice)
  • Acetylcysteine ​​- is a precursor to glutathione, which in turn is involved in the neutralization of toxins. The antioxidant effect of acetylcysteine ​​/ glutathione is based on the ability of –SH thiol groups to bind to oxidative radicals [4].
  • Taurine – “angioprotector”, contributes to the normalization of vascular function [5]. It also binds to bile acids, providing a weak hepatoprotective effect.

conclusions

  • Bilirubin is a marker that allows you to determine the pathology in the metabolism and functioning of the organs of the cardiovascular system, as well as in the liver and spleen.
  • It is recommended to take only people with impaired functioning of the above organs and with jaundice.
  • Co-administration of such a simple drug as acetylcysteine ​​with paracetamol or ibuprofen, for example, minimizes the load on the liver.
  • Once again, we recall about a healthy lifestyle, as well as about the fact that alcohol is very harmful to your body.

Lifext application why, what are the prospects

We made an application in which we implement all the methods of prolonging life. An early version has been released right now, where monitoring and individual evaluation of analyzes work.

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Disclaimer

The information posted on the Lifext Blog is for free reference. Our team makes every effort to provide users with accurate and reliable information, but at the same time does not exclude the possibility of errors. A doctor must be consulted for diagnosis and treatment.

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Sources

[1] T. Maruhashi, Y. Kihara, Y. Higashi, Bilirubin and endothelial function, J. Atheroscler. Thromb. 26 (2019) 688–696. doi: 10.5551 / jat.RV17035.
[2] M. Pawlak, P. Lefebvre, B. Staels, Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease, J. Hepatol. 62 (2015) 720-733. doi: 10.1016 / j.jhep.2014.10.10.039.
[3] T.D. Hinds, D.E. Stec, Bilirubin Safeguards Cardiorenal and Metabolic Diseases: a Protective Role in Health, Curr. Hypertens Rep. 21 (2019). doi: 10.1007 / s11906-019-0994-z.
[4] H.L. Liston, J.S. Markowitz, C.L. DeVane, Drug glucuronidation in clinical psychopharmacology, J. Clin. Psychopharmacol. 21 (2001) 500-515. doi: 10.1097 / 00004714-200110000-00008.
[5] T. Yanagita, S.Y. Han, Y. Hu, K. Nagao, H. Kitajima, S. Murakami, Taurine reduces the secretion of apolipoprotein B100 and lipids in HepG2 cells, Lipids Health Dis. 7 (2008) 1–6. doi: 10.1186 / 1476-511X-7-38.


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