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Names | |
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IUPAC name 3-[12-(2-Carboxyethyl)-3,18-diethenyl-2,7,13,17-tetramethyl-1,19-dioxo-10,19,21,22,23,24-hexahydro-1H-bilin-8-yl]propanoyl β-D-glucopyranosiduronic acid | |
Systematic IUPAC name [12(2)Z,102S,103R,104S,105S,106S]-34-(2-Carboxyethyl)-14-ethenyl-55-[(Z)-(3-ethenyl-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)methyl]-103,104,105-trihydroxy-13,33,54-trimethyl-15,8-dioxo-11,15-dihydro-31H,51H-9-oxa-1(2),3(2,5),5(2,3)-tripyrrola-10(2)-oxanadecaphan-12(2)-ene-106-carboxylic acid | |
Other names Bilirubin monoglucuronide | |
Identifiers | |
3D model (JSmol) | |
ChEBI | |
ChEMBL | |
ChemSpider | |
KEGG | |
PubChem CID | |
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Properties | |
C39H44N4O12 | |
Molar mass | 760.797 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Bilirubin glucuronide is a water-soluble reaction intermediate over the process of conjugation of indirect bilirubin. [1] Bilirubin glucuronide itself belongs to the category of conjugated bilirubin along with bilirubin di-glucuronide. [2] However, only the latter one is primarily excreted into the bile in the normal setting. [2] [3] [4] [5] [1]
Upon macrophages spot and phagocytize the effete Red Blood Corpuscles containing hemoglobin, [6] unconjugated bilirubin is discharged from macrophages into the blood plasma. [7] [8] Most often, the free and water-insoluble unconjugated bilirubin which has an internal hydrodren[ clarification needed ] bonding [9] will bind to albumin and, to a much lesser extent, high density lipoprotein in order to decrease its hydrophobicity and to limit the probability of unnecessary contact with other tissues [1] [9] and keep bilirubin in the vascular space from traversing to extravascular space including brain, and from ending up increasing glomerular filtration. [9] Nevertheless, there is still a little portion of indirect bilirubins stays free-of-bound. [9] Free unconjugated bilirubin can poison the cerebrum. [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Finally, albumin leads the indirect bilirubin to the liver. [1] [9] In the liver sinusoid, albumin disassociates with the indirect bilirubin and returns to the circulation while the hepatocyte transfers the indirect bilirubin to ligandin and glucuronide conjugates the indirect bilirubin in the endoplasmic reticulum by disrupting unconjugated bilirubin's internal hydrogen bonding, which is the thing that makes indirect bilirubin having the property of eternal half-elimination life and insoluble in water, [20] [9] [1] [21] [22] and by attaching two molecules of glucuronic acid to it in a two step process. [23] The reaction is a transfer of two glucuronic acid groups including UDP glucuronic acid sequentially to the propionic acid groups of the bilirubin, primarily catalyzed by UGT1A1. [23] [24] [5] In greater detail about this reaction, a glucuronosyl moiety is conjugated to one of the propionic acid side chains, located on the C8 and C12 carbons of the two central pyrrole rings of bilirubin. [25]
When the first step is completely done, the substrate bilirubin glucuronide (also known as mono-glucuronide [26] ) is born at this stage and is water-soluble and readily excreted in bile. [24] [9] Thereafter, so long as the second step of attachment of the other glucuronic acid to it succeeds (officially called "re-glucuronidated" [26] ), the substrate bilirubin glucuronide will turn into bilirubin di-glucuronide (8,12-diglucuronide [26] ) and be excreted into bile canaliculi by way of C-MOAT [note 1] [27] [28] [29] [30] and MRP2 [5] [31] as normal human bile along with a little amount of unconjugated bilirubin as much as only 1 to 4 percent of total pigments in normal bile. [9] [32] That means up to 96%-99% of bilirubin in the bile are conjugated. [9] [1]
Normally, there is just a little conjugated bilirubin escapes into the general circulation. [1] Nonetheless, in the setting of severe liver disease, a significantly greater number of conjugated bilirubin will leak into circulation and then dissolve into the blood [note 2] and thereby filtered by the kidney, and only a part of the leaked conjugated bilirubin will be re-absorbed in the renal tubules, the remainder will be present in the urine making it dark-colored. [1] [3]
The clinical significance of bilirubin glucuronide is involved in many conditions. Drugs that inhibit the activities of the components involved in bilirubin metabolism can give rise to accumulation of bilirubin in the blood. [5] In comparison, conjugation of some drugs is also usually impaired if the liver cannot normally metabolize indirect bilirubin. [5]
When excretion of bilirubin glucuronide by the kidney is detected in the urine through urine examination, meaning that a conspicuous amount of conjugated bilirubin is present and circulating in the blood. [3]
In Dubin–Johnson syndrome, impaired biliary excretion of bilirubin glucuronide is due to a mutation in the canalicular multiple drug-resistance protein 2 (MRP2). A darkly pigmented liver is due to polymerized epinephrine metabolites, not bilirubin. [33]
If it is the liver that cannot effectively transfer the indirect bilirubin into bilirubin glucuronide and further into bilirubin di-glucuronide, the consequence will be hyperbilirubinemia or intrahepatic (or hepatocellular) jaundice. [3]
Moreover, the unconjugated hyperbilirubinemia arises in case the components of liver transfer the indirect bilirubin into bilirubin glucuronide in the rate slower than they should be. [3] This condition is associated with either decreased uptake of bilirubin into hepatocytes (Rotor syndrome [34] ) or defective intracellular protein binding. [3]
In similar fashion, the conjugated hyperbilirubinemia emerges in case the components of the liver have difficulty turning bilirubin glucuronide into bilirubin di-glucuronide. [3] Note that biliary duct blockage can also lead to conjugated hyperbilirubinemia but the pathophysiology is that backflow of bilirubin di-glucuronide with little indirect bilirubin and bilirubin glucuronide from bile duct through liver into blood plasma. [3] [35] These conditions are associated with either defective intracellular protein binding (for the second time) or disturbed secretion into the bile canaliculi (Dubin–Johnson syndrome [34] ). [3]
Liver failure and hepatitis are the most etiological in liver-genesis hyperbilirubinemia. [3] In case of hyperbilirubinemia due to intrahepatic or extrahepatic bile ducts blockage, e.g. gallstone, the name is given as Post-hepatic (or obstructive) jaundice . [3]
Bilirubin concentration is not a sensitive early indicator of liver diseases as the liver may have reserved its capacity in removal of bilirubin to save energy and unreserved the previously reserved capacity when encountering a sudden rise of unconjugated bilirubin. [36] In short, there is still a chance for an ill liver to get rid of excessive unconjugated bilirubin in the blood plasma, displaying a total bilirubin level that is within normal reference range. [36]
In Crigler Najjar disease, there is an inherited deficiency of glucuronyl transferase resulting in high concentrations of unconjugated bilirubin appear in the plasma. [3] Furthermore, those affected may develop kernicterus (deposits of pigment in the brain) that can cause nerve degeneration. [3]
In Gilbert’s syndrome, glucuronyl transferase activity is reduced by approximately 70%, leading to mild accumulation of unconjugated bilirubin in the plasma. [3]
At birth, infants don't develop enough ability to conjugate bilirubin. [37] Up to 8% to 11% neonates will develop hyperbilirubinemia in the first week of their lives. [37] [19]
In jaundice owing to hemolysis (prehepatic, or hemolytic, jaundice), the pathophysiology is that overproduction of bilirubin from the extravascular or intravascular hemolysis overwhelms the capacity of the liver to excrete it. [3] The bilirubin present in the plasma is largely unconjugated in this setting as they haven't been taken up and conjugated by the liver. [3] In this case, total serum bilirubin increases while the ratio of direct bilirubin to indirect bilirubin remains 96 to 4 as up to 96%-99% of bilirubin in the bile are conjugated mentioned above. [9] [1]
Although there were some studies that showed an inverse correlation between serum bilirubin level and prevalences of ischemic coronary artery disease, [38] cancer mortality, [39] or colorectal cancer [40] in general population, the potential benefits of the chemopreventive function of bilirubin and their causative relations haven't been proved. [40] [9] [10] [13] [14] [15] [16] [17] [18] [19] [ excessive citations ]
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme metabolism, liver dysfunction, or biliary-tract obstruction. The prevalence of jaundice in adults is rare, while jaundice in babies is common, with an estimated 80% affected during their first week of life. The most commonly associated symptoms of jaundice are itchiness, pale feces, and dark urine.
Bilirubin (BR) is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged or abnormal red blood cells. In the first step of bilirubin synthesis, the heme molecule is stripped from the hemoglobin molecule. Heme then passes through various processes of porphyrin catabolism, which varies according to the region of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.
Liver function tests, also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), albumin, bilirubin, and others. The liver transaminases aspartate transaminase and alanine transaminase are useful biomarkers of liver injury in a patient with some degree of intact liver function.
Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentration in the blood is too high, a condition known as hyperbilirubinemia. Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of the central nervous system, potentially causing irreversible neurological damage. Depending on the level of exposure, the effects range from clinically unnoticeable to severe brain damage and even death.
Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice may occur.
A bili light is a light therapy tool to treat newborn jaundice (hyperbilirubinemia). High levels of bilirubin can cause brain damage (kernicterus), leading to cerebral palsy, auditory neuropathy, gaze abnormalities and dental enamel hypoplasia. The therapy uses a blue light (420–470 nm) that converts bilirubin into an (E,Z)-isomer that can be excreted in the urine and feces. Soft goggles are put on the child to reduce eye damage from the high intensity light. The baby is kept naked or only wearing a diaper, and is turned over frequently to expose more of the skin.
Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral palsy, or kernicterus.
Glucuronic acid is a uronic acid that was first isolated from urine. It is found in many gums such as gum arabic, xanthan, and kombucha tea and is important for the metabolism of microorganisms, plants and animals.
Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:
Dubin–Johnson syndrome is a rare, autosomal recessive, benign disorder that causes an isolated increase of conjugated bilirubin in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to Rotor syndrome. It is usually asymptomatic, but may be diagnosed in early infancy based on laboratory tests. No treatment is usually needed.
Crigler–Najjar syndrome is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner. The annual incidence is estimated at 1 in 1,000,000.
Uridine 5'-diphospho-glucuronosyltransferase is a microsomal glycosyltransferase that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is a glucuronidation reaction.
Rotor syndrome is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.
Lucey–Driscoll syndrome is an autosomal recessive metabolic disorder affecting enzymes involved in bilirubin metabolism. It is one of several disorders classified as a transient familial neonatal unconjugated hyperbilirubinemia.
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.
Neonatal cholestasis refers to elevated levels of conjugated bilirubin identified in newborn infants within the first few months of life. Conjugated hyperbilirubinemia is clinically defined as >20% of total serum bilirubin or conjugated bilirubin concentration greater than 1.0 mg/dL regardless of total serum bilirubin concentration. The differential diagnosis for neonatal cholestasis can vary extensively. However, the underlying disease pathology is caused by improper transport and/or defects in excretion of bile from hepatocytes leading to an accumulation of conjugated bilirubin in the body. Generally, symptoms associated with neonatal cholestasis can vary based on the underlying cause of the disease. However, most infants affected will present with jaundice, scleral icterus, failure to thrive, acholic or pale stools, and dark urine.
Bilirubin di-glucuronide is a conjugated form of bilirubin formed in bilirubin metabolism. The hydrophilic character of bilirubin diglucuronide enables it to be water-soluble. It is pumped across the hepatic canalicular membrane into the bile by the transporter MRP2.
Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cholangitis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, cholestasis, and chronic hepatitis C viral infection and other forms of viral hepatitis.
Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.
Hyperbilirubinemia is a clinical condition describing an elevation of blood bilirubin level due to the inability to properly metabolise or excrete bilirubin, a product of erythrocytes breakdown. In severe cases, it is manifested as jaundice, the yellowing of tissues like skin and the sclera when excess bilirubin deposits in them. The US records 52,500 jaundice patients annually. By definition, bilirubin concentration of greater than 3 mg/ml is considered hyperbilirubinemia, following which jaundice progressively develops and becomes apparent when plasma levels reach 20 mg/ml. Rather than a disease itself, hyperbilirubinemia is indicative of multifactorial underlying disorders that trace back to deviations from regular bilirubin metabolism. Diagnosis of hyperbilirubinemia depends on physical examination, urinalysis, serum tests, medical history and imaging to identify the cause. Genetic diseases, alcohol, pregnancy and hepatitis viruses affect the likelihood of hyperbilirubinemia. Causes of hyperbilirubinemia mainly arise from the liver. These include haemolytic anaemias, enzymatic disorders, liver damage and gallstones. Hyperbilirubinemia itself is often benign. Only in extreme cases does kernicterus, a type of brain injury, occur. Therapy for adult hyperbilirubinemia targets the underlying diseases but patients with jaundice often have poor outcomes.
then convert biliverdin to bilirubin and release it from the cell as free, insoluble bilirubin. This form of bilirubin also is referred to as indirect-reacting or unconjugated bilirubin.
However, when jaundice is present it is likely that many other potentially toxic materials have also accumulated in the blood as a consequence of their reflux from the bile or impaired secretion from the hepatocyte. This can lead to impaired mental function and malaise.
Conjugated bilirubin is excreted into canalicular bile by way of the canalicular multispecific organic anion transport (C-MOAT) system located in the canalicular membrane within the apical region of the hepatocyte.