Bilirubin, metabolism

The plasma of normal subjects contains 0.1-1 mg of bilirubin per deciliter (2-17 /zmol/L), mostly in the unconjugated form. Unconjugated bilirubin is known as indirect-reacting bilirubin and conjugated bilirubin as direct-reacting bilirubin (see Table 29-2). 

Jaundice occurs when plasma becomes supersaturated with bilirubin ( 2-2.5 mg/dL) and the excess diffuses into the skin, sclera, and other tissues. The sclera is particularly affected because it is rich in elastin, which has a high affinity for bilirubin. Reddish yellow pigments, particularly carotene and lycopene, may give a yellowish tinge to the skin but they do not usually produce scleral coloration. Hyperbilirubinemia may result from elevation of unconjugated or conjugated bilirubin levels. 

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Berk PD, Wolkoff AW Bilirubin metabolism and the hyperbilirubinemias. In Harrison s Principles of Internal Medicine, 15th ed. Braunwald E et al (editors). McGraw-Hill, 2001. 

G10. Gydell, K., Transient effect of nicotinic acid on bilirubin metabolism and formation of carbon monoxide. Acta Med. Scand. 167, 1 (1960). 

Beutler, E., Gelbart, T., and Demina, A. (1998) Racial variability in the UDP-glucuronosyl-transferase 1 (UGTIAI) promoter a balanced polymorphism for regulation of bilirubin metabolism Proc. Natl. Acad. Sci. U. S. A. 95, 8170-8174. 

Glucuronide synthesis is the rate-determining step in hepatic bilirubin metabolism. Drugs such as phenobarbital, for example, can induce both conjugate formation and the transport process. 

An effort has been made to cover the literature from January 1963 to October 1972. Extensive referencing to studies on bilirubin metabolism (L6, S3, Wll) and on glucuronoconjugation (D8, D9), including earlier work, can be found in the review articles cited. 

Serum ALP and total bilirubin (unconjugated and conjugated fractions) are traditionally used to monitor cholestatic injury. The ALP families of enzymes are zinc metalloproteases that are present in nearly all tissues. In the liver, ALP is immu-nolocalized to the microvili of the bile canaliculus [124]. Increased synthesis of ALP and its release into the circulation occurs within hours of cholestatic injury [129]. Serum assays of 5 -nucleotidase (5 -NT) or y-glutamyltransferase activity (GGT) are used to confirm the liver as the specific origin for the elevation of ALP. Increases in serum bilirubin or bile acids are usually the result of bile retention subsequent to impaired bile flow, increased production associated with accelerated erythrocyte destruction, or altered bilirubin metabolism [129]. 

Schmid, R., Congenital defects in bilirubin metabolism. J. Clin. Invest. 36, 927 (1957). 

Iyanagi T, Emi Y, Ikushiro S. Biochemical and molecular aspects of genetic disorders of bilirubin metabolism. Biochim Biophys Acta 1998 1407(3) 173-184. 

Know the biochemistry and physiology of bilirubin and urobilinogen, be able to describe their use as diagnostic tools in liver diseases, and recognize the various disorders of bilirubin metabolism. 

Figure 7.15 Degradation of heme and bilirubin metabolism. M, methyl V, vinyl P, propyl.

Finally, there are hereditary causes of non-conjugated, nonhemolytic hyperbilirubinemias. These are Crigler-Najjar types 1 and 2 and Gilbert s syndrome (discussed in the section on Genetic Diseases of Bilirubin Metabolism). 

Bosma PJ Inherited disorders of bilirubin metabolism./ Hepalol 38 107-117, 2003. 

Gilbert s syndrome - a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population. 

Three inherited disorders of bilirubin metabolism are associated with defects in bilirubin UGT-1 activity Gilbert s syndrome, and Crigler-Najjar syndrome types I and II. Dubin-Johnson syndrome is due to a defect in the protein pump that extrudes bilirubin from the hepatocyte... 

Table 2.7 Inherited disorders of hepatic bilirubin metabolism and transport [1,4]... 

A wide range of conditions fall into this gronp. They can be roughly categorised further into those causing cholestatic disease, chronic liver disease, acute liver failure/metabolic crisis, storage disorders, disorders of bilirubin metabolism. Table 3.5 snmmarises the types of liver disease that fall into each group. 

Disorders of bilirubin metabolism Gilbert s syndrome Dubin—Johnson syndrome Crigler—Najjar syndrome... 

Bilirubin metabolism involves the liver, the intestines, and the bloodstream. 

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