Bilirubin metabolism hepatic

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. 

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

Secretion across the canalicular membrane into bile appears to be the rate-limiting step in hepatic bilirubin metabolism. It is probably carrier-mediated, requires energy, is saturable, and is unaffected by bile salts. Bilirubin can be made water-soluble by conversion to its configurational isomers. These photobilirubins are formed when bilirubin is exposed to blue light of the 400- to 500-nm wavelength (Figure 29-14). Photobilirubins cannot form the intramolecular hydrogen bonds characteristic of the... 

An early observation about endogenous functions of PXR and CAR has been their implication in hepatic bile acid metabolism [48,49]. Most of the more recent findings on this topic are summarized in a number of reviews [9,50-52]. Briefly, CAR and PXR have been shown to play overlapping but not identical roles in hepatic bile acid detoxification [53,54]. Recent work has also drawn attention to the importance of PXR in cholesterol detoxification in the liver, kidney and intestine [55-59]. Both CAR and PXR are involved in bilirubin metabolism and clearance [60] activation of these pathways is of potential therapeutic interest in jaundice and chronic arthritis [61]. 

Urobilinogen is a product of bilirubin metabolism, formed as a result of bacterial action in the gut (faecal urobilinogen is referred to as stercobilinogen). It is absorbed into the blood and the greater part is re-excreted by the liver while a small part is excreted in the urine where it can be oxidized to urobilin. Decreased faecal and urinary urobilinogen excretion occurs in biliary obstruction. Increased urinary excretion of urobilinogen occurs when there is liver cell damage, as in hepatitis. 

The fact that jaundice was noticeably absent in adolescents treated in a prophylactic manner with isoniazid, despite the occurrence of abnormal SGPT values, prompted Cohen and McNamara to investigate the effects of isoniazid on bilirubin metabolism (3 ) using rats as an experimental model. They found that hepatic bilirubin glucuronyl-transferase activity was enhanced in the animals receiving the drug. Such enhanced activity could account for the absence of hyperbilirubinaemia in subjects with biochemical evidence of hepatic dysfunction whilst receiving isoniazid. 

Host factors can help to ensure selection of the most appropriate antimicrobial agent. Age is an important factor in antimicrobial selection. With regard to dose and interval, renal and hepatic function varies with age. Populations with diminished renal function include neonates and the elderly. Hepatic function in the neonate is not fully developed, and drugs that are metabolized or eliminated by this route may produce adverse effects. For example, sulfonamides and ceftriaxone may compete with bilirubin for binding sites and may result in hyperbilirubinemia and kernicterus. Gastric acidity also depends on... 

The over-production of bilirubin to the point at which the liver s capacity to metabolize is exceeded or if there is dysfunction of the liver itself due to damage or metabolic immaturity, can lead to a yellow discolouration of tissues called jaundice. The accumulation of unconjugated bilirubin in neonates, often as a result of antibody-mediated destruction of the baby s red cells is dangerous as serious and irreversible brain damage can occur. Acute or chronic damage to the adult liver (hepatitis) may cause jaundice but not brain damage. 

Part of the cholesterol newly synthesized in the liver is excreted into bile in a free non-esterified state (in constant, amount). Cholesteiol in bile is normally complexed with bile salts to form soluble cholic acids, Free cholesterol is not readily soluble and with bile stasis or decreased bile salt concentration may precipitate as gallstones. Most common gallstones are built of alternating layers of cholesterol and calcium bilirubin and consist mainly (80-90%) of cholesterol. Normally. 80% of hepatic cholesterol arising from blood or lymph is metabolized to cholic acids and is eventually excreted into the bile in the form of bile salts. 

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

Subsequent studies have shown (e.g. 5,6, Table I) that the liver of newborns is indeed deficient in enzymes needed not only for drug metabolism but also for the elimination of natural products. For example, because of the lack of UDP-glucuronyl transferase resulting in the inability to dispose of bilirubin, the newborn is at risk for brain damage by kernicterus. That PEP carboxykinase, the key catalyst of gluconeogenesis de novo is absent at 7 months and still at low titers 3 days after birth (Table I), probably contributes to the fact that transient hypoglycemia (which can also cause brain damage) represents a hazard to full term as well as premature infants. The immaturity of the hepatic enzyme composition imposes limitations on the choice of nutrients used to supplement or re-... 

The gestational age of the infant is a major factor in the development of neonatal hyperbilirubinemia. The more premature the infant is, the lower the level of expression of the enzymes necessary for synthesis of conjugated bilirubin (discussed in the section on Hepatic Metabolism of Bilirubin) and the more likely the child is to develop jaundice. Babies are not routinely screened for the cause of jaundice until the condition manifests itself. Testing would be instituted early if there were a sibling who had experienced prolonged jaundice, or if the mother is blood type O or is Rh negative. All mothers who have good prenatal care are tested for blood type and Rh antibodies. This alerts the physician to potential problems and allows the physician to anticipate the most common forms of jaundice, namely, ABO incompatibilities. 

Figure 22-3. Transport and hepatic metabolism of bilirubin. Bilirubin that is produced in phagocytes is transported to liver as an albumin-bilirubin complex. Uptake into the hepatocytes takes place in liver sinusoids. Within the hepatocyte, bilirubin is transported to the endoplasmic reticulum (microsomes) bound to glutathione S-transferase (GST). Bilirubin is made water soluble by addition of one or two glucuronic acid moieties obtained from UPD-glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. The product, conjugated bilirubin, is transported across the bile canalicular membrane for secretion into the biliary system, with subsequent movement into the intestines.

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