Bilirubin Metabolism

Excretory Liver Function—Bilirubin

The liver detoxifies and excretes many mostly lipophilic substances, which are either generated during metabolism (e.g., bilirubin or steroid hormones) or come from the intestinal tract (e.g., the antibiotic chloramphenicol). However, this requires prior biotransformation of the substances. In the first step of the process, reactive OH, NH2 or COOH groups are enzymatically added (e.g., by monooxy-genases) to the hydrophobic substances. In the second step, the substances are conjugated with glucuronic acid, acetate, glutathione, glycine, sulfates, etc. The conjugates are now water-soluble and can be either further processed in the kidneys and excreted in the urine, or secreted into bile by liver cells and excreted in the feces. Glutathione conjugates, for example, are further processed in the kidney excreted as mercapturic acids in the urine.

Carriers. The canalicular membrane of hepatocytes contains various carriers, most of which are directly fueled by ATP (see also p. 248). The principal carriers are: MDR1 (multidrug resistance protein 1) for relatively hydrophobic, mainly cationic metabolites, MDR3 for phosphatidylcholine (^ p. 248), and cMOAT (canalicular multispecific organic anion transporter = multidrug resistance protein MRP2) for conjugates (formed with glutathione, glucuronic acid or sulfate) and many other organic anions.

Bilirubin sources and conjugation. Ca. 85% of all bilirubin originates from the hemoglobin in erythrocytes; the rest is produced by other hemoproteins like cytochrome (^ A and B). When degraded, the globulin and iron components (^ p. 90) are cleaved from hemoglobin. Via intermediate steps, biliverdin and finally bilirubin, the yellow bile pigment, are then formed from the porphyrin residue. Each gram of hemoglobin yields ca. 35 mg of bilirubin. Free unconjugated bilirubin ("indirect" bilirubin) is poorly soluble in water, yet lipid-soluble and toxic. It is therefore complexed with albumin when present in the blood (2 mol bilirubin : 1 mol albumin), but not when absorbed by hepatocytes (^ A). Bilirubin is conjugated (catalyzed by glucuronyltransferase) with 2 molecules of UDP-glucuronate (synthesized from glucose, ATP and UTP) in the liver cells yielding bilirubin diglucuronide ("direct"

bilirubin). It is a water-soluble substance secreted into the biliary canaliculi by primary active transport mechanisms (cMOAT, see above).

Bilirubin excretion. 200-250 mg of bilirubin is excreted in the bile each day. Ca. 90% of it is excreted in the feces. In the gut, bacteria break bilirubin down into the colorless compound, stercobilinogen (^ B). It is partly oxidized into stercobilin, the brown compound that colors the stools. About 10% of all bilirubin diglu-curonide is deconjugated by intestinal bacteria and returned to the liver in this lipophilic form (partly as stercobilinogen) via enterohepatic circulation. A small portion (ca. 1%) reaches the systemic circulation and is excreted by the kidneys as urobilinogen = stercobilinogen (see below) (^ B). The renal excretion rate increases when the liver is damaged.

Jaundice. The plasma bilirubin concentration normally does not exceed 17 ^mol/L (= 1 mg/dL). Concentrations higher than 30 ^mol/L (1.8 mg/dL) lead to yellowish discoloration of the sclera and skin, resulting in jaundice (icterus). Types of jaundice:

1. Prehepatic jaundice. When excessive amounts of bilirubin are formed, for example, due to increased hemolysis, the liver can no longer cope with the higher load unless the plasma bilirubin concentration rises. Thus, unconjugated (indirect) bilirubin is mainly elevated in these patients.

2. Intrahepatic jaundice. The main causes are (a) liver cell damage due to toxins (Amanita) or infections (viral hepatitis) resulting in the impairment of bilirubin transport and conjugation; (b) deficiency or absence of the glucuronyltransferase system in the newborn (Crigler—Najjar syndrome); (c) inhibition of glucuronyltransferase, e.g., by steroids; (d) impaired secretion of bilirubin into the biliary canaliculi due to a congenital defect (Dubin-Johnson syndrome) or other reasons (e.g., drugs, steroid hormones).

3. Posthepatic jaundice: Impairment of the flow of bile occurs due to an obstruction (e.g., stone or tumor) in the bile ducts, usuallyaccompanied byele-vated serum concentrations of conjugated (direct) bilirubin and alkaline phosphatase—both of which are normal components of bile.

Types 2a, 2d and 3 jaundice are associated with increased urinary concentrations of conjugated biliru-bin, leading to brownish discoloration of the urine. In type 3 jaundice, the stools are gray due to the lack of bilirubin in the intestine and the resulting absence of stercobilin formation.

Bilirubin Kinetics Model
r- B. Bilirubin metabolism and excretion

Bilirubin

230 mg/day

Bilirubin

230 mg/day

Bilirubin Stercobilinogen

in urine (urobilin, etc.)

in urine (urobilin, etc.)

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