Page 263 - Color_Atlas_of_Physiology_5th_Ed._-_A._Despopoulos_2003

Excretory Liver Function—Bilirubin bilirubin). It is a water-soluble substance
secreted into the biliary canaliculi by primary
The liver detoxifies and excretes many mostly active transport mechanisms (cMOAT, see
lipophilic substances, which are either above).
generated during metabolism (e.g., bilirubin or Bilirubin excretion. 200–250 mg of bilirubin
steroid hormones) or come from the intestinal is excreted in the bile each day. Ca. 90% of it is
tract (e.g., the antibiotic chloramphenicol). excreted in the feces. In the gut, bacteria break
However, this requires prior biotransforma- bilirubin down into the colorless compound,
tion of the substances. In the first step of the stercobilinogen (! B). It is partly oxidized into
process, reactive OH, NH 2 or COOH groups are stercobilin, the brown compound that colors
enzymatically added (e.g., by monooxy- the stools. About 10% of all bilirubin diglu-
genases) to the hydrophobic substances. In the curonide is deconjugated by intestinal bacteria
Nutrition and Digestion cine, sulfates, etc. The conjugates are now circulation. A small portion (ca. 1%) reaches
second step, the substances are conjugated
and returned to the liver in this lipophilic form
with glucuronic acid, acetate, glutathione, gly-
(partly as stercobilinogen) via enterohepatic
water-soluble and can be either further
the systemic circulation and is excreted by the
processed in the kidneys and excreted in the
kidneys as urobilinogen = stercobilinogen (see
urine, or secreted into bile by liver cells and ex-
below) (! B). The renal excretion rate in-
creted in the feces. Glutathione conjugates, for
creases when the liver is damaged.
excreted as mercapturic acids in the urine.
does not exceed 17µmol/L (= 1 mg/dL). Concentra-
tions higher than 30µmol/L (1.8 mg/dL) lead to yel-
10 example, are further processed in the kidney Jaundice. The plasma bilirubin concentration normally
Carriers. The canalicular membrane of hepatocytes
contains various carriers, most of which are directly lowish discoloration of the sclera and skin, resulting
fueled by ATP (see also p. 248). The principal carriers in jaundice (icterus). Types of jaundice:
are: MDR1 (multidrug resistance protein 1) for rela- 1. Prehepatic jaundice. When excessive amounts
tively hydrophobic, mainly cationic metabolites, of bilirubin are formed, for example, due to increased
MDR3 for phosphatidylcholine (! p. 248), and hemolysis, the liver can no longer cope with the
cMOAT (canalicular multispecific organic anion higher load unless the plasma bilirubin concentration
transporter = multidrug resistance protein MRP2) for rises. Thus, unconjugated (indirect) bilirubin is mainly
conjugates (formed with glutathione, glucuronic elevated in these patients.
acid or sulfate) and many other organic anions. 2. Intrahepatic jaundice. The main causes are (a)
liver cell damage due to toxins (Amanita) or infec-
Bilirubin sources and conjugation. Ca. 85% of tions (viral hepatitis) resulting in the impairment of
all bilirubin originates from the hemoglobin in bilirubin transport and conjugation; (b) deficiency or
erythrocytes; the rest is produced by other absence of the glucuronyltransferase system in the
hemoproteins like cytochrome (! A and B). newborn (Crigler–Najjar syndrome); (c) inhibition of
When degraded, the globulin and iron com- glucuronyltransferase, e.g., by steroids; (d) impaired
ponents (! p. 90) are cleaved from hemoglo- secretion of bilirubin into the biliary canaliculi due to
a congenital defect (Dubin–Johnson syndrome) or
bin. Via intermediate steps, biliverdin and fi- other reasons (e.g., drugs, steroid hormones).
nally bilirubin, the yellow bile pigment, are 3. Posthepatic jaundice: Impairment of the flow
then formed from the porphyrin residue. Each of bile occurs due to an obstruction (e.g., stone or
gram of hemoglobin yields ca. 35 mg of biliru- tumor) in the bile ducts, usually accompanied by ele-
bin. Free unconjugated bilirubin (“indirect” vated serum concentrations of conjugated (direct) bil-
bilirubin) is poorly soluble in water, yet lipid- irubin and alkaline phosphatase—both of which are
soluble and toxic. It is therefore complexed normal components of bile.
Types 2a, 2d and 3 jaundice are associated with in-
with albumin when present in the blood (2 mol creased urinary concentrations of conjugated biliru-
bilirubin : 1 mol albumin), but not when ab- bin, leading to brownish discoloration of the urine. In
sorbed by hepatocytes (! A). Bilirubin is con- type 3 jaundice, the stools are gray due to the lack of
jugated (catalyzed by glucuronyltransferase) bilirubin in the intestine and the resulting absence of
with 2 molecules of UDP-glucuronate (synthe- stercobilin formation.
sized from glucose, ATP and UTP) in the liver
250 cells yielding bilirubin diglucuronide (“direct”
Despopoulos, Color Atlas of Physiology © 2003 Thieme
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