Metabolism of Iron and Heme
Bilirubin in the Intestinal Tract
Most bilirubin entering the intestine in bile is in the
diglucuronide form, which is very poorly absorbed in the
small and large intestines. In the lower small intestine
and colon, bacteria remove glucuronic acid residues
and reduce bilirubin to the colorless
Exposure to air oxidizes these to urobilin
and stercobilin, respectively, (i.e., red-orange pigments
that contribute to the normal color of stool and urine).
Other degradation products of bilirubin are present in
minor amounts in feces.
Urobilinogen is excreted mostly in the feces, but a small
fraction is absorbed from the colon, enters the portal cir-
culation, is removed by the liver, and is secreted into
bile. That which is not removed from the portal blood
by the liver enters the systemic circulation and is ex-
creted by the kidneys. Urobilinogen excretion in urine nor-
mally amounts to 1-4 mg per 24 hours, as opposed to the
/xmol) excreted in feces.
Lack of urobilinogen in the urine and feces indicates bil-
iary obstruction; stools are whitish (“clay-colored”) owing
to the absence of bile pigment. Urinary and fecal urobilino-
gen excretion increases in hemolytic anemia.
Disorders of Bilirubin Metabolism
The plasma of normal subjects contains 0.1-1 mg of
bilirubin per deciliter (2-17 /zmol/L), mostly in the un-
conjugated form. Unconjugated bilirubin is known as
indirect-reacting bilirubin and conjugated bilirubin as
direct-reacting bilirubin (see Table 29-2).
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 particu-
larly affected because it is rich in elastin, which has a high
affinity for bilirubin. Reddish yellow pigments, particu-
larly 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 uncon-
jugated or conjugated bilirubin levels.
Unconjugated hyperbilirubinemias result from imbalance
between the rates of production of pigment and of its up-
take or conjugation in the liver. Because of the large re-
serve capacity of the liver for conjugation and excretion of
bilirubin, increased production seldom elevates unconju-
gated serum bilirubin to more than 3-4 mg/dL. If a greater
increase occurs, some degree of liver dysfunction prob-
ably also occurs. These disorders are usually due to de-
creased uptake of pigment by hepatocytes or to failure
of these cells to store, transport, or conjugate bilirubin.
Bilirubinuria does not accompany these disorders. Except
in infancy or when pigment gallstones form, unconjugated
hyperbilirubinemias are benign.
may be the most common cause
of mild, persistent, nonhemolytic, unconjugated hyper-
bilirubinemia. Serum bilirubin concentration rarely ex-
ceeds 5 mg/dL and usually fluctuates between 1.3 and
3 mg/dL. Other liver function tests are normal. The syn-
drome is usually asymptomatic and is detected during
routine laboratory testing or examination for other dis-
ease. Lamily studies suggest that Gilbert’s syndrome is an
autosomal dominant disorder. The unconjugated hyper-
bilirubinemia in Gilbert’s syndrome is due to decreased
UDP-glucuronyltransferase activity resulting from an
insertion mutation found in the promoter region of the
enzyme. The wild-type promoter [TAJéTAA is mutated to
TAA. Mutations affecting the coding region of the
enzyme, although rare, also occur.
Crigler-Najjar syndrome type
/activity of hepatic
bilirubin UDP-glucuronyltransferase is undetectable and
bilirubin conjugates are absent from the serum, bile, and
urine, but biliary secretion of sulfobromophthalein and in-
docyanine green is normal. The disease is apparent shortly
after birth, kernicterus develops, and death commonly oc-
curs during the neonatal period. The effectiveness of pho-
totherapy is often transient. The enzyme is not inducible
by phénobarbital. This autosomal recessive defect occurs
in all races. The Gunn strain of Wister rats has a similar
genetic defect and has been used to study the syndrome.
Crigler-Najjar syndrome type II
(Arias syndrome) is
milder, usually benign, and caused by partial deficiency
of bilirubin UDP-glucuronyltransferase. Jaundice may
not appear until the second or third decade of life. The
monoglucuronide is the predominant pigment in bile. Phé-
nobarbital induces the enzyme. Dominant and recessive
inheritance patterns have been described. An accurate
diagnosis of type 1, as opposed to type 2 Crigler-Najjar
syndrome, is essential since orthotopic liver transplanta-
tion is an important therapy for type
Conjugated hyperbilirubinemias are due to intra- or extra-
hepatic reduction to bile flow (cholestasis) with spillage of
conjugated bilirubin into the bloodstream, which may oc-
cur from injury to the endothelial cells lining bile ductules
or from reverse pinocytosis, by the hepatocytes. Since the
serum bilirubin is mostly the water-soluble glucuronide,
bilirubinuria is usually present.
Abdominal tumors, gallstones, strictures, hepatitis, and
cirrhosis can mechanically block the biliary canaliculi or