section 29.3
Heme Catabolism
695
ducts. If obstruction affects only intrahepatic bile flow, hy-
perbilirubinemia occurs when 50% or more of the liver is
involved. Extrahepatic obstruction elevates serum biliru-
bin only if it increases the pressure in the canaliculi above
the maximum secretion pressure of the hepatocytes (about
250 mm Hg). Nonmechanical cholestasis can be caused by
bacterial infection, pregnancy, and sex steroids and other
drugs, or it may be genetically determined.
In cholestasis, bile salts and bile pigments are retained
and appear in the circulation, and steatorrhea and deficien-
cies of fat-soluble vitamins may occur. These deficiencies
are often manifested as hypoprothrombinemia (from lack
of vitamin K) and osteomalacia (from lack of vitamin D).
The magnitude depends on the degree of obstruction. If
blockage is complete, urinary urobilinogen will be absent
and the stools will have a pale, clay-like color.
Familial diseases include
Dubin-Johnson syndrome,
Rotor’s syndrome,
and
benign familial recurrent chole-
stasis.
Serum bilirubin values in Dubin-Johnson synd-
rome are the same as those found in Rotor’s syndrome
(Table 29-2). Very little is known about benign familial
recurrent cholestasis. All three disorders are uncommon
or rare, and all are benign. The liver in Dubin-Johnson
syndrome appears black on direct examination. The pig-
ment is not identical to melanin but may be a cate-
cholamine (perhaps epinephrine) polymer. The total uri-
nary coproporphyrin excretion is normal but about 80%
is the I isomer and the rest is the III isomer, the re-
verse of the normal ratio. This abnormality seems to be
diagnostic for the syndrome, provided the history and
physical examination are consistent with the diagnosis.
Obligate heterozygotes have urinary coproporphyrin pat-
terns intermediate between those of normal and affected
individuals, indicating autosomal recessive inheritance.
The hyperbilirubinemia, hepatic pigment, and urinary co-
proporphyrin abnormality may result from a defect in
porphyrin biosynthesis. Studies of sulfobromophthalein
clearance show normal storage but greatly decreased se-
cretion. Investigation of a mutation in Corriedale sheep,
which causes a similar condition, may help clarify this
poorly understood disorder.
In Rotor’s syndrome, patients lack the hepatic pigment
but have urinary coproporphyrin levels 2.5-5 times greater
than normal. Coproporphyrin type I is increased relative
to the type III isomer but not as much as in Dubin-Johnson
syndrome. Intrahepatic storage of sulfobromophthalein is
TABLE 29-2
Serum Bilirubin Levels in Normal and Some Abnormal Conditions
Condition
Bilirubin Values in mg/dL of Serum*
Total
Unconjugated
(indirect reacting)
Conjugated
(direct reacting)
Newborn
0.2-2.9
1
day
0 - 6
3 days
0.3-11
7 days
0.1-9.9
Normal (adult)
0
.
1 - 1
0.2-0.7
0.1-0.3
Hemolytic disorders (in adults)
2.2-3.4
2-3
0.2-0.4
Gilbert’s disease (probably a
1.2-3
1.1-2.7
Normal
heterogeneous group of diseases)
(rarely >5)
(rarely >5)
Glucuronyltransferase deficiency
Type I: Crigler-Najjar syndrome—
15-48
15-48
Negligible
complete deficiency
Type II: Crigler-Najjar syndrome—
6 - 2 2
6 - 2 2
Trace
partial deficiency
(up to 40 with
(up to 40 with
physiological stress)
physiological stress)
Dubin-Johnson syndrome
2.5-20
<50% of total
>50% of total
Cholestasis (severe form)
1 0
19
Cirrhosis (severe)
1 1
56
Hepatitis (acute/severe)
1 0
1.5
8.5
*To convert mg/dL to /rmol/L, multiply by 17.1.
