chapter 29
Metabolism of Iron and Heme
markedly decreased, but the rate of secretion is only mod-
erately depressed. Inheritance appears to be autosomal
Neonatal Hyperbilirubinemia
(Table 29-2). Birth interrupts normal placental elimina-
tion of pigment, and the “immature” liver of the neonate
must take over. Normally serum bilirubin levels rise on
the first day of life, reaching a maximum (rarely greater
than 10 mg/dL) by the third or fourth day. This type is
mostly unconjugated. If the placenta is functioning nor-
mally, jaundice will not be present at birth. If jaundice
is present at birth, a cause other than hepatic immaturity
must be sought.
low activity of bilirubin glucuronyltransferase and low
concentration of ligandin in the liver at birth. Secretion
of conjugated bilirubin into the bile is also reduced.
Hepatic immaturity may be partly due to diversion
in utero
of blood from the liver by the ductus venosus.
When this channel closes shortly after birth and normal
hepatic blood flow is established, concentrations of a num-
ber of substances rise within the hepatocytes and may in-
duce enzymes needed for their metabolism. Accumulation
of bilirubin in plasma may play an important role in hasten-
ing the maturation. Although the liver normally matures
1 - 2
weeks after birth, hypothyroidism can prolong
this process for weeks or months.
The neonate is at risk for kernicterus if the serum
unconjugated bilirubin level is higher than 17 mg/dL.
Kernicterus is characterized by yellow staining of clusters
of neuronal cell bodies in the basal ganglia, cerebellum,
and brain stem, leading to motor and cognitive deficits or
death. Immaturity and perhaps hypoxia make the blood-
brain barrier permeable to bilirubin and contribute to the
likelihood of kernicterus. The biochemical basis of biliru-
bin encephalopathy is due to many causes: inhibition
of RNA and protein synthesis, carbohydrate metabolism
(both cAMP-mediated and Ca
+-activated), phospholipid-
dependent protein kinases, enzymes involved in the elec-
tron transport system, and impaired nerve conduction.
A major complicating factor can be hemolytic anemia
such as that of
erythroblastosis fetalis
caused by Rh in-
compatibility between mother and child. The hemolysis
increases the rate of bilirubin formation, which soon over-
whelms the liver and produces severe jaundice and ker-
nicterus. Sickle cell anemia has a similar effect. Congenital
absence of bilirubin UDP-glucuronyltransferase (Crigler-
Najjar syndrome type 1) usually causes a kernicterus that is
fatal shortly after birth. Inhibition of glucuronyltransferase
by various drugs (e.g., novobiocin) or toxins can increase
the severity of neonatal jaundice. “Breast milk jaundice” is
due to the presence in breast milk of a substance (perhaps
pregnane-3a,20/l-diol) that inhibits bilirubin glucuronyl-
transferase, although the resulting unconjugated hyper-
bilirubinemia is seldom serious enough to cause neuro-
toxicity or to require discontinuation of breast-feeding.
Other risk factors for pathologic hyperbilirubinemia in-
clude Gilbert’s syndrome (discussed earlier) and glucose-
-phosphate dehydrogenase deficiency (Chapter 15).
during the
neonatal period. It can result from impaired hepatocel-
lular function or extrahepatic obstruction. Hepatocellular
defects can be caused by bacterial, viral, or parasitic in-
fections, cystic fibrosis,
i -antitrypsin deficiency, Dubin-
Johnson and Rotor’s syndromes, and other genetic disease.
Extrahepatic obstruction can be congenital (biliary atresia)
or acquired.
Treatment of neonatal jaundice is usually by photother-
apy. A decrease in bilirubin production in the neonatal
period can also be achieved by inhibiting the rate-limiting
enzyme of bilirubin formation from heme, namely, the
heme oxygenase. A potent competitive inhibitor of heme
oxygenase is the synthetic heme analogue tin (Sn4+)
protoporphyrin. When administered parenterally, the tin
protoporphyrin safely decreases bilirubin formation. Ex-
change transfusions also rapidly decrease plasma bilirubin
Supplemental Readings and References
B. R. Bacon, J. K. Olynyk, E. M. Brunt, et al.: HFE genotype in patients with
hemochromatosis and other liver disease.
A n n a ls o f In tern a l M ed icin e
N. C. Andrews: Disorders of iron metabolism.
N ew E n g la n d Jo u rn a l o f
M ed icin e
341, 1986 (1999).
J. D. Arnold, A. D. Mumford, J. O. Lindsay, et at: Hyperferritinaemia in
the absence of iron overload.
G u t
41,408 (1997).
M. C. Augustine: Hyperbilirubinemia in the healthy term newborn.
N u rse
P ra ctitio n er
24, 24 (1999).
B. R. Bacon, L. W. Powell, P. C. Adams, et al.: Molecular medicine and
hemochromatosis: at the crossroads.
G a stro en tero lo g y
116, 193 ( 1999)
J. D. Bancroft, B. Kreamer, and G. R. Gourlev: Gilbert syndrome accel-
erates development of neonatal jaundice.
J o u rn a l o f P ediatrics
132, 656
T. H. Bothwell and A. P. MacPhall: Hereditary hemochromatosis: etiologic.
pathologic, and clinical aspects.
S em in a rs in H em a to lo g y
35, 55 (1998).
S. S. Bottomley: Secondary iron overload disorders.
S em in a rs in H em a to lo g y
N. Chalasani, N. R. Chowdhury, J. R. Chowdhury, et al.: Kernicterus in an
adult who is heterozygous for Crigler-Najjar syndrome and homozygous
for Gilbert-type genetic defect.
G a stro en tero lo g y
112, 2099 (1997).
M. E. Conrad: Introduction: iron overloading disorders and iron regulation.
S em in a rs in H em a to lo g y
35, 1
R. W. I. Cooke: New approach to prevention of kernicterus.
L a n cet
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