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Pathogenesis and etiology of unconjugated hyperbilirubinemia

in the newborn
Author
Ronald J Wong, BA
Vinod K Bhutani,
FAAP

Section Editor
Steven A Abrams,
MD, Elizabeth B Rand, MD

Deputy Editor
MD Melanie S Kim, MD

Last literature review for version 17.2: Maio 1, 2009 | This topic last updated:
Outubro 2, 2007
INTRODUCTION Almost all newborn infants develop a total serum bilirubin (TSB)
level greater than 1 mg/dL (17 micromol/L), which is the upper limit of normal for adults.
As the TSB increases, it produces neonatal jaundice, the yellowish discoloration of the skin
and/or sclerae caused by bilirubin deposition [1].
Hyperbilirubinemia in infants 35 weeks gestation is defined as a TSB >95th percentile for
hours-of-age on the Bhutani nomogram [2]. Hyperbilirubinemia with a TSB >25 to 30
mg/dL (428 to 513 micromol/L) is associated with an increased risk for bilirubin-induced
neurologic dysfunction (BIND) (show figure 1), which occurs when bilirubin crosses the
blood-brain barrier and binds to brain tissue. The term "acute bilirubin encephalopathy"
(ABE) is used to describe the acute manifestations of BIND. The term "kernicterus" is used
to describe the chronic and permanent sequelae of BIND. Appropriate intervention is
important to consider in every infant with severe hyperbilirubinemia. However, even if
these infants are adequately treated, long-term neurologic sequelae (kernicterus) can
sometimes develop.
The pathogenesis and etiology of neonatal unconjugated hyperbilirubinemia is reviewed
here. The clinical features, evaluation, and treatment of this disorder are discussed
separately.
BILIRUBIN METABOLISM Knowledge of the basic steps in bilirubin metabolism is
essential to the understanding of the pathogenesis of neonatal hyperbilirubinemia. Bilirubin
metabolism is briefly reviewed here and is discussed in detail separately.
Bilirubin production Bilirubin is a product of heme catabolism. Approximately 80 to 90
percent of bilirubin is produced during the breakdown of hemoglobin from red blood cells
(RBCs) or from ineffective erythropoiesis. The remaining 10 to 20 percent is derived from
the breakdown of other heme-containing proteins, such as cytochromes and catalase.
Bilirubin is formed in two steps. The enzyme heme oxygenase (HO), located in the spleen
and liver as well as all nucleated cells, catalyzes the breakdown of heme, resulting in the
formation of equimolar quantities of carbon monoxide (CO) and biliverdin. Biliverdin then
is converted to bilirubin by the enzyme biliverdin reductase. Measurements of CO
production, such as end tidal CO (ETCO) or carboxyhemoglobin (COHb), both corrected

for inhaled CO, can be used as indices of in vivo bilirubin production, section on End-tidal
carbon monoxide concentration).
Bilirubin clearance and excretion Clearance and excretion of bilirubin occurs in the
following steps (show figure 1):

Hepatic uptake Circulating bilirubin, which is bound to albumin, is transported


to the liver. Bilirubin dissociates from albumin and is taken up by hepatocytes,
where it is processed for excretion.

Conjugation

In
hepatocytes,
uridine
diphosphogluconurate
glucuronosyltransferase (UGT) catalyzes the conjugation of bilirubin with
glucuronic acid, producing bilirubin diglucuronides and, to a lesser degree, bilirubin
monoglucuronides. Conjugated bilirubin, which is more water soluble than
unconjugated bilirubin, is excreted in bile.

Biliary excretion Conjugated bilirubin is secreted into the bile in an active


process that depends upon canalicular transporters, and then excreted into the
digestive tract (show figure 1). Conjugated bilirubin cannot be reabsorbed by the
intestinal epithelial cells. It is broken down in the intestine by bacterial enzymes
and, in the adult it is reduced to urobilin by bacterial enzymes. But at birth the
infant's gut is sterile and, subsequently, infants have far fewer bacteria in the gut, so
very little, if any, conjugated bilirubin is reduced to urobilin. Infants have betaglucuronidase in the intestinal mucosa, which deconjugates the conjugated bilirubin.
The unconjugated bilirubin can now be reabsorbed through the intestinal wall and
recycled into the circulation, a process known as the "enterohepatic circulation of
bilirubin".

NEONATAL JAUNDICE Nonpathologic jaundice is caused by normal neonatal changes


in bilirubin metabolism resulting in increased bilirubin production, decreased bilirubin
clearance, and increased enterohepatic circulation.

In term newborn infants, bilirubin production is two to three times higher than in
adults. This occurs because newborns have more red blood cells (hematocrit
between 50 to 60 percent) and a shorter red cell life span (approximately 85 days)
than adults. The increased turnover of more red blood cells produces more bilirubin.

Bilirubin clearance is decreased in newborns, mainly due to the deficiency of the


enzyme UGT. UGT activity in term infants at 7 days of age is approximately 1
percent of the adult liver and does not reach adult levels until 14 weeks of age [3,4].

There is an increase in the enterohepatic circulation of bilirubin, further increasing


the bilirubin load in the infant.

These normal physiologic alterations generally result in the mild unconjugated (indirectreacting) bilirubinemia that occurs in nearly all newborns [1].

In Caucasian and African-American infants, the mean peak TSB occurs 48 to 96


hours of age and is 7 to 9 mg/dL (120 to 154 micromol/L). The 95th percentile
ranges from 13 to 18 mg/dL (222 to 308 micromol/L) [5].

In some Asian infants, mean TSB levels can reach 10 to 14 mg/L (171 to 239
micromol/L) and can occur later, between 72 and 120 hours of age.

Primary neonatal jaundice resolves within the first one to two weeks after birth.
Peak TSB is also later in infants born at 35 to 37 weeks gestation. Physiologic jaundice
resolves within the first one to two weeks after birth, usually by the fifth day in Caucasian
and African-American infants, and by the 10th day in Asian infants.
Differences in TSB levels among races may result from specific genetic variations in
conjugating ability [1]. As an example, polymorphisms in the UGT gene (UGT1A1), due to
differences in the number of thymine-adenine (TA) repeats in the promoter region of the
gene, vary among individuals of Asian, African, and Caucasian ancestry [6]. These
polymorphisms correlate with decreases in UGT enzyme activity resulting in increased
TSB levels.
Another cause of racial variation in the development of neonatal jaundice results from a
common mutation in the UGT gene at Gly71Arg that occurs in Asians. This mutation leads
to an increased incidence of severe neonatal hyperbilirubinemia (approximately 20 percent)
in Asians [7].
HYPERBILIRUBINEMIA Hyperbilirubinemia (defined as a TSB >95th percentile for
hours-of-age on the Bhutani nomogram [2]) can be caused by certain pathologic conditions
or by exaggeration of the mechanisms responsible for neonatal jaundice. Identification of
the cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic
interventions can prevent severe hyperbilirubinemia.
The following features suggest severe hyperbilirubinemia [8]:

Jaundice in the first 24 hours (usually caused by increased bilirubin production due
to hemolysis)

Total serum bilirubin (TSB) greater than the age-in-hours specific 95th percentile
(show figure 2). The risk for severe hyperbilirubinemia and the threshold for
intervention based upon the hour-specific bilirubin value may be determined using
the newborn hyperbilirubinemia assessment calculator

Rate of TSB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour

Jaundice in a term newborn after 2 weeks of age

Direct (conjugated) bilirubin concentration >1.0 mg/dL (17 micromol/L) if the total
bilirubin is <5.0 mg/dL (86 micromol/L), or more than 20 percent of the total
bilirubin if the total bilirubin is >5.0 mg/dL (86 micromol/L) [9]. An increase in
direct (conjugated) bilirubin is suggestive of cholestasis.

CAUSES
Increased production The most common cause of pathologic indirect hyperbilirubinemia
is increased bilirubin production due to hemolytic disease processes that include the
following [5-7,10-13]:

Isoimmune-mediated hemolysis (eg, ABO or Rh(D) incompatibility).


Inherited red cell membrane defects (eg, hereditary spherocytosis and
elliptocytosis).
Erythrocyte enzymatic defects (eg, glucose-6-phosphate dehydrogenase (G6PD)
deficiency, pyruvate kinase deficiency, and congenital erythropoietic porphyria).
Sepsis is a known cause of hemolysis. The mechanism is not known; however, one
theory suggests that increased oxidative stress due to sepsis damages neonatal
erythrocytes that are susceptible to cell injury [5].

Other causes of increased bilirubin production due to increased red blood cell breakdown
include polycythemia or sequestration of blood within a closed space, which occurs in
cephalohematoma. Macrosomic infants of diabetic mothers (IDM) also have increased
bilirubin production due to either polycythemia or ineffective erythropoiesis.
Decreased clearance Inherited defects in UGT decrease bilirubin conjugation, thereby
reducing hepatic bilirubin clearance and increasing TSB levels. These disorders include
Crigler-Najjar syndrome types I and II and Gilbert's syndrome, which are briefly
summarized below and discussed in detail separately.
Crigler-Najjar syndrome There are two variants of Crigler-Najjar syndrome.
Crigler-Najjar syndrome type I (CN-I) Crigler-Najjar syndrome type I (CN-I) is the most
severe form of inherited UGT disorders. UGT activity is essentially absent, and severe
hyperbilirubinemia develops in the first two to three days after birth. Lifelong phototherapy
is required to avoid BIND unless liver transplantation is performed. The mode of
inheritance is autosomal recessive.

Crigler-Najjar syndrome type II Crigler-Najjar syndrome type II (CN-II) is less


severe than is CN-I. UGT activity in this disorder is low but detectable. Although
some affected children develop severe jaundice, the hyperbilirubinemia often
responds to phenobarbital treatment. CN-II usually is inherited in an autosomal
recessive manner, although autosomal dominant transmission occurs in some cases.

Gilbert's syndrome Gilbert's syndrome is the most common inherited disorder of


bilirubin glucuronidation. It results from a mutation in the promoter region of the UGT1A1

gene [14]. The mutation causes a reduced production of UGT, leading to unconjugated
hyperbilirubinemia.
In the United States, 9 percent of the population is homozygous and 42 percent
heterozygous for the Gilbert's mutation [15]. Newborns who are homozygous for the gene
mutation have a higher incidence of jaundice during the first two days after birth than
normal infants or those who are heterozygous [16].
The Gilbert's genotype is particularly clinically apparent when affected newborns have
increased bilirubin production or enhanced enterohepatic circulation. As an example, in one
study, infants with the normal Gilbert's genotype did not produce an increase in the
incidence of hyperbilirubinemia, 9.7 percent of the deficient infants and 9.9 percent of the
G6PD-sufficient normal infants had a TSB 15 mg/dL (257 micromol/L) [17]. However,
hyperbilirubinemia was more frequent in G6PD-deficient infants who were homozygous or
heterozygous for the Gilbert's mutation (50 and 32 percent, respectively). In another study
of male infants with G-6PD deficiency, mean total plasma bilirubin (TSB) was highest in
patients who were homozygotes (11.1 mg/dL [190 micromol/L]), followed by
heterozygotes for the Gilbert mutation (9.1 mg/dL [156 micromol/L]), and those without
the mutation (8.8 mg/dL [150 micromol/L]) [18].
The combination of an usually benign polymorphism of Gilbert's genotype coupled with
another factor that increases TSB may be the underlying cause of some of the rare cases of
infants with extremely high TSB levels (>25 mg/dL [428 micromol/L]) [19].
OATP-2 polymorphism In addition to the polymorphisms of the of the UGT gene
discussed above, a study of Taiwanese newborns reported that those with a polymorphic
variant of the organic anion transporter protein OATP-2 (also known as OATP-C) were
more likely to develop severe hyperbilirubinemia [20]. Furthermore, the combination of the
OATP-2 polymorphism with a UGT1A1 gene mutation increased this risk. Thus,
genetically defined impairments in hepatic bilirubin uptake and conjugation can be
important contributors to the development of neonatal hyperbilirubinemia.
Other causes Other causes of decreased bilirubin clearance include congenital
hypothyroidism and galactosemia, although in the latter case, infants typically present with
elevated conjugated hyperbilirubinemia. These conditions usually are identified by
metabolic screening programs, however, infants may develop severe and prolonged
jaundice before screening results become available.
Increased enterohepatic circulation The major causes of increased enterohepatic
circulation of bilirubin are breastfeeding failure jaundice, breast milk jaundice, or impaired
intestinal motility caused by functional or anatomic obstruction.
Breastfeeding failure jaundice Failure to establish effective breastfeeding has become an
increasing problem due to shortened postpartum length of stay for newborn infants and
their mothers. Maternal factors, such as improper technique, engorgement, cracked nipples,
and fatigue, as well as neonatal factors, such as ineffective suck, may not be addressed prior
to hospital discharge and result in ineffective breastfeeding.

Breastfeeding failure leads to a weight loss of the infant by the third or fifth day of life and
can also lead to hypovolemia, hypernatremia (serum sodium >150 mEq/L), and/or jaundice.
Increased surveillance is needed for infants born at 35 to 37 weeks gestation because they
are at increased risk for early difficulty with breastfeeding.
Breastfeeding failure jaundice is an exaggeration of neonatal jaundice. An increased
enterohepatic circulation together with a reduced enteral intake is thought to be primarily
responsible for increased TSB [3,21,22]. In one report, infants who were breastfed
compared to bottle-fed infants at day three of life were more likely to have TSB
concentrations >12.9 mg/dL (221 micromol/L), 8.9 versus 2.2 percent [23]. In another
report, infants fed human milk compared with those fed formula had higher TSB on day
three of life and lower volumes of stool and urine output during the first week of life [24].
Breast milk jaundice Breastfeeding failure jaundice that occurs in the first few days after
birth must be distinguished from breast milk jaundice, which typically begins after the first
three to five days, peaks within two weeks after birth, and progressively declines to normal
levels over 3 to 12 weeks [25].
One possible mechanism for increased TSB in breastfed compared to formula-fed infants is
the increased concentration of beta-glucuronidase in breast milk [26]. Beta-glucuronidase
deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing
enterohepatic circulation). Blocking the deconjugation of bilirubin through betaglucuronidase inhibition may provide a mechanism to reduce intestinal absorption of
bilirubin in breastfed infants [27].
Intestinal obstruction Ileus or anatomic causes of intestinal obstruction increase the
enterohepatic circulation of bilirubin and result in jaundice. TSB levels are frequently
higher with small bowel than with large bowel obstruction. As an example, jaundice occurs
in 10 to 25 percent of infants with pyloric stenosis when vomiting begins.
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SUMMARY

Total serum bilirubin (TSB) levels >1 mg/dL (17 micromol/L) occur in almost all
term and nearterm newborn infants. Infants with severe hyperbilirubinemia (TSB
>25 to 30 mg/dL [428 to 513 micromol/L]) are at risk for bilirubin-induced
neurologic dysfunction (BIND), presenting acutely as acute bilirubin
encephalopathy (ABE) and, if inadequately treated, long-term neurologic sequelae
or kernicterus.

Neonatal jaundice is primarily caused by normal neonatal alterations in bilirubin


metabolism including increased bilirubin production, decreased bilirubin clearance,
and increased enterohepatic circulation. These alterations generally result in mild

unconjugated (indirect-reacting) bilirubinemia with peak total serum bilirubin


(TSB) of 7 to 9 mg/dL (120 to 154 micromol/L) in Caucasian and African-American
infants and higher values in Asian infants, 10 to 14 mg/L (171 to 239 micromol/L).

Hyperbilirubinemia is caused by exaggeration of mechanisms that cause neonatal


jaundice or by pathologic conditions that increase bilirubin production, decrease
bilirubin clearance, or increase the enterohepatic circulation. Identification of the
cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic
interventions can prevent severe hyperbilirubinemia.

The following clinical findings are predictors for hyperbilirubinemia:

- Jaundice in the first 24 hours of life.


- TSB greater than the age-in-hours-specific 95th percentile (show figure 2).
- Conjugated bilirubin concentration >1.0 mg/dL (17 micromol/L) if the total bilirubin
is <5.0 mg/dL (86 micromol/L), or more than 20 percent of the total bilirubin if the total
bilirubin is >5.0 mg/dL (86 micromol/L). Conjugated bilirubinemia suggests neonatal
cholestasis.
- Rate of TSB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour.
- Jaundice in a term newborn after 2 weeks of age.

Causes of hyperbilirubinemia can be classified by pathogenesis as follows:

- Increased production Hemolytic disease, polycythemia, and sequestration of blood


within a closed space increase bilirubin production because of increased red cell
breakdown.
- Decreased clearance Inherited defects in uridine diphosphogluconurate
glucuronosyl transferase (UGT), such as Crigler-Najjar syndrome types I and II and
Gilbert's syndrome. In addition, metabolic disorders, such as congenital hypothyroidism,
galactosemia, and infants of diabetic mothers [28], can decrease bilirubin clearance.
- Increased enterohepatic circulation of bilirubin Breastfeeding failure jaundice,
breast milk jaundice, and impaired intestinal motility caused by functional or anatomic
obstruction increase enterohepatic circulation of bilirubin.
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GRAPHICSBilirubin

throughput

in

hepatocytes

Schematic representation of the steps involved in bilirubin (B) throughput in hepatocytes:


transport to the liver (primarily as albumin-bound bilirubin), uptake at the sinusoidal
membrane, intracellular binding, conjugation (glucuronidation), and canalicular excretion.
Sinusoidal bilirubin uptake requires inorganic anions, such as chloride, and is thought to be
mediated by carrier proteins. Within the hepatocyte, bilirubin binds to glutathione Stransferases (GSTs). GST-binding reduces the efflux of the internalized bilirubin, thereby
increasing the net uptake. GSTs also bind bilirubin glucuronides prior to excretion.
Bilirubin also enters hepatocytes by passive diffusion. Glucuronidation of bilirubin is
mediated by a family of enzymes, termed uridinediphosphoglucuronosyltransferase (UGT),
the most important of which is bilirubin-UGT-1 (UGT1A1). Conjugated bilirubin is
secreted actively across the bile canalicular membrane of the hepatocyte against a
concentration gradient that may reach 1:1000. The canalicular multi-drug resistance protein
2 (MRP2) appears to be the most important for the canalicular secretion of bilirubin.

Nomogram of hour-specific serum total bilirubin (STB) concentration in healthy term and
near-term
newborns

The red, blue, and green lines denote the 95th, 75th, and 40th percentiles, respectively. Risk
zones are designated according to percentile: high (STB 95th), high intermediate (95th >
STB 75th), low intermediate (75th > STB 40th), and low (STB < 40th). Infants with
values in the high risk zone are at increased risk for the development of clinically
significant hyperbilirubinemia requiring intervention. Courtesy of Vinod Bhutani, MD.
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