The term jaundice originated from the French jaune, which means “yellow.” Jaundice, or icterus (from the Greek ikteros ), refers to the yellow discoloration of the skin, sclerae, and other tissues caused by deposition of the bile pigment bilirubin. Jaundice is a sign that the serum bilirubin concentration has risen above normal levels (approximately 1.4 mg/dL after 6 months of age; 1 mg/dL = 17 mmol/L). The intensity of the yellow color is related directly to the level of serum bilirubin and the related degree of deposition of bilirubin into the extravascular tissues. The yellow skin of hypercarotenemia is not associated with yellow sclerae.
The term bilirubin is derived from Latin ( bilis , bile; ruber , red) and was used in 1864 by Städeler to describe the red-colored bile pigment. Bilirubin is formed from the degradation of heme-containing compounds ( Figure 16-1 ). The largest source for the production of bilirubin is hemoglobin. However, other heme-containing proteins are also degraded to bilirubin, including the cytochromes, catalases, tryptophan pyrrolase, and muscle myoglobin.
The formation of bilirubin is accomplished by cleavage of the tetrapyrrole ring of protoheme (protoporphyrin IX), which results in a linear tetrapyrrole. The first enzyme system involved in the formation of bilirubin is microsomal heme oxygenase. It is located primarily in the reticuloendothelial tissues and to a lesser degree in tissue macrophages and intestinal epithelium. This enzyme system results in reduction of the porphyrin iron (Fe 3+ to Fe 2+ ) and hydroxylation of the α-methine ( C ) carbon. This α-carbon is then oxidatively excised from the tetrapyrrole ring, yielding carbon monoxide. This excision opens the ring structure and is associated with oxygenation of the two carbons adjacent to the site of cleavage. The cleaved α-carbon is excreted as carbon monoxide, and the released iron can be reused by the body. The resultant linear tetrapyrrole is biliverdin IXα. The IX designation is a result of Fischer’s grouping of the protoporphyrin isomers, group IX being the physiologic source of bilirubin.
The stereospecificity of the enzyme produces cleavage almost exclusively at the α-carbon of the tetrapyrrole. This is unlike in vitro chemical oxidation, which results in cleavage at any of the four carbons (α, β, γ, and δ), linking the four pyrrole rings, and produces equimolar amounts of the α, β, γ, and δ isomers. The central (C10) carbon on biliverdin IXα is then reduced from a methine to a methylene group ( CH 2 ), thus forming bilirubin IXα. This is accomplished by the cytosolic enzyme biliverdin reductase. The ubiquity of this enzyme results in very little biliverdin ever being present in the circulation.
Bilirubin formation can be assessed by measurement of carbon monoxide production. Such assessments indicate that the daily production rate of bilirubin is 6 to 8 mg/kg per 24 hours in healthy, full-term infants and 3 to 4 mg/kg per 24 hours in healthy adults. In mammals, approximately 80% of bilirubin produced daily originates from hemoglobin. Degradation of hepatic and renal heme appears to account for most of the remaining 20%, reflecting the very rapid turnover of certain of these heme proteins. Although the precise fate of myoglobin heme is unknown, its turnover appears to be so slow as to be relatively insignificant.
Catabolism of hemoglobin occurs largely from the sequestration of erythrocytes at the end of their life span (120 days in adult humans, 90 days in newborns, and 50 to 60 days in rats). A small fraction of newly synthesized hemoglobin is degraded in the bone marrow. This process, termed ineffective erythropoiesis , normally represents less than 3% of daily bilirubin production, but may be substantially increased in persons with hemoglobinopathies, vitamin deficiencies, or heavy metal intoxication. Infants produce more bilirubin per unit body weight because their red blood cell (RBC) mass is greater and their RBC life span is shorter. In addition, hepatic heme proteins represent a larger fraction of total body weight in infants.
Bilirubin requires biotransformation to more water-soluble derivatives before excretion from the body. Bilirubin is not linear but rather has extensive internal hydrogen bonding, as shown in Figure 16-2 . The internal hydrogen bonding of bilirubin makes the molecule extremely hydrophobic and insoluble in aqueous media. Knowledge of this stereochemistry is important for understanding phototherapy.
When bilirubin is transported from its sites of production to the liver for excretion, a carrier molecule is necessary. Albumin serves this purpose and has a very high affinity for bilirubin (affinity constant ~10 8 ).
Bilirubin is taken up into the hepatocyte from the hepatic sinusoids by either passive diffusion or a high-affinity transport protein in the basolateral plasma membrane known as organic anion transporting polypeptide 2 (human OATP2, recently named OATP1B1, under new nomenclature; transporter symbol SLC21A6). OATP1B1 also transports bilirubin glucuronides and bromsulfophthalein and various drugs, and this carrier protein is competitively inhibited by simultaneous exposure to bromsulfophthalein or indocyanine green.
Once within the aqueous environment of the hepatocyte, bilirubin is again bound by a protein carrier, glutathione S -transferase, traditionally referred to as ligandin. This is a family of cytosolic proteins that have enzymatic activity and that bind nonsubstrate ligands. Although the affinity of purified glutathione S -transferase for bilirubin (acid dissociation constant = 10 6 ) is less than that of albumin, this compound is believed to be of importance in preventing bilirubin and its conjugates from refluxing into the circulation.
Bilirubin is conjugated with glucuronic acid of the hepatocyte. The glucuronic acid donor is uridine diphosphate glucuronic acid (UDP-glucuronic acid). The enzyme responsible for this conjugation is bilirubin glucuronosyltransferase (BGT). Several different classes of glucuronosyltransferases have been described, with different substrate specificity (e.g., thyroxine, steroids, bile acids, and xenobiotics). Catalysis of bilirubin by BGT results in both monoglucuronides and diglucuronides of bilirubin (BMGs and BDGs, respectively). This conjugation disrupts the internal hydrogen bonding of bilirubin, and the resulting glucuronide conjugates are more water soluble. Depletion of hepatic UDP-glucuronic acid results in decreased BDGs and increased BMGs. BGT activity for bilirubin can be induced by narcotics, anticonvulsants, contraceptive steroids, and bilirubin itself. Alternatively, BGT activity can be decreased by caloric and protein restriction. The specific isoform responsible for bilirubin conjugation is UGT1A1 (EC 184.108.40.206), which is part of the UDP-glycosyltransferase superfamily of enzymes encoded by the UGT1 gene complex on chromosome 2. More than 130 different mutations in the UGT1 gene have been described, which cause Gilbert’s syndrome and Crigler-Najjar syndromes I and II. After bilirubin conjugation, the BMGs and BDGs are excreted through the hepatocyte canalicular membrane into the bile canaliculi. This is accomplished by the ATP-dependent transporter known as canalicular multispecific organic anion transporter (cMOAT) or multidrug resistance-associated protein (MRP2). Mutations in the cMOAT/MRP2 gene cause Dubin-Johnson syndrome. In normal adult duodenal bile, 70% to 90% of the bile pigments are BDGs and 7% to 27% are BMGs. Smaller amounts of other bilirubin conjugates are also seen. However, in normal infants, there is decreased BGT activity in the liver, and duodenal bile contains less BDG and more BMG than in the adult. After the first week of life, the rate-limiting step in bilirubin clearance is secretion of bilirubin conjugates by the hepatocyte. Canalicular secretion of bilirubin conjugates can be increased by choleretic agents (e.g., phenobarbital, ursodeoxycholic acid ) and decreased by cholestatic agents (e.g., estrogens, anabolic steroids) or pathologic conditions (e.g., liver disease, sepsis).
Under normal conditions, there is evidence that bilirubin conjugates equilibrate across the sinusoidal membrane of hepatocytes. This results in the presence of small amounts of bilirubin conjugates in the systemic circulation. If there is diminished hepatic glucuronidation of bilirubin (e.g., in the neonate), there will be a decreased amount of bilirubin conjugates present in the serum.
In many pathologic circumstances, BMGs and BDGs are not excreted from the hepatocyte fast enough to prevent reflux into the circulation. The increased serum levels of bilirubin conjugates result in the spontaneous (nonenzymatic) transesterification of bilirubin glucuronide with an amino group on albumin, producing a covalent bond between albumin and bilirubin. This product is known as delta bilirubin or bilirubin-albumin. Delta bilirubin is not formed in hyperbilirubinemic conditions unless there is elevation of the conjugated bilirubin fraction. Delta bilirubin is direct-reacting (Van den Bergh’s test) and is cleared from the circulation slowly owing to the long (~20-day ) half-life of albumin.
When bilirubin conjugates enter the intestinal lumen, several possibilities for further metabolism arise. In adults, the normal bacterial flora hydrogenate various carbon double bonds in bilirubin to produce assorted urobilinogens. Subsequent oxidation produces the related urobilins. The large number of unsaturated bonds in bilirubin results in a large family of related reduction–oxidation products known as urobilinoids, which are excreted in the feces. The conversion of bilirubin conjugates to urobilinoids is important because it blocks the intestinal absorption of bilirubin, known as the enterohepatic circulation. Neonates lack an intestinal bacterial flora and are more likely to absorb bilirubin from the intestine. This difference in bile pigment excretion between adults and neonates is demonstrated in Figures 16-3 and 16-4 . Bilirubin conjugates in the intestine can also act as substrates for either bacterial or endogenous tissue β-glucuronidase. This enzyme hydrolyzes glucuronic acid from bilirubin glucuronides. The unconjugated bilirubin produced is absorbed more rapidly from the intestine. After birth, increased intestinal β-glucuronidase can increase the neonate’s likelihood of experiencing higher serum bilirubin levels. In a prospective randomized double-blind study, β-glucuronidase inhibition was shown to be associated with increased fecal bilirubin excretion and less jaundice in breast-fed neonates.
Neonates are at risk for the intestinal absorption of bilirubin because of the following: (1) their bile contains increased levels of BMG, which allows easier conversion to bilirubin; (2) they have within the intestinal lumen significant amounts of β-glucuronidase, which hydrolyzes bilirubin conjugates to more easily absorbed bilirubin; (3) they lack intestinal flora to convert bilirubin conjugates to urobilinoids; and (4) meconium, the intestinal contents accumulated during gestation, contains significant amounts of bilirubin and β-glucuronidase. Conditions that prolong meconium passage (e.g., Hirschsprung’s disease, meconium ileus, and meconium plug syndrome) are associated with hyperbilirubinemia. Earlier passage of meconium has been shown to be associated with lower serum bilirubin levels. The enterohepatic circulation of bilirubin can be blocked by the enteral administration of compounds that bind bilirubin, such as agar, charcoal, and cholestyramine.
Assessment of Jaundice
Measurements of serum bilirubin are very common in the newborn nursery, and in one study were made at least once in 61% of full-term newborn infants. Two components of total serum bilirubin can be measured routinely in the clinical laboratory: conjugated bilirubin (direct fraction in Van den Bergh’s test because the color change takes place directly, without the addition of methanol) and unconjugated bilirubin (indirect fraction). Although the terms direct and indirect are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and delta bilirubin. Elevation of either of these fractions can result in jaundice. There is a long history of undesirable variability in the measurement of serum bilirubin fractions. Of the various laboratory methods, the Jendrassik-Grof procedure is the method of choice for total bilirubin measurement, although this method also has problems. When the total serum bilirubin level is high, factitious elevation of the direct fraction has been reported. Experimental evidence indicates that the minute fraction of bilirubin that is not bound to albumin, referred to as the unbound or “free” bilirubin concentration, correlates more strongly with bilirubin toxicity than does total bilirubin concentration. There are no clinically established methods of measuring free bilirubin, although research and new technologies continue to advance.
Two newer methods have been developed that can more accurately determine the various bilirubin fractions (unconjugated, monoconjugated, diconjugated, and albumin-bound or delta): high-performance liquid chromatography (HPLC) and multilayered slides (Ektachem). HPLC analysis is superior but too expensive and time-consuming for the clinical laboratory. HPLC analysis of serum from normal human neonates in the first 4 days of life showed that unconjugated and conjugated bilirubin levels rise in parallel, with the conjugated fraction making up only 1.2% to 1.6% of total pigment (compared with 3.6% in adults). Because of the long half-life of delta bilirubin, the conjugated bilirubin measurement indicates relief from biliary cholestasis earlier than the direct bilirubin measurement does.
There are conflicting data regarding the relative accuracy of measurements of capillary and venous serum bilirubin. However, as Maisels pointed out, the literature regarding kernicterus, phototherapy, and exchange transfusion is based on bilirubin measurements in capillary samples.
Noninvasive transcutaneous methods to assess jaundice at the point of care are available and include BiliChek (Philips Healthcare, Andover, MA) and Jaundice Meter (Drager Medical, Telford, PA). A neonatal hour-specific total serum bilirubin nomogram has been developed that can predict the risk of subsequent hyperbilirubinemia based on total serum bilirubin (TSB) (see Figure 16-5 ) or transcutaneous bilirubin (TcB), thus facilitating follow-up and intervention for infants. Predischarge TcB/TSB measurement combined with specific clinical risk factors, such as gestational age, has been shown to best predict subsequent phototherapy use.
Infants usually are not jaundiced at birth because the placenta can clear bilirubin from the fetal circulation. However, during the first week of life, most if not all infants have elevated serum bilirubin concentrations (>1.4 mg/dL). As the serum bilirubin rises, the skin becomes more jaundiced in a cephalopedal manner. Icterus is first seen in the head and progresses caudally to the palms and soles. Kramer found the following serum indirect bilirubin levels as jaundice progressed: head and neck, 4 to 8 mg/dL; upper trunk, 5 to 12 mg/dL; lower trunk and thighs, 8 to 16 mg/dL; arms and lower legs, 11 to 18 mg/dL; palms and soles, more than 15 mg/dL. When the bilirubin level was higher than 15 mg/dL, the entire body was icteric. Jaundice is best appreciated by blanching the skin with gentle digital pressure under well-illuminated (white light) conditions. Visual assessment has been shown to be unreliable as a screening tool to detect significant neonatal hyperbilirubinemia.
Moderate jaundice (>12 mg/dL) occurs in at least 12% of breast-fed infants and 4% of formula-fed infants, and severe jaundice (>15 mg/dL) occurs in 2% and 0.3% of these infants, respectively.
Fundamentally, jaundice has only two causes: increased production or decreased excretion of bilirubin. These mechanisms are not mutually exclusive; specific examples are listed in Box 16-1 . One possible clinical approach to arrive at these diagnoses is presented in Figure 16-6 .
Increased Production of Bilirubin
Fetal–maternal blood group incompatibilities
Extravascular blood in body tissues
Red blood cell abnormalities
(hemoglobinopathies, membrane and enzyme defects)
Induction of labor
Decreased Excretion of Bilirubin
Increased enterohepatic circulation of bilirubin
Inborn errors of metabolism
Hormones and drugs
Obstruction of the biliary tree
Combined Increased Production and Decreased Excretion of Bilirubin
The high incidence of jaundice in otherwise completely normal neonates has resulted in the term physiologic jaundice. However, physiologic jaundice is merely the result of a number of factors involving increased bilirubin production and decreased excretion. Jaundice should always be considered to be a sign of possible disease and not routinely explained as physiologic. Specific characteristics of neonatal jaundice to be considered abnormal until proved otherwise include the following: (1) development of jaundice before 24 hours of age; (2) persistence of jaundice beyond 10 days of age, (3) a serum bilirubin concentration higher than 12 mg/dL at any time, and (4) elevation of the direct-reacting fraction of bilirubin (≥20% of TSB if TSB ≥5 mg/dL).
Factors associated with increased neonatal bilirubin levels are prematurity, low birth weight; certain races/ethnicities (Asian, Native American, and Greek); maternal medications (e.g., oxytocin); premature rupture of the membranes; increased weight loss after birth; delayed meconium passage; breast-feeding; and neonatal infection. Factors associated with decreased neonatal bilirubin levels include maternal smoking, black race, and certain drugs given to the mother (e.g., phenobarbital).
Neonatal Jaundice Caused by Increased Production of Bilirubin
The most common cause of severe early jaundice is fetal-maternal blood group incompatibility with resulting isoimmunization. Maternal sensitization develops because of leakage of erythrocytes from the fetal to the maternal circulation. When the fetal erythrocytes carry different antigens, they are recognized as foreign by the maternal immune system, which forms antibodies against them. These antibodies (immunoglobulin G, IgG) cross the placental barrier into the fetal circulation and bind to fetal erythrocytes. In Rh blood group incompatibility, sequestration and destruction of the antibody-coated erythrocytes takes place in the reticuloendothelial system of the fetus. In ABO incompatibility, hemolysis is intravascular, complement-mediated, and usually not as severe as in Rh disease. Significant hemolysis can also result from incompatibilities between minor blood group antigens (e.g., Kell). These conditions are associated predominantly with elevation of unconjugated bilirubin, but occasionally the conjugated fraction is also increased.
Rh incompatibility usually does not develop until the second pregnancy. Therefore, prenatal blood typing and serial testing of Rh-negative mothers for the development of Rh antibodies provide important information to guide possible intrauterine care. If maternal Rh antibodies develop during pregnancy, potentially helpful measures include serial amniocentesis (with bilirubin measurement), ultrasound assessment of the fetus, intrauterine transfusion, and premature delivery. The prophylactic administration of anti-D γ-globulin has been most helpful in preventing Rh sensitization, although non-D Rh antigens (E,e, C,c) can also cause hemolytic disease of the newborn. The newborn infant with Rh incompatibility can present with pallor, hepatosplenomegaly, and a rapidly developing jaundice in the first hours of life. If the problem is severe, the infant may be born with generalized edema (fetal hydrops). Laboratory findings in the neonate’s blood include reticulocytosis, anemia, a positive direct Coombs test, and a rapidly rising serum bilirubin level. Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease and is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34 to 51 µmol/L) of the exchange level. Exchange transfusion continues to be an important therapy for seriously affected infants.
ABO incompatibility usually manifests clinically with the first pregnancy. ABO hemolytic disease is largely limited to infants with blood group A or B who are born to group O mothers. ABO hemolytic disease is relatively rare in type A or B mothers. Development of jaundice is not as rapid as with Rh disease; a serum bilirubin concentration higher than 12 mg/dL on day 3 of life would be typical. Laboratory abnormalities include reticulocytosis (>10%) and a weakly positive direct Coombs test, although this is sometimes negative. Spherocytes are the most prominent feature seen in the peripheral blood smear of neonates with ABO incompatibility.
When extravascular blood is present within the body, the hemoglobin can be rapidly converted to bilirubin by tissue macrophages. Examples of this type of increased bilirubin production include cephalohematoma; ecchymoses; petechiae; occult intracranial, intestinal, or pulmonary hemorrhage; and swallowed maternal blood. The Apt test can be used to distinguish blood of maternal or infant origin because of differences in alkali resistance between fetal and adult hemoglobin.
Polycythemia (venipuncture hematocrit >65%) can cause hyperbilirubinemia because the absolute increase in RBC mass results in elevated bilirubin production through normal rates of erythrocyte breakdown. A number of mechanisms can result in neonatal polycythemia, including maternal–fetal transfusion, a delay in cord clamping, twin–twin transfusions, intrauterine hypoxia, and maternal diseases (e.g., diabetes mellitus). Therapy for symptomatic polycythemia is partial exchange transfusion (PET); therapy for asymptomatic polycythemia remains controversial. Crystalloids are as effective as colloids in PET and are cheaper, more readily available, and confer less risk of infection or anaphylaxis.
A number of specific abnormalities related to the RBC can result in neonatal jaundice, including hemoglobinopathies and RBC membrane or enzyme defects. Hereditary spherocytosis is not usually a neonatal problem, but hemolytic crises can occur and can manifest with a rising bilirubin level and a falling hematocrit. The characteristic spherocytes seen in the peripheral blood smear may be impossible to distinguish from those seen with ABO hemolytic disease. Other hemolytic anemias associated with neonatal jaundice include drug-induced hemolysis, deficiencies of the erythrocyte enzymes (e.g., glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency), and hemolysis induced by vitamin K or bacteria. α-Thalassemia can result in severe hemolysis and lethal hydrops fetalis. γβ-Thalassemia may also occur, with hemolysis and severe neonatal hyperbilirubinemia. Drugs or other substances responsible for hemolysis can be passed to the fetus or neonate across the placenta or via the breast milk. Co-inheritance of Gilbert’s syndrome along with the above hematologic abnormalities is associated with an increased incidence of hyperbilirubinemia in neonates and older individuals.
Induction of labor with oxytocin has been shown in some studies to be associated with neonatal jaundice. There is a significant association between hyponatremia and jaundice in infants of mothers who received oxytocin to induce labor. The explanation for this observation is not clear.
Neonatal Jaundice Caused by Decreased Excretion of Bilirubin
Increased enterohepatic circulation of bilirubin is an important factor in neonatal jaundice. Conditions that prolong meconium passage (e.g., Hirschsprung’s disease, meconium ileus, meconium plug syndrome) are associated with hyperbilirubinemia, presumably by allowing more time for intestinal bilirubin absorption. Earlier passage of meconium is associated with lower serum bilirubin levels. The enterohepatic circulation of bilirubin can be blocked by enteral administration of compounds that bind bilirubin, such as agar, charcoal, and cholestyramine.
Breast-feeding has been identified as a significant factor related to neonatal jaundice. Breast-fed infants have significantly higher serum bilirubin levels than formula-fed infants on each of the first 5 days of life, and this unconjugated hyperbilirubinemia can persist for weeks to months. Research has shown that bilirubin is a significant antioxidant, which is possibly of physiologic benefit in protecting against cellular damage by free radicals. Some distinguish this early jaundice during the first week of life as “breast-feeding jaundice” to differentiate it from the later breast-milk jaundice syndrome, which occurs after the first week of life and in which the breast milk supply is well established. There is probably overlap between these conditions and physiologic jaundice. Early reports linking breast milk and jaundice with a steroid (pregnane-3α,20β-diol) in some milk samples have not been confirmed by subsequent, larger studies employing more sensitive methods. There are conflicting data regarding the association of this jaundice with increased lipase activity in the breast milk, which results in increased levels of free fatty acids that could inhibit hepatic BGT. The enterohepatic circulation of bilirubin might be facilitated by the presence of β-glucuronidase or some other substance in human milk. Other factors possibly related to jaundice in breast-fed infants include caloric intake, fluid intake, weight loss, delayed meconium passage, intestinal bacterial flora, and inhibition of BGT by an unidentified factor in the milk. It has been suggested that a healthy, breast-fed infant with unconjugated hyperbilirubinemia, normal hemoglobin concentration, normal reticulocyte count, normal blood smear, no blood group incompatibility, and no other abnormality on physical examination may be presumed to have early breast-feeding jaundice.
Because there is no specific laboratory test to confirm a diagnosis of breast milk jaundice, it is important to rule out treatable causes of jaundice before ascribing the hyperbilirubinemia to breast milk. The American Academy of Pediatrics (AAP) provides recommendations for the evaluation and treatment of neonatal jaundice. The age of the infant is important in assessing the risk hyperbilirubinemia ( Figure 16-6 ) and the need for evaluation and treatment with either phototherapy ( Figure 16-7 ) or exchange transfusion ( Figure 16-8 ). If the bilirubin level is rising, published recommendations support encouraging mothers to breast-feed more frequently, with an average suggested interval between feeds of 2 hours, and no feeding of supplements. Nursing that is more frequent may not increase intake, but it has been suggested to increase peristalsis and stool frequency, thus promoting bilirubin excretion. However, one study comparing “frequent” (9 feedings per day) versus “demand” (6.5 feedings per day) feeding schedules during the first 3 days of life showed no significant relation between the frequency of breast-feeding and infant serum bilirubin levels in 275 infants. The point at which breast-feeding should be discontinued is controversial; recommendations include total bilirubin levels of 14, 15, 16 to 17, and 18 to 20 mg/dL. When breast-feeding is interrupted, formula feeding may be initiated for 24 to 48 hours, or breast and formula feeding can be alternated with each feeding. A fall in the serum bilirubin level of 2 to 5 mg/dL is consistent with a diagnosis of breast milk jaundice. Breast-feeding may then be resumed; although the serum bilirubin levels may rise for several days, they will gradually level off and decline. In one study, interruption of breast feeding for approximately 50 hours (during which time a formula was given) was shown to have the same bilirubin-lowering effect as a similar duration of phototherapy. If formula is substituted for breast milk for several days, it is not clear which formula would be most cost-effective in lowering serum bilirubin. However, it has been shown that neonates fed a casein hydrolysate have less jaundice than neonates fed a routine formula, that casein hydrolysate formula inhibits β-glucuronidase, and that the majority of the β-glucuronidase inhibition in hydrolyzed casein is due to l-aspartic acid. A controlled randomized double-blind study showed that feedings of minimal aliquots of L-aspartic acid or enzymatically hydrolyzed casein for β-glucuronidase inhibition resulted in increased fecal bilirubin excretion and less jaundice, without disruption of the breast-feeding experience.
There is much controversy about the potential dangers of hyperbilirubinemia in full-term and near-term newborns who do not have hemolytic disease. Regardless of whether hyperbilirubinemia in these infants causes mild neurodevelopmental or intellectual handicaps, there is no doubt that frank kernicterus in this population is rare. However, it appears that in the United States we have experienced a reemergence of classic kernicterus and warnings from the Centers for Disease Control and Prevention (CDC), the AAP, and The Joint Commission indicate that otherwise healthy full-term and near-term infants are at risk. Since 1992 there has been a voluntary kernicterus registry in the United States that, as of July 2013, contained 204 individuals (personal communication). Although G6PD deficiency is present in approximately one-third of these individuals with kernicterus, another third had no obvious etiology and appeared to be healthy breast-feeding infants.
Several inborn errors of metabolism can cause neonatal hyperbilirubinemia. Crigler-Najjar syndrome (CN), or congenital nonhemolytic jaundice, is characterized by a hereditary deficiency of hepatic BGT. This syndrome may be divided into CN1 and CN2 (Arias’ syndrome) according to the response to phenobarbital—a significant decrease of serum bilirubin in CN2 and no response in CN1. In CN1, serum bilirubin levels typically range from approximately 15 to 45 mg/dL and there is a risk of both neonatal and later kernicterus. Hyperbilirubinemia is less severe in CN2 patients, varying from approximately 8 to 25 mg/dL. CN2 is associated with a much lower incidence of kernicterus, although such damage has been documented. Bile pigment analysis has been reported to aid in the differentiation of CN1 from CN2 and in the differential diagnosis of unconjugated hyperbilirubinemia. In both forms of CN, traces of monoconjugates can be detected in serum and bile, but no diconjugates are present. Whereas phenobarbital can increase the level of serum monoconjugated bilirubin even in patients with CN1, the diagnosis of CN1 versus CN2 is based on finding a substantial decrease of unconjugated bilirubin in the serum after administration of phenobarbital in CN2. In the first months of life, a phenobarbital trial can still be unsuccessful in the presence of CN2. Therapy for CN1 hyperbilirubinemia can be safe and effective to prevent kernicterus and has included life long phototherapy, bilirubin binders (agar, cholestyramine, and calcium phosphate) to interrupt the enterohepatic circulation, plasmapheresis for acute episodes of severe hyperbilirubinemia related to intercurrent illness and, rarely, heme oxygenase inhibition to prevent bilirubin production. In CN1, orthotopic and auxiliary liver transplantation have been performed, even though liver function is otherwise normal, because of concern about kernicterus. Gene therapy for CN1 is appealing but remains experimental. Several mutations in the bilirubin UDP-glucuronosyltransferase ( UGT1 ) gene of CN1 and CN2 patients have been identified, which result in complete inactivation of this enzyme in CN1 patients and markedly reduced glucuronidation in CN2 patients.
Various hormones and drugs may cause development of neonatal unconjugated hyperbilirubinemia. Congenital hypothyroidism can manifest with serum bilirubin higher than 12 mg/dL before the development of other clinical findings. Similarly, hypopituitarism and anencephaly may be associated with jaundice caused by inadequate thyroxine, which is necessary for hepatic clearance of bilirubin.
Infants of diabetic mothers have prolonged and higher serum bilirubin levels than control patients. Explanations include prematurity, polycythemia, substrate deficiency for glucuronidation (secondary to hypoglycemia), and poor hepatic perfusion (secondary to either respiratory distress, persistent fetal circulation, or cardiomyopathy).
The Lucey-Driscoll syndrome consists of neonatal hyperbilirubinemia within families in which there is in vitro inhibition of BGT by both maternal and infant serum. It is presumed that this is caused by gestational hormones.
Drugs may interfere with the metabolism of bilirubin and result in hyperbilirubinemia or displacement of bilirubin from albumin. Such displacement increases the risk of kernicterus and can be caused by sulfonamides, moxalactam, or ceftriaxone (independent of its sludge-producing effect). The popular Chinese herb, Chuen-Lin, given to 28% to 51% of Chinese newborn infants, has been shown to have a significant effect in displacing bilirubin from albumin. Pancuronium bromide, chloral hydrate, and ibuprofen have been suggested as causes of neonatal hyperbilirubinemia. Jaundice may result from drug-induced liver disease.
Prematurity is frequently associated with unconjugated hyperbilirubinemia in the neonatal period. Hepatic UDP-glucuronosyltransferase activity is markedly decreased in premature infants and rises steadily from 30 weeks of gestation until reaching adult levels at 14 weeks after birth. In addition, there may be deficiencies for both uptake and secretion. Bilirubin clearance improves rapidly after birth. Intralipid has been suggested to decrease bilirubin-binding affinity for plasma proteins and increase free bilirubin, via increases in free fatty acids, which decrease bilirubin binding affinity of albumin in infants younger than 28 weeks of gestation.
Other pathophysiology leading to neonatal jaundice is reviewed elsewhere in this textbook and includes the following: (1) metabolic diseases (e.g., galactosemia, hereditary fructose intolerance, tyrosinemia, α1-antitrypsin deficiency, and PFIC); (2) hepatic hypoperfusion where inadequate perfusion of the hepatic sinusoids may not allow sufficient hepatocyte uptake and metabolism of bilirubin (e.g., patent ductus venosus with respiratory distress syndrome, congestive heart failure, and portal venous thrombosis); and (3) obstruction of the biliary tree (e.g., biliary atresia, choledochal cyst, cholangitis, cholelithiasis from sludge produced by ceftriaxone, total parenteral nutrition, or postsurgical fasting).
Neonatal Jaundice Caused by Increased Production and Decreased Excretion of Bilirubin
In neonatal diseases with jaundice caused by decreased excretion and increased production of bilirubin, both conjugated and unconjugated bilirubin fractions can be elevated. Bacterial sepsis increases bilirubin production by producing erythrocyte hemolysis as a result of hemolysins released by bacteria. Endotoxins released by bacteria can also decrease canalicular bile secretion.
Intrauterine infection is an important cause of neonatal hepatitis and jaundice and is reviewed elsewhere in this text. Congenital cirrhosis and hepatic fibrosis have also been reported as causes of jaundice in newborn infants. Abnormal erythrocytes may contribute to bilirubin production.
Toxicity of Neonatal Jaundice
Reviews of neonatal bilirubin toxicity and the mechanisms of bilirubin cytotoxicity have been published elsewhere. Yellow staining of brain nuclei in a severely jaundiced baby was first reported by Hervieux in 1847. The term kernikterus (from the German kern , “nuclei,” and the Greek ikterus , “jaundice” or “yellow”) was first used by Schmorl in 1903, when he described similar yellow staining of certain brain nuclei in six infants who died with severe neonatal jaundice. It has been suggested that the term kernicterus should be reserved for cases exhibiting classic symptoms and findings ( Table 16-1 ), with bilirubin encephalopathy used for all the other conditions of brain damage thought to be related to jaundice, although often these terms are used interchangeably. Although kernicterus was originally a pathologic term, it has also been used to describe the acute and chronic clinical conditions shown in Table 16-1 . Historically, the most common setting in which kernicterus has occurred is maternal–infant Rh (D) blood group incompatibility. Infants with hemolytic jaundice are more vulnerable to bilirubin toxicity than are newborns with nonhemolytic uncomplicated jaundice. However, hemolysis is not necessary for kernicterus. This is strikingly exemplified by CN, a disorder in which deficient hepatic bilirubin glucuronidation results in decreased bilirubin excretion with severe hyperbilirubinemia and, potentially, kernicterus. Kernicterus also has been identified in otherwise healthy breast-fed, full-term newborn infants with no evidence of hemolysis. Although the neonatal period is the most common time for bilirubin-related brain damage, the neurotoxicity of bilirubin has also been documented in adults with CN.