KERNICTERUS CAUSES HYPERBILIRUBINEMIA
Category: Child Health
Abstract : kernicterus causes: Be familiar with bilirubin metabolism to understand factors leading to an increased risk of kernicterus. Bilirubin is produced during the catabolism of the heme component of red blood cells. Red cell destruction is usually increased in the immediate neonatal period; it can be pathologically elevated in the presence of immune- or nonimmune-mediated hemolytic disease. The firs
kernicterus causes:
Be familiar with bilirubin metabolism to understand factors leading to an increased risk of kernicterus. Bilirubin is produced during the catabolism of the heme component of red blood cells. Red cell destruction is usually increased in the immediate neonatal period; it can be pathologically elevated in the presence of immune- or nonimmune-mediated hemolytic disease.
The first enzyme in the catabolic cascade leading to bilirubin is heme oxygenase. A constitutive form and an inducible form exist, which are induced by physiologic stressors. The creation of bilirubin, a potentially toxic water-insoluble compound, from biliverdin, a nontoxic water-soluble substance, consumes energy.
Because of its lipophilic nature, bilirubin must be bound to albumin to travel through the blood stream. In this state, it is not free to cross the blood-brain barrier and cause kernicterus. The albumin-bilirubin complex is carried to the liver, where bilirubin enters the hepatocyte for further metabolism. Once in the liver, bilirubin is conjugated via the action of uridine diphosphate glucuronyl transferase (UDPGT), an enzyme not fully functional until 3 - 4 months of life. Conjugated bilirubin is excreted into the intestinal tract via the biliary system. Beta-glucuronidase, present in the intestinal lumen of human neonates, deconjugates the conjugated bilirubin, allowing it to be reabsorbed across the intestinal lipid cell membranes back into the blood stream where it must be re-bound to albumin to repeat the cycle. This process, called enterohepatic recirculation, is a unique neonatal phenomenon and contributes significantly to physiologic jaundice.
To summarize, the body expends energy to convert biliverdin, a nontoxic, water-soluble, easily excreted compound, into bilirubin, a potentially toxic, water-insoluble, difficult-to-excrete product. Multiple mechanisms in the neonate, some of which are initiated by adverse physiologic events, act to promote and preserve the presence of bilirubin. These mechanisms extinguish as the neonate ages.
• Increased bilirubin production: Most of the circulating bilirubin in the neonate arises from destruction of circulating RBCs. Neonates produce bilirubin at more than double the daily rate of the average adult, primarily because of the larger circulating volume of RBCs and their shorter life span. Any event resulting in increased serum bilirubin load puts the infant at risk for hyperbilirubinemia.
o Polycythemia: Prenatal factors, such as maternal smoking, maternal illness, placental insufficiency, and gestation at altitude, can result in neonatal polycythemia. Obstetric factors, such as delayed clamping of the cord, stripping the cord, or holding the baby below the level of the introitus for a prolonged period, can result in increased RBC mass in the baby. This is particularly true for babies born in the absence of a trained birth attendant.
o Hemolysis: Immune hemolytic disease, most often Rh isoimmunization (erythroblastosis fetalis), is the prototype etiology for kernicterus. ABO isoimmunization, as well as minor blood group antigens, can also cause hemolytic disease in the newborn, usually of moderate severity. Infants born to mothers of blood type O negative are at greatest risk. Abnormalities of the red cell itself can also predispose to hemolysis. These can be grouped into membrane defects, such as hereditary spherocytosis and elliptocytosis; enzyme defects, such as G6PD deficiency and pyruvate kinase deficiency; and hemoglobinopathies, such as alpha and beta thalassemias. (Sickle cell disease does not typically cause hemolytic disease in the neonatal period.)
o Extravasated blood: Significant areas of bruising, such as severe cephalohematoma or peripheral ecchymoses from birth trauma, can result in an increased bilirubin load in the serum as the blood collection resolves. Internal areas of hemorrhage, such as pulmonary or intraventricular bleeds, can also be a significant occult source of serum bilirubin.
o Enzyme induction: As mentioned previously, heme-oxygenase-one (HO-1) is the inducible form of the first enzyme involved in the creation of bilirubin. This enzyme is activated by physiologic stressors, such as hypothermia, acidosis, hypoxia, and infection.
o Epidemiologic factors: East Asian and Native American babies produce bilirubin at higher rates than do white infants; African American infants have lower production rates than do infants of other racial groups. Male infants have higher serum bilirubin levels than females. Hyperbilirubinemia also runs in families; the etiology is unclear but may relate to genetically increased levels of beta-glucuronidase in the infant, in the mother's breast milk, or both (if the infant breast fed).
• Decreased elimination:
Even with normal bilirubin production, abnormalities in transport, excretion, or both can result in an increased level of free bilirubin in the serum.
o Albumin binding
Because of its lipophilic nature, bilirubin must be bound to carrier protein to be transported in the aqueous environment of the serum. Albumin has one primary high-affinity binding site for bilirubin and two lower-affinity sites. At physiologic pH, the amount of free bilirubin (eg, bilirubin not bound to albumin) is very low. This is important because only free bilirubin is available to cross the blood-brain barrier and cause neurotoxicity. Decreased albumin binding capacity, decreased albumin binding affinity, or both can serve to increase the amount of free serum bilirubin. Binding affinity is lower in neonates than in older infants and is lower still in premature and sick infants than in healthy term ones.
Decreased binding capacity can occur in hypoalbuminemia or if the binding sites are filled with other anions. Controversy exists regarding whether parenterally administered lipid can displace bilirubin from its albumin-binding site. If faced with dangerously high levels of serum bilirubin, restricting lipid administration to less than maximal levels may be prudent. Drugs, such as sulfisoxazole and ceftriaxone, can also compete for bilirubin-binding sites on the albumin molecule and must be used with caution or avoided in the neonatal period.
o Hepatic uptake and conjugation Albumin carries bilirubin to the liver, where it is incorporated into the hepatocyte by an acceptor protein called ligandin. Hepatic levels of ligandin do not reach adult values until around age 5 days, but they can be induced by administration of phenobarbital.
Once inside the hepatocyte, bilirubin is conjugated to a sugar moiety, glucuronic acid, via the enzyme UDPGT. Inherent neonatal deficiency of this enzyme is the principal etiology of physiologic jaundice. For the first 10 days of life, UDPGT is present at levels about 0.1% of adult values, and hyperbilirubinemia appears to be the primary stimulus to enzyme production.
Beyond physiologic jaundice, congenital inherited defects in UDPGT cause pathologic hyperbilirubinemia of varying severity. Crigler-Najjar syndrome type I is the virtual absence of UDPGT and is characterized by profound refractory hyperbilirubinemia with the ongoing risk of kernicterus at any point during an individual's lifespan. Currently, liver transplant is the only definitive therapy, although experimental therapies are under investigation. Patients with Crigler-Najjar syndrome type II (ie, Arias syndrome) have a similar clinical presentation as patients with type I. However, patients with type II respond dramatically to therapy with phenobarbital, which is how the diagnosis is made.
Gilbert syndrome is characterized by a benign chronic indirect hyperbilirubinemia without evidence of liver disease or abnormality. The genetic basis for this syndrome has recently been identified as an amplified triplet repeat in the coding gene for UDPGT, and investigations are continuing to clarify the possible role of Gilbert syndrome in infants with neonatal hyperbilirubinemia.
o Excretion
Once conjugated, water-soluble bilirubin is excreted in an energy-dependent manner into the bile canaliculi for ultimate delivery into the small intestine. Disruption in this system or obstruction in the biliary system results in accumulation of conjugated bilirubin in the serum, identified by an elevation in the direct fraction of total bilirubin. Direct hyperbilirubinemia in the neonate (defined as a direct fraction greater than one third of total bilirubin) is always pathologic, and an etiology must be pursued.
In the small intestine, conjugated bilirubin cannot be reabsorbed. Intestinal florae convert it into urobilinogen, which is excreted. In the neonate, the paucity of colonic bacteria impedes this conversion. Furthermore, the neonatal gut (but not that of the adult) produces beta-glucuronidase, an enzyme that deconjugates conjugated bilirubin, releasing free bilirubin for potential absorption across the intestinal cell lipid membrane into the blood stream. Breast milk also contains beta-glucuronidase, and breast milk feedings increase the level of this enzyme in the neonatal intestine. Combined with slow intestinal motility in the first few days of life, the above factors result in what is called enterohepatic recirculation of bilirubin back into the blood stream.
• Systemic factors: Various systemic conditions increase the risk of hyperbilirubinemia and the risk of kernicterus without severe hyperbilirubinemia.
o Galactosemia: Patients with this rare inborn error of metabolism may primarily present with hyperbilirubinemia, although the direct fraction typically increases during the second week of life. The baby may manifest other characteristic signs, such as hepatomegaly, poor feeding, or lethargy. Urine for reducing substances, but not glucose, is diagnostic. Many state newborn metabolic screens include a test for this disorder.
o Hypothyroidism: Although the etiology is unclear, prolonged indirect hyperbilirubinemia is one of the typical features of congenital hypothyroidism, and this diagnosis must be ruled out in any baby with hyperbilirubinemia persisting after age 2-3 weeks. Most state metabolic screens include an assay of thyroid function, although false-negative results and delayed receipt of results may necessitate individual testing in symptomatic infants.
o Drugs: Maternal administration of oxytocin, diazepam, or promethazine may result in increased serum bilirubin in the infant. Similarly, neonatal administration of pancuronium and chloral hydrate increases bilirubin levels. Additionally, some drugs, such as sulfonamides and some penicillins, can displace bilirubin from its albumin-binding site, effectively increasing the serum concentration of free bilirubin available to cross the blood-brain barrier.
o Acidosis: Systemic acidosis decreases the binding affinity of albumin for bilirubin, resulting in increased levels of free bilirubin in the blood stream. Ready availability of protons promotes the formation of bilirubin acid (free bilirubin anion plus 2 hydrogen ions); that moiety demonstrates increased binding and transport into neural cell membranes.
o Disrupted blood-brain barrier: The neonatal blood-brain barrier is more permeable to substances than is the adult's. Administration of hyperosmolar substances, hypercarbia, asphyxia, infection (particularly meningitis), and impaired autoregulation with variations in blood pressure all may weaken capillary tight junctions, increasing capillary permeability. This, in turn, might lower the concentration at which bilirubin is toxic to the CNS.
o Breast milk feedings
The well-described physiologic jaundice observed in the first few days of life, particularly in the breastfed infant, is called breastfeeding jaundice. Breastfeeding jaundice is thought to result from multiple mechanisms, described above, which promote production and inhibit excretion of bilirubin, as well as from insufficient milk intake because of reduced mammary gland milk production in the first few days postpartum. Breastfeeding jaundice should be distinguished from breast milk jaundice.
Some breastfed infants, while clinically thriving, continue to manifest an indirect hyperbilirubinemia of unidentifiable etiology for several months. If this is witnessed in a breastfed infant, the exclusion diagnosis of breast milk jaundice may be made. Such hyperbilirubinemia is thought to be caused by persistently high levels of as-yet-unidentified components in some women's breast milk, which result in persistence of the infant's hyperbilirubinemia. One clue may be a history of similar hyperbilirubinemia in other breastfed siblings. This entity is benign.
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