Hemoglobin released from red blood cells (RBCs) is broken down into heme and reduced to unconjugated (indirect) bilirubin, which is then bound to serum albumin. Unconjugated bilirubin is converted to water-soluble conjugated (direct) bilirubin in the liver and stored in the gallbladder as bile. Bile is released into the intestines to assist in digestion and cholesterol metabolism as well as absorption of lipids and fat-soluble vitamins. Hyperbilirubinemia can be due to an increase in either unconjugated bilirubin or conjugated bilirubin levels. Conditions causing increased RBC destruction or decreased conjugation lead to unconjugated hyperbilirubinemia. Conditions that impair secretion of bile from liver or gallbladder result in conjugated hyperbilirubinemia.

The patient’s age and the type of hyperbilirubinemia, whether direct or indirect, are important factors in determining the cause and treatment.

The most common causes of indirect/unconjugated hyperbilirubinemia in the first week of life are physiologic jaundice and breast milk jaundice.

Physiologic neonatal jaundice becomes visible by the second or third day, peaking by the fourth day and decreasing by seventh day of life. Physiologic jaundice is due to increased production of bilirubin following breakdown of fetal RBCs combined with limited conjugation of bilirubin by the liver. Sixty percent of full-term and 80% of preterm infants will be jaundiced in the first week after birth. In full-term infants, hyperbilirubinemia appears by the second or third day of life, peaks to around 10 to 12 mg/dL and disappears by four to five days. Six to seven percent of full-term infants have indirect bilirubin levels greater than 12.9 mg/dL, and less than 3% have levels greater than 15 mg/dL. In preterm infants, hyperbilirubinemia appears slower at around 3 to 5 days of life, peaks around 15 mg/dL, and disappears by 7 to 9 days.¹

Breast milk jaundice is a common cause of neonatal unconjugated hyperbilirubinemia. It is due to beta-glucuronidases and nonesterified fatty acids in breast milk that inhibit enzymes which conjugate bilirubin. Bilirubin levels peak at 2 to 3 weeks of life and may remain elevated for 3 weeks to 2 months and then resolve.

Other causes of unconjugated hyperbilirubinemia are birth trauma resulting in cephalhematomas/bruising and maternal–fetal blood group incompatibility such as ABO/Rh incompatibility that can cause excessive red blood cell breakdown.¹ Erythrocyte enzymatic defects such as G6PD and pyruvate kinase deficiency decrease RBC life span and cause hemolysis. Infections such as urinary tract infection and sepsis can impair hepatic conjugation, leading to unconjugated hyperbilirubinemia.² Inherited enzymatic disorders of hepatic uptake and conjugation such as Gilbert syndrome and Crigler–Najjar syndrome also lead to unconjugated bilirubinemia. In infants with pyloric stenosis, 10% to 25% develop jaundice due to impaired enterohepatic circulation, which corrects rapidly after surgery. Endocrine disorders such as congenital hypothyroidism cause impaired conjugation, leading to unconjugated or conjugated hyperbilirubinemia.³ Infants of diabetic mothers due to the large red cell mass and immature conjugation are prone to develop unconjugated hyperbilirubinemia. Finally, premature infants due to immature hepatic conjugation usually develop unconjugated hyperbilirubinemia⁴ (Fig. 74-1).

DIAGNOSIS

History, including prenatal and perinatal with identification of maternal blood type if possible, should be obtained. Family history should include a search for liver diseases, metabolic abnormalities, or hemolytic anemia. The presence of lethargy, fever/hypothermia, and poor feeding in an icteric neonate should alert the physician to the possibility of sepsis. History of nonbilious projectile emesis should raise concerns for pyloric stenosis. Urinary tract infections are associated with the onset of unconjugated hyperbilirubinemia after a week of age. In addition to scleral icterus, hepatomegaly, splenomegaly, cephalohematoma, and large areas of ecchymosis may be identified on a carefully performed physical examination.

ANCILLARY STUDIES

Initial studies include total and direct bilirubin to confirm the diagnosis. If hemolysis or anemia is suspected, a complete blood count with reticulocyte count, direct antibody test, blood type, serum albumin, and urine for reducing substances should be obtained. Testing for G6PD should be considered if suggested by ethnic or geographic origin. If serious bacterial infection is suspected, a full sepsis workup should be performed with prompt administration of antibiotics. Additional tests will be dictated depending on the history and physical exam, such as abdominal ultrasound for pyloric stenosis and thyroid function tests in suspected hypothyroidism.

MANAGEMENT AND COMPLICATIONS

Bilirubin level, chronologic age, gestational age, and clinical status of the patient are all considerations in the management. The goal is to prevent kernicterus, which results from the deposition of bilirubin in the brain, primarily in the basal ganglia. Kernicterus is associated with long-term impairment of coordination and hearing, and learning disabilities, with initial symptoms consisting of poor feeding, lethargy, ensuing opisthotonus, seizures, and death. The icteric newborn needs to be well hydrated and enterally fed to promote bilirubin excretion. When bilirubin rises significantly, phototherapy and/or exchange transfusion may be indicated. The specific level of serum bilirubin at which phototherapy should be initiated depends on factors such as gestational age, age of the infant, bilirubin level, and risk factors. To assist physicians in their decision to initiate phototherapy, the American Academy of Pediatrics has put forth guidelines, which are available on their website. These guidelines are for infants greater than or equal to 35 weeks’ gestation.⁵ It is important to remember that premature infants are at a greater risk for development of brain damage due to hyperbilirubinemia and hence require treatment at lower bilirubin levels. However, no specific evidence-based recommendations for initiating phototherapy in infants less than 35 weeks’ gestation exist. Consensus-based recommendations suggest that phototherapy should be initiated at 5 to 6 mg/dL in infants less than 28 weeks, 6 to 8 mg/dL in infants 28 to 29 weeks, 8 to 10 mg/dL in 30 to 31 weeks, 10 to 12 mg/dL in 32 to 33 weeks, and 12 to 14 mg/dL in infants 34 to 35 weeks’ gestation.⁶

For jaundiced breast-fed infants, interruption of breastfeeding should be discouraged. Phototherapy should be considered in these infants while continuing breastfeeding, making sure the baby is well hydrated.

Due to the risk of kernicterus, neurotoxicity, and encephalopathy, exchange transfusion must be considered when bilirubin levels are >20 mg/dL. Careful monitoring is necessary, especially for electrolyte or acid–base disturbance and infection.

Direct hyperbilirubinemia is defined as a conjugated bilirubin concentration >2 mg/dL, or if the concentration is greater than 20% total bilirubin. Neonatal direct hyperbilirubinemia is always abnormal and indicates hepatobiliary dysfunction. The most common causes of conjugated hyperbilirubinemia in neonates are biliary atresia, choledochal cyst, neonatal hepatitis, total parenteral nutrition, and metabolic disorders.⁷ Neonatal hepatitis has multiple etiologies including infections that could be viral or bacterial, idiopathic, and in association with total parenteral nutrition. TORCH infections (toxoplasmosis, other, rubella, cytomegalovirus [CMV], herpes, HIV) are the most common infectious causes. Neonatal hepatitis presents with prolonged jaundice, vomiting, and poor feeding. Symptoms usually appear in the first few weeks of life but may appear as late as 2 to 3 months. Physical examination may reveal hepatomegaly, altered mental status, or signs of a bleeding diathesis in addition to jaundice.⁸ Alpha 1-antitrypsin deficiency is the most common hereditary cause of both acute and chronic lung and liver disease that leads to conjugated hyperbilirubinemia, as well as the most common inherited disorder leading to liver transplantation.⁷ Patient presentation is highly variable and ranges from symptoms indistinguishable from idiopathic neonatal hepatitis to portal hypertension in older children. Diagnosis is based on alpha 1-antitrypsin (Pi) phenotype and liver biopsy.⁷

DIAGNOSIS AND ANCILLARY TESTING

Patient history should include a detailed prenatal and perinatal history. Family history should include the presence of childhood liver disorders and metabolic illnesses. Parents should be questioned about the presence of pale stools and dark urine, which raises the suspicion for cholestasis. Scleral icterus, hepatomegaly, and or splenomegaly may be present on physical examination (Fig. 74-2).

Diagnosis and identification of the pathologic cause is essential. Initial studies should include complete blood cell and platelet counts, coagulation studies, liver profile, and chemistry panel. TORCH titers, thyroid function tests, alpha 1-antitrypsin, and sweat test for cystic fibrosis should also be considered. Urine should be obtained for urinalysis and culture as well as for detecting reducing substances. A right upper quadrant ultrasound should be performed to identify anatomic abnormalities such as a choledochal cyst.

MANAGEMENT AND COMPLICATIONS

Neonates with direct hyperbilirubinemia require in-hospital admission and consultation with a pediatric gastroenterologist. Patients should be monitored closely for complications, particularly coagulopathy and cholestasis. Treatment depends on the underlying cause of jaundice.