A mother is concerned that her 12-day-old son’s face and chest are turning yellow. This infant was delivered vaginally after an uncomplicated term pregnancy. The baby had slight jaundice after the first day of life, but this resolved by the third day only to begin to return. The family history is significant for the father’s mildly elevated bilirubin level, which was noted on a routine checkup. With the exception of jaundice, his physical examination is normal. He is formula feeding well and shows no signs of illness.
What is the most likely diagnosis?
What is the next step in evaluating this patient?
ANSWERS TO CASE 19: Gilbert Syndrome
Summary: A healthy, 12-day-old, formula-fed male has jaundice.
• Most likely diagnosis: Gilbert syndrome.
• Next step: Serum bilirubin level.
1. Understand the etiology of physiologic neonatal jaundice.
2. Identify the causes of pathologic jaundice in a newborn.
3. Know the treatment for neonatal jaundice.
Neonatal hyperbilirubinemia results from higher rates of bilirubin production and a limited ability to excrete it. It includes physiologic jaundice and nonphysiologic jaundice. Gilbert syndrome, an example of a nonphysiologic cause of jaundice, is a genetic disorder of bilirubin metabolism, involving a decrease in the activity level of uridine diphosphate (UDP)-glucuronosyltransferase 1A1. Gilbert syndrome is a benign condition that does not require treatment; it has a prevalence rate of 2% to 10%. This infant’s father has a mildly elevated bilirubin that was incidentally discovered; he likely has Gilbert syndrome. Risk factors for neonatal physiologic jaundice include maternal diabetes, cephalohematoma, male gender, Asian origin, prematurity, polycythemia, trisomy 21, cutaneous bruising, delayed bowel movement, upper gastrointestinal obstruction, hypothyroidism, swallowed maternal blood, and a sibling with physiologic jaundice. A variety of pathologic conditions can cause nonphysiologic jaundice when excessive unconjugated bilirubin accumulates:
• Red blood cells (RBCs) are lysed at too rapid a rate.
• Transmission of unconjugated bilirubin to the liver is interrupted.
• Liver enzyme deficiencies preclude appropriate metabolism of the unconju-gated material.
Neonatal jaundice may present at birth or appear at any time during the neonatal period. Untreated severe unconjugated hyperbilirubinemia is potentially neurotoxic. Conjugated hyperbilirubinemia, although not neurotoxic, often signifies a serious underlying illness.
CONJUGATED (DIRECT) BILIRUBIN: Bilirubin chemically attached to a glucuronide by an enzymatic process in the liver.
ERYTHROBLASTOSIS FETALIS: Increased RBC destruction because of transplacental maternal antibody passage active against the infant’s RBC antigens.
HEMOLYSIS: Rapid breakdown of RBCs. Clinical and laboratory findings might include a rapid rise of serum bilirubin level (>0.5 mg/dL/h), anemia, pallor, reticulocytosis, and hepatosplenomegaly.
GILBERT SYNDROME: A genetic disorder of bilirubin metabolism, involving a decrease in the activity level of UDP-glucuronosyltransferase 1A1.
KERNICTERUS: A neurologic syndrome resulting from unconjugated bilirubin deposition in brain cells, especially the basal ganglia, globus pallidus, putamen, and caudate nuclei. Less mature or sick infants have greater susceptibility. Lethargy, poor feeding, and loss of Moro reflex are common initial signs.
POLYCYTHEMIA: A central hematocrit of 65% or higher, which can lead to blood hyperviscosity.
UNCONJUGATED (INDIRECT) BILIRUBIN: Bilirubin yet to be enzymatically attached to a glucuronide in the liver.
Physiologic jaundice comprises primarily unconjugated hyperbilirubinemia observed during the first week of life in approximately 60% of full-term infants and 80% of preterm infants.Physiologic jaundice is established by precluding known jaundice causes through history, clinical, and laboratory findings. Newborn infants have a limited ability to conjugate bilirubin and cannot readily excrete unconjugated bili-rubin. Jaundice usually begins on the face and then progresses to the chest, abdomen, and feet. Full-term newborns usually have peak bilirubin concentrations of 5 to 6 mg/dL between the second and fourth days of life.
Findings suggestive of nonphysiologic jaundice include: (1) appearance in the first 24 to 36 hours of life; (2) bilirubin rate of rise greater than 5 mg/dL/24 h; (3) bilirubin greater than 12 mg/dL in a full-term infant without other physiologic jaundice risk factors listed; and (4) jaundice that persists after 10 to 14 days of life. Nonphysiologic etiologies are commonly diagnosed in a jaundiced infant who has a family history of hemolytic disease or in an infant with concomitant pallor, hepatomegaly, splenomegaly, failure of phototherapy to lower bilirubin, vomiting, lethargy, poor feeding, excessive weight loss, apnea, or bradycardia. Causes of nonphysiologic jaundice include septicemia, biliary atresia, hepatitis, galactosemia, hypothyroidism, cystic fibrosis, congenital hemolytic anemia (eg, spherocytosis, maternal Rh or blood type sensitization), or drug-induced hemolytic anemia.
Jaundice presenting within the first 24 hours of life requires immediate attention;causes include erythroblastosis fetalis, hemorrhage, sepsis, cytomegalic inclusion disease, rubella, and congenital toxoplasmosis.Unconjugated hyper-bilirubinemia can cause kernicterus, the signs of which mimic sepsis, asphyxia, hypoglycemia, and intracranial hemorrhage. Lethargy and poor feeding are common initial signs, followed by a gravely ill appearance with respiratory distress and diminished tendon reflexes.
Approximately 2% of breast-fed full-term infants develop significant unconjugated bilirubin elevations (breast-milk jaundice) after the seventh day of life; concentrations up to 30 mg/dL during the second to third week can be seen. If breast-feeding is continued, the levels gradually decrease. Formula substitution for breast milk for 12 to 24 hours results in a rapid bilirubin level decrease; breastfeeding can be resumed without return of hyperbilirubinemia.
Infants with Gilbert syndrome may appear to have a prolonged physiologic neonatal jaundice. After the newborn period, patients will have a mildly elevated indirect bilirubin (<5 mg/dL) and are more likely to exhibit jaundice after fasting.
Full-term, asymptomatic, low-risk but jaundiced infants are monitored with serum bilirubin levels. Significant hyperbilirubinemia requires a diagnostic evaluation, including measurement of indirect and direct bilirubin concentrations, hemoglobin level, reticulocyte count, blood type, Coombs test (indirect Coombs measures antibodies to RBCs in the blood; direct Coombs test identifies antibodies on surface of the infant’s RBCs), and peripheral blood smear examination. Estimates of serum bilirubin concentrations that are based solely on clinical examination are not reliable. Noninvasive, transcutaneous measurement using multiwavelength spectral reflectance is an alternative to serum measurement.
Phototherapy is often used to treat unconjugated hyperbilirubinemia, with the unclothed infant placed under a bank of lights, the eyes shielded, and hydration maintained. The light changes the skin’s bilirubin isomerization into an excretable form. For full-term infants without hemolysis, phototherapy is initiated at the following bilirubin levels: 16-18 mg/dL at an age of 24 to 48 hours; 16-18 mg/dL at 49 to 72 hours; and more than or equal to 20 mg/dL at 72 hours or more.
Exchange transfusion is needed in a small number of jaundiced infants who do not respond to conservative measures. Small aliquots of the infant’s blood are removed via a blood vessel catheter and replaced with similar aliquots of donor blood. Risks of this procedure include air embolus, volume imbalance, arrhythmias, acidosis, respiratory distress, electrolyte imbalance, anemia or polycythemia, blood pressure fluctuation, infection, and necrotizing enterocolitis.
19.1 Which of the following decreases the risk of neurologic damage in a jaundiced newborn?
B. Displacement of bilirubin from binding sites by drugs such as sulfisoxazole
E. Maternal ingestion of phenobarbital during pregnancy
19.2 You are to return a telephone call to the mother of an 8-day-old infant who continues to have jaundice that was first noted on the second day of life. The latest data show that his most recent total and direct bilirubin levels are 12.5 and 0.9 mg/dL, respectively. You look over your chart and see that he and his mother have O type blood, the direct and indirect Coombs test is negative, his reticulocyte count is 15%, and a smear of his blood reveals no abnormal cell shapes. He is bottle-feeding well, produces normal stools and urine, and has gained weight well. Which of the following diagnoses remains in your differential diagnosis?
A. Gilbert syndrome
B. Disseminated intravascular coagulation (DIC)
E. An undiagnosed blood group isoimmunization
19.3 The hyperbilirubinemia associated with Crigler-Najjar syndrome type I is caused by which of the following?
A. Increased production of bilirubin
B. Impaired conjugation of bilirubin
C. Deficient hepatic uptake of bilirubin
D. Severe deficiency of uridine diphosphate-glucuronosyltransferase
E. Glucose-6-phosphate dehydrogenase deficiency
19.4 A 30-hour-old full-term infant has face and chest jaundice. He is breastfeeding well and has an otherwise normal examination. His bilirubin level is 15.5 mg/dL. Which of the following is the most appropriate course of action?
A. Recommend cessation of breast-feeding for 48 hours and supplement with formula.
B. Start phototherapy.
C. Wait 6 hours and retest the serum bilirubin level.
D. Start an exchange transfusion.
E. No action is needed.
19.1 E. Administration of phenobarbital induces glucuronyl transferase, thus reducing neonatal jaundice. Sepsis and acidosis increase the risk of neurologic damage by increasing the blood-brain barrier’s permeability to bilirubin. Hypoalbuminemia reduces the infant’s ability to transport unconjugated bilirubin to the liver, and similarly drugs that displace bilirubin from albumin elevate free levels of unconjugated bilirubin in the serum.
19.2 A. Gilbert syndrome would present with a negative Coombs test, a normal (or low) hemoglobin, a normal (or slightly elevated) reticulocyte count, and prolonged hyperbilirubinemia. Red cell morphology would be abnormal in DIC and spherocytosis, polycythemia would present with an elevated hemoglobin level (that listed above is normal for a newborn), and blood group isoimmunization would present with a positive Coombs test.
19.3 D. Although all infants are relatively deficient in uridine diphosphate-glucuronosyltransferase, those with Crigler-Najjar syndrome type I have a severe deficiency, causing high bilirubin levels and encephalopathy. Treatment is phototherapy. Encephalopathy is rare with Crigler-Najjar syndrome type II, in which bilirubin levels rarely exceed 20 mg/dL.
19.4 B. Although the etiology of the hyperbilirubinemia must be investigated, phototherapy should be started.
Physiologic jaundice, observed during the first week of life in the majority of infants, results from higher bilirubin production rates and a limited ability of excretion. The diagnosis is established by precluding known causes of jaundice based on history and clinical and laboratory findings.
Nonphysiologic jaundice is caused by septicemia, biliary atresia, hepatitis, galactosemia, hypothyroidism, cystic fibrosis, congenital hemolytic anemia, drug-induced hemolytic anemia, or antibodies directed at the fetal RBC.
High levels of unconjugated bilirubin may lead to kernicterus, an irreversible neurologic syndrome resulting from brain cell bilirubin deposition, especially in the basal ganglia, globus pallidus, putamen, and caudate nuclei. Less mature or sick infants are at greater risk. The signs and symptoms of kernicterus may be subtle and similar to those of sepsis, asphyxia, hypoglycemia, and intracranial hemorrhage.
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