Jaundice and Prolonged Hyperbilirubinemia in a 33-day-old Infant

A 33-day-old term boy with a medical history of ABO incompatibility (infant A+, mother O–, direct antiglobulin test negative) and hyperbilirubinemia requiring phototherapy and normal newborn screening presents with ongoing hyperbilirubinemia. The patient was born at 38 weeks after an uneventful pregnancy. His birthweight was 3,800 g (81st percentile), and he required intensive phototherapy for 24 hours before discharge from the newborn nursery. He was exclusively breastfed, stooling daily, and voiding normally. At a follow-up primary care visit on day 11 after birth he weighed 3,780 g (52nd percentile) and was noted to be significantly jaundiced. On day 12 after birth, his bilirubin level was found to be 20.8 mg/dL (355.76 µmol/L), direct bilirubin level was 0.30 mg/dL (5.13 µmol/L), and he was readmitted for phototherapy. At the time of discharge, his jaundice was notably improved, with a bilirubin level of 17.1 mg/dL (292.48 µmol/L). On day 31 after birth he was again noted to have significant jaundice, with a bilirubin level of 18.2 mg/dL (311.29 µmol/L) and a direct bilirubin level of 0.42 mg/dL (7.18 µmol/L), at which point he was referred to hematology. On day 33 after birth he was seen in the hematology clinic, where he weighed 4,850 g (68th percentile). Complete blood cell count showed a stable hemoglobin level of 13.1 g/dL (131 g/L) and a hematocrit value of 37.4%. Reticulocyte count was 33.8 × 103/μL (33.8 × 109/L), or 0.88%. Basic metabolic panel was normal. He underwent complete abdominal ultrasonography, which showed a normal-appearing liver, a normally distended gallbladder with no sludge or calculi, nondilated intrahepatic and extrahepatic bile ducts, and a normal spleen with no focal abnormalities. Hepatic function panel showed a significantly elevated total bilirubin level of 22.5 mg/dL (384.84 µmol/L) and a direct bilirubin level of 0.6 mg/dL (10.26 µmol/L); therefore, the decision was made to admit the patient for further evaluation.On admission, the mother of the patient reports feeling that breastfeeding is going well, with good milk production (milk supply since a few days after birth), and she is having no pain with latch. Her infant is having approximately 10 to 12 wet diapers a day, several of which have had yellow/green stool. The mother also reports that the patient’s sister required formula supplementation shortly after birth due to jaundice. In addition, the mother states that the baby has not had lethargy, vomiting, blood in stools, fevers, or seizures.On examination his vital signs are normal for age, including a temperature of 97.9°F (36.6°C), blood pressure of 104/55 mm Hg, and a respiratory rate of 36 breaths/min. Weight is currently 4,990 g (75th percentile). Head circumference is 38 cm (68th percentile). The patient is well-appearing and active. Anterior and posterior fontanelles are soft and flat, with no frontal bossing, bruising, or cephalohematoma. Scleral icterus is present, extraocular movements are intact, and pupils are equal, round, and reactive to light. Lung and cardiovascular examination findings are normal, with no murmurs and intact femoral pulses. Abdomen is mildly distended, soft, and nontender, and there is no hepatosplenomegaly or palpable masses. Neurologically, the patient is moving all extremities spontaneously and is interactive, with good tone, moro intact, and normal grasp and suck. Skin is diffusely jaundiced but has no hematomas, hemangiomas, or other notable lesions.Bilirubin level is 20.0 mg/dL (342.08 µmol/L). Hemoglobinopathy panel is normal, with 22.9% hemoglobin A, 76.9% hemoglobin F, and 0.2% hemoglobin A2. There is no evidence of hemolysis, with a normal lactate dehydrogenase level of 377 U/L (6.3 µkat/L), a haptoglobin level less than 3 mg/dL (<30 mg/L), a reticulocyte count of 33.8 × 103/μL (33.8 × 109/L), an immature reticulocyte fraction of 12%, and a normal red blood cell morphology. γ-Glutamyltransferase and α1-antitrypsin levels are also normal at 62 U/L (1.04 µkat/L) and 115 mg/dL (21.16 µmol/L), respectively. Thyroid function is normal, with a thyrotropin level of 2.080 mIU/L. Genetic testing and clinical course reveal the diagnosis.Jaundice can be visualized in children with bilirubin levels greater than or equal to 2 to 3 mg/dL (≥34.21–51.31 µmol/L) and is diagnosed during the newborn period in 60% of term and 80% of preterm infants. (1) When observed, a fractionated bilirubin level should be obtained to identify whether a patient has conjugated, unconjugated, or mixed hyperbilirubinemia. The patient in this case had unconjugated hyperbilirubinemia, which can be caused by overproduction of bilirubin (intravascular or extravascular hemolysis), defects in the glucuronidation process (Crigler-Najjar syndrome types 1 and 2, Gilbert syndrome [GS], or other UDP-glucuronosyltransferase 1A1 [UGT1A1] defects), reduced elimination of bilirubin due to increased enterohepatic circulation (intestinal obstruction, ileus), poor blood flow (heart failure or shock states), physiologic jaundice, or breastfeeding (breastfeeding jaundice, also called suboptimal intake jaundice, and breast milk jaundice). (1)(2)(3) Unconjugated hyperbilirubinemia may also be seen in disease states that cause cholestasis due to obstruction. This obstruction causes saturation of the glucuronidation pathway and accumulation of both unconjugated and conjugated bilirubin, leading to mixed hyperbilirubinemia. (1)(2)Age at onset may help narrow the differential diagnosis. Hemolysis due to maternal isoimmunization typically presents as jaundice in the first 12 to 24 hours after birth. Physiologic jaundice peaks in the first 3 to 5 days after birth and then slowly resolves over 2 to 3 weeks. Breastfeeding jaundice typically peaks in the first 3 to 5 days after birth, resolves by 2 weeks of age, and may be associated with other signs of dehydration, including weight loss and hypernatremia. (4)(5) Breast milk jaundice can be seen until up to 3 months of age. (5)(6)(7) Pathologic causes of unconjugated hyperbilirubinemia requiring intervention are typically refractory to phototherapy or lead to bilirubin levels much higher than would be expected in an age group (eg, jaundice ≤24 hours after birth, unconjugated hyperbilirubinemia [bilirubin level >20 mg/dL (>342.08 µmol/L)] at 14 days of age, or any unconjugated hyperbilirubinemia at >3 months of age). This should prompt a detailed history, complete blood cell count, alanine aminotransferase level, aspartate aminotransferase level, blood smear, and reticulocyte count. If there are signs of clinical instability, a prompt evaluation for sepsis is necessary with accompanying treatment. Anemia with an elevated reticulocyte count is concerning for hemorrhage or hemolysis (eg, disseminated intravascular coagulation, hereditary spherocytosis, or glucose-6-phosphate dehydrogenase deficiency). If the red blood cells have normal morphology, then consideration of hemorrhage or increased enterohepatic circulation must be considered. (1)(2) Other potential causes of elevated bilirubin level in this age group include hypothyroidism, infection, and poor weight gain.The evaluation showed no evidence of hemolysis, hypothyroidism, polycythemia, or conjugated hyperbilirubinemia. The patient was also outside of the age range for breastfeeding jaundice and had no evidence of infection or failure to thrive. Genetic testing showed 3 UGT1A1 gene defects: heterozygous for c.-41_-40dup (noncoding), c.10002del (p.Trp335Glyfs*31), and c.1473C>T (p.Ser488Phe). The patient’s bilirubin levels were higher than expected for UGT1A1 defect or breast milk jaundice alone. In addition, bilirubin levels improved after discontinuation of breastfeeding. The final diagnosis is prolonged hyperbilirubinemia due to a combination of breast milk jaundice and multiple UGT1A1 defects similar to GS.Breast milk jaundice causes unconjugated hyperbilirubinemia beyond 3 to 4 weeks of age and occurs in 20% to 30% of predominantly breastfed infants; 30% to 40% of these infants will have bilirubin levels greater than or equal to 5 mg/dL (≥85.52 µmol/L); however, levels rarely exceed 12.9 mg/dL (220.64 µmol/L). (5)(6) The pathophysiology of breast milk jaundice is likely multifactorial, with contributions including increased enterohepatic circulation, the presence of heme oxygenase-1 enzyme in breast milk (the rate-limiting enzyme for catabolism of heme to bilirubin) leading to bilirubin overproduction, and reduction in intestinal UGT1A1 expression. Other hypothesized contributory factors that are poorly understood include increased cytokines in human milk (interleukin-1, interleukin-11, and tumor necrosis factor), reduced antioxidant capacity and epidermal growth factor in human milk, alterations in the intestinal flora, and higher cholesterol and α-fetoprotein levels in breastfed infants. (5)(6)(7) The diagnosis is confirmed by history and unconjugated hyperbilirubinemia (bilirubin level, ≤12 mg/dL [≤205.25 µmol/L]). (5)(6) In an infant older than 2 to 3 weeks, an unconjugated bilirubin level greater than 12 mg/dL (>205.25 µmol/L) warrants further evaluation for causes other than isolated breast milk jaundice, including genetic, obstructive, hemolytic, infectious, or metabolic causes for hyperbilirubinemia. (2) Breast milk jaundice with coexisting causes for hyperbilirubinemia, such as hereditary spherocytosis and UGT1A1 defects (including GS), can lead to more severe presentations of breast milk jaundice. (8)(9) Bilirubin levels higher than 25 mg/dL (>427.60 µmol/L) significantly increase the risk of developing kernicterus, so guidelines recommend phototherapy, the addition of oral and/or intravenous hydration, and consideration of exchange transfusion when bilirubin levels reach 20 to 25 mg/dL (342.08–427.60 µmol/L). (2)(4)(10)(11)(12) Per the new American Academy of Pediatrics guidelines, formula supplementation is not necessary if an infant appears well-hydrated but may be implemented should the parents request it. (4)This patient had breast milk jaundice with concomitant UGT1A1 gene defects. UGT1A1 defects cause varying degrees of UDP-glucuronosyltransferase enzyme insufficiency/bilirubin glucuronidation deficiency and are seen in various syndromes, including GS, Crigler-Najjar syndrome types 1 and 2, and transient neonatal hyperbilirubinemia. (13) UGT1A1 defects are inherited in an autosomal recessive fashion. This patient’s UGT1A1 defects (heterozygous for c.-41_-40dup [noncoding], c.10002del [p.Trp335Glyfs*31], and c.1473C>T [p.Ser488Phe]) are consistent with UGT1A1-related hyperbilirubinemia, which clinically presents similarly to GS. There is a high prevalence of UGT1A1 gene variation in the general population, with GS at 5% to 10%. (14) Given the high prevalence of this condition and its benign course, it is reasonable to assume that a portion of neonates labeled as “breastmilk jaundice” may well have a UGT1A1 gene defect. Although the UGT1A1 defects found in this patient are rarely mentioned in the literature, there are several that have been well studied. The most common are UGT1A1*28 and UGT1A1*6. (15) UGT1A1*28 is common in African and European populations, and UGT1A1*6 is more commonly found in Asian populations. (13)GS is a hereditary condition that is most commonly caused by a homozygous polymorphism of A(TA)7TAA in the promoter region of UGT1A1, which decreases the liver’s glucuronidation capacity by approximately 70%. GS typically presents in adolescents as recurrent, transient unconjugated hyperbilirubinemia that is preceded by physiologic stressors, including dehydration, fasting, infection, menstruation, or overexertion. GS is a diagnosis of exclusion that can be confirmed by genetic testing. Other tests that can help confirm GS without genetic testing include measuring bilirubin levels before and after caloric restriction or a rifampin challenge. In GS, 12 to 48 hours of caloric restriction leads to a twofold to threefold increase in bilirubin levels. A rifampin challenge increases the bilirubin level by more than 1.9 after 2 to 6 hours if preceded by 12 to 24 hours of caloric restriction, or by more than 1.5 if not preceded by a fast. (14) Rifampin increases bilirubin level in GS due to cytochrome P450 induction leading to competition with excretory pathways in the liver. (16) This leads to exaggerated elevations in serum bilirubin levels in patients with UGT1A1 defects and has sensitivity of 93% to 100% and specificity of 93% to 100% for diagnosing GS. (16)(17) This testing is useful when genetic testing is difficult to obtain or unavailable.Breast milk jaundice rarely requires any intervention, and intervention should be avoided in well-appearing infants without evidence of bilirubin-induced encephalopathy. However, even in well-appearing infants, providers should consider phototherapy, oral and/or intravenous hydration, exchange transfusion, and briefly holding breastfeeding (12–24 hours) if the bilirubin level reaches 20 to 25 mg/dL (342.08–427.60 µmol/L) (2)(9) per the American Academy of Pediatrics guidelines. UGT1A1 defects similar to GS are also benign disease states with no indication for intervention. However, because some drugs are metabolized through the glucuronidation pathway, GS is theorized to predispose patients to toxicity to some medications, such as atazanavir or irinotecan. (3) Because this patient had both breast milk jaundice and UGT1A1 defects leading to severe hyperbilirubinemia (bilirubin level, >20 mg/dL [>342.08 µmol/L]), we briefly held breastfeeding. Total discontinuation of breastfeeding was not recommended to the family, but they wanted to discontinue breastfeeding entirely at the time of discharge.On admission, breastfeeding was supplemented with formula feeds. Despite these changes, on hospital day 1, his bilirubin level was noted to increase to 21.9 mg/dL (374.58 µmol/L). At that time, his parents were advised to trial 24 hours of formula-only feedings. After 24 hours without human milk, bilirubin levels decreased from 21.9 mg/dL (374.58 µmol/L) to 17 mg/dL (290.77 µmol/L). The patient continued to improve during his hospital stay, with notably improved jaundice and scleral icterus. Repeated serum bilirubin levels 1 week after discharge declined to 10.7 mg/dL (183.01 µmol/L). During admission and again at discharge, the family was counseled about the risks of UGT1A1 defects to future children. Because they were not planning on having any more children, they wanted to defer genetic testing until they had more time to consider its implications. Six months later, the patient’s jaundice issues have resolved, and he is thriving from a developmental and weight standpoint.Breast milk jaundice causes indirect hyperbilirubinemia beyond 3 to 4 weeks of age in 20% to -30% of breastfed infants, and indirect bilirubin levels frequently exceed 5 mg/dL (85.52 µmol/L) but rarely exceed 12 mg/dL (205.25 µmol/L). (2)(5)(6)Suspected breast milk jaundice with indirect bilirubin levels 12 mg/dL (≥205.25 µmol/L) should prompt evaluation for other causes of hyperbilirubinemia, such as UGT1A1 defects and glucose-6-phosphate dehydrogenase deficiency. (2)Breast milk jaundice with concomitant disease states, such as UGT1A1 defects, spherocytosis, or glucose-6-phosphate dehydrogenase deficiency, can cause severe hyperbilirubinemia (bilirubin level, ≥20 mg/dL [≥342.08 µmol/L]). (2)(7)(8)(10)(11)In well-appearing infants with breast milk jaundice, avoid discontinuing breastfeeding and/or supplementing unless the indirect bilirubin level is approaching 20 mg/dL (342.08 µmol/L). (2)(9)In breast milk jaundice, phototherapy should be initiated at a bilirubin level greater than or equal to 20 mg/dL (≥342.08 µmol/L). (2)(9)