A 5 day old male, ex-36.6 weeker, presents to the emergency department with jaundice. The patient’s mother states that he has turned more and more yellow over the last couple days. The patient has had good oral intake and wet diapers since birth.
The patient was born by vaginal delivery after mother was induced due to polyhydraminos and separation of the amniotic sac from the uterine wall. The patient had a 1 day stay in the NICU and was discharged home with a total bilirubin of 10.
In the ED, the patient was noted to have severe jaundice, lethargy, and sunsetting of the eyes concerning for kernicterus (Image 1). Two IV lines were placed, labs sent, fluid boluses started, phototherapy commenced, and a CT head obtained which was unremarkable. His total/direct bilirubin resulted at 38.5/1.1. The patient was admitted to PICU for further management.
In the PICU, the patient received antibiotics, phototherapy, and an exchange transfusion. He was noted to have unusual eye movements involving a persistent downgaze. Neurology was consulted and EEGs were performed which were normal.
As the bilirubin level decreased, the patient’s clinical condition improved. The patient was ultimately discharged and has been following up with primary care, neurology, and other outpatient providers for intermittent episodes of downgaze and possible neurological delay.
Image 1: Sunsetting of the eyes
http://mediphotos.blogspot.com/2012/01/appearance-of-sunset-sign-in-infant.html
What is this patient’s etiology of jaundice and elevated bilirubin?
Let’s first discuss hyperbilirubinemia in the newborn.
Many newborns have a total bilirubin greater than 1 mg/dl, and as the bilirubin level increases, the patient will look more jaundiced. Severely high bilirubin (>25 mg/dl) can cross the blood-brain barrier, causing kernicterus.1 Kernicterus is damage to the brain caused by deposition of unconjugated bilirubin in the brain stem and basal ganglia. Symptoms of kernicterus include trouble feeding, hypotonia, lethargy, seizures, and oculomotor paresis of upward gaze (sunsetting eyes).2
The spleen and the liver are involved in heme breakdown, which produces bilirubin. Bilirubin clearance begins at the liver, where hepatocytes conjugate the bilirubin, making it more water-soluble. The bilirubin is then secreted in bile and excreted into the digestive tract, where digestive enzymes reduce the bilirubin, aiding in its excretion in the stool. Infants, however, have few gut bacteria, and have beta-glucuronidase in their intestines, which deconjugates the conjugated bilirubin, resulting in bilirubin reabsorption.1,3
Nonpathological Hyperbilirubinemia:
Physiological neonatal jaundice results from the fact that: 1) Infants have more red blood cells with a shorter life span, resulting in increased bilirubin production; and 2) Infants lack some of the enzymes and gut bacteria necessary in the clearance and excretion of bilirubin.1,3-4
Breastfeeding jaundice occurs in the first week of life due to insufficient breast milk intake, resulting in insufficient bowel movements to excrete bilirubin. Breast milk jaundice, on the other hand, occurs in the 6th to 14th day of life, and it is hypothesized that the beta-glucuronidase in breast milk might lead to decreased conjugated bilirubin.1,3
Pathological Hyperbilirubinemia:
Pathological causes of neonatal jaundice can be attributed to increased bilirubin production and decreased clearance. Causes of increased production include isoantibodies (i.e ABO or Rh incompatibility); structural defects (i.e hereditary spherocytosis); enzymatic defects (i.e G6PD deficiency); birth trauma (i.e cephalohematomas), and polycythemia. Causes of decreased clearance can be caused by biliary atresia, Gilbert syndrome and Crigler-Najjar syndrome.1,3-5
Treatment:
Phototherapy should be started based on the patient’s total bilirubin level, age, and risk factors (i.e G6PD, lethargy, sepsis). Phototherapy works by converting bilirubin into lumirubin, which is water-soluble. Exchange transfusion is used in patients with elevated bilirubin levels and signs of acute encephalopathy. This procedure involves taking small volumes of the patient’s blood and replacing it with donor red cells, until the patient’s blood volume has been replaced twice.1,3-6
Now, back to our patient:
Unlikely causes of our patient’s jaundice and elevated bilirubin are hemoglobinopathies, such as HbS, HbC, or beta/alpha thalassemia because the patient presented at 5 days of age and would still have fetal hemoglobin. The patient’s blood type was O+ and the mother’s blood type was A+, so ABO incompatibility is also an unlikely etiology. The patient’s physical exam showed no evidence of bruises or cephalohematoma and the labs did not reveal polycythemia. The bilirubin level is too high for breastfeeding jaundice and the patient is too young for breastmilk jaundice. There is no clinical or laboratory evidence of microangiopathies, such as DIC, TTP, or HUS. The majority of the patient’s hyperbilirubinemia is indirect, decreasing the likelihood of a hepatic etiology. Although Crigler-Najjar syndrome could present with indirect hyperbilirubinemia, it is an inherited disorder and this patient has no family history of Crigler-Najjar.
G6PD and pyruvate kinase deficiency assays were sent during the patient’s hospital stay. The patient was found to have G6PD deficiency. G6PD is an enzyme that plays a crucial role in protecting red blood cells from breaking down prematurely from oxidizing free-radicals. Thus, neonates with G6PD deficiency are at risk for hemolytic jaundice.7,8 If those assays had come back negative, RBC membrane and enzyme panels would be sent at 6 months of age.
Samita Heslin is a current first year resident at Stony Brook Emergency Medicine.
@SamitaHeslin
References:
Wong, Ronald J., and Vinod K. Bhutani. "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn." UpToDate. Waltham, MA: UpToDate (2015).
Dysart, Kevin. “Kernicterus - Pediatrics.” Merck Manuals Professional Edition, Merck Manuals, Dec. 2018, www.merckmanuals.com/professional/pediatrics/metabolic,-electrolyte,-and-toxic-disorders-in-neonates/kernicterus.
Lauer, Bryon J., and Nancy D. Spector. "Hyperbilirubinemia in the newborn." Pediatrics in review 32.8 (2011): 341-349.
American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. "Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation." Pediatrics114.1 (2004): 297.
Dennery, Phyllis A., Daniel S. Seidman, and David K. Stevenson. "Neonatal hyperbilirubinemia." NEJM 344.8 (2001): 581-590.
Porter, Meredith L., and Beth L. Dennis. "Hyperbilirubinemia in the term newborn." American family physician 65.4 (2002).
Marzban, Asghar, and Noredien Mosavinasab. "Correlation between hemolysis and jaundice in Glucose 6-Phosphate Dehydrogenase deficient neonates." Acta Medica Iranica(2009): 379-382.
“Glucose-6-Phosphate Dehydrogenase Deficiency.” NORD (National Organization for Rare Disorders), 2017, rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/.