A Practical Guide to Evaluating and Treating Severe Neonatal Indirect Hyperbilirubinemia

KEY POINTS

• 1.

  We still need a universally accepted definition of severe hyperbilirubinemia; no particular thresholds of unconjugated or total bilirubin levels have been definitively associated with acute or chronic bilirubin encephalopathy.

• 2.

  Several measurements can be useful for the assessment of hemolysis, such as those of end-tidal carbon monoxide, blood levels of analytes such as carboxyhemoglobin and haptoglobin, reticulocyte percent and number, cell-free hemoglobin, and hemoglobinuria.

• 3.

  Hemolytic causes of hyperbilirubinemia include alloimmune hemolytic diseases. Nonimmune negative hemolytic disease can arise in red blood cell (RBC) enzymopathies, RBC membrane disorders, and globin disorders.

• 4.

  Phototherapy is the standard of care for all cases of hyperbilirubinemia. In severe hyperbilirubinemia, exchange transfusion may also be indicated. Efforts are ongoing to evaluate whether intravenous immunoglobins, metalloporphyrins, and phenobarbital might be useful in specific conditions.

Overview

There is no universal definition of severe hyperbilirubinemia because no threshold of laboratory values has been definitively associated with acute or chronic bilirubin encephalopathy. Some groups have suggested that the unconjugated fraction of bilirubin alone can cross the blood-brain barrier and cause bilirubin encephalopathy, and therefore only the unconjugated bilirubin fraction should be considered when evaluating a neonate for treatment of hyperbilirubinemia. Others have suggested that it is the unconjugated bilirubin, not bound to plasma proteins (e.g., albumin), that is more robustly associated with bilirubin encephalopathy. ^, Because none of these hypotheses have been upheld with uncontroversial evidence, we utilize the total serum bilirubin measurement in our evaluation of neonatal hyperbilirubinemia.

Understanding the evaluation and treatment of severe neonatal indirect hyperbilirubinemia is simplified by understanding the fundamental steps in heme metabolism and bilirubin conjugation and excretion ( Fig. 42.1 ). These crucial steps include (1) red blood cell (RBC) lysis or death, (2) the conversion of heme into biliverdin by heme oxygenase, and (3) the intrahepatic conjugation or glucuronidation of bilirubin by uridine diphosphate (UDP) glucuronosyl transferase (UGT1A1). In the most simple terms, hyperbilirubinemia is the result of either (1) excessive bilirubin production, (2) decreased bilirubin metabolism or elimination, or (3) a combination of the two. Aberrations in these crucial steps result in any of these broad etiologies.

This chapter will explore both well-established and innovative approaches to the evaluation and treatment of severe hyperbilirubinemia. Ultimately, the goal of evaluation and treatment of severe hyperbilirubinemia is to prevent bilirubin-induced neurologic dysfunction.

Determining Causes of Severe Hyperbilirubinemia

Determining the cause of severe indirect hyperbilirubinemia can have implications on immediate and long-term management of infants. Historically, our ability to identify the cause of severe hyperbilirubinemia has been poor. In the US voluntary Kernicterus Registry, conducted in the 1990s by Drs. Bhutani and Johnson, no clear explanation for the hyperbilirubinemia was identified in 55% of the 125 patients in the registry. Christensen et al. reported similar findings retrospectively in the Intermountain Healthcare system in the Western United States, where among 302,399 live births, 32 neonates had a total serum bilirubin >30 mg/dL. Of these 32, only 11 (65.6%) had an explanation found for their extreme hyperbilirubinemia and the remaining patients were listed as having “idiopathic” jaundice.

Subsequently, in a pilot registry in the state of Utah, Christensen successfully identified the cause of hyperbilirubinemia in all cases of acute bilirubin encephalopathy between 2009 and 2018 (seven cases). Two cases were caused by immune-mediated hemolysis. The remaining five had genetic mutations causing increased bilirubin production through hemolytic mechanisms. Two of these five patients also had a genetic mutation retarding bilirubin conjugation (Gilbert syndrome). This study, although small, illustrated the growing availability and value of genetic sequencing in seeking the diagnosis of Coombs-negative hemolytic jaundice (and even nonhemolytic jaundice). At least two laboratories in the United States offer next-generation sequencing panels designed to diagnose genetic causes of severe hyperbilirubinemia: ARUP Laboratories (Salt Lake City, Utah) and Mayo Clinic Laboratories (Rochester, Minnesota). Although these panels are labeled “hereditary hemolytic anemia” panels, they both also include genes involved in bilirubin transport, conjugation, and excretion. Due to cost, we reserve these panels for more severe cases when a narrower differential diagnosis does not lead us to a more directed approach to diagnosis.

Our general approach to evaluating severe hyperbilirubinemia is to first determine whether hemolysis (increased bilirubin production) is a contributing factor, keeping in mind that the presence of hemolysis does not exclude coinheritance of mutations that slow bilirubin elimination. In fact, it is our experience that cases where increased bilirubin production and retarded bilirubin elimination are both present result in the most severe hyperbilirubinemia. Determining whether the rate of bilirubin production is significantly increased will then help refine the differential diagnosis and guide the approach to the patient ( Fig. 42.2 ). Here, we will first discuss tools used to differentiate hemolytic from nonhemolytic jaundice. Then we will discuss the most common hemolytic and nonhemolytic causes of severe hyperbilirubinemia.