Historical estimates place the incidence of cholestasis among all neonates at 1 in 2500 live births.1 A recent retrospective data review found that among all infants cared for in a large hospital system in the United States who had at least 1 measured conjugated bilirubin level, 3 in 1000 had a peak conjugated (direct) bilirubin greater than 2.0 mg/dL2; however, in the majority of these patients a specific hepatobiliary disorder was not identified, and the peak bilirubin was relatively low (<5 mg/dL). The incidence of cholestasis in the neonatal intensive care unit (NICU) is significantly higher. In 1 series, cholestasis (defined as direct bilirubin > 1.0 mg/dL when total bilirubin is 5 mg or less or direct bilirubin > 20% of total bilirubin when the total bilirubin is above 5 mg/dL) was identified in 2% of all NICU patients.3 Risk factors that are common in this population include prematurity, low birth weight, sepsis, shock, surgery, and parenteral nutrition.4 Thus, although cholestatic liver disease is rare in general outpatient pediatrics, the neonatologist must be familiar with the initial triage and diagnostic evaluation, as well as supportive care, of the cholestatic infant.
Cholestasis refers to any impairment in the hepatic excretion of bile. Bile is an aqueous solution of bile acids, cholesterol, conjugated bilirubin, proteins, phospholipids, toxins and xenobiotic substances, and electrolytes. Biochemically, an increase in serum conjugated bilirubin is the most commonly identified marker of cholestasis. The usual rule of thumb is that a direct-reacting fraction of bilirubin greater than 2 mg/dL or greater than 15% of total bilirubin should be regarded as evidence of cholestasis. However, it is helpful to remember that direct and conjugated bilirubin are not identical. Unconjugated bilirubin is the product of heme breakdown, which in the liver is conjugated with glucuronic acid prior to secretion into bile. The traditional assay relies on the fact that conjugated bilirubin (the “direct-reacting fraction”) reacts much more readily with a diazo reagent than does unconjugated bilirubin (the “indirect-reacting fraction”), which is measured after the addition of an accelerating agent. Unconjugated bilirubin does participate, albeit more slowly, in the unaccelerated reaction, and when the concentration of unconjugated bilirubin is high, the direct bilirubin measurement will be spuriously elevated.5, 6 Laboratories that report conjugated and unconjugated fractions as such, rather than as direct and indirect fractions, are typically using a newer spectrophotometric method (Kodac BuBc), and some laboratories report measurements for both direct and conjugated bilirubin. The direct bilirubin measurement (ironically, an indirect estimate of the conjugated bilirubin concentration) is generally a higher number than the conjugated bilirubin measurement, and it also includes measuring the delta bilirubin or the bilirubin bound to albumin.
Physiology of Normal Bile Production and Excretion
Some understanding of bile acid physiology is necessary for an adequate description of cholestatic pathophysiology. The biochemistry and transport of bile acids is complex, and this discussion is restricted to the clinically salient points. Figure 39-1 provides a cartoon representation of the basic machinery of bile excretion.