FIG. 2.

Bilirubin–albumin binding, tissue loading, and kernicterus. (A) Gray horizontal and vertical lines indicate B_f aqueous solubility and intravascular B_T binding capacity, respectively. There is an exponential relationship between B_f and B_T/A (R² = 0.76; 95% confidence interval shaded gray) (Amish controls, gray triangles; UGTA1A c.222C>A homozygotes, purple circles; term newborns with idiopathic jaundice, green diamonds; preterm infants weighing less than 1 kg, blue triangles). (B) The proportion of B_T represented by B_f decreases exponentially with increasing values of K (R² = 0.69). (C) UGT1A1 c.222C>A homozygotes (CN1) as compared with jaundiced term newborns had similar albumin concentrations (left y-axis) and calculated values of K (right y-axis), whereas preterm babies weighing less than 1 kg had the lowest levels of both albumin and K (ANOVA P < 0.0001; Tukey’s post hoc test: *P < 0.05, **P < 0.01, ***P < 0.001). (D) B_T values (log10 scale) are plotted for 5 patients originally described by Crigler and Najjar (green diamonds⁽¹⁾), 4 neonates from the present cohort who developed kernicterus (blue diamonds), and 14 UGT1A1 c.222C>A homozygotes who escaped neurological injury (purple circles). Gray shading depicts the theoretical increase of B_T if produced at a steady rate of 3.7 ± 0.9 mg/kg per day and confined to the circulation. Within a normal range of albumin concentrations (3.5 and 4.5 g/dL), intravascular binding capacity (horizontal dashed line) saturates between 5 and 10 days of age and sets an upper limit on the concentration of intravascular B_T. Thereafter, unmeasured pigment binds to brain and other extravascular tissues and comes to comprise 60%-90% of the total bilirubin load at the time of kernicterus. (E) Neonates who developed kernicterus (blue diamonds) started phototherapy at a median age of 37 postnatal days as compared with 4 postnatal days of age for those who remained healthy (purple circles); initiation of phototherapy at 14 or more postnatal days of age (gray line) increased the likelihood of brain injury 3.5 fold. (F) All 4 neonates who suffered brain injury had a B_T/A greater than 1.0 mol:mol between 15 and 45 postnatal days of age. The presenting B_T/A was about 60% lower among the 24 remaining infants who did not develop kernicterus. As predictors of kernicterus during the neonatal period, B_T ≥ 30 mg/dL or B_T/A ≥ 1.0 mol:mol had equal specificity (93.3%) and PPV (80.0%).