Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury

Abstract

Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% +/- 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% +/- 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% +/- 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% +/- 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Figure 1

SF changes with increasing iron load. (A) SF changes in relation to number of transfusions in all randomized STOP and STOP2 patients. SF changes in relation to (B) TIL or (C) LIC. Thick lines represent median change; gray lines, 10th and 90th percentiles; and dashed lines, change in individual patients.

Figure 2

SF receiver operating characteristic area under the curve. SF ROC AUC for iron load determined by (A) TIL, (B) TIL limited to measures more than 50 mg/kg, or (C) LIC. Circles represent averages of 1000 random data sampling; bars, SD. ROC AUC represents the area under the curve of sensitivity plotted against 1 − specificity for all possible SF values for a given iron load level. The closer ROC AUC equals 1, the better SF is, as a discriminator of iron; the closer ROC AUC equals 0.5, the closer SF is to random.

Figure 3

Percentage of patients within given SF who have increased ALT levels. SF was plus or minus 1000 ng/mL level indicated (except for last level indicated left of chart). Percentages are averages from 1000 random data samplings; bars represent sampling SD: one observation within SF range per patient selected at each sampling; the same patient may be presented in more than 1 stratum.