Abstract

Iron overload in African Americans unexplained by erythrocyte transfusion has been reported in a woman with sickle cell anemia (

Castro et al.,
Blood
(
1998
)
92
(suppl):
13b
) and in a woman with undefined mild anemia (
Hitender et al.,
Am J Gastroenterol
(
2000
)
95
:
2580
). We evaluated a 41 year-old African American woman with sickle cell disease referred for management of congestive heart failure and recurrent stroke. She had received four units of erythrocyte transfusion over her lifetime, and had taken oral iron supplements intermittently for many years. Hemoglobin (Hb) was 7.6 g/dL, MCV 94 fL, MCH 20.7 pg, and RDW 23.3%. Erythrocyte MCV histogram revealed a small, distinct subpopulation of microcytes, but was also shifted right due to reticulocytosis (18.2%). Electrophoresis revealed 96.9% Hb S and 3.1% Hb A2. Transferrin saturation (TfSat) was 52%; serum ferritin (SF) was 1,362–3,065 ng/mL (4 measurements) without explanation other than iron overload. Serum transaminase levels were elevated. She declined liver biopsy. A desferrioxamine (DFO) urinary iron excretion test revealed 3,249 μg urinary Fe/24 h (reference range 100–300 μg urinary Fe/24 h). Thereafter, she took subcutaneous infusions of DFO five days weekly with fair compliance; other treatment included exchange transfusions (for management of strokes), hydroxyurea, and folic acid. Supplemental iron use was discontinued. Congestive heart failure improved; serum transaminase levels returned to normal. After 5.5 years of DFO infusions, SF was 561 ng/mL. We evaluated her iron-associated genes for pertinent mutations using denaturing high-performance liquid chromatography (dHPLC) and complete sequencing. She is heterozygous for a proximal promoter region mutation of ALAS2: C to G transversion at nucleotide −206 from the transcription start site, as defined by primer extension. HFE coding region mutations, including C282Y and H63D, were not detected; HFE alleles IVS4-44 C→T and IVS5-46 C→T were present. No single-nucleotide polymorphisms were detected in TFR2 (exons 2, 3; 5-13). This ALAS2 promoter mutation was first described in a Welsh family in which the heterozygous female proband had mild sideroblastic anemia, microcytosis, elevated TfSat and SF, and 87% reduction of ALAS2 mRNA in erythroid precursors, and had taken much supplemental iron (
Bekri et al.,
Blood
(
2003
)
102
:
698
). Peto et al. reported that iron overload due to ineffective erythropoiesis in females heterozygous for X-linked sideroblastic anemia may be severe even when anemia is mild (
Lancet
(
1983
)
1
:
375
). In women heterozygous for ALAS2 mutations, we propose that erythroid precursors without an ALAS2 mutation may sustain normal or near-normal levels of circulating erythrocytes and Hb, while erythroid precursors with an ALAS2 mutation stimulate iron absorption due to ineffective erythropoiesis and cause iron overload. In the present case, anemia due to the ALAS2 promoter mutation was partially masked by concurrent SS hemoglobinopathy, and iron overload was likely exacerbated by erythrocyte transfusion and iron supplements. We conclude that an ALAS2 promoter region mutation partly accounts for iron overload in the present patient with SS hemoglobinopathy, and that this or other ALAS2 mutations could explain the occurrence of non-transfusion iron overload in other African Americans with chronic anemia.

Author notes

Corresponding author