Sickle Cell Anemia Clinical Trial
Official title:
Hepcidin Levels in Sickle Cell Disease (SCD)
The investigators propose that patients with HbSβ-thalassemia have lower levels of hepcidin
and higher levels of GDF-15 than HbSS patients during the non-crisis, "steady states." In
addition, the investigators propose that when controlled for RBC transfusion, patients with
HbSβ-thalassemia will have higher levels of storage iron (based on serum ferritin).
Participants: Total number of subjects is 42 - 21 subjects with HbSS, and 21 subjects with
HbSβ-thalassemia ).
Procedures (methods): Eligible subjects with documented SCD (HbSS, HbS-β 0-thalassemia or
HbS-β+-thalassemia) followed at the University of North Carolina (UNC) Comprehensive Sickle
Cell Program will be evaluated in this single-center, prospective, cross-sectional study.
The patients will be screened for eligibility at the time of a routine sickle cell clinic
visit. Patients' data will be obtained in person at the time of evaluation and through
review of their medical records. Investigators will obtain information on SCD-related
clinical complications and obtain an estimate of the number of lifetime RBC transfusions.
Blood samples will be obtained for laboratory tests. Plasma samples for hepcidin, growth
differentiation factor 15 (GDF -15), and high-sensitivity CRP will be stored at -80 degrees
Celsius until analysis. Other routine laboratory studies including complete blood count
(CBC) with differential and reticulocyte count, serum iron profile and ferritin, and liver
function tests will be performed at the clinical laboratories of UNC Hospitals.The subjects
will have 30 ml. of blood drawn for this research study. Females of child bearing potential
will have a urine pregnancy test at the time of the study.
Sickle cell disease (SCD) refers to a group of inherited disorders characterized by the
presence of sickle hemoglobin (HbS) that are associated with episodes of acute illness and
progressive organ damage. The most common variant of SCD, sickle cell anemia (HbSS), refers
to homozygosity for the β S allele, with most of the remaining patients having sickle
hemoglobin C disease (HbSC) and sickle beta thalassemia (HbSβ-thalassemia).
SCD may be associated with iron overload that occurs following repeated red blood cell (RBC)
transfusions. However, in patients with beta thalassemia major, iron overload occurs due to
both repeated RBC transfusions and hyperabsorption of iron. The hyperabsorption of iron in
beta thalassemia occurs due to ineffective erythropoiesis and subsequent downregulation of
hepcidin. Thalassemia intermedia and major are the most studied human models of hepcidin
modulation by ineffective erythropoiesis alone and the combined and opposite effect of both
ineffective erythropoiesis and transfusion dependent iron overload, accordingly. Regular
transfusions induce massive iron loading but inhibit erythropoietic drive. Accordingly,
hepcidin production is higher in thalassemia major than in thalassemia intermedia although
still inappropriate to the massive transfusional iron loading that partially counteracts the
erythropoietic-dependent hepcidin down-regulation (Origa R et al, 2007; Kattamis A et al,
2006; Camberlein E et al, 2008). No differences in the steady-state levels of hepcidin was
observed when HbSS patients (N = 40) were compared with healthy hemoglobin AA (HbAA)controls
(N = 30) (85.3 ± 30 l μg/L vs. 83.5 ± 40 l μg/L) (Ezeh C et al, 2005).
Hepcidin is a 25-amino acid peptide produced mainly in the liver and is the major
physiological regulator of body iron stores and serum iron. It negatively regulates egress
of iron from cells, such as intestinal epithelial cells and macrophages. Growth
differentiation factor-15 (GDF-15) and twisted gastrulation protein homolog 1(TWSG1), two
transforming growth factor-β (TGF-β) superfamily members released from erythroid precursors,
have been proposed to contribute to hepcidin suppression in thalassemia, although it remains
unresolved whether GDF-15 and TWSG1 are markers of ineffective erythropoiesis or mediators
of hepcidin suppression in vivo.
With the presence of a thalassemia gene, patients with HbSβ-thalassemia (HbSβ0-thalassemia
and HbSβ+-thalassemia) may have an increased tendency to absorb excess iron compared to
patients with HbSS.
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