Study of Serum Hepcidin in Hereditary Hemolytic Anemias

Abstract

5168 Background: Thalassemia is the most common genetic disorder in Egypt composes a major health problem with an estimated carrier rate of 5. 3%-9%. Registered cases in large centers in Egypt September 2007 were 9912 cases, and in Cairo University hematology clinic were alone 2597 cases. Patients with thalassemia major requiring regular blood transfusions accumulate iron that is toxic to the heart, liver, and endocrine systems. Hepcidin, is a 25 amino-acid peptide hormone synthesized in the liver is a key regulator of iron homeostasis. Recently, hepcidin was reported to bind to the trans-membrane iron exporter “ferroportin” which is present on macrophages, the basolateral site of entrecotes, and in hepatocytes. Hepcidin induces the internalization and degradation of ferroportin. liver hepcidin controls reduction of iron uptake and release. There is also evidence for local production of hepcidin by macrophages, fat cells and cardiomyocytes. Thus, hepcidin is involved in different regulatory mechanisms that control iron imbalance. Objective: The aim of this study is to assess the level of serum hepcidin in hereditary chronic hemolytic anemias and correlate its level to the need for blood transfusion (frequency of blood transfusion) and the serum ferritin level. Study design: Seventy pediatric patients with hereditary chronic hemolytic anemias were the subjects of this study; 53 thalassemia major (TM), 10 thalassemia intermedia (TI), 4 congenital spherocytosis(CS) and 3 sickle cell disease(SCD) patients, mean age 7. 8+3. 9 years (range 1–14). Seventy normal children age and sex matched were studied as controls. Serum hepcidin was measured in all patients and controls by ELISA technique. Serum Hepcidin was measured in all patients one day pre transfusion and in 20 TM patients 3–4 days post transfusion. Results: Significant decrease in serum hepcidin levels in all patients compared to controls (mean 22. 9 ±6 vs 132. 4±16. 7 ng/ml, P <0. 001). Hepcidin levels were higher in TM (mean 23. 7±6. 2 ng/ml) than in TI patients (mean =21. 8±4 ng/ml) (Fig 1). The median number of blood transfusions in TM was 70/year (range18–120), in TI the median was 7/year (range 6–17). A 280% increase of serum hepcidin levels of pre transfusion levels was found post transfusion in TM patients (n=20). A significant positive correlation was found between serum hepcidin and frequency of blood transfusion (r=0. 4, p<0. 001), serum ferritin (r=0. 28, p <0. 05) and CRP (r=0. 4, p<0. 05). The hepcidin to ferritin ratio a marker of the hepcidin expression relative to the degree of iron burden was significantly less than one in TM and TI patients (0. 03± 0. 004 and 0. 025± 0. 002 respectively) and far from the level in normal controls (mean 2. 3±0. 7, P<0. 001). Hepcidin and hepcidin/ferritin ratio as markers of iron overload in our patients showed high sensitivity and specificity (99% and 98%, 97% respectively) (table 1, fig 2). Discussion and Conclusion: This study examined serum hepcidin and hepcidin/ferritin ratio in hereditary chronic hemolytic anemias, significant low levels were detected. The increase in serum hepcidin level in TM than TI and its marked increase post transfusion in TM patients can be explained by the positive correlation between frequency of blood transfusion and serum hepcidin level in this study. Hepcidin and hepcidin/ferritin ratio can be used as valid markers of iron overload in hereditary chronic hemolytic anemias. Evidence from laboratories around the world have converged on hepcidin as a rational therapeutic agent for treatment of B-thalassemia. Treatment with a hepcidin agonist, at a carefully defined dose, has the potential to ameliorate several aspects of TI due to the specific reduction of iron overload and splenomegaly. Testing this approach provides an exciting opportunity to improve the current management strategies for these diseases, and our study agrees with this approach. Disclosures: No relevant conflicts of interest to declare.

Role of Hepcidin in the Pathogenesis of Anemia Not Caused by Iron Deficiency

“…Based on the results in our study, the level of hepcidin in thalassemia group was higher than control group. This was in agreement with Origa et al [28], who found increased urinary hepcidin level in thalassemia major patients more than in control and in disagreement with Casanovas et al [29], and EL Beshlawy et al [30], who found that serum hepcidin levels are decreased in all patients of chronic hemolytic anemia, they suggested that the diseased erythron dysregulates iron homeostasis by inhibiting hepcidin synthesis, even in the presence of iron overload.…”

Hepcidin/Ferritin Ratios Differ Among Non‐Dialyzed Chronic Kidney Disease Patients, and Patients on Hemodialysis and Peritoneal Dialysis

“…viral and autoimmune hepatitis) (14,15) and hematological disease (e.g. hereditary hemochromatosis and hereditary hemolytic anemia) (16,17).…”

Avaliação de variantes do gene <i>TMPRSS6</i> e sua relação com o <i>status</i> de ferro em condições de eritropoese normal e aumentada

“…Além das hemocromatoses, outras doenças genéticas associadas com baixa produção de hepcidina são as anemias hemolíticas congênitas (talassemias, anemia falciforme, anemia sideroblástica, esferocitose hereditária, entre outras) (PASRICHA et al, 2013;BESHLAWY et al, 2012;KEARNEY et al, 2007). Embora as bases moleculares destas doenças não estejam diretamente relacionadas com a maquinaria de produção da hepcidina, muitas complicações destas síndromes hemolíticas são decorrentes da descompartimentalização corporal do ferro (GREER et al, 2009).…”

“…Antigos estudos ferrocinéticos em pacientes com esferocitose hereditária indicam que a demanda diária do mineral aos tecidos hematopoiéticos pode ser até seis vezes maior (150 mg) do que a de indivíduos saudáveis (CONRAD & BARTON, 1981apud LATUNDE-DADA et al, 2006FINCH et al, 1970). Apesar de, nesta condição, as concentrações circulantes de hepcidina se mostrem inversa e fortemente relacionadas com a atividade eritropoética (BESHLAWY et al, 2012;KEARNEY et al, 2007), uma sobrecarga de ferro clinicamente importante não é ocorrência comum, a menos que transfusões de sangue sejam frequentes (ROCHA et al, 2011;LATUNDE-DADA et al, 2006;MEYRICK, WEBB & COLE, 2002).…”

“…Nas β-talassemias intermedia e maior, anemias sideroblásticas e algumas anemias diseritropoéticas associadas com eritropoese ineficaz, as concentrações circulantes de hepcidina são inadequadamente baixas e há sobrecarga de ferro clinicamente importante (PASRICHA et al, 2013;BESHLAWY et al, 2012;KEARNEY et al, 2007). Assim como na esferocitose hereditária, o acúmulo de ferro nestas doenças é principalmente secundário às repetidas transfusões de sangue necessárias para o manejo da anemia.…”