All iron-loading anemias are characterized by ineffective erythropoiesis and share with hemochromatosis an insufficient hepcidin production. The extent of ineffective erythropoiesis rather than the degree of anemia correlates with the suppression of hepcidin synthesis. The latter effect is due to erythroferron (ERFE), a tumor necrosis factor alpha (TNFα)-like protein produced and released by erythroblasts stimulated by erythropoietin. In non-transfusion dependent βeta-thalassemia patients serum ERFE levels are high and hepcidin levels low despite iron overload, to ensure iron supply to the maturing erythroblasts. Since erythroblast differentiation is blocked, excess iron, unutilized for hemoglobin synthesis, interferes with erythroid maturation, aggravating ineffective erythropoiesis that in turn increases iron absorption in a vicious cycle. All iron-loading anemias share with beta-thalassemia variable levels of hepcidin inhibition by ERFE. The erythroblasts of MDS-RS have defective iron utilization in mitochondria and accumulate iron in these organelles, which cluster around the nucleus originating a ring appearance at Perls’ staining (see Fig. 1). Patients with MDS ringed sideroblasts usually have a somatic mutation in the spliceosome gene SF3B1 at the heterozygous state. Among others the ERFE gene is abnormally spliced resulting in an elongated protein that suppresses hepcidin more efficiently than the wild type hormone. Although iron overload is caused by hepcidin deficiency both in hemochromatosis and iron-loading anemias, molecular mechanisms are different: in the former hepcidin is low because of lack of BMP pathway activation in response to iron, in the latter hepcidin is low because of erythropoiesis-driven excessive inhibition.

Fig1. ASSESSMENT OF IRON STORES ON A BONE MARROW ASPIRATE. Iron stores are better assessed on the aspirate as opposed to the biopsy because the decalcification procedure required for processing the biopsy leaches out the iron and can lead to a false conclusion of absent stores. On the aspirate, a Prussian blue stain evaluates iron. This can demonstrate iron stores (blue reaction product), particularly in the cytoplasm of macrophages and histiocytes (A, B). Iron can also be seen in the cytoplasm of some erythroblasts (tiny blue cytoplasmic specks), which would allow these cells to be designated sideroblasts (C). These are in contrast to red blood cell precursors with abnormal mitochondria iron accumulation around the nucleus, or “ring sideroblasts” (C, inset).

Iron loading may be caused or aggravated by blood transfusions in patients with thalassemia major, Hb E/beta-thalassemia, Blackfan Diamond anemia, and other congenital anemia requiring transfusions since infancy, or in selected patients with sickle cell disease transfused for preventing recurrent complications such as stroke and painful crises. At risk are patients with acquired aplastic or refractory anemia and survivors from successful allogeneic bone marrow trans plantations, heavily transfused for the underlying disease and trans plantation procedure. The iron content of each unit of packed red cells is calculated assuming that 450 mL of blood with a mean hemoglobin concentration of 13.5 g/dL contains approximately 200 mg of iron. After receiving 20 units of transfused blood patients accumulate about 4 g extra iron with the risk of organ damage.

The toxicity of iron in both hemochromatosis and other dis orders is mediated by NTBI. This iron species appears in the circulation when saturation of transferrin outpaces 50% to 60%. NTBI is taken up in an uncontrolled way by a zinc transporter (ZIP14) in hepatocytes and acinar pancreatic cells and by other transporters like ZIP8, and low-voltage calcium channels in cardiomyocytes. NTBI favors the generation of ROS that damage proteins, lipids, DNA, and organelles, as lysosomes and mitochondria, causing cellular dysfunction, apoptosis, and death. In the liver, necrosis of the hepatocytes and the local inflammatory response mediate ROS-induced fibrogenesis by activating hepatic stellate and other mesenchymal cells to produce collagen. Liver fibrosis may progress over time to overt cirrhosis, while iron toxicity in other organs may lead to cardiomyopathy, diabetes mellitus, and other endocrine complications (Fig. 2). Iron-related damage of the hypothalamic-pituitary axis results in hypogonadotropic hypogonadism and low levels of gonadotropins and testosterone. The toxic manifestations are variable and depend not only on the iron burden, but also on the rate of iron accumulation and on the cellular pattern of deposition; the concomitant presence of chronic viral hepatitis or alcohol abuse are important cofactors of liver damage. Hypoxia is a further damaging cofactor in iron-loading anemias.

Fig2. CLINICAL COMPLICATIONS OF IRON OVERLOAD. The most important complications that may occur in all types of iron overload are indicated. Liver disorders, chronic fatigue, and arthropathy are more frequent in classic hemochromatosis. Cardiac disease and hypopituitarism are more frequent in juvenile hemochromatosis and in beta-thalassemia patients under chronic blood transfusions.

اخر الاخبار

اخبار العتبة العباسية المقدسة

متحف الكفيل يباشر صيانة المجموعة الرابعة من مقتنيات العتبة العسكرية المقدسة

ضمن برنامجها التبليغي اليومي.. شعبة الخطابة تنظم مجلسًا للوعظ والإرشاد

قسم الشؤون الفكرية يواصل إقامة مسابقة النور الزكي الرمضانية في ذي قار

المجمَع العلمي يواصل إقامة 18 ختمة قرآنية رمضانية في الديوانية

المزيد

الآخبار الصحية

دراسة: تناول القهوة يوميا يخفض خطر الإصابة بالاضطرابات النفسية

عرض شائع في الفم قد يكون مرتبطا بخطر الإصابة بأمراض خطيرة

نصائح عامة لاستخدام سماعات الرأس بأمان

تأثير اللياقة البدنية على الدماغ

المزيد

الآخبار التكنلوجية

ديدان الأرض تكشف تلوث التربة بالمعادن الثقيلة

خبير أرصاد جوية: ظاهرة النينيو القادمة قد تكون الأقوى خلال 10 سنوات

"ناسا" تكشف موعد إعادة إطلاق رحلتها المأهولة إلى القمر

علماء الجيولوجيا يفكون لغز الصدع العملاق تحت الماء في المحيط الأطلسي

المزيد

مواضيع ذات صلة

Pathogenesis of Cobalamin Deficiency

Clinical Manifestations of Iron Overload

Thyroid Disease in Pregnancy

Hypothyroidism

Hyperthyroidism

Clinical Manifestations of Iron Deficiency

Thyroid Imaging: nuclear Medicine Techniques - Thyroiditis

Thyroid Imaging: nuclear Medicine Techniques - Thyrotoxicosis

Pathobiology of Iron Deficiency

Outcome and Prevention of Infectious Diseases

Serum and Tissue Thyroid Hormone concentrations in NTI

Microorganism Entry, Invasion, and Dissemination: The Host’s Perspective