Iron physiology. Functionally available iron is normally found in hemoglobin,myoglobin, and enzymes (catalase and cytochromes). Additionally, ferritin is the physiological storage form (plasma ferritin is normally close to the total body Fe), and hemosiderin (Prussian blue positive) is iron precipitated in tissues in the form of degraded ferritin mixed with lysosomal debris.
Iron is transported in the blood stream by transferrin. Transferrin saturation is reported as a percentage; it represents the ratio of the serum iron to the total iron-binding capacity, multiplied by 100.
Dietary deficiency of iron is seen in elderly populations, children, and the poor. Increased demand for iron is seen in children and pregnant women. Additionally, iron deficiency can develop because of decreased absorption, either due to general-ized malabsorption or more specifically after gastrectomy (due to decreased acid, which is needed for ferrous absorption) or when there is decreased small intesti-nal transit time (causing “dumping syndrome”). Iron deficiency can also be due to chronic blood loss due to gynecologic (menstrual bleeding) or gastrointestinal causes (in the United States, think carcinoma; in the rest of the world, think hookworm).
The sequence of events during iron deficiency is as follows:
· Initially, decreased storage iron results in decreased serum ferritin anddecreased bone marrow iron on Prussian blue stains.
· The next stage is decreased circulating iron, which causes decreased serum iron, increased total iron binding capacity, and decreased % saturation.
· The last stage is formation of microcytic/hypochromic anemia, with decreased MCV, decreased MCHC, and high RDW.
Other clinical features of iron deficiency include increased free erythrocyte protoporphyrin (FEP), oral epithelial atrophy if Plummer-Vinson syndrome is present, koilonychia (concave or spoon nails with abnormal ridging and splitting), and pica (eating nonfood substances, e.g. dirt).
Anemia of chronic disease (AOCD) (or anemia of inflammation) is characterizedby iron being trapped in bone marrow macrophages, leading to decreased utilization of endogenous iron stores. Laboratory studies show increased serum ferritin with decreased total iron binding capacity. Increased IL-6 increases plasma hepcidin, which is a negative regulator of iron uptake in the small intestine and of iron release from macrophages.
Thalassemia syndromes are quantitative, not qualitative, abnormalities of hemo-globin. α-thalassemia has decreased α-globin chains with relative excess β chains, while β-thalassemia has decreased β-globin chains with relative excess α chains. It is hypothesized that the thalassemia genes have been selectively preserved in the human genome because the thalassemias provide a protective advantage to carriers exposed to diseases such as malaria.
α-thalassemia.There are a total of 4 α- globin chain genes, 2 from each parent.α-thalassemia is due to gene deletions in the α-globin chain genes, and the clini-cal manifestations depend upon the number of genes that are affected. α chains are normally expressed prenatally and postnatally; therefore, there is prenatal and postnatal disease. In normal individuals, 4 α genes (αα/αα) are present and 100% of the α chains are normal.
· In the silent carrier state, one deletion is present, and the total number ofgenes available is 3 (– α/αα), which produce 75% of the needed α chains. Individuals with the silent carrier state are completely asymptomatic and all lab tests are normal.
· In α-thalassemia trait, 2 deletions are present, and the total number of avail-able α genes is 2, which produce 50% of the needed α chains. The genotype cis (– –/αα) is seen in Asians, while the genotype trans (–α/–α) is seen in African Americans (offspring don’t develop hemoglobin H disease or hydrops fetalis).
· Hemoglobin H disease is characterized by 3 deletions, with the number ofαgenes being 1 (– –/– α), which produces 25% of the normal α chains. There is increased Hb H (β4,) which forms Heinz bodies that can be seen with crystal blue stain.
· Hydrops fetalis has 4 deletions and is lethal in utero, because the number ofgenes is 0 (– –/– –), producing 0% α chains.
β-thalassemia.There are a total of 2 β-globin chain genes. In contrast to the α-globinchain genes, the 2 β-globin chain genes are expressed postnatally only, and therefore there is only postnatal disease and not prenatal disease. The damage to the genes is mainly by point mutations, which form either some β chains (β+) or none (β0).
· β-thalassemia minoris seen when one of the β-globin chain genes has beendamaged. The condition is asymptomatic, and characterized on laboratory studies by increased hemoglobin A2 (8%) and increased hemoglobin F (5%).
· β-thalassemia intermediacauses varying degrees of anemia, but no transfu-sions are needed.
· β-thalassemia major(Cooley anemia). Patients are normal at birth, and symp-toms develop at about 6 months as hemoglobin F levels decline. Severe hemo-lytic anemia results from decreased erythrocyte life span. This severe anemia causes multiple problems:
§ Intramedullary destruction results in “ineffective erythropoiesis.”
§ Hemolysis causes jaundice and an increased risk of pigment (bilirubin) gallstones.
§ Lifelong transfusions are required, which result in secondary hemo chromatosis.
§ Congestive heart failure (CHF) is the most common cause of death.
Erythroid hyperplasia in the bone marrow causes “crewcut” skull x-ray and increased size of maxilla (“chipmunk face”). The peripheral blood shows microcytic/hypo-chromic anemia with numerous target cells and increased reticulocytes. Hemo-globin electrophoresis shows increased hemoglobin F (90%), normal or increased hemoglobin A2, and decreased hemoglobin A. Treatment is hematopoietic stem cell transplantation.
Sideroblastic anemia is a disorder in which the body has adequate iron stores, but isunable to incorporate the iron into hemoglobin. It is associated with ring sideroblasts (accumulated iron in mitochondria of erythroblasts) in bone marrow. Sideroblastic anemia may be either pyridoxine (vitamin B6) responsive or pyridoxine unrespon-sive; the latter is a form of myelodysplastic syndrome (refractory anemia with ring sideroblasts). The peripheral blood may show a dimorphic erythrocyte population. Laboratory studies show increased serum iron, ferritin, FEP, and % saturation of TIBC, with decreased TIBC.