Iron physiology. Functionally available iron is normally found in haemoglobin, myoglobin, and enzymes.
Iron Deficiency Anemia
Iron physiology. Functionally available iron is normally found in haemoglobin, 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 bloodstream 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 generalized malabsorption or more specifically after gastrectomy (due to decreased acid, which is needed for ferrous absorption) or when there is decreased small intestinal 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 and decreased 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 the formation of microcytic/hypochromic anaemia, 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 non-food substances, e.g. dirt).
Anaemia of chronic disease (AOCD) (or anaemia of inflammation) is characterized by 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 haemoglobin. 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 clinical manifestations depend upon the number of genes that are affected. α chains are normally expressed prenatally and postnatally; therefore, there is a 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 of genes available is 3 (– α/αα), which produce 75% of the needed αchains. Individuals with the silent carrier state are completely asymptomatic and all lab tests are normal.
- In the α-thalassemia trait, 2 deletions are present, and the total number of available αgenes 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 haemoglobin H disease or hydrops fetalis).
- Haemoglobin H disease is characterized by 3 deletions, with the number ofαgenes being 1 (– –/– α), which produces 25% of the normal αchains. 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 of genes is 0 (– –/– –), producing 0% αchains.
β-thalassemia.There are a total of 2 β-globin chain genes. In contrast to the α-globin chain genes, the 2 β-globin chain genes are expressed postnatally only, and therefore there is only postnatal disease and not a prenatal disease. The damage to the genes is mainly by point mutations, which form either some β chains (β+) or none (β0).
β-thalassemia minor is seen when one of the theβ-globin chain genes has been damaged. The condition is asymptomatic and characterized in laboratory studies by increased haemoglobin A2 (8%) and increased haemoglobin F (5%).
- β-thalassemia intermedia causes varying degrees of anaemia, but no transfusions are needed.
- β-thalassemia major(Cooley anaemia). Patients are normal at birth, and symptoms develop at about 6 months as haemoglobin F levels decline. Severe hemolytic anaemia results from a decreased erythrocyte life span. This severe anaemia 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 chromatolysis.
- 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 the maxilla (“chipmunk face”). The peripheral blood shows microcytic/hypo-chromic anaemia with numerous target cells and increased reticulocytes. Haemoglobin electrophoresis shows increased haemoglobin F (90%), normal or increased haemoglobin A2, and decreased haemoglobin A. Treatment is hematopoietic stem cell transplantation.
Sideroblastic anaemia is a disorder in which the body has adequate iron stores, but is unable to incorporate the iron into haemoglobin. It is associated with ring sideroblasts (accumulated iron in mitochondria of erythroblasts) in the bone marrow. Sideroblastic anaemia may be either pyridoxine (vitamin B6) responsive or pyridoxine unresponsive; the latter is a form of myelodysplastic syndrome (refractory anaemia 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.