Anemia

Anemia definition and introduction

Anemia is a condition of the blood characterized by too few red blood cells to support normal physiology. Anemia (AmE) or anaemia (BrE), from the Greek (Ἀναιμία) meaning "without blood", refers to a deficiency of red blood cells (RBCs) and/or hemoglobin. Homeostasis dictates that red cell production and destruction are usually balanced in an organism. Anemias are caused by either excess red cell destruction, or underproduction of red cells. Reduction in the red blood cell content of blood can have a wide range of clinical consequences, from no noticeable symptoms for gradual-onset anemia, to cardiovascular collapse and death from rapid, profound reductions, such as seen in bleeding.

The classification of anemia is commonly based on the etiology, or on the microscopic morphology of the red blood cells. Sometimes the morphology can give clues as to the etiology of anemia, as in the microcytic anemia of iron deficiency.

Hemoglobin is the pigmented protein in blood that carries oxygen; reductions in blood hemoglobin concentrations in anemia can lead to decreased oxygen delivery to tissues.

The measurement of anemia has changed with available technology. The spun hematocrit was one of the earliest indicators of anemia. Later, the development of the Coulter Counter automated the measurement of red blood cell size, and colorimetric assays facilitated the measurement of hemoglobin.

Classification

Production vs. destruction or loss

The "kinetic" approach to anemia yields what many argue is the most clinically relevant classification of anemia. This classification depends on evaluation of several hematological parameters, particularly the blood reticulocyte (precursor of mature RBCs) count. This then yields the classification of defects by decreased RBC production versus increased RBC destruction and/or loss. Clinical signs of loss or destruction include abnormal peripheral blood smear with signs of hemolysis; elevated LDH suggesting cell destruction; or clinical signs of bleeding, such as guiaic-positive stool, radiographic findings, or frank bleeding.

Red blood cell size

In the morphological approach, anemia is classified by the size of red blood cells; this is either done automatically or on microscopic examination of a peripheral blood smear. The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller than normal (under 80 fl), the anemia is said to be microcytic; if they are normal size (80-100 fl), normocytic; and if they are larger than normal (over 100 fl), the anemia is classified as macrocytic. This scheme quickly exposes some of the most common causes of anemia; for instance, a microcytic anemia is often the result of iron deficiency. In clinical workup, the MCV will be one of the most reliable pieces of information available; so even among clinicians who consider the "kinetic" approach more useful pragmatically, morphology will remain an important element of classification and diagnosis.

Other characteristics visible on the peripheral smear may provide valuable clues about a more specific diagnosis; for example, abnormal white blood cells may point to a cause in the bone marrow.

Microcytic anemia

• Iron deficiency anemia is the most common type of anemia overall and it has many causes. RBCs on often appear hypochromic (paler than usual) and microcytic (smaller than usual) when viewed with a microscope.

• Hemoglobinopathies -- much rarer (apart from communities where these conditions are prevalent)
  • Sickle-cell disease
  • Thalassemia

Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:

• Heme synthesis defect
  • Iron deficiency
  • Anemia of Chronic Disorders (which, sometimes, is grouped into normocytic anemia)
• Globin synthesis defect
  • alpha-, and beta-thalassemia
  • HbE syndrome
  • HbC syndrome
  • and various other unstable hemoglobin diseases
• Sideroblastic defect
  • Hereditary Sideroblastic anemia
  • Acquired Sideroblastic anemia including lead toxicity
  • Reversible Sideroblastic anemia

A mnemonic commonly used to remember causes of microcytic anemia is TAILS: T - Thalassemia, A - Anemia of chronic disease, I - Iron deficiency anemia, L - Lead toxicity associated anemia, S - Sideroblastic anemia.

Normocytic anemia

Normocytic anaemia is when the overall Hb levels are decreased, but the red blood cell size (MCV) remains normal. Causes include:

• Acute blood loss
• Anemia of chronic disease
• Aplastic anemia (bone marrow failure)

Macrocytic anemia

• Megaloblastic anemia due to a deficiency of either vitamin B12 or folic acid (or both) due either to inadequate intake or insufficient absorption. Folate deficiency normally does not produce neurological symptoms, while B12 deficiency does. Megaloblastic anemia is the most common cause of macrocytic anemia.
• Pernicious anemia is an autoimmune condition directed against the parietal cells of the stomach. Parietal cells produce intrinsic factor, required to absorb vitamin B12 from food. Therefore, the destruction of the parietal cells causes a lack of intrinsic factor, leading to poor absorption of vitamin B12.
• Alcoholism
• Methotrexate, zidovudine, and other drugs that inhibit DNA replication. This is the most common etiology in nonalcoholic patients.

Macrocytic anemia can be further divided into "megaloblastic anemia" or "non-megaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (6-10 lobes). The non-megaloblastic macrocytic anemias have different etiologies (i.e. there is unimpaired DNA synthesis,) which occur, for example in alcoholism.

The treatment for vitamin B12-deficient macrocytic and pernicious anemias was first devised by William Murphy who bled dogs to make them anemic and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to chemically isolate the curative substance and ultimately were able to isolate the vitamin B12 from the liver. For this, all three shared the 1934 Nobel Prize in Medicine. Symptoms of vitamin B12 deficiency include having a smooth, red tongue.

Dimorphic anemia

Here there are two types of anemia simultaneously, e.g., macrocytic hypochromic, due to hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid [1] or following a blood transfusion. One hint that this kind of anemia may exist is a wide RBC distribution width (RDW), which suggests a wider-than-normal range of sizes of red blood cells.

Underproduction anemias

Vitamin and mineral deficiency

Iron deficiency anemia

• Iron deficiency anemia is commonly caused by insufficient dietary intake or absorption of iron. Iron is an essential part of hemoglobin, and low iron levels result in decreased incorporation of hemoglobin into red blood cells. In the United States, 20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men. The principal cause of iron deficiency anemia in premenopausal women is blood lost during menses. Studies have shown that iron deficiency without anemia causes poor school performance and lower IQ in teenage girls. Iron deficiency is the most prevalent deficiency state on a worldwide basis. Iron deficiency affects women from different cultures and ethnicities. Iron found in animal meats are more easily absorbed by the body than iron found in non-meat sources; this is because of preferential absorption of heme iron in the hemoglobin and myoglobin found in meat. In countries where animal meats are only occasionally available in the diet, iron deficiency anemia is six to eight times more prevalent than in North America and Europe. Iron deficiency is sometimes the cause of abnormal fissuring of the angular (corner) sections of the lips (angular cheilitis).
• Iron deficiency anemia can also due to bleeding lesions of the gastrointestinal tract. Fecal occult blood testing, upper endoscopy and lower endoscopy are often performed to identify bleeding lesions. Iron deficiency in the elderly should indicate the possibility of an occult gastrointestinal tract malignancy.

Myelodysplastic syndrome

Myelodysplastic syndrome is a loosely-defined condition of ineffectual hematopoeisis by the bone marrow. The hallmark characteristics of myelodysplastic syndrome are:

• Cytogenetic abnormalities of bone marrow stem cells
• Morphological changes in marrow stem cells, in all three hematopoeitic cell lines
• Progressive cytopenias, usually starting in one cell line, then progressing to two or three
• Potential to transform to acute leukemia

Aplastic anemia

Aplastic anemia is clinical syndrome characterized by a hypoplastic bone marrow in the setting of pancytopenia. The pathogenesis of aplastic anemia is damage to the pluripotent stem cell reserves of the bone marrow.

Patterns of aplastic anemia include:

• Hereditary
• Drug-induced
• Radiation
• Infections
• Idiopathic

Anemia of chronic disease

Four mechanisms contribute to anemia in the context of inflammatory disease:

• Immune system cytokines shorten RBC lifespan by 10-20 days (citation).
• Poor iron reutilization from macrophage recirculation in the bone marrow
• Ineffectual hematopoeisis resonse to erythropoeitin, or inadequate erythropoeitin production
• Direct Cytokine inhibiton of erythropoeisis

Several categories of chronic diseases can contribute to anemia.

Chronic renal insufficiency

The production of red blood cells in the bone marrow depends on stimulation of erythroid stem cells by the growth factor, erythropoeitin. Erythropoeitin is principally manufactured in the kidneys, and the liver to a lesser extent. This hormone deficiency in renal disease leads to an anemia that is correctable with recombinant pharmacological erythropoeitin. A pair of articles in the New England Journal of Medicine in November, 2006 drew attention to the concept that excessive correction of anemia in renal failure patients did not improve cardiovascular function, and could in fact be deleterious. Patients treated to a higher target hemoglobin showed an improved quality of life, but had excess mortality, compared with patients treated to a lower target hemoglobin.

Chronic inflammatory disease

The anemia of chronic disease or anemia of chronic inflammatory disease consist of anemias caused by poor iron reutilization by the reticuloendothelial system and inappropriate cytokine production in the inflammatory state. Some commonly-cited causes of the anemia of chronic disease:

• Arthritis
• Lupus
• Infections
• Cancer

Heart disease

Congestive heart failure is a cited etiology of anemia.

• • A study demonstrated that most patients with anemia and congestive heart failure (CHF) are actually iron deficient. 18.9% of patients with CHF and anemia had no documented etiology of anemia, and therefore are said to have anemia of chronic disease
  • Anemia is a poor prognostic feature of CHF

Myeloma and other malignancies

The anemia of malignancy is multifactorial, and can stem directly from bleeding, bone marrow compartment replacement by malignant cells, hemolytic anemia, immunoglobulin deposition, chemotherapy, or immune-mediated pure red-cell aplasia