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.

Here is a simplified schematic of this approach:

Anemia

Reticulocyte production index shows inadequate production response to anemia.

Reticulocyte production index shows appropriate response to anemia = ongoing hemolysis or blood loss without RBC production problem.

No clinical findings consistent with hemolysis or blood loss: pure disorder of production.

Clinical findings and abnormal MCV: hemolysis or loss and chronic disorder of production*.

Clinical findings and normal MCV= acute hemolysis or loss without adequate time for bone marrow production to compensate**.

Macrocytic anemia (MCV>100)

Normocytic anemia (80<MCV<100)

Microcytic anemia (MCV<80)

* For instance, sickle cell anemia with superimposed iron deficiency; chronic gastric bleeding with B12 and folate deficiency; and other instances of anemia with more than one cause. ** Confirm by repeating reticulocyte count: ongoing combination of low reticulocyte production index, normal MCV and hemolysis or loss may be seen in bone marrow failure or anemia of chronic disease, with superimposed or related hemolysis or blood loss.

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.

Here is a schematic representation of how to consider anemia with MCV as the starting point:

Anemia

Macrocytic anemia (MCV>100)

Normocytic anemia (80<MCV<100)

Microcytic anemia (MCV<80)

High reticulocyte count

Low reticulocyte count

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

Iron (Fe) Deficiency - (writing words, will add/edit later) DMT-1, Duodenum, Transferrin, hypochromic, microcytic, high RDW, clathryn coated pit, free iron too toxic for cell (maybe this will go in subarticle), ferritin/hemosiderin (storage form), regulated by IRP (iron response protein) - binds to mRNA of ferritin blocks translation. when bound to TfR mRNA stabilizes increasing uptake of Fe.

Reasons for Fe def : Increase Losses (blood loss - uterus, GI, other), Increase requirements (growth, pregnancy), Decrease Intake (infants and children), and Decreased absorption

Aplastic anemia

(written in stream of consciousness style - will clean up later but feel free to start editing for me) Drugs, Radiation, Infections, Immune, Idiopathic

Drugs that cause aplastic probably are indirectly causing through immune response. Radiation is a direct cause. Infections like T.B. can cause aplastic anemia. If you had TB and aplastic anemia one would probably treat with immune suppression and addition to TB regimen. If you miss the underlying cause and treat with only immune suppression, you will kill the patient (faster?). (Debating whether to insert a famous example of a famous patient who died of this)

Anemia of chronic disease

Four mechanisms involved; some conditions utilize one mechanism more than others. 1. cytokine related macrophage activity shortens rbc life by 10-20 days. Failure to increase erythropoiesis leads to anemia 2. Not reusing iron 3. Blunted EPO response 4. Direct Cytokine inhibiton of erythropoeisis

Chronic renal insufficiency

underproduction of EPO. acidic pH makes 'burr' cells.