First question should be: “Is the patient producing enough red blood cells?“. This is why we check a reticulocyte count. If appropriately elevated, we can think about hemolysis or blood loss. “Hemolysis labs” (LDH, haptoglobin, and indirect bilirubin) as well as peripheral smear can help us differentiate the two. If the reticulocyte count is low or inappropriately normal (a reticulocyte production index can be calculated to assess appropriateness), then a lack of production is the cause of the anemia. This is usually due to a deficiency in one of the four things that RBCs require for production: EPO, iron, B12, or folate

Iron Study Interpretation

In Iron-Deficiency anemia, total body iron stores are decreased. The total iron binding capacity (TIBC) represents the available binding sites available on the transferrin molecule. This will be increased because of the low amounts of iron in the body despite the normal transferrin levels. Ferritin will also be low because the liver does not need to produce as much to carry iron through the body, again because of the low amount of iron in the body.

In Anemia of Chronic Disease, the inflammatory molecule hepcidin is produced by the liver. This prevents uptake of iron from the GI tract as well as iron release from the liver. This leads to low total body iron levels as well. This is an evolutionary attempt to decrease iron stores available to infectious agents in the bloodstream. With chronic inflammation, the liver uses its energy synthesizing inflammatory agents (such as hepcidin), and therefore does not generate as much transferrin, causing levels to decrease. The transferrin levels decrease proportionately more than the iron levels, causing a decrease in TIBC. Ferritin levels will be elevated in anemia of chronic disease, as it is elevated in all causes of inflammation.

B12/Folate and Homocysteine/Methylmalonic Acid

An inadequacy of either Vitamin B12 or folate may result in a macrocytic, megaloblastic anemia. This condition is further characterized by ineffective erythropoiesis, resulting in intramedullary hemolysis, which leads to elevated indirect bilirubin and LDH levels.

Homocysteine and methylmalonic levels may be checked with folate levels or if Vitamin B12 levels are indeterminate (2.2 – 4.1 ng/mL for folate, 200-400 for Vitamin B12).

Magnified blood sample demonstrating RBCs with central pallor as well as hyper-segmented neutrophils – indications of megaloblastic anemia

Because of the reactions shown above, an inadequate supply of folate will lead to an anemia, as well as a buildup of homocysteine, as the first reaction will not be able to move forward

With an inadequate supply of Vitamin B12, there is also stalling of the first reaction, leading to a buildup of homocysteine, however there will also be a buildup of methylmalonic acid because of the second reaction’s inability to occur. With this, there will also be a decreased amount of Succinyl-CoA available for myelin production and the patient will likely experience neuropathies in addition to anemia.

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