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Anemia

Approach to Anemia

Macrocytic Anemias

Macrocytic anemia refers to anemia in which red blood cells are large i.e. with a mean corpuscular volume (MCV) > 100 fL. Macrocytic anemias are divided into 2 groups: megaloblastic and non-megaloblastic.

  • Megaloblastic Anemias
    • Vitamin B12 (Cobalamin) deficiency
    • Folate deficiency
  • Non-megaloblastic anemias
    • Alcoholism
    • Hypothyroidism
    • Liver disease
    • Medications - e.g. chemotherapy, zidovudine, hydroxyurea
  • Acute myeloid leukemia
  • Myelodysplastic syndrome

Megaloblastic anemias have not only large red blood cells, but also hypersegmented (usually >5 lobes) neutrophils. This is because with megaloblastic anemias there is impaired DNA synthesis.

Folate and Cobalamin (B12) deficiency

Folate and Cobalamin deficiency can both cause megaloblastic anemia. To understand how these two are differentiated during diagnostic lab work, it is important to understand the biochemistry of a few reactions. Both folate and cobalamin are required for homocysteine to be converted to methionine. Only cobalamin, not folate, is required for the conversion of methylmalonyl-CoA to succinyl-Coa. Therefore, deficiency in either folate or cobalamin result in elevated homocysteine, and only a deficiency in cobalamin results in elevated methymalonic acid.

Vitamin B12 (Cobalamin) deficiency

Vitamin B12 is found in animal products such as meat and dairy. Daily requirement is 6-9 micrograms and total body stores are about 2-5 milligrams. Pure vegans who do not take supplements for B12 can develop deficiency after about 4-5 years.

A common cause of cobalamin deficiency is loss of intrinsic factor which is required for B12 absorption. This can occur with autoimmune gastritis (Pernicious anemia) or with gastrectomy.

Pernicious anemia is the most common cause in patients with northern European ancestry. It occurs due to production of autoantibodies against intrinsic factor. These patients typically have other autoimmune conditions. A feature of pernicious anemia is atrophic glossitis which presents as a smooth, shiny tongue. Patients also develop chronic atrophic gastritis which leads to decreased production of intrinsic factor by gastric parietal cells. The atrophic gastritis also leads to a 2-3 times increased risk of gastric cancer (intestinal type gastric cancer, gastric carcinoid tumors).

Cobalamin is a cofactor in many important reactions. It is a cofactor in the production of thymidylate and purine molecules in DNA. Because of this impaired DNA synthesis, RBCs can not mature in the bone marrow and remain in the immature megaloblastic form. These immature RBCs undergo hemolysis leading to increased bilirubin (results in jaundice) and increased lactate dehydrogenase (LDH) in blood. Neutrophils are also affected resulting in hypersegmented polymorphonuclear neutrophils. Myelin synthesis is also affected resulting in problems with nerve conduction which leads to neurological deficits (e.g. memory problems, dementia, irritability, peripheral neuropathy). The peripheral neuropathy is due to degeneration of the dorsal (posterior) columns in the spinal cord and it results in loss of position and vibration sense leading to ataxia which presents as a shuffling broad-based gait.

Folate supplementation can help with the anemia caused by vitamin B12 deficiency because folate is also used as a cofactor to turn homocystein into methionine. However, it does not help with the peripheral neuropathy and other neurologic problems that occur with B12 deficiency.

Folate Deficiency

Folate can be found in leafy greens. It only takes 4-5 months before folate levels drop enough for clinical symptoms to occur. However, in alcoholics, it can take as little as 1-2 months before clinically apparent folate deficiency develops.

The most common cause of folate deficiency in the U.S. is alcoholism. Another very common cause is diet e.g. strict vegan diet without supplementation. Alcohol impairs enterohepatic folate absorption. Certain antiepileptic medications can impair folate absorption in the small intestine e.g. antiepileptics such as phenytoin, primidone, and phenobarbital. Drugs that inhibit dihydrofolate reductase also result in a folate deficiency, examples include trimethoprim (at high doses) and methotrexate. Leucovorin (folinic acid) reverses the effect of methotrexate on folate levels and is used in patients receiving methotrexate as part of their chemotherapy regimen.

Myelodysplastic syndrome

This condition causes macrocytic anemia mainly in elderly patients. The key finding that helps distinguish this from other causes of macrocytic anemia is the presence of dysplastic cells in the bone marrow.

Microcytic Anemias

Iron deficiency anemia in childhood

Risk factors for iron deficiency anemia in infants<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""> include giving too much cow's milk (>24 oz/day) or limited iron in diet. <3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">Cow's milk can cause iron deficiency because the calcium and caseinophosphopeptides interfere with iron absorption in the intestine. Also, cow's milk does not have much iron and children who drink a lot may be replacing iron rich foods with milk.

Iron deficiency has a significant effect on RBCs. The number of RBCs produced in the bone marrow is decreased because of low iron stores. At the same time, the RBCs that are hypochromic, small (low MCV), and vary greatly in size (high RDW)

RBCs have reduced oxygen-carrying capacity and therefore deliver less oxygen to tissues leading to hypoxia. The body compensates for this hypoxia by increasing blood delivered to tissues i.e. increased cardiac output and heart rate. There may be a flow murmur heard because of the increased cardiac output.

Diagnosis is made when hemoglobin is < 11 g/dL, and RBC indexes show reduced MCV and elevated RDW. Prevention involves screening using hemoglobin during the 12 month visit.

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<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""><3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">Hemolytic Anemias
<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""><3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">
<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""><3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">Key laboratory findings of intravascular hemolysis include elevated indirect bilirubin, elevated LDH and low haptoglobin. The destruction of RBCs causes release of hemoglobin which binds haptoglobin and then both are cleared by the liver. Breakdown of heme in hemoglobin results in elevated indirect bilirubin. Destruction of cells including RBCs results in elevated LDH. 
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With extravascular hemolysis, there is elevated indirect bilirubin, but only a small elevation in LDH and a small decrease in or normal haptoglobin. This is because, RBCs are mainly destroyed by phagocytes in the reticuloendothelial system (spleen, lymph nodes, etc). Extravascular hemolysis is seen in autoimmune hemolytic anemia, hereditary spherocytosis and G6PD. To differentiate between AIHA and hereditary spherocytosis, both of which have spherocytes, a direct Coombs test is helpful
<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""><3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">
<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""><3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">Autoimmune Hemolytic Anemia (AIHA)

AIHA occurs due to autoantibodies against the RBC membrane. The antibodies remove pieces of the membrane resulting in a round/ spherical RBC shape. These spherocytes are destroyed by phagocytes in the spleen and are destroyed (extravascular hemolysis) and they are also destroyed within the blood vessels (intravascular) because they are fragile due to the antibody damage.

There are two main types of autoimmune hemolytic anemia: warm agglutinin disease and cold agglutinin disease. Both types can be complicated by lymphoproliferative disorders and they can also be caused by lymphoproliferative disorders! They both present with normocytic anemia, splenomegaly, reticulocytosis, elevated indirect bilirubin (jaundice, scleral icterus), slightly LDH, low normal haptoglobin.

Warm agglutinin disease can be caused by lymphoproliferative disorders (e.g. CLL), autoimmune diseases such as lupus, viral infections, drugs, or immunodeficiency disorders. The direct Coombs test is positive and has anti-IgG and/or anti-C3. Complications include venous thromboembolism and lymphoproliferative disorders. Treatment involves high-dose corticosteroids to reduce autoantibody production and if they don't work splenectomy.

Cold agglutinin disease can also caused by lymphoproliferative disorders but it can also be caused by certain infections such as infectious mononucleosis and mycoplasma pneumoniae. Patients when exposed to cold can develop livedo reticularis and acral cyanosis which resolve with warming. Complications can include ischemia and peripheral gangrene. Direct Coombs test is positive with anti-IgM and/or anti-C3. Treatment involves avoiding cold exposure as well as rituximab and/or fludarabine.

Microangiopathic hemolytic anemias

<1 6="" and="" are="" at="" children="" cow="" delayed="" e.g.="" factors="" for="" giving="" goat="" include:="" introduced="" introduction="" milk="" months="" nbsp="" normally="" of="" old="" or="" prematurity="" risk="" s="" solids="" soy="" they="" year=""><3 another="" day="" e.g.="" exposure="" factor="" home="" in="" is="" lead="" living="" nbsp="" older="" p="" risk="" servings="" to="">Disseminated intravascular coagulation
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