Microcytic and Normocytic Anemia: Symptoms, Evaluation, and Treatment

SUMMARY:

Anemia is simply defined as a decreased number of red blood cells. While there are many causes of anemia, this summary will primarily focus on two subtypes of anemia, microcytic and normocytic anemia. The workup for anemia varies based on risk factors, clinical presentation and symptoms, and overall clinical picture. Screening for anemia and specifically iron deficiency is recommended in pregnancy, children at one year of age, and when patients have signs or symptoms indicative of the disease. Iron deficiency can result from inadequate intake, decreased absorption, increased demand, or increased loss of iron, and treatment is therefore focused on the underlying cause.

Symptoms

General Anemia

  • Fatigue/generalized weakness
  • Shortness of breath
  • Pale skin or mucus membranes
  • Irregular or racing heartbeat
  • Systolic heart murmur: Specially in more severe or acute anemia

More Specific to Iron Deficiency

  • Pica: Unusual cravings for nonfood items such as ice, dirt, paint, or starch
  • Restless legs syndrome
  • Brittle nails or spooning of the nails, pale nail beds
  • Cracks at sides of mouth

Risk Factors/Causes

Iron Deficiency

  • Blood loss (acute or chronic)
    • Frequent blood donation or tests | Heavy menstrual periods | Injury or surgery | GI tract bleeding | Urinary tract bleeding
  • Inadequate Intake
    • Restrictive diets | More commonly in vegan/vegetarian diets
    • In children, diets with excessive cow’s milk consumption may lead to iron deficiency | While milk is high in many nutrients, it is low in iron and may lead to decreased iron absorption and lack of appetite for iron-rich foods
  • Lack or impairment of absorption
    • Inflammatory and digestive conditions: e.g., celiac disease, ulcerative colitis, Crohn’s disease or Helicobacter pylori infection
    • Gastrointestinal surgery: e.g. gastric bypass, gastrectomy, or small bowel resection
    • Genetic conditions which impair absorption such as TMRPSS6 gene mutation causing overproduction of hepcidin which blocks the uptake of iron in the intestine
  • Other medical conditions
    • End-stage renal disease or chronic kidney disease
    • Chronic inflammatory states such as congestive heart failure
    • Pregnancy
    • Gastrointestinal malignancy

Thalassemia Trait

  • Thalassemias are genetic conditions which effect the production of either the hemoglobin beta or alpha globin chain
  • Beta thalassemia is an autosomal recessive genetic condition, thus clinical manifestations of the disease depend on the individual being either heterozygous or homozygous for the gene
    • Heterozygous forms usually have no to minimal symptoms and may be incidentally found on routine lab work and subsequent evaluation.
    • Homozygous forms are usually more symptomatic and diagnosed at an earlier age
  • Alpha thalassemia is caused by the underproduction of the alpha globin chains
    • These globin chains are controlled by four genes
    • Patient presentation and symptoms depend on the number of gene mutations or deletions
  • All forms of thalassemia are more prevalent in persons of African, Mediterranean, and Southeast Asian descent thus family history and/or ethnicity can raise suspicion for these diseases
  • Management depends on the form and severity of the thalassemia especially in the case of homozygous beta thalassemia or multiple gene mutations in alpha thalassemia
    • May involve care from a hematologist

Anemia of Chronic Disease

  • Chronic medical conditions may induce a chronic inflammatory state, e.g., chronic infections or medical conditions such as congestive heart failure or diabetes
  • This form of anemia is usually mild and not progressive
  • Co-existing iron deficiency may also be present and should be evaluated
  • Treatment is usually centered on treating the underlying cause and routine monitoring

Lead Toxicity

  • Risk factors for lead toxicity include
    • Living in an older home which may contain lead paint
    • Infants with exposure to older toys which may contain lead paint
    • Geographic considerations
    • Socioeconomic status
    • Occupational history

Laboratory Evaluation

  • Initial Screen for Anemia
    • Complete Blood Count (CBC)
    • Hemoglobin | Hematocrit | Mean corpuscular volume (MCV)
    • Anemia definition: Hemoglobin level two standard deviations below normal for age and sex
      • Microcytic: MCV <80 fL
      • Macrocytic: MCV >100 fL
      • Normocytic: Normal MCV
  • Peripheral Blood Smear
    • Can help further characterize megaloblastic or microcytic anemia
    • Rules out other causes of anemia
  • Reticulocyte count
    • Evaluation of adequate, increased, or decreased production of red blood cells

Iron Deficiency Anemia

  • Can be present with either a microcytic or normocytic anemia
  • Iron levels
    • May be normal even if iron stores are low and thus cannot be ordered alone for workup of iron deficiency anemia
  • Ferritin
    • Protein which stores iron in the body
    • Definitive test for determination of iron deficiency
    • Thresholds vary, but generally levels <30ng/mL are indicative of iron deficiency
    • However, ferritin is an acute phase reactant and can be elevated in infection or chronic inflammation
  • Total iron-biding capacity (TIBC) and transferrin saturation
    • TIBC is high | Transferrin saturation low
    • Transferrin saturation thresholds vary, but generally <16% is suggestive for iron deficiency
    • Bone marrow is the gold standard to measure iron stores
  • All adult men and postmenopausal women with iron deficiency anemia should be screening for gastrointestinal malignancy, especially in those with no other obvious etiology
  • Celiac disease screening should be considered for adults with iron deficiency anemia, especially in those without another obvious etiology

Microcytic Anemia with Suspicion for Thalassemia

  • Ferritin level: Normal to high
  • Serum iron level: Normal to increased
  • TIBC and transferrin saturation: Normal to increased
  • Confirm diagnosis with hemoglobin electrophoresis
  • Can co-exist with iron deficiency anemia

Microcytic Anemia with Suspicion for Anemia of Chronic Disease

  • Ferritin level: Normal or high
  • Serum iron level: Decreased
  • TIBC and transferrin saturation: Decreased
  • History and exclusion of other causes of anemia is key for diagnosis

Microcytic Anemia with Suspicion for Lead Toxicity

  • Can co-exist with iron deficiency anemia
  • Serum lead levels can be obtained when history raises suspicion
  • Groups at highest risk for lead toxicity include:
    • Children <6 years | Live in houses at or below the poverty level | Live in housing built prior to 1978 | Immigrants, refugees, or recently adopted from outside of the US
    • Individuals at risk of housing inequity, such as communities of color
    • Pregnant individuals
    • Adults who work in industries with high risk of lead exposure
  • The CDC provides guidelines on which high-risks groups of children should be screened during well-child visits (see ‘Learn More – Primary Sources’ below)

Treatment for Iron-deficiency Microcytic Anemia

  • Mainstay of treatment is to identify the underlying cause and procedure with proper treatment

Oral Iron

  • Many formulations available | Dosing depends upon formulation
    • Most commonly used is ferrous sulfate 325mg
    • Most recent studies recommend every other day dosing for best absorption
  • Common side effects include
    • Nausea | GI discomfort | Constipation
  • Can be taken with vitamin C for increased absorption
  • Usually, a trial of 4 to 6 weeks of oral iron is considered prior to treating with IV iron
    • After one month of treatment, repeat labwork should show an increase in hemoglobin of 1g/dL to indicate an adequate response
    • Treatment with oral iron should continue for at least 3 months after correction of anemia to replete iron stores
  • Oral iron is best taken on an empty stomach
    • Doses can be taken with food to reduced side effects | However, this may decrease absorption by 40%
  • Medications such as proton pump inhibitors as well as patient factors that induce gastric acid hyposecretion (gastrectomy, vagotomy, gastric bypass) can reduce dietary iron and iron tablet absorption

Intravenous (IV) Iron

  • Can be considered in patients who
    • Cannot tolerate oral iron or
    • Cannot absorb oral iron preparations or
    • Do not have an adequate response after oral iron therapy
  • Total number of doses required, infusion time, and dosing frequency depends on the formulation
  • Newer formulations, iron sucrose and sodium ferric gluconate, have much lower side effect rates and profiles compared to the original formulation of iron dextran
  • Most common side effects of IV iron are
    • Headache | Nausea | Diarrhea | Rash

Blood Transfusion

  • Does not treat the underlying cause but can treat the anemia itself
  • Transfusion thresholds vary depending on symptoms, overall clinical status, and underlying medical conditions

Learn More – Primary Sources:

Iron Deficiency Anemia: Evaluation and Management (Short et al. American Family Physician, 2013)

National Heart, Lung, and Blood Institute: Iron-deficiency anemia

BMJ: Evaluation of Anemia

Evaluation of Microcytosis (Van Vranken et al. American Family Physician 2010)

CDC: Childhood Lead Poisoning Prevention