Resident Editor: Evan Walker, MD 

Faculty Editor: Patricia Cornett, MD

BOTTOM LINE ✔ Anemia is not a normal consequence of aging and can present with nonspecific symptoms ✔ Workup should be guided by MCV ✔ Microcytic anemia often requires ruling out GI malignancy

Background/Framework

• Definition: Reduced amount of circulating red blood cells (RBC). On lab tests: Hemoglobin (Hgb) or hematocrit (Hct) ≥2 standard deviations below the mean. Hgb <13.5 g/dL or Hct <41% (men); Hgb <12 g/dL or Hct <36% (women).
• Anemia is a sign, not a diagnosis.
• The rate of anemia increases with age after 50yo; however, it is not a normal consequence of aging.
• Anemia can be an independent predictor of mortality in CKD, CHF, and some malignancies

Signs and Symptoms

• Dependent on the degree of anemia and the rate at which it has evolved, as well as the oxygen demands of the patient. Symptoms are less likely in anemia that evolves slowly.
• History:
  • Possible Symptoms = exertional dyspnea, dyspnea at rest, varying degrees of fatigue, weakness, melena/black stool. However, most patients are asymptomatic.
  • Disorders that are worsened by/contribute to anemia and should prompt CBC: CHF, CKD, dementia, dizziness, depression, falls.
  • Always inquire about medications (over-the-counter/prescribed), EtOH use, family history of anemia, and diet history.
• Exam:
  • Non-specific/insensitive findings: pallor of the skin, nail bed, tongue. This includes:
    • Palmar crease pallor (exam of the palmar crease with the gentle extension of hands)
    • Conjunctival rim pallor (absence of contrast between anterior and posterior margins of the rim of the lower eyelid)
    • All have a wide range of sensitivity (19-70%)and specificity (70-100%) with wide inter-observer differences.
  • Look for signs of related illness:
    • Lymphadenopathy, hepatosplenomegaly, bone tenderness (which may signify the expansion of the marrow space due to infiltrative disease or lytic lesion)

Differential Diagnosis / Evaluation

Step-wise approach

1. Acuity: Is the anemia of recent origin, subacute, or lifelong? Recent anemia is almost always an acquired disorder (a notable exception is G6PD deficiency). Meanwhile, lifelong anemia, particularly if accompanied by positive family history is likely to be inherited (eg. hemoglobinopathies, hereditary spherocytosis). If pt has no recent labs, the presence/absence of symptoms can be a clue (ie. patients with hgb = 8 are less likely to have acute anemia if they are asymptomatic, but this should be verified by frequent re-checking of CBC).
2. Repeat CBC with RBC indices (MCV): Re-check in the euvolemic state as volume overload can lead to falsely decreased hemoglobin and dehydration can lead to under-detection of low hemoglobin. Of note, the classic algorithm based on MCV is less helpful in the elderly because changes in erythrocyte size do not often accompany anemia in this age group.

   MCV <80(microcytic)	Reduced iron availability (iron-deficiency anemia, anemia of inflammation/chronic disease) Reduced heme synthesis (lead poisoning, congenital sideroblastic anemias,) Reduced globin production(thalassemia, copper deficiency, zinc poisoning)
   MCV 80-100(normocytic)	Least specific category. Possible mixed micro/macro processes, CKD, acute blood loss. See below for more work-up.
   MCV >100(macrocytic)	Non-megaloblastic: alcohol abuse, liver disease, hypothyroidism, drugs (AZT, anticonvulsants, methotrexate, hydroxyurea), abnormal RBC maturation (myelodysplastic syndrome, leukemia), aplastic anemia, early B12 or folate deficiency Megaloblastic(usually MCV > 110, characterized by hypersegmented neutrophils on blood smear): vitamin B12 or folate deficiencies, drugs Hyperproliferative: reticulocytosis (chronic hemolytic anemia, recent bleeding, recent repletion of B12/folate)

3. Begin workup based on morphologic category and clinical suspicion (H&P)

MICROCYTIC (MCV<80)

• Most common dx: Iron Deficiency Anemia (see below)
• Focused Hx: Bleeding, nutrient intake, toxin exposure, FHx, malabsorption
  • Specific to iron deficiency: thinning hair, cheilosis, red tongue, restless leg
• Initial Workup: Reticulocyte count, Smear, Ferritin, TIBC, Transferrin Saturation, Iron. (Iron and TIBC have diurnal variation, with elevations later in the day, and with consumption of meat or iron pills. Ferritin is the most reliable/helpful test). FOBT → EGD/Colo.
• Additional workup (if above is normal): Hgb electrophoresis (if family history + for thalassemia and/or life-long anemia unresponsive to iron therapy), heavy metal levels.

  Evaluation of Iron Studies

  Ferritin	Iron	TIBC	Transferrin saturation	Differential diagnosis
  Low	Low	Increased	Decreased	Iron deficiency anemia
  Normal or Increased	Normal or Increased	Normal or Decreased	Normal or Decreased	Anemia of chronic disease

  Iron Deficiency Tips

  • Most common etiology in children = nutrition. In adults = occult blood loss
  • Clinical course: Iron deficiency (low ferritin) → anemia → microcytosis.
    • With treatment, these resolve in the reverse order
  • This diagnosis should always be coupled with an etiology
    • In adults, must r/o occult GI bleed: EGD/Colo
  • Evaluation of Ferritin

    Ferritin Level	Likelihood Ratio for Dx of Iron Deficiency Anemia
    ↓↓↓ Ferritin (<15)	51.8
    ↓↓Ferritin (15-24)	8.8
    ↓Ferritin (25-34)	2.5
    ↔ or ↑ Ferritin (>100)	0.08

  • In chronic inflammation, ferritin can be falsely elevated and less reliable. Transferrin saturation <10% can be diagnostic of iron deficiency anemia in these cases and can warrant an empiric trial of iron

NORMOCYTIC (MCV 80-100)

• Virtually all etiologies of anemia are normocytic in the early stages
• Nonspecific category of anemia – can be:
  • Decreased production of normal-sized RBC (Anemia of chronic disease, CKD, aplastic anemia, hypothyroid, hypogonadism)
  • Destruction of RBC (hemolysis)
  • Early blood loss
  • Increased plasma volume (pregnancy, volume overload)
  • A mixture of microcytic and macrocytic anemia
• Check TREND of MCV. **For example, a decreasing MCV from 95 -> 82 indicates a progressive microcytic process, though the MCV is still technically ‘normocytic.’**
• Initial workup: Blood Smear (define subpopulations of micro or macro RBCs), reticulocyte index (see below), BMP, LFT, TSH
• The goal is to narrow differential diagnosis into one of the above etiologies:

  Etiology	Possible Findings
  Decreased production of RBC	Retic Index <2, Cr↑ (CKD), TSH↑
  Destruction of RBC	Retic Index >3, bilirubin↑, LDH↑, haptoglobin ↓, Coombs Testing +
  Blood Loss	History, workup of occult bleed as in ‘Microcytic’
  Increased Plasma Volume	History, Exam consistent with volume overload
  A mixture of Micro/Macro	Subpopulations of RBC on blood smear

MACROCYTIC (MCV>100)

• Focused Hx: Comorbid medical conditions, medications, EtOH intake (≥80g EtOH, or 1 bottle of wine/day, can cause macrocytosis), diet, neurologic symptoms
• MED REVIEW IS ESSENTIAL: methotrexate, zidovudine, alkylating agents, trimethoprim/sulfamethoxazole, among others
• Initial Workup: Smear (look for hyperseg neutrophils == megaloblastic anemia), Retic index (see below), B12 (see below), TSH, LFTs
• Look at other cell lines: If concurrently abnormal WBC or platelets, suspect bone marrow process/MDS, refer to hematology for consideration of Bone Marrow Biopsy

1. Interpretation of Tests for Normocytic/Macrocytic Anemia

   Evaluation of Reticulocyte Index (RI)
   Formula:Reticulocyte index = reticulocytes x (hct/45) / CF

   Units:
   Hct (Hematocrit): % CF (Maturation correction factor): When the marrow is greatly stimulated, marrow reticulocytes enter the circulation prematurely. The index must be corrected to account for the longer circulation time of those ‘shift reticulocytes’.The correction factor depends on the severity of the anemia.

   RI > 3 (normal marrow response to anemia)

   Blood loss: evaluate for active GI bleeding (stool exam), GU bleeding, recent trauma RBC destruction: inherited hemolytic anemias (hereditary spherocytosis, sickle cell, thalassemia major); acquired hemolytic anemias (autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura, malaria, paroxysmal nocturnal hemoglobinuria) If no obvious active bleeding send LDH, indirect and direct bilirubin, direct Coombs, peripheral smear. Consider urgent referral to Hematology.

   RI <2 (inadequate response to anemia) ↓

   Primary bone marrow failure: aplastic anemia/red cell aplasia; myelophthisis (replacement of bone marrow with tumor, granulomas, fibrosis, etc) clonal marrow disorders (leukemia, myelodysplasia, paroxysmal nocturnal hemoglobinuria) Secondary bone marrow failure: Anemia of chronic disease, lack of nutrients (iron/B12/folate) from diet, malabsorption, or blood loss bone marrow suppression (drugs, chemo, irradiation) low level of trophic hormones like EPO (CKD), thyroid hormone (hypothyroidism), androgens (hypogonadism) hypersplenism (usual anemia with mild pancytopenia) multiple myeloma infection: HIV/AIDS, Parvovirus B19

   Evaluation of Vitamin B12/MMA

   ↓↓Vitamin B12 (<200)	Vitamin B12 deficiency (see treatment below)
   ↓Vitamin B12 (200-300)	Send Methylmalonic Acid (MMA)level; if elevated: Vitamin B12 deficiency diagnosed, proceed to treatment
   ↔Vitamin B12or ↔MMA	Continue evaluation for other causes of anemia

   **Sensitivity of serum B12 levels to dx functional B12 deficiency has recently been disputed, with one study showing the sensitivity of 19% for a cutoff of 200 pg/mL. If suspicion is high, send concurrent MMA for a functional test, regardless of B12 level.**

   Evaluation of peripheral smear

   Can yield diagnostic clues or confirmatory evidence. Always review the smear yourself, accompanied by an experienced examiner.

   • Schistocytes/helmet cells (microangiopathic hemolytic anemia)
   • Target cells (liver disease, hemoglobinopathies, thalassemias, post-splenectomy, iron deficiency)
   • Burr cells (cells with regular broad-based projections called echinocytes)(uremia, artifact from smear preparation)
   • Spur cells (cells with irregular narrow-based projections called acanthocytes)(severe liver disease, abetalipoproteinemia)
   • Spherocytes (hereditary spherocytosis, autoimmune hemolytic anemia, hemoglobin C, transfusions)
   • Elliptocytes (hereditary elliptocytosis, iron deficiency, myelodysplasia)
   • Nucleated RBCs (hemolysis, profound stress or hypoxemia, myelophthisic processes (especially myelofibrosis)
   • Teardrop cells (dacrocytes)(myelophthisic processes (especially myelofibrosis), myelodysplasia, megaloblastic anemias, thalassemia major, iron deficiency anemia)
   • Basophilic stippling (lead and heavy metal poisoning, alcohol use, thalassemia, hemoglobinopathies, sideroblastic anemias)
   • Hypochromia: iron deficiency anemia
   • Howell-Jolly bodies: post-splenectomy/hyposplenism
   • Heinz bodies: G6PD deficiency following exposure to oxidative stress, thalassemias
2. If no etiology found:
   • Does the patient have Chronic Kidney Disease?: treat with EPO, evaluate response.
   • Consider SPEP/SFLC, especially if concurrent CKD of unknown cause, hypercalcemia, or bone pain.
   • ConsiderHIV/HCV as other independent causes of anemia.
   • Consider checking testosterone in men.
   • Unidentified cause of anemia (33% of cases in the elderly): Consider Hematology referral for bone marrow biopsy (myelodysplastic syndrome account for 1/6 of unexplained anemia) and supportive therapy (transfusions for symptomatic anemia versus trial of erythropoiesis-stimulating agents), especially if hemoglobin <10.

Treatment of Common Causes 

Iron Deficiency Anemia: Important to evaluate for GI cancer. Men of any age or non-menstruating women should be referred for endoscopic evaluation (EGD/colo).

• Ferrous Sulfate 325 mg PO once daily. More frequent dosing does not lead to more absorbed iron and can worsen side effects (GI upset/pain) and reduce adherence.
• Iron absorption requires an acidic environment → food, PPI, and chronic gastritis worsen absorption
  • Have patients take iron on empty stomach, with orange juice, or rxAscorbic Acid 500mg daily
• Re-check hgb in 1-3 months (adequate response ↑1-3 g/dL), and after response, treat for additional 3 months to refill body’s iron stores, which can remain deficient even when anemia corrected
• IV iron if failure of PO treatment. Check formulary for IV iron formulation, use dose calculator found online – uses body weight, current hgb level, the concentration of the iron product. One example regimen: Sodium Ferric Gluconate (Ferrlecit) 125mg IV qWeek.

• The isk of anaphylaxis with IV iron is lower than historically reported, due to the discontinuation of high-molecular-weight iron dextran. In general, avoid giving IV iron to patients with a history of hypersensitivity, and pre-medicate patients with asthma or multiple drug allergies with methylprednisolone 125mg IV. Following these rules, current formulations have ~0.0005% risk of severe adverse events.

B12 Deficiency: Rates as high as 12% in the elderly.

• Vitamin B12 1mg IM qWeek x 8 weeks
• Or Vitamin B12 1-2mg PO qday x 90-120 days
• Reticulocytosis happens within days, with normal hemoglobin within weeks.

When to Refer

• Bone marrow failure (need for bone marrow biopsy) and most diagnoses of hemolysis are appropriate for referral.
• If acute significant hemoglobin drops and/or very symptomatic, send for more urgent evaluation and possible transfusion.

References

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McGee, S.Evidence-based physical diagnosis. 3rd edition. Philadelphia: Elsevier, 2012.

Moretti D et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126(17):1981-9.

Patel KV. Epidemiology of anemia in older adults. Semin Hematol. 2008. 45(4): 210-217.

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Schrier, S. (2018, Jan 30). Causes and diagnosis of iron deficiency and iron-deficiency anemia in adults. Retrieved from http://www.uptodate.com

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