Anemia – 3: Macrocytic & Normocytic

On to the Macrocytic & Normocytic anemias.   A relatively short topic.


A few easily-diagnosed entities cause elevated MCVs :



If you see a high MCV on a CBC (even if there’s no anemia), then order:

  • Vitamin B12 & Folic Acid levels
  • TSH
  • Liver function tests

A high MCV is often a marker for Closet Alcoholism.  Ongoing intake of 5 drinks/day will do it.  If LFTs are elevated (though they often aren’t), an AST>ALT ratio virtually clinches the diagnosis before confession.

Trivia —

  • Automated counters may mistake reticulocytes (immature RBCs) as macrocytes; consider a reticulocyte count to confirm.  Reticulocytosis occurs in acute blood loss and hemolytic anemias (also during replacement for Iron- or B12-/Folate-deficiencies).
  • The presence of cold agglutinins can cause RBC clumping, which appears very macrocytic to automated counters [occurs in autoimmune hemolytic anemia, some malignancies, and during Mycoplasma infections or mononucleosis].

Let’s say there’s a high MCV and all the above labs are normal, but the B12 level is in a low-normal range [different laboratories have different reference values].  Order levels of:

  • Methylmalonic Acid (MMA)
  • Homocysteine (HC)

These are intermediaries in synthesis of certain proteins; the process requires adequate Vitamin B12.  Not enough B12, the intermediaries can’t be used, and accumulate.  Elevated MMA & HC levels are therefore an equivalent for B12 deficiency.

Vitamin B12 deficiency is surprisingly common among the elderly.  If you suspect it for one of the above reasons, order an Intrinsic Factor Antibody (IFA) to diagnose Pernicious Anemia [requiring daily B12 injections IM for 1 week, then weekly for 4-8 weeks, then monthly injections for a lifetime].

Actually, only 90% of Pernicious Anemia is IFA-positive.  The other 10% is diagnosed by the gold standard Shilling Test which is no longer available.

Actually, a new pathway for B12 absorption was recently detected, which bypasses Intrinsic Factor.  So Pernicious Anemia can be treated orally with high doses of B12 [1 to 2 mg daily].  A colleague tried this, & found out Medicaid / Medicare didn’t pay because it was OTC.

Actually, the really bad thing about Pernicious Anemia is Neuro damage (central or peripheral), not the anemia.  So treat regardless of how well the patient feels.  Work up B12 deficiency based on high MCV alone, even without anemia.  Base treatment on levels of B12 or MMA & HC, even if IFA-negative.

Coincidentally, I just found a series in which almost 10% of newly-diagnosed Multiple Myeloma patients were B12 deficient.  So if a patient is IFA-negative, treat, but also consider a serum protein electrophoresis (SPEP).  Certainly do an SPEP if there’s also a high Calcium, high Creatinine, or high serum globulin (total Protein minus Albumin > 4 g/dL).

Macrocytic Anemia with completely normal tests for B12, Folic Acid, Thyroid Disease & Liver Disease, and no reticulocytosis, goes to Hematology to R/O blood dyscrasias & malignancies.  This is especially true if WBCs & Platelets are decreased in addition to RBCs (pancytopenia).

NORMOCYTIC ANEMIA  —  Normal MCV  (80-100)

The broad categories are few:

Acute Hemorrhage —  Blood loss ultimately causes Iron-Deficiency, a microcytic anemia.  But it takes a while for iron stores to deplete, & then for the newly-produced microcytes to occupy enough of the RBC population and become a noticeable proportion of the MCV.  So at the onset of acute hemorrhage, the MCV is normocytic.

There’s no diagnostic quandary, however, because the source of hemorrhage will be clinically obvious.  Just be sure to query patients with  new onset normocytic anemia about melena.

Actually, if they do report “black stools” (not merely “dark”), make sure it’s not due to Iron or Pepto-Bismol (“the pink medicine”).  If in doubt, eyeball a stool smear then & there in the exam room.  Melena is truly black; guaiac it, & it turns strongly positive in 1-2 seconds.  If you have to wait a while, it’s not melena.

Hemolysis  —  Many acute & chronic conditions can cause RBCs to break apart within blood vessels.  Look them up if you diagnose a Hemolytic Anemia.  How to diagnose it?

Reticulocyte count (“Retics”):  The initial test for a Normocytic Anemia:

  • Normal:   ≤1%
  • Hemorrhage:  3% – 5%
  • Hemolysis:  close to 10% or higher

To confirm Hemolysis, order additional tests:

  • Total Bilirubin —  elevated, most of it unconjugated or indirect
  • LDH (lactose dehydrogenase)  —  elevated
  • Maybe a Haptoglobin  —  decreased
An increased LDH + decreased Haptoglobin is 90% sensitive for Hemolysis.
A normal LDH + normal Haptoglobin is >90% sure there’s no Hemolysis.

Certainly:  Order a manual (meaning “visual”) Peripheral Smear.  A lab tech looks under the microscope, and can identify various types of distorted RBCs that a) confirm hemolysis, and b) give a clue to the etiology.  Better if a pathologist or hematologist performs it, if you can arrange that.

Anemia of Chronic Disease (ACD)  —  The most common cause of Normocytic Anemia.  It’s a “garbage bag diagnosis;” a wide variety of conditions including acute inflammation or infection, medication effect, old age, and a whole host of illnesses such as renal failure, malignancy, collagen-vascular diseases, etc. etc.  Pathogenesis is complex, but essentially the bone marrow just won’t produce.

The anemia is usually mild, rarely drops below an Hb 10 gm / Hct 30%.  In the lethal Aplastic Anemia, counts keep dropping & dropping.

Key Test:  Reticulocyte Count ≤1%.  We say “they’re not Reticking” (Reh-TICK-ing).

Main Step:  Review the other blood cell lines.  If there’s not just anemia but decreased WBC & Platelet counts as well (pancytopenia), this could be a form of Myelodysplasia which warrants a Hematology referral with probable bone marrow biopsy (most myelodysplasia presents with a high, macrocytic MCV).

Perform a good H&P.  But in the absence of specific symptoms, DON’T embark on a “grope-a-gram,” like ordering pan-CT scans and big rheumatology panels.  At most, consider an erythrocyte sedimentation rate (ESR, Sed Rate) or C-Reactive Protein (CRP).

Or don’t.  One specialist I heard lecture concluded, “a high ESR definitely proves the lab was open that day.”  A normal ESR is <20-30 mm/hr., higher with age.  Formula:    Normal ESR = < ½ the age [add 5 for women]

Values around 60, in the absence of specific symptoms, are virtually useless.  But an extremely high ESR can’t be ignored.  Very few diseases generate ESRs that border 100:  multiple myeloma, giant-cell (temporal) arteritis, HIV, disseminated TB, subacute bacterial endocarditis, occasionally renal failure.  A persistent undiagnosed ESR that high warrants a trip to Rheumatology.  This is why I prefer the ESR, because there’s no equivalent “extremely high CRP.”

Younger patients with “Anemia of Chronic Disease” may deserve a little more attention to seek a diagnosis.  Still, it’s very hard to diagnose a lab result in the absence of any symptoms.  Of course, you probably ordered the H&H due to some symptoms to begin with.  Let those be your guide.

SUMMARY  —  Work-Up of Normocytic Anemia

1.  Look for Clinical Clues:
  • Hx of recent bleed, or melena (Acute Hemorrhage)
  • Jaundice (Hemolysis)
  • High RDW  (Mixed Anemia)
2.  Order Basic Labs:
  • Reticulocyte Count
  • Ferritin, Iron, TIBC (for any possible iron deficiency)
  • B12, Folate  (for any possible deficiency)
Assuming above labs don’t identify a deficiency state:
  • Retics <1%  =  Anemia of Chronic Disease (ACD)
  • Retics around 3% suggest Acute Blood Loss (seek source)
  • Retics near 10% = Hemolysis (order Bili, LDH, Haptoglobin)
Most Common Dx:  Anemia of Chronic Disease
  • Good H&P for clinical clues as to underlying condition
  • Order an ESR (if you’re a believer)
  • Cancer Screening: As appropriate for age / risk factors

Interesting Case

A friend (early 20’s) was diagnosed by her provider with a mild anemia, labs as follows: Hct. 32, MCV 88, RDW 14, Ferritin 4.  How could that be?

  • A Ferritin of 4 is certainly Iron Deficiency.
  • MCV of 88 with normal RDW (no mixed anemia) certainly isn’t.

STOP…..  think it over a little before moving down to my tentative conclusion [or follow the maze below; sort of like Musak® while on hold on the phone]

My Conclusion (final resolution still pending):

She’s certainly iron deficient, but to a very minimal degree; not enough to drop the MCV, much less the Hct.  So even though iron stores are low (low ferritin), the anemia itself isn’t due to iron deficiency.  Must be ACD.  She had what sounded like a significant viral lower respiratory tract infection, which might have done it.  We’ll see.

And that’s it for Anemia.  See also our prior posts on Microcytic Anemia, and our general Introduction to Lab Tests (re: RBCs).

2 responses to “Anemia – 3: Macrocytic & Normocytic

  1. Pingback: Pedal Edema | DiagnosisDude

  2. can ACD be caused by food allergy? thank you.
    (Did your friend have an infection that caused her iron deficiency? )

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