Anemia – 2: Microcytic

Last posting we discussed a general Introduction to Lab Tests for RBCs.  Today, we begin with specific types of Anemia.

MICROCYTIC ANEMIA —  low MCV (<80)

Recalling the causes of Microcytic Anemia:

• Iron Deficiency
• Thalassemia Minor
• Anemia of Chronic Disease (MCV 75-80)
• Lead Poisoning [rare]
• Sideroblastic Anemia [rare]

The main differentials to differentiate [redundancy?] are between Iron Deficiency (most common & likely) & Thalassemia Minor (alpha [α] or beta [β]).  “Minor,” also called “Trait,” means asymptomatic heterozygous carrier.  Full-blown homozygous α- or β-Thalassemia Major present in early childhood with fulminant hemolytic anemia (or cause stillbirth).

FIRST  —  Look for Iron Deficiency by ordering serum Iron Studies:  Ferritin, Iron, & Total Iron Binding Capacity (TIBC).

**  Ferritin = Iron stores (primarily in the bone marrow, liver, & spleen).  A low Ferritin by definition = Iron Deficiency.  How low is a low Ferritin?  Certainly <15 ng/mL, maybe even <40.

Lab “normals” are defined by Bell Curves: 2 standard deviations from the mean for that lab (95% of population).  Since iron deficiency is common, some of those 95% of “normal” are iron deficient.  I’ve seen lab normals for ferritin range “10-150 ng/mL”.  A ferritin of 10 isn’t a bit “normal” whatsoever!!!

Natural History of Iron Deficiency:

• First, Ferritin decreases
• Next, MCV decreases
• Finally, H&H decrease (frank anemia)

**  Iron & TIBC are calculated together with a constant [lab does this for you] to give the Transferrin Saturation Percent (as a %).  Think of what the words all mean, & it’s easy to understand:

• Iron = Iron [duh].  Low iron means low iron (but see “confounders” below).
• “Total Iron Binding Capacity” = ability of transferrin (protein that transports iron) to bind iron.  If there’s a deficiency in iron, there’s great capacity to bind it (elevated TIBC).
• Transferrin Sat % = How much of transferrin is saturated with iron.  If it’s poorly saturated (a low trans sat %), that’s because there’s not much iron around to transport (i.e. iron deficiency).

Don’t order a serum “transferrin;” what you want to know how much of the protein is saturated with iron.  That’s the “Transferrin Saturation Percent,” calculated when you order “Serum Iron + TIBC.”

Confounders :  Both Ferritin & Iron are acute-phase reactants.  When there’s “inflammation,” “chronic disease,” etc. present, Ferritin values rise (like a sed rate) & Iron values fall (termed “negative acute-phase reactant;” serum albumin is another).

• Low Ferritin = Iron Deficiency for sure, but normal or even high Ferritin doesn’t rule it out.
• Low Trans Sat % provides good evidence for Iron Deficiency (thus the calculation involving TIBC, instead of simply relying on serum iron).
• Normal Ferritin + Normal Trans Sat % speak very strongly against Iron Deficiency.

Some settings rely on an elevated “Zinc Protoporphyrin” (ZPP, a.k.a. FEP for “free erythrocyte protoporphyrin”), synthesized instead of hemoglobin if iron’s unavailable (Iron Deficiency), or can’t be used (Anemia of Chronic Disease).  The advantage of this test is that it’s done by spectrometry; once a lab buys the spectrometer, they no longer have to pay for reagents.

DIGRESSION  —  We’re seeking parameters for Iron-Deficiency, but what if we find Iron-Overload?  That implies a high Ferritin, and a high Transferrin Saturation Percent, which in the context of a microcytic anemia suggests Sideroblastic Anemia.  The anemia may be quite severe.

• Order a peripheral smear to be viewed by the lab’s Pathologist.
• Presence of “ringed sideroblasts” confirms the diagnosis.
• Then order a Lead level (one cause) & send to Hematology, to distinguish among the many other variants.
• Send microcytic anemia with high Ferritin & high Trans Sat % to Heme anyway.

Back to more common Microcytic Anemias.  A low Ferritin (or high ZPP) clinches the Dx of Iron Deficiency.  So, what if Ferritin & Trans Sat % are both normal?

NEXT  —  Consider Thalassemia Trait (either α- or β-).  Occurs among people of Mediterranean, African, Arabian, South Asian, or even Asian descent.  These also include all of Latin America and Carribean; i.e. almost everyone except pure northern European.  For a concise [?] discussion of Thalassemia genetics & risk in pregnancy, click here.

Order a Hemoglobin Electrophoresis.  It identifies both qualitative & quantitative hemoglobinopathies.  “Qualitative” ones are like Sickle Cell (HbS), completely abnormal molecules (which cause hemolytic anemia, not microcytic).  The heterozygous Thalassemia Minors are “quantitative” problems, involving abnormal quantities of the different normal types of hemoglobin that most everyone has (HbA, HbA₂, & HbF).

The following table outlines the possible Hb Electrophoresis findings for the vast majority of adults & older children incidentally discovered to have Thalassemia Traits:

Normal Range of Normal Hemoglobins

•  Hb A (≥97%)           • Hb A₂  (≤2.5%)           • Hb F (<1%)

Thalassemias

α-Thalassemia Minor Hb A normal  (? ↑) Hb A2 normal  (? <1%) Hb F normal  (? sl ↑)

β-Thalassemia Minor Hb A ↓  (≤95%) Hb A2 ↑  (≥3.5%) Hb F normal or ↑

Persons with β-Thalassemia Minor usually have MCVs very low (<70) for the degree of anemia (Hct ±30).  Those with α-Thal Minor have higher MCVs, in the 70’s.  All should have normal RDWs, since all RBCs have been the same size (microcytic) since birth (these are genetic conditions, after all).

BUT WAIT  —  Before drawing a Hb Electrophoresis, look back through the chart.  If the patient ever had a normal H&H, with normal MCV, forget it — they don’t have a Thalassemia Trait.

BEWARE  —  It may be impossible to diagnose β-Thal Minor in the presence of co-existing Iron Deficiency (low Ferritin).  The Hb Electrophoresis will appear falsely normal.  Always correct the deficiency with iron therapy before searching for Thalassemias.  If you’re curious why, click here.

As you’ve noticed, α-Thalassemia Minor has an essentially normal Hb Electrophoresis.  As such, it would seem that Microcytic Anemia, with:

• normal Ferritin + normal Trans. Saturation % [i.e. NOT Iron-Deficient]; AND
• normal Hb Electrophoresis [i.e. NOT β-Thal Minor]; AND
• Normal RDW (same-sized RBCs without recent change)
• Therefore equals α-Thalassemia Minor as the diagnosis.

But what about the other entities in our table?

Anemia of Chronic Disease (ACD) usually causes a Normocytic Anemia, although the MCV could be slightly microcytic (e.g. 75-80).  Suspect this if the Hb / Hct hover around 10 gm / 30%; α-Thalassemia Minor wouldn’t fall so low.  We’ll discuss ACD next posting.

Lead Poisoning only causes anemia at significantly high levels that would be symptomatic with constitutional and GI symptoms, arthralgias/myalgias, or cognitive disturbances.  Such patients with undiagnosed microcytic anemia warrant a lead level.

But let’s say we confirm IRON DEFICIENCY ANEMIA, because:

• Ferritin is low
• Transferrin Saturation Percent is low (calculated by the lab from a ↓ serum Iron and ↑ TIBC)
• RDW elevated if the anemia is new (some microcytes, some older normocytes)
• RDW closer to normal if the anemia is >4 months (all microcytes, no differences)

Then we have to:

1. Correct the Anemia (which confirms our Dx)
2. Identify the Cause, which is invariably blood loss.

Correcting Iron-Deficiency

Prescribe Ferrous Sulfate (FeSO₄) 325 mg (= 65 mg elemental iron).  If the Hct is in the low 30’s, B.I.D. is probably fine.  If it’s lower, go for T.I.D.  Worst case, they only manage 2 a day.  Give the iron with food; it’s better tolerated, & anemic GI tracts absorb it just fine.

Recheck H&H and Ferritin in 3-4 weeks; both should be improved.  If not, question adherence.  Consider a reticulocyte count, but low retics might mean either bone marrow suppression or simple non-compliance.  Go for another month…….

If adherence is clearly a problem, switch to Ferrous Citrate.  It’s better tolerated because 325 mg = only 40 mg of elemental iron.  But a pill in the mouth is better than 2 FeSO₄’s in the bottle.  Ferrous Citrate T.I.D. [even B.I.D.] will bump the numbers.  Another option is to order IV Iron, just to prove the Dx.  Watch out for anaphylactic fatalities, however.

Eventually complete 8 months of Iron Tx: 4 to correct the Anemia (RBC lifespan = 120 days) + another 4 to replace Iron Stores.  Further treatment depends on the underlying cause.  In terms of ongoing follow-up, always order a Ferritin along with blood counts.  It’s the low serum Ferritin that defines Iron Deficiency.

Determining the Cause of Iron-Deficiency

This is the bottom line.  You don’t want to keep pushing iron tablets while your patient dies of colon cancer.  In the U.S., never attribute to diet it’s unless truly faddish, or situations like housebound elderly, mental illness, alcoholic.  Stomachs always manage to find and extract iron.

For menstruating teens and women, menstrual blood loss is probably the etiology.  No need to seek more obscure diagnoses, unless she insists that her periods are really light and short.  Worry a little more about women in their upper 40s, approaching the age of malignancies — the more normal the menses, and worse the anemia, the more it warrants a G-I investigation.  Certainly send anyone with severe or hard-to-correct iron deficiency (implying ongoing blood loss).

For persistent iron deficiency due to really heavy menses, rule out a bleeding diathesis.  Look mainly for von Willebrand Disease and Thrombocytopenia.

Other conditions causing Iron Deficiency (men & women) include:

• Celiac Disease.  Common.  Definitely order the antibody for tissue-Transglutaminase (tTG), the IgA fraction. [prevalence around 1:400]
• Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu syndrome).  Ask about epistaxis & check the mouth for telangiectasias.  Can cause fatal pulmonary & cerebral AVMs.  [prevalence ~1:6,000]
• Gastric Bypass

Women >50, all men with significant anemia, and anyone with melena require a G-I referral for colonoscopy and/or upper endoscopy.  Perhaps you can skip this in younger persons with a history truly convincing for peptic ulcer disease or gastritis, as long as you can rapidly treat the stomach & correct the anemia.  If G-I doesn’t find anything via scopes from both directions, they’ll probably order a capsule video study of the small bowel (though minimal yield).

• Re: melena: don’t be fooled by ingestion of iron or Pepto-Bismol (“the pink liquid”).  Do a brief rectal exam to eyeball stool (truly black).  Hemoccult turns positive in 1-2 seconds.  Otherwise, it’s not “melena”.

If the G-I evaluation is normal, it’s a tough one.  Some people have occult G-I A-V malformations or other angiodysplasias that bleed intermittently.  Aggressive work-ups can include laparotomy, but that depends on how severe, recalcitrant, & recurrent the anemia is.

Next Posting we’ll conclude with discussions of Macrocytic & Normocytic Anemias.