Iron Deficiency Anemia and Its Close Mimics: A Comprehensive Review for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

Iron deficiency anemia (IDA) remains the most prevalent nutritional deficiency worldwide, affecting approximately 1.2 billion individuals. While seemingly straightforward, IDA diagnosis and management present numerous challenges, particularly in distinguishing it from closely mimicking conditions such as anemia of chronic disease (ACD), thalassemia trait, and sideroblastic anemia. This review provides an evidence-based approach to IDA with practical diagnostic pearls and therapeutic strategies for the practicing internist.

Introduction

Iron deficiency anemia represents the final stage of iron depletion, following depletion of iron stores and iron-deficient erythropoiesis. The challenge for internists lies not merely in diagnosing IDA, but in identifying its underlying cause and distinguishing it from conditions that present similarly. Misdiagnosis can lead to inappropriate iron supplementation, missed malignancies, or delayed treatment of chronic diseases.

Pathophysiology: Beyond the Basics

Iron homeostasis is tightly regulated through hepcidin, a hepatic peptide that controls iron absorption and release from stores. In true iron deficiency, low iron levels suppress hepcidin production, allowing increased iron absorption via duodenal enterocytes and enhanced release from macrophages. This compensatory mechanism fails in chronic disease states where inflammatory cytokines (particularly IL-6) stimulate hepcidin production despite low circulating iron, creating functional iron deficiency.

Pearl #1: The hepcidin-ferroportin axis explains why inflammatory markers are crucial in distinguishing IDA from ACD. Elevated hepcidin in inflammation blocks ferroportin, trapping iron in macrophages despite total body iron sufficiency.

Clinical Presentation: What Textbooks Don't Tell You

Classic Features

The typical manifestations include fatigue, pallor, dyspnea on exertion, palpitations, and reduced exercise tolerance. Severe, chronic IDA may produce koilonychia (spoon nails), angular cheilitis, glossitis, and pica.

Subtle Presentations (Oysters)

Oyster #1: Restless Legs Syndrome (RLS): Up to 25% of IDA patients report RLS symptoms that resolve with iron repletion, even when hemoglobin remains in low-normal range. Screen for ferritin <75 μg/L in all RLS patients.

Oyster #2: Pagophagia (Ice Pica): This specific craving for ice is highly predictive of iron deficiency. One study showed 87% specificity when present. Ask specifically: "Do you chew ice throughout the day?"

Oyster #3: Postural Orthostatic Tachycardia Syndrome (POTS): Iron deficiency can mimic or exacerbate POTS, particularly in young women. Consider IDA screening in patients with unexplained tachycardia and orthostatic intolerance.

Oyster #4: Cognitive Dysfunction: Even mild IDA (hemoglobin 10-11 g/dL) impairs attention, memory, and processing speed. This may be the primary complaint, especially in elderly patients misattributed to dementia.

Diagnostic Approach: The Devil in the Details

Initial Laboratory Evaluation

Standard Parameters:

Complete blood count with red cell indices
Serum ferritin
Serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT)
Peripheral blood smear
Reticulocyte count

Interpreting the Numbers: Diagnostic Pearls

Pearl #2: The Ferritin Conundrum Ferritin <30 μg/L is diagnostic of IDA, but this cutoff misses many cases. As an acute-phase reactant, ferritin can be falsely elevated by inflammation, infection, malignancy, or liver disease.

In patients with chronic disease or inflammation (CRP >5 mg/L), use ferritin <100 μg/L as the cutoff
In heart failure, ferritin <100 μg/L or TSAT <20% indicates iron deficiency regardless of inflammation
In chronic kidney disease, ferritin <500 μg/L with TSAT <30% suggests functional iron deficiency

Pearl #3: The MCV Myth Not all IDA is microcytic! Approximately 30-40% of IDA patients have normocytic anemia, particularly early in the course or when coexisting with vitamin B12/folate deficiency. Never exclude IDA based on normal MCV alone.

Hack #1: The Mentzer Index To distinguish IDA from beta-thalassemia trait when MCV is low:

Mentzer Index = MCV/RBC count
If <13: favor thalassemia trait
If >13: favor IDA
Accuracy: approximately 95%

Alternative: RDW is typically elevated (>15%) in IDA but normal in thalassemia trait.

Pearl #4: The Zinc Protoporphyrin (ZPP) Test This underutilized test measures protoporphyrin accumulation when iron isn't available for heme synthesis. ZPP is:

Elevated in IDA (>60 μmol/mol heme)
Normal in thalassemia trait
Markedly elevated in lead poisoning
Elevated in ACD but usually less than in IDA

Pearl #5: Reticulocyte Hemoglobin Content (CHr) CHr <28 pg indicates insufficient iron availability for erythropoiesis and can detect functional iron deficiency before anemia develops. Particularly useful in CKD patients on erythropoiesis-stimulating agents.

Advanced Testing: When to Go Further

Soluble Transferrin Receptor (sTfR):

Elevated in IDA (>2.9 mg/L) as erythroid precursors upregulate transferrin receptors
Normal in ACD (unless coexisting iron deficiency)
Unaffected by inflammation
sTfR/log ferritin ratio >2 strongly suggests IDA over ACD

Hack #2: The sTfR-Ferritin Index When sTfR unavailable, use: (sTfR × 100) ÷ log(ferritin)

1.5: IDA likely
<1.5: ACD likely

Bone Marrow Examination: Prussian blue staining for iron stores remains the gold standard but is rarely necessary. Reserve for diagnostically challenging cases, particularly suspected sideroblastic anemia or when multiple pathologies coexist.

The Close Mimics: Diagnostic Differentiation

Anemia of Chronic Disease/Inflammation (ACD)

ACD affects 30-60% of hospitalized patients and often coexists with IDA (20-30% of cases).

Classic Laboratory Pattern:

Ferritin: normal to elevated (often 30-200 μg/L)
TSAT: low (<20%)
TIBC: low to normal (opposite of IDA where TIBC is high)
Iron: low
Inflammatory markers: elevated (CRP, ESR)
sTfR: normal (elevated if concurrent IDA)

Pearl #6: The TIBC Trick TIBC is the most useful discriminator between pure IDA and pure ACD:

TIBC >400 μg/dL → IDA
TIBC <300 μg/dL → ACD
TIBC 300-400 μg/dL → overlap zone, use sTfR

Hack #3: The Serum Hepcidin Assay Though not widely available, hepcidin measurement definitively distinguishes:

IDA: low hepcidin (<5 ng/mL)
ACD: high hepcidin (>20 ng/mL)
Mixed: intermediate values

Thalassemia Trait (Alpha or Beta)

Clinical Clues:

Family history or ethnic background (Mediterranean, African, Southeast Asian)
Lifelong "anemia" without symptoms
MCV profoundly low (<70 fL) relative to mild anemia
Normal or elevated RBC count (>5.0 million/μL)

Laboratory Differentiation:

RDW: normal (<15%) in thalassemia, elevated in IDA
Hemoglobin electrophoresis (beta-thalassemia): elevated HbA2 (>3.5%)
Alpha-thalassemia: requires genetic testing; HbH prep may show HbH bodies
Ferritin: normal to high (thalassemia patients accumulate iron)

Oyster #5: Never give iron to thalassemia trait patients without confirmed deficiency—it causes harmful iron overload.

Pearl #7: The Target Cell Sign Abundant target cells on peripheral smear with microcytosis strongly favor thalassemia over IDA. IDA typically shows hypochromic, pencil-shaped cells (elliptocytes).

Sideroblastic Anemia

This heterogeneous group involves defective heme synthesis despite adequate iron. May be congenital (rare) or acquired (alcohol, lead, copper deficiency, medications, myelodysplastic syndrome).

Diagnostic Features:

Microcytic or dimorphic anemia
Elevated ferritin (often >500 μg/L)
High TSAT (>50%)
Ring sideroblasts on bone marrow (>15% of erythroblasts)
Elevated serum iron

Pearl #8: Suspect acquired sideroblastic anemia in alcoholics with macrocytic anemia that has concurrent microcytic features (dimorphic picture). Check serum copper and zinc levels.

Lead Poisoning

Though uncommon, lead poisoning presents identically to IDA with microcytic anemia, elevated ZPP, and basophilic stippling on smear.

When to Suspect:

Occupational exposure (battery manufacturing, renovation/painting)
Unusual hobbies (pottery, stained glass)
Immigrant populations using traditional remedies
Children with developmental delays

Hack #4: Check blood lead level if ZPP >100 μmol/mol heme or if basophilic stippling present.

Copper Deficiency Anemia

Increasingly recognized, particularly post-gastric bypass surgery or with chronic zinc supplementation (zinc competes with copper absorption).

Features:

Anemia (may be normocytic or microcytic)
Neutropenia
Peripheral neuropathy or myelopathy
Low serum copper (<70 μg/dL) and ceruloplasmin

Oyster #6: Always check copper in unexplained anemia with concurrent cytopenias or neurological symptoms, especially with history of gastric surgery or zinc supplementation.

Identifying the Source: Where is the Iron Going?

Once IDA is confirmed, the internist's priority shifts to identifying the underlying cause.

Categorizing Blood Loss

Gastrointestinal (most common in men and postmenopausal women):

Occult malignancy (colon cancer, gastric cancer)
Peptic ulcer disease
Vascular ectasias (especially in elderly with aortic stenosis—Heyde syndrome)
Inflammatory bowel disease
Celiac disease
H. pylori gastritis
NSAID gastropathy

Gynecological (premenopausal women):

Menorrhagia (most common cause)
Uterine fibroids
Endometriosis

Other:

Chronic hematuria (glomerulonephritis, urological malignancy)
Frequent blood donation
Intravascular hemolysis with hemoglobinuria

Malabsorption Causes

Pearl #9: The Celiac Connection Celiac disease causes IDA in up to 15% of cases, often without GI symptoms. Check tissue transglutaminase IgA with total IgA in all unexplained IDA, especially if refractory to oral iron.

Other Causes:

Atrophic gastritis (including autoimmune and H. pylori-associated)
Post-gastrectomy/gastric bypass
Inflammatory bowel disease
Small intestinal bacterial overgrowth (SIBO)

Hack #5: The PPI Problem Proton pump inhibitors impair non-heme iron absorption by 50-60%. If patient takes PPIs, consider H2-blockers or discontinuation during iron repletion.

Increased Demand

Pregnancy and lactation
Adolescent growth spurts
Chronic blood donation

Investigation Algorithm: Step-by-Step Approach

For Premenopausal Women:

Detailed menstrual history (duration, frequency, clots, number of pads/tampons)
If menorrhagia present, gynecological evaluation
If menstruation normal, proceed as for men (GI evaluation)

For Men and Postmenopausal Women:

Bidirectional endoscopy (upper and lower) is standard of care
If negative, consider video capsule endoscopy for small bowel
Screen for celiac disease
Consider urine analysis for hematuria

Pearl #10: The Dual Pathology Principle Finding one source doesn't exclude another. If GI workup shows only minor lesion (e.g., small hemorrhoids), consider additional causes. Up to 10% have multiple bleeding sources.

Oyster #7: In elderly patients with both anemia and aortic stenosis, look for vascular ectasias (Heyde syndrome). Severe calcific aortic stenosis causes acquired von Willebrand syndrome, leading to GI bleeding from angioectasias.

Treatment: Beyond "Take Your Iron"

Oral Iron Therapy

First-Line Options:

Ferrous sulfate 325 mg (65 mg elemental iron) daily to three times daily
Alternative: ferrous gluconate, ferrous fumarate

Pearl #11: The Dosing Sweet Spot Hepcidin upregulation limits absorption when multiple doses given. Studies show alternate-day dosing (100-200 mg elemental iron every other day) achieves similar absorption to daily dosing with 50% fewer side effects. This improves compliance dramatically.

Hack #6: Take Iron with Vitamin C Ascorbic acid (200 mg) with iron increases absorption by 30-40% by maintaining iron in reduced (Fe2+) form. Orange juice works.

What to Avoid:

Calcium (blocks absorption)
Tea, coffee (tannins inhibit absorption)
Antacids, PPIs (require acidic environment)
Take iron 2 hours apart from these substances

Managing Side Effects: Gastrointestinal symptoms (nausea, constipation, diarrhea) affect 20-40% of patients.

Start with lower doses (30-60 mg elemental iron) and increase gradually
Try different formulations (gluconate better tolerated than sulfate)
Consider newer preparations: ferrous bisglycinate chelate, polysaccharide iron complex
Take with food if necessary (reduces absorption 40-50% but better than non-compliance)

Pearl #12: The Stool Color Reassurance Warn patients that stools will turn black/dark green. This is harmless but causes alarm if unexpected.

Response Monitoring

Expected Timeline:

Reticulocytosis: peaks at 7-10 days
Hemoglobin rise: 2 g/dL by 3 weeks, 1 g/dL per week thereafter
Symptom improvement: often within 1-2 weeks, before significant Hb rise
Complete correction: 6-8 weeks
Store repletion: requires 3-6 months of continued therapy

Hack #7: Check Reticulocyte Count at 1 Week If reticulocyte count hasn't risen by day 7-10, consider:

Non-compliance
Ongoing bleeding exceeding replacement
Malabsorption
Incorrect diagnosis
Concurrent vitamin B12/folate deficiency

Pearl #13: The Ferritin Target Continue iron for 3-6 months after Hb normalization to replenish stores. Target ferritin >50 μg/L (some experts recommend >100 μg/L to prevent rapid recurrence).

Intravenous Iron: When and Which?

Indications:

Intolerance to oral iron despite optimization
Malabsorption (celiac disease, IBD, post-gastric surgery)
Need for rapid repletion (preoperative optimization, heavy ongoing losses)
Chronic kidney disease (especially on ESAs)
Heart failure
Functional iron deficiency in inflammatory conditions

Available Preparations:

Iron sucrose: safe, requires multiple infusions (200 mg per dose)
Ferric carboxymaltose: single high-dose infusion (750-1000 mg), excellent safety
Iron isomaltoside: single high-dose infusion (1000 mg)
Low molecular weight iron dextran: requires test dose, anaphylaxis risk (now rarely used)

Pearl #14: Calculate the Deficit Total iron deficit (mg) = [Target Hb - Actual Hb] × weight (kg) × 2.4 + 500 mg (stores)

Example: 60 kg woman, Hb 8 g/dL, target 13 g/dL: = [13-8] × 60 × 2.4 + 500 = 1,220 mg

Hack #8: The Hypophosphatemia Heads-Up Ferric carboxymaltose causes transient hypophosphatemia in 30-70% of patients through FGF23 elevation. Usually asymptomatic but can cause severe myalgia or osteomalacia with repeated dosing. Check phosphate 2 weeks post-infusion and supplement if <2 mg/dL.

Pearl #15: The Pregnancy Exception IV iron is safe in pregnancy but avoid during first trimester. Ferric carboxymaltose and iron isomaltoside have best safety data.

Refractory IDA: The Diagnostic Challenge

If inadequate response despite adequate therapy:

Confirm compliance (ask directly, check pharmacy refills)
Exclude ongoing blood loss (repeat stool occult blood, consider gynecologic evaluation)
Reassess diagnosis:
- Check sTfR (should be very elevated in true IDA)
- Consider bone marrow examination
- Evaluate for thalassemia trait, sideroblastic anemia
- Check copper, vitamin B12, folate
Consider malabsorption:
- Celiac serology
- H. pylori testing and treatment
- SIBO evaluation (hydrogen breath test)
- Consider capsule endoscopy
Evaluate for IRIDA (iron-refractory iron deficiency anemia):
- Rare genetic disorder with inappropriately elevated hepcidin
- Poor response to oral iron, partial response to IV iron
- Diagnosis: TMPRSS6 gene mutation
- Management: high-dose IV iron, consider ESAs

Special Populations

Chronic Kidney Disease

Target ferritin 200-500 μg/L, TSAT 20-30%
IV iron superior to oral in dialysis patients
Functional iron deficiency common with ESA therapy

Heart Failure

Check iron status in all HF patients regardless of anemia
Iron deficiency (ferritin <100 μg/L or ferritin 100-300 μg/L with TSAT <20%) present in 30-50%
IV ferric carboxymaltose improves symptoms, quality of life, exercise capacity, and hospitalizations
Benefits occur even without anemia

Oyster #8: The AFFIRM-AHF trial showed IV iron post-hospitalization for acute HF reduced recurrent hospitalizations by 25%. This is a game-changer for HF management.

Athletes

"Sports anemia" involves foot-strike hemolysis, GI losses (especially runners), and hematuria
Female athletes particularly vulnerable
Maintain ferritin >30 μg/L (many experts recommend >50 μg/L)
Low ferritin impairs athletic performance even without anemia

Elderly

Never attribute IDA to "old age"—always investigate
Malignancy risk significantly elevated (colon cancer in 6-12%)
More likely to have multiple contributing factors
May tolerate lower doses (30-60 mg elemental iron every other day)

Pregnancy

Screen all pregnant women at first visit and 24-28 weeks
Requirements increase from 1 mg/day to 4-6 mg/day
Ferritin <30 μg/L: treat even without anemia
Oral iron 60-120 mg elemental iron daily (WHO recommendation)
IV iron if oral intolerant, non-compliant, or after 28 weeks with persistent IDA

Key Takeaways for Clinical Practice

Don't assume: IDA may not be microcytic; MCV can be normal in 30-40% of cases
Context matters: Interpret ferritin in light of inflammatory status
Think beyond absorption and loss: Consider demand, chronic disease, and mixed etiologies
Investigate thoroughly: Finding one source doesn't preclude others
Optimize oral therapy: Every-other-day dosing improves compliance with similar efficacy
Don't fear IV iron: Modern preparations are safe and highly effective when oral fails
Follow through: Monitor response, replete stores, and address underlying causes
Consider mimics: Use sTfR, TIBC, and clinical context to distinguish IDA from ACD and thalassemia
Screen strategically: Check celiac, H. pylori in unexplained or refractory cases
Treat the patient: Consider functional status, comorbidities, and symptom burden, not just Hb number

Conclusion

Iron deficiency anemia remains a diagnostic and therapeutic challenge requiring systematic evaluation, thoughtful differentiation from mimics, and individualized management. By applying the pearls, recognizing the oysters, and using the diagnostic hacks outlined in this review, internists can optimize care for this ubiquitous condition while avoiding the pitfalls of misdiagnosis and treatment failure. The key lies not in viewing IDA as a simple nutritional deficiency, but as a clinical syndrome requiring comprehensive investigation and tailored intervention.

Selected References

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