Iron Deficiency Anemia

Slide 1 · Iron Deficiency Anemia

Iron homeostasis · Pathogenesis · Morphology · Diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain absorption, transport, storage, recycling, and hepcidin control of iron.

Distinguish inadequate intake, malabsorption, increased need, and chronic blood loss.

Predict the morphologic and laboratory changes as stores become exhausted.

Connect iron deficiency with clinical findings and cause-directed evaluation.

Slide 3 · A defect in hemoglobin synthesis

Iron depletion ultimately restricts hemoglobin production in erythroid precursors.

Erythrocytes become smaller and contain less hemoglobin.

The established blood-film phenotype is microcytic and hypochromic.

Anemia is a late consequence of sustained negative iron balance.

Core pathophysiologic distinction

The primary lesion is inadequate iron availability for erythropoiesis—not defective DNA synthesis.

Slide 4 · Who is susceptible?

Iron deficiency is common worldwide; Burden is greater in low-resource settings.

Toddlers and adolescents have substantial growth-related requirements.

Menstruating and pregnant individuals face additional iron demands or losses.

In adult males and postmenopausal females, occult gastrointestinal loss is especially important.

Slide 5 · Iron homeostasis is a balance

Dietary uptake

Transferrin transport

Marrow use / storage

Fixed iron losses

Absorption is regulated at the proximal duodenum.

Iron excretion lacks a comparable regulated physiological pathway.

Net deficiency develops when absorbed iron fails to replace losses and demand.

Slide 6 · Daily iron turnover and intake

A typical United States diet as containing 10–20 mg of iron daily.

Only a fraction of ingested iron enters the circulation.

Ordinary iron losses arise mainly from shedding of skin and intestinal epithelial cells.

The textbook estimates baseline loss at about 1–2 mg per day.

Why deficiency accumulates

Small chronic deficits matter because physiological iron excretion is not adjustable to match dietary insufficiency.

Slide 7 · Functional iron is used, not stored

Hemoglobin

Myoglobin

Iron enzymes

Most body iron is in the functional compartment.

Hemoglobin contains the largest fraction of functional iron.

Myoglobin, catalase, and cytochromes account for additional functional needs.

Slide 8 · Ferritin sequesters iron safely

Ferritin is a protein–iron complex found in hepatocytes and tissue macrophages.

Macrophage stores are prominent in the spleen and bone marrow.

Intracellular iron sequestration limits free-iron toxicity.

Circulating ferritin broadly reflects body iron storage under ordinary conditions.

Diagnostic relevance

Ferritin links the storage compartment to a clinically accessible laboratory measurement.

Slide 9 · Hemosiderin and stainable iron

Hemosiderin aggregates form after partial lysosomal degradation of ferritin.

Iron-containing granules react with potassium ferrocyanide.

The Prussian blue reaction yields a blue-black pigment.

Overloaded tissue macrophages preferentially store iron as hemosiderin.

Histochemical implication

The stain becomes diagnostically useful when demonstrating absent marrow storage iron in iron deficiency.

Slide 10 · Transferrin is the plasma shuttle

Liver synthesis

Plasma transferrin

Transferrin receptor

Erythroid precursor

Transferrin binds iron in plasma and delivers it to target cells.

Developing erythroblasts express high-affinity transferrin receptors.

Receptor-mediated endocytosis brings iron into the erythroid compartment.

Slide 11 · Macrophages recycle erythrocyte iron

Circulating RBCs

~120-day lifespan

Macrophage uptake

Iron reused

Senescent red cells are ingested predominantly in spleen, liver, and marrow.

Macrophages recover iron from hemoglobin.

Recovered iron re-enters the transferrin pool for new erythrocytes.

Slide 12 · Dietary uptake complements recycling

Absorption primarily replaces unavoidable losses.

Intestinal absorption

Transferrin iron

Marrow erythropoiesis

RBC recycling

Slide 13 · Dietary iron occurs in two forms

Property

Heme iron

Nonheme iron

Typical source

Animal products

Vegetable products

Uptake

Relatively bioavailable

Less efficient / variable

Limitation

Distinct luminal handling

Requires Fe³⁺ reduction

Slide 14 · Heme iron follows a distinct entry route

Heme iron in animal foods is more absorbable than nonheme iron.

Apical heme uptake uses transporters that as incompletely characterized.

Intracellular heme metabolism releases Fe²⁺.

Liberated Fe²⁺ joins the cellular iron pool.

Mechanistic qualification

Do not draw a fully established single heme transporter: Uptake mechanisms remain incompletely characterized.

Slide 15 · Nonheme iron requires reduction

Luminal Fe³⁺

Ferrireductase

Fe²⁺

DMT1 entry

Dietary nonheme iron is commonly ferric (Fe³⁺).

Brush-border ferrireductases generate ferrous (Fe²⁺) iron.

Divalent metal transporter 1 (DMT1) mediates apical uptake.

Slide 16 · Two fates of iron in an enterocyte

Decision

Iron storage

Iron export

Molecular site

Cytosolic ferritin

Basolateral ferroportin

Immediate fate

Retained inside enterocyte

Transferred to plasma

Clinical meaning

May be lost at cell shedding

Supplies circulating transferrin

Slide 17 · Ferroportin enables iron export

Enterocyte Fe²⁺

Ferroportin

Oxidation to Fe³⁺

Transferrin loading

Ferroportin is a basolateral exporter of cellular iron.

Hephaestin and ceruloplasmin support oxidation before transferrin binding.

Ferroportin also mediates release of iron from macrophage stores.

Slide 18 · Hepcidin is the systemic iron gate

Hepcidin is a peptide synthesized in the liver.

It binds ferroportin and promotes its internalization and degradation.

This reduces iron export from enterocytes into plasma.

It also restrains iron release from macrophages.

Functional consequence

Higher hepcidin → less iron reaches transferrin → reduced availability to erythroid precursors.

Slide 19 · Iron repletion increases hepcidin

Increased iron stores

Hepatic hepcidin ↑

Ferroportin ↓

Absorption ↓

High iron availability signals hepatic hepcidin production.

Enterocyte ferritin retains more of the incoming iron.

Iron trapped in enterocytes is lost when epithelial cells are shed.

Slide 20 · Iron depletion suppresses hepcidin

Stores become low

Hepatic hepcidin ↓

Ferroportin persists

Absorption ↑

Low iron stores physiologically reduce hepcidin synthesis.

Lower hepcidin facilitates iron movement from enterocytes and macrophages.

This compensation cannot overcome major ongoing loss or very poor intake.

Slide 21 · Inflammation restricts iron availability

Inflammatory mediators increase hepatic hepcidin production.

High hepcidin reduces macrophage iron export and intestinal transfer.

Iron can be sequestered despite sufficient body stores.

This mechanism helps explain anemia of chronic inflammation.

Absolute vs functional restriction

Iron deficiency = lack of total body stores. Inflammatory iron restriction = inadequate access to iron retained in storage.

Slide 22 · Three hepcidin states

Setting

Expected hepcidin effect

Physiologic outcome

Low storage iron

Hepcidin decreases

Greater ferroportin activity

Iron-replete state

Hepcidin rises

Intestinal export restrained

Systemic inflammation

Hepcidin rises

Macrophage iron sequestration

Slide 23 · Four etiologic routes converge

Inadequate intake

Malabsorption

Increased demand

Chronic blood loss

All four mechanisms create negative iron balance over time.

Multiple contributors may coexist in one patient.

Identification of the primary cause is as important as recognition of the anemia.

Slide 24 · Total iron content is not bioavailability

Animal-source heme iron is more efficiently absorbed.

Plant-source inorganic iron has variable fractional absorption.

A diet may contain iron yet deliver too little absorbable iron.

Food composition and intestinal physiology both affect the final absorbed amount.

Source comparison

Roughly 20% absorption of heme iron versus 1–2% of nonheme iron in the dietary context discussed.

Slide 25 · Daily requirement rises with loss and growth

Approximately 1 mg/day absorbed iron to sustain normal balance.

Ingested requirements exceed absorbed requirements because uptake is incomplete.

Adult females may require higher dietary intake because of reproductive iron losses.

Prolonged mismatch gradually depletes iron reserves.

Clinical inference

The relevant variable is the net absorbed amount, not simply milligrams written on a diet record.

Slide 26 · Infants are vulnerable to inadequate intake

Milk contains very little iron relative to rapid early growth needs.

The source lists human breast milk iron as approximately 0.3 mg/L.

Cow’s milk has poorly bioavailable iron despite a higher content.

Limited dietary iron can become consequential as infant requirements rise.

Teaching application

A history of milk-dominant feeding should be evaluated alongside growth and dietary iron sources.

Slide 27 · Adolescents combine growth and dietary risk

Growth expands circulating red-cell mass and iron requirements.

Adolescent girls may additionally lose iron through menstruation.

Inadequate iron intake can compound physiological demand.

The risk therefore reflects several mechanisms rather than age alone.

Slide 28 · Pregnancy raises the iron requirement

Maternal expansion

Fetal demand

Greater iron need

Stores may fall

Pregnancy is specifically identified as a high-demand state.

Closely spaced pregnancies can magnify depletion where intake is limited.

Clinical risk is driven by demand relative to absorption and pre-existing reserves.

Slide 29 · Low-resource settings: Compounded deficits

The diet may rely more heavily on relatively poorly absorbed inorganic iron.

Overall food availability may be restricted.

Hookworm and other parasites may contribute chronic blood loss.

Intake and ongoing loss can act simultaneously.

Combined etiology

The higher burden cannot be understood as dietary lack alone; Parasitic blood loss may be important.

Slide 30 · Nutritional risk occurs across the lifespan

Population

Context

Mechanistic link

Infants

Milk provides little iron

High growth demand

Socioeconomic deprivation

Restricted food availability

Low intake

Older adults

Limited meat / restricted diet

Low intake

Vegans

No animal-derived heme iron

Lower iron bioavailability

Slide 31 · Malabsorption limits iron delivery

Adequate ingestion

Impaired gut uptake

Low net absorption

Depleted stores

Malabsorptive disorders may cause iron deficiency despite adequate intake.

Sprue, steatorrhea-associated disorders, and chronic diarrhea.

Feeding more iron is not synonymous with absorbing more iron.

Slide 32 · Gastrectomy can reduce iron absorption

Gastric surgery alters conditions encountered by luminal iron.

Reduced proximal duodenal acidity can impair iron uptake.

Faster passage of contents through the duodenum reduces absorption opportunity.

A surgical history is therefore mechanistically relevant.

Why surgery matters

Both luminal chemistry and contact time can limit transfer of dietary iron across the duodenum.

Slide 33 · Malabsorptive disease deserves a mechanism-based history

Sprue is a recognized cause of impaired iron absorption.

Chronic diarrhea and steatorrhea can likewise compromise uptake.

An affected patient may present with anemia before the intestinal disorder is recognized.

Iron loss from other sites must still be assessed when clinically relevant.

Slide 34 · Dietary modifiers influence nonheme iron uptake

Enhance absorption

Mechanism or context

Inhibit absorption

Ascorbic / citric acid

Favorable dietary milieu

Tannates in tea

Amino acids / sugars

Source-listed enhancers

Carbonates

—

Source-listed inhibitors

Oxalates / phosphates

These are source-listed interactions; Do not interpret the table as treatment guidance.

Slide 35 · Chronic blood loss is the major acquired route

Small recurrent hemorrhages remove hemoglobin-bound iron.

Iron reserves are mobilized to replace lost erythrocytes.

If losses outpace absorption, storage pools are gradually exhausted.

The bleeding source may be clinically occult.

Mechanistic significance

In high-income settings, chronic blood loss as the most common cause of iron deficiency.

Slide 36 · Gynecologic blood loss can dominate the history

Menstrual blood loss reduces available body iron.

Additional pregnancy-related demand may coexist.

Gynecologic disease may be the principal clinical manifestation.

Persistent iron deficiency requires attention to the source as well as replacement.

Slide 37 · Adult men: Exclude gastrointestinal bleeding

Occult gastrointestinal hemorrhage is a priority in adult males with iron deficiency.

Postmenopausal women require the same level of concern.

Potential lesions include gastrointestinal cancer.

Assigning deficiency to diet without investigation may miss significant disease.

Clinical warning

The source strongly emphasizes gastrointestinal blood loss until proven otherwise in these groups.

Slide 38 · Potential blood-loss routes

Route

Clinical context

Pathologic consequence

Gastrointestinal

Occult or visible GI hemorrhage

Progressive body-iron loss

Genital

Menstrual or other genital bleeding

Loss plus possible increased demand

Urinary

Bleeding into urinary tract

Chronic iron loss

External

Recurrent external hemorrhage

Net negative iron balance

Slide 39 · Different causes, shared final pathway

Absorbed iron insufficient

Ferritin stores mobilized

Iron supply falls

Hemoglobin output falls

The etiology varies by patient, but the biochemical endpoint is similar.

Iron transport first draws on an existing storage reserve.

Established anemia signals advanced depletion relative to initial imbalance.

Slide 40 · Depletion progresses in recognizable stages

Negative iron balance

Storage depletion

Biochemical deficiency

Microcytic anemia

Early stages may precede measurable reductions in hemoglobin.

Serum iron and transferrin saturation fall as available iron becomes inadequate.

Microcytic hypochromic anemia follows severe depletion of stores.

Slide 41 · Early depletion may be clinically silent

Body stores initially buffer a period of negative iron balance.

Hemoglobin and hematocrit can remain within their usual ranges.

Serum iron and transferrin saturation may initially remain maintained.

Absence of anemia therefore does not exclude an emerging storage deficit.

Timing of abnormality

The earliest deficit is in reserve iron, not necessarily in circulating hemoglobin.

Slide 42 · Biochemical restriction precedes anemia

Continued depletion lowers circulating serum iron.

Transferrin saturation decreases as available plasma iron falls.

Marrow erythroid activity can increase while anemia has not yet appeared.

This stage illustrates compensated but increasingly iron-restricted erythropoiesis.

Compensatory response

The marrow attempts to replace red cells but is progressively constrained by iron supply.

Slide 43 · Established iron deficiency impairs erythropoiesis

Stores exhausted

Iron delivery limited

Hemoglobin synthesis ↓

Hb / Hct decline

Anemia emerges after the capacity of storage reserves is exhausted.

Serum iron, ferritin, and transferrin saturation are reduced.

Microcytosis and hypochromia become typical blood-film findings.

Slide 44 · Why iron deficiency causes microcytosis

Restricted iron availability reduces hemoglobin production.

New erythrocytes contain less total hemoglobin.

The resulting peripheral red-cell population is smaller than normal.

The morphologic descriptor for these cells is microcytic.

Structure–function link

Cell size reflects the inadequate hemoglobin production that accompanies iron-restricted erythropoiesis.

Slide 45 · Why cells become hypochromic

Reduced hemoglobin content makes red cells visibly paler.

Normal central pallor occupies about one third of cell diameter.

Established deficiency enlarges the central pale region.

In marked cases, only a thin peripheral rim remains pink.

Blood-film correlate

The enlarged pale zone is a morphologic consequence of inadequate hemoglobin synthesis.

Slide 46 · Microcytosis and hypochromia: Schematic

Normal erythrocyte

Iron-deficient erythrocyte

Central pallor ≈ one third

Enlarged central pallor

A normal-sized erythrocyte has central pallor around one third of its diameter.

Iron-deficient red cells are both smaller and paler.

This is an editable schematic—not an authentic blood smear.

Slide 47 · Pencil cells indicate shape variation

Original morphology schematic

Iron-deficient smears may include elongated, narrow “pencil” cells.

Poikilocytosis denotes variation in red-cell shape.

Interpret pencil cells in combination with microcytosis, hypochromia, and iron studies.

Slide 48 · The bone marrow attempts compensation

Marrow examination may show a mild to moderate increase in erythroid precursors.

Increased erythroid activity does not guarantee effective hemoglobinization.

Iron substrate shortage limits erythrocyte production quality.

Peripheral microcytosis remains an important visible end point.

Cellular response

The marrow responds to anemia, but proliferation alone cannot correct unavailable iron.

Slide 49 · Absent storage iron has histochemical value

Marrow aspirate

Prussian blue stain

Macrophage iron absent

Iron deficiency supported

Normal marrow macrophages may contain stainable iron.

Iron deficiency produces absence of demonstrable storage iron.

The source identifies Prussian blue of aspirate smears as the relevant method.

Slide 50 · Complete blood count findings

Hemoglobin and hematocrit are depressed in established iron deficiency anemia.

Red-cell size decreases, producing a microcytic pattern.

Reduced hemoglobinization produces hypochromia.

Peripheral films may show modest poikilocytosis and pencil cells.

Slide 51 · Ferritin reports the status of stores

Serum ferritin generally correlates with the storage compartment.

Ferritin values below 12 μg/L in iron deficiency.

Depleted macrophage stores correspond to reduced tissue stainable iron.

Ferritin interpretation must be integrated with the clinical context and other iron tests.

Storage compartment

A very low ferritin is consistent with exhausted body-iron reserves; It is not just a reflection of serum transport iron.

Slide 52 · Serum iron falls as delivery becomes inadequate

Transferrin carries iron to tissues, especially erythroid precursors.

Progressive deficiency reduces circulating serum iron.

Low serum iron reflects limited plasma transport availability.

Serum iron must be interpreted together with binding capacity and ferritin.

Interpretive limitation

Low serum iron alone is not specific: Inflammatory anemia may also reduce circulating iron.

Slide 53 · Total iron-binding capacity increases

Total plasma iron-binding capacity reflects the transferrin pool.

In established uncomplicated iron deficiency, transferrin rises.

Consequently, total iron-binding capacity is increased.

This behavior contrasts with the source-described inflammatory anemia pattern.

Reason for high TIBC

The plasma expands its iron-binding capacity even though too little iron is available to occupy it.

Slide 54 · Transferrin saturation quantifies occupancy

Serum iron ↓

Binding capacity ↑

Saturation fraction ↓

Often <15%

Transferrin saturation expresses the fraction of iron-binding sites occupied.

Iron deficiency combines low iron availability with increased binding capacity.

Transferrin saturation below 15% in established disease.

Slide 55 · Integrated laboratory pattern of iron deficiency

Test / feature

Direction

Meaning

Hemoglobin / hematocrit

↓

Established anemia

MCV / cell coloration

↓ / hypochromic

Deficient hemoglobin production

Serum ferritin / iron

↓ / ↓

Depleted stores and transport iron

TIBC / transferrin saturation

↑ / ↓

Unoccupied binding capacity

Slide 56 · Iron deficiency vs inflammation-associated anemia

Parameter

Iron deficiency

Chronic inflammation

Serum iron

Low

Low

Iron-binding capacity

High

Reduced

Ferritin / storage iron

Depleted

Increased or sequestered

Hepcidin

Reduced

Increased

Slide 57 · Hepcidin is low in uncomplicated deficiency

Depleted reserves reduce hepatic hepcidin output.

Lower hepcidin permits persistence of ferroportin.

This favors intestinal iron absorption and macrophage iron export.

Inflammation can alter this regulatory response.

Adaptive response

The low-hepcidin response is compensatory: It seeks to restore circulating iron access.

Slide 58 · Anemia produces nonspecific manifestations

Common manifestations relate to reduced hemoglobin-mediated oxygen transport.

Clinical symptoms may be less revealing than the underlying cause.

Gastrointestinal or gynecologic features can dominate the presentation.

Pregnancy, malnutrition, and malabsorptive symptoms may provide etiologic clues.

Slide 59 · Severe chronic deficiency affects other tissues

Iron is needed for enzymes outside erythroid cells.

Long-standing depletion may disturb epithelial and mucosal tissues.

Systemic manifestations extend beyond the degree of anemia alone.

The textbook links these changes to depletion of iron-containing enzymes.

Beyond hemoglobin

Iron deficiency is not exclusively a red-cell disease; It can impair iron-dependent cellular functions.

Slide 60 · Skin and mucosal manifestations

Feature

Tissue involved

Association

Koilonychia

Nail plate

Chronic iron deficiency

Alopecia

Hair follicles

Long-standing depletion

Atrophic glossitis

Tongue mucosa

Epithelial atrophy

Gastric / intestinal change

Gastrointestinal mucosa

Atrophy or malabsorption

Slide 61 · Pica and pagophagia

Pica involves cravings for nonfood materials or atypical food ingredients.

Examples in the source include clay, flour, and ice.

Craving ice specifically is termed pagophagia.

Pica is not pathognomonic; It can occur in other clinical contexts.

Clinical interpretation

Pica with central-nervous-system iron depletion but also notes other, non–iron-deficiency associations.

Slide 62 · Plummer–Vinson syndrome

Microcytic anemia

Atrophic glossitis

Esophageal webs

This rare syndrome combines three source-described clinical findings.

The esophageal lesion is a web rather than a generalized mucosal atrophy alone.

Association is clinically useful but should not be presumed in routine iron deficiency.

Slide 63 · Diagnosis has two linked questions

Is anemia iron deficient?

Which process depleted iron?

What lesion needs attention?

Blood counts and iron tests establish the hematologic syndrome.

History and examination localize possible blood loss, poor intake, or malabsorption.

Iron repletion without etiologic assessment may miss serious underlying disease.

Slide 64 · Response to iron supports the diagnosis

In uncomplicated cases, oral iron leads to a reticulocyte rise in about 5–7 days.

A steady increase in blood counts follows.

Red-cell indices subsequently normalize as erythropoiesis recovers.

The result reflects restoration of substrate for hemoglobin production.

Temporal sequence

Reticulocytosis is an early marrow response; It precedes complete correction of circulating indices.

Slide 65 · Recovery unfolds in a sequence

Oral iron supplied

Reticulocytes rise

Blood counts improve

Indices normalize

The early reticulocyte response signals resumption of productive erythropoiesis.

Correction of hemoglobin follows over time rather than immediately.

Etiologic treatment remains necessary if losses or malabsorption persist.

Slide 66 · Case: Adolescent with increased demand

Clinical vignette

An adolescent presents with fatigue and a diet providing limited iron. A blood film is microcytic and hypochromic. Serum ferritin and iron are low, and binding capacity is increased.

Reasoning task

Which mechanisms should be considered? Why do the red cells become small and pale?

Slide 67 · Case: Anemia in an older adult

Clinical vignette

A postmenopausal patient develops microcytic anemia and very low ferritin. There is no obvious external hemorrhage. The patient reports fatigue but few additional symptoms.

Reasoning task

What important underlying cause must be investigated? Why is dietary attribution insufficient?

Slide 68 · Case: Low serum iron with inflammation

Clinical vignette

A patient with chronic inflammatory illness has anemia and reduced serum iron. Total iron-binding capacity is not increased, and ferritin is not depleted.

Reasoning task

Is this the typical uncomplicated iron-deficiency pattern? Which pathway explains the difference?

Slide 69 · Putting iron studies into context

Observation

Supports depleted stores

Supports inflammatory restriction

Ferritin

Decreased

Often preserved / elevated

TIBC

Increased

Decreased

Macrophage stores

Reduced or absent

Retained

Mechanism

Net iron deficit

Hepcidin-mediated trapping

Slide 70 · Clinical synthesis

Iron balance depends chiefly on regulated intestinal uptake and recycling—not regulated excretion.

Chronic loss, poor intake, malabsorption, and high demand converge on depleted ferritin stores.

Inadequate hemoglobin synthesis produces microcytic, hypochromic erythrocytes and pencil cells.

Low ferritin / iron, high TIBC, and low saturation support established deficiency.

Always search for the cause; Gastrointestinal bleeding is critical in adult men and postmenopausal women.

Slide 71 · Reference and figure provenance

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Chapter 14: Red Blood Cell and Bleeding Disorders; Iron Deficiency Anemia, pp. 595–599.

Primary reading includes iron physiology, etiology, blood morphology, iron studies, and clinical features.

All illustrations in this lecture are original editable PowerPoint schematics; no textbook artwork or synthetic clinical specimen is reproduced.