Understand iron deficiency, iron overload, and heme metabolism disorders as tested on ASCP BOC hematology exam.

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Chapter 9 โ€” DISORDERS OF IRON KINETICS & HEME METABOLISM

ASCP Board Exam ยท Lab-Focused Study Guide
Iron Deficiency Anemia ยท Anemia of Chronic Inflammation ยท Sideroblastic Anemia ยท Lead Poisoning ยท Porphyrias ยท Hemochromatosis ยท Practice Questions

1 ยท Priority Table & Quick Foundation

Topic Priority Why It’s Tested
Iron study patterns in microcytic anemias (IDA, thal minor, ACI, sideroblastic, lead) โ€” Table 20-1 HIGH The single most-tested table in this area
Three stages of iron deficiency and which tests change first HIGH ‘Stage 2 before frank anemia’ interpretation questions
Causes and risk groups for IDA (intake, need, absorption, chronic loss) HIGH ‘Most common cause in men/postmenopausal women’ = GI bleeding
Anemia of chronic inflammation: hepcidin, IL-6, lactoferrin, ferritin; iron studies HIGH Most common anemia in hospitalized patients
IDA vs ACI algorithm: % sat, ferritin cutoffs, sTfR/log ferritin HIGH Coexisting IDA in inflammation
Sideroblastic anemia: ring sideroblasts, causes, pyridoxine HIGH Prussian blue morphology and mechanism
Lead poisoning: ALA dehydratase, ferrochelatase, basophilic stippling, ZPP, pyrimidine 5โ€ฒ-nucleotidase HIGH Case questions with stippling
Hereditary hemochromatosis (HFE C282Y, H63D), screening with % sat and ferritin, phlebotomy HIGH Iron overload questions
Response to iron therapy timeline MEDIUM CHr 2 days, retic 5โ€“10 days, Hb 2โ€“3 weeks
Erythropoietic porphyrias (CEP, EPP, XLEPP) MEDIUM Enzyme/inheritance/photosensitivity matching
Hemochromatosis types 1โ€“5 (HJV, HAMP, TFR2, ferroportin, FTH1) MEDIUM Juvenile forms = teens
Transfusion-related hemosiderosis & chelation (desferrioxamine) MEDIUM Can’t phlebotomize transfusion-dependent patients
Epidemiology percentages, lead sources, march hemoglobinuria LOW Occasional recall
๐ŸŽฏ KEY POINT โ€” Where to spend your time

Focus: Table 20-1 (iron studies across the five microcytic conditions), the three stages of iron deficiency, hepcidin in ACI, ring sideroblasts, lead’s two enzyme targets, HFE hemochromatosis screening and treatment. Skim: epidemiology numbers, non-HFE hemochromatosis genes beyond their names, and porphyria urine/feces patterns.

Quick Foundation โ€” from zero

  • Hemoglobin needs three parts: iron, protoporphyrin (the ring) and globin. Missing any one โ†’ microcytic, hypochromic anemia.
  • Iron deficiency anemia (IDA) โ€” not enough body iron (empty stores).
  • Anemia of chronic inflammation (ACI) โ€” plenty of iron, but hepcidin locks it inside macrophages.
  • Sideroblastic anemia โ€” iron is there, but it can’t be put into protoporphyrin, so it piles up in mitochondria around the nucleus (ring sideroblasts). Lead poisoning is the classic acquired form.
  • Porphyrias โ€” enzyme defects in making protoporphyrin; precursors accumulate and cause photosensitivity.
  • The body can’t excrete iron, so the opposite problem โ€” iron overload โ€” happens with hereditary hemochromatosis (hepcidin too low) or repeated transfusions.
  • (Globin problems โ€” thalassemias โ€” are the next chapter.)
๐Ÿ’ก Analogy

Heme is a car: the chassis is protoporphyrin and the engine is iron. IDA = no engines in the warehouse. ACI = engines in the warehouse but the gate (hepcidin) is locked. Sideroblastic = engines delivered but the assembly robot (ferrochelatase or ALA synthase) is broken, so engines pile up on the factory floor (ring sideroblasts). Hemochromatosis = the gatekeeper never closes, and engines flood every building.

๐Ÿฅ Why this matters clinically

All of these can look alike on a CBC (microcytic, hypochromic). Giving iron to a patient with ACI, thalassemia or sideroblastic anemia doesn’t help and can cause iron overload. The iron studies and the marrow iron stain separate them.

Concept Plain-English Explanation
Sideropenia Low serum iron
Iron-restricted erythropoiesis RBC precursors get too little iron โ€” in both IDA and ACI
Ring sideroblast Nucleated RBC with iron-loaded mitochondria circling the nucleus (Prussian blue)
FEP / ZPP Protoporphyrin left without iron; zinc may take iron’s place
Hemosiderosis Excess stored iron (e.g., from transfusions) โ€” may progress to organ damage
Hemochromatosis Iron overload with parenchymal organ damage; hereditary forms from faulty hepcidin regulation
Porphyria Disease of impaired porphyrin production; precursors accumulate
Chelation Drugs that bind iron (or lead) so it can be excreted in urine

2 ยท Core Content Tables

2.1 Iron Deficiency Anemia โ€” Etiology

Cause Mechanism Examples / Who
Inadequate intake Daily loss ~1 mg (skin, gut epithelium) not replaced Elderly living alone, poor diet; cow’s milk infants
Increased need Expanding erythron / tissue growth Infancy (esp. premature), childhood, adolescence; pregnancy and nursing (loss of ~900 mg per pregnancy)
Impaired absorption Iron can’t cross enterocyte or be reduced Celiac disease; matriptase-2 mutation (persistent hepcidin โ†’ ferroportin inactivated); โ†“ gastric acid (aging, gastrectomy, bariatric surgery, antacids); iron-binding drugs
Chronic blood loss Heme iron lost faster than replaced GI: ulcers, gastritis (alcohol, aspirin), tumors, parasites (hookworm โ€” Necator, Ancylostoma; Trichuris, Schistosoma), diverticulitis, colitis, hemorrhoids ยท menorrhagia, fibroids ยท urinary tract ยท chronic intravascular hemolysis (PNH) ยท march hemoglobinuria (runners, soldiers)

Men and postmenopausal women lose only ~1 mg/day, so IDA in these groups most often means chronic GI bleeding โ€” investigate. Infants need iron-supplemented formula or supplements by ~6 months when fetal stores deplete.

2.2 Stages of Iron Deficiency (Rodak Figure 20-1)

Stage Compartment Depleted Hb Serum Iron TIBC Ferritin Other Findings
Normal โ€” N N N N Negative iron balance compensated by โ†‘ absorption (โ†“ hepcidin)
1 ยท Storage iron depletion Storage N N N โ†“ Latent/subclinical; โ†“ marrow iron; no symptoms; RBCs normal (120-day life)
2 ยท Transport iron depletion Storage exhausted + transport N โ†“ โ†‘ โ†“ โ†“ CHr (first erythroid sign), โ†‘ RDW begins, โ†‘ FEP, โ†‘ sTfR, โ†“ hepcidin, no stainable marrow iron โ€” iron-deficient erythropoiesis, still no anemia
3 ยท Functional iron depletion (IDA) Functional โ†“ โ†“ โ†‘ โ†“โ†“ Microcytic, hypochromic; โ†‘ FEP and sTfR; โ†“ CHr; โ†‘ EPO; symptoms

Stage 1 prevalence (U.S.): 14.4% of 1โ€“2-year-olds, 3.7% of 3โ€“5-year-olds, 9.3% of 12โ€“19-year-old and 9.2% of 20โ€“49-year-old females. Most patients aren’t diagnosed until late stage 2 or stage 3, because routine CBC results stay normal until then.

2.3 IDA โ€” Clinical & Laboratory Findings

Feature Details
Symptoms Fatigue, weakness, shortness of breath on exertion; pallor (conjunctiva, mucous membranes, palmar creases)
Specific signs Glossitis (sore tongue), angular cheilosis, koilonychia (spoon nails, long-standing), pica โ€” dirt, clay, laundry starch, most commonly ice (pagophagia)
CBC โ†“ Hb; RDW >15% expected and may precede the Hb fall (early, sensitive indicator); progressively โ†“ MCV, MCH, MCHC; โ†“ RBC and Hct; low absolute retic (nonregenerative)
Blood film Anisocytosis, microcytosis, hypochromia; occasional target cells and elliptocytes but no characteristic shape; polychromasia may be seen early; thrombocytosis possible with chronic bleeding; WBCs normal
Iron studies โ†“ serum iron, โ†“ ferritin, โ†‘ TIBC (transferrin up โ€” transcriptional/post-translational response), โ†“โ†“ % saturation
CHr Like MCH but for retics only; drops within days โ†’ sensitive, early indicator even in stage 2 (MCH lags weeksโ€“months)
Special tests โ†‘ FEP/ZPP (fluorometric) and โ†‘ sTfR (immunoassay) โ€” not particularly valuable for routine diagnosis
Bone marrow Not indicated for uncomplicated IDA (therapeutic trial is cheaper). If done: early erythroid hyperplasia (โ†“ M:E) that later subsides; polychromatic normoblasts with nuclearโ€“cytoplasmic asynchrony โ€” bluish, ‘shaggy‘ cytoplasm, irregular membranes; no stainable iron
๐Ÿงช PRE-ANALYTICAL โ€” Iron studies
  • Fasting morning serum; stop iron supplements beforehand; avoid hemolysis (falsely โ†‘ serum iron) โ€” see Chapter 5*
  • Draw iron studies before transfusion or iron therapy
  • Check CRP/inflammation โ€” ferritin is an acute phase reactant
  • Use the same units for SI and TIBC when calculating % saturation

2.4 IDA โ€” Treatment & Response

Feature Details
First step Treat the underlying cause (hookworms, tumors, ulcers)
Oral iron Ferrous sulfate, 3 tablets/day, 65 mg elemental iron each; empty stomach; nausea/constipation reduce adherence; โ‰ฅ6 months
Parenteral iron Iron dextrans for malabsorption (achlorhydria, celiac, matriptase-2 mutations); notable side effects
Transfusion Rarely warranted unless Hb dangerously low
Response timeline CHr corrects within 2 days ยท retic โ†‘ in 5โ€“10 days ยท Hb โ†‘ in 2โ€“3 weeks ยท normal Hb by ~2 months ยท continue 3โ€“4 more months to refill stores
Film during recovery Biphasic (dimorphic) population โ€” old microcytes + new normocytes โ€” for months
No response Nonadherence, continued occult loss, poor absorption, or another cause (e.g., thalassemia)

2.5 Anemia of Chronic Inflammation (ACI)

Feature Details
Name Formerly ‘anemia of chronic disease’; inflammation is the unifying factor. Most common anemia in hospitalized patients. Chronic blood loss is not a cause
Associated conditions Chronic inflammatory disorders (rheumatoid arthritis), chronic infections (TB, HIV), malignancies (e.g., Hodgkin lymphoma)
Central feature Sideropenia despite abundant iron stores (impaired ferrokinetics)
Mechanism 1 โ€” hepcidin (main) Activated macrophages โ†’ IL-6 โ†’ liver โ†‘ hepcidin (acute phase reactant) โ†’ ferroportin degraded โ†’ โ†“ intestinal absorption and โ†“ release from macrophages/hepatocytes โ†’ iron sequestered (likely an antibacterial defense)
Mechanism 2 โ€” lactoferrin Neutrophil granule protein released in inflammation; avidity for iron > transferrin; delivers iron to macrophages/liver โ€” RBC precursors lack lactoferrin receptors
Mechanism 3 โ€” ferritin โ†‘ plasma ferritin binds iron; RBC precursors lack ferritin receptors
Mechanism 4 โ€” cytokines TNF-ฮฑ, IL-1 (macrophages), IFN-ฮณ (T cells) โ†’ โ†“ erythroid proliferation, blunted response to EPO, โ†“ renal EPO production
Blood picture Mild anemia, Hb usually 8โ€“10 g/dL, no reticulocytosis; usually normocytic, normochromic; microcytosis/hypochromia in about one-third (may mean coexisting IDA); may have leukocytosis/thrombocytosis
Iron studies โ†“ serum iron, โ†“ TIBC (reflects abundant stores), % sat normal or โ†“, ferritin normal or โ†‘; โ†‘ FEP; โ†“ CHr; sTfR normal
Marrow Hypoproliferative; Prussian blue: abundant iron in macrophages but not in erythroblasts (marrow not usually needed)
Treatment Control the underlying condition; EPO + iron in select patients (costly)

2.6 IDA With Inflammation โ€” Diagnostic Algorithm (Rodak Figure 20-5)

Feature Details
Start Anemia + evidence of inflammation โ†’ transferrin saturation
% sat โ‰ฅ15% Rule out other causes of anemia
% sat <15% and ferritin <30 ng/mL Iron deficiency anemia
% sat <15% and ferritin >100 ng/mL Anemia of inflammation
% sat <15% and ferritin 30โ€“100 ng/mL (equivocal) Measure sTfR โ†’ sTfR/log ferritin
sTfR/log ferritin >2 ACI with true iron deficiency
sTfR/log ferritin <1 Anemia of inflammation alone
Thomas plot CHr vs sTfR/log ferritin can separate them further (Chapter 5)

2.7 Iron Studies in Microcytic, Hypochromic Anemias (Rodak Table 20-1)

Test Iron Deficiency Thalassemia Minor Anemia of Chronic Inflammation Sideroblastic Anemia Lead Poisoning
Serum ferritin โ†“ โ†‘/N โ†‘/N โ†‘ N
Serum iron โ†“/N โ†‘/N โ†“ โ†‘ Variable
TIBC โ†‘ N โ†“ โ†“/N N
% Saturation โ†“ โ†‘/N โ†“/N โ†‘ โ†‘
FEP/ZPP โ†‘ N โ†‘ โ†‘ โ†‘ (marked)
Marrow iron (Prussian blue) No stainable iron โ†‘/N โ†‘/N โ†‘ N
Sideroblasts in marrow None N None/very few โ†‘ (ring) N (ring)
Other special tests โ€” โ†‘ Hb Aโ‚‚ (ฮฒ-thal minor) Tests for inflammatory disorders or cancer โ€” โ†‘ ALA in urine; โ†‘ whole-blood lead

2.8 Sideroblastic Anemias

Feature Details
Definition Impaired protoporphyrin production or iron incorporation โ†’ iron accumulates in mitochondria of developing RBCs
Hallmark Ring sideroblasts โ€” Prussian blue iron granules encircling the nucleus of normoblasts
CBC May be microcytic, hypochromic (often dimorphic*)
Iron studies โ†‘ serum iron, โ†‘ ferritin, โ†“/N TIBC, โ†‘ % saturation, โ†‘ FEP/ZPP; โ†‘ marrow iron
Hereditary X-linked and autosomal forms; some respond to pharmacologic pyridoxine (vitamin Bโ‚†) โ€” cofactor of ALA synthase (glycine + succinyl CoA โ†’ ALA)
Acquired Primary (refractory) sideroblastic anemia ยท secondary to drugs/toxins: antituberculosis drugs (isoniazid), chloramphenicol, alcohol, lead, chemotherapy
Treatment Remove the drug or toxin
๐Ÿงช PRE-ANALYTICAL โ€” Marrow iron stain for ring sideroblasts*
  • Aspirate smear with spicules, stained with Prussian blue (acidic potassium ferrocyanide) and a positive control
  • Count ring sideroblasts among erythroid precursors โ€” granules must encircle the nucleus (โ‰ฅโ…“ of circumference by WHO criteria), not just be scattered
  • Peripheral blood: Pappenheimer (siderotic) granules in RBCs (Chapter 8)

2.9 Lead Poisoning

Feature Details
Exposure Leaded paint in homes built before the 1970s (dust from renovation, peeling paint), occupational exposure; toddlers/crawling infants at special risk
Clinical Children: CNS damage, impaired mental development; children and adults: peripheral neuropathy, abdominal cramping, vomiting, seizures
Target 1 ALA dehydratase (PBG synthase) โ†’ ALA accumulates โ†’ โ†‘ urine ALA
Target 2 Ferrochelatase (heme synthase) โ†’ iron and protoporphyrin accumulate โ†’ โ†‘ FEP/ZPP (measured in RBC extract)
Target 3 Pyrimidine 5โ€ฒ-nucleotidase โ†’ undegraded ribosomes aggregate โ†’ coarse basophilic stippling (larger than in other anemias โ€” ‘true punctate basophilia’); not pathognomonic but should always prompt consideration of lead
Target 4 Pentose phosphate (HMP) shunt impaired โ†’ oxidant sensitivity like G6PD deficiency โ†’ hemolytic component; retic may be quite elevated in acute poisoning
Anemia Usually normocytic, normochromic; microcytic, hypochromic with chronic exposure; more profound in children; marrow erythroid hyperplasia or sometimes hypoplasia
Also An example of both acquired sideroblastic anemia and acquired porphyria
Lab โ†‘ whole-blood lead, โ†‘ urine ALA, markedly โ†‘ FEP/ZPP; iron stores normal; ring sideroblasts may be present
Treatment Remove source; chelation with EDTA salts โ†’ lead excreted in urine
๐Ÿงช PRE-ANALYTICAL โ€” Blood lead*
  • Whole blood in a certified lead-free (tan-top Kโ‚‚EDTA or approved) tube; skin cleaned thoroughly โ€” capillary samples are easily contaminated, so confirm elevated capillary results with venous blood
  • ZPP rises slowly (weeks) and doesn’t reflect acute exposure; iron deficiency also raises ZPP

2.10 Porphyrias

Feature Details
Definition Diseases of impaired production of the porphyrin component of heme; acquired (lead) or hereditary (single enzyme deficiencies)
Mechanism Products before the block accumulate in erythrocytes and hepatocytes, leak out, are excreted in urine or feces (diagnostic), and deposit in tissues
Clinical Many accumulated products are fluorescent โ†’ photosensitivity with severe burns on sun exposure; fluorescence of teeth and bones in childhood; psychosis in some (historically in European monarchies)
Hematologic relevance Only three have hematologic manifestations (erythropoietic porphyrias); the rest mostly affect liver cells
Diagnostic trick Fluorescence: FEP measurement; marrow erythroblasts glow bright red under a fluorescent microscope
Feature Congenital Erythropoietic Porphyria (CEP) Erythropoietic Protoporphyria (EPP) X-linked EPP (XLEPP)
Enzyme Uroporphyrinogen III synthase deficiency Ferrochelatase deficiency ALA synthase 2 โ€” gain of function
Gene UROS FECH ALAS2
Inheritance Autosomal recessive Autosomal dominant X-linked dominant
Clinical Photosensitivity, hemolytic anemia Photosensitivity; anemia mild if present Photosensitivity; mild microcytic, hypochromic anemia ยฑ retic response
RBC porphyrins Uro โ†‘โ†‘โ†‘, copro โ†‘โ†‘ Protoporphyrin โ†‘โ†‘โ†‘ Protoporphyrin โ†‘
Urine Uro โ†‘โ†‘โ†‘, copro โ†‘โ†‘ (PBG N) Normal Normal
Feces Copro โ†‘ Protoporphyrin โ†‘โ†‘ Protoporphyrin N or โ†‘
Confirmatory โ†“โ†“โ†“ UROS activity; genetic testing โ†“โ†“ ferrochelatase activity; genetic testing โ†‘โ†‘ ALA synthase activity; โ†‘โ†‘ FEP and ZPP

2.11 Iron Overload โ€” Etiology

Feature Details
Basic problem No excretion mechanism; acquisition > ~1 mg/day loss โ†’ ferritin โ†’ hemosiderin โ†’ storage overwhelmed โ†’ parenchymal damage
Acquired: transfusion-related hemosiderosis Repeated transfusions (sickle cell anemia, ฮฒ-thalassemia major); transfused iron far exceeds the ~1 mg/day normally added
Hereditary hemochromatosis Mutations in iron regulatory genes impair hepcidinโ€“ferroportin regulation โ†’ continued absorption despite full stores. Autosomal recessive (classic HFE)
HFE genetics HFE on chromosome 6 (short arm), HLA class Iโ€“like, near HLA-A. Main mutations: C282Y (Cys282Tyr โ€” most common) and H63D (His63Asp). Homozygous HFE โ‰ˆ 5 per 1,000 northern Europeans; heterozygosity ~13%
HFE mechanism Normal HFE binds ฮฒโ‚‚-microglobulin (needed to reach the surface) โ†’ binds TfR1 โ†’ released when TfR1 binds transferrin โ†’ binds TfR2 โ†’ signal for hepcidin. Mutant HFE fails to bind ฮฒโ‚‚-microglobulin/reach the surface or fails to bind TfR1 โ†’ โ†“ hepcidin โ†’ ferroportin always active
Type Gene / Protein Normal Function Onset
1 โ€” HFE-associated HFE / hereditary hemochromatosis protein Inhibits TfR1 iron uptake; regulates hepcidin 30โ€“40 y
2A โ€” juvenile HFE2 (HJV) / hemojuvelin Regulates hepcidin expression Teensโ€“20
2B โ€” juvenile HAMP / hepcidin Downregulates ferroportin in macrophages and enterocytes Teensโ€“20
3 TFR2 / transferrin receptor 2 Hepatocyte iron uptake; regulates hepcidin 20โ€“40 y, mild
4 โ€” ferroportin disease SLC40A1 / ferroportin-1 Transports iron out of enterocytes and macrophages 30โ€“40 y
5 FTH1 / ferritin heavy chain Iron storage (one Japanese family)

2.12 Iron Overload โ€” Pathogenesis & Clinical Picture

Feature Details
Mechanism Storage capacity exhausted โ†’ free Feยฒโบ + Oโ‚‚ โ†’ superoxide and free radicals โ†’ lipid peroxidation of cell, mitochondrial, nuclear and lysosomal membranes โ†’ lysosomal enzyme release โ†’ irreversible cell death. Vitamins E and C moderate, but are overwhelmed
Target organs Skin (golden/bronze from hemosiderin) ยท liver (cirrhosis, jaundice, hepatocellular carcinoma โ€” p53 mutations) ยท pancreas (diabetes) โ†’ ‘bronze diabetes‘ ยท heart (congestive heart failure)
Iron load Classic HFE: 20โ€“30 g of iron by clinical onset at 40โ€“60 y โ€” >10ร— normal stores; 1โ€“2 mg/day excess over many years
Penetrance Disease rarer than C282Y frequency predicts; depends on mutation, zygosity, diet, environment. Ascorbic acid and alcohol increase absorption
Sex difference Clinical disease more common and earlier in men โ€” menstruation and childbirth delay it in women (gene frequency is equal). Homozygotes develop disease faster

2.13 Iron Overload โ€” Laboratory Diagnosis & Treatment

Feature Details
Four purposes of testing Screen ยท diagnose cause of organ damage ยท identify mutation (family counseling) ยท monitor treatment
Screening โ†‘ transferrin saturation or โ†‘ serum ferritin โ€” among the earliest findings; population screening remains controversial
Presentation Nonspecific complaints (abdominal pain) or incidental โ†‘ ALT; โ†“ albumin (liver synthetic function) may help
Confirmation Genetic testing for known mutations โ€” also for unaffected family members
Degree of overload Serum ferritin; monitor treatment with ferritin, Hb and Hct
Tissue damage Liver biopsy with iron stain and fibrosis grading
Hereditary treatment Therapeutic phlebotomy โ€” weekly ~500 mL early, then maintenance about every 3 months for life; aim for mild anemia (Hb monitored instead of iron studies)
Transfusion-dependent treatment Can’t phlebotomize โ†’ iron chelation: desferrioxamine (subcutaneous; iron excreted in urine) or newer oral chelators
๐Ÿงช PRE-ANALYTICAL โ€” Hemochromatosis screening*
  • Fasting transferrin saturation is preferred (serum iron rises after meals and supplements)
  • Ferritin is also raised by inflammation, liver injury, alcohol and malignancy โ€” pair it with % saturation
  • HFE genotyping on EDTA whole blood (DNA)

*From general hematology/laboratory practice or cross-referenced chapters, not stated in Rodak Ch. 20.

3 ยท Visual Memory Hooks

๐Ÿง  IDA causes
โ€œIn, Need, Absorb, Bleedโ€ โ†’ inadequate intake, increased need, impaired absorption, chronic blood loss.
๐Ÿง  IDA stages
โ€œStore, Transport, Functionโ€ โ†’ ferritin falls first; then SI โ†“/TIBC โ†‘/CHr โ†“; then Hb โ†“.
๐Ÿง  IDA signs
โ€œSpoon, Smooth, Split, Snack on iceโ€ โ†’ koilonychia, glossitis, cheilosis, pagophagia.
๐Ÿง  First to fall
โ€œFerritin first, CHr in days, RDW before Hbโ€.
๐Ÿง  Iron therapy response
โ€œ2 days, 5โ€“10 days, 2โ€“3 weeks, 2 monthsโ€ โ†’ CHr, retics, Hb rise, normal Hb.
๐Ÿง  ACI
โ€œHepcidin Hides the iron in a Hospitalโ€ โ†’ IL-6 โ†’ hepcidin โ†’ iron locked in macrophages; most common anemia in hospitalized patients.
๐Ÿง  TIBC direction
โ€œIDA: TIBC Up ยท ACI: TIBC Downโ€ โ†’ the single best separator.
๐Ÿง  IDA vs ACI cutoffs
โ€œUnder 30 is Iron, Over 100 is Inflammation, In between ask sTfRโ€.
๐Ÿง  Sideroblastic causes
โ€œLIACโ€ โ†’ Lead, Isoniazid (anti-TB), Alcohol, Chloramphenicol (+ chemotherapy).
๐Ÿง  Pyridoxine
โ€œB6 helps ALA Synthase Startโ€ โ†’ pyridoxine is ALA synthase’s cofactor.
๐Ÿง  Lead targets
โ€œLead Lurks at ALA-D, Ferrochelatase, and 5โ€ฒ-Nucleotidaseโ€ โ†’ โ†‘ ALA, โ†‘ ZPP, stippling.
๐Ÿง  Porphyrias
โ€œCEP = Can’t make Uro-III (recessive); EPP = Ferrochelatase fails (dominant); XLEPP = ALAS2 too Loud (X-linked)โ€.
๐Ÿง  Hemochromatosis
โ€œC282Y on chromosome 6 โ€” Bronze Diabetes, Bad liver, Broken heartโ€.
๐Ÿง  Juvenile HH
โ€œHepcidin and Hemojuvelin Hit Hard, in the teensโ€.
๐Ÿง  Treatment
โ€œPhlebotomy for the Hereditary, Chelation for the Transfusedโ€.

Pattern Triggers

If you seeโ€ฆ Thinkโ€ฆ Becauseโ€ฆ
โ†“ SI, โ†‘ TIBC, โ†“ % sat, โ†“ ferritin, โ†‘ RDW Iron deficiency Stores empty โ†’ more transferrin made
Normal CBC except RDW 15%, โ†“ SI, โ†‘ TIBC, โ†“ ferritin Stage 2 iron deficiency Before frank anemia
IDA in a man or postmenopausal woman with adequate diet Chronic GI bleeding Only 1 mg/day normal loss
Mild normocytic anemia, โ†“ SI, โ†“ TIBC, โ†‘ ferritin, RA/TB/cancer Anemia of chronic inflammation Hepcidin traps iron; ferritin acute phase
Marrow: abundant macrophage iron, none in erythroblasts Anemia of chronic inflammation Iron sequestered
% sat <15%, ferritin 30โ€“100, sTfR/log ferritin >2 ACI with coexisting iron deficiency sTfR rises with true cellular iron lack
Microcytosis, โ†‘ SI, โ†‘ ferritin, โ†‘ % sat, ring sideroblasts Sideroblastic anemia Iron can’t enter protoporphyrin
Patient on isoniazid or chloramphenicol with new microcytic/dimorphic anemia Drug-induced sideroblastic anemia Heme synthesis inhibited
Child in old house, coarse basophilic stippling, markedly โ†‘ ZPP Lead poisoning Ferrochelatase and 5โ€ฒ-nucleotidase inhibited
Severe sunburn tendency + โ†‘โ†‘โ†‘ RBC protoporphyrin Erythropoietic protoporphyria Ferrochelatase deficiency
Photosensitivity + hemolytic anemia + โ†‘โ†‘โ†‘ urine uroporphyrin Congenital erythropoietic porphyria UROS deficiency
โ†‘ % sat, โ†‘ ferritin, โ†‘ ALT, bronze skin, diabetes, man 40โ€“60 HFE hereditary hemochromatosis โ†“ hepcidin โ†’ unregulated absorption
Iron overload in a teenager Juvenile hemochromatosis (HJV or HAMP) Accelerated accumulation
ฮฒ-thalassemia major on regular transfusions, โ†‘ ferritin Transfusion-related hemosiderosis โ†’ chelation Can’t phlebotomize
Microcytosis, normal iron studies, โ†‘ Hb Aโ‚‚ ฮฒ-thalassemia minor Globin, not iron, problem

Commonly Confused Pairs

Feature A B
IDA vs ACI โ†“ ferritin, โ†‘ TIBC, no marrow iron, โ†‘ sTfR N/โ†‘ ferritin, โ†“ TIBC, macrophage iron present, sTfR normal
IDA vs thal minor โ†“ ferritin, โ†‘ RDW, โ†‘ FEP N/โ†‘ ferritin, normal RDW*, โ†‘ Hb Aโ‚‚
ACI vs sideroblastic โ†“ SI, โ†“ sat, no sideroblasts โ†‘ SI, โ†‘ sat, ring sideroblasts
Lead vs IDA (both โ†‘ ZPP) N ferritin, marked ZPP, stippling, โ†‘ urine ALA โ†“ ferritin, no stippling
Ring sideroblast vs Pappenheimer body Marrow normoblast with iron ringing the nucleus Iron granules in circulating RBCs
Hepcidin in ACI vs HH โ†‘ (acute phase, IL-6) โ†“ (faulty regulation)
Hereditary HH vs transfusional hemosiderosis Phlebotomy Chelation (desferrioxamine)
Type 1 (HFE) vs type 2 (juvenile) Onset 30โ€“40 y Teensโ€“20
EPP vs XLEPP Ferrochelatase loss, autosomal dominant ALAS2 gain of function, X-linked dominant
CHr vs MCH Reflects the last 1โ€“2 days; drops early Average of all RBCs; lags weeksโ€“months

Timeline Table

Marker / Event Onset Peak Duration Best Exam Use
Ferritin fall (stage 1) First change โ€” Before anemia Earliest lab sign of IDA
CHr fall (stage 2) Days after iron-deficient cells leave marrow โ€” โ€” Earliest erythroid sign
RDW rise Stage 2 >15% โ€” Precedes Hb fall
Hb fall (stage 3) Late โ€” โ€” Why IDA is diagnosed late
CHr after iron therapy Within 2 days โ€” โ€” Earliest response
Retic after iron therapy 5โ€“10 days โ€” โ€” Marrow response
Hb after iron therapy 2โ€“3 weeks Normal by ~2 months Continue 3โ€“4 more months Refill stores
Dimorphic film after therapy Weeks โ€” Several months Old microcytes + new normocytes
Iron loss per pregnancy โ€” ~900 mg โ€” Pregnancy risk
HFE hemochromatosis symptoms Men 40โ€“60 y (type 1: 30โ€“40) 20โ€“30 g iron โ€” Late onset; earlier in men
Juvenile hemochromatosis Teensโ€“20 โ€” โ€” HJV, HAMP
Phlebotomy schedule Weekly ~500 mL โ€” Maintenance ~every 3 months for life Treatment monitoring

4 ยท Diagnostic Flowcharts

Flowchart 1 โ€” Microcytic, hypochromic anemia: which disorder? (Table 20-1 logic)

MCV โ†“, MCH โ†“ โ†’ Serum ferritin first
Ferritin โ†“ โ†’ Iron deficiency โ†’ find the cause (GI bleed, menses, diet, need, absorption)
Ferritin N/โ†‘, SI โ†“, TIBC โ†“ โ†’ Anemia of chronic inflammation
Ferritin N/โ†‘, SI โ†‘, % sat โ†‘ โ†’ Sideroblastic anemia โ†’ marrow for ring sideroblasts; drug/toxin history
Ferritin N, basophilic stippling, marked โ†‘ FEP/ZPP โ†’ Lead poisoning โ†’ whole-blood lead, urine ALA
Iron studies N/โ†‘, โ†‘ Hb Aโ‚‚ โ†’ ฮฒ-thalassemia minor
โš ๏ธ Common mistake: treating every microcytic anemia with iron. Only IDA responds; thal, ACI and sideroblastic patients can become iron-overloaded.

Flowchart 2 โ€” Anemia with inflammation: is there also iron deficiency? (Figure 20-5)

Anemia + inflammation โ†’ Transferrin saturation
โ‰ฅ15% โ†’ Look for other causes
<15% and ferritin <30 ng/mL โ†’ Iron deficiency anemia
<15% and ferritin >100 ng/mL โ†’ Anemia of inflammation
<15% and ferritin 30โ€“100 ng/mL โ†’ sTfR/log ferritin: >2 โ†’ ACI + iron deficiency; <1 โ†’ ACI alone
โš ๏ธ Common mistake: calling a ferritin of 60 ng/mL ‘normal’ in a patient with active rheumatoid arthritis.

Flowchart 3 โ€” Timing: stages of iron deficiency

Negative iron balance begins โ†’ โ†“ hepcidin โ†’ โ†‘ absorption; tests normal
Stage 1 โ†’ โ†“ ferritin, โ†“ marrow iron; Hb normal
Stage 2 โ†’ โ†“ SI, โ†‘ TIBC, โ†“ CHr, โ†‘ RDW, โ†‘ FEP, โ†‘ sTfR; Hb still normal
Stage 3 โ†’ โ†“ Hb, microcytic/hypochromic; symptoms
After treatment โ†’ CHr (2 d) โ†’ retic (5โ€“10 d) โ†’ Hb (2โ€“3 wk) โ†’ normal Hb (~2 mo) โ†’ continue 3โ€“4 mo
โš ๏ธ Common mistake: expecting MCV or Hb to fall first. Ferritin and CHr change long before them.

Flowchart 4 โ€” Suspected iron overload

โ†‘ ALT, bronze skin, diabetes, heart failure, or family history โ†’ Transferrin saturation + ferritin
Both โ†‘, no transfusion history โ†’ HFE genotyping (C282Y, H63D)
HFE negative, onset in teens โ†’ Consider HJV/HAMP (juvenile), TFR2, ferroportin
Chronic transfusions (sickle cell, ฮฒ-thal major) โ†’ Transfusion-related hemosiderosis
Tissue damage assessment โ†’ Liver biopsy with iron stain and fibrosis grading
Treatment โ†’ Hereditary โ†’ phlebotomy ยท transfused โ†’ desferrioxamine/oral chelators
โš ๏ธ Common mistake: phlebotomizing a transfusion-dependent anemic patient. They need chelation instead.

Flowchart 5 โ€” Heme synthesis defect: which enzyme?

โ†‘ urine ALA + โ†‘ ZPP + coarse stippling โ†’ Lead: ALA dehydratase + ferrochelatase
โ†‘โ†‘โ†‘ RBC protoporphyrin, photosensitivity, autosomal dominant โ†’ EPP: ferrochelatase deficiency
โ†‘ FEP/ZPP, X-linked, โ†‘โ†‘ ALA synthase activity โ†’ XLEPP: ALAS2 gain of function
โ†‘โ†‘โ†‘ uroporphyrin (RBC, urine), hemolysis, recessive โ†’ CEP: uroporphyrinogen III synthase
Ring sideroblasts, pyridoxine-responsive, X-linked โ†’ Hereditary sideroblastic anemia (ALA synthase*)
โš ๏ธ Common mistake: assuming โ†‘ FEP always means iron deficiency. It rises whenever iron isn’t inserted into protoporphyrin โ€” lead, ACI, sideroblastic anemia, EPP.

5 ยท 25 High-Yield Facts

# Fact
1 Iron deficiency results from inadequate intake, increased need, impaired absorption or chronic blood loss.
2 The body loses about 1 mg of iron per day through desquamated skin and intestinal epithelium.
3 In men and postmenopausal women with adequate diets, iron deficiency most often results from chronic GI bleeding.
4 Stage 1 iron deficiency shows only decreased ferritin and marrow iron; Hb is normal.
5 Stage 2 iron deficiency shows โ†“ serum iron, โ†‘ TIBC, โ†“ CHr and โ†‘ RDW before anemia develops.
6 Stage 3 iron deficiency is frank microcytic, hypochromic anemia.
7 An RDW above 15% is expected in iron deficiency and may precede the drop in hemoglobin.
8 Iron deficiency has no characteristic poikilocyte; occasional target cells and elliptocytes may occur.
9 Pagophagia (ice craving), koilonychia, glossitis and angular cheilosis are signs of iron deficiency.
10 Iron-deficient marrow shows no stainable iron and ‘shaggy’ polychromatic normoblasts with blue cytoplasm.
11 After iron therapy, CHr corrects in 2 days, retics rise in 5โ€“10 days and Hb rises in 2โ€“3 weeks.
12 Anemia of chronic inflammation is the most common anemia in hospitalized patients.
13 In ACI, IL-6 raises hepcidin, which degrades ferroportin and traps iron in macrophages.
14 ACI shows โ†“ serum iron, โ†“ TIBC and normal or โ†‘ ferritin, with a normal sTfR.
15 ACI is usually a mild normocytic, normochromic anemia with Hb 8โ€“10 g/dL.
16 With inflammation, ferritin <30 ng/mL indicates iron deficiency and >100 ng/mL indicates ACI.
17 Ring sideroblasts are the hallmark of sideroblastic anemias, where iron accumulates in mitochondria.
18 Sideroblastic anemia shows โ†‘ serum iron, โ†‘ ferritin and โ†‘ transferrin saturation.
19 Isoniazid, chloramphenicol, alcohol, lead and chemotherapy can cause acquired sideroblastic anemia.
20 Pyridoxine (Bโ‚†), the cofactor of ALA synthase, improves some hereditary sideroblastic anemias.
21 Lead inhibits ALA dehydratase and ferrochelatase, raising urine ALA and FEP/ZPP.
22 Lead inhibits pyrimidine 5โ€ฒ-nucleotidase, causing coarse basophilic stippling.
23 EPP is due to ferrochelatase deficiency; CEP to uroporphyrinogen III synthase deficiency; XLEPP to ALAS2 gain of function.
24 Classic hereditary hemochromatosis is caused by HFE mutations (C282Y, H63D) on chromosome 6 that lower hepcidin.
25 Hereditary hemochromatosis is treated with phlebotomy; transfusion-related hemosiderosis with iron chelators such as desferrioxamine.
โญ EXAM TIP โ€” The single most testable pattern

Ferritin and TIBC split the microcytic anemias: IDA = ferritin โ†“, TIBC โ†‘ ยท ACI = ferritin N/โ†‘, TIBC โ†“ ยท Sideroblastic = ferritin โ†‘, SI โ†‘, % sat โ†‘, ring sideroblasts ยท Lead = ferritin N, stippling, marked ZPP ยท Thal minor = iron studies N, โ†‘ Hb Aโ‚‚.

Quick Interpretation Table

Lab Finding Clinical Interpretation
Hb 3.0, MCV 66.3, MCH 18.1, MCHC 27.3, RDW 20% in a frail elderly woman Severe microcytic, hypochromic anemia with anisocytosis โ€” iron deficiency most likely (diet or GI bleeding)
Normal CBC except RDW 15%; โ†“ SI, โ†‘ TIBC, โ†“ % sat, โ†“ ferritin Stage 2 iron deficiency
Hodgkin lymphoma, Hb 10.8, normal indices, abundant macrophage iron Anemia of chronic inflammation (โ†“ SI, โ†“ TIBC, N % sat, N ferritin)
% sat 10%, ferritin 60 ng/mL, sTfR/log ferritin 2.5, RA ACI with coexisting iron deficiency
โ†‘ SI, โ†‘ ferritin, โ†‘ % sat, ring sideroblasts Sideroblastic anemia
Mild microcytic anemia, polychromasia, basophilic stippling, renovating old house Lead poisoning โ†’ serum/whole-blood lead
% sat 80%, ferritin 1,500 ng/mL, C282Y homozygous HFE hereditary hemochromatosis

๐ŸŽด Flashcards โ€” Active Recall Practice

How it works: tap the card to flip it. Then mark it โœ“ Knew It or โœ— Review Again (buttons unlock after flipping). Use ๐Ÿ”€ Shuffle to randomize and ๐Ÿ Finish anytime โ€” your summary appears at the end, and you can drill only the cards you missed.

๐Ÿ“ Practice Quiz โ€” Test Your Knowledge

How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.

๐Ÿชค Trap Questions โ€” Beat the Examiner

Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.

8 ยท Rapid Revision Sheet

๐Ÿ“– READ THIS 2 HOURS BEFORE YOUR EXAM

IDA Causes

  • Intake ยท need ยท absorption ยท chronic loss
  • Loss ~1 mg/day ยท pregnancy ~900 mg
  • Men/postmenopausal โ†’ GI bleed
  • Hookworm, march hemoglobinuria, matriptase-2
  • Infants: supplement by 6 months

IDA Stages

  • 1: โ†“ ferritin, โ†“ marrow iron; Hb N
  • 2: โ†“ SI, โ†‘ TIBC, โ†“ CHr, โ†‘ RDW, โ†‘ FEP/sTfR; Hb N
  • 3: โ†“ Hb, micro/hypo
  • RDW >15% may precede โ†“ Hb

IDA Therapy

  • Ferrous sulfate 65 mg Fe, 3/day, โ‰ฅ6 mo
  • CHr 2 d ยท retic 5โ€“10 d ยท Hb 2โ€“3 wk
  • Normal Hb ~2 mo + 3โ€“4 mo more
  • Dimorphic film for months

ACI

  • Most common in hospitalized patients
  • IL-6 โ†’ โ†‘ hepcidin โ†’ ferroportin โ†“
  • Lactoferrin, ferritin, TNF/IL-1/IFN-ฮณ
  • Hb 8โ€“10 ยท normocytic (โ…“ micro)
  • โ†“ SI, โ†“ TIBC, N/โ†‘ ferritin, N sTfR

IDA vs ACI Cutoffs

  • % sat <15% โ†’ ferritin
  • <30 = IDA ยท >100 = ACI
  • 30โ€“100 โ†’ sTfR/log ferritin
  • >2 = ACI + IDA ยท <1 = ACI

Table 20-1

  • IDA: ferritin โ†“, TIBC โ†‘, no marrow iron
  • Thal minor: iron N, โ†‘ Hb Aโ‚‚
  • ACI: SI โ†“, TIBC โ†“, ferritin N/โ†‘
  • Sideroblastic: SI โ†‘, ferritin โ†‘, sat โ†‘, ring
  • Lead: ferritin N, FEP โ†‘โ†‘, urine ALA โ†‘

Sideroblastic & Lead

  • Ring sideroblasts = mitochondrial iron
  • Isoniazid, chloramphenicol, alcohol, lead, chemo
  • Hereditary X-linked; pyridoxine (ALAS cofactor)
  • Lead: ALA-D, ferrochelatase, 5โ€ฒ-nucleotidase
  • Coarse stippling ยท EDTA chelation

Porphyrias

  • CEP: UROS, AR, hemolysis, uro โ†‘โ†‘โ†‘
  • EPP: FECH, AD, RBC protoporphyrin โ†‘โ†‘โ†‘
  • XLEPP: ALAS2 gain, X-linked dominant
  • All: photosensitivity

Hemochromatosis

  • HFE chr 6 ยท C282Y, H63D ยท AR
  • Homozygous ~5/1000 N. Europeans
  • โ†“ hepcidin โ†’ ferroportin always on
  • 20โ€“30 g iron at 40โ€“60 y ยท men earlier
  • Juvenile: HJV, HAMP (teens)

Overload Management

  • Screen: โ†‘ % sat, โ†‘ ferritin
  • Confirm: genetic testing
  • Tissue: liver biopsy
  • Hereditary โ†’ phlebotomy (weekly 500 mL, then q3 mo)
  • Transfusional โ†’ desferrioxamine / oral chelators

9 ยท Final Memory Map

  • ๐Ÿงฒ IRON & HEME DISORDERS
    • Iron Deficiency Anemia
      • Causes: intake, need, absorption, chronic loss
      • Stages 1 โ†’ 2 โ†’ 3
      • โ†“ ferritin, โ†‘ TIBC, โ†“ sat, โ†‘ RDW, โ†“ CHr
      • Treat cause + oral iron; response timeline
    • Anemia of Chronic Inflammation
      • IL-6 โ†’ hepcidin โ†’ iron sequestered
      • Lactoferrin, ferritin, cytokines
      • โ†“ SI, โ†“ TIBC, N/โ†‘ ferritin, N sTfR
      • Algorithm with sTfR/log ferritin
    • Sideroblastic Anemias
      • Ring sideroblasts
      • Hereditary (X-linked, pyridoxine) / acquired (drugs, alcohol, lead)
      • โ†‘ SI, โ†‘ ferritin, โ†‘ sat
    • Lead Poisoning
      • ALA dehydratase, ferrochelatase, 5โ€ฒ-nucleotidase, HMP
      • โ†‘ urine ALA, โ†‘โ†‘ ZPP, coarse stippling
      • Old paint ยท EDTA chelation
    • Porphyrias
      • CEP (UROS), EPP (FECH), XLEPP (ALAS2)
      • Photosensitivity ยท fluorescence
    • Iron Overload
      • Transfusion hemosiderosis vs hereditary hemochromatosis
      • HFE C282Y/H63D ยท types 2โ€“5
      • Free radicals โ†’ liver, pancreas, skin, heart
      • Phlebotomy vs chelation



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