Iron Deficiency and Sideroblastic Anemia

Iron deficiency — blood loss (the dominant mechanism in adults)

• Occult GI bleeding: colorectal carcinoma, gastric cancer, peptic ulcer, angiodysplasia, NSAID/aspirin gastropathy, hookworm (Ancylostoma duodenale, Necator americanus) in returning travelers or endemic regions.
• Menstrual and obstetric loss: heavy menstrual bleeding is the single most common cause in premenopausal women; peripartum hemorrhage compounds it.
• Intravascular hemolysis with urinary iron loss: mechanical valve hemolysis, paroxysmal nocturnal hemoglobinuria (hemosiderinuria).

Iron deficiency — intake, absorption, and demand

• Malabsorption: celiac disease, autoimmune atrophic gastritis, H. pylori infection, post-gastrectomy or Roux-en-Y bypass (duodenal bypass removes the absorptive site), chronic PPI use (iron requires gastric acid to be reduced to Fe²⁺).
• Increased demand: infancy, adolescent growth spurt, pregnancy and lactation; excessive unmodified cow's milk in toddlers causes both low intake and occult gut blood loss.
• Genetic: iron-refractory iron deficiency anemia from TMPRSS6 mutation with inappropriately high hepcidin — the classic oral-iron non-responder.

Sideroblastic — hereditary (non-modifiable)

• ALAS2 (X-linked): most common inherited form, frequently pyridoxine-responsive; SLC25A38 (autosomal recessive) and mitochondrial DNA deletions (Pearson syndrome, with exocrine pancreatic insufficiency).

Sideroblastic — acquired (largely modifiable)

• Clonal marrow disease: MDS with ring sideroblasts, strongly associated with SF3B1 mutation.
• Drugs and toxins: isoniazid, cycloserine, and other pyridoxine antagonists; linezolid and chloramphenicol (mitochondrial ribosome/protein synthesis inhibition); chronic alcohol use.
• Lead poisoning: inhibits ALA dehydratase and ferrochelatase.
• Copper deficiency: excess zinc ingestion, bariatric surgery, or malabsorption — copper is required for ferroxidase-dependent iron mobilization.

Iron Deficiency Anemia

• Negative iron balance leading to depletion of iron stores (ferritin <30 ng/mL) → reduced serum iron → decreased transferrin saturation → impaired iron delivery to erythroid precursors in bone marrow
• Decreased heme synthesis due to insufficient iron as a cofactor for ferrochelatase (final enzyme in heme biosynthesis pathway), leading to reduced hemoglobin production and microcytic, hypochromic RBCs
• Loss of iron-dependent enzymes affecting myoglobin synthesis (muscle weakness), cytochrome oxidase (fatigue), peroxidase (impaired immune function), and collagen cross-linking (koilonychia, esophageal webs)
• Common etiologies include chronic blood loss (GI bleeding most common in adults), inadequate dietary intake, malabsorption (celiac disease, post-gastrectomy), increased demands (pregnancy, lactation, infancy), and hemolysis with iron loss in chronic intravascular hemolysis
• Two-phase progression: Phase 1 (iron depletion) → Phase 2 (iron-deficient erythropoiesis) → Phase 3 (iron deficiency anemia with clinical manifestations)

Sideroblastic Anemia

• Defective mitochondrial iron incorporation into protoporphyrin IX due to mutations affecting heme synthesis pathway enzymes, most commonly ALAS2 gene mutations (X-linked dominant, predominantly affects males) or acquired mutations in STEAP3, GLRX5, SLC25A38, and others
• Accumulation of iron in mitochondria of erythroid precursors forming characteristic ring sideroblasts (>15% diagnostic threshold) visible on Prussian blue staining as iron-laden rings encircling the nucleus
• Mitochondrial oxidative stress from excess iron generates reactive oxygen species (ROS), promoting apoptosis of erythroid precursors and ineffective erythropoiesis (intramedullary hemolysis)
• Paradoxical iron overload despite anemia: serum iron, ferritin, and transferrin saturation typically elevated or high-normal; iron accumulates in spleen, liver, and heart causing secondary hemochromatosis
• Classification: Hereditary (X-linked most common, rarely autosomal recessive), acquired idiopathic, or secondary to medications (isoniazid, pyridoxine antagonists), alcohol, lead poisoning, copper deficiency, or myelodysplastic syndromes (5-10% of MDS cases)

Iron Deficiency Anemia

• Constitutional symptoms: fatigue, dyspnea on exertion (due to reduced oxygen-carrying capacity), palpitations, dizziness, syncope
• Tissue iron deficiency effects: koilonychia (spoon nails, pathognomonic but late finding), pagophagia (ice chewing, highly specific pica), pica for unusual substances (starch, dirt), angular cheilitis (cracks at corners of mouth), glossitis (sore, beefy tongue), esophageal webs (Plummer-Vinson syndrome when combined with dysphagia and strictures)
• Restless leg syndrome (often improves with iron repletion)
• Increased infection susceptibility due to impaired T-cell and neutrophil function (iron-dependent enzyme deficiencies)
• Delayed development and behavioral issues in children; increased pregnancy complications (preterm delivery, low birth weight, maternal mortality)
• Important clinical pearl: many patients are asymptomatic until hemoglobin drops significantly; absence of symptoms does not exclude IDA

Sideroblastic Anemia

• Mild to moderate anemia in hereditary forms; often asymptomatic or minimally symptomatic relative to hemoglobin level due to gradual onset allowing compensation
• Constitutional symptoms similar to IDA if hemoglobin sufficiently low
• Secondary hemochromatosis features (in chronic cases): hepatomegaly with cirrhosis, cardiac arrhythmias and heart failure (iron deposition in myocardium), diabetes mellitus (pancreatic beta-cell destruction), hypogonadism, arthropathy
• Bleeding complications in acquired forms (particularly MDS-associated) due to thrombocytopenia or coagulopathy
• No response to iron therapy and worsening of iron burden, distinguishing from IDA
• Important distinction: sideroblastic patients may appear relatively well despite significant anemia due to chronic adaptation

Iron Deficiency Anemia

• Complete Blood Count (CBC): microcytic (MCV <80 fL), hypochromic (MCH <27 pg, MCHC <32 g/dL) anemia; normal or slightly elevated RBC count; RDW elevated (reflects anisocytosis); normal platelet count (unless concurrent bleeding disorder)
• Peripheral blood smear: microcytic hypochromic cells, pencil cells (target cells with central pallor), occasional polychromasia
• Iron studies (gold standard for diagnosis):
• Serum iron: LOW (<50 µg/dL; normal 60-170)
• Ferritin: LOW (<15 ng/mL in non-inflamed patients; <30 ng/mL highly suggestive; note: ferritin is acute phase reactant, falsely elevated in inflammation/infection/malignancy)
• Transferrin saturation: LOW (<15%; normal 25-35%)
• TIBC (Total Iron Binding Capacity): HIGH (>360 µg/dL; normal 250-425) as body upregulates transferrin production
• Reticulocyte count: initially normal or elevated (appropriate response) but may be inappropriately low if concurrent kidney disease or bone marrow suppression
• Soluble transferrin receptor: NOT affected by inflammation; superior to ferritin in inflammatory states; >8.5 mg/L suggests iron deficiency
• Bone marrow examination: rarely needed for diagnosis; shows hypocellular iron stores (Prussian blue stain: no stainable iron) and dyserythropoiesis
• Diagnostic algorithm:

1. 1.Identify microcytic anemia
2. 2.Check ferritin and transferrin saturation (or soluble transferrin receptor)
3. 3.If iron deficiency confirmed, pursue cause: fecal occult blood testing, upper endoscopy ± colonoscopy (GI bleeding), serologies for celiac disease, assess dietary intake
4. 4.Rule out thalassemia trait (normal iron studies, elevated RBC count, target cells, elevated Hb A2 on electrophoresis)

Sideroblastic Anemia

• CBC: microcytic or normocytic anemia (MCV variable); normal or high reticulocyte count despite anemia (ineffective erythropoiesis); normal or elevated platelet count (in hereditary forms; may be low in MDS-associated)
• Peripheral blood smear: dimorphic RBC population (hypochromic microcytic cells mixed with normal cells) is characteristic; occasional target cells, nucleated RBCs in severe cases
• Iron studies (opposite of IDA):
• Serum iron: NORMAL or HIGH (>150 µg/dL)
• Ferritin: NORMAL or HIGH (often >200 ng/mL)
• Transferrin saturation: NORMAL or HIGH (>45%)
• **TIBC:

Immediate stabilisation

• Transfuse packed RBCs only for hemodynamic instability, active hemorrhage, or symptomatic anemia (angina, syncope); most iron deficiency is chronic and does not require transfusion. AABB supports a restrictive threshold in stable hospitalized patients.

Iron deficiency — first line

• Oral iron salts: ferrous sulfate is the representative agent. Give on an empty stomach with vitamin C; avoid co-administration with PPIs, calcium, or tea. Alternate-day or once-daily (rather than TID) dosing raises fractional absorption because each dose triggers a hepcidin surge that blocks absorption for roughly 24 hours.
• Expected response: reticulocytosis within about a week, hemoglobin rising over subsequent weeks; continue several months after hemoglobin normalizes to refill stores.

Escalation / second line

• IV iron (ferric carboxymaltose, iron sucrose, ferumoxytol, low-molecular-weight iron dextran) for oral intolerance, malabsorption (celiac, post-bariatric), ongoing losses exceeding oral absorption, inflammatory bowel disease, second/third-trimester pregnancy, and CKD — KDIGO addresses iron use in CKD anemia, and ACOG endorses IV iron when oral therapy fails in pregnancy.
• Erythropoiesis-stimulating agents only in CKD or chemotherapy-associated anemia, and only after iron repletion.

Sideroblastic anemia

• Withdraw the offender: isoniazid, linezolid, chloramphenicol, alcohol; chelate lead (succimer, or EDTA/dimercaprol for encephalopathy); replete copper.
• Pyridoxine (vitamin B6) trial — cofactor for ALAS2; hereditary X-linked forms may respond dramatically.
• MDS with ring sideroblasts: per NCCN, ESAs for low-risk disease and luspatercept (activin receptor ligand trap) for transfusion-dependent *SF3B1*-associated disease; allogeneic HSCT is the only curative option.
• Iron chelation (deferasirox, deferoxamine) for transfusional iron overload.

Complications of iron deficiency

• High-output heart failure and demand ischemia: severe anemia lowers viscosity and raises cardiac output; signals are a widened pulse pressure, flow murmur, or new angina/ST depression — an emergency requiring transfusion.
• Missed underlying malignancy: iron deficiency in an adult man or postmenopausal woman is colorectal cancer until proven otherwise; failure to scope is the classic management error.
• Plummer-Vinson syndrome: postcricoid webs with dysphagia, associated with esophageal squamous cell carcinoma risk.
• Neurodevelopmental impairment in infants and toddlers, only partly reversible with repletion.
• Obstetric complications: preterm birth, low birth weight, and reduced tolerance of peripartum hemorrhage.

Complications of iron therapy

• GI intolerance: nausea, constipation, and black stools — a distractor for melena; check occult blood rather than assuming bleeding.
• Acute iron overdose in children: pediatric ingestion of adult tablets causes hemorrhagic gastroenteritis, anion-gap metabolic acidosis, and shock — a true emergency treated with deferoxamine.
• IV iron reactions: infusion-related hypotension/flushing and rare anaphylaxis (highest historically with high-molecular-weight dextran); ferric carboxymaltose causes FGF23-mediated hypophosphatemia, which can produce osteomalacia with repeated dosing.

Complications of sideroblastic anemia and its treatment

• Secondary hemochromatosis from ineffective erythropoiesis plus transfusion: hepatic fibrosis/cirrhosis, diabetes, hypogonadism, arthropathy.
• Cardiac iron deposition: restrictive/dilated cardiomyopathy and conduction disease — heart failure or arrhythmia here is an emergency; cardiac MRI T2* quantifies myocardial iron.
• Leukemic transformation of MDS with ring sideroblasts to AML, heralded by rising blasts, worsening cytopenias, or new circulating blasts.
• Chelator toxicity: deferoxamine causes ototoxicity and retinopathy; deferasirox causes nephrotoxicity, hepatotoxicity, and GI hemorrhage.
• Lead encephalopathy in plumbism — seizures and cerebral edema, an emergency.

• Ferritin is the first lab to fall and a low ferritin is essentially diagnostic of iron deficiency; because it is an acute-phase reactant, use soluble transferrin receptor or a higher ferritin cut-off when inflammation is present.
• The single best next step in a man or postmenopausal woman with new iron deficiency anemia is bidirectional endoscopy (ACG), not simply starting iron. Replacing iron without finding the source is the trap.
• Iron studies pattern recognition: iron deficiency = low ferritin, high TIBC/transferrin, low saturation; anemia of chronic disease = low iron, low TIBC, high-normal or high ferritin (hepcidin-mediated sequestration); sideroblastic = high iron, high ferritin, high saturation. Anemia of chronic inflammation is the most common distractor for a microcytic anemia with a low serum iron.
• Thalassemia trait mimic: microcytosis out of proportion to the anemia, normal RDW, high-normal RBC count, and normal iron studies. Iron deficiency raises RDW early; a Mentzer index (MCV/RBC) above 13 favors iron deficiency, below 13 favors thalassemia trait.
• Pagophagia (ice chewing) and koilonychia are the iron-deficiency buzzwords; restless legs improving after repletion is a favorite soft clue.
• Basophilic stippling plus ring sideroblasts plus abdominal pain and a wrist drop = lead poisoning; a child with lead exposure needs a venous blood lead level, then chelation by level.
• Isoniazid causes sideroblastic anemia and peripheral neuropathy through pyridoxine antagonism — the tested answer is co-administer vitamin B6.
• Copper deficiency (post-bariatric surgery or zinc excess) produces sideroblastic anemia with neutropenia and myeloneuropathy — a mimic of B12 deficiency that iron and B12 will not fix.
• **Ring sideroblasts on Prussian blue with an SF3B1 mutation** in an older adult means MDS with ring sideroblasts; luspatercept is the agent examiners link to it.