Medical School · Year 2 · Hematology Oncology · includes a quiz and discussion video

Lecture 02: Anemia Overview and Iron Deficiency

Unit 2.9: Hematology and Oncology

Learning Objectives

By the end of this lecture, students will be able to:

1. Define anemia and describe its clinical manifestations
2. Explain the pathophysiologic classification of anemia
3. Describe iron metabolism and homeostasis
4. Explain the causes and diagnosis of iron deficiency anemia
5. Describe the treatment of iron deficiency anemia
6. Explain anemia of chronic disease and its differentiation from iron deficiency

Lecture Outline

I. Definition and Classification

Anemia is defined as a reduction in the oxygen-carrying capacity of blood, typically measured by hemoglobin concentration or hematocrit falling below established reference ranges for age and sex. For adult men, anemia is defined as hemoglobin below 14 grams per deciliter or hematocrit below 40 percent. Adult women are considered anemic when hemoglobin falls below 12 grams per deciliter or hematocrit below 37 percent. During pregnancy, the definition adjusts to hemoglobin below 11 grams per deciliter due to physiologic hemodilution. These thresholds represent population-derived values and may require clinical judgment in individual patients.

The pathophysiologic classification of anemia provides a mechanistic framework for understanding and diagnosing the underlying cause. Decreased production encompasses conditions where the bone marrow fails to generate adequate red blood cells, including nutritional deficiencies, bone marrow failure syndromes, and infiltrative processes. Increased destruction or hemolysis occurs when red blood cell survival is shortened below the normal 120-day lifespan through intrinsic cell defects or extrinsic factors. Blood loss represents the third major category, occurring through acute hemorrhage or chronic occult bleeding that gradually depletes iron stores. Many patients have multiple contributing mechanisms requiring comprehensive evaluation.

The morphologic classification based on mean corpuscular volume offers a practical approach to narrowing the differential diagnosis. Microcytic anemia with MCV below 80 femtoliters suggests iron deficiency, thalassemia, anemia of chronic disease, or less commonly sideroblastic anemia and lead poisoning. Normocytic anemia with MCV between 80 and 100 femtoliters includes acute blood loss, hemolytic anemias, early nutritional deficiencies, chronic disease, and bone marrow failure or infiltration. Macrocytic anemia with MCV exceeding 100 femtoliters most commonly results from vitamin B12 or folate deficiency, liver disease, hypothyroidism, or myelodysplastic syndromes. Combining MCV classification with reticulocyte count and clinical context efficiently directs workup.

The clinical approach to anemia follows a systematic evaluation beginning with confirmation and classification. Initial steps include confirming anemia with hemoglobin and hematocrit, then reviewing the MCV to classify by red cell size. The reticulocyte count distinguishes hypoproliferative anemias from those with adequate marrow response. Peripheral blood smear examination provides morphologic clues that may immediately suggest specific diagnoses. Subsequent testing is guided by the classification, with iron studies for microcytic anemia, B12 and folate for macrocytic anemia, and hemolysis markers and direct antiglobulin testing for normocytic anemia with elevated reticulocyte count.

<image>Panel A: Flowchart algorithm for anemia classification beginning with MCV determination and branching to specific diagnoses based on additional testing. Panel B: Comparison of pathophysiologic categories showing decreased production, increased destruction, and blood loss with representative conditions. Panel C: Bar graph showing normal hemoglobin ranges by age and sex with anemia thresholds indicated. Panel D: Pie chart demonstrating relative frequency of different anemia types in primary care populations.</image>

II. Clinical Manifestations

Symptoms of anemia reflect inadequate oxygen delivery to tissues and the compensatory responses attempting to maintain tissue oxygenation. General symptoms include fatigue, weakness, and malaise that may be subtle initially and worsen as hemoglobin decreases further. Cardiovascular manifestations result from increased cardiac output attempting to compensate for reduced oxygen-carrying capacity, causing dyspnea on exertion, palpitations, and in severe cases, anginal chest pain. Neurologic symptoms include lightheadedness, syncope, and headache from cerebral hypoxia. Cognitive effects such as poor concentration and irritability may develop, particularly in chronic anemia affecting school or work performance.

Physical examination findings in anemia vary with severity and acuity of onset. Pallor represents the most characteristic sign, best assessed in the conjunctivae, palmar creases, and nail beds where melanin does not obscure color changes. Tachycardia develops as a compensatory mechanism to increase cardiac output and oxygen delivery. Flow murmurs may be heard at the cardiac apex or pulmonary outflow tract, resulting from high-output circulation through valves. Hypotension suggests acute blood loss with inadequate volume compensation. Specific signs may point to underlying etiology, including koilonychia or spoon-shaped nails in severe iron deficiency, angular cheilitis with cracking at mouth corners, and glossitis with a smooth painful tongue.

Symptom severity correlates imperfectly with hemoglobin level, depending significantly on the rate of hemoglobin decline and patient comorbidities. Mild anemia with hemoglobin between 10 and 12 grams per deciliter may be asymptomatic, particularly when developing gradually. Moderate anemia with hemoglobin of 8 to 10 grams per deciliter typically causes fatigue with activity. Severe anemia with hemoglobin between 6 and 8 grams per deciliter produces fatigue at rest and dyspnea. Life-threatening anemia below 6 grams per deciliter risks congestive heart failure, angina, and altered mental status. Patients with cardiovascular disease may become symptomatic at higher hemoglobin levels due to limited compensatory reserve.

Compensatory mechanisms allow remarkable tolerance of chronic anemia when hemoglobin decreases gradually. Increased cardiac output through higher heart rate and stroke volume improves oxygen delivery despite reduced oxygen content per unit blood volume. Elevated 2,3-diphosphoglycerate shifts the oxygen-hemoglobin dissociation curve rightward, facilitating oxygen unloading to tissues. Redistribution of blood flow prioritizes vital organs including the brain and heart at the expense of skin, kidneys, and splanchnic circulation. Increased erythropoietin stimulates bone marrow erythropoiesis when production capacity remains intact. These compensatory mechanisms explain why patients with chronic anemia may function surprisingly well at hemoglobin levels that would be catastrophic if occurring acutely.

<image>Panel A: Human figure diagram showing organ system manifestations of anemia including cardiac, neurologic, and general symptoms at different anatomic sites. Panel B: Photographs demonstrating physical examination findings including conjunctival pallor, koilonychia, and angular cheilitis. Panel C: Graph correlating hemoglobin level with symptom severity showing threshold effects and individual variation. Panel D: Illustration of compensatory mechanisms including increased cardiac output, rightward oxygen dissociation curve shift, and flow redistribution.</image>

III. Reticulocyte Count

The reticulocyte count measures immature red blood cells containing residual ribosomal RNA, providing assessment of bone marrow erythropoietic response to anemia. Reticulocytes normally spend one to two days in peripheral circulation before maturing into fully developed red blood cells. The normal reticulocyte count ranges from 0.5 to 2.5 percent or 25,000 to 75,000 cells per microliter in absolute terms. This parameter serves as the critical indicator distinguishing anemias with appropriate bone marrow response from those with inadequate or hypoproliferative erythropoiesis. Elevated reticulocyte counts indicate active erythropoiesis responding to hemolysis or blood loss, while low counts suggest production problems.

The corrected reticulocyte count adjusts for the degree of anemia to provide a more accurate assessment of marrow response. Because reticulocyte percentage represents a fraction of total red cells, anemia artificially elevates the percentage even without increased reticulocyte production. The correction formula multiplies the reticulocyte percentage by the ratio of patient hematocrit to normal hematocrit, using 45 percent as the reference value. For example, a patient with 6 percent reticulocytes and hematocrit of 22.5 percent has a corrected count of 3 percent rather than 6 percent. This adjustment reveals whether apparent reticulocytosis represents truly increased production or merely reflects a smaller denominator of total red cells.

The reticulocyte production index provides further refinement by accounting for premature reticulocyte release from bone marrow during severe anemia. When erythropoietin levels rise substantially, reticulocytes are released earlier and take longer to mature in circulation. The maturation factor adjusts for this extended circulation time, ranging from 1.0 at normal hematocrit to 2.5 at severely reduced hematocrit of 15 percent. Dividing the corrected reticulocyte count by the maturation factor yields the reticulocyte production index. An RPI exceeding 2 indicates appropriate marrow response to anemia, typically seen in hemolysis or after acute blood loss. An RPI below 2 indicates inadequate or hypoproliferative response requiring investigation of production problems.

Interpretation of reticulocyte parameters guides the diagnostic approach to anemia classification. Elevated reticulocyte count or RPI greater than 2 with anemia indicates either hemolysis or blood loss with intact bone marrow response, directing evaluation toward hemolytic markers, bleeding source investigation, or both. Low reticulocyte response with RPI below 2 indicates hypoproliferative anemia from nutritional deficiency, bone marrow failure, chronic disease, or marrow infiltration. The combination of anemia type based on MCV and reticulocyte response efficiently categorizes anemias and guides subsequent specific testing. Automated reticulocyte parameters including immature reticulocyte fraction and reticulocyte hemoglobin content provide additional information in selected clinical scenarios.

<image>Panel A: Diagram illustrating reticulocyte maturation from bone marrow release through peripheral blood circulation to mature red blood cell. Panel B: Step-by-step calculation example showing raw reticulocyte percentage, corrected count, and reticulocyte production index with clinical interpretation. Panel C: Two-by-two grid classifying anemias by MCV and reticulocyte response with representative diagnoses in each category. Panel D: Graph showing maturation factor values corresponding to different hematocrit levels.</image>

IV. Iron Metabolism

Iron distribution in the body reflects its essential roles in oxygen transport, enzymatic reactions, and energy metabolism. The total body iron content of approximately 3 to 4 grams is distributed among several compartments with hemoglobin containing the largest fraction at approximately 2,500 milligrams representing functional iron actively carrying oxygen. Storage iron in the form of ferritin and hemosiderin totals approximately 1,000 milligrams, located primarily in liver, bone marrow, and spleen macrophages. Myoglobin in skeletal and cardiac muscle contains approximately 300 milligrams. Transport iron bound to transferrin in plasma constitutes only about 3 milligrams despite its critical role in iron delivery. Various iron-containing enzymes throughout the body account for trace amounts essential for cellular metabolism.

Iron absorption occurs primarily in the duodenum and proximal jejunum through highly regulated mechanisms that match uptake to body needs. Dietary iron exists in two forms with differing absorption efficiency. Heme iron from meat sources is absorbed intact through specific transporters and has higher bioavailability than non-heme iron from plant sources. Non-heme ferric iron must be reduced to the ferrous state by duodenal cytochrome b before absorption via the divalent metal transporter 1. Absorption enhancers include vitamin C, which maintains iron in the reduced ferrous state, and meat factors that improve non-heme iron uptake. Absorption inhibitors include phytates in cereals and legumes, tannins in tea and coffee, and calcium, all of which form insoluble complexes with iron.

Iron transport and storage involve specialized proteins that maintain iron in safe, bioavailable forms while preventing toxic free iron reactions. Ferroportin is the sole cellular iron exporter, releasing iron from enterocytes, macrophages, and hepatocytes into circulation. Transferrin, the plasma iron carrier, has two high-affinity binding sites for ferric iron and delivers iron to cells throughout the body via transferrin receptor-mediated endocytosis. Ferritin stores intracellular iron in a soluble, non-toxic form accessible for mobilization when needed. Hemosiderin represents aggregated, partially degraded ferritin containing insoluble iron deposits that accumulate with iron overload. Serum ferritin reflects total body iron stores and serves as the most useful single test for assessing iron status.

Hepcidin functions as the master regulator of systemic iron homeostasis, controlling absorption and release from storage sites. This peptide hormone produced primarily by hepatocytes binds to ferroportin on cell surfaces, causing its internalization and degradation. When hepcidin levels are high, ferroportin is degraded, blocking iron export from enterocytes and macrophages and effectively reducing iron availability. Iron excess and inflammation both increase hepcidin production through distinct signaling pathways. Conversely, iron deficiency, anemia, and hypoxia suppress hepcidin, allowing increased iron absorption and release from stores. This regulatory system explains why inflammatory states cause iron sequestration despite adequate total body iron, producing the anemia of chronic disease.

<image>Panel A: Body diagram showing iron distribution among hemoglobin, storage sites, myoglobin, and transport compartments with approximate quantities. Panel B: Cross-section of duodenal enterocyte illustrating iron absorption mechanisms including DMT1, ferroportin, and hepcidin regulation. Panel C: Schematic of transferrin-mediated iron delivery to erythroid precursors via transferrin receptor endocytosis. Panel D: Feedback loop diagram demonstrating hepcidin regulation by iron status, inflammation, and erythropoietic signals.</image>

V. Iron Deficiency Anemia

Iron deficiency results from an imbalance between iron requirements and supply, progressing through predictable stages before anemia develops. Blood loss represents the most common cause in adults, including gastrointestinal bleeding from ulcers, malignancy, or angiodysplasia, and menstrual losses in premenopausal women. Decreased dietary intake rarely causes deficiency alone in developed countries but contributes when combined with increased losses. Malabsorption from celiac disease, inflammatory bowel disease, gastric bypass surgery, or Helicobacter pylori infection impairs iron uptake despite adequate intake. Increased physiological demands during pregnancy, lactation, and childhood growth spurts may outstrip absorption capacity even with adequate diet.

Iron deficiency progresses through three stages with distinct laboratory findings reflecting sequential depletion of compartments. In stage one, negative iron balance depletes storage iron while functional iron remains adequate, producing isolated low ferritin with normal hemoglobin and MCV. Stage two represents iron-deficient erythropoiesis when stores are exhausted and supply to erythroid precursors becomes insufficient, causing low serum iron, elevated total iron-binding capacity, reduced transferrin saturation below 20 percent, and beginning microcytosis. Stage three constitutes overt iron deficiency anemia with decreased hemoglobin, frankly microcytic and hypochromic red cells, and marked abnormalities in all iron parameters. Understanding this progression explains why ferritin decreases earliest while MCV changes occur late.

Clinical features of iron deficiency extend beyond anemia to include specific manifestations related to tissue iron depletion. Pica describes cravings for non-food substances including ice (pagophagia), dirt (geophagia), or starch, representing a curious phenomenon whose mechanism remains unclear. Koilonychia or spooning of fingernails occurs in severe prolonged deficiency when nail matrix iron depletion alters keratin formation. Angular cheilitis causes painful cracking at the corners of the mouth. Glossitis produces a smooth, painful tongue with papillary atrophy. Plummer-Vinson syndrome, the triad of iron deficiency anemia, dysphagia from esophageal webs, and glossitis, represents severe mucosal effects of prolonged deficiency. Restless legs syndrome shows strong association with iron deficiency even before anemia develops.

Diagnosis of iron deficiency relies on laboratory evaluation showing the characteristic pattern of depleted stores and inadequate iron supply. Serum ferritin below 30 nanograms per milliliter is the most sensitive and specific single test, though values up to 100 may indicate deficiency in the setting of inflammation. Serum iron is decreased and total iron-binding capacity elevated, reflecting increased transferrin synthesis attempting to capture limited iron. Transferrin saturation below 20 percent indicates inadequate iron delivery to tissues. Red blood cell indices show decreased MCV and mean corpuscular hemoglobin concentration in established deficiency. Elevated red cell distribution width reflects anisocytosis as iron-replete and iron-depleted populations coexist. Reticulocyte count is inappropriately low for the degree of anemia, indicating hypoproliferative response.

<image>Panel A: Timeline showing progression through three stages of iron deficiency with corresponding laboratory parameter changes at each stage. Panel B: Photographs of clinical findings including koilonychia, angular cheilitis, glossitis, and pallor in iron-deficient patients. Panel C: Peripheral blood smear showing hypochromic microcytic red blood cells with increased central pallor and pencil cells. Panel D: Comparison table of iron study results in iron deficiency versus normal values highlighting diagnostic thresholds.</image>

VI. Treatment of Iron Deficiency

Evaluation for underlying cause must accompany treatment of iron deficiency anemia to identify and address the source of iron loss or malabsorption. In premenopausal women, menstrual losses should be quantified, as heavy menstrual bleeding is the most common cause and may warrant gynecologic evaluation. In postmenopausal women and all men, gastrointestinal evaluation with upper endoscopy and colonoscopy is mandatory to exclude malignancy. Celiac disease serology and Helicobacter pylori testing should be considered in patients with malabsorption features or refractory deficiency. The finding of iron deficiency anemia in an adult requires presumption of blood loss until proven otherwise, making source identification essential regardless of response to iron therapy.

Oral iron therapy remains the first-line treatment for iron deficiency due to effectiveness, safety, and low cost. Ferrous sulfate at 325 milligrams per tablet contains 65 milligrams of elemental iron and is typically administered three times daily. Alternative ferrous salts include gluconate with 38 milligrams elemental iron per 325 milligram tablet and fumarate with 106 milligrams elemental iron per 325 milligram tablet. The goal is 150 to 200 milligrams of elemental iron daily in divided doses. Ferrous preparations are better absorbed than ferric forms due to greater solubility in the alkaline small intestinal environment. Various formulations allow selection based on patient tolerance and preference.

Administration technique significantly affects iron absorption and tolerability. Taking iron on an empty stomach maximizes absorption but increases gastrointestinal side effects including nausea, constipation, and abdominal discomfort. Vitamin C taken with iron enhances absorption by maintaining iron in the reduced ferrous state and chelating iron to prevent precipitation. Proton pump inhibitors and antacids reduce absorption by increasing gastric pH. Dairy products, coffee, and tea contain substances that form insoluble complexes with iron and should be avoided around dosing times. When side effects limit compliance, reducing the dose or switching to every-other-day dosing may improve tolerability while maintaining response, as recent evidence suggests intermittent dosing allows sufficient absorption while reducing hepcidin-mediated absorption inhibition.

Intravenous iron is indicated when oral therapy fails, is contraindicated, or when rapid repletion is required. Severe gastrointestinal intolerance preventing adequate oral intake represents a common indication. Malabsorptive conditions including celiac disease, inflammatory bowel disease, and prior bariatric surgery often require parenteral administration. Ongoing losses exceeding oral replacement capacity, as with heavy menstrual bleeding or hemodialysis, may necessitate intravenous therapy. Preoperative preparation when time does not permit oral repletion benefits from rapid parenteral loading. Multiple intravenous formulations are available including iron sucrose requiring multiple smaller infusions, ferric gluconate commonly used in dialysis, and newer high-dose formulations such as ferumoxytol and ferric carboxymaltose that allow total replacement in one or two infusions.

<image>Panel A: Algorithm for evaluating the source of iron deficiency based on patient demographics and clinical features. Panel B: Comparison of oral iron formulations showing elemental iron content, typical dosing, and relative advantages. Panel C: Diagram illustrating factors enhancing and inhibiting iron absorption with practical recommendations. Panel D: Decision tree for choosing between oral and intravenous iron therapy based on clinical circumstances.</image>

VII. Response to Treatment

Expected response to iron therapy follows a predictable timeline that allows monitoring of treatment effectiveness. Subjective improvement in energy and well-being may occur within days of starting therapy, even before measurable hemoglobin changes. Reticulocyte count peaks between days 5 and 10, reflecting increased erythropoiesis as iron becomes available for hemoglobin synthesis. Hemoglobin begins rising within 2 to 4 weeks and should increase by approximately 1 gram per deciliter every 2 to 3 weeks. Hemoglobin normalizes within approximately 2 months in uncomplicated cases. Iron stores require 3 to 6 months of continued therapy beyond hemoglobin normalization to fully replenish, and premature discontinuation leads to recurrent deficiency.

Monitoring during treatment ensures adequate response and guides therapy duration. Hemoglobin should be checked every 4 to 8 weeks until normalized, with expected increases of 1 to 2 grams per deciliter per month. After hemoglobin normalizes, ferritin measurement confirms store repletion, with a goal of 50 to 100 nanograms per milliliter before discontinuing therapy. Continuing iron for 3 to 6 months after hemoglobin normalization allows full store replenishment. Some clinicians monitor reticulocyte count early in treatment to confirm response before hemoglobin changes become apparent. Following completion of therapy, periodic monitoring may be indicated to detect recurrence, particularly if the underlying cause cannot be fully corrected.

Failure to respond to iron therapy requires systematic evaluation for contributing factors. Noncompliance with oral iron due to side effects or complex dosing regimens is common and should be addressed through patient education, dose adjustment, or formulation change. Ongoing blood loss exceeding the rate of repletion may cause persistent anemia despite appropriate therapy. Incorrect diagnosis should be reconsidered, particularly thalassemia trait which presents with similar microcytosis but does not respond to iron. Malabsorption from undiagnosed celiac disease, Helicobacter pylori infection, or prior gastric surgery may prevent adequate iron uptake. Concurrent deficiencies of vitamin B12 or folate may limit erythropoietic response. Medication interactions with proton pump inhibitors or antacids may reduce absorption.

Transfusion is reserved for specific circumstances in iron deficiency anemia given the availability of effective iron replacement therapy. Hemodynamic instability from acute blood loss requires transfusion to restore oxygen-carrying capacity regardless of iron status. Symptomatic anemia with cardiac symptoms, severe dyspnea, or altered mental status may warrant transfusion while iron therapy takes effect. The transfusion threshold varies with clinical context, generally ranging from 7 to 8 grams per deciliter in stable patients but higher in those with cardiovascular disease or active ischemia. Transfusion addresses the immediate oxygen-carrying deficit but does not address underlying iron deficiency, making iron replacement essential even after transfusion. Each unit of transfused red blood cells contains approximately 200 to 250 milligrams of iron, contributing to but not replacing dedicated iron therapy.

<image>Panel A: Timeline graph showing expected changes in reticulocytes, hemoglobin, and ferritin during iron replacement therapy over weeks to months. Panel B: Flowchart for evaluating failure to respond to iron therapy with systematic investigation of potential causes. Panel C: Monitoring schedule checklist showing recommended parameters and timing during treatment. Panel D: Comparison of indications for transfusion versus iron therapy alone based on hemoglobin level and symptoms.</image>

VIII. Anemia of Chronic Disease (Inflammation)

Anemia of chronic disease, also termed anemia of inflammation, represents the second most common cause of anemia worldwide after iron deficiency. The pathogenesis centers on hepcidin-mediated iron sequestration triggered by inflammatory cytokines rather than true iron deficiency. Common underlying conditions include chronic infections such as tuberculosis and HIV, autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus, and malignancies of various types. The severity is typically mild to moderate with hemoglobin usually remaining between 8 and 10 grams per deciliter. Understanding this entity prevents inappropriate iron therapy and directs attention to treating the underlying inflammatory condition.

The pathophysiology involves multiple mechanisms that collectively impair erythropoiesis and limit iron availability. Inflammatory cytokines, particularly interleukin-6, stimulate hepatic hepcidin production through the JAK-STAT signaling pathway. Elevated hepcidin causes ferroportin degradation, trapping iron within macrophages that have recycled senescent red blood cells and within enterocytes that have absorbed dietary iron. This functional iron deficiency limits iron delivery to erythroid precursors despite adequate or even increased total body iron stores. Additionally, inflammatory cytokines suppress erythropoietin production and directly inhibit erythroid progenitor proliferation. Modest shortening of red cell survival through extravascular hemolysis contributes to anemia in some cases.

Laboratory findings in anemia of chronic disease show a distinctive pattern that distinguishes it from iron deficiency anemia. Hemoglobin is decreased, typically mild to moderate in degree. Mean corpuscular volume is normal or slightly reduced, contrasting with the marked microcytosis of severe iron deficiency. Serum iron is decreased similarly to iron deficiency, reflecting reduced circulating iron. The key distinguishing feature is total iron-binding capacity, which is decreased or normal in chronic disease versus elevated in iron deficiency, reflecting adequate or reduced transferrin synthesis. Ferritin is normal or elevated because iron stores remain intact despite sequestration, whereas ferritin is low in iron deficiency. Transferrin saturation falls in the low-normal range of 10 to 20 percent.

Distinguishing iron deficiency from anemia of chronic disease has important therapeutic implications, particularly when both conditions coexist. Ferritin below 30 nanograms per milliliter reliably indicates iron deficiency, while ferritin above 100 nanograms per milliliter effectively excludes it. Intermediate ferritin values between 30 and 100 nanograms per milliliter create diagnostic uncertainty, particularly in inflammatory states that elevate ferritin independently of iron stores. Soluble transferrin receptor, which increases in iron deficiency but remains normal in chronic disease, helps distinguish these conditions. The ratio of soluble transferrin receptor to log ferritin exceeding 2 suggests iron deficiency while values below 1 suggest anemia of chronic disease. Bone marrow iron staining remains the gold standard, showing absent iron stores in deficiency and present stores in chronic disease, but is rarely necessary for diagnosis.

<image>Panel A: Diagram showing hepcidin-mediated iron sequestration in macrophages with inflammatory cytokine signaling pathways. Panel B: Side-by-side comparison of laboratory findings in iron deficiency anemia versus anemia of chronic disease highlighting key distinguishing features. Panel C: List of common inflammatory conditions associated with anemia of chronic disease organized by category. Panel D: Algorithm for differentiating iron deficiency from anemia of chronic disease using ferritin, TIBC, and supplementary tests.</image>

IX. Other Microcytic Anemias

Sideroblastic anemias comprise a heterogeneous group of disorders characterized by abnormal heme synthesis resulting in iron accumulation within mitochondria of erythroid precursors. The characteristic finding is ring sideroblasts on iron-stained bone marrow aspirate, showing iron-laden mitochondria encircling the nucleus. Inherited forms include X-linked sideroblastic anemia from ALAS2 mutations, often responsive to pyridoxine supplementation. Acquired causes include myelodysplastic syndromes, alcohol toxicity, lead poisoning, isoniazid therapy, and copper deficiency. Laboratory findings show elevated serum iron and ferritin despite microcytic anemia, and peripheral smear may reveal dimorphic red cell populations with both normal and hypochromic microcytic cells.

Lead poisoning causes microcytic anemia through inhibition of multiple enzymes in the heme synthesis pathway. Specifically, lead inhibits delta-aminolevulinic acid dehydratase and ferrochelatase, the first and last enzymes in protoporphyrin synthesis. The resulting anemia is typically mild, and microcytosis may be subtle. The peripheral blood smear characteristically shows basophilic stippling from ribosomal aggregates in red blood cells. Additional clinical manifestations include gastrointestinal symptoms such as abdominal pain and constipation, peripheral neuropathy with wrist and foot drop, and in severe cases, encephalopathy with cognitive impairment. Diagnosis requires measurement of blood lead level. Treatment involves removing the exposure source and chelation therapy with agents such as succimer or calcium disodium EDTA for significant toxicity.

Thalassemia trait represents an important consideration in microcytic anemia that does not respond to iron therapy. This inherited disorder of globin chain synthesis produces marked microcytosis out of proportion to the mild or absent anemia, contrasting with iron deficiency where MCV decreases parallel to hemoglobin. The peripheral smear shows target cells, microcytosis, and sometimes basophilic stippling. Crucially, iron studies are normal or elevated, reflecting adequate or increased iron stores. The Mentzer index, calculated as MCV divided by red blood cell count, helps distinguish thalassemia trait from iron deficiency, with values below 13 suggesting thalassemia and above 13 suggesting iron deficiency. Hemoglobin electrophoresis confirms the diagnosis and identifies the specific thalassemia type.

Copper deficiency represents an uncommon but important cause of anemia that may be microcytic or macrocytic. Risk factors include prior gastric bypass surgery, excessive zinc supplementation which interferes with copper absorption, and prolonged parenteral nutrition without adequate copper. Beyond anemia, copper deficiency causes neutropenia and a myeloneuropathy resembling subacute combined degeneration from vitamin B12 deficiency. Diagnosis requires measurement of serum copper and ceruloplasmin, both of which are decreased. The bone marrow may show ring sideroblasts and vacuolated precursors. Treatment with copper supplementation leads to hematologic improvement, though neurologic damage may be only partially reversible if diagnosis is delayed.

<image>Panel A: Bone marrow iron stain showing ring sideroblasts with perinuclear iron granule distribution characteristic of sideroblastic anemia. Panel B: Peripheral blood smear demonstrating basophilic stippling in red blood cells from lead poisoning. Panel C: Comparison of microcytic anemia findings in iron deficiency, thalassemia trait, and sideroblastic anemia. Panel D: Clinical photograph of blue gum line (Burton's line) and wrist drop in chronic lead poisoning.</image>

X. Clinical Cases and Summary

A 35-year-old woman presents with fatigue and heavy menstrual periods, found to have hemoglobin of 9.2 grams per deciliter and MCV of 72 femtoliters indicating microcytic anemia. Ferritin of 8 nanograms per milliliter confirms depleted iron stores, and elevated TIBC reflects increased transferrin synthesis attempting to capture limited iron. This classic presentation of iron deficiency anemia from menstrual blood loss warrants oral iron therapy with ferrous sulfate 325 milligrams three times daily. Gynecologic evaluation should address the heavy menstrual bleeding as the underlying cause. Response monitoring includes checking hemoglobin at 4-week intervals with expected normalization within 2 months, followed by ferritin measurement to confirm store repletion before discontinuing therapy.

A 65-year-old man with rheumatoid arthritis on chronic methotrexate therapy presents with hemoglobin of 10.5 grams per deciliter and MCV of 85 femtoliters indicating mild normocytic anemia. Ferritin of 250 nanograms per milliliter demonstrates adequate iron stores, distinguishing this from iron deficiency. Low TIBC further supports anemia of chronic disease rather than iron deficiency. The mild degree of anemia and clear inflammatory underlying condition are characteristic of anemia of inflammation. Management focuses on optimizing treatment of the underlying rheumatoid arthritis. Iron supplementation is not indicated given adequate stores, and attempting iron therapy would be ineffective due to hepcidin-mediated absorption suppression. Erythropoiesis-stimulating agents may be considered if anemia significantly impacts quality of life despite optimal disease control.

A 55-year-old patient with Crohn's disease presents with hemoglobin of 8.5 grams per deciliter and MCV of 78 femtoliters. Ferritin of 45 nanograms per milliliter falls in the indeterminate range where inflammation may falsely elevate values despite true iron deficiency. Elevated soluble transferrin receptor suggests iron deficiency superimposed on chronic inflammation, representing a common clinical scenario of combined deficiency. Management requires addressing both the iron deficiency and the underlying inflammatory bowel disease. Intravenous iron is preferred given likely malabsorption from intestinal disease, and treatment of Crohn's disease should be optimized. This case illustrates the diagnostic challenge when iron deficiency and anemia of chronic disease coexist.

The diagnostic approach to microcytic anemia can be summarized algorithmically based on ferritin and iron study patterns. When MCV is below 80 femtoliters, ferritin is the first test to order. Low ferritin below 30 nanograms per milliliter confirms iron deficiency, directing evaluation toward blood loss sources and treatment with iron replacement. Normal or elevated ferritin prompts consideration of thalassemia trait, anemia of chronic disease, or sideroblastic anemia. Hemoglobin electrophoresis identifies thalassemia, while clinical context and inflammatory markers distinguish chronic disease. For normocytic and macrocytic anemias, reticulocyte count and additional directed testing complete the evaluation, with B12, folate, and thyroid studies indicated for macrocytic presentations.

<image>Panel A: Case-based illustration showing laboratory results and clinical features of iron deficiency anemia in a young woman with menorrhagia. Panel B: Comparison of case presentations showing iron deficiency, anemia of chronic disease, and combined deficiency with distinguishing features. Panel C: Complete diagnostic algorithm for anemia evaluation beginning with MCV classification and proceeding through directed testing. Panel D: Summary table of treatment approaches for different anemia types including oral iron, intravenous iron, and disease-specific therapy.</image>

Summary

• Anemia is defined as hemoglobin below 14 g/dL in men and below 12 g/dL in women, classified by mechanism as decreased production, increased destruction, or blood loss
• MCV classification divides anemias into microcytic, normocytic, and macrocytic categories, each with characteristic differential diagnoses
• Reticulocyte count distinguishes hypoproliferative anemias from those with appropriate marrow response, with RPI above 2 indicating adequate response
• Iron metabolism involves absorption in the duodenum, transport by transferrin, storage as ferritin, and regulation by hepcidin
• Iron deficiency progresses through stages of depleted stores, iron-deficient erythropoiesis, and finally iron deficiency anemia with characteristic low ferritin and high TIBC
• Oral iron therapy with ferrous sulfate is first-line treatment, requiring 3 to 6 months to fully replenish stores after hemoglobin normalizes
• Intravenous iron is indicated for malabsorption, intolerance, or need for rapid repletion
• Anemia of chronic disease results from hepcidin-mediated iron sequestration triggered by inflammation, showing normal or elevated ferritin with low TIBC
• Distinguishing iron deficiency from anemia of chronic disease is critical because treatment differs fundamentally

Key Terms

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