Anemia Defisiensi Besi (ADB)

01Pathophysiology

Iron is a core component of the heme group within hemoglobin, and it is also essential for myoglobin function and numerous enzymatic processes throughout the body. Iron absorption occurs primarily in the duodenum and proximal jejunum, regulated by the hepatic peptide hepcidin. When systemic iron stores are adequate, hepcidin is upregulated; it binds to ferroportin on enterocytes and macrophages, causing ferroportin degradation and thereby blocking iron export into the plasma. In iron deficiency, hepcidin levels drop, allowing maximal absorption of dietary iron. Despite this compensatory mechanism, when losses or demands exceed intake, stores become progressively depleted.

The disease evolves through a predictable three-stage progression. In the earliest phase, iron stores in the bone marrow and liver are consumed, and serum ferritin falls, but hemoglobin remains normal. As the deficit worsens, circulating iron becomes insufficient for effective erythropoiesis: serum iron drops, the liver produces more transferrin in an attempt to scavenge available iron (reflected as rising TIBC), and transferrin saturation falls below 20%. Finally, in the third stage, hemoglobin synthesis is clearly impaired, and the bone marrow releases smaller (microcytic) and paler (hypochromic) red blood cells. The red cell distribution width (RDW) rises because the marrow produces a mixture of normal-sized older cells and newly formed small cells.

The clinical symptoms follow directly from this mechanism. Reduced hemoglobin means diminished oxygen-carrying capacity, producing fatigue, pallor, tachycardia, and exertional dyspnea. Pica (particularly pagophagia, the craving for ice) is a well-recognized but incompletely understood manifestation thought to be driven by iron's role in central neurotransmitter metabolism. Rapidly dividing epithelial tissues are especially iron-dependent, which explains the mucosal and skin findings: atrophic glossitis (smooth tongue from papillary atrophy), angular cheilitis, and koilonychia (upward curving of thin, brittle nails due to impaired keratin synthesis). In severe, long-standing IDA, fibrotic changes can develop in the upper esophagus, forming the esophageal webs of Plummer-Vinson syndrome (also called Paterson-Brown-Kelly syndrome), which presents as dysphagia for solids and carries a heightened risk of esophageal squamous cell carcinoma.

02Classification and Clinical Manifestation

Stages of Iron Deficiency

Clinical Manifestations by System

03Diagnostic Workup

The best initial test for any anemia workup is a complete blood count (CBC) with red cell indices and a peripheral blood smear. In IDA, you will find a low hemoglobin with a low MCV (microcytic), low MCH and MCHC (hypochromic), and an elevated RDW. The elevated RDW is a discriminating feature: it reflects the variability in red cell size (anisocytosis) that results from a mixture of older normal-sized cells and newly produced small iron-deficient cells. On the smear, look for pencil cells (elongated elliptocytes) and occasional target cells.

Once microcytic anemia is identified, the next step is an iron studies panel. The single most useful laboratory value is serum ferritin. A ferritin below 30 ng/mL in an otherwise healthy individual strongly suggests IDA, and a level below 12 ng/mL is essentially diagnostic. However, ferritin is also an acute phase reactant; it can be falsely elevated in patients with concurrent infection, inflammation, liver disease, or malignancy. In these settings, a normal ferritin does not exclude IDA. When clinical suspicion remains high despite a "normal" ferritin, the soluble transferrin receptor (sTfR) becomes invaluable. Unlike ferritin, sTfR is not affected by inflammation. An elevated sTfR in the setting of anemia and concurrent inflammation points strongly toward true iron deficiency. The ratio $\frac{\text{sTfR}}{\log (\text{ferritin})}\backslash frac\{\backslash text\{sTfR\}\}\{\backslash log(\backslash text\{ferritin\})\}$ can further improve diagnostic accuracy in mixed states (a ratio >2 favors IDA even in the presence of chronic disease).

The gold standard for diagnosing IDA is a bone marrow biopsy with Prussian blue staining, which demonstrates absent stainable iron in marrow macrophages. In practice, this test is almost never necessary because noninvasive iron studies are usually sufficient. It is reserved for cases of diagnostic uncertainty.

A critically important principle for exam purposes: in any male patient or postmenopausal female diagnosed with IDA, you must search for a source of gastrointestinal blood loss. The standard approach includes both a colonoscopy and an upper endoscopy (esophagogastroduodenoscopy). Colorectal carcinoma is the most feared etiology in this population, and missing it is a high-yield testing point. In premenopausal women, menstrual blood loss is by far the most common cause, and a GI workup is not required unless menstrual losses do not adequately explain the degree of anemia or if the patient does not respond to iron supplementation. In children, consider dietary causes (excessive cow's milk consumption displaces iron-rich foods and can cause occult intestinal blood loss) and celiac disease.

04Management and Treatment

Acute stabilization. For patients with severe, symptomatic anemia (hemoglobin below 7 g/dL or signs of cardiovascular compromise such as chest pain, hemodynamic instability, or high-output heart failure), the immediate intervention is packed red blood cell transfusion. This is purely a bridge measure and does not address the underlying iron deficit. Once the patient is stabilized, iron repletion must follow.

Oral iron therapy remains the first-line treatment for the majority of patients. Ferrous sulfate is the preferred formulation because of its high elemental iron content and low cost. The standard dose is 325 mg (containing approximately 65 mg of elemental iron) taken two to three times daily. For optimal absorption, advise the patient to take each dose on an empty stomach (one hour before or two hours after meals) with a source of vitamin C (e.g., a glass of orange juice or 250 mg ascorbic acid tablet), which converts ferric iron to the more absorbable ferrous form. Patients should avoid concurrent intake of calcium supplements, dairy products, antacids, proton pump inhibitors, tetracyclines, and tea or coffee, all of which impair iron absorption. A common side effect of oral iron is GI intolerance (nausea, constipation, dark stools, abdominal discomfort). If intolerance is limiting, reducing the dose to once daily or switching to alternate-day dosing can maintain efficacy while improving adherence; recent evidence suggests that alternate-day dosing may actually enhance fractional iron absorption by allowing hepcidin levels to reset.

Monitoring the response is essential. The earliest marker of effective treatment is a rise in reticulocyte count within 5 to 7 days of starting therapy. Hemoglobin should increase by approximately 1 to 2 g/dL every 2 to 3 weeks. If there is no response by 4 to 6 weeks, reconsider the diagnosis, reassess adherence, and evaluate for ongoing blood loss or malabsorption. A critically tested point: iron therapy must be continued for 3 to 6 months after the hemoglobin has normalized to ensure complete replenishment of body iron stores (reflected by normalization of ferritin to >50 ng/mL).

Intravenous iron is indicated in the following scenarios: (1) documented malabsorption (celiac disease, inflammatory bowel disease, post-gastrectomy), (2) intolerance to oral iron despite dose adjustments, (3) ongoing losses that exceed the capacity of oral replacement, and (4) chronic kidney disease patients receiving erythropoietin therapy, where IV iron is the standard of care. Ferric carboxymaltose is favored in outpatient settings because it allows delivery of a large dose (750 mg per infusion, repeated once at day 7 for a total of 1500 mg) in a short infusion time without the need for a test dose. Iron sucrose is commonly used in dialysis patients. Iron dextran carries a higher risk of anaphylaxis and requires a test dose before full infusion; it is used less frequently now.

Treating the underlying cause is not optional. Iron supplementation without addressing the source of loss will only result in recurrence. As noted above, a colonoscopy and EGD are mandatory in men and postmenopausal women. In premenopausal women with heavy menstrual bleeding, referral to gynecology for evaluation of fibroids, endometriosis, or hormonal management is the appropriate next step.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on IDA questions is by confusing it with thalassemia trait. Both conditions produce microcytic anemia, and a vignette describing a young patient of Mediterranean or Southeast Asian descent with mild microcytosis will tempt students toward thalassemia. The key discriminator is the iron panel: a low ferritin and high TIBC confirm IDA, while normal or elevated ferritin with a normal TIBC points to thalassemia. Another helpful clue is the RDW: it is elevated in IDA (variable cell sizes) but characteristically normal in thalassemia (uniformly small cells). Keep the Mentzer index in your toolkit as a quick check ($\frac{MCV}{RBCcount}\backslash frac\{MCV\}\{RBC\backslash \; count\}$, where values above 13 favor IDA).

A second major trap involves ferritin interpretation in the setting of inflammation. A vignette may describe a patient with rheumatoid arthritis or another chronic inflammatory condition who has microcytic anemia and a "normal" ferritin of 80 ng/mL. Students often dismiss IDA because the ferritin appears adequate. However, in the presence of active inflammation, a ferritin up to 100 ng/mL does not reliably exclude iron deficiency. The correct next step in such a scenario is to check the soluble transferrin receptor or the sTfR:log(ferritin) ratio.

Third, never forget the mandatory GI workup in men and postmenopausal women with newly diagnosed IDA. A vignette presenting a 60-year-old man with fatigue and microcytic anemia is not asking you to prescribe iron and move on. The tested concept is: the next best step is colonoscopy (and often EGD) to exclude colorectal carcinoma. Prescribing iron without investigating the source of blood loss is a classic wrong answer.

Finally, be aware of the Plummer-Vinson triad: iron deficiency anemia, esophageal webs, and dysphagia. This is a frequently tested association, and the vignette will typically describe a middle-aged woman with long-standing anemia who now presents with difficulty swallowing solids. Recognize it, and remember that it confers an increased risk of squamous cell carcinoma of the esophagus, not adenocarcinoma.

The core competency being tested across IDA questions is the ability to correctly interpret an iron studies panel in context, distinguish IDA from its microcytic mimics, identify when further investigation for an underlying cause is mandatory, and sequence the management appropriately (stabilize, replete, investigate, and treat the source).