Anemias

Whatever the cause, every anemia converges on the same physiology: fewer circulating red cells means less hemoglobin, less oxygen-carrying capacity, and tissue hypoxia. That single chain explains the shared presentation of every type — fatigue, weakness, and exertional dyspnea (starved tissues), pallor of the skin and conjunctivae (blood shunted away from the skin toward core organs), and tachycardia with palpitations (the heart compensating by raising output). Hypoxia also stimulates erythropoietin secretion, driving the marrow to make more red cells — which is exactly why a healthy marrow’s response (the reticulocyte count) becomes a diagnostic clue.

The numbers that define anemia belong to the WHO (2024 guideline): hemoglobin < 13.0 g/dL in men, < 12.0 g/dL in nonpregnant women, and < 11.0 g/dL in pregnancy (first/third trimester; < 10.5 in the second). Reference ranges vary by lab, but WHO owns the thresholds. Severity matters clinically: cardiovascular compensation can produce systolic flow murmurs and, in extreme anemia, high-output heart failure — and at Hgb below roughly 7–8 g/dL, exertional chest pain warns that anemia can precipitate acute coronary syndrome.

The MCV sorts anemias into three families. Microcytic (< 80 fL): iron deficiency — the cause of about 66% of anemia worldwide — plus thalassemia, sideroblastic anemia, anemia of inflammation, and lead. Normocytic (80–100 fL): anemia of inflammation/CKD, aplastic anemia, pure red cell aplasia. Macrocytic (> 100 fL): the megaloblastic pair — B12 and folate deficiency — and nonmegaloblastic causes (myelodysplastic syndrome, alcohol use, hypothyroidism, drugs).

The reticulocyte count answers a different question: is the marrow responding? A reticulocyte production index ≥ 3 means the marrow is compensating appropriately — think hemolysis or acute blood loss. An index < 2 means the marrow itself is the problem — a production failure from iron, B12, or folate deficiency, marrow failure, or CKD. After hemolysis begins, reticulocytosis takes 3–5 days to appear.

The iron studies then separate look-alikes. Iron deficiency: low serum iron, high TIBC, low ferritin — the empty-warehouse pattern. Anemia of chronic disease: low serum iron but low TIBC and high ferritin — iron is present but locked away. Ferritin < 30 ng/mL is 92% sensitive and 98% specific for absent iron stores.

Iron deficiency is the most common nutritional deficiency causing anemia, affecting over 2 billion people. In developed countries the leading cause is blood loss — from the GI tract or menstruation — not diet; malabsorption (celiac disease, atrophic gastritis, H. pylori, bariatric surgery) also contributes. That is why the workup rule matters so much: occult GI bleeding is easily overlooked, and in an adult with no clear etiology — classically a man or postmenopausal woman — guidelines recommend both esophagogastroduodenoscopy and colonoscopy. The anemia may be a bleeding lesion talking.

B12 deficiency develops slowly — the liver stores enough B12 that deficiency takes 2–5 years to appear even with absent absorption. In pernicious anemia, autoimmune gastritis destroys the parietal cells that make intrinsic factor; without the B12–intrinsic-factor complex, B12 cannot be absorbed in the terminal ileum. Other causes: gastrectomy or gastric bypass, terminal-ileum disease or resection (Crohn), a strict vegan diet of about 3 years, nitrous oxide, and metformin. What makes B12 deficiency dangerous is the neurologic damage: defective myelin synthesis produces paresthesias, ataxia, loss of proprioception and vibration sense, and — late — subacute combined degeneration of the spinal cord. These neuro findings can appear without any anemia at all.

Folate deficiency produces the same megaloblastic, macrocytic picture — but no neurologic damage. Body stores of folate are small, so deficiency develops in only 8–16 weeks; chronic alcohol use, pregnancy (rapid cell division raises demand), malabsorption, and drugs like methotrexate and phenytoin are the classic causes. The distinction is a two-way exam hook: neuro signs point to B12, and the metabolic markers confirm it — methylmalonic acid and homocysteine both elevated = B12 deficiency; homocysteine elevated with normal MMA = folate deficiency. And it carries a treatment trap: giving folate alone corrects the anemia while B12-related neurologic damage silently progresses — always replete B12 first or alongside.

Aplastic anemia is bone marrow failure: a hypocellular marrow with fatty replacement produces pancytopenia — all three cell lines fall. Each line failing tells its own story, and together they form the exam triad: anemia (fatigue, pallor, dyspnea, tachycardia), thrombocytopenia (petechiae, bruising, mucosal bleeding), and neutropenia (fever and infection). Infection + bleeding + fatigue together should always make you think marrow failure. About 65% of cases are idiopathic/autoimmune; drugs (chloramphenicol, chemotherapy), benzene, viral infections (including hepatitis), and inherited syndromes cause the rest.

Hemolytic anemia is the opposite problem: production is fine, but red cells are destroyed before their normal 120-day lifespan ends. Heme breakdown outpaces the liver’s ability to conjugate bilirubin, so the signature is jaundice with elevated indirect (unconjugated) bilirubin, plus elevated LDH spilled from ruptured cells, elevated reticulocytes as the marrow compensates, and low haptoglobin — consumed as it binds free hemoglobin, and the most sensitive marker. A positive direct antiglobulin (Coombs) test identifies an autoimmune cause. Causes range from inherited (sickle cell disease, thalassemia, hereditary spherocytosis, G6PD deficiency) to acquired (autoimmune, drugs, prosthetic valves, transfusion reactions).

Anemia of chronic disease/CKD is a normocytic, hypoproliferative anemia with two mechanisms stacked. Chronic inflammation raises hepcidin, which degrades ferroportin and locks iron inside its stores — a functional iron deficiency despite a normal or high ferritin. In CKD, the failing kidneys add the primary lesion: decreased erythropoietin production. Anemia begins as GFR falls below 60 mL/min/1.73 m², and at least 90% of dialysis-dependent patients eventually develop it — which is why the ESA drug class exists.