Biochemical aspects of anemia

Definition of Anemia

A condition defined by a low number of circulating red blood cells (RBCs) or hemoglobin (Hb), resulting in diminished oxygen-carrying capacity and tissue hypoxia.

WHO Diagnostic Criteria - Nonpregnant women

Hb < 12 g/dL

WHO Diagnostic Criteria - Pregnant women

Hb < 11 g/dL

WHO Diagnostic Criteria - Men

Hb < 13 g/dL

Gender Differences in Hemoglobin

At puberty, male androgen production increases, causing male hemoglobin levels to be 1.5–2 g/dL higher than women's.

Tissue Hypoxia Symptoms

Fatigue, weakness, dyspnea, and angina

Brain Hypoxia Symptoms

Headache, faintness, and dim vision

Redistribution of Blood Symptoms

Pallor in the skin, mucous membranes, conjunctiva, and nail beds

Compensation Symptoms in Anemia

Tachycardia and palpitations occur as the body increases cardiac output to compensate.

Acute Onset Anemia Symptoms

Systolic flow murmur, dizziness, syncope, and excessive sleeping (in infants)

Slow-Developing Anemia

Can result in a 50% loss of RBC mass before any symptoms even appear.

Microcytic Hypochromic Anemias MCV

MCV < 80 fL

Causes of Microcytic Hypochromic Anemias

Insufficient hemoglobin production due to defects in Iron, Globin, or Porphyrin

Iron-Deficiency Anemia Pathology

Most common global cause. Iron is required for heme, mitochondrial function, DNA synthesis, and enzymatic reactions.

Iron-Deficiency Anemia Causes

Inadequate intake/absorption, heavy menstruation, or chronic GI bleeding. Occult blood loss must always be excluded, especially in older patients.

Iron-Deficiency Anemia Lab Findings

Low serum iron, low ferritin, increased TIBC, increased serum transferrin receptor. RDW can be normal or elevated.

Ferritin in Inflammation

Ferritin is an acute-phase reactant, so a normal ferritin does not definitively rule out iron deficiency if inflammation is present.

Thalassemia Pathology

Autosomal recessive disorders causing decreased/abnormal globin chain synthesis. Severity depends on the number of mutated/deleted genes.

Thalassemia Genetics

Alpha-thalassemia = deletions on chromosome 16. Beta-thalassemia = mutations on chromosome 11.

Normal Hemoglobin Types

HbA (α2β2), HbA2 (α2δ2), Fetal HbF (α2γ2)

Thalassemia Lab Findings

Normal or increased RBC count, normal/increased ferritin, normal/increased serum iron, normal TIBC.

Sideroblastic Anemia Pathology

Impaired heme production causes excess iron to deposit in the mitochondria of RBC precursors (forming ringed sideroblasts). Can be microcytic or normocytic.

Sideroblastic Anemia Congenital Cause

X-linked mutation in the δ-aminolevulinic acid (ALA) synthase gene.

Sideroblastic Anemia Acquired Causes

Isoniazid (inhibits pyridoxine), Lead poisoning (inhibits δ-ALA dehydratase and ferrochelatase), Chronic alcohol abuse (toxic to erythroid precursors).

Sideroblastic Anemia Lab Findings

Increased serum iron, increased ferritin, and increased transferrin saturation.

Normocytic Normochromic Anemias MCV

MCV 80–100 fL

Anemia of Chronic Disease Pathology

Inflammatory cytokines (TNF-α, IL-6, IL-1β) and hepcidin interrupt iron release from macrophages and decrease intestinal iron absorption. Erythropoietin production is also decreased.

Anemia of Chronic Disease Common Triggers

Malignancy, arthritis, renal insufficiency, heart failure, COPD, and chronic infections (e.g., sepsis, TB, osteomyelitis).

Anemia of Chronic Disease Lab Findings

Low serum iron, low TIBC, normal or increased ferritin. Usually normocytic, but progressive cases can become microcytic.

RBC Underproduction Pathology

Bone marrow failure characterized by a paradoxically low or normal reticulocyte count.

Aplastic Anemia

Destruction of myeloid stem cells leading to pancytopenia (low RBCs, neutropenia, thrombocytopenia). Triggered by drugs/chemicals.

Other RBC Underproduction Causes

Pure red cell aplasia, bone marrow infiltration (tumor, granuloma, fibrosis).

Hemolytic Anemia Pathology

Premature destruction of RBCs.

Hemolytic Anemia Acquired Causes

Immune-mediated, infection (malaria), microangiopathic, blood transfusions, hypersplenism.

Sickle Cell Disease

Autosomal recessive mutation replacing glutamic acid with valine at the 6th position of the beta chain (forming HbS). Deoxygenation/stress makes RBCs rigid, sickled, and adhesive.

G6PD Deficiency

X-linked. G6PD is key in the hexose monophosphate (HMP) shunt. Deficiency halts glutathione metabolism, leaving RBCs vulnerable to oxidative injury/lysis.

Hereditary Spherocytosis

Autosomal defect in membrane proteins (ankyrin and spectrin). Cells become fragile spheres instead of biconcave disks, leading to rapid splenic sequestration and destruction.

General Hemolytic Lab Findings

Reticulocytosis, high erythropoietin, indirect hyperbilirubinemia, elevated LDH, and decreased haptoglobin.

Macrocytic Anemias MCV

MCV > 100 fL

Megaloblastic vs Non-Megaloblastic Macrocytic Anemias

Megaloblastic: defective DNA synthesis causing delayed nuclear maturation. Non-megaloblastic: pathology linked to lipid deposition on the RBC membrane.

Folate Deficiency

Folate is absorbed in the upper jejunum, found in greens/cereals (easily destroyed by cooking). Deficiency caused by inadequate diet (alcoholics) or increased demand (pregnancy).

Vitamin B12 Deficiency

B12 is absorbed in the terminal ileum but requires binding to Intrinsic Factor (IF) secreted by gastric parietal cells. B12 acts as a coenzyme to convert folate to its active form.

Pernicious Anemia

A specific macrocytic anemia caused by a lack of gastric mucosal secretion of Intrinsic Factor, meaning B12 cannot be absorbed.

Non-Megaloblastic Macrocytic Anemia - Liver Disease

Most common cause (often associated with alcoholism). Alcoholics can have mixed anemias due to both liver toxicity and poor diet.

Non-Megaloblastic Macrocytic Anemia - Drugs

Antiretrovirals, phenytoin, chemo agents (antimetabolites like methotrexate), valproic acid, and azathioprine can induce macrocytosis.