Understanding Anemia: Types and Pathophysiology

Anemia Overview

• Anemia is a group of diseases characterized by a decrease in hemoglobin (Hb) or red blood cells (RBCs), which reduces the blood's oxygen-carrying capacity.
• The WHO defines anemia as Hb less than 13 g/dL (<130 g/L; <8.07 mmol/L) in men and less than 12 g/dL (<120 g/L; <7.45 mmol/L) in women.

Pathophysiology of Anemia

• Anemia can result from hypoproliferative disorders, maturation disorders, or hemorrhage/hemolysis.
• Hypoproliferative anemia involves marrow damage and/or iron deficiency that can be stimulated by renal, inflammatory, or metabolic diseases.
• Maturation disorders include cytoplasmic defects like thalassemia, iron deficiency, sideroblastic anemia, and nuclear maturation defects like folate or Vitamin B12 deficiencies or refractory anemia.
• Hemorrhage/hemolysis anemias are due to blood loss, intravascular hemolysis, autoimmune disease, hemoglobinopathy, or metabolic/membrane defects.

Morphologic Classification

• Based on cell size, anemia is classified as macrocytic, microcytic, or normocytic.
• Macrocytic anemia involves larger than normal cells associated with Vitamin B12 or folic acid deficiency.
• Microcytic anemia has smaller than normal cells and is associated with iron deficiency.
• Normocytic anemia is associated with recent blood loss or chronic disease.

Iron Deficiency Anemia (IDA)

• IDA is caused by inadequate dietary intake, poor gastrointestinal absorption, increased iron demand, blood loss, and chronic disease.

Vitamin B12 and Folic Acid Deficiency Anemias

• Vitamin B12 and folic acid deficiency anemias are caused by inadequate dietary intake, decreased absorption, and inadequate utilization.
• Deficiency of intrinsic factor leads to decreased Vitamin B12 absorption, i.e., Pernicious Anemia.
• Folic acid deficiency anemia can result from hyper-utilization in pregnancy, hemolytic anemia, myelofibrosis, malignancy, chronic inflammatory disorders, long-term dialysis, or growth spurts.

Other Causes of Anemia

• Drugs like phenytoin or methotrexate can cause anemia by reducing folate absorption or through folate antagonism.
• Anemia of inflammation (AI) is associated with infectious or inflammatory processes, tissue injury, and release of proinflammatory cytokines.

Factors Affecting Anemia

• Age-related reductions in bone marrow reserve can make elderly patients more susceptible.
• Pediatric anemias are often due to primary hematologic abnormalities.
• The risk of IDA is increased by rapid growth spurts and dietary deficiency.

Clinical Presentation

Acute-Onset Anemia

• Characterized by cardiorespiratory symptoms, including palpitations, angina, orthostatic light-headedness, and breathlessness.

Chronic Anemia

• Characterized by weakness, fatigue, headache, orthopnea, dyspnea on exertion, vertigo, faintness, cold sensitivity, pallor, and loss of skin tone.

Iron Deficiency Anemia (IDA)

• Characterized by glossal pain, smooth tongue, reduced salivary flow, Pica (compulsive eating of nonfood items), and Pagophagia (compulsive eating of ice).

Vitamin B12 Deficiency

• Neurologic effects of vitamin B12 deficiency include numbness and ataxia, which may occur in the absence of hematologic changes.
• Psychiatric findings, including irritability, depression, and memory impairment may also occur.
• Anemia with folate deficiency is not associated with neurologic symptoms.

Diagnosis

• Rapid diagnosis is essential because anemia can be a sign of an underlying pathology.
• The initial evaluation includes a complete blood cell count (CBC), reticulocyte index, and stool examination for occult blood.
• The earliest and most sensitive laboratory change for IDA is decreased serum ferritin, interpreted with decreased transferrin saturation and increased total iron-binding capacity (TIBC); Hb, hematocrit (Hct), and RBC indices remain normal until late stages.
• Macrocytic anemias show mean corpuscular volume usually elevated to greater than 100 fL.
• Vitamin B12 and folate concentrations help differentiate between deficiency anemias.
• A vitamin B12 value less than 200 pg/mL (<148 pmol/L), along with appropriate peripheral smear and clinical symptoms, is diagnostic of vitamin B12 deficiency.
• A decreased RBC folate concentration (<150 ng/mL [<340 nmol/L]) appears to be a better indicator of folate-deficiency than a decreased serum folate concentration (<3 ng/mL [<7 nmol/L]).
• AI diagnosis is usually one of exclusion.
• Serum iron is usually decreased; serum ferritin is normal or increased, and TIBC is decreased, unlike IDA.
• Bone marrow reveals an abundance of iron; peripheral smear reveals normocytic anemia.
• Elderly patients with symptomatic anemia should undergo a CBC with peripheral smear and reticulocyte count.
• Diagnosing anemia in pediatric populations requires age- and sex-adjusted norms for lab values.

Treatment

Goals of Treatment

• Alleviate signs and symptoms, correct the underlying etiology, restore necessary substrates for RBC production, replace body stores, and prevent long-term complications.

Iron Deficiency Anemia (IDA)

Major Causes

• Inadequate dietary intake, especially in young infants (18 months to 3 years), those in poverty, and those with poor nutrition.
• Increased physiological iron requirements for growth, prematurity, rapid growth in adolescence, and pregnancy (third trimester).
• Reduced iron absorption due to celiac disease, post-gastrectomy, and gluten-induced enteropathy.
• Blood loss includes menstruation, menorrhagia, gastrointestinal malignancy, and chronic hemorrhage (salicylate and non-steroidal anti-inflammatory drugs, and hookworm infection).
• Serum ferritin concentration correlates with body iron stores; serum ferritin of < 15 mg/L is virtually specific for iron deficiency.
• Serum ferritin being an acute-phase reactant, a normal result does not exclude it.
• In chronic diseases, ferritin < 50 mg/L may be associated with reduced storage iron, while ferritin > 50 mg/L generally indicate the presence of iron stores.
• Soluble transferrin receptor measurements help differentiate iron deficiency from chronic disease anemia.

Oral Iron Therapy

• Oral iron therapy with soluble ferrous iron salts, not enteric coated or slow/sustained release, is recommended at a daily dosage of 150 to 200 mg elemental iron divided in two or three doses.
• Iron preparations are the preferred treatment due to effectiveness, safety, and low cost.
• Iron can be administered as simple iron salts (e.g., ferrous sulfate, fumarate, or gluconate) or in saccharated form.
• Administration of 200 mg ferrous sulfate three times daily provides 180 mg elemental iron, with up to 30% absorption.
• Hemoglobin will increase by 1 g in the first week; a 2 g/dL rise after 3 weeks suggests adequate response.
• Daily administration for 1–3 months will correct anemia due to iron deficiency.
• Therapy should continue for 3 months, until hemoglobin normalizes and iron stores are replenished (serum ferritin > 50 m/L).
• Liquid iron formulations for children can stain teeth and include ferrous sulfate solution (5 mL contains 12 mg elemental iron), iron polymaltose solutions, and polysaccharide-iron complex (5 mL contains 100 mg elemental iron).
• Prophylactic oral iron during pregnancy, gastrectomy, for patients receiving erythropoietin due to chronic renal disease, pernicious anemia, or low-birth-weight/premature infants.
• Lower doses of oral iron (e.g., 200 mg ferrous sulfate daily) are prescribed.

Pharmacology

• Ferrous sulfate replaces iron stores found in hemoglobin, myoglobin, and enzymes; allows oxygen transport via hemoglobin.
• Bioavailability: 5-10% (20-30% during deficiency).
• Reticulocytosis onset: 3-10 days; increased hemoglobin value: 2-4 weeks.
• Iron vital in transport proteins (hemoglobin, myoglobin) and enzymes (CYP450s, catalase, peroxidase, metalloflavoproteins).
• Storage in the reticuloendothelial system and bone marrow.
• Total body iron content is 3.5-4.5 g in an adult, with 70% in hemoglobin, 5% in myoglobin, and 0.2% in enzymes.
• About 25% of iron is stored as ferritin or hemosiderin.
• About 2% (80mg) comprises the 'labile iron pool' and about 0.08% (3 mg) is bound to transferrin (a specific iron-binding protein).

Parenteral Iron

• Parenteral iron is rarely indicated and should only be administered if there is proven iron deficiency and oral iron cannot be tolerated, ongoing blood loss so severe that oral therapy is insufficient to maintain iron stores, and inadequate gastrointestinal iron absorption.
• Parenteral iron formulations include iron dextran (ferric hydroxide complexed with dextrans, 50 mg/mL), administered via deep intramuscular injection, slow intravenous injection or infusion.
• Iron sucrose (ferric hydroxide complexed with sucrose, 20 mg/mL) is delivered via slow intravenous injection or infusion and is not recommended for children.
• Iron is best absorbed from meat, fish, and poultry.
• Administer iron 1 hour before meals because food interferes with absorption, though administration with food may be needed to improve tolerability.
• Consider parenteral iron for patients with iron malabsorption, intolerance of oral iron therapy, or non-adherence.
• To estimate Total parenteral iron needed to correct anemia:Total iron deficit Body weight [kg] x (Target Hb – Actual Hb) [g/l] x 2.4 + Iron stores [mg] ;500 mg iron for iron stores is recommended if the body weight is above 35 kg.
• Add 600 mg iron (women) or 1000 mg (men) to replenish stores.
• Carboxymaltose is available in parenteral iron preparations with similar efficacy but different molecular sizes, pharmacokinetics, bioavailability, and adverse effect profiles.

Malabsorption

• Folate deficiency may be unmasked by effective iron therapy; it is likely in pregnancy due to fetal requirements.

Factors Reducing Oral Iron Absorption

• Partial gastrectomy reduces gastric acid and iron deficiency is more common than vitamin B12 deficiency.
• Drug-iron binding interactions; tetracyclines chelate iron, causing malabsorption; oral bisphosphonates and magnesium trisilicate reduce iron absorption.

Adverse Effects

Oral Iron

• Nausea, epigastric pain, diarrhea, and constipation.
• Can be reduced with lower doses, divided doses, alternative salts (ferrous gluconate), and/or taking iron with food.

Intravenous Iron

• Include immediate, severe, potentially life-threatening anaphylactoid reactions, fever, and arthropathy, therefore monitor closely during administration, and facilities for cardiopulmonary resuscitation should be available.
• History of allergic disorders including asthma, eczema, and anaphylaxis is a contraindication.

Intramuscular Iron

• Painful, may permanently stain skin.
• Less severe manifestations include urticaria, rashes, and nausea; delayed reactions such as arthralgia, myalgia, and fever.
• Has been associated with soft tissue sarcomas.
• Avoid oral iron preparations 24 hours prior or 5 days after intravenous iron to prevent adverse reactions from saturation of transferrin binding capacity.

Drug Interactions

• Iron chelates drugs, including tetracyclines, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, norfloxacin, and ofloxacin, reducing absorption.
• Iron also forms stable complexes with thyroxine, captopril, and bisphosphonates; separate administration by 2 hours.
• Ascorbic acid increases iron absorption, though not clinically important routinely.
• Antacids, tea (tannins), and bran reduce iron absorption.

Vitamin B12 Deficiency Anemia

Causes

• Inadequate dietary intake (elderly and vegans).
• Pernicious anemia due to autoimmune destruction of gastric parietal cells, producing atrophic mucosa and reduced intrinsic factor secretion.
• Malabsorption syndromes.
• Drugs including metformin, aminosalicylic acid, nicotine, phenytoin, and high-dose vitamin C.
• Subclinical disease.
• Megaloblastic anemia (macrocytic anemia with oval macrocytes and hypersegmented neutrophils).
• Subacute combined degeneration of the brain, spinal cord, and peripheral nerves.

Treatment

• Oral vitamin B12 supplementation is effective, even in pernicious anemia, due to the B12 absorption pathway being indepedent from intrinsic factors; Initiate oral cobalamin at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daily.
• Parenteral therapy is recommended if neurologic symptoms are present.
• Regimen of IM cyanocobalamin 1000 mcg daily for 1 week, then weekly for 1 month, and then monthly.
• Initiate daily oral cobalamin administration after symptoms resolve.

Contraindications

• Vitamin B12 should not be administered for undiagnosed anemia.
• Proper hematological and biochemical workup is essential prior to therapy.
• A single dose can interfere with the hematological picture for weeks and result in delayed diagnosis.

Folate Deficiency Anemia

• Deficiency of folic acid causes megaloblastic anemia, impairing purine/pyrimidine production, essential for DNA.
• Features are indistinguishable from Vitamin B12 deficiency.
• It is critical to determine which hematic is deficient, because an incorrect treatment can have severe consequences.
• Folic acid supplements may specifically accelerate progression of subacute combined degeneration of the spinal cord because of vitamin B12 deficiency.

Treatment

• Oral folate, 1 mg daily for 4 months, is usually sufficient, unless the etiology cannot be corrected.
• With malabsorption, a 1 to 5 mg daily dose may be needed.

Anemia of Inflammation (AI)

• Treatment is less specific than other anemias and should correct reversible causes.
• Reserve iron therapy for IDA, iron is not effective when inflammation is present.
• Limit RBC transfusions to inadequate oxygen transport episodes and Hb of 7 to 8 g/dL (70-80 g/L; 4.34-4.97 mmol/L).
• Erythropoiesis-stimulating agents (ESAs) can be considered, but response may be impaired (off-label).
• The initial dosage for epoetin alfa is 50 to 100 units/kg three times weekly and darbepoetin alfa 0.45 mcg/kg once weekly.
• ESA use may result in iron deficiency and ESA therapy is supplemented with oral iron therapy.

Adverse Effects of AI Treatment

• Increases in blood pressure, nausea, headache, fever, bone pain, and fatigue.
• Hb must be monitored.
• Hemoglobin increases greater than 12 g/dL (>120 g/L; >7.45 mmol/L) or greater than 1 g/dL (>10 g/L; >0.62 mmol/L) every 2 weeks are associated with increased mortality and cardiovascular events.
• In patients with anemia of critical illness, parenteral iron is associated with a theoretical infection risk.
• Routine use of ESAs or RBC transfusions is not supported by clinical studies.

Anemia in Pediatric Populations

• Infants Aged 9–12 Months: Administer iron sulfate 3–6 mg/kg/day (elemental iron) divided once or twice daily between meals for 4 weeks; continue for two months to replace iron pools.
• Titrate Vitamin B12 dose/schedule based on clinical and lab responses; use 1 mg daily dose of folate.

Evaluation of Therapeutic Outcomes

IDA

• Modest reticulocytosis in few days with Hb increase by 2 weeks implies positive response to oral Fe therapy.
• Reevaluate treatment if reticulocytosis does not occur.
• Hb should normalize after 2 months, and continue treatment up to 12 months until iron replenished and ferritin normalized

Megaloblastic Anemia

• Signs/symptoms should improve within days after starting with vitamin B12/folate treatment and use can treat neurologic symptoms.

Common Responses

• Reticulocytosis should occur within 3 to 5 days.
• Hb begins to rise a week after starting vitamin B12 treatment and should normalize in 1 to 2 months.
• Hct should rise within 2 weeks after starting folate treatment and should normalize within 2 months.
• Reticulocytosis should occur within a few days.
• Monitor iron, TIBC, transferrin saturation, and ferritin levels at baseline and when periodic during therapy.
• Discontinue ESAs if a clinical response does not occur after 8 weeks.
• Pediatrics: Monitor Hb, Hct, and RBC indices in 4 to 8 weeks, and premature infants should be checked weekly.