Pharmacology of Hematinics (Iron, Vitamin B12, Folic Acid)

1. Introduction/Overview

Hematinics constitute a fundamental class of therapeutic agents essential for the synthesis of hemoglobin and the normal maturation of erythrocytes. These substances, primarily comprising iron, vitamin B₁₂ (cobalamin), and folic acid, serve as critical substrates or cofactors in biochemical pathways governing erythropoiesis. Deficiencies in any one of these hematinic factors can lead to distinct yet sometimes overlapping forms of anemia, characterized by impaired red blood cell production and resultant tissue hypoxia. The clinical management of these deficiency states represents a cornerstone of hematological therapeutics, with implications spanning general medicine, obstetrics, pediatrics, and geriatrics. A thorough understanding of their pharmacology is therefore indispensable for rational prescribing and optimal patient outcomes.

The global burden of anemia, largely attributable to iron deficiency, underscores the profound clinical relevance of this topic. Beyond simple replacement therapy, the pharmacology of hematinics involves complex regulatory mechanisms of absorption, transport, and cellular utilization. Furthermore, the therapeutic application of these agents extends beyond the treatment of overt deficiency to include prophylactic use in high-risk populations and, in the case of folic acid, the prevention of specific congenital malformations. The interplay between these nutrients, particularly vitamin B₁₂ and folic acid, presents unique diagnostic and therapeutic challenges that necessitate precise pharmacological knowledge.

Learning Objectives

• Describe the biochemical roles of iron, vitamin B₁₂, and folic acid in erythropoiesis and other critical cellular functions.
• Explain the mechanisms of action, including molecular and cellular pharmacodynamics, for each major hematinic agent.
• Compare and contrast the pharmacokinetic profiles of oral and parenteral iron, vitamin B₁₂, and folic acid, including factors influencing absorption and disposition.
• Identify the approved therapeutic indications, common adverse effects, and significant drug interactions associated with hematinic therapy.
• Formulate appropriate therapeutic strategies for hematinic use in special populations, including pregnant patients, pediatric and geriatric individuals, and those with renal or hepatic impairment.

2. Classification

Hematinics are classified based on their chemical nature and specific role in hematopoiesis. The primary classification distinguishes between agents that are integral components of the hemoglobin molecule and those that act as essential coenzymes in nucleic acid synthesis required for cell division in the erythroid lineage.

Chemical and Functional Classification

1. Iron Preparations:

Iron is administered in ferrous (Fe²⁺) or ferric (Fe³⁺) forms. Oral preparations are predominantly ferrous salts due to their superior absorbability.

• Oral Iron Salts: Ferrous sulfate, ferrous gluconate, ferrous fumarate, ferrous succinate, and polysaccharide-iron complexes.
• Parenteral Iron Formulations:
  • Iron Dextran: High molecular weight and low molecular weight complexes.
  • Iron Sucrose: A complex of ferric hydroxide in sucrose.
  • Sodium Ferric Gluconate: A ferric hydroxide-gluconate complex.
  • Ferric Carboxymaltose: A ferric hydroxide complex with carboxymaltose.
  • Iron Isomaltoside: A ferric hydroxide complex with isomaltoside.

2. Vitamin B₁₂ (Cobalamin) Preparations:

These are classified based on the ligand attached to the cobalt atom in the corrin ring. The active coenzyme forms are methylcobalamin and adenosylcobalamin, while therapeutic preparations are typically stable analogs.

• Cyanocobalamin: A synthetic, stable form that is converted in the body to active cofactors. It is the most common form used in oral and parenteral preparations.
• Hydroxocobalamin: A natural form with greater protein-binding affinity and longer tissue retention, often preferred for intramuscular injection, especially in cases of cyanide poisoning or pernicious anemia.
• Methylcobalamin: An active coenzyme form available in some oral and parenteral formulations.

3. Folic Acid and Folates:

Folic acid refers specifically to pteroylmonoglutamic acid, the synthetic, oxidized form used in supplements and fortified foods. Naturally occurring folates in food are reduced polyglutamate forms.

• Folic Acid (Pteroylmonoglutamic Acid): The standard synthetic supplement.
• Folinic Acid (Leucovorin, 5-formyltetrahydrofolate): A reduced, active folate that does not require dihydrofolate reductase for activation. It is used clinically to bypass methotrexate inhibition and in other specific settings.
• L-Methylfolate (5-Methyltetrahydrofolate): The primary circulating and biologically active form, available as a medical food or supplement for individuals with genetic polymorphisms in folate metabolism.

3. Mechanism of Action

The mechanisms of action for hematinics are deeply rooted in fundamental biochemistry, where each agent fulfills a non-redundant role. Their pharmacodynamic effects are primarily mediated through incorporation into functional molecules or service as indispensable cofactors for enzymes critical for DNA synthesis and cellular metabolism.

Iron

Iron’s principal mechanism is its incorporation into heme, the oxygen-binding prosthetic group of hemoglobin, myoglobin, and cytochromes. Heme synthesis occurs in the mitochondria of erythroid precursors, requiring the insertion of ferrous iron into protoporphyrin IX by the enzyme ferrochelatase. Beyond erythropoiesis, iron is a critical component of iron-sulfur clusters found in enzymes of the mitochondrial electron transport chain (e.g., NADH dehydrogenase, succinate dehydrogenase) and other proteins involved in redox reactions and energy metabolism. Iron also serves as a cofactor for ribonucleotide reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides, a rate-limiting step in DNA synthesis. The therapeutic effect in iron deficiency anemia is the restoration of normal hemoglobin synthesis, leading to the production of normocytic, normochromic red blood cells and correction of tissue iron stores.

Vitamin B₁₂ (Cobalamin)

Vitamin B₁₂ functions as a coenzyme for two crucial mammalian enzymes:

1. Methionine Synthase (Methyltransferase): Methylcobalamin serves as an intermediate methyl carrier in this reaction, which catalyzes the conversion of homocysteine to methionine. This reaction has dual significance. First, it regenerates methionine, required for protein synthesis and for the synthesis of S-adenosylmethionine (SAM), the universal methyl donor for numerous methylation reactions involving DNA, RNA, proteins, and neurotransmitters. Second, it concurrently regenerates tetrahydrofolate (THF) from methyl-THF, thus linking vitamin B₁₂ and folate metabolism. Impairment of this reaction traps folate as methyl-THF, leading to a functional folate deficiency (“methylfolate trap”) and inhibiting purine and thymidine synthesis.
2. L-Methylmalonyl-CoA Mutase: Adenosylcobalamin is the cofactor for this mitochondrial enzyme, which isomerizes L-methylmalonyl-CoA to succinyl-CoA. This is a key step in the catabolism of odd-chain fatty acids and certain amino acids (valine, isoleucine, methionine, threonine) into the citric acid cycle. Deficiency leads to accumulation of methylmalonic acid, a diagnostic marker, and may contribute to neurological dysfunction.

The hematological manifestations of B₁₂ deficiency (megaloblastic anemia) are primarily a consequence of the impaired methionine synthase activity and the resultant disruption of DNA synthesis. Neurological complications, including subacute combined degeneration of the spinal cord, are thought to arise from a combination of impaired methylation reactions critical for myelin maintenance and possibly the accumulation of toxic metabolites like methylmalonic acid.

Folic Acid

Folic acid, after reduction to its active tetrahydrofolate (THF) forms, acts as a carrier of one-carbon units (methyl, methylene, formyl, formimino, methenyl) in numerous biosynthetic reactions. Its most critical roles in hematopoiesis involve:

• De Novo Purine Synthesis: THF cofactors are required at two steps: the transfer of a formyl group for the synthesis of the purine ring precursors, specifically in the formation of glycinamide ribonucleotide (GAR) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR).
• Pyrimidine Synthesis (Thymidylate Synthesis): The enzyme thymidylate synthase uses 5,10-methylenetetrahydrofolate as both a one-carbon donor and a reductant to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). This is the sole de novo pathway for thymidine production, a nucleotide unique to DNA.

Deficiency of folate leads to impaired DNA synthesis, causing slowing of nuclear maturation while cytoplasmic development proceeds normally. This nuclear-cytoplasmic asynchrony results in megaloblastic changes in rapidly dividing cells, most prominently in the bone marrow, leading to the production of large, oval-shaped erythrocytes (macrocytic anemia) with hypersegmented neutrophils. The mechanism is identical to that seen in vitamin B₁₂ deficiency due to the functional folate deficiency induced by the methylfolate trap.

4. Pharmacokinetics

Iron

Absorption: Iron absorption is a tightly regulated process occurring primarily in the duodenum and proximal jejunum. Heme iron from meat sources is absorbed more efficiently (15-35%) via a specific heme transporter. Non-heme inorganic iron (Fe³⁺) must first be reduced to the ferrous (Fe²⁺) state by duodenal cytochrome B (DcytB) before transport across the enterocyte apical membrane by the divalent metal transporter 1 (DMT1). Absorption is enhanced by an acidic environment (gastric acid), ascorbic acid, and amino acids, while it is inhibited by phytates, phosphates, tannins (in tea), calcium, and antacids. The hormone hepcidin, produced by the liver, is the master regulator of iron homeostasis; it downregulates iron absorption and release from macrophages by inducing the internalization and degradation of ferroportin, the sole cellular iron exporter. In iron deficiency, hepcidin levels are low, enhancing absorption.

Distribution: Absorbed iron is either stored within the enterocyte as ferritin or exported into plasma via ferroportin. In plasma, ferrous iron is oxidized to ferric iron by ceruloplasmin and bound to transferrin, the plasma transport protein. Transferrin-bound iron is delivered to tissues, especially bone marrow erythroid precursors, which express high levels of transferrin receptor 1 (TfR1). Iron is stored in hepatocytes and reticuloendothelial macrophages as ferritin or hemosiderin.

Metabolism and Excretion: Iron has no specific excretory pathway. Minimal amounts are lost through sloughing of enterocytes, skin cells, and in sweat. The primary route of iron loss is through blood loss (menstruation, gastrointestinal bleeding). The body conserves iron efficiently through recycling by macrophages that phagocytose senescent erythrocytes. Pharmacokinetic parameters for oral iron are highly variable. For parenteral iron, the complex is taken up by the reticuloendothelial system, where iron is released from the carbohydrate shell and enters the plasma transferrin pool. The half-life of the iron-carbohydrate complex itself varies: iron sucrose (t_1/2 ≈ 6 hours), ferric carboxymaltose (t_1/2 ≈ 16 hours), and iron dextran (t_1/2 > 20 hours).

Vitamin B₁₂

Absorption: This is a complex, multi-step process requiring intact gastric, pancreatic, and ileal function. Dietary B₁₂ is bound to proteins and must be released by gastric acid and pepsin. It then binds to R-binders (haptocorrins) from saliva. In the duodenum, pancreatic proteases degrade the R-binders, releasing B₁₂ to bind with intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells. The IF-B₁₂ complex is resistant to digestion and travels to the terminal ileum, where it binds to cubam receptors (cubilin and amnionless) on ileal enterocytes for receptor-mediated endocytosis. A small fraction (≈1%) is absorbed by passive diffusion across the entire intestinal tract, which is the basis for high-dose oral therapy in malabsorption states. Hydroxocobalamin exhibits greater protein binding and longer retention than cyanocobalamin.

Distribution: In plasma, transcobalamin II (TCII) binds the absorbed B₁₂ and mediates its delivery to all cells. A significant portion is also bound to transcobalamin I (haptocorrin). The liver serves as the primary storage site, holding several years’ worth of B₁₂. The volume of distribution is approximately 0.4 L/kg.

Metabolism and Excretion: Within cells, cyanocobalamin is decyanated to hydroxocobalamin and then converted to the active coenzymes, methylcobalamin and adenosylcobalamin. Vitamin B₁₂ undergoes enterohepatic circulation. The terminal half-life of cyanocobalamin in plasma is approximately 6 days, but the biological half-life from hepatic stores is on the order of 1-2 years. Excretion is primarily via bile, with most being reabsorbed; a small amount is lost in urine.

Folic Acid

Absorption: Dietary folates exist as polyglutamates. Intestinal brush-border conjugase enzymes hydrolyze these to monoglutamates before absorption, which occurs primarily in the proximal jejunum via the proton-coupled folate transporter (PCFT) and the reduced folate carrier (RFC). Synthetic folic acid (pteroylmonoglutamate) is absorbed rapidly and completely via a saturable, carrier-mediated process at physiological doses (≤ 400 µg). At pharmacological doses (> 1 mg), a significant portion is absorbed via passive diffusion. Absorption is optimal at a slightly acidic pH and can be impaired by certain drugs (e.g., sulfasalazine, anticonvulsants) and in malabsorptive disorders.

Distribution: Absorbed folate is reduced and methylated in the enterocyte to 5-methyltetrahydrofolate (5-MTHF), the primary circulating form. It is transported bound loosely to albumin. Folate distributes widely to all tissues, with uptake mediated by the RFC and other transporters. The total body store of folate is relatively small (5-20 mg), sufficient for only 2-4 months.

Metabolism and Excretion: Intracellular folates are reconverted to polyglutamate forms to be retained and enhance coenzyme activity. Folate is actively taken up by the renal tubules but is also excreted in urine, especially when plasma levels exceed the renal reabsorption threshold. A significant amount is also excreted in bile and undergoes enterohepatic recirculation. Unmetabolized folic acid may appear in plasma and urine following high-dose supplementation. The plasma half-life of folate is short (a few hours), but the turnover of body stores is slower.

5. Therapeutic Uses/Clinical Applications

Iron

• Iron Deficiency Anemia (IDA): The primary indication. Oral iron is first-line for uncomplicated IDA. Parenteral iron is reserved for cases of oral intolerance, malabsorption, non-compliance, chronic kidney disease (especially with erythropoiesis-stimulating agents), inflammatory bowel disease with active disease, heavy ongoing blood loss, or when a rapid repletion is needed (e.g., late pregnancy, pre-operative).
• Prophylaxis: Routine supplementation is recommended during pregnancy. It may also be considered in populations with high risk of deficiency, such as infants with low birth weight, menstruating individuals with heavy blood loss, and patients with chronic kidney disease.
• Restless Legs Syndrome: Intravenous iron may be effective in patients with low or low-normal ferritin levels.
• Heart Failure: Intravenous iron (particularly ferric carboxymaltose) is indicated in patients with chronic heart failure and iron deficiency (with or without anemia) to improve exercise capacity and symptoms.

Vitamin B₁₂

• Pernicious Anemia: An autoimmune condition with atrophy of gastric mucosa and loss of intrinsic factor, necessitating lifelong parenteral (intramuscular or subcutaneous) or high-dose oral B₁₂ replacement.
• Other Causes of B₁₂ Deficiency: Including malabsorption syndromes (celiac disease, Crohn’s disease), gastric bypass surgery, chronic pancreatitis, fish tapeworm (Diphyllobothrium latum) infestation, and strict vegan diet without supplementation.
• Prophylaxis: Recommended following total gastrectomy or ileal resection.
• Cyanide Poisoning: Hydroxocobalamin is a first-line antidote, as it binds cyanide to form cyanocobalamin, which is excreted renally.
• Hereditary Deficiency Disorders: Such as Imerslund-Gräsbeck syndrome (cubilin/amnionless defect) or transcobalamin II deficiency.

Folic Acid

• Megaloblastic Anemia due to Folate Deficiency: Caused by nutritional deficiency, malabsorption, increased requirements (pregnancy, hemolytic anemias), or drug-induced (methotrexate, trimethoprim, phenytoin).
• Prevention of Neural Tube Defects (NTDs): Periconceptional supplementation (at least 400 µg/day) significantly reduces the risk of spina bifida and anencephaly. Higher doses (4-5 mg/day) are recommended for women with a previous NTD-affected pregnancy.
• Prophylaxis in Chronic Hemolytic Anemias: (e.g., sickle cell disease, hereditary spherocytosis) where erythropoietic turnover is high.
• Methotrexate “Rescue”: Folinic acid (leucovorin) is administered after high-dose methotrexate to “rescue” normal cells from folate antagonism, limiting toxicity while allowing the antineoplastic effect on tumor cells.
• Hyperhomocysteinemia: Folic acid, often with B₁₂ and B₆, is used to lower plasma homocysteine levels, though the cardiovascular benefit of this intervention remains uncertain.

6. Adverse Effects

Iron

Oral Iron: Gastrointestinal side effects are common and dose-related, including nausea, epigastric pain, constipation, diarrhea, and dark-colored stools. These effects often limit adherence. Taking iron with food can reduce irritation but also decreases absorption.

Parenteral Iron: Adverse reactions can be classified as:

1. Minor infusion reactions: Myalgia, arthralgia, flushing, headache, nausea. These are often self-limiting.

2. Hypersensitivity reactions: Ranging from urticaria and pruritus to life-threatening anaphylaxis. The risk is historically highest with high-molecular-weight iron dextran, leading to the requirement of a test dose. Newer complexes (iron sucrose, ferric carboxymaltose) have a lower incidence of serious reactions but are not risk-free.

3. Laboratory disturbances: Transient elevation in serum ferritin and transferrin saturation; hypophosphatemia is a notable and sometimes prolonged effect of ferric carboxymaltose, potentially leading to osteomalacia in severe, chronic cases.

4. Extravasation: Can cause persistent brown skin staining and local tissue irritation.

Iron Overload (Hemosiderosis/Hemochromatosis): A serious risk of chronic excessive iron administration, leading to deposition in the liver, heart, pancreas, and endocrine glands, causing organ dysfunction (cirrhosis, cardiomyopathy, diabetes). This is a particular concern in patients with hereditary hemochromatosis or transfusion-dependent anemias.

Vitamin B₁₂

Vitamin B₁₂ is generally very safe and well-tolerated, even at high doses, due to its water-soluble nature and efficient renal excretion.

• Hypersensitivity: Rare allergic reactions to injectable formulations (cyanocobalamin or hydroxocobalamin) or their preservatives (e.g., benzyl alcohol) have been reported, manifesting as urticaria, itching, or anaphylaxis.
• Transient Reactions: Mild, transient diarrhea, polycythemia vera exacerbation, and peripheral vascular thrombosis have been reported rarely.
• Hypokalemia: Rapid regeneration of erythrocytes during treatment of severe megaloblastic anemia can cause a sudden intracellular shift of potassium, leading to hypokalemia, which requires monitoring.
• Acneiform Eruptions: Particularly associated with hydroxocobalamin therapy.

Folic Acid

Folic acid is also exceptionally safe at standard doses.

• Masks Vitamin B₁₂ Deficiency: This is the most significant adverse effect from a clinical perspective. High-dose folic acid (> 0.4 mg/day) can correct the hematological abnormalities (megaloblastic anemia) of vitamin B₁₂ deficiency while allowing the neurological damage (subacute combined degeneration) to progress undetected and untreated. This underscores the necessity of ruling out B₁₂ deficiency before initiating folic acid therapy for anemia.
• Gastrointestinal Effects: Nausea, anorexia, bloating, and flatulence can occur, especially at high doses.
• Allergic Reactions: Rash, pruritus, erythema, and bronchospasm are rare.
• Neurological Effects: Sleep disturbances, vivid dreams, irritability, and exacerbation of seizure frequency in epileptic patients, particularly those on phenobarbital or phenytoin, have been reported.
• Potential Cancer Risk: Epidemiological studies have raised questions about high folic acid intake potentially promoting the growth of pre-existing neoplasms (e.g., colorectal adenomas), though evidence remains inconclusive and controversial.

7. Drug Interactions

Iron

• Antacids, H2-Receptor Antagonists, Proton-Pump Inhibitors: By increasing gastric pH, they reduce the solubility and conversion of ferric to ferrous iron, impairing absorption.
• Tetracyclines, Fluoroquinolones, Bisphosphonates, Levothyroxine: Oral iron can form insoluble complexes with these drugs in the gastrointestinal tract, drastically reducing the absorption of both agents. Administration should be separated by at least 2-4 hours.
• Cholestyramine: May bind iron and decrease its absorption.
• Ascorbic Acid (Vitamin C): Enhances iron absorption by reducing ferric iron to the more soluble ferrous form and by forming absorbable complexes.
• Chloramphenicol: May delay the hematological response to iron therapy by inhibiting erythroid maturation.

Vitamin B₁₂

• Metformin, Proton-Pump Inhibitors, H2-Receptor Antagonists: Long-term use can interfere with B₁₂ absorption, likely by altering intestinal calcium-dependent membrane processes or reducing intrinsic factor secretion, potentially leading to deficiency.
• Aminoglycosides, Colchicine, Para-aminosalicylic Acid, Neomycin: May impair intestinal absorption of B₁₂.
• Nitrous Oxide: Anesthetic exposure oxidizes and inactivates the cobalt atom in methylcobalamin, inhibiting methionine synthase activity. Acute or chronic exposure can precipitate or exacerbate B₁₂ deficiency neuropathy.
• Folic Acid: As described, high doses can mask the hematological signs of B₁₂ deficiency.

Folic Acid

• Antiepileptic Drugs (Phenytoin, Phenobarbital, Primidone, Carbamazepine): These drugs may impair folate absorption and metabolism. Conversely, folic acid supplementation can reduce serum levels of these anticonvulsants, potentially leading to loss of seizure control.
• Methotrexate, Trimethoprim, Pyrimethamine: These drugs are dihydrofolate reductase inhibitors, creating a functional folate deficiency. Folic acid or folinic acid supplementation is used to mitigate toxicity without reversing therapeutic effect (in the case of methotrexate for autoimmune diseases, low-dose folic acid is used; for cancer chemotherapy, folinic acid rescue is employed).
• Sulfasalazine: Inhibits folate absorption and conversion to its active forms.
• Oral Contraceptives: May lower serum folate levels, though clinical significance is debated.
• Zinc: High-dose folic acid supplementation may interfere with zinc absorption.

8. Special Considerations

Pregnancy and Lactation

Iron: Requirements increase significantly during pregnancy (≈1000 mg total). Prophylactic oral iron (27-30 mg elemental iron daily) is routinely recommended to prevent maternal anemia and adverse fetal outcomes (preterm birth, low birth weight). Parenteral iron is safe and effective for treating IDA in pregnancy when oral therapy fails. Iron is excreted minimally in breast milk, and supplementation in lactating individuals is generally safe.

Vitamin B₁₂: Deficiency during pregnancy is associated with neural tube defects and adverse neurodevelopmental outcomes in the offspring. Vegan and vegetarian mothers are at high risk. Supplementation is safe and essential in deficient individuals. B₁₂ is excreted in breast milk; adequate maternal intake ensures sufficient levels for the infant.

Folic Acid: Periconceptional folic acid supplementation (400-800 µg/day) is a standard public health recommendation to prevent neural tube defects. For women with a previous NTD-affected pregnancy, a dose of 4-5 mg/day is advised. Folic acid is considered safe during pregnancy and lactation, and adequate intake is crucial for supporting rapid cell proliferation.

Pediatric Considerations

Iron: Full-term infants are born with adequate stores for 4-6 months. Iron-fortified formula or supplementation is recommended for breastfed infants after 4 months. Preterm and low-birth-weight infants have lower stores and require earlier and often higher-dose supplementation. Liquid formulations of oral iron are used, with care to avoid dental staining. Dosage is based on mg of elemental iron per kg of body weight.

Vitamin B₁₂ and Folic Acid: Deficiencies are rare in healthy children with balanced diets but can occur in those with restrictive diets, malabsorption, or inborn errors of metabolism. Dosing is weight-based. In infants born to B₁₂-deficient mothers, deficiency can present with severe neurological impairment and failure to thrive, requiring prompt treatment.

Geriatric Considerations

This population is at increased risk for deficiencies due to multiple factors: poor dietary intake, atrophic gastritis (leading to reduced acid and intrinsic factor), polypharmacy (with drugs like PPIs and metformin), and chronic diseases. A high index of suspicion is required. Oral iron may be poorly tolerated due to GI side effects or constipation. Parenteral iron may be advantageous. Neurological manifestations of B₁₂ deficiency can mimic dementia, making diagnosis and treatment critical.

Renal and Hepatic Impairment

Renal Impairment: Patients with chronic kidney disease (CKD), especially those on dialysis, frequently have anemia of chronic disease combined with iron deficiency due to blood loss and impaired mobilization. Intravenous iron is a mainstay of therapy, often co-administered with erythropoiesis-stimulating agents. Dosing intervals for some IV iron products may need extension in severe renal impairment. Folic acid and B₁₂ are removed by dialysis and require replacement; however, routine high-dose supplementation is not typically needed unless a deficiency is documented.

Hepatic Impairment: The liver is central to iron storage and the synthesis of hepcidin, transferrin, and other proteins. In advanced liver disease, iron metabolism is often dysregulated. Iron supplementation should be used with caution and only in cases of documented deficiency, as there is a risk of exacerbating iron overload. Vitamin B₁₂ and folate stores may be reduced in chronic liver disease due to poor intake or malabsorption.

9. Summary/Key Points

• Hematinics (iron, vitamin B₁₂, folic acid) are essential for DNA synthesis and hemoglobin production. Deficiencies lead to distinct anemias: microcytic hypochromic (iron), macrocytic megaloblastic (B₁₂ and folate).
• Iron is absorbed as Fe²⁺ via DMT1 in the duodenum, regulated by hepcidin. It is incorporated into heme and iron-sulfur clusters. Oral iron is first-line for IDA; parenteral formulations are used for intolerance, malabsorption, or rapid correction.
• Vitamin B₁₂ absorption is complex, requiring intrinsic factor and ileal receptors. It acts as a cofactor for methionine synthase and methylmalonyl-CoA mutase. Deficiency causes megaloblastic anemia and potentially irreversible neurological damage. Treatment is typically parenteral or high-dose oral.
• Folic acid, after conversion to THF, carries one-carbon units for purine and thymidine synthesis. Deficiency causes megaloblastic anemia. Periconceptional supplementation prevents neural tube defects. It can mask the hematological signs of B₁₂ deficiency.
• Major adverse effects include GI intolerance with oral iron, hypersensitivity with IV iron, and the risk of B₁₂ deficiency masking with folic acid.
• Significant drug interactions exist: antacids/PPIs reduce iron absorption; metformin/PPIs can cause B₁₂ deficiency; anticonvulsants interact with folate; and iron chelates several drugs (tetracyclines, levothyroxine).
• Special populations require tailored approaches: routine iron and folate in pregnancy; vigilance for deficiency in the elderly and those with CKD; and weight-based dosing in pediatrics.

Clinical Pearls

• Always investigate the underlying cause of a hematinic deficiency (e.g., GI blood loss for iron, pernicious anemia for B₁₂) rather than simply replacing the nutrient.
• Measure serum ferritin as the most specific indicator of iron stores; a level < 30 µg/L is diagnostic of iron deficiency in most clinical settings.
• Check serum B₁₂ and folate levels before initiating therapy for macrocytic anemia. If B₁₂ deficiency is suspected, measure methylmalonic acid and homocysteine, which are elevated even in early, subclinical deficiency.
• In a patient with megaloblastic anemia, never treat with folic acid alone without first excluding B₁₂ deficiency to avoid precipitating neurological deterioration.
• For oral iron, advise taking it on an empty stomach with ascorbic acid (e.g., orange juice) for best absorption, but if GI side effects occur, taking it with food is acceptable to improve adherence despite reduced absorption.
• The response to hematinic therapy is characterized by a reticulocyte count peak in 5-10 days, followed by a rise in hemoglobin of about 1-2 g/dL per week. Iron therapy should continue for 3-6 months after hemoglobin normalizes to replenish stores.

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