L-7 Iron Deficiency Anemia Case Study

• Hematopoietic pharmacology is focused on drugs used to treat anemias.

Case Study 1: Iron Deficiency Anemia (IDA)

• Alice, a 40-year-old woman, presents with concerns about OTC products like Aleve (naproxen) causing IDA, bleeding.
• She reports belly pain, fatigue, and has been using OTC Aleve for arthritis, increasing from twice daily to two tablets twice daily over 7 months.
• Burning pain starts after meals, unrelieved by antacids. Patient has a history of peptic ulcer disease (PUD), prescribed ranitidine PRN.
• Family history includes a mother with peptic ulcer disease.
• Current meds include Aleve (naproxen) and Mylanta, moderate alcohol consumption.
• Head, eyes, ears, nose, throat are normal.
• Stool showed fecal occult blood (FOB).
• Lab results showed hypochromic microcytic RBC and RBC count of 3.4 x 10³/mm³ (normal 4.7 to 6.1 for males).
• An assessment includes possible IDA secondary to NSAID-induced gastropathy and EGD with biopsy.
• The final diagnosis was IDA from NSAID-induced gastritis.
• Treatment plan included Ranitidine + iron.
• Hgb increased from 9.93 g/dL to 14.2 g/dL over six months (normal 13-17.5 for men, 12-15.5 for women).
• Hematocrit % improves from 29% to 42% in 6 months.
• MCV measures 78-90 micrometer³ (normal 80-100 millions/microL).
• Transferrin saturated 24 to 42 (normal 170-370 mg/dL).
• Ferritin ranges from 69 to 163 (12 to 300 ng/mL normal).
• Stool guaiac test is negative.
• Ascorbate can increase iron absorption by chelating with ferric iron.

Case: Vitamin B12 Deficiency

• Larry, a 70-year-old man reports feeling terrible for a year.
• Lab testing reveals B12 levels less than 200pg/mL, high methyl malonic acid, and high homocysteine. Normal range is 200-900pg/ml
• Blood smear shows macrocytic anemia with megaloblastic changes.
• There is ventricular dysfunction, CNS issues occur with cobalamin deficiency.
• Treatment lasts a few months.

Case: Folate Deficiency

• Kenny, an 85-year-old man, presents with irritability and restlessness.
• RBC folate level is 33 ng/ml (normal is 165 to 760) with B12 also checked.
• Folate in serum is normal at 2-10ng/ml (less than 3 is severe).

Goals for Anemia Treatment

• Understand the mechanism of absorption of iron, folic acid and vitamin B12.
• Identify biochemical systems impaired in B12 and folic acid deficiencies.
• Understand why folic acid corrects erythropoietic lesions but not neurological lesions in pernicious anemia.
• Know the physiologic role of iron.
• Symptoms associated with iron toxicity.
• Treatment alternatives for aplastic anemia.
• Functions, clinical uses, and side effects of erythropoietin and other hematopoietic growth factors.

Prototype Drugs Discussed

• Vitamin B12 deficiency anemia: Oral and parenteral Vitamin B12 (cobalamin).
• Folic acid deficiency anemia: Folic acid.
• Iron deficiency anemia: Iron dietary supplements and Parenteral Iron Therapy.
• Iron toxicity: Deferoxamine.
• Anemia of Chronic Disease: Erythropoietin.
• Anemia of Chronic renal failure: Erythropoietin.
• Bone Marrow Deficiency states: Colony-stimulating factors.

Iron Metabolism

• Iron is a component of hemoglobin, myoglobin, and cytochrome enzymes, important for oxygen transport, muscle iron storage, and cellular energy.
• Average adult contains 4 g of iron, with two-thirds in hemoglobin, 13% in myoglobin, and the rest in ferritin and hemosiderin.
• Diet: 12 to 15 mg of iron daily, in ferric non-absorbed form (Fe3+), ionized by stomach, then reduced to ferrous state (Fe2+) for absorption in duodenum.
• Daily losses: 1 mg in adult males/post-menopausal females, 1.5 to 3 mg in menstruating females.
• Children and pregnant women have increased iron demands.
• Intestinal epithelial cells absorb inorganic iron via divalent metal transporter 1 (DMT1) and heme iron via heme carrier protein 1 (HCP1).
• Absorbed or released heme iron is transported into blood by ferroportin (FP) and stored as ferritin (F).
• Iron in blood is transported by transferrin (Tf) to erythroid precursors in bone marrow for hemoglobin (Hgb) synthesis in RBCs, or to hepatocytes for ferritin storage.
• The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes for internalization.
• After iron release, TfR-Tf complex is recycled.
• Macrophages phagocytize senescent erythrocytes (RBC), reclaim iron from RBC hemoglobin, and export it or store it as ferritin.
• Transferrin receptor density is regulated based on the iron requirement of specific cells.
• Iron is stored within macrophages of the reticuloendothelial system as ferritin or hemosiderin. Ferritin consists of a ferric hydroxy-phosphate core and protein shell called apoferritin.
• Older RBCs broken down in spleen and marrow by phagocytic breakdown resulting in amino acids and porphyrin.
• Porphyrin heme splits to iron that returns to iron pool, and to biliverdin that reduces to bilirubin.
• Bilirubin is released into plasma, binds to albumin, transported to liver for glucuronide conjugation, and excreted via bile.

Iron Deficiency Anemia (IDA)

• About 25% of anemia patients have IDA often due to inadequate diet/absorption, increased demands, blood loss, certain diseases, NSAIDs, decreased animal protein/ascorbic acid, chronic alcoholism, prolonged illness, poor nutrition.
• IDA is associated with increased risk of infections and developmental delays.
• Oral preparations: Ferrous sulfate, Ferrous fumarate, Ferrous choline citrate, ferrous gluconate, and polysaccharide iron complex.
• Absorption varies with food, orange juice doubles absorption, while tea and coffee reduce it by half.
• Maximal iron absorption occurs in reduced ferrous form in duodenum where stomach acid stops iron precipitating.
• Iron forms insoluble complexes preventing absorption in alkaline environments.
• Preferred iron preparations non-enteric coated ferrous.
• IDA patients are administered approximately 200 mg iron daily in divided doses.
• Therapy can be done with food for patients who experience nausea and vomiting when administered on an empty stomach.
• A hemoglobin level of less than 3gms over a 3-week period is unacceptable and further evaluation is necessary.
• Therapeutic doses increase hemoglobin values by approximately 1gm per week. To restore complete iron stores, it may require 3 to 6 months of therapy.
• Parenteral Iron Forms: Iron dextran, INFED, Dexferrum, and Pri-Dextra, Sodium ferric gluconate complex-Ferrlecit, Iron Sucrose (Venofer).
• Iron-deficiency anemia patients with malabsorption syndromes or patients intolerant to oral iron preparations, a combination of ferric hydroxide and dextran is used parenterally (intramuscular or intravenous by multiple slow injections) in 50mg/ml.
• When given intravenous the dose must not exceed 50mg of iron per minute and not to exceed 100 mg or iron dextran daily.
• Sodium ferric gluconate complex in sucrose (Ferrlecit) is approved by the FDA for use in the US in chronic renal disease.
• Iron sucrose has been found to produce fewer anaphylactic reactions than iron dextran.
• After Iron sucrose (Venofer) administration, iron sucrose is approved for iron deficiency anemia in chronic hemodialysis patients who are receiving supplemental erythropoietin therapy.
• Parenteral iron administration restores iron stores rapidly when compared to oral administration and may take months for replenishent.
• Blood transfusions treat IDA but are used with extreme caution.
• Adverse Reactions include arthralgias, myalgias, flushing malaise and fever.
• Parenteral formulations are reserved for those who are intolerant or not able to take oral formulations.
• GI upsets and local irritation.
• Discoloration of feces, constipation, diarrhea, nausea and vomiting are all seen with iron therapy.
• IM administration can cause discomfort, necrosis and atrophy.

Iron Toxicity and Treatment

• Being an OTC drug, it remains a major poisoning in children that results in organ damage.
• Toxicity occurs due to 1) direct corrosive effect on mucosal tissue resulting in necrosis and perforation and 2) Cellular toxicities due to lactic acidosis.
• Clinical presentation of toxicity includes bloody vomiting, Diarrhea, massive fluid and blood loss into Gl tract that may cause shock, renal failure and death.
• Even after survival abrupt relapse with coma, seizures, metabolic acidosis, and hepatic failure.
• Treatment includes proper ventilation, administration of deferoxamine (from streptomyces), a chelating agent that chelates iron, excreted renally with orange or pink-red urine.

Megaloblastic Anemias

• Megaloblastosis results from interference in in folic acid and vitamin B12 that will interfere with nucleic acid synthesis.
• Dietary folates are absorbed and in a series of reactions catalyzed by vitamin B12, dietary folates are converted to 5-methyl tetrahydrofolate which is then converted via a B12 reaction to THF. After gaining a carbon, THF is converted to a folate cofactor (5, 10 methylene tetrahydrofolate). Thymidylate synthetase enzyme uses 5, 10 METHF to synthesize nucleic acids. DHF is converted to THF and can be used again to produce 5, 10 METHF.

Vitamin B12 (Cyanocobalamin) Deficiency Anemia

• Pernicious anemia has an annual incidence of 1 in 10000.
• Causes include inadequate intake, decreased absorption, and inadequate utilization.
• The ultimate source of vitamin B12 is from microbial synthesis.
• Other vitamin B12 sources are meat especially liver, eggs and dairy products.
• Cobalamin can be absorbed by both an intrinsic factor-dependent and intrinsic factor-independent route.
• Deficiency results from low dietary levels or poor intestinal absorption; due to poor receptor mediated uptake or transport in the distal ileum.

Iron deficiency Anemia

• Decrease in production of intrinsic factor causes congenital pernicious anemia.
• Patients can have normal B12 levels, yet present clinical evidence of B12 deficiency.

Oral B12 Therapy

• Treats pernicious is done in larger doses; Cobalamin is absorbed by "intrinsic factor-dependent" as well as "intrinsic factor-independent" pathways.
• Parenteral B12 therapy recommended 800 to 1000 micro-g of cyanocobalamin or hydroxocobalamin for 1 to 2 weeks and then monthly injections.
• Hydroxocobalamin, preferred as it is highly protein bound.
• Vitamin B12 deficiencies can be treated with intranasal cyanocobalamin formulations (Nascobal).
• Most patients respond rapidly to therapy; bone marrow becomes normoblastic after 24 hours, reticulocytosis is evident within a few days, the hemoglobin begins to rise after the first week, and the leukocytes and platelet counts normalize after 7 days.
• Potential adverse effects of B12-induced reticulocytosis include hyperuricemia and hypokalemia, sodium retention and rebound thrombocytosis.

Neurological Problems with B12 Deficiency

• Alterations in vibratory and position sense.
• Memory loss.
• Ataxia.
• Demyelination.
• Neuronal cell death.
• Paresthesia.

Folic Acid Deficiency Anemia

• Folic acid functions as a cofactor in the synthesis of purines and pyrimidines of DNA biosynthesis.
• Major causes of deficiency include inadequate intake, decreased absorption, hyper-utilization, and inadequate utilization.
• Folate deficiency caused by (a) increased demand in pregnancy and lactation, hemolytic anemia, malignancy (b) poor absorption due to intestinal malfunctions, (c) alcoholism and (d) use of drugs that are dihydrofolate reductase blockers
• Section 1 shows the vitamin B12-dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin B12 deficiency.
• Section 2 shows the deoxythymidine monophosphate (dTMP) cycle.
• Section 3 shows shows the pathway by which folic acid enters the tetrahydrofolate cofactor pool.

Treatment of Folic Acid Deficiency Anemia

• Administer 1-5 mg daily, is well absorbed in the small intestine for 4 months.
• Food sources include yeast, liver, kidney and green vegetables.
• Prophylactic folate therapy during pregnancy may be a useful preventive measure for megaloblastic anemias.
• Vitamin supplementation (800 to 1000 micrograms daily) Folic acid(Folvite), oral preparation, Leucovorin : Oral and parenteral as Calcium salt (Wellcovorin).

Remember

• Symptoms associated with folate-deficiency are similar to those of vitamin B12 deficiency; major difference between two disease entities is relative absence of neurological manifestations in folate deficiency.
• Folic acid alone can mask the B12 deficiency and result in B12 related irreversible neurological dysfunction and disease.
• Therefore megaloblastic anemia should be best treated with a combination of folate and cyanocobalamin.

Use of Erythropoietin (EPO)

• EPO are used in the treatment of anemias of chronic disease, associated with infectious, inflammatory, hepatic is used in the treatment of chronic renal failure.
• Darbepoetin Alfa (Aranesp)
• Epoetin Alfa (Epogen), and Epoetin Beta (NeoRecormon, Beceumen, Epoch, Epogin etc.)
• Recombinant erythropoietin was released by the FDA in 1989.
• Erythropoietin is a 34,000 MW glycosylated protein.
• Administration of recombinant human erythropoietin is effective in treating the anemias of renal failure, anemias of AIDS and anemias of chronic diseases, and AIDS with the half-life of approximately 10 hours. Subcutaneous injections result in peak plasma levels in 5-24 hours.
• It also decreases the need for allogenic blood transfusion in surgery patients .
• Erythropoietin is also useful for the treatment of anemia due to primary bone marrow disorders and secondary anemias; anemia is not indicated for patients needing immediate correction of severe anemia.
• Major side effect with epoetin is elevated diastolic pressure in 30-47%.
• Iron deficiency may arise
• Causes thrombosis if hematocrit rises rapidly
• Causes seizures for people with preexisting disorders.

Myeloid Growth Factors

• In the treatment of endothelial cells marrow fibroblasts and Colony Stimulating Factors.
• Granulocyte CSF (r-HuG-CSF, Filgrastim, Neupogen is the synthetic form-bacterial recombinant product)
• Granulocyte macrophage CSF (r-HuGM-CSF, Sargramostim, Leukine is the synthetic form-yeast recombinant product)
• Pegfilgrastim (Neulasta), filgrastim conjugated with PEG for longer 1/2 life
• Used in short-term treatment for primary bone marrow deficiency that increase neutrophil counts.