Nutritional Deficiency Anemias

1. Nutritional Deficiency Anemias Darshan Mehta, MD Department of Internal Medicine University of Illinois-Chicago

2. Anemia • Definition • Reduction in blood transport of oxygen due to a deficiency in red blood cells • Parameters of Anemia • Hematocrit – Percentage of blood volume as RBCs • Hemoglobin – Concentration of hemoglobin in blood • Mean Corpuscular Volume (MCV) – Average size of RBC • Mean Corpuscular Hemoglobin (MCH) – Average hemoglobin content of RBC • RDW – range of deviation around average

3. Mechanisms of Anemia • Marrow production defects (hypoproliferation) • Low reticulocyte count • Little or no change in red cell morphology (a normocytic, normochromic anemia • Red cell maturation defects (ineffective erythropoiesis) • Slight to moderately elevated reticulocyte count • Macrocytic or microcytic anemia • Decreased red cell survival (blood loss/ hemolysis).

4. Microcytic (<80 fL)   Iron deficiency   Thalassemia  Anemia of chronic disease Macrocytic (>100 fL) Vitamin B12 deficiency Folate deficiency   Myelodysplasia Chemotherapy Liver disease    Increased reticulocytosis Myxedema Normocytic Anemia of chronic disease Aplasia Protein-energy malnutrition Chronic renal failure Post-hemorrhagic Classification of anemias by MCV

5. History and Physical Exam Eating ice or clay Dyspnea Conjunctival pallor Chest Pain Medications Laboratory evaluation CBC with differential Peripheral Smear Reticulocyte count Iron Studies Initial Evaluation

6. Nutrient Roles in Erythropoesis

7. Iron Stores • Humanscontain ~2.5 g of iron, with 2.0 - 2.5 g circulating as part of heme in hemoglobin • Another ~0.3 g found in myoglobin, in heme in cytochromes, and in Fe-S complexes • Iron stored in body primarily as protein complexes (ferritin and hemosiderin)

8. Intake Dietary iron intake Medicinal iron Red cell transfusions Injection of iron complexes Excretion Gastrointestinal bleeding Menses Losses can be as much as 4 - 37mg/menstrual cycle Other forms of bleeding Loss of epidermal cells from the skin and gut Nutritional Iron Balance

9. Iron Absorption • Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories) • Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed • Heme iron> Organic iron (Ferrous gluconate) > Inorganic iron (ferrous sulfate) • Average iron intake in an adult male is 15 mg/d with 6% absorption; average female, the daily intake is 11 mg/d with 12% absorption • Acid pH and presence of reducing agents: ascorbic acid (vitamin C) reduces Fe+++ to Fe++ which promotes passage across intestinal mucosa • Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50% • Takes place in the mucosa of the proximal small intestine • Absorption increase to 20% in iron-deficient persons

10. Dietary Sources of Iron • Red meat > poultry & fish • In U.S., 20 mg iron added/lb of flour • Baked bread contains ~28 mg iron/kg • Equivalent to the iron content of beef • Iron cooking pots • Plants are generally not good sources because of oxalate, phytate, tannins, etc. • Spinach has a lot of iron, but has ~780 mg oxalate/100 g Note - Heme iron absorption from diet not affected by ascorbate or phytate

11. Iron Exchange • 80% of iron passing through the plasma transferrin pool is recycled from broken-down red cells • Absorption of about 1 mg/d is required from the diet in men, 1.4 mg/d in women to maintain homeostasis

12. Facts and Figures Most common cause of anemia 500 million cases worldwide Prevalence is higher in less developed countries Unique Physical Exam findings Cheilosis fissures at the corners of the mouth Koilonychia spooning of the fingernails Iron Deficiency Anemia

14. Increased demand for iron and/or hematopoiesis Rapid growth in infancy or adolescence Pregnancy Erythropoietin therapy Increased iron loss Chronic blood loss Menses Acute blood loss Blood donation Phlebotomy as treatment for polycythemia vera Decreased iron intake or absorption Inadequate diet Malabsorption from disease (sprue, Crohn's disease) Malabsorption from surgery (post-gastrectomy) Acute or chronic inflammation Causes of Iron Deficiency

15. Iron Deficiency Anemia • Hypochromic red cell • Microcytic cell • Target cell

16. Stages of Iron Deficiency

17. Treatment of Iron Deficiency • Red Blood Cell Transfusion • Oral Iron Therapy • Ferrous sulfate • Ferrous fumarate • Ferrous gluconate • Parenteral Iron

18. Iron Supplementation in special populations • Pregnant Women • During the last two trimesters, daily iron requirements increase to 5 to 6 mg • Infancy • Normal-term infants are born with sufficient iron stores to prevent iron deficiency for the first 4–5 months of life • Thereafter, enough iron needs to be absorbed to keep pace with the needs of rapid growth • Nutritional iron deficiency is most common between 6 and 24 months of life

19. Megaloblastic Anemia • Due to impaired DNA synthesis • Affects cells primarily having relatively rapid turnover, especially hematopoietic precursors and gastrointestinal epithelial cells • Cell division is sluggish, but cytoplasmic development progresses normally, so megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. • Megaloblastic erythroid progenitors tend to be destroyed in the marrow • Marrow cellularity is often increased but production of red blood cells (RBC) is decreased

20. Causes of Megaloblastic Anemia • Vitamin B12 Deficiency • Inadequate intake: vegans (rare)  • Malabsorption  • Defective release of cobalamin from food  • Gastric achlorhydria • Partial gastrectomy • Drugs that block acid secretion  • Inadequate production of intrinsic factor (IF)  • Pernicious anemia • Total gastrectomy • Disorders of terminal ileum • Sprue • Regional enteritis • Intestinal resection • Competition for cobalamin  • Fish tapeworm (Diphyllobothrium latum) • Bacteria: "blind loop" syndrome  • Drugs: p-aminosalicylic acid, colchicine, neomycin

21. Clinical Manifestations of Vitamin B12 Deficiency • Hematologic • Macrocytic Anemia • Gastrointestinal • Glossitis • Anorexia • Diarrhea • Neurologic (found in 3/4th of individuals with pernicious anemia) • Numbness and paresthesia in the extremities, Weakness, Ataxia • Sphincter disturbances • Disturbances of mentation • Mild irritability and forgetfulness to severe dementia or frank psychosis. • Demyelination, Axonal degeneration, and then Neuronal death • Last stage is irreversible

22. Megaloblastic Anemia • Macrocytic RBC • Hypersegmented Neutrophil

23. Vitamin B12 Absorption – Oral Phase

24. Vitamin B12 Absorption – Gastric Phase

25. Vitamin B12 Absorption – Intestinal Phase

26. Vitamin B12 Deficiency • Any interruption along this path can result in cobalamin deficiency • Gastrectomy results in low production of IF • Terminal ileal resection (>100 cm), decreases the site of absorption of B12-IF complex

27. Pernicious Anemia • Most common cause of cobalamin deficiency • Caused by the absence of IF • Atrophy of the mucosa • Autoimmune destruction of parietal cells • Seen in individuals of northern European descent and African Americans • Men and women are equally affected • Disease of the elderly, the average patient presenting near age 60

28. Diagnosis of Vitamin B12 Deficiency • Macrocytosis • Peripheral blood smear • Cobalamin levels • Elevated serum methylmalonic acid and homocysteine levels • Schilling Test

29. Schilling Test • Measures B12 deficiency • Detects IF deficiency • Detects abnormal results in patients with genetic defects in B12 absorption, bacterial overgrowth of the small bowel, resection/bypass of terminal ileum, and pancreatic insufficiency

30. Stage 1 • Oral dose of radiolabeled cobalamin given simultaneously with an IM injection unlabeled cobalamin • 24 Hour Urine collection • Amount radiolabeled activity is measured • Normal absorption of B12 and normal renal function will excrete > 7% of radiolabeled B12

31. Stage 2 • If stage 1 is abnormal, then test is repeated following 60 mg of oral IF • If the level of urinary radiolabeled B12 normalizes, then this indicates pernicious anemia

32. Stage 3 • Small intestine bacterial overgrowth may cause B12 malabsorption and an abnormal result in stage 1 that is not corrected with IF administration in stage 2 • Broad spectrum antibiotics are given for one week to eliminate intestinal bacteria and then stage 1 should normalize

33. Stage 4 • If pancreatic insufficiency exists, B12 malabsorption may occur • Normalization after pancreatic enzyme therapy suggests pancreatic origin

34. Causes of Megaloblastic Anemia • Folate Deficiency • Inadequate intake: unbalanced diet (common in alcoholics, teenagers, some infants)  • Increased requirements  • Pregnancy • Infancy • Malignancy • Increased hematopoiesis (chronic hemolytic anemias) • Chronic exfoliative skin disorders • Hemodialysis  • Malabsorption  • Sprue • Drugs: Phenytoin, barbiturates, (?) ethanol   • Impaired metabolism • Inhibitors of dihydrofolate reductase: methotrexate, pyrimethamine, triamterene, pentamidine, trimethoprim • Alcohol • Rare enzyme deficiencies: dihydrofolate reductase, others

35. Treatment of Vitamin B12 Deficiency • Replacement therapy • Parenteral treatment given weekly intramuscularly for 8 weeks, followed by intramuscularly every month for the rest of the patient's life. • Daily oral replacement therapy

36. Folate Deficiency • More often malnourished than those with cobalamin deficiency • Gastrointestinal manifestations • More widespread and more severe than those of pernicious anemia • Diarrhea is often present • Cheilosis • Glossitis • Neurologic abnormalities do not occur

37. Stages of folate deficiency • Negative folate balance (decreased serum folate) • Decreased RBC folate levels and hypersegmented neutrophils • Macroovalocytes, increased MCV, and decreased hemoglobin

38. Diagnosis of folate deficiency • Peripheral blood and bone marrow biopsy look exactly like B12 deficiency • Plasma folate <3 ng/ml—fluctuates with recent dietary intake • RBC folate—more reliable of tissue stores <140 ng/ml • Only increased serum homocysteine levels but NOT serum methylmalonic acid levels

39. Treatment of folate deficiency • Oral replacement therapy • Folate prophylaxis • Women planning pregnancy are advised to take 400 g folic acid daily before conception and until 12 weeks of pregnancy to prevent neural-tube defects (5 mg/day for women with a previous affected pregnancy) • Folate fortification of cereal grains at 1·4 mg/kg has been made mandatory in the USA as an additional method of improving the folate status of the population. • Prophylactic folate is also recommended in other states of increased demand such as long-term hemodialysis and chronic haemolytic disorders

40. Inappropriate Treatment of Pernicious Anemia With Folate • Vitamin B12 deficiency anemia can be temporarily corrected by folate supplementation • However, this does not correct the neurologic deficits • Folate “draws” vitamin B12 away from neurologic system for RBC production and can exacerbate combined systems degeneration