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

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Presentation on theme: "Nutritional Deficiency Anemias Darshan Mehta, MD Department of Internal Medicine University of Illinois-Chicago."— Presentation transcript:

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

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

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

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

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

6 Nutrient Roles in Erythropoesis

7 Iron Stores Humans contain ~2.5 g of iron, with 2.0 - 2.5 g circulating as part of heme in hemoglobin Humans contain ~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 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) Iron stored in body primarily as protein complexes (ferritin and hemosiderin)

8 Nutritional Iron Balance Intake Intake Dietary iron intake Dietary iron intake Medicinal iron Medicinal iron Red cell transfusions Red cell transfusions Injection of iron complexes Injection of iron complexes Excretion 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

9 Iron Absorption Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories) 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 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) 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 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 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% 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 Takes place in the mucosa of the proximal small intestine Absorption increase to 20% in iron-deficient persons Absorption increase to 20% in iron-deficient persons

10 Dietary Sources of Iron Red meat > poultry & fish Red meat > poultry & fish In U.S., 20 mg iron added/lb of flour In U.S., 20 mg iron added/lb of flour Baked bread contains ~28 mg iron/kg Baked bread contains ~28 mg iron/kg Equivalent to the iron content of beef Equivalent to the iron content of beef Iron cooking pots Iron cooking pots Plants are generally not good sources because of oxalate, phytate, tannins, etc. 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 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 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 Absorption of about 1 mg/d is required from the diet in men, 1.4 mg/d in women to maintain homeostasis

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

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

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

16 Stages of Iron Deficiency

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

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

19 Megaloblastic Anemia Due to impaired DNA synthesis Due to impaired DNA synthesis Affects cells primarily having relatively rapid turnover, especially hematopoietic precursors and gastrointestinal epithelial cells 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. 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 Megaloblastic erythroid progenitors tend to be destroyed in the marrow Marrow cellularity is often increased but production of red blood cells (RBC) is decreased Marrow cellularity is often increased but production of red blood cells (RBC) is decreased

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

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

22 Megaloblastic Anemia Macrocytic RBC Macrocytic RBC Hypersegmented Neutrophil 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 Any interruption along this path can result in cobalamin deficiency Gastrectomy results in low production of IF Gastrectomy results in low production of IF Terminal ileal resection (>100 cm), decreases the site of absorption of B12-IF complex Terminal ileal resection (>100 cm), decreases the site of absorption of B12-IF complex

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

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

29 Schilling Test Measures B12 deficiency Measures B12 deficiency Detects IF 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 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 Oral dose of radiolabeled cobalamin given simultaneously with an IM injection unlabeled cobalamin 24 Hour Urine collection 24 Hour Urine collection Amount radiolabeled activity is measured Amount radiolabeled activity is measured Normal absorption of B12 and normal renal function will excrete > 7% of radiolabeled B12 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 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 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 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 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 If pancreatic insufficiency exists, B12 malabsorption may occur Normalization after pancreatic enzyme therapy suggests pancreatic origin Normalization after pancreatic enzyme therapy suggests pancreatic origin

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

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

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

37 Stages of folate deficiency 1. Negative folate balance (decreased serum folate) 2. Decreased RBC folate levels and hypersegmented neutrophils 3. Macroovalocytes, increased MCV, and decreased hemoglobin

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

39 Treatment of folate deficiency Oral replacement therapy Oral replacement therapy Folate prophylaxis 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 B 12 deficiency anemia can be temporarily corrected by folate supplementation However, this does not correct the neurologic deficits Folate “draws” vitamin B 12 away from neurologic system for RBC production and can exacerbate combined systems degeneration


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