Nutritional Deficiency Anemias

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Nutritional Deficiency Anemias

• Darshan Mehta, MD
• Department of Internal Medicine
• University of Illinois-Chicago

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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

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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).

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Classification of anemias by MCV

• Microcytic (lt80 fL)  
• Iron deficiency  
• Thalassemia 
• Anemia of chronic disease
• Macrocytic (gt100 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

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Initial Evaluation

• 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

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Nutrient Roles in Erythropoesis
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Iron Stores

• 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
• Iron stored in body primarily as protein
  complexes (ferritin and hemosiderin)

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Nutritional Iron Balance

• 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

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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 irongt Organic iron (Ferrous gluconate) gt
  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

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Dietary Sources of Iron

• Red meat gt 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

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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

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Iron Deficiency Anemia

• 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

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Causes of Iron Deficiency

• 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

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Iron Deficiency Anemia

• Hypochromic red cell
• Microcytic cell
• Target cell

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Stages of Iron Deficiency
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Treatment of Iron Deficiency

• Red Blood Cell Transfusion
• Oral Iron Therapy
• Ferrous sulfate
• Ferrous fumarate
• Ferrous gluconate
• Parenteral Iron

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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
  45 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

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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

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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

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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

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Megaloblastic Anemia

• Macrocytic RBC
• Hypersegmented Neutrophil

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Vitamin B12 Absorption Oral Phase
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Vitamin B12 Absorption Gastric Phase
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Vitamin B12 Absorption Intestinal Phase
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Vitamin B12 Deficiency

• Any interruption along this path can result in
  cobalamin deficiency
• Gastrectomy results in low production of IF
• Terminal ileal resection (gt100 cm), decreases the
  site of absorption of B12-IF complex

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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

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Diagnosis of Vitamin B12 Deficiency

• Macrocytosis
• Peripheral blood smear
• Cobalamin levels
• Elevated serum methylmalonic acid and
  homocysteine levels
• Schilling Test

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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

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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 gt 7 of radiolabeled B12

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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

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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

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Stage 4

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

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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

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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

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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

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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

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Diagnosis of folate deficiency

• Peripheral blood and bone marrow biopsy look
  exactly like B12 deficiency
• Plasma folate lt3 ng/mlfluctuates with recent
  dietary intake
• RBC folatemore reliable of tissue stores lt140
  ng/ml
• Only increased serum homocysteine levels but NOT
  serum methylmalonic acid levels

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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 14
  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

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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