Nutritional Deficiency Nutritional Deficiency AnemiasAnemias

Darshan Mehta, MDDarshan Mehta, MD

Department of Internal Department of Internal MedicineMedicine

University of Illinois-ChicagoUniversity of Illinois-Chicago

AnemiaAnemia

DefinitionDefinition Reduction in blood transport of oxygen due to a Reduction in blood transport of oxygen due to a

deficiency in red blood cellsdeficiency in red blood cells Parameters of AnemiaParameters of Anemia

Hematocrit – Percentage of blood volume as RBCsHematocrit – Percentage of blood volume as RBCs Hemoglobin – Concentration of hemoglobin in Hemoglobin – Concentration of hemoglobin in

bloodblood Mean Corpuscular Volume (MCV) – Average size Mean Corpuscular Volume (MCV) – Average size

of RBCof RBC Mean Corpuscular Hemoglobin (MCH) – Average Mean Corpuscular Hemoglobin (MCH) – Average

hemoglobin content of RBChemoglobin content of RBC RDW – range of deviation around averageRDW – range of deviation around average

Mechanisms of AnemiaMechanisms of Anemia

Marrow production defects (Marrow production defects (hypoproliferationhypoproliferation)) Low reticulocyte countLow reticulocyte count Little or no change in red cell morphology (a Little or no change in red cell morphology (a

normocytic, normochromic anemia normocytic, normochromic anemia Red cell maturation defects (Red cell maturation defects (ineffective ineffective

erythropoiesiserythropoiesis)) Slight to moderately elevated reticulocyte count Slight to moderately elevated reticulocyte count Macrocytic or microcytic anemiaMacrocytic or microcytic anemia

Decreased red cell survival (Decreased red cell survival (blood loss/ blood loss/ hemolysishemolysis). ).

Classification of anemias by Classification of anemias by MCVMCV

Microcytic (<80 fL)  Microcytic (<80 fL)   Iron deficiency  Iron deficiency   Thalassemia Thalassemia  Anemia of chronic Anemia of chronic

diseasedisease Macrocytic (>100 fL)Macrocytic (>100 fL)

Vitamin B12 deficiencyVitamin B12 deficiency Folate deficiency  Folate deficiency   MyelodysplasiaMyelodysplasia ChemotherapyChemotherapy Liver disease   Liver disease    Increased Increased

reticulocytosisreticulocytosis MyxedemaMyxedema

NormocyticNormocytic Anemia of chronic Anemia of chronic

diseasedisease AplasiaAplasia Protein-energy Protein-energy

malnutritionmalnutrition Chronic renal failureChronic renal failure Post-hemorrhagicPost-hemorrhagic

Initial EvaluationInitial Evaluation

History and History and Physical ExamPhysical Exam Eating ice or clayEating ice or clay DyspneaDyspnea Conjunctival pallorConjunctival pallor Chest PainChest Pain MedicationsMedications

Laboratory Laboratory evaluationevaluation CBC with CBC with

differentialdifferential Peripheral SmearPeripheral Smear Reticulocyte countReticulocyte count Iron StudiesIron Studies

Nutrient Roles in Nutrient Roles in ErythropoesisErythropoesis

Iron StoresIron Stores

HumansHumans contain ~2.5 g of iron, with contain ~2.5 g of iron, with 2.0 - 2.5 g circulating as part of 2.0 - 2.5 g circulating as part of heme in hemoglobinheme in hemoglobin

Another ~0.3 g found in myoglobin, Another ~0.3 g found in myoglobin, in heme in cytochromes, and in Fe-S in heme in cytochromes, and in Fe-S complexescomplexes

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

Nutritional Iron BalanceNutritional Iron Balance

IntakeIntake Dietary iron intakeDietary iron intake Medicinal iron Medicinal iron Red cell Red cell

transfusions transfusions Injection of iron Injection of iron

complexes complexes

ExcretionExcretion Gastrointestinal Gastrointestinal

bleedingbleeding MensesMenses

Losses can be as Losses can be as much as 4 - much as 4 - 37mg/menstrual cycle37mg/menstrual cycle

Other forms of Other forms of bleedingbleeding

Loss of epidermal Loss of epidermal cells from the skin cells from the skin and gut and gut

Iron AbsorptionIron Absorption Dietary iron content is closely related to total caloric intake Dietary iron content is closely related to total caloric intake

(approximately 6 mg of elemental iron per 1000 calories)(approximately 6 mg of elemental iron per 1000 calories) Iron bioavailability is affected by the nature of the foodstuff, Iron bioavailability is affected by the nature of the foodstuff,

with heme iron (e.g., red meat) being most readily absorbedwith heme iron (e.g., red meat) being most readily absorbed Heme iron> Organic iron (Ferrous gluconate) > Inorganic iron Heme iron> Organic iron (Ferrous gluconate) > Inorganic iron

(ferrous sulfate)(ferrous sulfate) Average iron intake in an adult male is 15 mg/d with 6% Average iron intake in an adult male is 15 mg/d with 6%

absorption; average female, the daily intake is 11 mg/d with absorption; average female, the daily intake is 11 mg/d with 12% absorption12% absorption Acid pH and presence of reducing agents:Acid pH and presence of reducing agents: ascorbic acid ascorbic acid

(vitamin C) reduces Fe(vitamin C) reduces Fe+++ +++ to Feto Fe++ ++ which promotes passage which promotes passage across intestinal mucosaacross intestinal mucosa

Vegetarians are at an additional disadvantage because Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50% reduce iron absorption by about 50%

Takes place in the mucosa of the proximal small intestineTakes place in the mucosa of the proximal small intestine Absorption increase to 20% in iron-deficient personsAbsorption increase to 20% in iron-deficient persons

Dietary Sources of IronDietary Sources of Iron

• Red meat > poultry & fishRed meat > poultry & fish

• In U.S., 20 mg iron added/lb of flourIn U.S., 20 mg iron added/lb of flour• Baked bread contains ~28 mg Baked bread contains ~28 mg

iron/kgiron/kg

• Equivalent to the iron content of Equivalent to the iron content of

beefbeef

• Iron cooking potsIron cooking pots

• Plants are generally not good Plants are generally not good sources because of oxalate, sources because of oxalate, phytate, tannins, etc. phytate, tannins, etc.

• Spinach has a lot of iron, but has Spinach has a lot of iron, but has ~780 mg oxalate/100 g~780 mg oxalate/100 g

Note - Heme iron absorption Note - Heme iron absorption from diet not affected by from diet not affected by ascorbate or phytateascorbate or phytate

Iron ExchangeIron Exchange

80% of iron passing 80% of iron passing through the plasma through the plasma transferrin pool is transferrin pool is recycled from broken-recycled from broken-down red cellsdown red cells

Absorption of about 1 Absorption of about 1 mg/d is required from mg/d is required from the diet in men, 1.4 the diet in men, 1.4 mg/d in women to mg/d in women to maintain homeostasis maintain homeostasis

Iron Deficiency AnemiaIron Deficiency Anemia

Facts and FiguresFacts and Figures Most common Most common

cause of anemiacause of anemia 500 million cases 500 million cases

worldwideworldwide Prevalence is higher Prevalence is higher

in less developed in less developed countriescountries

Unique Physical Unique Physical Exam findingsExam findings CheilosisCheilosis

fissures at the fissures at the corners of the mouthcorners of the mouth

KoilonychiaKoilonychia spooning of the spooning of the

fingernails fingernails

Causes of Iron DeficiencyCauses of Iron Deficiency Increased demand for Increased demand for

iron and/or iron and/or hematopoiesishematopoiesis Rapid growth in infancy Rapid growth in infancy

or adolescenceor adolescence PregnancyPregnancy Erythropoietin therapyErythropoietin therapy

Increased iron lossIncreased iron loss Chronic blood lossChronic blood loss MensesMenses Acute blood lossAcute blood loss Blood donationBlood donation Phlebotomy as Phlebotomy as

treatment for treatment for polycythemia verapolycythemia vera

Decreased iron intake Decreased iron intake or absorptionor absorption Inadequate dietInadequate diet Malabsorption from Malabsorption from

disease (sprue, Crohn's disease (sprue, Crohn's disease)disease)

Malabsorption from Malabsorption from surgery (post-surgery (post-gastrectomy)gastrectomy)

Acute or chronic Acute or chronic inflammationinflammation

Iron Deficiency AnemiaIron Deficiency Anemia

Hypochromic red Hypochromic red cellcell

Microcytic cellMicrocytic cell Target cellTarget cell

Stages of Iron DeficiencyStages of Iron Deficiency

Treatment of Iron DeficiencyTreatment of Iron Deficiency

Red Blood Cell TransfusionRed Blood Cell TransfusionOral Iron TherapyOral Iron Therapy

Ferrous sulfateFerrous sulfateFerrous fumarateFerrous fumarateFerrous gluconateFerrous gluconate

Parenteral IronParenteral Iron

Iron Supplementation in special Iron Supplementation in special populationspopulations

Pregnant WomenPregnant Women During the last two trimesters, daily iron During the last two trimesters, daily iron

requirements increase to 5 to 6 mg requirements increase to 5 to 6 mg InfancyInfancy

Normal-term infants are born with sufficient Normal-term infants are born with sufficient iron stores to prevent iron deficiency for the iron stores to prevent iron deficiency for the first 4–5 months of lifefirst 4–5 months of life

Thereafter, enough iron needs to be absorbed Thereafter, enough iron needs to be absorbed to keep pace with the needs of rapid growth to keep pace with the needs of rapid growth

Nutritional iron deficiency is most common Nutritional iron deficiency is most common between 6 and 24 months of life between 6 and 24 months of life

Megaloblastic AnemiaMegaloblastic Anemia Due to impaired DNA synthesisDue to impaired DNA synthesis Affects cells primarily having relatively rapid Affects cells primarily having relatively rapid

turnover, especially hematopoietic precursors turnover, especially hematopoietic precursors and gastrointestinal epithelial cellsand gastrointestinal epithelial cells

Cell division is sluggish, but cytoplasmic Cell division is sluggish, but cytoplasmic development progresses normally, so development progresses normally, so megaloblastic cells tend to be large, with an megaloblastic cells tend to be large, with an increased ratio of RNA to DNA.increased ratio of RNA to DNA.

Megaloblastic erythroid progenitors tend to be Megaloblastic erythroid progenitors tend to be destroyed in the marrowdestroyed in the marrow

Marrow cellularity is often increased but Marrow cellularity is often increased but production of red blood cells (RBC) is production of red blood cells (RBC) is decreaseddecreased

Causes of Megaloblastic Causes of Megaloblastic AnemiaAnemia

Vitamin B12 DeficiencyVitamin 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 achlorhydriaGastric achlorhydria Partial gastrectomyPartial gastrectomy Drugs that block acid secretion Drugs that block acid secretion  Inadequate production of intrinsic factor (IF) Inadequate production of intrinsic factor (IF) 

Pernicious anemiaPernicious anemia Total gastrectomyTotal gastrectomy

Disorders of terminal ileumDisorders of terminal ileum SprueSprue Regional enteritisRegional enteritis Intestinal resectionIntestinal resection

Competition for cobalamin Competition for cobalamin  Fish tapeworm (Fish tapeworm (Diphyllobothrium latumDiphyllobothrium latum)) Bacteria: "blind loop" syndrome Bacteria: "blind loop" syndrome  Drugs: Drugs: pp-aminosalicylic acid, colchicine, neomycin-aminosalicylic acid, colchicine, neomycin

Clinical Manifestations of Clinical Manifestations of Vitamin B12 DeficiencyVitamin B12 Deficiency

HematologicHematologic Macrocytic AnemiaMacrocytic Anemia

GastrointestinalGastrointestinal GlossitisGlossitis AnorexiaAnorexia DiarrheaDiarrhea

Neurologic (found in 3/4Neurologic (found in 3/4thth of individuals with pernicious of individuals with pernicious anemia)anemia) Numbness and paresthesia in the extremities, Weakness, Numbness and paresthesia in the extremities, Weakness,

AtaxiaAtaxia Sphincter disturbancesSphincter disturbances Disturbances of mentation Disturbances of mentation

Mild irritability and forgetfulness to severe dementia or frank Mild irritability and forgetfulness to severe dementia or frank psychosis. psychosis.

Demyelination, Axonal degeneration, and then Neuronal deathDemyelination, Axonal degeneration, and then Neuronal death Last stage is irreversibleLast stage is irreversible

Megaloblastic AnemiaMegaloblastic Anemia

Macrocytic RBCMacrocytic RBC HypersegmenteHypersegmente

d Neutrophild Neutrophil

Vitamin B12 Absorption – Oral Vitamin B12 Absorption – Oral PhasePhase

Vitamin B12 Absorption – Gastric Vitamin B12 Absorption – Gastric PhasePhase

Vitamin B12 Absorption – Vitamin B12 Absorption – Intestinal PhaseIntestinal Phase

Vitamin B12 DeficiencyVitamin B12 Deficiency

Any interruption along this path can Any interruption along this path can result in cobalamin deficiencyresult in cobalamin deficiencyGastrectomy results in low production of Gastrectomy results in low production of

IFIFTerminal ileal resection (>100 cm), Terminal ileal resection (>100 cm),

decreases the site of absorption of B12-decreases the site of absorption of B12-IF complexIF complex

Pernicious AnemiaPernicious Anemia

Most common cause of cobalamin Most common cause of cobalamin deficiencydeficiency

Caused by the absence of IFCaused by the absence of IF Atrophy of the mucosaAtrophy of the mucosa Autoimmune destruction of parietal cellsAutoimmune destruction of parietal cells

Seen in individuals of northern European Seen in individuals of northern European descent and African Americans descent and African Americans

Men and women are equally affectedMen and women are equally affected Disease of the elderly, the average patient Disease of the elderly, the average patient

presenting near age 60presenting near age 60

Diagnosis of Vitamin B12 Diagnosis of Vitamin B12 DeficiencyDeficiency

MacrocytosisMacrocytosisPeripheral blood smearPeripheral blood smearCobalamin levelsCobalamin levelsElevated serum methylmalonic acid Elevated serum methylmalonic acid

and homocysteine levels and homocysteine levels Schilling TestSchilling Test

Schilling TestSchilling Test

Measures B12 deficiencyMeasures B12 deficiencyDetects IF deficiency Detects IF deficiency Detects abnormal results in patients Detects abnormal results in patients

with genetic defects in B12 with genetic defects in B12 absorption, bacterial overgrowth of absorption, bacterial overgrowth of the small bowel, resection/bypass of the small bowel, resection/bypass of terminal ileum, and pancreatic terminal ileum, and pancreatic insufficiencyinsufficiency

Stage 1Stage 1

Oral dose of radiolabeled cobalamin Oral dose of radiolabeled cobalamin given simultaneously with an IM given simultaneously with an IM injection unlabeled cobalamininjection unlabeled cobalamin

24 Hour Urine collection 24 Hour Urine collection Amount radiolabeled activity is Amount radiolabeled activity is

measuredmeasuredNormal absorption of B12 and normal Normal absorption of B12 and normal

renal function will excrete > 7% of renal function will excrete > 7% of radiolabeled B12radiolabeled B12

Stage 2Stage 2

If stage 1 is abnormal, then test is If stage 1 is abnormal, then test is repeated following 60 mg of oral IFrepeated following 60 mg of oral IF

If the level of urinary radiolabeled If the level of urinary radiolabeled B12 normalizes, then this indicates B12 normalizes, then this indicates pernicious anemiapernicious anemia

Stage 3Stage 3

Small intestine bacterial overgrowth Small intestine bacterial overgrowth may cause B12 malabsorption and may cause B12 malabsorption and an abnormal result in stage 1 that is an abnormal result in stage 1 that is not corrected with IF administration not corrected with IF administration in stage 2in stage 2

Broad spectrum antibiotics are given Broad spectrum antibiotics are given for one week to eliminate intestinal for one week to eliminate intestinal bacteria and then stage 1 should bacteria and then stage 1 should normalizenormalize

Stage 4Stage 4

If pancreatic insufficiency exists, B12 If pancreatic insufficiency exists, B12 malabsorption may occurmalabsorption may occur

Normalization after pancreatic Normalization after pancreatic enzyme therapy suggests pancreatic enzyme therapy suggests pancreatic originorigin

Causes of Megaloblastic Causes of Megaloblastic AnemiaAnemia

Folate DeficiencyFolate Deficiency Inadequate intake: unbalanced diet (common in Inadequate intake: unbalanced diet (common in alcoholicalcoholics, teenagers, s, teenagers,

some infants) some infants)  Increased requirements Increased requirements 

PregnancyPregnancy InfancyInfancy MalignancyMalignancy Increased hematopoiesis (chronic hemolytic anemias)Increased hematopoiesis (chronic hemolytic anemias) Chronic exfoliative skin disordersChronic exfoliative skin disorders Hemodialysis Hemodialysis 

Malabsorption Malabsorption  SprueSprue Drugs: Phenytoin, barbiturates, (?) ethanol  Drugs: Phenytoin, barbiturates, (?) ethanol  

Impaired metabolismImpaired metabolism Inhibitors of dihydrofolate reductase: methotrexate, pyrimethamine, Inhibitors of dihydrofolate reductase: methotrexate, pyrimethamine,

triamterene, pentamidine, trimethoprim triamterene, pentamidine, trimethoprim AlcoholAlcohol Rare enzyme deficiencies: dihydrofolate reductase, othersRare enzyme deficiencies: dihydrofolate reductase, others

Treatment of Vitamin B12 Treatment of Vitamin B12 DeficiencyDeficiency

Replacement therapy Replacement therapy Parenteral treatment given weekly Parenteral treatment given weekly

intramuscularly for 8 weeks, followed by intramuscularly for 8 weeks, followed by intramuscularly every month for the rest intramuscularly every month for the rest of the patient's life.of the patient's life.

Daily oral replacement therapyDaily oral replacement therapy

Folate DeficiencyFolate Deficiency

More often malnourished than those More often malnourished than those with cobalamin deficiencywith cobalamin deficiency

Gastrointestinal manifestations Gastrointestinal manifestations More widespread and more severe than More widespread and more severe than

those of pernicious anemiathose of pernicious anemiaDiarrhea is often presentDiarrhea is often presentCheilosis Cheilosis Glossitis Glossitis

Neurologic abnormalities do not occurNeurologic abnormalities do not occur

Stages of folate deficiencyStages of folate deficiency

1.1. Negative folate balance (decreased Negative folate balance (decreased serum folate)serum folate)

2.2. Decreased RBC folate levels and Decreased RBC folate levels and hypersegmented neutrophilshypersegmented neutrophils

3.3. Macroovalocytes, increased MCV, Macroovalocytes, increased MCV, and decreased hemoglobinand decreased hemoglobin

Diagnosis of folate deficiencyDiagnosis of folate deficiency

Peripheral blood and bone marrow Peripheral blood and bone marrow biopsy look exactly like B12 deficiencybiopsy look exactly like B12 deficiency

Plasma folate <3 ng/ml—fluctuates Plasma folate <3 ng/ml—fluctuates with recent dietary intakewith recent dietary intake

RBC folate—more reliable of tissue RBC folate—more reliable of tissue stores <140 ng/mlstores <140 ng/ml

Only increased serum homocysteine Only increased serum homocysteine levels but NOT serum methylmalonic levels but NOT serum methylmalonic acid levels acid levels

Treatment of folate Treatment of folate deficiencydeficiency

Oral replacement therapyOral replacement therapy Folate prophylaxisFolate 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

Inappropriate Treatment of Pernicious Inappropriate Treatment of Pernicious Anemia With FolateAnemia 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