• Anemia = reduction in the quantity of hemoglobin or in the number of RBCs in blood relative to standards.
• Classification of Nutritional Anemias:

• Storage: Hemoglobin – 70%, storage (hemosiderin, ferritin) – 25%, plasma iron and iron-containing enzymes 5%.
• Requirements: Iron stores are not regulated by excretion. Major control is rate of intestinal absorption. Percent of iron absorbed is therefore variable (3-35%).
• Higher requirements in: infancy, adolescence, fertile females, pregnancy, premature infants.
• Sequence of Iron Deficiency:
• (1) Loss of storage iron (hemosiderin, ferritin)
• (2) Increased serum iron-binding capacity
• (3) Decreased serum iron concentration
• (4) Decreased percent transferrin (transport protein) saturation
• (5) Increased free RBC protoporphyrin (precursor of heme) – increased when iron supply is insufficient
• (6) Decreased hemoglobin (10-12 g/dL) Þ mild anemia
• (7) Decreased mean cell volume – RBC hypochromia and microcytosis with anemia
• note: Transferrin receptor (disulfide-linked transmembrane glycoprotein) plays a role in iron uptake. Though most is on cell membrane, soluble transferrin receptor (sTfR) circulates in blood and can be used as an indicator of iron deficiency when increased. Further, a lack of transferrin receptor can also lead to iron deficiency.
• Non-Hematologic Abnormalities of Iron Deficiency:
• Striated muscle dysfunction - ß work capacity.
• Behavioral changes, Impaired psychomotor development, Impaired intellectual performance – in infants and children between 6 months and 2 years of age.
• Immunity – abnormal cellular immune response, abnormal PMN function.
• Gastrointestinal - ß acid secretion, gut mucosal damage (bleeding).
• Causes of Iron-deficiency Anemia:
• Inadequate intake from diet
• Increased demand – infancy, adolescence, pregnancy
• Blood loss
• Decreased absorption – severe diarrhea, severe gut disease
• Prematurity
• Dietary Iron Sources and Factors Affecting Availability and Utilization:
• Increase in absorption of non-heme iron during pregnancy – 5 fold at week 24, 9 fold at week 36.
• Individual’s iron stores – low stores, higher percent absorption.
• Type of iron in diet – Heme iron (Hgb and Mgb in meat, fish, poultry) has higher rate of absorption than Non-Heme iron (inorganic iron salts.) Ferrous (Fe²⁺) salts absorbed best.
• Enhancing factors – factors which Ý rate of absorption of non-heme iron: ascorbic acid, and "meat factor" (identity unknown, present in beef, poultry, and fish).
• Inhibiting factors – antacids, dietary fiber.
• Iron Toxicity: Ferrous salts from supplements can be toxic to young children who ingest too much at once. This is the most common reported emergency to poison control centers.

• Function: Cu is found in a number of proteins, including cytochrome a-a₃ and ceruloplasmin (albumin-bound Cu).
• Ceruloplasmin functions as a ferroxidase enzyme converting ferrous iron to ferric iron (Fe²⁺Þ Fe³⁺).
• Fe³⁺ is the form necessary for transferrin transport. Therefore, Cu deficiency can mimic iron deficiency! Results hypochromic, microcytic anemia, which is unresponsive to iron therapy.
• Clinical: Manifestations of Cu deficiency: hypochromic, microcytic anemia, neutropenia, bone abnormalities.
• Tests: Nutritional status can be determined by measuring serum copper and serum ceruloplasmin.
• Deficiency: More common in preterm infants (reduced liver copper stores and high growth rate), infants fed cow-milk (low in copper), malnourished kids, total parenteral nutrition (often lacking/low in trace minerals), malabsorption syndromes (celiac disease, short bowel syndrome), infants with prolonged or recurrent diarrheal episodes, abnormal bile loss, intestinal resection, high oral intake of zinc decreases copper absorption (competitive inhibition), penicillamine or other cation-chelating agents, Menkes Syndrome (rare inherited defect in copper transport).

Folic Acid – pteroylglutamic acid – deficiency leads to megaloblastic anemia

• Folic acid (folate) is reduced to THF and used in the one-carbon pool.
• Six Metabolic Roles:
• (1) Conversion of homocystein to methionine – N⁵-Methyl-THF is a methyl donor and utilizes vitamin B₁₂ as a cofactor.
• (2) Conversion of serine to glycine – THF is an acceptor of a methyl group from serine and utilizes vitamin B₆ (pyridoxine) as a cofactor.
• (3) Histidine metabolism
• (4) Synthesis of thymidylate – rate-limiting step in DNA synthesis.
• (5) Synthesis of purines
• (6) Utilization of generation of formate
• Food Sources/Absorption/Storage:
• Best sources – green leafy vegetables, some fruits
• Absorbed in duodenum, jejunum.
• Synthetic folic acid (monoglutamate form in vitamin pills) 100% absorbed on empty stomach, 85% after meal.
• Food folates (polyglutamates Þ monoglutamate in small intestine).
• Therefore, only need half as much synthetic folic acid if ingested in an empty stomach!
• Liver main storage site, sufficient for only a few months.
• Hematologic Features of Deficiency:
• Megaloblastic anemia – large, abnormal immature RBCs.
• Increased mean corpuscular volume (MCV)
• Hypersegmentation of nucleus of leukocytes.
• Causes of Deficiency:
• Inadequate intake
• Increased requirements – rapid growth, pregnancy.
• Decreased absorption – GI disease – sprue, drugs: phenytoin, barbiturates
• Impaired metabolism – congenital, antimetabolites used in cancer treatment (methotrexate)
• Folate in Foods: Folate is highly susceptible to oxidative destruction: 50-90% destroyed by prolonged cooking.
• High folate: lentils, blackeyed peas, legumes, orange juice, asparagus, beets, broccoli, corn, spinach.

Vitamin B₁₂ – cobalamin – deficiency leads to pernicious anemia (megaloblastic)

• Folate-cobalamin interaction is critical for normal synthesis of purines and pyrimidines.
• General:
• Only source is animal products (meat and milk)
• Actively absorbed in terminal ileum dependent on intrinsic factor secreted by parietal cells in stomach.
• Liver is main storage site, sufficient for about 2-5 years, if eating animal based diet.
• Hematologic features: B₁₂ deficiency is same as folic acid deficiency.
• Non-Hematologic features: sore, smooth tongue, neurologic syndrome (sensory changes, paresthesia in extremities), failure of myelination of long tracts of spinal cord (depending on duration neurologic complications may/not be reversible).
• Causes of Deficiency:
• Deficient intake – strict vegetarian, vegan, infant breast fed by B₁₂ deficient mother.
• Decreased absorption - ß intrnsic factor with congenital pernicious anemia, gastric resection, ileal resection, achlorhydria, hypochlorhydria.
• Treatment of Megaloblastic Anemia:
• Food fortified with B₁₂ (fortified soy milk), or B₁₂ pill.
• Pernicious anemia (lack of intrinsic factor) treated with intramuscular injections of B_12.
• Gastric atrophy (ß acid secretion) take oral supplement of 25ug-1mg B₁₂, 1% absorbed by mass action.
• Folic acid in large doses correct megaloblastic anemia of B₁₂ deficiency, but not neurologic probs. Therefore, Vit B₁₂ deficiency can be masked.