Objectives. But first: What s in blood? Introduction. Overview: Erythrocytes. Erythrocytes, cont. 4/21/2016

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1 Objectives Nutritional Deficiencies That May Cause Anemia Lee Ellen Brunson-Sicilia, MHS, MLS(ASCP) CM 1. Discuss the role that various nutrients play in red blood cell formation. 2. List sources of nutrients involved in red blood cell formation. 3. Describe the clinical and laboratory features of anemias related to nutrient deficits. Introduction Anemia Functionally defined as a decrease in the competence of blood to carry oxygen to tissues Decrease in the normal concentration of hemoglobin (Hgb) and/or erythrocytes (RBCs) One of the most common problems encountered in clinical medicine Is not a disease Cause must be identified for proper treatment But first: What s in blood? Overview: Erythrocytes Red blood cells (RBC) Produced in bone marrow Anucleate Biconcave disks 120-day life span Do not normally leave the vessel Primary Functions: Carry O 2 to tissues Carry CO 2 lungs (via hemoglobin) Erythrocytes, cont million/µl 1

2 Overview: Hemoglobin (Hgb) The iron-containing pigment of the red blood cells that functions to carry oxygen from the lungs to the tissue 33% of RBC volume 90% of dry RBC weight 1 Hgb = 4 heme rings + 4 globin chains + 4 iron atoms 1 hemoglobin carries 4 O 2 molecules Hgb Structure Where is Hgb made? How does anemia develop? Anemia develops if: The bone marrow RBC production is impaired. RBC loss or destruction exceeds the maximum capacity of the marrow RBC production. The bone marrow must increase production to meet demands of anemia. Marrow can compensate for decreased survival, to a point. Usual Diagnostic Criteria Decreased Hgb Hematocrit Packed RBC volume Tells what fraction of patient s whole blood is RBCs Decreased Hct 2

3 Signs and Symptoms of Anemia May range from slight fatigue or barely noticeable physiologic changes to lifethreatening reactions Depends on: Rate of onset Severity of decreased production or blood loss Ability of body to adapt General Physical Findings Fatigue Lethargy Skin pallor Dyspnea Pale conjunctiva Hypotension Heart abnormalities Enlarged organs Adaptations to Anemia Increase in erythropoietin production Increase in oxygenated blood flow Cardiac output and circulation rate Blood flow to vital organs (heart and brain) Oxygen uptake Deepening the amount of inspiration Increase respiration rate Increase in oxygen utilization by tissue Adaptations to Anemia Patients respond differently to similar changes in Hgb Severity of anemia Competency of the cardiovascular and respiratory systems O 2 requirements of the individual (physical and metabolic activity) Duration of the anemia Disease or condition that caused the anemia Presence and severity of coexisting disease Causes of Anemia Nutritional deficit Blood loss Bone marrow disorders Accelerated RBC destruction Stem cell arrest or damage Nutrients Required for RBC Production Iron Vitamin B 12 Folate Hereditary 3

4 Iron in the body Iron Deficiency Iron is required by every cell in the body Generation of energy Cellular growth and proliferation Oxygen transport Total concentration is ~20mg/lb body weight Hgb makes up major fraction of body iron: 0.5mg iron/ml blood Iron in the body, cont mL RBC destroyed each day 85% recycled to developing RBC in bone marrow Rest is stored in liver, GI tract and marrow Very limited mechanism for excretion Lose ~1 mg per day Daily intake requirement for iron is 1 mg Iron Balance Iron overload can result if body s capacity is exceeded Critical processes inhibited if iron is limited Iron Transport Transferrin (Tf) Plasma transport protein, made in the liver 2 homologous lobes Each lobe contains an iron-binding site for Fe 3+ Mediates iron exchange between RBC and the tissues 4

5 Iron Storage Iron Storage Ferritin Short-term storage for iron Readily available for erythropoiesis Found in the bone marrow, liver, spleen Serum levels reflect tissue storage Caution: Ferritin increases in the presence of inflammation could mask anemia. Hemosiderin Long-term storage for iron; iron released slowly Bone marrow and liver primarily Yellow to brown refractile inclusions Iron Absorption Foods Rich in Iron Iron homeostasis depends on balance of Absorption of iron Total body requirements 2 forms of dietary iron Heme iron (ferrous) animal sources Non-heme iron (ferric) vegetables Heme iron Beef or chicken liver Clams or mussels Oysters Non-heme iron Soybeans Lentils Pinto beans Garbanzo beans Tofu Enriched breakfast cereals Impact Iron Absorption Factors Affecting GI Iron Absorption Enhance Orange juice Vitamin C Pickles Soy Sauce Vinegar Alcohol Inhibit Tea Coffee Oregano Cow s milk Calcium Some medications Prevacid Prilosec Availability of iron Condition of GI tract Activity of bone marrow Tissue iron stores Oxygen content of blood Systemic inflammation or infection Hgb concentration in blood 5

6 Lab Assessment of Iron Serum Iron iron in serum Serum Ferritin iron in storage Transferrin saturation % bound with iron Iron Deficiency Anemia (IDA) Most common nutritional deficiency in the world Prevalent in countries where Unfortified grain major part of diet Meat is scarce Hookworm infestation is common TIBC total iron binding capacity Causes of IDA Increased iron demands Growth spurts in infants and children Pregnancy and nursing Lack of iron intake Poor diet Conditions that diminish absorption Causes, cont. Blood loss Menorrhagia women of child-bearing age GI bleed men and post-menopausal women Ulcers Hiatal hernias Alcoholic gastritis Excessive aspirin ingestion Hemorrhoids Hookworm infestation Pathophysiology IDA develops in sequential stages Due to a negative iron balance: losing more iron than is absorbed Stages Iron depletion Iron deficient erythropoiesis Iron deficiency anemia (IDA) Pathophysiology Stage I Iron depletion Iron stores are exhausted: serum ferritin Serum iron and transferrin saturation in peripheral blood still normal. No anemia RBC morphology is normal. Iron absorption in gut. 6

7 Pathophysiology Stage 2 Iron deficient erythropoiesis Ferritin and hemosiderin depleted Serum iron and serum ferritin, TIBC Transferrin saturation Hgb still normal RBCs may be slightly microcytic Pathophysiology Stage 3 IDA All lab tests for iron status become abnormal Microcytic, hypochromic anemia Represents advanced stage of severe iron deficiency Clinical Features Onset is usually insidious Takes months to years (more rapid if blood loss) Symptoms appear as anemia develops Variety of other abnormalities appear Koilonychia - concavity of nails Glossitis inflammation of the tongue Muscle dysfunction Inability to regulate body temperature Gastritis Heart palpitations Koilonychia Glossitis Clinical Features Pica syndrome Unusual craving for ingesting unnatural items Phagophagia (ice-eating) Geophagia (dirt/clay-eating) Amylophagia (starch-eating) Infants: perform worse in mental and motor development Children: irritability, loss of memory, difficulties in learning Laboratory Features of IDA Peripheral blood Microcytic (small): MCV Hypochromic (pale): MCHC Variation in RBC size (anisocytosis) Variation in RBC shape (poikilocytosis) Target cells, elliptocytes, teardrop cells Increased PLT count in some cases 7

8 Microcytic, hypochromic anemia of iron deficiency. Compare size of RBCs to nucleus of small lymphocyte in center. Therapy Treat underlying disorder Administer iron Oral administration Parenteral administration Observe for response Defined as an of 1 gm/hemoglobin in 1 month Retic response begins about the 3 rd day Hgb normal within 6-10 weeks B 12 and folate in the body B 12 and Folate Deficiencies Both required for DNA synthesis and cell maturation Deficiency in either will affect all blood cell lines: RBCs, WBCs and PLTs. Deficiencies cause megaloblastic anemia Vitamin B 12 Also called cobalamin Required for neurologic function Present in most foods of animal origin ~3-5 μg/day is needed for normal functions Only 70% taken in is absorbed in GI tract Half stored in liver, rest is in heart and kidneys Organ stores last 3-5 years B 12 Absorption Released from food by peptic digestion at a low ph in the stomach Binds to intrinsic factor (IF) from parietal cells that line the GI tract IF-B 12 complex resists digestion, is taken to mucosal cells in lower small intestine. Vitamin B 12 is taken to tissues via bloodstream, bound to transcobalamin. 8

9 Foods Rich in B 12 Clams Beef liver Fortified breakfast cereals Trout Salmon Tuna Vitamin B 12 Deficiency: Pernicious Anemia Most common cause of B12 deficiency Caused by absence of IF secondary to immune destruction of gastric mucosa Vitamin B 12 can not be absorbed Disease of older adults: > 40 years of age Autoimmune disease Most common in persons of Scandinavian and northern European ancestry Other Causes of B 12 Malabsorption Gastrectomy or intestinal resection Diseases that prevent binding of IF-B 12 complex in the ileum: Crohn s disease, Celiac disease Bacterial overgrowth Tapeworm infestation Certain medications Prevacid, Prilosec Pepcid, Zantac Metformin Other Causes of Vitamin B 12 Deficiency Nutritional deficiency Rare in the U.S. Vegetarians Pregnant women Other causes Transcobalamin deficiency Nitrous oxide abuse Defective IF receptors in ileum Zollinger-Ellison syndrome Folate Folate is a B-vitamin that is naturally present in many foods. A form of folate, called folic acid, is used in dietary supplements and fortified foods. 1998: FDA requires food companies to add folic acid to grain products sold in the U.S. Recommended daily intake: Adults ~400μg Liver stores: 3-6 month supply 9

10 Folate Absorption Takes place throughout the small intestine Most absorption takes place in upper portion of small intestine (proximal jejunum). Crosses into bloodstream and is transported throughout the body Foods Rich in Folate* Beef liver Spinach Black-eyed peas Fortified cereals White rice Asparagus Enriched pastas Brussels sprouts *NOTE: Folate is destroyed by heat. Folate Importance Embryogenesis Neural tube defects: Spina bifida Cleft palate Anencephaly Growth Pregnancy Lactation Causes of folate deficiency Inadequate diet Most often seen in poor and elderly Alcoholics Increased requirement Hemolytic anemias Myeloproliferative disorders Metastatic cancers Pregnancy Causes of folic acid deficiency Malabsorption Intestinal diseases affecting the upper small intestine: Crohn s disease, Celiac disease Overgrowth of bacteria Drug inhibition Oral contraceptives Long-term anticoagulant drugs Anti-epileptics: Dilantin, Carbatrol, Depacon Megaloblastic: Clinical Findings Onset is insidious Anemic symptoms Other symptoms Digestive tract Genitourinary tract Lemon yellow skin Neurological disturbances 10

11 Megaloblastic: Clinical Findings Megaloblastic Anemia Vitamin B 12 deficiency only Neurological disturbances Tingling, numbness, weakness of the extremities Abnormal gait Loss of memory, depression, irritability; megaloblastic madness 95% of megaloblastic anemias Deficiency of folic acid ( intake) Deficiency of vitamin B 12 ( intrinsic factor) Megaloblastic Anemia Very large RBCs and precursors in marrow: megaloblasts Very large RBCs in peripheral blood ( MCV) Nuclear maturation defect Anemia Due to ineffective hematopoiesis (not Hgb defect) Disrupted DNA development Delayed nuclear maturation prevents cell division Megaloblastic: Lab Findings Megaloblastic: Lab Findings Peripheral blood Macrocytic, normochromic anemia Affects all 3 cell lines: RBC, WBC, PLT Distinguishing features on blood smear Oval macrocytes (RBCs) Howell-Jolly Bodies Hypersegmented neutrophils > 5 lobes Can be seen in the absence of macrocytosis Sensitive and specific for megaloblastic anemia Anisocytosis and poikilocytosis Reticulocytopenia 11

12 Megaloblastic: Lab Findings Vitamin B 12 levels Serum folate Intermediates in folate and vitamin B 12 metabolism Methylmalonic acid (MMA) Normal in folate def. in vitamin B 12 def. Homocysteine levels in both vitamin B 12 and folate def. Megaloblastic: Lab Findings Ineffective erythropoiesis results in hemolysis in the marrow, causing increases in: Serum iron Indirect bilirubin Urobilinogen Lactate dehydrogenase Therapy First determine which deficiency exists Vitamin B 12 or Folate Oral supplements if malabsorption is not cause IM injections B 12 : sublingual tablets or intranasal gels Therapy, cont. Specific therapy Marrow responds rapidly to correct treatment Retic response after 4 th day Hgb rises ~2-3 g/dl every 2 weeks WBC abnormalities disappear more slowly days Reverse peripheral neuropathy of vitamin B 12 deficiency PA lifelong therapy References McKenzie, Shirlyn B., Clinical Laboratory Hematology, 3 rd ed. Pearson, Greer, John P., et al. Wintrobe s Clinical Hematology, 12 th ed. Lippincott Williams & Wilkins, National Institutes of Health, Office of Dietary Supplements website: 12