An Approach to Anemia MED 341 AbdulKareem AlMomen

An Approach to Anemia (MED 341) Abdul-Kareem Al-Momen, MD, FRCPC College of Medicine, KSU 1430 -1431 H(2009 -2010)

Definition: Anemia is defined as a reduction in one or more of the major RBC measurements: hemoglobin concentration, hematocrit, or RBC count to a degree lower than normal values for the tested population : newborn, childhood, adulthood (males & females), and sea level

Hb (gm/L) 200 +/20 110 +/10 Newbor n Chld. Adult: Male 160 +/Female 20 Sea Level 14 +/- 20 Jeddah 150 g/L Albaha 190 G/l PCV (Hct)% 60 +/- 20 33 +/- 3 48 42 +/+/- 5 5 47 % 58 %

Anemia? Production? Destruction? The key test is the …. .

The reticulocyte count Increased reticulocytes (greater than 2 -3% or 100, 000/mm 3 total) are seen in blood loss and hemolytic processes.

The reticulocyte count To be useful the reticulocyte count must be adjusted for the patient's hematocrit, because when hematocrit is low, reticulocytes are released earlier (faster) from the marrow so one can adjust for this phenomenon as follows: Corrected retic. = Patients retic. x (Patients Hct/45) Example: Hb 70 g/L, PCV (Hct) = 20, Retics. = 16 % Corrected Retics. = 16 X 20/45 = 7

The reticulocyte count Reticulocyte Production index (RPI) = corrected retic. count/Maturation time (Maturation time = 1 for Hct=45%, 1. 5 for 35%, 2 for 25%, and 2. 5 for 15%. ) Example: PCV = 20 %, Retics. = 16, Corrected Retics=7 RPI = 7/2 = 3. 5 Absolute reticulocyte count = retic x RBC number.

Causes of Anemia (kinetic approach) Decreased erythrocyte production Bone marrow suppression Bone marrow infiltration Nutritional deficiencies Decreased erythropoietin production Inadequate marrow response to erythropoietin

Causes of Anemia Erythrocyte loss • Hemorrhage : Bleeding tendencies, Menorrhagea, Anticoagulation Liver disease Hemolysis: Autoimmune, None-immune, (MAHA, RBC defects, Hypersplenism)

Dilutional Anemia Dilutional- A patient's plasma volume increases with pregnancy, laying down possibly responsible for as much as a 3 -6% drop in the hematocrit in the first two days of hospitalization.

Morphological Approach (big versus small) First, measure the size of the RBCs: MCV (femtoliters) = 10 x HCT(percent) ÷ RBC (millions/µL)

High MCV>115 B 12, Folate Drugs that impair DNA synthesis (AZT, chemo. , azathioprine) MDS

Normal MCV Normocytic normocytic Anemia of chronic disease Mixed deficiencies Renal failure Endocrinopaties

Low MCV Microcytic Iron deficiency Thalassemia trait Anemia of chronic disease (30 -40%) Sideroblastic anemias Lead poisoning

Iron deficiency anemia Iron deficiency is a common form of malnutrition that affects more than 2 billion people globally.

Iron Deficiency Anemia Smear: hypochromic and microcytic (low MCV) RBCs, usually not seen unless Hct 30% platelet count is often elevated Ferritin: a measure of total body iron stores, but also an acute phase reactant <15 g/l = Fe deficiency, 150 g/l = Not Fe deficiency 15 -150 g/l = ?

Iron Deficiency Anemia Low Iron Saturation (Fe/TIBC ratio) Fe (not reliable) TIBC Fe/TIBC (% saturation) 15% BM bx: absent Fe stores Gold standard Therapeutic Trial of Oral Iron

Iron Compartments in a 70 kg person

Increased iron requirements • Blood loss • Gastrointestinal disorders (esophageal varices, hemorrhoids) • Extensive and prolonged menstruation • Pulmonary (hemoptysis, pulmonary hemosiderosis), urologic, or nasal disorders • Dialysis • Hookworm infestation • Intravascular hemolysis with hemoglobinuria • Paroxysmal nocturnal hemoglobinuria • Cardiac valve prostheses • Rapid growth in body size between 2 and 36 months of age • Pregnancy and lactation

Inadequate iron supply • Poor nutritional intake in children (not a common independent mechanism in adults but often a contributing factor) • Malabsorption • Gastric bypass surgery for ulcers or obesity • Achlorhydria from gastritis or drug therapy • Severe malabsorption (for example, celiac disease [nontropical sprue]) • Abnormal transferrin function • Congenital atransferrinemia • Autoantibodies to transferrin receptors

Oral iron failure? Incorrect diagnosis (eg, thalassemia) anemia of chronic disease? Patient is not taking the medication Not absorbed (enteric coated? ) Rapid iron loss?

Intravenous Iron Therapy Iron sacharate (Ferrosac), 200 mg in 100250 cc normal saline IV over one hour daily to the total dose required (Weight {kg} x Hb deficit {target Hb-current Hb] x 4). Ferric gluconate (Ferrlecit ) in patients on renal dialysis. The number of allergic reactions is lower than that from iron dextran

Differentiation of anemia of chronic disease and iron deficiency anemia by laboratory measures

Utility of supraphysiologic doses of erythropoietin in the setting of inflammatory block.

B 12/Folate Deficiency Etiology: Anemia-- Vitamin B 12 and folate are needed for DNA synthesis deoxyuridate to thymidylate , including RBC precursors Deficiency B 12 - Dietary intake, acid-pepsin in the stomach, pancreatic proteases, gastric secretion of intrinsic factor, an ileum with Cbl-IF receptors (fish tapeworm) Folate-- Poor dietary intake Et. OH, malabsorption, increased demand (pregnancy, hemolytic anemias), inhibitors of DHFR

B 12/Folate Deficiency (2) Dx: Smear: Macrocytic (High MCV) RBCs, +/- hypersegmented neutrophils, +/- modest neutropenia, but… the diagnosis of B 12 def. was made in patients in whom only 29 percent had anemia, and only 36 percent had a MCV greater than 100 f. L (Pruthi RK, Tefferi A, Mayo Clin Proc 1994 Feb; 69(2): 144 -50) B 12 Low serum B 12, elevated serum methylmalonic acid levels Anti-IF Abs, Schilling test (? ), PA accounts for 75% Folate Serum folate level-- can normalize with a single good meal

B 12/Folate Deficiency (3) Tx: B 12 deficiency: B 12 1 mg/month IM, or 1 -2 mg/day po Folate deficiency: Improved diet, folate 1 mg/day Monitor for a response to therapy. Pernicious Anemia – monitor for gi cancers.

Cobalamin deficiency and neurological problems Subacute combined degeneration of the dorsal and lateral spinal columns. Well known study of B 12 deficiency in the nursing home population (Carmel R Karnaze DS, JAMA 253: 1284, 1985) Vitamin B-12 deficiency is present in up to 15% of the elderly population as documented by elevated methylmalonic acid in combination with low or low-normal vitamin B-12 concentrations. Is oral B 12 good enough? Association between nitrous oxide anesthesia and development of neurological symptoms responsive to B 12 in patients with subclinical cobalamin deficiency (methionine? ).

Diagnostic tests for Vit. B 12 Deficiency Test Serum methylmalonic acid and serum homocysteine MCV>115, smear, CBC Antibodies to IF and Parietal cells Schilling test Spot urine for homocysteine

Sideroblastic Anemias Heterogenous grouping of anemias defined by presence of ringed sideroblasts in the BM Etiologies: Hereditary (rare), type of porphyria Myelodysplasia Et. OH Drugs (INH, Chloramphenicol) Tx: Trial of pyridoxine for hereditary or INH induced SA

Hemolytic Anemias Hemolytic anemias are either acquired or congenital. The laboratory signs of hemolytic anemias include: 1. Increased LDH (LDH 1) - sensitive but not specific. 2. Increased indirect bilirubin - sensitive but not specific*. 3. Increased reticulocyte count - specific but not sensitive 4. Decreased haptoglobin - specific but not sensitive. 5. Urine hemosiderin - specific but not sensitive. *The indirect bilirubin is proportional to the hematocrit, so with a hematocrit of 45% the upper limit of normal is 1. 00 mg/dl and with a hematocrit of 22. 5% the upper limit of normal for the indirect bilirubin is 0. 5 mg/dl. Since tests for hemolysis suffer from a lack of sensitivity and specificity, one needs a high index of suspicion for this type of anemia.

Hereditary anemias 1 - RBC memberane defects : e. g. Heriditary Spherocytosis 2 -Reduced Globin Chains: e. g. α thalassemia ( reduced α chain ) , & β thalassemia ( reduced β chain) 3 -Abnormal amino-acid sequence e. g. Sickle Cell Anemia 3 -Enzymopathies : e. g G 6 PD deficiency

Hemoglobinopathies Sickle cell disease/anemia Thalassemias

The hemoglobin electrophoresis reveals Hb. A 2 is 1%, Hb. F is 0. 5%, and Hb. H is 16%.

Sickle Cell Anemia / Disease Hb SS due to replacement of glutamic acid by valine at position 6 on the β globin chain Hb. S molecule are less soluble , tend to form crystals and fibers, which leads to RBC deformity , sickling , vaso-occlusion & hemolysis

Complications of Sickle Cell Disease 1 - Vaso-occlusion , with recurrent painful episodes (mild-moderate-severe ) Acute chest syndrome Recurrent infection (URT & chest ) Splenic sequestration Priapism Thrombo-embolic disease (CVA, PE, DVT)

SCD Complication: (cont. ) Avascular necrosis (head of femur & humerus) Tendency for Osteo-myelitis ( salmonella) Leg ulcers Gall stones

Presipitators of Vaso. Occlusive Episodes 1 -Hypoxia : - low atmospheric oxygen , Lung diseases , heart diseases 2 -Increased blood viscosity: increased Hb/Hct , dehydration, infection , general anesthesia 3 -Extreme hot/cold weather 4 -Unknown causes

Management of SCD Vaccination Antibiotic prophylaxis Avoidance of hypoxia and extreme weathers Increase fluid intake Treatment of acute episodes Exchange transfusion /transfusion Prevention: premarital screening & genetic counseling

β Thalassemia 2 β genes on chromosome # 11 give 2 β globin chains. ββ = normal -β = β thalassemia trait (hypochromic , microcytic anemia, asymptomatic , confused with iron deficiency anemia )

Thalassemia Major (Homozygous β Thalassemia ) No β chains Severe intramedullary hemolysis Severe hemolytic anemia Jaundice + Pallor Bone marrow expansion Hepatosplenomegaly Delayed puperty Iron overload ( absorption + hemolysis )

H. Spherocytosis RBC = Spheres (not biconcave )_ Reduced survival (hemolytic anemia ) Jaundice, Splenomegaly Gall stones Reticulocytosis Increased direct billirubin

Treatment 1 -Folic acid 2 -Splenectomy after vaccination against S. Pneomoniae & H. Influenzae ﺯ Malaria avoidance / prophylaxis

Enzymopathies : G 6 PD Deficiency G 6 PD is essential for the production of the anti-oxidant Glutathione Acute hemolysis upon exposure to oxidative stress food (fava beans), drugs (e. g. sulfa derivatives ), chemicals or infection X- linked