IRON DEFICIENCY ANEMIA Dr. Kunhikannan Dept. of Gen. Medicine Kannur Medical College

Absorption of Iron Iron absorbed from upper SI in the form of Ferrous Iron Iron gets attached to an intracellular iron carrier in mucosal cells of intestine where it is oxidised to ferric state Intracellular iron carrier delivers a variable portion of absorbed iron to plasma which is carried away to various parts of the body in combination with iron carrier protein, transferrin

Absorption of Iron Remainder iron is stored as mucosal ferritin in which iron is not absorbed but is lost from body after 3-4 days Absorption of iron is controlled by amount of iron stores When iron stores are reduced absorption is enhanced & vice versa

Iron deficiency anemia It is the condition in which there is anemia and clear evidence of iron deficiency It is the most common cause of anemia

Causes of iron deficiency Increased demand of iron. Increased iron loss. Decreased iron intake / absorption.

Increased demand for iron Rapid growth in infancy / adolescence. Pregnancy Erythropoietin therapy Increased iron loss c/c blood loss Menses a/c blood loss Blood donation Phlebctomy as treatment for polycythemia vera

Decreased iron intake or absorption Malabsorption Sprue c/c disease Mal absorption from surgery Post gastrectomy a/c or c/c inflammation

Clinical features General symptoms Fatigue, lassitude, dyspnoea, palpitation. Dizziness, headache, syncope, tinnitus, vertigo Irritability, sleep disturbances. Lack of concentration. Throbbing in head and ears. Parasthesia in fingers and toes. Anorexia, indigestion, nausea. Anemia, intermittent claudication, transient cerebral ischemia. Amenorrhoea. Symptoms of cardiac failure.

Signs Pallor of skin palms and oral mucosa, nail beds and palpebral conjunctiva. Tachycardia. Wide pulse pressure. Edema. Cervical venous hum. Ejection systolic murmur best heard in pulmonary area. Cardiac dilatation. Signs of cardiac failure.

Clinical presentation of iron deficiency anemia. Pregnancy, adolescence, periods of rapid growth and an intermittent h/o blood loss of any kind should alert to possible iron deficiency. Appearance of iron deficiency in an adult male means GI blood loss until proved otherwise.

Characteristics of iron deficiency Angular stomatitis. Glossitis. Brittle finger nails. Platynychia. Koilonychia. Pica Carving for strange items-coal, earth, tomatoes, greens, starch and ice PLUMMER VINSON SYNDROME PATTERSON-KELLY SYNDROME Sideropenic dysphagias Occurs in long standing iron deficiency

Iron deficiency-features Iron deficiency anemia. Glossitis. Koilonychia. Postcricoid web dysphagia Intermittent & more for solids than liquids Demonstrated endoscopically / barium meal. Dilatation required in case of severe obstruction Increased risk of Sq cell Ca of pharynx and esophagus. Treatment is with iron. For early diagnosis, upper GI endoscopy , every yr

Investigations To confirm iron deficiency anemia Hemoglobin - reduced. MCV – reduced (microcytosis, <80fl ) Peripheral smear study Microcytosis, hypochromia. Elliptical cells and poikilocytes in severe cases. Reticulocyte count normal elevated- blood loss with enough iron stores or on iron therapy. Red Cell Indices Normal Hb Males: 13-18 gm/dL Females: 12-16 gm/dL

Investigations MCV is volume of RBC Normocytic: 90+-8 fl Microcytic: <80 fl Macrocytic: >100 fl MCH. It is amount of Hb in 1 RBC. Normal: 27-32 pg MCHC. It is the average concentration of Hb in 1 RBC Normal: 31-37 gm/dL Hypochromia: <31g/dL Hyperchromia: >31 g/dL Serum iron and Total Iron Binding Capacity (TIBC) Serum iron – circulating iron bound to transferrin TIBC - indirect measure of circulating transferrin In normal adults, total amount of iron that serum transferrin can bind is 300 μg/dL. But actual amount of iron bound to transferrin is 100 μg/dL. So the percentage saturation

Investigations In normal adults, total amount of iron that serum transferrin can bind is 300 μg/dL. But actual amount of iron bound to transferrin is 100 μg/dL. So the percentage saturation is 33% Serum iron can vary from 10-40% Its levels are influenced by recent iron medications Serum iron shows diurnal variations. Highest value in morning and lowest in evening

Investigations Normal range for serum iron is 50-150 ug/dL TIBC normal range 300-360 ug/dL Transferrin saturation which is normally 25-50% is obtained by formula Serum iron x 100 TIBC Iron deficiency states are associated with saturation levels below 18%

SERUM FERRITIN Iron is stored complexed to protein as ferritin or hemosiderin Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferrittin accumulates within the cells of RE system, protein aggregates are formed as hemosiderin Iron in hemosiderin can be extracted for release by RE cells Serum ferritin levels is the convenient lab test to estimate the iron stores as serum ferritin levels correlates with total body iron stores under steady state condn. CONTD.

SERUM FERRITIN Normal values for ferritin varies according to age & gender. Adult males have serum ferritin values of 100 ug/L while adult female average 30 ug/L As iron stores are depleted, serum ferritin falls to <15 ug/L. such levels diagnostic of absent body iron stores It is unaffected by recent iron intake It is the first abnormal lab test in iron deficiency

7. EVALUATION OF BONE MARROW IRON STORES Serum ferritin has largely supplanted bone marrow aspirates for determination of storage iron Serum ferritin levels is a better indicator of iron overload than marrow iron stain 20-40% sideroblasts have visible ferritin granules in their cytoplasm, represents iron in excess of that needed for hemoglobin synthesis In states in which release if iron from storage sites is blocked, RE iron will be detectable and there will be few or no sideroblasts

8. RED CELL PROTOPORPHYRIN LEVELS When heme synthesis is impaired, protoporphyrin accumulate within RBCs Normal value <30ug/dL of RBCs In iron deficiency, value I excess of 100ug/dL is seen

MOST COMMON CAUSE OF INCREASED RBC PROTOPORPHYRIN Absolute or relative iron deficiency Lead poisoning

9. Serum Levels of Transferrin Receptor Protein (TRP) Erythroid cells have highest number of TRP TRP is released by cells into circulation Serum levels of TRP reflect the total erythroid marrow mass TRP is elevated in absolute iron deficiency Normal value: 4-9 ug/L Number of receptors increases with depletion of iron & vice versa Concentration of serum transferrin receptor correlates with rate of erythropoeisis In iron deficiency serum transferrin receptor increases due to increased erythropoeisis whereas in anemia of chronic disease, serum transferrin receptor decreases due to decreased erythropoeisis

Microcytic Hypochromic Anemia Pathogenic Classification: Disorders of iron metabolism Iron deficiency anemia Anemia of Chronic disorders Disorders of Globin synthesis Alpha & Beta thalassemias Hemoglobin E Syndrome Hemoglobin C Syndrome Sideroblastic anemia

Iron deficiency anemia LABORATORY FEATURES IN MICROCYTIC HYPOCHROMIC ANEMIA Iron deficiency anemia Serum iron low Serum Ferritin low TIBC High Percentage Saturation – low Bone marrow Sideroblast – Low Iron stores – Low Beta thalassemia Trait Serum Iron N or High Serum Ferritin N or High TIBC Normal Percentage saturation Sideroblast Normal Iron stores High

E. Sideroblastic anemia -Serum Iron – high -Serum Ferritin - High LABORATORY FEATURES IN MICROCYTIC HYPOCHROMIC ANEMIA Anemia of Chronic Disease Serum iron –High Serum Ferritin – High Percentage Saturation – Normal or High TIBC – Low Bone marrow Iron stores increased E. Sideroblastic anemia -Serum Iron – high -Serum Ferritin - High -Percentage saturation - high

To determine the cause of Iron Deficiency following investigations may be done mainly to check for chronic blood loss from GIT Stool (Occult blood & Hook worm) Zigmoidoscopy Colonoscopy Upper GI endoscopy Barium meal Barium enema Urine for Schistosomias Investigation for malabsorption

DIFF. DIAGNOSIS OF MICROCYTIC HYPOCHROMIC ANEMIA Iron def. anemia Thalassemia Chronic inflammatory disease with inadequate iron supply to erythroid marrow Myelodysplastic Syndrome

Impaired hemoglobin synthesis with mitochondrial dysfunction DIFF. DIAGNOSIS OF MICROCYTIC HYPOCHROMIC ANEMIA Thalassemia Serum iron level normal or increased Transferrin saturation normal or increased Chronic Inflammatory Disease Anemia is normocytic & normochromic Ferritin level normal or increased TIBC below normal MyeloDysplastic Syndromes Impaired hemoglobin synthesis with mitochondrial dysfunction Iron values reveal normal stores & more than adequate supply to bone marrow

MANAGEMENT OF IRON DEFICIENCY ANEMIA

Appropriate approach is determined by the severity & cause Elderly patients with severe iron deficiency anemia & cardiovascular instability require RED CELL TRANSFUSION Younger persons who have compensated for the anemia can be treated more conservatively with iron replacement For majority, oral iron therapy will suffice Specific diagnostic tests & appropriate therapy take priority inpatients with unusual blood loss or malabsorption

ONCE IRON DEFICIENCY ANEMIA IS DIAGNOSED & ITS CAUE IS MADE, THERE ARE 3 MAJOR APPROACHES

1. RED CELL TRANSFUSION Reserved for those with anemia, cardiovascular instability, continued and excessive blood loss & those who require immediate intervetion Transfusion corrects anemia acutely & transfused red cells provide a source of iron for reutilization

2. ORAL IRON THERAPY Adequate in asymptomatic patients with established anemia iron deficiency anemia Common used iron salts: Ferrous sulphate (30% elemental iron tabs.) Ferrous gluconate (12% elemental iron tabs.) Ferrous fumarate (33% elemental iron tabs.) DOSE 1 tab. 2 to 3 times a day Ideally, in empty stomach since food inhibit absorption

COMPLICATIONS OF ORAL IRON THERAPY gastrointestinal distress most prominent seen in 15-20% of patients abdominal pain, nausea, vomiting or constipation – lead to non compliance major impediment can be relieved by taking iron with food or changing to controlled release preparations or using liquid preparations

RESPONSE TO ORAL IRON THERAPY Typically RBC count begin to increase within 4 to 7 days of therapy Peak at 1.5 weeks

FAILURE OF ORAL IRON THERAPY May be due to Not taking the tablets Continuing blood loss Ingestion of certain drugs which reduce iron absorption (antacids, H2 receptor blockers, proton pump inhibitors, tetracyclins) Severe malabsorption Wrong diagnosis

PARENTERAL IRON THERAPY INDICATIONS Gastro intestinal intolerance to oral iron Severe malabsorption When rate of iron loss exceeds rate at which iron can be absorbed to correct anemia associated with rheumatoid arthritis, late pregnancy & following major operations Anemia associated with chronic renal failure (along with erythropoietin) In patients with regular hemodialysis

PARENTERAL IRON THERAPY Used in 2 ways To administer the total dose of iron required to correct the hemoglobin deficit and provide patient with atleast 500 mg of iron stores Give repeated small doses over a protracted period (common in dialysis centers to augment the response to erythropoietin therapy) Amount of iron reqd. calculated by the formla – body wt. (kg) X 2.3 X (15 pts. Hemoglobin g/dL + 500 or 1000 mg (for stores)

PARENTERAL IRON THERAPY Anaphylaxis is a concern with i.v. iron dextran (Imferon) not a concern with newer preparations like i.v. sodium ferric gluconate & iron sucrose

TOXICITY Arthralgias Skin rash Fever

If a large dose of iron dextran is to be given (>100 mg) Dilute with 5% Dextrose in water or 0.9% NaCl solution Infuse it over 60-90 min. A test dose (25 mg) can be given, but a slow infusion of a largeer dose will give same kind of early warning If chest pain, wheezing, hypotension occur, stop infusion immediately Iron Dextran (Imferon) can also be given deep i.m.ly, but is ideal for i.v. use. It is the most commonly used preparation