Nutritional Deficiency Anemias DR BINOD KUMAR SINGH Associate Professor, PMCH, Patna CIAP Executive board member- 2015 NNF State president,Bihar- 2014 IAP State secretary,Bihar-2010-2011 NNF State secretary,Bihar-2008-2009 - Consultant Neonatologist & Pediatrician Shiv Shishu Hospital :K-208, P.C Colony.Hanuman Nagar, Patna – 800020 Web site : www.shivshishuhospital.com

Anemia Definition Hemoglobin level is more than two standard deviation below the mean for childs age & sex -Cut off for Hb and hematocrit(WHO)

Mechanisms of Anemia Marrow production defects (hypoproliferation) Low reticulocyte count Little or no change in red cell morphology (a normocytic, normochromic anemia Red cell maturation defects (ineffective erythropoiesis) Slight to moderately elevated reticulocyte count Macrocytic or microcytic anemia Decreased red cell survival (blood loss/ hemolysis).

Classification of anemias by MCV Microcytic (<80 fL)   Iron deficiency   Thalassemia  Anemia of chronic disease Macrocytic (>100 fL) Vitamin B12 deficiency Folate deficiency   Myelodysplasia Chemotherapy Liver disease    Increased reticulocytosis Myxedema Normocytic Anemia of chronic disease Aplasia Protein-energy malnutrition Chronic renal failure Post-hemorrhagic

Initial Evaluation Signs: History/Symptoms Pallor, dark knuckles Koilonychia Laboratory evaluation CBC with differential Peripheral Smear Reticulocyte count Iron Studies B12 level Serum/Folate level R/E of stool & urine History/Symptoms Pica Easy fatigue Poor concentration Dyspnea on exertion pallor Tingling and numbness in extremities Tinnitus Chest Pain Medications

Nutrient Roles in Erythropoesis

Iron Stores Humans contain ~2.5 g of iron, with 2.0 - 2.5 g circulating as part of heme in hemoglobin Another ~0.3 g found in myoglobin, cytochromes, and Fe-S complexes Iron is stored in body primarily as protein complexes (ferritin and hemosiderin) Healthy newborn have body iron store of 250mg(80ppm) decreases to 60ppm in first 6month of life because milk is poor source of iron

Nutritional Iron Balance Intake Dietary iron intake Medicinal iron Red cell transfusions Injection of iron complexes Excretion Gastrointestinal bleeding Menses Losses can be as much as 4 - 37mg/menstrual cycle Other forms of bleeding Loss of epidermal cells from the skin and gut

Iron Absorption Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories) Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed Heme iron> Organic iron (Ferrous gluconate) > Inorganic iron (ferrous sulfate) Average iron intake in an adult male is 15 mg/d with 6% absorption; average female, the daily intake is 11 mg/d with 12% absorption Acid pH and presence of reducing agents: ascorbic acid (vitamin C) reduces Fe+++ to Fe++ which promotes passage across intestinal mucosa Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50% Takes place in the mucosa of the proximal small intestine Absorption increase to 20% in iron-deficient persons

Dietary Sources of Iron Red meat > poultry & fish Iron cooking pots Plants are generally not good sources because of oxalate, phytate, tannins, etc. Spinach has a lot of iron, but has ~780 mg oxalate/100 g Note - Heme iron absorption from diet not affected by ascorbate or phytate

Iron Exchange 80% of iron passing through the plasma transferrin pool is recycled from broken-down red cells Absorption of about 1 mg/d is required from the diet in men, 1.4 mg/d in women to maintain homeostasis

Iron Deficiency Anemia Facts and Figures Most common cause of anemia 500 million cases worldwide Prevalence is higher in less developed countries Unique Physical Exam findings Cheilosis fissures at the corners of the mouth Koilonychia spooning of the fingernails

Plummer vinson syndrome Marrow iron store

Causes of Iron Deficiency Increased demand for iron and/or hematopoiesis Rapid growth in infancy or adolescence Pregnancy Erythropoietin therapy Increased iron loss Chronic blood loss Menses Acute blood loss Blood donation Phlebotomy as treatment for polycythemia rubra vera Decreased iron intake or absorption Inadequate diet Malabsorption from disease (sprue, Crohn's disease) Malabsorption from surgery (post-gastrectomy) Acute or chronic inflammation

Iron Deficiency Anemia Hypochromic red cell Microcytic cell Target cell

Stages of Iron Deficiency

Stages of Iron Deficiency Stage 1: moderate depletion of iron stores; no dysfunction Stage 2: Severe depletion of iron stores; no dysfunction Stage 3: Iron deficiency Stage 4: Iron deficiency (dysfunction and anemia)

Treatment of Iron Deficiency Red Blood Cell Transfusion Oral Iron Therapy Ferrous sulfate Ferrous fumarate Ferrous gluconate Parenteral Iron

Children Adults Elemental iron 3-6mg/kg/day, contd.. 4-6 months Check Hb at 4 weeks Adults Ferrous sulphate/gluconate/fumarate Iron polymaltose complex Elemental iron 200mg/day Parentral Iron:-total dose-iron required(mg)=wt(kg)X2.3X(15-pt hb in gm/dl)+(500 to 1000mg)

Indication for parentral iron therapy Intolerance to oral iron. Malabsorption. Ongoing blood loss at a rate where oral replacement cannot match iron loss. Iv route is preferred over im route.

Reasons for nonresponse to hematinic therapy for iron deficiency anemia Poor compliance with therapy Poorly absorbed iron preparation Use of H2 blocker or PPI causing achlorhydria. Interaction with food and medication. Associated vit B12 or folic acid deficiency. Underlying hemolytic anemia inflammation or infection.

Malabsorption eg- coeliac disease giardiasis,H pylori infection High rate of ongoing blood loss. Alternative etiology eg- sideroblastic anemia.

Diet for Iron Deficiency: In adults, limit milk intake - 500 mL/day Avoid excess caffeine Eat iron-rich foods Protein foods Vegetables  Meats  Greens  Fish & Shelfish Dried peas & beans  Eggs Fruits Grains  Dried fruit  Iron-fortified breads  Juices Dry cereals  Most fresh fruits  Oatmeal

Iron Supplementation in special populations Pregnant Women During the last two trimesters, daily iron requirements increase to 5 to 6 mg Infancy Normal-term infants are born with sufficient iron stores to prevent iron deficiency for the first 4–5 months of life Thereafter, enough iron needs to be absorbed to keep pace with the needs of rapid growth Nutritional iron deficiency is most common between 6 and 24 months of life

Megaloblastic Anemia Due to impaired DNA synthesis Affects cells primarily having relatively rapid turnover, especially hematopoietic precursors and gastrointestinal epithelial cells Cell division is sluggish, but cytoplasmic development progresses normally, so megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. Megaloblastic erythroid progenitors tend to be destroyed in the marrow Marrow cellularity is often increased but production of red blood cells (RBC) is decreased

Causes of Megaloblastic Anemia Vitamin B12 Deficiency Inadequate intake: vegans (rare)  Malabsorption  Defective release of cobalamin from food  Gastric achlorhydria Partial gastrectomy Drugs that block acid secretion  Inadequate production of intrinsic factor (IF)  Pernicious anemia Total gastrectomy Disorders of terminal ileum Sprue Regional enteritis Intestinal resection Competition for cobalamin  Fish tapeworm (Diphyllobothrium latum) Bacteria: "blind loop" syndrome  Drugs: p-aminosalicylic acid, colchicine, neomycin

Clinical Manifestations of Vitamin B12 Deficiency Hematologic Macrocytic Anemia Gastrointestinal Glossitis Anorexia Diarrhea Neurologic (found in 3/4th of individuals with pernicious anemia) Numbness and paresthesia in the extremities, Weakness, Ataxia Sphincter disturbances Disturbances of mentation Mild irritability and forgetfulness to severe dementia or frank psychosis. Demyelination, Axonal degeneration, and then Neuronal death Last stage is irreversible

Megaloblastic Anemia Macrocytic RBC Hypersegmented Neutrophil

Vitamin B12 Absorption – Oral Phase

Vitamin B12 Absorption – Gastric Phase

Vitamin B12 Absorption – Intestinal Phase

Vitamin B12 Deficiency Any interruption along this path can result in cobalamin deficiency Gastrectomy results in low production of IF Terminal ileal resection (>100 cm), decreases the site of absorption of B12-IF complex

Pernicious Anemia Most common cause of cobalamin deficiency Caused by the absence of IF Atrophy of the mucosa Autoimmune destruction of parietal cells Seen in individuals of northern European descent and African Americans Men and women are equally affected Disease of the elderly, the average patient presenting near age 60

Diagnosis of Vitamin B12 Deficiency Macrocytosis Peripheral blood smear Cobalamin levels Elevated serum methylmalonic acid and homocysteine levels Schilling Test

Schilling Test Measures B12 deficiency Detects IF deficiency Detects abnormal results in patients with genetic defects in B12 absorption, bacterial overgrowth of the small bowel, resection/bypass of terminal ileum, and pancreatic insufficiency

Stage 1 Oral dose of radiolabeled cobalamin given simultaneously with an IM injection unlabeled cobalamin 24 Hour Urine collection Amount radiolabeled activity is measured Normal absorption of B12 and normal renal function will excrete > 7% of radiolabeled B12

Stage 2 If stage 1 is abnormal, then test is repeated following 60 mg of oral IF If the level of urinary radiolabeled B12 normalizes, then this indicates pernicious anemia

Stage 3 Small intestine bacterial overgrowth may cause B12 malabsorption and an abnormal result in stage 1 that is not corrected with IF administration in stage 2 Broad spectrum antibiotics are given for one week to eliminate intestinal bacteria and then stage 1 should normalize

Stage 4 If pancreatic insufficiency exists, B12 malabsorption may occur Normalization after pancreatic enzyme therapy suggests pancreatic origin

Causes of Megaloblastic Anemia Folate Deficiency Inadequate intake: unbalanced diet (common in alcoholics, teenagers, some infants)  Increased requirements  Pregnancy Infancy Malignancy Increased hematopoiesis (chronic hemolytic anemias) Chronic exfoliative skin disorders Hemodialysis  Malabsorption  Sprue Drugs: Phenytoin, barbiturates, (?) ethanol   Impaired metabolism Inhibitors of dihydrofolate reductase: methotrexate, pyrimethamine, triamterene, pentamidine, trimethoprim Alcohol Rare enzyme deficiencies: dihydrofolate reductase, others

Treatment of Vitamin B12 Deficiency Replacement therapy 250-1000 ugm im Young children 250-500ugm since tremor & extrapyramidal toxicity Daily for 1-2week the weekly until Hct normal

Folate Deficiency More often seen in malnourished than those with cobalamin deficiency Gastrointestinal manifestations More widespread and more severe than those of pernicious anemia Diarrhea is often present Cheilosis Glossitis Neurologic abnormalities do not occur

Stages of folate deficiency Negative folate balance (decreased serum folate) Decreased RBC folate levels and hypersegmented neutrophils Macroovalocytes, increased MCV, and decreased hemoglobin

Diagnosis of folate deficiency Peripheral blood and bone marrow biopsy look exactly like B12 deficiency Plasma folate <3 ng/ml—fluctuates with recent dietary intake RBC folate—more reliable of tissue stores, <140 ng/ml Only increased serum homocysteine levels but NOT serum methylmalonic acid levels

Treatment of folate deficiency Oral replacement therapy :1-5mg daily for 3-4wks Folate prophylaxis Women planning pregnancy are advised to take 400 micro gm 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) Prophylactic folate is also recommended in other states of increased demand such as long-term hemodialysis and chronic haemolytic disorders

Inappropriate Treatment of Pernicious Anemia 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 degeneration of cord