Irion defitient and megaloblastic anemias

Iron deficient and megaloblastic anemias

Atanas Stanchev MD

University Hospital”Alexandrovska”

Clinic of Hematology

Anemia

Red cells development

Normal red cellSize 7µмMCV 82-98flMCH 27-32pgMCHC 310-340g/l

Anemia is a symptom of disease that requires

investigation to determine the underlying aetiology.

Anemia is strictly defined as a decrease in red blood

cell (RBC) mass.

In practice, anemia is usually discovered and

quantified by measurement of the RBC count, hemoglobin

(Hb) concentration, and hematocrit (Hct)

Normal value

Parameter Men Women

Hb 140-180g/l 120-160g/l

Er. 4.6 – 6.6 T/l 4.2 – 5.4 T/l

Hct 40 – 54% 34 – 46%

Iron 12.5 – 26.5mol/l 10.7 - 23 mol/l

Ferritin 30 – 180 g/l 20 – 180 g/l

TIBC 40-75 mol/l 40-75 mol/l

Definition for anemia (WHO)

• Men Hb<130g/l

• Women Hb<120g/l

• Pregnant women Hb<100g/l

Classification

• Mild Hb90g/l

• Intermediate Hb.60-90g/l

• Severe Hb<60g/l

Iron deficiency anemia

•Iron deficiency is defined as a decreased total iron body content

•Iron deficiency anemia occurs when iron deficiency is sufficiently severe to diminish erythropoiesis and cause the development of anemia

•Iron deficiency is the most prevalent single deficiency state on a worldwide basis

•In healthy subjects, the body concentration of iron is regulated carefully by absorptive cells in the proximal small intestine

•Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis

Dietary iron enters the enterocyte after being reduced to the ferrous state by duodenal cytochrome b (Dcytb) and being transported by the divalent metaltransporter (DMT1). Hephaestin facilitates iron export by ferroportin. Hepatocytes take up either free or transferrin-bound iron and release it back into the circulation via the action of ferroportin. Ferroportin also releases iron from macrophages. Ferroportin-mediated release of iron is inhibited by hepcidin.

Iron metabolism

Total amount of iron in adult male is 3.5-4.0g. (75% in Hb.; 10% in Myoglobine; 20% Iron stores (Ferritin; Hemostiderin)

• 10ml. whole blood contain 5mg. Iron

• Daily loss of Iron is 1mg.. Menstruating women loose additional 25-30mg. Iron for a month

•In normal daily food there is app. 12-15mg. Iron; 3.5mg. entering intestinal mucosa; 1-1.5mg. can be absorbed

• Only Fe++ (ferro) form can be absorbed; Absorption increase in presence of Ascorbic acid and diminish in presence of phosphates and oxalates

• Iron stores

•Ferritin (active)(N 50-150ug/l)

•Hemosiderin (inactive)

Causes for 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 vera

• Decreased iron intake or absorption

• Inadequate diet

• Malabsorption from disease (sprue, Crohn's disease)

• Malabsorption from surgery (post-gastrectomy)

• Acute or chronic inflammation

Symptoms:

• Fatigue

• Tachycardia

• Pallor

• Koilonychia

• Glossitis

• Angular stomatitis

• Gastric atrophy.

• Head ache

Laboratory:• CBC with differential

•Red cells morphology (blood smear)

•Red cells indices (MCV; MCH; MCHC)

•Serum Iron; TIBC; Ferritin; TrSat (N 30-50%)

•Bone marrow aspirate with Perl’s staining (Iron stores)

•Testing stool for the presence of hemoglobin

•Gastroscopy

•Colonoscopy

• Gynecologist consultation

Treatment

• Establishing the diagnosis and reason for the iron deficiency

• The iron deficiency should be treated with oral iron therapy, and the underlying etiology should be corrected so the deficiency does not reocur.

• The most economical and effective medication in the treatment of iron deficiency anemia is the oral administration of ferrous iron salts (ferrous sulfate)

• Reserve parenteral iron for patients who are either unable to absorb oral iron or who have increasing anemia despite adequate doses of oral iron. It is expensive and has greater morbidity than oral preparations of iron.

Reticulocytosis on day 3-4 , max. on day 10

Drug Name

•Ferrous sulfate -Mainstay treatment for treating patients with iron deficiency anemia. They should be continued for about 2 mo after correction of the anemia and its etiological cause in order to replenish body stores of iron. Ferrous sulfate is the most common and cheapest form of iron utilized. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less

intestinal discomfort because they contain a smaller dose of iron (25-50 mg).

Contraindications

•Documented hypersensitivity; microcytic anemias without laboratory

documentation of iron deficiency

Interactions

•Calcium supplementation decreases bioavailability of iron when metals are ingested simultaneously; absorption is enhanced by ascorbic acid; interferes with tetracycline absorption; food and antacids impair absorption

Prognosis:

• Iron deficiency anemia is an easily treated disorder with an excellent outcome; however, it may be caused by an underlying condition with a poor prognosis, such as neoplasia. Similarly, the prognosis may be altered by a comorbid condition such as coronary artery disease.

Medical Pitfalls:

•Failure to investigate the etiology of the iron deficiency anemia causing a delayed or missed diagnosis of neoplasm•Anaphylaxis pursuant to the use of parenteral iron therapy in patients who should be treated with oral iron

Megaloblastic anemia

• Megaloblastic anemias are a heterogeneous group of disorders that share common morphologic characteristics

• The most common causes of megaloblastosis are cobalamin (vitamin B-12) and folate deficiencies (vitamin B9)

• Folate deficiency is usually due to folate-poor diets but may also occur in patients with sprue, during pregnancy, and in patients on antifolate or other medications

• The molecular basis for megaloblastosis is a failure in the synthesis and assembly of DNA

The assimilation of cobalamin. On entering the stomach, dietary cobalamin (Cbl) forms a complex with R binding protein. As this protein is digested in the small intestine, cobalamin is transferred to intrinsic factor (IF). This complex passes through the intestine until it reaches specific receptors on the mucosa of the distal ileum. The internalized Cbl is then transferred to transcobalamin II (TC II), which circulates in the plasma until it binds to receptors on cells throughout the body and is internalized.

Folate is essential for the de novo synthesis of purines, serving as an intermediate carrier of 1-carbon fragments used in the biosynthesis of these compounds. Its active form is tetrahydrofolate (THF)..

COBALAMIN DEFICIENCY

I. Inadequate intake: vegetarians (rare)

II. Malabsorption

A. Defective release of cobalamin from food: (Gastric achlorhydria; Partial gastrectomy; Drugs that block acid secretion)

B. Inadequate production of intrinsic factor (IF): ( Pernicious anemia; Total gastrectomy; Congenital absence or functional abnormality of IF (rare))

C. Disorders of terminal ileum: (Tropical sprue; Nontropical sprue; Regional enteritis; Intestinal resection; Neoplasms and granulomatous disorders (rare); Selective cobalamin malabsorption )

D. Competition for cobalamin: (Fish tapeworm (Diphyllobothrium latum); Bacteria: "blind loop" syndrome; Drugs: p-aminosalicylic acid, colchicine, neomycin)

III. Other

A. Nitrous oxide

B. Transcobalamin II deficiency (rare)

FOLIC ACID DEFICIENCYI. Inadequate intake: unbalanced diet (alcoholics, teenagers, some infants)II. Increased requirements

A. PregnancyB. InfancyC. MalignancyD. Increased hematopoiesis (chronic hemolytic anemias)E. Chronic exfoliative skin disordersF. Hemodialysis

III. MalabsorptionA. Tropical sprueB. Nontropical sprueC. Drugs: Phenytoin, barbiturates, ethanol

IV. Impaired metabolismA. Inhibitors of dihydrofolate reductase: methotrexate, triamterene,

pentamidine, trimethoprimB. AlcoholC. Rare enzyme deficiencies: dihydrofolate reductase, others

Clinical

1. Hematologycal symptoms: anemia; rare granulocyto or thrombocytopenia

2. Gastrointestinal symptoms: mucosal trophic changes; loss of appetite, weight loss, nausea, and constipation.

3. Neurological symptoms: paresthesias in the feet and fingers, poor gait, and memory loss. At later stages, patients can have severe disturbances in gait, loss of position sense, blindness due to optic atrophy, and psychiatric disturbances. In some patients, neurological impairment can occur without anemia. Therefore, neurological symptoms may range from mild to severe, and cobalamin deficiency should be considered even with minimal neurological symptoms and the absence of anemia.

Laboratory

1. Peripheral blood smear: hyperchromic megalocytes;

MCV>110fl.; MCH>34pg.; normal MCHC;

hypersegmented neutrophils; Low Reticulocyte count

2. Bone marrow: megaloblastic erythropoiresis: increased

erythroid/ myeloid ratio; Howell-Joly bodies(nuclear

fragments); giant myeloid precursors

3. Hight serum Iron level; High LDH and iBill level; Low

serum level of Cobalamin and Folic acid

Workup

1. Gastroscopy with biopsy

2. Schilling test

3. Neurologic status

4. anti IF Ab

Differential

1. MDS

2. Chemotherapy

3. Gastric cancer

4. Alcohol addiction

5. Bone marrow metastasis

This marrow section demonstrates so-called nuclear-cytoplasmic dissociation; The slow nuclear maturation is related to a decrease in DNA synthesis related to an insufficient supply of reduced folate to synthesize thymidylate. DNA synthesis inhibitors can produce this picture, as can folate and B12 deficiency.

Treatment

•Most patients with megaloblastosis are treated with cobalamin and folate therapy to treat deficiencies in these substances

•Transfusion therapy should be restricted to patients with severe, uncompensated, and life-threatening anemia

•Because megaloblastic anemias usually develop gradually, most patients have adjusted to low Hb levels and do not require transfusions.

•Cobalamin (1000 mcg) should be given parenterally daily for 2 weeks, then weekly until the hematocrit value is normal, and then monthly for life. This dose is large, but it may be required in some patients

•Folate should be administered orally (150-400 (400-800)g/d)

Prevention:

•Patients who have undergone either total or partial gastrectomies should receive lifelong monthly doses of cobalamin (1000 mcg IM).

Prognosis:

•Prognosis is good if the etiology of megaloblastosis is identified and appropriate treatment is instituted. However, patients are at risk for complications of anemia, such as cardiac impairment and hypokalemia, during therapy for cobalamin deficiency.

Medical Pitfalls:

•Failure to avoid treating patients with potential cobalamin deficiency with folate alone because this may lead to severe neuropsychiatric disease

•Failure to recognize and treat incipient neuropsychiatric impairment

•Failure to administer folate during pregnancies to avoid abnormal fetal development

•Failure to appropriately investigate macrocytosis

Bone marrow aspirate in megaloblastic anaemia showing early, intermediate and late megaloblasts and a giant metamyelocyte [arrow].

Bibliography:

• P. Apostolov, Internal medicine , 2004

•Harrison’s Principles of Internal medicine, 15th Edition

•B. Bain, Hematology image bank

•Marcel E Conrad, MD, Anemia, eMedicine 2004

•Marcel E Conrad, MD , Iron deficiency anemia, eMedicine 2004

•Paul Schick, MD, Megaloblastic anemia, eMedicine 2002