Anemia

Introduction

• Not a single disease• Results from a number of different pathologies• Defined as a reduction from the normal quantity of

Hb in blood• Who defines anemia as Hb levels less than 13 g/dl for

males and less than 12 g/dl for females• Low Hb levels results in decreased oxygen carrying

capacity of blood

Epidemiology

• Most common condition resulting in significant morbidity and mortality

• Worldwide: Over 50% of pregnant women and 40 % of infants are anemic

Aetiology

Two different mechanisms:1. Reduced Hb synthesis (due to lack of nutrient

or bone marrow failure)

Reduced proliferation of precursors or defective maturation of precursors or both

Aetiology (contd…)

• Increased Hb loss due to haemorrhage (red cell loss) or hemolysis (red cell destruction)

(More than one cause can be found in a patient)

Normal erythropoiesisPluripotent stem cell

Erythroid burst forming unit

Erythroid colony forming unit Within BM

Erythroblast

Reticulocyte Peripheral blood

Mature red cell

Normal erythropoiesis (contd…)

• Erythropoietin production si impaired n condictions such as RA, cancer and Sickle cell anemia

• Each day about 2 *1011 erythrocytes enter the circulation

• Normally survive for 120 days

Normal erythropoiesis (contd…)

• Destroyed by reticuloendothelial system found in spleen and BM

• Iron is removed from haem component of Hb and transported back into bone marrow for reuse

Normal erythropoiesis (contd…)

• Pyrole ring from globin is excreted as conjugated bilirubin by the liver and the polypeptide portion enters the body’s protein pool

Clinical manifestations• Mildest form: tiredness and lethargy, reduced

mental performance

• Non-specific signs and symptoms associated with anemia:

Tiredness, Pallor, Fainting, Exertional dyspnea, Tachycardia, Palpitations, Worsening angina, Worsening cardiac failure, Exacerbation of intermittent claudication

Investigations• No place for blind treatment

• Anemia is a consequence of reduced concentration of Hb in each red cell and/or reduced number of red cells in peripheral circulation

• Imp parameter: Hb concentration of blood, including its size , shape and color, MCV to determine type of anemia

• Bone marrow examination

Iron deficiency anemia

• Epidemiology: 20% of world’s population

• Cause: diet deficient in iron, parasitic infestations and multiple pregnancies

• Aetiology: Blood loss, GI bleeding (most likely), Haemorrhoids, nosebleeds or postpartum haemorrhage

Iron deficiency anemia

Causes of Iron deficiency anemia

• Inadequate iron absorptionDietary deficiencyMalabsorption

• Increased physiological demand• Loss through bleeding

Pathophysiology

• Elimination not controlled physiologically• Homeostasis maintained by controlling iron absorption• Absorption inefficient• Iron bound to haem is better absorbed than iron found

in vegetables• Phosphates and phytates leads to formation of

unabsorbable complex, while ascorbic acid increases iron absoprtiopn

Pathophysiology (contd…)

• Anemia a result of mismatch between body’s iron requirement and iron absoprtion

• Fortified milk given to children up to the age of 18 months increases Hb levels and improve performance

• Iron malabsoprtion occurs in patients with coleliac disease and in 50% patients following gastrectomy

Pathophysiology (contd…)

• During pregnancy: dilutional anemia• Some of the increased demand is met by

stopping menstruation

Whatever the cause might be inadequate iron absorption leads

to anemia

Clinical manifestations

• Pale skin and mucous membrane• Painless glossitis• Angular stomatitis• Koilonychia• Dysphagia• Pica• Atrophic gastritis

Investigations

• Serum iron, Total iron binding capacity (TIBC) and serum ferritin

• Aim: To correct anemia and replenish iron stores

Important to resolve the underlying cause as far

as possible

Treatment

• Folic acid use during pregnancy• Prophylaxis in menorrhagia, after partial

gastrectomy and in some low birth weight infants

• Continue for 6 months to both correct anemia and replenish body stores

• Standard treatment: 200 mg three times a day

Treatment (contd…)

• It takes 1 to 2 weeks for Hb level to rise to 1 g/dl

• N and abdominal pain occurs in some patients• Alternative salts of iron are tried• Absorption is 15% of intake during the first 2-3

weks but falls off to an average of 5% thereafter

• Modified release oral preparations also available

Treatment (contd…)

• There is little place for parenteral iron• In renal patients, a regular weeks dose is often

given and patients’ serum ferritin monitored to check for iron overload

MEGALOBLASTIC ANEMIA

• They are macrocytic anemia (raised MCV)• Abnormality in the maturation of

haemopoietic cells in the bone marrow• Two causes: Folate deficiency and Vit. B12

deficiency anemia• Pernicious anemia is a specific disease caused

by malabsorption of Vit B12

Aetiology

Folate deficiency anemia

• Readily available in normal diet (Fruit, green vegetables and yeast)

• Folate deficiency either due to folic acid deficiency anemia or increased folate utilization

Aetiology (contd…)

Vitamin B12 deficiency anemia • Inadequate intake or malabsorption (dueto

removal of distal ileum)• Dietary source: Food of animal origin• Daily requirements: 1-2 micrograms

Pathophysiology

• Common: inhibition of DNA synthesis in maturing cells

Folate deficiency anemia

Dietary folate Gut

Folate monoglutamate

Methyltetrahydrofolate monoglutamate

Tetrahydrofolate monoglutamate Bone

Tetrahydrofolate polyglutamate marrow

Folate co-enzymes Dihydrofolate Polyglutamate

Pathophysiology of Vit. B12 deficiency anemia

• Absorption occurs by an active process• Enzyme in the stomach release Vit. B12 from protein complexes• One molecule of Vit. B12 combine with one molecule of

glycoprotein (called intrinsic factor)• There are specific receptors in the distal ileum for intrinsic

factor-Vit B12 complex• Vit B12 enters the ileal cell and is then transported through the

blood attached to transport proteins• A total gastrectomy always leads to Vit. B12 deficiency• Onset of anemia is usually delayed

Pathophysiology of pernicious anemia

• Autoimmune in origin• Patients typically have a gastric atrophy and no or

virtually no intrinsic factor secretion• Two different intrinsic factor antibodies have been

produced in serum of patients with pernicious anemia

• Gastric parietal antibodies found (in 90% patients)

Clinical manifestations• Glossitis• Angular stomatitis• Altered bowel habit• Anorexia• Mild jaundice• Insiduous onset• Sterility• Bilateral peripheral neuropathy• Melanin skin pigmentation• Fever

Investigations

Folic acid deficiency anemia

• Symptomless initially• Large oval red cells• Anisocytosis and poikilocytosis• Thrombocytopenia

Investigations (contd…)

Vit B12 deficiency anemia

• Serum Vit B12 level• Serum folate level• Measuring absorption of Vit. B12 (by Schilling

test)• Parietal cell antibodies (not accurately

diagnostic)

Treatment

• Necessary to establish whether the patient with megaloblastic anemia has Vit. B12 deficiency or folic acid deficiency or both

Treatment of folate deficiency anemia

• Replacement therapy• Duration of treatment depends on cause• Changes in dietary habit or removal of any

precipitating factor• Normal daily requirement approx. 100 micrograms

per day• Dose: 5-15 mg per day for 4 months• Parenteral folic acid treatment not normally required

Treatment of folate deficiency anemia during pregnancy

• Folate requirement increases in pregnancy and is higher in twin pregnancies

• Prophylaxis with folate ( 350-500 micrograms) frequently given during pregnancy

Treatment of Vit. B12 deficiency anemia

• Require life long replacement therapy• Transfusion not normally given• If emergency transfusion deemed necessary, packed cells may

be given• Diuretics also given• Definite diagnosis should be made before starting treatment• Std. treatment: Hydroxocobalamin 1 mg IM repeated five

times at 3 day intervals to replenish body stores, followed by maintenance dose, usually 1 mg IM every 3 months.

Sideroblastic anemias

• Group of conditions diagnosed by finding ring siderobalst in the BM

• Both hereditary and acquired forms present

Aetiology

• In hereditary forms, there is X chromosome linked pattern of inheritance

• Both autosomal dominant and autosomal recessive families present

• Defect: Reduced activity of the enzyme 5-aminolevulinate synthase (ALAS)

Pathophysiology

• Examination of BM shows number of erythroblasts that have iron granules surrounding the cell nucleus (known ad ring sideroblast)

• Low levels of ALAS in hereditary forms• Drugs and toxins: Alcohol, Isoniazid in slow

acetylators, Dose of Chloramphenicol over 2 g

Clinical manifestations

• Develop on infancy or childhood• Severe or mild anemia• Splenomegaly• Idiopathic forms tends to develop insiduously

(middle age or later)• Many becoem asymptomatidc for long

periods

Investigations

• In heriditary fomrs: red cells in peripheral blood are hypochromic and microcytic

• Increased iron stores in BM• Serum iron and ferritin high• In acquired forms: Peripheral blood has hypochromic

cells which may be either normocytic or macrocytic• Common finding: Presence of sideroblast in BM

Treatment

• For hereditary forms: 200 mg daily Pyridoxine• Frequent blood transfusion required in

unresponsive patients• Desferrioxamine given i.v or s.c• Oral Vit. C

Hemolytic anemias

• Reduced life span of erythrocytes• Imbalance between rate of destruction and

rate of production• Presence of both genetic and acquired

disorders

Aetiology of Sickle cell anemia

• They have a different form of Hb (Hb S)• Patients with homozygous Hb S develop many

problems including anemia• Sickle cell trait is usually asymptomatic• The offspring from a father with a trait and a mother

with a trait has a 1 in 4 chance of having sickle cell disease

•

Aetiology of Thalassaemias

• No alpha chain production or reduced production of a chain

• Heterozygotes are symptomless

Aetiology of G6PD deficiency

• Large variants of G6PDdeficiency• It is an enzyme involved in the production of

reduced glutathione

Pathophysiology of Sickle cell disease

• Membrane of red cells containing Hb S is damaged (lead to IC dehydration)

• Polymerization of Hb S occurs when the patients blood is deoxygenated

• These two processes lead to crescent-shaped cells (known sickle cell)

Pathophysiology of Sickle cell disease (contd…)

• Sickle cells are less flexible than normal cells• This leads to local tissue hypoxia• Anemia results from an increased red cell

destruction

Pathophysiology of Thalassemia

• Reduced or absent production of globin beta chain• Leads to relative excess of alpha chain, when

unpaired become unstable and precipitate in red cell precursors

• Ineffective erythropoiesis• In alpha thalassemia, deficiency of alpha chain leads

to an excess of beta or gamma chains

Pathophysiology of Thalassemia (contd…)

• Erythropoiesis is less affected but Hb produced is unstable when the cells are in circulation and precipitate as the cells grow older

Pathophysiology of G6PD deficiency

• Essential for the production of reduced form of NADPF in RBC

• NADPH is needed to keep gluthathione in reduced form

• Glutathione helps RBC deal with oxidative stress

• In G6PD deficiency Hb becomes oxidised and Heinz bodies are form

Clinical manifestations

• Malaise• Fever

Abdominal pain• Dark urine• Jaundice

Clinical manifestations of Sickle cell anemia

• Chronic anemia, arthralgia, fatigue, splenomegaly. Crisis precipitated by infection, fever. Dehydration, hypoxia or acidosis. Severe pain is a common feature.

Clinical manifestations of thalassemia

• Causes Erythropoietin production to increase andresulst in expansion of BM

• Bone deformity and growth retardation• Spleen becomes enlarged

Clinical manifestations of G6PD deficiency

• Two forms• This form is self-limiting

Treatment

• Sickle cell anemia: prophylactic antibiotics (Penicillin V 250 mg b.d), pneumococcal vaccine, hydroxyurea is effective.

• Thalassemia: transfusion, desferroxamine and deferiprone

• G6PD deficiency: causative oxidising agent stopped and general supportive measures adopted. No specific drug treatment for this disorder