ANAEMIA

Dr R. Z. Azma

Anaemia
Defination: Anaemia - haemoglobin (Hb) - red blood cells (RBC) (reduction of more than 10% of the normal value of Hb or total number of RBC for age and sex)

Reference ranges for Hbs at different ages

Age group Newborn (< 1 week) 6 months old Children (1 16 years) Adults Men Women

Hb range (g/dl) 14 22 11 14 11 15 13 16 12 - 14

Anaemia
Clinical grading (Adults) Mild (Hb > 10 g/dl) Moderate (Hb 7 10 g/dl) Severe (Hb < 7 g/dl) Asymptomatic Pallor, lethargy Dyspnoea, vertigo headache Tachycardia hypotension

Mechanisms of anaemia
Production of RBCs depends on:
Haemopoietic stem cells (to function satisfactorily) Erythroid precursor cells (normal maturation and released into circulation) Hb synthesis (to function normally)

Mechanisms of anaemia
1. Decreased production
Ineffective erythropoiesis
Deficiency of B12/folate Abnormal synthesis of haemoglobin (thalassaemia) Aplastic anaemia/marrow failure

Decreased effective erythropoiesis

2. Increased blood loss

Gastrointestinal bleeding haemolysis

3. Increased destruction

Classification of anaemia
1. Morphological
Based on red cell indices and blood film
Hypochromic microcytic anaemia (MCV , MCH) Normochromic normocytic anaemia (MCV N, MCH N) Normochromic macrocytic anaemia (MCV , MCH N)

2. Pathophysiological
Based on causes of anaemia
Iron deficiency anaemia Megaloblastic anaemia Haemolytic anaemia

Classification of anaemia
MCV mean corpuscular volume (fl) MCH mean corpuscular Hb (pg) MCV (80 100 fl) MCV (< 80 fl) MCV (>100 fl) Normocytic Microcytic Macrocytic

MCH (27 - 32 pg) MCH (< 27 pg)

Normochromic Hypochromic

Physiological adaptations to anaemia Reduced delivery of oxygen to tissues Increased erythropoietin secretion by kidneys More rapid delivery of blood
Heart rate and respiratory rate increased Cardiac output increased

Increased in RBC 2,3 DPG shifts oxygen dissociation curve to the right.

Iron deficiency anaemia

A form characterized by low or absent iron store, low serum iron conc, low transferrin saturation, elevated transferrin, low Hb conc or hematocrit, n hypochromic, microcytic rbc

Epidemiology
Iron deficiency anaemia (IDA) is the commonest macronutrient deficiency in man despite abundant iron content in the earth crust. 30% of world population 50% of pregnant women 20% women 3% of men

Aetiology
IDA - reduction in iron supply to red cell precursors. Causes
1. Dietary - defective intake of iron: poverty, religious tenets, vegetarian 2. Increase physiological requirement infants, children, pregnancy 3. Blood loss - GIT (peptic ulcer, haemorrhoids), menorrhagia. 4. Malabsorption partial gastrectomy, gluten induced enteropathy

Aetiology
IDA - reduction in iron supply to red cell precursors. Causes
1. Dietary - defective intake of iron: poverty, religious tenets, vegetarian 2. Increase physiological requirement infants, children, pregnancy 3. Blood loss - GIT (peptic ulcer, haemorrhoids), menorrhagia. 4. Malabsorption partial gastrectomy, gluten induced enteropathy

Clinical features
Symptoms Anaemia Lethargy Dyspnoea Headache Poor concentration Palpitation IDA deficiency Dysphagia Signs Anaemia Pallor Tachycardia IDA deficiency Painless glossitis Angular stomatitis Koilonychia Skin atrophy

Clinical features

Koilonychia in severe iron deficiency aneamia Hiatus hernia can cause IDA

Laboratory investigations
Full blood count FBC
Hb MCV MCH.

Peripheral blood film Serum iron and TIBC Serum ferritin Bone marrow iron (rarely)

Laboratory investigations
Typical results seen in iron def. anaemia
Reduced Haemoglobin Reduced MCV, MCH, MCHC Peripheral blood film: hypochromic microcytic anaemia Reduced serum iron with raised TIBC Reduced serum ferritin Absent iron stores in bone marrow

Full blood picture of iron deficiency anaemia

Treatments
To correct anaemia and replenish iron stores:
Oral iron Parenteral iron

Treat the underlying causes.

Megaloblastic Anaemia
Characterized by megaloblast in bm, such s PA

Megaloblastic anaemia
Causes Vitamin B12 deficiency Folate deficiency

Megaloblastic anaemia
Impaired synthesis of DNA due to reduced supply of the immediate precursors of DNA
dA(adenine)TP and dG(guanine)TP (purines) dT(thymine)TP and dC(cytosine)TP (pyrimidines)

Folate def: impairs in synthesis of dTTP

folate is coenzyme for thymidylate synthesis.

Vit B12 - cofactor to convert methyl THF which enters the cell fr plasma to THF.

Megaloblastic anaemia
Lack of B12 slow demethylation of methyl THF THF purine synthesis

Ineffective haemopoiesis

supply of precursors needed for DNA synthesis

incomplete replication of chromosomal DNA apoptosis of NRBC in BM

In severe def affect all 3 cell lines (pancytopenia)

Vit B12 def

CAUSES Malabsorption
Gastric causes
Pernicious anaemia Congenital IF absence/abn fx Total/partial gastrectomy

Intestinal causes
Fish tapeworm Intestinal stagnant loop syndrome Ileal resection Crohns ds

Inadequate dietary intake

Vegetarian poverty

Pernicious anaemia
MA,affect older adults due 2 failure of gastric mucosa 2 secrete adequate n potent IF Severe lack of IF gastric atrophy. Autoimmune in origin May a/w myxoedeme, Hashimotos ds, Addisons ds, vitiligo, hypoparathyroidism & hypogammaglobulinaemia. Occur in families, F > M, 60 yr, blood gp A incidence of Ca stomach. Thin stomach wall, plasma cell & lymphoid infiltrate of the lamina propria

Pernicious anaemia : (L) normal, (R) atrophy of all coats, loss of gastric glands & parietal cells & infiltration of the lamina propria by lymphocytes & plasma cells achlorhydria & sec. of IF is absent.

Pernicious anaemia : showing premature greying, blue eyes & vitiligo

Marked vitiligo

Pernicious anaemia
Antibodies : - 90% ; parietal cell Ab in serum - 50% ; type I or blocking Ab to IF ( inhibit IF bind to B12 ) - 35% ; type II or precipitating Ab to IF, inhibits its ileal binding site. - 50% ; IF Ab, inhibit IF fx in gastric juice. Congenital PA : presentation develop after age of 2 ( Cong. Lack of IF )

Folate def
CAUSES Nutritional vegetarian, poverty, goats milk anaemia Malabsorption tropical sprue, Coeliac ds, partial gastrectomy, Crohns ds Excess utilization pregnancy, haematological ds, inflammatory ds. Excess urinary loss active liver ds, CHF Drugs anticonvulsants, hyroxyurea Others alcoholism, intensive care.

Coeliac disease

Coeliac disease (gluten-sensitive enteropathy or coeliac sprue) is disease of small intestine. Gluten (substance found in wheat, barley and rye) activates the immune system and causing damage to the delicate lining of the small bowel responsible for absorbing nutrients and vitamins. Histological section of jejunal bx villous atrophy with absence of vili and hypertrophy of the mucosal crypts

Figure 1: Healthy villi of the small intestine (as seen under the microscope).

Figure 2: Damaged villi of the small intestine.

Figure 3: Villi completely destroyed by the immune system. Absence of vili and hypertrophy of the mucosal crypts

Clinical features
Symptoms and signs of anaemia Weakness Tiredness Shortness of breath Pale Angina Heart failure Symptoms and signs of b12/folate deficiency Glossitis Angular cheilosis Neurological symptoms

Clinical features

Lemon-yellow appearance
combination anaemia & jaundice ( excessive Hb breakdown in BM due to ineffective erythropoiesis )

Glossitis - the tongue is beefy-red & painful due to impaired DNA synthesis in the mucosal epithelium.

Angular cheilosis due to impaired proliferation of epithelial cells

Clinical features
Neurological symptoms : - numbness - spastic ataxia : demyelination of the lateral & posterior columns - Brain involvement : optic atrophy somnolence dementia frank psychosis

General tissue effects of cobalamin & folate deficiency Severe def. will affect rapidly growing ( DNAsynthesizing ) tissues :
Marrow : megaloblastic anaemia Macrocytosis of epithelial cell surfaces ; mouth, stomach, small intestine,respiratory, urinary & female genital tracts. Prematurity maternal c folate def. Neural tube defects folate def in early pregnancy

VITAMIN B12 NEUROPATHY

Cobalamine def may cause:

( Subacute combined degeneration of the cord )

bilateral peripheral neuropathy / degeneration of the post. & pyramidal tracts of the spinal cord Rarely: optic atrophy and mental abnormalities

Long term def in infancy leads to poor brain development & impaired intellectual development. Cause : accumulation of S adenosyl homocysteine ( excessive homocysteine entry, no B12 to convert to methionine )

Pernicious anaemia : cross section of spinal cord of a pt who died c severe vit B12 neuropathy ( subacute combined degeneration of the spinal cord ). There is demyelination of the lateral & posterior columns

Laboratory findings

FBC: Anaemia, in severe def pancytopenia, high MCV, normal MCH.

PBF: Macrocytosis with anisopoikilocytosis

PBF: Hypersegmented neutrophils

BMA: Hypercellular - megaloblasts with dyserythropoiesis..

giant metamyelocytes

..hyperpolypoid megakaryocytes.

Other blood investigations

Serum folate low in folate deficiency Serum B12 low in B12 deficiency

Management
Folate deficiency Tablet folic acid daily B12 deficiency Intramuscular hydroxocobalamin, every 3 months. Those with Subacute combined degeneration of the cord if treat with folate without B12, worsen the condition.

HAEMOLYTIC ANAEMIA
Any of heterogenous grp of inherited anemias characterized by shortened rbc survival, lack of spherocytosis, n normal osmotic fragility with erythrocyte membrane defects, multiple intracellular enz def or other defect or unstable Hb

Haemolytic anaemia
Normal RBC lifespan is 120 days after which they are removed by RES (marrow, liver, spleen). Haemolytic anaemia anaemia due to increased rate of red cell destruction. Erythroid hyperplasia and anatomical expansion of the marrow.

Haemolytic anaemia
The normal adult marrow is capable of producing red cells 6 - 8x more than normal rate, provided that there is adequate supply of iron, folate and B12. HA is seen when the red cell survival is less than 30 days. Mechanism:
Intravascular: haemolysis occur in circulation Extravascular: removal of RBC in the RES

Clinical features
Pallor Mild Jaundice Splenomegaly Some may have painful right abdomen (chronic haemolysis pigment gallstone) Haematuria (intravascular haemolysis) Bossing of frontal and parietal bones mongoloid appearance (marrow expansion in chronic haemolysis)

Laboratory findings
Anaemia with reticulocytosis. PBF showed: spherocytes with polychromatic cells (reticulocytes).

Spherocytes

Laboratory findings
serum bilirubin urine and faecal urobilinogen serum haptoglobin Bone marrow: erythroid hyperplasia compensation mechanism Ultrasound of abdomen gallstone

Laboratory findings
Features of intravascular haemolysis (others similar with extravascular haemolysis) Fragmented red cells (schizocytes) seen in PBF. Haemosiderinuria (iron storage protein, derived from the breakdown of Hb in the renal tubular cells) Haemoglobinaemia S Haemoglobinuria

Classification of HA

Hereditary haemolytic anaemia Acquired haemolytic anaemia

Classification of HA
HEREDITARY HAEMOLYTIC ANAEMIA Membrane defects
Hereditary Spherocytosis

Metabolic defects
G6PD def

Haemoglobin defects
Defective synthesis (thalassaemia /) Abnormal variants (eg. Hb S, Hb C, unstable)

H. Elliptocytosis / H. Pyruvate kinase def Pyropoikilocytosis

H. Stomatocytosis
South-east Asian ovalocytosis

Pyrimidine 5nucleotidase def

Glutathione synthase def

ACQUIRED HAEMOLYTIC ANAEMIA

IMMUNE

NON-IMMUNE

AUTOIMMUNE

ALLOIMMUNE

INFECTIONS

Warm autoimmune HA

Haemolytic Transfusion Reaction

FRAGMENTATION SYND
CHEMICAL AND PHYSICAL AGENTS

Cold autoimmune HA

Haemolytic Disease of Newborn

DRUGS

G6PD deficiency
G6PD catalyses the first step of pentose phosphate pathway to produce NADPH. Def of G6PD NADPH production lack of reduced glutathione (GSH) which protect the membrane Hb & other cell structure fr oxidant damage.

G6PD deficiency
Mild G6PD deficiency is usually asymptomatic. It is present in all cells but patient become symptomatic in response to oxidant stress (drugs, fava beans) or infections. In severe G6PD patient may have chronic haemolytic anaemia. Clinical findings: anaemia, mild jaundice, haematuria

G6PD deficiency
Lab findings; FBP: red cells with contracted Hb in ghost membrane blister cells, bite cells, NRBC Haemoglobinuria Haemosiderinuria Screening test: Ultraviolet spot test negative G6PD assay (quantitative): low
(The screening and quantitative tests should not be done during acute event)

Thalassaemia
Results from a reduced synthesis of or chains. Autosomal recessive inheritance Classifications:
Genetic
If no globin chain is synthesized at all 0 / 0thalassaemia If some is still produced + / +-thalassaemi

Clinical

Thalassaemia
Clinical classifications classified according to degree of severity of symptoms:
1. Major = severe anaemia and transfusion dependent. 2. Intermedia = anaemia and splenomegaly 3. Minor = symptomless carrier only show changes in red cell indices (hypochromic microcytic red cells).

Symptomatic for HA:

thal major,Hb Barts and HbH ds

 Thalassaemia
thalassaemia syndromes majority of genetic lesions are point mutations. thalassaemia trait ( o or +) - asymptomatic (clinically minor) thalassaemia major (o o or o +) symptomatic:
Either no chain (o) or small amounts (+) are synthesized. Excess chains precipitate in erythroblasts and in mature red cells causing ineffective erythropoiesis and haemolysis.

 Thalassaemia

Beta thal major inheritance

 Thalassaemia
Clinical features (major):
Severe anaemia Hepatosplenomegaly excessive red cell destruction and extramedullary haemopoiesis. Expansion of bones marrow hyperplasia thalassaemic facies.

 Thalassaemia
These are usually due to gene deletions Asymptomatic in 1 or 2 gene deletions (/- , - /- or /--) Symptomatic when 3 or 4 gene deletions (-/-- or -/--). Hb H 3 gene deletions, small amount chain available excess beta chain forming tetramers (4) and precipitate in red cells (known as H inclusions).

 Thalassaemia

Hb H inheritance

Patient survived till old age and some times require blood transfusion (thalassaemia intermedia).

 Thalassaemia
Hb Barts, no available globin chain:
failure foetal Hb synthesis (eg. Hb F). Excess chain forming tetramers (4 known as Hb Barts). death in utero or at birth
Hydrop fetalis inheritance