Transcript IDA-Maj-Gen-M-Ayyub-Megaloblastic-anaemia
PROBLEM ?
A 9 year old girl has presented with history of progressive pallor for the last 6 months General physical examination reveals marked pallor while abdominal examination is unremarkable Full blood counts show – TLC 8 x 10 9 /l – Hb 7.5 g/dl – Platelet count 300 x 10 9 /l – MCV 60 fl – MCH 17pg – MCHC 18 g/dl
PROBLEM ?
What is the most likely diagnosis ?
What investigations you will carry out to confirm the diagnosis ?
Out line management.
IRON DEFICIENCY ANAEMIA
Iron deficiency anaemia is the most common of all the anaemias encountered in clinical practice. Yet it is most often mismanaged.
HYPOCHROMIC MICROCYTIC ANAEMIA
Iron deficiency anaemia Thalassaemia trait Anaemia of chronic disorder Sideroblastic anaemia
IRON BALANCE
Iron is the most abundant metal in human body, about 3.5 gm in an adult man; yet the body rigorously conserves it like a trace element.
Intestinal absorptio n 1 mg/day Stores 1 gm
IRON CYCLE
Hb synthesis & Erythropoiesis Plasma iron 13-32 umol/l Loss 1 mg/day RBC 2.3 gm RBC destruction & Hb catabolism
TOTAL BODY IRON
Adult male (50 mg/kg) Adult female (35 mg/kg) • Hb • Stores • Mb • Enzymes 2.3 gm 1.0 gm 0.14 gm 0.06 6m 3.5 gm 2.5 gm
IRON BALANCE
Daily loss Average daily in-take 1-2 mg 10-15 mg Normally absorbed (10%) 1-2 mg Enhancement in deficiency 3-5 (20-25% 0f in-take) mg
IRON ABSORPTION - 1
Cells regulate iron acquisition through post transcriptional control of apoferritin and transferrin receptor synthesis.
mRNA of both proteins contain iron responsive elements (IRE) capable of binding iron regulatory proteins (IRP) 1 & 2.
Binding of these proteins has opposing effects on two mRNAs.
IRON ABSORPTION - 2
Transferrin receptor synthesis is directly influenced by the rate of erythropoiesis and indirectly by amount of storage iron (ferritin)
IRON ABSORPTION - 3
Rate of erythropoiesis/amount of ferritin Transferrin receptor synthesis Transferrin synthesis/secretion in bile Apoferritin and transferrin/mobilferrin in intestinal cell
IRON DEFICIENCY
For an individual to become iron deficient, a prolonged period (approximately 6 years), of negative iron balance is required .
IRON DEFICIENCY - STAGES
A. Pre - latent iron deficiency Reduction in iron stores without reduction in plasma iron. Serum ferritin & bone marrow iron are reduced.
B. Latent iron deficiency Exhaustion of iron stores without reduction in Hb concentration. Plasma iron decreases, TIBC increases and transferrin saturation decreases.
C. Iron deficiency anaemia Hb concentration starts declining. Early stage is discovered by chance. Late stage (Hb 8.0 gm) is symptomatic.
IRON DEFICIENCY ANEMIA PATHOGENESIS - 1 Continued negative iron balance Depletion of iron stores Reduction in plasma iron Reduction in Hb synthesis (Increase in free erythrocyte protoporphyrin, hypochromia, microcytosis) Anaemia
IRON DEFICIENCY ANAEMIA PATHOGENESIS - 2 Negative iron balance results from: •Increases requirements (females) or slow and steady loss (occult blood loss) •Decreased in-take (poverty, habits) •Combination of the two (most common) exceeding the physiological limits of absorption adjustment
IRON DEFICIENCY ANAEMIA PATHOGENESIS - 3 Takes about eight years to develop iron deficiency It takes another 2-3 years to become symptomatic Patients with rapidly developing anaemia seldom become iron deficient as iron is replaced by way of red cell transfusions administered to treat it.
DIAGNOSTIC METHODS - 1
A. Assessment of Iron stores a. Serum ferritin b. Bone marrow iron B. Plasma Iron studies a. Plasma iron b. Serum transferrin (TIBC) c. Transferrin saturation
DIAGNOSTIC METHODS - 2
C. Serum Transferrin receptors D. Red Cell Parameters Early stage a. Red cell free protoporphyrin b. Red cell indices Late stage a. Definite anaemia b. More marked changes in red cell indices and morphology
MANAGEMENT The most important component of effective management for IDA is to find out the cause of chronic negative iron balance and to treat it.
Replacement therapy alone will not be able to induce sustained remission.
CAUSES OF IRON DEFICIENCY-1 Increased requirements Decreased in-take Impaired absorption Increased loss (blood loss, 1 ml = 0.5 mg iron )
CAUSES OF IRON DEFICIENCY-3 INFANCY AND CHILD HOOD Prematurity (reduced transfer ) Low birth weight (reduced iron store) Inadequate in-take Increased requirement (with growth) Uncommon vascular anomalies Milk allergy
CAUSES OF IRON DEFICIENCY-4 REPRODUCTIVE FEMALES Menstural disturbances Frequent pregnancies Dietary habits / Pica Hiatus hernia
CAUSES OF IRON DEFICIENCY-5 Hook worms (AD 0.2 ml, NA 0.05 ml / worm / day) Schistosomiasis Ulcerative lesions of GIT Chronic Aspirin ingestion (1-4 ml / day with 02 Tab) Haemorrhoids Neoplasms Runners anaemia (50% of joggers and runners) Nosocomial (ITC 42 ml / day)
INVESTIGATIONS TO DETERMINE THE CAUSE Careful history Thorough physical examination Urine for Hb, haemosidrin, ova Faeces for ova, parasites, occult blood Radiological, Endoscopic examinations Others
CAUSES OF IRON DEFICIENCY-2 Age Sex Socio-economic factors Occupation
REPLACEMENT THERAPY-1 Oral administration is best approach Addition of other elements has no advantage Enteric coating and sustained release reduce absorption Modification of dietary habits greatly improve absorption
RESPONSE
Optimal response with 200 mg elemental iron / day For children 1.5-2 mg / kg / day elemental iron Peak reticulocyte (5-10%) between 5th - 10th day Hb at 03 weeks 60% to normal, normal in 2 months Indices normal in 6 months.
INDICATIONS FOR PARENTAL THERAPY Anatomical lesions of upper GIT Functional lesions of upper GIT Rapid loss Extreme intolerance Consistent non-compliance Haemodialysis
CALCULATION OF REQUIREMENT Requirement (mg ) = ( 15 - pt Hb g / dl )x BW (kg)x 3 Either 2 mg I/M daily Or Total dose I/V
REPLACEMENT THERAPY-2 “ Gain in patient acceptance is more important than the reduced absorption of iron “
CAUSES OF FAILURE Incorrect diagnosis Complicating illness Inadequate prescription Continuing loss / malabsorption Non compliance
PREVENTION
Premature infants : Infants : Pregnancy Others : : 02 mg / kg / day at 02 months 01 mg / kg / day at 04 months 60 mg ( one Tab of 300 mg ) daily According to loss
IN THE NAME OF ALLAH THE BENEFICENT AND THE MERCIFUL
IRON DEFICIENCY ANAEMIA
Maj Gen Muhammad Ayyub MBBS (Pesh), Ph.D (London), FRC Path (UK), Consultant Haematologist & Commandant Army Medical College, Rawalpindi
β THALASSAEMIA TRAIT
Heterozygous state of β thalassaemia Usually asymptomatic Significance of diagnosis Prenatal counselling Prenatal diagnosis Un necessary iron replacement therapy?
LABORATORY INVESTIGATIONS
Blood complete picture Haemoglobin – Mild anaemia as compared to iron deficiency Red cell indices – Hypochromic microcytic Platelet count – Normal RDW – Normal
LABORATORY INVESTIGATIONS
RBC morphology Hypochromic microcytic blood picture with mild poikilocytosis and target cells Definite diagnosis Haemoglobin electrophoresis – Hb A 2 > 3.5%
SIDEROBLASTIC ANAEMIA
Refractory anaemia due to defect in haem synthesis Defined by presence of > 15% ring sideroblasts in bone marrow out of marrow erythroblasts Ring sideroblast?
CLASSIFICATION
Hereditary X linked Mitochondrial Autosomal Acquired Primary – Myelodysplasia Secondary – Alcohol, lead, Anti TB, megaloblastic anaemia etc
MANAGEMENT
Blood transfusion Pyridoxine Thiamine Folic acid
DIFFERENTIAL DIAGNOSIS - 1 IDA THAL TR Hb. (gm/dl) Dimorphism 8.0
MCV (fl) MCHC (gm/dl) Aniso/Poikilo 1-3+ Basophilic stippling 0 Target cells 74 28 + + 12.0
68 31 + 2+ 5% 0 CHR DIS 10.0
86 32 + 0 + + SIDERO 6.0
77 25 1-3+ 2+ 2+ 3+
DIFFERENTIAL DIAGNOSIS - 2 Serum iron Transferrin Saturation Ferritin Transferrin receptors IDA THAL TR N N N N N CHR DIS SIDERO N N N
A 42 years old female presented with h/o pallor and generalized weakness and numbness lower limbs for one year.
General physical exam revealed marked pallor, red beffy tongue. Abdominal exam is unremarkable. FBC TLC 3.0 x 10 9 /l HB Platelet MCV 6.5 g/dl 100 x 10 9 /l 112 fl MCH 30 pg
INTRODUCTION
Megaloblastic anaemias are a group of disorders characterised by the presence of distinctive morphological appearance (megaloblastic) of erythroid cells in the bone marrow.
Majority of the cases have vitamin B12 or folate dificiency
CAUSES
Vitamin B12 deficiency
Folale deficiency
Defective Vitamin B12 or folate metabolism
Transcobalamin II deficiency
Antifolate drugs
Defects of DNA synthesis
Congenital orotic aciduria
Acquired alcohol, hydroxyurea
MACROCYTOSIS
Megaloblastic
Vitamin B12 deficiency
Folate deficiency
Non megaloblastic
Physiological
– –
Pregnancy Infants
Pathological
– –
Alcohol Liver disease
– – – –
Myeloma MDS Myxodema Reticulocytosis
MACROCYTOSIS, A PRACTICAL APPROACH
Check history for alcohol and liver disease
Check complete blood counts for evidence of marrow disease
Check B12 and folate levels
Check LFTs and S TSH
Check reticulocyte count
PATHOPHYSIOLOGY
Methyl tetrahydro folate homocysteine B12 Methionine Tetrahydro folate Tetrahydro folate polyglutamate 5,10 methylene THF polyglutamate DHF polyglutamate DNA
Biochemistry of B
12
Homocysteine Methylmalonyl-CoA methionine synthase B12 methylfolate MMCoA mutase B12 Methionine Succinyl-CoA
CLINICAL FEATURES
Anaemia Jaundice (lemon yellow tint) Glossitis, angular stomatitis Peripheral neuropathy Cardiovascula effects Features due to thrombocytopenia
VITAMIN B12 DEFICIENCY
CAUSES
Nutritional
Malabsorption
–
Gastric pernicious anaemia, intrinsic factor def
–
Intestinal intestinal stagnant loop syndrome, ileal resection, fish tape worm
Stomach Normal
Pernicious Anemia
Pernicious Anemia Stomach Acid + IF Normal gastric parietal cells Atrophic gastritis Achlorhydria No IF
VITAMIN B12 TRANSPORT & ABSORPTION
Dietary cobalamin Haptocorrins (saliva) Intrinsic factor (Gastric parietal cells) Cubilin receptors (Ileum) Transcobalamin II (plasma) Bone marrow and other tissues
VITAMIN B12
NUTRITIONAL ASPECTS
Normal daily intake
Source
Daily requirement
Body stores
Maximum absorption
Enterohepatic circulation
Plasma transport
Therapeutic form 7-30 ug Animal origin only 1-2 ug 2-3 mg 2-3 ug /day 5-10 ug/day transcobalamin II hydroxycobalamin
FOLIC ACID DEFICIENCY
CAUSES
Nutritional
Malabsorption
Excess utilization
–
Physiological
–
Pathological
Haematological diaeases
Malignant diseases Inflammatory diseases pregnancy, lactation
Miscellaneous liver disease, drugs, intensive care
FOLIC ACID ABSORPTION & TRANSPORT
Dietary folate Methyl THF Duodenum & jejunum
(
Absorption) Plasma Bound Unbound
FOLIC ACID
NUTRITIONAL ASPECTS
Daily intake
Source
Daily requirment
Body stores
Maimum aborption
Enterohepatic
Therapeutic form 200-250 ug Animal and plant origin 100-150 ug 10-12 mg 50-80% of dietary intake 90ug/day folic acid
LABORATORY DIAGNOSIS
Mporphology
macrocytosis with macro ovalocytes & hypersegmented neutrophils
Anisopoikilocytosis
NRBCs
Basophilic stippling
Howell jolly bodies
LABORATORY DIAGNOSIS
Unconjugated bilirubin
Serum LDH
Serum hydroxybutyrate
Serum methylmalonate
Serum Homocysteine increased increased increased increased increased
LABORATORY DIAGNOSIS
VITAMIN B12 AND FOLATE LEVELS S vitamin B12 B12 deficiency Low Folate deficiency normal S folate Red cell folate Raised Low low low
LABORATORY DIAGNOSIS
BONE MARROW EXAMINATION
Megaloblastic & heperplastic erythropoiesis
Myelopoiesis shows giant myelocytes & metamyelocytes
Increased iron
BONE MARROW APPEARANCE
LABORATORY DIAGNOSIS
Investigations for cause of megaloblastic anaemia Anti intrinsic factor antibodies Antiparietal cell antibodies Antigliadin antibodies Duodenal biopsy Endoscopy Barium studies Schilling test DICOPAC test