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Microcytic anemias

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Microcytic anemiasIron deficiency anemia (IDA)

Anemia of chronic diseases

Thalassemia trait

Sideroblastic anemia

Lead poisoning

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IDA Iron homeostasis (metabolism and

requirements) Prevalence of IDA: affects almost 500 million

people worldwide. Developing countries: combination of

pathological blood loss (e.g. intestinal hookworm)and the limited bioavailability of iron in predominantly vegetarian diets.

Developed countries: less common in adults (0.2% in men, 2.6% in premenopausal women and 1.9% in postmenopausal women), but common in infants and young children.

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Normal values

Adult males, mean Hb 15.5 g/dl (lower

limit of normal 13.5g/dl

Adult females, mean Hb 14 g/dl (lower

limit of normal 11.5g/dl

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IDA Causes: Blood loss Menorrhagia GI bleeding (hookworm, peptic ulcer, hiatus hernia, inflammatory bowel

disease, carcinoma, hemorrhoids –piles) Hematuria

Increased physiological requirements Infant and adolescent growth Premenopausal women Pregnancy

Malabsorption Coeliac disease Post-gastrectomy Atrophic gastritis

Dietary Vegetarians especially in combination with increased physiological

requirement Seldom sole cause 6

Management

History and examination:

Laboratory investigation:

Investigation of underlying cause:

Treatment:

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IDAClinical features: rapidly developing anemia is

more debilitating

General symptoms and signs: fatigue, weakness, dyspnea, palpitation, headache, tinnitus, lack of concentration and chest pain (due to exacerbation of angina pectoris). Pallor of skin and mucous membranes.

Symptoms and signs specific to IDA: nail fattening and koilonychia (concave or spoon-shaped nails), sore tongue (glossitis) and papillary atrophy, angular stomatitis, dysphagia due to an esophageal web (Plummer-Vinson syndrome). Psychomotor delay and behavioral problems in young children

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IDA

Symptoms and signs due to the underlying

cause of IDA: heavy periods (menorrhagia),

indigestion or a change in bowel habit,

bleeding per rectum, hematuria.

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HistorySymptoms of anemia

Onset of symptoms

Duration of symptoms

Associated symptoms, angina

Symptoms related to possible causes of anemia

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HistoryDietary history (vegetarian), Abnormal

feeding habits (PICA)

Drug history (NSAID, steroids, warfarin)

History of chronic diseases

History of bleeding (GIT, menorrhagia etc)

History of dysphagia (PVS)

History of surgery (gastrectomy)

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Physical examinationPallor of skin and mucous membranes

Angular stomatitis

Tongue, colour, smoothness, (atrophic glossitis)

Pulse (tachycardia)

Hands (pallor of palmer creases)

Nails (Koilonychia, platenychia)

Signs of underlying diseases – CTD, CLD, CRF,

chronic infections (TB), IBD, SBE

malignancy .etc 12

Investigations

Peripheral blood film:

Hypochromic microcytic anemia (low MCH & MCV)

Anisocytosis (variation in red cell size)

Poikilocytosis (variation in red cell shape)

Occasional target cells

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Tests to confirm IDA

TestResultTestResultComment

HemoglobinLow

Red blood cellsReduced

FerritinLowLevel increased in chronic

inflammation & liver disease

Transferrin saturation

LowLow levels in elderly and

chronic disease

Serum ironLowLevels fluctuate & low in chronic disease

TIBCHighLow in anemia of chronic disease

BM ironLowInformative but invasive

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Investigation of underlying diseaseAbdominal and pelvic ultrasound

Barium studies of GIT

Faecal occult blood

Urinalysis for hematuria

Upper and lower GI endoscopy

Gynecological referral if appropriate

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Treatment Correct cause if possible

Correction of low Hb

Oral iron (ferrous sulphate 200mg TDS → ↑Hb

by 2gm/dl every three weeks) – adequate

response, continue for at least 6/12 to replace

body stores

Parenteral iron

Blood transfusion 18

Treatment Failure to respond to oral iron

Wrong diagnosis

Non-compliance

Malabsorption

Continued bleeding

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TreatmentBlood transfusion :-

Avoid if possible

Give packed cells

Diuretics if elderly

Symptomatic anemia, dyspnea (CCF), angina

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Anemia of chronic diseasesAnemia is proportional to disease activity

MCV → normal or reduced

Serum iron → reduced

Transferrin saturation → normal or reduced

TIBC → normal or reduced

Ferritin → normal or increased

Marrow iron → normal or increased 21

Thalassemia trait

Mild anemia: Hb concentration 10-14g/dl

MCV → very much reduced (out of proportion

to the degree of anemia

Serum iron → normal

Transferrin saturation → normal

TIBC → normal

Ferritin → normal

Marrow iron → normal 22

Sideroblastic anemiaAnemia: any severity

MCV → normal, reduced or increased

Serum iron → normal or increased

Transferrin saturation → normal or increased

TIBC → normal or reduced

Ferritin → normal or increased

Marrow iron → normal or increased

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Lead poisoningLead absorption is increased by dietary

deficiency of ironPre-school children are at most riskAnemia is normocytic or mildly hypochromicLead accumulation in mitochondria of

erythroblasts inhibits delivery of iron to protoporphyrin and thus haem synthesis

Ringed sideroblasts may resultMeasurement of the increased

protoporphyrin which remains in the red cells is used as a screen for lead poisoning

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Macrocytic anemias

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Macrocytic anemias

Macrocytosis with normoblastic bone marrow

Macrocytosis with megaloblastic bone marrow

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Macrocytosis with non-megaloblastic bone marrow

MCV of 100-110flNormal serum vitamin B₁₂ and folateCauses:Alcohol (direct toxic effect on erythropoiesis)Liver disease (deranged cholesterol metabolism

on the lipid component of red cell membrane)MDS (impaired DNA synthesis)HypothyroidismPregnancyNeonatesReticulocytosis

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Megaloblastic anemiaDelayed maturation of nucleus of red cell

precursors in BM due to defective synthesis of

DNA, red cells either die in BM (ineffective

erythropoiesis) or enter blood stream as

enlarged misshapen cells with reduced survival

time.

Commonly due to vitamin B₁₂ or folate

deficiency or both28

Vitamin B₁₂ deficiencyCauses:

Deficiency of gastric intrinsic factor (PA,

gastrectomy)

Intestinal malabsorption (ileal resection/Crohn’s

disease, stagnant loop syndrome, tropical sprue, fish

tapeworm and congenital malabsorption)

Dietary deficiency (vegans)29

Pernicious anemiaAutoimmune disorderIgG autantibodies targeted against gastric

parietal cells and the B₁₂ transport protein intrinsic factor (IF) → reduced availability of the B₁₂-IF complex which is absorbed in the terminal ileum

Gastric parietal cell atrophy and achlorhydria, a more generalized epithelial cell atrophy and megaloblastic anemia

Disease is common in Northern Europe in women >40 years of age and is familial

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Pernicious anemiaPremature greying of hair blue eyes and may

develop other autoimmune disorders (vitiligo, thyroid disease and addison’s disease

Slight jaundice caused by the hemolysis of ineffective erythropoiesis.

Patients usually have symptoms of anemia and the generalized epithelial abnormality can manifest as glossitis and angular stomatitis

Demyelination of the dorsal and lateral columns of the spinal cord results in SCDC (sensory ataxia)

Increased incidence of carcinoma of the stomach 31

Diagnosis Blood count and film:

macrocytic anemia (↑MCV ranging from 100-

140fl). MCV may be normal if IDA, thalassemia

or anemia of chronic disease coexist

Pancytopenia

Hypersegmented neutrophils

Anisopoikilocytosis

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Diagnosis Bone marrow: hyperplastic and megaloblastic

erythropoiesis with unbalanced development of the nucleus and cytoplasm →premature cell death and mild hyperbilirubinemia

Estimation of vitamin B₁₂ and folate levelsLow vitamin B₁₂Serum folate may be elevated and red cell

folate reduced (folate is trapped in it’s extracellular methyl FH₄ form)

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Diagnosis Autoantibodies:

PCA are found more commonly in the serum than

IFA (90% vs 50%)

IFA→ almost diagnostic of PA

PCA → occur in about 15% of healthy elderly

people and in association with other autoimmune

diseases

Antibodies may also be detected in gastric juice35

Diagnosis

Tests for vitamin B₁₂ absorption: Schilling test

Patients swallow B₁₂ labelled with radioactive

cobalt and absorption is usually measured

indirectly by quantifying urinary excretion. If

malabsorption is corrected by adding IF to

the oral dose, PA is the likely cause. 36

Treatment IM injections of vitamin B₁₂ 1000µg (1mg) –

hydroxycobalamin are given over the first few weeks and then one injection every three months for life

Prediction of response: Reticulocytosis 6-7 days after the start of therapy

Blood transfusion is best avoided as it may lead to circulatory overload

Hypokalemia occasionally requires correction

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Folate deficiencyCauses:Dietary deficiencyMalabsorption (coeliac disease, tropical

sprue, small bowel disease or resection)Increased requirement (pregnancy, HA,

myeloproliferative/malignant/inflammatory disorders)

Drug induced suppression of DNA synthesis (folate antagonists, metabolic inhibitors and prolonged use of nitrous oxide)

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Folate deficiencyClinical picture and investigations:

Symptoms of anemia or of an underlying disease

Initial tests are as for PA with a macrocytic

anemia and a megaloblastic BM

Both serum and red cell folate levels are reduced

in significant deficiency but red cell folate is a

better measure of tissue folate stores

Investigation for malabsorption: Jejeunal biopsy 39

Folate deficiencyTreatment: oral folic acid 5mg once daily for

several months (depending on the underlying

cause)

Prophylaxis: increased demands (pregnancy

and HA)

vitamin B₁₂ deficiency must be excluded

before folate is prescribed (SCDC) 40

Aplastic anemia

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Aplastic anemia

Pancytopenia resulting

from BM failure or

aplasia42

Aplastic anemia (AA)

Primary

Congenital

Acquired - idiopathic

Secondary

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Secondary AAIonizing radiation – accidental exposure ( RT, Radioactive isotopes, nuclear power

stations)Chemicals – benzene, TNT, insecticides, hair

dyes, DDTDrugs – regularly cause BM suppression

(busulphan, cyclophosphamide), occasionally cause BM suppression (chloramphenicol, sulphonamides, gold, phenylbutazone)

Infections – viral hepatitis, EBV, HIVPregnancy 44

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Hemopoietic growth factors

Interleukin -1

IL – 4

IL – 5

IL – 6

IL – 7

IL – 11

Thrombopoietin – TPO

Erythropoietin – EPO

G-CSF

GM-CSF

M-CSF

Interferon - α

Interleukin – 3

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Etiology of AA

Autoimmune disease, recovery of patients following use of immunosuppressive agents with antilymphocyte globulin (ALG) or cyclophosphamide

Severe damage to either the pleuripotential stem cell population (the seed) or the microenvironment of BM in which they develop (the soil) or to a combination of both

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Congenital AA – Fanconi anemia☺FeaturesAutosomal recessiveAplastic anemiaHypoplastic kidneys Absent or hypoplastic thumb or radiusMicrocephalyMental retardationAge of presentation: 5 –10 years10% → AMLTreatment – Androgens +/- BMTAndrogens – remission rarely lasts > two years – virilization

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AA – Clinical featuresPeak age incidence → 30 years

M>F

Insidious or acute onset

Symptoms and signs are because of

Anemia

Leukopenia (increased susceptibility to infection)

Thrombocytopenia (increased bleeding tendency)

Lymphadenopathy and hepatosplenomegaly are not a

feature 50

AA – Clinical featuresAnemia – Pallor, headache, dyspnea, lethargy etc.

Infections – Mouth & throat, pnemonia, septicemia

Bleeding – Bruizes, gums, epistaxis, menorrhagia

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AA – Laboratory findingsAnemia Normocytic normochromic Macrocytic (MCV 95-110fl) Reticulocytopenia in relation to degree of

anemia

Leukopenia Granulocytopenia (<1500/cmm) Lymphopenia in severe cases Neutrophils appear normal Neutrophil alkaline phosphatase (NAP) score ↑

Thrombocytopenia – <10,000/cmm in severe cases

Peripheral blood smear (PBS)→No abnormal cells52

BM in AAHypoplastic, loss of hemopoietic tissue, ↑fat content

>75%

Trephine biopsy – patchy cellular areas in a

hypoplastic background

Main cells are lymphocytes & plasma cells,

megakaryocytes in particular are reduced or absent

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Diagnosis & DD

Drug-induced AA

BM infiltration – carcinoma,TB, lymphoma

Leukemia, myelodysplastic syndrome, multiple

myeloma

Hypersplenism

Megaloblastic anemia

Myelosclerosis or myelofibrosis

Paroxysmal nocturnal hemoglobinuria (PNH)―↑Retics

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Management Supportive care for BM failureTreat the underlying causeSpontaneous recovery of mild and moderate

cases, severe cases are usually fatalAllogeneic BMT, treatment of choice <40

years of age who have HLA – identical sibling (or identical twin) donor

GVHD & graft rejection are the main problems in those who have the disease for quite some time and have had multiple blood transfusions

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Management ALG / ATGCR is much less common compared with BMTMajor toxicity – Hypersensitivity & Serum sickness

which can be controlled by steroids Elderly patients and those without suitable donors

are treated with ALG or ATG

They remove suppressor killer T cells thought to have damaging effect on hemopoietic stem cells

Given with steroids to ↓ their side effects (fever, BP changes and skin rashes)

If no response in 4/12, a 2nd course prepared in a different spp. May be tried

50%-60% of patients respond to ALG and up to 80% to a combined ALG, steroids, and cyclosporine 57

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Management High dose MP, an alternative to ALG, no extra

advantageHemopoietic growth factors

1- GM-CSF & G-CSF - ↑ WC (not lasting response)

2- IL 3 - ↑ platelets, effective only in mild to moderate cases

Androgens, oxymethalone - ↑ Hb, little effect on leukocytes and platelets. Side effects ( virilization, cholestatic jaundice, and rarely hepatocellular carcinoma.), If no response in 4-6/12, stop the drug, gradual reduction in the dose if there is a response.

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