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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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