microcytic anemia

1. microcytic anemia

2. • The World Health Organization defines Anemia as:[1]
• Hb <11 g/dL in children under 5 years and in pregnant women
• Hb <11.5 g/dL in children aged 5 to 11 years
• Hb <12 g/dL in children aged 12 to 14 years and in women (aged over 15 years)
• Hb <13 g/dL in men (aged over 15 years)
• HB <12 g/dL in women.

3. • The American Society of Hematology defined anemia as Hb<13.6 g/dl for men and <12g/dl
for women.
• Anemia is the most common hematological disorder seen in general medical practice.
• Risk factors include extremes of age, female sex, lactation, and pregnancy.
• severity scale for Anemia :-
• Life-threatening Anemia: Hb <65 g/L (<6.5 g/dL)
• Severe Anemia: Hb <80 g/L (<8 g/dL)
• Mild to moderate Anemia: Hb 80 to 110 g/L (8-11.0 g/dL)

5. • MCV – Mean corpuscular volume (MCV) is the average volume (size) of the RBCs.
• (MCV in femtoliters [fL] = 10 x HCT [in percent] ÷ RBC [in millions/microL])
• MCH – Mean corpuscular hemoglobin (MCH) is the average hemoglobin content in a RBC.
• (MCH in picograms [pg]/cell = hemoglobin [in g/dL] x 10 ÷ RBC [in millions/microL])
• MCHC – Mean corpuscular hemoglobin concentration (MCHC) is the average hemoglobin
concentration per RBC.
• (MCHC in grams [g]/dL = hemoglobin [in g/dL] x 100 ÷ HCT [in percent]).
• RDW – Red cell distribution width (RDW) is a measure of the variation in RBC size RDW =
[standard deviation/MCV] x 100).

6. • Reticulocyte production

7. General clinical information
• Family history of a specific type of anemia such as sickle cell disease or thalassemia
• Causes of acquired anemia
• Dietary practices (eg, vegan diet lacks vitamin B12)
• Travel (eg, acquired parasitic infections)
• Infections
• Bleeding (heavy menses, melena)
• Chronicity of the anemia
• Symptoms or conditions that would suggest hemolysis
• Dark urine
• Jaundice
• History of gallstones
• Anemia with certain food or drug exposures (fava beans, oxidant drugs)
• Symptoms or findings that suggest kidney or liver disease or hypersplenism

9. CAUSES OF MICROCYTOSIS

10. Iron deficiency
• Iron deficiency and iron deficiency anemia (IDA) may be seen in individuals of any age but
are especially common in children and menstruating females.
• Iron deficiency is more frequently due to blood loss that exceeds iron intake.
• In females with heavy menstrual periods or pregnancy, the cause is obvious. In others, the
source of blood loss may not be immediately apparent.
• A search for the source of blood loss is almost always indicated, especially in individuals over
50 years of age with new onset iron deficiency, for whom colorectal cancer is not an
uncommon underlying cause of blood loss. Another cause is reduced iron absorption as in H.
Pylori and celiac disease.

11. Epidemiology
• The global prevalence of Anemia is reported to be approximately 33%, and iron deficiency is
the most common cause.
• The prevalence of IDA varies widely across different regions of the world, with the lowest
prevalence in higher income regions (e.g., North America and western Europe) and highest
prevalence in lower income regions (e.g., southern Asia and Caribbean).

12. Aetiology
• IDA has many causes and is not an end diagnosis in and of itself.
• Diagnosis of IDA should prompt further investigation to determine the cause, and to correct if possible.
• inadequate dietary iron intake
• Impaired iron absorption (e.g., due to achlorhydria, gastric surgery, or coeliac disease)
• Increased iron loss because of bleeding, usually in the gastrointestinal tract (e.g. haemorrhoids, salicylate
ingestion, peptic ulcer disease, hiatal hernia, diverticulosis, neoplasm, ulcerative colitis, hookworm, milk
allergy in infants, Meckel's diverticulum).
• Other causes of iron loss include menorrhagia, blood loss from hemodialysis, runner's Anemia,
schistosomiasis, trichuriasis, blood donation, hemoglobinuria, self-induced bleeding, idiopathic pulmonary
hemosiderosis, Goodpasture's syndrome, hereditary hemorrhagic telangiectasia, angiodysplasia, and
disorders of haemostasias
• Increased iron requirements of young children (e.g., due to growth, and inadequate dietary iron intake),
pregnancy, or lactation PPIs
• Unknown cause.

13. Pathophysiology
• Iron is required for the formation of hemoglobin, myoglobin, and haem enzymes
• essential for red blood cell (RBC) production and cellular processes (e.g., cell metabolism,
DNA replication/repair, and cell cycle regulation)
• The body does not have a regulatory pathway for iron excretion. Physiological iron loss
occurs through menstrual bleeding, sweating, skin desquamation, and urinary/faecal
excretion.
• Men and post-menopausal women lose approximately 1 mg of iron daily, and menstruating
women lose approximately 2 mg of iron daily.
• Pregnancy results in a net loss of approximately 580 mg of iron during the gestation period
due to expansion of maternal RBC mass and growth of the fetus and placenta, with the
highest loss occurring in the third trimeste

14. History and exam
• Fatigue does not appear to be increased in patients with mild-to-moderate anemia
(hemoglobin from 8 to 12 g/dL) and treatment of this range of anemia does not necessarily
lead to improvements in fatigue.
• Dyspnoea
• Pica in up to 55%
• Restless legs syndrome
• Headache
• Exercise intolerance
• Exertional dyspnea
• Weakness

15. Findings on examination
• Esophageal web, which may be accompanied by dysphagia (eg, Plummer-Vinson or
Patterson-Kelly syndrome; rare)
• Alopecia (rare) in especially severe cases
• Chlorosis pale, faintly green complexion; extremely rare)
• Patients with more severe anemia may have tachycardia, a cardiac murmur, or (rarely)
hemodynamic instability

16. Iron studies
• Serum iron the test measures circulating iron, most of which is bound to the transport protein
transferrin
• Serum transferrin Transferrin is a circulating transport protein for iron
• Transferrin saturation ransferrin saturation (TSAT) is the ratio of serum iron to TIBC: (serum
iron ÷ TIBC x 100)
• Serum ferritin is a circulating iron storage protein that is increased in proportion to body iron
stores.

19. screnning
• The CDC recommends periodic screening for Anemia with haemoglobin checks among high-risk populations of infants, preschool
children, pregnant women, and women of childbearing age.
• The American Academy of Family Physicians (AAFP) concludes that there is insufficient evidence to recommend routine
screening for IDA in pregnant women and in children aged 6 to 24 months.
• Start with a CBC including review of MCV. Obtain iron studies only if anemia or microcytosis is found. This may be most
reasonable for individuals with a lower risk of iron deficiency and those for whom returning for a second test would not be
overly burdensome.
• The frequency of screening is individualized:
• Annual screening may be reasonable for those at the highest risk, such as menstruating females with heavy periods.
• Less frequent, or even one-time screening, may be reasonable for other individuals, especially males and postmenopausal
females.
• Screening of adolescent and adult females of childbearing age every 5 years with a hemoglobin or hematocrit, with more
frequent screening (yearly) if there is extensive menstrual blood loss, low iron intake, or a history of iron deficiency

20. INITIAL CONSIDERATIONS
• all patients with iron deficiency anemia and most with iron deficiency without anemia should
be treated
• Routine iron administration to individuals without iron deficiency is not advised.
• Treatment of iron deficiency and iron deficiency anemia involves more than simply replacing
iron

22. Oral versus IV iron
• Settings in which one route or the other may be preferable include the following:
• ●Oral
• Oral supplements are the only form of iron available to many patients
• For many patients, oral iron may be more cost effective due to the lack of need for monitored infusion.
• Use of oral iron avoids the need for IV access and monitored infusion.
• Use of oral iron eliminates the potential for infusion reactions and/or anaphylaxis.
• Oral supplements are generally used for infants, children, and adolescents.
• ●IV
• IV iron is appropriate for patients who are unable to tolerate gastrointestinal side effects of oral iron.
• individuals with abnormal uterine bleeding in which oral iron cannot keep up with losses, individuals who are pregnant in the second or third
trimester.
• IV iron may be needed for those with severe/ongoing blood loss .
• Gastric surgery (bypass, resection) that reduces gastric acid may severely impair intestinal absorption of oral iron.
• Inflammatory bowel disease.
• Malabsorption syndromes (celiac disease, Whipple's disease, bacterial overgrowth) may limit absorption of oral iron.
• In the second trimester of pregnancy, if the Hb is less than 10.5 g/dL, or at any time in the third trimester, at which oral iron is unlikely to supply
adequate iron to the developing fetus

23. Change from oral to IV
• Patients not responding to oral iron or who are intolerant of oral iron can be considered for
intravenous iron replacement.
• if haemoglobin response with oral iron is (<1.0 g/dL) at day 14
• Intravenous iron should be considered as a first-line treatment for selected patients with
inflammatory bowel disease, including those with active disease or previous intolerance of oral
iron.
• Intravenous iron may be considered before or after surgery for patients with IDA who: are unable
to tolerate, absorb, or adhere to oral iron
• Intravenous iron increases the response to erythropoiesis stimulating agents in patients with
cancer and chemotherapy-related Anemia
• In women with postnatal Anemia, use of ferric carboxymaltose may restore haemoglobin and
ferritin levels faster than other intravenous iron preparations

24. Oral
• ferrous sulfate (20 to 30% elemental iron per mg ferrous sulfate salt but can vary by
manufacturer): adults: 50-100 mg orally three times daily
• ferrous fumarate (33% elemental iron per mg ferrous fumarate salt ): adults: 50-100 mg orally
three times daily
• ferrous gluconate (approximately 10 to 14% elemental iron per mg ferrous gluconate salt)
: adults: 50-100 mg orally three times daily
• ferric maltol: adults: 30 mg orally twice daily

25. IV
• Iron dextran is only available as a low-molecular-weight preparation. dverse effects include
anaphylaxis, arthralgias, and myalgias.
• Iron sucrose has a similar safety profile to low-molecular-weight iron dextran
• Sodium ferric gluconate complex has a superior safety profile compared with iron dextran
• Ferric carboxymaltose has superior safety and efficacy compared with oral iron
• Ferumoxytol has a more convenient dosing schedule than iron dextran and iron sucrose s
safe to use in patients with chronic kidney disease, but if haemodialysis is required, it should
be given >1 hour after haemodialysis when blood pressure has stabilized
• Ferric derisomaltose can also be given as a single infusion; therefore, dosing is more
convenient than other preparations. It has superior efficacy and is faster acting than iron
sucrose

26. Side effects (oral iron)
• These include metallic taste , nausea, flatulence, constipation, diarrhea, epigastric distress,
and/or vomiting.
• Patients may also be bothered by itching and by black/green or tarry stools that stain
clothing or cause anxiety about bleeding.
• As a result, compliance with oral iron administration may be low.

27. Monitoring
• The British Society of Gastroenterology recommends regular laboratory follow-up after
replacement of iron.
• Haemoglobin concentration and red cell indices should be measured every 3 months for a year,
again after one further year, and thereafter when symptomatic.
• This depends upon the underlying cause of the IDA. Uncomplicated IDA secondary to multiple
pregnancies has a very good prognosis with relatively simple treatment.
• However, if the IDA is secondary to a gastrointestinal cancer, prognosis is dependent upon tumor
staging.
• Once the haemoglobin is corrected, it takes an additional 6 months or so of iron replacement
therapy to replenish iron stores.
For patients receiving oral iron, we often re-evaluate the patient two weeks after starting.
we generally see patients four to eight weeks after the iron has been administered.

28. Anemia of chronic disease
(ACD)

29. Aetiology
• is principally caused by inflammation.
• Various processes (e.g., infection, neoplasm, autoimmune reactions, and injury to tissue from
trauma and major surgery) trigger release of pro-inflammatory cytokines.
• Systemic changes in iron metabolism, regulated by the inflammatory cytokine cascade and
hepcidin (an iron-regulatory peptide hormone produced by the liver), decrease red blood cell
(RBC) production and reduce RBC survival
• A range of underlying conditions can result in release of pro-inflammatory cytokines, often
with activation of the reticuloendothelial system.These cytokines trigger changes in
intracellular iron metabolism (notably up-regulation of hepcidin synthesis and ferritin
transcription).
• Interleukin (IL)-6 and IL-1 play a role in some inflammatory states and they have been shown
to directly up-regulate hepcidin synthesis

30. • Hepcidin and erythroferrone are the major regulators of iron metabolism.
• Hepcidin negatively regulates free iron by increased expression of divalent metal transporter
1 and down-regulation of ferroportin.
• Hepcidin also causes iron-trapping in macrophages, decreased iron absorption in the
gastrointestinal tract, splenic sequestration of iron, and impaired bone marrow
responsiveness to erythropoietin. Erythroferrone, a protein hormone produced by erythroid
progenitor cells in response to erythropoietin, makes iron available for erythropoiesis by
inhibiting the production of hepcidin.

31. Classification
• vascular and autoimmune disorders (e.g., RA, SLE, dermatomyositis, polymyalgia
rheumatica, scleroderma, inflammatory bowel disease)
• Chronic infection, including occult illness (e.g., TB, chronic fungal infections, hepatitis,
osteomyelitis, HIV)
• Acute infection (e.g., pneumonia, pyelonephritis, endocarditis, cellulitis, abscess)
• Chronic disease (e.g., chronic kidney disease, congestive heart failure, chronic pulmonary
disease)
• Malignancy (e.g., lymphomas, carcinomas, sarcomas)
• Critical illness and major trauma.

32. Symptoms and signs
• Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with
exercise are non-specific symptoms of Anemia.
• There may be a history of an underlying autoimmune, malignant, or infectious disorder;
recent major surgery, major trauma, or a critical illness; or of chronic kidney disease,
congestive heart failure, or chronic pulmonary disease
• fever, anorexia, night sweats, arthralgia, myalgia, weight loss, the presence of a mass,
adenopathy, hepatomegaly, splenomegaly, decreased breath sounds with rales, stiff neck,
rash, abdominal tenderness, and tenderness of joints, shoulder girdle, or bones.

33. investigations
• Full blood count, peripheral blood smear, reticulocyte count, serum iron and ferritin, total iron-
binding capacity (TIBC), transferrin saturation, and creatinine are part of the initial workup.
• The ACD syndrome is defined by the following constellation of laboratory test results:
• Mild to moderate Anemia that is either normocytic normochromic or microcytic hypochromic
• Otherwise normal red blood cell (RBC) morphology
• Normal or elevated serum ferritin
• Transferrin saturation <15%.

34. • ACD/AI is most likely when all (or most) of the following are present :
• Normochromic, normocytic anemia (HB between 10 and 12 g/dL)
• Low reticulocyte count (or inappropriately low for the degree of anemia)
• Low serum iron (generally <60 mcg/dL)
• Normal to low serum transferrin (generally <300 mcg/dL)
• Low transferrin saturation (TSAT; generally <20 percent)
• Normal to increased serum ferritin (>100 mcg/L)
• Elevated CRP (generally >5 mg/L)
• ESR

35. Management
• Initial treatment in patients with mild to moderate Anemia (Hb [8 to 11 g/dL])
• if the underlying disorder can be ameliorated or cured, the Anemia usually improves or
dissipates.
• Patients with mild to moderate ACD can usually be managed with simple observation.
• Treatment of Anemia in cancer and chronic renal disease do not recommend routine, ongoing
RBC transfusion principally because of the risks of iron overload

36. • Iron deficiency should be ruled out prior to initiating therapy. Because ESAs often produce
functional iron deficiency in iron-replete subjects, supplementary iron therapy may be
required to achieve an adequate therapeutic response
• a ferritin <100 mcg/L and a transferrin saturation (TSAT) <20 percent are typical indicators of
iron deficiency in individuals with ACD/AI
• People without iron deficiency – We generally do not give iron to individuals with ACD/AI
who are iron replete.

37. erythropoiesis-stimulating agents (ESAs)
• do not use ESAs in individuals with ACD/AI, with the following exceptions in which an ESA
may be appropriate:
• Individuals with CKD who may have a deficiency of erythropoietin
• Selected individuals with cancer who are receiving chemotherapy.
• Selected patients with low-risk myelodysplastic syndromes
• Certain individuals with inflammatory bowel disease or rheumatologic disorders who do not
have an adequate improvement in hemoglobin with iron supplementation
• Selected individuals scheduled for elective surgery
• are strongly recommended for Anemia in CKD due to low erythropoietin
• Red blood cell transfusion may be required until benefits from ESA therapy become manifest

38. severe (Hb [<8 g/dL]) OR life-threatening (Hb [<6.5 g/dL])
• RBC transfusion
• treatment should begin with the number of RBC units needed to raise Hb to 90 to 100 g/L

39. Emerging therapies
• epcidin and ferroportin – Studies are underway using agents capable of altering/inhibiting
the function of hepcidin (eg, hepcidin antagonists) and increasing the iron export activity of
the hepcidin receptor (ferroportin) to alleviate the various disorders of iron metabolism
associated with increased levels of hepcidin, including ACD/.However, this approach has yet
to demonstrate conclusive efficacy in clinical trials.
• Prolyl hydroxylase inhibitors – Prolyl hydroxylase inhibitors (PHI) stabilize hypoxia-inducible
factor (HIF), promote production of endogenous EPO, and increase intestinal iron absorption.
Their efficacy has been explored especially in anemia associated with CKD. Positive results
have been demonstrated in randomized trials in individuals undergoing dialysis or those with
predialysis CKD [128,129]. Treatment with these compounds for anemia of CKD is approved in
China, Japan, and Europe but not in United States. Their role in ACD/AI has yet to be
demonstrated [130].

41. Beta-thalassaemia
• The underlying pathophysiology of beta-thalassaemia syndromes is ineffective
erythropoiesis.
• When the production of beta-globin chains is deficient or absent, the imbalance between
alpha and beta chains leads to precipitation of the excess alpha chains in erythroid
precursors and maturing red cells, resulting in membrane damage and cell destruction.
• The inability of these cells to survive is the cause of ineffective erythropoiesis, resulting in
Anemia and a compensatory erythroid hyperplasia.

42. Bone marrow features of iron deficncy anemia
• Cellularity – increased
• Erythroid hyperplasia
• Micronormoblastic reaction
•  Normoblast are smaller
•  Late micronormoblast demonstrates
persistent basophilia and fraying of
cytoplasmic borders indicating lack of
complete hemoglobinization
• Myelopoiesis – Normal
• Megakaryopoiesis – Normal
• Depleted bone marrow iron

44. Bone marrow features of anemia chronic
disease
• Bone marrow aspirate demonstrating increased
iron staining in a fragment representing increased
marrow iron stores. . This finding is present in a
patiet with anemia of chronic disease.
• Normal iron staining in
• histiocytes is shown for Comparison

45. Genotypic classification
• Silent carrier: completely asymptomatic with normal haematological parameters.
• Beta-thalassaemia minor (trait): usually asymptomatic; diagnosis is made based on
screening when there is a positive family history, or during a work-up for mild Anemia; the
mild microcytic Anemia is often misdiagnosed as iron deficiency Anemia.
• Beta-thalassaemia intermedia: usually a similar presentation to beta-thalassaemia major
but as a toddler or older child; symptoms are usually less pronounced, and the course is
usually more insidious.
• Beta-thalassaemia major (also called Cooley's Anemia): complete absence of haemoglobin
A; often presents at a few months of age with progressive pallor and abdominal distension;
perinatal history is most often uneventful, and the infant may be pale, possibly with poor
feeding and decreased activity; hepatosplenomegaly and bony abnormalities are often
present at presentation, most often of the skull (frontal and parietal bossing, and chipmunk
facies).

47. Bone marrow features of thalassemia
•  Hypercellular
•  Erythroid hyperplasia
•  M:E ratio 1:5
•  Dyserythropoisis
•  Myelopoisis and megakaryopoisis are normal
•  Bone marrow iron increased
• Dr. Monika Nema

48. Bone marrow features of thalassemia
• Top and bottom panels show bone
• marrow aspirate and
• biopsy, respectively, from a case of
• thalassemia trait.
• The bone marrow has increased
• numbers of erythroid precursors (a
• low myeloid to erythroid ratio)
• related to the increased peripheral
• RBC destruction in this disease.

50. sideroblastic anemia:
• a heterogeneous group of disorders associated with
• various defects in the porphyrin biosynthetic
• pathway:
• -porphyrn biosynthesis defects
• -diminished heme synthesis
• -increased cellular iron uptake
• characterized by the association of anemia with
• presence of ringed sideroblast (a normoblast containing
• excessive deposits of iron within mitochondria) in bone
• marrow

51. • Sub-types:
• 1-Hereditary Sideroblastic Anemias:
• -hereditary sex-linked -inheritance undetermined
• 2-Acquired Sideroblastic Anemias
• 1-primary (idiopathic) sideroblastic anemia
• 2-secondary (drug- or toxin-induced) sideroblastic anemia
• -anti TB drugs (isoniazid, cycloserine, pyrazinamide)
• lead poisoning chloramphenicol thanol
• clinical: characterized by hypochromic, often microcytic, red cells in the blood usually mixed with normochromic cells
• hypochromic anemia ,hyperferremia ,increased transferrin saturation
• Lab: serum iron: increased
• TIBC: decreased
• % saturation: greatly elevated
• bone marrow: - markedly increased iron storage
• - erythroid hyperplasia
• - increased sideroblasts

52. • Treatment:Treatment of sideroblastic anemia may include
• 1- removal of toxic agents;
• 2- administration of pyridoxine, thiamine, or folic acid;
• 3-transfusion (along with antidotes if iron overload develops from
• transfusion);
• 4- other medical measures; or bone marrow or liver transplantation.

53. • Thank you