This document provides definitions and classifications for anemia. It begins by defining anemia based on hemoglobin concentration ranges for males, females, and pregnant females. It then discusses classifying anemia based on morphology, etiology/mechanism, impaired red blood cell production, hemolytic anemias, and blood loss. Specific types of anemia are then discussed in more detail, including iron deficiency anemia, vitamin B12 deficiency, folate deficiency, and anemia of chronic disease. Causes, clinical features, investigations, and treatment are outlined for each type.

1. DEPARTMENT OF INTERNAL MEDICINE
HEMATOLOGY UNIT.
DR M. KATASO MD
HEMATOGY UNIT COG 1,2

2. DEFFINITION
• Anemia is defined as a hemoglobin (Hb) concentration below the reference range for the
age and sex of an individual.
• Adult males 13.0–17.0
• Adult females (non pregnant) 12.0–15.5
• Pregnant females 11.0–14.0

3. ANEMIA CLASSIFICATION
• Anemia is not a diagnosis, always look for a cause
• Approach can be
1. Morphologic
2. Mechanistic /Etiologic/Pathologic

4. ETIOLOGIC/MECHANISM APPROACH

5. ANEMIA 2/2 IMPAIRED RED CELL PRODUCTION

6. HEMOLYTIC ANEMIAS

7. BLOOD LOSS

8. MORPHOLOGIC APPROACH BY P/S

9. ANEMIA CLASSICATION BY MCV
• MCV < 80FL: MICROCYTIC ANEMIA. Think the following
1. Iron deficiency anemia
2. Thalassemia's
3. Anemia of chronic illness
4. Lead poisoning
5. Sideroblastic anemia
• Remember the mnemonic: TAILS .

10. APPROACH TO MICROCYTIC ANEMIA

11. ANEMIA CLASSIFICATION BY MCV
• MCV> 100FL: MACROCYTIC ANEMIA. Think the following
1. B12 deficiency
2. Folic acid deficiency
3. Hemolysis ( 2/2 reticulocytes)

12. APPROACH 2 MACROCYTIC ANEMIA

13. ANEMIA CLASSIFICATION BY MCV
• MCV BETWEEN 80 & 100FL: NORMOCYTIC. Think the following
1. Chronic disease
2. Early IDA
3. SCA

14. APPROACH 2 NORMOCYTIC ANEMIA

15. ANEMIA WITH SUSPECTED
HEMATOLOGICAL ABNORMALITIES

16. IRON DEFFICIENCY ANEMIA
• Iron deficiency is the most common cause of anemia in the world
• The body has limited ability to absorb iron.
• Iron frequently lost through hemorrhage.
• Most iron occur in insoluble ferric (Fe³⁺) form, which has poor bioavailability.
• Ferrous (Fe²⁺) is more readily absorbed.
• Iron classified as:
1. Non-haem iron , mainly derived from cereals
2. Haem iron derived from hemoglobin and myoglobin in red or organ meats.
• Haem iron is better absorbed than non-haem iron

17. IDA
IRON DISTRIBUTION IN BODY
• It is distributed into:
1. Hemoglobin (Hb) : 66%
2. Iron stores as ferritin and hemosiderin :
25%
3. Myoglobin (in muscles) : 3%
4. Parenchymal iron (in enzymes, etc.) :
6%
IRON DAILY REQUIREMENTS
• To make good average daily loss, iron
requirements are:
1. Adult male : 0.5–1 mg (13 µg/kg)
2. Adult female (menstruating) : 1–2 mg
(21 µg/kg)
3. Infants : 60 µg/kg
4. Children : 25 µg/kg
5. Pregnancy (last 2 trimesters): 3–5 mg
(80 µg/kg)

18. IDA
• IRON ABSORPTION.

19. IDA
• ABSORPTION,TRANSPORT, UTILIZATION, STORAGE & EXCRETION
1. Absorption: it occurs in the duodenum. Dietary iron is present either as haeme or as
inorganic iron. Absorption of haeme iron is better (up to 35% compared to inorganic
iron which averages 5%) and occurs directly without the aid of a carrier .However, it is
a smaller fraction of dietary iron. The major part of dietary iron is inorganic and in the
ferric form. It needs to be reduced to the ferrous form before absorption. Two separate
iron transporters in the intestinal mucosal cells function to effect iron absorption. At the
luminal membrane the divalent metal transporter 1 (DMT1) carry's ferrous iron into the
mucosal cell. This along with the iron released from haeme is transported across the
basolateral membrane by another iron transporter ferroportin (FP) .
2. Transport :Free iron is highly toxic. As such, on entering plasma it is immediately
converted enzymatically to the ferric form and complexed with a glycoprotein
transferrin (Tf). Iron circulates in plasma bound to Tf (two Fe3+ residues per molecule).

20. IDA
• ABSORPTION, TRANSPORT, UTILIZATION, STORAGE & EXCRETION.
3. Storage: After entering the storage cells through TfRs, iron is stored in RE cells (in
liver, spleen, bone marrow), as well as in hepatocytes and myocytes as ferritin and
haemosiderin.
4. Excretion: daily excretion in adult male is 0.5–1 mg, mainly as exfoliated g.i. mucosal
cells, some RBCs and in bile (all lost in feces). Other routes are desquamated skin, very
little in urine and sweat. In menstruating women, monthly menstrual loss may be
averaged to 0.5–1 mg/day. Excess iron is required during pregnancy for expansion of
RBC mass, transfer to fetus and loss during delivery; totaling to about 700 mg. This is
to be met in the later 2 trimesters.

21. CAUSES OF IRON DEFFICIENCY ANEMIA

22. IDA
• CLINICAL FEATURES
1. PICA-abnormal cravings e.g. for ice or soil
2. Brittle nails
3. Spoon-shaped nails (koilonychia)
4. Atrophy of the papillae of the tongue
5. Angular stomatitis
6. Brittle hair,
7. A syndrome of dysphagia and glossitis (Plummer–Vinson or Paterson–Brown–Kelly
syndrome.
8. Clinical features of underlying cause if any e.g. Portal hypertension with bleeding
varices.

23. INVESTIGATION.
BLOOD COUNT & FILM
1. Microcytosis
2. Hypochromasia
3. Poikilocytosis
4. Anisocytosis
5. Target cells are seen.
6. ↑RDW
IRON STUDIES
1. ↓Serum iron
2. ↑Iron-binding capacity
3. ↓Serum ferritin.
4. ↑Serum soluble transferrin receptors.
5. ↓Transferrin saturation

24. OTHER INVESTIGATIONS
1. Upper & lower GI endoscopy
2. Stool M/C/S & occult blood
3. Pelvic USS
4. Bone marrow biopsy

25. TREATMENT
• Look for and treat the underlying cause
• Give iron to correct the anemia and replace iron stores.
• Give oral iron such as ferrous sulphate (200 mg three times daily)
• Iron replacement should be for 6 months.
• When Hb and MCV are normal it should taken for at least 6 months to replenish Fe
stores.
• In severe IDA, Ferrous sucrose infusion can be given up to 1000mg over 2 weeks.
• Response to iron therapy can be monitored using the reticulocyte count and Hb level, with
an expected rise in hemoglobin of 1 g/dL per week

26. VITAMIN B12 DEFICIENCY
• Deficiency of vit B12 and folic acid, which are B group vitamins, results in megaloblastic
anemia characterized by the presence of large red cell precursors in bone marrow and
their large and short-lived progeny in peripheral blood. Vit B12and folic acid are therefore
called maturation factors.
• Vitamin B₁₂ is synthesized by certain microorganism.
• Humans do not synthesize Vitamin B₁₂ and dependent on animal sources. It is found in
meat, fish, eggs and milk, but not in plants. Average adult stores about 2–3 mg, mainly in
the liver It may take 2 years or more after absorptive failure before B₁₂ deficiency
develops.
• Main natural cobalamins are:
• Deoxy adenosyl-cobalamin
• Methyl-cobalamin
• Hydroxocobalamin

27. VITAMIN B12
• ABSORPTION & TRANSPORT.
• Vitamin B₁₂ is absorbed in the terminal ileum.
• Initially vitamin B₁₂ binds to a protein (‘R’ binder) derived from saliva.
• Released from the ‘R’ binder by pancreatic enzymes to bind to intrinsic factor(IF).
• IF is secreted by gastric parietal cells along with H⁺ ions.
• It combines with vitamin B₁₂ and carries it to specific receptors on the surface of the
mucosa of the ileum
• Vitamin B₁₂ enters the ileal cells while intrinsic factor remains in the lumen and is
excreted.
• Vitamin B12 is transported from the enterocytes to the bone marrow and other tissues by
the glycoprotein transcobalamin II (TCII)

28. VIT B12 DEFFICIENCY
• Main function of B₁₂ is methylation of homocysteine to methionine
• Demethylation of methyl THF polyglutamate to THF takes place at the same time.
• THF is a substrate for folate polyglutamate synthesis that is key in DNA synthesis.
• Vitamin B₁₂ is also neurological function.
• Deoxyadenosyl cobalamin is a coenzyme for the conversion of methylmalonyl CoA to
succinyl CoA
• Succinyl CoA plays a key role in the citric acid cycle, ketone metabolism and heme
synthesis.

29. VIT B12 DEFICIENCY ANEMIA

30. VITAMIN B12 DEFFICIENCY

31. PERNICIOUS ANEMIA
• PA is an autoimmune disorder characterized by atrophic gastritis with loss of parietal cells
in the gastric mucosa.
• It occurs more frequently in fair-haired and blue-eyed individuals and those with blood
group A.
• There is consequent failure of intrinsic factor production and vitamin B₁₂ malabsorption.
• Clinical features include:
1. Yellow lemon skin discolouration
2. Glossitis
3. Angular stomatitis

32. PA
• Neurological features include:
1. A progressive polyneuropathy involving the peripheral nerves
2. Involvement of the posterior and lateral columns of the spinal cord→subacute
combined degeneration of the spinal cord.
3. Symmetrical paraesthesiae in the fingers and toes
4. Early loss of vibration sense and proprioception
5. Progressive weakness and ataxia.
6. Paraplegia may result
7. Dementia, psychiatric problems, hallucinations, delusions
8. Optic nerve atrophy

33. INVESTIGATION
1. Haematological findings :Shows the
features of a megaloblastic anemia
2. Serum vitamin B12 :Usually well
below
3. Bone marrow :Shows the typical
features of megaloblastic erythropoiesis
4. Serum methylmalonic acid (MMA)
and homocysteine(HC) : Raised in B12
deficiency.
• Autoantibodies
1. Anti-parietal cell and
2. anti-intrinsic factor antibodies usually
positive
3. Anti-parietal cell more specific
• Schilling test: Able to evaluate other
causes of B₁₂ deficiency such as bacterial
overgrowth.
• Serum Bilirubin & LDH: Usually raised
due ↑ due ineffective erythropoiesis

34. TREATMENT
• Initially Hydroxocobalamin 1000 μg can be given intramuscularly for 7 days
• It is then at 1000 μg weekly for 4 week
• For patients with PA it is then given every 3 months at 1000 μg for the rest of the patient’s
life.
• Alternatively, it is now recommended that oral B₁₂ is given at 2mg per day.
• Rationale is that 1–2% of an oral dose is absorbed by diffusion and does not require IF

35. FOLATE DEFICIENCY
• Folate together with Vitamin B₁₂ is a key micronutrient in the synthesis of DNA.
• Major dietary sources of folate are, liver, green vegetables, yeast and nuts.
• Adult body store of folate comprise 10-15mg
• Normal daily requirement of folate is 0.1-0.2mg and may last 4 months in absence of
exogenous source.
• Folate absorption occurs rapidly in the proximal jejunum.
• Megaloblastic anemia patients should not be treated empirically with folate alone.
• If they lack vitamin B₁₂,giving folic acid alone would potentially precipitate subacute
combined degeneration of the spinal cord.

36. CAUSES OF FOLATE DEFICIENCY

37. CLINICAL FEATURES
• Patient may present as follows:
1. Asymptomatic
2. Present with symptoms of anemia.
3. Symptoms of the underlying cause.
4. Glossitis can occur

38. FOLATE DEFICIENCY
INVESTIGATION
1. FBC shows megaloblastic picture
2. ↓RBC folate
3. Serum folate may be normal
4. In suspected occult gastrointestinal
5. disease small bowel biopsy should be
performed
6. Evaluate for possible cause
TREATMENT
1. Folate deficiency can be corrected by
giving 5 mg of folic acid daily.
2. Treatment should be given for about 4
months to replace body stores.
3. Any underlying cause, e.g. coeliac
disease, should be treated.
4. Prophylactic folic acid is given in
chronic hematological disorders where
there is rapid cell turnover such as
Sickle cell anemia.

39. ANEMIA OF CHRONIC DISEASE
• Anemia of chronic disease(AOCD) is a hypo proliferative anemia that develops in
response to systemic illness or inflammation.
• Anemia of chronic disease appears to be a highly coordinated and genetically conserved
adaptive response to systemic disease.
• AOCD is characterized by:
1. Restriction of Fe absorption from the GIT
2. Sequestration of Fe into macrophages
3. Suppression of erythropoietin production, inhibition of erythropoiesis and decreased
RBC survival.

40. AOCD
• Sequestration of Fe within macrophages could have the following beneficial effects:
1. Iron is an essential nutrient required for the growth of many microorganisms.
2. Iron loading promotes infection and facilitates the growth of malignant cells
3. Hypoferremia is therefore thought to be an innate antimicrobial strategy.
4. Decreased bone marrow production reduces nutrient utilization in times of stress

41. AOCD
1. In inflammatory diseases, cytokines released by activated leukocytes and other cells exert
multiple effects that contribute to the reduction in hemoglobin levels
2. Cytokines IFN-ᵧ,TNF-α, IL-1ᵦ,IL-6 have been implicated in pathogenesis of AOCD.
3. Cytokines, especially IL-6 promote hepcidin synthesis in the liver.
4. Hepcidin binds to ferroportin on the enterocytes and macrophages leading to internalization and
degradation of ferroportin
5. This results in sequestration of Fe within the macrophages restricts its absorption for the GIT.
6. Overall result is limiting iron availability to erythroid precursors
7. There is inhibition of erythropoietin release from the kidney IL-1ᵦ and TNF-α
8. Direct inhibition of the proliferation of erythroid progenitors IFN-ᵧ,TNF-α, IL-1ᵦ.
9. Augmentation of erythrophagocytosis by reticuloendothelial macrophages by ,TNF-α

42. AOCD
INVESTIGATION
1. FBC shows normocytic normochromic
picture
2. ↓Serum iron
3. Normal or ↓Transferrin
4. ↓Transferrin saturation
5. Normal or ↑ ferritin
6. Normal soluble transferrin receptors
7. TIBC normal
8. ↓Serum erythropoietin
TREATMENT
• Treat underlying cause
• Transfuse if there is indication or if
hemoglobin less than 8 g/dL,
• Give erythropoietic agents e.g. epoetin-
alpha, darbepoetin-alpha, and epoetin-
beta.
• Novel agents include:
1. IL-6 antagonist- Tocilizumab
2. Direct hepcidin antagonists
3. Ferroportin agonist