ANAEMIA
• The main function of the red blood cells is oxygen transport. Hence
a functional definition of anaemia is 'a state in which the circulating
red-cell mass is insufficient to meet the oxygen requirements of the
tissues'.
• However, many compensatory mechanisms can be brought into play
to restore the oxygen supply to the vital centers and therefore in
clinical practice this definition is of limited value.
• For this reason anaemia is usually defined as 'a reduction of the
haemoglobin concentration, red-cell count, or hematocrit to below
normal levels'.
• It has been extremely difficult to establish a normal range of
haematological values, and hence the definition of anaemia usually
involves the adoption of rather arbitrary criteria. For example, the
World Health Organization recommends that anaemia
should be considered to exist in adults whose
haemoglobin levels are lower than 13 g/dl (males) or 12
g/dl (females).
DEFINITIONS IN HAEMATOLOGY
Mean corpuscular
volume (MCV)
Haematocrit
Red cells count
N = 80 – 96 μ
Mean corpuscular
haemaglobin (MCH) =
Haemaglobin x 10
Red cells count
N = 27 – 33 pg
Mean corpuscular
=
haemaglobin
concentration (MHCH)
Haemaglobin x 10
Haematocrit
N = 32 – 35 g/dL
=
Clinical features
Symptoms (all non - specific):
– fatigue
– headaches
– faintness
– breathlessness
– angina of effort
– intermitent claudication
– palpitations
Signs:
1. Non / specific signs include:
– pallor
– tachycardia
– a full pulse
– systolic flow murmur
– cardiac failure
– ankle oedema
– rarely papilloedema and retinal haemorrhage in an acute
bleed
2. Specific signs:
– koilonychia – spoon-shape nails seen in iron deficiency
anaemia
– jaundice – haemolytic anaemia
– bone deformities – thalassemia major
– leg ulcers – sickle cell disease
Classification:
1. Hypochromic microcytic with low mean corpuscular volume
(MCV)
2. Normochromic normocytic with a normal MCV
3. Macrocytic with a high MCV
Special investigations:
– bone marrow aspiration from the sternum or posterior illiac
crest is performed to:
– confirm a diagnostic made from peripheral blood count
– determine the cellularity of the marrow
– determine the type of erythropoiesis
– determine the proportion of the various lines
– see wether the marrow is unfiltrated
– determine the size of the iron stores
MYCROCYTIC ANAEMIA
– small cells (microcytes)
– low MCV (< 80 μL)
– ↓ iron content
–ragged normoblasts
}
Iron deficiency anaemia
– small cells (microcytes)
– low MCV (< 80 μL)
– normal iron content hyperplastic
}
Thalassaemia
Sideroblastic anaemia
1. IRON DEFICIENCY
– the commonest cause of mycrocitic anaemia
– the average daily diet contains 15 – 20 mg of iron, but only 10%
is absorbed
– absorption:
 duodenum and jejunum
 ferrous iron is absorbed better than ferric
 gastric acidity helps to keep iron in the ferrous state and
soluble in the upper gut
– transport in the blood:
 transported in the plasma bound to transferin, beta globuline
synthesized in the liver
– iron stores – in the tissues as ferritin and haemosiderin (1000 –
1500 mg)
– requirements:
 each day 0.5 – 1 mg of iron are lost in the faeces, urine and
sweat
 menstruating women lose 0.7 mg iron / day of menstruation
 pregnancy and groth ↑ iron demand
CAUSES OF IRON DEFICIENCY
1. Poor intake
2. Decreased absorption
3. Increased demands
4. Blood loss
The commonest cause of iron
deficiency:
 Blood lost from G.I. tract
 Menstruation
• The average American diet contains 10–15 mg
of iron per day. About 10% of this amount is
absorbed. Absorption occurs in the stomach,
duodenum, and upper jejunum.
• Dietary iron present as heme is efficiently
absorbed (10–20%) but non heme iron less so
(1–5%), largely because of interference by
phosphates, tannins and other food constituents.
• Small amounts of iron—approximately 1 mg/d—
are normally lost through exfoliation of skin and
mucosal cells.
• There is no physiologic mechanism for
increasing normal body iron losses.
• Menstrual blood loss plays a major role in iron
metabolism. The average monthly menstrual
blood loss is approximately 50 mL or about
0.7 mg/d. However, menstrual blood loss may
be five times the average.
• To maintain adequate iron stores, women with
heavy menstrual losses must absorb 3–4 mg of
iron from the diet each day.
• This strains the upper limit of what may
reasonably be absorbed and women with
menorrhagia of this degree will almost always
become iron deficient without iron
supplementation.
• By far the most important cause of iron
deficiency anemia is blood loss, especially
gastrointestinal blood loss.
• Prolonged aspirin use, or the use of other
anti-inflammatory drugs, may cause it
even without a documented structural
lesion.
• Iron deficiency demands a search for a
source of gastrointestinal bleeding if other
sites of blood loss (menorrhagia, other
uterine bleeding and repeated blood
donations) are excluded.
• Chronic hemoglobinuria may lead to iron
deficiency since iron is lost in the urine,
but this is uncommon.
• Traumatic hemolysis due to a prosthetic
cardiac valve and other causes of
intravascular hemolysis (eg, paroxysmal
nocturnal hemoglobinuria) should also be
considered.
• Frequent blood donors may also be at risk
for iron deficiency.
Symptoms and Signs
• -anemia syndrome
• s/s due to iron defficiecy
• s/s due to disease which cause chronic blood
lose
• Severe deficiency causes skin and mucosal
changes, including a smooth tongue, brittle
nails, and cheilosis.
• Dysphagia because of the formation of
esophageal webs (Plummer–Vinson syndrome)
also occurs.
Clinical features
• In humans, unusual syndromes of food craving (pica) have been
recorded and appear to respond to iron supplementation: this
includes craving for soils and the ingestion of silica-rich earths as a
cult practice in black populations of the Southern United States—
geophagia.
• Pagophagia (ice-craving) combined with the abnormal taste
preferences of pregnancy may account for the bizarre food craving
that constitutes part of the folklore of pregnancy.
• Severe iron deficiency may occasionally be associated with
splenomegaly and the signs of underlying disease include peripheral
oedema (hypoalbuminaemia associated with massive hookworm
infection) and oronasal telangiectasia associated with Osler–
Rendu–Weber disease (hereditary haemorrhagic telangiectasia).
Clinical features:
– brittle nails
– spoon – shaped nails (koilonychia)
– atrophy of the papillae of the tongue
– angular stomatitis
– brittle hair
– dysphagia and glossitis (plummer – Vinson or Paterson Brown
Kelly syndrome)
– parotid gland enlargement, splenomegaly and failure to grow
Smooth, bald,
burning tongue;
Iron deficiency
anemia
Cancer of uterus
Gastric cancer/ colonic
cancer
PeptIc ulcer
investigations:
–Ht, Hb, RBC low ; teiculocyte low
–the red cells are microcytic (MCV < 80 fL) and hypochromic
(MCH < 27 pg)
– poikilocytosis (variation in shape) and anisocytosis (variation in
size)
– target cells
– hypersegmentation of polymorphs
– serum iron falls
– iron blinding capacity ↑
– bone marrow – erythroid hyperplasia with ragged normoblasts
– ring sideroblast
other investigations:
– the G.I. tract - endoscopy
Poikilocytosis is a term which indicates that red cells of
abnormal shape are present on the blood film. Of itself it is
fairly non-specific. Some particular types of poikilocyte are
very informative, however.
Bone marrow in iron deficiency
Iron deficiency develops in stages
• The first is depletion of iron stores. At this point, there is
anemia and no change in red blood cell size. The serum
ferritin will become abnormally low. A ferritin value less
than 12 mcg/L is a highly reliable indicator of iron
deficiency. Bone marrow biopsy for evaluation of iron
stores is now rarely performed because of intraobserver
variation in its interpretation.
• After iron stores have been depleted, red blood cell
formation will continue with deficient supplies of iron.
Serum iron values decline to less than 30 mcg/dL and
transferrin levels rise, leading to transferring saturation of
less than 15%.
• In the early stages, the MCV remains normal.
Subsequently, the MCV falls and the blood
smear shows hypochromic microcytic cells (see
blood smear).
• With further progression, anisocytosis (variations
in red blood cell size) and poikilocytosis
(variation in shape of red cells) develop.
• Severe iron deficiency will produce a bizarre
peripheral blood smear, with severely
hypochromic cells, target cells, hypochromic
pencil-shaped cells and occasionally small
numbers of nucleated red blood cells. The
platelet count is commonly increased.
Differential Diagnosis
• Other causes of microcytic anemia include anemia of
chronic disease, thalassemia and sideroblastic
anemia.
• Anemia of chronic disease is characterized by normal or
increased iron stores in the bone marrow and a normal
or elevated ferritin level; the serum iron is low, often
drastically so, and the total iron-binding capacity (TIBC)
is either normal or low.
• Thalassemia produces a greater degree of microcytosis
for any given level of anemia than does iron deficiency.
Red blood cell morphology on the peripheral smear is
abnormal earlier in the course of thalassemia.
Iron Deficiency Anemia
Essentials of Diagnosis
• Serum ferritin < 12 mcg/L.
• Caused by bleeding unless proved
otherwise.
• Responds to iron therapy.
2. sideroblastic anaemia
Classification:
A. Congenital:
– “X” linked disease – transmitted by females
B. Acquired:
– primary or idiopathic
– secondary:
 drugs
 alcohol
 lead
 myeloproliferative disorders
 leukaemias
 secondary carcinoma
 other systemic disorders (connective tissue
disease)
• The sideroblastic anemias are a heterogeneous group of
disorders in which hemoglobin synthesis is reduced
because of failure to incorporate heme into
protoporphyrin to form hemoglobin.
• Iron accumulates, particularly in the mitochondria.
• A Prussian blue stain of the bone marrow will reveal
ringed sideroblasts, cells with iron deposits encircling the
red cell nucleus.
• The disorder is usually acquired. Sometimes it
represents a stage in evolution of a generalized bone
marrow disorder (myelodysplasia) that may ultimately
terminate in acute leukemia.
• Other causes include chronic alcoholism and lead
poisoning.
• Patients have no specific clinical features other
than those related to anemia.
• The anemia is usually moderate, with
hematocrits of 20–30%, but transfusions may
occasionally be required.
• Although the MCV is usually normal or slightly
increased, it may occasionally be low, leading to
confusion with iron deficiency.
• The peripheral blood smear characteristically
shows a dimorphic population of red blood cells,
one normal and one hypochromic.
• In cases of lead poisoning, coarse basophilic
stippling of the red cells is seen.
• The diagnosis is made by examination of the bone
marrow.
• Characteristically, there is marked erythroid
hyperplasia, a sign of ineffective erythropoiesis
(expansion of the erythroid compartment of the bone
marrow that does not result in the production of
reticulocytes in the peripheral blood).
• The iron stain of the bone marrow shows a
generalized increase in iron stores and the presence
of ringed sideroblasts.
• Other characteristic laboratory features include a
high serum iron and a high transferrin saturation.
• In lead poisoning, serum lead levels will be elevated.
3.thalassaemia
Deficiency in the synthesis of the globin chains of haemoglobin
in addition, the accumulation of abnormal chains within the red
cell leads to its early destruction.
The severity of the thalassaemia will depend on the amount of
the haemoglobin A2 and F present.
Clinically β-thalassaemia can be divided into:
– thalassaemia major, with severe anaemia
– intermedia, with moderate anaemia rarely requiring transfusion
– minor, the symptomless heterozygous carrier state
symptoms:
– failure to thrive
– intermittent infection
– severe anaemia
– extramedullary haemopoiesis → hepatosplenomegaly and bone
expansion  thalassaemic facies
investigation:
– blood count:
 moderate to severe anaemia (↓MCV, MCH↓)
 reticulocyte ↑
 white cells and platelets = N
– blood film:
 hypochromic and microcytic picture
 Howell – Jolly bodies
– high ferritin levels
– haemoglobin electrophoresis (HbF ↑; HbA absent)
β-Thalassaemia trait (minor)
– asymptomatic
– no anaemia, red cells hypochromic and microcytic
α-Thalassaemia
– two main form:
 deletion of only alpha chain gene
deletion of both alpha chain genes → no alpha chains are
produced
Thalassemia major
Thalassemia minor
Differential Diagnosis
• Mild forms of thalassemia must be differentiated
from iron deficiency.
• Compared to iron deficiency anemia, patients
with thalassemia have a lower MCV, a more
normal red blood count and a more abnormal
peripheral blood smear at modest levels of
anemia. Iron studies are normal.
• Severe forms of thalassemia may be confused
with other hemoglobinopathies.
• The diagnosis is made by hemoglobin
electrophoresis.
The Thalassemias
Essentials of Diagnosis
• Microcytosis out of proportion to the
degree of anemia.
• Positive family history or lifelong personal
history of microcytic anemia.
• Abnormal red blood cell morphology with
microcytes, acanthocytes, and target cells.
• In -thalassemia, elevated levels of
hemoglobin A2 or F.
Anaemia of chronic disorders
(ACD)
• This is the rather unsatisfactory phrase used to cover the
most common of the normochromic, normocytic
anaemias, namely, those found in association with
chronic infection, all forms of inflammatory diseases, and
in malignant disease. It is very important for clinicians to
be able to identify the main features of this type of
anaemia.
• Although it may be extremely mild and asymptomatic,
the presence of this blood picture should always alert the
clinician to the possibility of there being a serious
underlying disease.
General Considerations
• Many chronic systemic diseases are associated
with mild or moderate anemia.
• Common causes include chronic infection or
inflammation, cancer and liver disease.
• The anemia of chronic renal failure is somewhat
different in pathophysiology, involving reduced
production of erythropoietin and is usually more
severe.
Pathogenesis
• The precise mechanism of the anaemia of chronic disorders is still
not understood. Several different pathological processes that occur
in response to inflammation conspire to cause a defective
proliferation of red cell progenitors. In addition, at least in some
cases, there may be a mild haemolytic component.
• The most constant feature of ACD is a low serum iron level despite
adequate iron stores in the reticuloendothelial elements of the bone
marrow. This abnormal accumulation of iron in the storage cells,
together with a low serum iron level in the blood, suggests that there
is a block in the release of iron to the developing red cell precursors.
This phenomenon may be observed within 24 h after major surgery,
for example. There is also a reduced concentration of transferrin,
and turnover studies suggest that this reflects a decreased rate of
production.
Clinical and laboratory
findings
• The anaemia of chronic disorders is usually mild. In
patients with severe inflammation the haematocrit may
fall to levels at which symptoms are experienced.
• Although the anaemia is usually normocytic and
normochromic there may be mild hypochromia with a
slight reduction in the MCH and MCV, particularly in
children.
• Occasionally there may be marked microcytosis.
Microcytosis should prompt consideration of concomitant
iron deficiency, especially in patients who might have
gastrointestinal bleeding, for example individuals with
inflammatory bowel disease or rheumatoid arthritis on
aspirin.
• The reticulocyte count is in the normal range.
• The clinical features are those of the causative
condition. The diagnosis should be suspected in
patients with known chronic diseases; it is
confirmed by the findings of low serum iron, low
TIBC and normal or increased serum ferritin.
• In cases of significant anemia, coexistent iron
deficiency or folic acid deficiency should be
suspected.
• Decreased dietary intake of folate or iron is
common in these ill patients, and many will also
have ongoing gastrointestinal blood losses.
• Patients undergoing hemodialysis regularly lose
both iron and folate during dialysis.
Anemia of Chronic Disease
Essentials of Diagnosis
• Anemia, normocytic or microcytic.
• Normal or increased iron stores.
• Underlying chronic disease.
Megaloblastic anaemias
• The megaloblastic anaemias are a group of disorders
characterized by a macrocytic anaemia and distinctive
morphological abnormalities of the developing haemopoietic
cells in the bone marrow. In severe cases, the anaemia may be
associated with leucopenia and thrombocytopenia.
• Megaloblastic anaemia arises because of inhibition of DNA
synthesis in the bone marrow, usually due to deficiency of one or
other of two water-soluble B vitamins, vitamin B 12 (B12,
cobalamin) or folate. B12 deficiency may also cause a severe
neuropathy but whether this occurs with folate deficiency is
controversial. In a minority of cases, megaloblastic anaemia arises
because of a disturbance of DNA synthesis due to a drug or a
congenital or acquired biochemical defect that causes a disturbance
of B 12 or folate metabolism or affects DNA synthesis independent
of B12 or folate.
Macrocytic anaemia
The presence in the bone marrow of erytroblasts with delayed
nuclear maturation because of defective DNA synthesis
(megaloblasts).
Occurs in:
– vitamin B12 deficiency
– folic acid deficiency
– diseritropoetic anaemia
Haematological values:
– anaemia
– MCV > 96 fL
– blood film (peripheral): macrocytes and hypersegmented
polymorphs
– neutropenia
– thrombocytopenia
Pathology
• There is a gastritis in which all layers of the body and
fundus of the stomach are atrophied with loss of normal
gastric glands, mucosal architecture and absence of
parietal and chief cells, but mucous cells lining the
gastric pits are well preserved.
• An infiltrate of plasma cells and lymphocytes with an
excess of CD8 cells occurs and intestinal metaplasia
may be present.
• The antral mucosa is remarkably well preserved except
in hypogammaglobulinaemia and, like the fundus, shows
an increased number of gastrin-secreting cells.
Clinical features
• The general features of megaloblastic anaemia are
similar, whatever the underlying cause. Particular clinical
features may point to the underlying disease, whethe
pernicious anaemia or some other cause.
• In pernicious anaemia, the anaemia usually develops
gradually, perhaps over several years, and symptoms
may not occur until it is severe.
• The most common complaints are due to the anaemia,
while loss of mental and physical drive, numbness, or
difficulty in walking suggest neuropathy.
Clinical features
• Psychiatric disturbances are common and range from
mild neurosis to severe organic dementia. They may
occur in the absence of anaemia or macrocytosis.
• Mild jaundice is frequent. Loss of appetite and weight,
indigestion, and episodic diarrhoea are frequent.
• An intercurrent infection may precipitate severe anaemia
and thus symptoms.
• Older patients may present with congestive heart failure.
• In a few patients, bruising due to thrombocytopenia is
marked.
• On the other hand, many patients are diagnosed
because a routine blood test is made.
Clinical features
• The typical patient with pernicious anaemia has fair hair
(prematurely grey), with blue eyes, and wide
cheekbones.
• Physical signs, if present, are those of anaemia, perhaps
with mild jaundice, giving the patient a so-called lemonyellow tint.
• A few patients with either B 12 or folate deficiency
develop a widespread brown pigmentation, affecting nail
beds and skin creases particularly, but not mucous
membranes, which is reversible with the appropriate
therapy.
• The biochemical basis for this is not clear, nor for the
depigmentation that also occurs rarely.
Clinical features
• The tongue may be red, smooth, and shiny, occasionally
with ulcers.
• A mild pyrexia up to 38°C is common in patients with
moderate to severe anaemia.
• The liver may be enlarged while the cardiovascular
system shows changes due to anaemia.
• Patients with pernicious anaemia may also have features
of an associated disorder on presentation, most
commonly myxoedema. Other thyroid disorders, vitiligo,
carcinoma of the stomach, Addison's disease and
hypoparathyroidism, may precede, occur simultaneously
with or follow the onset of the anaemia.
vitamin b12 (Addison – Biermer
anaemia)
– average daily diet 5 – 30 μg B12
–average adult stores 1000 μg – liver
–absorption and transport:
gut → binder complex (R binder + B12) → intrinsec
factor (glycoprotein from the gastric juice)
Transcobalamin
Ileum → → → → → → → → → → Marrow
Pernicious anaemia (Addison – Biermer) affect:
– particularly nordic people: fair – haired; blue – eyed.
–association with other autoimmune diseases: thyroid disease,
Addison’s disease, vitiligo
– higher incidence of gastric carcinoma
Causes of vitamin b12 deficiency:
– low dietary intake (vegans)
– impaired absorption:
A. stomach (gastrectomy)
B. small bowel:
– coeliac disease
– tropical sprue
– bacterial overgrowth
– ileal disease or resection
C. pancreas:
– chronic pancreatic disease
– Zollinger – Ellison syndrome
D. miscellaneous and rare:
– fish tape worm (diphyllobothrium latum)
– congenital deficiency:
– intrinsec factor
– transcobalamin III
– nitrous oxide (inactivates B12)
Partial gastrectomy
• Iron deficiency usually accounts for the anaemia that
occurs in up to half of subjects after this operation.
• Subnormal serum B 12 levels develop in about 18 per
cent of patients from about 2 years postoperatively.
About 6 per cent develop megaloblastic anaemia due to
the deficiency.
• In most of these patients, malabsorption of B 12 is due to
an abnormal jejunal flora.
• The exact incidence of B 12 deficiency depends mainly
on the size of the remnant, which tends to be smaller if
the operation is subtotal and the peptic ulcer gastric
rather than duodenal.
• Vagotomy and pyloroplasty is not a cause of B 12
deficiency.
Clinical features:
1. Anaemic syndrome
2. Neurological syndromes:
 Peripheral neuropathy progressively involving
posterior and lateral columns of the spinal cord:
– symmetrical paraesthesia in the fingers and toes
– loss of vibration sense and proprioception
– progressive weakness and ataxia
– paraplegia
 Mental changes:
– somnolence
– irritability
– psychosis
– dementia
the
• Peripheral nerves are usually affected first, and
patients complain initially of paresthesias.
• The posterior columns next become impaired
and patients complain of difficulty with balance.
• In more advanced cases, cerebral function may
be altered as well and on occasion dementia
and other neuropsychiatric changes may
precede hematologic changes.
• Neurologic examination may reveal decreased
vibration and position sense but is more
commonly normal in early stages of the disease.
3. Digestive syndrome:
– glossitis (red sore tongue)
– angular stomatitis
– hepatosplenomegaly
– gastric atrophy and achlorhydria
4. Others:
– skin – lemon-yellow tint due to hyperbilirubinaemia
– heart – failure
– fever
• The megaloblastic state also produces
changes in mucosal cells, leading to
glossitis, as well as other vague
gastrointestinal disturbances such as
anorexia and diarrhea.
• Patients are usually pale and may be
mildly icteric.
Investigations:
– peripheral blood film shows features of megaloblastic anaemia:
↓ reticulocytes
– the serum bilirubin ↑ (uncojugated)
– bone marrow → megaloblastic erythropoiesis
– the Schilling test (a radioactive dose of B12 is given orally and
the total body activity is measured), B12 LEVEL LOW
– G.I. investigations → endoscopy
• The megaloblastic state produces an anemia of variable
severity that on occasion may be very severe. The MCV is
usually strikingly elevated, between 110 and 140 fL.
However, it is possible to have vitamin B12 deficiency with a
normal MCV. Occasionally, the normal MCV may be
explained by coexistent thalassemia or iron deficiency, but in
other cases the reason is obscure.
• The peripheral blood smear is usually strikingly abnormal,
with anisocytosis and poikilocytosis. A characteristic
finding is the macro-ovalocyte, but numerous other
abnormal shapes are usually seen . The neutrophils are
hypersegmented . Typical features include a mean lobe
count greater than four or the finding of six-lobed
neutrophils.
• The reticulocyte count is reduced. Because vitamin B12
deficiency affects all hematopoietic cell lines, in severe cases
the white blood cell count and the platelet count are reduced
and pancytopenia is present.
• Bone marrow morphology is characteristically abnormal.
• Marked erythroid hyperplasia is present as a response
to defective red blood cell production (ineffective
erythropoiesis).
• Megaloblastic changes in the erythroid series include
abnormally large cell size and asynchronous
maturation of the nucleus and cytoplasm—ie,
cytoplasmic maturation continues while impaired DNA
synthesis causes retarded nuclear development.
• In the myeloid series, giant metamyelocytes are
characteristically seen.
Bone marrow
pernicious anaemia
• The diagnosis of vitamin B12 deficiency is made by
finding an abnormally low vitamin B12 (cobalamin) serum
level.
• Whereas the normal vitamin B12 level is > 240 pg/mL,
most patients with overt vitamin B12 deficiency will have
serum levels < 170 pg/mL, with symptomatic patients
usually having levels < 100 pg/mL. A level of 170–240
pg/mL is borderline.
• When the serum level of vitamin B12 is borderline, the
diagnosis is best confirmed by finding an elevated level
of serum methylmalonic acid (> 1000 nmol/L).
• However, elevated levels of serum methylmalonic acid
can be due to renal insufficiency.
Differential Diagnosis
• Vitamin B12 deficiency should be differentiated
from folic acid deficiency, the other common
cause of megaloblastic anemia, in which red
blood cell folate is low while vitamin B12 levels
are normal.
• The distinction between vitamin B12 deficiency
and myelodysplasia (the other common cause
of macrocytic anemia with abnormal
morphology) is based on the characteristic
morphology and the low vitamin B12 and
elevated methylmalonic acid levels.
Vitamin B12 Deficiency
Essentials of Diagnosis
• Macrocytic anemia.
• Macro-ovalocytes and hypersegmented
neutrophils on peripheral blood smear.
• Serum vitamin B12 level less than 100
pg/mL.
Folic acid
Daily requirement 100 μg
Causes of folate deficiency:
– poor intake:
– old age
– poor social conditions
– starvation
– alcohol excess
– poor intake due to anorexia:
– G.I. disease (partial gastrectomy, coeliac disease, Crohn’s
disease, cancer)
– excess utilization
causes
A. Physiological:
 pregnancy
 lactation
 prematurity
B. Pathological:
 haemolysis
 malignant disease
 inflammatory disease
 metabolic disease
 haemolysis
– malabsorption
– antifolate drugs
• By far the most common cause of folate deficiency is
inadequate dietary intake.
• Alcoholic or anorectic patients, persons who do not eat
fresh fruits and vegetables, and those who overcook
their food are candidates for folate deficiency.
• Reduced folate absorption is rarely seen, since
absorption occurs from the entire gastrointestinal tract.
However, drugs such as phenytoin, trimethoprimsulfamethoxazole, or sulfasalazine may interfere with
folate absorption.
• Folic acid requirements are increased in pregnancy,
hemolytic anemia and exfoliative skin disease, and in
these cases the increased requirements (five to ten
times normal) may not be met by a normal diet.
• Patients with increased folate requirements should
receive supplementation with 1 mg/d of folic acid.
Symptoms and Signs
• The features are similar to those of vitamin
B12 deficiency, with megaloblastic anemia
and megaloblastic changes in mucosa.
• However, there are none of the neurologic
abnormalities associated with vitamin B12
deficiency.
Laboratory Findings
• Megaloblastic anemia is identical to
anemia resulting from vitamin B12
deficiency.
• However, the serum vitamin B12 level is
normal.
• A red blood cell folate level of less than
150 ng/mL is diagnostic of folate
deficiency.
Differential Diagnosis
• The megaloblastic anemia of folate deficiency should be
differentiated from vitamin B12 deficiency by the finding
of a normal vitamin B12 level and a reduced red blood
cell folate or serum folate level.
• Alcoholic patients, who often have folate deficiency, may
also have anemia of liver disease. This latter macrocytic
anemia does not cause megaloblastic morphologic
changes but rather produces target cells in the
peripheral blood.
• Hypothyroidism is associated with mild macrocytosis but
also with pernicious anemia.
Folic Acid Deficiency
Essentials of Diagnosis
• Macrocytic anemia.
• Macro-ovalocytes and hypersegmented
neutrophils on peripheral blood smear.
• Normal serum vitamin B12 levels.
• Reduced folate levels in red blood cells or
serum.
Normocytic anaemia
1. Acute blood loss
2. Aplastic anaemia
3. Anaemia of chronic disease
4. Haemolytic anaemia
1. Acute blood loss
Stage I:
– Hb, Ht, Rc, N or ↑
– white cells ↑
– platelets ↑
Stage II (2 – 4 days):
– Hb, Ht, Rc ↓
– reticulocytosis
– ↓ white cells
– ↓ platelets
Stage III (2 – 3 weeks):
–Hb, Ht, Rc
–Wc
–Platelets
}
N
2. Aplastic anaemia
Aplasia of the bone marrow with peripheral blood pancytopenia.
Causes:
– congenital: Fanconi’s anaemia
– acquired:
– chemicals, drugs, insecticides
– ionizing radiation
– infections: viral hepatitis measles
– miscellaneous infection: tuberculosis
– tyhmona
– pregnancy
– unknown
General Considerations
• Aplastic anemia is a condition of bone marrow
failure that arises from injury to or abnormal
expression of the stem cell.
• The bone marrow becomes hypoplastic, and
pancytopenia develops.
• The most common pathogenesis of aplastic
anemia appears to be autoimmune suppression
of hematopoiesis by a T cell-mediated cellular
mechanism.
clinical features:
– anaemia
– bleeding (ecchymoses, bleeding gums and epistaxis)
– infection (fungal infections)
•Patients come to medical attention because of the
consequences of bone marrow failure.
•Anemia leads to symptoms of weakness and fatigue,
neutropenia causes vulnerability to bacterial infections and
thrombocytopenia results in mucosal and skin bleeding.
•Physical examination may reveal signs of pallor, purpura,
and petechiae.
•Other abnormalities such as hepatosplenomegaly,
lymphadenopathy, or bone tenderness should not be
present, and their presence should lead to questioning the
diagnosis.
investigations:
– elevated serum iron
– low haemoglobin
– white cell
– count 500 / mmc
– platelet 20,000 / mmc
– reticulocytes virtual absent
– hypocellular or aplastic bone marrow
Aplastic Anemia
Essentials of Diagnosis
• Pancytopenia.
• No abnormal cells seen.
• Hypocellular bone marrow.
3. Haemolytic anaemia
The red cells normally survives about 120 days, but in
haemolysis the cell survival times are considerably shortened.
Causes of haemolytic anaemia:
A. Inherited:
1. red cell membrane defect:
– hereditary spherocytosis
– hereditary eliptocytosis
2. haemoglobin abnormalities:
– thalassaemia
– sickle cell disease
3. metabolic defects:
– glucose 6 phosphate dehydrogenize deficiency
– pyruvate kinase deficiency
(Causes of haemolytic anaemia)
B. Acquired:
1. immune:
– autoimmune
– isoimmune (Rh or ABO incompatibility)
2. non-immune:
– membrane
defects:
paroxysmal
nocturnal
haemoglobinuria, liver disease, renal disease
– mechanical: damaged vessels, valve prosthesis, march
haemoglobinuria
3. miscellaneous:
– infections
– drugs and chemicals
– hypersplenism
site of haemolysis:
1. Intravascular – red cells are rapidly destroyed within the
circulation, haemoglobin is liberated;
2. Extravascular – red cells are removed from the circulation by
macrophages in the reticuloendothelial system (liver and
spleen)
evidence for haemolysis:
Increased red cell breakdown leads to:
– iron ↑
– stercobilinogen ↑
– elevated serum bilirubin (unconjugated)
– excess urinary urobilinogen
– reduced plasma haptoglobin
– abnormal red cell fragments in peripheral blood
Increased red cell production leads to:
– reticulocytosis
– erythroid hyperplasia of the bone marrow
clinical findings:
– skin – jaundice
– splenomegaly
– abdominal pain (infarction or acute sequestration as in sickle
syndromes)
– gall stones
– growth impaired (e.g. spherocytosis)
– ulcers on the leg
– dark urine (in haemolytic crises)
– black in pmn
– septic necrosis of the bone (sickle sdr.)
– papillary necrosis affecting the kidney → haematuria (S.S.)
– painful priaprism
– cerebral damage
Peripherical blood in
hemolytic anaemia
Polycythaemia
Is defined as a haemoglobin level greater than 18 g/dL, a red
cell count above 6x1012/L. The red cell volume is greater than 36
mL/kg in males and 32 mL/kg in females.
Causes of polycythaemia
Primary:
– Polycythaemia vera
Secondary:
A. due to an appropriate increase in erythropoetin:
– high altitude
– lung disease
– cardiovascular disease (right left shunt)
– heavy smoking
B. due to an inappropriate increase in erithropoetin:
– renal disease, carcinoma, Wilms tumor
– hepatocellular carcinoma
– adrenal tumors
– cerebellar haemangioblastoma
– massive uterine fibroma
Relative:
– stress or spurious polycythaemia
– dehydration
– burns
Policitemia vera
Caused by chronic sustained proliferation of the erithroid
population of the bone marrow.
↑ red cell volume
↑ blood viscosity
compensated by an
increase plasma
volume and
cardiac output
Ht ↑ ↑ ↑
 myocardial infarction
stroke
clinical findings:
 tiredness
 depression
 vertigo
 tinitus and visual disturbance
 hypertension
 angina
 intermitent claudication
 tendency to bleed
 itching after bath
 peptic ulcerations
Symptoms
• Most patients present with symptoms related to expanded blood
volume and increased blood viscosity.
• Common complaints include headache, dizziness, tinnitus, blurred
vision, and fatigue.
• Generalized pruritus, especially following a warm shower or bath,
may be a striking symptom and is related to histamine release from
the increased number of basophils present.
• Patients may also initially complain of epistaxis. This is probably
related to engorgement of mucosal blood vessels in combination
with abnormal hemostasis due to qualitative abnormalities in platelet
function.
• 60% of patients are men and the median age at presentation is 60
years. Polycythemia rarely occurs in persons under age 40 years.
Signs
• Physical examination reveals plethora and engorged retinal
veins. The spleen is palpable in 75% of cases but is nearly
always enlarged when imaged.
• Thrombosis is the most common complication of polycythemia
vera and the major cause of morbidity and death in this
disorder. Thrombosis appears to be related both to increased
blood viscosity and abnormal platelet function.
• Uncontrolled polycythemia leads to a very high incidence of
thrombotic complications of surgery and elective surgery
should be deferred until the condition has been treated.
• Paradoxically, in addition to thrombosis, increased bleeding
also occurs. There is a high incidence of peptic ulcer disease.
investigations:
 ↑ Hb, ↑ Ht, ↑WBC, ↑platelets
 erythroid hyperplasia and abnormal megakaryocytes in bone
marrow
 red cell volume ↑
 serum uric acid levels ↑
 leucocyte alkaline phosphatase (LAP) ↑
 vitamin B12 binding protein is ↑
Differential Diagnosis
• Spurious polycythemia, in which an
elevated hematocrit is due to contracted
plasma volume rather than increased red
cell mass, may be related to diuretic use
or may occur without obvious cause.
Differential Diagnosis
• A secondary cause of polycythemia should be suspected if
splenomegaly is absent and the high hematocrit is not accompanied
by increases in other cell lines.
• Arterial oxygen saturation should be measured to determine if
hypoxia is the cause. A smoking history should be taken;
carboxyhemoglobin levels may be elevated in smokers.
• A renal CT scan or sonogram may be considered to look for an
erythropoietin-secreting cyst or tumor.
• A positive family history should lead to investigation for congenital
high-oxygen-affinity hemoglobin.
• An absence of a mutation in JAK2 suggests a different diagnosis.
However, JAK2 mutations are also commonly found in the
myeloproliferative disorders essential thrombocytosis and
myelofibrosis.
Differential Diagnosis
• Polycythemia vera should be differentiated from other
myeloproliferative disorders.
• Marked elevation of the white blood count (above
30,000/mcL) suggests chronic myeloid leukemia. This
disorder is confirmed by the presence of the bcr/abl
fusion gene.
• Abnormal red blood cell morphology and nucleated red
blood cells in the peripheral blood are seen in
myelofibrosis. This condition is diagnosed by bone
marrow biopsy showing fibrosis of the marrow.
• Essential thrombocytosis is suggested when the
platelet count is strikingly elevated.
Polycythemia Vera
Essentials of Diagnosis
•
•
•
•
•
JAK2 mutation.
Increased red blood cell mass.
Splenomegaly.
Normal arterial oxygen saturation.
Usually elevated white blood count and
platelet count.