ANAEMIA

Definition/Introduction

It is defined as a reduction of red cell mass or hemoglobin concentration below the range of
values occurring in healthy persons of same age, sex and cultural background or geographical
location.

Physiological adjustments to anaemia

a. Increased cardiac output. b. Increased synthesis of 2,3-DPG (2,3-diphosphoglycerate)

c. Higher levels of erythropoietin

Note; 2,3-DPG shifts O2 dissociation curve to the right implying increased release of oxygen to
the tissues.

Classification of anaemia

Different classifications have been used but for the purpose of this lecture, we shall adopt the
classification that relates to red cell production and lysis, whole blood loss.

RED CELL PRODUCTION

A. ANAEMIA OF INADEQUATE PRODUCTION

i. Iron deficiency anaemia
ii. Megaloblastic anaemia
a. Folate deficiency
b. Vitamin B12 deficiency
iii. Anaemia of chronic illness
iv. Congenital hypoplastic anaemia
v. Acquired pure red blood cell anaemia

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Iron deficiency anaemia

Anaemia resulting from lack of sufficient iron for synthesis of hemoglobin is the most common
hematologic disease of infancy and childhood. 30% of the global population suffer from iron
deficiency anaemia and most of the people affected live in the developing countries.

To maintain positive iron balance in childhood, 1mg of iron must be absorbed daily. The body of
a new born contains about 0.5g of iron while that of an adult contains 5g. To get from one point
to the other, 0.8mg must be absorbed daily for the first 15years of life. Absorption of dietary iron
is 10%, so diet containing 8-10mg of iron daily is necessary for optimal iron metabolism.

High Hb concentration of the newborn infant falls during the 1st 2-3months of life. Considerable
amount of iron is reclaimed and stored. These reclaimed stores are usually sufficient for blood
formation in the 1st 6-9months of life in term babies. In LBW infants or those with perinatal
blood loss, stored iron may be depleted earlier and dietary sources become paramount. In term
infants, anaemia caused solely by inadequate dietary iron is unusual before 6months and usually
occurs at 9-24months due to increased physiological demand (growth spurt).

Sources of iron

Iron is found in food in two forms, heme and non-heme iron. Heme iron, which makes up 40 percent
of the iron in meat, poultry, and fish, is well absorbed. Non-heme iron, 60 percent of the iron in animal
tissue and all the iron in plants (fruits, vegetables, grains, nuts) is less well absorbed.

Causes

a. Dietary deficiency
b. Peptic ulcer disease
c. Meckel diverticulum
d. Polyps/ haemangiomas
e. Hookworm infestation
f. Helicobacter pylori
g. Pulmonary hemosiderosis may cause unrecognized lung bleeds
h. PICA (geophagia….eating of soil, pagophagia… eating of ice)

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Clinical manifestation

Non-Specific Symptoms

Iron deficiency can cause fatigue, irritability, dizziness, breathlessness, and headache, loss of
appetite. One may attribute these symptoms to anaemia but these symptoms are seen in patients
with iron deficiency even in the absence of anaemia. Iron therapy has been shown to correct
many of these manifestations.

Skin and Hair

Iron deficiency results in brittle nails that have longitudinal ridges. The nails become thin, brittle
and become flat (platonychia) or concave and spoon shaped (koilonychia). Hair may become thin
and brittle.

A. Platonychia B. platonychia

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 c. koilonychia

Digestive system

Next to blood the effects of iron deficiency are most pronounced on the digestive system

1. Tongue: Iron deficiency causes atrophy of the papillae of the tongue. The filiform papillae of
the anterior part of the tongue are the first to be affected. The fungiform papillae of the
posterior tongue atrophy later, resulting in a smooth or patchy red tongue.  Papillary atrophy
results in soreness of the tongue. The changes reverse after about 1-2 weeks of iron therapy.

A. Normal tongue B. Depapillated tongue (geographic tongue)

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2. Mouth: Iron deficiency results in angular stomatitis. This anomalies is not specific to iron
deficiency may be seen in pyridoxine and riboflavin deficiency.

Angular stomatitis

3. Dysphagia: Iron deficiency results in the formation of webs at the junction of hypopharynx
and oesophagus. These manifest as dysphagia that has an insidious onset. The patients
complain of discomfort on swallowing, initially for solids, at the level of the cricoid cartilage.
Mild dysphagia may be corrected by iron replenishment but dysphagia persists in most
patients despite iron replenishment and dilatation may be needed.
4. Pica: Pica is craving for non-nutritive substances like chalk, paint and ice. Pagophagia, the craving for
ice is a common form of pica

Neuromuscular/neurocognitive Symptoms

Iron deficiency impairs performance of muscles. Children with iron deficiency show irritability,
are disruptive, have impaired attention span and may show scholastic impairment. Iron
deficiency has also been shown to be associated with developmental delay, ischaemic stroke and
raised intracranial pressure.

Effect on Immunity and Infections

Iron deficiency decreases the number of T lymphocytes and impairs phagocytosis. This however
does not appear to result in an increased risk of infections.

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Menstrual Anomalies

While menstrual anomalies can be a cause of iron deficiency, they can often be a consequence of
iron deficiency. Only response to treatment can tell which of the two is the case in a given
patient.

Skeletal Expansion

Young patients who have prolonged iron deficiency may develop bone changes similar to
haemolytic anaemia or thalassaemia because of bone marrow expansion.

Biochemical Signs

In progressive iron deficiency anaemia, a sequence of biochemical and haematological events

occur.

1st the tissue iron store represented by marrow hemosiderin disappears

2nd serum ferritin also decrease precipitously.

3rd as serum iron level decreases, the total iron binding capacity increases and the % of saturation
of transferrin falls below normal

4th when the availability of iron becomes rate limiting for Hb synthesis, free erythrocyte
protoporphyrins (FEP) accumulates

5th as the deficiency progresses the RBCs become smaller than normal and their Hb content
decreases

6th with increasing deficiency the RBCs become deformed and misshapen and present
characteristic microcytosis, hypochromia, poikilocytosis and anisocytosis. There is increased red
cell distribution width (RDW).

WBCs are normal but there is Thrombocytosis due to increased erythropoietin which is known to
have some structural homology with TPO.

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The red blood cells here are normal. They have a zone of central pallor about 1/3 the size of the
RBC. The RBC's demonstrate minimal variation in size (anisocytosis) and shape (poikilocytosis).

Hypochromic/microcytic anaemia. Note different sizes (anisocytosis) and shapes

(poikilocytosis)

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Differential diagnosis

1. αandβ thalassemia trait; in β thalassemia trait there is increased fetal hemoglobin but
serum iron, transferrin, ferritin are normal. The thalassemias may also have evidence of
haemolysis.
2. Anaemia of chronic illness; in this condition, both the serum iron level and binding
capacity are reduced and serum ferritin level is normal or elevated. Transferrin receptor is
elevated in iron deficiency while it is within normal limit in anaemia of chronic illness.
3. Lead poisoning; both lead poisoning and iron deficiency anaemia are associated with
increased FEP. However there is elevated blood lead and urinary corproporphyrin level

Investigations

a. Low PCV and Hb

b. Peripheral film shows microcytosis, hypochromia (central RBC pallor >1/3 of
RBC diameter), anisocytosis, poikilocytosis, increased red cell distribution width
(RDW).
c. Low MCV, MCH, ferritin, and serum iron
d. Increased transferrin and transferrin receptors.
e. WBC is normal.
f. There may be Thrombocytosis due to the effect of EPO.

Treatment

o The regular response of iron deficiency anaemia to adequate amounts of iron is an

important diagnostic feature.
o Oral administration of simple ferrous salts (sulfate, gluconate, fumerate) provides
inexpensive and satisfactory therapy.
o A daily dose of 4-6mg/kg elemental iron in 3 divided doses provides an optimal amount
of iron for the stimulated bone marrow to use.
o Parenteral iron has no advantage over oral.
o Note that 20% of ferrous sulphate is elemental iron

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 Responses to Iron Therapy in Iron-Deficiency Anemia
TIME AFTER IRON
ADMINISTRATION RESPONSE
12–24 hr Replacement of intracellular iron enzymes; subjective
improvement; decreased irritability; increased appetite
36–48 hr Initial bone marrow response; erythroid hyperplasia
48–72 hr Reticulocytosis, peaking at 5–7 days
4–30 days Increase in hemoglobin level
1–3 mo Repletion of stores

MEGALOBLASTIC ANAEMIA

o The megaloblastic anaemias are characterized by megaloblasts which are large abnormal
red cell precursors in the bone marrow and macrocytes in the peripheral blood.
o Megaloblastic anemia is an anemia that results from inhibition of DNA synthesis during red
blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the
G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division,
which presents as macrocytosis
o Almost all instances of megaloblastic anaemia are attributable to deficiency of folate and
Vit B12 (cyanocobalamine).

Folic Acid Deficiency

o Folates are abundant in many foods, including green vegetables, fruits, and animal organs
(e.g., liver, kidney).
o Folates are heat labile and water soluble, and consequently boiling or heating folate
sources leads to decreased amounts of the vitamin.
o Naturally occurring folates are in a polyglutamated form and are absorbed less efficiently
than the monoglutamate species (i.e., folic acid). Folate conjugase activity in the
intestinal brush border aids the hydrolysis of polyglutamates to the monoglutamate
thereby enhancing absorption. Folic acid is absorbed throughout the small intestine, and
there is an active enterohepatic circulation.

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 o Before it enters the blood stream, monoglutamate is hydrolysed to dihydrofolate and then
to biologically active tetrahydrofolate by dihydrofolate reductase. It is then transported
to target tissues. In the storage tissues, it is polyglutamated and stored.
o Body stores of folate are limited, and megaloblastic anemia occurs after 2–3 months on a
folate-free diet.

AETIOLOGY.

Inadequate Folate Intake.

o Anemia due to decreased folate intake usually becomes manifest under clinical
conditions that have increased vitamin requirements (e.g., pregnancy, growth in infancy,
chronic hemolysis).

Decreased absorption.

o Malabsorption due to chronic diarrhoeal states or diffuse inflammatory disease can lead to folate
deficiency.
o Megaloblastic anemia due to folic acid deficiency can occur in celiac disease or chronic
infectious enteritis, or in association with entero-enteric fistulas.
o With both inflammatory bowel disease and diarrhea, some of the decreased folate absorption may
be caused by impaired folate conjugase activity.
o Certain anticonvulsant drugs (e.g., phenytoin, primidone, phenobarbital) can impair absorption of
folic acid, and many patients treated with these drugs have low serum levels of folic acid.

Congenital Abnormalities in Folate Metabolism.

o Megaloblastic anemia resulting from congenital dihydrofolate reductase deficiency is a

very rare disorder that is due to an inability to form biologically active tetrahydrofolate.
o Affected individuals have developed severe megaloblastic anemia in early infancy. These
patients were treated successfully with large doses of folic acid or folinic acid.

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Drug-Induced Abnormalities in Folate Metabolism.

o A number of drugs have anti–folic acid activity as their primary pharmacologic effect and
regularly produce megaloblastic anemia.
o Methotrexate binds to dihydrofolate reductase and prevents formation of tetrahydrofolate,
the active form. Pyrimethamine, used in the therapy of toxoplasmosis, and trimethoprim,
used for treatment of various infections, may induce folic acid deficiency and,
occasionally, megaloblastic anemia.
o Therapy with folinic acid (5-formyltetrahydrofolate) usually is beneficial.

Laboratory findings

Magloblastic anaemia showing macrocytic RBCs and hypersegmented neutrophils

Clinical features

Non-hematological

Common symptoms of folate deficiency include diarrhea, weakness and shortness of breath,
nerve damage associated with weakness and limb numbness (peripheral neuropathy), mental
confusion, forgetfulness or other cognitive deficits, mental depression, sore or swollen tongue,

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peptic or mouth ulcers, headaches, palpitations, irritability, and behavioral disorders. Low levels
of folate can also lead to homocysteine accumulation. Neural tube defect is a feature.

Hematological findings

The blood film can point towards vitamin deficiency:

 Decreased red blood cell (RBC) count and hemoglobin levels

 Increased mean corpuscular volume (MCV, >95 fl)
 Normal mean corpuscular hemoglobin concentration (MCHC, 32–36 g/dL)
 The reticulocyte count is decreased due to destruction of fragile and abnormal megaloblastic
erythroid precursor.
 Neutrophils may show multisegmented nuclei ("senile neutrophil"). This is thought to be due to
decreased production and a compensatory prolonged lifespan for circulating neutrophils, which
increase numbers of nuclear segments with age.
 Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
 Serum lactate dehydrogenase level which is a marker of ineffective erythropoiesis is high.
 Neutropenia and thrombocytopenia may be present in long standing and severe deficiency.
 Increased homocysteine level which is a marker for ineffective DNA synthesis.

Treatment.

 Folic acid orally or parenterally (0.5-1mg)

 With the above treatment, haematologic response is expected within 72hrs
 High doses of 1-5mg have also been used.

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 VITAMIN B12 DEFICIENCY

Vitamin B12, also called cobalamin, is a water-soluble vitamin with a key role in the normal
functioning of the brain and nervous system, and formation of blood cells. It is one of the eight B
vitamins and it is normally involved in the metabolism of every cell of the human body,
especially DNA synthesis and regulation, fatty acid and amino acid metabolism.
Microorganisms, primarily bacteria, are the only organisms known to synthesize B12. These
bacteria are thought to live in water, soil, and the digestive tracts of animals. In animals, B12 is
normally attached to a protein either for transport or storage.

Ingested cobalamine combine with R-protein and IF secreted by parietal cells. In the duodenum,
pancreatic proteases break off the R-protein while the IF-cobalamine complex is absorbed in the
distal ileum. After B12 is absorbed into the intestinal cells, it attaches to transcobalamin II
(TC2). Transcobalamin II is made in the intestinal cells where it picks up B12 and transports it to
all body tissues through the blood and cerebrospinal fluid . While transcobalamin II transports
B12 to cells, about 3/4 of the B12 in the blood is stored on haptocorrin (aka transcobalamin I and
cobalophilin). Once the B12-TC2 complex arrives at the cell where it is needed, B12 is released
from TC2 in the form of hydroxocobalamin. It is then turned into methylcobalamin or
adenosylcobalamin which are the active forms of the vitamin. Transcobalamin II also transports
B12 to the liver for storage on transcobalamin III. Children and adults have sufficient vitamin
B12 stores to last for 3-5years

AETIOLOGY

Inadequate intake

Because vitamin B12 is present in many foods, dietary deficiency is rare except in strict
vegetarian

Lack of intrinsic factor

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Megaloblastic anaemia resulting from intrinsic factor deficiency is called pernicious anaemia.
There are two types;

a. Congenital pernicious anaemia; presents with failure to thrive before the age of
3years. Gastric histology and acid secretion are normal but IF is absent in the
gastric secretions. There are no antibodies to intrinsic factor and no
endocrinopathies.

b. Juvenile pernicious anaemia; occurs in older children and is similar to pernicious

anaemia in adult. Gastric atrophy and decreased secretion of acid and pepsin are
commonly associated with antibodies to IF or to parietal cells. Endocrinopathies
such as hypothyroidism, hypoparathyroidism, Addison’s disease may be seen.

Impaired absorption

 Utilization of Vitamin B12 in the intestinal lumen by the fish tapeworm diphyllobothrium
latum or bacterial consumption of B12 in intestinal diverticuli or blind loops results in
deficiency.

 Regional enteritis or surgical resection of terminal ileus can result in B12 malabsorption

 Imerslund-Grasbeck syndrome is a congenital autosomal recessive disorder characterized

by ileal B12 mal-absorption, proteinuria and megaloblastic anaemia in the first two years
of life.

 B12 absorption and transport are decreased in transcobalamin II deficiency.

Clinical manifestation

The main syndrome of vitamin B12 deficiency is Biermer's disease (pernicious anemia). It is
characterized by a triad of symptoms:

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 1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the
inhibition of DNA synthesis.
2. Gastrointestinal symptoms. These symptoms (diarrhoea, heart burn, dyspepsia) are
thought to be due to defective DNA synthesis inhibiting replication in a site with a high
turnover of cells. This may also be due to the autoimmune attack on the parietal cells of
the stomach. There is an association with GAVE syndrome (gastric antral vascular
ectasia commonly called watermelon stomach) and pernicious anemia

Water melon gastric antrum

3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished

vibration or soft touch sensation), subacute combined degeneration of spinal cord,
seizures or even symptoms of dementia and or other psychiatric symptoms may be
present. The presence of peripheral sensory-motor symptoms or subacute combined
degeneration of spinal cord strongly suggests the presence of a B 12 deficiency instead of folate
deficiency. Dementia and depression have been associated with this deficiency as well, possibly
from the under-production of methionine because of the inability to convert homocysteine into
this product. Methionine is a necessary cofactor in the production of several neurotransmitters.

Each of those symptoms can occur either alone or along with others. The neurological complex,
defined as myelosis funicularis, consists of the following symptoms:

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 1. Impaired perception of deep touch, and vibration, loss of light touch, very annoying and
persistent paresthesias
2. Ataxia of dorsal chord type
3. Decrease or loss of deep muscle-tendon reflexes
4. Pathological reflexes — Babinski, Rossolimo (Rossolimo's sign is a clinical sign in which
percussion of the tips of the toes causes an exaggerated flexion of the toes).

Treatment

A prompt haematological response follows parenteral administration of Vitamin B12 (1mg),

usually with reticulocytosis in 2-4days. If there is evidence of neurologic involvement 1mg
should be injected i.m daily for at least 2weeks.

Maintenance therapy is necessary throughout patient’s life. Monthly i.m administration of 1mg
Vit B12 is sufficient.

ANAEMIA OF CHRONIC DISEASE

This type of anaemia complicates a number of chronic systemic diseases such as chronic
pyogenic infections (bronchiectasis, osteomyelitis) chronic inflammatory processes (rheumatoid
arthiritis, SLE, ulcerative colitis)

Pathogenesis

a. Some organisms causing chronic infection may release some chemical

compounds that may lyse the red cells causing anaemia
b. There is blunted response of the bone marrow to erythropoietin.
c. Chronic infections and inflammatory processes cause the release of cytokines IL-
1, TNF and IL-6 which lead to the production of hepcidin. Hepcidin has been
found to decrease intestinal iron absorption and release of iron from macrophages.

Clinical manifestations

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 a. Mild to moderate anaemia in addition to the features of the underlying disease.

Laboratory findings

Hb=6-9g/dl

Anaemia is usually normochromic and normocytic though some patients may have hypochromic
and microcytic anaemia. In these patients serum iron and transferrin levels are low.

Treatment

Anaemia does not respond to iron or haematinics unless there is concomitant deficiency.
Transfusions raise the Hb temporary but they are rarely indicated. If the underlying systemic
disease is controlled, the anaemia resolves.

ANAEMIA OF RENAL DISEASE

The major cause of this anaemia is decreased EPO production because of damage to the renal
cells that produce this hormone. The anaemia is normocytic. Iron studies are normal.

DIAMOND BLACKFAN ANAEMIA (CONGENITAL HYPOPLASTIC ANAEMIA)

This disease could be sporadic, autosomal dominant or recessive. The primary defects are in the
erythroid progenitor cells, where there is intrinsic defect that results in increased programmed
cell death (apoptosis). Profound anaemia becomes evident by 2-6months of age.

Features include short stature, craniofacial dysmorphism (wide set eyes, snub-nose, thick lips).
There may be triphalangeal thumb, supernumerary thumb, bifid thumb, weak radial pulse and
flattening of thenar eminence.

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 The 3 images are those of Diamond Blackfan Anaemia

Corticosteroid therapy is beneficial in ¾ of the patients. Chronic transfusion for those who do not
respond to steroid.

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