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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2826_Библиотеки_им_академика_М_И_Перельмана.pdf
5
Blood consists of red cells, white cells, platelets and plasma. Plasma is the
liquid component of blood which contains soluble fibrinogen and in which the
other components are suspended. Serum is what remains after the formation
of the fibrin clot.
Haemopoiesis is the formation of blood cells. The haemopoietic system
includes the bone marrow, liver, spleen, lymph nodes and thymus. There is
huge turnover of cells, with the red cells surviving 120 days, platelets around
7 days but granulocytes only 7 hours. The bone marrow is the only source of
blood cells during normal childhood and adult life.
Pluripotent stem cells give rise to:
• Common lymphoid progenitor cells, which give rise to pre-T cells (and
then T suppressor, T helper and natural killer cells) and pre-B cells (and
then B cells and plasma cells).
• Mixed myeloid progenitor cells, which give rise to colony-forming
units committed to the production of red cells, platelets, monocytes,
neutrophils, eosinophils and basophils. Production is stimulated by
growth factors such as erythropoietin (red cells), thrombopoietin
(platelets), granulocyte colony stimulating factor, or G-CSF (neutrophils)
and interleukin-5 (eosinophils). Other factors such as tumour necrosis
factor (TNF) and transforming growth factor beta (TGF-β) are inhibitory.
Reticulocytes are young red cells recently released from the bone marrow
which still contain RNA. They are larger than mature red cells and normally
represent 0.5%–2.5% of total circulating red blood cells. The reticulocyte
count gives a guide to the erythroid activity in the bone marrow and there is
normally an increase with haemorrhage, haemolysis and after treatment with
specific haematinics in deficiency states.
Haematological disease
ANAEMIA
The principal function of haemoglobin (Hb) is to deliver oxygen to the tissues
from the lungs. Hb is a tetramer consisting of two pairs of globin polypeptide
chains. A haem group, consisting of a single molecule of protoporphyrin IX
bound to a single ferrous ion (Fe2+) is linked covalently at a specific site to each
globin chain. Oxygenation and deoxygenation of Hb occur at the haem iron.
Anaemia is present when there is a decrease in the level of Hb in the
blood below the reference range for the age and sex of the individual.
Reduction of Hb is usually accompanied by a fall in red cell count (RCC)
and packed cell volume (PCV, haematocrit), although an increase in plasma
194 Haematological disease
Table 5.1 Normal values for adult peripheral blood
Male Female
Hb (g/L)
PCV (haematocrit, L/L)
RCC (1012/L)
135–175
0.4–0.54
4.5–6.0
MCV (fL)
MCH (pg)
MCHC (g/L)
RDW (%)
WCC (109/L)
Platelets (109/L)
ESR (mm/h)
Reticulocytes
ESR, erythrocyte sedimentation rate; Hb, haemoglobin; MCH, mean corpuscular
haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean
corpuscular volume of red cells; PCV, packed cell volume; RCC, red cell count; RDW, red
blood cell distribution width (an increase indicates greater variation in red cell size with
both large and small red cells); WCC, white cell count.
0.5%–2.5% (50–100 × 109/L)
115–160
0.37–0.47
3.9–5.0
80–96
27–32
320–360
11–15
4.0–11.0
150–400
<20
volume (as with massive splenomegaly) may cause anaemia with a normal
RCC and PCV (‘dilutional anaemia’). The normal values for these indices
are given in Table 5.1, all of which are measured using automated cell
counters as part of a routine full blood count (FBC). Anaemia should also
be evaluated with the white blood cell and platelet counts, reticulocyte
count (indicating marrow activity) and the blood film (abnormal red cell
morphology may indicate the diagnosis).
Clinical features
Symptoms depend on the severity and speed of onset of anaemia. A very
slowly falling level of Hb allows for haemodynamic compensation and
enhancement of the oxygen-carrying capacity of the blood, and thus patients
with anaemia may be asymptomatic. In general, elderly people tolerate
anaemia less well than young people. The symptoms are non-specific and
include fatigue, faintness and breathlessness. Angina pectoris and intermittent claudication may occur in those with coexistent atheromatous arterial
disease. On examination the skin and mucous membranes are pale; there
may be a tachycardia and a systolic flow murmur. Cardiac failure may occur
in elderly people or those with compromised cardiac function.
Anaemia 195
Table 5.2 Classification of the anaemias based on the mean
corpuscular volume (MCV)
Small cells
(microcytes)
Low MCV (<80 fL)
Iron deficiency
Anaemia of chronic
disease
Thalassaemia
Sideroblastic anaemia
Normal-sized cells
Normal MCV
Acute blood loss
Anaemia of chronic
disease
Combined deficiency,
e.g. iron and folate
Marrow infiltration/
fibrosis
Endocrine disease
Haemolytic anaemias
Large cells
(macrocytes)
HighMCV (>96 fL)
Megaloblastic
Vitamin B12 deficiency
Folate deficiency
Normoblastic
Alcohol
↑ Reticulocytes, e.g.
haemorrhage,
haemolysis
Liver disease
Hypothyroidism
Drug therapy, e.g.
azathioprine
Classification of anaemia (Table 5.2)
Anaemia is not a final diagnosis, and a cause should be sought. Causes are
classified according to the measurement of red blood cell size (mean corpuscular volume [MCV]). This classification is useful because the type of anaemia
indicates the underlying causes and necessary investigations. Irrespective of
the cause, most patients with chronic anaemia do not require blood transfusion and the appropriate management, unless severely anaemic, is treatment
of the underlying cause.
Microcytic anaemia
Microcytosis usually reflects a decreased Hb content within the red blood
cell and is then often associated with a reduction in the mean corpuscular
Hb (MCH) and mean corpuscular Hb concentration (MCHC), producing a hypochromic appearance on the blood film. The causes of microcytic anaemia are
listed in Table 5.2: α- or β-thalassaemia minor (p. 208–209) is associated
with a microcytosis usually in the absence of anaemia.
196 Haematological disease
100
disease
Concentration (µmol/L)
Iron deficiency
Iron is necessary for the formation of haem and iron deficiency is the most
common cause of anaemia worldwide. The average daily diet in the UK
contains 15–20 mg of iron, although normally only 10% of this is absorbed,
mainly in the duodenum. Body iron content is regulated by alteration in
intestinal iron absorption. Factors that promote intestinal absorption include
gastric acid, iron deficiency and increased erythropoietic activity. Elimination
of iron is fixed at 1 mg/day and occurs through shedding of skin and mucosal
cells and excretion in sweat, urine and faeces. In women there is an additional loss during menses, and pre-menopausal women may often border on
iron deficiency. There are two forms of dietary iron:
• Non-haem iron forms the main part of dietary iron and is derived from
fortified cereals and vegetables. It is dissolved in the low pH of the
stomach and reduced from the ferric to the ferrous form by a brush
border ferric reductase before transportation across the mucosal cells.
• Haem iron is derived from Hb and myoglobin in red or organ meats.
Haem iron is better absorbed than non-haem iron.
Iron is transported in the plasma bound to the protein transferrin, which
is synthesized in the liver and normally about one-third saturated with
iron (Fig. 5.1). Most of the body’s iron content is incorporated into Hb in
developing erythroid precursors and mature red cells. Most of the remaining
body iron is stored as ferritin and haemosiderin in hepatocytes, skeletal
muscle and reticuloendothelial macrophages.
90
80
70
60
50
40
30
20
10
0
Normal
Fig. 5.1 Serum iron and total iron-binding capacity (transferrin) in normal
subjects, iron deficiency anaemia and anaemia of chronic disease.
Iron
deficiency
Serum iron
Iron-binding
capacity
Anaemia
of chronic
Anaemia 197
Causes of iron deficiency
Causes of iron deficiency are:
• Blood loss: this is the commonest cause of iron deficiency and usually
occurs from the uterus (e.g. menstrual losses) or the gastrointestinal
tract. On a worldwide basis, hookworm is a common cause of intestinal
blood loss and iron deficiency.
• Increased demands such as growth and pregnancy.
• Decreased absorption, e.g. small bowel disease or post-gastrectomy.
The key molecule regulating iron absorption is hepcidin, which acts by
regulating the activity of the iron-exporting protein ferroportin. High levels
of hepcidin (occurring in inflammatory states via inflammatory cytokines),
will destroy ferroportin and limit iron absorption, and low levels of
hepcidin (e.g. in anaemia, low iron stores, hypoxia) will encourage iron
absorption.
• Poor intake: this is rare in developed countries.
Clinical features
Symptoms and signs are the result of anaemia (p. 194) and of decreased
epithelial cell iron, which causes brittle hair and nails, atrophic glossitis and
angular stomatitis.
Investigations
• Blood count and film. The red cells are microcytic (MCV <80 fL) and
hypochromic (MCH <27 pg). There is anisocytosis (variation in size) and
poikilocytosis (variation in shape).
• Serum ferritin reflects iron stores and is low. However, ferritin is an
acute-phase reactant, and in the presence of inflammatory or malignant
disease, levels may be within the normal range in the presence of iron
deficiency.
• Serum iron is low and the total iron-binding capacity (TIBC) is high,
resulting in a transferrin saturation (serum iron divided by TIBC) <19%
(see Fig. 5.1).
• Serum soluble transferrin receptor numbers increase in iron deficiency.
• Bone marrow examination is generally unnecessary.
Iron deficiency is almost always the result of chronic, often occult,
gastrointestinal blood loss in men and in post-menopausal women, and
further investigation of the gastrointestinal tract is required to determine
the cause of the blood loss (see p. 89). Iron deficiency anaemia in premenopausal women is usually the result of menstrual blood loss. In this
group the only investigation necessary is serology for coeliac disease, and
endoscopic investigation only if there are intestinal symptoms or a family
history of colorectal cancer (two first-degree relatives or one <45 years
of age).
198 Haematological disease
Differential diagnosis
This is from other causes of a microcytic/hypochromic anaemia (see Table 5.2).
In thalassaemia, sideroblastic anaemia and anaemia of chronic disease, the
iron stores are normal or increased.
Management
• Find and treat the underlying cause.
• Oral iron, e.g. ferrous sulphate or ferrous gluconate (p. 239). A response
to iron treatment is characterized by an increase in the reticulocyte count
followed by an increase in Hb at a rate of about 10 g/L every week until
the Hb concentration is normal.
• Parenteral iron (deep intramuscular or intravenous infusion) may be used
when patients are intolerant or there is a poor response to oral iron, e.g.
severe malabsorption.
Anaemia of chronic disease
This occurs in patients with chronic inflammatory diseases (such as rheumatoid
arthritis), chronic infections (such as tuberculosis), malignancy and chronic
kidney disease. There is a normochromic, normocytic or microcytic anaemia.
Characteristic laboratory findings include low serum iron levels, low total
iron-binding capacity (see Fig. 5.1) and increased or normal serum ferritin.
The mechanisms responsible for these effects include decreased release of
iron from bone marrow to developing erythroblasts, inadequate erythropoietin
response to the anaemia and high levels of hepcidin expression. Hepcidin binds
to the export transport protein ferroportin in the iron-absorbing cells in the
duodenum, thereby causing its degradation, with a consequent reduction in the
transport of iron from duodenal cells into the plasma. Measurement of hepcidin
levels is emerging as a useful test to help distinguish anaemia of chronic disease
from iron deficiency anaemia. Treatment of anaemia of chronic disease is that of
the underlying cause. Recombinant erythropoietin is sometimes used (p. 387).
Sideroblastic anaemia
Sideroblastic anaemia is a rare disorder of haem synthesis characterized by a
refractory anaemia with hypochromic cells in the peripheral blood and ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts with iron deposited
in mitochondria and reflect impaired utilization of iron delivered to the developing erythroblast. It may be inherited or acquired (secondary to myelodysplasia,
myeloid leukaemia, alcohol excess, lead toxicity, isoniazid). Treatment is to withdraw the causative agents and some cases respond to pyridoxine (vitamin B6).
Macrocytic anaemia
Macrocytosis is a rise in mean cell volume of the red cells above the
normal range. Macrocytic anaemia can be divided into megaloblastic
Anaemia 199
and non-megaloblastic types, depending on the bone marrow findings. In
practice, macrocytosis is usually investigated without performing a bone
marrow examination. The initial investigation is measurement of serum
vitamin B12 and red cell folate.
Megaloblastic anaemia
Megaloblastic anaemia is characterized by the presence in the bone marrow
of developing red blood cells with large immature nuclei (megaloblasts). The
underlying mechanism is defective DNA synthesis, which may also affect
the white cells (causing hypersegmented neutrophil nuclei with six lobes,
and sometimes leucopenia) and platelets (causing thrombocytopenia). The
most common cause of megaloblastic anaemia is deficiency of vitamin B12 or
folate, both of which are necessary for the synthesis of DNA (see Table 5.2).
Vitamin B12 deficiency
Animal products (meat and dairy products) provide the only dietary source of
vitamin B12 for humans. The daily requirement is 1 μg, which is easily supplied by a balanced Western diet (containing 5–30 μg daily). Vitamin B12 is
liberated from protein complexes in food by gastric acid and pepsin and binds
to a vitamin B12-binding protein (‘R’ binder) derived from saliva. Free vitamin
B12 is then released by pancreatic enzymes and becomes bound to intrinsic
factor, which, along with H+ ions, is secreted from gastric parietal cells. This
complex is delivered to the terminal ileum, where vitamin B12 is absorbed and
transported to the tissues by the carrier protein transcobalamin II. Vitamin
B12 is stored in the liver, where there is sufficient supply for 2 or more years.
About 1% of an oral dose of vitamin B12 is absorbed ‘passively’ without the
need for intrinsic factor, mainly through the duodenum and ileum. The causes
of vitamin B12 deficiency are listed in Table 5.3.
Pernicious anaemia
Pernicious anaemia is an autoimmune condition in which there is atrophic
gastritis (plasma and lymphoid cell infiltration in the fundus) with loss of
parietal cells and hence failure of intrinsic factor production and vitamin B12
malabsorption. There is also achlorhydria. It is the most common cause of
vitamin B12 deficiency in adults in Western countries.
Epidemiology
This disease is common in elderly people and many cases are undiagnosed.
It is more common in women and in people with fair hair and blue eyes.
There is an association with other autoimmune diseases, particularly thyroid
disease, Addison’s disease and vitiligo.
Clinical features
The onset of pernicious anaemia is insidious, with progressively increasing
symptoms of anaemia. There may be glossitis (a red sore tongue), angular
200 Haematological disease
Table 5.3 Vitamin B12 deficiency – causes
Low dietary intake
Vegans
Impaired absorption
Stomach
Pernicious anaemia
Gastrectomy
Congenital deficiency of intrinsic factor
Small bowel
Ileal disease or resection, e.g. Crohn’s disease
Coeliac disease
Tropical sprue
Bacterial overgrowth
Fish tapeworm (Diphyllobothrium latum)
Abnormal utilization
Congenital transcobalamin II deficiency (rare)
Nitrous oxide (inactivates vitamin B12)
stomatitis and mild jaundice caused by excess breakdown of haemoglobin.
Neurological features can occur with very low levels of serum vitamin B12
and include a polyneuropathy caused by symmetrical damage to the peripheral nerves and posterior and lateral columns of the spinal cord (subacute
combined degeneration of the cord). The latter presents with progressive
weakness, ataxia and eventually paraplegia if untreated. Dementia and
visual disturbances due to optic atrophy may also occur. There is a higher
incidence of gastric carcinoma with pernicious anaemia than in the general
population.
Investigation of vitamin B12 deficiency
• Blood count and film. There is a macrocytic anaemia (MCV often
>110 fL) with hypersegmented neutrophil nuclei and, in severe cases,
leucopenia and thrombocytopenia.
• Serum vitamin B12 is low, frequently <50 ng/L (normal >160 ng/L).
• Red cell folate may be reduced because vitamin B12 is necessary to
convert serum folate to the active intracellular form.
• Serum autoantibodies. Parietal cell antibodies (not specific) are present in
90% and intrinsic factor antibodies (specific to the diagnosis) in 50% of
patients with pernicious anaemia.
• Serum bilirubin may be raised as a result of excess breakdown of Hb,
due to ineffective erythropoiesis in the bone marrow.
• In most cases, the cause is apparent from the history and autoantibody
screen. A small bowel barium follow-through (to look at the terminal
Anaemia 201
ileum) and distal duodenal biopsies (to look for coeliac disease) may be
necessary in some patients.
• Bone marrow examination shows a hypercellular bone marrow with
megaloblastic changes. This is not necessary in straightforward cases.
Differential diagnosis
Vitamin B12 deficiency must be differentiated from other causes of megaloblastic anaemia, principally folate deficiency, but this is usually clear from
the blood levels of these two vitamins. Pernicious anaemia should be distinguished from other causes of vitamin B12 deficiency (see Table 5.3).
Management
Treatment is with intramuscular hydroxocobalamin (vitamin B12, p. 239) or
oral vitamin B12 2 mg per day.
Folate deficiency
Folate is found in green vegetables and offal such as liver and kidney. It is
absorbed in the upper small intestine. The daily requirement for folate is
100–200 μg and a normal mixed diet contains 200–300 μg. Body stores are
sufficient for about 4 months, but folate deficiency may develop much more
rapidly in patients who have a poor intake and excess utilization of folate,
for example patients in intensive care. The main cause of folate deficiency
is poor intake, which may occur alone or in combination with excessive
utilization or malabsorption (Table 5.4).
Clinical features
Symptoms and signs are the result of anaemia (p. 194). Unlike vitamin B12
deficiency, there is no neuropathy.
Investigations
The FBC may show the findings of a megaloblastic anaemia. Red cell folate
is low (normal range 160–640 μg/mL) and is a more accurate guide to tissue
folate than serum folate, which is also usually low (normal range 4.0–18
μg/L). If the history does not suggest dietary deficiency as the cause, further
Table 5.4 Causes of folate deficiency
Poor intake Old age, poverty, alcohol excess (also impaired
Malabsorption Coeliac disease, Crohn’s disease, tropical sprue
Excess utilization Physiological: pregnancy, lactation, prematurity
Drugs Phenytoin, trimethoprim, sulfasalazine, methotrexate
utilization), anorexia
Pathological: chronic haemolytic anaemia, malignant
and inflammatory diseases, renal dialysis
202 Haematological disease
investigations such as endoscopic small bowel biopsy should be performed
to look for small bowel disease.
Management
The underlying cause must be treated and folate deficiency corrected by giving oral folic acid 5 mg daily for 4 months (p. 239); higher daily doses may
be necessary with malabsorption. In megaloblastic anaemia of undetermined
cause, folic acid alone must not be given, as this will aggravate the neuropathy of vitamin B12 deficiency. Prophylactic folic acid is given to patients with
chronic haemolysis (5 mg weekly).
Prevention of neural tube defects with folic acid. To prevent first
occurrence of neural tube defects, women should be advised to take folate
supplements (at least 400 μg/day) before conception and during pregnancy.
Larger doses (5 mg daily) are recommended for mothers who have diabetes
or who already have an infant with a neural tube defect.
Differential diagnosis
A raised MCV with macrocytosis on the peripheral blood film can occur with
a normoblastic rather than a megaloblastic bone marrow (Table 5.5). The
most common cause of macrocytosis in the UK is alcohol excess. The exact
mechanism for the large red cells in each of these conditions is uncertain,
but in some it is thought to be due to altered or excessive lipid deposition on
red cell membranes.
Table 5.5 Causes of macrocytosis other than megaloblastic
anaemia
Physiological
Pregnancy
Newborn
Pathological
Alcohol excess
Liver disease
Reticulocytosis (e.g. due to haemolysis)
Hypothyroidism
Haematological disorders:
Myelodysplastic syndrome
Sideroblastic anaemia
Aplastic anaemia
Drugs:
Hydroxycarbamide (hydroxyurea)
Azathioprine
Cold agglutinins