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159
Case 59: Shortness of Breath and Heartburn
its own an indication for blood transfusion. A healthy patient with iron deficiency should be
expected to recover his normal haemoglobin levels with adequate iron supplements. Oral fer-
rous sulphate is available, and if not tolerated, other products such as ferrous fumarate can be
an alternative. If oral iron is not eective, intravenous iron can be given and is usually very
eective in treating iron deficiency.
A common threshold for transfusion is a haemoglobin level of 80 g/L or less, but this in itself
is not an absolute indication. Young patients with iron deficiency and a haemoglobin level
of less than 80 g/L who are not symptomatic are expected to recover well with iron supple-
ments. The patient’s symptoms—chest pain or dizziness—and clinical signs—low BP and
tachycardia—should be taken into consideration when deciding on whether to give a blood
transfusion. (Note: Patients with a history of ischaemic heart disease usually need a higher
level of haemoglobin. Therefore, the haemoglobin level may need to be maintained at 100 g/L
or higher.)
KEY POINTS
•
Iron-deficiency anaemia is commonly caused by dietary deficiencies, but all
patients need to be assessed for possible blood loss because of a GI lesion, and
if indicated, appropriate investigations should be arranged.
•
In practice a low transferrin saturation is a good indicator of iron deficiency in the
body.
•
Blood transfusion should not be given based on low haemoglobin levels alone:
the patient’s symptoms and signs need to be taken into consideration.
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CASE 60: RAISED WHITE CELL COUNT IN AN
ASYMPTOMATIC INDIVIDUAL
A healthy 65-year-old man undergoes routine blood tests as part of a ‘well-man screen’ by his
GP. His past medical history includes appendicectomy and inguinal hernia repair. He does
not take any regular medications.
Examination
Cardiovascular and respiratory examinations are normal. He has no organomegaly or
lymphadenopathy.
INVESTIGATIONS
Haemoglobin 142
White cell count 20.1
Neutrophils 5
Lymphocytes 14
Platelets 350
Mean cell volume 86
The remainder of his blood tests were unremarkable, including urea and electrolytes, liver
function, thyroid function and prostate specific antigen (PSA).
The patient is referred to the haematology clinic, where further investigations are
performed, including a blood film (
Figure 60.1) and immunophenotyping.
Immunophenotype of lymphocytes: CD5/19/20/23+ve and CD79b negative.
The haematologist elects to adopt a ‘watch-and-wait’ treatment strategy and discharges
the man to receive follow-up blood tests with his GP. The blood tests do not show
significant changes over time.
Three years later, the patient develops increasing fatigue. On examination, there is
conjunctival pallor and mild scleral icterus but no lymphadenopathy or organomegaly.
Direct antiglobulin test is positive. A repeat blood test is arranged, which shows:
Haemoglobin 98
White cell count 30.1
Neutrophils 5
Lymphocytes 24
Platelets 250
Mean cell volume 86
QUESTIONS
1. What are the common causes of lymphocytosis?
2. Based on the initial blood results and the blood film, what is the likely diagnosis?
3. Explain how the results from the latest blood tests (at 3 years) relate to the
patient’s underlying diagnosis.
4. What are the indications of treatment for this condition?
DOI: 10.1201/9781003242697-63
161
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100 Cases in Clinical Pathology and Laboratory Medicine
162
ANSWERS
The initial full blood count shows a lymphocytic leucocytosis. Causes of lymphocytosis
include:
•
Infection, both acute (e.g., infectious mononucleosis, mumps, herpes simplex/zoster,
and HIV) and chronic (tuberculosis and syphilis)
•
Inflammation
•
Chronic lymphoid leukaemias, most commonly chronic lymphocytic leukaemia (CLL)
•
Acute lymphoblastic leukaemia (ALL)
•
Non-Hodgkin’s lymphoma
In the absence of symptoms (such as features of infection) and signs (such as lymphadenopa-
thy and organomegaly), and with normal thyroid function, the most likely diagnosis in this
case is CLL. This is corroborated by the blood film shown in
Figure 60.1, which shows
increased numbers of small, mature lymphocytes with scant cytoplasm. As these cells are
fragile, they may be disrupted in the process of making smears, giving rise to ‘smudge cells’
that are seen in film. Immunophenotyping is required to confirm the diagnosis of CLL, and
the phenotype of CD5, CD20 and CD23 positivity is characteristic of CLL.
CLL is the most common leukaemia in the Western world. Typically, it is picked up via
an incidental lymphocytosis in an asymptomatic individual. Diagnosis requires an absolute
lymphocytosis of at least 5 × 10
9
/L and an appropriate lymphocyte immunophenotype.
Common cytogenetic abnormalities in CLL include deletions of chromosomes 11, 13 and 17
(del 11q, del 13q, del 17p), as well as trisomy 12. About 50% of cases also show evidence of
somatic hypermutation of the immunoglobulin heavy-chain gene (IGVH).
Figure 60.1 Blood film showing increased numbers of small, mature lymphocytes with scant
cytoplasm. Being fragile, they have been disrupted in the process of making smears, giving
rise to ‘smudge cells’.
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Case 60: Raised White Cell Count in an Asymptomatic Individual
163
The disease is staged according to the Binet classification. Typically, patients with Binet stage
A disease require no immediate treatment. Symptomatic stage B and all stage C patients
receive chemotherapy. Options for treatment include conventional chemotherapy combined
with immunotherapy, e.g., fludarabine, cyclophosphamide and rituximab (FCR) or more
targeted treatments, e.g., ibrutinib (inhibitor of BTK enzyme) or venetoclax (inhibitor of
BCL2). The aim of the treatment is generally disease control rather than cure. Younger
patients with refractory disease may be considered for allogeneic stem cell transplantation,
which is potentially curative but has a significant morbidity and mortality rate.
The patient’s blood results at 3 years highlight an important complication of CLL. They show
a normocytic anaemia (as well as a marked lymphocytosis). The latter represents progression
of CLL, but the absence of neutropenia and thrombocytopenia suggests that marrow infiltra-
tion is not severe. However, taken together with the positive direct antiglobulin test (DAT),
the most likely explanation for the anaemia is haemolytic (immune mediated). Autoimmune
haemolytic anaemia is sometimes seen in CLL as a result of autoantibody generation by
lymphocytes against red blood cells. This produces pallor (due to anaemia) and icterus (as a
result of increased destruction of red cells, leading to an unconjugated hyperbilirubinaemia).
Not all patients require treatment. Adverse prognostic features include stage B or C disease
at diagnosis, male gender, rapid lymphocyte doubling time (<1 year), presence of del 11q and
del 17p, TP53 mutation, trisomy 12, positivity for CD38 expression and high ZAP-70 expres-
sion. There is also a possibility that CLL may transform into a high-grade lymphoma, diuse
large B-cell lymphoma or Hodgkin’s lymphoma (a so-called Richter transformation).
KEY POINTS
•
CLL is the most common form of leukaemia in the Western world.
•
CLL is a lymphoproliferative disorder of mature lymphocytes and typically pres-
ents as an incidental finding in asymptomatic patients.
•
Treatment is not always indicated, but careful monitoring is required.
•
Autoimmune haemolytic anaemia is a known complication of CLL, caused by auto-
antibody production by diseased lymphocytes against red blood cells.
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CASE 61: WORSENING FATIGUE AND BLEEDING
GUMS
A 35-year-old woman presents to her GP with fatigue. She visited the GP surgery 4 weeks ago
with the same problem. At that time all of her routine blood tests (including thyroid function
tests) were reported as normal. Today she has noticed some gum bleeding while brushing
her teeth. She does not have a cough, urinary symptoms, weight loss or fevers. She has no
significant past medical history.
Examination
Her observations are normal. She appears pale. Examinations of her cardiovascular, respira-
tory and abdominal systems are normal.
INVESTIGATIONS
Haemoglobin 89
White cell count 1.9
Neutrophils 0.9
Lymphocytes 0.8
Platelets 13
Mean corpuscular volume 106
Sodium 141
Potassium 5.0
Urea 5.0
Creatinine 70
Bilirubin 20
Aspartate aminotransferase 70
Alkaline phosphatase 160
C-reactive protein 13
Her blood film is shown in
Figure 61.1.
QUESTIONS
1. What is the diagnosis?
2. What other tests do you need to arrange?
3. What is your management plan for this patient?
DOI: 10.1201/9781003242697-64
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100 Cases in Clinical Pathology and Laboratory Medicine
166
ANSWERS
The patient has pancytopenia with blast cells in the circulation consistent with a diagno-
sis of acute leukaemia. The patient is lethargic due to the anaemia. She is also bleeding
because of low platelets. She is at increased risk of infections due to neutropenia. Blast
cells are immature cells that turn into mature blood cells in the bone marrow. In acute
leukaemia, an arrest in the maturation process keeps these cells at their early non-func-
tioning stage, and they begin to divide rapidly; the increased proliferation occupies space
in the bone marrow, thereby disturbing the normal haemopoiesis and eventually leading
to pancytopenia.
The blast cells eventually leak out into the circulation, and they can be seen on a peripheral
blood film. They are usually large in size (causing a higher MCV reading in the full blood
count) with an open chromatin appearance. They are also light in colour compared to the
nuclei of mature cells, which are smaller and darker. Blast cells have a high nucleus-to-cyto-
plasmic ratio (a large nucleus in scanty cytoplasm).
Distinguishing between acute myeloid leukaemia (AML) and acute lymphoid leukaemia
(ALL) using morphological features alone is possible; however, this is not always easy. More
detailed analysis of the cells is usually carried out to determine the exact diagnosis
Figure 61.1 Blood film showing neutropenia, thrombocytopenia and blast cells.
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Case 61: Worsening Fatigue and Bleeding Gums
167
Other investigations will include a bone marrow biopsy. The biopsy provides tissue that can
be examined for:
•
Further morphological assessment, as the percentage of blast cells would be much
higher in the bone marrow. The general haemopoietic status of the bone marrow
can also be assessed.
•
Immunophenotyping studies to test the CD markers on the blast cells, which should
provide a more accurate assessment of their nature.
•
Cytogenetic studies, as certain chromosomal abnormalities are associated with
adverse prognosis, which will influence treatment options (e.g., whether to oer the
patient stem cell transplant or not).
•
Molecular studies, e.g., FLT3 mutation in AML or BCR-ABL fusion in ALL.
Clotting studies are important. Variants such as acute promyelocytic leukaemia (APML) are
associated with disseminated intravascular coagulation (DIC), which can be life threatening,
especially with a very low platelet count.
The patient is neutropenic, so she needs close observation. Fever should initiate septic screen-
ing and administration of intravenous antibiotics as a matter of urgency (according to local
neutropenic sepsis guidelines).
This patient would also benefit from a platelet transfusion. Haematologists usually aim
for a level of greater than 20 × 10
9
/L, especially if the patient is septic. This patient’s
deranged liver function tests may represent leukaemic infiltration or another pathology
of the liver. Blood tests for a liver screen and an abdominal ultrasound scan should be
arranged.
Acute leukaemia can infiltrate other organs, especially the central nervous system (CNS) in
ALL. A careful screening of the patient’s symptoms, asking her about headaches and clini-
cal examination to exclude neurological signs, is essential. If there is any suspicion of CNS
involvement, a CT scan of the brain is needed, and a lumbar puncture should be performed
to evaluate the cerebrospinal fluid (CSF) for the presence of leukaemic cells.
The initial treatment will be chemotherapy, but an allogenic stem cell transplant may
be required. Therefore, it would be useful to know whether she has siblings who can be
tested as potential future donors of stem cells. Otherwise, a search for a matched unre-
lated donor will be required to find suitable human leukocyte antigen (HL A)–matched
stem cells.
KEY POINTS
•
Acute leukaemia is a medical emergency that needs to be excluded in any patient
with an isolated cytopenia or pancytopenia.
•
Neutropenic sepsis is a serious complication of acute leukaemia. It can occur at
presentation or during treatment and needs to be treated urgently with intrave-
nous antibiotics without any delay.
•
The exact treatment of acute leukaemia will depend on the type of leukaemia,
which can be determined through immunophenotyping, cytogenetics and molec-
ular studies.
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