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Case 67: Pneumonia with Abnormal Liver Function
189
QUESTIONS
1.
What is the most likely diagnosis?
2. What other tests would you order to confirm the diagnosis?
3. What is your management plan?
4. What other advice would you give the patient regarding his lifestyle and his
family?
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100 Cases in Clinical Pathology and Laboratory Medicine
190
ANSWERS
The patient had abnormal liver function tests (LFTs) at the time of his diagnosis with pneu-
monia. Sometimes this can be attributed to the infection. However, the LFTs remained
abnormal 6 weeks after, and this suggests an alternative underlying liver pathology.
The level of ferritin increases with infection or inflammation. But at such a high level and
in absence of viral liver disease, iron studies are necessary to evaluate iron status. The best
test for this is transferrin saturation. In view of the elevated transferrin saturation levels, iron
overload is the most likely explanation, and the most common cause for this in the Western
world is haemochromatosis.
Haemochromatosis is one of the most common genetic conditions found in Northern Europe.
It has four types. The most common is type 1, involving mutation in the HFE gene, for which
the homozygous state is strongly associated with iron overload. The second most common is
the H63D mutation.
Approximately one in eight people are carriers of the C282Y genetic mutation of the HFE
gene. The function of this gene is to regulate another gene, the transferrin receptor gene,
and hepcidin expression. The transferrin receptors are molecules through which transfer-
rin binds to the cell, thereby allowing iron uptake into the cell. Hepcidin is a small peptide,
expressed predominately in the liver, and is involved in iron absorption and reducing iron
release from macrophages.
Patients with haemochromatosis are usually asymptomatic; the disease is usually discovered
on routine screening. This patient clearly was asymptomatic. The only signs of disease were
persistently deranged LFTs, which prompted further investigation. The main lesson to be
drawn is not to overlook abnormal LFTs, which could have been attributed to his atypical
bacterial chest infection. It is important to follow up such results after patient discharge from
hospital to ensure resolution once the chest infection has cleared.
Following a confirmation of the diagnosis, screen the patients for further possible complica-
tions. Increased iron absorption from the gut encourages iron deposition in tissues. Iron
could accumulate in the pancreas, causing diabetes mellitus; in the pituitary gland, causing
hypogonadism; in the joints, causing arthralgia and arthritis; and in the heart, causing car-
diomyopathy. The clinical assessment of haemochromatosis needs to address symptoms and
signs of dysfunction in all of these organs. Appropriate tests for the function of these organs
may be necessary: fasting glucose, luteinising hormone (LH), follicle-stimulating hormone
(FSH), prolactin, testosterone, x-rays of joints and, if indicated, echocardiogram.
Excessive iron removal by venesection needs to be started. It is usually done at the haema-
tology day unit by the nursing sta. The patient attends regular sessions of venesection (450
mL is usually removed each time), initially weekly, until the ferritin level is below 50 g/L.
Once this is reached, the frequency of venesection will depend on regular monitoring of fer-
ritin to keep it below the level of 50 g /L. Some patients will need to come every 2 weeks,
but eventually most patients are established on 4- to 6-weekly sessions. Venesections may be
associated with symptoms of dizziness and headaches.
All patients need to be advised about their dietary intake of iron, which needs to be reduced.
Also alcohol intake ought to be reduced to avoid further liver damage.
Since haemochromatosis is an inherited condition, all first-degree family members of the
patients are advised to have transferrin saturation and haemochromatosis gene tests.
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Case 67: Pneumonia with Abnormal Liver Function
191
KEY POINTS
•
Haemochromatosis is a common inherited condition causing excessive iron
absorption.
•
Patients commonly present asymptomatically with either abnormal LFTs or ele-
vated ferritin.
•
Transferrin saturation is the best test to indicate iron overload.
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CASE 68: RECURRENT EPISTAXIS
A 25-year-old man presents to the emergency department with epistaxis. He has been bleed-
ing for 2 hours, and it is not responding to local pressure and ice application. The doctors call
an ear, nose and throat (ENT) surgeon, who upon inspection finds a bleeding vessel in the
left nostril and carries out cauterisation.
After 2 weeks, the patient returns to the emergency department with further bleeding. A
repeat cauterisation is carried out, and an ENT surgery outpatient follow-up is arranged for
a week later. Before the date of the follow-up, he returns to the emergency department again
with bleeding from the right nostril.
Examination
At the clinic review the ENT surgeon advises that cauterisation is not the best option for the
patient’s recurrent bleeding, and he suggests vessel embolisation by interventional radiology
to prevent further bleeding in the future.
The patient is booked for the procedure and has the following pre-procedure blood tests.
INVESTIGATIONS
Haemoglobin 101
White cell count 9.0
Platelets 500
Mean corpuscular volume 75
Urea and electrolytes are unremarkable.
Clotting screen:
Prothrombin time 11
Activated partial
thromboplastin time 52
Factor VIII 60% of normal level
Factor IX Normal level
QUESTIONS
1. How would you interpret these results? What is the differential diagnosis?
2. What further tests need to be done to confirm the diagnosis?
3. What is your management plan?
DOI: 10.1201/9781003242697-71
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100 Cases in Clinical Pathology and Laboratory Medicine
194
ANSWERS
This is a real case of a patient where there was a significant delay in making the correct diag-
nosis. The patient presented with recurrent epistaxis that needed more than treatment in the
emergency department. The epistaxis should have been investigated further before sending
the patient home.
One important feature here is that he is bleeding from both nostrils. If this is simply a local
vessel causing the bleed, then the bleeding is expected to be from one nostril only. The fact
that both nostrils are involved should arouse suspicion that the patient may have a clotting
dis order.
The patient’s microcytic anaemia is likely to be due to iron deficiency secondary to recurrent
bleeding. His slight thrombocytosis is likely to be secondary to bleeding as well.
He has a normal PT but slightly prolonged APTT, which heightens suspicion for factor VIII
and factor IX abnormalities. Factor VIII and factor IX deficiencies (i.e. haemophilia) tend
to present with joint bleeding and usually at an early age. The level of factor VIII in haemo-
philia B is usually very low. This patient has a slightly low level, which is inconsistent with
haemophilia B. However, von Willebrand factor deficiency can cause moderately low levels
of factor VIII.
This patient has mucosal bleeding, which makes von Willebrand disease (VWD) the most
likely diagnosis. VWD is the most common inherited bleeding disorder. The VW factor is an
important element in haemostasis. It is produced predominantly by the vascular endothelium
and has two main functions:
•
Binding to collagen at sites of vascular injury and then capturing circulating plate-
lets to form the initial primary haemostasis plug
•
Stabilising factor VIII in the circulation by protecting it from degradation, which is
why it is considered a co-factor for factor VIII
VWD can be caused by either quantitative or qualitative abnormalities of the VW factor.
Patients often present in their second or third decades of life or after prolonged bleeding
from a minor procedure like a tooth extraction. The usual bleeding is from mucosal surfaces,
bruising, epistaxis or menorrhagia.
The patient needs to have a repeat test of factor VIII and factor IX levels as a confirmation
and VW screening before any intervention is carried out. The usual VW screen includes level
and functional activity. VWF:Ag measures the level of the factor, and VWF:RCo measures
its activity. These tests could have been done fairly quickly, and they could have spared the
patient recurrent hospital attendance and unnecessary interventions.
Artery embolisation procedures should be delayed until the confirmation of the diagnosis of
VWD. For any future episodes of epistaxis, anti-fibrinolytic drugs such as tranexamic acid
should be tried as a first line. Tranexamic acid works by stabilising the blood clot and usually
prevents further bleeding. For recurrent bleeding not responding to tranexamic acid alone,
desmopressin should be used. Intravenous desmopressin usually works within 30 minutes to
produce a rise in factor VIII and VW factor levels. If this fails, then intravenous VW fac-
tor concentrate needs to be given. Such products are available only in tertiary haematology
referral centres, where patients with haemophilia and VWD are usually treated. Regular
follow-up is needed with the haematology team, and patient education for these conditions
is essential.
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Case 68: Recurrent Epistaxis
195
KEY POINTS
•
Any patient presenting with recurrent bleeding needs to have a coagulation
screen.
•
VWD is an inherited bleeding disorder that needs to be excluded in any patient
with recurrent bleeding.
•
An isolated prolonged APTT needs further evaluation and discussion with the hae-
matology team, especially if the patient is presenting with bleeding or bruising.
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CASE 69: BRUISING AFTER A PNEUMONIA
A 65-year-old woman is admitted to hospital with a community-acquired pneumonia. She was
initially treated by her GP with oral antibiotics, but without any improvement, so she was admit-
ted to hospital for IV antibiotics. She had no previous medical history apart from an appendi-
cectomy at age 17. Over the next 48 hours she showed significant improvement in her symptoms
and she was ready for discharge. The doctor is preparing her discharge letter when he is called by
nursing sta to review the patient, as the patient reports some concerns regarding her skin.
Examination
The FY1 doctor examines the skin and finds some bruising over the arms and forearms. He
conducts further examination and discovers that the patient has significant bruising over her
back and upper legs. Otherwise, she feels well.
He sends an urgent clotting screen and decides not to delay her discharge, based on her feel-
ing well and the limited number of beds in the hospital. The patient is sent home without
reviewing the blood results.
Upon arriving home, the patient’s bruising got worse, and the next morning she noticed some
blood in her urine.
The FY1 doctor had meant to check the blood results the next day, but didn’t have a chance because
of his busy morning. The patient attended the emergency department in the afternoon with exten-
sive bruising and epistaxis. The emergency department doctors repeated her clotting screen.
INVESTIGATIONS
Clotting screen prior to discharge:
Prothrombin time
Activated partial
13
thromboplastin time 90
Fibrinogen 2.3
Clotting screen after being readmitted to the emergency department with worsening
bruising and epistaxis:
Prothrombin time
Activated partial
14
thromboplastin time 120
Fibrinogen 2.1
VWF:Ag and VWF:RCo: Both normal
Factor VIII: 30% of normal
Factor IX: 95% of normal
QUESTIONS
1. What further questions would you ask the patient?
2. How would you interpret the clotting result s, and what is the mos t likely diagnosis?
3. What is your management plan?
DOI: 10.1201/9781003242697-72
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100 Cases in Clinical Pathology and Laboratory Medicine
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ANSWERS
When faced with a patient with bruising, there are several issues that doctors need to be
aware of:
•
Any previous history of bruising, as this may well be a normal variation in the popu-
lation, and some patients may bruise more easily than others. However, this can be
considered a normal variation only after a careful assessment.
•
Bleeding needs to be excluded, so ask the patient about any epistaxis, haematuria,
menorrhagia and haemoptysis. The major medical emergency you need to be aware
of is intracranial bleeding, so careful assessment of the patient for any symptoms of
headache, drowsiness or limb weakness is essential.
•
Another important part of history is any previous surgical intervention, including
tissue biopsy or dental work, as this would give a very good idea regarding previous
haemostasis functioning. This patient had in fact had an appendicectomy many
years ago, and she reports no complications.
In this patient, PT and fibrinogen are within a normal range; however, the APTT is pro-
longed. Since PT measures the activities of factors II, V, VII and X, this screen shows that
these factors also are essentially normal.
APTT measures the activities of factors VIII, IX, XI and XII. The conclusion is that this
patient has some abnormalities in one of these factors, and given that factors VIII and IX are
the most clinically significant, their level of activities needs to be assessed.
Von Willebrand factor (VWF) is an important co-factor for factor VIII. VWF:Ag measures
the level of the factor, and VWF:RCo measures its activity. Both tests are normal in this
patient.
Factor VIII is low, and in a patient with previously unreported bleeding symptoms, this
is likely to be acquired haemophilia A. This disorder presents similarly to congenital hae-
mophilia, with bleeding subcutaneously or into the muscles, but rarely into the joints. The
pathology is the result of autoantibodies associated with certain conditions which are directed
against factor VIII. These antibodies can be found in autoimmune conditions such as sys-
temic lupus erythematosus (SLE), lympho-proliferative conditions, malignancy, and infec-
tions. They can also be idiopathic, without any known associations.
Stabilising the patient is the first priority: any bleeding needs to be stopped and treated
promptly. Urgent FBC needs to be sent to assess haemoglobin level and the possible need for
blood transfusion.
If there is significant continuous bleeding, a bypassing agent needs to be used to correct the
clotting deficiency. Two options are available: (1) activated prothrombin complex concen-
trate factor eight inhibitor bypassing activity (FEIBA) and (2) recombinant factor VIIa. Both
preparations aim to bypass the deficiency and activate the clotting cascade further down
from factor VIII, to eventually convert fibrinogen into fibrin and form a clot at the site of
va scular i nju r y.
Regardless of the bleeding, once the diagnosis is confirmed, the treatment aimed at eradi-
cating the autoantibody needs to be started. The first line is steroids, and response is usually
monitored with factor VIII serial levels. If there is no response, other options are cyclophos-
phamide, azathioprine or rituximab.
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