Doctors’ Newsletter
WINTER 2008
Introducing
GynaePath
Page 2
GynaePath
Pages 4-6
Illness in the Returning Traveller
Dr Colin Goldschmidt
Dr Ian Chambers
Page 3
New DHM Pathologists
Page 6
Pathology Update
Pages 7-8
Thyroid Function Tests and Pregnancy
Pages 9-11
Myeloma AL-Amyloidosis
and Free Light Chain Assays
Dr Karl Baumgart
Page 12
Introducing GynaePath
"Your Patients are our Priority"
Dr Nick Taylor
“We take it personally”
“We take it personally”
GynaePath
Specialist Gynaecological Pathologists
Excellence in Gynaecological Pathology
Dr Colin Goldschmidt
Chief Executive Officer
Pathologists are central to the
operations of the Douglass Hanly
Moir Pathology (DHM) practice. Our
commitment to Medical Leadership
means that we operate like a
medical practice - not unlike your
own clinical practice – except that
we predominantly see specimens
instead of patients!
Over the years, the pathologist team
at DHM has expanded both in number
and in sub-specialist expertise. We
now boast comprehensive specialist
pathologist coverage of all pathology
disciplines and sub-disciplines and
we firmly believe that this will provide
benefits to you in your daily clinical
practice. As a pathologist myself (albeit
a non-practising one), I am immensely
proud and honoured to work alongside
such a talented group.
We are delighted that four new
pathologists have joined DHM from
Symbion Laverty Pathology (see
opposite page). Professor Peter
Russell and Drs Jenny Roberts,
Clare Biro and Suzanne Hyne
are all specialist gynaecological
pathologists who formed the core
pathologist group in gynaecology at
Symbion Laverty, stemming from the
original Colin Laverty gynaecological
pathology practice. This group of
new pathologists joins an already
established team of highly talented
pathologists at DHM, including a
dedicated team of gynaecological
pathologists headed up by Professor
Annabelle Farnsworth.
The merger of the two gynaecological
pathologist groups has allowed us to
create a unique centre of excellence in
gynaecological pathology – GynaePath.
GynaePath is a specialist
gynaecological pathology unit within
DHM.
2
It is essentially a boutique “practice
within a practice”, solely dedicated
to excellence in gynaecological
histopathology and cytology. All Pap
smears and gynae histopathology will
be streamed within the DHM laboratory,
processed separately, handled
by dedicated staff, and reported
exclusively by the ten-plus GynaePath
pathologist group, lead by Professor
Annabelle Farnsworth. GynaePath
will use distinctive, customised, pink
request forms and report forms.
Teaching and research will be a feature
of this unit and we have established
easy access to this pathologist group
- facilitating consultation services for
gynaecologists and women’s health
practitioners.
The GynaePath concept promotes the
pooling and enrichment of specialist
expertise; in order to create what
I believe is an unparalleled centre
of excellence in gynaecological
pathology in Australia. We present initial
information about this exciting initiative
on the back page of this publication
and will provide you with further details
of the service offerings in the near
future.
On behalf of the expanded DHM
pathologist team, I wish to thank all
existing and new referrers for their
support of our practice.
With my warm regards,
Dr Colin Goldschmidt
MB BCh, FRCPA
CEO Douglass Hanly Moir Pathology/
Barratt & Smith Pathology
CEO Sonic Healthcare
New DHM Pathologists
Professor Peter Russell BSc (Med), MB, BS, MD, FRCPA, RANZCOG (Hon)
Professor Peter Russell is a histopathologist specialising in gynaecological and
reproductive pathology, with special involvement in the diagnosis of ovarian pathology
and research interests which presently encompass all aspects of gynaecological
neoplasia and reproductive failure. His pathology training was at Royal Prince Alfred
Hospital and the University of Cincinnati, Ohio. He has been a salaried specialist
histopathologist at Royal Prince Alfred Hospital since 1974, including being Head
of Department and Area Director from 1995-2002, and was awarded an MD from
the University of Sydney in 1991, for research work in the field of ovarian neoplasia.
As Professor in Pathology, Professor Russell conducts postgraduate teaching at
the University of Sydney central campus and at Royal Prince Alfred Hospital. He is
an active member of several specialty societies and government committees and
served several years on the executive of the International Society of Gynecological
Pathologists (including a term as President) and the Australian Society of Colposcopy
and Cervical Pathology (currently as Secretary). He is sole or co-author of more than
200 journal articles, several dozen book chapters and three textbooks, two of which
are in their second edition. He has been Pathology Director of the international assisted
reproductive technology organisation, Sydney IVF, since 1993 and has recently had the
singular distinction of being awarded Honorary Fellowship in the Royal Australian and
New Zealand College of Obstetricians and Gynaecologists, for services to the Fellows
and aims of the College.
Dr Clare Biro MB, BS (Hons), BSc (Med), FRCPA, FIAC
Dr Clare Biro is a graduate of the University of New South Wales and trained as a
pathologist at Royal Prince Alfred Hospital, Sydney. After a year as a Staff Specialist
at RPAH, she joined Colin Laverty and Associates (later part of Symbion Laverty
Pathology), where she worked for 19 years, the last five as Head of Gynaecological
Cytology. She joined Douglass Hanly Moir in July 2008. Dr Biro is a specialist
gynaecological histopathologist and cytopathologist and has published papers in this
area. She is a member of the Royal College of Pathologists’ Cytopathology Advisory
Committee and the NSW PAP Test Register Advisory Committee. Dr Biro is also
actively involved in the College’s Cytopathology Quality Assurance Program and is
the convenor of the new Gynaecological Module of the Anatomical Pathology Quality
Assurance Program.
Dr Suzanne Hyne MB, BS (Hons), FRCPA, FIAC
Dr Suzanne Hyne is a medical graduate of the University of Sydney. Her pathology
training was at Royal Prince Alfred Hospital and Royal Alexandra Hospital for Children,
Sydney. She was a specialist gynaecological pathologist at Dr Colin Laverty and
Associates, then Symbion Laverty Pathology until June 2008 and held a consultant
pathologist position in Norwich, UK during 2005. Dr Hyne is a specialist gynaecological
histopathologist and cytopathologist, joining Douglass Hanly Moir in July 2008. She has
published papers in gynaecological cytology. Dr Hyne is a member of the NSW Cervical
Screening Program/Pap Test Register Clinical Advisory Committee and formerly the
NSW Pap Test Register Advisory Committee, since 2005. She was a member of the
NSW Pap Test Register Laboratory Taskforce Committee from 2002-2004. Dr Hyne
is a member of the Royal College of Pathologists of Australasia Quality Assurance
Anatomical Pathology Gynaecological module committee.
Dr Jennifer Roberts MB, BS (Hons), FRCPA, MIAC
Dr Jennifer Roberts is a medical graduate of the University of Queensland and
undertook her specialty training at Royal Brisbane Hospital and The Royal Women’s
Hospital, obtaining her fellowship of the Royal College in 1993. Since that time, she has
worked in both hospital and private practice and, for the last 13 years, has specialised
in gynaecological histopathology and cytopathology as a senior pathologist at Symbion
Laverty Pathology. Her particular interests are glandular neoplasia of the cervix and
the role of new technologies in cervical screening and she has published extensively
in both areas. Most recently, she has co-authored two chapters of a major textbook
Pathology of the Female Reproductive Tract. She is a frequent speaker at local and
national meetings and, with a strong commitment to teaching, has been involved in
many workshops and tutorials, both within Australia and internationally.
3
Illness in the Returning Traveller
Dr Ian Chambers
Director of Microbiology and Immunoserology
It is estimated that approximately
50% of people returning to
developed countries from travel
in developing countries will suffer
some kind of travel-related health
problem, either while overseas or on
their return home. About 10% will
be sufficiently unwell to cause them
to consult a medical practitioner
and as a result, primary care
physicians are increasingly being
called upon to assess, investigate
and manage illnesses which have
been acquired overseas. This article
is intended to provide an overview
of the commonest and more
clinically significant infections in
returning travellers, and to provide a
framework for the assessment and
management of such patients.
Categories of Illness in
Returning Travellers
What are the Most
Important Travel-Related
Health Problems?
Enterotoxigenic E. coli is the most
common cause of traveller’s diarrhoea,
but many other bacterial, protozoan
and viral pathogens may need to be
considered. Some of these are listed in
Table 1.
This depends on the perspective from
which importance is assessed.
The most common health problem
in travellers returning from countries
where enteric infection is endemic
is diarrhoea. However, while severe
infections and protracted illnesses
occasionally occur, the importance of
traveller’s diarrhoea relates to its high
incidence rather than its high morbidity.
This also applies to acute respiratory
tract infections and some sexually
acquired infections, such as chlamydia
and gonorrhoea.
Plasmodium falciparum malaria, on the
other hand, is encountered much less
frequently than traveller’s diarrhoea,
but is potentially fatal if diagnosis and
treatment are delayed. Falciparum
malaria, therefore, and other conditions,
such as typhoid, rickettsial infections
and leptospirosis, are travel-health
problems of relatively low incidence
but great importance because of their
potential morbidity and mortality.
Over and above any significance to the
health of an afflicted individual, some
travel-related infections have public
health significance. For example, the
presence in northern Queensland of
suitable mosquito vectors for dengue
and chikungunya viruses means
that the establishment of a local
cycle of infection and transmission is
possible if a viraemic traveller remains
unrecognised and public health action
not taken.
4
Traveller’s Diarrhoea
Diarrhoea is estimated to affect 20-50%
of travellers to developing countries,
approximately half of whom will have
a short illness (3-5 days) requiring no
medical consultation or management.
About 10%, however, will be sufficiently
unwell to present to their doctor on
return.
Laboratory investigation and/or
antimicrobial treatment of most
cases of mild diarrhoea are usually
unnecessary. However, those with more
severe or prolonged symptoms, or who
are febrile or have blood in their stool,
may benefit from the identification and
treatment of a specific pathogen.
Table 1:
Causes of Traveller’s Diarrhoea
(in order of approximate incidence)
Enterotoxigenic E.coli
Campylobacter jejuni
Salmonella enteritica
Shigella species
Giardia intestinalis
Cryptosporidium parvum
Vibrio species
Entamoeba histolytica
Cyclospora cayatenesis
Rotavirus/Norovirus
Febrile Illness
Between 2% and 12% of travellers
experience a febrile illness in relation
to their travel, and establishing the
presence or absence of fever is
important for any patient presenting
with an apparently travel-related
illness. When fever is confirmed, exotic
infections such as malaria, typhoid,
dengue etc must be considered, but
it should also be remembered that
Illness in the Returning Traveller
travellers also acquire infections which
are common in non-travellers, eg EBV
and CMV.
Important Travel-Related Febrile
Illnesses
Short Incubation (<10 Days)
Dengue fever
Gastroenteritis
Influenza
Enteric fever (paratyphoid)
Rickettsial infection (eg spotted fevers)
Intermediate Incubation (10-21 Days)
Malaria
Enteric fever (typhoid)
Scrub typhus
Brucellosis
Leptospirosis
Q Fever
Of these, most disease is caused by
P. vivax and P. falciparum, the latter
being of greater importance because
of its lethal potential and because of its
resistance to some anti-malarial drugs.
A patient may develop malaria
despite taking what would appear
to be adequate prophylaxis. In fact,
about half of the cases diagnosed in
Australia have been taking specific antimalarial chemoprophylaxis. Therefore,
such a history should never exclude
consideration and exclusion of this
diagnosis. Many cases result from
misjudging the need for precautions,
or from stopping prophylaxis too soon
after leaving an endemic area.
Diagnosis of malaria is usually
by examination of blood
films, supplemented by an
immunochromatographic test (ICT)
to detect antigen. A single negative
examination does NOT exclude
infection and repeat films every 612 hours over 36-48 hours may be
required for confident exclusion. Malaria
serology is rarely useful.
Malaria can also mimic other
conditions, and may be co-present
with other febrile illnesses, such as
pneumonia.
Malaria
Viral hepatitis (A, B, C, E)
Schistosomiasis
HIV
Treatment is supportive and
spontaneous resolution the norm.
Haemorrhagic complications require
hospital management.
Enteric Fevers
Enteric fevers are caused by Salmonella
typhi and S. paratyphi. Transmission
occurs by the faecal-oral route and
incubation is generally 1-3 weeks,
occasionally longer. There are few
specific features at onset, but, as
with malaria, the diagnosis should be
considered in any returning traveller
with fever. Typhoid vaccines provide
only approximately 70% protection, so
a history of vaccination is irrelevant.
Diagnosis is made by culture of blood,
stool and possibly urine. Serology is
rarely useful in the diagnosis of typhoid
or paratyphoid fever.
Others
Dengue fever is caused by an arbovirus
which is transmitted by the bite of an
Aedes aegyptii mosquito. Infection
is characterised by an acute febrile
illness, often with intense myalgia, rash
and thrombocytopenia. Haemorrhagic
complications are also possible.
•
•
•
•
•
•
•
•
It has a short incubation time (usually
Unless there are specific aspects
Dengue Fever
Long Incubation (> 21 days)
3-7 days) and is readily diagnosed
serologically. There are four serotypes
which infect humans. Infection with one
serotype does not provide immunity
to the others and, in fact, such reinfections can be more severe than the
first.
Rickettsial infection (spotted fevers, scrub typhus, etc)
Leptospirosis
Viral hepatitis
Other arboviral infections
HIV
Brucellosis
Amoebiasis
Non-exotic infections (EBV, CMV, respiratory viruses, etc)
Tuberculosis
Amoebic liver abscess
Malaria
If a malarious area has been visited,
this diagnosis usually becomes the first
and most important one to consider
and exclude.
Four species of malaria most
commonly infect humans:
•
•
•
•
Plasmodium vivax
P. falciparum
P. malariae
P. ovale
5
Illness in the Returning Traveller
of history or clinical presentation,
these diagnoses are considered and
progressively excluded if the results of
initial investigations do not provide the
diagnosis.
Laboratory Investigation of Febrile
Traveller
•
•
•
•
•
•
•
Full blood count and CRP
Liver function tests
Blood cultures (x 2-3)
Blood film(s) for malarial parasites
Stool microscopy and culture
Other cultures as appropriate (urine, wounds, etc).
Serology (arboviral, other viral, rickettsial, parasitic, etc
Eosinophilic Syndromes
A number of infectious and atopic
conditions may cause persistent
eosinophilia in a patient with a history
of recent travel. Parasitic causes are
the most common and a number of
investigations are available to exclude
the most common.
Causes of Significant Eosinophilia
(>5OO/mm3)
Atopy
Gastrointestinal parasites (eg,
trichuris, hookworm, ascaris)
Strongyloidiasis
Schistosomiasis
Cutaneous larva migrans
Investigations
Direct and serological examination
for parasites
unproven. In such individuals, an
empiric course of ivermectin or
albendazole is sometimes considered
after discussion with an infectious
diseases physician.
Conclusion
Apart from traveller’s diarrhoea and
acute respiratory infections, most
travellers are less likely to experience
illness than they are accidents or thefts.
However, the occasionally encountered
exotic disease may be life-threatening
and therefore an appreciation of the
range of travel-related infectious
diseases and how to diagnose them is
important. Illness in a returning traveller
deserves careful assessment to ensure
early diagnosis and effective treatment.
In some cases of persistent
eosinophilia, a parasitic cause may
be strongly suspected but remains
If you have any enquiries, please contact Dr Ian Chambers on (02) 98 555 312
Pathology Update
Tissue-Typing Tests at
Douglass Hanly Moir
Pathology & the Sonic
Clinical Institute
Selected tissue-typing tests for
the identification of susceptibility
for certain diseases, as well as
cell-mediated serious adverse
drug reactions, have been wellestablished.
The tests we routinely offer with
high-resolution molecular methods
are:
COELIAC TISSUE-TYPING
We report the presence
or absence of HLA-DQ2 or DQ8
which are necessary permissive
genes for Coeliac disease.
Medicare rebate is available. It is
performed on a dedicated EDTA
specimen or a buccal swab for
children, if specially requested.
HLA-B*1502 detection in Asian and
Chinese persons is used prior to
commencement of Carbamazepine
to reduce risk of severe cutaneousadverse drug reactions. There is
no Medicare rebate, our fee is $50.
A dedicated EDTA specimen is
required.
HLA-B27 is used to add weight
to the diagnosis of ankylosing
spondylitis, acute anterior uveitis,
iritis, psoriatic arthritis, Reiter’s
syndrome and Crohn’s disease.
Medicare rebate is available. A
dedicated EDTA specimen is
required.
HLA-B*5701 detection is used
for any person prior to initiation
of the anti-retroviral Abacavir, to
reduce risk of severe cutaneousadverse drug reactions. There is a
Medicare rebate. A dedicated EDTA
specimen is required.
If you have any enquiries, please contact Dr Karl Baumgart on (02) 98 555 286
6
Thyroid Function Tests and Pregnancy
Interpretation of thyroid function
tests in pregnancy can be difficult
for several reasons. Firstly, there
are various physiological changes
in pregnancy that may, in some
patients, lead to results outside of
the non-pregnant reference intervals.
Occasionally, these changes may
lead to transient hyperthyroidism
near the end of the first trimester.
Furthermore, the incidence of true
autoimmune thyroid disease is
increased during pregnancy. Finally,
a significant number of women
will develop post-partum thyroid
disease.
Dr Nick Taylor
Director of Chemical Pathology
Central Automated Laboratory
Physiological Changes
in Thyroid Function in
Pregnancy
Various physiological changes in thyroid
function occur in normal pregnancy1.
The changes in thyroid function seen
in the first trimester are largely due
to high concentrations of hCG. Due
to structural homology with TSH,
hCG has weak thyroid stimulating
activity. The maximum effect of hCG
on thyroid function is seen when
hCG concentrations reach their peak
at 10-12 weeks gestation. In most
women, a small rise in FT4 and fall in
TSH is observable, although analyte
concentrations usually remain within
the non-pregnant reference intervals.
Up to 20% of pregnant women show
a fall in TSH, but most do not manifest
any symptoms of thyroid dysfunction.
About 2% of pregnant women will
show a high FT4 and suppressed
TSH and develop symptoms and
signs of hyperthyroidism. This
syndrome has been called “gestational
transient hyperthyroidism” and is
often associated with hyperemesis
gravidarum. This condition must be
differentiated from true hyperthyroidism,
most commonly due to Grave’s
disease.
Case 1
Female 34y, 9 weeks gestation,
vomiting.
TSH
<0.04 mIU/L*
(0.5-4.5)
FT4
29 pmol/L*
(10-20)
FT3
9.6 pmol/L*
(3.5-6.0)
The patient has hyperthyroidism.
Her ß-hCG was 210,000 IU/L and
TSH-receptor antibodies were
not detected. These findings
favour a diagnosis of “gestational
transient hyperthyroidism”
rather than Grave’s disease. The
hyperthyroidism resolved without
treatment during the second
trimester.
In the second and third trimesters, FT4
usually falls to 20-40% below the nonpregnant mean, although again, most
remain within the reference interval.
Occasionally, FT4 falls slightly below the
reference interval.
Thyroid Disease in
Pregnancy
Normal maternal thyroid function
is essential to the well-being of the
developing foetus. The foetal thyroid
gland does not become active until
about 12 weeks gestation2. Prior to
this, an adequate supply of maternal
thyroid hormone is essential for normal
foetal neurological development.
Mothers with undiagnosed or
inadequately treated hypothyroidism
have an increased rate of foetal
loss and IQ deficit in their offspring.
Intellectual impairment has even been
noted in the offspring of women with
subclinical hypothyroidism (mild thyroid
failure) in early pregnancy. In the
US, pre-pregnancy or first trimester
screening for thyroid dysfunction,
has been recommended1. A similar
approach is being considered in
the UK2. The subject has also been
raised in Australia3 although there is
currently no official recommendation for
screening.
7
Thyroid Function Tests and Pregnancy
Changes in the maternal immune
system in pregnancy influence the
course of autoimmune thyroid disease.
This affects both the onset of new
disease and relapse of existing disease,
both of which are increased in pregnant
women.
Because of the increased requirement
for thyroxine in pregnancy, women on
thyroxine replacement usually need
their dose to be increased. Most
women on thyroxine replacement will
require a dosage increase of 25-50 ug/
day. The aim of therapy is to normalise
FT4 and TSH; preferably with FT4 in
the upper half of the reference interval
and TSH in the lower half.
Post-Partum Thyroiditis
Post-partum thyroiditis occurs within
2-6 months of delivery in about 5%
of pregnancies in iodine replete areas
and is associated with positive antithyroid peroxidase (TPO) antibodies2.
The presence of anti-TPO antibodies
in early pregnancy predicts a 30-50%
chance of post-partum thyroiditis
developing.
There is usually an initial transient
thyrotoxic phase which can be
differentiated from Grave’s disease
by the absence of TSH-receptor
antibodies. There follows a hypothyroid
phase lasting up to six months. This
may require treatment, if symptomatic.
Case 3
Female 32y, post-partum fatigue.
Thyroid function results on presentation at 12 weeks post-partum (PP) and
on follow up three weeks later were:
Case 2
Female 28y, 8 week antenatal
visit.
TSH 6.3 mIU/L*
(0.5-4.5)
FT4 2 pmol/L*
(10-20)
The patient has subclinical
hypothyroidism. She was
immediately commenced on
thyroxine replacement.
12w pp
15w pp
TSH (mIU/L)
0.29*
8.9*
(0.5-4.5)
FT4 (pmol/L)
14
9*
(10-20)
Anti-TPO (IU/mL)
3450*
–
(<60)
This patient has post-partum thyroiditis. It is likely that a transient
hyperthyroid phase occurred before to initial presentation. The results show a
typical transition to hypothyroidism.
Summary
Diagnosis and treatment of thyroid disease are most important in pregnancy, particularly in the
first trimester when the foetus is totally dependent upon an adequate maternal supply of thyroid
hormone.
References:
1. Demers LM, Spencer CA, ‘Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease’, NACB Laboratory Medicine Practice Guidelines, 2002.
2. UK Guidelines for the Use of Thyroid Function Tests, July 2006.
3. Stockgit J, ‘Current Strategies for Thyroid Function Testing’, Common Sense Pathology, July 2003.
If you have any enquiries, please contact Dr Nick Taylor on (02) 98 555 599
8
Myeloma AL-Amyloidosis and Free Light Chain Assays
Multiple myeloma has become the
second most common haematologic
malignancy after chronic lymphatic
leukaemia. Many more patients
have a monoclonal gammopathy of
uncertain significance.
Our major diagnostic tools for
identifying patients with myeloma,
or paraprotein-related disorders,
have been serum and urine
electrophoresis and immunofixation
electrophoresis. Although a
considerable advance on the original
method of Dr Henry Bence Jones,
these tests have limitations for the
diagnosis of predominant ‘light chain
only’ myeloma.
Dr Karl Baumgart
Director of Immunology
In recent years, assays have been
developed for the detection of
free light chains in serum using
antibodies that bind specifically to
light chain epitopes that are only
exposed in free, but not heavy chain
bound light chains.
Reflecting the clinical utility of new
generation free light chain assays,
the Medicare Benefits Schedule
now contains an item number for
measurement of free light chains.
What Are Free Light
Chains?
Light chains include antigen-specific
and constant-domains and are normally
bound to the outside surface of the
immunoglobulin heavy chain in a 1:1
ratio. In the constant-domain there is
a hidden surface which is the target of
assays to measure circulating free light
chains (Figure 1).
Where Do Free Light
Chains Come From?
Light chains are produced by: pre-B
cells (abnormal in pre-B cell leukaemia),
activated or memory B cells (abnormal
in chronic lymphocytic leukaemia),
mature memory B cells (abnormal in
follicular centre cell lymphoma and
Burkitt’s lymphoma), IgM-secreting
B cells (abnormal in Waldenstrom’s
macroglobulinaemia), as well as by
plasma cells (abnormal in monoclonal
gammopathy of undetermined
significance, myeloma and AL
amyloidosis).
Healthy persons produce 500 mg/
day of free light chains - this relative
excess (40%) production of light to
heavy chains allows plasma cells to
'waste' some light chains so they can
achieve proper conformation of intact
immunoglobulin molecules. Twice as
many plasma cells produce kappa as
they do lambda light chains. In serum,
lambda free light chains are dimeric
and kappa free light chains are usually
monomeric.
Where Do Free Light
Chains Go?
Serum free light chains are cleared and
metabolised in the kidneys according
to their molecular size. It has been
determined that monomeric kappa light
chains are cleared at 40% of the GFR
in 2-4 hours, while dimeric lambda
light chains are cleared at 20% of the
GFR in 3-6 hours. Fenestrations in the
glomerular basement membrane do
not permit filtration of proteins greater
than 60 kDa, and filter progressively
fewer proteins greater than 20 kDa.
The proximal tubules can process and
reabsorb between 10-30 g of protein
a day. Therefore the 500 mg/day of
normally produced light chains are fully
absorbed and the 1-10 mg/day of free
light chains normally detected in the
urine probably enter lower down the
renal tract, often with secretory IgA.
Tamm-Horsfall protein (produced by
the distal tubule to prevent ascending
urinary infections) aggregates into
polymers of 20-30 molecules. TammHorsfall protein also specifically binds
free light chains that can result in the
waxy casts characteristic of light chain
myeloma. In the absence of impaired
renal function, abnormal serum free
light chains are not usually detected
until production exceeds 10-30 g/day.
Therefore free light chain abnormalities
will be detectable much earlier in serum
than in the urine.
What Are the ‘Normal
Ranges’ for Serum Free
Light Chains?
Serum free light chain concentrations
are higher with: age, impaired renal
function, in increased production due
to polyclonal B cell activation, and with
9
Myeloma AL-Amyloidosis and Free Light Chain Assays
increased production by abnormal Blineage clones.
Monoclonal free light chains may have
unusual charge or other molecular
characteristics that affect the chemistry
of assays used in their detection,
resulting in under or over-estimation.
Measurement of free light chain
concentrations does not establish
clonality in the way that immunofixation
electrophoresis, or a skeletal survey
showing lytic lesions, or a bone marrow
biopsy showing clusters of plasma
cells, can.
Previously available assays for total
serum kappa and lambda light chains
include free and heavy chain bound
forms. In these assays the kappa
concentration is usually double that
of lambda - reflecting production.
Conversely, the new generation
assays for free kappa and lambda
concentrations use antisera that
bind epitopes only exposed on free
light chains. In these assays the free
kappa concentration is nearly half
that of the free lambda concentration.
The inversion of the free kappa/free
lambda ratio is a consequence of the
much faster clearance of the normally
monomeric free kappa compared to
the slower clearance of the normally
dimeric free lambda light chains
(Figures 1 & 2).
Reference Intervals
Reference ranges for free kappa light
chains are 3.3-19.4 mg/L and for free
lambda light chains are 5.7-26.3 mg/L
with a free kappa/free lambda ratio of
0.26-1.65 (Figure 2).
In disorders with polyclonal increases
in free light chains due to increased
synthesis or decreased renal clearance,
the kappa/lambda ratio is preserved.
With progressive loss of renal function,
including with ageing, there can be a
mild increase in kappa/lambda ratio.
When a monoclonal gammopathy
is present, only one of the free light
chain concentrations will increase;
therefore the kappa/lambda ratio will be
abnormal and the free kappa and free
lambda light chain concentrations will
usually be abnormal - with one elevated
and one reduced.
10
When Should I Consider
Requesting Free Light
Chains?
When a person is suspected of having
a plasma cell dyscrasia or monoclonal
gammopathy, serum free light chain
assays should now be requested. In
persons with a known paraprotein,
excess free light chain production will
be identified much earlier than by urine
electrophoresis or urine immunofixation
electrophoresis. This will allow better
stratification of risk of progression
and is particularly useful in identifying
individuals for risk of renal failure. Mild
unexplained hypogammaglobulinaemia
or low serum immunoglobulin levels
should be investigated by serum
free light chain assays to exclude
monoclonal light chain disease.
Similarly, serum free light chain assays
should be requested to confirm
AL amyloidosis if imaging such as
echocardiography reveals a ‘speckled
pattern’, or histology shows amyloid on
tissue biopsy.
When Does Medicare
Reimburse Serum Free
Light Chain Studies?
The Medical Benefits Schedule item
71200 provides for reimbursement
of detection and quantitation of free
kappa or lambda light chains in serum
for the diagnosis or monitoring of
amyloidosis, myeloma, or plasma cell
dyscrasias.
Advantages of Free Light
Chain Assays
The finding of an increase in either free
kappa or lambda light chains in serum,
combined with an abnormal kappa/
lambda ratio is pathognomonic of a
monoclonal light chain disorder. It is the
most sensitive test for detecting and
monitoring such disorders.
Serum free light chains are primarily
cleared through the renal glomeruli
and then metabolised in the proximal
tubules. Normal free light chain
production is 500 mg per day and the
renal absorptive capacity is 10-30 g per
day. Production must increase many
times before urine contains significant
amounts of free light chains,hence
serum free light chains are more
sensitive than are EPG-IFE (Figure 2).
Possible Myeloma or
Plasma Cell Dyscrasia
Serum EPG + IFE, Beta-2Microglobulin, Serum Free Light
Chains, FBC +/- Urine EPG-IFE
Serum Free Light Chains
Reference Intervals
kappa
3.3 -19.4 mg/L
lambda
5.7 - 26.3 mg/L
kappa
lambda ratio
0.26 - 1.65 mg/L
Disadvantages of Free
Light Chain Assays
Free light chain assays do not
definitively prove clonality in the way
that electrophoresis can. Interpretation
of results may be difficult with
advanced renal failure. Since extremely
high levels of monoclonal light chain
paraproteins may result in ‘antigen
excess’ in the assay, requests for
light chain assays should always
be accompanied by a request for
concurrent serum electrophoresis and
immunofixation electrophoresis, to allow
accurate analysis. Monoclonal free
light chains and intact immunoglobulin
paraproteins may have unusual charge
or chemical properties that distort the
results.
Light Chain Multiple
Myeloma
A serum EPG-IFE will demonstrate a
monoclonal light chain in half of the
patients with light chain myeloma
(although hypogammaglobulinaemia will
be the usual finding in the other half).
Serum free light chain assays are more
sensitive than urine immunofixation
electrophoresis of concentrated
samples (which can only detect
monoclonal bands in some patients).
Since the serum free light chain assays
are not only sensitive, but quantitative,
they are also the single best test for
monitoring light chain only disease.
Myeloma AL-Amyloidosis and Free Light Chain Assays
Non-Secretory Multiple
Myeloma
Conventional serum and urine
immunofixation electrophoresis will not
detect a monoclonal band in 5% of
patients with myeloma who are then
considered to have non-secretory
myeloma. Abnormal free light chain
assay results have been found in 90%
of patients previously classified as nonsecretory myeloma.
AA and AL Amyloidosis
Amyloidosis is diagnosed by the finding
of birefringent green fluorescence on
Congo Red stained tissue under a
polarizing microscope. Although there
are specific immunoperoxidase stains
that can identify AA and AL amyloid,
these stains are not always reliable
and other unusual causes of amyloid
may result from over-production
of endocrine or other proteins.
Since conventional serum and urine
immunofixation electrophoresis will only
detect some patients with monoclonal
light chains, the serum free light chain
assays should be performed when
amyloid has been detected.
AL amyloidosis results from the
accumulation of intact or fragments of
monoclonal free light chains produced
by a slowly growing clone of plasma
cells. Patients most commonly present
with heart or renal failure but may also
present with involvement of the skin,
tongue, peripheral nerves or other
organs. Certain light chain genetic
and protein sequences determine
the tissue tropism that is observed.
Although median survival is 12 months,
some persons who respond well to
chemotherapy may live many years.
AL amyloidosis more commonly affects
males (65%), is uncommon (<10%)
with concurrent myeloma and is less
than 20% as common as myeloma. It
is rare before age 40 with the median
age at presentation of 70. In persons
with AL amyloid, the serum EPG and
IFE may be normal. However, persons
with renal involvement often develop
nephrotic syndrome with low albumin,
elevated alpha-2-globulins and low
gammaglobulin fraction. Immunofixation
electrophoresis may reveal a small
lambda light chain band on serum or
urine.
Figure 1: Intact Immunoglobulin and Free Light Chains
Figure 2: Serum Free Light Chain Concentrations
in a selection of clinical conditions. (LCMM,
light chain multiple myeloma;IIMM intact
immunoglobulin multiple myeloma; pIgG,
polyclonal hypergammaglobulinaemia; NSMM,
non-secretory multiple myeloma). (Figures
provided by the Binding Site Ltd, Serum Free
Light Chain Analysis, 4th Edition, AR Bradwell,
Birmingham 2006).
If you have any enquiries, please contact Dr Karl Baumgart on (02) 98 555 286
11
Introducing GynaePath
“Your Patients are our Priority”
The merger of two specialist pathologist groups has allowed us to create a unique
centre of excellence in gynaecological pathology
– GynaePath –
A Unique Service
GynaePath Pathologist Team
Professor Annabelle Farnsworth
•
GynaePath represents the largest
specialist gynaecological and reproductive pathology practice in Australia.
The establishment of GynaePath is a result of the merger of specialist gynaecological pathologists from Douglass Hanly Moir Pathology and previously from Symbion Laverty Pathology.
GynaePath offers the unique expertise of a team of internationally recognised specialist gynaecological pathologists, spearheaded by Professor Annabelle Farnsworth (Director of GynaePath) and Professor Peter Russell.
Professor Peter Russell
•
•
•
GynaePath pathologists are actively involved with numerous professional committees and organisations, forging relationships with clinicians and special interest groups at national and international level. They are strongly committed to teaching and research, and many hold academic appointments.
• The collective expertise and experience
of this group of pathologists is unrivalled in this country.
•
This centre of excellence offers a comprehensive gynaecological pathology service operating as a boutique laboratory within and supported by the full resources of Douglass Hanly Moir Pathology, Australia’s largest pathology laboratory.
Contact Details
Gynaecolgical Pathologists
All Hours
Toll Free
Results
Dr Erica Ahn
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98 556 200
98 555 222
1800 222 365
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DOUGLASS HANLY MOIR PATHOLOGY • ABN 80 003 332 858
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