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INSIDE
Non-hepatic
causes

Underestimated
severity of liver
disease

Rare diagnoses

Drug-induced liver
damage

Non-alcoholic
fatty liver disease

Minor the authors

abnormalities
of LFTs
Professor
Geoffrey C Farrell
professor of hepatic medicine,
Australian National University
Medical School, and director,
gastroenterology and hepatology
unit, Canberra Hospital, Garran,
Introduction ACT.

ABNORMAL liver tests can be very Table 1: Pathology of liver abnormalities

useful when the pattern of changes Pattern Hyperbiliru– Hepatitis Cholestasis Cirrhosis Infiltration Minor, non-
corresponds to clinical suspicion (normal range) binaemia (hepato- specific
about diagnoses, such as viral hepa- cellular injury)
titis or biliary obstruction. In recent
community surveys, 3-10% of Serum 50 50 (may be 50 (may be 25 (often normal, 15 10
apparently healthy individuals have bilirubin normal or very normal, or high with Dr Shivakumar Chitturi
LFT abnormalities, particularly (< 20 μmol/L) high, with very high with decompensation) senior staff specialist,
GGT and ALT elevation. These are jaundice) complete gastroenterology and hepatology
nearly always relatively minor (that biliary unit, Canberra Hospital, Garran,
is, less than a threefold increase obstruction ACT.
above the normal range) and not ALP (<110 90 120 450 150 300 100
specific to the diagnostic patterns of U/L)
the major conditions shown in table ALT (<40 U/L) 25 800 75 60 30 75
1.
AST (<40 U/L) 15 500 60 80 20 50
There are several issues raised by
these seemingly trivial LFT abnor- GGT (<35 U/L) 25 100 350 75 250 75
malities. For example, the patient Albumin (35- 42 42 42 34 40 42
may not have liver disease and the 53 g/L)
Professor Narci Teoh
apparent ‘liver function’ abnormali- Comments Gilbert’s Acute hepatitis Biliary Note AST higher Metastatic Fatty liver, professor of medicine, Australian
ties are caused by the involvement and examples syndrome, (A, B, C, E), obstruction than ALT — also malignancy, cirrhosis, National University Medical
of another tissue and/or another haemolytic drug-induced (order found in alcoholic hepatocellular chronic School, and senior staff specialist,
disease, or they may suggest alco- anaemia (order liver injury ultrasound), hepatitis; globulins carcinoma hepatitis, gastroenterology and hepatology
holism. FBC) (isoniazid), drug-induced often increased; (order CT infiltration, unit, Canberra Hospital, Garran,
In addition, LFT abnormalities chronic hepatitis liver injury, low platelets scan), drug effects ACT.
in an asymptomatic person can be (autoimmune — primary biliary sarcoidosis
confusing when hepatic imaging albumin may be cirrhosis etc (examine for
shows one or more lesions that, in low) lymph nodes;
the absence of LFT abnormalities, thoracic CT)
would usually suggest a benign con- Copyright © 2013
Australian Doctor
dition, such as a haemangioma, sim- and extent of LFT abnormalities is Most commonly, however, these setting because a fatty liver is the
All rights reserved. No part of this
ple cyst or focal nodular hyperplasia a poor guide to the treatment indi- minor non-specific test abnormali- forerunner of diabetes, cardiovascu- publication may be reproduced,
(FNH). cations for hepatitis B and hepatitis ties reflect non-alcoholic fatty liver lar outcomes, common cancers, cir- distributed, or transmitted in any
Conversely, the ‘unspectacular’ C. On the other hand, minor LFT disease (NAFLD), the most preva- rhosis and liver cancer. This article form or by any means without
nature of the LFT abnormalities abnormalities may be the first clue lent form of liver disease in Austral- discusses the issues raised by minor, the prior written permission of
the publisher.
may underestimate the severity of to a less common but important ian adults and children. People with non-specific liver test abnormalities For permission requests, email:
important liver disease, particu- form of liver disease that is yet to this common condition deserve opti- and their management. howtotreat@cirrusmedia.com.au
larly cirrhosis, and the presence develop clinical manifestations. mal management in the community cont’d next page

www.australiandoctor.com.au 11 October 2013 | Australian Doctor | 25

 How To Treat – Minor abnormalities of LFTs

Non-hepatic causes
ABNORMALITIES of one or more
of the clinical chemistry tests con-
ventionally misnamed as ‘LFTs’
might not be the result of liver
disease. Some of the non-hepatic
causes of minor LFT abnormalities
are listed in table 2.
Hyperbilirubinaemia
Hyperbilirubinaemia — in which
there is a minor increase in serum
unconjugated bilirubin and no
bilirubinuria on a dipstick, and
where other LFTs are normal —
may point to Gilbert’s syndrome
or haemolysis.
Gilbert’s syndrome is common
(occurring in at least 3% of the
population), and so are NAFLD
and hepatitis C. About one in 30
patients with NAFLD or hepatitis
C also have Gilbert’s syndrome.
In such cases, GGT and ALT may
be raised in addition to the hyper-
bilirubinaemia. This is potentially
confusing because even minor
elevation of serum bilirubin in the
context of any chronic liver disease
often indicates cirrhosis (table 3).
Hence, patients with a raised
bilirubin, GGT and ALT should be
carefully assessed and considered
for referral to a gastroenterologist
or hepatologist.
There is a genetic test for Gil-
bert’s syndrome based on a
polymorphism of the promoter
sequence for bilirubin UDP-glu-
curonosyltransferase 1A1. While
not widely available, it can be per-
formed in some molecular diag-
nostic laboratories and is useful in
confusing situations.
Serum alkaline phosphatase
Serum alkaline phosphatase
(abbreviated as ALP or SAP) is
often raised without other bio-
chemical abnormalities. This can
rarely occur with liver or biliary
tract disorders, for example with
a stone in the common bile duct
or hepatic malignancy, but more
commonly it has a non-hepatic
aetiology.
Bone disease, such as Paget’s
disease, a fracture (including fra-
gility fractures) or metastatic
malignancy is most often the cause
of a raised ALP. This is usually
simple to confirm by the history,
physical examination, radiology
or a bone scan. It is possible to
estimate the heat-stable isoform of
ALP, which indicates origin from
liver rather than bone, although
this investigation is not widely
Figure 1: Raised liver
Table 2: LFT abnormalities caused by conditions other than
hepatobiliary disorders enzymes can occur
in patients with
Abnormality Examples Comments extrahepatic disorders,
Raised serum Haemolytic anaemia, Check for bilirubinuria, such as thyrotoxicosis in
bilirubin; all else massive haematoma splenomegaly, FBC, blood this man with proptosis.
normal film, reticulocyte count
Raised ALP; Bone disease, eg, Consider the full clinical
normal GGT, ALT, Paget’s, fractures, picture — examine bones,
serum bilirubin metastases; also breasts, prostate etc; rare
and albumin found in cardiac failure manifestation of cirrhosis,
(bilirubin may be raised) hepatic malignancy
Strikingly Alcoholism, other Revisit the history and
increased GGT, medications talk to significant others;
other tests normal — especially exclude macrocytosis and ;
or (eg, AST) anticonvulsants establish any relationship with
minimally altered medication use
Low serum Nephrotic syndrome; Cause usually obvious
albumin, other inflammatory bowel (urinalysis, history); may available and may be expensive for Serum albumin
tests normal disease; protein- be more perplexing with the patient. A simpler approach is Serum albumin concentration is
losing enteropathy; raised globulins — exclude to exclude a concomitant increase determined by the rate of albumin
malnutrition such as myeloma, lymphoma, in GGT that together would suggest synthesis in the liver, but also by
from eating disorder; haematological malignancy liver disease. A practice point worth its distribution, haemodilution
burns remembering is that in a hospital set- (eg, explaining the fall during the
Raised AST, ALT Myositis, Perform muscle enzyme tests; ting and in patients with other major second trimester of pregnancy)
normal rhabdomyolysis may be more confusing if medical illnesses, increases in ALP and rate of degradation or loss
ALP also elevated — possible are often associated with cardiac of the protein. Low values can
hepatic involvement with failure or with systemic inflamma- therefore reflect impaired hepatic
polymyalgia rheumatica, tion, not liver disease. synthetic function in cirrhosis,
vasculitis (check CRP, etc) but are also found in nephrotic
Gamma-glutamyl transpeptidase syndrome, protein-losing enter-
Minor, non- Extrahepatic malignancy Need to distinguish from
GGT arises uniquely from liver, opathy, inflammatory bowel dis-
specific (raised (renal); chronic much more common NAFLD
but increases occur in response to ease, under-nutrition and tissue
ALT, GGT, infections or other (with hepatic ultrasound),
chronic excessive alcohol intake cachexia associated with condi-
ALP — various inflammatory conditions and from cirrhosis; consider
and to treatment with microso- tions such as starvation and eating
combinations) referral to physician
mal enzyme-inducing agents such disorders, burns, coeliac disease,
as anticonvulsants. This phenom- Crohn’s disease, myeloma and
Table 3: Clues to cirrhosis in patients without liver failure enon reflects increased synthesis other malignancy.
Clue Findings that Comments and release of GGT and is often Thus, the significance of low
suggest cirrhosis termed ‘enzyme induction’. In some serum albumin depends on the
Physical Hard liver edge Highly specific (exclude malignancy) instances, there may also be minor clinical context of these disorders
examination Spider naevi Spider naevi are the most sensitive and increases in serum ALT (or AST with (they are usually but not always
specific sign for cirrhosis alcohol) and/or ALP, thereby posing obvious), as well as clinical or
a greater challenge for discerning the other laboratory evidence of
Platelet count Thrombocytopenia Usually low in cirrhosis; progressive
difference between a ‘drug effect’ vs chronic liver disease (table 3).
decline in patients with hepatitis C or
drug-induced or other form of liver
NAFLD indicates advancing hepatic
and hepatobiliary disease. In some LFTs in systemic disease
fibrosis; note alcohol may suppress
community surveys, minor elevation As intimated for ALP, LFT abnor-
platelets (reversible)
of GGT alone is a risk factor for sub- malities can occur in several extra-
Alpha- Often high with Very useful in general practice. Any sequent onset of type 2 diabetes. A hepatic diseases that may or may
fetoprotein cirrhosis new increase in AFP, or elevated family history of diabetes should be not be associated with significant
(AFP) absolute values >10-fold should arouse sought and the patient assessed for liver pathology. Important ones
suspicion for hepatocellular carcinoma overweight and central obesity. include thyrotoxicosis (figure
(order liver ultrasound) 1), coeliac disease, extrahepatic
Serum Any increase A diagnostic and prognostic marker for Serum aspartate transaminase malignancy (particularly renal),
bilirubin cirrhosis AST arises from muscle, lung, vasculitis and other systemic
AST and ALT AST: ALT ratio Low sensitivity but reasonable brain and other tissues as well as inflammatory disorders.
>0.80 specificity for cirrhosis, but also occurs liver, whereas ALT is liver-specific. Consideration therefore needs to
with alcohol (with or without cirrhosis) If the clinical chemistry laboratory be given to a full history, screening
routinely performs AST in its ‘LFT of thyroid function, CRP, testing
Serum ‘Borderline low’ In cirrhosis, progressive decline of panel’ (most do not), an isolated for urinary infection and haema-
albumin serum albumin over months or years AST increase should alert the cli- turia, and hepatic imaging by CT
often precedes presentation with nician to possible muscle disease. scan. Referral to a hepatologist
ascites Other muscle-related enzymes is particularly indicated if this is
Serum total Raised Common with cirrhosis but lacks both such as creatine kinase should then clearly a new condition and/or the
globulin sensitivity and specificity be estimated. patient appears to be unwell.

Underestimated severity of liver disease

MINOR LFT abnormalities can
underestimate the severity of liver
disease or the need for treatment,
particularly cirrhosis, chronic hep-
atitis B and hepatitis C or haemo-
chromatosis.
Cirrhosis
It is very important to make
the diagnosis of cirrhosis when
patients are well. This is because
the significant complications of
bleeding oesophageal varices,
hepatic decompensation (ascites,
muscle wasting, hepatic encepha-
lopathy), hepatocellular carci-
noma (HCC) and metabolic bone
disease can all be ameliorated
(prevented, delayed or better out-
comes ensured) with early diag-
nosis and key interventions. A
contemporary key issue in liver
disease is for doctors to improve
their skills in making an early
diagnosis of cirrhosis.
LFTs may be normal in patients
with cirrhosis of any cause,
including alcoholic liver disease
if the patient has stopped drink-
ing. However, minor LFT abnor-
malities are common, and some
changes suggest cirrhosis as out-
lined in table 3. Often cardinal
signs of cirrhosis are readily appar-
ent on careful physical examina-
tion; the two most important and
reliable findings that indicate high
probability of cirrhosis are a hard
liver edge (figure 2A) and spider
naevi (figure 2B).
Investigations
Even more commonly, the platelet
count is low because its regulatory
peptide, thrombopoietin, is synthe-
sised in the liver (platelet destruc-
tion by splenomegaly may also
occur). Serial platelet count is a
very useful indicator of the fibrotic
progression of chronic liver dis-
orders, particularly with chronic
hepatitis C and B infections — the
platelet count is the hepatologist’s
most reliable ‘liver function test’.
A slightly raised alpha-fetoprotein
(AFP) level is another common
finding with cirrhosis. However,
possibly because of reimburse-
ment issues, AFP is under-utilised
as a ‘cirrhosis screen’ in general
practice. In more advanced cir-
rhosis, impaired synthesis of clot-
ting factors can result in prolonged
prothrombin time or INR.
Imaging
Contemporary high-quality imag-
ing may also provide diagnostic
information in cirrhosis, such as a
dilated portal vein, splenomegaly,
varices and thickening of the gall
bladder wall (which often por-
tends the development of ascites).
In advanced cases, nodularity or
unevenness of the surface of the
liver may be evident on ultra-
sonography (ask for a surface
view) or CT scan. The liver ultra-
sound may also show increased
echogenicity; this is often confused
with the similar change in fatty

26 | Australian Doctor | 11 October 2013 www.australiandoctor.com.au

liver disease, but the latter also
causes posterior attenuation of the
ultrasound shadow and blurring
of hepatic vessels (figure 3). When
doctors suspect cirrhosis, refer-
ral to a hepatologist or liver clinic
is recommended so that more
detailed clinical assessment and
investigations can be expedited.
The latter include transient elas-
tography (figure 4), a convenient,
non-invasive test of liver ‘ stiffness’
that has high diagnostic accuracy
for detecting advanced hepatic
fibrosis or for excluding signifi-
cant fibrosis.
Chronic hepatitis C
virus infection
A normal ALT and/or variable
elevations of ALT and GGT often
occur in chronic hepatitis C virus
(HCV)-infected individuals. Find-
ing out the duration of infection
(>20 years) and the pattern of
LFTs during the past decade is
important. Increased ALT levels
may reflect active HCV infection
but are also found with fatty liver,
which may occur concomitantly in
over 60% of patients with hepati-
tis C and/or with alcohol misuse.
In turn, some elevation of ALT
increases the risk of developing
cirrhosis and its complications of
liver failure and hepatocellular car-
cinoma. Conversely, some patients
with severe forms of chronic hepa-
titis C, including cirrhosis, have
completely normal LFTs, and the
absolute values of ALT (which
often fluctuate) are a poor guide to
the severity of liver disease.
AST:ALT ratio
Regardless of aetiology, a clue to
cirrhosis is a reversal in the ratio
of serum AST:ALT. Normally
the AST:ALT ratio should be less
than 0.8. Most laboratories per-
form serum ALT when ‘LFTs’ are
ordered as this is the most sensitive
and specific test for hepatocyte
injury. However, it is also useful
to ask for AST when one suspects
cirrhosis or alcohol abuse. An
AST:ALT ratio greater than 0.8
has a high specificity, albeit rela-
tively poor sensitivity, for cirrho-
sis. These changes can occur with
HCV infection, in which case cir-
rhosis is likely, but they can also
be features of concomitant alco-
holic liver disease.
Investigations
Complementary investigations in
the workup and ongoing review
of someone with chronic HCV
include an FBC, with particular
attention to platelets, serum albu-
min, prothrombin time or INR,
HCV RNA PCR and HCV geno-
typing. If the patient is known
or suspected to have cirrhosis,
the plan should also include six-
monthly hepatic imaging (ultra-
sound or CT) and AFP and to
screen for treatable hepatocellular
carcinoma. Irrespective of inves-
tigations, a thorough physical
examination and reliable alcohol
history are warranted. A hard liver
edge, spider naevi, splenomegaly
and other signs of portal hyperten-
sion, ascites, muscle wasting, and
subclinical hepatic encephalopa-
thy are cardinal clinical features of
cirrhosis. Together with the need
to discuss possible treatment of
HCV (which is about to undergo a
A B
Figure 3: Key features of fatty liver disease on hepatic ultrasound. Compared with the renal cortex or spleen, increased
echogenicity is evident. Image also shows posterior attenuation of the ultrasound shadow and blurring of hepatic
vessels. Increased echogenicity alone is non-specific and can occur with cirrhosis.
Regardless of
aetiology, a clue to
cirrhosis is a reversal
in the ratio of serum
AST:ALT.
major change with potent new
agents), concern about the severity
of HCV-related liver disease is an
indication for referral to a hepa-
tologist.
Chronic hepatitis B
virus infection
Despite possessing a normal physi-
cal examination and normal ALT
level, people who have chronic
hepatitis B virus (HBV) infec-
tion (often referred to as carriers)
should not be presumed to be, nor
told that they are, healthy. For
instance, an ALT of 38 IU/L (nor-
mal <40), is no longer regarded
as normal by hepatologists. More
appropriate healthy (true nor-
mal) values are <20 IU/L for lean
women and <30 for lean men.
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Figure 2: A: The hepatocellular carcinoma is a high
correct technique for level of HBV replication, deter-
mined by serum HBV DNA level
examining the liver;
a hard protuberant (one test is reimbursable). If a liver
liver (and spleen in test abnormality, no matter how
left upper quadrant) minor, is due to chronic hepatitis B
is evident in a (with or without cirrhosis) and the
man with Wilson’s individual’s HBV DNA is >10,000
disease who is
IU/mL, referral to a hepatologist
known to have
cirrhosis. B: Spider is strongly recommended. In this
naevi. situation, antiviral therapy may be
indicated. Agents such as tenofovir
and entecavir are highly effective,
with minimal adverse effects or
drug–drug interactions.
Fatty liver
People with chronic HBV infection
often also have NAFLD, and this
is at least as common as chronic
hepatitis as the cause for minor
LFT abnormalities. Metabolic risk
factors should be assessed, includ-
ing weight gain, physical activ-
ity, waist circumference, BMI,
and investigations for conditions
associated with the metabolic syn-
drome (eg, diabetes, dyslipidae-
mia).
Where raised ALT and GGT is
suspected to be due to fatty liver
rather than hepatitis B, HBV DNA
levels and ultrasound may help
elucidate the diagnosis. Indeter-
minate levels of HBV DNA (ie,
1000-10,000 IU/mL) and com-
plex cases should be referred to a
hepatologist. Annual reviews are
recommended since values may
fluctuate, which is associated with
a higher risk of poor outcomes.
Risk when immunosuppressed
Figure 4: Transient People who have chronic HBV
elastography unit infection without LFT abnormali-
used for testing liver
stiffness in order to
ties should also be advised to alert
identify advanced
all their healthcare profession-
als of this infection to avoid the
liver fibrosis and
cirrhosis. The value bombshell of a potentially fatal
shown (11.4 kPa) hepatitis B flare in someone who
indicates highly likely appeared not to have active dis-
cirrhosis in a patient ease. This is especially important if
with non-alcoholic they are about to undergo immu-
fatty liver disease. nosuppressive therapies, such as
chemotherapy for solid or haema-
tological malignancies, anti-TNF
agents, or high-dose prednisone.
Under such circumstances, the
risk of HBV reactivation is very
high, and this can lead to death
from fulminant hepatic failure. All
patients who are HBsAg positive
should be referred to a hepatolo-
gist or specialist experienced in
the management of chronic HBV
infection prior to commencement
of profound immunosuppressive
therapy so that antiviral prophy-
laxis (lamivudine or entecavir)
can be instituted. During and after
Thus ALT (and AST) values in chemotherapy, monthly monitor-
persons who are HBsAg positive ing of liver tests and three-monthly
require close scrutiny and reflec- HBV DNA should be undertaken.
tion: several surveys have noted
that values between one- and two- Haemochromatosis
fold increased above the upper LFTs are typically normal in
limit of the stated normal range haemochromatosis, even with cir-
are actually more likely to be asso- rhosis. However, minor increases
ciated with established cirrhosis in ALT, AST and GGT may be
than are higher elevations. important clues to concomitant
alcohol dependence or obesity and
Cirrhosis/hepatocellular carcinoma diabetes-related steatosis, both of
People with chronic HBV infec- which increase the risk of cirrhosis
tion, particularly after the age of in patients with haemochromato-
30, have a substantial risk of devel- sis. Thus, LFT abnormalities in
oping fibrosis, cirrhosis and/or patients with iron storage disease
hepatocellular carcinoma, particu- are indications for assessment of
larly if HBV infection was acquired alcohol intake, obesity and glucose
early in life (eg, via maternal trans- tolerance, and referral to a hepa-
mission). The most important pre- tologist where appropriate.
dictor of subsequent cirrhosis or cont’d next page
11 October 2013 | Australian Doctor | 27
 How To Treat – Minor abnormalities of LFTs
Rare diagnoses
LFT abnormalities may be a clue to
rare but treatable liver disorders.
The rare disorders are uncommon
even in a hepatologist’s practice
and they include: primary bil-
iary cirrhosis, primary sclerosing
cholangitis, autoimmune hepatitis
and rarer forms of autoimmune
hepatobiliary disease, alpha-1
anti-trypsin deficiency, Wilson’s
disease and inherited metabolic
and canalicular transporter defi-
ciencies.
Figure 5 shows a patient with
primary biliary cirrhosis. Note,
however, that not all patients
Table 4: Uncommon liver diseases: what to look for, what to order, when to refer
Disorder
Coeliac disease
Primary biliary cirrhosis (PBC)
Primary sclerosing cholangitis
(PSC)
Autoimmune hepatitis (AIH, formerly Young, middle-aged or older — women
“chronic active hepatitis”)
Wilson’s disease
Alpha1-antitrypsin deficiency
Canalicular transporter deficiency
(progressive familial intrahepatic
cholestasis)
Drug-induced liver injury
OVER 600 drugs have been assoc-
iated with drug-induced liver
injury. The leading causes include
paracetamol, antimicrobials (eg,
flucloxacillin, amoxycillin-clavu-
lanic acid, cephalosporins, keto-
conazole, terbinafine), NSAIDs
(diclofenac), anticonvulsants (phe-
nytoin, carbamazepine, sodium
valproate), anti-tuberculosis
agents (eg, isoniazid, pyrazina-
mide, rifampicin), platelet inhibi-
tors (clopidogrel) and heparins.
Minor elevations of serum ALT/
AST, usually less than three times
the upper limit of normal, are
noted in up to 3% of patients in
clinical trials. Values usually settle
without specific intervention and
are not associated with signs or
symptoms of liver injury. This pat-
tern of liver tests is seen with many
drugs (eg, all heparins, isoniazid)
28 | Australian Doctor | 11 October 2013
with primary biliary cirrhosis look
like this. The diagnosis should be
suspected in a patient with unex-
plained LFT abnormalities (partic-
ularly but not exclusively ALP and
GGT) and confirmed by a positive
anti-mitochondrial antibody test.
Because these conditions are
uncommon, other doctors will
rarely encounter them. On the
other hand, since most of them are
now very treatable there is an onus
not to miss these liver diseases.
This poses a challenge to diagnose
them when minor abnormalities
of LFTs are the only features at
Clues to the diagnosis
Abnormal LFTs in lean patient; coeliac
disease may or may not be diagnosed
previously
Middle-aged to older women of northern
European ancestry; itch; fatigue;
concomitant autoimmune thyroid disease
or family history of same; LFTs more likely
to reflect cholestasis (see table 1), but may
not; xanthelasma and lipid disorders
Men > women; 70% cases associated
with inflammatory bowel disease; LFTs
more likely to reflect cholestasis
> men; ALT >300 IU/L; personal or family
history of other autoimmune disease; often
but not always have fatigue and other
symptoms of hepatitis; hard liver edge if
have cirrhosis; spider naevi
Family history (autosomal recessive); acute
or subacute hepatitis in person <30 years
of age or cirrhosis in young-middle age
with neurological disorder and Kayser–
Fleischer corneal rings
With or without emphysema; family history; Low serum alpha1-antitrypsin level;
any age — present with cholestasis in Pi genotyping
children, with cirrhosis in adults
Rare autosomal recessive disorders
(several types based on which transport
protein is defective); may or may not have
had childhood liver disease or features of
cholestasis
and is not the forerunner of acute
liver injury. Conversely, a simult-
aneous increase of serum bilirubin
(particularly with jaundice) can be
associated with serious liver injury
and death in up to 10%. This com-
bination of results is used during
drug development to flag agents
with potential for serious liver tox-
icity. Any disturbance of liver syn-
thetic function (albumin, platelet
count, prothrombin time/INR) also
necessitates immediate discontinu-
ation of the suspect drug.
Symptoms vs LFT abnormalities
Another key point is that non-spe-
cific symptoms (nausea, malaise,
facial swelling) may precede liver-
related features of serious drug-
induced liver injury. It follows that
any new symptoms developing after
commencement of a new drug (or
presentation. Clinical clues can
include the family history, subtle
features of cirrhosis, unexplained
symptoms (fatigue, itch, crypto-
genic neurological symptoms), the
presence of other autoimmune dis-
orders (personal and family hist-
ory) and exclusion of the usual
explanations for the LFT changes
(alcohol, hepatitis C, NAFLD) and
other more common causes (table
4).
A standard battery of tests
(known as a ‘liver panel’) may also
be useful for unexplained liver test
abnormalities (table 5).
Specific diagnostic tests and
comments
Anti-TTG; consider referral to a
gastroenterologist
Anti-mitochondrial antibody (AMA;
use a laboratory that gives specificity
— it should be anti-M2)
Magnetic resonance cholangio­
pancreatography changes: beading,
structuring, proximal dilatation;
p-ANCA positive; must be referred
to gastroenterologist owing to
high risk of colorectal cancer and
cholangiocarcinoma
ANA >1:80; smooth muscle
antibody (SMA) >1:40; liver-kidney
microsomal antibody (LKM) — rare
type 2 AIH; high IgG; a dangerous
disorder, can occasionally be hard
to diagnose: referral is strongly
indicated
Urgent referral for acute or subacute
cases when suggestive clinical
picture; low serum ceruloplasmin
(false negative 10% cases); high
serum or urinary copper (many false
positives); elective referral for well
patients
A cause of unexplained cirrhosis in
young adults or older children and
adolescents — refer all such cases
for specialist assessment, even if
LFT abnormalities are minor
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Figure 5: Patient
with primary
biliary cirrhosis.
Confirmation
with a
positive anti-
mitochondrial
antibody test is
necessary.
Table 5: A useful ‘liver panel’ for general practice*
Test What to do if positive, and when to refer
Anti-HCV HCV RNA (PCR) — genotype if detectable;
AFP; liver ultrasound. Refer for full assessment
if patient desires this, if duration of HCV
infection >15 years, age >50
HBsAg HBV DNA, AFP, liver ultrasound if age >30
years. Refer for full assessment if patient
desires this, if age >30 and HBV DNA >10,000
IU/L (any one value); important to indicate
that treatment of HBV is highly effective at
suppressing viral replication >5 logs and
this normalises ALT, and prevents disease
progression, greatly diminishing risk of
hepatocellular carcinoma particularly before
cirrhosis develops
Fasting BSL; HbA1c; lipids Overweight patient with central obesity and
family history of diabetes or fatty liver: suspect
NAFLD and perform ultrasound. Refer for
full assessment if patient desires, if age >50,
diabetes and NAFLD, high serum ferritin, fatty
liver for >10 years, BMI >30 kg/m2
ANA, SMA, LKM; Check titres significant (see table 4) but
immunoglobulins (IgG level) otherwise refer for full assessment of possible
autoimmune hepatitis, particularly if patient
unwell.
Anti-mitochondrial antibody Refer for treatment of primary biliary cirrhosis
(M2 specificity)
FBC Macrocytosis may occur with otherwise
undisclosed alcohol dependence (but also
in cirrhosis), similarly for thrombocytopenia;
likewise recheck values for AST and GGT and
consider discussion of alcohol history with
relative/partner of patient
Serum alpha1-antitrypsin Refer if low and suspect alpha1-antitrypsin
deficiency
Serum ceruloplasmin Refer if low and suspect Wilson’s disease;
values may be low in cirrhosis
Coeliac serology Often neglected in lean patient with abnormal
LFTs: refer to gastroenterologist
*Refer all patients with clinical findings suggestive of cirrhosis
dose alteration) should be evaluated
carefully. Timely discontinuation of
the drug is important; the single
most reproducible characteristic
of fatal cases of drug-induced liver
injury is continued ingestion of the
drug after liver injury has occurred.
Patient education and supervision
by prescribing doctors is critical.
Identifying the culprit drug
The newly added drug is the most
likely offending agent. However,
changes in drug dose, inter-current
illness or co-prescription of other
drugs can precipitate drug-induced
liver injury in patients on previ-
ously well-tolerated drugs, and
the track record of known forms
of drug-induced liver injury (eg,
amoxycillin/clavulanic acid) needs
to be taken into account.
cont’d page 30
 How To Treat – Minor abnormalities of LFTs
from page 28
Temporal relationships
Response to stopping the sus-
pect drug can be useful in mak-
ing a diagnosis. Normalisation
of ALT may be expected within
three months in hepatocellular
reactions, but improvements in
LFTs can take several months with
cholestatic reactions (eg, flucloxa-
cillin or oral contraceptive-associ-
ated cholestasis).
Abnormalities in liver tests may
occur for the first time several weeks
after stopping oxy-penicillins. A
detailed drug history including over-
the-counter medication and comple-
mentary and alternative medicines
is therefore essential for someone
with unexplained LFTs. For certain
drugs, use for more than six months
does not always guarantee safety.
Examples include nitrofurantoin,
which can cause chronic hepatitis,
and minocycline, which has been
linked to drug-induced autoimmune
hepatitis.
LFT pattern
While LFT profile patterns (table
1) can be helpful in seeking cul-
prit drugs in the setting of polyp-
harmacy, ‘signature’ patterns (eg,
flucloxacillin and cholestasis, iso-
Non-alcoholic fatty liver disease
Up to 30% of Australians have
NAFLD. The entire pathological
spectrum of NAFLD, from simple
steatosis through to hepatocellular
carcinoma, may be present despite
LFTs being normal. For example,
in community-based studies using
magnetic resonance spectroscopy,
an accurate method of quantifying
liver fat, about 70% of patients
with NAFLD have normal LFTs.
There has also been debate in
the recent literature on the most
appropriate reference ranges for
serum transaminases. An ALT
>30U/L (for men) and >19U/L (for
women) is suggested as a more
accurate indicator of liver injury
than the upper limits of normal
often stated in report forms (typ-
ically 40U/L, but up to 55U/L).
Case studies
Case study 1
BERYL, a 58-year-old obese woman
with treated hypothyroidism, com-
plains of itch at night. As part of
a routine workup, the following
LFTs come to light: serum bilirubin
25μmol/L (<20), ALT 48U/L (<40),
aspartate AST 28U/L (<40), ALP
175U/L (<110), GGT 75U/L (<35),
albumin 42g/L (35-53), globulins
40g/L (25-35). Hepatic ultrasonog-
raphy shows diffusely increased
echogenicity and gallstones in the
gall bladder, but no features of cir-
rhosis or portal hypertension.
Assuming she has NAFLD, would
you send her to a dietitian and
encourage gym membership, or per-
form additional investigations (and
which ones)?
Commentary
Beryl complains of pruritus, which
is not a symptom of NAFLD, and
she has another autoimmune dis-
ease. So although the increased
30 | Australian Doctor | 11 October 2013
niazid and hepatitis) may not always
be present in so-called ‘mixed reac-
tions’, and more than one pattern
can occur with a single drug.
Specific drugs
Paracetamol
Paracetamol is the safest simple
analgesic for patients with cirrho-
sis. However, in cases where liver
injury develops with therapeutic
doses of paracetamol, drug levels
may be misleading and can delay
commencement of treatment. This
is most likely after several days of
relatively high dosing when fast-
ing (eg, in sick children), or with
excessive alcohol intake, or in
patients who have multiple serious
illnesses. Very high ALT levels (>50
times upper limit of normal) should
always prompt consideration of
paracetamol-related liver injury.
Statins
The use of statins in patients with
NAFLD, a disorder with strong
links to metabolic syndrome
and its cardiovascular outcomes,
should not be questioned. Deaths
from cardiovascular disease are
the leading cause of mortality in
patients with fatty liver. However,
initial concerns of hepatotoxicity
These revised cut-offs are based on
community values for lean adults,
and reflect levels of ALT usually
attained after successful treatment
of hepatitis C, autoimmune hepati-
tis and NAFLD. It is also salient to
note that GGT and/or ALT values
in the top quartile of the commun-
ity range are a strong predictor for
later onset of type 2 diabetes: the
link is via NAFLD.
The pathology of NAFLD mim-
ics that of alcoholic liver disease.
There is no diagnostic test that
accurately differentiates the two
conditions. Reliance on an accu-
rate alcohol history (with all its
caveats) is the only recourse.
Interpretation of LFTs
NAFLD (and NASH) cannot be
and the use of vague meaningless
terms such as ‘hepatic dysfunction’
in product information sheets have
led to underprescribing of these
drugs. Baseline ALT abnormalities
are common in patients with fatty
liver, and statin use in patients
with and without baseline abnor-
malities of liver tests has not been
associated with more frequent or
disproportionate increases in ALT
or AST, while randomised trials
have established the safety of sta-
tin use in patients with chronic
hepatitis C and NAFLD.
A rise in serum ALT or AST is
commonly observed (occurring
in 1-3% of cases) after initiation
of statin treatment, but cases of
statin-induced liver injury are
rare (<1 in a million). As a result
of accumulated evidence, the US
Food and Drug Administration
no longer mandates routine liver
function tests in statin users.
The most compelling case for sta-
tin use in patients with NAFLD is
the likelihood of harm when patients
are denied these drugs. In a post-hoc
analysis of the Greek Atorvastatin
and Coronary Heart Disease Evalu-
ation study (GREACE), there was
a 68% risk reduction in cardiovas-
cular events among patients with
excluded on the basis of normal
LFTs (see box below). On the
other hand, very high levels of
serum ALT or AST (>250U/L) are
unlikely to be due to NAFLD (or
alcohol). Seek evidence of viral or
autoimmune hepatitis, drugs (par-
acetamol) or herbal medication
use. A high serum ferritin in the
absence of increased transferrin
iron saturation is a very common
finding in patients with NAFLD.
Patients with any abnormalities of
liver synthetic function have a high
likelihood of advanced hepatic fibro-
sis. Non-invasive assessment of liver
fibrosis with transient elastography,
or liver biopsy should be considered.
Such presentations are uncommon.
As mentioned already, an AST/
ALT ratio >0.8 is another feature of
www.australiandoctor.com.au
NAFLD (defined by raised ALT) and
abnormal liver tests (10% vs 30% in
untreated patients), which was sig-
nificantly higher than the protection
conferred in those without NAFLD.
Methotrexate
Methotrexate had a vexed history of
causing cirrhosis when it was used
in high daily dose as part of cancer
chemotherapy and for psoriasis, par-
ticularly among patients who drank
alcohol to excess. In the modern
era, with methotrexate being given
under strict dose guidelines as a
once a week schedule, severe hepatic
fibrosis, including cirrhosis and its
outcomes, is now a rare complica-
tion. However, patients who have
abnormal LFTs while taking metho-
trexate require clinical assessment.
Many will have type 2 diabetes, obe-
sity and resultant NAFLD, which
appears to be a strong risk factor
for methotrexate fibrosis. In this
context, a liver biopsy used to be the
only reliable means of establishing
the safety of long-term methotrexate
therapy. Today, use of transient elas-
tography technology has virtually
replaced the need for liver biopsy
to establish presence or absence of
significant hepatic fibrosis in these
patients.
advanced hepatic fibrosis in NAFLD
and other liver diseases, but can also
occur with alcoholic hepatitis.
Increased mortality
Patients with NAFLD have about
1.7-fold increased standardised
mortality. The excess of deaths is
from cardiovascular events, com-
mon cancers, cirrhosis and hepa-
tocellular carcinoma.
Traditionally, NAFLD patients
with abnormal liver tests were
asked to undergo lifestyle changes
and everyone (including the treat-
ing physician) was satisfied if the
serum ALT normalised. However,
larger clinical studies indicate that
serum GGT, ALT and AST are not
a robust end point for therapeutic
intervention.
echogenicity on ultrasound sug-
gests steatosis, it could equally well
reflect significant hepatic fibrosis or
cirrhosis. There is a minor increase
in serum bilirubin that could also
indicate cirrhosis (table 3). Other-
wise, LFTs do not help much here
as the findings are non-specific,
although the slightly higher ALP (in
relation to other test results) could
be due to cholestasis.
Primary biliary cirrhosis should be
excluded as a cause of pruritus; it is
much more common in women than
men and is associated with autoim-
mune thyroiditis. In the case of Beryl,
a strongly positive anti-mitochon-
drial antibody test (1:2560, with
M2 specificity) confirmed the diag-
nosis of primary biliary cirrhosis,
and a transient elastography study
suggested cirrhosis was unlikely. She
was started on ursodeoxycholic acid
(15mg/kg) and six months later her
LFTs were completely normal, indi-
cont’d page 32
References
1. S chneider AL, et al. Liver
enzymes race, gender and dia-
betes risk: the Atherosclerosis
Risk in Communities (ARIC)
study. Diabetic Medicine 2013;
30:926-33.
2. B jörnsson E. Review article:
drug-induced liver injury in
clinical practice. Alimentary
Pharmacology and Therapeu-
tics 2010;32:3-13.
3. C halasani N, et al. Patients
with elevated liver enzymes
are not at higher risk for statin
hepatotoxicity. Gastroenterol-
ogy 2004;126:1287-92.
4. A thyros VG, et al. Safety and
efficacy of long-term statin
treatment for cardiovascular
events in patients with coronary
heart disease and abnormal
liver tests in the Greek Ator-
vastatin and Coronary Heart
Disease Evaluation (GREACE)
Study: a post-hoc analysis.
Lancet 2010; 376:1916-22.
Further reading
Cyproterone and cirrhosis
• Cirrhosis in a child with
hypothalamic syndrome and
central precocious puberty
treated with cyproterone
acetate. European Journal of
Pediatrics 1999; 158:367-70.
MTX
• Visser K, et al. Multinational
evidence-based
recommendations for the
use of methotrexate in
rheumatic disorders with a
focus on rheumatoid arthritis:
integrating systematic literature
research and expert opinion
of a broad international panel
of rheumatologists in the
3E Initiative. Annals of the
Rheumatic Diseases 2009;
68:1086-93.
NAFLD
• Farrell GC, Larter CZ.
Nonalcoholic fatty liver
disease:from steatosis to
cirrhosis. Hepatology 2006;
43:S99–112.
• Chitturi S, et al. Nonalcoholic
fatty liver in Asia: Firmly
entrenched and rapidly
gaining ground. Journal
of Gastroenterology and
Hepatology 2011; 26:163-72.
• Kowdley KV, et al. Serum ferritin
is an independent predictor
of histologic severity and
advanced fibrosis in patients
with nonalcoholic fatty liver
disease. Hepatology 2012;
55:77-85.
 How To Treat – Minor abnormalities of LFTs
from page 30
cating an excellent prognosis.
Case study 2
Richard is a 74-year-old man who
has a history of prostate cancer that
was treated with radiotherapy and
cyproterone acetate 12 years ago.
He now complains of non-specific
abdominal pain. You find a hard
liver edge during examination of
the abdomen. He had developed
prolonged jaundice while taking
cyproterone acetate and it was dis-
continued.
The following LFTs are obtained:
serum bilirubin 15 μmol (<20), ALT
28U/L (<40), AST 18U/L (<40), ALP
275U/L (<110), GGT 25U/L (<35),
albumin 42g/L (35-53) and globu-
lins 30g/L (25-35). Which one or
more of the following investigations
is/are strongly indicated: bone scan,
PSA, abdominal (liver) ultrasound,
iron studies, and hepatitis serology?
Commentary
Richard has normal liver tests but
a raised ALP. With his history of
prostate cancer, PSA and a bone
scan are strongly indicated as the
alkaline phosphatase may be of
bony origin, not liver. In addition,
however, the finding of a hard liver
Key issues about cirrhosis
Making an early diagnosis of cirrhosis is essential
Conclusion
IN the present age of excellent diag-
This allows important complications like bleeding oesophageal varices,
nostic tests for the common forms
hepatocellular carcinoma, muscle wasting/malnutrition and fractures to be
of chronic viral hepatitis (hepatitis
prevented or ameliorated
B and C), LFTs play a lesser role in
LFTs may be normal in cirrhosis of any cause diagnosis, although subtle changes,
Two cardinal signs of cirrhosis are often present on physical examination: a together with astute clinical assess-
hard liver edge and spider naevi ment, platelet count and AFP allow
doctors to diagnosis cirrhosis at an
The platelet count is the hepatologists most reliable ‘liver function test’
early stage. This is very important to
(table 3)
prevent variceal bleeding, advanced
A slightly raised serum alpha-fetoprotein (AFP) is common: AFP is under- (untreatable) cases of hepatocellular
utilized as a “cirrhosis screen” in general practice carcinoma and metabolic bone dis-
High quality CT or ultrasound may provide diagnostic information such as ease.
dilated portal vein, nodular liver outline, splenomegaly, varices, thickened In overweight patients and those
gallbladder wall with a family history of diabetes,
Increased echogenicity may be due to fibrosis and is often confused with fatty even minor changes in GGT and
liver (which also often shows posterior attenuation of the ultrasound shadow ALT are an important pointer to invasive and the logistics daunting
and blurring of hepatic vessels) future metabolic disease (includ- for the size of the affected popu-
ing cardiovascular events and com- lation. Meanwhile, transient elas-
Any suspicion of cirrhosis is an indication for specialist referral to expedite
mon obesity-related cancers). This is tography is proving useful for the
definitive assessments, such as transient elastography or liver biopsy
the ideal time to diagnosis NAFLD detection of advanced fibrosis in
and institute the lifestyle changes this setting, as in hepatitis B and C.
edge most likely indicates cirrhosis liver damage caused by cyproter- (increased physical activity, modest Very few cases of liver disease in a
and an abdominal ultrasound or one acetate. weight reduction) needed to pre- general practice setting will not be
CT scan would be useful to estab- He was then found to have vent premature mortality from these attributable to NAFLD, alcohol,
lish if there is any other evidence portal hypertension with large common problems. HBV or HCV, and while autoanti-
of cirrhosis, and to completely oesophageal varices on CT scan It is possible in the future that bodies and more specialised meta-
exclude hepatic malignancy. and gastroscopy. new biomarkers of liver injury, bolic tests are widely available, it
Richard was found to have cir- These have now been banded inflammation and fibrosis may may be appropriate to refer such
rhosis, in this case as a late com- endoscopically, thereby preventing be introduced for assessment of atypical cases for a specialist opin-
plication of severe drug-induced any likelihood of variceal bleeding. NAFLD cases, as liver biopsy is ion.

Instructions

How to Treat Quiz
Minor abnormalities of LFTs
— 11 October 2013
1. Which TWO statements are correct
regarding minor abnormalities of LFTs?
a) Less than 1% of apparently healthy
individuals have minor abnormalities of LFTs
b) LFTs are considered to be relatively minor if
the value is lower than a threefold increase
above the normal range
c) Most commonly, minor abnormalities in LFTs
are associated with non-alcoholic fatty liver
disease (NAFLD)
d) The severity of abnormalities in the LFTs
correlates with the degree of end-stage liver
disease
2. Which TWO statements are correct
regarding the interpretation of individual
LFT indices?
a) It is impossible to tell whether a raised ALP is
coming from the liver or the bone
b) Serum albumin concentration does not
simply reflect hepatic synthetic function
c) ALT arises from muscle, lung, brain and other
tissues as well as liver, whereas AST is liver-
specific
d) GGT arises uniquely from the liver
3. W
 hich THREE of the following patterns of
abnormalities in LFTs may correspond to
associated non-hepatic causes?
a) M
 inor elevation of GGT alone is a risk factor for
subsequent onset of type 2 diabetes
b) An isolated rise in serum bilirubin may suggest
the presence of a massive haematoma
c) A
 n isolated rise in ALP may suggest underlying
cardiac failure
Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points.
We no longer accept quizzes by post or fax.
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d) Low serum albumin is a reflection of
malnutrition only
4. Which THREE additional test abnormalities
can help identify an unrecognised cirrhosis
when LFT abnormalities are minor?
a) Low INR reflecting impaired synthetic function
b) Thrombocytopenia, reflecting reduced
thrombopoeitin synthesis
c) A progressive rise in alpha-fetoprotein (AFP)
corresponding to the progression of cirrhosis
to hepatocellular carcinoma
d) Posterior attenuation of the ultrasound
shadow and blurring of hepatic vessels on liver
ultrasound
5. Which THREE statements are correct
regarding minor abnormalities of LFTs in
patients suspected to have uncommon liver
conditions?
a) Coeliac disease should be excluded in lean
patients with minor abnormalities of LFTs
b) A cholestatic picture in patients with
inflammatory bowel disease may indicate
primary sclerosing cholangitis
c) Ceruloplasmin may be falsely negative in 10%
of Wilson’s disease
d) A hepatocellular pattern in a suspected
individual may prompt exclusion of primary
biliary cirrhosis
6. Which TWO statements are correct
regarding LFTs in drug-induced liver
damage?
a) A rise in transaminases after initiating statins
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www.australiandoctor.com.au/education/how-to-treat
occurs frequently in >35% of patients
b) Very high ALT levels (>50 times upper
limit of normal) should always prompt
consideration of paracetamol-related liver
injury
c) A complete resolution of LFT abnormalities
occurs within six weeks of stopping
fluxcloxacillin in cases of flucloxacillin-
induced liver injury
d) Despite safer prescribing guidelines,
patients on methotrexate with abnormal
LFTs require further assessment
7. Which TWO statements are correct
regarding LFTs in NAFLD?
a) An ALT >30U/L for men and >19U/L for
women may be a more accurate indicator of
liver injury than the current given ranges
b) High normal GGT and/or ALT levels may
reflect NAFLD that predicts the development
of type 2 diabetes in the future
c) Very high levels of serum ALT or AST
(>250U/L) are most likely due to NAFLD
d) An AST:ALT ratio of 1:3 suggests that the
LFT abnormalities are due to NAFLD, not
alcoholic liver disease
8. Agnes is a 57-year-old woman with
chronic HBV infection. Which TWO
statements are correct regarding her
diagnosis and presentation?
a) An assessment for cirrhosis is not
necessary at her age
b) She should inform all her doctors of her
hepatitis B status
c) A normal physical examination and
normal ALT level precludes any further
management
d) A n assessment of her metabolic risk factors
should be made
9. A gnes has a BMI of 31 and has minor
LFT abnormalities. Which TWO
statements are correct regarding her
assessment and investigations?
a) An AST:ALT ratio >0.80 is both a sensitive
and specific screening test for underlying
cirrhosis
b) W here LFT abnormalities may be either
due to fatty liver or hepatitis B virus (HBV),
HBV DNA levels and ultrasound may help
elucidate the diagnosis
c) Spider naevi are the most sensitive and
specific sign of cirrhosis
d) W ith minor abnormalities, HBV DNA levels
are not required
10. Which TWO statements are correct
regarding Agnes’ prognosis and ongoing
management?
a) If her HBV DNA level is >10,000 IU/mL,
antiviral therapy may be indicated
b) A >10-fold increase in AFP over the normal
range should prompt further investigations
c) The level of HBV replication is not a good
predictor of subsequent cirrhosis or
hepatocellular carcinoma
d) Agnes should not be given a statin because
her risk of hepatotoxicity is higher than her
risk from metabolic syndrome

CPD QUIZ UPDATE

The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2011-13 triennium.
You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept how to treat Editor: Dr Steve Liang
the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. Email: steve.liang@cirrusmedia.com.au

Next week Anosmia and parosmia are conditions that are commonly caused by sinonasal disease, primarily rhinitis and rhinosinusitis. Such olfactory disturbance is often associated with age and is
usually classed as either a conductive (odorant delivery) or receptive (chemosensation) condition. The next How to Treat investigates the aetiology, assessment and treatment of these olfactory conditions.
The authors are Associate Professor Richard Harvey, program head and conjoint associate professor, rhinology and skull base surgery, University of NSW and St Vincent’s Hospital, Darlinghurst, and
clinical associate professor, Macquarie University, North Ryde; and Dr Pascal Bou-Haider, neuroradiologist, St Vincent’s Hospital, Darlinghurst, NSW.

32 | Australian Doctor | 11 October 2013 www.australiandoctor.com.au