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inside
What are LFTs?
Diagnostic
patterns of
LFT changes
LFTs and
investigation of
liver disease
Five common
LFT challenges

The authors

PROFESSOR GEOFF FARRELL,

professor of hepatic medicine,
Australian National University
Medical School, and
gastroenterology and
hepatology unit, The Canberra
Hospital, Garran, ACT.

Abnormal liver
function tests

ASSOCIATE PROFESSOR
NARCI TEOH,
associate professor of
medicine, Australian National
University Medical School,
and gastroenterology and
hepatology unit, The Canberra
Hospital, Garran, ACT.

Background
CONTEMPORARY practitioners
are well versed in how to manage
symptomatic patients with diagnostic patterns of liver biochemical
tests, such as those that suggest hepatitis, biliary obstruction or medical
cholestasis, or hepatic malignancy.
More challenging are the everyday

encounters with non-specific and

non-spectacular changes in LFTs,
often performed for health screening or miscellaneous reasons and in
people who are overtly well.
This article discusses some typical scenarios for reflection on what
doctors need to think about and do

next, interspersed with some general

comments on the significance of
abnormal LFTs for people taking
medications, the overweight, those
living with hepatitis B or C virus
infections, and those who may have
cirrhosis.
contd next page

Remember Pneumococcal
Vaccination This Year
Reference: 1. NHMRC The Australian
Immunisation Handbook. 9th Edition 2008,
Chapter 3.15. CSL Biotherapies Pty Ltd
ABN 66 120 398 067, 45 Poplar Road,
Parkville, 3052. 8180B AD

5 year pneumococcal vaccination boosters are due

for anyone rst vaccinated in 2005.1

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9 April 2010 | Australian Doctor |

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HOW TO TREAT Abnormal liver function tests

Five common LFT challenges

all normal). He has gained
10kg in weight since his
second marriage 18 months
ago. What further investigations might be useful,
and how would you treat
him?

BEFORE reading on, GPs

are invited to consider the
following cases in light of
their current knowledge.

Case 1
AF is a 24-year-old son of a
family friend who recently
returned from Mexico. He
complains of profound
malaise for 10 days, with
intermittent vomiting and
dark urine. He completed a
four-week course of doxycycline two weeks ago, taken
for recurrence of acne.
He had combined hepatitis A and B vaccination
before travel, and has antibodies to both hepatitis A
(total, not IgM) and hepatitis
B (anti-HBs alone). His
bilirubin level is 25mmol/L
(normal range <20), AST
5800 U/L (normal range
<40), ALT 4600 U/L (normal
<40), with albumin, total
protein and alkaline phosphatase normal. What are the
possible diagnoses, and does
he need urgent referral?

Case 3

Case 2
BL, a 45-year-old successful car dealer, presents with
a letter from an insurance
company indicating he has
been refused an incomeprotection policy because of
abnormal LFTs (ALT 70
U/L; GGT 90 U/L [normal
range <50]; bilirubin, albumin, alkaline phosphatase

NO, a 55-year-old executive

assistant to a government
minister, was diagnosed with
chronic hepatis C virus (HCV)
infection in 1992. When
reviewed from time to time,
LFTs have been normal and
she became lost to follow-up.
On presenting for a muchdelayed Pap smear, NOs GP
persuades her to have repeat
LFT testing, and also orders
an AST test. The results show
bilirubin 25mmol/L, ALT 60
U/L, AST 80 U/L, GGT 250
U/L, albumin 34g/L (normal
range 35-53). What could be
going on here? How would
you approach the situation
with NO, who is far from
enchanted with the medical
model?

Case 4
VW, a 32-year-old IT consultant who emigrated from
Burma in 1998, has known
since student days that, like
several other family members, he is hepatitis B positive. He has always assumed
he is healthy because only
two of three tests are positive (HBsAg positive, antiHBc positive, HBeAg negative). You confirm this
serological picture, and antiHCV is not detectable. LFTs
appear satisfactory, with
ALT 38 U/L. Is this normal?
How would you test
whether he is indeed a
healthy carrier?

Case 5
DT, a 56-year-old retired
submariner, has had three
drinks a day for the past five
years but drank more heavily during his time in the
Navy. He has type 2 diabetes
(HbA1C 6.8%), easy-to-control hypercholesterolaemia
and hypertension, without a

recent change in medication.

As his new GP, now that
he has moved to a rural
area, you find he is mildly
anaemic (Hb 11.5g/L) with
iron deficiency, and a platelet
9
count of 120 10 /L
(normal range 150-400
9
10 /L). ALT was 30 U/L,
AST 50 U/L, bilirubin
normal, albumin 32g/L,
normal alkaline phosphatase; alfa-fetoprotein 3
kU/mL (normal range <12).
Abdominal CT is normal
apart from possible early
portal hypertension.
You send him to a city
gastroenterologist, who performs gastroscopy and
colonoscopy. Finding no
abnormality other than gastric erosions, which he
attributes to aspirin use, the
gastroenterologist sends DT
back to you, indicating he
would be happy to see him
again if hepatic synthetic
function deteriorates. How
should you manage this
patient?

What are LFTs?

LIVER function tests is a timehonoured term for tests performed
in clinical chemistry laboratories
when one is considering or wants to
exclude liver or biliary disease.
However, LFTs is a misnomer, as
few of the individual tests are specific for the liver, and most do
not truly reflect liver function
(though several do indicate disease)
(table 1).
For example, serum bilirubin
level may be elevated for diverse
reasons (table 2). Importantly, even
minor increases in serum bilirubin
accurately reflect impaired liver
function in the presence of cirrhosis,
and bilirubin is a key prognostic
factor in chronic cholestasis with
cirrhosis, such as primary biliary
cirrhosis. Likewise, serum albumin
concentration may be low for a
variety of reasons (table 3).

Utility of AST (as well as ALT)

Most auto-analysers perform ALT
assays when LFTs are ordered,
and this is the most sensitive and
specific test for hepatocyte injury.
However, it can be very useful to
order AST as well when one suspects alcoholic liver disease or cirrhosis (any cause).

Table 1: Causes of elevated liver enzymes

Pattern
Hepatocellular pattern
ALT more than five times the
upper limit of normal (ULN)
GGT raised
Alkaline phosphatase less
than twice the ULN

Cholestatic pattern
Alkaline phosphatase more
than twice the ULN
GGT raised more than five
times the ULN
ALT less than five times
the ULN

Possible causes

Table 2: Different reasons for elevated serum bilirubin

concentration
A. Not liver disease (other LFTs normal)

Acute viral hepatitis

(A,B,C,E in travellers)
Drug-induced liver injury
Chronic hepatitis B or C
Alcoholic hepatitis (remember to order
an AST test see text)
Non-alcoholic fatty liver disease (NAFLD)
and non-alcoholic steatohepatitis (NASH)
Autoimmune hepatitis
Rarer causes
CMV or EBV hepatitis; Wilsons disease
(children, young adults); alfa-1-antitrypsin
deficiency
NB: Haemochromatosis alone rarely
causes abnormal LFTs consider alcohol
and NAFLD (diabetes) in C282Y
homozygotes with abnormal biochemistry

Biliary obstruction:
Choledocholithiasis
Pancreatic cancer
Cholangiocarcinoma
Medical:
Drug-induced liver injury
Primary biliary cirrhosis
Primary sclerosing cholangitis
Neoplastic infiltration of liver
Sarcoidosis

Haemolytic anaemia (eg, spherocytosis)

Gilberts syndrome
Cardiac failure
Severe bacterial infection and critically ill patients (pneumonia, Gramnegative septicaemia, ICU jaundice)
B. Hepatobiliary disease
Hepatitis acute or chronic, any cause (ALT typically elevated > fivefold,
except with alcoholic liver disease)
Cholestasis biliary obstruction or medical causes (alkaline phosphatase
and GGT substantially elevated, ALT less so)
Cirrhosis the only condition in which level of bilirubin reflects liver
function (minor changes may be important)

Table 3: Common causes of low serum albumin

Impaired synthesis due to poor nutrition (lack of amino acid building blocks)
Enhanced breakdown (cachexia of malignancy, HIV, etc)
Haemodilution (second trimester of pregnancy, venous blood taken from
drip arm)
Protein loss (nephrotic syndrome, protein-losing enteropathy)
Cirrhosis even borderline low values may be significant

In both cases, the usual ALT:AST

ratio of >2 is lost; instead, it falls to
0.8. An ALT:AST ratio of 0.8 has
relatively poor sensitivity but high
specificity for cirrhosis. Some

hepatic drug reactions also feature

disproportionate increases in AST
as well as ALT levels, as does
Wilsons disease in children and
young adults.

Diagnostic patterns of LFT changes

Hepatitis
MAJOR elevations of ALT
(more than fivefold) indicate
hepatitis, which in the community is usually viral:
Hepatitis A, B or C.
Hepatitis E after travel to
endemic regions (Mexico,
south-east and south Asia,
western China).
In young people, occasionally EpsteinBarr virus, with
other features of infectious
mononucleosis, or cytomegalovirus.

30

| Australian Doctor | 9 April 2010

However, up to 10% of
cases may be due to drugs.
These include those prescribed
by doctors (or alternative
medicine practitioners) within
the previous 6-12 weeks in the
case of adverse drug reactions,
but occasionally inadvertent
or deliberate paracetamol poisoning, or the use of recreational agents, such as ecstasy.
Hepatotoxicity due to drug
overdose and adverse drug
reactions are more frequent
causes of abnormal LFTs in

hospital inpatients (figure 1A).

Major elevations of ALT,
often with jaundice and
reduced serum albumin level,
are also found with autoimmune hepatitis. Note that the
older term chronic active hepatitis is no longer used by
hepatologists because 25% of
cases present acutely. The
diagnosis and treatment of this
condition rest on recognising
the autoimmune pathogenesis
(association with family or
personal history of autoim-

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mune conditions, autoantibodies, high serum IgG).

When suspected, phone consultation with a specialist is recommended, as treatment with
prednisone and azathioprine
needs to be instituted promptly
in severe cases while awaiting
formal review by the hepatologist as soon as possible.

Cholestasis
The other classic pattern of
LFT abnormalities is
cholestasis, when serum alka-

line phosphatase is elevated

more than twofold in association with major elevation of
GGT.
Practitioners
should
remember that cholestasis is
not only due to biliary
obstruction
(so-called
obstructive jaundice), but is
often attributable to non-surgical conditions, especially
drug reactions (figure 1B). It
may also:
Occur in pregnancy
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HOW TO TREAT Abnormal liver function tests

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(cholestasis of pregnancy).
Complicate viral hepatitis.
Reflect other autoimmune
liver diseases, such as primary biliary cirrhosis, sclerosing cholangitis and atypical cases of autoimmune
hepatitis.
Jaundice and bilirubinuria
(reflecting conjugated hyperbilirubinaemia) is often present with cholestasis, but not
always, depending on the
severity of impaired bile flow
or extent of biliary obstruction.
One feature of the cholestatic pattern of LFTs that often
confuses doctors is the concomitant elevation of ALT;
this often occurs with
cholestasis because bile-acid
accumulation in the liver is
hepatotoxic. The resultant
mixed picture is not particularly helpful diagnostically,
except that it is rather
common with hepatic drug
reactions.
In a patient with biliary
pain or acute pancreatitis,
ALT elevation is more indicative of gallstone disease than
concomitant liver disease.
However, the latter is possible
when there is cholestasis with
coincident non-alcoholic fatty
liver disease (NAFLD)
especially with type 2 diabetes
or alcoholic liver disease.
The more severe and acute
the biliary obstruction, the
higher the ALT level. Values
exceeding 500 IU/L are occasionally seen the day after
complete biliary obstruction,
and such patients must be
referred urgently for ultrasonography and gastroenterological intervention to relieve
the obstruction.

Figure 1: Drug reactions are a relatively common and important cause of abnormal LFTs in general
practice, or in hospital settings. Patterns of LFT changes may resemble viral hepatitis.
A: A case of enalapril hepatitis liver cell injury with lobular and portal-tract inflammation are
evident, the latter including neutrophils and eosinophils; ALT peaked at 800 U/L;) or cholestasis
B: Terbinafine hepatitis there is no portal tract oedema or inflammation to suggest biliary
obstruction. Instead bile plugs are evident (orange pigment collectors) and there is feathery
degeneration of liver cells containing bile pigment. The patient presented with elevation of serum
alkaline phosphatase, thought to be due to biliary obstruction.

Table 4: What does a raised serum GGT level mean?

More than any other liver biochemical test, GGT needs to be
considered in context of the clinical problem and the results of
other LFTs

GGT level increases with any pattern of hepatobiliary disease

(hepatitis, cholestasis, infiltration, cirrhosis)

For increases in serum alkaline phosphatase level,

concomitant elevation of GGT level indicates alkaline
phosphatase is of liver origin, not bone origin as in disorders
such as Pagets disease or metastases

Changes in GGT level are one of the few biochemical markers

of excessive alcohol intake: useful when monitoring patients
attempting alcohol abstinence

Isolated elevated GGT level may occur in NAFLD, but usually

with ALT abnormalities, fluctuating with weight changes, and
other results (lipids, blood glucose)

Isolated elevated GGT level may be explained by drug therapy,

particularly anticonvulsants

In a well person with normal hepatic/abdominal imaging,

isolated elevation of GGT level is sometimes never explained
(and should then be ignored)

The distractions of GGT

elevation
ple, the value of raised GGT
in supporting a diagnosis of
cholestasis was mentioned
above.
GGT is located on the surface (outer plasma membrane)

Among currently used LFTs,

the one that causes doctors the
most confusion is the GGT. In
some ways it is the least useful
single test, but it is invaluable
in niche contexts. For exam-

of hepatocytes, and so is readily shed into blood when:

Hepatocellular
injury
occurs.
Synthesis is stimulated.
Bile-acid levels rise (bile

acids may cleave GGT from

the plasma membrane by
their detergent effects).
Thus, serum GGT levels
increase no matter what the
pathophysiological type of
hepatobiliary
disease,
whether it be hepatitis or
cholestasis (most causes,
although not in pregnancy).
In addition, unsafe levels of
alcohol intake and a wide
range of drugs increase GGT
levels by acting as enzymeinducing agents that stimulate
its synthesis and release from
the liver.
Changes in GGT are one of
the few biochemical markers
of alcohol dependence.
Improvement during abstinence, or exacerbation with
recidivism, is useful when
monitoring patients in general
practice. In dealing with this
common problem, blood test
results such as GGT can
sometimes serves as a focus
for discussion about progress
and unfinished business.
Another attribute in
favour of GGT testing is its
sensitivity as an indicator of
hepatic infiltration. Along
with serum alkaline phos-

phatase, increases are a relatively sensitive marker for

hepatic malignancy, or disorders such as sarcoidosis.
But in the 21st century, a rise
in GGT level typically, but
not always in association
with minor ALT elevation,
is most often indicative of
fatty liver disease, as discussed later.
In summary, more than any
other liver biochemical test,
GGT needs to be considered
in the context of the clinical
problem and the results of
other LFTs (table 4).
We have been known to
recommend to occasional
worried well individuals to
discontinue measuring their
repeatedly abnormal GGT
when it is an isolated abnormality. However, such
people must:
Be asymptomatic.
Not be alcohol dependent.
Have a healthy lifestyle
(exercise, food portions,
diet).
Have normal waist circumference.
Have repeatedly normal
appearances on hepatic
ultrasound (or CT).

Other assessments
Physical signs
Cardinal physical signs of cirrhosis
include:
Hard liver edge.
Spider naevi.
Splenomegaly and other signs of
portal hypertension.
Ascites.
Muscle wasting.
Subclinical hepatic encephalopathy
(neuro-psychiatric and neuro-physiological deficits but with a normal
mental and neurological status on
global clinical examination).

Other liver tests

After clinical examination, hepatologists wondering whether a patient
may have cirrhosis pay as much
attention to tests that are not part
of routine LFTs (plus AST) as they
do to serum bilirubin and albumin
concentrations. Key additional
liver tests include:
Platelet count.
Prothrombin time (PT) or INR.

32

| Australian Doctor | 9 April 2010

chronic hepatitis C or NAFLD, even

borderline thrombocytopenia is a
fairly accurate indicator of stage 3
(bridging) fibrosis or cirrhosis (stage 4
fibrosis).
The traditional explanation for this
and the sometimes accompanying
leucopenia is hypersplenism secondary to portal hypertension. Decreased
platelet survival is likely to play a role,
but more important is reduced blood
levels of thrombopoietin, a protein
that regulates platelet synthesis and
release and whose synthesis is
decreased in the cirrhotic liver. The
readily available platelet count has
become the hepatologists surrogate
liver function test.

In ill patients, serum creatinine and

serum sodium.
Platelet count

As a matter of course, patients suspected or known to have chronic liver

disease will be ordered an FBC as
well as LFTs. Anaemia is an important complication of portal hypertension, most often from iron deficiency
caused by chronic blood loss due to
portal hypertensive gastropathy, but
occasionally from more substantial
bleeding from the same lesions, a
peptic ulcer or oesophago-gastric
varices. Leucocytosis may indicate
bacterial infection, alcoholic hepatitis
or hepatocellular carcinoma.
However, gastroenterologists and
hepatologists are most concerned
with checking for thrombocytopenia.
Circulating levels of platelets fall as
fibrotic liver disease progresses,
almost linearly in relation to fibrotic
severity. In a patient with what might
otherwise seem like run of the mill
www.australiandoctor.com.au

tion early enough to consider transfer

to a liver transplantation unit (which
should be consulted when such a
patient is under observation).
Serum creatinine and sodium

These indices are very valuable in

considering the prognosis for patients
with decompensated cirrhosis. For
example, creatinine is now part of
the Method for assessment of Endstage Liver Disease (MELD) score
used to determine the priority for
organ allocation in Australia/New
Zealand, and all international liver
transplantation programs. This specialised aspect will not be discussed
further here.

PT and INR

Serum bile acids

Impaired synthesis of clotting facIn

acute hepatitis, paracetamol hepatotoxicity and other instances of clinically significant liver injury, daily
monitoring of PT or INR is essential
to detect hepatic functional deteriora-

Specialists sometimes use two other

tests as supportive evidence when
assessing particular patterns of liver
test abnormalities.
The first is measurement of serum
bile acid levels. This test is rarely

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Use of LFTs for monitoring drug safety

Figure 2: Hepatocellular carcinoma complicates cirrhosis. It is usually incurable

when >5cm in diameter and when presenting with symptoms. Screening by
six-month ultrasound and alpha fetoprotein is an important aspect of
preventive medicine for the patient with cirrhosis, along with varices and bone
health.

performed these days, and needs to

be sent to reference laboratories.
Its value is to confirm cholestasis
in contexts where other evidence is
ambiguous. With the advent of
more sophisticated ways to image
the liver, biliary tract and pancreas,
this is rarely required, but fasting
serum bile acid levels may be useful
for monitoring early onset of
cholestasis of pregnancy in a
woman at high risk (because of a
previous episode).

Serum alphafetoprotein
The second test is serum alpha-fetoprotein (AFP), an oncofetal protein
whose serum levels rise during pregnancy, with hepatocellular carcinoma (HCC) (figure 2) and rare
sarcomas. However, in a patient
suspected of having chronic liver
disease, a minor rise in AFP is often
found with cirrhosis, minor being

A large number of drugs has been associated with drug-induced liver injury.
However, there are only a few instances
in which monitoring with LFTs is recommended (other than in package inserts
for these agents).
For most agents, evidence supporting
efficacy of LFT screening to prevent the
onset of severe hepatotoxicity is completely lacking. Symptoms are more
important than LFT changes for early
detection of adverse drug reactions.
Thus, patients should be advised to
report even non-specific symptoms such
as malaise, nausea, dyspepsia, facial discomfort and fever.
For truly problematic agents isoniazid remains at the top of the list, with a
risk of serious liver injury of about 1%,
depending on age LFTs should be
measured to ensure practitioners discuss
openly with patients the risk of liver
injury and the need to report onset of
new symptoms. Only in this way will the
continuing instances of acute liver failure
referred for liver transplantation be
avoided.
Agents in which LFT monitoring is
recommended are listed in table 5. It is
sometimes neglected with methotrexate
use, and although the importance of
methotrexate as a cause of cirrhosis is
much reduced with use of contemporary
safe doses (up to 25mg/week as a single
dose), LFT measurement on a quarterly
basis is advisable to monitor patients at
higher risk.
Note that the list in table 5 does not
include the statins. These incredibly
important agents (to prevent cardiac
events, and possibly reduce risk of
dementia) have garnered a reputation as
hepatotoxins that is totally undeserved.
The evidence against statins being an
important cause of liver disease is summarised in table 6. They must be prescribed when they are indicated.

10-50 kU/mL (normal range <12).

Higher values are more suggestive
of primary liver cancer. Hepatic
imaging (CT) should therefore
always be performed before concluding that a raised AFP is due to
uncomplicated cirrhosis.

Imaging
When LFTs are abnormal, other
tests are used to diagnose the cause
and severity of liver disease. GPs
can perform hepatitis serology, and
judicious hepatic imaging (ultrasonography if they suspect biliary
obstruction or fatty change, CT
scan if they suspect malignancy).
Patients with cholestasis or severe
hepatitis should usually be referred
for urgent specific diagnosis and
treatment. The timing and prereferral workup depend on individual clinical and social contexts (see
case study discussions below).

Table 5: Medications for which

regular LFT monitoring is
recommended
Isoniazid
Methotrexate
Synthetic retinoids
Ketoconazole
Terbinafine (see figure 1B)
Certain anticancer drugs
Prolonged therapy with minocycline

Table 6: The undeserved

reputation of statins as
hepatotoxins
On the evidence of hundreds of
thousands of cases:
Fewer than 5% of people taking statins
develop LFT changes
These are nearly always minor and
resolve spontaneously, even during
drug continuation
Severe drug-induced liver injury from
statins is exceedingly rare
Patients with abnormal LFTs are no
more likely to develop significant liver
injury while on statins, and so
LFT monitoring is not warranted
Most patients taking statins have
metabolic syndrome, and are therefore
at high risk of NAFLD, itself a very
common cause of ALT abnormality

Five common LFT challenges revisited

Hepatitis usually but
not always
straightforward
Case 1 revisited

AF has some form of acute

hepatitis. Possible diagnoses
include viral hepatitis, druginduced liver injury, autoimmune hepatitis and Wilsons
disease (because he is only
24 years old).
Hepatitis A and B are
unlikely if recommended
immunisation schedules
were completed, but hepatitis C still needs to be
excluded. If risk factors for
HCV are present (injecting
drug use or recent sexual
exposure [with someone
who could have had acute
hepatitis C]), perform PCR
for HCV RNA even with a
negative anti-HCV.
The travel history is
important here, and negative
tests for hepatitis A, B and C
should prompt ordering of a
hepatitis E test. Mexico is a
high-risk country for this
waterborne virus, which
causes severe acute hepatitis.
Hepatitis E antibody tests
need to be sent to a reference laboratory.
Cytomegalovirus and
EpsteinBarr virus can cause

Figure 3: Just as for every patient with metabolic and

cardiovascular problems, those with abnormal LFTs should
have proper anthropometric assessment by their doctor,
including measurement of waist circumference as well as BMI.
As in the older Australian male below, central obesity (>94cm in
men, >80cm in women) is nearly always present in those with
non-alcoholic fatty liver disease, even without obesity.

hepatitis in young adults;

other clinical and laboratory
features of infectious
mononucleosis are usually

evident sore throat,

headache, monocytosis.
Tetracyclines are a relatively common cause of
drug-induced liver injury in
todays society. The absolute
risk is low (<1 per 100,000
exposed), but these agents
are often prescribed in
repeated or prolonged
courses. This seemed the
most likely diagnosis in AFs
case, as he recovered rapidly
and was anti-HEV negative.
However, it was also
important to exclude
autoimmune hepatitis, which
can present acutely. Antinuclear (ANA), smooth muscle,
and liver/kidney microsomal
antibodies were all negative
in this case. ANA may be
positive with tetracycline
hepatitis.
Should AF be referred
urgently? It is often helpful
to discuss such a case by
phone with a specialist colleague. If the PT is normal
and the patient is reasonably
comfortable, hospital admission is not required.
Repeated vomiting or any
suggestion of clouding of
consciousness are reasons for
urgent referral, as they may
indicate impending acute

www.australiandoctor.com.au

liver failure; likewise, any

abnormality of PT/INR.
Failure of other symptoms
and ALT to settle over 1-2
weeks should prompt the GP
to refer for specialist investigation and treatment.

Fatty liver disease so

common and so treatable
Case 2 revisited

With his recent change in life

circumstances, increasingly
sedentary occupation and
age, BL is now over-nourished. Careful doctors will
perform BMI and waist circumference measurements
on a large proportion of
their patients (many of
whom are overweight but
not huge) (figure 3).
BL is now motivated by
his rejection by the insurance
company and his personal
need to provide security for
his new family. So this is a
great time to intervene for
someone with over-nutrition.
Most likely his minor LFT
abnormalities are due to
NAFLD. The more severe
form of this condition is
pathologically similar to
alcoholic hepatitis and is
termed NASH.
However, first we need to

exclude alcohol as a cause

with a reliable history, supported by absence of biomarkers such as a disproportionately high GGT level
or macrocytosis on the
blood film.
He may also have
acquired HCV or HBV from
earlier behaviours (IV drug
use, sexual exposure), about
which the GP should judiciously enquire before ordering hepatitis B and C serology. Assuming this history is
negative, it is important to
go straight to the nitty
gritty and look for evidence
of the metabolic abnormalities so strongly associated
with NAFLD/NASH, and
look for steatosis by hepatic
imaging. Ultrasound is
appropriate for this, as it is
reasonably sensitive for more
severe forms of NAFLD
(figure 4).
The metabolic abnormalities associated with fatty
liver include:
Serum lipids (low HDL,
high LDL, hypertriglyceridaemia).
Fasting hyperglycaemia.
Abnormal glucose tolerance test (this should be
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HOW TO TREAT Abnormal liver function tests

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performed if fasting blood

glucose level is 5.6mmol/L).
Hypertension may also be
present.
The metabolic syndrome
per se requires lifestyle intervention, with or without a
fatty liver. In BLs case, a
family history of diabetes
and its complications in his
maternal grandmother and
two aunts might be compelling reasons to reduce
food portions, adopt a heart
healthy or diabetic diet, and
engage in 20-30 minutes of
aerobic exercise on a daily
basis (using a pedometer
might help with motivation
and objective measurement).
If serum cholesterol is elevated and there is a strong
family history of CVD there
is a strong indication to prescribe a statin. Presence of
minor LFT abnormalities is
far from a contraindication
(table 6) it is almost an
indication! Nonetheless,
LFTs are useful biomarkers
to monitor BLs progress with
his metabolic challenges.
Modest weight reduction
with normalisation of waist
circumference (<95 cm)
should greatly improve his
LFTs, while resuming an
exercise program may also
contribute to blood pressure
and glycaemic control.

Hepatitis C what has

changed?

Figure 4: Use of hepatic ultrasonography to detect fatty liver disease. This illustration shows not only increased echogenicity anteriorly
(towards top of figure) as appreciated by the snow storm appearance, but also deep attenuation of the ultrasound signal posteriorly
(because so much signal is reflected, none remains to penetrate that far) and blurring of hepatic vessels.

Liver/kidney contrast

Deep attenuation
Hepatic imaging (ultrasound or CT).
Irrespective of whether a
reliable alcohol history is
obtained, referral to a specialist or liver clinic is
strongly advisable here
because NO is no longer on
a smooth course; whatever
has changed, she is now very
likely to have, or be developing, cirrhosis. Further, the
challenges of discontinuing
alcohol and considering hepatitis C antiviral therapy
before it is too late need to
be tackled.

Case 3 revisited

We need to know how long

NO has had chronic HCV
infection, most likely since
she was a teenager experimenting with drugs (ie, >35
years). The presence of
normal LFTs during the last
decade would generally indicate less active hepatitis and
lower risk of developing
fibrotic liver disease leading
to cirrhosis and its complications of liver failure and
hepatocellular carcinoma.
So the most immediate
concerns would be the
modest (but highly informative) rise in bilirubin level
and the borderline low serum
albumin level (normal range
35-53g/L); her value of 36g/L
would be unusual in a
healthy person.
The real clue, though, is
the reverse ratio of AST:ALT
(see earlier), and possibly the
rather high value of GGT.
These changes can occur
with hepatitis C alone, in
which case cirrhosis is likely,
but they are also features of
alcoholic liver disease. Given
her attitude to healthcare,
this aspect will need to be
addressed with considerable
skill and sensitivity, particularly on this first visit.
Investigations to be performed during this holding
operation should include:
FBC, with particular attention to platelets and macrocytosis.
PT/INR.
AFP.
HCV RNA (PCR).
HCV genotyping.

34

| Australian Doctor | 9 April 2010

Blurring of vessels

The healthy hepatitis B

carrier no longer exists
B aware!
Case 4 revisited

Despite normal physical

examination and normal
ALT levels, people with
chronic HBV infection (often
called carriers) should not
be presumed to be, or told,
that they are healthy. Like
other HBsAg-positive individuals, VW should still see
his doctor or specialist annually for review.
He still has a risk of developing fibrosis, cirrhosis
and/or liver cancer. This is
even more likely if the HBV
was acquired vertically and
if he has persistently high
levels of HBV replication,
determined by serum HBV
DNA level (one test is reimbursable, but discuss the reliability
of
pathology
providers with the specialists
in your area, as there can be
major differences in tests
used).
Referral to a hepatologist
for ongoing follow-up/management is highly recommended in this situation, as
antiviral therapy may be
indicated; agents such as
tenofovir and entecavir are
highly effective, with minimal adverse effects or
drugdrug interactions.
In VWs case, LFTs show
ALT 38 U/L (NR <40),
which hepatologists do not
regard as normal for a lean
individual. If it is due to
chronic hepatitis B with or
without cirrhosis, HBV DNA

will be >10,000 IU/mL and

referral is strongly recommended.
If HBV DNA is <100
IU/mL, the borderline ALT is
not due to hepatitis B. People
with chronic HBV infection
are not immune from
NAFLD, so measure the
waistline and proceed to
investigate as for case 3. Inbetween cases of HBV DNA
(100-10,000 IU/mL) might
appropriately be referred to a
hepatologist.
People with chronic hepatitis B should also be advised
to alert their healthcare professionals to their infection,
especially if they are about
to undergo immunosuppressive therapies (eg, chemotherapy for solid or haematological malignancies, anti-TNF
agents or high-dose prednisone). Under such circumstances, the risk of HBV
reactivation is very high and
can lead to death from fulminant hepatic failure.
All patients who are
HBsAg positive should therefore be referred to a hepatologist or specialist experienced
in the management of
chronic hepatitis B before
starting profound immunosuppressive therapy, so that
antiviral prophylaxis can be
instituted (lamivudine or
entecavir). During and after
chemotherapy, close monitoring of liver tests (at least
monthly) and HBV DNA (at
least three monthly) should
be undertaken under the
guidance of a specialist.

Yellow submarine
preventing your cirrhotic
patient from sinking
further with
complications
Case 5 revisited

This patients thrombocytopenia and low albumin

level are fairly accurate indicators of advanced fibrosis
or cirrhosis. Not surprisingly,
you (and we) are concerned
that DTs gastroenterologist
has taken a narrow view of
the patients normal endoscopic procedures and potential health issues; hopefully

better informed and motivated specialist colleagues

would take a broader perspective of preventive issues
in GI and liver disease.
However, GPs do have an
important role to play in
caring for patients with cirrhosis such as DT, who are
at risk of serious complications. Some of these are
highly preventable and their
impending onset can readily
be detected by simple screening tests (see below).
In addition, DT should be
strongly encouraged and regularly reminded to reduce his
alcohol intake to a maximum
of two standard drinks a day,
with several alcohol-free days
during the week, or to abstain
from alcohol altogether if these
levels of restraint cannot be
achieved consistently.
In all patients with cirrhosis, pay attention to optimal
nutrition and avoid excessive
salt (which may precipitate
ascites) and aspirin and
NSAIDs because of their gastrointestinal bleeding and
renal side effects both
important issues in cirrhosis.
Screening for oesophageal
and gastric varices should
still be undertaken, despite
the recent normal gastroscopy. The findings of
mild splenomegaly on DTs
CT scan result is suggestive
of early portal hypertension.
His next surveillance gastroscopy should be scheduled
for two years hence. The frequency of screening gastroscopy and institution of
prophylactic banding of
varices depends on the size
and number of varices, and
signs of recent haemorrhage
detected on each occasion of
surveillance.
Regular screening for HCC
is strongly advised for
patients with cirrhosis (figure
2). The schedule is sixmonthly ultrasound and AFP,
and screening is ineffective
unless a supervised program
is undertaken, that is, one in
which the patient and their
doctor are committed to take
appropriate action based on
test results, and ideally which

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includes reminders to perform the tests regularly every

six months (our tip is to
anchor the program to the
patients birthday month).
Being male, coupled with
previous and possibly ongoing excessive alcohol intake
(>20g/day) and diabetes (the
latter two risk factors aggravate ongoing liver injury and
inflammation) increase DTs
risk for HCC. His glycaemic
control and weight likewise
need to be fastidiously managed.
Early detection of suspicious lesions or AFP changes
should lead to referral to a
multidisciplinary liver cancer
team for management. Most
Australian cities have developed such units now, and
patients with small (asymptomatic) HCCs may be
offered curative treatment by
resection or, ideally, by liver
transplantation.
Finally, remember the bone
health of your patients with
chronic liver disease. Patients
such as DT (male and
female) are at risk of osteoporosis and fractures, especially if they:
Smoke.
Are aged over 60.
Are obese or underweight
(BMI <25).
Are using corticosteroids.
Have had a previous fracture.
Annual bone densitometry
(DEXA, MBS #12315:
chronic liver disease) and 25hydroxy-vitamin D level are
useful investigations. If vitamin D levels are <60nmol/L,
treat with a vitamin D supplement, 3000-5000 IU/day.
Advise optimal calcium
intake, regular weight-bearing exercise and consider bisphosphonate therapy (eg,
risedronate 35mg once a
week) if:
The DEXA T score is
<3.0.
The T score is < 1.5 and
the patient has been using
corticosteroids for longer
than three months.
The patient has had a previous minimal trauma fracture.

Summary
IN summary, non-specific
abnormalities of LFTs are
common in asymptomatic
patients. They most often
indicate NAFLD in overweight patients. NAFLD
increases standardised mortality by 80%. Treatment of
such patients should therefore include full work-up
and management for diabetes, dyslipidaemia and
metabolic syndrome.
Patients with HCV or
HBV infections and those
with a history of heavy alcohol intake and abnormal
liver tests need careful investigation and specialist referral to establish whether cirrhosis is likely. The GP
should continue to play a
role with such patients, not
only with supportive and
general medical care but in
assisting in preventing nutritional, bone and gastrointestinal and liver complications.

Online resource
Gastroenterological
Society of Australia:
digestivehealthfoundation.
gesa.org.au

contd page 36

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HOW TO TREAT Abnormal liver function tests

GPs contribution

DR SANDRA VAN DER

WATER
Gordon, NSW

Case study
ESTELLE, 34, and mother of
four children, usually comes
to the practice for routine Pap
smears and repeat prescriptions of her oral contraceptive
pill (Yaz).
In October 2009 she presented with severe right-sided
upper-quadrant abdominal
pain radiating subcostally.
Although it reminded her of
previous biliary colic, she had
had a cholecystectomy in
2004.
She is a social drinker and
moderately overweight, with
a BMI of 30. She was very
tender in the right upper quadrant, urinalysis was negative

and she was placed on Buscopan and a low-fat diet. Initial

investigations were organised.
Ultrasound showed absent
gallbladder, mild fatty infiltration of the liver and mild
prominence of the intrahepatic
ducts. Blood tests revealed all
LFTS elevated: ALP 115, GGT
303, AST 270, LD 428 and
ALT 169. Serology showed
immunity to hepatitis A and
B and was negative for hepatitis C.
On review three days later
she was asymptomatic, with
the abdomen not tender.
Progress LFTs one week later
were normal apart from an
isolated raised GGT (176).
Three months later she re-presented with spasmodic rightsided pains and tender right
colon. She had lost 12kg on
the low-fat diet and was using
Nexium prn for epigastric discomfort.
LFTS were repeated and
showed GGT 128, ALT 47
and normal serum amylase
level. She was Helicobacter
pylori negative and an

tion of new stones within the

biliary system sometimes
occurs. Sclerosing cholangitis
should also be considered.

abdominopelvic CT scan
detected no abnormality. Her
abdominal pains settled with
mebeverine and a low-caffeine
diet.

Questions for the author

At the initial presentation,
Estelle had some form of acute
hepatitis, which settled very
quickly in three days. What
are the possible causes (given
she claims to be a social
drinker only)?
Presentation with severe
right-sided upper quadrant
pain radiating subcostally is
not suggestive of either hepatitis or fatty liver disease, but of

How to Treat Quiz

biliary colic. The test results

(AST higher than ALT) are
also atypical for viral or drug
hepatitis, but would be consistent with choledocholithiasis,
as would the intrahepatic duct
dilatation. Rapid resolution of
ALT elevation, as in this case,
also occurs with passage of
gallstones. Naturally, one
would want to be very confident about the alcohol history.
Biliary colic more than five
years after cholecystectomy is
highly unlikely to be due to
retained stones, but in such a
gallstone-prone person (note
her cholecystectomy age 28
and obesity [BMI 30]), forma-

Are there any other tests we

should have done at the time?
It was reasonable to use
clinical judgement and
observe, but if the clinical picture had not settled rapidly,
the next test would be magnetic resonance cholangiopancreatography. Lipase
should also be tested. One
would also consider referral to
a gastroenterologist for possible endoscopic retrograde
cholangiopancreatography.
Are the persistent elevations of
GGT and ALT three months
later indicative of fatty liver
disease? She has lost 12kg in
weight, bringing her BMI near
to the normal range. Does
weight loss result in reversal
of fatty liver and return of
LFTs to normal?
Yes. She is still overweight,
and the critical consideration is
whether central obesity (waist

circumference) has been

reversed. Follow-up imaging is
indicated here to make sure
that biliary dilation has
resolved, and there is no
hepatic infiltration other than
with steatosis.
Her gut symptoms also
appear unresolved, and it may
be advisable to order an
abdominal CT which
would help find diverticular
disease, etc., while providing
reassurance about hepatobiliary/pancreatic disease and
consider
referral
for
colonoscopy.
What role, if any, does her
contraceptive pill (Yaz), play
in this scenario?
This combination contains
oestradiol, which may increase
her risk of gallstone formation, but she appears to have
been taking this agent for
some years and, unless there is
a hepatic space-occupying
lesion (which was not seen on
ultrasonography), there is no
likely implication of Yaz in
this clinical picture.

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Abnormal liver function tests

9 April 2010
1. Which TWO statements are correct?
a) All liver function tests performed in a
routine biochemical screen accurately and
specifically reflect liver function
b) Elevated serum bilirubin level is specific for
hepatitis or cholestasis
c) Serum bilirubin level accurately reflects
impaired liver function in the presence of
cirrhosis
d) Non-hepatic causes of low albumin include
poor nutrition, enhanced catabolism, loss by
proteinuria or protein-losing enteropathy
2. Which THREE statements are correct?
a) Serum AST is the most sensitive and
specific test for hepatocyte injury
b) The usual ALT:AST ratio of >2 may fall to
0.8 in alcoholic liver disease or cirrhosis
c) Some hepatic drug reactions also feature
disproportionate increases in AST as well as
ALT
d) ALT levels >5 times normal indicate hepatitis
3. Which THREE statements are correct?
a) In the community, the most common causes
of acute hepatitis are hepatitis viruses (A, B,
C), and drugs
b) Drug-induced hepatitis can be caused by
antibiotics, NSAIDs, antidiabetic agents,
antihypertensives, paracetamol poisoning,
herbal and over-the-counter medicines, and
recreational drugs
c) Autoimmune hepatitis does not present with
the typical elevation in ALT characteristic of
other types of hepatitis

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d) In severe cases of autoimmune hepatitis,

urgent treatment with prednisone and
azathioprine is needed
4. Which TWO statements are correct?
a) In cholestasis, serum alkaline phosphatase
level is elevated more than twofold, with high
levels of GGT
b) In cholestasis the biliary obstruction is always
due to a surgical cause
c) Medical causes of cholestasis include drugs,
hepatitis, automimmune liver diseases and
liver malignancy
d) Jaundice and bilirubinuria is invariably
present with cholestasis
5. Which THREE statements are correct?
a) ALT level may be elevated in cholestasis
because bile-acid accumulation in the liver is
hepatotoxic
b) Increased serum levels of GGT occur when
there is hepatocellular injury, when synthesis
is stimulated, or when bile acid levels rise
c) An increase in serum GGT levels is specific
for the cholestasis of pregnancy
d) Alcohol excess and a wide range of drugs
increase GGT levels by acting as enzymeinducing agents that stimulate its synthesis
and release from the liver
6. Which THREE statements are correct?
a) GGT is a sensitive marker of hepatic
infiltration such as that of hepatic malignancy
b) A rise in GGT level, typically but not always in
association with minor ALT-level elevation, is

indicative of fatty liver disease

c) The platelet count and prothrombin time (PT)
or INR are valuable additional tests in
assessing liver disease
d) The anaemia that can occur with liver
disease is due to vitamin B12 deficiency
7. Which TWO statements are correct?
a) Platelet levels increase in parallel with the
severity of fibrotic liver disease
b) Thromobocytopenia is in part due to reduced
blood levels of thrombopoietin, a hepatic
protein whose synthesis is decreased in
cirrhosis
c) Impaired synthesis of clotting factors 2, 7, 9
and 10, leading to PT prolongation, always
responds to vitamin K administration
d) Serum alpha-fetoprotein (AFP) is an oncofetal
protein whose serum levels rise during
pregnancy and with cirrhosis or
hepatocellular carcinoma
8. Which TWO statements are correct?
a) Liver CT is the most appropriate imaging
investigation when biliary obstruction or fatty
change is suspected
b) LFT changes are more important than
symptoms for early detection of adverse drug
reactions
c) Non-specific symptoms such as malaise,
nausea, dyspepsia, facial discomfort and
fever are important early indicators of drugrelated hepatic reactions
d) Drugs for which LFT monitoring is
recommended include isoniazid, synthetic

retinoids, ketoconazole, terbinafine, and

long-term use of tetracyclines
9. Which THREE statements are correct?
a) Antinuclear, smooth muscle, and liver/kidney
microsomal antibodies are associated with
autoimmune hepatitis
b) Minor and isolated LFT abnormalities such as
ALT 70 U/L and GGT 90 U/L are consistent
with non-alcoholic fatty liver disease (NAFLD)
c) NAFLD is associated with elevated serum
lipid levels, hyperglycaemia, and
hypertension
d) Statins are contraindicated in people with
NAFLD and hypercholesterolaemia because
of their hepatic side effects
10. Which THREE statements are correct?
a) People with chronic hepatitis B virus (HBV)
infection may have progressive liver disease
despite a normal physical examination and
normal ALT level
b) In those with chronic hepatitis B, persistently
high levels of HBV replication (serum HBV
DNA level >10,000 IU/mL) warrant referral to
a hepatologist for antiviral therapy
c) Immunosuppressive therapies (eg,
chemotherapy, anti-TNF agents or high-dose
prednisone) in those with chronic hepatitis B
may reactivate the hepatitis and lead to death
from fulminant hepatic failure
d) Regular screening for hepatocellular
carcinoma is not recommended for people
with cirrhosis, as there is no curative
treatment available

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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 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.

HOW TO TREAT Editor: Dr Giovanna Zingarelli

Co-ordinator: Julian McAllan
Quiz: Dr Giovanna Zingarelli

NEXT WEEK The prevalence of atopy in our population is about 20%, and atopic dermatitis (also known as atopic eczema) appears to be on the increase, not just in Australia but worldwide. The next How
to Treat focuses on management of this condition. The author is Dr Gayle Fischer, paediatric dermatologist, The Royal North Shore Hospital, St Leonards, and senior lecturer in dermatology, University of
Sydney, NSW.

36

| Australian Doctor | 9 April 2010

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