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CP, Sep, p363-66, how to_FAQ
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Vol 1
September 2009
Clinical Pharmacist
How to interpret liver function tests
By Gareth Nickless, DipClinPharm,
MRPharmS
any pharmacists will, at some
stage, have needed to interpret a
patient’s liver function tests (LFTs)
and decide whether any of his or her
medicines required dose reduction or
cessation.
Although drug-induced liver disease is
relatively uncommon, medicines should
always be considered as a possible cause of
liver dysfunction (and pharmacists should
be vigilant for such events and report all
suspected reactions to the Medicines and
Healthcare products Regulatory Agency
using the yellow card scheme). Over 600
medicines have been associated with
hepatotoxic reactions.
M
Liver function assessment
LFTs involve detecting the levels of several
biochemical markers in the bloodstream.
While advice on adjusting the doses of
medicines for patients with renal disease is
plentiful (eg, ‘The renal drug handbook’),
there is no equivalent publication for
patients with abnormal LFTs or hepatic
dysfunction. Furthermore, LFTs cannot
quantify liver function in the same way that
creatinine clearance quantifies renal
function. Instead, practitioners rely on
information in summaries of product
characteristics, the British National
Formulary and, where available, in
published guidelines for treatment of
specific diseases.
Although abnormal LFTs can indicate a
hepatobiliary problem that warrants further
investigation, they should not be assessed in
isolation. The presence of other signs and
symptoms of liver disease (eg, ascites,
varices) should also be considered.
The common biochemical markers
measured in LFTs are explained below.
IN SHORT
Pharmacists are likely to come across
patients whose liver function tests are
abnormal. However, assessing LFTs
alone will not offer pharmacists the full
story.
Knowing the likely cause of abnormal
LFTs can help determine whether the
abnormalities are caused by a medicine,
or whether any doses of medicines need
to be changed to compensate.
Bilirubin A by-product of haem
metabolism, bilirubin is conjugated by
hepatocytes for excretion. When
hepatocytes are damaged (due to acute
hepatitis or cirrhosis), they are unable to
perform this function sufficiently, resulting
in raised levels of unconjugated bilirubin
and, ultimately, jaundice.
Serum bilirubin levels can also be raised
as a result of cholestasis — a condition
where the movement of bile from the liver
to the gallbladder is inhibited (this can be
caused by intrahepatic factors, such as viral
hepatitis or a bacterial abscess, or
extrahepatic factors, such as gallstones).
Haemolysis, as seen in autoimmune
haemolytic anaemia, can also raise
bilirubin levels.
commonly produced by liver cells. In
response to acute hepatocellular damage (eg,
acute hepatitis), the levels of these enzymes
in the bloodstream can rise significantly.
Transaminase levels are not usually
affected for patients with cholestasis;
however, gallstones lodged in the common
bile duct can result in transaminase
enzymes and biliary enzymes (alkaline
phosphatase [ALP] and gamma
glutaryltransferase [GGT]) all being raised
— indicating hepatitis and cholestasis.
Transaminase levels may be normal (or
only marginally raised) in patients with
cirrhosis since there is little remaining
healthy liver tissue to produce them.
Gamma glutaryltransferase Produced
by hepatocytes and bile ducts, GGT is an
enzyme for which levels can be raised 10to 20-fold in patients with cholestasis. Its
levels can also be raised, but often less so, in
patients with cirrhosis.
Alkaline phosphatase ALP isoenzymes
are found in hepatocytes, bile canaliculi
epithelial cells, bone and intestine. Raised
ALP levels are commonly seen in both
intra- and extrahepatic cholestasis, and in
Paget’s disease. If a patient’s GGT is also
raised, this can help to confirm whether a
raised ALP is of hepatobiliary origin.
Transaminase enzymes Alanine
Albumin The level of serum carrier
aminotransferase (ALT) and aspartate
aminotransferase (AST) enzymes are most
protein albumin is useful for assessing a
liver’s synthetic function. Since albumin’s
Box 1: Child-Pugh scores to classify chronic liver disease
PARAMETER
SCORE
1
2
3
Bilirubin (μmol/L)
Albumin (g/L)
INR
Ascites
<35
>35
<1.7
None
35–50
28–35
1.8–2.3
Moderate or
easily treated
>50
<28
>2.3
Severe or
intractable
Grade of hepatic
encephalopathy
None
1–2
3–4
Once all points have been tallied, chronic liver disease is classified as indicated below:
Gareth Nickless is lead clinical liaison
tutor/practitioner at Wirral University
Teaching Hospital NHS Foundation Trust.
E: [email protected]
POINTS
CLASS
5–6
7–9
10–15
A
B
C
ONE-YEAR SURVIVAL
100%
81%
45%
TWO-YEAR SURVIVAL
85%
57%
35%
PRACTICE TOOLS
Patients with abnormal liver function tests are encountered commonly by pharmacists. It is therefore
helpful to know how to amend patients’ treatments and when such amendments might be necessary
363
CP, Sep, p363-66, how to_FAQ
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September 2009
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Vol 1
plasma half-life is approximately 20 days, it
will take at least a week for levels to fall
below the reference range as a result of
liver damage or dysfunction. Consequently,
albumin levels are a useful indicator of
chronic liver dysfunction.
Other conditions can cause a more
rapid reduction in albumin levels, such as
the catabolic effects of severe infection.
Rob Bouwman | Dreamstime.com
PRACTICE TOOLS
364
26/8/09
Coagulation measures Raised
prothrombin time and international
normalised ratio can indicate hepatobiliary
disease in patients for two reasons. First,
vitamin K absorption might be impaired by
the absence of bile in the gut (eg, because
of cholestasis). Second, the damaged
hepatocytes (eg, in cirrhosis or acute
hepatitis) will be unable to synthesise
adequate clotting factors.
Child-Pugh score
If a patient has been diagnosed with
chronic liver disease, the Child-Pugh score
(see Box 1, p363) can be used to assess the
severity of his or her disease. However, its
use in guiding drug dosing is limited
because two patients with the same severity
of chronic liver disease (as determined
using Child-Pugh) could have markedly
different metabolic capacities.
As a result, few drugs use this scoring
system in their product information to
suggest specific dose reductions —
caspofungin is an exception which
recommends a dose of 35mg daily (instead
of the usual 50mg daily) for patients with
Child-Pugh class B disease.
Effects of medicines on the liver
Medicines can affect the liver in many
ways, ranging from minor abnormalities of
reported LFTs to significant hepatic
necrosis. In some cases, the reaction has
been serious enough to warrant a
medicine’s withdrawal from the market (eg,
troglitazone — the first marketed
thiazolidinedione).
Some reactions are predictable and occur
in a dose-related manner (eg, in paracetamol
overdose) whereas others are idiosyncratic
(eg, cholestasis caused by chlorpromazine).
For most drugs, pre-existing liver
dysfunction does not generally increase the
risk of developing drug-induced liver
disease, although sodium valproate and
methotrexate are notable exceptions.
Polypharmacy may increase the risk of
hepatotoxic reactions. For example, nonsteroidal anti-inflammatory drugs are more
likely to cause liver disease if they are
Box 2: How some medicines can affect liver function tests
Penicillins Moderate and asymptomatic rises in serum
transaminases have been observed in patients taking penicillins.
There have also been reports of cholestatic jaundice, especially for
flucloxacillin and co-amoxiclav (due to the clavulanic acid
component). Signs and symptoms usually occur during or shortly
after a course of treatment, but may be delayed for two weeks or
longer after the course has finished. The risk is increased for
males, elderly patients and those who receive a course of treatment
that exceeds 14 days. This reaction is usually reversible, but can
be severe and potentially fatal.
monitoring LFTs for all patients with known chronic liver disease. If
transaminases rise to more than five times the ULN, or bilirubin
rises above the ULN, treatment with rifampicin, isoniazid and
pyrazinamide should be stopped.
Once LFTs have recovered, these medicines can be restarted
sequentially (as outlined in the guidelines) with LFTs being
monitored daily. The National Institute for Health and Clinical
Excellence has recently published guidance on the management of
TB, but it does not suggest how treatment should be restarted in
such circumstances.
Statins Moderate rises of transaminases (ie, less than three times
the upper limit of normal [ULN]) have been reported following the
use of all statins. This increase may be transient or sustained. The
general advice from manufacturers is to discontinue therapy if the
rise is progressive (ie, more than three times the ULN and
persistent).
Phenytoin Phenytoin is an enzyme inducer and it is common for
three- to five-fold increases in gamma glutaryltransferase to be
observed during treatment. Hepatotoxicity that requires withdrawal
of the drug is less common. If hypoalbuminaemia is observed in
patients who are taking phenytoin, more of the drug will be
unbound in plasma. Consequently, a corrected concentration of
phenytoin should be calculated as follows:
Methotrexate Abnormal LFTs and hepatic cirrhosis have been
reported from the use of methotrexate, therefore regular monitoring
is required. If abnormal LFTs develop, treatment should be
stopped. In some cases (eg, when patients have been taking a
particularly high dose), it may be possible to restart treatment at a
lower dose once the LFTs return to normal.
Antituberculous drugs Modest rises in transaminases are not
uncommon in patients with tuberculosis (TB). The British Thoracic
Society guidelines for the management of TB3 recommend
Corrected concentration =
Measured plasma concentration (μmol/L)
(0.9 × serum albumin (g/L) / 44) + 0.1
Herbal medicines Increased use of herbal medicines has led to
their greater recognition as a cause of liver injury. Kava and black
cohosh are commonly associated with hepatotoxic reactions. Most
suspected reactions that have been reported to the UK Committee
on Safety of Medicines regarding radix polygoni multiflori have
described hepatobiliary disorders.
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prescribed at the same time as drugs that
are hepatotoxic. Also, inducers of
cytochrome P450 2E1 (eg, alcohol,
rifampicin) raise the risk of hepatotoxicity
caused by paracetamol and isoniazid.
Appropriate action
Since abnormal LFTs do not always
indicate hepatic dysfunction and may not
be drug-induced, changes to a patient’s
drug therapy are not always needed.
Nonetheless, if abnormal LFTs (with or
without clinical jaundice) are observed, the
following should be considered:
Are the abnormal values significant? If enzyme
levels are more than twice the upper limit of
normal (ULN), this is generally considered
to be significant. However, for some drugs
FAQ
Page 366
larger increases may be considered
acceptable (see examples, Box 2, p364).
When were the patient’s medicines started?
Predictable hepatotoxic reactions usually
have a latency period ranging from hours
to weeks, whereas idiosyncratic reactions
can take several months to occur.
Does the patient have a history of hepatotoxic
drug reactions? There is known crosssensitivity between some groups of
medicines (eg, between phenothiazines,
tricyclic antidepressants and NSAIDs).
Have any other tests been performed that offer
alternative explanations for the abnormal
LFTs? When there is another explanation
for deranged LFTs (eg, gallstones or
pancreatic cancer), many medicines can be
continued as normal. If medicines are
stopped and the patient’s LFTs improve,
the changes are likely to be drug-induced.
References
1
North-Lewis P (editor). Drugs and the Liver. London:
Pharmaceutical Press; 2008.
2
Walker R, Whittlesea C. Clinical Pharmacy and
Therapeutics. 4th edition. London: Churchill
Livingstone; 2007.
3
Joint tuberculosis committee of the British Thoracic
Society. Chemotherapy and management of
tuberculosis in the United Kingdom: recommendations
1998. Thorax 1998;53:536–48.
NOTE Clinical Pharmacist PRACTICE TOOLS do not
constitute formal practice guidance. Articles in
the series have been commissioned from
independent authors who have summarised useful
clinical skills.
Oseltamivir for patients with renal impairment
Q
UK Medicines Information summarises
the evidence for this frequently
asked question:
Can oseltamivir be used for
patients with renal impairment or
on renal replacement therapies?
Oseltamivir carboxylate (the active
metabolite of oseltamivir phosphate)
is excreted entirely in the urine
through glomerular filtration and tubular
secretion. Oseltamivir is generally well
tolerated, but gastrointestinal side effects
and dizziness may appear with increasing
doses, particularly in patients with renal
failure.
Renal clearance of oseltamivir
carboxylate decreases linearly with
reduction in creatinine clearance (CrCl).
Adults with mild-to-moderate renal
impairment (CrCl not below 30ml/min)
can receive the normal adult dose. The
manufacturer recommends oseltamivir dose
reduction for adults with severe renal
impairment (CrCl 10–30ml/min):
A
This FAQ is taken from a “Medicines
Q&A” produced by UK Medicines
Information. The full document,
including references, is available from
www.nelm.nhs.uk.
Published 24 June
2009, expires 19
June 2011
● For treatment of influenza: 75mg
once daily or 30mg twice daily
● For prophylaxis of influenza: 75mg
every second day or 30mg once daily
The manufacturer states that oseltamivir
is not recommended for patients with CrCl
<10ml/min or those receiving renal
replacement therapy (RRT). In these
patients zanamivir is the preferred option
for both prophylaxis and treatment.
For patients with CrCl <10ml/min it
has been suggested that a 30mg dose of
oseltamivir (repeated every 10 days where
necessary) is suitable for treatment or
prophylaxis of influenza.
Oseltamivir carboxylate is removed
through dialysis. There is no definitive dose
guidance available for patients on RRT and
reference sources provide conflicting advice.
● For patients undergoing
haemodialysis, a pharmacokinetic
study has shown that 30mg
oseltamivir administered after
alternate dialysis sessions provides an
exposure to oseltamivir carboxylate
that has been shown to be clinically
effective in other patient groups.
● There are no published data
documenting the use of oseltamivir
in patients receiving
haemodiafiltration or high flux
haemodialysis. A dose of 75mg post
dialysis has been suggested
empirically.
● For patients undergoing continuous
ambulatory peritoneal dialysis, the
Oseltamivir is the active ingredient in Tamiflu
most commonly suggested dose is
30mg (repeated every week where
necessary) for treatment or
prophylaxis of influenza.
● For patients receiving continuous
renal replacement therapies, both a
reduced dose (as for CrCl
10–30ml/min) and the normal adult
dose have been suggested. The
absence of tubular secretion in anuric
patients should also be considered.
The decision to prescribe oseltamivir,
and which dose to use, for a patient with
CrCl <10ml/min or on RRT lies with the
prescribing doctor and should be based on
an appropriate assessment of the likely risk
versus benefit ratio. If oseltamivir is
prescribed in this situation (which is outside
the terms of the product licence) the
patient must be monitored closely for
efficacy, adverse effects and signs of toxicity.