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Vol 1 September 2009 Clinical Pharmacist 363

Patients with abnormal liver function tests are encountered commonly by pharmacists. It is therefore

PRACTICE TOOLS
helpful to know how to amend patients’ treatments and when such amendments might be necessary

How to interpret liver function tests


By Gareth Nickless, DipClinPharm, commonly produced by liver cells. In
MRPharmS IN SHORT response to acute hepatocellular damage (eg,
acute hepatitis), the levels of these enzymes
Pharmacists are likely to come across
any pharmacists will, at some in the bloodstream can rise significantly.

M stage, have needed to interpret a


patient’s liver function tests (LFTs)
and decide whether any of his or her
patients whose liver function tests are
abnormal. However, assessing LFTs
alone will not offer pharmacists the full
story.
Transaminase levels are not usually
affected for patients with cholestasis;
however, gallstones lodged in the common
medicines required dose reduction or Knowing the likely cause of abnormal bile duct can result in transaminase
cessation. LFTs can help determine whether the enzymes and biliary enzymes (alkaline
Although drug-induced liver disease is abnormalities are caused by a medicine, phosphatase [ALP] and gamma
relatively uncommon, medicines should or whether any doses of medicines need glutaryltransferase [GGT]) all being raised
always be considered as a possible cause of to be changed to compensate. — indicating hepatitis and cholestasis.
liver dysfunction (and pharmacists should Transaminase levels may be normal (or
be vigilant for such events and report all only marginally raised) in patients with
suspected reactions to the Medicines and Bilirubin A by-product of haem cirrhosis since there is little remaining
Healthcare products Regulatory Agency metabolism, bilirubin is conjugated by healthy liver tissue to produce them.
using the yellow card scheme). Over 600 hepatocytes for excretion. When
medicines have been associated with hepatocytes are damaged (due to acute Gamma glutaryltransferase Produced
hepatotoxic reactions. hepatitis or cirrhosis), they are unable to by hepatocytes and bile ducts, GGT is an
perform this function sufficiently, resulting enzyme for which levels can be raised 10-
Liver function assessment in raised levels of unconjugated bilirubin to 20-fold in patients with cholestasis. Its
LFTs involve detecting the levels of several and, ultimately, jaundice. levels can also be raised, but often less so, in
biochemical markers in the bloodstream. Serum bilirubin levels can also be raised patients with cirrhosis.
While advice on adjusting the doses of as a result of cholestasis — a condition
medicines for patients with renal disease is where the movement of bile from the liver Alkaline phosphatase ALP isoenzymes
plentiful (eg, ‘The renal drug handbook’), to the gallbladder is inhibited (this can be are found in hepatocytes, bile canaliculi
there is no equivalent publication for caused by intrahepatic factors, such as viral epithelial cells, bone and intestine. Raised
patients with abnormal LFTs or hepatic hepatitis or a bacterial abscess, or ALP levels are commonly seen in both
dysfunction. Furthermore, LFTs cannot extrahepatic factors, such as gallstones). intra- and extrahepatic cholestasis, and in
quantify liver function in the same way that Haemolysis, as seen in autoimmune Paget’s disease. If a patient’s GGT is also
creatinine clearance quantifies renal haemolytic anaemia, can also raise raised, this can help to confirm whether a
function. Instead, practitioners rely on bilirubin levels. raised ALP is of hepatobiliary origin.
information in summaries of product
characteristics, the British National Transaminase enzymes Alanine Albumin The level of serum carrier
Formulary and, where available, in aminotransferase (ALT) and aspartate protein albumin is useful for assessing a
published guidelines for treatment of aminotransferase (AST) enzymes are most liver’s synthetic function. Since albumin’s
specific diseases.
Although abnormal LFTs can indicate a
hepatobiliary problem that warrants further Box 1: Child-Pugh scores to classify chronic liver disease
investigation, they should not be assessed in PARAMETER SCORE
isolation. The presence of other signs and 1 2 3
symptoms of liver disease (eg, ascites, Bilirubin (μmol/L) <35 35–50 >50
varices) should also be considered. Albumin (g/L) >35 28–35 <28
The common biochemical markers INR <1.7 1.8–2.3 >2.3
measured in LFTs are explained below. Ascites None Moderate or Severe or
easily treated 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
POINTS CLASS ONE-YEAR SURVIVAL TWO-YEAR SURVIVAL
tutor/practitioner at Wirral University
5–6 A 100% 85%
Teaching Hospital NHS Foundation Trust.
E: g.d.nickless@ljmu.ac.uk
7–9 B 81% 57%
10–15 C 45% 35%
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364 Clinical Pharmacist September 2009 Vol 1

plasma half-life is approximately 20 days, it


PRACTICE TOOLS

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

Rob Bouwman | Dreamstime.com


the catabolic effects of severe infection.

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 As a result, few drugs use this scoring troglitazone — the first marketed
hepatocytes (eg, in cirrhosis or acute system in their product information to thiazolidinedione).
hepatitis) will be unable to synthesise suggest specific dose reductions — Some reactions are predictable and occur
adequate clotting factors. caspofungin is an exception which in a dose-related manner (eg, in paracetamol
recommends a dose of 35mg daily (instead overdose) whereas others are idiosyncratic
Child-Pugh score of the usual 50mg daily) for patients with (eg, cholestasis caused by chlorpromazine).
If a patient has been diagnosed with Child-Pugh class B disease. For most drugs, pre-existing liver
chronic liver disease, the Child-Pugh score dysfunction does not generally increase the
(see Box 1, p363) can be used to assess the Effects of medicines on the liver risk of developing drug-induced liver
severity of his or her disease. However, its Medicines can affect the liver in many disease, although sodium valproate and
use in guiding drug dosing is limited ways, ranging from minor abnormalities of methotrexate are notable exceptions.
because two patients with the same severity reported LFTs to significant hepatic Polypharmacy may increase the risk of
of chronic liver disease (as determined necrosis. In some cases, the reaction has hepatotoxic reactions. For example, non-
using Child-Pugh) could have markedly been serious enough to warrant a steroidal anti-inflammatory drugs are more
different metabolic capacities. medicine’s withdrawal from the market (eg, 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 monitoring LFTs for all patients with known chronic liver disease. If
transaminases have been observed in patients taking penicillins. transaminases rise to more than five times the ULN, or bilirubin
There have also been reports of cholestatic jaundice, especially for rises above the ULN, treatment with rifampicin, isoniazid and
flucloxacillin and co-amoxiclav (due to the clavulanic acid pyrazinamide should be stopped.
component). Signs and symptoms usually occur during or shortly Once LFTs have recovered, these medicines can be restarted
after a course of treatment, but may be delayed for two weeks or sequentially (as outlined in the guidelines) with LFTs being
longer after the course has finished. The risk is increased for monitored daily. The National Institute for Health and Clinical
males, elderly patients and those who receive a course of treatment Excellence has recently published guidance on the management of
that exceeds 14 days. This reaction is usually reversible, but can TB, but it does not suggest how treatment should be restarted in
be severe and potentially fatal. such circumstances.

Statins Moderate rises of transaminases (ie, less than three times Phenytoin Phenytoin is an enzyme inducer and it is common for
the upper limit of normal [ULN]) have been reported following the three- to five-fold increases in gamma glutaryltransferase to be
use of all statins. This increase may be transient or sustained. The observed during treatment. Hepatotoxicity that requires withdrawal
general advice from manufacturers is to discontinue therapy if the of the drug is less common. If hypoalbuminaemia is observed in
rise is progressive (ie, more than three times the ULN and patients who are taking phenytoin, more of the drug will be
persistent). 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 Measured plasma concentration (μmol/L)
Corrected concentration =
is required. If abnormal LFTs develop, treatment should be (0.9 × serum albumin (g/L) / 44) + 0.1
stopped. In some cases (eg, when patients have been taking a
particularly high dose), it may be possible to restart treatment at a Herbal medicines Increased use of herbal medicines has led to
lower dose once the LFTs return to normal. their greater recognition as a cause of liver injury. Kava and black
cohosh are commonly associated with hepatotoxic reactions. Most
Antituberculous drugs Modest rises in transaminases are not suspected reactions that have been reported to the UK Committee
uncommon in patients with tuberculosis (TB). The British Thoracic on Safety of Medicines regarding radix polygoni multiflori have
Society guidelines for the management of TB3 recommend described hepatobiliary disorders.
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366 Clinical Pharmacist September 2009 Vol 1

prescribed at the same time as drugs that larger increases may be considered pancreatic cancer), many medicines can be
PRACTICE TOOLS

are hepatotoxic. Also, inducers of acceptable (see examples, Box 2, p364). continued as normal. If medicines are
cytochrome P450 2E1 (eg, alcohol, stopped and the patient’s LFTs improve,
rifampicin) raise the risk of hepatotoxicity When were the patient’s medicines started? the changes are likely to be drug-induced.
caused by paracetamol and isoniazid. Predictable hepatotoxic reactions usually
have a latency period ranging from hours References
Appropriate action to weeks, whereas idiosyncratic reactions 1 North-Lewis P (editor). Drugs and the Liver. London:
Pharmaceutical Press; 2008.
Since abnormal LFTs do not always can take several months to occur. 2 Walker R, Whittlesea C. Clinical Pharmacy and
indicate hepatic dysfunction and may not Therapeutics. 4th edition. London: Churchill
Livingstone; 2007.
be drug-induced, changes to a patient’s Does the patient have a history of hepatotoxic 3 Joint tuberculosis committee of the British Thoracic
drug therapy are not always needed. drug reactions? There is known cross- Society. Chemotherapy and management of
tuberculosis in the United Kingdom: recommendations
Nonetheless, if abnormal LFTs (with or sensitivity between some groups of 1998. Thorax 1998;53:536–48.
without clinical jaundice) are observed, the medicines (eg, between phenothiazines,
following should be considered: tricyclic antidepressants and NSAIDs).

Are the abnormal values significant? If enzyme Have any other tests been performed that offer NOTE Clinical Pharmacist PRACTICE TOOLS do not
constitute formal practice guidance. Articles in
levels are more than twice the upper limit of alternative explanations for the abnormal
the series have been commissioned from
normal (ULN), this is generally considered LFTs? When there is another explanation independent authors who have summarised useful
to be significant. However, for some drugs for deranged LFTs (eg, gallstones or clinical skills.

Oseltamivir for patients with renal impairment


FAQ

UK Medicines Information summarises ● For treatment of influenza: 75mg

Q the evidence for this frequently


asked question:
once daily or 30mg twice daily
● For prophylaxis of influenza: 75mg
every second day or 30mg once daily
Can oseltamivir be used for
patients with renal impairment or The manufacturer states that oseltamivir
on renal replacement therapies? is not recommended for patients with CrCl
<10ml/min or those receiving renal
Oseltamivir carboxylate (the active replacement therapy (RRT). In these

A metabolite of oseltamivir phosphate)


is excreted entirely in the urine
through glomerular filtration and tubular
patients zanamivir is the preferred option
for both prophylaxis and treatment.
For patients with CrCl <10ml/min it
secretion. Oseltamivir is generally well has been suggested that a 30mg dose of
tolerated, but gastrointestinal side effects oseltamivir (repeated every 10 days where
Oseltamivir is the active ingredient in Tamiflu
and dizziness may appear with increasing necessary) is suitable for treatment or
doses, particularly in patients with renal prophylaxis of influenza.
failure. Oseltamivir carboxylate is removed most commonly suggested dose is
Renal clearance of oseltamivir through dialysis. There is no definitive dose 30mg (repeated every week where
carboxylate decreases linearly with guidance available for patients on RRT and necessary) for treatment or
reduction in creatinine clearance (CrCl). reference sources provide conflicting advice. prophylaxis of influenza.
Adults with mild-to-moderate renal ● For patients receiving continuous
impairment (CrCl not below 30ml/min) ● For patients undergoing renal replacement therapies, both a
can receive the normal adult dose. The haemodialysis, a pharmacokinetic reduced dose (as for CrCl
manufacturer recommends oseltamivir dose study has shown that 30mg 10–30ml/min) and the normal adult
reduction for adults with severe renal oseltamivir administered after dose have been suggested. The
impairment (CrCl 10–30ml/min): alternate dialysis sessions provides an absence of tubular secretion in anuric
exposure to oseltamivir carboxylate patients should also be considered.
that has been shown to be clinically
effective in other patient groups. The decision to prescribe oseltamivir,
● There are no published data and which dose to use, for a patient with
This FAQ is taken from a “Medicines documenting the use of oseltamivir CrCl <10ml/min or on RRT lies with the
Q&A” produced by UK Medicines in patients receiving prescribing doctor and should be based on
Information. The full document, haemodiafiltration or high flux an appropriate assessment of the likely risk
including references, is available from
haemodialysis. A dose of 75mg post versus benefit ratio. If oseltamivir is
www.nelm.nhs.uk.
dialysis has been suggested prescribed in this situation (which is outside
Published 24 June
2009, expires 19 empirically. the terms of the product licence) the
June 2011 ● For patients undergoing continuous patient must be monitored closely for
ambulatory peritoneal dialysis, the efficacy, adverse effects and signs of toxicity.