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Information ⬇

Hepatic Impairment

Patients with hepatic impairment may have the following:

General Principles of Prescribing in Hepatic Impairment

Liver function tests (LFTs) are a poor marker of hepatic metabolising capacity. Many patients with chronic liver disease are asymptomatic or have fluctuating clinical symptoms. LFTs help evaluate hepatic damage but tell us little about hepatic function.

There are few clinical studies relating to the use of psychotropic drugs in people with hepatic disease. The following principles should be adhered to:

  1. Prescribe as few drugs as possible.
  2. Use lower starting doses, particularly of drugs that are highly protein bound. Tricyclic antidepressants (TCAs), SSRIs (except citalopram), trazodone and antipsychotics may have increased free plasma levels, at least initially. This will not be reflected in measured (total) plasma levels. Use lower doses of drugs known to be subject to extensive first-pass metabolism. Examples include TCAs and haloperidol.
  3. Be cautious with drugs that are extensively hepatically metabolised (most psychotropic drugs). Lower doses may be required. Exceptions are sulpiride, amisulpride, lithium and gabapentin, which all undergo no or minimal hepatic metabolism.
  4. Leave longer intervals between dosage increases. The half-life of most drugs is prolonged in hepatic impairment and the duration of action is longer. Accumulation is more likely. Time to steady state is prolonged.
  5. If albumin is reduced, consider the implications for drugs that are highly protein bound, and if ascites is present, consider the increased volume of distribution for water-soluble drugs.
  6. Avoid medicines with a very long half-life or those that need to be metabolised to render them active (pro-drugs).
  7. Always monitor carefully for adverse effects, which may be delayed.
  8. Avoid drugs that are very sedative because of the risk of precipitating hepatic encephalopathy.
  9. Avoid drugs that are very constipating because of the risk of precipitating hepatic encephalopathy.
  10. Avoid drugs that are known to be hepatotoxic in their own right (e.g. monoamine oxidase inhibitors [MAOIs], chlorpromazine). Pre-existing liver disease does not increase the risk of drug-induced hepatotoxicity, but it may be more catastrophic if it does occur.
  11. Choose a low-risk drug (see the tables in this section) and monitor LFTs weekly, at least initially. If LFTs deteriorate after a new drug is introduced, consider switching to another drug. Note that cross-hepatotoxicity between drugs is possible, especially if they are structurally related.1

These rules should always be observed in severe liver disease (low albumin, increased clotting time, ascites, jaundice, encephalopathy, etc.). The information here and following should be interpreted in the context of the patient's clinical presentation.

Antipsychotics in Hepatic Impairment2

One-third of patients who are prescribed antipsychotic medication have at least one abnormal LFT and in 4% at least one LFT is elevated three times above the upper limit of normal.3 Transaminases are most often affected and this generally occurs within 1-6 weeks of treatment initiation.3 Only rarely does clinically significant hepatic damage result.3 Later in the treatment, the development of metabolic syndrome (obesity, insulin resistance) may be linked to the emergence of non-alcoholic fatty liver disease.4, 5

Table 8.1 summarises antipsychotic medications used in hepatic impairment.

Table 8.1 Antipsychotics in Hepatic Impairment.

DrugComments

Amisulpride678

Predominantly renally excreted, so dosage reduction should not be necessary as long as renal function is normal. Uncommonly associated with rises in transaminases and rarely hepatocellular injury.9
Aripiprazole671011Extensively hepatically metabolised. Limited data that hepatic impairment has minimal effect on pharmacokinetics. Manufacturer states no dosage reduction required in mild to moderate hepatic impairment, but caution required in severe impairment. Small number of reports of hepatotoxicity, increased LFTs, hepatitis and jaundice.39121314
Asenapine6711Hepatically metabolised. Manufacturer advises to avoid use in severe hepatic disease (sevenfold increase in asenapine exposure). No dose adjustment required in mild to moderate disease,15 but be aware of the possibility of increased plasma levels in patients with moderate impairment. Transient, asymptomatic rises in transaminases, AST and ALT are common, especially early in treatment. Single case report of mild cholestatic liver injury that resolved on stopping treatment.16
Brexpiprazole717Little information. Use no more than 3mg/day (schizophrenia) or 2mg/day (depression or agitation in Alzheimer's disease) in moderate or severe hepatic failure. Long half-life (~90 hours).
Cariprazine718Occasional, non-clinically relevant increases in ALT and AST. No dosage adjustment is required in patients with mild or moderate hepatic failure; not advised in severe hepatic disease (has not been evaluated). Long half-life (~2-4 days). Hepatitis has been reported.
Clozapine1671920Very sedative and constipating. Contraindicated in active liver disease (associated with nausea, anorexia or jaundice), progressive liver disease or hepatic failure. In less severe disease, start with 12.5mg and increase slowly, using plasma levels to gauge metabolising capacity and guide dosage adjustment. More frequently associated with changes in liver enzymes than other antipsychotics. Transient elevations in AST, ALT and GGT to over twice the normal range occur in up to a third of people, resolving spontaneously in 6-12 weeks.21 Clozapine-induced hepatitis, jaundice, cholestasis and liver failure have been reported. Clozapine should be discontinued if these develop. Successful rechallenge following hepatitis has been described.2223
Flupentixol/zuclopenthixol672425Both are extensively hepatically metabolised. Abnormal LFTs and (rarely) jaundice have been reported with flupentixol.6 Small, transient elevations in transaminases, cholestatic hepatitis and jaundice6 have been reported in some patients treated with zuclopenthixol. One report of flupentixol-induced hepatitis.26 No other literature reports of use or harm.27 Reduce doses by 50% in patients with compromised hepatic function. Depot preparations are best avoided, as altered pharmacokinetics will make dosage adjustment difficult and adverse effects from accumulation more likely.
Haloperidol6Extensively hepatically metabolised. Halve initial doses, adjust dose with smaller increments and at longer intervals. Transient and asymptomatic elevations in LFTs reported in 20% of patients.28 Isolated reports of cholestasis, acute hepatic failure, hepatitis and abnormal LFTs.67
Iloperidone71129Hepatically metabolised. Reduce dose in moderate impairment (twofold increase in active metabolites) and avoid completely in severe hepatic impairment (no studies done). No dose reduction necessary in mild impairment. Infrequent reports of cholelithiasis.
Lumateperone3031Hepatically metabolised to active metabolites. No dose adjustment required in mild impairment. Increased exposure to lumateperone in moderate and severe impairment; manufacturer recommends dose of 21mg daily. Increases in transaminases reported in licensing trials.
Lurasidone6711Hepatically metabolised. No dose adjustment is required in mild hepatic impairment. Manufacturer recommends a starting dose of 18.5mg (20mg) in moderate or severe hepatic impairment, and a maximum dose of 74mg (80mg)/day in moderate impairment (1.7-fold increase in exposure) and of 37mg (40mg)/day in severe impairment (threefold increase in exposure). Increases in ALT reported infrequently.
Olanzapine16711Although extensively hepatically metabolised, the pharmacokinetics of olanzapine seem to change little in severe hepatic impairment. It is sedative and anticholinergic (can cause constipation) so caution is advised. Start with 5mg/day in moderate or severe impairment and consider using plasma levels to guide dosage (aim for 20-40mcg/L). Dose-related, transient, asymptomatic elevations in ALT and AST are very common in physically healthy adults, particularly early in treatment. Along with clozapine, more often associated with drug-induced liver injury than other antipsychotics.3233
Paliperidone6711Mainly excreted unchanged so no dosage adjustment required for mild to moderate impairment. May be a good choice for patients with pre-existing hepatic disease.34353637 However, no data are available with respect to severe hepatic impairment, so caution required. Rises in transaminases and GGT reported, and some cases of jaundice and hepatic steatosis.38 One case report of hepatotoxicity with risperidone that did not remit on switching to paliperidone - it is possible that paliperidone may cause hepatotoxicity.39
Phenothiazines6732All cause sedation and constipation. Transient abnormalities in LFTs reported. Associated with cholestasis and some reports of fulminant hepatic cirrhosis. Best avoided completely in hepatic impairment, some phenothiazines are actively contraindicated. Chlorpromazine is particularly hepatotoxic and is also associated with rare cases of immune-mediated obstructive jaundice which may progress to liver disease.
Pimavanserin7Active metabolite has a very long half-life (200 hours) but hepatic impairment does not appear to affect plasma concentrations. Manufacturer advises that no dose adjustment is required. No reports of hepatotoxicity.
Quetiapine671140Extensively hepatically metabolised but short half-life. Clearance reduced by a mean of 30% in hepatic impairment so start at 25mg/day (IR preparation) or 50mg/day (XL preparation) and increase in 25-50mg/day increments. Can cause sedation and constipation. Transient rises in AST, ALT and GGT reported, as well as jaundice and hepatitis.41 Severe hepatic toxicity probably more common with quetiapine (1.65% of patients) than other SGAs.41 Several cases of fatal hepatic failure and of hepatocellular damage reported. A number of studies describe safe use in patients with alcohol dependence.424344
Risperidone16711Extensively hepatically metabolised and highly protein bound. Those with severe impairment should start at 0.5mg bd and increase by 0.5mg bd at a maximum rate of weekly for doses above 1.5mg bd. Risperidone Consta can be started at 12.5mg, or 25mg every 2 weeks if 2mg daily oral dosing has been tolerated. Okedi should be started at 75mg, after confirming tolerability of 3mg oral risperidone. Perseris can be given at 90mg monthly if 3mg oral risperidone is tolerated, and Uzedy at 50mg monthly if 2mg oral is tolerated. Transient, asymptomatic elevations in LFTs, cholestatic hepatitis, jaundice and rare cases of hepatic failure have been reported. Cross-hepatotoxicity with paliperidone has been reported.39 Steatohepatitis may arise as a result of weight gain.45
Sulpiride67Almost completely renally excreted with a low potential to cause sedation or constipation. Dosage reduction should not be required. Rises in hepatic enzymes are common. Isolated case reports of cholestatic jaundice and primary biliary cirrhosis.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; bd, twice a day; GGT, gamma-glutamyl transferase.

Antidepressants in Hepatic Impairment2

Of those treated with antidepressants, 0.5-3% develop asymptomatic mild elevation of hepatic transaminases.46 Onset is normally between several days and 6 months of treatment initiation and the elderly are more vulnerable.46 Frank, clinically significant liver damage however is rare and mostly idiosyncratic (unpredictable and not related to dose). Cross-toxicity within class has been described.46

Table 8.2 lists antidepressants commonly used in hepatic impairment.

Table 8.2 Antidepressants in Hepatic Impairment.

DrugComments
Agomelatine67464748

Liver injury including hepatic failure, liver enzyme increases more than 10 x ULN, and hepatitis reported, most commonly in first months of treatment. Contraindicated in hepatic impairment, including cirrhosis and active liver disease. Dose-related increase in transaminases reported; perform LFTs at baseline, 3, 6, 12 and 24 weeks during initiation and at each dose increase, and thereafter where clinically indicated. Stop treatment if transaminases rise more than 3 x ULN. Use cautiously where other risk factors for hepatic disease are present.

Under current monitoring restrictions, risk of liver injury is no higher than for other antidepressants.4950 Almost all reactions are reversible on stopping agomelatine.47

Brexanolone728No dose adjustment required in hepatic impairment. Does not appear to be hepatotoxic, although experience is limited.
Citalopram75152Hepatically metabolised and accumulates in chronic dosing. Dosage reduction required in renal impairment because of the extended half-life of citalopram in renal impairment which results in steady-state concentrations at a given dose to be about twice as high as those found in patients with normal renal function. Greater risk of QT interval prolongation because of higher drug exposure. Restrict the maximum daily dose to 20mg in hepatic impairment. Exercise caution due to the increased risk of bleeding seen with all SSRIs.
Duloxetine675354555657Hepatically metabolised. Clearance markedly reduced even in mild impairment. Reports of hepatocellular injury (liver enzyme increases more than 10 x ULN) and, less commonly, jaundice. Hepatic failure, sometimes fatal, has been reported. Contraindicated in hepatic impairment.
Escitalopram75859Hepatically metabolised and accumulates in chronic dosing. Longer half-life and 60% higher exposure in mild to moderate impairment. Initiate the dose at 5mg daily for the first 2 weeks, maximum dose 10mg daily. Careful dose titration in severe hepatic impairment. Be aware of increased risk of bleeding and QT prolongation.
Fluoxetine676061626364Extensively hepatically metabolised with a long half-life (further increased in hepatic insufficiency). Kinetic studies demonstrate accumulation in compensated cirrhosis. Dose reduction (of at least 50%) or alternate-day dosing is recommended. Attainment of steady state is delayed. Asymptomatic increases in LFTs found in 0.5% of healthy adults. Rare cases of hepatitis reported.
Fluvoxamine72865Hepatically metabolised and accumulates in chronic dosing. Dose adjustments are necessary in hepatic impairment. Low risk of hepatotoxicity. Raised LFTs rarely reported and do not require dose change or fluvoxamine discontinuation. Be mindful of increased risk of bleeding.
Levomilnacipran, milnacipran728No dose adjustment required in hepatic impairment, although the manufacturers of milnacipran advise avoiding in chronic liver disease, alcohol use or severe hepatic dysfunction. Increased liver enzymes have been reported, and hepatitis with milnacipran. Discontinue use if jaundice or liver dysfunction occurs.
MAOIs6766Rare cases of fatal hepatic necrosis, hepatotoxicity and jaundice with phenelzine. Rarely hepatitis is reported with tranylcypromine, and one isolated case of fatal hepatotoxicity with moclobemide. Doses of moclobemide should be reduced to half or one-third in hepatic impairment. Selegiline has not been associated with liver injury, although one study reported serum enzyme elevations in 41% of patients (other studies found no changes). Transdermal doses do not need to be adjusted in mild or moderate impairment (no data for severe impairment).67 Selegiline orodispersible tablets should be started at 1.25mg/day in mild to moderate impairment and are contraindicated in severe disease. Non-selective MAOIs are contraindicated in patients with hepatic impairment.
Mirtazapine6768Hepatically metabolised and sedative. 50% dose reduction recommended based on kinetic data. Mild, asymptomatic increases in LFTs seen in healthy adults (ALT>3 times the upper limit of normal in 2%). Few cases of cholestatic and hepatocellular damage reported. Has been used safely in patients with primary biliary cholangitis.69
Paroxetine707172Hepatically metabolised and accumulates in chronic dosing. Dose adjustments are necessary in hepatic impairment. Raised LFTs and rare cases of hepatitis, with or without jaundice, including chronic active hepatitis, have been reported. Paroxetine has demonstrated mild to moderate antipruritic effects in cholestatic pruritus. Be aware of increased risk of bleeding.
Reboxetine677350% reduction in starting dose advised. Does not seem to be associated with hepatotoxicity.
Sertraline7287274

Hepatically metabolised and accumulates in chronic dosing. Use a low or less frequent dose in mild hepatic impairment. Avoid in patients with moderate (Child-Pugh score 7-10) or severe hepatic impairment (Child-Pugh score 10-15).

Rare instances of acute liver injury, with or without jaundice, have been described. Sertraline is used in the management of cholestatic pruritus. Be aware of increased risk of bleeding.

Tricyclics6,7,75

All are hepatically metabolised, highly protein bound and will accumulate. They vary in their propensity to cause sedation and constipation. All are associated with raised LFTs and rare cases of hepatitis. Sedative TCAs such as trimipramine, imipramine, dothiepin (dosulepin) and amitriptyline are best avoided.
Venlafaxine/desvenlafaxine677677Dosage reduction of 50% advised in mild and moderate hepatic impairment. Rare cases of hepatitis reported.
Vilazodone7No dose adjustment required in hepatic impairment. Does not appear to affect liver enzymes and no cases of hepatotoxicity, but data are limited, and all other SSRIs have been linked to liver toxicity.
Vortioxetine67879Extensively metabolised in the liver. Little experience in hepatic impairment, but pharmacokinetic studies suggest no dose reduction is required. Does not seem to be associated with hepatotoxicity, but experience is limited and all other SSRIs are implicated in rare instances of liver toxicity.

ALT, alanine aminotransferase; LFTs, liver function tests; MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants; ULN, upper limit of normal.

Mood Stabilisers in Hepatic Impairment6, 7, 80

Recommendations for the use of mood-stabilising medications in hepatic impairment are summarised in Table 8.3.

Table 8.3 Mood Stabilisers in Hepatic Impairment.

DrugComments
Carbamazepine6780Extensively hepatically metabolised and potent inducer of CYP450 enzymes (this can cause modest elevations in gamma-glutamyl transferase and alkaline phosphatase, which in themselves are not an indication for stopping6). In chronic stable disease, caution is advised. Associated with hepatitis, cholangitis, cholestatic and hepatocellular jaundice, and hepatic failure (rare). Adverse hepatic effects are most common in the first 2 months of treatment.80 Hepatocellular damage is often associated with a poor outcome. Vulnerability to carbamazepine-induced hepatic damage may be genetically determined.80 Avoid use in acute liver disease. In chronic liver disease reduce starting dose by 50%7 and titrate up slowly, using plasma levels to guide dosage. Stop if liver function tests (LFTs) deteriorate.
Lamotrigine28Manufacturers advise 50% reduction in initial dose, dose escalation and maintenance dose in moderate hepatic impairment and 75% reduction of these parameters in severe hepatic impairment. Discontinue if there is lamotrigine-induced rash (which can be serious). Elevated LFTs and hepatitis reported. Women, children and patients taking valproate appear to be at increased risk of lamotrigine-related hepatotoxicity.
Lithium7Not metabolised so dosage reduction not required as long as renal function is normal. Use serum levels to guide dosage and monitor more frequently if ascites status changes (volume of distribution will change). Asymptomatic and transient LFT abnormalities reported in small proportion of patients on long-term therapy.28 One case of ascites and one of hyperbilirubinaemia reported over many decades of lithium use worldwide.
Valproate81Highly protein bound and hepatically metabolised. Reduce doses and closely monitor LFTs in hepatic impairment. Use plasma levels (measure free levels; total concentrations may appear to be normal) to guide dosage. Contraindicated in severe and/or active hepatic impairment or family history of severe impairment. Impairment of usual metabolic pathway can lead to generation of hepatotoxic metabolites via alternative pathway. Risk of liver toxicity is increased in people with hepatic insufficiency if salicylates are used concomitantly. Associated with elevated LFTs and serious hepatotoxicity including fulminant hepatic failure (sometimes fatal). Mitochondrial disease, learning disability, polypharmacy, metabolic disorders and underlying hepatic disease may be risk factors. Particularly hepatotoxic in very young children. The greatest risk is in the first 3 months of treatment.

Stimulants in Hepatic Impairment6, 7, 82

Recommendations for the use of stimulant medications in hepatic impairment are outlined in Table 8.4.

Table 8.4 Stimulants in Hepatic Impairment.

DrugComments
Atomoxetine83Reduce initial and target dose by 50% in moderate impairment, and by 75% in severe impairment. Very rare reports of liver toxicity, manifested by elevated hepatic enzymes, and raised bilirubin with jaundice. Manufacturer states ‘discontinue in patients with jaundice or laboratory evidence of liver injury, and do not restart'.
Dexamfetamine/lisdexamfetamine8485Little experience in liver disease. Manufacturers recommend cautious dose titration. Very rarely associated with abnormal liver function, two case reports of hepatotoxicity.8687
Methylphenidate88Mild and transient elevations in liver enzymes have been reported. Rare reports of liver dysfunction and hypersensitivity reactions. Limited experience in liver disease.

Sedatives in Hepatic Impairment

Table 8.5 summarises recommended sedatives in hepatic impairment.

Table 8.5 Sedatives in Hepatic Impairment.

DrugComments
BenzodiazepinesExtensively hepatically metabolised. Prolonged duration of effect particularly for drugs with active metabolites (diazepam, midazolam, clonazepam). Lorazepam, oxazepam and temazepam do not have active metabolites and are preferred. Lorazepam is considered the best tolerated in advanced liver disease28 and is commonly used in alcohol withdrawal. Liver enzyme elevations are uncommon and liver injury very rare.28
Melatonin789Complex handling of melatonin in liver impairment. Reduced clearance and prolonged half-life contribute to higher circulating levels of endogenous melatonin in daytime hours; negative feedback and accumulation of toxic products results in reduced endogenous production. Relevance to dosing of exogenous melatonin is unclear, although toxicity of melatonin is minimal. Manufacturer advises avoiding in moderate or severe liver disease. Rarely associated with changes in liver function tests (LFTs).
Promethazine7Extensive hepatic metabolism. Manufacturers advise caution in liver impairment. Jaundice reported with high doses. Despite widespread use, no reports of LFT abnormalities or toxicity with lower doses.28
Z drugs79091Hepatically metabolised, but all have a relatively short half-life. Reduce initial doses in mild to moderate impairment (use zopiclone 3.75mg, zolpidem 5mg, zaleplon 5mg). Avoid in severe impairment. Manufacturers warn that benzodiazepines as a class may precipitate encephalopathy. Zaleplon is subject to significant first-pass metabolism and zolpidem plasma concentrations and half-life are significantly increased in hepatic impairment. These agents should be used with caution.92 Although zopiclone has the longer half-life, this may not be clinically relevant except in severe disease.90 Zopiclone and zaleplon have not been associated with hepatotoxicity. There are rare reports of abnormal LFTs and a single case of liver injury with zolpidem.28 There is one case of acute liver injury with eszopiclone (a zopiclone isomer).93

Other Psychotropics in Hepatic Impairment

Table 8.6 gives a summary of other psychotropics recommended in hepatic impairment.

Table 8.6 Other Psychotropics in Hepatic Impairment.

DrugComments
Bremelanotide7No dose adjustment required in mild to moderate hepatic impairment. Use with caution in severe impairment; adverse effects more likely.30 One case of acute hepatitis reported.
Deutetrabenazine628Not studied in hepatic impairment but, based on experience with tetrabenazine, use is contraindicated. Limited information available but clinically relevant hepatotoxicity not reported. Occasional asymptomatic rises in ALT.
GabapentinLargely renally excreted but occasional cases of liver toxicity reported.9495
Lemborexant, daridorexant, suvorexant730No dose adjustments in mild or moderate impairment required for suvorexant. For lemorexant and daridorexant, no dose adjustment in mild impairment (risk of increased somnolence). In moderate impairment, starting and maximum dose of 5mg for lemborexant, 25mg for daridorexant. None is recommended in severe impairment. Little experience but hepatotoxicity not reported.96
Pitolisant630Extensively hepatically metabolised. No dose adjustment in mild impairment. In moderate impairment the half-life is doubled; daily dose can be increased 2 weeks after initiation, daily maximum 17.8mg. Manufacturers recommend monitoring patients with hepatic impairment for increased QTc. Contraindicated in severe impairment. Hepatic enzyme increases are uncommon. No reports of liver injury.
PregabalinNot metabolised and largely renally excreted.97 Rare cases of hepatoxicity.9899
Solriamfetol6Not metabolised. No known problems in liver impairment, no reports of liver injury.
Valbenazine728Hepatically metabolised pro-drug of α -dihydrotetrabenazine. Unlike deutetrabenazine, valbenazine is not contraindicated in liver disease, but maximum dose of 40mg in moderate to severe impairment. Few data, but no reports of clinically relevant liver injury other than a single report of reactivation of pre-existing hepatitis C.

ALT, alanine aminotransferase.

Summary of Recommended Psychotropics in Hepatic Impairment

Table 8.7 gives an outline of the drug groups of psychotropics recommended for use in hepatic impairment.

Table 8.7 Psychotropic Drug Groups in Hepatic Impairment.

Drug groupRecommended drugs
Antipsychotics

Sulpiride/amisulpride: no dosage reduction required if renal function is normal

Paliperidone: if depot required.

AntidepressantsParoxetine, sertraline, citalopram, escitalopram or vortioxetine: start at low dose. Titrate slowly (if required) as above.
Mood stabilisersLithium: use plasma levels to guide dosage. Care needed if ascites status changes.
Sedatives

Lorazepam, oxazepam, temazepam: short half-life with no active metabolites. Use low doses with caution, as sedative drugs used in severe disease can precipitate hepatic encephalopathy.

Zopiclone: 3.75mg with care in moderate hepatic impairment.

Drug-Induced Hepatic Damage

Hy's rule is defined as alanine aminotransferase (ALT) more than three times the upper limit of normal combined with serum bilirubin more than two times the upper limit of normal. This is recommended by the US Food and Drug Administration (FDA) to assess the hepatotoxicity of new drugs.80

Drug-induced hepatic damage can be due to:

  • Direct dose-related hepatotoxicity (type 1 adverse drug reaction). A small number of drugs fall into this category (e.g. paracetamol, alcohol).
  • Hypersensitivity reactions (type 2 adverse drug reaction). These can present with rash, fever and eosinophilia. Almost all drugs have been associated with cases of hepatotoxicity; the frequency varies.

Almost any type of liver damage can occur, ranging from mild transient asymptomatic increases in LFTs to fulminant hepatic failure. See Tables 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, for details of the hepatotoxic potential of individual drugs.

Risk factors for drug-induced hepatotoxicity include:100

  • Increasing age.
  • Female gender.
  • Alcohol consumption.
  • Co-prescription of enzyme-inducing drugs.
  • Genetic predisposition.
  • Obesity.
  • Pre-existing liver disease (small effect).

When interpreting LFTs, remember that:101

  • About 12% of the healthy adult population have one LFT outside (above or below) the normal reference range.
  • Up to 10% of patients with clinically significant hepatic disease have normal LFTs.
  • Individual LFTs lack specificity for the liver, but more than one abnormal test greatly increases the likelihood of liver pathology.
  • The absolute values of LFTs are a poor indicator of disease severity.

When monitoring LFTs consider the following:

  • Ideally LFTs should be measured before treatment starts so that ‘baseline' values are available.
  • LFT elevations of over two times the upper limit of the normal reference range are rarely clinically significant.
  • Most drug-related LFT elevations occur early in treatment (first month) and are transient. They may indicate adaptation of the liver to the drug rather than damage per se. Transient LFT elevations may also occur during periods of weight gain.102
  • If LFTs are persistently elevated more than threefold, continuing to rise or accompanied by clinical symptoms, the suspected drugs should be withdrawn.
  • When tracking change, >20% change in liver enzymes is required to exclude biological or analytical variation.

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