Adverse effects of drugs on the liver

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15 Adverse effects of drugs on the liver

An adverse drug reaction (ADR) is an effect that is unintentional, noxious and occurs at doses used for diagnosis, prophylaxis and treatment. A hepatic drug reaction is an ADR which predominantly affects the liver.

Drugs can induce almost all forms of acute or chronic liver disease, with some drugs producing more than one type of hepatic reaction. Although not a particularly common form of ADR, drugs should always be considered as a possible cause of liver disease.

Epidemiology

The incidence of drug-induced liver disease (DILD) has continued to rise steadily since the late 1960s, although the incidence of idiosyncratic reactions for most drugs remains low, occurring at therapeutic doses from 1 in every 1000 patients to 1 in every 100,000 patients. DILD is not usually life-threatening; however, for the small number of patients who develop drug-induced acute liver failure (ALF) the prognosis is poor, with a 60–80% mortality rate, unless they receive a liver transplant. The incidence and severity of DILD is shown in Fig. 15.1. It is estimated that 15–40% of ALF cases may be attributable to drugs. Classification of ALF suggests three classes: hyperacute, acute and subacute (Table 15.1).

In the early 1990s, acute overdose with paracetamol accounted for 30,000–40,000 hospital admissions and over half the cases of ALF referred to liver units. It is the definite cause of approximately 100 deaths a year in the UK. ALF induced by paracetamol has become an important indication for liver transplantation. Hepatotoxicity induced by such drugs as halothane, the antituberculous agents (isoniazid and rifampicin), psychotropics, antibiotics and cytotoxic drugs still continue to cause concern.

Many drugs cause elevated liver enzymes with apparently no clinically significant adverse effect, although in a few patients there may be significant hepatotoxicity. For example, isoniazidcauses elevated liver enzymes in 10–36% of patients taking the drug as a single agent. However, only 1% suffer significant hepatotoxicity, with the liver function tests (LFTs) of the majority returning to normal if therapy is discontinued. Other examples of drugs that elevate liver enzymes are shown in Table 15.2.

Table 15.2 Examples of drugs that elevate liver enzymes

Drug Percentage of patients with increase in transaminases
Cefaclor 11%
Cefixime 0.7%
Ciprofloxacin 5%
Chlorpromazine 50%
Diclofenac 15%
Donepezil MHRA reportsa
Efavirenz 4%
Heparin/LWMH 5%
Isoniazid 10–36%
Naproxen 4%
Norfloxacin 0.1%
Nevirapine 12%
Niacin 50%
Rifampicin 15–30%
Sodium valproate 11%
SSRIs MHRA reportsa
Statins 1–2%
Sulphonamides 10%

a Available at: http://www.mhra.gov.uk

Although it is not possible to identify patients who will suffer ADRs manifesting in hepatic toxicity, a number of risk factors have been identified.

Risk factors

Concurrent diseases and pregnancy

Pre-existing renal disease, diabetes, pregnancy and poor nutrition may all affect the ability of the liver to metabolise drugs effectively and may put the patient at risk of developing liver damage. Table 15.3 summarises the host factors that may predispose a patient to drug hepatotoxicity.

Table 15.3 Examples of host factors that predispose to drug hepatotoxicity

Host factor Drug example
Pre-existing liver disease Methotrexate, aspirin, sodium valproate
Age
Older Halothane, isoniazid, chlorpromazine, co-amoxiclav, nitrofuratoin
Younger Aspirin, sodium valproate
Gender
Female Halothane, isoniazid, nitrofurantoin, flucloxacillin, chlorpromazine, erythromycin
Male Sodium valproate (in prepubescent boys), co-amoxiclav
Genetics Halothane, chlorpromazine, phenytoin, carbamazepine, phenobarbital, paracetamol, flucloxacillin
Enzyme induction Paracetamol, halothane, isoniazid, sodium valproate
Polypharmacy NSAIDs if used with other hepatotoxic drugs
Isoniazid with rifampicin or pyrazinamide
Sodium valproate with phenytoin
Paracetamol with zidovudine
Concurrent diseases
Diabetes mellitus Methotrexate
Renal failure Allopurinol, i.v. tetracycline
Malnutrition Paracetamol
HIV positive with hepatitis C or B co-infection Antiretroviral agents

Aetiology

Drug-induced hepatotoxicity may present as an acute insult that may or may not progress to chronic disease, or it can present as an insidious development of chronic disease. The type of lesion may be cytotoxic (cellular destruction) or cholestatic (impaired bile flow). Cytotoxic damage may be further classified as necrotic (cell death) or steatic (fatty degeneration). The liver damage resulting from drug toxicity often presents as a mixed picture of cytotoxic and cholestatic injury. The mechanisms of drug-induced hepatic damage can be divided into intrinsic (type A) and idiosyncratic (type B) hepatotoxicity (Table 15.4). Intrinsic hepatotoxicity is predictable, dose-dependent and usually has a short latency period ranging from hours to weeks. The majority of individuals who take a toxic dose are affected and exhibit the same type of injury. Examples are paracetamol, salicylates, methotrexate and tetracycline. Other examples are presented in Table 15.5. Toxicity may be avoided by ensuring the doses listed are not exceeded.

Table 15.5 Examples of dose-related drug-induced hepatotoxicity

Drug Toxic dose
Paracetamol Single dose >10 g
Tetracycline >2 g daily (oral), increased risk of toxicity in pregnancy and renal failure
Methotrexate Weekly dose >15 mg
Cumulative dose >2 g in 3 years, increased risk of toxicity in pre-existing liver disease, alcohol abuse, diabetes
6-Mercaptopurine >2.5 mg/kg
Vitamin A Chronic use of 40,000 units daily
Cyclophosphamide Daily dose >400 mg/m2
Salicylates Chronic use >2 g daily
Anabolic steroids High dose >1 month
Oral contraceptive Increased risk with higher oestrogen content, older preparations
Duration of treatment
Iron Single dose >1 g

Idiosyncratic reactions occur at a low frequency, typically less than 1 in 100 individuals who are exposed to the drug. The latency period is variable, ranging from 5 to 90 days from the initial ingestion of the drug. The type of injury is less predictable and not dose-related. This type of reaction may be due to either drug hypersensitivity or a metabolic abnormality. Examples of drugs that induce idiosyncratic reactions are chlorpromazine, halothane and isoniazid.

The precise mechanisms resulting in DILD are often not completely understood, although injury to the hepatocytes may result directly from interference with intracellular function, membrane integrity or indirectly by immune-mediated damage to cells.

Cholestasis

Some drugs injure bile ducts and cause partial or complete obstruction of the common bile duct, resulting in retention of bile acids and the condition known as cholestasis. Cholestasis caused by anabolic and contraceptive steroids is due to inhibition of bilirubin excretion from the hepatocyte into the bile.

The penicillins, although commonly associated with allergic drug reactions, are a very rare cause of liver disease. The isoxazoyl group present in the synthetic β-lactamase resistant oxypenicillins has been implicated as a cause of liver injury. Acute cholestatic hepatitis has increasingly been reported during treatment with flucloxacillin, and in some countries this has become the most important cause of drug-induced cholestatic hepatitis. The incidence appears to be about twice that of the related isoxazoyl penicillins cloxacillin and dicloxacillin. Moreover, there is likely to be underreporting due to a delay in onset of up to 42 days after stopping treatment. Female sex, age over 55 years, longer courses and high daily doses also seem to be associated with a higher risk of liver reaction to flucloxacillin.

Rifampicin causes hyperbilirubinaemia by inhibiting uptake of bilirubin by the hepatocyte as well as inhibiting bilirubin excretion into bile. This is generally not an indication for interrupting rifampicin therapy, although liver function will need to be closely monitored. Other therapeutic agents affect sinusoidal or endothelial cells, which may result in veno-occlusive disease or fibrosis. Vitamin A affects the fat storing cells, causing toxicity that leads to fibrosis.

Pathophysiology

The range of DILDs is illustrated in Table 15.6. Increased serum level of hepatobiliary enzymes without clinical liver disease occurs with variable frequency between drugs but for some agents it may occur in up to half the patients who receive a drug. This may reflect subclinical liver injury.

Table 15.6 Examples of adverse drug reactions on the liver

Adverse reaction Drugs associated with reaction
Hepatocellular necrosis Paracetamol
Propylthiouracil
Salicylates
Iron salts
Allopurinol
Dantrolene
Halothane
Ketoconazole
Isoniazid
Mithramycin
Cocaine
‘Ecstasy’ (methylenedioxymetamphetamine, MDMA)
Fatty liver Amiodarone
Tetracyclines
Steroids
Sodium valproate
l-Asparaginase
Cholestasis Oral contraceptives
Carbimazole
Anabolic steroids
Ciclosporin
Cholestasis with hepatitis Chlorpromazine
Tricyclic antidepressants
Erythromycin
Flucloxacillin
Co-amoxiclav
ACE inhibitors
Sulphonamides
Sulphonylureas
Phenytoin
NSAIDs
Cimetidine
Ranitidine
Trazodone
Granulomatous hepatitis Phenytoin
Allopurinol
Carbamazepine
Clofibrate
Hydralazine
Sulphonamides
Sulphonylureas
Acute hepatitis Dantrolene
Isoniazid
Phenytoin
Chronic active hepatitis Methyldopa
Nitrofurantoin
Isoniazid
Fibrosis and cirrhosis Methotrexate
Methyldopa
Vitamin A (dose-related)
Vascular disorders Azathioprine
Dactinomycin
Dacarbazine

Clinical manifestations

The clinical features of drug-induced hepatotoxicity vary widely, depending on the type of liver damage caused.

Investigations

Various types of investigation are used in the diagnosis of drug-induced hepatotoxicity, with the number and type of tests depending on the clinical presentation. Unfortunately, available laboratory tests do not provide ideal markers for DILD and the diagnosis is generally one of exclusion.

Treatment

The aim of treatment for drug-induced hepatotoxicity is complete recovery. This relies on correct diagnosis, withdrawal of any and all suspected drugs, and supportive therapy, which may include liver transplantation where appropriate.

Diagnosis

Drug-induced hepatic injury should be suspected in every patient with jaundice while ruling out other causes of liver disease by the clinical history and the results of investigations. The typical process in screening patients presenting with jaundice is outlined in Fig. 15.2 and the general approach to the differential diagnosis of acute hepatitis is set out in Fig. 15.3.

Drugs that are commonly prescribed, such as NSAIDs, antimicrobials and antihypertensive agents, are more likely to be implicated in DILD, although the frequency for the individual agents is low. Identifying the causative agent and stopping it is important in reducing the morbidity and mortality associated with DILD. Recovery normally follows discontinuation of a hepatotoxic drug. Serious toxicity or ALF may result if the drug is continued after symptoms appear or the serum transaminases rise significantly. Failure to discontinue the drug may give grounds for claims of negligence.

A detailed and thorough drug history, including use of oral contraceptives, over-the-counter medicines, vitamins, herbal preparations and illicit drug use, should be obtained. Examples of herbal and dietary preparations implicated in causing liver damage are listed in Box 15.1. Attention to the duration of treatment with a specific drug and the relationship to the onset of symptoms is important. The likelihood of a drug-related disease is greatest when the abnormality begins between 5 and 90 days after taking the first dose and within 15 days of taking the last dose. The latent period, that is, the time between starting therapy and the appearance ofsymptoms, may vary but for many drugs is sufficiently reproducible to be of some diagnostic value.

Predisposing factors for liver toxicity should also be noted. If the liver injury is accompanied by fever, rash and eosinophilia, the likelihood of drug-induced disease increases, although lack of these features does not exclude it. Unequivocal diagnosis cannot be made in most circumstances, and improvement on withdrawal of the implicated drug may provide the strongest evidence for drug-induced disease. Time for resolution of the abnormalities is dependent on the individual drug and type of liver disease. In some cases, several months may elapse.

Idiosyncratic reactions may also need to be considered and the literature consulted for previous reports. A key component of secondary prevention is the reporting of all suspected hepatic drug reactions to the appropriate monitoring agency, particularly for newer agents with fewer published cases. Many drugs are approved and licensed before the idiosyncratic reactions are identified as there is little chance of detecting the reaction in the phase III studies which typically involve 300 patients. To detect a single case of clinically significant hepatic injury due to a drug with 95% confidence, the number of patients included in the trial must be about three times the incidence of the reaction. Idiosyncratic reactions occur in about 1 in 10,000 patients so to detect the reaction, the clinical trial would have to study 30,000 patients. Practice points for diagnosing DILD are shown in Box 15.2.

Management

If clinical or laboratory signs of hepatic failure appear, hospitalisation is mandatory.

After withdrawal of the drug, attempts to remove it from the body are only relevant for acute hepatotoxins such as paracetamol, metals or toxic mushrooms such as Amanita phalloides (death cap).

If patients present a few hours post-ingestion, any unabsorbed drug may best be removed by gastric lavage, rather than by use of emetics.

Paracetamol-induced hepatotoxicity

Paracetamol causes a dose-related toxicity resulting in centrilobular necrosis. It normally undergoes the phase II reactions of glucuronidation and sulphation. However, paracetamol is metabolised by cytochrome P450 2E1 to N-acetyl-p-benzoquinoneimine (NABQI) if the capacity of the phase II reactions is exceeded or if cytochrome P450 2E1 is induced. After normal doses of paracetamol, NABQI is detoxified by conjugation with glutathione to produce mercaptopurine and cysteine conjugates. Following overdose, tissue stores of glutathione are depleted, allowing NABQI to accumulate and cause cell damage. Illness, starvation and alcohol deplete glutathione stores and increase the predisposition to paracetamol toxicity, while acetylcysteine and methionine provide a specific antidote by replenishing glutathione stores.

Ingestion of doses as low as 10–15 g of paracetamol have been reported to cause severe hepatocellular necrosis. Removal of unabsorbed paracetamol by gastric lavage may be worth-while if more than 150 mg/kg body weight has been taken and the patient presents within 4 h of ingestion. Activated charcoal may also be administered to reduce further absorption of paracetamol and facilitate removal of unmetabolised paracetamol from extracellular fluids. This may lessen the effect of any methionine given. A plasma paracetamol concentration should be taken as soon as possible but not within 4 h of ingestion due to the fact that a misleading and low level may be obtained because of continuing absorption and distribution of the drug. The plasma concentration measured should be compared with a standard nomogram reference line of a plot of plasma paracetamol concentration against time in hours after ingestion. This may be a semilogarithmic (Fig. 15.4) or linear (Fig. 15.5) plot. Generally, administration of intravenous acetylcysteine is the treatment of choice for paracetamol overdose when the blood paracetamol level is in the range predictive of possible or probable liver injury (see Fig. 15.4). Patients allergic to acetylcysteine may receive oral methionine.

Acetylcysteine is most effective within 8 h of overdose. However, late administration in patients who present more than 16–24 h post-ingestion may be appropriate. Acetylcysteine administered at this stage will not counteract the oxidative effects of paracetamol but it may have a cytoprotective role in hepatic failure, and has been shown to reduce morbidity and mortality in patients who have already developed ALF.

Patient care

Patients may be at risk of drug-induced hepatotoxicity from prescribed drugs or from purchased drugs. Additionally, children may be at risk from medicines that are not stored properly. Parents should be reminded to store all medicines in child resistant containers and out of reach. Deaths from liver failure have occurred in children following overdose with drugs commonly available, such as iron tablets.

Patient counselling

Patients who purchase preparations containing paracetamol should be made aware of the danger of overdosing, which may occur if other preparations containing paracetamol are taken simultaneously. Since 1994 the European guidelines on package labelling have required products containing paracetamol to warn patients of the need to avoid other products containing paracetamol. The pack size of paracetamol sold from general sales outlets has been limited to 16 tablets or capsules (32 where paracetamol is sold under the supervision of a pharmacist) with the aim of limiting availability and reducing residual stocks in the home. This appears to have reduced the incidence of ALF secondary to paracetamol overdose.

All patients should be advised of potential side effects. This information needs to be reinforced with the use of patient information leaflets.

Patients and their carers should be helped to recognise signs of liver disorder and know to report immediately symptoms such as malaise, nausea, fever and abdominal discomfort that may be significant, although non-specific during the first few weeks of any change of therapy. If these are accompanied by elevated LFTs, the drug should be discontinued.

Patients who recover from drug-induced hepatotoxicity should be informed of the causative agent, warned to avoid it in the future, and advised to inform their doctor, dentist, nurse and pharmacist about the occurrence of such an event.

Parents of children commenced on sodium valproate should be warned to report side effects that may be suggestive of liver injury such as the onset of anorexia, abdominal discomfort, nausea and vomiting. Early features include drowsiness and disturbed consciousness. Fever may also be present. The time to onset is between 1 and 4 months in the majority of cases.

The challenge for all members of the health care team is to alert patients to the potentially toxic effects of drugs without creating so much concern that they fail to comply with vital medication. For the limited number of drugs presented in Table 15.8, careful monitoring of LFTs during the first 6 months of treatment is advisable, although not always practical. Thereafter, regular monitoring of LFTs is appropriate in patients who are at greater risk of hepatotoxicity. Such patients would include those with known liver disease, those taking other hepatotoxic drugs, those aged over 40 years, and heavy alcohol consumers. Surveillance should be particularly frequent in the first 2 months of treatment. In patients with no risk factors and normal pretreatment liver function, LFTs need only be repeated if fever, malaise, vomiting, jaundice or unexplained deterioration during treatment occurs.

Table 15.8 Examples of drugs where regular monitoring of liver function is recommended

Drug Baseline measurementa Frequency of monitoring
Anti-TB therapy (isoniazid, rifampicin, pyrazinamide) Yes Patients with pre-existing chronic liver disease: check LFTs regularly, every week for the first 2 weeks, then twice a week for the first 2 months.
Patients with normal liver function tests and no evidence of pre-existing liver disease: regular monitoring is not necessary but LFTs repeated if signs of liver dysfunction develop, for example, fever, malaise, vomiting or jaundice.
Patients with raised pretreatment hepatic transaminases: Two or more times normal: check LFTs weekly for 2 weeks, then twice a week until normal. Under two times normal: check LFTs at 2 weeks. If these transaminases have fallen, further tests are only needed if symptoms occur
Amiodarone Yes LFTs checked every 6 months
Cyproterone Yes Recheck if any symptoms
Dantrolene Yes Repeat LFTs after first 6 weeks of therapy
Itraconazole Yes Monitor LFTs if therapy continues for more than 1 month. Recheck if any symptoms
Ketoconazole Yes LFTs checked on weeks 2 and 4 of therapy and then every month
Methotrexate Yes LFTs checked every 2 weeks for the first 2 months, then monthly for 4 months, then every 3 months
Methyldopa Yes Check LFTs at intervals during the first 6–12 weeks of treatment
Micafungin Yes Periodic monitoring of LFTs recommended. Recheck if any symptoms
Nevirapine Yes Check LFTs every 2 weeks for the first 2 months, then at month 3 and then regularly
Pioglitazone Yes Periodic monitoring of LFTs recommended. Recheck if any symptoms
Rosiglitazone Yes Periodic monitoring of LFTs recommended. Recheck if any symptoms.
Sodium valproate Yes Check LFTs regularly during the first 6 months of therapy
Statins Yes LFTs checked 12 weeks after initiation or after a dose increase and periodically thereafter
Sulfasalazine Yes LFTs checked every 2 weeks for the first 2 months, then monthly for 4 months then every 3 months
Tipranavir Yes Check LFTs on weeks 2, 4 and 8 of treatment and then every 2–3 months
Vildagliptin Yes LFTs checked every 3 months for the first year and then periodically

a Baseline and subsequent liver function tests (LFTs) difficult to interpret in critically ill patients as LFTs will be affected by multiple factors

Since many drugs cause elevation of LFTs there may be difficulty in assessing when to stop a drug, particularly when treating an individual for tuberculosis or epilepsy. An empirical guideline is that the drug should be stopped if the levels of alanine transaminase exceed three times the upper limit of the reference range. Any clinical features of liver disease or drug allergy would require immediate discontinuation of the drug. Conversely, a raised γ-glutamyl transpeptidase level and elevated alanine transaminase level in the absence of symptoms often reflect microsomal induction and would not indicate drug-induced injury.

It should be noted that monitoring of LFTs is not a complete safeguard against hepatotoxicity, as some drug reactions develop very quickly, and the liver enzymes are an unreliable indicator of fibrosis.

Minimising the risk of DILD

Cholestatic jaundice has been reported to occur in about 1 in 6000 patients treated with co-amoxiclav. The risk of acute liver injury with co-amoxiclav is approximately six times that of amoxicillin and increases with treatment courses above 14 days. Hence, the indications for co-amoxiclav have been restricted to cover infections caused by amoxicillin-resistant β-lactam-producing infections.

Patients admitted for procedures requiring a general anaesthetic should be questioned about past exposure and any previous reactions to halothane. Halothane is well known to be associated with hepatotoxicity, particularly if patients are re-exposed. Repeated exposure to halothane within a period of less than 3 months should be avoided, while some increase in risk persists regardless of the time interval since last exposure. Unexplained jaundice or delayed-onset post-operative fever in a patient who has received halothane is an absolute contraindication to future use in that individual. Patients with a family history of halothane-related liver injury should also be treated with caution.

The individuals at greatest risk of halothane hepatitis are obese, post-menopausal women. Halothane may be present in detectable amounts even in theatres equipped with scavenging devices, and it is possible for these small concentrations to provoke a reaction in a highly sensitised individual. If electing to avoid halothane, a halothane-free circuit and operating theatre should be used. Cross-hepatotoxicity with other haloalkanes is a possibility, and enflurane should also be avoided. Isoflurane appears to be safe, as no reports of cross-sensitivity have been published. Some anaesthetists would prefer to use total intravenous anaesthesia in patients who have had a reaction to halothane.

Although hepatic ADRs are rare for most drugs, when they do occur they can cause significant morbidity and mortality. Over 600 drugs have been associated with hepatotoxicity and any new drug released on to the market may have the potential to cause hepatotoxicity. Pemoline, troglitazone and tolcapone are examples of drugs withdrawn from the market due to reports of serious hepatic reactions. These examples help to highlight the importance of post-marketing surveillance and yellow card reporting.

Appropriate selection of drugs, an awareness of predisposing factors and avoidance of toxic dose thresholds and potentially hepatotoxic drug–drug interactions will minimise the risk to patients.

Practice points for patient care and minimising the risk of DILD are outlined in Box 15.4.

Case studies

Case 15.1

Mr V, a 39-year-old male, presented to his local hospital following a paracetamol overdose. He had recently separated from his wife, had not been eating properly, went on an alcohol binge and then on impulse had taken approximately 70 paracetamol tablets. He self-referred himself to his local hospital 28 h after the overdose. At presentation he was feeling nauseous and had right subcostal pain. His results at this time were:

  Actual value (normal range)
Paracetamol 18 mg/mL
Albumin 26 g/dL (30–50 g/L)
Alanine transaminase 5435 units/L (0–50 units/L)
Bilirubin 50 µmol/L (<17 µmol/L)
Alakline phosphatase 66 units/L (30–135 units/L)
Prothrombin time 57 s (9.8–12.6 s)
Creatinine 133 (35–125 µmol/L)
Urea 5.6 (0–7.5 mmol/L)

Other test results:

Hepatitis screen negative

Autoantibody screen negative

At this stage, supportive treatment was given. However, he deteriorated, with worsening test results and the development of encephalopathy. He was then transferred to a tertiary intensive care unit, with a diagnosis of ALF secondary to paracetamol overdose. His test results on admission to the intensive care unit were:

  Actual value (normal range)
Albumin 22 g/dL (30–50 g/L)
Alanine transaminase 12,477 units/L (0–50 units/L)
Bilirubin 71 µmol/L (<17 µmol/L)
Alakline phosphatase 73 units/L (30–135 units/L)
Prothrombin time 90.8 s (9.8–12.6 s)
Arterial pH 7.226 (7.350–7.450)
Lactate 6.9 (0.4–2.2 mmol/L)
Creatinine 336 (35–125 µmol/L)
Urea 7.4 (0–7.5 mmol/L)

He was put on the liver transplant urgent list and received an orthotopic liver transplant (OLT) the following day.

Answers

Although Mr V had acutely ingested alcohol at the time of paracetamol overdose, this is not a risk factor for a worse prognosis. Theoretically, acute alcohol ingestion competes with paracetamol for CYP2E1 metabolism resulting in lower formation of NAPQI and thus less toxicity. Chronic alcohol consumption induces the CYP2E1 enzyme resulting in increased NAPQI production and increased risk of hepatotoxicity.

The fact that Mr V had not been eating properly may have resulted in depleted glutathione stores and a worse prognosis.

Mr V developed hepatorenal syndrome, this is a poor prognostic indicator and has an associated mortality of 50–100%.

A poor prognosis is also associated with the following:

Prothrombin time >36 s
Creatinine >200 µmol/L
pH <7.3
Encephalopathy Present
Cerebral oedema Present
Time from onset of jaundice to encephalopathy 0–7 days

2. A plasma paracetamol level needs to be taken as soon as possible, although not within the first 4 h following paracetamol overdose. A toxic screen should be performed to exclude other drug overdoses. Supportive therapy with intravenous fluids and oxygen, if necessary, should be given. This patient should also be treated with N-acetylcysteine. Treatment with N-acetylcysteine is particularly beneficial when administered within 8 h of paracetamol overdose when the blood paracetamol level is in the range predictive of possible or probable liver injury (see Fig. 15.4). However, late administration in patients who present more than 16–24 h post-ingestion is also appropriate. Acetylcysteine administered at this stage will not counteract the oxidative effects of paracetamol but it may have a cytoprotective role in hepatic failure, improving haemodynamics and oxygen use. Late administration of N-acetylcysteine has been shown to reduce morbidity and mortality in patients who have already developed hepatic failure. Available data for use of N-acetylcysteine following paracetamol overdose suggests that, although the evidence for benefit is limited, it should be given to patients with overdose (Brok et al., 2006).

Answers

2. Monitoring of liver function tests in patients taking a statin is recommended in the Summary of Product Characteristics, and hence should be monitored for medico legal reasons (McKenney et al., 2006). It is recommended to monitor liver function tests at baseline and then at 12 weeks or after a dose increase. However, the true value for monitoring liver function test is not clear as it does not identify those at risk of liver damage, is expensive and may lead to patient anxiety and unnecessary cessation of statin therapy. Moreover, hepatic function does not appear to be compromised by statin use and there is no apparent link between an elevation in liver function tests and the development of toxicity (McKenney et al., 2006).

In this case, the simvastatin was switched to pravastatin before a repeat liver function test. Follow-up liver function tests showed that the ALT had returned to within the normal range. It is highly probable that this rise in ALT on simvastatin would have been transient and had the patient continued with simvastatin the ALT would have normalised. However, the patient was anxious, did not want to risk any progression of liver toxicity and was keen to switch to an alternative statin.

Answers

1. Hepatotoxicity among HIV-infected persons taking nevirapine is a well recognised adverse effect. The incidence of an asymptomatic increase in hepatic aminotransferase levels is reported as approximately 5–15%, with the incidence of clinically symptomatic hepatitis among persons taking nevirapine of approximately 4% (Martínez et al., 2001). It is recommended that all patients commencing on nevirapine undergo close monitoring during the first 18 weeks of treatment, with liver function tests performed at baseline, then every 2 weeks for the first 2 months again after a further 1 month and regularly thereafter.