Adverse effects of drugs on the liver

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15 Adverse effects of drugs on the liver

B.E. Featherstone

Key points

• Approximately 20–30% of acute liver failure cases are attributed to drugs.
• Risk of drug-induced liver disorders increases with age and is generally more common in women.
• Generally, drug-induced liver damage is either dose-related or idiosyncratic.
• Drugs can cause all types of liver disorder and should always be considered in patients presenting with liver-related problems.
• The clinical features of drug-induced hepatotoxicity vary widely, depending upon the type of liver damage caused.
• Treatment of drug-induced hepatotoxicity relies on correct diagnosis, prompt withdrawal of the causative agent and supportive therapy.
• Patients given potentially hepatotoxic drugs should be monitored regularly and taught how to recognise signs of liver dysfunction and advised to report symptoms immediately.
• Drugs causing dose-related hepatic toxicity may do so at lower doses in patients with liver disease than in patients with normal liver function and idiosyncratic reactions may occur more frequently in patients with existing liver disease.
• Any new drug has the potential to cause hepatotoxicity. Post-marketing surveillance is important to highlight new potential hepatotoxic effects.

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).

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Fig. 15.1 The spectrum of drug-induced liver disease. ALF, acute liver failure; ALT, alanine transferase; ULN, upper limit of normal; % incidence of population taking medication.

Table 15.1 Characteristics of the different types of acute liver failure (Richardson and O’Grady, 2002)

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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

Pre-existing liver disease

Pre-existing liver disease may increase the risk of developing drug-induced hepatic injury with agents such as methotrexate, cytotoxic agents, aspirin and sodium valproate. In general, patients with liver disease are more likely to suffer ADRs. A past medical history of DILD from any medication has been shown to be a predictor of future DILD from other drugs.

Age

It is generally accepted that the elderly are at an increased risk of ADRs. There are multiple reasons for this, including higher exposure rates and decreased metabolism. Drug-induced hepatic injury is more likely to occur in elderly patients than in those under 35 years of age. Similarly, halothane hepatitis and isoniazid or chlorpromazine hepatotoxicity are more likely in patients over 40 years of age. The severity of the reactions also appears to increase with age, especially in those over 60 years. Sodium valproate toxicity, on the other hand, demonstrates an increased risk of developing serious or fatal hepatotoxicity in those under 3 years, with risk decreasing as age advances. Aspirin is an example of another drug causing hepatotoxicity, specificallyin children. Reye’s syndrome in children has been linked to the use of aspirin following a viral illness; it is life-threatening and associated with coma, seizures and liver failure. A cholestatic presentation of DILD is more common in older patients and hepatocellular damage is generally more common in younger patients.

Gender

The frequency of drug-induced hepatotoxicity is thought to be more common in females than males, particularly with halothane, isoniazid, flucloxacillin, chlorpromazine, erythromycin and nitrofurantoin. However, evidence from a recent series of more than 600 cases of DILD found that female gender was not a risk factor. There is weak evidence of a gender difference in toxicity of sodium valproate, being more common in boys before puberty and in females after puberty. Cholestatic jaundice associated with co-amoxiclav has been reported to be more common in males than females.

Genetics

Genetic differences that affect an individual’s ability to metabolise certain drugs may predispose to DILD. For example, both fast and slow acetylators may be more susceptible to isoniazid-induced liver damage. The conventional view is that rapid acetylators are at risk of increased toxic reactions due to transformation of acetylhydrazine by cytochrome P450 into a reactive metabolite; other studies suggest slow acetylation may result in toxicity due to formation of hydrazine, which is toxic in itself. When starting, isoniazid monitoring of LFTs is recommended monthly for the first 3 months, as toxicity is most likely to occur early in therapy.

Halothane-induced injury has been reported for multiple family members.

It is thought that a genetic predisposition to allergic forms of drug hypersensitivity could be a factor in some types of liver disease. Flucloxacillin liver injury has been associated with the human leukocyte antigen B*5701. Having this HLA haptotype confers an 80-fold increase in susceptibility to liver injury with flucloxacillin.

Enzyme induction

Alcohol, rifampicin and other drugs that induce cytochrome P450 isoenzyme 2El potentiate the risk of hepatotoxicity with other drugs such as paracetamol, isoniazid and halothane. The role of alcohol as a risk factor for DILD is, however, not clear-cut and acute and chronic alcohol consumption may have different effects.

Concomitant therapy with other anticonvulsants, particularly phenytoin and phenobarbital, is a risk factor for toxicity with sodium valproate, where 90% of cases of liver injury are associated with combination therapy.

Polypharmacy

A typical example of this is seen with NSAIDs. The risk of liver disease with NSAIDs is normally extremely low but is increased when NSAIDs are used with other hepatotoxic drugs.

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 15.4 Characteristics of intrinsic and idiosyncratic hepatotoxic reactions

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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.

Necrosis

Necrosis is characterised by cytotoxic cellular breakdown (hepatocellular destruction) and is generally associated with a poor prognosis. Drugs commonly associated with DILD have a variable propensity to cause hepatic necrosis. For example, hepatic necrosis has been reported in 3% of cases with co-amoxiclav DILD compared to 89% in individuals with halothane-induced liver injury cases.

Paracetamol causes hepatic necrosis when its normal metabolic pathway is saturated. Subsequent metabolism occurs by an alternative pathway that produces a toxic metabolite which covalently binds to liver cell proteins and causes necrosis.

Steatosis

In steatosis, hepatocytes become filled with small droplets of lipid (microvesicular fatty liver) or occasionally with lipid droplets that are much larger (macrovesicular fatty liver).Tetracyclines are thought to cause steatosis by interfering with synthesis of lipoproteins that normally remove triglycerides from the liver.

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

Hepatocellular necrosis

In severe cases, acute hepatocellular necrosis presents with jaundice and LFT abnormalities, including a modestly raised alkaline phosphatase and a markedly elevated alanine aminotransferase level of up to 200 times the upper limit of the reference range. Prolongation of the prothrombin time occurs but depends on the severity of the injury, increasing dramatically in severe cases. Microscopy reveals necrosis of the hepatocytes in a characteristic pattern.

Steatosis

Steatosis (fatty liver) is the accumulation of fat droplets within liver cells and is associated with abnormal LFTs, although the elevation of alanine aminotransferase is not as high as that seen in acute hepatocellular necrosis. Hyperammonia, hypoglycaemia, acidosis and clotting factor deficiency may also be present. Histologically, the liver damage resembles the acute fatty liver of pregnancy. Fat distribution within the hepatocyte is either microvesicular, as occurs with tetracycline, aspirin and sodium valproate, or macrovesicular where the hepatocyte cell nucleus is displaced to the periphery by a single large fat droplet. This type of damage occurs typically with steroids, methotrexate, alcohol and amiodarone.

A less severe, more chronic form of fatty liver, steatohepatitis, also occurs. Steatohepatitis differs from diffuse fattychange. Notably, the clinical symptoms and biochemistry resemble chronic parenchymal disease and the histology is similar to that seen in alcoholic hepatitis. Amiodarone is an example of a drug that can cause chronic steatohepatitis associated with phospholipidosis.

Cholestasis

Cholestasis without hepatitis is associated with a raised bilirubin and a normal or minimally raised alanine aminotransferase level. No inflammation or hepatocellular necrosis is seen. In contrast, cholestasis associated with hepatitis presents with raised bilirubin, alanine aminotransferase and alkaline phosphatase levels and a certain amount of liver damage.

Granulomatous hepatitis

Granulomatous hepatitis occurs with modestly elevated LFTs and, usually, normal synthetic liver function. Histology reveals granulomas and tissue eosinophilia.

Acute hepatitis

Acute hepatitis resembles viral hepatitis with LFTs raised in proportion to the severity of the hepatocellular damage. The best indicator of severity is the prothrombin time. Histologically, necrosis and cellular degeneration are seen in combination with an inflammatory infiltrate.

Chronic active hepatitis

Chronic active hepatitis may present as an acute injury or progress to cirrhosis. Serum transaminases are usually raised and albumin is low. The histology resembles that of autoimmune chronic active hepatitis and is associated with circulating autoantibodies. Methyldopa is an example of a drug that can cause chronic active hepatitis.

Fibrosis

In patients with fibrosis, the serum transaminase levels may be only slightly raised, and are not good predictors of hepatic damage. Microscopy shows deposition of fibrous tissues. Fibrosis may proceed to cirrhosis. Such damage may be seen with long-term methotrexate use.

Vascular disorders

A variety of drugs can cause veno-occlusive disease, which is characterised by non-thrombotic narrowing of small centrilobular veins, and is typically caused by cytotoxic agents and some herbal remedies. Use of oral contraceptives or cytotoxic agents may exacerbate an underlying thrombotic disorder and increase the risk of the Budd–Chiari syndrome (obstruction of the large veins) developing.

Tumours

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