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

Tumours

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