Introduction

The liver is the main site of metabolism for drugs and other exogenous compounds. As most drugs are taken orally the liver is the portal to the tissues for such compounds following absorption from the gastrointestinal tract. The liver is, therefore, a vulnerable organ, being exposed to both the parent drug carried from the G.I. tract via the portal vein and to any metabolites produced which then enter the systemic circulation via the hepatic vein. However, despite this vulnerability, the liver is not the major target for adverse drug reactions, only about 9.5% of these involve the liver (¹). Although drug-induced hepatic damage may not be particularly common in general patient populations the case fatality rate is often high, and the severity of drug-induced hepatic injury is such that drugs are a major cause of hepatic failure( ² ). For example, the case fatality rate from halothane-induced hepatic failure may be as high as 50 %.

Chemical agents such as those used in laboratories and industries, natural chemicals (e.g. microcystins) and herbal remedies can induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxins. More than 900 drugs have been implicated in causing liver injury. chemicals often cause subclinical injury to liver which manifests only as abnormal liver enzyme tests. Drug induced liver injury is responsible for 5 % of all hospital admissions and 50 % of all acute liver failures (³). Drug related hepatotoxicity is an important cause of morbidity and mortality and indeed is the most common reason for withdrawing new drugs.

Drugs and other exogenous compounds may affect the liver in various ways. Acetaminophen, in general is regarded as a very safe drug. Nevertheless, overdose (often deliberate) of acetaminophen is a common cause of hepatic injury, accounting for ~40 % of cases of acute liver failure in the USA (⁴). Hepatotoxicity is one of the most important adverse drug reactions associated with anti-tuberculosis drugs that may limit their use. Aspirin and the salicylates have recently been recognized as potentially hepatotoxic (⁵). Phenylbutazone can cause acute liver injury without involvement of other systems with therapeutic doses and following over dosage. In this review various types of drug induced hepatotoxicity, mechanisms of drug induced hepatotoxicity and various class of drugs used in different clinical therapies causing hepatotoxicity has been dealt with.

Types Of Drug Induced Hepatotoxicity

Drug-induced liver injury covers a variety of types, and includes most of the clinical and pathological expressions of liver damage (⁶). The various types are shown in Figure 1 and discussed below in brief.

Figure1: Types of drug induced hepatotoxicity

1. Interference with bilirubin uptake, excretion and conjugation:

This may be viewed as a variant of cholestatic toxicity. For example; Rifampicin may interfere with bilirubin transport giving rise to hyperbilirubinaemia (⁷).

2. Cytotoxic injury:

This refers to overt damage to the parenchyma and is a much more serious effect than the above (⁸).

3. Cholestatic injury:

This type involves arrested bile flow and jaundice and may appear similar to biliary obstruction. It is less serious than cytotoxic injury, with a lower fatality rate.

4. Mixed cytotoxic and cholesatic injury:

Cytotoxic hepatic damage may sometimes be combined with cholestasis, for instance occasionally seen after p-aminosalicylic acid therapy (⁹).

5. Fatty liver:

Fatty liver (steatosis) may be considered as a type of cytotoxic injury, but it may also be a form of chronic hepatic damage.

6. Cirrhosis:

Macronodular cirrhosis may directly follow acute hepatic damage and primary biliary cirrhosis may result from cholestatic jaundice.

7. Phospholipidosis:

This may result from the use of drugs such as Coralgil, (4, 4’-diethylaminoethoxyhexestrol dihydrochloride), and is characterised by hepatocytes full of lipid (¹⁰).

8. Liver tumours:

Neoplastic lesions may result from drug use. Benign, liver cell adenomas have been associated with the use of contraceptive steroids (¹¹) but liver cell carcinoma associated with these drugs is more uncertain.

9. Vascular lesions:

Hepatic vein occlusion, such as that due to the thrombogenic effect of contraceptive steroids, may result in hepatic damage.

10. Chronic active hepatitis:

This is a progressive necroinflammatory liver disease which may have many causes including drugs.

11. Subacute hepatic necrosis:

This syndrome consists of progressive, overt serious liver disease with jaundice and eventual cirrhosis.

Table 1 below gives some of the important drugs of various classes causing hepatotoxicity along with their structural data.

Table 1: Important examples of drugs causing hepatotoxicity.

Mechanisms Of Drug Induced Hepatotoxicity

Certain drugs will produce predictable liver damage in the majority of cases, such as after overdoses, for instance. Others however will cause liver injury only rarely and unpredictably. There is thus a whole spectrum varying between these extremes. In some cases the mechanism may involve the parent compound; in others a metabolite may be responsible.

The various mechanisms are shown in Figure 2 and will now be discussed using specific examples, according to the type of injury.

Figure 2: Mechanisms of drug induced hepatotoxicity

1. Interference with bilirubin transport and conjugation:

A number of drugs interfere with bilirubin transport and lead to elevated plasma bilirubin or hyperbilirubinaemia. Novobiocin inhibits UDP glucuronosyl transferase and may lead to elevated plasma levels of unconjugated bilirubin especially in neonates (⁴²). Rifampicin, the antibiotic used in the treatment of tuberculosis inhibits both uptake and excretion of bilirubin in a dose related manner, giving rise to elevated plasma levels of both conjugated and unconjugated bilirubin. This is due to blockade of uptake at the plasma membrane of the hepatocyte (⁴³).

2. Cytotoxic injury:

Direct, overt damage to hepatic parenchyma may be caused by a number of drugs. However, it may have a variety of underlying mechanisms. Paracetamol causes predictable centrilobular hepatic necrosis in experimental animals as well as man after overdoses (^{44, 45}). It is well characterized and the mechanism partially understood. The liver damage is predictable and is due to direct cytotoxicity of a metabolite as indicated by extensive studies on both experimental animals (⁴⁶) and man (⁴⁷). Paracetamol is metabolised by three pathways, (Figure 3), two of which are conjugation reactions, and remove the major portion of the drug rapidly. A minor pathway accounting for about 5 % of the dose, catalysed by the microsomal enzymes yields a reactive metabolite, thought to be N-acetyl-p-benzoquinone imine. Following normal doses this is detoxified by conjugation, both chemical and enzyme catalysed, with the ubiquitous tripeptide glutathione, and excreted as the N-acetylcysteine derivative in the urine. After overdoses however, the amount of reactive metabolite is sufficient to deplete the available hepatic glutathione. The reactive metabolite then reacts covalently with cellular macromolecules. The mechanism by which this binding causes cellular damage is unknown. Isoniazid and iproniazid which are substituted hydrazine drugs may produce a hepatocellular, cytotoxic type of damage.

Figure 3: Metabolism of paracetamol showing proposed metabolic activation and its involvement in the toxicity

3. Cholestasis:

This type of reaction is the result of inability of the hepatocyte to secrete bile due to impaired bile salt secretion (⁴⁸).

Drug induced cholestatic reactions are classified as –

1] Steroid-induced cholestasis.

2] Sensitivity type of cholestasis.

1] Steroid-induced cholestasis:

E.g. C-17 substituted testosterones including orally active anabolic and androgenic agents and oral contraceptives. The jaundice induced by steroids is usually mild and reversible when the drug is stopped (⁴⁹). The reaction is dose related and develops after an initial period of medication. Bromsulphathelein (BSP) excretion is usually impaired. This reaction is predicted by –

[1] Structure of the compound – C-17 substituted testosterone.

[2] BSP excretion curves in man and rat.

[3] Electron microscopic examination of the rat liver following the administration of the drug would reveal an appreciable number of canaliculi changes such as dilation and loss of microvilli (⁵⁰).

2] Sensitivity type of cholestasis:

This type of reaction is usually associated with the phenothiazines like chlorpromazine, trifluoperazine, promazine, pecazine, etc. It is not dose-related and develops after an initial period of sensitization of 1-4 weeks or previous exposure. The common symptoms noticed are rashes, fever, eosinophilia and blood dyscrasias. The jaundice simulates surgical obstructive type, lasts for l-4 weeks and recovery is complete.

4. Mixed cytotoxic/cholestatic injury:

This type of liver injury covers damage with varying proportions of cytotoxic and cholestatic involvement. For example chlorpromazine may cause mixed hepatocanalicular jaundice with parenchymal injury as well as cholestasis. Conversely, p-aminosalicylic acid may cause mixed hepatocellular liver injury.

5. Fatty liver (steatosis):

Tetracycline is an antibiotic which may occasionally cause fatty liver after large (1.5 g/day) intravenous doses. This toxic effect is very rare after oral doses and occurs more commonly in females than males. This toxic effect of tetracycline is direct, predictable and dose dependent, and can be reproduced in experimental animals.

Figure 4: Postulated mechanisms for tetracycline induced fatty liver

The major effect seems to be inhibition of transport of lipid out of the hepatocyte, which can be detected within 30 min of dosing in experimental animals. This effect may well be due to the inhibition of protein synthesis caused by tetracycline which will inhibit the production of the apolipoprotein complex involved in transport of the very low density lipoprotein (VLDL) out of the hepatocyte (⁵¹). Alternative or additional mechanisms may involve decreased fatty acid oxidation, increased triglyceride uptake or increased fatty acid uptake. (Figure 4)

6. Chronic active hepatitis, cirrhosis and sub-acute necrosis:

Chronic active hepatitis, sometimes associated with cirrhosis is associated with the use of a number of drugs such as oxyphenisatin a-methyldopa, nitrofurantoin and isoniazid. Long term administration of the antitubercular drug isoniazid leads to hepatic dysfunction in a significant proportion of recipients (10-20%). This is usually mild and subclinical and subsides despite continued therapy. However, some 0.1-1% of patients develops severe hepatic injury. Pre-existing liver dysfunction, such as alcoholic cirrhosis increases susceptibility. The mechanism of isoniazid induced hepatic damage involves production of a toxic metabolite. The findings of Mitchell et al (⁵²) suggested that rapid acetylation might be a predisposing factor as it was reasoned that this would produce more of the metabolite acetylisoniazid and hence more acetylhydrazine. Acetylisoniazid and especially acetylhydrazine are extremely hepatotoxic causing centrilobular hepatic necrosis, in experimental animals in which the microsomal enzymes are induced by phenobarbitone.

7. Phospholipidosis:

This syndrome may be caused by a number of different drugs, and various organs may be affected. Hepatic phospholipidosis has been caused by the drug Coralgil, a coronary dilator. The features of this form of hepatic damage are an accumulation of phospholipids in hepatocytes, bile duct proliferation and inflammation in the portal area. The mechanism is thought to involve the formation of complexes between lipid micelles or liposomes, and the drug in question. The interaction between phospholipids and the drug is believed to alter the surface charge of the phospholipid micelle or liposome in such a way that the ability of phospholipases to break them down is impaired (⁵³).

8. Liver tumors:

Anabolic steroids have been implicated as responsible for primary hepatocellular carcinomas and adenomas. Similarly use of contraceptive steroids has been connected with liver tumours, particularly the oestrogenic components. The mechanism(s) is unknown (⁵⁴).

9. Non-specific changes:

Certain hypotensives, vasodilators, anti-inflammatory agents and oral contraceptives cause a transient increase in transaminase levels which revert to normal level after the drug is stopped. These reactions cannot be predicted (⁵⁵).

Drugs Causing Hepatotoxicity

1. Analgesics:

Acetaminophen (paracetamol) is among the most commonly used analgesics. It effectively reduces fever and mild to moderate pain, and is regarded, in general, as a very safe drug. Hepatic injury with acetaminophen is not only associated with overdose or use of high doses; rather, it can be encountered with chronic use at lower doses (<4g/ day), particularly in the presence of other predisposing factors, such as chronic alcohol consumption (⁵⁶). Damage to the liver following acetaminophen ingestion is not due to the drug itself, but due to a toxic metabolite that is generated through the cytochrome P4₅₀ group of enzymes in the liver. This metabolite is usually rendered harmless through an interaction with the endogenous antioxidant, glutathione. However, when there is overproduction of the acetaminophen metabolite, glutathione stores in the liver become depleted, and the metabolite begins to accumulate and cause tissue injury. Hepatic injury can be limited through administration of N-acetylcysteine, which replenishes liver levels of glutathione.

Aspirin have recently been recognized as potentially hepatotoxic. Almost all reported cases have occurred in children and young adults with connective tissue disorders such as Still's disease, rheumatoid arthritis and systemic lupus erythematosus, and females have been affected more often than males. Aspirin has been involved in the great majority of cases. About 50 % of patients with juvenile rheumatoid arthritis have evidence of some degree of liver injury as shown by elevation of plasma aminotransferases during conventional high-dosage aspirin therapy (⁵⁷). Other drug in this category includes gabapentin which shows hepatotoxicity as one of its side effects (⁵⁸).

2. Anti-tuberculosis drugs:

Hepatotoxicity is one of the most important adverse drug reactions associated with anti-tuberculosis drugs that may limit their use. Previous studies showed transient elevations of serum hepatocellular enzymes (e.g. alanine aminotransferase and aspartate aminotransferase) in approximately 10 % of patients who received a standard combination chemotherapy including isoniazid and rifampicin, of these 1–2 % patients withdrew from the treatment because of severe hepatotoxicity that ultimately led to fulminant hepatitis. Although the occurrence of drug induced hepatotoxicity is difficult to predict, it has been observed that certain patients are at higher risk during the course of anti-TB chemotherapy (^59-66). Other anti-tuberculosis drugs that can cause hepatotoxicity are pyrazinamide, rifabutin (⁶⁷).

3. Anti-hyperlipidemics:

The anti-hyperlipidemic drug with the highest potential for hepatic injury is the sustained-release formulation of niacin. HMG CoA reductase inhibitors, otherwise known as statins, very rarely cause clinically significant liver injury, although asymptomatic elevation in aminotransferases is common. The notion that ezetimibe may have less risk of hepatotoxicity has recently been challenged and it may not be a “safe alternative” to statins in patients with pre-existing liver disease (⁶⁸). The pattern of liver injury from anti-hyperlipidemics is typically hepatocellular or mixed in nature with rare instances of pure cholestatic picture (⁶⁹).

1] HMG CoA reductase inhibitors (Statins):

Initial studies of statins performed on animals revealed that very high doses of statins may cause hepatotoxicity, but typical therapeutic doses of the drug were not associated with significant liver injury (^{70, 71}) High doses of lovastatin caused significant hepatocellular necrosis in rabbits. This pattern of injury was also seen in a guinea pig model exposed to high doses of simvastatin. However, hepatocellular necrosis from statins is exceptionally rare in humans (⁷²).

a ] Atorvastatin:

Atorvastatin-related hepatotoxicity has been associated with a mixed pattern of liver injury typically occurring several months after the initiation of the medication.

b] Lovastatin:

Mixed hepatic injury in hepatocellular and cholestatic patterns has been noted with the use of lovastatin.

c] Simvastatin:

Simvastatin hepatotoxicity is hypothesized to occur due to drug-drug interactions.

d] Pravastatin:

Pravastatin has been reported to cause acute intrahepatic cholestasis. In this case, liver toxicity occurred within 2 months after initiating the drug and it resolved within 2 months after its discontinuation.

2] Niacin:

Unsupervised use of the sustained-released formulation of niacin often leads to its dose-related toxicity and should be discouraged ^(73-75). The onset of hepatotoxicity generally appears anywhere from 1 week to 48 months after the initiation of the drug and usually subsides with discontinuation (^76-78).

3] Ezetimibe:

Recent studies have noted that ezetimibe may rarely cause hepatotoxicity in the form of severe cholestatic hepatitis and acute autoimmune hepatitis. The mechanism of toxicity may be related to the metabolism of the drug; it is rapidly absorbed and glucuronidated, yielding an active metabolite and there is significant enterohepatic recirculation (⁷⁹).

4. Anti-hypertensive Drugs:

Methyl dopa is used in the treatment of hypertension. Both minor and severe forms of liver damage have been reported in patients receiving methyl dopa. The former consists of asymptomatic, and often transient, rises of serum transaminases and according to various reports is found in two to 10 % of patients receiving the drug (^80-82). The liver damage, which may take the form of acute hepatitis, chronic active hepatitis or cholestasis occurs more commonly in women (⁸³) and there is not the same close temporal relationship between the time of onset of overt clinical hepatic injury, which in 50 % of cases occurs after four weeks. In vitro studies have shown that the drug is metabolised by both human and rat liver microsomes, by the cytochrome P4₅₀ system, with consequent covalent binding to cellular macromolecules (⁸⁴). This covalent binding is inhibited by a variety of agents, including glutathione, ascorbic acid and superoxide dismutase (⁸⁵) consistent with the oxidation of methyl dopa by cytochrome P4₅₀-generated superoxide anions to a reactive quinone or semi-quinone.

5. Anaesthetic Agents:

Halothane, the most widely used anaesthetic is now accepted as causing hepatic injury. Multiple exposures are a major factor which may predispose the patient to liver injury, particularly if re-exposure occurs within 3 months. Obese patients and females seem more susceptible but children and young adults less so. A series of investigations carried out in the Liver Unit identified an antibody directed against a hepatocyte surface antigen altered by a halothane metabolite (⁸⁶). The altered antigenic determinant probably results from oxidative halothane metabolism which generates trifluroacetylated proteins. (Figure 5)

Figure 5: Mechanisms underlying predictable and immune mediated hepatotoxicity from halothane

It is likely that all individuals exposed to the drug generate altered hepatocyte membrane determinants but only a small minority mounts an immunological reaction against them (⁸⁷). The fact that many patients with severe halothane hepatitis have circulating antibodies directed against other organs in the body strongly suggests an underlying, genetically determined defect in immune regulation (⁸⁸). In contrast, some patients with hepatitis from the drug have no evidence of immune involvement, and liver damage in these cases is probably the result of overproduction of a hepatotoxic derivative produced by reductive halothane metabolism. Preferential stimulation of this pathway in experimental animals produces dose related hepatotoxicity (⁸⁹).

6. Drugs used in Anti-retroviral therapy:

Giuseppe Lapadula et al. reported the importance of stavudine as a possible causative agent of hepatotoxicity, even in the absence of other signs of mitochondrial toxicity. Stavudine is a drug used in anti-retroviral therapy. Highly active anti-retroviral therapy (HAART) is associated with a number of serious and potentially life-threatening adverse events, including drug-induced hepatotoxicity. In patients with chronic viral hepatitis coexistence, HAART-related hepatotoxicity develops more frequently or sooner, and also in a more severe form (⁹⁰).

Conclusion

It is clear that drugs may cause a wide variety of hepatic lesions. In some cases these may be indistinguishable pathologically and biochemically from lesions due to other causes. Drug-induced hepatic damage ranges from the unpredictable and non-dose related to that occurring predictably after overdoses. Drug heptatotoxicity may involve metabolism to toxic, reactive intermediates and covalent interactions with cell constituents, interference, with membrane transport or with cellular biochemistry such as protein synthesis, or immunological mechanisms. The occurrence of hepatic damage may be modified by differences in immune responsiveness and genetic, dietary and other factors. Various clinical therapies should involve drug induced hepatotoxicity as an important parameter. In conclusion intensive research on drugs available in the market and those under clinical trials has to be conducted so as to answer the questions to the management of drug inducing hepatotoxicity. Future researches will have to take into account the multi-factorial aspects of drug induced hepatic injury.