Drugs and Toxins

Introduction

This chapter deals with the pathology of the important liver lesions attributed to drugs and toxins, with their recognition and with their differential diagnosis. There are hundreds of hepatotoxic drugs and other chemicals, and new reports of adverse drug reactions appear regularly in the literature under the acronym DILI (drug-induced liver injury). Heightened awareness of DILI during the last two decades has resulted in the creation of multicentre networks and databases in the United States, the United Kingdom, Europe and Asia which serve as ongoing resources for reporting and evaluation of new cases, data retrieval and correlation, phenotype characterisation and standardisation of nomenclature. The LiverTox website ( http://livertox.nih.gov/index.html ), developed by the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine in the United States, is a new and easily accessible source of information on over 1200 different medications, herbal agents and supplements. Other search engines available on the internet, such as PubMed, are additional resources to consult when DILI is suspected. If a liver biopsy is obtained in order to determine the cause of hepatitis, jaundice, acute liver failure or other type of liver disease, the pathologist should bear in mind that a drug cannot be exonerated simply because an adverse reaction has not been reported; there is always a first time.

Chemical injury is not confined to drugs listed in pharmacopoeias. Herbal medicines and dietary supplements, illicit drugs, criminally administered poisons, industrial chemicals, vitamins and foods have all been held responsible for liver disease. Drugs used for the treatment of liver disease have themselves been suspected of causing liver damage.

In his foreword to the second edition of Stricker’s Drug-Induced Hepatic Injury , Zimmerman wrote: ‘virtually all known acute and chronic hepatic lesions can result from drug injury’. This important observation implies that drugs should be considered as a possible cause of any liver lesion found on biopsy, but some lesions are more often produced by drugs than others. Hepatocellular necrosis, hepatitis and cholestasis in particular should arouse a greater degree of suspicion, especially if no other cause has been found. Also, some groups of drugs are associated with particular kinds of injury; non-steroidal anti-inflammatory drugs (NSAIDs), for example, are often associated with hepatocellular injury, while neuroleptic drugs mostly cause cholestasis. However, these are generalisations and a drug which causes a dose-related hepatocellular necrosis in one patient may cause non-dose-related hepatitis, cholestasis or granulomas in another.

The diagnostic pathologist should be aware of the potential of drugs and other substances to cause this wide variety of acute and chronic liver lesions and should know which lesions are most likely to be drug induced. He or she should be familiar with their likely course and outcome, and the main points of similarity and difference from other, non-drug-related liver diseases. Finally, the pathologist should know where to look up the effects of individual drugs. The LiverTox site is found at http://livertox.nih.gov/php/searchchem.php .

Classification and mechanisms

Drugs may be regarded as producing liver injury in three main ways: direct, indirect and idiosyncratic hepatotoxicity ( Table 8.1 ). Direct (predictable) hepatotoxins are those which predictably produce liver damage when taken in sufficient quantities: the chemical or its metabolites cause structural damage to cells and organelles. The type of damage is often characteristic of a particular drug; for example, the typical result of paracetamol (acetaminophen) overdose is hepatocellular necrosis and steatosis. Direct hepatotoxicity can often be studied in laboratory animals. This type of hepatotoxicity is also frequently zonal in distribution; examples of this are the perivenular lesions of paracetamol and carbon tetrachloride and the periportal necrosis seen in phosphorus and ferrous sulphate toxicity. In indirect hepatotoxicity the chemical interferes with a specific metabolic pathway or cell component. Agents in the class include monoclonal antibodies (e.g., checkpoint inhibitors and anti-tumor necrosis factor drugs such as infliximab) that may cause an immune-mediated hepatitis, sometimes with autoimmune histologic and serologic features.

The more common kind of drug-related liver damage is idiosyncratic (unpredictable) . Only a small proportion of patients on a particular drug is affected, so that the adverse reaction is not detected in initial human trials. Antibiotics and psychoactive drugs are the most common cause of idiosyncratic DILI in Western countries. Many different mechanisms for idiosyncratic hepatotoxicity have now been elucidated. They include individual genetic variation in the metabolism of drugs, and the development of immune reactions to a drug or its metabolites. The immune reactions may be directed to neoantigens produced by the binding of reactive metabolites to hepatic drug-metabolising enzymes of the P450 system. In some instances the distinction between an idiosyncratic and intrinsic drug reaction is difficult to make. Typical idiosyncratic damage may follow a small dose of the offending drug, and cannot easily be studied in the laboratory. With the exception of a few drugs shown to cause liver damage in patients using a particular metabolic pathway, idiosyncratic drug injury is unpredictable in the sense that the susceptibility of individual patients cannot be tested before the drug is given.

Most intrinsic hepatotoxins produce liver damage within a few hours or days, whereas in the idiosyncratic type of injury there is often a latent period of many days, weeks or months before liver disease becomes apparent. The latent period tends to shorten with repeated administration of the drug. Because of the latent period and the tendency for idiosyncratic injury to mimic non-drug-related liver diseases, clinicians and pathologists need to be alert to the possibility of idiosyncratic drug injury if diagnostic errors are to be avoided. The clinician may be helped by compiling specific data and by using a causality scale. The pathologist may be helped by finding a suspicious or characteristic pattern of injury. Conclusive proof that a particular drug or combination of drugs is responsible is often impossible to obtain, although rechallenge (usually inadvertent) can provide strong circumstantial evidence. Liver injury may follow inadvertent rechallenge many years after a first episode. Biochemical evidence of improvement after drug withdrawal is occasionally supported by a return to normal histology.

Commonly implicated and newer agents

The growth of international databases and registries of drug hepatotoxicity has provided more comprehensive information pertaining to the risks and likelihood of specific drugs and other agents causing liver injury. For example, amoxicillin–clavulanate is the most implicated agent in DILI in prospective studies from Spain, the United States and Iceland. Isoniazid and nitrofurantoin are also among the top five implicated drugs.

While such commonly implicated agents naturally warrant consideration in cases of suspected DILI, new and newly popularised agents also require exclusion. The immune checkpoint inhibitors are a case in point for which the histologic features of liver injury have become better recognised as their use in cancer immunotherapy has grown in recent years. Immune checkpoint inhibitors block two downstream regulators of immunity: cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death ligand 1 (PD-L1). Ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-L1) are commonly used checkpoint inhibitors that have resulted in fibrin-ring granulomas and lobular hepatitis on liver biopsy. Pembrolizumab also has been associated with prominent lobular hepatitis, mild bile-duct injury with mild portal vein endotheliitis and numerous necroinflammatory collections of Kupffer cells and lymphocytes resembling microgranulomas. Certain checkpoint inhibitors also may cause biliary injury, such as pembrolizumab-associated secondary sclerosing cholangitis. Even the highly successful direct-acting antiviral agents such as sofosbuvir that have revolutionised the treatment of hepatitis C virus are not necessarily exempt from hepatotoxicity, as a recent study has suggested. Biologic agents used in the treatment of rheumatic diseases require careful monitoring because serious liver and systemic injury may occur, such as the development of hepatosplenic T-cell lymphoma following the use of tumour necrosis factor-alpha (TNF-α) inhibitors infliximab, adalimumab and etanercept.

Morphological categories

The categories described in the following sections represent the main changes attributed to drugs and toxins, apart from alcohol-related liver damage ( Ch. 7 ), neoplasms ( Ch. 11 ) and vascular lesions ( Ch. 12 ). A mixture of lesions may be found in the same liver: amiodarone, for example, produces both phospholipidosis and steatohepatitis, but by different mechanisms. As already indicated, a single drug may give rise to different forms of hepatotoxicity in different patients. Phenylbutazone, for example, can cause necrosis, cholestasis, granuloma formation or combinations of these, while the NSAIDs nimesulide and diclofenac can cause either severe hepatitis or cholestasis.

Adaptation

Not all changes seen under the microscope necessarily represent liver damage. The increase in endoplasmic reticulum produced by long-term treatment with anticonvulsant drugs is commonly regarded as an adaptive phenomenon. By light microscopy, this increase is seen as an abundance of pale-staining cytoplasm in hepatocytes ( Fig. 8.1 and see Fig. 4.4 ), which is difficult to distinguish from simple abundance of glycogen on a haematoxylin–eosin (H&E)-stained section.

Non-hepatitic liver-cell damage

One of the most common manifestations of intrinsic hepatotoxicity is steatosis . As discussed in Chapter 7 , this may be macrovesicular or microvesicular. Macrovesicular steatosis, in which the nucleus of the hepatocyte is displaced by one or more fat vacuoles easily visible by light microscopy, is produced by chlorinated hydrocarbons and methotrexate, for example. It is common in patients on total parenteral nutrition, although underlying disease may also contribute to the liver changes. In patients treated with gold compounds for rheumatoid arthritis, intralobular lipogranulomas (focal accumulations of lipid-containing macrophages) have been found to contain gold pigment in the form of fine black or brown granules. These were also seen within portal lipid droplets.

Causes of the more serious microvesicular steatosis ( Fig. 8.2 ) include treatment with the anticonvulsant drug valproate and with the nucleoside analogue fialuridine. An increased risk of acute liver failure with valproate use is seen in individuals with underlying mutations in the POLG1 gene for mitochondrial DNA polymerase gamma. This leads to the combination of microvesicular steatosis with mitochondrial abnormalities, found also in Reye’s syndrome ( Ch. 13 ). Similar changes are reported after using zidovudine, didanosine ( Fig. 8.3 ) and other nucleoside reverse transcriptase inhibitors in highly active antiretroviral therapy (HAART) for acquired immunodeficiency syndrome (AIDS). In the microvesicular form of steatosis the fat within the hepatocytes is finely divided and is not always obvious with conventional stains. The hepatocyte nuclei remain in their normal central location, in contrast to macrovesicular steatosis. There is a variable degree of associated hepatocellular necrosis.

Several drugs, among them amiodarone and trimethoprim-sulfamethoxazole (co-trimoxazole), are causes of acquired phospholipidosis . Similar changes have been reported in patients receiving total parenteral nutrition. Lamellar inclusions are seen within hepatocytes and other cells by electron microscopy ( see Fig. 17.3 ). Light microscopy of conventionally stained sections is not diagnostic.

In acute arsenic intoxication, a striking increase in hepatocyte mitoses has been reported, accompanied by ballooning, cholestasis and mild inflammation. Markers of cell proliferation were also markedly increased.

An unusual form of cell injury is produced by cyanamide, used in alcohol aversion therapy. Periportal hepatocytes contain large, pale-staining cytoplasmic inclusion bodies , giving the cells a superficial resemblance to the ground-glass cells of chronic type B hepatitis ( see Figs 4.4 and 9.13 ). The inclusions are, however, orcein-negative and diastase–periodic acid–Schiff-positive.

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