In addition to the many inherited disorders already described in this book, nerves and muscles can be affected by a wide range of drugs and toxins. Some drug-related myopathies, such as those caused by statins, steroids and alcohol, are common, while others are very rare. The widespread use of statins has resulted in these drugs becoming the commonest defined cause of myalgia and hyperCKaemia in clinical practice. It is important that the pathologist is aware of these conditions and is able to recognize them, since withdrawal of the culpable agent usually allows full recovery; otherwise, the consequences can be serious or even fatal.
Myotoxicity from drugs and toxins can result from a number of mechanisms, including direct injury to muscle cell membranes, organelles or proteins, through immunopathic processes, and as a result of secondary systemic effects, such as ischaemia and electrolyte disturbances. Drugs and toxins have also provided useful paradigms of muscle disease and have helped to elucidate cellular mechanisms. For example, zidovudine, used in the treatment of AIDS, threw light on mitochondrial DNA turnover, and the recent delineation of statin myositis has shown how innate immune mechanisms provoked by muscle fibre injury can lead to secondary autoimmune attack and a progressive myopathy.
A number of reviews have been published on drug-induced and toxic myopathies since the seminal work of , most recently and .
As with muscle diseases, in general, it is possible to classify drug and toxic effects on skeletal muscle in a number of ways, including clinical syndromes that arise, the pathogenic actions of the drugs or toxins and by pathological features. Within the context of this book, this chapter concentrates on the pathology, which is discussed under 8 main categories ( Table 23.1 ).
|Dominant Pathology||Mechanism||Drugs Commonly Involved|
|NECROTIZING MYOPATHY AND RHABDOMYOLYSIS||Myotoxicity||Alcohol, statins, fibrates|
|Inhibition of acetylcholinesterase||Organophosphates|
|Myotoxicity||Opiates, amphetamine and derivatives|
|Hypokalaemia||Diuretics, liquorice derivatives, alcohol|
|Impaired protein metabolism||Retinoids|
|Myofibrillar myopathy-like||Impaired protein metabolism||Emetine (ipecac)|
|Inflammtory myopathy (including immune-mediated necrotizing myopathy)||Immune mediated||Statins, immune checkpoint inhibitors, d-penicillamine|
|Eosinophilia myalgia syndrome||Immune mediated||L-tryptophan|
|Macrophagic myofasciitis||Immune-mediated local reaction||Vaccine with aluminium-based adjuvant|
|MITOCHONDRIAL MYOPATHY||Inhibition of mitochondrial polymerase-γ||Nucleoside analogues, ciclosporin, germanium|
|MYOSIN HEAVY CHAIN LOSS (critical illness myopathy)||Impaired protein metabolism, ion channel and mitochondrial dysfunction, immobilization||Neuromuscular blockade in combination with steroids and mechanical ventilation|
|TYPE 2 FIBRE ATROPHY||Impaired protein metabolism||Alcohol, corticosteroids|
|Autophagic vacuoles with myelinoid and curvilinear bodies||Inhibition of lysosomes||Chloroquine, amiodarone|
|Autophagic vacuoles||Inhibition of microtubular polymerization||Colchicine|
|Featureless||Hypokalaemia||Diuretics, liquorice derivatives, alcohol, amphotericin|
|NEUROMYOPATHY||Inhibition of microtubular polymerization||Vincristine|
|FOCAL NECROSIS, INFLAMMATION AND FIBROSIS||Repeat local injection||Antibiotics, opiates|
Clinical presentations include acute or subacute painful proximal myopathy , rhabdomyolysis and chronic progressive myopathy . Some drugs and toxins produce a specific pathology, but others can cause a variety of pathological changes and clinical presentations. For example, alcohol can cause an acute or subacute painful myopathy and may precipitate rhabdomyolysis, but, paradoxically, more often produces a slowly progressive painless myopathy. Focal muscle disease due to localized toxic effects may also occur.
Necrosis and Rhabdomyolysis
Many drugs and toxins can precipitate muscle fibre necrosis of varying degrees, resulting in an acute or subacute painful myopathy, characterized by generalized myalgia and muscle tenderness, especially in proximal muscles, and a marked increase in creatine kinase (CK) levels ( ). Toxicity may result from the direct myotoxic action of drugs, by immune reactions resulting in inflammation, or by causing severe acute hypokalaemia (see Table 23.1 ). Some drugs and toxins have several modes of myotoxic action, and some are unknown. In addition to the necrosis, phagocytosis and fibre regeneration occur, together with non-specific changes such as variation in fibre size and an increase in internal nuclei.
Rhabdomyolysis is widespread acute muscle fibre necrosis, resulting in the dissolution of many muscle fibres; it can be induced by most of the drugs or toxins that cause an acute or subacute painful myopathy ( ). Alcohol and opiates (particularly heroin and cocaine) and other drugs of abuse are common culprits. Statins have been frequently implicated in the recent past but less so since their potential myotoxicity has been recognized. Anaesthetic agents can also cause rhabdomyolysis, and some snake venoms have widespread toxic effects in addition to those that result in only focal necrosis. There have also been a number of reports of rhabdomyolysis, including fatalities, following ingestion of certain types of wild mushrooms ( ). In addition to toxic effects, rhabdomyolysis with myoglobinuria can also occur in hereditary myopathies and idiopathic inflammatory disorders (see Table 20.2 ).
Agents causing acute rhabdomyolysis generally do so by precipitating metabolic failure of muscle fibres, with acute breakdown of sarcolemmal membranes. This may result in a massive leakage of intracellular contents such as myoglobin and CK, and an influx of calcium, causing further cellular disruption. Depending on when or where the biopsy is performed, pronounced fibre necrosis may be seen, but it is not uncommon to see surprisingly little pathology in the muscle, even with a CK over a 1000 × the normal limit.
Alcohol is a common cause of muscle injury, damaging the muscle membranes, probably through the action of acetaldehyde and free radicals. This is reflected in increases in sarcoplasmic reticulum calcium adenosine triphosphatase (ATPase) activity and cholesterol metabolites ( ). Necrotizing alcoholic myopathy presents with muscle swelling, cramping and pain, which may be focal and often follow a period of intense drinking. Although alcohol can induce necrosis and rhabdomyolysis, sometimes associated with severe hypokalaemia, a more common myotoxic effect is type 2 fibre atrophy, which is associated with a mild chronic and frequently painless myopathy (see later).
Opiates and other ‘street’ drugs of abuse are also common causes of muscle fibre necrosis but are more often implicated in drug-induced rhabdomyolysis. Stimulant drugs, such as phencyclidine (PCP, ‘angel dust’), are thought to induce necrosis through extreme motor hyperactivity.
Statins are inhibitors of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, the precursor of cholesterol. They reduce cholesterol synthesis and lower LDL (low-density lipoprotein) cholesterol levels in the blood, and also have immunosuppressive and neuroprotective actions. However, they also affect cholesterol metabolism in cell membranes, and this is potentially damaging to the sarcolemma, sarcoplasmic reticulum and mitochondria. It should be noted that any agent that significantly reduces cholesterol levels could have such an effect. For example, toxic myopathy has also been reported in individuals using red yeast rice, a dietary supplement used as an alternative to cholesterol-lowering drugs ( ).
Adverse reactions involving skeletal muscle are the commonest side effects of these drugs and myotoxicity has been reported in between 1 and 10% of patients ( ). A number of clinical syndromes have been identified ( Table 23.2 ), but it should be noted that results from a meta-analysis demonstrated that mild muscle problems such as myalgia occur in about the same frequency in patients on statin treatment as in controls given placebo ( ):
HyperCKaemia and myalgia may occur independently, or in concert, in about 5–10% of patients. However, mild musculoskeletal problems may also occur independently of statin treatment ( ). If raised, the CK level does not usually exceed 10 × the upper control range, although it may increase further after exercise, which typically worsens the myalgia. Biopsy is not usually required but, if undertaken, occasional necrotic or ragged-red fibres may be seen.
More severe myotoxicity can result in an acute or subacute painful proximal myopathy , with more dramatic pathological changes, including focal inflammatory responses around necrotic fibres. If statin induced, withdrawal usually results in symptom resolution and normalization of CK within 2–3 months ( ).
Rhabdomyolysis is the most extreme toxic manifestation of statins, occurring in about one per million prescriptions, and can be fatal ( ).
Chronic myopathy may develop in a small proportion of cases . Occasionally, there is no improvement in symptoms or fall in CK when the statin is stopped, and the myopathy continues to progress. This is an indication for biopsy. Pathological changes such as ongoing necrosis, inflammation, fibre vacuolation and ragged-red fibres ( ) can be seen, and studies have established that a secondary immune-driven pathology can develop, although this is a rare event occurring in 2 or 3 of 100,000 patients treated with statins ( ) (see statin myositis below).
In other cases, myopathy can evolve insidiously following introduction of a statin because the drug unmasks an underlying primary neuromuscular disease , such as inclusion body myositis (IBM), a metabolic myopathy, amyotrophic lateral sclerosis (ALS) or myasthenia gravis. It is not established that statins worsen the clinical course of the underlying myopathy.
|HyperCKaemia||Asymptomatic. CK increases with exercise. Resolves with drug withdrawal||Normal, or isolated necrotic fibres|
|Myalgia ± hyperCKaemia||Normal muscle strength. Resolves with drug withdrawal||Normal, or isolated necrotic fibres. Mitochondrial pathology may be seen|
|Acute or subacute painful proximal myopathy||Symmetrical proximal weakness, myalgia, raised CK. Resolves within 2–3 months of statin cessation||More widespread fibre necrosis, some macrophage activity, myopathic changes and regeneration. Sometimes mitochondrial and focal inflammatory changes|
|Rhabdomyolysis||Acute, severe proximal myopathy, often myalgia, CK usually > 30,000 U/L, myoglobinuria||As above but may show surprisingly little abnormality|
|Immune-mediated necrotizing myopathy||Muscle weakness, high CK (> 10 × normal) and progression despite statin cessation (> 2 months). HMGCR autoantibodies are present in two-thirds of cases||Muscle fibre necrosis and regeneration. MHC-class I may be up-regulated but inflammation is usually not prominent|
|Unmasking of other myopathies||Unmasking myopathies such as metabolic myopathies, inflammatory myopathies and ALS, with or without aggravation of the course||Same as underlying disease|
Statin myotoxicity appears to result principally from injury to muscle fibre membrane systems. Sarcolemmal damage allows an influx of calcium, resulting in cycles of fibre necrosis. Experimental studies have shown accumulation of subsarcolemmal autophagic lysosomes, with degeneration of mitochondria and the sarcoplasmic reticulum, followed by marked necrosis and regeneration with macrophage infiltration ( ) ( Fig. 23.1 ). In addition, statins have effects on a number of metabolic and signalling pathways. For example, statins inhibit the biosynthesis of coenzyme Q 10 (CoQ10, ubiquinone), which participates in electron transport during oxidative phosphorylation. It is noteworthy that inhibition of mevalonate kinase, but not enzymes more distal in the cholesterol synthesis pathway, causes muscle fibre damage. This enzyme is essential for isoprenylation, which is vital for optimal function of a number of muscle and nuclear membrane proteins, including lamin A/C and the dystroglycans, and also for ubiquinone biosynthesis. Serum levels of CoQ10 are reduced by half in patients taking statins. However, 50% of the body’s ubiquinone is obtained through the diet, and muscle CoQ10 levels remain normal in statin myopathy. Furthermore, CoQ10 supplementation does not seem to protect against statin myotoxicity, so the role of CoQ10 deficiency in statin myotoxicity is unclear ( ).
There are also analogies between statin myopathy and the myopathy of selenium deficiency, and it has been suggested that these drugs might inhibit selenium metabolism in muscle ( ).
The toxicity of different statins is broadly proportional to their lipophilicity and their dependence on cytochrome P450 ( CYP3A4 ); statins are generally metabolized in the liver, except pravastatin, which is cleared principally through the kidneys. Thus, cerivastatin was withdrawn because the incidence of rhabdomyolysis with this drug was orders of magnitude greater than for other statins, owing to its high lipophilicity and bioavailability. There is also some evidence that toxicity is dose related, but evidence from meta-analyses of randomized controlled trials and primary care data is conflicting regarding the relative myotoxicity of individual drugs ( ). This may be because endogenous genetic factors also play a part. Genome-wide association studies have shown that certain mutations in SLCO1B1 , which encodes the hepatic anion transporter OATP1B that imports statins into hepatocytes for catabolism, strongly increase susceptibility to myotoxicity ( ), as do particular mutations in CYP3A4, COQ2 (involved with ubiquinone synthesis) and certain 5HT (5-hydroxytryptamine; serotonin) genes. As noted, statins can unmask previously asymptomatic primary myopathies, and there have been a number of reports of cases of previously asymptomatic McArdle disease, Pompe disease, carnitine palmitoyl transferase (CPT) deficiency, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and multiple acyl-CoA dehydrogenase deficiency that were revealed in this way. However, patients with statin rhabdomyolysis typically show no abnormalities in the genes for these diseases ( ).
What is clear, however, is that the myotoxicity of statins can be greatly increased by co-administration of a number of other drugs that depend on cytochrome P450, in particular gemfibrozil, amiodarone, ciclosporin, macrolide antibiotics, warfarin, digoxin, antiretrovirals and azole antifungicides ( ).
Fibrates , which have a number of actions, including reduction of hepatic triglyceride release, are sometimes used to lower cholesterol in patients who are intolerant of statins. These drugs can occasionally cause muscle fibre injury independently ( ), by up-regulation of lipoprotein lipases, but are more often implicated when used in conjunction with statins through increased inhibition of hepatic cytochrome P450. In this context, gemfibrozil is significantly more myotoxic than fenofibrate. Clofibrate may also cause myotonia through its effects on membrane lipids, as also observed experimentally with lovastatin ( ).
Steroids generally cause a slowly progressive painless myopathy with atrophy of type 2 fibres (see later), but large doses of intravenous hydrocortisone can precipitate myonecrosis. High daily doses of oral prednisolone or dexamethasone (over 100 mg daily) can cause myopathic weakness within 2 weeks in cancer patients ( ), probably through the combined effects of the steroids and paraneoplastic processes. Intravenous steroids given in conjunction with neuromuscular blockade, usually in intensive care, can cause an acute quadriplegic myopathy, although in that situation the pathology and pathogenesis are different (see ‘ Myosin Heavy Chain Loss’ section below).
Large doses of vitamin E and vitamin A derivatives, such as etretinate and isotretinoic acid , used in the treatment of acne and other skin disorders, can cause muscle necrosis, and the amoebicide emetine , the active component of ipecac, used mainly as an emetic in the management of acute poisoning, may also cause this syndrome. However, here, the drug affects the myofibrillar architecture, resulting in changes reminiscent of myofibrillar myopathy with disruption of myofibrils and cytoplasmic bodies ( ) (see Ch. 16 ). Cardiotoxicity can similarly be a feature. Antipsychotics , such as haloperidol and the atypical antipsychotics, can have mild myotoxic effects, resulting in CK levels of around 1000 U/L, probably through blockade of 5HT receptors in the sarcolemma.
With regard to toxins, organophosphates inhibit acetylcholinesterase at the neuromuscular junction, causing excessive acetylcholine accumulation and calcium influx into muscle cells, and resulting in myonecrosis. A muscle biopsy will generally show a mixed picture of ongoing fibre necrosis with macrophage activity, together with regeneration, but relatively little inflammatory infiltration.
Severe hypokalaemia can also lead to necrosis and an acute painful myopathy. This has been reported in association with alcohol (often with accompanying hypokalaemia and hypomagnesaemia), diuretics (particularly long-acting agents such as chlortalidone), purgatives, amphotericin B (which causes renal potassium loss) and glycyrrhizic acid derivatives (liquorice, carbenoxolone). A sustained fall in serum potassium to around 1–2 mM, with severe hypochloraemic alkalosis, can cause a profound flaccid, areflexic weakness but with florid changes on electromyography (EMG), reflecting muscle fibre necrosis and membrane damage. Scattered fibre necrosis may be seen in the biopsy, but, typically, this is an acute-on-chronic presentation, and there are also changes of more long-standing damage, such as type 2 fibre atrophy and vacuole-like structures.
A number of drugs exert myotoxic effects through inflammation. Because of their widespread use, statins are now the most common cause of this phenomenon. It is recognized that statins can provoke myasthenia gravis, vasculitis, lupus erythematosus and autoimmune hepatitis and clearly have actions on immune effectors ( ). As noted previously, some patients develop a statin myopathy that fails to resolve with drug withdrawal and may develop clinical and pathological features of an inflammatory myopathy. These conditions are referred to generically as statin myositis or statin-associated autoimmune myopathy ( ). Immune-mediated necrotizing myopathy (IMNM), or necrotizing autoimmune myopathy (NAM), is characterized by muscle fibre necrosis and macrophage infiltration of necrotic fibres and focal or generalized moderate major histocompatibility class I (MHC-I) up-regulation but no or minor lymphocytic cell infiltration (see Ch. 22 ).
NAMs are principally humorally mediated. Most cases prove to be paraneoplastic or associated with anti-SRP. In keeping with this, a strong association has been found between statin-induced NAM and autoantibodies to the statin target enzyme HMG-CoA reductase (HMGCR) ( ). It is likely that the initial muscle necrosis leads to innate immune responses that in some cases provoke a secondary autoimmune response. This might include pathogenic autoantibodies, as may occur in patients with primary genetic myopathies who develop anti-acetylcholine receptor antibodies (AChR-Abs) ( ). Notably, occasional patients may develop anti-HMGCR autoantibodies without statin exposure ( ), but found that 24 of 26 patients who were positive for anti-HMGCR autoantibodies and were > 50 years old were on statin medication before onset of disease.
Patients with statin myositis require steroids and immunosuppression, which in the case of IMNM is often protracted, requiring multiple agents, including interventions effective against humoral mediators.
An emerging group of inflammatory myopathies are associated with usage of immune checkpoint inhibitors that block either the cytotoxic T-lymphocyte antigen-4 (CTLA4) or the programmed cell death protein-1 (PD-1/PD-L1) pathways. These immune checkpoint inhibitors have dramatically changed the care and prognosis of many advanced cancers. A variety of skeletal muscle complications have been reported, including myasthenia gravis and various inflammatory and necrotizing myopathies ( ).
Inflammatory myopathy has also been reported in connection with d-penicillamine treatment for rheumatoid disease, scleroderma and systemic sclerosis, Wilson disease and cystinuria. Recovery follows withdrawal of the drug, although steroids may be required. Fatal myocarditis has also been reported. It should be noted that this drug more commonly precipitates antibody-positive myasthenia gravis. Other drugs reported to induce inflammatory myopathy include L-dopa, phenytoin, procainamide, leuprorelin, propylthiouracil and cimetidine . Polymyositis has also been reported with α -interferon treatment for chronic viral hepatitis, although in some reports it is unclear whether the drug or hepatitis C virus precipitates this. Ciguatera poisoning may also cause inflammatory myopathy.
Eosinophilic myofasciitis was reported with the use of L-tryptophan in the 1980s and early 1990s but was eventually shown to be due to adulterants in batches of the drug from certain US manufacturers. Macrophagic myofasciitis was reported from France at the end of the 1990s ( ). This appears to be due to aluminium in certain vaccination products ( ) (see Ch. 22 ; Fig. 22.30 ).
Zidovudine (azidothymidine, AZT), a nucleoside analogue reverse-transcriptase inhibitor (NRTI), is used in the treatment of HIV infection, usually in combination with other elements of highly active antiretroviral therapy (HAART). It inhibits mitochondrial DNA (mtDNA) polymerase-γ (POLG), resulting in marked depletion of mtDNA and increased amounts of somatic mtDNA deletions and features typical of a mitochondrial myopathy ( ) (see Ch. 18 ). Other NRTIs tend to cause neuropathy, again through mitochondrial injury, although fialuridine and stavudine were also reported to cause a mitochondrial myopathy ( ). Clinically, large doses of AZT cause a subacute painful proximal myopathy in HIV-positive patients, evolving over months, with high CK, weight loss and increase in plasma lactate. Lower doses cause myalgia and fatigue. Recovery occurs following drug withdrawal, over 1–2 months. Biopsy shows aggregates of abnormal mitochondria, resulting in ragged-red fibres, large numbers of cytochrome c oxidase (COX)-negative fibres and, ultrastructurally, abnormal mitochondria ( ) ( Fig. 23.2 ).