CIMB, Vol. 45, Pages 78-91: Liver Damage and microRNAs: An Update

Drug-induced liver injury (DILI) is an unusual but important adverse event of several drug classes. Its occurrence is estimated to be 14 to 19 cases per 100,000 persons, with 30% of cases showing jaundice as predominant symptom [30,31]. DILI is answerable for 3 to 5% of hospitalization for jaundice [32] and is the most common cause of acute liver failure in Western countries [33,34]. Numerous risk factors have been linked with its development [35]. Compared to children, adults seem to be at higher risk for DILI, although the pediatric population is prone to develop DILI with the use of valproic acid, anticonvulsants, antimicrobials, aspirin, or propylthiouracil [36,37]. A similar pattern has been observed in female patients, but they are not at higher risk of all-cause DILI [38,39,40]. HLA alleles, genetic polymorphisms of the CYP450 and other drug-processing enzymes have been recognized and linked to DILI. In this frame, CYP polymorphisms have been categorized in five metabolic phenotypes: (i) poor metabolizers, (ii) intermediate metabolizers, (iii) normal metabolizers, (iv) rapid metabolizers, and (v) ultra-rapid metabolizers [41]. Furthermore, drugs that are processed via CYP2C19 or CYP2C9 seem to be related to a greater risk of DILI than medicines processed by CYP2D6 or CYP3A. Drug–drug interactions can also yield hepatotoxicity. Alcohol use and malnutrition can also contribute to DILI, as observed in acetaminophen-mediated toxicity [42]. DILI is classically categorized as direct idiosyncratic [43] or indirect injury. Drugs produce direct hepatotoxicity with intrinsic liver toxicity. This injury is predictable, common, dose-dependent, and replicable in animal models. It occurs within one to five days after high therapeutic planned doses or overdose [44]. Agents trigger idiosyncratic hepatotoxicity with little or no intrinsic toxicity and only cause liver injury in rare cases [31,45]. It develops irrespective of drug dose, route, or administration duration and is related to a wide spectrum of clinical pattern presentation [37]. Indirect hepatotoxicity occurs when a drug promotes liver injury as part of its mechanism of action instead of a direct insult to the liver as in the case of checkpoint inhibitors [46] or monoclonal antibodies used for autoimmune diseases. Several pathophysiological mechanisms can contribute to DILI, among these are the direct impairment of hepatocellular structure (e.g., tetracycline, valproic acid, and tamoxifen-induced mitochondrial malfunction) and function, or the production of a metabolite that affects the structural and functional integrity of the liver. Additional mechanisms are the synthesis of a reactive drug metabolite that produces new antigenic entities through the binding with hepatic proteins. These drug–protein adducts are in turn targeted by hosts’ defenses triggering a systemic hypersensitivity response that damages the liver [47,48,49]. Understanding pathophysiological mechanisms enables idiosyncratic DILI to be categorized in two forms: immune-mediated (allergic] and non-immune-mediated (non-allergic) [50]. Typical of immune-mediated idiosyncratic DILI is a shorter latency (1–6 weeks] compared to non-immune-mediated reactions (1 month to 1 year] [51,52]. However, exceptions can occur with the appearance of immune reactions after a very long latency (e.g., nitrofurantoin) [53] and in some cases even after drug cessation (e.g., sulfonamides, erythromycin, and amoxicillin-clavulanate) [52]. Generally, DILI is due to a dose-dependent toxicity, however most drugs with hepatotoxic potential provoke idiosyncratic liver injury. Paracetamol is the most common cause of direct liver injury leading to hepatic acute injury or liver failure in supratherapeutic dosage [54]. This is because cytochrome-P450--mediated acetaminophen hepatic metabolism produces a highly reactive (toxic) intermediate metabolite (i.e., N-acetyl-p-benzquinamides (NAPBQI) [55]. Normally, NAPBQI undergoes detoxification by glutathione conjugation in phase II reaction. However, during acetaminophen’s overdose, a high level of the toxic metabolite is produced, thus overwhelming the detoxification process. This process in turn leads to hepatocellular necrosis. Reports have demonstrated that liver injury mediated by this metabolite can be attenuated by the administration of acetylcysteine—a precursor of glutathione—acting as scavenger of the toxic metabolite [56]. Other important causes of direct DILI are methotrexate and amiodarone, of which chronic use induces liver fibrosis and cirrhosis in a dose- and time-dependent fashion. Acute hepatic necrosis can also be induced by high doses of aspirin, acetaminophen, niacin, and several antineoplastic agents [57,58,59]. Regarding idiosyncratic DILI, the causative drugs have diverse clinical phenotypes mimicking both acute and chronic liver disease. Acute hepatocellular hepatitis is frequently drug-induced idiosyncratic liver injury [31,37,60] and the agents usually involved are isoniazid, nitrofurantoin, and diclofenac [45,60,61,62]. Many drugs known as causative agents of acute hepatocellular injury can also lead to a chronic hepatocellular pattern [14,32] after months or years of exposure. Autoantibodies are frequently present and common causes of drug-induced, autoimmune-like chronic liver injury are nitrofurantoin, minocycline, hydralazine, methyldopa, statins, and fenofibrate [62,63]. Further clinical manifestations of idiosyncratic hepatotoxicity are the occurrence of cholestatic hepatitis or mixed hepatitis, both with favorable outcomes. Drug-induced cholestatic liver injury is often related to the administration of amoxicillin–clavulanate, cephalosporins, terbinafine, azathioprine, and temozolomide [63,64,65,66,67,68], while macrolide antibiotics and fluoroquinolone, sulfonamides, and phenytoin are common causes of drug-induced mixed hepatitis. Although the improvements in drug design and preclinical screening for toxic effects have led to drugs with better safety profiles and fewer hepatotoxic effects, many recently approved agents are still issue of concern—among these are the kinase and other targeted enzyme inhibitors. Most are antineoplastic drugs that induce transient increase in hepatic serum enzyme levels in a substantial proportion of patients, even though they rarely provoke jaundice or clinically apparent liver injury (e.g., imatinib, bortezomib, nilotinib, ribociclib, and pazopanib), [69]. Additionally, remarkable are MABs, which are frequently prescribed for cancer chemotherapy, however their therapeutic use has expanded, encompassing autoimmune diseases, migraines, hypercholesterolemia, and management after organ transplantation. Most monoclonal antibodies do not show hepatotoxicity except for those with immunomodulatory properties. Beside the classical pharmaceutical agents, one issue of concern is the hepatotoxic potential of herbal and dietary supplements (HDS). In a prospective study, HDS have been recognized as the most likely causative agent in 16% of cases of DILI [70]. However, the lack of a precise definition of DILI provoked by herbal and dietary supplements as well as the use of multiple HDS agents or the presence of a single implicated supplement of various compounds [70] mean that the attribution of herbal-induced liver injury to a single constituent is difficult. Remarkably, the clinical phenotype of hepatotoxicity related to herbal and dietary supplements is acute hepatocellular hepatitis, often severe and with a high rate of fulminant hepatic failure requiring liver transplantation [70]. Frequently involved components include green tea extracts (Camellia sinensis). Table 1 summarizes the drugs inducing DILI. The theoretical active molecular constituents are catechins, which at high doses cause liver injury in animal models. However, it must be pointed out that the amount of green tea used in the animal models were much higher than those in commercial supplements, thus the injury in humans was idiosyncratic and maybe immune-mediated [71].

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