- •
Type A, or intrinsic, adverse drug reactions are dose-related, predictable toxic effects of medications, such as acute liver failure resulting from acetaminophen overdose.
- •
Type B or idiosyncratic adverse drug reactions are less related to dose and are associated with drug, patient, and environmental risk factors, which can be difficult to predict.
- •
Resources such as LiverTox assist with earlier detection of idiosyncratic adverse reactions in postmarketing use and can help guide diagnosis and
Adverse Drug Reactions: Type A (Intrinsic) or Type B (Idiosyncratic)
Section snippets
Key points
Type A (intrinsic) adverse drug reactions
Adverse drug reactions classified as Type A, or intrinsic, are defined as predictable adverse effects associated with an agent and are related to dose.7 As the dose of the administered agent increases, the risk of adverse event increases with it, in accordance with the pharmacologic profile of the agent.7, 8 Type A adverse effects are predictable side effects and may also be characterized as drug toxicities. Because of their predictable nature, Type A adverse effects generally have relatively
Type B (idiosyncratic) adverse drug reactions
Type B adverse drug reactions, or idiosyncratic drug reactions, are unanticipated adverse effects associated with an agent.7 They result from a combination of factors unique to the individual.5, 8, 10, 11, 12 Differences between Type A and Type B adverse drug reactions are summarized in Table 2. Although it is difficult to estimate the true incidence of idiosyncratic drug-induced liver injury due to incomplete recognition and reporting, it is thought to range from 1 in 1000 to 1 in 200,000,
Predicting drug-induced liver injury
Several methods have been used to predict the occurrence of and severity of drug-induced liver injury. The most well-known and frequently cited of these is Hy’s Law. Named for the late Dr Hyman Zimmerman, whose research and clinical insight formed much of the basis for current thinking on hepatotoxicity, Hy’s Law helps to evaluate the risk of drug-induced injury developing into ALF. Briefly, Hy’s Law is based on observations that when jaundice becomes evident in combination with drug-induced
Resources for clinicians
Initially launched in 2012, LiverTox (available at: www.livertox.nih.gov) is a free online resource that allows clinicians to access current, comprehensive information about hepatotoxicity caused by medications and to assist with diagnosis and management of drug-induced liver injury.3 The LiverTox Web site was created as a collaborative effort between the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Division of Specialized
Isoniazid
The ways in which idiosyncratic drug-induced injury is identified have evolved over time. The current architecture drug-induced liver injury monitoring in the United States is depicted in Fig. 2. Electronic resources have allowed for much quicker identification of these uncommon adverse events. The isoniazid experience demonstrates the challenges posed in identifying idiosyncratic injury in the past. Isoniazid is an antituberculosis antibiotic that causes aminotransferase elevations in about
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
A class of medications often linked to idiosyncratic drug-induced injury is the HMG-CoA reductase inhibitors. Commonly referred to as statins, these medications have been known to cause transient transaminitis; however, several large, randomized, prospective studies have shown that persistent aminotransferase elevations are not significantly different when compared with placebo.41, 42, 43 A retrospective review of Scandinavian patients treated with statin therapy estimated the rate of
Summary
Drug-induced liver injury is a problem associated with significant clinical impact in the United States. Classifying adverse drug events as intrinsic or idiosyncratic can help clinicians better understand the underlying mechanisms behind the response. Although intrinsic Type A response are reasonably well understood due to their predictable occurrence with increased exposure, the mechanisms and risk factors associated with Type B idiosyncratic responses are less clear. With the emergence of
References (46)
- et al.
Drug-induced liver injury
- et al.
Adverse drug reactions: definitions, diagnosis, and management
Lancet
(2000) 152-Toxin- and drug-induced liver disease
An update on drug-induced liver injury
J Clin Exp Hepatol
(2012)- et al.
Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury
Gastroenterology
(2014) - et al.
Risk of acute liver failure in patients with drug-induced liver injury: evaluation of Hy’s law and a new prognostic model
Clin Gastroenterol Hepatol
(2015) - et al.
Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis
Pathol Biol
(2012) - et al.
Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases
Clin Gastroenterol Hepatol
(2013) - et al.
Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing
J Hepatol
(2012) Yes! Statins can be given to liver patients
J Hepatol
(2012)
Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States
Ann Intern Med
Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop
Hepatology
LiverTox database
Liver transplantation for acute liver failure from drug induced liver injury in the United States
Liver Transpl
Idiosyncratic drug hepatotoxicity
Nat Rev Drug Discov
Idiosyncratic toxicity: a convergence of risk factors
Annu Rev Med
N-Acetyl cysteine does not prevent liver toxicity from chronic low dose plus sub-acute high dose paracetamol exposure in young or old mice
Fundam Clin Pharmacol
ACG clinical guideline: the diagnosis and management of focal liver lesions
Am J Gastroenterol
Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives
Gastroenterology
Idiosyncratic adverse drug reactions: current concepts
Pharmacol Rev
Drug-induced liver injury with autoimmune features
Semin Liver Dis
Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals
Hepatology
Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats
J Pharmacol Exp Ther
Cited by (31)
Drug toxicity and forensic pharmacokinetics
2022, Pharmacokinetics and Toxicokinetic Considerations - Vol IIMolecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways
2021, Food and Chemical ToxicologyCitation Excerpt :DILI is defined as a liver injury that is unequivocally elicited by drugs or herbs, leading to liver test abnormalities or liver dysfunction, with the exclusion of other etiologies. DILI has been typically classified into intrinsic and idiosyncratic (Iasella et al., 2017). Intrinsic DILI generally is dose-dependent and predictable (e.g., acetaminophen toxicity), whereas idiosyncratic DILI (iDILI) is unpredictable and does not depend directly on dose.
A 3D microfluidic liver model for high throughput compound toxicity screening in the OrganoPlate®
2021, ToxicologyCitation Excerpt :Furthermore, DILI drugs broadly fall into intrinsic (predictable, high dose) and idiosyncratic (dependent on host factors, toxic at therapeutic doses) liver toxicity. Acetaminophen, amiodarone and tetracycline are examples of intrinsic liver toxicity and valproic acid, phenytoin and diclofenac are examples of idiosyncratic responses (Iasella et al., 2017). At the cellular level clinical hepatotoxicity has been associated with mitochondrial toxicity, generation of oxidative stress, bile salt exporter protein (BSEP) inhibition and highly associated with dual mitochondrial and BSEP inhibition (Aleo et al., 2014; Pereira et al., 2012).
Genome-wide Study Identifies Association between HLA-B<sup>∗</sup>55:01 and Self-Reported Penicillin Allergy
2020, American Journal of Human GeneticsCitation Excerpt :Type A reactions are more predictable and related to the pharmacological action of a drug, whereas type B reactions are idiosyncratic, less predictable, largely dose independent, and typically driven by hypersensitivity reactions involving the immune system.5 Although type B reactions are less frequent (<20%) than type A reactions, they tend to be more severe and more often lead to the withdrawal of a drug from the market.6 One of the most common causes of type B reactions are antibiotics,5 typically from the beta-lactam class, with the prevalence of penicillin allergy estimated to be as high as 25% in some settings.7,8
Disclosure Statement: The authors have nothing to disclose.