Drug-Induced Liver Injury in Aged Adults

Drug-induced liver injury (DILI) is an important cause of hospitalization and of medication deregistration. In old age, susceptibility to DILI is suffering from changes in physiology and increased inter individual variability, compounded by an increased prevalence of disease and therefore the frailty syndrome. While dose-related or predictable DILI reactions are often detected in preclinical trials, the occurrence of rare hypersensitivity or idiosyncratic reactions can't be reliably predicted from preclinical studies or maybe by clinical trials. The limited participation of older adults in clinical trials means the susceptibility of this population to DILI is essentially unknown. Vigilance during clinical trials and post marketing surveillance must be universally practiced. A systematic approach should be taken to work out not only which medicines are hepatotoxic and will be far away from the market, but also the hepatotoxicity risks from marketed drugs to consumers with different characteristics, many of whom are older people.

Optimizing the safety and efficacy of medications in older people is complex and multi-factorial. With adulthood, there's a rise in disease that medications may provide benefit. The incidence of serious adverse drug reactions also increases with increasing age, even after controlling for increased medication use. Most adverse drug reactions (ADRs) in older people, including drug-induced liver injury (DILI), are dose-related.

In all age groups, a crucial susceptibility factor for hepatotoxicity is genetic variability. In older people, this might be compounded by the massive inter individual variation in response to medications, further increasing the risks of toxicity and poor efficacy. This is a specific concern in frailty, a condition of increased vulnerability to adverse events. Monitoring for clinical response is important to optimise efficacy and reduce toxicity. However, the detection of adverse effects of medicines in older patients could also be complicated by nonspecific presentation as geriatric syndromes. In this editorial we describe the epidemiology and management of DILI, with particular concern to old age.

Epidemiology

DILI is an important cause of hospital admissions and deregistration of medications. Hospital admissions for ADRs have increased steadily over the last decade in older Australians. In Spain, 45% of cases of DILI reported from 1994-2004 occurred in patients aged >60 years.

Drug-induced hepatotoxicity has been of accelerating interest thanks to the withdrawal of variety of medicine shortly after being put onto the market. Troglitazone was withdrawn from the market within the UK in 1999 and in US in 2000. Lumiracoxib was withdrawn from the market in 2007 by the Australian Therapeutics Goods Association due to reports of great liver injury, including fulminant liver failure. New Zealand, Canada and the European Union followed suit. A recent systematic investigation by the WHO Collaborating Centre for International Drug Monitoring reported that the five commonest drugs related to fatalities during 1969-1990 were paracetamol, troglitazone, valproate, stavudine and halothane. After 1990, the foremost common drug related to a fatal outcome shifted from halothane (immuno-allergic DILI) to paracetamol (dose-dependant DILI).

Early intervention is important because the aim of treatment is to stop progression to acute liver failure. Idiosyncratic reactions necessitate prompt recognition of the symptoms due to DILI as this is often the key to stopping the drug and reducing the extent of liver injury. The highly variable nature of idiosyncratic symptoms means this is often not the case. Paracetamol remains the sole hepatotoxin to possess effective pharmacotherapy, N-acetylcysteine (NAC), supported well-established nomograms. The advantage of NAC extends beyond those that have developed fulminant hepatic failure. In older people, increased age is related to increased time to presentation which can be explained partially by the upper proportion of accidental overdose in older patients. By the time older adults present, it's going to be too late to realize enjoy NAC, despite it being indicated for late presenters (10-24 hours postoverdose).

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