Review Article

Drug-induced Liver Injury in the Context of Nonalcoholic Fatty Liver Disease

A Physiopathological and Clinical Integrated View

Fernando Bessone; Melisa Dirchwolf; María Agustina Rodil; María Valeria Razori; Marcelo G. Roma

Disclosures

Aliment Pharmacol Ther. 2018;48(9):892-913. 

In This Article

Abstract and Introduction

Abstract

Background: Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms.

Aims: To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH).

Methods: A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic.

Results: Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor.

Conclusions: The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.

Introduction

Obesity is an increasingly growing epidemic, with its worldwide prevalence having nearly doubled over the past three decades.[1] Its hepatic manifestation is nonalcoholic fatty liver disease (NAFLD), a term that includes a broad range of liver disease ranging from simple steatosis, present in 70% of obese and diabetic patients, to nonalcoholic steatohepatitis (NASH), described in 10%–20% of patients with steatosis.[2,3] In the case of obese patients, metabolic syndrome and its more common associated consequences, insulin resistance (IR) and dyslipidaemia, are major causal factors of NAFLD, and this explains the high prevalence of this disease among them.

NAFLD and its main associated comorbidity, obesity, may be intertwined with drug-induced liver injury (DILI): there is increasing awareness of potential DILI risk factors in NAFLD patients for a growing number of drugs,[4] and DILI may present as lesions that resemble those of NAFLD.[5] This review will summarise the main clinical and experimental evidence supporting these two aspects of DILI in the fatty liver context, ie, how DILI can influence the development or accelerate progression of the fatty liver disease and how the susceptibility to and outcome of DILI may be influenced by NAFLD. The pathogenic alterations underlying these relationships will be also discussed in detail. Special emphasis will be paid to the mechanisms by which certain drugs induce hepatic steatosis (DIS) and/or steatohepatitis (DISH) by triggering pathological events similar to those occurring in NAFLD development and progression. They involve exacerbation of predisposing factors (eg, obesity, diabetes), steatotic factors (eg, exacerbated lipid hepatic synthesis/uptake), inflammatory factors (eg, accumulation of lipotoxic fatty acids and oxidative stress), and fibrogenic factors (eg, enhanced collagen deposition). These harmful effects not only can mimic the hits that trigger the development and/or progression of NAFLD in the normal liver, but also aggravate similar alterations pre-existing in a fatty liver. In addition, the hepatotoxic potential of drugs can be influenced by the alterations in drug-metabolic systems that occur in the NAFLD context, and they will be also reviewed here. Finally, obesity as a risk factor for DILI in the NAFLD context will be discussed in this review. Although controversial, there is accumulating evidence relating obesity to an increased risk of DILI; this has been reported not only in experimental models but also in some observational studies and clinical trials.[4] Whether this elevated risk reflects higher exposure to medication (polypharmacy) or the existence of sharing/exacerbating pathophysiological pathways in obese patients with pre-existing NAFLD or NAFLD risk factors will be further discussed.

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