The role of alcohol consumption on acetaminophen induced liver injury: Implications from a mathematical model

Highlights

• Clinical studies show that ingestion of alcohol may increase the risk of APAP induced liver injury.

• The rate of hepatocyte damage in APAP overdose patients depends on trade-off between induction and inhibition of CYP enzyme.

• Model the dual role of alcohol to determine how the timing of alcohol ingestion affects APAP metabolism and resulting liver injury.

• Capture condition of a patient of single time APAP overdose who may be an acute or chronic alcohol user.

Abstract

Acetaminophen (APAP) overdose is one of the predominant causes of drug induced acute liver injury in the U.S and U.K. Clinical studies show that ingestion of alcohol may increase the risk of APAP induced liver injury. Chronic alcoholism may potentiate APAP hepatotoxicity and this increased risk of APAP toxicity is observed when APAP is ingested even shortly after alcohol is cleared from the body. However, clinical reports also suggest that acute alcohol consumption may have a protective effect against hepatotoxicity by inhibiting microsomal acetaminophen oxidation and thereby reducing N-acetyl-p-benzoquinone imine (NAPQI) production. The aim of this study is to model this dual role of alcohol to determine how the timing of alcohol ingestion affects APAP metabolism and resulting liver injury and identify mechanisms of APAP induced liver injury. The mathematical model is developed to capture condition of a patient of single time APAP overdose who may be an acute or chronic alcohol user. The analysis suggests that the risk of APAP-induced hepatotoxicity is increased if APAP is ingested shortly after alcohol is cleared from the body in chronic alcohol users. A protective effect of acute consumption of alcohol is also observed in patients with APAP overdose. For example, simultaneous ingestion of alcohol and APAP overdose or alcohol intake after or before few hours of APAP overdose may result in less APAP-induced hepatotoxicity when compared to a single time APAP overdose. The rate of hepatocyte damage in APAP overdose patients depends on trade-off between induction and inhibition of CYP enzyme.

Introduction

Acetaminophen (APAP) overdose and toxicity is one of the predominant causes of acute liver failure in the United States claiming to take about 500 lives annually (Rumack and Matthew, 1975, Paulose-Ram et al., 2003, Ostapowicz et al., 2002, Nourjah et al., 2006). APAP overdose here is defined as intake of more than 5gm of APAP in one sitting (Remien et al., 2012, Remien et al., 2014). APAP(A) when ingested, is rapidly absorbed in the body leading to the synthesis of toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI) within hepatocytes by several P450 cytochromes (see Ben-Shachar et al., 2012, Rumack and Matthew, 1975, Lee, 2003, Miners and Kissinger, 1979)). NAPQI(N) then binds with glutathione (GSH), a well regulated antioxidant found within hepatocytes and is easily eliminated (see Mitchell et al., 1973, Riches et al., 2009). However when overdose of APAP(A) is ingested, NAPQI(N) exhausts the GSH(G) reserve and unconjugated NAPQI binds to hepatocellular proteins and other cellular components, damaging hepatocytes. N-acetylcysteine (NAC) a GSH(G) precursor helps to counter the toxicity and limit the liver injury and thus it works as a very efficient antidote, but timing is an important aspect here (see Smilkstein et al., 1988, Read et al., 1986, Brotodihardjo, 1992, Reddyhoff et al., 2015). Initial administration of NAC of 150 mg/kg within an hour followed by decreasing the dose over next 20 h is the usual mode of treatment for an APAP overdose patient (see Ben-Shachar et al., 2012). NAC treatment within 8–12 h of APAP overdose prevents hepatotoxicity but a late administration of NAC for a sufficiently high overdose amount may result in severe c ase of hepatotoxicity and low survival rate. APAP induced hepatotoxicity in patients is believed to be affected by alcohol intake (ethanol, EToH) with some even reporting death due to this liver injury (Lesser et al., 1986, McClain et al., 1980). Various studies indicate that alcohol regulates the formation of NAPQI by induction of cytochrome enzymes P450CYP2E1, CYP1A2 and CYP3A4 (Lucas et al., 1995, Raucy et al., 1989, Patten et al., 1993, Chen, 1998). However, the most significant contribution in modulating NAPQI is known to occur through CYP2E1 induction. Alcohol ingestion thus affects NAPQI formation, depending on the amount of alcohol consumption and the time lag between alcohol and APAP ingestion. Thus timing of the intake of alcohol and APAP ingestion is crucial in determining the risk of APAP hepatotoxicity.

It has been suggested in many clinical studies see (Maddrey, 1987, Bray et al., 1991, Zimmerman and Maddrey, 1995, Draganov et al., 2000) that patients with chronic alcoholism have increased risk of severe hepatotoxicity from single overdose of APAP. Patients with chronic alcoholism are at higher risk to develop APAP-induced liver injury due to induction of CYP2E1 also known as MEOS, the microsomal alcohol oxidizing system, responsible for production of NAPQI from APAP. An elevated rate of CYP2E1 activity amounts to conversion of a greater proportion of APAP to NAPQI and thereby increases the risk of APAP induced liver failure.

Alcohol (Ethanol) also acts as substrate for CYP2 and inhibits the metabolism of other substrates in the enzyme by binding it to the active site (see Chien et al., 1997, Thummel et al., 2000, Lieber, 1997). For example, clinical studies suggest that in the c ase of acute alcohol ingestion CYP2E1 inhibits microsomal APAP oxidation leading to decreased NAPQI production (see Guerri and Grisolia, 1980, Thummel et al., 2000). Hence the protective effect of alcohol ingestion due to inhibition of CYP2E1 is limited to the acute c ase.

Thus, the simultaneous induction and inhibition effect of alcohol on CYP2E1 may play an important role in determining the extent of liver damage in APAP overdose in conjunction with alcohol ingestion. The relative timing may be critical. Alcohol ingestion can both alleviate and aggravate APAP induced liver toxicity depending on the amount of alcohol(captured as Ethanol (EtoH)) consumption and the timing of last alcohol and APAP ingestion (see Banda et al., 1982, Rumack et al., 1981, Rumack, 1984, Critchley et al., 1983, Schmidt et al., 2002). Remien et.al. have developed a mathematical Model for Acetaminophen induced Liver Damage to describe acute liver injury due to one time APAP overdose (Remien et al., 2012). The Model for Acetaminophen induced Liver Damage (MALD) uses a patient’s aspartate aminotransferase (AST), alanine aminotransferase (ALT), and international normalised ratio (INR) measurements on admission to estimate overdose amount, time elapsed since overdose, and outcome in terms of hepatotoxicity. Here we have extended this modeling framework to incorporate varying level of alcohol consumption and different mechanisms leading to hepatotoxicity. The effect of alcohol on APAP metabolism and hepatotoxicity are captured by mechanisms such as the induction and inhibition effect of alcohol on the CYP2E1 enzyme.

In the present study, the model uses single time APAP overdose and time varying alcohol ingestion to estimate hepatocyte damage. The model also explores APAP overdose patients that are either post/prior (to overdose) acute or chronic alcohol users. The goal of the paper is to highlight how alcohol ingestion impact the progression of liver damage in APAP overdose patients. In particular, the study aims to understand the role of time and frequency of alcohol consumption post a single time APAP ingestion aggravates or alleviate conditions of APAP induced liver injury.

We organize the paper as follows. Section 2 provides a detailed description of the mathematical model. Equilibrium points and stability analysis are discussed in Section 2.2. We also provide a bifurcation analysis with respect to an important parameter here. Numerical simulation of the mathematical model to understand the extent of liver injury due to single time APAP overdose along with alcohol ingestion at different times is presented in Section 3. This model is also simulated for chronic and acute use of alcohol. We conclude with a discussion in Section 4.