Acetaminophen‐Induced Liver Damage in Hepatic Steatosis

Abstract

One of the most used painkillers is acetaminophen (APAP), which is safe at the right dose. However, several studies have described populations susceptible to APAP-induced liver damage, mainly in livers with steatosis. Thus, clinicians should consider the presence of obesity and other chronic liver diseases like nonalcoholic fatty liver disease (NAFLD) when indicating treatment with APAP. Liver damage from this drug is generated through its metabolite N-acetyl-pbenzoquinone imine, which is detoxified with glutathione (GSH). Prior depletion of GSH in steatotic hepatocytes plays a key role in APAP-induced hepatotoxicity in people with obesity and NAFLD. The knowledge about the damage to the liver or APAP in susceptible people like the obese and those with NAFLD is of great relevance for the sanitary sector because it would imply strategies of different therapeutic approach in such patients. This paper reviews the role of APAP in liver damage in the presence of obesity, NAFLD, and nonalcoholic steatohepatitis.Since it was first introduced in clinical practice in 1955, acetaminophen-also known as APAP or paracetamol-has become the most commonly used analgesic/antipyretic in the world. At a therapeutic dose (< 4 g/day in adults, or < 60-75 mg/kg/day in children), it is considered safe and very effective. However, at doses exceeding 4 g/day, it can cause potentially fatal acute liver injury (ALI). The first cases of APAP-induced hepatotoxicity, due to either intentional or accidental ingestion, date back to 1966. 1 Since then, APAP has been considered the principal cause of ALI in Western countries, leading to around 26,000 hospitalizations and 500 deaths in the United States alone. 2 The metabolic activation of APAP through the CYP450 enzymes produces a toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI). One dose above the recommended maximum intake can increase production of NAPQI, with the subsequent generation of reactive oxygen species (ROS) and the formation of adducts in proteins and other biomolecules. Recent research into the etiology of NAPQI toxicity has focused on the mitochondrial damage and the depletion of mitochondrial glutathione (mGSH).Accumulated evidence shows that some populations are more susceptible to APAP-induced liver damage, including people with obesity, chronic alcohol consumption, viral hepatitis, acute and chronic malnutrition, and nonalcoholic fatty liver disease (NAFLD). Based on a preliminary observation that NAFLD increased the risk of ALI due to APAP overdose sevenfold, one retrospective study investigated the molecular mechanisms that increase the susceptibility of the steatotic hepatocytes to the APAP-induced cellular damage, even at a therapeutic dose. 3 Both murine and cell-based models have provided evidence that implicates the biotransformation of APAP to its toxic metabolite NAPQI in this process, through the cytochrome P450 family: CYP2E1, CYP3A4, CYP2D6, and CYP1A2. 4 Both NAPQI adducts and the detoxification process (in which GSH is used and depleted) have been re...

Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

“…These models disclosed higher cytotoxicity of APAP [257], troglitazone [236] and a mixture of benzo[a]pyrene and J o u r n a l P r e -p r o o f ethanol [240,247] in NAFLD cells compared with the non-steatotic cells. Regarding APAP toxicity [257], these in vitro investigations confirmed previous studies carried out in obese mice and humans with NAFLD [228,232,244]. Furthermore, mechanistic investigations showed that higher CYP2E1 activity in lipid-loaded HepaRG cells was, at least in part, responsible for higher APAP cytotoxicity [257].…”

“…This paradigm implies two possible scenarios. First, drugs such as APAP (in the context of overdose), halothane and isoflurane may cause more severe and/or more frequent ALF in individuals with NAFLD [228,232]. Second, pharmaceuticals such as irinotecan, methotrexate and tamoxifen seem to be more hepatotoxic in obese patients than in lean individuals by triggering the transition from steatosis to NASH, and/or worsening pre-existing steatosis, necroinflammation and fibrosis [55,233,234].…”

Treatments in Covid-19 patients with pre-existing metabolic dysfunction-associated fatty liver disease: A potential threat for drug-induced liver injury?

“…In addition, these models unveiled increased cytotoxicity of acetaminophen [ 50 ], troglitazone [ 52 ] and a mixture of benzo[a]pyrene and ethanol [ 51 , 53 ] in MAFLD cells compared with non-steatotic cells. Regarding acetaminophen [ 50 ], these in vitro investigations confirmed previous studies carried out in obese mice with MAFLD [ 44 , 45 , 57 ]. In contrast, we found that ritonavir was less cytotoxic in MAFLD cells compared with the non-steatotic cells [ 52 ].…”

“…DILI in MAFLD seems to occur as two distinct clinical situations [ 38 , 39 , 43 ]. First, some drugs such as acetaminophen and some antibiotics may cause more severe and/or more frequent acute liver injury ( Table 2 ) [ [43] , [44] , [45] ]. Regarding, acetaminophen, it should be pointed out that its hepatotoxicity is mainly observed after overdose but some cases of liver injury (sometimes severe) may also occur with recommended therapeutic dosing [ 39 , 46 , 47 ].…”

Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update

“…Several studies reported that its administration is more dangerous in patients already suffering from NAFLD, NASH or obesity. APAP-induced liver damage is related to the CYP3A4 and CYP2E1-mediated generation of its metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by glutathione (GSH) [ 208 ]. In already compromised hepatocytes, as they are in NAFLD or NASH, GSH stores are poor because of the increased activity of CYP450, in particular CYP2E1, which is post-transductionally upregulated by insulin.…”