Mechanisms of Drug-induced Liver Injury

Abstract

Synopsis Drug induced liver injury (DILI) represents a broad spectrum of liver manifestations. However, the most common manifestation is hepatocyte death following drug intake. DILI can be predictable and dose dependent with notable example of acetaminophen toxicity. Idiosyncratic DILI occurs in an unpredictable fashion at low frequencies implying that environmental and genetic factors alter the susceptibility of individuals to the insult (drugs). An biochemical stress is usually initiated by drugs and their reactive metabolites through covalent binding or direct damage to mitochondria, which leads to oxidative stress, activation of stress signaling pathways, impairment of mitochondrial function, endoplasmic reticulum stress, etc. The ultimate cell death pathways converges at mitochondria through acting on mitochondrial outer-membrane permeability (MOMP) or mitochondrial permeability transition (MPT). The striking HLA associations with idiosyncratic DILI highlight the critical role of the adaptive immune response in pathogenesis, which is now believed to be unmasked in genetically susceptible individuals by the biochemical stress in the liver triggered by drug and/or metabolites. The drug-induced biochemical stress may also contribute to the severity of injury by sensitizing hepatocytes to the lethal effects of the immune response. Adaptive mechanisms including antioxidant signaling (such as Nrf2 signaling) , mitophagy, autophagy, unfolded protein response, anti-inflammatory and immune tolerance dampen and ameliorate injury. All together, the development and severity of injury is determined on the battle between the hazardous stress and adaptive responses within the hepatocytes and the innate and adaptive immune systems.

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury

“…In the latter case, albumin-bound toxins might persist longer in the circulation, or albumin binding might decrease toxicity by decreasing free toxin levels. Indeed, one of the most commonly used analgesics, acetaminophen (para-acetylaminophenol, APAP), is known to bind albumin in the circulation (32) and is toxic to the liver at high doses (33,34). When ingested in excess (above 10 g/d or 200 mg/kg for humans), the hepatocyte glucuronide pathway is saturated, resulting in the production and accumulation of a toxic byproduct, N-acetyl-p-benzo-quinoneimine (NAPQI) (35).…”

“…When ingested in excess (above 10 g/d or 200 mg/kg for humans), the hepatocyte glucuronide pathway is saturated, resulting in the production and accumulation of a toxic byproduct, N-acetyl-p-benzo-quinoneimine (NAPQI) (35). NAPQI depletes glutathione (GSH) and binds in particular to mitochondrial proteins, mainly to the amino acid cysteine, causing oxidative stress, mitochondrial damage, and ultimately hepatocyte death (34,36). We therefore hypothesized that FcRn affects the sensitivity of the liver to toxins, using APAP as a model of liver toxicity.…”

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

“…The risk factors associated with DILI include age (<18 or >65years), obesity, pregnancy, concomitant alcohol consumption, and certain genetic polymorphisms (such as cytochrome P450 polymorphisms). It has been suggested that susceptible populations should not be subjective to re-challenge with drugs suspected of causing DILI [49,[50][51][52][53]. These injuries resemble almost all known liver diseases and there are no pathognomonic findings, even upon liver biopsy, that clarify the diagnosis of DILI.…”

“…Therefore, when the clinician suspects of DILI, it is essential to gather additional clinical and laboratory information necessary for differential diagnosis of the cause. The most important key point is to exclude other causes of liver disease (existence of acute/chronic hepatitis, nonalcoholic steatohepatitis [NASH], biliary tract diseases (stones, sand), obesity/metabolic syndrome, circulatory problems, congestive heart failure, concomitant exposure to other hepatotoxic drugs, alcohol or hepatotoxins) [51][52][53]. Some of the drugs that induce DILI and the mechanisms underlying their toxicity are summarized in Table 1 [54-78].…”

Acute Pain Management in the Emergency Department: Emphasis on NSAIDs

“…At higher doses, however, NAPQI causes potentially life-threatening liver damage [65]. Acetaminophen toxicity is a leading cause of poisoning and liver damage in the U.S. [66] Albeit rare, idiosyncratic drug-induced liver injury can occur unpredictably even in therapeutic dose ranges, implying that environmental and/or genetic factors may influence individual susceptibilities [67]. In the U.S., the Food and Drug Administration (FDA) has required new warning labels on acetaminophen products to alert consumers about the risks of acetaminophen [68].…”