From the Guidelines
Hepatocellular injury is primarily caused by factors such as acetaminophen-induced hepatotoxicity, hepatitis A and B infections, other drugs, and various toxic agents, as well as metabolic disorders and alcohol consumption, as evidenced by recent studies 1. The causes of hepatocellular injury can be categorized into several main groups, including:
- Viral infections, such as hepatitis A and B, which can lead to liver inflammation and damage 1
- Medications and toxins, such as acetaminophen, which can cause liver cell damage and necrosis 1
- Metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD), which can lead to liver inflammation and scarring 1
- Alcohol consumption, which can cause liver damage and inflammation, particularly in individuals who drink excessively 1
- Other factors, such as autoimmune hepatitis, Wilson's disease, and hemochromatosis, which can also cause liver damage and inflammation 1
It is essential to identify the underlying cause of hepatocellular injury to provide appropriate management and treatment. For medication-induced injury, the offending drug should be discontinued immediately, and for alcoholic liver injury, complete abstinence from alcohol is essential 1. Supportive care, including maintaining hydration, proper nutrition, and avoiding additional hepatotoxic substances, is also crucial in managing hepatocellular injury. In severe cases, N-acetylcysteine (NAC) may be used, particularly for acetaminophen toxicity, as recommended in recent guidelines 1. Regular monitoring of liver function tests is important to track recovery, which may take weeks to months depending on the severity and cause of the injury.
From the FDA Drug Label
A small fraction of an ingested dose is metabolized in the liver by the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite which preferentially conjugates with hepatic glutathione to form the nontoxic cysteine and mercapturic acid derivatives which are then excreted by the kidney ... The increased formation of reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis. The cause of hepatocellular (liver cell) injury is the depletion of glutathione stores and the binding of a reactive metabolite to protein molecules within the hepatocyte, resulting in cellular necrosis. This occurs when a large overdose of acetaminophen is ingested, saturating the glucuronide and sulfate conjugation pathways and leading to increased formation of the reactive metabolite via the P-450 pathway 2.
From the Research
Causes of Hepatocellular Injury
The causes of hepatocellular (liver cell) injury can be attributed to various factors, including:
- Drug-induced liver injury (DILI) 3, 4, 5, 6
- Acetaminophen overdose, which is the leading cause of drug-induced acute liver failure in many developed countries 3, 4
- Mitochondrial oxidative stress, considered to be the predominant cellular event in acetaminophen-induced liver injury 3
- Other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration 3
- Methylprednisolone pulse therapy, which has been associated with liver injury of varying severity 5
- Increased reactive oxygen species levels, mitochondria dysfunction, presence of elevated apoptosis and necrosis, and bile duct injuries associated with immune-mediated pathways 6
Mechanisms of Hepatocellular Injury
The mechanisms underlying hepatocellular injury are complex and involve multiple pathways, including:
- Idiosyncratic liver injury, which occurs spontaneously and may involve immune responses 6
- Intrinsic liver injury, which occurs in a dose-dependent manner 6
- Hepatocellular, cholestatic, or mixed liver injury, which may be categorized based on the type of liver damage 6
- Immune-mediated pathways, which may contribute to bile duct injuries and liver damage 6
Risk Factors and Prevention Strategies
Risk factors for hepatocellular injury include:
- Drug exposure, particularly to acetaminophen and other hepatotoxic agents 3, 4, 5, 6
- Delayed treatment, which may reduce the effectiveness of antidotes such as N-acetylcysteine 4, 7
- Prolonged treatment with N-acetylcysteine, which may impair liver regeneration 7 Prevention strategies are critical, as incidences of hepatocellular injury occur frequently, and treatment options are limited once the injury has developed 6