What are the causes and symptoms of hepatic (liver) injury?

From the Guidelines

Liver injury can be caused by various factors, including medications, alcohol, viral infections, and toxins, and its symptoms include jaundice, abdominal pain, fatigue, nausea, and dark urine, and treatment depends on the cause but typically involves removing the offending agent, as recommended by the most recent guidelines 1. The causes of liver injury can be diverse, ranging from medication-induced liver injury, alcoholic liver injury, to viral infections and toxins. According to the latest study published in 2021 1, it is essential to evaluate patients with elevated liver chemistries for alternative etiologies, including a thorough history and review of their medications to exclude other causes of drug-induced liver injury.

• Common symptoms of liver injury include: + Jaundice (yellowing of skin and eyes) + Abdominal pain + Fatigue + Nausea + Dark urine
• Treatment of liver injury depends on the cause, but typically involves: + Removing the offending agent + Supportive care, including maintaining hydration, correcting electrolyte imbalances, and monitoring liver function tests (ALT, AST, bilirubin, albumin, and prothrombin time) + In cases of medication-induced liver injury, stopping the suspected drug immediately, as recommended by the guidelines 2 + In cases of alcoholic liver injury, complete abstinence from alcohol is essential + For acetaminophen-induced liver injury, N-acetylcysteine (NAC) at a loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours for 17 doses is the standard treatment The management of immune checkpoint inhibitor (ICI)-related liver toxicity is outlined in Figure 4 of the 2021 study 1, which provides a comprehensive approach to diagnosing and managing ICI-related liver injury.
• The guidelines recommend: + Evaluating patients with elevated liver chemistries for alternative etiologies + Considering liver biopsy in patients with grade 2 hepatitis or higher + Using systemic glucocorticoids or potential ICI discontinuation as needed + Monitoring liver function tests regularly during recovery It is crucial to prioritize the patient's safety and well-being by seeking immediate medical attention if liver injury is suspected, as prompt treatment can significantly improve outcomes and reduce the risk of chronic liver disease, cirrhosis, or liver failure, as emphasized by the latest evidence 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY (Antidotal) ... However, following ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the P-450 pathway 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 causes of hepatic (liver) injury include:

• Ingestion of a large overdose (150 mg/kg or greater) of acetaminophen
• Saturation of the glucuronide and sulfate conjugation pathways
• Increased formation of reactive metabolite via the P-450 pathway
• Depletion of hepatic stores of glutathione The symptoms of hepatic (liver) injury are not directly stated in the label, but it is mentioned that the reactive metabolite may bind to protein molecules within the hepatocyte resulting in cellular necrosis 3

From the Research

Causes of Hepatic Injury

• Drug-induced liver injury (DILI) is a common cause of hepatic injury, with nearly all classes of medications capable of causing liver disease 4, 5, 6
• Acetaminophen overdose is a significant cause of acute liver failure 7, 8
• Other substances, such as antibiotics, antiepileptics, and antituberculous drugs, can also cause liver injury 7
• Herbal and dietary supplements have been associated with DILI 5

Symptoms of Hepatic Injury

• Clinical symptoms of DILI are often identical to those of other liver diseases 4
• Some patients may present with symptoms of systemic hypersensitivity 4
• Acute liver failure can cause encephalopathy, with severity assessment critical for diagnosis 7
• Jaundice, hepatitis, and acute liver failure are potential symptoms of hepatic injury 7

Risk Factors for Hepatic Injury

• Pre-existing liver disease and genetic susceptibility may predispose individuals to DILI 4
• No definite risk factors for DILI have been established, but certain medications and substances are more commonly associated with liver injury 5, 6