What medication can cause massive upper gastrointestinal (GI) bleeding, elevated liver enzymes, metabolic acidosis, respiratory acidosis, and high coagulation levels, particularly in a patient with a history of liver disease or polypharmacy?

Acetaminophen (Paracetamol) Toxicity

Acetaminophen is the medication that causes massive upper GI bleeding, elevated liver enzymes, metabolic acidosis, respiratory acidosis, and coagulation abnormalities, particularly when taken in overdose (>12g in adults) or at lower doses in patients with pre-existing liver disease. 1, 2

Clinical Presentation and Mechanism

Acetaminophen hepatotoxicity leads to acute liver failure, which directly causes the constellation of symptoms described:

• Hepatotoxicity occurs at doses >3-4 grams/day, and at lower doses in patients with chronic alcohol use or liver disease 1
• Adults typically require ingestion of approximately 12g or more before serious hepatotoxicity develops, though chronic excessive dosing at lower amounts can also cause liver failure 2
• Peak serum transaminase activities (elevated liver enzymes) usually occur 48-96 hours after acute ingestion 2

Coagulation Abnormalities

The liver synthesizes clotting factors, and acute liver failure from acetaminophen causes severe coagulopathy:

• Acute and chronic liver diseases cause coagulation disorders due to decreased synthesis of clotting and inhibitor factors, decreased clearance of activated factors, and quantitative/qualitative platelet defects 3
• This coagulopathy directly leads to increased bleeding risk, including massive upper GI bleeding 3
• Patients with acetaminophen-induced liver failure develop coagulopathy with hepatic encephalopathy within 26 weeks of first symptoms 4

Metabolic and Respiratory Acidosis

Liver failure causes complex acid-base disturbances:

• The most common acid-base disorder in liver disease is respiratory alkalosis, but metabolic acidosis alone or in combination with respiratory alkalosis is also common 5
• As the liver's metabolic function worsens, particularly with renal dysfunction and hemodynamic compromise, acid-base disorders ensue 5
• Patients can present with both metabolic and respiratory acidosis simultaneously in severe hepatic failure 5

Critical Diagnostic Pitfall

Acetaminophen may be undetectable in plasma when patients present with established liver failure:

• More than half (52%) of patients with acetaminophen-induced acute liver failure have undetectable plasma acetaminophen levels on presentation 4
• Patients can present in liver failure days after ingestion with undetectable serum acetaminophen concentrations 2
• Clinicians should not exclude acetaminophen toxicity because of undetectable levels or withhold N-acetylcysteine when acetaminophen toxicity is suspected 4

High-Risk Populations

Certain patients are at dramatically increased risk even at therapeutic doses:

• Patients with pre-existing liver disease, cirrhosis, or chronic alcohol use develop hepatotoxicity at lower doses 1
• Acetaminophen should be limited to ≤3 g/day in most patients due to hepatotoxicity concerns 1
• One patient died from liver failure after taking large doses of both acetaminophen and imatinib, highlighting dangerous drug interactions 1

Treatment

N-acetylcysteine (NAC) is the definitive treatment and should be administered immediately when acetaminophen toxicity is suspected:

• NAC was given to 94.7-95.9% of patients with acetaminophen-induced liver failure, regardless of detectable acetaminophen levels 4
• NAC prevents hepatotoxicity by maintaining intracellular glutathione stores to detoxify the toxic metabolite NAPQI 2
• NAC also improves outcomes in patients who present with established acute liver failure 2
• Patients with acute liver failure may require orthotopic liver transplantation 2

Additional Context on GI Bleeding Risk

While acetaminophen causes the described syndrome through hepatotoxicity, NSAIDs cause direct GI bleeding through different mechanisms:

• NSAIDs are associated with gastritis, peptic ulcer disease, and interfere with platelet aggregation, but they do not typically cause the combination of elevated liver enzymes, acidosis, and coagulopathy seen with acetaminophen 1
• Acetaminophen overdose deaths (881 in 2010) represent a significant portion of pharmaceutical overdose deaths, though less than opioids (16,651) 1