A 68-year-old man is brought to the emergency department due to 2 days of progressive confusion and lethargy. His symptoms started approximately 4 days ago with malaise, nausea, and vomiting. The patient has hypertension and chronic back pain due to spinal stenosis. Laminectomy 4 years ago provided limited symptom improvement. The patient's medications include daily losartan and as-needed hydrocodone-acetaminophen. His wife says that for the past 2 weeks he has been taking additional acetaminophen for a severe toothache. The patient smokes a pack of cigarettes and drinks 2 shots of whiskey daily. He has a remote history of intravenous drug abuse. His blood pressure is 110/60 mm Hg, pulse is 108/min, and BMI is 32 kg/m². The patient is sleepy but wakes when spoken to and follows instructions. He is oriented to person and place. There is mild scleral icterus. Cardiopulmonary examination is unremarkable, and a smooth and tender liver edge is palpable 3 cm below the right costal margin. The patient has a mild flapping tremor of both hands. Laboratory results are as follows: Which of the following is the most likely diagnosis in this patient?

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11ec25c8_d19c_9742_bc81_bf56f35fb6b9_MD0003_00 This patient has acute liver failure (ALF) likely due to acetaminophen toxicity in the setting of chronic alcohol use. Diagnosis of ALF requires the triad of elevated aminotransferases (markedly elevated in this patient), signs of hepatic encephalopathy (confusion, somnolence, and flapping tremor consistent with asterixis in this patient), and synthetic liver dysfunction (evidenced by INR >1.5). Cirrhosis or underlying liver disease should not be present. Acetaminophen toxicity is the most common cause of ALF in many developed countries and can be seen in intentional overdose (suicide attempt) or accidental overdose in patients taking multiple sources of acetaminophen (such as this patient). Toxicity results from overproduction of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which leads to hepatic necrosis. NAPQI is normally safely detoxified through glucuronidation in the liver, but this pathway becomes overwhelmed in overdose. Chronic alcohol use is thought to potentiate acetaminophen hepatotoxicity by depleting glutathione levels and impairing the glucuronidation process. On the other hand, N-acetylcysteine increases glutathione levels and binds to NAPQI, so it is an effective antidote for acetaminophen overdose when given early. Acute renal insufficiency is common in ALF, especially when acetaminophen induced, due to the drug's direct renal tubular toxicity. Hyperbilirubinemia is common as well, but acetaminophen hepatotoxicity is characterized by relatively low serum bilirubin compared with that in other etiologies of ALF. (Choice A) Acute alcoholic hepatitis typically causes mild to moderate aminotransferase elevation (<500 U/L) in patients who drink heavily (>100 g/day). The AST/ALT ratio is usually >2:1. (Choice B) Hepatitis C causes chronic hepatitis and may lead to cirrhosis but is not typically associated with ALF. Hepatitis A, B, D, and E are more typical causes of ALF. (Choice C) Ischemic hepatitis can result from severe hypotension (eg, shock liver) or Budd-Chiari syndrome (hepatic vein thrombosis) and is a potential cause of ALF. This patient has not had significant hypotension and lacks right upper quadrant pain, which is typically severe in Budd-Chiari syndrome. (Choices D and F) Nonalcoholic steatohepatitis is a chronic condition that is associated with metabolic syndrome and may lead to liver cirrhosis. Both nonalcoholic steatohepatitis and cirrhosis are characterized by normal to moderately elevated aminotransferase levels, and elevation >1000 U/L is not consistent with either diagnosis. Educational objective: Acute liver failure (ALF) is characterized by elevated aminotransferases, encephalopathy, and INR >1.5. Acetaminophen toxicity is a common cause of ALF that may be potentiated by chronic alcohol use. > References: Acute liver failure. (http://www.ncbi.nlm.nih.gov/pubmed/22447259) Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. (http://www.ncbi.nlm.nih.gov/pubmed/16317692) Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose. (http://www.ncbi.nlm.nih.gov/pubmed/11929388)

A 68-Year-Old Man Is Brought to the Emergency Department Due