What are 1–2 differential diagnoses for each category (hepatic/intrahepatic, vascular, infectious, toxic/metabolic, gastrointestinal/biliary obstructive, endocrine, neurologic) in a 28‑year‑old woman with altered mental status and markedly elevated transaminases (AST approximately 4,200 U/L, ALT approximately 5,400 U/L) and a problem list of depression and seasonal allergies?

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Differential Diagnoses for Altered Mental Status with Severe Transaminitis (AST 4,200 U/L, ALT 5,400 U/L) in a 28-Year-Old Female

Hepatic/Intrahepatic:

  • Acute viral hepatitis (A, B, C, E): Superimposed hepatitis A, B, C, or E typically presents with AST or ALT >400 IU/ml and serum bilirubin >3 mg/dl, with hepatitis E particularly relevant in young women of childbearing age 1.

  • Autoimmune hepatitis (AIH): Can present with acute hepatocellular injury and markedly elevated transaminases, particularly in young women; may manifest as hyperacute exacerbation of undiagnosed AIH with altered mental status from hepatic encephalopathy 1.

  • Drug-induced liver injury (DILI): Given the history of depression, consider hepatotoxic medications (antidepressants, acetaminophen overdose); DILI presents with ALT >5× ULN and can cause acute liver failure with encephalopathy 1, 2.

  • Wilson's disease: First manifestation or acute decompensation in a young woman can present with modest aminotransferase elevations (<500 IU/ml), severe coagulopathy, mild-to-moderate encephalopathy, and Coombs-negative hemolysis; AST/ALT ratio >2.2 and ALP/total bilirubin ratio <4 are characteristic 1.

Vascular:

  • Ischemic hepatitis (shock liver): Causes marked transaminase elevation (often >1,000 IU/ml, can exceed 4,000 IU/ml) with deep coagulopathy and altered mental status from the underlying shock state; requires confirmation of vascular patency on ultrasound and echocardiography to assess cardiac function 1, 3.

  • Budd-Chiari syndrome: Acute hepatic vein thrombosis can cause severe transaminitis, hepatic encephalopathy, and altered mental status; more common in young women with hypercoagulable states or oral contraceptive use 1.

Infectious:

  • Acute viral hepatitis (HAV, HBV, HCV, HEV): Elevated ALT with anti-HAV IgM, HBsAg with anti-HBc IgM, or HCV RNA; hepatitis E is particularly relevant in young women and can cause acute liver failure 1.

  • Herpes simplex virus (HSV) hepatitis: Can cause fulminant hepatic failure with severe transaminitis and altered mental status, particularly in immunocompromised or pregnant patients 1.

  • Bacterial sepsis with secondary hepatic dysfunction: Systemic infection can cause both altered mental status and transaminase elevation through hypoperfusion and direct hepatic involvement 1, 4.

Toxic/Metabolic:

  • Acetaminophen overdose: Given depression history, intentional or unintentional overdose is critical to exclude; causes severe hepatocellular injury with ALT often >5,000 IU/ml and altered mental status from hepatic encephalopathy or direct CNS effects 1, 2.

  • Acute alcohol intoxication or withdrawal: Alcohol-related conditions are common causes of altered mental status in patients with liver disease; alcoholic hepatitis typically shows AST/ALT ratio >2, but acute alcohol toxicity can present with various patterns 1.

  • Hepatic encephalopathy from acute liver failure: Hyperammonaemia from any cause of acute hepatocellular necrosis leads to confusion, asterixis, and progressive obtundation; a low ammonia level should point toward non-hepatic etiologies 1.

  • Metabolic/endocrine disorders: Hypoglycemia, hyponatremia, hyperthyroidism, or hypothyroidism can cause altered mental status and may coexist with or exacerbate hepatic dysfunction 1, 5.

GI/Biliary (Obstructive):

  • Acute choledocholithiasis with ascending cholangitis: Can present with marked transaminase elevation (ALT may exceed AST, mimicking acute hepatitis) plus fever, right upper quadrant pain, and altered mental status from sepsis; requires urgent ERCP 6.

  • Acute biliary obstruction from malignancy: Pancreatic or biliary malignancy causing sudden complete obstruction can produce severe transaminitis and altered mental status from cholangitis or metabolic derangement 6.

Endocrine:

  • Thyroid storm: Severe hyperthyroidism can cause altered mental status, fever, and mild-to-moderate transaminase elevation; more common in young women 1, 5.

  • Adrenal crisis: Acute adrenal insufficiency presents with altered mental status, hypotension, and can cause mild transaminase elevation; consider in patients on chronic corticosteroids 1.

  • Diabetic ketoacidosis or hyperosmolar hyperglycemic state: Can cause altered mental status and mild transaminase elevation; diabetes is a risk factor for NAFLD but would not typically cause this degree of transaminitis 1.

Neurologic (Primary or Secondary):

  • Intracranial hemorrhage or stroke: Primary CNS disorders are the most frequent cause of altered mental status in ED patients (35% of cases); can occur with concurrent liver disease or as a complication of coagulopathy from acute liver failure 4, 7.

  • Seizures (postictal state): Can cause transient altered mental status and mild transaminase elevation from muscle injury (check CK to differentiate); febrile convulsions are more common with influenza 1, 4.

  • Encephalitis (viral, autoimmune): Direct CNS infection or autoimmune encephalitis can present with altered mental status, fever, and may have concurrent hepatic involvement; HSV encephalitis can cause both hepatitis and encephalitis 1, 7.

  • Wernicke-Korsakoff syndrome: Thiamine deficiency from alcohol misuse or malnutrition can cause acute confusion, ataxia, and ophthalmoplegia; may coexist with alcoholic liver disease 1.

  • Psychiatric disorders (severe depression, psychosis): Given the history of depression, consider primary psychiatric causes, though these are diagnoses of exclusion and would not explain the severe transaminitis 1, 4.

Critical Next Steps:

Immediate priorities include airway protection to prevent aspiration, transfer to a monitored setting, and concurrent investigation of both the altered mental status and the severe transaminitis 1. Obtain acetaminophen level, viral hepatitis serologies (HAV IgM, HBsAg, anti-HBc IgM, HCV antibody, HEV serology), comprehensive metabolic panel, coagulation studies (PT/INR), ammonia level, blood and urine toxicology screen, pregnancy test, and right upper quadrant ultrasound with Doppler to assess vascular patency 1, 2. Brain imaging (CT or MRI) should be considered given the first episode of altered mental status and the severity of presentation 1. The combination of severe transaminitis (ALT >5,000 U/L) and altered mental status in a young woman with depression mandates urgent evaluation for acetaminophen overdose, acute viral hepatitis, Wilson's disease, and ischemic hepatitis 1, 2, 3.

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Evaluation and Management of Mildly Elevated Transaminases

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Guideline

Causes of Chronic Alkaline Phosphatase (ALP) Elevation

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

7
Research

Altered Mental Status in the Emergency Department.

Seminars in neurology, 2019

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