What is the most likely diagnosis in a 48‑year‑old female chronic alcoholic with alkaline phosphatase 461 U/L, AST 165 U/L, ALT 36 U/L, total bilirubin 7 mg/dL, ammonia 65 µmol/L, and NT‑proBNP 2512 pg/mL?

Diagnosis: Severe Alcoholic Hepatitis with Cholestatic Features

This 48-year-old female chronic alcoholic most likely has severe alcoholic hepatitis (AH) with prominent cholestatic features, evidenced by the characteristic AST/ALT ratio >4.5, marked hyperbilirubinemia, and disproportionately elevated alkaline phosphatase. 1

Key Diagnostic Features Supporting Alcoholic Hepatitis

Laboratory Pattern Analysis

• AST 165 U/L with ALT 36 U/L yields an AST/ALT ratio of 4.6, which far exceeds the diagnostic threshold of >1.5 for alcoholic hepatitis and is highly specific for alcohol-related liver injury 1

• Both transaminases remain <400 IU/mL, which is characteristic of AH and helps distinguish it from drug-induced liver injury or ischemic hepatitis where levels typically exceed 1,000 IU/mL 1

• Total bilirubin of 7 mg/dL exceeds the diagnostic threshold of >3 mg/dL required for AH diagnosis, indicating significant hepatocellular dysfunction and cholestasis 1

• Alkaline phosphatase of 461 U/L is markedly elevated, suggesting a prominent cholestatic component that can occur in severe AH with intrahepatic cholestasis (bilirubinostasis) 1

Severity Assessment

• The elevated NT-proBNP of 2512 pg/mL suggests circulatory dysfunction or cardiac stress, which may indicate systemic inflammatory response syndrome (SIRS) or early organ dysfunction commonly seen in severe AH 1

• Ammonia level of 65 µmol/L is mildly elevated (normal <50 µmol/L), which can occur in AH with hepatic encephalopathy, though levels >100 µmol/L would predict severe encephalopathy with 70% accuracy 2

• Calculate the Maddrey Discriminant Function (mDF) using the formula: 4.6 × (PT patient - PT control) + total bilirubin (mg/dL); if mDF ≥32, this defines severe AH with 30-50% 28-day mortality without treatment 1

• Calculate the MELD score using bilirubin, INR, and creatinine; a MELD >20-21 indicates severe disease with high 90-day mortality 1

Critical Differential Diagnoses to Exclude

Wilson Disease Must Be Ruled Out

• Although the patient is 48 years old (older than typical Wilson disease presentation), the AST/ALT ratio >2.2 and elevated bilirubin warrant exclusion 1, 3

• Check **ceruloplasmin levels (<20 mg/dL suggests Wilson disease)** and 24-hour urinary copper excretion (>100 µg, usually >500 µg/24h in Wilson disease) 1

• Calculate the alkaline phosphatase to total bilirubin ratio: ALP 461 ÷ bilirubin 7 = 66, which is >4 and argues against Wilson disease (Wilson disease typically shows ratio <4) 1, 3

• The AST/ALT ratio of 4.6 exceeds the 2.2 threshold that has 94% sensitivity for Wilson disease, but the ALP/bilirubin ratio >4 makes Wilson disease unlikely 3

Other Mandatory Exclusions

• Obtain abdominal imaging (ultrasound or CT) to exclude biliary obstruction, as the elevated ALP requires ruling out extrahepatic cholestasis 1

• Test for viral hepatitis (HBsAg, anti-HCV, HEV RNA), autoimmune hepatitis (ANA, anti-smooth muscle antibodies, IgG levels), and drug-induced liver injury by detailed medication history including over-the-counter and herbal products 1

Assessment for Acute-on-Chronic Liver Failure (ACLF)

Evaluate for Extrahepatic Organ Failures

• The elevated NT-proBNP suggests possible circulatory dysfunction, which is one component of ACLF; assess for vasopressor requirement (defines circulatory failure) 1, 4

• Check for kidney failure (creatinine ≥2.0 mg/dL), brain failure (grade III-IV hepatic encephalopathy), respiratory failure (PaO₂/FiO₂ <200 or mechanical ventilation need), and coagulation failure (INR >2.5) using CLIF-SOFA criteria 1, 4

• ACLF occurs in 30-57% of Western cases with severe AH as the precipitating event and dramatically worsens prognosis with 28-day mortality ranging from 31-72% 1, 4

• Younger age, systemic inflammatory response (check leukocyte count, C-reactive protein), and bacterial infections are independent predictors of ACLF development 4

Diagnostic Classification and Biopsy Considerations

Three-Tiered Classification System

• This patient likely has "probable AH" if heavy alcohol use within the past 60 days is confirmed (>40 g/day for women, >50-60 g/day for men for >6 months with <60 days abstinence) and no confounding factors exist 1, 5

• If confounding factors are present (atypical medications, uncertain alcohol history, or consideration of corticosteroid therapy), this becomes "possible AH" requiring liver biopsy for confirmation 1, 5

• Transjugular liver biopsy is preferred over percutaneous approach in the setting of likely coagulopathy and possible ascites in this patient 1, 5

Histologic Confirmation Considerations

• Only 70-80% of clinically presumed AH cases show histologic confirmation, meaning clinical diagnosis alone carries a 10-50% risk of misclassification 5

• Biopsy should be strongly considered before initiating corticosteroids (if mDF ≥32 or MELD >20) to confirm the diagnosis and exclude alternative etiologies 1, 5

• Histologic hallmarks include macrovesicular steatosis plus ≥1 of: neutrophil infiltration, hepatocyte ballooning, or Mallory-Denk bodies, with additional features of cholestasis (bilirubinostasis), megamitochondria, and chicken-wire fibrosis 1

Common Pitfalls and Caveats

• Do not assume AH diagnosis without confirming recent heavy alcohol use within 60 days; obtain collateral history from family members as patients may underreport consumption 1, 5

• The markedly elevated ALP (461 U/L) is atypical for uncomplicated AH and mandates imaging to exclude biliary obstruction or infiltrative disease, though intrahepatic cholestasis can occur in severe AH 1

• Ammonia level of 65 µmol/L is only mildly elevated; levels >100 µmol/L predict severe hepatic encephalopathy, and levels >200 µmol/L are associated with 55% risk of intracranial hypertension 2

• The elevated NT-proBNP may reflect circulatory dysfunction from SIRS, cardiac stress from alcohol cardiomyopathy, or volume overload from cirrhosis; echocardiography should evaluate right and left ventricular function 1

• Before initiating corticosteroids for severe AH, definitively exclude active infection (spontaneous bacterial peritonitis, pneumonia, urinary tract infection) as infection is an absolute contraindication to steroid therapy 1