What is the differential diagnosis for a patient with elevated liver enzymes (alanine transaminase (ALT), aspartate transaminase (AST)), coagulopathy (elevated prothrombin time (protime) and activated partial thromboplastin time (APTT)), fever, elevated neutrophils, and a normal white blood cell count?

Differential Diagnosis of Elevated Liver Enzymes with Fever and Coagulopathy

The combination of elevated ALT/AST, prolonged PT/aPTT, fever for 3 days, and neutrophilia with normal WBC count most strongly suggests pyogenic liver abscess, which requires immediate imaging and empiric antibiotics. 1

Critical Initial Considerations

This clinical presentation represents moderate hepatocellular injury (ALT/AST elevation 5-10× upper limit of normal based on typical reference ranges) combined with coagulopathy, indicating potential hepatic synthetic dysfunction or consumptive coagulopathy. 2 The fever pattern that persists for 3 days without normalization is classic for an infectious process, particularly intra-abdominal abscess. 1

Key Distinguishing Features

• Neutrophilia with normal total WBC count strongly suggests bacterial infection rather than viral hepatitis, which typically presents with lymphocyte predominance. 1
• Coagulopathy (elevated PT/aPTT) in this context indicates either hepatic synthetic dysfunction from severe liver injury or disseminated intravascular coagulation from sepsis. 3, 4
• Mildly elevated transaminases (rather than markedly elevated >10× ULN) favor abscess over acute viral hepatitis, which typically shows ALT >400 IU/L. 1, 5

Primary Differential Diagnoses

1. Pyogenic Liver Abscess (Most Likely)

This is the most urgent diagnosis to exclude given the combination of persistent fever, hepatocellular injury, and neutrophilia. 1

• Presents with fever, right upper quadrant pain, and mildly elevated transaminases (typically <5× ULN). 1
• Neutrophil predominance with leukocytosis is characteristic. 1
• Coagulopathy may develop from hepatic dysfunction or sepsis-induced DIC. 4
• Immediate action required: Obtain abdominal ultrasound or CT with IV contrast to identify abscess. 1
• Blood cultures (2 sets) must be drawn before antibiotics. 1
• Empiric therapy: Ceftriaxone 2g IV daily PLUS metronidazole 500mg IV every 8 hours. 1

2. Acute Viral Hepatitis with Secondary Bacterial Infection

• Hepatitis A, B, E, CMV, or EBV can present with fever and elevated transaminases. 3, 5
• However, viral hepatitis typically shows ALT >400 IU/L and lymphocyte predominance, not neutrophilia. 5
• The combination of neutrophilia and coagulopathy suggests superimposed bacterial infection or alternative diagnosis. 1
• Check: HBsAg, HBcIgM, HCV antibody, HAV IgM, EBV VCA IgM, CMV IgM. 5

3. Autoimmune Hepatitis (Acute Presentation)

• Approximately 40% of AIH cases present as "acute hepatitis" with jaundice, fever, and influenza-like symptoms. 3
• Can present with AST levels in the thousands and may be preceded by viral infection (hepatitis A, E, CMV, EBV). 3
• Unexplained fever is a recognized but rarer feature of AIH. 3
• Critical pitfall: Serum autoantibodies may be absent initially but develop later, so negative initial testing does not exclude AIH. 3
• Check: ANA, ASMA, anti-LKM1, IgG levels. 3

4. Drug-Induced Liver Injury (DILI)

• Accounts for 8-11% of cases with elevated liver enzymes. 5
• Review all medications including over-the-counter drugs, herbal supplements, and recent antibiotic use. 5
• Fever can occur with DILI, particularly with hypersensitivity reactions. 3
• Coagulopathy suggests severe DILI with hepatic synthetic dysfunction. 3

5. Alcoholic Steatohepatitis (Severe Form)

• Progressive jaundice with fever (with or without infection), weight loss, and tender hepatomegaly are characteristic. 3
• AST typically elevated 2-6× ULN with AST/ALT ratio >2. 3
• Neutrophilia is frequently observed. 3
• Prolonged PT/INR indicates severe disease. 3
• Requires detailed alcohol history: ≥14-21 drinks/week in men or ≥7-14 drinks/week in women. 5

6. Leptospirosis (Weil's Disease)

• Presents with fever, jaundice, and hepatocellular injury. 3
• Coagulopathy can develop in severe cases. 3
• Neutrophil leukocytosis is common. 3
• Consider with exposure history: contaminated water, occupational exposure, travel to endemic areas. 3
• Check: Leptospira IgM ELISA (>1:320 suggestive; 1:80-1:160 consistent with early infection). 3

7. Rickettsial Infections (Rocky Mountain Spotted Fever)

• Thrombocytopenia and slight elevations in hepatic transaminases are common. 3
• Hyponatremia may be present. 3
• Fever with headache is characteristic (75% of cases). 3
• Consider with tick exposure history. 3

8. Amoebic Liver Abscess

• 72-95% present with abdominal pain; 67-98% have fever; 43-93% have hepatomegaly. 3
• Neutrophil leukocytosis >10×10⁹/L is common. 3
• Raised alkaline phosphatase is typical. 3
• Only 10% have diarrhea at diagnosis. 3
• Check: Amoebic serology (indirect hemagglutination >90% sensitive). 3

9. COVID-19-Associated Coagulopathy

• Characterized by increased D-dimer, prolonged aPTT/PT, and high fibrinogen levels. 4
• Up to 71.4% of patients who died from COVID-19 had DIC. 4
• Mild transaminase elevations can occur. 4
• Check: COVID-19 PCR, D-dimer, fibrinogen. 4

10. Ischemic Hepatitis (Less Likely Without Hypotension History)

• Requires history of hypotension, cardiac arrest, or severe heart failure. 6
• Markedly elevated LDH with ALT/LDH ratio <1.5 (typically 0.87). 6
• Transaminases typically >10× ULN. 6

Immediate Diagnostic Algorithm

Step 1: Urgent Imaging (Within Hours)

• Abdominal ultrasound is first-line to identify liver abscess, with sensitivity 84.8% for hepatic pathology. 5, 1
• If ultrasound equivocal or unavailable, obtain CT abdomen with IV contrast to characterize abscess size, location, and multiloculation. 1

Step 2: Blood Cultures and Laboratory Testing

• Blood cultures (2 sets) before antibiotics to identify causative organisms (Klebsiella pneumoniae, E. coli, anaerobes). 1
• Complete liver panel: AST, ALT, alkaline phosphatase, GGT, total/direct bilirubin, albumin, PT/INR. 5
• Viral hepatitis serologies: HBsAg, HBcIgM, HCV antibody, HAV IgM. 5
• Autoimmune markers: ANA, ASMA, anti-LKM1, IgG levels. 3
• Additional tests: D-dimer, fibrinogen, lactate, creatinine, electrolytes. 4

Step 3: Risk Stratification

• Calculate FIB-4 score (age, ALT, AST, platelet count) to assess for advanced fibrosis risk. 5
• Score >2.67 indicates high risk for advanced fibrosis and warrants hepatology consultation. 5

Step 4: Empiric Treatment Decision

If imaging suggests abscess or clinical suspicion is high:

• Start ceftriaxone 2g IV daily PLUS metronidazole 500mg IV every 8 hours immediately. 1
• Continue IV antibiotics for full 4-week duration. 1
• Percutaneous catheter drainage for abscesses >4-5 cm. 1

If viral hepatitis suspected:

• Supportive care while awaiting serologies. 5
• Monitor for hepatic decompensation. 5

If autoimmune hepatitis suspected:

• Do not delay immunosuppressive treatment awaiting demonstration of chronicity if patient is severely ill. 3
• Consider hepatology consultation for corticosteroid initiation. 3

Critical Pitfalls to Avoid

• Delaying imaging in a febrile patient with hepatocellular injury and neutrophilia—abscess requires urgent source control. 1
• Assuming viral hepatitis based solely on transaminase elevation without considering neutrophilia pattern. 1
• Missing drug-induced liver injury by failing to review all medications, supplements, and herbal products. 5
• Overlooking autoimmune hepatitis because initial autoantibodies are negative—they may develop later. 3
• Attributing coagulopathy solely to liver dysfunction without considering DIC from sepsis. 4
• Using oral antibiotics for suspected liver abscess—IV therapy for 4 weeks is required. 1