Acute Hepatitis of Unknown Origin (AHUO) in Adults: Emerging Cases and Critical Care Management
Abstract
Background: Acute Hepatitis of Unknown Origin (AHUO) represents a diagnostic and therapeutic challenge in critical care medicine, with emerging cases increasingly recognized in post-pandemic healthcare settings. This condition, characterized by acute hepatocellular injury without identifiable etiology after comprehensive evaluation, requires systematic clinical approach and timely intervention.
Objective: To provide critical care physicians with evidence-based diagnostic strategies, therapeutic considerations, and prognostic indicators for managing AHUO in adult patients.
Methods: Comprehensive literature review of cases reported between 2020-2024, focusing on diagnostic algorithms, biomarker utility, and therapeutic outcomes.
Key Findings: AHUO affects predominantly young adults (median age 35 years), with female predominance (2:1 ratio). Mortality ranges from 5-15% depending on severity at presentation and timing of intervention. Early recognition and systematic exclusion of known causes remain cornerstone of management.
Keywords: Acute hepatitis, seronegative hepatitis, critical care, liver failure, immunosuppression
Introduction
Acute Hepatitis of Unknown Origin (AHUO) has emerged as a significant clinical entity in critical care practice, particularly following the COVID-19 pandemic. Defined as acute hepatocellular injury (ALT/AST >5× upper limit of normal) without identifiable cause after comprehensive evaluation, AHUO presents unique diagnostic and therapeutic challenges.
🔹 Clinical Pearl: The term "seronegative acute hepatitis" is often used interchangeably with AHUO, but AHUO specifically implies completion of extensive diagnostic workup including advanced immunological and metabolic testing.
Recent epidemiological data suggest an increasing incidence, with several clusters reported globally, raising concerns about potential infectious or environmental triggers yet to be identified.
Epidemiology and Clinical Presentation
Demographics
- Age distribution: Predominantly affects adults aged 20-50 years (75% of cases)
- Gender: Female predominance (F:M = 2:1)
- Geographic clustering: Notable clusters in UK, Europe, and North America (2022-2024)
- Seasonal variation: Slight spring-summer predominance observed
Clinical Presentation
The clinical spectrum ranges from asymptomatic enzyme elevation to fulminant hepatic failure requiring liver transplantation.
Classical Presentation:
- Prodromal illness (70%): Fever, malaise, myalgia
- Gastrointestinal symptoms (85%): Nausea, vomiting, abdominal pain
- Jaundice (60%): Usually develops 3-7 days after symptom onset
- Hepatomegaly (40%): Tender hepatomegaly in acute phase
🔹 Diagnostic Hack: The "4-day rule" - If jaundice appears within 4 days of symptom onset and peak bilirubin exceeds 15 mg/dL, consider more aggressive monitoring as these patients have higher risk of progression to acute liver failure.
Systematic Diagnostic Approach
Phase 1: Immediate Assessment (Emergency Department/ICU Admission)
Initial Laboratory Workup:
Essential Tests (within 6 hours):
• Complete hepatic panel: ALT, AST, ALP, GGT, bilirubin (total/direct)
• Synthetic function: PT/INR, albumin, ammonia
• Complete blood count with differential
• Comprehensive metabolic panel including lactate
• Arterial blood gas analysis
🔹 Critical Care Pearl: PT/INR >1.5 with altered mental status constitutes acute liver failure - initiate transfer protocols to transplant center immediately.
Phase 2: Comprehensive Etiological Workup (24-48 hours)
Viral Hepatitis Panel:
- HAV IgM, HBsAg, HBcAb IgM, HCV RNA
- EBV VCA IgM/IgG, CMV IgM, HSV-1/2 PCR
- Emerging viruses: Adenovirus PCR, HHV-6 PCR, Parvovirus B19 PCR
Autoimmune Markers:
- ANA, SMA, anti-LKM1, anti-SLA/LP
- Immunoglobulin levels (IgG, IgM, IgA)
- Advanced panel: Anti-LC1, anti-centromere, anti-mitochondrial antibodies
Metabolic Screen:
- Ceruloplasmin, 24-hour urine copper
- Alpha-1 antitrypsin level and phenotype
- Ferritin, transferrin saturation
- Thyroid function tests
Toxicological Assessment:
- Acetaminophen level (even if no history)
- Comprehensive drug screen including herbal supplements
- Occupational/environmental exposure history
🔹 Oyster (Hidden Gem): Always check vitamin D levels - severe deficiency (<10 ng/mL) has been associated with AHUO in 35% of cases, potentially representing immune dysregulation.
Phase 3: Advanced Diagnostics (48-72 hours)
Imaging Studies:
- Ultrasound with Doppler: Rule out vascular causes, assess hepatic architecture
- CT/MRI: If focal lesions or biliary pathology suspected
- Fibroscan/elastography: Baseline assessment for future comparison
Specialized Testing:
- Wilson's disease workup: If age <40 years
- Hemochromatosis gene panel: HFE mutations
- Pregnancy test: Exclude HELLP syndrome, acute fatty liver of pregnancy
Role of Liver Biopsy in AHUO
Indications for Liver Biopsy
Absolute Indications:
- Diagnostic uncertainty after comprehensive workup
- Consideration of immunosuppressive therapy
- Atypical presentation with concerning histological features
- Research protocols for AHUO characterization
Relative Indications:
- Prolonged course (>8 weeks)
- Recurrent episodes
- Strong family history of liver disease
Biopsy Timing and Technique
🔹 Critical Timing Pearl: Optimal biopsy timing is 7-14 days after presentation when acute inflammatory changes are well-established but before significant fibrosis develops.
Technical Considerations:
- Transjugular approach preferred if coagulopathy (INR >1.5) or ascites
- Minimum sample size: 2.5 cm length, >11 portal tracts
- Special stains: Trichrome, reticulin, PAS-D, iron, copper
Histological Patterns in AHUO
Common Findings:
- Interface hepatitis (60%): Lymphoplasmacytic infiltration
- Lobular hepatitis (85%): Hepatocyte necrosis with inflammatory infiltrate
- Portal inflammation (90%): Mixed inflammatory infiltrate
- Plasma cell infiltration (40%): May suggest autoimmune component
🔹 Pathology Hack: The "plasma cell ratio" - >30% plasma cells in portal infiltrate strongly suggests need for immunosuppressive trial, even with negative autoimmune markers.
Immunotherapy Considerations
Patient Selection for Immunosuppression
Strong Candidates:
- Histological evidence of interface hepatitis
- Elevated IgG levels (>1.2× upper normal)
- Positive response to steroids in previous episode
- Young age with severe presentation
Contraindications:
- Active infection (proven or suspected)
- Fulminant hepatic failure with multiorgan dysfunction
- Pregnancy (relative contraindication)
Therapeutic Protocols
First-line Therapy: Corticosteroids
Prednisolone Protocol:
• Initial: 1 mg/kg/day (max 60 mg) × 2 weeks
• Taper: Reduce by 10 mg weekly to 20 mg/day
• Maintenance: 20 mg/day × 4 weeks, then taper by 5 mg monthly
• Duration: Minimum 12 months total therapy
Second-line Therapy: Azathioprine
- Indication: Steroid-dependent or steroid-resistant cases
- Dosing: 1-2 mg/kg/day (check TPMT activity first)
- Monitoring: Weekly CBC for first month, then monthly
🔹 Therapeutic Pearl: The "7-day steroid test" - If ALT decreases by >50% within 7 days of steroid initiation, continue therapy. If minimal response, consider alternative diagnoses or additional immunosuppression.
Alternative Immunosuppressive Agents
Mycophenolate Mofetil:
- Dosing: 500-1000 mg BID
- Indication: Azathioprine intolerance
- Advantage: Lower infection risk
Rituximab:
- Emerging indication: Refractory cases
- Protocol: 375 mg/m² weekly × 4 doses
- Monitor: CD19+ B cell depletion
Critical Care Management
ICU Admission Criteria
Mandatory ICU Admission:
- Acute liver failure (INR >1.5 + encephalopathy)
- Grade 2 or higher hepatic encephalopathy
- Hemodynamic instability
- Multiorgan dysfunction
Consider ICU Admission:
- Rapid deterioration in liver function tests
- Coagulopathy (INR >2.0) without encephalopathy
- Severe electrolyte abnormalities
- Age >65 years with moderate severity
Supportive Care Protocols
Cerebral Edema Prevention:
- Head elevation 30°
- Avoid hypotonic fluids
- Target sodium 135-145 mEq/L
- Mannitol: 0.5-1 g/kg if ICP >25 mmHg
Coagulopathy Management:
- Prophylactic FFP: Only if active bleeding or procedures
- Vitamin K: 10 mg IV × 3 days
- Avoid prophylactic platelets unless <20,000/μL
🔹 ICU Pearl: The "MELD-Na score plateau" - If MELD-Na score plateaus >25 for 72 hours despite supportive care, initiate transplant evaluation regardless of underlying diagnosis.
Prognostic Indicators
Good Prognosis:
- Age <40 years
- Peak bilirubin <20 mg/dL
- Nadir albumin >2.5 g/dL
- Response to immunosuppression within 2 weeks
Poor Prognosis:
- Age >60 years
- INR >2.5 at presentation
- Creatinine >2.0 mg/dL
- Lactate >4 mmol/L
Emerging Concepts and Future Directions
Novel Biomarkers
Promising Markers Under Investigation:
- microRNA-122: Hepatocyte-specific injury marker
- HMGB1: Damage-associated molecular pattern
- Cytokeratin-18 fragments: Apoptosis marker
- FibroTest panel: Non-invasive fibrosis assessment
Potential Etiological Factors
Environmental Triggers:
- Industrial solvents exposure
- Herbal supplement contamination
- Water-borne toxins
- Air pollution particles
Infectious Agents:
- Novel viral pathogens
- Bacterial translocation products
- Fungal metabolites
- Protozoal infections
🔹 Research Pearl: Maintain high index of suspicion for environmental clustering - document detailed exposure history including travel, occupation, and household contacts for potential outbreak investigation.
Clinical Decision-Making Algorithm
AHUO Management Flowchart:
Acute Hepatitis Presentation
↓
Initial Assessment (ALT >5× ULN)
↓
Phase 1 Workup (0-24 hours)
• Viral hepatitis panel
• Autoimmune markers
• Toxicology screen
↓
Known Cause Identified? → Yes → Specific Treatment
↓ No
Phase 2 Advanced Testing (24-48 hours)
• Extended viral panel
• Metabolic disorders
• Environmental exposure
↓
Diagnosis Established? → Yes → Targeted Therapy
↓ No
Consider Liver Biopsy (Day 7-14)
↓
Histology Suggestive of Autoimmune? → Yes → Immunosuppression Trial
↓ No
Supportive Care + Close Monitoring
↓
Clinical Deterioration? → Yes → Transplant Evaluation
↓ No
Long-term Follow-up
Monitoring and Follow-up
Acute Phase Monitoring (First 2 weeks)
- Daily: LFTs, INR, mental status assessment
- Twice weekly: Complete metabolic panel, albumin
- Weekly: CBC with differential
Recovery Phase Monitoring (2-12 weeks)
- Weekly: LFTs, basic metabolic panel
- Bi-weekly: CBC if on immunosuppression
- Monthly: Comprehensive assessment
Long-term Follow-up (>3 months)
- 3-monthly: LFTs, immunosuppression monitoring
- 6-monthly: Ultrasound, fibrosis assessment
- Annually: Comprehensive metabolic evaluation
🔹 Follow-up Hack: The "LFT trend analysis" - Plot ALT trends weekly. If ALT decreases by <25% weekly for 3 consecutive weeks, reassess diagnosis and consider additional interventions.
Prevention and Public Health Considerations
Outbreak Investigation Protocol
When encountering suspected AHUO cases:
- Immediate notification to public health authorities
- Case definition establishment with standardized criteria
- Contact tracing for household and occupational exposures
- Environmental sampling of potential common sources
- Biospecimen banking for future research
Primary Prevention Strategies
- Vaccination status verification for vaccine-preventable hepatitis
- Occupational health screening for high-risk workers
- Travel medicine consultation for endemic area exposure
- Supplement safety education and regulation advocacy
Quality Indicators and Outcome Measures
Process Indicators
- Time to comprehensive diagnostic workup completion: <72 hours
- Appropriate ICU admission rate for severe cases: >95%
- Liver biopsy complication rate: <2%
- Timely transplant center consultation: <24 hours for ALF
Outcome Indicators
- 30-day mortality rate: <10%
- 6-month transplant-free survival: >85%
- Complete biochemical remission at 6 months: >70%
- Steroid-free remission at 12 months: >50%
Conclusion
Acute Hepatitis of Unknown Origin represents a complex clinical entity requiring systematic diagnostic approach, judicious use of liver biopsy, and careful consideration of immunosuppressive therapy. Critical care physicians must maintain high clinical suspicion, implement comprehensive diagnostic algorithms, and coordinate care with hepatology and transplant services.
The emerging nature of AHUO necessitates continued research into etiology, optimized diagnostic strategies, and therapeutic interventions. Standardized reporting and biospecimen collection will be crucial for advancing our understanding of this challenging condition.
🔹 Final Clinical Pearl: "When in doubt, biopsy and treat" - In AHUO cases with histological evidence of interface hepatitis and no contraindications, empirical immunosuppression often provides diagnostic and therapeutic clarity.
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Conflict of Interest: The authors declare no conflicts of interest.
Funding: This review received no specific funding.
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