Acute Hepatitis of Unknown Origin (AHUO) in Adults: Emerging Cases and Critical Care Management

Dr Neeraj Manikath, Claude.ai

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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Friday, August 1, 2025