In a patient with primary sclerosing cholangitis who develops month-long fatigue, fever, and a marked rise in liver enzymes after receiving the Shingrix vaccine, what is the most likely cause and how should the work‑up be approached?

Acute Hepatitis Following Shingrix Vaccination in PSC Patient

The most likely cause is drug-induced liver injury (DILI) from the Shingrix vaccine, and the work-up should systematically exclude other acute hepatic insults—particularly acute viral hepatitis, bacterial cholangitis, autoimmune hepatitis overlap, and biliary obstruction—before attributing the presentation to vaccine-related injury.

Most Likely Diagnosis: Drug-Induced Liver Injury

Given the temporal relationship (month-long symptoms following Shingrix), marked transaminase elevation, and fever, DILI from the vaccine is the leading consideration 1. The Shingrix FDA label documents that fatigue (54-64%), fever (18-28%), and gastrointestinal symptoms occur commonly in the week following vaccination 2. However, prolonged month-long symptoms with marked liver enzyme elevation are not typical vaccine reactions and suggest a more serious hepatic process.

Critical Work-Up Algorithm

First-Line Exclusions (Urgent)

1. Acute Cholangitis

• While PSC patients classically present with cholangitis (fever, jaundice, right upper quadrant pain), you must rule this out immediately 3
• Obtain blood cultures, assess for sepsis
• Perform urgent MRCP or ultrasound to evaluate for new dominant stricture or biliary obstruction
• If imaging suggests obstruction or clinical deterioration occurs, ERCP may be needed

2. Viral Hepatitis Panel

• Test for hepatitis A, B, C, D, and E 1
• Critical: Check for HBV reactivation, especially relevant given the immunomodulatory effects of adjuvanted vaccines 1
• Include CMV and EBV if immunosuppression is present

3. Autoimmune Hepatitis Overlap Syndrome

• Measure IgG levels, ANA, anti-smooth muscle antibodies (ASMA) 1
• Key distinction: PSC-AIH overlap can present with abrupt transaminase elevations and fever 4, 5, 6
• This overlap occurs in a subset of PSC patients and may be triggered by drugs 1

Second-Line Evaluation

4. Biliary Obstruction/Cholelithiasis

• Ultrasound to exclude gallstones, bile duct dilation 1
• Review recent MRCP findings for interval changes

5. Medication Review

• Document ALL medications, supplements, and over-the-counter products 1
• Temporal relationship: DILI typically occurs within 5-90 days of drug exposure
• Consider stopping any non-essential hepatotoxic agents

6. Alcohol Assessment

• Quantify alcohol intake to exclude alcoholic hepatitis 1

Diagnostic Liver Biopsy Consideration

When to biopsy 1:

• If autoimmune markers are positive (to distinguish AIH overlap from DILI)
• If causality remains uncertain after excluding above etiologies
• If considering immunosuppression (biopsy can show interface hepatitis in AIH vs. other patterns in DILI)

Common Pitfalls to Avoid

1. Do not assume this is PSC progression: Abrupt elevations in liver tests should NOT be attributed to underlying PSC without excluding acute processes 1

2. Do not overlook overlap syndrome: PSC-AIH overlap can emerge years after PSC diagnosis and may be drug-triggered 4, 5

3. Do not dismiss the vaccine connection: While Shingrix is generally safe with no increased serious adverse events in trials 2, individual idiosyncratic DILI reactions can occur

4. Do not delay cholangitis treatment: If fever persists with cholestatic pattern, empiric antibiotics and biliary decompression may be life-saving

Shingrix Safety Context

The FDA label shows that in immunocompetent adults, systemic reactions (fatigue 54%, fever 18-28%) typically resolve within 1-3 days 2. Month-long symptoms with marked transaminase elevation are NOT typical vaccine reactions and warrant full hepatic work-up. The vaccine did not increase serious adverse events or death in clinical trials 2, but post-marketing idiosyncratic reactions remain possible.

Management Approach

• Stop any potentially hepatotoxic medications (except those essential for PSC/IBD management)
• Monitor closely: Serial liver enzymes, coagulation studies, bilirubin
• Consider empiric antibiotics if cholangitis cannot be excluded
• If AIH overlap confirmed: Add corticosteroids ± azathioprine to ursodeoxycholic acid 4, 6
• If DILI confirmed: Supportive care, monitor for resolution (typically 1-3 months)

The diagnosis requires systematic exclusion rather than assumption, as multiple acute hepatic processes can mimic each other in PSC patients 3, 1.