Differential Diagnoses for Worsening Palmar Rash with Elevated Liver Enzymes
The most likely diagnosis is syphilitic hepatitis, despite negative initial syphilis serology, and this patient requires immediate repeat syphilis testing with both nontreponemal and treponemal tests, along with consideration of other viral exanthems and drug reactions.
Primary Differential: Syphilitic Hepatitis
Syphilitic hepatitis remains the leading diagnosis given the constellation of palmar rash, elevated transaminases (ALT 82, AST 63), and mildly elevated alkaline phosphatase (109) and GGT (52). 1, 2, 3
Why Syphilis Despite Negative Serology?
- Timing of initial testing may have been too early - the patient was tested only 3 days into symptom onset, and treponemal antibodies typically appear 1-4 weeks after infection while nontreponemal antibodies (RPR) appear slightly later but are reliably positive by 4-6 weeks. 4
- Repeat testing is now indicated at 2 weeks - serologic tests become positive well before 63 days in the vast majority of syphilis infections, and testing at this 2-week mark should capture seroconversion if secondary syphilis is present. 4
- Syphilitic hepatitis occurs in 38% of HIV-infected patients with early syphilis, though this patient is HIV-negative, the condition is likely under-diagnosed in the general population. 5
Clinical Features Supporting Syphilitic Hepatitis
- Palmar involvement is characteristic - secondary syphilis classically presents with maculopapular rash involving palms and soles. 6, 4
- Hepatic pattern matches - syphilitic hepatitis typically presents with mild-to-moderate transaminase elevation (ALT 82, AST 63) with disproportionate alkaline phosphatase elevation (109) and elevated GGT (52), representing cholestatic injury. 1, 2, 7
- Progressive worsening over 2 weeks aligns with untreated secondary syphilis evolution. 7
Secondary Differentials
Drug Reaction (DRESS Syndrome or Drug-Induced Hepatitis)
- DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) should be considered, though eosinophil count is normal (0.1). 6
- Obtain detailed medication history including any antibiotics, anticonvulsants, or antiretrovirals started in the past 2-8 weeks, as these are common culprits. 6
- Key distinguishing feature: DRESS typically shows eosinophilia (absent here) and occurs 2-8 weeks after drug initiation. 6
Viral Hepatitis with Exanthem
- Acute viral hepatitis (A, B, C, E) can present with rash and transaminitis, though palmar distribution is atypical. 6
- EBV or CMV can cause maculopapular rash with hepatitis, particularly in young patients. 6
- Parvovirus B19 is already excluded by negative serology, which would have been a consideration for palmar rash. 6
HIV Seroconversion Syndrome
- Acute HIV infection can present with maculopapular rash and transaminitis 2-4 weeks after exposure, though HIV testing was negative. 6
- Consider repeat HIV testing at 4-6 weeks if sexual exposure occurred within the window period, as initial testing may have been too early. 6, 4
Emtricitabine (FTC) Reaction
- If patient was started on HIV PrEP or treatment, FTC causes asymptomatic maculae on palms or soles in 1.5% of patients and increased ALT in 0.9%. 6
- This is unlikely given no mention of antiretroviral therapy, but medication history should confirm. 6
Immediate Diagnostic Workup
Essential Testing Now (at 2 weeks)
- Repeat syphilis serology with both RPR/VDRL and treponemal test (FTA-ABS or TP-PA) - this is the single most important test, as serologic conversion should have occurred by now if secondary syphilis is present. 8, 4
- Complete medication history focusing on any new medications started 2-8 weeks before rash onset. 6
- Viral hepatitis serologies if not already done: Hepatitis A IgM, Hepatitis B surface antigen and core IgM, Hepatitis C antibody with reflex RNA, Hepatitis E IgM. 6
- EBV and CMV serologies (IgM and IgG) to evaluate for acute viral infection. 6
- Repeat HIV testing if initial test was within potential window period. 6, 4
Additional Considerations
- Autoimmune hepatitis panel (ANA, anti-smooth muscle antibody, anti-LKM) if viral and syphilitic causes are excluded. 1
- Abdominal ultrasound to evaluate hepatobiliary tree if cholestatic pattern persists. 2
Management Algorithm
If Repeat Syphilis Testing is Positive
- Treat immediately with benzathine penicillin G 2.4 million units IM as a single dose for secondary syphilis. 8, 4
- Expect liver enzymes to improve within 2-4 weeks after appropriate antibiotic therapy - this confirms the diagnosis of syphilitic hepatitis. 1, 2, 7
- Follow-up RPR at 6 and 12 months to document fourfold decline in titer, confirming treatment success. 8, 4
- Notify and treat sexual contacts from the past 6 months plus duration of symptoms. 4
If Syphilis Testing Remains Negative
- Pursue drug reaction workup - discontinue any potentially offending medications started within 8 weeks of symptom onset. 6
- Consider skin biopsy of rash if diagnosis remains unclear, which can help differentiate between drug reaction, viral exanthem, and other causes. 8
- Monitor liver enzymes weekly - improvement after drug discontinuation supports drug-induced hepatitis. 6
Critical Pitfalls to Avoid
- Do not dismiss syphilis based on initial negative serology alone - testing at 3 days was likely too early for antibody detection. 4
- Do not delay repeat syphilis testing - at 2 weeks post-symptom onset, serologic tests should be positive if secondary syphilis is present. 4
- Do not overlook sexual history - a comprehensive detailed sexual history is key to diagnosis of syphilitic hepatitis and often missed in initial evaluations. 7
- Do not assume elevated liver enzymes are unrelated to the rash - the combination of palmar rash and hepatitis is pathognomonic for syphilitic hepatitis until proven otherwise. 1, 2, 5
- Do not forget to test for HIV - HIV coinfection significantly affects syphilis management and monitoring. 8, 4