In an HIV‑positive adult with CD4 15 cells/µL and suspected primary CNS lymphoma, who has rising aspartate aminotransferase, alanine aminotransferase, gamma‑glutamyl transferase, mild hyperglycemia, and decreasing lactate dehydrogenase and Epstein‑Barr virus polymerase chain reaction while awaiting stereotactic brain biopsy, what is the most appropriate next step in management?

Management of Rising Liver Enzymes in HIV-Positive Patient with Suspected Primary CNS Lymphoma Awaiting Biopsy

Proceed urgently with stereotactic brain biopsy without further delay, as the decreasing LDH and EBV PCR suggest possible spontaneous tumor regression or alternative diagnosis, while rising transaminases may indicate drug-induced liver injury or opportunistic infection requiring definitive tissue diagnosis to guide appropriate therapy. 1

Interpretation of Laboratory Trends

Favorable CNS Disease Markers

• Decreasing LDH (217 → 185 → 162 U/L) and dramatically falling EBV PCR (30 → <0.6 mg/L) suggest either spontaneous tumor regression, response to inadvertent treatment effect, or that the diagnosis may not be primary CNS lymphoma. 2, 3
• In HIV-positive patients with CD4 15 cells/µL, EBV DNA is detected in CSF of only 7-13% of cases without lymphoma, and can be present with cerebral toxoplasmosis or pyogenic brain abscesses, limiting its diagnostic specificity. 4
• The falling inflammatory markers make empiric anti-toxoplasma therapy response a consideration, though this was not explicitly mentioned in the clinical scenario. 4

Concerning Hepatic Trends

• Rapidly rising transaminases (AST 53→88 U/L; ALT 162→304 U/L; GGT 66→126 U/L) over just 2 days indicate acute hepatocellular injury requiring urgent evaluation. 1
• In severely immunocompromised patients (CD4 <50 cells/µL), this pattern raises concern for:
  • Drug-induced liver injury from antiretroviral therapy, prophylactic medications, or empiric antimicrobials
  • Opportunistic hepatic infections (CMV hepatitis, disseminated fungal infection, mycobacterial disease)
  • Systemic lymphoma with hepatic involvement (though this would contradict the diagnosis of primary CNS lymphoma) 1

Mild Hyperglycemia

• Glucose 120 mg/dL with prior fluctuations likely reflects stress hyperglycemia, corticosteroid effect if administered, or HIV-related metabolic derangement rather than a primary diagnostic concern. 1

Urgent Diagnostic Priorities

Proceed Immediately with Stereotactic Biopsy

• Histopathological confirmation via stereotactic biopsy is mandatory and remains the gold standard for primary CNS lymphoma diagnosis, with diagnostic accuracy of 73-97%. 1, 5
• The biopsy should not be further delayed because primary CNS lymphoma in HIV-positive patients exhibits extremely high proliferative activity (Ki-67 >90%), and the decreasing biomarkers suggest the window for diagnosis may be narrowing. 1
• If corticosteroids were administered at any point, they must be stopped and repeat contrast-enhanced MRI obtained before biopsy to confirm the target lesion remains visible and adequately enhancing. 1, 6, 5

Critical Pre-Biopsy Considerations

• Verify no corticosteroids have been given in the evaluation period, as steroids cause rapid cytotoxic regression and render 20-60% of biopsies non-diagnostic. 4, 6, 5
• Obtain fresh contrast-enhanced MRI within 14 days of planned biopsy to account for rapid tumor dynamics. 1
• Target periventricular or corpus callosum lesions showing homogeneous or thick irregular enhancement rather than thin ring enhancement, as these patterns predict lymphoma. 4

Parallel Hepatic Evaluation

Immediate Hepatic Work-Up (While Scheduling Biopsy)

• Review all medications for hepatotoxic agents, particularly antiretroviral therapy, trimethoprim-sulfamethoxazole (if used for PCP prophylaxis), and any empiric antimicrobials. 1
• Obtain hepatitis serologies (HBV, HCV), CMV PCR, and consider abdominal imaging if systemic lymphoma is a concern (though FDG-PET/CT has higher false-positive rates in HIV patients). 1
• Check for disseminated opportunistic infections given CD4 15 cells/µL: blood cultures for mycobacteria, fungal antigens, and CMV viremia. 1, 4

Infection Prophylaxis Considerations

• Ensure PCP prophylaxis is in place (trimethoprim-sulfamethoxazole or alternative if causing hepatotoxicity). 1
• Consider antifungal prophylaxis with fluconazole given CD4 <100 cells/µL, though monitor for drug-drug interactions with antiretroviral therapy. 1
• Monitor for CMV disease as CD4 <100 cells/µL warrants surveillance. 1

Alternative Diagnostic Pathway (Only If Biopsy Contraindicated)

CSF Analysis as Second-Line Approach

• If stereotactic biopsy becomes medically contraindicated due to coagulopathy or clinical deterioration, CSF examination is the only valid alternative, though it facilitates diagnosis in <20% of cases. 5
• CSF studies should include: flow cytometry for monotypic B cells, MYD88 L265P mutation, IL-10 levels, and IgVH clonality assessment. 1, 5
• Conventional CSF cytology alone has 20-60% false-negative rate, especially with low sample volume or prior corticosteroid exposure. 4

Differential Diagnosis Considerations

Alternative CNS Infections at CD4 15 cells/µL

• CMV encephalitis occurs in ~13% of patients with CD4 <50 cells/µL and can present with ring-enhancing lesions. 4
• Progressive multifocal leukoencephalopathy (PML) from JC virus remains a notable differential. 4
• Cryptococcal meningoencephalitis with parenchymal lesions or tuberculous meningitis with tuberculomas should be considered. 4
• Cerebral toxoplasmosis remains the most common cause of ring-enhancing lesions in HIV patients, though the dramatic fall in inflammatory markers without documented anti-toxoplasma therapy is atypical. 4

Critical Pitfalls to Avoid

• Do not delay biopsy for further "observation" of laboratory trends—the decreasing LDH and EBV PCR may indicate loss of diagnostic opportunity. 1
• Do not administer corticosteroids for symptom control without first obtaining tissue diagnosis, as this renders biopsies non-diagnostic in a substantial proportion of cases. 1, 6, 5
• Do not rely on imaging or biomarkers alone for diagnosis, as cerebral opportunistic infections mimic lymphoma and FDG-PET/CT has higher false-positive rates in HIV patients. 1, 4
• Do not assume systemic lymphoma based on rising liver enzymes without tissue confirmation, as this would change the diagnosis from primary to secondary CNS lymphoma and alter treatment. 1

Antiretroviral Therapy Management

• Continue effective antiretroviral therapy throughout the diagnostic process and any subsequent chemotherapy to ensure sustained viral suppression and improve immune recovery. 1
• Check drug-drug interactions carefully between antiretroviral agents and any hepatotoxic medications using resources like hiv-druginteractions.org. 1
• Modify antiretroviral regimen if necessary to avoid drug-drug interactions or hepatotoxicity, but do not discontinue therapy. 1