A Rare Case of Early-Onset Steroid-Refractory Fulminant Hepatitis Following Dual Checkpoint Inhibition in Melanoma Initially Presenting With Hemorrhagic Brain Metastasis

Introduction

Melanoma remains a major global health concern, with an estimated 331 647 new cases reported worldwide in 2022. ¹ As the disease advances, central nervous system (CNS) involvement becomes a frequent site of spread, with ~10% to 40% of patients developing melanoma brain metastases (MBM). Among these cases, up to half demonstrate intratumoral hemorrhage, which occurs far more commonly than in other solid-tumor metastases, yet it remains uncommon for melanoma to initially present as acute intracranial hemorrhage. ²

The emergence of immune checkpoint inhibitors (ICIs) has markedly improved outcomes in advanced melanoma. Combination immunotherapy with ipilimumab and nivolumab has demonstrated a 5-year overall survival of 52%, compared with 44% for nivolumab alone and 26% for ipilimumab alone. ³ This regimen also achieves high intracranial activity, with ~57% of MBM achieving radiographic improvement. ⁴

However, combination therapy is associated with higher rates of immune-related adverse events (irAEs). Immune-mediated hepatitis is a recognized toxicity of programmed cell death protein-1 (PD-1; eg, nivolumab) and cytotoxic T-lymphocyte-associated protein-4 (eg, ipilimumab) inhibitors, with severe hepatitis occurring in 1.8% of patients on PD-1 monotherapy and 2.6% with ipilimumab; incidence rises substantially to 20% with combination therapy. ⁵ ICI-related hepatitis typically presents with asymptomatic transaminase elevation and responds to treatment cessation and corticosteroids, ⁵ whereas fulminant liver failure is rare (<1%) but can be rapidly progressive and life-threatening, often refractory to immunosuppression. ⁶

We report a case of melanoma initially presenting with hemorrhagic MBM and subsequently complicated by early-onset, fulminant, steroid-refractory immune-mediated hepatitis following combination ICI therapy.

Case Presentation

A 54-year-old man with no significant past medical history presented to the emergency department with acute confusion and aphasia that began ~7 hours prior to arrival. According to his wife, his mental status had progressively worsened since onset.

Initial neuroimaging revealed a right frontal hemorrhagic mass measuring 6.5 × 3.8 × 3.4 cm with 8 mm midline shift and he subsequently underwent emergent craniotomy and mass resection, with biopsy consistent with high-grade malignant melanoma. Pathologic analysis was negative for BRAF V600 mutation. Computed tomography imaging of chest, abdomen, and pelvis demonstrated pulmonary and hepatic lesions consistent with stage IV metastatic melanoma. On hospital day 15, the patient was discharged with near baseline mentation, seizure prophylaxis, and plan for outpatient immunotherapy.

Twelve days after diagnosis, the patient started Cycle 1 Day 1 of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) regimen. Cycle 2 Day 1 was administered 3 weeks later, and was initially well tolerated with no reported AEs and normal pretreatment laboratory results. However, ~5 weeks after the initiation of ipilimumab and nivolumab, surveillance work-up revealed elevated transaminases. In response, immunotherapy was held, and oral prednisone (1 mg/kg) was initiated.

Approximately 8 weeks after Cycle 1 Day 1, the patient was admitted for worsening encephalopathy. Initial laboratory results (Table 1) demonstrated an aspartate aminotransferase (AST) of 1300 U/L (reference range: 13-39 U/L), alanine aminotransferase (ALT) of >2500 IU/L (reference range: 7-52 IU/L), alkaline phosphatase of 180 IU/L (reference range: 34-104 IU/L), creatinine of 1.1 mg/dL (reference range: 0.7-1.3 mg/dL), total bilirubin of 20.9 mg/dL (reference range: 0.3-1.0 mg/dL), prothrombin time of 52.7 seconds (reference range: 12.4-14.4 seconds), international normalized ratio (INR) of 5.8 (reference range: 0.9-1.1 seconds), ammonia of 253 µg/dL (reference range: 25-90 µg/dL), and leukocytosis of 25.2 K/µL (reference range: 3.8-10.8 K/µL) with neutrophilia of 20.1 K/µL (reference range: 1.6-7.8 K/µL). Infectious work up including urine and blood cultures, respiratory pathogens panel, cerebrospinal fluid meningitis and encephalitis panel, ethanol level, urine drug screen, and acetaminophen level were negative. Magnetic resonance imaging of the brain demonstrated progression of the CNS lesions, now measuring 7.1 × 4.2 × 3.4 cm and with 8 mm midline shift (Figure 1).

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Table 1.

Initial Laboratory Results During Second Hospitalization.

Laboratory test	Value	Reference range
AST	1300 U/L	13-39 U/L
ALT	>2500 IU/L	7-52 IU/L
ALP	180 IU/L	34-104 IU/L
Total bilirubin	20.9 mg/dL	0.3-1.0 mg/dL
PT	52.7 s	12.4-14.4 s
INR	5.8	0.9-1.1
Ammonia	253 µg/dL	25-90 µg/dL
White blood cells	25.2 K/µL	3.8-10.8 K/µL
Absolute neutrophil count	20.1 K/µL	1.6-7.8 K/µL
Creatinine	1.1 mg/dL	0.7-1.3 mg/dL
Infectious work-up (including urine and blood cultures, respiratory pathogens panel, cerebrospinal fluid meningitis, and encephalitis panel)	Negative
Ethanol serum levels	Negative
Urine drug screen	Negative
Acetaminophen serum level	Negative

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; PT, prothrombin time.

Laboratory values reflect the patient’s initial evaluation during the second hospitalization. Reference ranges correspond to institutional standards. Reported ALT value exceeded the upper limit of laboratory quantification. Infectious work-up included blood and urine cultures, respiratory pathogen panel, and cerebrospinal fluid meningitis/encephalitis panel, all of which were negative.

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Figure 1.

Axial (A) and coronal (B) contrast-enhanced brain MRI showing a right frontal hemorrhagic mass (yellow arrowheads) measuring 7.1 × 4.2 × 3.4 cm with 8 mm midline shift. MRI, magnetic resonance imaging.

During the second hospitalization, the patient was intubated for airway protection and subsequently admitted to the intensive care unit. Intravenous methylprednisolone (1 mg/kg every 24 hours) was initiated; however, due to progressive and steroid-refractory ICI-related hepatitis, a single dose of tocilizumab (800 mg) was administered as a life-saving measure. A liver biopsy could not be obtained due to the patient’s coagulopathy in the setting of his liver failure. Broad-spectrum antibiotics were initiated for empiric infection coverage, and lactulose and rifaximin were started for hepatic encephalopathy secondary to fulminant ICI-induced hepatitis. Despite multidisciplinary management, the patient experienced continued clinical deterioration, progressing to shock with multiorgan failure. Following goals-of-care discussions with his family, he was transitioned to comfort-focused care and died shortly thereafter.

Discussion

This case illustrates 2 rare and severe complications of metastatic melanoma: presentation with hemorrhagic brain metastasis and early-onset, fulminant, steroid-refractory hepatitis from checkpoint inhibitor therapy. While melanoma commonly metastasizes to the CNS, hemorrhagic metastasis as the initial clinical manifestation is exceptionally rare; to our knowledge only one other case has been reported to date. ⁷

The emergence of ICIs, particularly the combination of nivolumab and ipilimumab, has markedly improved outcomes in advanced melanoma. ³ However, this therapeutic success is blunted by an increased incidence of irAEs, notably hepatotoxicity. ⁵

In our patient, his significant transaminitis (AST of 1300 U/L; ALT >2500 U/L), hyperbilirubinemia (20.9 mg/dL), coagulopathy (INR of 5.8), and encephalopathy were consistent with acute liver failure ⁸ ; while its correlation with ICIs was deemed to be probable based on a Naranjo score of 6 points (Table 2). ⁹ Additionally, the presence of hepatic metastases at diagnosis may have reduced underlying hepatic reserve, potentially increasing susceptibility to immune-mediated injury and contributing to the severity of acute liver failure observed in this case. No alternative causes such as infection, drug toxicity, or metabolic liver disease were identified. ICI-induced liver failure is exceedingly rare with an incidence of 0.1% to 0.2%. ¹⁰ However, it is important to highlight that a pharmacovigilance study conducted in 2018, described that from 613 cases of ICI-associated fatal AEs, ~20% were associated with hepatic injury.^10,11

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Table 2.

The Naranjo ADR Probability Scale Questionnaire.

To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score	Yes	No	Do not know	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0	+1
2. Did the adverse event appear after the suspected drug was given?	+2	−1	0	+2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	+1	0	0	0
4. Did the adverse event reappear when the drug was re-administered?	+2	−1	0	0
5. Are there alternative causes that could have caused the reaction?	−1	+2	0	+2
6. Did the reaction reappear when a placebo was given?	−1	+1	0	0
7. Was the drug detected in blood (or other fluids) at toxic concentrations?	+1	0	0	0
8. Was the reaction worsened when the dose was increased or lessened when dose was decreased?	+1	0	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
			Total	6

Abbreviation: ADR, adverse drug reaction.

The Naranjo ADR Probability Scale is a validated, questionnaire-based algorithm designed to estimate the likelihood of a causal relationship between a drug and an observed adverse event. It incorporates weighted criteria including temporal correlation, alternative etiologies, drug concentration data, dose–response relationships, and prior patient experience. Based on the cumulative score, the adverse event is classified as definite (≥9), probable (5-8), possible (1-4), or doubtful (0). The assessment is performed on an individual drug basis and does not account for pharmacologic interactions; the presence of confounding factors may reduce the assigned probability of causality.

Typically, immune-related hepatitis presents between 8 and 12 weeks after therapy initiation and often responds to corticosteroids and ICI discontinuation. ¹² In contrast, our patient developed significant transaminitis by week 5 and progressed to fulminant liver failure between weeks 8 and 9; well before the median onset for immune-related hepatitis reported in the literature.

The rapid clinical decline in our case is also noteworthy. When compared with other reported cases of rapidly fulminant hepatitis, we identified a patient with gastric cancer treated with nivolumab who developed fulminant hepatitis 5 months after therapy initiation. ¹³ Another reported case involved a patient with uveal melanoma who developed liver failure within 3 weeks of starting nivolumab, although this patient had undergone chemosaturation with percutaneous hepatic perfusion 2 months prior to ICI initiation. ¹⁴ In contrast, our patient had not received liver-directed therapies and expired within ~2 months from ICI initiation, highlighting the aggressive nature of this irAE.

Typically, fulminant ICI-induced hepatitis is managed with high-dose corticosteroids, and in steroid-refractory cases, second-line immunosuppressive agents such as mycophenolate mofetil, tacrolimus, or azathioprine are recommended. ¹² However, rapid clinical deterioration in fulminant presentations may limit the ability to assess response to conventional agents, as described in other reported cases of ICI-associated liver failure. ¹⁴ Tocilizumab was selected in our patient because IL-6 receptor blockade has demonstrated activity in steroid-refractory immune-related toxicities and has shown potential benefit in refractory hepatitis by targeting a central cytokine driving inflammatory amplification. ¹⁵

A recent meta-analysis estimated that ~16% of ICI hepatitis cases are steroid-refractory. Among patients requiring second-line therapy, mycophenolate mofetil was used in over 80% of cases, with infliximab and azathioprine employed less frequently. ¹⁶ Furthermore, about 40% of patients were rechallenged with immunotherapy, and recurrence occurred in roughly 22% of those rechallenged. ¹⁶ These data highlight both the uncommon but clinically significant nature of steroid-refractory hepatitis and the measurable risk of recurrence after high-grade toxicity. Notably, this analysis did not include interleukin-6-directed therapies such as tocilizumab, and evidence supporting their use in this setting remains limited. Further investigation into IL-6 inhibition is warranted, particularly in rapidly progressive or fulminant presentations where conventional second-line strategies may be insufficient.

Conclusion

This case highlights 2 rare and severe phenomena, namely the initial presentation of melanoma with hemorrhagic CNS metastasis and early-onset, steroid-refractory fulminant hepatitis from checkpoint blockade. These findings suggest the need for close hepatic monitoring during the initial cycles of dual ICI therapy. Notably, the patient’s fulminant hepatitis progressed too rapidly to allow assessment of conventional immunosuppressive therapies (eg, mycophenolate mofetil, tacrolimus, or azathioprine), prompting the use of tocilizumab, for which current evidence is limited to case reports. However, clinical deterioration persisted. Early escalation to agents such as tocilizumab may be considered in fulminant cases, although supporting data remain limited. Additionally, the hemorrhagic nature of the initial CNS presentation underscores the aggressive biology of this melanoma and contributed to the patient’s overall poor prognosis.