Immune Checkpoint Inhibitor-Related Hepatitis: Beyond the Guidelines

Vol. 30, Issue 3 (September 2025)

Dauris Rosario Lora, MD
Transplant Hepatology Fellow
Department of Internal Medicine, Division of Digestive Diseases and Nutrition
Rush University Medical Center
Chicago, Illinois, USA

 

Zoë Post MD, MSc
Fellow Physician, Gastroenterology & Hepatology
Rush University Medical Center
Chicago, Illinois, USA
 

 

Nancy S. Reau, MD, 
Professor
Department of Internal Medicine, Division of Digestive Diseases and Nutrition
Rush University Medical Center
Chicago, Illinois, USA

 

I - Introduction

Immune checkpoint inhibitors (ICIs) are a form of cancer immunotherapy designed to enhance the body’s immune response against malignant cells. Although many promising targets for ICIs exist, only a few have been approved to date. These agents, targeting cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PDL1),
function by blocking inhibitory immune pathways, thereby augmenting T-cell-mediated tumor recognition and destruction.¹ First approved for metastatic melanoma in 2011, ICIs have since transformed the oncology landscape; they are considered a cornerstone of cancer therapy, alongside surgery, chemotherapy, and radiation. ICIs are currently approved by the U.S. Food and Drug Administration (FDA) for a wide range of malignancies, including melanoma, non-small cell lung cancer, lymphoma, esophageal carcinoma, gastric cancer, and hepatocellular carcinoma.²

However, the immune activation triggered by checkpoint blockade can result in immune-related adverse events (irAEs), affecting multiple organ systems, including the gastrointestinal tract and liver.³ Immune checkpoint inhibitor-related hepatitis (ICIH) has emerged as a clinically significant entity due to its potential severity, diagnostic complexity, and management challenges. This brief review aims to provide a focused overview of the epidemiology, pathophysiology, clinical manifestations, diagnostic approach, and management strategies for ICI-related hepatitis. It will also highlight current challenges and potential future research directions to foster continued investigation into this evolving field of pharmacotherapy.

II - Pathophysiology

T-cell activation requires two key signals. First, the T-cell receptor (TCR) must recognize and bind to an antigen presented in the context of a major histocompatibility complex (MHC) molecule on an antigen-presenting cell (APC). Second, co-stimulatory signaling occurs through the interaction of CD28 on T-cells with B7 ligands (CD80/CD86) on APCs. This activation cascade is tightly regulated by inhibitory checkpoint molecules (CTLA-4, PD-1, and PD-1L), which serve to suppress excessive immune activation and prevent autoimmunity. However, tumors exploit these pathways to evade T-cell-mediated immune surveillance. Monoclonal antibodies targeting CTLA-4 and PD-1 enhance T-cell-mediated anti-tumor immunity and have been shown to induce durable tumor regression in several malignancies.¹

The precise pathophysiology of ICIH remains incompletely understood. However, there is evidence that PD-L1 is expressed on hepatic stellate cells, Kupffer cells, and dendritic cells—components of the liver’s unique immunologic environment. Together with CTLA-4-expressing CD4* regulatory T-cells (Tregs), these elements contribute to immune tolerance by downregulating T-cell activation and preventing autoimmune responses. It has been proposed that ICIs disrupt this balance, promoting expansion of pro-inflammatory T helper cell subsets (Th1 and Th17), upregulation of cytotoxic T lymphocytes, and enhanced activity of macrophages and natural killer cells within the liver. Simultaneously, ICIs may downregulate anti-inflammatory cytokines such as interleukin (IL)-10, IL-35, and transforming growth factor-beta (TGF-β), further tipping the balance toward immune-mediated hepatocellular injury.⁴

III - Epidemiology

The reported incidence of ICIH varies widely, largely based on irAE data from clinical trials submitted to the FDA (Table 1). In most trials, the occurrence and severity of irAEs are assessed using standardized criteria, such as the Common Terminology Criteria for Adverse Events (CTCAE). Hepatotoxicity is typically defined by elevations in liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin, relative to the upper limit of normal (ULN).⁴

Table 1. Incidence of Hepatitis by Immune Checkpoint Inhibitor, based on rates from clinical trials. Adapted from Peeraphatdit et al. 2020.

There is reported variation of ICIH according to which agent is used, its dosage, the grade of severity (Table 1), and if the patient was treated with monotherapy or in combination with
any other ICI. Overall incidence in all grades of ICIH is reported to be between 0%-30%. In the case of severe ICIH (grade 3 or 4), it is 0%-20%. CTLA-4 inhibitors (e.g, ipilimumab, tremelimumab) have the highest rate of ICIH, with evidence mostly reporting a rate of 3%-15%, out of which 1%-10% are severe ICIH. Most reported hepatotoxicity is observed with higher doses (10 mg/kg) of ipilimumab. PD-L1 inhibitors (e.g, atelizumab, durvalumab, avelumab) have shown similar rates to CTLA-4, albeit less severe cases (1%-17% overall, 3%-5% grade 3/4). Monotherapy with PD-1 has been shown to have the lowest rates, with a rate of 0%-3% and less than <1% being grade 3 or 4.5 Although the reasons are not fully understood, it is theorized that CTLA-4 inhibition results in broader activation of T cells compared to PD-1 blockade, which acts at a more downstream point in T-cell regulation. Additionally, CTLA-4 inhibitors may impair regulatory T-cell function in the gastrointestinal tract, contributing to a loss of tolerance to hepatic and intestinal autoantigens.⁵ Finally, as expected, combination therapy with CTLA-4 and PD-1 blockade also results in higher rates of irAEs, including ICIH. In this group, ICIH of any grade occurs in 18%-22% overall, with 8%-11% having severe hepatitis.⁴

Retrospective data on patients treated with PD-1 inhibitors have demonstrated a significantly higher risk of developing ICIH among those with a history of chronic liver disease. In particular, studies have identified metabolic dysfunction-associated steatotic liver disease (MASLD) as an independent risk factor for hepatotoxicity.6 Additionally, data from clinical
trials of PD-1 inhibitors in hepatocellular carcinoma (HCC) have shown that treatment-related ALT elevations of any grade occur in approximately 5%-15% of patients, with grade 3–4 elevations reported in about 4%.^{8, 9} Celsa et al.,¹⁰ also demonstrated a significantly higher amount of all-grade ICIH in HCC patients compared to other advanced solid tumors.

IV - Clinical Manifestations and Diagnosis

In most cases, ICIH is detected incidentally through routine liver chemistries obtained during post-treatment monitoring. The median time to onset is typically between 8 and 12 weeks after initiation of therapy, although cases can present as early as 2 to 3 weeks and as late as 21 months after initiation of treatment. Severe presentations may include fever, jaundice, right upper quadrant abdominal pain,
and, rarely, acute liver failure.¹¹ Depending on the grade of liver enzyme elevations, the severity of ICIH can be classified from grade 1 to 4, according to the CTCAE criteria (Figure 1).

Figure 1. American Gastroenterology Association Treatment Guidelines for ICIH, Adapted from Dougan et al. and Liu Z et al., using Biorender. ALT – alanine aminotransferase; AST – aspartate aminotransferase; ALP – alkaline phosphatase; ULN – upper limit of normal; BSL – baseline; ICI – immune checkpoint inhibitor; MMF – mycophenolate mofetil; AZA – azathioprine.

Clinical presentation and biochemical patterns may vary depending on the class of immune checkpoint inhibitor used. Retrospective multicenter studies have demonstrated a roughly even distribution among cholestatic, hepatocellular, and mixed patterns of liver enzymes elevation at presentation. However, more severe cases, often associated with anti-CTLA-4 based regimens, have been more frequently linked to a hepatocellular pattern. In contrast, cholestatic injury patterns have been more commonly observed in association with anti-PD-1/PD-L1 therapies.¹² Unlike Autoimmune Hepatitis (AIH), ICIH is usually not associated with high-titer autoantibodies or marked hypergammaglobulinemia.³

Perhaps the most important role of the clinician in managing ICIH is to exclude alternative causes of liver injury. Providers should be aware of factors associated with higher risk of ICIH, such as underlying chronic liver disease and MASLD.⁷ Patients with cancer are at increased risk for a broad range of hepatic insults, including biliary compression, ischemic hepatopathy, opportunistic infections, drug-induced liver injury, and thromboembolic disease, among others. As such, ICIH remains a diagnosis of exclusion and should only be considered after a comprehensive evaluation has ruled out other etiologies. This workup should include a detailed history and medication review, viral serologies (including hepatotropic and non-hepatotropic viruses), and imaging studies, such as abdominal ultrasound or cross-sectional imaging, to assess the hepatobiliary tree and hepatic vasculature.¹³

Of note, liver biopsy is usually reserved for unclear diagnosis or atypical and/or refractory clinical courses despite adequate treatment.^{3, 13} Histologic examination typically reveals lobular hepatitis with dense inflammatory infiltrates predominantly composed of CD8+ T lymphocytes, hepatocyte apoptosis, necrosis, and occasionally granulomatous inflammation. Other patterns include varying degrees of biliary duct injury, lymphocytic cholangitis, and in rare cases, acquired ductopenia.¹⁴ Interestingly, plasmacytosis is less commonly found in ICIH, suggesting a distinct autoimmune etiology to AIH.¹²

V - Current Treatment Guidelines

The current treatment guidelines for ICIH are largely based on expert opinion and extrapolated from various case series. Management of ICIH depends on the severity of liver injury, typically guided by the CTCAE. Mild cases (Grade 1), characterized by elevations of transaminases less than three times the ULN, generally require vigilant observation without cessation of immunotherapy. Close monitoring of liver enzymes every 1–2 weeks is recommended to detect any progression of liver injury early.¹³

Moderate cases (Grade 2), with elevations between three and five times the ULN, and bilirubin elevations between one and a half and three times the ULN, necessitate withholding immunotherapy temporarily and initiating corticosteroid therapy, usually oral prednisone at 0.5–1 mg/kg/day or equivalent.^{11, 13} Consultation with a gastroenterologist or hepatologist is recommended at this point. Liver function should be monitored closely, with weekly follow-ups and gradual tapering of corticosteroids once transaminase levels decline significantly or normalize.¹³

Grade 3 hepatotoxicity, defined as elevations in liver enzymes greater than five times the ULN or total bilirubin greater than three times the ULN, requires immediate discontinuation of ICI therapy. High-dose corticosteroids, such as methylprednisolone at 1–2 mg/kg/day, should be initiated promptly, followed by a planned taper over 4 to 6 weeks.¹³

Patients with confirmed or suspected grade 4 ICIH, characterized by AST or ALT levels exceeding 20 times ULN, total bilirubin >10× ULN, or evidence of hepatic decompensation (e.g., ascites, encephalopathy), should be hospitalized, ideally at a transplant center with expertise in liver failure management.¹³ ICI therapy should be permanently discontinued.^{4, 11, 13} These patients should be started on intravenous methylprednisolone at 2 mg/kg/day or an equivalent regimen, with a taper over 4 to 6 weeks if clinical improvement is observed.¹³ It is important to note that although evidence suggests higher rates of acute rejection in patients who have received immunotherapy prior to liver transplantation, this history alone does not preclude consideration for transplant in the absence of other contraindications. Therefore, in cases of acute liver failure due to ICIH, timely transfer to a transplant-capable center is essential and should be arranged as early as possible.¹⁵

VI - To Steroid or Not to Steroid?

Although there is evidence suggesting that grade 2 or lower ICIH may resolve spontaneously without corticosteroid therapy, the optimal timing for initiating steroids in severe cases (grade 3 or 4) remains controversial.¹² Some studies report that 10% to 50% of patients with grade ≥3 ICIH experience spontaneous resolution following discontinuation of ICI therapy alone.¹⁶ Moreover, other reports suggest that corticosteroids may lead to a slower resolution of liver injury, with rates of resolution 33% to 50% slower than those untreated.^{12, 17} Moreover, emerging evidence suggests that the currently recommended corticosteroid dosing may be higher than necessary. Studies by Li et al. demonstrated that patients with grade 3 or 4 ICIH who received 1 mg/kg/day of methylprednisolone had comparable clinical outcomes and a lower risk of steroid-related complications compared to those treated with higher-dose regimens.¹⁸ Budesonide, a corticosteroid traditionally used in AIH due to its favorable side effect profile, has also demonstrated efficacy in the treatment of grade 3 ICIH.¹⁹

Overall, these data highlight an evolving area where further studies are needed to establish the optimal corticosteroid dose and timing. In the absence of definitive evidence, treatment should be individualized: in patients at low risk of steroid-related complications, higher-dose regimens may be appropriate, whereas those at higher risk (e.g., with diabetes or osteopenia) may be better managed with lower-dose protocols or budesonide when appropriate.

VII - ICIH Refractory to Steroids: Next Steps and Emerging Treatment Options

In cases where there is no clinical response to corticosteroids within 48 to 72 hours, mycophenolate mofetil (MMF) is the most commonly used second-line treatment for ICIH, typically administered at a dose of 500 to 1,000 mg twice daily.²⁰ Both European and American guidelines currently recommend MMF for the management of steroid-refractory ICIH.^{13, 20} However, though it appears to be a safe and effective option, high-quality comparative data are lacking, and its superiority over other second-line immunosuppressive agents has not been definitively established. An American Society of Clinical Oncology (ASCO) abstract reported that early initiation of MMF (≤3 days after ICIH onset) in addition to systemic steroids led to significantly faster ALT recovery (72.3% vs 41.7% at Day 7; p=0.02) and lower cumulative steroid exposure compared to later MMF addition.²²

ASCO has recommended azathioprine (AZA) 1–2 mg/kg/day as an alternative second-line agent for steroid-refractory ICIH, as long as there is no concomitant thiopurine methyltransferase (TPMT) deficiency to avoid life-threatening bone marrow suppression. This recommendation is likely extrapolated from the data of AZA and its metabolites as a viable treatment for AIH, however, supporting data is limited to case reports.²³ Unfortunately, azathioprine has a delayed onset of action and carries the risk of hepatotoxicity from its metabolites, including the potential to cause cholestatic acute liver injury in rare cases.²⁴ While waiting for TPMT testing in acute ICIH, treatment may be delayed.²⁵ However, a complete blood count can help assess marrow reserve and support safety if the TPMT status is unknown.

Calcineurin inhibitors, including cyclosporine and tacrolimus, have also been explored in the management of steroid-refractory ICIH, based on their established role in liver transplant recipients. Both agents have been reported to lower liver enzymes in grade 3–4 ICIH when added to corticosteroids or MMF, with case reports describing normalization of liver function and clinical improvement.²⁶

Other third-line immunosuppressive agents have been proposed for use when both corticosteroids and MMF fail. Anti-thymocyte globulin (1.5 mg/kg) has been used in combination with steroids and/or MMF with success.27 Infliximab (5 mg/kg/dose) is generally not recommended in ICIH due to its rare potential for hepatotoxicity. However, in select cases of steroid-refractory ICIH, particularly when accompanied by concomitant ICI-related colitis or when patients are unable to tolerate or fail to respond to other immunosuppressive agents, infliximab has demonstrated moderate success with varying degrees of safety.²⁸

The use of Tocilizumab for irAEs is a current area of investigation. IL-6 has been shown to potentially treat and prevent irAEs without decreasing ICI efficacy. Early results of a Phase II clinical trial showed that in patients being treated for metastatic melanoma with ipilimumab and nivolumab, the addition of tocilizumab decreases the risk of developing irAEs by at least 12% (34% expected rate vs 22% actual rate).²⁹ Moi et al. showed success in treating three patients, steroidrefractory ICIH, with 1-2 doses of tocilizumab 8 mg/kg/dose.³⁰

Interestingly, ursodeoxycholic acid (UDCA) may also have a role in the management of ICIH. Similarly, Hountondji et al. had adequate results in treating ICIH patients presenting with cholestatic patterns with steroids along with UDCA.¹²

VIII - When Should You Restart ICIs?

Current society guidelines recommend permanent discontinuation of ICIs following the development of grade 3 or 4 ICIH, primarily due to the risk of recurrent hepatotoxicity.¹³ Large observational studies have demonstrated a higher likelihood of ICIH recurrence when it is the initial irAE, with a reported recurrence rate of 8.5%.³¹ However, other studies have reported lower recurrence rates when patients were rechallenged with a different class of ICI, specifically switching from CTLA-4 inhibitors to anti-PD-1 or anti-PD-L1 agents (Li et al.). The ESMO guidelines outline three potential strategies for restarting ICIs: switching between classes (e.g., from anti-CTLA-4 to anti-PD-L1 or vice versa), resuming the same class or specific agent, or restarting ICIs alongside prophylactic immunosuppressive therapy.³²

While permanent discontinuation remains the standard for severe ICIH, rechallenge decisions are increasingly approached on a case-by-case basis. The identification of prognostic markers may help guide safer patient selection for rechallenge, whether with the same or an alternative ICI agent. Potential markers include the presence of CLD, as well as levels of interleukins such as IL-6 and IL-17.³

Ultimately, the decision should weigh the risks and benefits carefully: if immunotherapy is critical to disease control, rechallenge may be appropriate with close monitoring, whereas if the expected oncologic benefit is marginal, prioritizing liver preservation is often the preferred strategy.

IX - Conclusion and Future Questions

As the indications for immune checkpoint inhibitors continue to expand across oncology, the incidence of ICI-related hepatitis is expected to rise correspondingly. While current treatment guidelines emphasize corticosteroid-based therapy and recommend permanent discontinuation of ICIs in severe cases, growing clinical experience and evolving evidence suggest that a more nuanced approach may be warranted, particularly for patients who are steroid-refractory or may be considered for rechallenge. Although some studies have suggested that underlying chronic liver diseases, such as MASLD and cirrhosis, may increase the risk of hepatotoxicity, the evidence remains limited and somewhat conflicting. Future efforts should focus on generating robust data to guide the management of ICIH, including the development of clearer indicators for corticosteroid initiation, comparative studies evaluating the efficacy and safety of second-line immunosuppressants, and the identification of reliable predictors of recurrence. Such data would not only help refine our approach to ICIH but also improve patient outcomes while preserving access to life-saving immunotherapies.

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