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. 2019 Sep 9;25(2):105–111. doi: 10.1634/theoncologist.2018-0162

Workup and Management of Immune‐Mediated Hepatobiliary Pancreatic Toxicities That Develop During Immune Checkpoint Inhibitor Treatment

Christine Hsu 1, John L Marshall 2, Aiwu Ruth He 2,✉
PMCID: PMC7011649  PMID: 32043797

Abstract

Immune checkpoint inhibitor treatment has been approved by the U.S. Food and Drug Administration for the treatment of a wide range of cancer types, including hepatocellular carcinoma. Workup and management of immune‐mediated hepatitis, pancreatitis, or cholangitis that develops during immune checkpoint inhibitor treatment can be challenging. Immune‐mediated hepatitis can be particularly challenging if patients have underlying viral hepatitis or autoimmune hepatitis. Patients with positive hepatitis B virus DNA should be referred to a hepatologist for antiviral therapy prior to immune checkpoint inhibitor treatment. With untreated hepatitis C virus (HCV) and elevated liver enzymes, a liver biopsy should be obtained to differentiate between HCV infection and immune‐mediated hepatitis due to anti‐programmed cell death protein 1 (PD‐1) therapy. If autoimmune serologies are negative, then this supports a case of immune‐mediated hepatitis secondary to anti‐PD‐1 therapy, rather than autoimmune hepatitis. In this case, an empiric steroid therapy is reasonable; however, if the patient does not respond to steroid therapy in 3–5 days, then liver biopsy should be pursued. The incidence of immune checkpoint‐induced pancreatitis is low, but when it does occur, diagnosis is not straightforward. Although routine monitoring of pancreatic enzymes is not generally recommended, when pancreatitis is suspected, serum levels of amylase and lipase should be checked. Once confirmed, a steroid or other immunosuppressant (if steroids are contraindicated) should be administered along with close monitoring, and a slow tapering dosage once the pancreatitis is under control. Patients should then be monitored for recurrent pancreatitis. Finally, immune therapy‐related cholangitis involves elevated bilirubin and alkaline phosphatase and, once diagnosed, is managed in the same way as immune‐mediated hepatitis.

Key Points

  • Immune‐mediated hepatitis, pancreatitis, and cholangitis are found in patients receiving or who have previously received immune checkpoint inhibitors.

  • To work up immune‐mediated hepatitis, viral, and autoimmune serologies, liver imaging will help to differentiate immune‐mediated hepatitis from hepatitis of other etiology.

  • Hepatology consult may be considered in patients with a history of chronic liver disease who developed hepatitis during immune checkpoint inhibitor treatment.

  • Liver biopsy should be considered to clarify the diagnosis for case in which the hepatitis is refractory to steroid or immunosuppressant treatment.

  • Immune‐mediated pancreatitis is treated with steroid or other immunosuppressant with a slow tapering and should be monitored for recurrence.

Short abstract

Management of immune‐mediated hepatitis, pancreatitis, or cholangitis that develops during treatment with immune checkpoint inhibitors can be challenging for patients with hepatocellular carcinoma. A case report is presented, along with known case series, to provide guidance on diagnosis and treatment.

Case Report

A male patient aged 67 years was diagnosed with chronic viral hepatitis C (HCV) infection and cirrhosis in 2012. He achieved a serological viral response (SVR) of his HCV infection in 2013. He had a magnetic resonance imaging (MRI) scan in 2014 and was diagnosed with hepatocellular carcinoma (HCC) according to American Association for the Study of Liver Diseases (AASLD) criteria. He had two right hepatic lesions, each over 3 cm, and was beyond Milan Criteria for liver transplantation. Hence, the patient underwent transarterial chemoembolization to downstage the disease and was listed for orthotopic liver transplantation (OLT). In 2015, a repeat MRI revealed an overall enlargement of lobular confluent mass in the right hepatic lobe, which disqualified him for OLT (Fig. 1). Subsequently, the patient underwent a percutaneous liver biopsy, which revealed grade 2 HCC. He participated in a phase I study of nivolumab in the treatment of advanced hepatocellular carcinoma (NCT01658878) in subjects with or without viral hepatitis and started nivolumab. The patient had a partial response to nivolumab therapy 6 weeks after its initiation (36% reduction in target lesion size). The tumor continued to shrink while he continued nivolumab therapy, and almost a year later, a computed tomography scan showed that his target lesions had shrunk by 55% since study baseline, and response has been durable since.

Figure 1.

Figure 1

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Treatment response of advance HCC to nivolumab treatment.

Six months from the start of nivolumab treatment, liver function tests showed grade 3 elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and grade 2 elevation of bilirubin. The patient started prednisone therapy (1 mg/kg daily; 70 mg total), and his transaminases decreased to grade 1 after 9 days of treatment, after which time he was tapered off prednisone. However, the patient developed symptoms of hyperglycemia (thirst and polyuria), and his blood glucose had elevated to 380 mg/dL. He became noncompliant with oral steroid treatment and was admitted into hospital in 2017 for the treatment of steroid‐induced hyperglycemia and recurrent hepatitis. Then, he was started on mycophenolate mofetil (MMF) therapy (1,000 mg twice daily), and his transaminase improved to grade 2 after 2 days of treatment, and grade 1 after 9 days of treatment. He resumed tapering prednisone and also started MMF dose reduction.

The hepatitis recurred on MMF alone at 50 mg daily—AST, ALT, total bilirubin, and alkaline phosphatase levels were 365 U/L, 160 U/L, 1.6 U/L, and 447 U/L, respectively. He was restarted on high doses of MMF (1,000 mg twice daily) and once his condition had normalized was slowly tapered off MMF once more, over more than 4 months. He discontinued MMF entirely without any further recurrence of hepatitis.

Therapeutic Intervention

Immunotherapy aims to unleash the immune response against cancer cells. Nivolumab is an antibody directed at programmed cell death protein 1 (PD‐1), which was approved by the U.S. Food and Drug Administration in 2017 for the second‐line treatment of advanced HCC. Approval was based on a nonrandomized, open‐label, phase I/II study (CheckMate 040), in which nivolumab showed a median overall survival of 15 months, an overall response rate of 19%, and a median duration of response of 16.6 months 1. Continued approval may depend on confirmation of clinical benefit from the phase III, randomized, controlled CheckMate 459 trial, which completed patient enrollment in 2016. A report of results from this trial is expected this year. Phase III studies in patients with advanced HCC comparing nivolumab with sorafenib in the first line and comparing pembrolizumab with placebo in the second line are ongoing (NCT02576509 and NCT02702401).

Immune Checkpoint Inhibitor‐Induced Hepatitis

Patient presentation of immune‐mediated hepatitis secondary to anti‐PD‐1 or other immune checkpoint inhibitor therapy varies. In the CheckMate 040 open‐label dose‐escalation and ‐expansion trial, transaminase elevations were reported overall in 15%–21% of the patients at various concentrations of the drug; grade 3–4 AST/ALT elevations were noted in 6%–10% of patients only. In our case described above, the patient presented with grade 3 AST/ALT elevation. In a meta‐analysis of nine randomized controlled trials including patients with a range of solid tumors treated with PD‐1 inhibitors, this therapy increased the risk of developing hepatic adverse events (AEs) when taking all grades of toxicity into account but not when only considering grade 3 or 4 hepatic AEs 2. The risk of hepatotoxicity was higher for combination nivolumab plus ipilimumab compared with ipilimumab alone 2. Various questions arise: What would be the recommended hepatology workup prior to starting checkpoint inhibitors? Could baseline liver disease or elevated liver enzymes contribute to increased risk of hepatotoxicity? If patients were then to start checkpoint inhibitor therapy and experience subsequent hepatotoxicity, how would it present and how could it best be evaluated and managed?

Would Elevated Baseline Liver Enzymes Contribute to an Increased Risk of Severe Hepatotoxicity?

In one small study of 27 patients with mild baseline liver enzyme elevation (<3 × the upper limit of normal [ULN]) who received nivolumab, the worsening liver enzymes that required hospitalization or dose delays occurred in 30% and the risk of grade 3 hepatitis AE occurred in only one patient (3.7%) 3. Although the study was small, the authors concluded that treatment was associated with tolerable side effects, and worsening of organ dysfunction was infrequent and manageable 3. Given the lack of effective systemic chemotherapy for HCC together with the promise of treatment benefits, it is likely that the benefits of checkpoint inhibitor therapy outweigh the risks; patients with baseline elevated liver enzymes generally should be advised to proceed with close monitoring. The CheckMate 040 clinical trial allows enrollment of patients with grade 2 elevation in ALT and AST at baseline.

What Would Be the Recommended Hepatology Workup Prior to Starting Checkpoint Inhibitors?

Given that HCV and hepatitis B virus (HBV) are viruses that cause immune‐mediated hepatic injury, the act of purposefully increasing T‐cell activity comes with the concern that nivolumab would exacerbate underlying viral infection. In a series of seven patients with metastatic melanoma or non‐small cell lung cancer (NSCLC), who also had chronic HCV, HBV, or past HBV infection, anti‐PD‐1 therapy was associated with only one case (a patient with HCV) of grade 2 elevation in ALT/AST according to the Common Terminology Criteria for Adverse Events 4. The patient was subsequently treated with sofosbuvir and ledipasvir, with normalization of liver enzymes 4. Grade 1 AEs were observed in only two patients: one patient with chronic HBV and the other with prior HBV exposure 4. The series does not mention if the patients were treated with HBV antiviral therapy; however, one patient died from metastatic disease, whereas the other experienced normalization of liver enzymes 4. HBV reactivation was described in one case report in the setting of anti‐PD‐1 therapy 5. This patient had human immunodeficiency virus (HIV) and was positive for isolated hepatitis B core antibody (HBc Ab), although HBV load was undetectable prior to commencing treatment with anti‐PD‐1 therapy for metastatic NSCLC 5. On checkpoint inhibitor (anti‐PD‐1) therapy, the patient's AST/ALT levels increased to 520 U/mL and 474 U/mL, and his HBV load was 170 million IU/mL approximately 15 months after starting therapy. He was treated with tenofovir, and his liver enzymes have since normalized 5.

Viral Hepatitis B Infection or Reactivation

To evaluate for chronic, occult, or past HBV exposure prior to initiation of anti‐PD‐1 therapy, baseline HBV serology should be obtained including hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), and HBc Ab (Fig. 2A). The HBs Ab does not seem to be entirely protective; thus, reactivation has been described in patients who are positive for both HBc Ab and HBs Ab 6, 7, 8. One series of 62 patients with HBc Ab–positive and HBs Ag–negative status underwent hematopoietic stem cell transplantation, and of the patients who had HBV reactivation, 76.9% had positive HBs Ab with titers <100 mIU/mL 8. We recommend that if a patient has a positive HBc Ab or HBs Ag, then they should be referred to hepatology for consideration of whether they should undergo antiviral therapy prior to starting anti‐PD‐1 treatment. In the case of HBV reactivation, the viral load increases before the liver enzymes increase, without the necessary HBV seroconversion. Therefore, for those not receiving antiviral therapy when on anti‐PD‐1 therapy, we strongly suggest monitoring HBV viral load periodically while on PD‐1 treatment.

Figure 2.

Figure 2

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Workup and management of immune mediated hepatitis. Workup and treatment of immune mediated hepatitis (A); guideline to withhold or discontinue immune checkpoint inhibitor treatment (B); difference between the diagnosis and treatment of autoimmune hepatitis and immune‐mediated hepatitis (C).

Abbreviations: ANA, antinuclear antibody; ALT, alanine aminotransferase; ASMA, anti–smooth muscle antibody; AST, aspartate aminotransferase; CMV, cytomegalovirus; EBV, Epstein‐Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; IgG, immunoglobulin G; ULN, upper limit of normal; VZV, varicella zoster virus.

Viral Hepatitis C Infection

In 2013, a double‐blind, placebo controlled, proof‐of‐concept study evaluated anti‐PD‐1 therapy in the actual treatment of patients with HCV 9. This study was based on the concept that T‐cell exhaustion and dysfunction leads to a lack of viral clearance and persistent chronic HCV infection, and the PD‐1 inhibitor‐induced increase in T‐cell activity, through inhibition of cytokine production, would allow viral clearance. The primary endpoint was reduction of hepatitis C by ≥0.5log10 IU/mL on two consecutive visits 9. Of 45 patients, 5 (11%) achieved the primary endpoint 9. Only one patient experienced a grade 4 AE for hepatitis 9. Thus, anti‐PD‐1 therapy does not seem to exacerbate HCV; in fact, it may even be beneficial. In the CheckMate 040 trial, the inclusion criteria did not discount patients on the basis of HCV treatment and viral clearance, and no severe HCV reactivations were reported. This phenomenon was addressed by a case report of two patients with hepatitis C who were treated with anti‐PD‐1 therapy without experiencing any adverse events 10. The first patient had hepatitis C genotype 1a with stage 2–3 fibrosis and started pembrolizumab therapy for metastatic melanoma without prior HCV treatment 10. Her liver enzymes were mildly increased at baseline, and she completed 12 weeks of HCV therapy with ledipasvir/sofosbuvir. When assessed after nine cycles of pembrolizumab, HCV viral load was undetectable 10. As HCC generally arises in the background of chronic liver disease, patients who are being treated with nivolumab for HCC have generally already had their hepatitis C serology tested. However, we do not necessarily advise holding nivolumab therapy to fulfill hepatitis C treatment. In support of this notion, recent data suggest that in patients with hepatitis C–related cirrhosis and stable HCC, treatment of hepatitis C is associated with increased risk of HCC recurrence 11. The theory is that hepatitis C serves as a form of immune surveillance for HCC and, once removed, HCC could recur. However, this is a currently controversial theory, and literature supports HCV therapy to reduce HCC risk in patients without a history of HCC 12, 13. Thus, we propose ensuring tumor stability prior to commencing HCV treatment and awaiting further studies.

Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) develops in a subset of patients with nonalcoholic fatty liver disease. NASH results from lipid‐induced hepatocyte injury, leads to the activation of innate immune cell–mediated inflammation, progressive fibrosis, cirrhosis, and then HCC development. Currently, there are no data on whether immune‐mediated hepatitis from immune checkpoint inhibitors differs in liver with viral hepatitis or NASH. It is unknown whether there is any effect of immune checkpoint inhibitors on the progression of NASH. On the other hand, immunotherapy is being developed in the treatment of NASH 14.

Presentation and Management of Hepatotoxicity

In the original CheckMate 040 trial, 1.8% (35/1,994) of patients developed immune‐mediated hepatitis as a result of receiving nivolumab treatment, with a median onset of 3.3 months. All patients required high‐dose steroids (at least 40 mg) for a median duration of 23 days, and two patients even required mycophenolate treatment. Complete resolution occurred in 74% of patients. Thus, guidelines in the nivolumab package insert advise starting corticosteroid therapy at a dose of 1–2 mg/kg if grade 3 or 4 hepatitis is apparent, and 0.1–1 mg/kg in the case of grade 1–2 hepatitis while nivolumab treatment is put on hold (Fig. 2B). Nivolumab binds the programmed cell death ligand 1 on cancer cells and blocks its interaction with PD‐1 to prevent inactivation of T lymphocytes, thus enhancing T lymphocyte antineoplastic effects. Given that nivolumab enhances T‐lymphocyte and immune activity, it was originally thought that any immune‐mediated hepatitis would be similar to autoimmune hepatitis. However, we are slowly learning through various described case reports and case series that the histopathology of immune‐mediated hepatitis can be varied and often different from the histopathology of autoimmune hepatitis (Fig. 2C). It can even be considered a misnomer to classify them equally; autoimmune serologies (antinuclear antibody [ANA], anti–smooth muscle antibody, serum immunoglobulin G) that are typically elevated in autoimmune hepatitis are often negative in anti‐PD‐1 immune‐mediated hepatitis. Pathology of autoimmune hepatitis shows predominantly plasma cell infiltration, interface hepatitis, and typically advanced fibrosis suggestive of chronicity. However, in the series of seven patients treated with nivolumab or ipilimumab, none of the patients with immune‐mediated hepatitis had positive ANA or anti–smooth muscle antibody 15. Additionally, the pathology showed lobular hepatitis with milder portal inflammation 15. Only one patient had centrilobular confluent necrosis and plasmacytosis that are consistent with autoimmune hepatitis 15. This was corroborated by another case series of 11 patients treated with ipilimumab who had biopsies that revealed panlobular hepatitis and zone 3 hepatitis and a mixed inflammatory infiltrate composed of T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils 16. Central vein endotheliitis was present in eight cases 16. Only one patient had mildly elevated ANA; the rest showed no evidence of this antibody 16. The same concept was further illustrated in another case series of five patients, where the liver biopsies showed predominantly lobular hepatitis, with lymphohistiocytic inflammation in the portal areas, particularly in zone 3, and increased eosinophils and central vein endotheliitis 17. Plasma cells could be present, but this was not a predominant feature. All except one patient had negative autoimmune markers 17. Interestingly, the pattern of injury appears to most resemble that of acute T‐cell‐mediated cellular rejection after liver transplant, with mixed inflammatory infiltrates in the portal tracts and venular endotheliitis. Also similar to transplant patients, one of the patients in the series responded to steroids and tacrolimus 17.

In most cases reported, patients responded to steroid therapy 16, 17, 18, 19. However, some select patients have been steroid refractory or have relapsed in the setting of steroid tapering, and have responded to MMF, antithymocyte immunoglobulin, and even ursodiol 12, 13, 15. A patient with metastatic melanoma who was treated with nivolumab had relapsing hepatitis in the setting of steroid tapering and required MMF therapy at a dose of 2 g per day 20. In another case report, a patient with metastatic melanoma was treated with a combination of ipilimumab and nivolumab, during which time she required antithymocyte globulin therapy for 5 days in conjunction with prednisolone therapy in order to normalize her liver enzymes 13. In a more recent case series, the authors observed that patients with immune‐mediated hepatitis have pathological findings of ductopenia, biliary injury, and vanishing bile duct syndrome 21. Whereas two patients died from progressive metastatic melanoma, one patient treated with nivolumab underwent ursodiol and steroid therapy, after which his liver enzymes normalized 21.

Workup for Patients Who Develop Hepatitis While on Immune Checkpoint Blockade Therapy

Based on these case series, we advise that patients who are treated with anti‐PD‐1 therapy and develop hepatitis be evaluated in the following manner: Initially, a serological workup for viral hepatitis and autoimmune hepatitis (Fig. 2A) should be obtained. Patients should then be referred to a hepatologist for multidisciplinary care. If the patient has untreated HCV and develops elevated liver enzymes, we strongly advise obtaining a liver biopsy to differentiate HCV infection versus immune‐mediated hepatitis from anti‐PD‐1 therapy. Both immune‐mediated hepatitis and HCV have portal tract inflammation. However, HCV involves predominantly lymphocytic infiltration, whereas immune‐mediated hepatitis appears to involve more of a mixed inflammatory infiltrate comprising eosinophils, histiocytes, and lymphocytes.

Treatment for Hepatitis Developed While a Patient Receives Immune Checkpoint Blockade Therapy

Given that HCC mostly arises in the background of chronic liver disease, patients with positive HBV DNA should be referred to a hepatologist for antiviral therapy. In patients with HCV who are receiving anti‐PD‐1 therapy and develop grade 2 or higher hepatic AE, we recommend obtaining a liver biopsy and strongly suggest concurrent treatment for HCV with steroids and direct‐acting antiviral therapy. Patients should be followed simultaneously by a hepatologist. If the autoimmune serologies are negative, then this supports a case of immune‐mediated hepatitis secondary to anti‐PD‐1 therapy, rather than autoimmune hepatitis. We also propose that empiric steroid therapy is reasonable; however, if the patient does not respond to steroid therapy in 3–5 days, then we would advise pursuing liver biopsy. If the biopsy shows liver injury that is more consistent with vanishing bile duct syndrome or ductopenia, with no or even minimal inflammation, we would highly consider ursodiol therapy and tapering steroid therapy in order to avoid pathological fractures secondary to chronic steroid therapy. If a patient's liver biopsy shows panlobular hepatitis or portal tract inflammation, then we would propose treatment with steroid therapy, followed by MMF or even tacrolimus if unresponsive. Again, the liver biopsies of this immune‐mediated hepatitis appear more likely to mimic T‐cell‐mediated acute cellular rejection in transplanted liver, which is treated with steroids, tacrolimus, and MMF. Lastly and more importantly, given the increasing use of anti‐PD‐1 therapy, there should be more research devoted to investigating the risk factors associated with hepatotoxicity, the pathogenesis of this immune‐mediated hepatitis, and treatment options other than steroids.

Immune Blockade–Induced Pancreatitis

Immune checkpoint–induced pancreatitis remains a complicated immune‐related adverse event for diagnosis and management of pancreatitis. Pancreatitis is a clinical diagnosis in which two of the following three components are present: elevation in amylase or lipase (3 × the ULN per the Classification of Acute Pancreatitis); characteristic symptoms of severe epigastric pain; or typical radiographic findings including but not limited to necrosis of the pancreas, peripancreatic inflammatory change, the sentinel loop sign (dilated air‐filled duodenum or jejunum), the colon cutoff sign (dilated large bowel to the level of the splenic flexure), loss of the left psoas shadow, ascites, or a gasless abdomen 22. The incidence of pancreatitis in patients receiving immune checkpoint inhibitor therapy is low (anti‐cytotoxic T‐lymphocyte‐associated protein 4 [CTLA4], 0.9%–3%; anti‐PD‐1, 0.5%–1.6%; anti‐CTLA4 + anti‐PD‐1, 1.2%–2.1%) [23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34], although the incidence of elevated amylase and lipase is much higher (anti‐PD‐1, 14% [amylase] and 8% [lipase]; anti‐CTLA4 + anti‐PD‐1, 4% and 2%) 35.

The diagnosis and management of immune checkpoint–induced pancreatitis faces many challenges. Challenge group one is whether routine monitoring of pancreatic enzymes is necessary and whether grade 3 or 4 elevations of amylase and lipase should be considered dose‐limiting toxicities for any new immune checkpoint inhibitor tested in patients with cancer even if the diagnosis of pancreatitis is not made. The etiology of amylase and lipase elevation often remains unclear as they are nonspecific and may be elevated because of organ failure 36, bowel obstruction 37, diabetic ketoacidosis 38, or HIV infection 39. Therefore, routine monitoring of pancreatic enzymes is not recommended, unless pancreatitis is suspected 40.

Challenge two is that pancreatitis due to immune checkpoint inhibitors may have variable presentations and therefore is not a straightforward diagnosis. Nonpancreatic abdominal pain or intermittent diarrhea have been reported as clinical symptoms of immune‐mediated pancreatitis 41. Whether immune checkpoint inhibitors are currently being administered or have just been administered, patients should be monitored for clinical symptoms of pancreatitis. When clinically indicated, serum levels of amylase and lipase need to be checked. If amylase or lipase levels are elevated, abdominal imaging should be considered for the evaluation of pancreatitis although image features of pancreatitis may not be found in patients with immune‐mediated pancreatitis. When immune‐mediated pancreatitis is diagnosed, a steroid (1–2 mg/kg) or other immunosuppressant (if steroids are contraindicated) should be started with close monitoring, and a slow tapering down of dosage should ensue. Given that the course of immune‐mediated pancreatitis is not well defined, patients should be monitored for recurrent pancreatitis when the pancreatitis has resolved and they have been completely tapered off steroids.

Challenge three is that the long‐term sequelae of immune‐mediated pancreatitis or chronic elevation of amylase or lipase without any relevant clinical condition are unclear. It has been reported that even several months after normalization of pancreatic serum enzymes and clinical remission, secondary pancreatic insufficiency, both endocrine and exocrine, may occur 42, 43, 44. Given the increasing number of patients with cancer in remission who have been treated with immune checkpoint inhibitors, vigilant monitoring for secondary pancreatic insufficiency is warranted.

Immune Blockade–Induced Cholangitis

Immune therapy–related cholangitis involving elevated bilirubin and alkaline phosphatase is managed in the same way as immune‐mediated hepatitis (described above). Isolated cholangitis presented as secondary sclerosing cholangitis has been reported 45, 46. In these cases, endoscopic retrograde cholangiography showed irregular narrowing and widening of the entire intrahepatic biliary system. Histologically, CD8+ T cells had infiltrated the biliary epithelium of the extrahepatic bile duct. Sclerosing cholangitis secondary to pembrolizumab administration was diagnosed, and high‐dose corticosteroids were administered. However, laboratory data showed only a moderate response. Although very rare, immune checkpoint inhibitors can cause severe and irreversible sclerosing cholangitis.

Author Contributions

Conception/design: Christine Hsu, John L. Marshall, Aiwu Ruth He

Provision of study material or patients: Christine Hsu, John L. Marshall, Aiwu Ruth He

Manuscript writing: Christine Hsu, John L. Marshall, Aiwu Ruth He

Final approval of manuscript: Christine Hsu, John L. Marshall, Aiwu Ruth He

Disclosures

John L. Marshall: Merck (C/A, H). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Acknowledgments

We thank Marion L. Hartley, Ph.D., for her editing assistance during the composition of this manuscript.

Disclosures of potential conflicts of interest may be found at the end of this article.

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