Secondary sclerosing cholangitis with hemobilia induced by pembrolizumab: Case report and review of published work

Koya, Yudai; Shibata, Michihiko; Shinohara, Nobuhiko; Nebuya, Satoru; Oe, Shinji; Honma, Yuichi; Senju, Michio; Sato, Naoko; Harada, Masaru

doi:10.1111/hepr.13329

Cited by 32 publications

(42 citation statements)

References 18 publications

(31 reference statements)

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“…52 The histopathologic patterns of CPI-induced hepatobiliary injury include panlobular hepatitis, portal inflammation with bile duct injury, granulomas, steatosis or steatohepatitis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. [52][53][54][55][56] Liver Panlobular Hepatitis.-Panlobular hepatitis is the most commonly observed pattern of CPI therapy-induced liver injury. This pattern injury often presents with elevation of the liver enzymes aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), with proportionately lower hyperbilirubinemia.…”

Section: Patterns Of Injury To the Liver Andmentioning

confidence: 99%

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

Patil

Zhang

2020

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Immune checkpoint inhibitors (CPIs), including cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors and the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, are being increasingly used for treating many advanced malignancies. However, CPI therapy is also associated with gastrointestinal and hepatobiliary adverse effects. Objectives.— To review the adverse effects of CPI therapy on the gastrointestinal tract and hepatobiliary system. To describe histopathologic patterns and discuss differential diagnostic considerations in the diagnosis of CPI injuries. Data Sources.— Published peer-reviewed literature in the English language and personal experience in the diagnosis of CPI injuries. Conclusions.— The pathologic manifestations of CPI therapy–induced gastrointestinal and hepatobiliary injury are broad. The patterns of esophageal CPI injury include lymphocytic inflammation and ulcerative esophagitis, while those of gastric injury include chronic active gastritis, lymphocytic gastritis, focal enhancing gastritis, and periglandular inflammation. The duodenal injury may present as duodenitis with villous blunting and granulomas. We also noticed active colitis, microscopic colitis, chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes in colonic injuries. The reported histologic features of hepatobiliary injuries are panlobular hepatitis, centrilobular necrosis, portal inflammation with bile duct injury, steatosis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. In summary, we here discuss the pathologic features and differential diagnosis of CPI therapy–induced gastrointestinal and hepatobiliary injury. Recognition of CPI injury is important to determine the proper management that often includes cessation of CPI therapy; and administration of steroids or other immunosuppressive agents, based on severity of injury.

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Section: Patterns Of Injury To the Liver Andmentioning

confidence: 99%

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

Patil

Zhang

2020

Archives of Pathology &Amp; Laboratory Medicine

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“…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.…”

Section: Immune Blockade-induced Cholangitismentioning

confidence: 99%

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

Hsu¹,

Marshall

2019

The Oncologist

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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.

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“…The histopathological findings of liver biopsy showed steatosis in two of five patients. In contrast, regarding PD‐1 inhibitor‐associated cholangitis, 12 cases had been reported, 8 received nivolumab, and 4 received pembrolizumab . The median cycles to development of cholangitis was four courses (range 1–12 cycles).…”

Section: Discussionmentioning

confidence: 99%

“…In patients with grade ≥ 2 hepatic AEs, liver biopsy is recommended for diagnosing hepatic irAEs and determining the need for immediate steroid treatment. Histopathological findings of hepatic irAEs demonstrate that CD8‐positive T lymphocytes infiltrate in a pan lobular manner in hepatitis and rarely infiltrate the portal tract in cholangitis . However, liver biopsies cannot be performed in all patients with grade ≥ 2 hepatic AEs due to complications and patient conditions.…”

Section: Discussionmentioning

confidence: 99%

“…A recent meta‐analysis of anti‐programmed cell death‐1 (PD‐1) and its ligand (PD‐L1) revealed that increases in all‐grade aspartate aminotransferase and alanine aminotransferase levels ranged from 2% to 5% after treatment with nivolumab, pembrolizumab, and atezolizumab, while the incidence of hepatitis was <2%, with an incidence of high‐grade hepatitis development in approximately 1% of patients . Serum ALP and gamma‐glutamyl transferase levels were increased in approximately 1% of patients with various cancers, while the incidence of cholangitis was very rare . These findings indicate that increases in serum hepatobiliary enzyme levels may occasionally occur during ICI treatment, but serious hepatotoxicity may be less frequent.…”

Section: Introductionmentioning

confidence: 99%

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Non‐alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor

Sawada

Hayashi

Nakajima

et al. 2019

J of Gastro and Hepatol

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Background and Aim Because of their survival benefits, immune checkpoint inhibitors (ICIs) are widely administered to patients with various advanced‐stage malignancies. During ICI treatment, drug‐induced liver injury (DILI) occasionally occurs. In particular, hepatic immune‐related adverse events (irAEs) are rare but serious and fatal. In patients with hepatic irAEs, immediate steroid treatment is generally recommended; however, the risk factors for ICI‐associated DILI remain unknown. In the present study, we identified a risk factor for ICI‐associated DILI. Methods We retrospectively analyzed 135 patients treated with anti‐programmed cell death‐1 (PD‐1) antibodies, such as nivolumab and pembrolizumab, at Asahikawa Medical University Hospital. We investigated grade ≥ 2 hepatotoxic AEs during anti‐PD‐1 therapy, and PD‐1 inhibitor‐associated DILI was then diagnosed according to the Digestive Disease Week Japan (DDW‐J) 2004 scale. The risk factors for PD‐1 inhibitor‐associated DILI were identified by Cox hazard analysis. Results Thirty‐six patients developed grade ≥ 2 hepatic AEs during anti‐PD‐1 therapy. Among them, eight patients were diagnosed with PD‐1 inhibitor‐associated DILI based on the DDW‐J 2004 scale. Cox hazard analysis revealed that non‐alcoholic fatty liver disease (NAFLD) was a risk factor for PD‐1 inhibitor‐associated DILI. In addition, we revealed that the outcomes of patients with the DDW‐J 2004 score = 3 were improved without steroid treatment. Conclusions NAFLD is a potential risk factor for PD‐1 inhibitor‐associated DILI based on the DDW‐J 2004 scale. The DDW‐J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD‐1 inhibitor‐associated DILI.

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Secondary sclerosing cholangitis with hemobilia induced by pembrolizumab: Case report and review of published work

Cited by 32 publications

References 18 publications

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

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

Non‐alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor

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