Pembrolizumab as a Cause of Cholangiopathy in a Patient With Metastatic Melanoma

Stuart, Laura; Lambourne, B; Turner, Paul; Jones, David; Plummer, Ruth; Cresti, Nicola; Dyson, Jessica

doi:10.1002/hep.31089

Cited by 15 publications

(6 citation statements)

References 4 publications

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“…Notably, baseline liver enzyme levels did not affect the incidence of each type of liver injury, and almost all patients showed normal immunoglobulin G (IgG) levels and negative results for anti-nuclear antibodies (86.0%) and anti-mitochondrial M2 antibodies (95.3%). 15 [13,23] 16 [11,21] 15 [9,22] 0.837 GGT (baseline) * (U/L) 34 [22,49] 28 [19,45] 28 [20,47] 38…”

Section: Resultsmentioning

confidence: 99%

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

et al. 2021

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BackgroundThe clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury. MethodsWe evaluated the characteristics and clinical course of immune-related liver injury in 1087 patients treated with ICIs for advanced malignancies between August 2014 and December 2020. ResultsDuring the follow-up period (median, 270 days), 56 patients (5.2%) had immune-related liver injury (≥Grade 3). The liver-injury patterns were hepatocellular (n = 25, 44.6%), mixed (n = 10, 17.9%), or cholestatic (n = 21, 37.5%), and the median time to onset of liver injury was 36, 85, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (P = 0.036). Corticosteroids were administered to 29 (51.8%) patients. While liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns (mixed, n = 8; cholestatic, n = 7), and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with in ltration of T cells positive for CD3 and CD8, but not CD4 or CD20. ConclusionThe incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differs according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

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Section: Resultsmentioning

confidence: 99%

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

et al. 2021

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“…Overlap is a condition in which multiple diseases coexist, such as autoimmune hepatitis and primary sclerosing cholangitis. The possibility of irHepatitis-irSC overlap should also be considered, as Stuart et al preciously reported one case [ 26 ]. In 16 patients who underwent a liver biopsy out of 536 irHepatitis patients, more than half of them presented with bile duct injury [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of clinical features between immune-related sclerosing cholangitis and hepatitis

et al. 2021

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SummaryBackground Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis. Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness. Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P < 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively. Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020)

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“…Notably, baseline liver enzyme levels did not affect the incidence of each type of liver injury, and almost all patients showed normal immunoglobulin G (IgG) levels and negative results for anti-nuclear antibodies (86.0%) and anti-mitochondrial M2 antibodies (95.3%). The number of dose from rst ICI administration to liver injury ** (times) [11,22] 15 [13,23] 16 [11,21] 15 [9,22] 0.837 GGT (baseline) * (U/L) 34 [22,49] 28 [19,45] 28 [20,47] 38…”

Section: Resultsmentioning

confidence: 99%

“…These results indicate that the response to corticosteroids in patients with liver injuries marked by an increase in biliary enzyme (i.e., ALP and γglutamyl transpeptidase [GGT]) levels was poor. ICIs are reported to rarely induce immune-related cholangitis 8,18,19 , which is characterized by predominant elevation of biliary enzymes, while liver transaminase levels are only moderately increased. A recent case report showed the utility of UDCA administration in patients with immune-mediated cholangitis induced by anti-PD-1 antibody that showed resistance to high-dose corticosteroids 19 .…”

Section: Discussionmentioning

confidence: 99%

“…ICIs are reported to rarely induce immune-related cholangitis 8,18,19 , which is characterized by predominant elevation of biliary enzymes, while liver transaminase levels are only moderately increased. A recent case report showed the utility of UDCA administration in patients with immune-mediated cholangitis induced by anti-PD-1 antibody that showed resistance to high-dose corticosteroids 19 . The pathogenesis of immune-related liver injury is different from that of classical autoimmune liver diseases such as AIH or primary biliary cholangitis (PBC) 20 .…”

Section: Discussionmentioning

confidence: 99%

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Clinical Features and Outcomes Based on Liver Injury Patterns in Liver Injury Caused by Immune Checkpoint Inhibitors

Ito

Ishigami

Yamamoto

et al. 2021

Preprint

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BackgroundThe clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury.MethodsWe evaluated the characteristics and clinical course of immune-related liver injury in 1087 patients treated with ICIs for advanced malignancies between August 2014 and December 2020. ResultsDuring the follow-up period (median, 270 days), 56 patients (5.2%) had immune-related liver injury (≥Grade 3). The liver-injury patterns were hepatocellular (n = 25, 44.6%), mixed (n = 10, 17.9%), or cholestatic (n = 21, 37.5%), and the median time to onset of liver injury was 36, 85, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (P = 0.036). Corticosteroids were administered to 29 (51.8%) patients. While liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns (mixed, n = 8; cholestatic, n = 7), and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20. ConclusionThe incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differs according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

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Pembrolizumab as a Cause of Cholangiopathy in a Patient With Metastatic Melanoma

Cited by 15 publications

References 4 publications

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies

Comparison of clinical features between immune-related sclerosing cholangitis and hepatitis

Clinical Features and Outcomes Based on Liver Injury Patterns in Liver Injury Caused by Immune Checkpoint Inhibitors

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