Berry Philip, Kotha Sreelakshmi, Zen Yoh, Papa Sophie, El Menabawey Tareq, Webster George, Joshi Deepak, Heneghan Michael
Department of Hepatology, Guy's and St Thomas' Foundation Trust, London, UK.
Department of Histopathology, King's College Hospital, London, UK.
Liver Int. 2023 Jan;43(1):147-154. doi: 10.1111/liv.15340. Epub 2022 Jun 23.
Cholestatic liver dysfunction is common in immune-related hepatitis (irH) during treatment with immune checkpoint inhibitors (CPI) for malignancy. We investigated the spectrum of bile duct injury and associated natural history in this cohort.
Clinical, laboratory, radiological and histopathological data in patients with evidence of bile duct injury during CPI treatment from 2018 to 2020 was collected in three tertiary hospitals.
In this study, ten patients with confirmed bile duct disease were identified. Pembrolizumab was most commonly implicated (8/10). Median CPI cycles prior to bile duct injury was 6. Median alanine aminotransferase and alkaline phosphatase were 225 U/L and 1549 U/L respectively. Clinical jaundice was seen in 6/10 and radiological evidence of bile duct pathology in 8/10. Of five patients, who had liver biopsy, three cases (including two cases with normal MRCP) showed primary sclerosing cholangitis (PSC) like changes with periductal fibrosis. All patients were treated first-line with prednisolone following cessation of CPI, three with mycophenolate mofetil and one with tacrolimus, with clinical response in four patients. Five patients died after a mean follow-up of 27 weeks; cause of death was primarily related to progression of malignancy.
Within this heterogeneous cohort, we identified that CPI-related cholangiopathy responded poorly to immunosuppression and potentially progressed to bile duct loss. Thorough radiological and histological assessment is recommended, as identification of the cholangiopathy-associated phenotype may permit more informed advice regarding prognosis. Further data is required to determine detailed immunological characterisation in order to identify individuals at an increased risk of developing cholangiopathy.
在恶性肿瘤患者接受免疫检查点抑制剂（CPI）治疗期间，胆汁淤积性肝功能障碍在免疫相关性肝炎（irH）中很常见。我们调查了该队列中胆管损伤的范围及相关自然病史。
收集了2018年至2020年期间在三家三级医院接受CPI治疗且有胆管损伤证据的患者的临床、实验室、放射学和组织病理学数据。
在本研究中，确定了10例确诊胆管疾病的患者。派姆单抗最常涉及（8/10）。胆管损伤前CPI的中位疗程为6个周期。丙氨酸转氨酶和碱性磷酸酶的中位数分别为225 U/L和1549 U/L。6/10的患者出现临床黄疸，8/10的患者有胆管病变的放射学证据。在进行肝活检的5例患者中，3例（包括2例磁共振胰胆管造影正常的患者）表现为原发性硬化性胆管炎（PSC）样改变伴导管周围纤维化。所有患者在停用CPI后首先接受泼尼松龙一线治疗，3例联合霉酚酸酯，1例联合他克莫司，4例有临床反应。5例患者在平均随访27周后死亡；死亡原因主要与恶性肿瘤进展有关。
在这个异质性队列中，我们发现与CPI相关的胆管病对免疫抑制反应不佳，并可能进展为胆管丧失。建议进行全面的放射学和组织学评估，因为识别胆管病相关表型可能有助于提供更明智的预后建议。需要进一步的数据来确定详细的免疫学特征，以识别发生胆管病风险增加的个体。
