Lazzaroni Massimiliano, Angelini Francesco, Guglielmi Rinaldo, Novizio Roberto, Iadevaia Anjali, Andreadi Aikaterini, Papini Enrico
Department of Systems Medicine, Session of Endocrinology and Metabolic Diseases, University of Rome Tor Vergata, Rome, Italy.
Regina Apostolorum Hospital, Medical Oncology Unit, Albano Laziale, Rome, Italy.
Endocr Metab Immune Disord Drug Targets. 2025 Jul 31. doi: 10.2174/0118715303409910250725043347.
INTRODUCTION/BACKGROUND: Immune checkpoint inhibitors (ICIs) play a central role in advanced cancer treatment, but they are associated with immune-related adverse events (irAEs) that include two cases of hypercalcemia induced by the programmed death-1 (PD-1) inhibitor, pembrolizumab. We report a unique case of a colon cancer patient treated with pembrolizumab who acutely developed life-threatening hypercalcemia.
This case presents a seventy-five-year-old woman suffering from colon adenocarcinoma with liver metastasis undergoing pembrolizumab therapy. Shortly after its second administration, she developed severe hypercalcemia (21 mg/dL) with acute kidney failure. Serum intact parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrP), 25-OH vitamin D, and 1,25-OH vitamin D were suppressed while computerized tomography (CT) imaging ruled out relevant osteolytic or granulomatous lesions. Treatment included hydration, infusion of zoledronic acid, and high-dose glucocorticoids. The patient's serum calcium levels normalized, andher condition improved. Primary hyperparathyroidism, ectopic PTHrP secretion, and ectopic 25(OH) D-1-hydroxylase expression were ruled out by clinical and laboratory data. Notably, experimental models of PD-1/PD-L1 inhibition have demonstrated increased bone resorption. Although the absence of specific bone turnover markers and a recent 18FDG-PET/CT scan partly limits the understanding of the pathophysiological mechanism, immune-mediated osteoclast activation represents a potential pathophysiological mechanism of acute reversible hypercalcemia.
The present case is unique due to its early onset, absence of calcitriol and PTHrP elevation, and rapid response to corticosteroids. Serum calcium should be assessed both before each ICI's dose administration and throughout treatment in case of symptoms suspicious for hypercalcemia to prevent the onset and progression of this rare but critical irAE.
引言/背景：免疫检查点抑制剂（ICIs）在晚期癌症治疗中发挥着核心作用，但它们与免疫相关不良事件（irAEs）有关，其中包括两例由程序性死亡-1（PD-1）抑制剂帕博利珠单抗引起的高钙血症。我们报告了一例接受帕博利珠单抗治疗的结肠癌患者急性发生危及生命的高钙血症的独特病例。
该病例为一名75岁患有肝转移的结肠腺癌女性，正在接受帕博利珠单抗治疗。在第二次给药后不久，她出现了严重高钙血症（21mg/dL）并伴有急性肾衰竭。血清完整甲状旁腺激素（PTH）、甲状旁腺激素相关肽（PTHrP）、25-羟基维生素D和1,25-二羟基维生素D均受到抑制，而计算机断层扫描（CT）成像排除了相关的溶骨性或肉芽肿性病变。治疗包括补液、输注唑来膦酸和大剂量糖皮质激素。患者的血清钙水平恢复正常，病情好转。临床和实验室数据排除了原发性甲状旁腺功能亢进、异位PTHrP分泌和异位25（OH）D-1-羟化酶表达。值得注意的是，PD-1/PD-L1抑制的实验模型已证明骨吸收增加。尽管缺乏特定的骨转换标志物以及最近的18FDG-PET/CT扫描在一定程度上限制了对病理生理机制的理解，但免疫介导的破骨细胞激活代表了急性可逆性高钙血症的一种潜在病理生理机制。
本病例因其发病早、维生素D和PTHrP未升高以及对皮质类固醇反应迅速而独特。在每次给予ICI之前以及整个治疗过程中，若出现高钙血症可疑症状，均应评估血清钙水平，以预防这种罕见但严重的irAE的发生和进展。
