Department of Pediatrics, Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, Division of Endocrinology, University Children's Hospital Zurich, Zurich, Switzerland.
Department of Pediatrics, Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
J Steroid Biochem Mol Biol. 2023 Jul;231:106301. doi: 10.1016/j.jsbmb.2023.106301. Epub 2023 Mar 27.
Idiopathic Infantile Hypercalcemia (IIH) is characterized by hypercalcemia and hypercalciuria owing to PTH-independent increases in circulating concentrations of 1,25(OH)2D. At least 3 forms of IHH can be distinguished genetically and mechanistically: infantile hypercalcemia-1 (Hypercalcemia, Infantile, 1; HCINF1) due to CYP24A1 mutations results in decreased inactivation of 1,25(OH)2D; HCINF2 due to SLC34A1 mutations results in excessive 1,25(OH)2D production; and HCINF3 in which a variety of gene variants of uncertain significance (VUS) have been identified and where the mechanism for increased 1,25 (OH)2D is unclear. Conventional management with dietary calcium and vitamin D restriction has only limited success. Induction of the P450 enzyme CYP3A4 by rifampin can provide an alternate pathway for inactivation of 1,25(OH)2D that is useful in HCINF1 and may be effective in other forms of IIH. We sought to assess the efficacy of rifampin to decrease levels of serum 1,25(OH)2D and calcium, and urinary calcium concentrations in subjects with HCINF3, and to compare the response to a control subject with HCINF1. Four subjects with HCINF3 and the control subject with HCINF1 completed the study using rifampin 5 mg/kg/day and 10 mg/kg/day each for 2 months separated by a 2-month washout period. Patients had age-appropriate intake of dietary calcium plus 200 IU vitamin D/day. Primary outcome was efficacy of rifampin to lower serum concentrations of 1,25(OH)2D. The secondary outcomes included the reduction of serum calcium, urinary calcium excretion (as random urine calcium: creatinine (ca:cr) ratio) and serum 1,25(OH)2D/PTH ratio. Rifampin was well tolerated and induced CYP3A4 at both doses in all subjects. The control subject with HCINF1 showed significant response to both rifampin doses with decreases in the serum concentration of 1,25(OH)2D and the 1,25(OH)2D/PTH ratio while the serum and urine ca:cr levels were unchanged. The four patients with HCINF3 showed reductions in 1,25(OH)2D and urinary ca:cr after 10 mg/kg/d, but hypercalcemia did not improve and there were variable responses in 1,25(OH)2D/PTH ratios. These results support further longer-term studies to clarify the usefulness of rifampin as a medical therapy for IIH.
特发性婴儿高钙血症 (IIH) 的特征是由于甲状旁腺激素非依赖性循环浓度 1,25(OH)2D 增加而导致高钙血症和高钙尿症。至少可以从遗传和机制上区分出 3 种形式的 IIH：由于 CYP24A1 突变导致的婴儿高钙血症 1 (Hypercalcemia, Infantile, 1; HCINF1) 导致 1,25(OH)2D 失活减少；由于 SLC34A1 突变导致的 HCINF2 导致 1,25(OH)2D 过度产生；以及在 HCINF3 中已鉴定出多种具有不确定意义的基因变异 (VUS)，并且增加 1,25(OH)2D 的机制尚不清楚。用膳食钙和维生素 D 限制进行的常规治疗仅取得有限的成功。利福平诱导的 P450 酶 CYP3A4 可以提供 1,25(OH)2D 失活的替代途径，这在 HCINF1 中很有用，并且在其他形式的 IIH 中可能有效。我们试图评估利福平降低 HCINF3 受试者血清 1,25(OH)2D 和钙以及尿钙浓度的疗效，并比较 HCINF1 对照受试者的反应。使用利福平 5mg/kg/天和 10mg/kg/天，每位 HCINF3 受试者和 HCINF1 对照受试者各进行 2 个月的治疗，然后进行为期 2 个月的洗脱期。患者的膳食钙摄入量和 200IU 维生素 D/天保持在年龄适宜的水平。主要疗效终点是利福平降低血清 1,25(OH)2D 浓度的疗效。次要终点包括血清钙、尿钙排泄量（随机尿钙：肌酐 (ca:cr) 比值）和血清 1,25(OH)2D/PTH 比值的降低。利福平在所有受试者中均耐受良好，两种剂量均诱导了 CYP3A4。患有 HCINF1 的对照受试者对两种利福平剂量均有明显反应，血清 1,25(OH)2D 浓度和 1,25(OH)2D/PTH 比值降低，而血清和尿 ca:cr 水平不变。四名 HCINF3 患者在服用 10mg/kg/d 后 1,25(OH)2D 和尿 ca:cr 均降低，但高钙血症并未改善，1,25(OH)2D/PTH 比值的反应各不相同。这些结果支持进行更长时间的研究，以阐明利福平作为 IIH 医学治疗的有效性。
