The PTH-calcium curve and the set point of calcium in primary and secondary hyperparathyroidism
原发性和继发性甲状旁腺功能亢进症的 PTH 钙曲线和钙设定点

Methods. The PTH-ICa relationship and the set point of ICa were evaluated in 19 patients with primary HPT (1-HPT), 16 normocalcaemic patients with secondary HPT (2-HPT; PTH $344\pm 191\mathrm{pg}/\mathrm{ml}$$344\pm 191\mathrm{pg}/\mathrm{ml}$344+-191pg//ml344 \pm 191 \mathrm{pg} / \mathrm{ml} ), 19 hypercalcaemic patients with secondary HPT (3-HPT; PTH $806\pm 254\mathrm{pg}/\mathrm{ml}$$806\pm 254\mathrm{pg}/\mathrm{ml}$806+-254pg//ml806 \pm 254 \mathrm{pg} / \mathrm{ml} ) and 14 healthy volunteers, by inducing hypocalcaemia and hypercalcaemia in order to maximally stimulate or inhibit PTH secretion. In five 1-HPT patients the PTH-ICa curve was restudied after normalization of serum ICa by pamidronate. Parathyroid gland volume was determined by measuring gland size at parathyroidectomy or by means of high-resolution color Doppler ultrasonography.
方法。通过诱导低钙血症和高钙血症以最大限度地刺激或抑制 PTH 分泌，对 19 名原发性 HPT（1-HPT）患者、16 名继发性 HPT（2-HPT；PTH $344\pm 191\mathrm{pg}/\mathrm{ml}$$344\pm 191\mathrm{pg}/\mathrm{ml}$344+-191pg//ml344 \pm 191 \mathrm{pg} / \mathrm{ml} ）正常钙血症患者、19 名继发性 HPT（3-HPT；PTH $806\pm 254\mathrm{pg}/\mathrm{ml}$$806\pm 254\mathrm{pg}/\mathrm{ml}$806+-254pg//ml806 \pm 254 \mathrm{pg} / \mathrm{ml} ）高钙血症患者和 14 名健康志愿者的 PTH-ICa 关系和 ICa 设定点进行了评估。帕米膦酸钠使血清 ICa 恢复正常后，重新研究了 5 名 1-HPT 患者的 PTH-ICa 曲线。通过测量甲状旁腺切除术时的腺体大小或通过高分辨率彩色多普勒超声波检查来确定甲状旁腺的体积。
Results. In 1-HPT patients the PTH-ICa curve, constructed using maximal PTH secretion induced by hypocalcaemia as $100\mathrm{\%}$$100\mathrm{\%}$100%100 \%, was shifted to the right, the set point of ICa was increased, and the slope of the curve was reduced when compared to normal subjects. After normalization of baseline serum ICa by pamidronate, a shift of the PTH-ICa curve towards normal and a reduction in the set point of ICa was observed. However, basal PTH and maximal PTH secretion induced by hypocalcaemia increased, minimal PTH secretion induced by hypercalcaemia remained increased and the slope of the curve did not change significantly. The alterations in the PTH-ICa relationship in hypercalcaemic patients with secondary HPT were similar to those found in 1-HPT patients. In
结果与正常人相比，1-HPT 患者以低钙血症引起的最大 PTH 分泌为 $100\mathrm{\%}$$100\mathrm{\%}$100%100 \% 构建的 PTH-ICa 曲线向右偏移，ICa 的设定点升高，曲线斜率降低。帕米膦酸钠使基线血清 ICa 恢复正常后，观察到 PTH-ICa 曲线向正常值移动，ICa 的设定点降低。然而，低钙血症诱导的基础 PTH 和最大 PTH 分泌增加，高钙血症诱导的最小 PTH 分泌仍然增加，曲线的斜率没有显著变化。继发性 HPT 高钙血症患者 PTH-ICa 关系的变化与 1-HPT 患者相似。在

normocalcaemic patients with secondary HPT baseline PTH, maximal and minimal PTH secretion and parathyroid gland size were reduced compared to 3-HPT patients. Compared to normal subjects, 2-HPT patients showed greater calcium-induced minimal PTH secretion. The increase in non-suppressible PTH secretion resulted in a rightward shift of the PTH-ICa curve and an increase in the set point of ICa. A strong correlation was found, in both primary and secondary HPT, between the set point of ICa and baseline serum ICa, and between parathyroid gland size and baseline PTH, maximal PTH and minimal PTH. Multivariate regression analysis showed that baseline serum ICa was the main determinant of the set point of ICa in both primary and secondary HPT.
与3-HPT患者相比，血钙正常的继发性HPT患者的基线PTH、最大和最小PTH分泌以及甲状旁腺大小均有所减少。与正常人相比，2-HPT 患者的钙诱导最小 PTH 分泌量更大。非抑制性 PTH 分泌的增加导致 PTH-ICa 曲线右移，ICa 设定点升高。在原发性和继发性HPT中，ICa的设定点与基线血清ICa之间、甲状旁腺大小与基线PTH、最大PTH和最小PTH之间都存在很强的相关性。多变量回归分析表明，基线血清ICa是原发性和继发性HPT的ICa设定点的主要决定因素。
Conclusions. (i) The regulation of PTH secretion by calcium is abnormal in secondary as well as in primary HPT. (ii) Parathyroid gland enlargement in secondary HPT is associated with reduced sensitivity to serum ICa and resistance of parathyroid gland to calciummediated PTH suppression, resulting ultimately in PTH hypersecretion, despite hypercalcaemia. (iii) The set point of calcium is strongly dependent on baseline serum calcium, and the PTH-ICa relationship can be affected by variations in serum ICa concentrations. Thus, when the set point of calcium and the PTH-ICa relationship are evaluated, possible differences in baseline serum ICa concentration among the patients should be taken into account.
结论(i) 继发性 HPT 和原发性 HPT 的钙对 PTH 分泌的调节均不正常。(ii) 继发性 HPT 的甲状旁腺增大与对血清 ICa 的敏感性降低和甲状旁腺对钙介导的 PTH 抑制的抵抗力降低有关，最终导致 PTH 分泌过多，尽管存在高钙血症。(iii) 钙的设定点在很大程度上取决于血清钙基线，血清 ICa 浓度的变化会影响 PTH-ICa 关系。因此，在评估钙的设定点和 PTH-ICa 关系时，应考虑到患者之间可能存在的血清 ICa 基线浓度差异。

Key words: hypercalcaemia; parathyroid hormone; primary hyperparathyroidism; secondary hyperparathyroidism; serum ionized calcium; set point of calcium
关键词： 高钙血症；甲状旁腺激素；原发性甲状旁腺功能亢进症；继发性甲状旁腺功能亢进症；血清离子化钙；钙设定点

The extracellular calcium concentration is the primary determinant of parathyroid hormone (PTH) secretion. Mayer and Hurst [1] first demonstrated the inverse sigmoidal relationship between serum calcium and PTH. Their results documented the sensitivity of the parathyroids to small variations in serum calcium over periods of several minutes, slight decreases in serum
细胞外钙浓度是甲状旁腺激素（PTH）分泌的主要决定因素。梅尔和赫斯特[1]首次证明了血清钙与 PTH 之间的反三次方关系。他们的研究结果表明，甲状旁腺对血清钙在几分钟内的微小变化、血清钙的轻微下降、血清钙的微小升高和血清钙的微小降低都很敏感。
calcium triggering PTH secretion, whereas small increases reducing PTH release. To asses the secretory behaviour of the parathyroids in humans, serum ionized calcium levels are raised by infusing calcium salts and lowered by infusing either sodium EDTA or citrate to elicit reciprocal changes in serum PTH levels and obtain the sigmoidal PTH-calcium curve [2,3]. In recent years, these dynamic tests of parathyroid gland function have been widely used to examine the regulation of PTH release by calcium in patients with either primary or secondary hyperparathyroidism (HPT), since in vitro studies on dispersed parathyroid cells have shown that alterations in the PTH release by calcium may contribute to excess PTH secretion either in primary or in secondary HPT $[4,5]$$[4,5]$[4,5][4,5].
钙离子水平升高会触发 PTH 分泌，而钙离子水平小幅升高则会减少 PTH 的释放。为了评估人体甲状旁腺的分泌行为，可通过输注钙盐提高血清离子钙水平，再通过输注乙二胺四乙酸钠或枸橼酸钠降低血清离子钙水平，从而引起血清PTH水平的相互变化，并获得PTH-钙曲线[2,3]。近年来，这些甲状旁腺功能的动态检测方法被广泛应用于原发性或继发性甲状旁腺功能亢进（HPT）患者PTH释放的钙调控，因为对分散的甲状旁腺细胞进行的体外研究表明，钙对PTH释放的改变可能导致原发性或继发性HPT患者PTH分泌过多 $[4,5]$$[4,5]$[4,5][4,5] 。

In vivo studies have documented that the regulation of PTH secretion by calcium is altered in primary HPT since the PTH-calcium curve is shifted to the right and the set point for calcium is increased [6,7]. On the contrary, conflicting results have been reported in in vivo studies on uraemic patients, particularly with respect to set point for calcium. In fact, some authors did not find differences in set point values between normal subjects and patients with secondary HPT $[8,9]$$[8,9]$[8,9][8,9] or between uraemic patients with different degree of secondary HPT [10], while other authors documented a rightward shift of the curve and the increase in the set point with the worsening of secondary HPT [11]. Moreover, Felsenfeld et al. [12,13] found differences in the curve and in the set point in dialysis patients with different forms of osteodystrophy, while Goodman et al. [14] did not show differences in calcium-sensing by parathyroids between dialysis patients with adynamic bone disease and those with secondary HPT. Indridason et al. [15] suggested that parathyroid gland enlargement rather than calcium sensing abnormalities plays a predominant role in PTH hypersecretion in uraemic patients. Recent studies have shown that the PTH-calcium curve and the set point of calcium can be modified by changes in baseline serum calcium $[16,17]$$[16,17]$[16,17][16,17], and this might explain, at least partly, the conflicting results reported in uraemic patients, particularly when patients with different baseline serum calcium are compared.
体内研究表明，原发性 HPT 患者钙对 PTH 分泌的调节发生了改变，因为 PTH-钙曲线右移，钙的设定点升高 [6,7]。相反，对尿毒症患者进行的体内研究却发现了相互矛盾的结果，尤其是在钙的设定点方面。事实上，一些作者没有发现正常人与继发性 HPT 患者 $[8,9]$$[8,9]$[8,9][8,9] 之间或不同程度继发性 HPT 的尿毒症患者之间的设定值差异 [10]，而另一些作者则记录了随着继发性 HPT 的恶化，曲线右移和设定值增加的情况 [11]。此外，Felsenfeld 等人[12,13] 发现患有不同形式骨营养不良的透析患者的曲线和设定点存在差异，而 Goodman 等人[14] 则未发现患有动力性骨病的透析患者和继发性 HPT 患者的甲状旁腺对钙的感应存在差异。Indridason等人[15]认为，尿毒症患者PTH分泌过多的主要原因是甲状旁腺增大，而不是钙感应异常。最近的研究表明，PTH-钙曲线和钙的设定点可因基线血清钙 $[16,17]$$[16,17]$[16,17][16,17] 的变化而改变，这可能至少部分解释了在尿毒症患者中报告的相互矛盾的结果，尤其是在比较不同基线血清钙的患者时。

The goals of the present study were to: (i) evaluate whether the regulation of PTH secretion by calcium in patients with primary and secondary HPT differs from normal; (ii) evaluate the relationship between the parathyroid gland mass, the alterations in calciummediated PTH secretion and the severity of HPT; (iii) determine whether serum calcium concentration per se can affect the set point of calcium and the PTHcalcium relationship.
本研究的目的是(i)评估原发性和继发性HPT患者钙对PTH分泌的调节作用是否与正常人不同；(ii)评估甲状旁腺质量、钙介导的PTH分泌变化和HPT严重程度之间的关系；(iii)确定血清钙浓度本身是否会影响钙的设定点和PTH钙的关系。

We studied 19 patients with primary HPT (1-HPT) and 35 patients undergoing regular dialysis affected by secondary HPT (PTH $>200\mathrm{pg}/\mathrm{ml})$$>200\mathrm{pg}/\mathrm{ml})$> 200pg//ml)>200 \mathrm{pg} / \mathrm{ml}). The uraemic patients were divided into two groups (2-HPT and 3-HPT) according to baseline serum calcium concentration: 16 normocalcaemic patients ( 12 on haemodialysis, four on CAPD) were allocated in the 2-HPT group, whereas 19 hypercalcaemic (ionized calcium $>1.28\mathrm{mmol}/\mathrm{l}$$>1.28\mathrm{mmol}/\mathrm{l}$> 1.28mmol//l>1.28 \mathrm{mmol} / \mathrm{l} ) patients ( 14 on haemodialysis, five on CAPD), were considered as affected by tertiary HPT and allocated in the 3-HPT group. All dialysis patients underwent a bone biopsy. The patients showed either mild lesions of secondary HPT or overt osteitis fibrosa. None of the patients had evidence of bone aluminum deposition as assessed by histochemical staining and none were taking aluminumcontaining medications. Most of the dialysis patients had previously been treated with calcitriol, but vitamin D therapy was discontinued for at least 1 month prior to study. The patients affected by 1-HPT were hypercalcaemic and were studied before parathyroidectomy. All later had surgically documented primary HPT, due to parathyroid adenoma, with postoperative normalization of serum calcium levels. Also 16 of 19 patients with 3-HPT and one patient with 2HPT underwent total or subtotal parathyroidectomy after parathyroid gland function was investigated by dynamic tests. The patient with 2-HPT underwent parathyroidectomy because of very high PTH levels ( $805\mathrm{pg}/\mathrm{ml}$$805\mathrm{pg}/\mathrm{ml}$805pg//ml805 \mathrm{pg} / \mathrm{ml} ) and calcaemia in the upper normal range $(1.26\mathrm{mmol}/\mathrm{l})$$(1.26\mathrm{mmol}/\mathrm{l})$(1.26mmol//l)(1.26 \mathrm{mmol} / \mathrm{l}).
我们研究了 19 名原发性 HPT（1-HPT）患者和 35 名接受常规透析的继发性 HPT（PTH $>200\mathrm{pg}/\mathrm{ml})$$>200\mathrm{pg}/\mathrm{ml})$> 200pg//ml)>200 \mathrm{pg} / \mathrm{ml}) ）患者。根据基线血清钙浓度，尿毒症患者被分为两组（2-HPT 和 3-HPT）：16 名正常钙血症患者（12 名接受血液透析，4 名接受 CAPD）被分配到 2-HPT 组，而 19 名高钙血症（离子钙 $>1.28\mathrm{mmol}/\mathrm{l}$$>1.28\mathrm{mmol}/\mathrm{l}$> 1.28mmol//l>1.28 \mathrm{mmol} / \mathrm{l} ）患者（14 名接受血液透析，5 名接受 CAPD）被视为受三级 HPT 影响，并被分配到 3-HPT 组。所有透析患者都接受了骨活检。患者表现为继发性 HPT 的轻微病变或明显的纤维性骨炎。经组织化学染色评估，所有患者都没有骨铝沉积的迹象，也没有服用含铝药物。大多数透析患者之前都接受过降钙素三醇治疗，但在研究前至少有一个月停止了维生素 D 治疗。1-HPT患者为高钙血症患者，在甲状旁腺切除术前接受了研究。后来，所有患者都因甲状旁腺腺瘤而被手术证实为原发性HPT，术后血清钙水平恢复正常。此外，19名3-HPT患者中有16名和1名2-HPT患者在通过动态检测检查甲状旁腺功能后，接受了甲状旁腺全切除术或次全切除术。2-HPT患者接受甲状旁腺切除术的原因是PTH水平非常高（ $805\mathrm{pg}/\mathrm{ml}$$805\mathrm{pg}/\mathrm{ml}$805pg//ml805 \mathrm{pg} / \mathrm{ml} ），而血钙在正常范围的上限 $(1.26\mathrm{mmol}/\mathrm{l})$$(1.26\mathrm{mmol}/\mathrm{l})$(1.26mmol//l)(1.26 \mathrm{mmol} / \mathrm{l}) 。

The dynamic tests of parathyroid gland function were performed in the 191-HPT, 16 2-HPT and 193-HPT patients by inducing acute changes in serum ionized calcium (ICa) in order to maximally stimulate (PTH stimulation test) or inhibit (PTH inhibition test) PTH secretion. Fourteen volunteer subjects with normal renal function (N) were also evaluated. In five patients with 1-HPT, the dynamic tests of parathyroid secretion were repeated when a stable reduction of serum ICa was achieved by pamidronate therapy ( $30-60\mathrm{mg}$$30-60\mathrm{mg}$30-60mg30-60 \mathrm{mg} i.v.), in order to evaluate whether changes in serum calcium concentration could affect the PTH-ICa relationship. Pamidronate infusion reduced serum ICa in all patients within 3-7 days; dynamic parathyroid tests were performed after 2-4 days of stable ICa levels. The baseline characteristics and laboratory data of the patients are summarized in Table 1.
对191例HPT、16例2-HPT和193例HPT患者进行了甲状旁腺功能动态检测，通过诱导血清离子化钙（ICa）的急性变化来最大限度地刺激（PTH刺激试验）或抑制（PTH抑制试验）PTH的分泌。此外，还对 14 名肾功能正常的志愿者（N）进行了评估。在5名1-HPT患者中，当帕米膦酸盐治疗（ $30-60\mathrm{mg}$$30-60\mathrm{mg}$30-60mg30-60 \mathrm{mg} 静脉注射）使血清ICa稳定下降时，再次进行了甲状旁腺分泌动态试验，以评估血清钙浓度的变化是否会影响PTH-ICa的关系。帕米膦酸钠输注可在3-7天内降低所有患者的血清ICa；在ICa水平稳定2-4天后进行动态甲状旁腺检测。表1汇总了患者的基线特征和实验室数据。

The PTH stimulation test was performed by inducing hypocalcaemia by infusing NaEDTA ( $20\mathrm{mg}/\mathrm{kg}/\mathrm{h}$$20\mathrm{mg}/\mathrm{kg}/\mathrm{h}$20mg//kg//h20 \mathrm{mg} / \mathrm{kg} / \mathrm{h} for $150\min )$$150\min )$150min)150 \mathrm{~min}). PTH inhibition test was performed, 1 week later, by inducing hypercalcaemia by infusing ${\mathrm{CaCl}}_2(4\mathrm{mg}/\mathrm{kg}/\mathrm{h}$${\mathrm{CaCl}}_2(4\mathrm{mg}/\mathrm{kg}/\mathrm{h}$CaCl_(2)(4mg//kg//h\mathrm{CaCl}_{2}(4 \mathrm{mg} / \mathrm{kg} / \mathrm{h} of elemental Ca for 150 min ). PTH and ICa were determined at baseline, and after 10, 20, 30 and 60 min and then every 15 min . For the analysis of the PTH-ICa relationship the following terms were used: (i) maximal PTH stimulation (PTHmax), that is the highest level of PTH induced by hypocalcaemia; this level was reached in all patients between 75 and 120 min and thereafter PTH levels remained stable or decreased. (ii) Maximal PTH inhibition (PTHmin), that is the lowest level of PTH induced by hypercalcaemia; this level was reached in all patients between 60 and 105 min and thereafter PTH levels remained stable. (iii) The set point of calcium, which was calculated as either the ICa value at the midrange between PTHmin and PTHmax, as defined by Brown et al. [4], or the ICa value at which PTHmax was reduced by $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% [12]. The sensitivity of parathyroid cells to ICa variations was determined by calculating the slope of the sigmoidal curve, according to Messa et al. [9]. The PTHICa curves were constructed using PTHmax as $100\mathrm{\%}$$100\mathrm{\%}$100%100 \% to factor for differences in absolute PTH levels between the patients, and to provide an assessment of individual parathyroid cell function. From the data obtained by PTH stimulation and inhibition tests, individual PTH-ICa curves were constructed for each patient using both the fourparameter model as described by Brown et al. [4] and the
PTH刺激试验是通过注入NaEDTA（ $20\mathrm{mg}/\mathrm{kg}/\mathrm{h}$$20\mathrm{mg}/\mathrm{kg}/\mathrm{h}$20mg//kg//h20 \mathrm{mg} / \mathrm{kg} / \mathrm{h} 为 $150\min )$$150\min )$150min)150 \mathrm{~min}) 。一周后，通过输注 ${\mathrm{CaCl}}_2(4\mathrm{mg}/\mathrm{kg}/\mathrm{h}$${\mathrm{CaCl}}_2(4\mathrm{mg}/\mathrm{kg}/\mathrm{h}$CaCl_(2)(4mg//kg//h\mathrm{CaCl}_{2}(4 \mathrm{mg} / \mathrm{kg} / \mathrm{h} 元素钙150分钟诱导高钙血症，进行PTH抑制试验。）分别在基线、10、20、30和60分钟后测定PTH和ICa，然后每隔15分钟测定一次。在分析 PTH-ICa 关系时使用了以下术语：(i) 最大 PTH 刺激（PTHmax），即低钙血症诱导的最高 PTH 水平；所有患者均在 75 至 120 分钟内达到该水平，此后 PTH 水平保持稳定或下降。(ii) 最大 PTH 抑制（PTHmin），即高钙血症诱导的最低 PTH 水平；所有患者均在 60 至 105 分钟之间达到该水平，此后 PTH 水平保持稳定。(iii) 钙的设定点，其计算方法是布朗等人[4]定义的 PTHmin 和 PTHmax 之间的中点 ICa 值，或 PTHmax 降低 $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% 时的 ICa 值[12]。根据 Messa 等人[9]的方法，甲状旁腺细胞对 ICa 变化的敏感性是通过计算正弦曲线的斜率来确定的。PTHICa曲线是以PTHmax为 $100\mathrm{\%}$$100\mathrm{\%}$100%100 \% 构建的，以考虑患者之间PTH绝对水平的差异，并对个体甲状旁腺细胞功能进行评估。根据PTH刺激和抑制试验获得的数据，使用布朗等人[4]所述的四参数模型和 "PTH-ICa "模型构建了每位患者的PTH-ICa曲线。

Table 1. Patients characteristics
表 1.患者特征

polynomial regression analysis (Microsoft Excel 5.0 statistical package), as described elsewhere [18]. A fourth degree polynomial equation was used in the polynomial regression analysis to describe the sigmoidal PTH-ICa relationship and calculate the set point of calcium as $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% of PTHmax. Successful fits of the individual ICa-PTH data were achieved in each patient ( $r$$r$rr ranging from 0.93 to $0.99,P<0.001$$0.99,P<0.001$0.99,P < 0.0010.99, P<0.001 ).
多项式回归分析（Microsoft Excel 5.0 统计软件包），如其他文献[18]所述。多项式回归分析中使用了四度多项式方程来描述 PTH-ICa 的曲线关系，并以 PTHmax 的 $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% 计算钙的设定点。每位患者的 ICa-PTH 数据都能成功拟合（ $r$$r$rr 从 0.93 到 $0.99,P<0.001$$0.99,P<0.001$0.99,P < 0.0010.99, P<0.001 ）。

PTH was measured by using a two-site immunoradiometric assay (Nichols Institute, Allegro IRMA PTH kit, normal: $10-65\mathrm{pg}/\mathrm{ml}$$10-65\mathrm{pg}/\mathrm{ml}$10-65pg//ml10-65 \mathrm{pg} / \mathrm{ml} ), ICa by using a selective ion electrode (ICA2 Radiometer, normal: $1.15-1.28\mathrm{mmol}/1$$1.15-1.28\mathrm{mmol}/1$1.15-1.28mmol//11.15-1.28 \mathrm{mmol} / 1 ). Parathyroid glands were assessed by measuring the gland size at parathyroidectomy, or by means of high-resolution color Doppler ultrasonography performed with an Acuson XP10ART machine (Acuson Corp, Maintainview, CA) using a 7.5 MHz linear phased array transducer. The volume of each gland was calculated, assuming it to be ellipsoid; thus, the volume of a gland with three-dimensional values of $X,Y$$X,Y$X,YX, Y, and $Z$$Z$ZZ (in cm ) was calculated as $(\mathrm{X}\times \mathrm{Y}\times \mathrm{Z})\times \pi /6$$(\mathrm{X}\times \mathrm{Y}\times \mathrm{Z})\times \pi /6$(XxxYxxZ)xx pi//6(\mathrm{X} \times \mathrm{Y} \times \mathrm{Z}) \times \pi / 6. The volume reported for each patient was the sum of the volumes of the detected glands. In our Institute, the sensitivity and specificity of highresolution ultrasound for detecting enlarged parathyroid glands are 90 and $95\mathrm{\%}$$95\mathrm{\%}$95%95 \%, respectively [19]. Previously [19], we reported a strong correlation $(y=1.08\times +0.17,r=0.91,n=$$(y=1.08\times +0.17,r=0.91,n=$(y=1.08 xx+0.17,r=0.91,n=(y=1.08 \times+0.17, r=0.91, n= 42) between parathyroid gland size determined after surgery (range: $0.01-5.23{\mathrm{cm}}^3$$0.01-5.23{\mathrm{cm}}^3$0.01-5.23cm^(3)0.01-5.23 \mathrm{~cm}^{3} ) and by ultrasonography (range: $0.01-4.96{\mathrm{cm}}^3$$0.01-4.96{\mathrm{cm}}^3$0.01-4.96cm^(3)0.01-4.96 \mathrm{~cm}^{3} ), and documented that ultrasonography was able to detect also small parathyroid glands (the smallest gland measuring $0.4\times 0.3\times 0.2\mathrm{cm}$$0.4\times 0.3\times 0.2\mathrm{cm}$0.4 xx0.3 xx0.2cm0.4 \times 0.3 \times 0.2 \mathrm{~cm}, corresponding to a volume of $0.013{\mathrm{cm}}^3$$0.013{\mathrm{cm}}^3$0.013cm^(3)0.013 \mathrm{~cm}^{3} ).
PTH通过双点免疫放射测定法（Nichols研究所，Allegro IRMA PTH试剂盒，正常值： $10-65\mathrm{pg}/\mathrm{ml}$$10-65\mathrm{pg}/\mathrm{ml}$10-65pg//ml10-65 \mathrm{pg} / \mathrm{ml} ）测量，ICa通过选择性离子电极（ICA2 Radiometer，正常值： $1.15-1.28\mathrm{mmol}/1$$1.15-1.28\mathrm{mmol}/1$1.15-1.28mmol//11.15-1.28 \mathrm{mmol} / 1 ）测量。通过测量甲状旁腺切除术时的腺体大小，或使用Acuson XP10ART机器（Acuson Corp, Maintainview, CA）的7.5 MHz线性相控阵换能器进行高分辨率彩色多普勒超声检查，对甲状旁腺进行评估。计算每个腺体的体积时，假定腺体为椭圆形；因此，腺体的三维值 $X,Y$$X,Y$X,YX, Y 和 $Z$$Z$ZZ （单位：厘米）的体积计算为 $(\mathrm{X}\times \mathrm{Y}\times \mathrm{Z})\times \pi /6$$(\mathrm{X}\times \mathrm{Y}\times \mathrm{Z})\times \pi /6$(XxxYxxZ)xx pi//6(\mathrm{X} \times \mathrm{Y} \times \mathrm{Z}) \times \pi / 6 。每位患者报告的体积是检测到的腺体体积之和。在我院，高分辨率超声检测甲状旁腺肿大的敏感性和特异性分别为90和 $95\mathrm{\%}$$95\mathrm{\%}$95%95 \% [19]。在此之前[19]，我们报道了手术后确定的甲状旁腺大小（范围： $0.01-5.23{\mathrm{cm}}^3$$0.01-5.23{\mathrm{cm}}^3$0.01-5.23cm^(3)0.01-5.23 \mathrm{~cm}^{3} ）与超声波检查（范围： $0.01-4.96{\mathrm{cm}}^3$$0.01-4.96{\mathrm{cm}}^3$0.01-4.96cm^(3)0.01-4.96 \mathrm{~cm}^{3} ）之间的强相关性 $(y=1.08\times +0.17,r=0.91,n=$$(y=1.08\times +0.17,r=0.91,n=$(y=1.08 xx+0.17,r=0.91,n=(y=1.08 \times+0.17, r=0.91, n= 42），并记录了超声波检查也能检测到小的甲状旁腺（最小的腺体大小为 $0.4\times 0.3\times 0.2\mathrm{cm}$$0.4\times 0.3\times 0.2\mathrm{cm}$0.4 xx0.3 xx0.2cm0.4 \times 0.3 \times 0.2 \mathrm{~cm} ，对应的体积为 $0.013{\mathrm{cm}}^3$$0.013{\mathrm{cm}}^3$0.013cm^(3)0.013 \mathrm{~cm}^{3} ）。

Results have been reported as means $\pm$$\pm$+-\pm SD. The data obtained were tested by Student’s $t$$t$tt test for paired or unpaired data and by analysis of variance, as appropriate. Simple linear regression was used to analyse the relationship between the set point of calcium and the slope of the PTH-ICa curve and gland volume, baseline serum ICa and phosphate, baseline PTH, PTHmax and PTHmin. Multiple regression analysis was used to evaluate the factors that could affect the set point of calcium and the slope of the PTH-ICa curve in primary and in secondary HPT. For this analysis baseline serum ICa , baseline PTH , serum phosphate, and parathyroid gland volume (measured by ultrasonography) were considered as independent variables.
结果以平均值 $\pm$$\pm$+-\pm SD报告。对于配对或非配对数据，采用学生 $t$$t$tt 检验，并酌情采用方差分析对所获得的数据进行检验。简单线性回归用于分析钙的设定点和 PTH-ICa 曲线斜率与腺体体积、基线血清 ICa 和磷酸盐、基线 PTH、PTHmax 和 PTHmin 之间的关系。多元回归分析用于评估影响原发性和继发性 HPT 的钙设定点和 PTH-ICa 曲线斜率的因素。在该分析中，基线血清 ICa、基线 PTH、血清磷酸盐和甲状旁腺体积（通过超声波测量）被视为自变量。

The parathyroid secretory parameters of patients with 1-HPT, 2-HPT and 3-HPT compared to normal subjects are reported in Table 2.
与正常人相比，1-HPT、2-HPT 和 3-HPT 患者的甲状旁腺分泌参数见表 2。

The volume of parathyroid adenoma ranged from 0.07 to $8.9{\mathrm{cm}}^3$$8.9{\mathrm{cm}}^3$8.9cm^(3)8.9 \mathrm{~cm}^{3}, the gland weight from 0.05 to 14 g . As expected baseline ICa, baseline PTH, PTHmax, PTHmin, and the serum ICa levels at which maximal and minimal PTH secretion occurred were greater in 1-HPT than in N. Although 1-HPT patients displayed a spectrum of PTH suppressibility, as a group, their minimal PTH secretion induced by hypercalcaemia, evaluated as either absolute value (Table 2) or per cent of maximal PTH secretion (range: $8-51\mathrm{\%}$$8-51\mathrm{\%}$8-51%8-51 \%, mean: $21\pm 12\mathrm{\%}$$21\pm 12\mathrm{\%}$21+-12%21 \pm 12 \% ) was greater than in N (range: $6-13\mathrm{\%}$$6-13\mathrm{\%}$6-13%6-13 \%, mean: $8\pm 2,P<0.001$$8\pm 2,P<0.001$8+-2,P < 0.0018 \pm 2, P<0.001 ) (Figure 1). Moreover, minimal and maximal PTH secretion were achieved at greater ICa levels than in N. Thus, in 1-HPT the PTH-ICa curve, constructed using PTHmax as $100\mathrm{\%}$$100\mathrm{\%}$100%100 \%, was shifted to the right and upward and the set point was increased in comparison to N, as shown in Figure 1, in which the set point of ICa, the serum ICa levels at maximal PTH secretion and inhibition for each individual patient are reported. The set point of ICa (calculated as midpoint) corresponded to a PTH level of $62\pm 8\mathrm{\%}$$62\pm 8\mathrm{\%}$62+-8%62 \pm 8 \% of maximal PTH, compared to $55\pm 3\mathrm{\%}$$55\pm 3\mathrm{\%}$55+-3%55 \pm 3 \% in N $(P<0.001)$$(P<0.001)$(P < 0.001)(P<0.001). The slope of the curve was significantly reduced in 1-HPT ( $298\pm 107\mathrm{\%}$$298\pm 107\mathrm{\%}$298+-107%298 \pm 107 \%, range: $155-438\mathrm{\%}$$155-438\mathrm{\%}$155-438%155-438 \% ) compared to N ( $475\pm 86\mathrm{\%}$$475\pm 86\mathrm{\%}$475+-86%475 \pm 86 \%, range: $335-647\mathrm{\%})$$335-647\mathrm{\%})$335-647%)335-647 \%), suggesting a reduced sensibility of the glands to serum ICa changes.
甲状旁腺腺瘤的体积从0.07到 $8.9{\mathrm{cm}}^3$$8.9{\mathrm{cm}}^3$8.9cm^(3)8.9 \mathrm{~cm}^{3} 不等，腺体重量从0.05到14克不等。不出所料，1-HPT患者的基线ICa、基线PTH、PTHmax、PTHmin以及PTH分泌最大值和最小值的血清ICa水平均高于N型患者。虽然1-HPT患者的PTH抑制能力各不相同，但作为一个群体，他们在高钙血症诱导下的最小PTH分泌量（以绝对值（表2）或最大PTH分泌量的百分比来评估）（范围： $8-51\mathrm{\%}$$8-51\mathrm{\%}$8-51%8-51 \% ，平均： $21\pm 12\mathrm{\%}$$21\pm 12\mathrm{\%}$21+-12%21 \pm 12 \% ）高于N型患者（范围： $6-13\mathrm{\%}$$6-13\mathrm{\%}$6-13%6-13 \% ，平均： $8\pm 2,P<0.001$$8\pm 2,P<0.001$8+-2,P < 0.0018 \pm 2, P<0.001 ）（图1）。因此，在 1-HPT 中，以 PTHmax 为 $100\mathrm{\%}$$100\mathrm{\%}$100%100 \% 构建的 PTH-ICa 曲线与 N 相比向右上移，设定点升高，如图 1 所示，图中报告了每个患者的 ICa 设定点、PTH 最大分泌时的血清 ICa 水平以及抑制情况。ICa 的设定点（按中点计算）对应于最大 PTH $62\pm 8\mathrm{\%}$$62\pm 8\mathrm{\%}$62+-8%62 \pm 8 \% 的 PTH 水平，而 N $(P<0.001)$$(P<0.001)$(P < 0.001)(P<0.001) 的 PTH 水平为 $55\pm 3\mathrm{\%}$$55\pm 3\mathrm{\%}$55+-3%55 \pm 3 \% 。与N（ $475\pm 86\mathrm{\%}$$475\pm 86\mathrm{\%}$475+-86%475 \pm 86 \% ，范围： $335-647\mathrm{\%})$$335-647\mathrm{\%})$335-647%)335-647 \%) ）相比，1-HPT（ $298\pm 107\mathrm{\%}$$298\pm 107\mathrm{\%}$298+-107%298 \pm 107 \% ，范围： $155-438\mathrm{\%}$$155-438\mathrm{\%}$155-438%155-438 \% ）的曲线斜率明显降低： $335-647\mathrm{\%})$$335-647\mathrm{\%})$335-647%)335-647 \%) ，表明腺体对血清 ICa 变化的敏感性降低。
In the five patients treated with pamidronate, baseline serum ICa decreased from $1.45\pm 0.04$$1.45\pm 0.04$1.45+-0.041.45 \pm 0.04 to $1.25\pm 0.06\mathrm{mmol}/\mathrm{l}$$1.25\pm 0.06\mathrm{mmol}/\mathrm{l}$1.25+-0.06mmol//l1.25 \pm 0.06 \mathrm{mmol} / \mathrm{l}. The reduction of serum ICa stimulated parathyroid gland and induced a significant increase in baseline PTH and maximal PTH secretion (Table 3). The modifications of minimal PTH (as either absolute value or per cent of PTHmax) were not significant. The ICa concentrations at maximal PTH secretion and inhibition decreased. As a consequence of these secretory parameter changes, a leftward shift of the PTH-ICa curve and a reduction of the set point of ICa were observed in these five patients after the reduction in serum ICa levels. The decrease in the set point of ICa was directly correlated with the decrease in baseline serum ICa ( $\mathrm{y}=0.9\times +0.26,r=$$\mathrm{y}=0.9\times +0.26,r=$y=0.9 xx+0.26,r=\mathrm{y}=0.9 \times+0.26, r= $0.82,P<0.05$$0.82,P<0.05$0.82,P < 0.050.82, P<0.05 ). The effect of serum ICa reduction on the sigmoidal PTH-ICa curve in one of our patients is reported in Figure 2. Figure 3 shows the shift to the left of the composite regression line between probit PTH and ICa , after reduction of baseline serum ICa in the five patients treated with pamidronate. The set point of ICa, calculated after probit transformation of per cent PTH secretion, decreased from $1.42\pm 0.05$$1.42\pm 0.05$1.42+-0.051.42 \pm 0.05 to $1.19\pm 0.07\mathrm{mmol}/1(P<0.05)$$1.19\pm 0.07\mathrm{mmol}/1(P<0.05)$1.19+-0.07mmol//1(P < 0.05)1.19 \pm 0.07 \mathrm{mmol} / 1(P<0.05) after normalization of basal serum ICa.
在接受帕米膦酸钠治疗的五名患者中，基线血清ICa从 $1.45\pm 0.04$$1.45\pm 0.04$1.45+-0.041.45 \pm 0.04 降至 $1.25\pm 0.06\mathrm{mmol}/\mathrm{l}$$1.25\pm 0.06\mathrm{mmol}/\mathrm{l}$1.25+-0.06mmol//l1.25 \pm 0.06 \mathrm{mmol} / \mathrm{l} 。血清 ICa 的降低刺激了甲状旁腺，导致基线 PTH 和最大 PTH 分泌显著增加（表 3）。最小 PTH 的变化（绝对值或 PTHmax 的百分比）并不显著。最大 PTH 分泌和抑制时的 ICa 浓度下降。由于这些分泌参数的变化，这五名患者在血清 ICa 水平降低后，PTH-ICa 曲线左移，ICa 设定点降低。ICa 设定点的降低与基线血清 ICa 的降低直接相关（ $\mathrm{y}=0.9\times +0.26,r=$$\mathrm{y}=0.9\times +0.26,r=$y=0.9 xx+0.26,r=\mathrm{y}=0.9 \times+0.26, r= $0.82,P<0.05$$0.82,P<0.05$0.82,P < 0.050.82, P<0.05 ）。图 2 报告了血清 ICa 下降对我们其中一名患者的 PTH-ICa 曲线的影响。图 3 显示了帕米膦酸钠治疗的五名患者在降低基线血清 ICa 后，probit PTH 与 ICa 之间的复合回归线向左移动的情况。基础血清 ICa 正常化后，经过 PTH 分泌百分比 probit 转换计算得出的 ICa 设定点从 $1.42\pm 0.05$$1.42\pm 0.05$1.42+-0.051.42 \pm 0.05 降至 $1.19\pm 0.07\mathrm{mmol}/1(P<0.05)$$1.19\pm 0.07\mathrm{mmol}/1(P<0.05)$1.19+-0.07mmol//1(P < 0.05)1.19 \pm 0.07 \mathrm{mmol} / 1(P<0.05) 。

Table 2. PTH secretory parameters
表 2.PTH 分泌参数

PTHmax $=$$=$== maximal PTH secretion induced by hypocalcaemia; PTHmin $=$$=$== minimal PTH secretion induced by hypercalcaemia; PTH $\mathrm{\%}=$$\mathrm{\%}=$%=\%= baseline PTH secretion as a per cent of PTHmax; PTHmin $\mathrm{\%}=$$\mathrm{\%}=$%=\%= minimal PTH secretion as a per cent of PTHmax; set point $50=$$50=$50=50= ICa level at which maximal PTH secretion is reduced by $50\mathrm{\%}$$50\mathrm{\%}$50%50 \%; set point mid $=\mathrm{ICa}$$=\mathrm{ICa}$=ICa=\mathrm{ICa} level at midrange between PTHmax and PTHmin; ICamax and ICamin $=\mathrm{ICa}$$=\mathrm{ICa}$=ICa=\mathrm{ICa} level at PTHmax and PTHmin.
PTHmax $=$$=$== 由低钙血症引起的最大 PTH 分泌；PTHmin $=$$=$== 由高钙血症引起的最小 PTH 分泌；PTH $\mathrm{\%}=$$\mathrm{\%}=$%=\%= 基线 PTH 分泌占 PTHmax 的百分比；PTHmin $\mathrm{\%}=$$\mathrm{\%}=$%=\%= 最小 PTH 分泌占 PTHmax 的百分比；设定点 $50=$$50=$50=50= 最大 PTH 分泌减少 $50\mathrm{\%}$$50\mathrm{\%}$50%50 \% 的 ICa 水平；设定点中间值 $=\mathrm{ICa}$$=\mathrm{ICa}$=ICa=\mathrm{ICa} PTHmax 和 PTHmin 之间的中间值；ICamax 和 ICamin $=\mathrm{ICa}$$=\mathrm{ICa}$=ICa=\mathrm{ICa} PTHmax 和 PTHmin 的水平。
${}^{\mathrm{a}}=P<0.001$${}^{\mathrm{a}}=P<0.001$^(a)=P < 0.001{ }^{\mathrm{a}}=P<0.001 vs N and 2-HPT; ${}^{\mathrm{b}}=P<0.001$${}^{\mathrm{b}}=P<0.001$^(b)=P < 0.001{ }^{\mathrm{b}}=P<0.001 among the groups; ${}^{\mathrm{c}}=P<0.001$${}^{\mathrm{c}}=P<0.001$^(c)=P < 0.001{ }^{\mathrm{c}}=P<0.001 and ${}^{\mathrm{d}}=<0.05$${}^{\mathrm{d}}=<0.05$^(d)=<0.05^{\mathrm{d}}=<0.05 vs 3-HPT; ${}^{\mathrm{e}}=P<0.001$${}^{\mathrm{e}}=P<0.001$^(e)=P < 0.001{ }^{\mathrm{e}}=P<0.001 and ${}^{\mathrm{f}}=P<0.05\mathrm{vs}\mathrm{N}$${}^{\mathrm{f}}=P<0.05\mathrm{vs}\mathrm{N}$^(f)=P < 0.05vsN{ }^{\mathrm{f}}=P<0.05 \mathrm{vs} \mathrm{N}; ${}^{\mathrm{g}}=P<0.001$${}^{\mathrm{g}}=P<0.001$^(g)=P < 0.001{ }^{\mathrm{g}}=P<0.001 vs 2-HPT; ${}^{\mathrm{h}}=P<0.001$${}^{\mathrm{h}}=P<0.001$^(h)=P < 0.001{ }^{\mathrm{h}}=P<0.001 vs 2-HPT and 3-HPT.
${}^{\mathrm{a}}=P<0.001$${}^{\mathrm{a}}=P<0.001$^(a)=P < 0.001{ }^{\mathrm{a}}=P<0.001 对 N 和 2-HPT； ${}^{\mathrm{b}}=P<0.001$${}^{\mathrm{b}}=P<0.001$^(b)=P < 0.001{ }^{\mathrm{b}}=P<0.001 组间； ${}^{\mathrm{c}}=P<0.001$${}^{\mathrm{c}}=P<0.001$^(c)=P < 0.001{ }^{\mathrm{c}}=P<0.001 和 ${}^{\mathrm{d}}=<0.05$${}^{\mathrm{d}}=<0.05$^(d)=<0.05^{\mathrm{d}}=<0.05 对 3-HPT； ${}^{\mathrm{e}}=P<0.001$${}^{\mathrm{e}}=P<0.001$^(e)=P < 0.001{ }^{\mathrm{e}}=P<0.001 和 ${}^{\mathrm{f}}=P<0.05\mathrm{vs}\mathrm{N}$${}^{\mathrm{f}}=P<0.05\mathrm{vs}\mathrm{N}$^(f)=P < 0.05vsN{ }^{\mathrm{f}}=P<0.05 \mathrm{vs} \mathrm{N} ； ${}^{\mathrm{g}}=P<0.001$${}^{\mathrm{g}}=P<0.001$^(g)=P < 0.001{ }^{\mathrm{g}}=P<0.001 对 2-HPT； ${}^{\mathrm{h}}=P<0.001$${}^{\mathrm{h}}=P<0.001$^(h)=P < 0.001{ }^{\mathrm{h}}=P<0.001 对 2-HPT 和 3-HPT。