Clinical Characteristics and Risk Factors of Normocalcemic Primary Hyperparathyroidism

doi:10.12114/j.issn.1007-9572.2022.0712

Chinese General Practice ›› 2023, Vol. 26 ›› Issue (11): 1369-1374.DOI: 10.12114/j.issn.1007-9572.2022.0712

• Original Research • Previous Articles Next Articles

Clinical Characteristics and Risk Factors of Normocalcemic Primary Hyperparathyroidism

1. Department of Endocrinology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
2. Department of Thyroid Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China

Received:2022-07-20 Revised:2022-12-20 Published:2023-04-15 Online:2023-02-01
Contact: SHEN Shanmei
About author:
HUANG Z Y, SU L, SANG J F, et al. Clinical characteristics and risk factors of normocalcemic primary hyperparathyroidism [J]. Chinese General Practice, 2023, 26 (11): 1369-1374.

正常血钙型原发性甲状旁腺功能亢进症的临床特征及影响因素研究

1．210008　江苏省南京市，南京大学医学院附属鼓楼医院内分泌科
2．210008　江苏省南京市，南京大学医学院附属鼓楼医院甲状腺外科

通讯作者: 沈山梅
作者简介:
黄泽宇，苏磊，桑剑锋，等.正常血钙型原发性甲状旁腺功能亢进症的临床特征及影响因素研究[J].中国全科医学，2023，26（11）：1369-1374. [www.chinagp.net]
作者贡献：黄泽宇分析资料、起草论文、统计分析并对论文整体负责；苏磊、桑剑锋实施研究并提供技术和材料支持；赵茹、韩晨、王茜选取研究对象并采集数据；顾天伟、毕艳、朱大龙指导论文并提供资助；沈山梅负责审核究结果、指导修改论文，负责最终版本修订并对论文整体负责。
基金资助:
国家自然科学基金重点项目(82030026)

Abstract

Abstract:

Background

Normocalcemic primary hyperparathyroidism (NCPHPT), as a new phenotype of primary hyperparathyroidism (PHPT), has gained increasing attention. NCPHPT is easily misdiagnosed in clinical practice, and its risk factors need to be evaluated further.

Objective

To investigate the clinical features of NCPHPT and to explore its risk factors.

Methods

Patients diagnosed with PHPT (n=153) were retrospectively selected from Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from January 2016 to December 2021, and divided into an experimental group (NCPHPT group) and a hypercalcemia PHPT group according to the corrected total serum calcium level. Meanwhile, individuals undergoing physical examination with normal parathyroid function were selected as the control group. The differences in clinical characteristics, glucose and bone metabolism, imaging and pathology results among the groups were compared. Multivariate Logistic regression analysis was used to analyze the risk factors of NCPHPT.

Results

The number of cases in NCPHPT, hypercalcemia PHPT and control groups was 36, 117 and 50, respectively. For biochemical indices, compared with healthy control group, the levels of alkaline phosphatase (AKP), uric acid (UA), and parathyroid hormone (PTH) were much higher in NCPHPT group, while serum phosphorus was much lower (P<0.05). Compared with hypercalcemia PHPT group, the NCPHPT group had notably lower levels of serum calcium, AKP, serum creatinine (Scr), UA and PTH, and significantly higher serum phosphorus level and estimated glomerular filtration rate (eGFR) (P<0.05). In terms of glucose metabolism, the glycated hemoglobin (HbA_1c), and insulin resistance index (HOMA-IR) in NCPHPT group were much higher than those in the control group (P<0.05), the FPG, fasting insulin (FIns) and HOMA-IR in hypercalcemia PHPT were much higher than that in control group (P<0.05). In terms of bone metabolism indices and bone mineral density, the NCPHPT group had much higher levels of P1NP, serum β-crosslaps (β-CTX), osteocalcin (OC) and calcitonin (CT), and obviously lower bone mineral density of the L_1-4 lumbar vertebrae and femoral neck than the control group (P<0.05). Compared with hypercalcemia PHPT group, the levels of P1NP, β-CTX, OC and CT were much lower while the bone mineral density of femoral neck was much higher in the NCPHPT group (P<0.05). Parathyroid occupying lesions in both the NCPHPT group and the hypercalcemia PHPT group were more prevalent in the lower pole. There was no statistically significant difference in diameter, location and ectopia between the NCPHPT group and the hypercalcemia PHPT group (P<0.05). The rate of multiglandular lesions was higher in the NCPHPT group than the hypercalcemia PHPT group (P<0.05). There was no statistically significant difference between the two groups when comparing the types of pathology (χ²=8.556, P>0.05). Multivariate Logistic regression analysis showed that urolithiasis〔OR=2.462, 95%CI (1.178, 3.552), P=0.011〕, decreased serum phosphorus〔OR=0.027, 95%CI (0.001, 0.711), P=0.031〕and increased AKP〔OR=2.809, 95%CI (1.422, 8.020), P=0.037〕were relevant factors for NCPHPT.

Conclusion

Patients with NCPHPT have many clinical symptoms such as elevated blood pressure, abnormal glucose metabolism, abnormal bone mineral density and urolithiasis. The presence of urolithiasis, hypophosphatemia and increased AKP indicates the possible existence of NCPHPT, which can be used for early Screening of NCPHPT to reduce the misdiagnosis rate.

Key words: Hyperparathyroidism, primary, Normocalcemic primary hyperparathyroidism, Bone metabolism, Glucose metabolism disorders, Root cause analysis, Disease attributes

摘要：

背景

正常血钙型原发性甲状旁腺功能亢进症（NCPHPT）作为原发性甲状旁腺功能亢进症（PHPT）的一种新类型近年来逐渐受到重视，该类型在临床中易被误诊，其相关影响因素也有待探究。

目的

分析NCPHPT的临床特征，探讨发生NCPHPT的影响因素。

方法

回顾性选取2016年1月至2021年12月在南京大学医学院附属鼓楼医院确诊为PHPT的患者153例，根据校正血钙水平分为正常血钙组和高钙组；并以同期行健康体检且甲状旁腺功能正常者作为健康对照组。比较生化指标、糖代谢、骨代谢、影像学及病理学在不同组间的差异，采用多因素Logistic回归分析探究发生NCPHPT的影响因素。

结果

153例PHPT患者中正常血钙组36例、高钙组117例，健康对照组50例。在生化指标方面，与健康对照组相比，正常血钙组患者的碱性磷酸酶（AKP）、尿酸（UA）、甲状旁腺激素（PTH）水平升高，血磷降低（P<0.05）；与高钙组相比，正常血钙组患者血钙、AKP、血肌酐（Scr）、UA、PTH降低，血磷及估算肾小球滤过率（eGFR）升高（P<0.05）。在糖代谢方面，与健康对照组相比，正常血钙组的糖化血红蛋白（HbA_1c）、胰岛素抵抗指数（HOMA-IR）升高（P<0.05），高钙组空腹血糖（FPG）、空腹胰岛素（FIns）、HOMA-IR升高（P<0.05）。在骨代谢指标及骨密度方面，正常血钙组的Ⅰ型前胶原氨基端延长肽（P1NP）、Ⅰ型前胶原C端肽β降解产物（β-CTX）、骨钙素（OC）、降钙素（CT）较健康对照组高，第1腰椎~第4腰椎（L_1~4）及股骨颈密度较健康对照组降低（P<0.05）；与高钙组相比，正常血钙组的P1NP、β-CTX、OC、CT均降低，股骨颈密度升高（P<0.05）。正常血钙组及高钙组甲状旁腺占位均好发于下极。正常血钙组和高钙组病变的直径、位置和异位情况比较，差异无统计学意义（P>0.05）；正常血钙组多腺体病变率高于高钙组（P<0.05）；两组病理类型比较，差异无统计学意义（χ²=8.556，P>0.05）。多因素Logistic回归分析显示合并泌尿系结石〔OR=2.462，95%CI（1.178，3.552），P=0.011〕、低血磷〔OR=0.027，95%CI（0.001，0.711），P=0.031〕和高AKP〔OR=2.809，95%CI（1.422，8.020），P=0.037〕是发生NCPHPT的危险因素。

结论

NCPHPT患者存在血压升高、糖代谢紊乱、骨密度异常以及泌尿系统结石等临床症状，合并泌尿系结石、低血磷和高AKP提示存在发生NCPHPT的风险，临床上可应用于NCPHPT的早期筛查，降低误诊率。

关键词: 甲状旁腺功能亢进，原发性, 正常血钙型原发性甲状旁腺功能亢进症, 骨代谢, 葡萄糖代谢障碍, 影响因素分析, 疾病特征

HUANG Zeyu,SU Lei,SANG Jianfeng, et al. Clinical Characteristics and Risk Factors of Normocalcemic Primary Hyperparathyroidism[J]. Chinese General Practice, 2023, 26(11): 1369-1374. DOI: 10.12114/j.issn.1007-9572.2022.0712.
黄泽宇,苏磊,桑剑锋等. 正常血钙型原发性甲状旁腺功能亢进症的临床特征及影响因素研究[J]. 中国全科医学, 2023, 26(11): 1369-1374. DOI: 10.12114/j.issn.1007-9572.2022.0712.

Figures/Tables 5

References 24

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组别	例数	一般资料					生化指标
组别	例数	性别（男/女）	年龄（岁）	BMI （kg/m²）	收缩压（mm Hg）	舒张压（mm Hg）	血钙（mmol/L）	血磷（mmol/L）	血钾（mmol/L）	AKP （U/L）	Scr （μmol/L）	eGFR 〔ml·min^-1·（1.73 m²）^-1〕	UA （μmol/L）	PTH （pmol/L）
健康对照组	50	22/28	46.9±15.4	24.1±4.1	123±19	77±8	2.42±0.19	1.03±0.16	3.93±0.19	65.9±19.6	55.4±15.7	129.8±30.0	98.2±73.1	5.2±1.7
正常血钙组	36	12/24	51.5±14.1	24.2±3.4	133±20^a	83±8^a	2.62±0.12	0.84±0.19^a	4.02±0.23	105.7±68.9^a	56.5±13.8	118.1±33.1	332.1±86.4^a	33.0±26.2^a
高钙组	117	34/83	52.5±15.8	23.6±3.8	130±20	86±12	3.08±0.30^b	0.71±0.18^ab	4.15±1.47	265.3±88.5^ab	76.9±43.9^ab	104.1±40.1^b	396.8±123.4^ab	58.8±47.6^ab
F（χ²）值		3.510^c	2.339	0.908	3.183	12.860	136.282	57.740	0.715	154.204	9.417	9.074	137.272	36.150
P值		0.173	0.100	0.602	0.044	<0.001	<0.001	<0.001	0.490	<0.001	<0.001	0.002	<0.001	<0.001
组别	糖代谢指标				骨代谢指标				骨密度（g/cm³）
组别	HbA_1c（%）	FPG（mmol/L）	FIns（μU/ml）	HOMA-IR	P1NP（μg/L）	β-CTX（μg/L）	OC（μg/L）	CT（ng/L）	L_1~4	股骨颈
健康对照组	5.27±1.42	4.79±0.65	10.12±6.31	2.18±1.84	59.73±34.73	0.51±0.27	17.11±5.61	2.00±0.70	1.23±0.12	1.01±0.13
正常血钙组	5.72±0.15^a	5.13±0.81	12.87±8.24	5.83±2.09^a	82.40±29.40^a	0.97±0.36^a	46.28±23.95^a	4.59±2.89^a	0.93±0.16^a	0.95±0.12^a
高钙组	5.46±0.32	5.31±1.52^a	16.12±10.83^a	6.08±3.00^a	171.39±38.52^ab	1.50±0.92^ab	77.28±33.30^ab	4.93±2.93^a	0.87±0.11^a	0.72±0.10^ab
F（χ²）值	3.802	3.045	7.402	40.930	201.000	33.823	87.733	23.579	145.263	142.226
P值	0.024	0.050	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001

组别	例数	一般资料					生化指标
组别	例数	性别（男/女）	年龄（岁）	BMI （kg/m²）	收缩压（mm Hg）	舒张压（mm Hg）	血钙（mmol/L）	血磷（mmol/L）	血钾（mmol/L）	AKP （U/L）	Scr （μmol/L）	eGFR 〔ml·min^-1·（1.73 m²）^-1〕	UA （μmol/L）	PTH （pmol/L）
健康对照组	50	22/28	46.9±15.4	24.1±4.1	123±19	77±8	2.42±0.19	1.03±0.16	3.93±0.19	65.9±19.6	55.4±15.7	129.8±30.0	98.2±73.1	5.2±1.7
正常血钙组	36	12/24	51.5±14.1	24.2±3.4	133±20^a	83±8^a	2.62±0.12	0.84±0.19^a	4.02±0.23	105.7±68.9^a	56.5±13.8	118.1±33.1	332.1±86.4^a	33.0±26.2^a
高钙组	117	34/83	52.5±15.8	23.6±3.8	130±20	86±12	3.08±0.30^b	0.71±0.18^ab	4.15±1.47	265.3±88.5^ab	76.9±43.9^ab	104.1±40.1^b	396.8±123.4^ab	58.8±47.6^ab
F（χ²）值		3.510^c	2.339	0.908	3.183	12.860	136.282	57.740	0.715	154.204	9.417	9.074	137.272	36.150
P值		0.173	0.100	0.602	0.044	<0.001	<0.001	<0.001	0.490	<0.001	<0.001	0.002	<0.001	<0.001
组别	糖代谢指标				骨代谢指标				骨密度（g/cm³）
组别	HbA_1c（%）	FPG（mmol/L）	FIns（μU/ml）	HOMA-IR	P1NP（μg/L）	β-CTX（μg/L）	OC（μg/L）	CT（ng/L）	L_1~4	股骨颈
健康对照组	5.27±1.42	4.79±0.65	10.12±6.31	2.18±1.84	59.73±34.73	0.51±0.27	17.11±5.61	2.00±0.70	1.23±0.12	1.01±0.13
正常血钙组	5.72±0.15^a	5.13±0.81	12.87±8.24	5.83±2.09^a	82.40±29.40^a	0.97±0.36^a	46.28±23.95^a	4.59±2.89^a	0.93±0.16^a	0.95±0.12^a
高钙组	5.46±0.32	5.31±1.52^a	16.12±10.83^a	6.08±3.00^a	171.39±38.52^ab	1.50±0.92^ab	77.28±33.30^ab	4.93±2.93^a	0.87±0.11^a	0.72±0.10^ab
F（χ²）值	3.802	3.045	7.402	40.930	201.000	33.823	87.733	23.579	145.263	142.226
P值	0.024	0.050	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001

组别	例数	直径（cm）	左侧/右侧	上极/下极	异位〔n（%）〕	多腺体病变〔n（%）〕
正常血钙组	36	2.06±1.00	25/15	11/29	0	4（11.11）
高钙组	117	2.23±1.04	52/61	34/79	4（3.42）	0
t（χ²）值		-0.979	3.210^a	0.095^a	—	—
P值		0.329	0.073	0.757	0.573	0.004

组别	例数	直径（cm）	左侧/右侧	上极/下极	异位〔n（%）〕	多腺体病变〔n（%）〕
正常血钙组	36	2.06±1.00	25/15	11/29	0	4（11.11）
高钙组	117	2.23±1.04	52/61	34/79	4（3.42）	0
t（χ²）值		-0.979	3.210^a	0.095^a	—	—
P值		0.329	0.073	0.757	0.573	0.004

组别	例数	腺瘤	腺癌	增生	侵犯包膜	细胞异型性
正常血钙组	36	34（94.44）	0	2（5.56）	0	1（2.78）
高钙组	117	104（88.89）	3（2.56）	10（8.55）	15（12.82）	16（13.68）

Clinical Characteristics and Risk Factors of Normocalcemic Primary Hyperparathyroidism

正常血钙型原发性甲状旁腺功能亢进症的临床特征及影响因素研究

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自变量	变量名	赋值
性别	X1	男=1，女=2
年龄（岁）	X2	≤40=1，40~49=2，50~59=3，≥60=4
BMI（kg/m²）	X3	<18.5=1，18.5~23.9=2，24.0~27.9=3，≥28=4
高血压病史	X4	是=1，否=2
合并泌尿系结石	X5	是=1，否=2
合并骨密度异常	X6	骨量减少=1，骨质疏松=2，骨量正常=3
血钙（mmol/L）	X7	≤2.75=1，>2.75=2
血磷（mmol/L）	X8	<0.96=1，0.96~1.62=2，>1.62=3
血钾（mmol/L）	X9	<3.5=1，3.5~5.5=2，>5.5=3
AKP（U/L）	X10	≤185=1，>185=2
Scr（μmol/L）	X11	≤106=1，>106=2
eGFR〔ml·min^-1·（1.73 m²）^-1〕	X12	60~90=1，>90=2
UA （μmol/L）	X13	≤420=1，>420=2
HbA_1c（%）	X14	≤6=1，6.1~6.4=2，≥6.5=3
FPG （mmol/L）	X15	<6.1=1，6.1~6.9=2，≥7.0=3
P1NP （μg/L）	X16	实测值
β-CTX（μg/L）	X17	实测值
OC （μg/L）	X18	≤70=1，>70=2
CT （ng/L）	X19	<2=1，≥2=2

自变量	B	SE	Wald χ²值	P值	OR（95%CI）
合并泌尿系结石	0.901	0.243	13.744	0.011	2.462（1.178，3.552）
骨密度异常	-0.916	0.477	3.686	0.055	0.400（0.157，1.019）
血磷	-3.612	1.021	12.510	0.031	0.027（0.001，0.711）
AKP	1.033	0.312	10.958	0.037	2.809（1.422，8.020）
Scr	0.021	0.010	4.041	0.054	1.021（1.001，1.042）
UA	0.068	0.120	0.327	0.567	1.071（0.827，1.354）
OC	0.013	0.022	0.346	0.556	1.013（0.970，1.058）
CT	0.092	0.208	0.194	0.659	1.096（0.719，1.647）

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