背景：原发性甲状旁腺功能亢进是一种甲状旁腺激素分泌异常升高的内分泌疾病，可导致包括骨骼系统在内的多系统病变。甲状旁腺切除术是最为有效的干预措施，在术后各系统症状得以缓解。西方国家实验室筛查较为普及，甲状旁腺功能亢进得以早期诊断，以无症状型为主。然而，在我国甲状旁腺功能亢进多为症状型，可出现骨代谢异常等多种骨骼受累表现，给患者带来巨大身体和经济负担。然而，既往研究多针对无症状型甲状旁腺功能亢进，对症状型甲状旁腺功能亢进导致的骨代谢异常研究相对较少。

目的：本文纳入就诊于我院症状型甲状旁腺功能亢进患者，并在甲状旁腺切除术后对骨代谢情况进行三年随访记录。分析甲状旁腺功能亢进患者基线数据特点；基线资料与骨密度和骨生化指标关系，并对手术干预后骨密度改善特点及骨生化指标变化情况进行研究。

方法：本研究纳入2010年1月至2015年12月就诊于我院并接受病变甲状旁腺切除手术的甲状旁腺功能亢进患者，患者在接受甲状旁腺切除术后进行36个月随访记录。搜集患者入院后基线资料，测定I型胶原羧基端肽β特殊序列（β-CTX）、总I型前胶原氨基端延长肽（P1NP）、N-端骨钙素（OC）等反映骨吸收、骨生成代谢指标。在患者入院前和甲状旁腺切除术后6个月、1年、2年、3年使用双能X线骨密度测量法（DXA）测量骨密度，并在同样时间段测定实验室生化指标。通过箱式图对骨密度、骨生化指标与基线数据的相关性进行分析。观察术后骨密度及骨生化指标的变化特点，采用单因素和多因素logistic回归，分析基线资料与患者术后骨密度改善之间的关联。

结果：本研究共纳入105例患者，平均年龄46.37岁，女性65人占多数（62%），合并骨痛（67%）、骨质疏松（73%）、泌尿系结石（34%）等多系统症状。甲状旁腺功能亢进患者腰椎腰1-4（0.82±0.22 g/cm²）、全髋（0.65±0.20 g/cm²）等部位骨密度较正常值明显降低，P1NP（456.86±442.20 ng/ml）、β-CTX（1.94±1.47 ng/ml）、OC（159.42±108.22 ng/ml）等骨代谢标志物浓度较正常范围显著异常。

甲状旁腺切除术后单因素logistic回归分析显示高血压（比值比[OR]：0.032；95%置信区间[CI]：0.001-0.475：P=0.012），甲状旁腺激素水平（比值比[OR]：1.006；95%置信区间[CI]：1.004-1.009；P=0.044）与术后骨密度增加具有相关性。然而，在调整潜在混杂因素后，这些结果并不显著。此外，L1-L4、股骨颈、全髋部位骨密度在术后12个月明显升高，分别为1.13±0.21 g/cm²、0.90±0.20 g/cm²、0.88±0.20 g/cm²，在甲状旁腺切除术前、后差异有统计学意义(P < 0.05)。术前升高的骨生化指标甲状旁腺激素（1053.44±1068.37 pg/ml）、碱性磷酸酶（554.32±663.85 mmol/L）、钙（2.89±0.35 mmol/L）下降至甲状旁腺激素（80.22±68.16 pg/ml）、碱性磷酸酶（104.18±64.86 mmol/L）、钙（2.25±0.22 mmol/L），差异有统计学意义（P < 0.05）。

结论：本研究表明，症状型甲状旁腺功能亢进以女性为主，患者各部位骨密度普遍降低，且以皮质骨为主的髋部下降最为明显。此外，患者骨代谢指标往往异常，预示骨转化活动加强；甲状旁腺切除术后各部位骨密度增加，术后2年内增加明显，在第3年增加趋势有所放缓。同时，手术干预后骨生化标志物浓度逐步恢复，骨形成过程加强。

Background: Primary hyperparathyroidism is an endocrine disease which the secretion of parathyroid hormone is abnormally increased. It can lead to multiple system diseases affecting the skeletal system. Parathyroidectomy is the most effective intervention, and symptoms of various systems can be relieved after the surgery. In Western countries, with the  popularization of laboratory screening, early diagnosis has been achieved. Therefore, the asymptomatic hyperparathyroidism is much more commonly found. However, in our country, it is mostly symptomatic hyperparathyroidism, which may have manifestations about skeletal involvement such as abnormal bone metabolism, and it is difficult to make a clear clinical diagnosis. Studies on abnormal bone metabolism caused by patients with symptomatic hyperparathyroidism are relatively rare.

Purpose: This article mainly talks about patients with hyperparathyroidism in our hospital, and followed up on bone metabolism for three years after parathyroidectomy. The author tries to observe the characteristics of baseline data of patients with hyperparathyroidism, and study the improvement degree of bone mineral density and changes in bone biochemical indicators after surgical intervention.

Methods: Data of patients undertaken parathyroidectomy for primary hyperparathyroidism admitted to our hospital from January 2010 to December 2015 were collected. The patients was followed up for 36 months after parathyroidectomy. After admission, patients’ baseline data were collected. The data about C-terminal cross-linking telopeptides of type I collagen (CTX), total type I procollagen amino-terminal extension peptide (P1NP), N-terminal osteocalcin (OC), and etc. were indicators reflecting bone resorption and osteogenesis metabolism. Dual-energy X-ray bone mineral density measurement (DXA) and the biochemical issues above were taken to measure bone mineral density before admission and at 6month, 1year, 2 years, 3 years follow-up after 

 

parathyroidectomy. We analyzed the correlation between bone mineral density, bone biochemical indexes and baseline data through box plots, and observe the characteristics of postoperative change  of bone mineral density and bone biochemical indexes. Analyzed the relationship between parathyroid hormone level and postoperative improvement of bone mineral density, with the confounding factors adjusted by multi-factor logistic regression.

Results: A total of 105 patients were enrolled in this study, with an average age of 46.37 years old. Women accounted for 62%. These patients usually had multiple system symptoms such as bone pain (67%), osteoporosis (73%), and urinary calculi (34%). In patients with hyperparathyroidism, the bone mineral density of lumbar spine (0.82±0.22 g/cm2) and hip (0.65±0.20 g/cm2) was significantly reduced while P1NP (456.86±442.20 ng/ml), β-CTX (1.94±1.47) ng/ml), OC (159.42±108.22 ng/ml) and other bone metabolism markers concentrations were significantly abnormal.

Single factor logistic regression analysis showed hypertension (odds ratio [OR]: 0.032; 95% confidence interval [CI]: 0.001-0.475; P =0.012), parathyroid hormone levels (odds ratio [OR]: 1.006; 95% confidence interval [CI]: 1.004—-1.009; P = 0.044) were correlated with the increase of bone mineral density postoperatively. However, after adjusting potential confounding factors, these outcomes were not significant. In addition, there was a statistically significant increase in bone mineral density of L1-L4, femoral neck and the total hip to 1.13±0.21 g/cm2、0.90±0.20 g/cm2、0.88±0.20 g/cm2 after parathyroidectomy (P <0.05). The biochemical characters of PTH (1053.44±1068.37 pg/ml), ALP (554.32±663.85 mmol/L), calcium (2.89±0.35 mmol/L) that were elevated before surgery decreased postoperatively to 80.22±68.16 pg/ml (PTH), 104.18±64.86 mmol/L (ALP), 2.25±0.22 mmol/L (calcium), the difference was statistically significant (P <0.05).

Conclusions: This study shows that the majority of patients with hyperparathyroidism are women, and the bone density is generally reduced. Meanwhile, the hip, which is mainly cortical bone, presented with the most significant decrease. In addition, abnormal bone metabolic indicators indicate a significant increase in bone transformation activity. The bone density of various parts after parathyroidectomy increased significantly in the first 2 years, and this trend slowed down in the third year. At the same time, the concentration of bone biochemical markers gradually returned to normal level after surgical intervention, and the bone formation process was strengthened.

目录
第一章 文献综述 1
1.1 背景 1
1.2 甲状旁腺的解剖特点 1
1.3 甲状旁腺功能亢进流行病学特点变迁 2
1.4 甲状旁腺功能亢进多系统临床表现 3
1.5 甲状旁腺功能亢进骨代谢指标及影像学表现 5
1.5.1 骨代谢指标检查 5
1.5.2 骨骼系统异常影像学评估 10
1.6 甲状旁腺功能亢进的临床管理 14
1.7 讨论 16
第二章 引言 18
2.1 科学问题 18
2.2 研究内容 19
第三章 对象与方法 20
3.1 研究设计 20
3.2 研究对象 20
3.3 临床基线数据 20
3.4 骨生化和骨密度资料搜集 21
3.5 统计分析 21
第四章 结果 22
4.1 研究对象基线数据分析 22
4.2 甲状旁腺功能亢进患者骨密度与基线数据相关性分析 23
4.3 甲状旁腺切除术后骨密度改善情况研究 28
4.4 甲状旁腺功能亢进患者骨生化指标与基线数据相关性分析 34
4.5 甲状旁腺切除术后骨生化指标变化情况研究 42
第五章 讨论 46
第六章 结论与展望 52
参考文献 53
附录 62
致谢 71


北京大学学位论文原创性声明和使用授权说明 72
个人简历、在学期间发表的学术论文与研究成果 73

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