肾上腺性库欣综合征与无功能腺瘤患者的凝血功能比较及其影响因素

doi:10.19723/j.issn.1671-167X.2023.06.017

摘要/Abstract

摘要：

目的: 总结肾上腺性库欣综合征(Cushing syndrome, CS)患者凝血功能相关指标的特点, 为临床更好地识别肾上腺性CS的高凝状态, 预防并发症, 提供理论依据。方法: 本研究为回顾性研究, 在北京大学第一医院住院电子病历系统中检索2014年1月至2019年6月出院诊断为肾上腺性CS患者的病历资料, 以体重指数、性别、出院时间匹配的肾上腺无功能腺瘤患者为对照, 比较两组患者的临床特点及凝血功能的相关指标。结果: 肾上腺性CS组活化部分凝血活酶时间(activated partial thromboplastin time, APTT)、凝血酶原时间(prothrombin time, PT)均较对照组显著缩短[(29.22±3.39) s vs. (31.86±3.63) s, P < 0.001;(10.67±1.08) s vs. (10.96±0.84) s, P=0.008], D-二聚体与纤维蛋白降解产物(fibrin degradation products, FDP)水平均显著升高。血清皮质醇节律的曲线下面积与PT、APTT呈显著负相关, 与FDP、D-二聚体水平呈显著正相关。Logistic回归分析提示, 皮质醇曲线下面积增大、糖化血红蛋白升高是CS患者发生高凝的独立危险因素(P < 0.05)。结论: 肾上腺性CS患者较无功能肾上腺腺瘤患者更易出现高凝状态, 因此, 对于肾上腺性CS患者, 尤其是高皮质醇水平及高糖化血红蛋白的患者, 需要关注其高凝状态及血栓发生的风险。

关键词: 库欣综合征, 非促肾上腺皮质激素依赖性, 血液凝固, 皮质醇, 糖化血红蛋白

Abstract:

Objective: To investigate the coagulation function indicators and identify influence factors of hypercoagulability in patients with adrenocorticotropic hormone (ACTH) independent Cushing syndrome (CS). Methods: In our retrospective study, the electronic medical records system of Peking University First Hospital was searched for the patients diagnosed with ACTH independent CS on discharge from January 2014 to June 2019. Nonfunctional adrenal adenoma patients were chosen as control group and matched 1 ∶1 by body mass index (BMI), gender, and discharge date. Clinical features and coagulation function indicators were compared between the two groups. Results: In the study, 171 patients were included in each group. Compared with control group, activated partial thromboplastin time (APTT), and prothrombin time (PT) in ACTH independent CS group were significantly lower [(29.22±3.39) s vs. (31.86±3.63) s, P < 0.001; (29.22±3.39) s vs. (31.86±3.63) s, P < 0.001], and both D-dimer and fibrin degradation products (FDP) levels were significantly higher (P < 0.05). Percentage of APTT levels under the lower limit of reference range in the CS patients was significantly higher than that in nonfunctional group (21.6% vs. 3.5%, P < 0.001). Percentage of D-dimer levels over the upper limit of reference range in the CS patients was significantly higher than that in nonfunctional group (13.5% vs. 6.6%, P=0.041). There were three patients with deep venous thrombosis and one patient with pulmonary embolism in CS group, however none was in control group. The area under curve (AUC) of serum cortisol rhythm (8:00, 16:00 and 24:00) levels was negatively associated with the levels of PT (r=-0.315, P < 0.001) and APTT (r=-0.410, P < 0.001), and positively associated with FDP (r=0.303, P < 0.001) and D-dimer levels (r=0.258, P < 0.001). There were no differences in coagulation function indicators among different histopathologic subgroups (adrenocortical adenoma, adrenocortical hyperplasia, oncocytic adenoma, adrenocortical carcinoma). With Logistic regression analysis, the AUC of cortisol and glycosylated hemoglobin A1c (HbA1c) levels were independent risk factors for hypercoagulability in the ACTH independent CS patients (P < 0.05). Conclusion: ACTH independent CS patients were more likely in hypercoagulable state compared with nonfunctional adrenal adenoma, especially in ACTH independent CS patients with higher levels of cortisol AUC and HbA1c. These patients should be paid attention to for the hypercoagulability and thrombosis risk.

Key words: Cushing syndrome, Adrenocorticotropic hormone independent, Blood coagulation, Cortisol, Glycated hemoglobin

中图分类号:

R586.2

王薇,王佳宁,虞巍,朱赛楠,高莹,张俊清. 肾上腺性库欣综合征与无功能腺瘤患者的凝血功能比较及其影响因素[J]. 北京大学学报（医学版）, 2023, 55(6): 1062-1067.

Wei WANG,Jia-ning WANG,Wei YU,Sai-nan ZHU,Ying GAO,Jun-qing ZHANG. Comparison of coagulation function between adrenocorticotropic hormone independent Cushing syndrome and nonfunctional adrenal adenoma and its influence factors[J]. Journal of Peking University (Health Sciences), 2023, 55(6): 1062-1067.

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参考文献 15

1	李乐乐, 窦京涛, 杨国庆, 等. 库欣综合征病因谱特征分析[J]. 中华医学杂志, 2016, 96 (31): 2454- 2457.
2	Stuijver DJF , Zaane B , Feelders RA , et al. Incidence of venous thromboembolism in patients with Cushing's syndrome: A multicenter cohort study[J]. J Clin Endocrinol Metab, 2011, 96 (11): 3525- 3532. doi: 10.1210/jc.2011-1661
3	刘之慧, 卢琳, 陈适, 等. 库欣综合征和肥胖症患者凝血功能的改变及影响因素[J]. 中华医学杂志, 2016, 96 (11): 850- 853.
4	中华医学会内分泌学分会. 库欣综合征专家共识(2011年)[J]. 中华内分泌代谢杂志, 2012, 28 (2): 96- 102.
5	中华医学会内分泌学分会. 原发性醛固酮增多症诊断治疗的专家共识(2020版)[J]. 中华内分泌代谢杂志, 2020, 36 (9): 727- 736. doi: 10.3760/cma.j.cn311282-20200615-00444
6	中华医学会内分泌学分会. 嗜铬细胞瘤和副神经节瘤诊断治疗专家共识(2020版)[J]. 中华内分泌代谢杂志, 2020, 36 (9): 737- 750. doi: 10.3760/cma.j.cn311282-20200629-00482
7	Silverstein MD , Heit JA , Mohr DN , et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population-based study[J]. Arch Intern Med, 1998, 158 (6): 585- 593. doi: 10.1001/archinte.158.6.585
8	Naess IA , Christiansen SC , Romundstad P , et al. Incidence and mortality of venous thrombosis: A population-based study[J]. J Thromb Haemost, 2007, 5 (4): 692- 699. doi: 10.1111/j.1538-7836.2007.02450.x
9	White RH . The epidemiology of venous thromboembolism[J]. Circulation, 2003, 107 (23 Suppl 1): 14- 18.
10	Ross NS . Epidemiology of Cushing's syndrome and subclinical disease[J]. Endocrinol Metab Clin North Am, 1994, 23 (3): 539- 546. doi: 10.1016/S0889-8529(18)30082-3
11	Abdollahi M , Cushman M , Rosendaal FR . Obesity: Risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use[J]. Thromb Haemost, 2003, 89 (3): 493- 498. doi: 10.1055/s-0037-1613379
12	Wang W , Wang J , Shen C , et al. Neutrophil-lymphocyte ratio as an initial screening biomarker for differential diagnosis of Cushing's syndrome from nonfunctional adenoma in patients with an adrenal mass[J]. Biomed Res Int, 2021, 2021, 6635594.
13	Hochberg Z , Pacak K , Chrousos GP . Endocrine withdrawal syndromes[J]. Endocr Rev, 2003, 24 (4): 523- 538.
14	Van Zaane B , Nur E , Squizzato A , et al. Hypercoagulable state in Cushing's syndrome: A systematic review[J]. J Clin Endocrinol Metab, 2009, 94 (8): 2743- 2750.
15	Nieman LK , Biller BMK , Findling JW , et al. Treatment of Cu-shing's syndrome: An endocrine society clinical practice guideline[J]. J Clin Endocrinol Metab, 2015, 100 (8): 2807- 2831.

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Items	CS (n=171)	Nonfunctional adrenal mass (n=171)	P value
Male	57 (33.33)	57 (33.33)
Age/years	47.16±13.80	54.18±11.15	< 0.001
BMI/(kg/m²)	26.0±3.8	26.1±3.7	0.797
Hypertension	139 (81.3)	111 (64.9)	0.001
Diabetes	59 (34.5)	48 (28.1)	0.200
SBP/mmHg	144.3±18.8	138.2±18.0	0.002
DBP/mmHg	88.1±14.8	80.1±12.6	< 0.001
HbA1c/%	6.4±1.1	6.4±1.3	0.870
FPG/(mmol/L)	5.8±2.1	5.9±1.8	0.688
Plasma K⁺/(mmol/L)	3.54±0.44	3.72±0.34	< 0.001
TG/(mmol/L)	1.66±0.81	1.74±1.12	0.454
TCHO/(mmol/L)	5.00±1.17	4.57±0.98	< 0.001
LDL-C/(mmol/L)	3.04±0.85	2.71±0.74	< 0.001
Neutrophil count/(×10⁹/L)	5.26±2.14	4.01±1.32	< 0.001
NLR	3.45(2.44，5.60)	2.14(1.76，3.00)	< 0.001
8:00 serum cortisol/(μg/dL)	17.18 (12.53, 24.46)	12.35 (9.72, 16.88)	< 0.001
16:00 serum cortisol/(μg/dL)	13.92 (9.28, 21.62)	6.63 (5.05, 9.48)	< 0.001
24:00 serum cortisol/(μg/dL)	12.42 (7.07, 19.64)	2.60 (1.76, 4.51)	< 0.001
Serum cortisol AUC/[(μg/dL)·h]	341.4 (242.6，521.1)	188.9 (150.9，233.2)	< 0.001
8:00 ACTH/(ng/L)	1.78 (0.99, 5.79)	18.46 (12.30, 26.61)	< 0.001
16:00 ACTH/(ng/L)	1.52 (0.99, 4.04)	10.12 (7.31, 16.13)	< 0.001
24:00 ACTH/(ng/L)	1.20 (0.99, 2.63)	6.90 (3.86, 11.62)	< 0.001
24 h urine cortisol/(μg/24 h)	1 034.4 (588.1, 1 929.3)	545.4 (413.8, 719.5)	< 0.001

Items	CS (n=171)	Nonfunctional adrenal mass (n=171)	P value
DVT	3 (1.75)	0	0.082
PE	1 (0.58)	0	0.317
PT/s	10.67±1.08	10.96±0.84	0.008
INR	1.02±0.10	1.02±0.10	0.396
APTT/s	29.22±3.39	31.86±3.63	< 0.001
FIB/(g/L)	2.85±0.61	2.97±0.58	0.055
D-dimer/(mg/L)	0.09 (0.05, 0.16)	0.07 (0.04, 0.11)	0.013
FDP/(mg/L)	1.2 (0.6, 2.0)	0.9 (0.5, 1.7)	0.041
TT/s	14.20±1.51	14.40±1.06	0.168
Platelet count/(×10⁹/L)	231.0±59.4	224.9±52.7	0.312

Items	Adrenocortical adenoma (n=82)	Adrenocortical hyperplasia (n=11)	Oncocytic adenoma (n=35)	Adrenocortical carcinoma (n=5)	P
PT/s	10.65±0.85	10.28±0.82	10.84±1.84	10.78±0.68	0.637
APTT/s	28.90±3.75	28.63±2.53	28.62±3.17	29.18±1.99	0.972
FIB/(g/L)	2.80±0.69	2.84±0.51	2.87±0.55	2.96±0.73	0.920
D-dimer/(mg/L)	0.09 (0.04, 0.15)	0.11 (0.05, 0.28)	0.09 (0.05, 0.20)	0.14 (0.08, 0.31)	0.663
FDP/(mg/L)	1.2 (0.6, 2.0)	1.3 (0.2, 2.4)	1.3 (0.5, 2.1)	2.9 (1.5, 4.6)	0.151
TT/s	14.32±1.15	14.33±2.54	13.62±2.24	14.38±1.04	0.266

Risk factors	β	OR (95% CI)	P value
Serum cortisol AUC	0.488	1.63 (1.09, 2.43)	0.017
24 h urine cortisol	-0.027	0.97 (0.92, 1.03)	0.315
HbA1c	0.484	1.62 (1.06, 2.48)	0.025
Neutrophil count	0.179	1.20 (0.88, 1.64)	0.262
NLR	-0.041	0.96 (0.80，1.15)	0.664

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