跳到主要內容

臺灣博碩士論文加值系統

(44.200.194.255) 您好!臺灣時間:2024/07/24 05:30
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:林瑞祥
研究生(外文):LIN, JUI-HSIANG
論文名稱:原發性皮質醛酮症的醛固酮分泌腺瘤與自主性皮質酮分泌的關聯性研究
論文名稱(外文):Relationship between aldosterone-producing nodules and autonomous cortisol secretion in primary aldosteronism
指導教授:邱惠雯邱惠雯引用關係吳允升王偉傑王偉傑引用關係
指導教授(外文):CHIU, HUI-WENWU, VIN-CENTWANG, WEI-JIE
口試委員:陳永昌鄭朝文林彥宏鄭彩梅邱惠雯吳允升王偉傑
口試委員(外文):CHEN, YUNG-CHANGCHENG, CHAO-WENLIN, YEN-HUNGZHENG, CAI-MEICHIU, HUI-WENWU, VIN-CENTWANG, WEI-JIE
口試日期:2022-05-31
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:臨床醫學研究所博士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:中文
論文頁數:48
中文關鍵詞:原發性醛酮症自主性皮質醇分泌腎上腺瘤多發性醛固酮結節多發性醛固酮小 結節醛固酮瘤
外文關鍵詞:primary aldosteronismautonomous cortisol secretionadrenal adenomamultiple aldosterone-producing nodulesmultiple aldosterone-producing micronodulesaldosterone-producing adenoma
相關次數:
  • 被引用被引用:0
  • 點閱點閱:191
  • 評分評分:
  • 下載下載:8
  • 收藏至我的研究室書目清單書目收藏:0
部分單側原發性醛酮症患者中意外發現合併自主性皮質醇分泌,目前尚未發現有單側原發性醛酮症合併自主性皮質醇分泌的病理分析。因為皮質醇分泌與原發性醛酮症都會導致高些壓與生化數據異常,因此腎上腺瘤有原發性醛酮症合併皮質醇分泌對腎上腺切除術後的預後影響是相當重要的議題。
我們選擇了61位接受腎上腺開刀治療腎上腺瘤帶有原發性皮質醛酮症合併自主性皮質醇分泌的患者來病理切片檢查,我們比對生物資料庫的the Cancer Genome Atlas (TCGA) 與 Kyoto Encyclopedia of Genes and Genomes (KEGG)。研究結果得知,多發性醛固酮結節/多發性醛固酮小結節佔單側原發性皮質醛酮症患者的流行率為65.6%,32%的單側原發性皮質醛酮症患者同時合併有自主性皮質醇分泌。自主性皮質醇分泌合併多發性醛固酮結節/多發性醛固酮小結節的腎上腺腫瘤勝算比(Odds Ratio)為3.08 (p= 0.004) ,同時腎上腺腫瘤超過1.98公分合併有多發性醛固酮結節/多發性醛固酮小結節容易產生自主性皮質醇分泌。藉由轉錄組分析看到單側原發性皮質醛酮症合併多發性醛固酮結節/多發性醛固酮小結節比缺乏多發性醛固酮結節/多發性醛固酮小結節的患者有更多的HSD3B7表現(p= 0.004)。單側原發性皮質醛酮症合併自主性皮質醇分泌的患者在腎上腺切除術後的臨床預後比沒有合併自主性皮質醇分泌更差(OR 0.15, p= 0.037)。多發性醛固酮結節/多發性醛固酮小結節出現在2/3的單側原發性皮質醛酮症,同時1/3的單側原發性皮質醛酮症合併有自主性皮質醇分泌。
總結,腎上腺腫瘤出現多發性醛固酮結節/多發性醛固酮小結節有明顯的HSD3B7/ CYP11B1信息傳遞,多發性醛固酮結節/多發性醛固酮小結節與較大的腎上腺腫瘤交互作用與自主性皮質醇分泌有關,導致於單側原發性皮質醛酮症的高血壓恢復率較低。
Unilateral primary aldosteronism (uPA) is associated with autonomous cortisol secretion (ACS) in some patients. The histopathological features of uPA combined with ACS has not been documented. We selected 61 uPA patients in association with ACS. The adrenal gland with the adenoma were investigated by immunohistochemical staining from 61 uPA patients undergoing unilateral adrenalectomy. Bioinformatics analysis involving Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Cancer Genome Atlas (TCGA) was utilized. The prevalence of multiple aldosterone-producing nodules or micronodules (mAPN/mAPM) was 65.6% in uPA patients.32% uPA patients had concurrent ACS, and ACS were combined with mAPN/mAPM (OR= 3.08, p= 0.004) and larger tumor size (> 1.98 cm). Transcriptome analysis showed more dominance of HSD3B7 over-expression in uPA with the presence of mAPN/mAPM than the absence of mAPN/mAPM (p= 0.004). Immunohistochemistry confirmed and TCGA bioinformatics validated the relationship that a novel linkage of dominant steroidogenic genes of HSD3B7 expression was on the contrary with CYP11B1 expression. uPA with concurrent ACS is a risk factor for decreased complete clinical success (OR 0.15, p= 0.037). Concurrent mAPN/mAPM were identified in 2/3 uPA patients, and concomitant ACS were found in 1/3 patients with uPA. Adenomas with surrounding mAPN/mAPM had a significance of steroidogenic HSD3B7/ CYP11B1 signaling, and mAPN/mAPM interacted with larger adenoma size was linked to co-existent ACS, and complete clinical success was lower in those uPA patients.
List of abbreviations i
Table contents ii
中文摘要 iv
Abstract vi
1. Introduction 1
1.1 High cardiovascular risk in primary aldosteronism 1
1.2 Autonomous cortisol secretion in unilateral primary aldosteronism 2
2. Materials and methods 3
2.1 Study enrollment 3
2.2 Data collection and definitions 4
2.3 Specimens and immunohistochemical staining 5
2.4 Identification of mAPN/mAPM 6
2.5 Transcriptome sequencing 6
2.6 Reproducibility of the bioinformatic dataset and functional annotation 7
2.7 Outcome Measures 8
2.8 Statistical Analysis 8
2.9 Ethics Committee Approval 9
3. Results 10
3.1 Subject enrollment 10
3.2 Factors associated with outcomes 10
3.3 Factors associated with ACS 11
3.4 Transcriptome analysis of steroidogenesis profiles in adenoma tissues 12
3.5 Validation of HSD3B7 and CYP3A5 in the adrenal gland using the TCGA databank 12
3.6 Validation of HSD3B7/CYP3A5 in tissue specimens using immunohistochemistry 13
3.7 Positioning of HSD3B7/CYP3A5 in KEGG pathway analysis 13
4. Discussion 14
4.1 Higher frequency of cardiovascular risk in primary aldosteronism 14
4.2 Statin therapy for plasma aldosterone concentration 15
4.3 HSD3B7 in adenoma was correlated with increased cortisol secretion 16
4.4 Factors associated with ACS 17
4.5 Association of HSD3B7 with ACS 17
4.6 Factors associated with outcomes 19
5. Conclusion and Perspective 20
5.1 mAPN/mAPM and CYP11B1 signaling 20
5.2 Perspective 20
References 21
Table 1. Baseline characteristics of unilateral primary aldosteronism patients divided according to the presence of multiple aldosterone-producing micronodules (mAPN/mAPM) in specimen. 27
Table 2. Baseline characteristics of unilateral primary aldosteronism patients divided into the status of autonomous cortisol secretion (ACS) ¶ according to low dose dexamethasone suppression test. 29
Table 3. Significant factors associated between complete clinical success (hypertension-remission) and complete biochemical success by multivariable logistic regression model 31
Table 4. Risk factors related with autonomous cortisol secretion (ACS) ¶ in unilateral primary aldosteronism patients by multivariable logistic regression. 32
Figures and legends 34
Figure 1. 34
Figure 2. 37
Figure 3. 38
Figure 4. 39
Figure 5. 40
Figure 6. 41
Figure 7. 42
Figure 8. 44
Figure 9. 45
Figure 10. 46
Appendix 47


References
1.Wu KD, Liao TS, Chen YM, Lai MK, Chen SJ, Su CT, et al. Preoperative diagnosis and localization of aldosterone-producing adenoma by adrenal venous sampling after administration of metoclopramide. J Formos Med Assoc. 2001;100(9):598-603.
2.D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008 Feb 12;117(6):743-53.
3.Young Jr. WF. Minireview: Primary aldosteronism—Changing concepts in diagnosis and treatment. Endocrinology. 2003;144(6):2008-213.
4.Persell S. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011;57(6):1076-80.
5.Strauch B, Zelinka T, Hampf M, Bernhardt RWJ, J. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens. 2003;17(5):349-52.
6.Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005 Apr 19;45(8):1243-8.
7.Lin JH, Lin YF, Wang WJ, Lin YF, Chueh SC, Wu VC, et al. Plasma Aldosterone Concentration as a Determinant for Statin Use Among Middle-Aged Hypertensive Patients for Atherosclerotic Cardiovascular Disease. J Clin Med 2018;7(11):382.
8.Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):3024-5.
9.Pencina MJ, Navar-Boggan AM, D’Agostino RB, Sr., Williams K, Neely B, Sniderman AD, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370(15):1422-31.
10.Johnson KM, Dowe DA. Accuracy of Statin Assignment Using the 2013 AHA/ACC Cholesterol Guideline Versus the 2001 NCEP ATP III Guideline: Correlation With Atherosclerotic Plaque Imaging. J Am Coll Cardiol. 2014;64(9):910-9.
11.Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, et al. American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines. 2013 American College of Cardiology/American Heart Association guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S49-73.
12.Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016;175(2):G1-G34.
13.Araujo-Castro M, Núñez M, Marazuela M. Autonomous Cortisol Secretion in Adrenal Incidentalomas. Endocrine. 2019;64(1):1-13.
14.Tang L, Li X, Wang B, Ma X, Li H, Gao Y, et al. Clinical Characteristics of Aldosterone- And Cortisol-Coproducing Adrenal Adenoma in Primary Aldosteronism. Int J Endocrinol. 2018;2018:4920841.
15.Nishimoto K, Nakagawa K, Dan L, Kosaka T, Oya M, Mikami S, et al. Adrenocortical zonation in humans under normal and pathological conditions. J Clin Endocrinol Metab. 2010;95(5):2296-305.
16.Nishimoto K, Seki T, Kurihara I, Yokota K, Omura M, Nishikawa T, et al. Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism. J Clin Endocrinol Metab. 2016;101(1):6-9.
17.Fushimi Y, Tatsumi F, Sanada J, Shimoda M, Kamei S, Nakanishi S, et al. Concurrence of overt Cushing's syndrome and primary aldosteronism accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex: case report. BMC Endocr Disord. 2021;21(1):163.
18.Lin YH, Wang SM, Wu VC, Lee JK, Kuo CC, Yen RF, et al. The association of serum potassium level with left ventricular mass in patients with primary aldosteronism. European journal of clinical investigation. 2011;41(7):743-50.
19.Wu VC, Kuo CC, Chang HW, Tsai CT, Lin CY, Lin LY, et al. Diagnosis of primary aldosteronism: comparison of post-captopril active renin concentration and plasma renin activity. Clinica chimica acta; international journal of clinical chemistry. 2010;411(9-10):657-63.
20.Lin YH, Lee HH, Liu KL, Lee JK, Shih SR, Chueh SC, et al. Reversal of myocardial fibrosis in patients with unilateral hyperaldosteronism receiving adrenalectomy. Surgery. 2011;150(3):526-33.
21.Wu VC, Hu YH, Er LK, Yen RF, Chang CH, Chang YL, et al. Case detection and diagnosis of primary aldosteronism - The consensus of Taiwan Society of Aldosteronism. J Formos Med Assoc. 2017;116(12):993-1005.
22.Wu VC, Chueh SC, Chang HW, Lin LY, Liu KL, Lin YH, et al. Association of kidney function with residual hypertension after treatment of aldosterone-producing adenoma. Am J Kidney Dis. 2009;54(4):665-73.
23.Wu VC, Lo SC, Chen YL, Huang PH, Tsai CT, Liang CJ, et al. Endothelial progenitor cells in primary aldosteronism: a biomarker of severity for aldosterone vasculopathy and prognosis. J Clin Endocrinol Metab. 2011;96(10):3175-83.
24.Wu VC, Huang KH, Peng KY, Tsai YC, Wu CH, Wang SM, et al. Prevalence and clinical correlates of somatic mutation in aldosterone producing adenoma-Taiwanese population. Sci Rep. 2015;5:11396.
25.Lin YH, Wu XM, Lee HH, Lee JK, Liu YC, Chang HW, et al. Adrenalectomy reverses myocardial fibrosis in patients with primary aldosteronism. Journal of hypertension. 2012 Aug;30(8):1606-13.
26.Er LK, Lin MC, Tsai YC, Hsiao JK, Yang CY, Chang CC, et al. Association of visceral adiposity and clinical outcome among patients with aldosterone producing adenoma. BMJ Open Diabetes Res Care. 2020;8(1).
27.Peng KY, Liao HW, Chan CK, Lin WC, Yang SY, Tsai YC, et al. Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success. Hypertension. 2020;76(5):1537-44.
28.Gomez-Sanchez CE, Qi X, Velarde-Miranda C, Plonczynski MW, Parker CR, Rainey W, et al. Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol. 2014;383(1-2):111-7.
29.Williams TA, Gomez-Sanchez CE, Rainey WE, Giordano TJ, Lam AK, Marker A, et al. International Histopathology Consensus for Unilateral Primary Aldosteronism. J Clin Endocrinol Metab. 2021;106(1):42-54.
30.Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A. 2015;112(33):E4591-9.
31.Williams TA, Gomez-Sanchez CE, Rainey WE, Giordano TJ, Lam AK, Marker A, et al. International histopathology consensus for unilateral primary aldosteronism. J Clin Endocrinol Metab. 2020:Online ahead of print.
32.Kometani M, Yoneda T, Aono D, Karashima S, Demura M, Nishimoto K, et al. Impact of aldosterone-producing cell clusters on diagnostic discrepancies in primary aldosteronism. Oncotarget. 2018;9(40):26007-18.
33.Meyer LS, Handgriff L, Lim JS, Udager AM, Kinker IS, Ladurner R, et al. Single-Center Prospective Cohort Study on the Histopathology, Genotype, and Postsurgical Outcomes of Patients With Primary Aldosteronism. Hypertension. 2021:HYPERTENSIONAHA12117348.
34.Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, et al. Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 2016;30(2):363.
35.Feng C, Sun Y, Ding G, Wu Z, Jiang H, Wang L, et al. PI3Kβ Inhibitor TGX221 Selectively Inhibits Renal Cell Carcinoma Cells With Both VHL and SETD2 Mutations and Links Multiple Pathways. Sci Rep. 2015;5:9465.
36.Wu CH, Wu VC, Yang YW, Lin YH, Yang SY, Lin PC, et al. Plasma aldosterone after seated saline infusion test outperforms captopril test at predicting clinical outcomes after adrenalectomy for primary aldosteronism. Am J Hypertens. 2019.
37.Chan CK, Kim JH, Chueh E, Chang CC, Lin YF, Lai TS, et al. Aldosterone level after saline infusion test could predict clinical outcome in primary aldosteronism after adrenalectomy. Surgery. 2019;166(3):362-8.
38.Chao CT, Wu VC, Kuo CC, Lin YH, Chang CC, Chueh SJ, et al. Diagnosis and management of primary aldosteronism: an updated review. Annals of medicine. 2013;45(4):375-83.
39.Yen RF, Wu VC, Liu KL, Cheng MF, Wu YW, Chueh SC, et al. 131I-6beta-iodomethyl-19-norcholesterol SPECT/CT for primary aldosteronism patients with inconclusive adrenal venous sampling and CT results. J Nucl Med. 2009;50(10):1631-7.
40.Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol. 2017.
41.Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, et al. Relationships of plasma renin levels with renal function in patients with primary aldosteronism. Clin J Am Soc Nephrol. 2007 Jul;2(4):722-31.
42.Iacobellis G, Petramala L, Cotesta D, Pergolini M, Zinnamosca L, Cianci R, et al. Adipokines and cardiometabolic profile in primary hyperaldosteronism. J Clin Endocrinol Metab. 2010 May;95(5): 2391-8.
43.Syed SB, Qureshi MA. Association of aldosterone and cortisol with cardiovascular risk factors in prehypertension stage. Int J Hypertens. 2012;2012:906327.
44.Fallo F, Pilon C, Urbanet R. Primary aldosteronism and metabolic syndrome. Horm Metab Res. 2012 Mar;44(3):208-14.
45.Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006 Dec 5;48(11):2293-300.
46.Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab. 2014;99(3):827-34.
47.Meyer L, Wang X, Sušnik E, Burrello J, Burrello A, Castellano I, et al. Immunohistopathology and Steroid Profiles Associated With Biochemical Outcomes After Adrenalectomy for Unilateral Primary Aldosteronism. 2018;72(3):650-7.
48.Nishimoto K, Tomlins S, Kuick R, Cani A, Giordano T, Hovelson D, et al. Aldosterone-stimulating Somatic Gene Mutations Are Common in Normal Adrenal Glands. Proc Natl Acad Sci U S A. 2015;112(33):E4591-9.
49.Omata K, Tomlins S, Rainey W. Aldosterone-producing cell clusters in normal and pathological states. Horm Metab Res. 2017;49(12):951-6.
50.Omata K, Anand SK, Hovelson DH, Liu CJ, Yamazaki Y, Nakamura Y, et al. Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals. J Endocr Soc. 2017;1(7):787-99.
51.Kubota-Nakayama F, Nakamura Y, Konosu-Fukaya S, Azmahani A, Ise K, Yamazaki Y, et al. Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies. Hum Pathol. 2016;54:165-73.
52.Nishimoto K, Koga M, Seki T, Oki K, Gomez-Sanchez E, Gomez-Sanchez C, et al. Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism. Mol Cell Endocrinol. 2017;441:124-33.
53.Platek T, Orso E, Zapala B, Polus A, Kiec-Wilk B, Piwowar M, et al. Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy. Medicine (Baltimore). 2018;97(49):e13353.
54.Palakuzhiyil SV, Christopher R, Chandra SR. Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy. World J Biol Chem. 2020;11(3):99-111.
55.Kazaryan A, Mala E. Does tumor size influence the outcome of laparoscopic adrenalectomy? J Laparoendosc Adv Surg Tech A. 2001;11(1):1-4.
56.Lim JS, Rainey W. The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease. Horm Metab Res. 2020;52(6):427-34.
57.https://www.kegg.jp/kegg-bin/highlight_pathway?scale=1.0&map=map04927&keyword=HSD3B.


QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top