臺灣博碩士論文加值系統

背景︰KCNJ5體細胞突變為原發性皮質醛酮症重要的致病機轉，且與疾病嚴重程度相關。然而KCNJ5突變狀態僅能經由腎上切除術後的組織所獲得。NP-59腎上腺造影為分子影像，以非侵入性的方式評估原發性皮質醛酮症的功能狀態以及疾病程度。本研究探討NP-59腎上腺造影與KCNJ5突變狀態的關聯，並期藉由NP-59腎上腺造影預測原發性皮質醛酮症的KCNJ5突變狀態。
方法：62位具有NP-59腎上腺造影且在一年內接受腎上腺切除術並有KCNJ5突變狀態的原發性皮質醛酮症病患被納入研究。從NP-59腎上腺造影中得到的兩個半定量指標，患側腎上腺與肝臟對比值(ALR)以及患側腎上腺對對側腎上腺對比值(CON)，用以比較在有無KCNJ5突變的差異性。NP-59腎上腺造影預測原發性皮質醛酮症的KCNJ5突變狀態的能力以Youden’s index所得到的最佳切點分析之。
結果：在62位原發性皮質醛酮症病患中，20位具有KCNJ5突變，42位無KCNJ5突變。有KCNJ5突變者的ALR顯著高於無KCNJ5突變者(p值為0.0031)，而CON則呈現邊緣性的偏高(p值0.0833)。在ALR切點為2.10與CON切點為1.95下，NP-59腎上腺造影預測KCNJ5突變的能力最佳，其敏感度與特異度分別為85%、57%與45%、 93%。在具有突變的病患中，16位G151R點突變的病患其ALR明顯低於另外4位L168R點突變的病患(p值為0.0471)。
結論：原發性皮質醛酮症中的KCNJ5突變導致較高的NP-59攝取，在腎上腺造影中包含經背景值校正後的患側腎上腺攝取以及患側與對側腎上腺攝取比值皆呈現偏高。具有KCNJ5突變的病人中，具有G151R點突變者其 ALR明顯低於具有L168R點突變者。藉由以上發現可推論NP-59腎上腺掃描可以非侵入性的方式評估原發性皮質醛酮症病患的KCNJ5突變狀態。

Purpose: Somatic KCNJ5 mutation accounts for the pathophysiology of primary aldosteronism (PA) and is associated with disease severity. However, mutation status can only be identified by surgical specimen from adrenalectomy. NP-59 adrenal scintigraphy is a noninvasive molecular imaging assessing disease activity. The study aimed to evaluate the correlation between NP-59 adrenal scintigraphy and somatic KCNJ5 mutation, and possible predictive value of somatic KCNJ5 mutation by NP-59 adrenal scintigraphy among PA patients underwent adrenalectomy.
Methods: Sixty-two PA patients received adrenalectomy within 1 year after NP-59 adrenal scintigraphy with available KCNJ5 mutation status were included. The differences of adrenal to liver ratio (ALR) and lesion to contralateral ratio of bilateral adrenal glands (CON) derived from NP-59 adrenal scintigraphy among patients with and without KCNJ5 mutation were evaluated. Cutoff values from Youden’s index were used for the predictive ability of NP-59 adrenal scintigraphy in KCNJ5 mutation.
Results: Twenty patients had KCNJ5 mutation and 42 patients were wild type. ALR was significantly higher in patients with KCNJ5 mutation than those without KCNJ5 mutation (p=0.0031), while CON showed borderline higher in patients with KCNJ5 mutation (p=0.0833). With ALR and CON cutoff of 2.10 and 1.95, NP-59 adrenal scintigraphy showed the best predictive value of KCNJ5 mutation and the sensitivity and specificity were 85%, 57% and 45%, 93%, respectively. Sixteen patients had G151R point mutation (KCNJ5- G151R) and 4 had L168R point mutation (KCNJ5-L168R), which former one had significantly lower ALR (p=0.0471).
Conclusion: Somatic KCNJ5 mutation of PA patients lead to significantly higher NP-59 uptake, in terms of background-corrected adrenal uptake of lesion side (ALR) and lesion to non-lesion side adrenal ratio (CON). APAs with KCNJ5-G151R point mutation showed significantly lower ALR than those with KCNJ5-L168R point mutation. The findings suggested that NP-59 adrenal scintigraphy may predict KCNJ5 mutation in noninvasive way.

博士論文審定書 1
致謝 2
中文摘要 4
Abstract 6
Table of Contents 8
1. Introduction 10
1.1 Primary aldosteronism 10
1.2 Lateralization 12
1.3 KCNJ5 mutation 14
2. Literature review 16
2.1 KCNJ5 mutation: genotype and phenotype 16
2.2 KCNJ5 mutation and post-surgical outcome 19
2.3 Molecular imaging as a predictor of KCNJ5 mutation 23
3. Objectives 26
4. Materials and Methods 27
4.1 Study population 27
4.2 Protocol and interpretation of NP-59 adrenal scintigraphy 27
4.3 KCNJ5 sequencing 28
4.4 Statistical analysis 29
5. Results 31
5.1 Patient Characteristics 31
5.2 Correlation between clinical/biochemical profiles and KCNJ5 mutation 31
5.3 Correlation between NP-59 adrenal scintigraphy and KCNJ5 mutation 32
5.4 G151R and L168R Point Mutations 33
6. Discussion 35
6.1 Adrenal cortical imaging of nuclear medicine 35
6.2 Association of KCNJ5 mutation and NP-59 adrenal scintigraphy 36
6.3 Impact on clinical management 40
6.4 Study limitation 43
6.5 Future direction 43
7. References 45
8. Figures and Tables 54

1.Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955; 45(1): 3-17.
2.Hundemer GL, Vaidya A. Primary Aldosteronism Diagnosis and Management: A Clinical Approach. Endocrinol Metab Clin North Am 2019; 48(4): 681-700.
3.Conn JW. Plasma Renin Activity in Primary Aldosteronism. Importance in Differential Diagnosis and in Research of Essential Hypertension. JAMA 1964; 190: 222-5.
4.Conn JW, Rovner DR, Cohen EL. Normal and Altered Function of the Renin-Angiotensin-Aldosterone System in Man: Applications in Clinical and Research Medicine. Ann Intern Med 1965; 63: 266-84.
5.Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101(5): 1889-916.
6.Kayser SC, Dekkers T, Groenewoud HJ, et al. Study Heterogeneity and Estimation of Prevalence of Primary Aldosteronism: A Systematic Review and Meta-Regression Analysis. J Clin Endocrinol Metab 2016; 101(7): 2826-35.
7.Monticone S, Burrello J, Tizzani D, et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol 2017; 69(14): 1811-20.
8.Monticone S, D'Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2018; 6(1): 41-50.
9.Wu VC, Chueh SJ, Chen L, et al. Risk of new-onset diabetes mellitus in primary aldosteronism: a population study over 5 years. J Hypertens 2017; 35(8): 1698-708.
10.Velema MS, de Nooijer AH, Burgers VWG, et al. Health-Related Quality of Life and Mental Health in Primary Aldosteronism: A Systematic Review. Horm Metab Res 2017; 49(12): 943-50.
11.Huang KH, Yu CC, Hu YH, et al. Targeted treatment of primary aldosteronism - The consensus of Taiwan Society of Aldosteronism. J Formos Med Assoc 2019; 118(1 Pt 1): 72-82.
12.Young WF, Jr. Diagnosis and treatment of primary aldosteronism: practical clinical perspectives. J Intern Med 2019; 285(2): 126-48.
13.Funder JW. Primary aldosteronism as a public health issue. Lancet Diabetes Endocrinol 2016; 4(12): 972-3.
14.Rossi GP, Pitter G, Bernante P, Motta R, Feltrin G, Miotto D. Adrenal vein sampling for primary aldosteronism: the assessment of selectivity and lateralization of aldosterone excess baseline and after adrenocorticotropic hormone (ACTH) stimulation. J Hypertens 2008; 26(5): 989-97.
15.Young WF, Jr., Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin North Am 1988; 17(2): 367-95.
16.Vonend O, Ockenfels N, Gao X, et al. Adrenal venous sampling: evaluation of the German Conn's registry. Hypertension 2011; 57(5): 990-5.
17.Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004; 136(6): 1227-35.
18.Daunt N. Adrenal vein sampling: how to make it quick, easy, and successful. Radiographics 2005; 25 Suppl 1: S143-58.
19.Rossi GP, Barisa M, Allolio B, et al. The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism. J Clin Endocrinol Metab 2012; 97(5): 1606-14.
20.Letavernier E, Peyrard S, Amar L, Zinzindohoue F, Fiquet B, Plouin PF. Blood pressure outcome of adrenalectomy in patients with primary hyperaldosteronism with or without unilateral adenoma. J Hypertens 2008; 26(9): 1816-23.
21.Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001; 135(4): 258-61.
22.Waldmann J, Maurer L, Holler J, et al. Outcome of surgery for primary hyperaldosteronism. World J Surg 2011; 35(11): 2422-7.
23.Sarkar SD, Beierwaltes H, Ice RD, et al. A new and superior adrenal scanning agent, NP-59. J Nucl Med 1975; 16(11): 1038-42.
24.Sarkar SD, Cohen EL, Beierwaltes WH, Ice RD, Cooper R, Gold EN. A new and superior adrenal imaging agent, 131I-6beta-iodomethyl-19-nor-cholesterol (NP-59): evaluation in humans. J Clin Endocrinol Metab 1977; 45(2): 353-62.
25.Gross MD, Valk TW, Swanson DP, Thrall JH, Grekin RJ, Beirewaltes WH. The role of parmacologic manipulation in adrenal cortical scintigraphy. Semin Nucl Med 1981; 11(2): 128-48.
26.Gross MD, Freitas JE, Swanson DP, Brady T, Beierwaltes WH. The normal dexamethasone-suppression adrenal scintiscan. J Nucl Med 1979; 20(11): 1131-5.
27.Weinberger MH, Grim CE, Hollifield JW, et al. Primary aldosteronism: diagnosis, localization, and treatment. Ann Intern Med 1979; 90(3): 386-95.
28.Mansoor GA, Malchoff CD, Arici MH, Karimeddini MK, Whalen GF. Unilateral adrenal hyperplasia causing primary aldosteronism: limitations of I-131 norcholesterol scanning. Am J Hypertens 2002; 15(5): 459-64.
29.Yen RF, Wu VC, Liu KL, 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.
30.Lu CC, Wu VC, Wu KD, et al. Prognostic value of semiquantification NP-59 SPECT/CT in primary aldosteronism patients after adrenalectomy. Eur J Nucl Med Mol Imaging 2014; 41(7): 1375-84.
31.Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331(6018): 768-72.
32.Byrd JB, Turcu AF, Auchus RJ. Primary Aldosteronism. Circulation 2018; 138(8): 823-35.
33.Taguchi R, Yamada M, Nakajima Y, et al. Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab 2012; 97(4): 1311-9.
34.Wu VC, Huang KH, Peng KY, et al. Prevalence and clinical correlates of somatic mutation in aldosterone producing adenoma-Taiwanese population. Sci Rep 2015; 5: 11396.
35.Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP. A Meta-Analysis of Somatic KCNJ5 K(+) Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma. J Clin Endocrinol Metab 2015; 100(8): E1089-95.
36.Vilela LAP, Rassi-Cruz M, Guimaraes AG, et al. KCNJ5 somatic mutation is a predictor of hypertension remission after adrenalectomy for unilateral primary aldosteronism. J Clin Endocrinol Metab 2019.
37.Scholl UI, Abriola L, Zhang C, et al. Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma. J Clin Invest 2017; 127(7): 2739-50.
38.Azizan EA, Murthy M, Stowasser M, et al. Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. Hypertension 2012; 59(3): 587-91.
39.Boulkroun S, Beuschlein F, Rossi GP, et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension 2012; 59(3): 592-8.
40.Akerstrom T, Crona J, Delgado Verdugo A, et al. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One 2012; 7(7): e41926.
41.Arnesen T, Glomnes N, Stromsoy S, et al. Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway. Langenbecks Arch Surg 2013; 398(6): 869-74.
42.Rossi GP, Cesari M, Letizia C, et al. KCNJ5 gene somatic mutations affect cardiac remodelling but do not preclude cure of high blood pressure and regression of left ventricular hypertrophy in primary aldosteronism. J Hypertens 2014; 32(7): 1514-21; discussion 22.
43.Williams TA, Lenders JWM, Mulatero P, 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; 5(9): 689-99.
44.Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022): 957-67.
45.Kazerooni EA, Sisson JC, Shapiro B, et al. Diagnostic accuracy and pitfalls of [iodine-131]6-beta-iodomethyl-19-norcholesterol (NP-59) imaging. J Nucl Med 1990; 31(4): 526-34.
46.Celen O, O'Brien MJ, Melby JC, Beazley RM. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg 1996; 131(6): 646-50.
47.Nocaudie-Calzada M, Huglo D, Lambert M, et al. Efficacy of iodine-131 6beta-methyl-iodo-19-norcholesterol scintigraphy and computed tomography in patients with primary aldosteronism. Eur J Nucl Med 1999; 26(10): 1326-32.
48.Nomura K, Kusakabe K, Maki M, Ito Y, Aiba M, Demura H. Iodomethylnorcholesterol uptake in an aldosteronoma shown by dexamethasone-suppression scintigraphy: relationship to adenoma size and functional activity. J Clin Endocrinol Metab 1990; 71(4): 825-30.
49.Ishimura J, Kawanaka M, Fukuchi M. Clinical application of SPECT in adrenal imaging with iodine-131 6 beta-iodomethyl-19-norcholesterol. Clin Nucl Med 1989; 14(4): 278-81.
50.La Cava G, Imperiale A, Olianti C, et al. SPECT semiquantitative analysis of adrenocortical (131)I-6 beta iodomethyl-norcholesterol uptake to discriminate subclinical and preclinical functioning adrenal incidentaloma. J Nucl Med 2003; 44(7): 1057-64.
51.Nagai T, Solis BA, Koh CS. An approach to developing adrenal-gland scanning. J Nucl Med 1968; 9(11): 576-81.
52.Counsell RE, Ranade VV, Blair RJ, Beierwaltes WH, Weinhold PA. Tumor localizing agents. IX. Radioiodinated cholesterol. Steroids 1970; 16(3): 317-28.
53.Varma VM, Blair RJ, Beierwaltes WH, et al. Radiolabeled cholesterol as an adrenal scanning agent. 1971; 12: 176.
54.Beierwaltes WH, Lieberman LM, Ansari AN, Nishiyama H. Visualization of human adrenal glands in vivo by scintillation scanning. JAMA 1971; 216(2): 275-7.
55.Lieberman LM, Beierwaltes WH, Conn JW, Ansari AN, Nishiyama H. Diagnosis of adrenal disease by visualization of human adrenal glands with 131 I-19-iodocholesterol. N Engl J Med 1971; 285(25): 1387-93.
56.Beierwaltes WH, Sturman MF, Ryo U, Ice RD. Imaging functional nodules of the adrenal glands with 131-I-19-iodocholesterol. J Nucl Med 1974; 15(4): 246-51.
57.Hogan MJ, McRae J, Schambelan M, Biglieri EG. Location of aldosterone-producing adenomas with 131I-19-iodocholesterol. N Engl J Med 1976; 294(8): 410-4.
58.Hwang I, Balingit AG, Georgitis WJ, Sisson JC, Shapiro B. Adrenocortical SPECT using iodine-131 NP-59. J Nucl Med 1998; 39(8): 1460-3.
59.Chang CC, Chen YY, Lai TS, et al. Taiwan mini-frontier of primary aldosteronism: Updating detection and diagnosis. J Formos Med Assoc 2021; 120(1 Pt 1): 121-9.
60.Kitamoto T, Omura M, Suematsu S, Saito J, Nishikawa T. KCNJ5 mutation as a predictor for resolution of hypertension after surgical treatment of aldosterone-producing adenoma. J Hypertens 2018; 36(3): 619-27.
61.Vilela LAP, Rassi-Cruz M, Guimaraes AG, et al. KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism. J Clin Endocrinol Metab 2019; 104(10): 4695-702.
62.Chang YY, Tsai CH, Peng SY, et al. KCNJ5 Somatic Mutations in Aldosterone-Producing Adenoma Are Associated With a Worse Baseline Status and Better Recovery of Left Ventricular Remodeling and Diastolic Function. Hypertension 2020: Hypertensionaha12015679.
63.Lv Z, Fan J, Xu J, et al. Value of (18)F-FDG PET/CT for predicting EGFR mutations and positive ALK expression in patients with non-small cell lung cancer: a retrospective analysis of 849 Chinese patients. Eur J Nucl Med Mol Imaging 2018; 45(5): 735-50.
64.Yip SS, Kim J, Coroller TP, et al. Associations Between Somatic Mutations and Metabolic Imaging Phenotypes in Non-Small Cell Lung Cancer. J Nucl Med 2017; 58(4): 569-76.
65.Kawada K, Toda K, Nakamoto Y, et al. Relationship Between 18F-FDG PET/CT Scans and KRAS Mutations in Metastatic Colorectal Cancer. J Nucl Med 2015; 56(9): 1322-7.
66.Nagarajah J, Ho AL, Tuttle RM, Weber WA, Grewal RK. Correlation of BRAFV600E Mutation and Glucose Metabolism in Thyroid Cancer Patients: An (1)(8)F-FDG PET Study. J Nucl Med 2015; 56(5): 662-7.
67.Chen R, Zhou X, Liu J, Huang G. Relationship Between 18F-FDG PET/CT Findings and HER2 Expression in Gastric Cancer. J Nucl Med 2016; 57(7): 1040-4.
68.Seccia TM, Mantero F, Letizia C, et al. Somatic mutations in the KCNJ5 gene raise the lateralization index: implications for the diagnosis of primary aldosteronism by adrenal vein sampling. J Clin Endocrinol Metab 2012; 97(12): E2307-13.
69.Zheng FF, Zhu LM, Nie AF, et al. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension 2015; 65(3): 622-8.
70.Osswald A, Fischer E, Degenhart C, et al. Lack of influence of somatic mutations on steroid gradients during adrenal vein sampling in aldosterone-producing adenoma patients. Eur J Endocrinol 2013; 169(5): 657-63.
71.Lechner B, Lechner K, Heinrich D, et al. THERAPY OF ENDOCRINE DISEASE: Medical treatment of primary aldosteronism. Eur J Endocrinol 2019; 181(4): R147-R53.
72.Dekkers T, Prejbisz A, Kool LJS, et al. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes Endocrinol 2016; 4(9): 739-46.
73.Parthasarathy HK, Menard J, White WB, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens 2011; 29(5): 980-90.
74.de Gasparo M, Joss U, Ramjoue HP, et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 1987; 240(2): 650-6.
75.Williams TA, Reincke M. MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited. Eur J Endocrinol 2018; 179(1): R19-R29.
76.Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens 2004; 22(11): 2217-26.
77.Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens 2001; 19(3): 353-61.
78.Dietz JD, Du S, Bolten CW, et al. A number of marketed dihydropyridine calcium channel blockers have mineralocorticoid receptor antagonist activity. Hypertension 2008; 51(3): 742-8.
79.Deinum J, Riksen NP, Lenders JW. Pharmacological treatment of aldosterone excess. Pharmacol Ther 2015; 154: 120-33.
80.Tauber P, Penton D, Stindl J, et al. Pharmacology and pathophysiology of mutated KCNJ5 found in adrenal aldosterone-producing adenomas. Endocrinology 2014; 155(4): 1353-62.
81.Caroccia B, Prisco S, Seccia TM, Piazza M, Maiolino G, Rossi GP. Macrolides Blunt Aldosterone Biosynthesis: A Proof-of-Concept Study in KCNJ5 Mutated Adenoma Cells Ex Vivo. Hypertension 2017; 70(6): 1238-42.
82.Williams TA, Monticone S, Mulatero P. KCNJ5 mutations are the most frequent genetic alteration in primary aldosteronism. Hypertension 2015; 65(3): 507-9.
83.Monticone S, Buffolo F, Tetti M, Veglio F, Pasini B, Mulatero P. GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism. Eur J Endocrinol 2018; 178(3): R101-r11.