Case Discussion Aldosteronism (Conn's disease) < Case presentation > The patient was a 61-year-old man who had hypertension under anti-hypertensive treatment for 12 years. Recently, his blood pressure fluctuated despite medication  with good compliance. However, an episode of hypertensive urgency with systolic blood pressure up to 220mmHg and diastolic pressure exceeding 120 mmHg was noted. He complained of excessive fatigability, both leg weakness, and mild leg edema in the pretibial area in recent two months. He visited a drugstore to buy some over- the- contour medications, such as calcium channel antagonist, angiotensin-receptor blocker and αblocker. However, his blood pressure remained above 200/100 mmHg, which were equal in both arms, after taking these medications. On physical examination, no renal bruits were heard. Renal sonography revealed bilateral renal parenchymal disease without renal atrophy. Twenty-four-hour blood pressure monitoring not only confirmed marked hypertension but also showed extreme dipping during night-time. < Course and Treatment > On admission, the serum potassium was 3.06 mmol/dL and the blood gas analysis showed metabolic alkalosis. A chest radiograph revealed cardiomegaly. The captopril test(Table 1)showed the supine plasma renin acitivity (PRA) and plasma aldosterone were (ALD) were 37.2 (ng/ml/hr), and 0.03 (ng/dl), respectively after 25mg of captopril. The plasma aldosterone/ plasma renin activity ratio was 1240 (ng/dl/ng per ml/h), well above the cut-off level of 30 (ng/dl/ng per ml/h). The results were consistent with a diagnosis of primary aldosteronism. The postural test was performed and showed a negative result without aldosterone elevation after ambulation, which was compitable with aldosterone- producing adenoma. A renal computer tomographic scan of the adrenal gland was subsequently undertaken, which showed a small nodule at the superior aspect of the left adrenal gland with a diameter of 8mm. He received laparoscopic partial adrenalectomy after the diagnosis of aldosterone –producing adenoma.  After discharge, he was followed-up in the out-patient clinic and his blood pressure was 125/80 mmHg without necessitating any antihypertensive drugs. < Laboratory and Image Study > Table 1. 1. CBC/DC Date WBC RBC  Hb  Hct MCV MCHC Plt    /ul M/ul g/dl % fL % K/ul Dec 10 5980 4.4 12.6 36.9 83.9 34.1 272 2. Biochemistry BUN Cre  Na K Cl Ca T.protein AST albumin T-bil mg/dL  mg/dL  mmol/L mmol/L mmol/L mmol/L  g/dL U/L g/dL mg/dL 26.5 (<24) 0.8 (<1.3) 142 (135-145)  3.06 (3.5-5.3) 104 (98-108) 2.2 (2.02-2.6) 7.24(6.6-8.7) 29 (<37) 3.61 (3.5-5.0) 0.3 (0.2-1.0)   Arteril blood gas : PH 7.45, PCO2 41.3,  PO2 92.5, HCO3 28.6, BE 4.7 (7.35-7.45) (35-45)  (80-100) (22-26)  (-3~+3) TSH 0.9 (0.1-3.8 μIU/mL) Free T4  22.9 (9.8-23.8 ng/dl) Cortisol DL (8am) 9.55 (am: 5 ~ 25 (μg/dL) ) Cortisol DL (4pm) 8.42 (pm: 2.5 ~ 12.5 (μg/dL) ) ACTH (8am) 12.7 ( 10 ~ 65 (pg/mL) ) ACTH (4pm) 10.4 ( 10 ~ 65 (pg/mL) ) 24 HR. URINE VMA 6.743 ( 1~7 (mg/24h) ) Urine ( 24 hrs 2300 ml)      Cre Na K Cl Ca  mg/dL mmol/L  mmol/L  mmol/L mmol/L 38.8 120 24.2 106 3.42 Daily K loss : 55.66mmol/d ；Daily Na loss : 276 mmol/d 24 Hr Ccr : 77.45 ml/min (> 75) Urinary potassium to creatinine ratio [UK /U cre (nmol/nmol)]: 5.54 ( <2.5) 3. Diagnosis test        【Captopril test】 Time  PRA(ng/ml/hr) ALD(ng/dl) ALD / PRA ratio (ARR)  0’ 0.13 27.8 213.8 30’ 0.03 37.2 1240     * (注 1 ) A positive screening test was considered when the aldosterone-renin ratio (ARR) was more than 30 (ng/dL per ng/mL/hr) and the plasma aldosterone concentration (ALD) was more than 10 ng/dL (> 277 pmol/L). 【Posture Change test】   PRA  (ng/ml/hr)  ALD (ng/dl) ALD / PRA ratio (ARR) Before 0.24 45.6 190 After 0.42 17.3 41.2 ** (注 2) A positive postural test was defined by an ambulatory plasma aldosterone level that was either lower than the supine baseline level or that was increased less than 30% above that value (1, 2) < Analysis >            根據Conn的描敘，原發性皮質醛酮症起因於皮質醛酮素瘤，是一種可治癒的高血壓疾病。原發性皮質醛酮症患者的皮質醛酮分泌是部分自主的，其血清中腎素的濃度是低的，並且不會被體液擴張或是鈉鹽攝取過量所抑制。原發性皮質醛酮症的盛行率在沒有經過篩選的高血壓病人中顯然是不低，尤其是皮質醛酮和腎素(ARR)比例這個篩選方式被發現之後，認為是佔了高血壓病人中百分之十五。在一個沒有接受高血壓治療的病人測量血漿中皮質醛酮素濃度及血漿中腎素活性的比值(ARR) (注 1)，是一個比較可以接受用來分辨本質性高血壓和原發性皮質醛酮症的篩檢方法。皮質醛酮素瘤在女性較常發生，在兒童則很少發生。雙側腎上腺增生症在男生發生率較高，發生的年齡也高過皮質醛酮素瘤。原發性皮質醛酮症的臨床特徵並不具特異性。有些病人是完全沒有症狀或只有很輕的症狀，有些病人則有高血壓(例如：頭痛)、低血鉀(例如：多尿和夜尿、或是肌肉痙攣)或兩者都有的症狀。有時候，嚴重的肌肉無力、感覺異常、手腳痙攣或麻痺癱瘓可能會由於嚴重的低血鉀症而顯的明顯。而且這個現象又在亞洲、特別是在中國人顯的更為常見。除一些很小的腫瘤之外，CT scan可以偵測到大部分的腎上腺腫瘤。雙側腎上腺增生(IHA)的病人，兩側腎上腺會增大或正常大小。但有一些雙側腎上腺增生的病人，一側的腎上腺可見到一結節；而皮質醛酮素瘤(APA)的病人，可能兩側都看到結節。      單側皮質醛酮素瘤，手術去除腫瘤為最佳選擇。大部分病人術後高血壓都能有明顯下降或恢復正常。術前可給予spironolactone治療血壓，其反應的好壞可作為手術結果的預測因子，雙側腎上腺增生(BAH)以藥物治療為最佳方式，單側或雙側腎上腺切除對血壓的控制效果都不佳。 【Reference】 Fontes RG, Kater CE, Biglieri EG, Irony I 1991 Reassessment of the predictive value of the postural stimulation test in primary aldosteronism. Am J Hypertens 4:786-791 Nomura K, Toraya S, Horiba N, Ujihara M, Aiba M, Demura H 1992 Plasma aldosterone response to upright posture and angiotensin II infusion in aldosterone-producing adenoma. J Clin Endocrinol Metab 75:323-327 Ahlawat SK, Sachdev A 1999 Hypokalaemic paralysis. Postgrad Med J 75:193-197 Nishizaka MK, Calhoun DA 2005 Primary aldosteronism: diagnostic and therapeutic considerations. Curr Cardiol Rep 7:412-417 Williams JS, Williams GH, Raji A, Jeunemaitre X, Brown NJ, Hopkins PN, Conlin PR 2006 Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia. J Hum Hypertens 20:129-136 Racine MC, Douville P, Lebel M 2002 Functional tests for primary aldosteronism: value of captopril suppression. Curr Hypertens Rep 4:245-249 Espiner EA, Ross DG, Yandle TG, Richards AM, Hunt PJ 2003 Predicting surgically remedial primary aldosteronism: role of adrenal scanning, posture testing, and adrenal vein sampling. J Clin Endocrinol Metab 88:3637-3644 腎性高血壓及原發性皮質醛酮過高症，吳允升．吳寬墩；當代醫學、94年7月　　第三十二卷第七期，528頁 繼續教育考題 1. (E)  A diagnosis of secondary hypertension should be considered in the following situations except A  age at onset younger than 30 or older than 60 years B  stable hypertension that becomes difficult to control C  clinical occurrence of a hypertensive crisis D  the presence of signs or symptoms of a secondary cause such as   hypokalemia or metabolic alkalosis that is not explained by diuretic therapy E all of above 2. (D)  下列哪一種非為 renal K loss? (Spotting urine [K]/[Cre] > 2.5 mmol/ mmol) A  Aldosteronism B  Liddle's syndrome C  Bartter's syndrome D  Thyrotoxic periodic paralysis 3. (B)  何者不是發生hypokalemic periodic paralysis的高危險群? A  barium poisoning B  Gordon's syndrome C  hyperthyroidism D  aldosteronism 4. (B)  在resistant hypertension 的病人primary aldosteronism 的盛行率為多少? A  2~5% B  10~20% C  28~36% D  35~43% 5. (A)  Primary aldosteronism 病人的臨床表現何者最少見? A  Hypertension with normokalaemia B  Metabolic alkalosis C  Low renin (PRA) D  High serum aldosterone/PRA ratioNormotension (ARR ratio) 6. (C)  有關於plasma aldosterone to plasma renin activity ratio (ARR) for PA何者為非? A  Screening test for aldosteronism B  high negative predictive value even in the setting of ongoing antihypertensive therapy C  可以區別aldosterone producing adenma或 bilateral adrenal hyperplasia D  Sensitivity and specificity of ARR > or =35 for PA were 95.4% and 28.3% at baseline 7. (B)  有關於captopril test for PA何者為非? A  An ARR > 30 with aldosterone > 10 ng/dL after administration of captopril was defined as a positive test B  可以區別aldosterone producing adenoma或 bilateral adrenal hyperplasia C  使用captopril test可以增加ARR for PA 的Sensitivity and specificity D  Patients with elevated aldosterone/renin ratios require confirmatory testing to demonstrate nonsuppressive autonomous aldosterone production. 8. (D)  有關於postural test for PA何者為非? A  可以區別aldosterone producing adenma或 bilateral adrenal hyperplasia B  An ambulatory plasma aldosterone level that was either lower than the supine baseline level or that was increased less than 30% above that value means positive C  Most patients with adenomas had a positive postural stimulation test result. D  Bilateral adrenal hyperplasia (BAH) showed a fall in plasma aldosterone. 9. (A)  如果是屬於aldosterone producing adenoma的aldsoteronsim 該如何治療? A  laparoscopic adrenalectomy B  chemotherapy C  radiotherapy D  pharmacotherapy 10. (D)  如果是屬於bilateral adrenal hyperplasia的aldsoteronsim 該如何治療? A  laparoscopic adrenalectomy B  chemotherapy C  radiotherapy D  pharmacotherapy

答案解說 ( E ) ( D ) ( B ) Hypokalaemic paralysis is a relatively uncommon but potentially life-threatening clinical syndrome. If recognised and treated appropriately, patients recover without any clinical sequellae. The syndrome of hypokalaemic paralysis represents a heterogeneous group of disorders characterized clinically by hypokalaemia and acute systemic weakness. Most cases are due to familial or primary hypokalaemic periodic paralysis; sporadic cases are associated with numerous other conditions including barium poisoning, hyperthyroidism, renal disorders, certain endocrinopathies and gastrointestinal potassium losses. 3 ( B ) Recent evaluations indicate that primary aldosteronism (PA) is common in patients with hypertension. In patients with mild to moderate hypertension the prevalence of PA is 5% to 10%, whereas in subjects with resistant hypertension the prevalence is approximately 20%. As such, PA has become the most common secondary cause of hypertension. 4 ( A ) The prevalence of primary hyperaldosteronism in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations.5 ( C ) Determination of the plasma aldosterone to plasma renin activity ratio is an effective screen for PA in that it has a high negative predictive value even in the setting of ongoing antihypertensive therapy. Its specificity, however, is low such that a high ratio is suggestive of PA but must be confirmed by demonstration of high and autonomous secretion of aldosterone. ( B ) Baseline and postcaptopril (50 mg orally) aldosterone to plasma renin activity ratio (ARR) all used as screening tool. Sensitivity and specificity of A/R > or =35 were 95.4% and 28.3% at baseline, compared with 100% and 67.9% after captopril. Patients with elevated aldosterone/renin ratios require confirmatory testing to demonstrate nonsuppressive autonomous aldosterone production.6 ( D ) 7 ( A ) Patients with PA may have either bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA). Hypertension in patients with APA can be cured or at least significantly ameliorated by unilateral adrenalectomy. ( D ) Patients with PA may have either bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA). In patients with BAH, the diagnosis of the underlying cause of hypertension is fundamental for targeted pharmacotherapy with aldosterone receptor antagonists.