Primary Hyperaldosteronism Secondary to Unilateral ... - Springer Link

2006 by the Socie´te´ Internationale de Chirurgie Published Online: 4 December 2006

World J Surg (2007) 31: 72–79 DOI: 10.1007/s00268-005-0594-8

Primary Hyperaldosteronism Secondary to Unilateral Adrenal Hyperplasia: an Unusual Cause of Surgically Correctable Hypertension. A review of 30 cases Brian K. P. Goh, MBBS, MRCS, MMed (Surgery),1 Yeh-Hong Tan, MBBS, FRCS,2 Kenneth T. E. Chang, MBBS, FRCPath,3 Peter H. K. Eng, MBBS, FRCP,4 Sidney K. H. Yip, MBBS, FRCS,2 Christopher W. S. Cheng, MBBS, FRCS2 1

Department Department 3 Department 4 Department 2

of of of of

Surgery, Singapore General Hospital, Outram Road, Singapore 169608 Urology, Singapore General Hospital, Outram Road, Singapore 169608 Pathology, Singapore General Hospital, Outram Road, Singapore 169608 Endocrinology, Singapore General Hospital, Outram Road, Singapore 169608

Abstract Introduction: Unilateral adrenal hyperplasia (UAH) is a rare, surgically correctable cause of primary hyperaldosteronism (PH). We report 2 cases and review the literature for cases of PH secondary to UAH successfully treated via surgery. Methods: Two cases of UAH treated at our institution were retrospectively reviewed. In addition, we reviewed 28 cases of UAH previously reported in the English literature. Results: Median patient age was 49 (range: 10–62) years, with a male to female ratio of 1.7:1. All patients were hypertensive, with a median preoperative systolic and diastolic blood pressure of 170 (range: 135–250) mmHg and 110 (range: 75–140) mmHg, respectively. Most patients were hypokalemic, with a median serum potassium level of 2.8 (range: 1.4–3.9) mmol/l. Ten out of 13 patients (77%) who underwent postural studies had a decrease or no change in the plasma aldosterone level, suggesting a unilateral source of hyperaldosteronism, and 9/17 patients (53%) who underwent a computed tomography (CT) scan were correctly localized. Twelve patients underwent adrenal scintigraphy with or without dexamethasone suppression, of whom 6 (50%) were correctly localized. In 1 patient, adrenal scintigraphy demonstrated localization to the opposite gland. Adrenal venous sampling (AVS) was performed in 22 patients and successfully localized the lesion in all the patients. At a median follow-up of 12 (range: 3–96) months postsurgery, 47% of patients (14/30) were completely cured of their hypertension and 50% (15/30) had improved control. All 30 patients were cured of hypokalemia. Conclusion: Although the existence of UAH remains controversial, it is increasingly accepted as a unique pathologic entity and has an excellent outcome after unilateral adrenalectomy.

Presented in part at the 2nd Biennial Congress of the European Society of Endocrine Surgeons, Krakow, 18-20 May 2006 (oral presentation). Correspondence to: Brian K. P. Goh, MBBS, MRCS, MMed (Surgery), e-mail: [email protected]

A

lthough previously considered a rarity, primary hyperaldosteronism (PH) is now considered to be the one of the most common cause of secondary hypertension. It was first described in 1955 by Jerome Conn as

Goh et al.: Primary Hyperaldosteronism Secondary to Unilateral Adrenal Hyperplasia

a syndrome characterized by hypertension, hypokalemia, and excessive urinary excretion of aldosterone in association with adrenal cortical adenoma.1 However, we now know that there are various subtypes of PH, of which aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) account for over 95% of all cases.2 Less common subtypes include glucocorticoidremediable aldosteronism3 and hyperaldosteronism secondary to adrenal carcinoma.4 Very rarely, PH is caused by unilateral adrenal hyperplasia (UAH). Ever since the first case of UAH was reported by Ross in 1965,5 there have been less than 50 cases reported in the English literature.2,5–25 We report 2 additional cases of this rare condition and review the literature regarding its unique biochemical features and the outcome after surgical intervention.

METHODS We report 2 patients with a pathologically confirmed diagnosis of PH secondary to UAH treated at the Department of Urology, Singapore General Hospital. In addition, 28 cases of PH secondary to UAH reported in the English literature between 1965 and August 2005 with the pertinent individual clinicopathologic data were reviewed.2,5–23 The 30 patients were analyzed with particular attention to their demographic features, preoperative blood pressure and potassium levels, results of localization studies, and outcome after surgery. All results were presented as median (range).

RESULTS Case Reports Case Report 1 A 56-year-old man was newly diagnosed with hypertension 2 months prior to admission with hypokalemic periodic paralysis. On admission, he had a poorly controlled blood pressure of 180/100 mmHg, a low serum potassium concentration of 1.6 mmol/l, normal sodium of 138 mmol/l, and a serum bicarbonate of 31.2 mmol/l. His thyroid function test was normal. After correction of his hypertension and hypokalemia, he was discharged with long-acting nifedipine [30 mg every morning (o.m.)], atenolol (50 mg o.m.), and potassium supplement of 1.2 g o.m. He was followed up at the outpatient clinic and

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had a blood pressure of 160/100 mmHg and potassium of 3.5 mmol/l on the above medications. Biochemical evaluation revealed a random plasma aldosterone of 642 pg/ml and plasma renin activity (PRA) of 0.15 ng/ml per hour. The 24-hour urine collection showed a urinary aldosterone of 37.3 lg/day (normal: 6.0–25 lg/day) and a urinary potassium of 93 mmol/day (normal: 4– 42 mmol/day). He subsequently underwent a postural test after salt loading. At 08:00 in a supine position, the PRA was 0.22 ng/ml per hour, plasma aldosterone was 113 pg/ml, and cortisol was 361 nmol/l. At 12:00, in an erect position, his PRA was not detectable, plasma aldosterone was 129 pg/ml, and cortisol was 138 nmol/l. The 24-hour urine collection showed urine aldosterone 37.8 lg/day and urine potassium of 85 mmol/day. A computed tomography (CT) scan was then performed, which revealed a 1-cm nodule in his right adrenal gland, suggesting an adrenal adenoma and a normal left adrenal gland. He subsequently underwent laparoscopic right adrenalectomy, which was uncomplicated. Histological examination of the gland showed nodular hyperplasia with no adenoma. There were several uncapsulated circumscribed nodules composed of nests of cells with abundant pale cytoplasm (Fig. 1). He was followed up for 20 months and remained normotensive without antihypertensives and had a normal serum potassium concentration.

Case Report 2 A 57-year-old Chinese woman with hypertension for 2 years on captopril 25 mg three times a day (t.d.s) was referred to us by her family physician for low potassium of 2.3 mmol/l. During her first visit, she had a blood pressure of 135/75 mmHg. Laboratory investigations revealed random plasma aldosterone of 158 pg/ml and PRA of 0.22 ng/ml per hour. After salt loading, her 24-hour urinary potassium excretion was 29 mmol. A CT scan revealed a right 0.8 · 0.5 cm adenoma, with a normal left gland (Fig. 2). Postural study was attempted but the patient could not maintain an erect posture due to her severe bilateral osteoarthritis of her knees. She underwent right laparoscopic adrenalectomy for presumed aldosterone-secreting adenoma, which was uncomplicated. A 0.7-cm adrenal nodule was found intraoperatively. However, final histology revealed only macronodular hyperplasia with no adenoma. There were well-demarcated nodules composed of cells with pale cytoplasm and focal nuclear pleomorphism (Fig. 3). On review at 48 months, the patient had a normal blood pressure and serum potassium concentration of 4.0 mmol/l.

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Figure 2. Computed tomography (CT) scan of case 2, demonstrating the 8 · 5 mm adenoma.

Figure 1. Low-power picture of case 1. A. Well-circumscribed hyperplastic nodule. B. Nests of cells with abundant pale cytoplasm. [Hematoxylin and eosin (H&E); original magnifications: A, · 20; B, · 100].

Clinicopathological Features of the 30 Patients with UAH The demographic and biochemical features of the 30 patients with UAH are listed in Table 1. Table 2 summarizes the results of localization studies and the outcome after surgery of the patients. Median patient age was 49 (range: 10–62) years, with a male to female ratio of 1.7:1. All patients were hypertensive, with a median preoperative systolic and diastolic blood pressure of 170 (range: 135–250) mmHg and 110 (range: 75–140) mmHg, respectively. Most patients were hypokalemic at presentation, with a median serum potassium level of 2.8 (range: 1.4–3.9) mmol/l. Seventeen of the 30 lesions occurred on the right side, and 21/25 patients underwent open adrenalectomy. Ten out of 13 patients (77%) who underwent postural studies had a decrease or no change in the plasma

aldosterone level, suggesting a unilateral source of hyperaldosteronism and 9/17 patients (53%) who underwent a CT scan were correctly localized. Three patients had magnetic resonance imaging (MRI) without CT scan, of which 2 were correctly localized. Twelve patients underwent adrenal scintigraphy with or without dexamethasone suppression, of whom 6 (50%) were correctly localized, 4 showed bilateral uptake, and 1 demonstrated bilateral diminished uptake. In another patient, adrenal scintigraphy demonstrated localization to the opposite gland20. Adrenal venous sampling (AVS) was performed in 22 patients and successfully localized the lesion in all the patients. At a median follow-up of 12 (range: 3–96) months postsurgery, 47% of patients (14/30) were completely cured of their hypertension and a further 50% (15/30) had improved control. Furthermore, all patients were cured of hypokalemia. The summary of patientsÕ clinicopathologic features are summarized in Table 3.

DISCUSSION UAH is extremely rare, with a reported prevalence of only 0.1% of hypertensive patients26. However, it is probably more common than believed due to underdiagnosis of this condition. It is highly likely that some patients treated medically for BAH without prior AVS may be suffering from this disorder, especially those in institu-


Figure 3. Histology pictures of case 2. A. Well-circumscribed hyperplastic nodule. B. Nests of cells with abundant pale cytoplasm. [Hematoxylin and eosin (H&E); original magnifications: A,· 20; B, · 100].

tions where AVS is rarely performed. UAH predominantly affects males and almost always occurs in patients in their 40s to 60s, although the youngest reported case was in a 10-year-old boy.10 Presently, although it is being increasingly accepted as a unique pathological cause of PH, the existence of UAH remains controversial. This is because the follow-up for cases of UAH reported in the literature have been relatively short, with a median follow-up time in our series of only 12 months, including 9 patients with follow-ups of less than a year. It remains to be seen if these patients with UAH will remain cured with longer follow-up or whether they would experience a relapse of PH and thus prove eventually to be cases of bilateral disease. Cases of initial ‘‘success’’ of unilateral adrenalectomy for BAH reported in the literature lend further support to the argument that hyperplasia of the adrenal glands in BAH may occur at different times.13

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In the present review, it may be argued that several of the cases may not represent ‘‘true’’ cases of PH secondary to UAH. Case 1 in this series is widely accepted as the first reported case of UAH.5 However, although the patient was initially cured of PH via unilateral adrenalectomy, he eventually developed a relapse of hyperaldosteronism more than 2 years after surgery. The patient remained cured of his hypertension and hypokalemia, but labarotomy investigations suggested excessive secretion of aldosterone from the remaining adrenal gland. In contrast, case 12 demonstrated improvement of hypertension and hyperaldosteronism after unilateral adrenalectomy but developed a relapse of his hypertension after 6 months. However, his plasma aldosterone and renin levels remained normal. A major criticism of this case was that although AVS demonstrated elevated aldosterone levels on the left side, it was not performed for the right due to failure of cannulation of the right adrenal vein.13 It may also be argued that case 3 in this series may not even represent a true case of PH, as the plasma aldosterone to renin ratio was not conclusive for hyperaldosteronism.6 In this study, we included all histological forms of adrenal hyperplasia with unilateral aldosterone production as UAH. These included micronodular, macronodular, and diffuse hyperplasia. Hence, the entity labeled by Omura et al. and Hirono et al. as unilateral multiple adrenocortical micronodules (UMN) was also included in this study.22,23 The existence of UMN as a unique and separate entity from UAH remains controversial, as both conditions are similar morphologically and functionally. The principal differences between the 2 entities according to Omura et al. is that in UMN, the nodules were poorly encapsulated, cytochrome P-450c17 were absent in the nodules, and there was an absence of 3b-hydroxysteroid dehydrogenase (3b-HSD) in the zona glomerulosa of the affected gland. In contrast, UAH had well-encapsulated nodules containing cytochrome P-450c17, and 3b-HSD in the zona glomerulosa.22 However, other reports in the literature have not revealed consistent histopathological findings for UAH, with both encapsulated and unencapsulated forms being described.19 Presently, there is continuing debate about the optimal evaluation for subtyping patients with PH. The main aim of subtyping is to distinguish between unilateral disease, which is surgically treatable, from bilateral disease. Although AVS is the gold standard in diagnosing a lateralizing source of excess aldosterone, many clinicians forgo this test due to the technical difficulties and potential complications.20 They instead rely on noninvasive tests, such as postural studies, CT scans and adrenal scans.

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Goh et al.: Primary Hyperaldosteronism Secondary to Unilateral Adrenal Hyperplasia Table 1. Demographic and biochemical data of patients with unilateral adrenal hyperplasia (UAH)

Case no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Reference 5

Ross Weinberger6 Weinberger6 Ganguly7 Mendlowitz8 Ganguly9 Ganguly9 Ganguly9 Oberfield10 Kem11 Dye12 Sasagawa13 Pignatelli14 Rao15 Chen16 Otsuka17 Morioka18 Morioka18 Haenel19 Magill2 Magill2 Mansoor20 Katayama21 Omura22 Omura22 Omura22 Omura22 Hirono23 Goh Goh

Age

Gender

Side

60 27 57 45 57 46 62 41 10 NA 48 46 52 48 38 46 62 61 50 NA NA 52 43 60 46 50 46 46 56 57

M F M M M F M M M NA M M F F M F M M M NA NA M M F F F F M M F

L R R R L R L L L R R L L R R L L L R R R R L R L R R L R R

K (mmol/l) 2.8 3.8 3.9 3.4 2.5–2.9 3.2–3.7 2.9–3.8 1.9–4.0 1.4 2.9 3.1 2.9 3.6–5.0 1.6 1.9 2.1 2.7 2.5 3.2 3.2 3.5 2.8–3.2 3.0 Normal Normal Normal Normal 3.6 1.6 2.3

BP (mmHg) 210/120 160/110 170/110 160/115 240/140 210/120 200/112 198/112 150/100 NA 200/120 170/100 160–250/105–140 170/110 150/90 160/110 170/100 160/90 150/84 NA NA 160–190/100–108 140/94 220/108 196/98 180/100 168/94 126–142/94–110 180/100 135/75

PRA (ng/ml/h) NA 0.6 2.1 < 0.02 < 0.00 < 0.5 < 0.5 < 0.5 0.07 NA 0.7 0.43 0.07 0.4 < 0.3 < 0.1 0.16 < 0.1 < 1.0 NA NA 0.2 0.3 0.2 < 0.1 0.1 0.7 0.3 0.15 0.22

PAC (pg/ml)

Op

NA 460 210 196 NA 142 782 242 290 1930 380 286 605 680 302 345 416 330 335 NA NA 140 352 210 199 208 136 76 642 158

Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Open Lap Open Open Lap Open NA NA NA NA NA Lap Lap

BP: blood pressure; PRA: plasma renin activity; PAC: plasma aldosterone concentration; M: male; F: female; R: right; L: left; Op: operation type; Lap: laparoscopy; NA: not applicable.

Our study demonstrates that the response of patients with UAH to postural tests is unpredictable. Of the 13 patients who underwent postural studies, only 10 (77%) had a decrease or no change in the plasma aldosterone level, suggesting a unilateral source of hyperaldosteronism. This is similar to the sensitivity of 65% seen in patients with APA.27 However, despite its low sensitivity, the postural test is still useful in detecting unilateral lesions due to its high positive predictive value of close to 100%.27 The sensitivity of CT scan in detecting an APA has been shown to be approximately 58%–75%, with values approaching 85% using high-resolution scans.2 Thus, it would seem logical that CT scan would be more unreliable in diagnosing patients with UAH. In the present analysis, CT examination correctly localized UAH in 9/17 patients (53%). Another 3 patients had MRI without CT scan, of whom 2 were correctly localized. Thus, these results may seem to suggest that preoperative lateralization of UAH with CT or MRI is reasonably sensitive.

However, one must be wary when interpreting these results, as our study is potentially biased. It is highly likely that in many institutions, including ours, where AVS is not routinely performed, many cases of UAH missed by radiological investigations are wrongly diagnosed as BAH and thus treated medically. Hence, UAH successfully diagnosed via cross-sectional imaging are more likely to be reported in the literature, and the patient population in this review may not be a true reflection of patients with UAH. Adrenal scintigraphy was unreliable in the detection of hyperaldosteronism secondary to UAH in the present study. Only 6/12 patients (50%) with UAH who underwent adrenal scintigraphy with or without dexamethasone suppression were correctly localized. In contrast, AVS was the most accurate test, successfully localizing UAH in all 22 patients for whom it was performed. Hence, the existence of UAH lends support to the argument that AVS should be performed before patients with PH (with negative cross-sectional imaging studies)


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Table 2. Results of localization studies and outcome after surgery of patients with unilateral adrenal hyperplasia (UAH) Case

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Reference

Ross5 Weinberger6 Weinberger6 Ganguly7 Mendlowitz8 Ganguly9 Ganguly9 Ganguly9 Oberfield10 Kem 11 Dye12 Sasagawa13 Pignatelli14 Rao15 Chen16 Otsuka17 Morioka18 Morioka18 Haenel19 Magill2 Magill2 Mansoor20 Katayama21 Omura22 Omura22 Omura22 Omura22 Hirono23 Goh Goh

Postural effect on PAC

AVS

NA fl, 1,000 fi 390 ›, 80 fi 410 M, 196 fi 206 NA ›, 142 fi 202 M, 782 fi 845 fl, 242 fi 206 fl, 646 fi 398 NA NA NA fl, 605 fi 449 ›, 132 fi 231 fl, 381 fi 297 M, 354 fi 355 NA NA NA NA NA NA NA NA NA NA NA M, 93 fi 140 M, 113 fi 129 NA

NA R R R L R L L L NA NA L NA R NA L L NA R R R R L R L R R L NA NA

CT

MRI

Scinti NP59

NA NA NA NA NA NA NA NA NA NA L L L NA NA L L L NA Bilat › Normal Normal L Normal Normal Normal La Normal R R

NA NA NA NA NA NA NA NA NA NA NA L NA Normal R L NA NA R NA NA NA NA NA NA NA NA NA NA NA

NA NA Bilat R>L NA NA NA NA L d3, Bilat d5 R NA Bilat L NA R L Bilat Bilat NA NA NA La No uptake NA NA NA NA NA NA NA

F/U period

2y 3.5 y 3.5 y 3y 6y 3m 3m 3m 1y NA 6m 6m 3m 1y 1y 2y 8y 7m 1y NA NA 6m 1y 2y 2y 2y 2y NA 20 m 14 m

Outcome Hypt

Hypokal

Cured Cured Cured Cured Improved Improved Improved Improved Cured Improved Improved No change Cured Cured Cured Cured Cured Cured Cured Improved Improved Improved Improved Imp/curedb Imp/curedb Imp/curedb Imp/curedb Improved Cured Cured

Cured NA NA Cured Cured Cured Cured Cured Cured NA Cured Cured Normal Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured Cured

PAC: plasma aldosterone concentration; AVS: adrenal venous sampling; CT: computed tomography; MRI: magnetic resonance imaging; Scinti: scintigraphy; F/U: follow-up; Hypt: hypertension; Hypokal: hypokalemia; NA: results not available; Bilat: bilateral; R: right; L: left; y: year; m: month; d: day. a Wrong side. b Not known if cured or improved.

are treated for BAH and started on medical treatment.28 This is to avoid missing a unilateral, and hence potentially curable, lesion. However, this may only be true in institutions where AVS is performed frequently and its complication rate is low, as the risks of missing a unilateral lesion should be carefully balanced against the risks associated with AVS. Furthermore, AVS is a technically demanding procedure associated with a high failure rate of 26% for the right adrenal vein.24 The present analysis demonstrates that patients with PH secondary to UAH have excellent outcomes after surgical treatment. Ninety-seven patients were completely cured or had improved control of their hypertension at a median follow-up of 1 year after surgery.

Furthermore, all patients were cured of hypokalemia. These excellent results are similar to those of unilateral adrenalectomy for aldosteronoma, whereby up to 90% of patients were cured or had improved hypertensive control, and almost all patients had resolution of hypokalemia.29,30 In contrast, patients with BAH frequently experience rapid recurrence of their hypokalemia and hypertension within 1–2 weeks after unilateral adrenalectomy.25 Hence, unilateral adrenalectomy should be the treatment of choice for patients with PH secondary to UAH. Although only 4 of the 25 patients underwent laparoscopic adrenalectomy, we propose that laparoscopy should be the preferred approach for UAH, as this procedure has become the treatment of choice and has

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Table 3. Summary of the clinicopathological features of the 30 patients Characteristic No. of patients Median age (years) Gender (M:F ratio) Hypertensive Median preoperative systolic blood pressure (BP) (mmHg) Median preoperative diastolic BP (mmHg) Median potassium (K+) level (mmol/l) Localization, right side Correct localization CT Adrenal scintigraphy Adrenal venous sampling Median follow-up (months) Outcome Hypertension cured Hypertension improved Normokalemia

30 50 (10–62) 1.7:1 30 170 (135–250)

110 (75–140) 2.8 (1.4–3.9) 17 9/17 6/12 22/22 12 (3–96) 14/30 15/30 30/30

replaced open surgery for the removal of adrenal tumours.29 Laparoscopic adrenalectomy demonstrates the many benefits of minimally invasive surgery, including decreased postoperative pain, shortened hospitalization, more rapid convalescence, decrease in overall cost, and decreased morbidity with the smaller incisions and shorter postoperative recovery time.29 In conclusion, UAH is an unusual cause of PH, with excellent outcome after unilateral adrenalectomy. However, long-term follow-up in larger numbers of patients is required to determine if this is a truly unique clinicopathologic entity or whether UAH may just represent BAH presenting initially with asymmetrical hyperplasia and aldosterone production.

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