Strategies for subtyping primary aldosteronism.

Adrenal venous sampling (AVS) is a crucial method for the lateralization of primary aldosteronism (PA). It is advised to halt the use of the patient's antihypertensive medications and correct hypokalemia prior to undergoing AVS. Hospitals equipped to conduct AVS should establish their own diagnostic criteria based on current guidelines. If the patient's antihypertensive medications cannot be discontinued, AVS can be performed as long as the serum renin level is suppressed. The Task Force of Taiwan PA recommends using a combination of adrenocorticotropic hormone stimulation, quick cortisol assay, and C-arm cone-beam computed tomography to maximize the success of AVS and minimize errors by using the simultaneous sampling technique. If AVS is not successful, an NP-59 (131 I-6-ß-iodomethyl-19-norcholesterol) scan can be used as an alternative method to lateralize PA. We depicted the details of the lateralization procedures (mainly AVS, and alternatively NP-59) and their tips and tricks for confirmed PA patients who would consider to undergo surgical treatment (unilateral adrenalectomy) if the subtyping shows unilateral disease.

Evaluation of standardized uptake value on 131I-6ß-iodomethyl-19-norcholesterol scintigraphy for diagnosis of primary aldosteronism and correspondence with adrenal venous sampling.

PURPOSE: Adrenal venous sampling (AVS) is a reliable method for lateralization of adrenal hormone secretion, which is important for discriminating between aldosterone-producing adenoma and bilateral adrenal hyperplasia, both of which cause primary aldosteronism (PA). The aim of this study was to evaluate the diagnostic accuracy of the maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) of 131I-6ß-iodomethyl-19-norcholesterol (NP-59) single-photon emission computed tomography (SPECT) for PA and its correspondence with AVS. METHODS: Adrenal NP-59 scintigraphy was performed in 14 patients with suspected PA, and AVS was also performed in 7 of them. SUVmax and SUVmean of the adrenal lesions on the dominant side and their ratios to the values on the non-dominant side (SUVRmax and SUVRmean, respectively) were calculated on SPECT images using ordered-subset conjugate gradient minimization (OSCGM) and three-dimensional ordered-subset expectation maximization (3D-OSEM) reconstruction algorithms. RESULTS: SUVmax and SUVmean on NP-59 SPECT images were significantly higher for aldosterone-producing adenoma than for bilateral adrenal hyperplasia or non-functioning adenoma and slightly superior to SUVRmax and SUVRmean (P = 0.0475 and P = 0.0447 vs. P = 0.124 and P = 0.132, respectively, with OSCGM). The respective areas under the receiver-operating characteristic curve for SUV and SUVR were 0.933 and 0.725 with OSCGM and 0.844 and 0.750 with 3D-OSEM, while SUVmax and SUVRmax had exactly the same diagnostic accuracy as SUVmean and SUVRmean. SUV and SUVR were associated with the diagnostic features on AVS and consistent with lateralization by AVS in most patients. CONCLUSION: In this study, SUV on NP-59 SPECT helped in the diagnosis of PA and was consistent with the results of AVS in nearly all cases.

Predicting Treatment Response in Primary Aldosteronism Using 11 C-Metomidate Positron Emission Tomography.

BACKGROUND: Appropriate treatment of primary aldosteronism (PA) depends on accurate lateralization. 11 C-metomidate (MTO) is a tracer used in PET that provides functional information about the adrenal cortex. We aimed to perform MTO PET for patients with PA who are managed according to the guideline and to verify its correlation with other lateralization modalities and usefulness in outcome prediction. METHODS: Seventeen patients with PA who underwent MTO PET and had ≥1 lateralization modality (adrenal venous sampling and/or NP-59 adrenal scintigraphy) were included. SUV max of each adrenal gland (higher uptake side, HSUV max ; lower uptake side, LSUV max ) and the ratio of HSUV max to LSUV max (contrast) were compared with lateralization modalities, postsurgical outcomes, and medical treatment outcomes. Cutoff values were used as outcome predictors. RESULTS: HSUV max and LSUV max increased in the order of bilateral, unilateral, and negative findings of CT, with opposite order of contrast. High discordant rate between MTO PET and other lateralization modalities was noted. Biochemical responders (n = 8) had significantly lower HSUV max and LSUV max than nonresponders, and clinical responders (n = 6) had borderline lower HSUV max than nonresponders. By optimal cutoff values of HSUV max and LSUV max , MTO PET was able to predict biochemical and clinical outcomes in patients with medical treatment. CONCLUSION: According to adrenal CT findings, MTO PET presented different uptake patterns. Patients with PA under medical treatment showed significantly lower tracer uptake in responders. Thus, MTO PET may be a useful imaging biomarker to predict medical treatment outcome. Multicenter prospective study with a larger number of patients is needed for further validation.

Development of Fluorinated NP-59: A Revival of Cholesterol Use Imaging with PET.

Imaging of cholesterol use is possible with the 131I scintiscanning/SPECT agent NP-59. This agent provided a noninvasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact. A 18F analog would address these shortcomings while retaining the ability to image cholesterol use. The goal of this study was to prepare and evaluate a 18F analog of NP-59 to serve as a PET imaging agent for functional imaging of the adrenal glands based on cholesterol use. Previous attempts to prepare such an analog of NP-59 have proven elusive. Preclinical and clinical evaluation could be performed once the new fluorine analog of NP-59 production was established. Methods: The recent development of a new reagent for fluorination along with an improved route to the NP-59 precursor allowed for the preparation of a fluorine analog of NP-59, FNP-59. The radiochemistry for the 18F-radiolabeled 18F-FNP-59 is described, and rodent radiation dosimetry studies and in vivo imaging in New Zealand rabbits was performed. After in vivo toxicity studies, an investigational new drug approval was obtained, and the first-in-humans images with dosimetry using the agent were acquired. Results: In vivo toxicity studies demonstrated that FNP-59 is safe for use at the intended dose. Biodistribution studies with 18F-FNP-59 demonstrated a pharmacokinetic profile similar to that of NP-59 but with decreased radiation exposure. In vivo animal images demonstrated expected uptake in tissues that use cholesterol: gallbladder, liver, and adrenal glands. In this first-in-humans study, subjects had no adverse events and images demonstrated accumulation in target tissues (liver and adrenal glands). Manipulation of uptake was also demonstrated with patients who received cosyntropin, resulting in improved uptake. Conclusion: 18F-FNP-59 provided higher resolution images, with lower radiation dose to the subjects. It has the potential to provide a noninvasive test for patients with adrenocortical diseases.

NP-59 Adrenal Scintigraphy as an Imaging Biomarker to Predict KCNJ5 Mutation in Primary Aldosteronism Patients.

Purpose: Somatic KCNJ5 mutation occurs in half of unilateral primary aldosteronism (PA) and is associated with more severe phenotype. Mutation status can only be identified by tissue sample from adrenalectomy. NP-59 adrenal scintigraphy is a noninvasive functional study for disease activity assessment. This study aimed to evaluate the predictive value of NP-59 adrenal scintigraphy in somatic KCNJ5 mutation among PA patients who received adrenalectomy. Methods: Sixty-two PA patients who had NP-59 adrenal scintigraphy before adrenalectomy with available KCNJ5 mutation status were included. Two semiquantitative parameters, adrenal to liver ratio (ALR) and lesion to contralateral ratio of bilateral adrenal glands (CON) derived from NP-59 adrenal scintigraphy, of mutated and wild-type patients were compared. Cutoff values calculated by receiver-operating characteristic (ROC) analysis were used as a predictor of KCNJ5 mutation. Results: Twenty patients had KCNJ5 mutation and 42 patients were wild type. Patients harboring KCNJ5 mutation had both higher ALR and CON (p = 0.0031 and 0.0833, respectively) than wild-type patients. With ALR and CON cutoff of 2.10 and 1.95, the sensitivity and specificity to predict KCNJ5 mutation were 85%, 57% and 45%, 93%, respectively. Among 20 patients with KCNJ5 mutation, 16 showed G151R point mutation (KCNJ5- G151R) and 4 showed L168R point mutation (KCNJ5-L168R), which former one had significantly lower ALR (p=0.0471). Conclusion: PA patients harboring somatic KCNJ5 mutation had significantly higher NP-59 uptake regarding to ALR and CON than those without mutation. APAs with KCNJ5-L168R point mutation showed significantly higher ALR than those with KCNJ5-G151R point mutation.

Imaging of hepatic drug transporters with [131I]6-ß-iodomethyl-19-norcholesterol.

We examined whether [131I]6-ß-iodomethyl-19-norcholesterol (NP-59), a cholesterol analog, can be used to measure function of hepatic drug transporters. Hepatic uptake of NP-59 with and without rifampicin was evaluated using HEK293 cells expressing solute carrier transporters. The stability of NP-59 was evaluated using mouse blood, bile, and liver, and human liver S9. Adenosine triphosphate-binding cassette (ABC) transporters for bile excretion were examined using hepatic ABC transporter vesicles expressing multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1-4, breast cancer resistance protein (BCRP), or bile salt export pump with and without MK-571 and Ko143. Single photon emission computed tomography (SPECT) was performed in normal mice injected with NP-59 in the presence or absence of Ko143. Uptake of NP-59 into HEK293 cells expressing organic anion transporting polypeptide (OATP)1B1 and OATP1B3 was significantly higher than that into mock cells and was inhibited by rifampicin. NP-59 was minimally metabolized in mouse blood, bile, and liver, and human liver S9 after 120 min of incubation. In vesicles, NP-59 was transported by MRP1 and BCRP. Excretion of NP-59 into bile via BCRP was observed in normal mice with and without Ko143 in the biological distribution and SPECT imaging. NP-59 can be used to visualize and measure the hepatic function of OATP1B1, OATP1B3, and BCRP.

Case detection and diagnosis of primary aldosteronism - The consensus of Taiwan Society of Aldosteronism.

BACKGROUND/PURPOSE: Even though the increasing clinical recognition of primary aldosteronism (PA) as a public health issue, its heightened risk profiles and the availability of targeted surgical/medical treatment being more understood, consensus in its diagnosis and management based on medical evidence, while recognizing the constraints of our real-world clinical practice in Taiwan, has not been reached. METHODS: The Taiwan Society of Aldosteronism (TSA) Task Force acknowledges the above-mentioned issues and reached this Taiwan PA consensus at its inaugural meeting, in order to provide updated information of internationally acceptable standards, and also to incorporate our local disease characteristics into the management of PA. RESULTS: When there is suspicion of PA, a plasma aldosterone to renin ratio (ARR) should be obtained initially. Patients with abnormal ARR will undergo confirmatory laboratory and image tests. Subtype classification with adrenal venous sampling (AVS) or NP-59 nuclear imaging, if AVS not available, to lateralize PA is recommended when patients are considered for adrenalectomy. The strengths and weaknesses of the currently available identification methods are discussed, focusing especially on result interpretation. CONCLUSION: With this consensus we hope to raise more awareness of PA among medical professionals and hypertensive patients in Taiwan, and to facilitate reconciliation of better detection, identification and treatment of patients with PA.

NP-59 test for preoperative localization of primary hyperaldosteronism.

PURPOSE: Adrenal venous sampling is generally considered the gold standard to identify unilateral hormone production in cases of primary hyperaldosteronism. The aim of this study is to evaluate whether the iodine-131-6-ß-iodomethyl-19-norcholesterol (NP-59) test may represent an alternative in selected cases. METHODS: Patients submitted to laparoscopic adrenalectomy for suspected primary hyperaldosteronism (n = 27) were retrospectively reviewed. When nuclear medicine tests were preoperatively performed, their results were compared with the histopathologic findings and clinical improvement. RESULTS: Nuclear medicine tests were realized in 13 patients. In 11 (84.6%), a planar anterior and posterior NP-59 scintigraphy was performed and a SPECT/TC in two (15.4%). Scintigraphy indicated a preoperative lateralization in 12 out of 13 patients (92.3%). When the value of NP-59 tests was based on pathologic results, it showed a sensitivity of 90.9% and a positive predictive value of 83.3%. When the nuclear medicine test's performance was based on postoperative blood pressure control, both sensitivity and positive predictive value were 91.6%. CONCLUSIONS: Nuclear medicine tests represent a useful tool in the preoperative localisation of primary hyperaldosteronism with a high sensitivity and positive predictive value. In patients with contraindications to adrenal venous sampling like contrast allergies, or when it is inconclusive, scintigraphy can represent a useful and non-invasive alternative.

Hormonal, Radiological, NP-59 Scintigraphy, and Pathological Correlations in Patients With Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease (PPNAD).

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing's syndrome that may occur in an isolated form or as part of Carney complex. The diagnosis of this disease can be difficult preoperatively because computed tomography (CT) scan can be normal or suggest unilateral adrenal lesion, which can impede the correct diagnosis of bilateral adrenal disease. OBJECTIVE: The aim of our study was to describe the results of preoperative imaging (adrenal [6ß-(131)I]iodomethyl-19-norcholesterol] [NP-59] scintigraphy and standard adrenal CT scan) and their correlations with clinical, pathological, and genetics investigations in patients with PPNAD. PATIENTS AND METHODS: Seventeen patients with ACTH-independent syndrome due to PPNAD were investigated with a standard adrenal CT scan and NP-59 scintigraphy. Hormonal, pathological, and genetics data were analyzed. RESULTS: Four males and 13 females (median age, 27 y) were included. PPNAD was isolated in 11 patients (with PRKAR1A mutation, n = 7; and without PRKAR1A mutation, n = 4) and was associated with extra-adrenal manifestations of Carney complex in six patients (with PRKAR1A mutation, n = 4; and without PRKAR1A mutation, n = 2). Standard adrenal CT scan revealed micronodules in 11 patients, macronodules in three patients, and was normal in three patients. All patients demonstrated bilateral adrenal radiocholesterol uptake. Adrenal uptake was asymmetrical in 10 of 17 patients (59%). Asymmetrical uptake correlated with the presence of macronodules at pathological analysis (P = .03). CONCLUSION: Standard adrenal CT scan most often reveals micronodules but there is no specific CT imaging. NP-59 scintigraphy always shows a bilateral adrenal uptake confirming the bilateral nature of the disease, but asymmetrical scintigraphic uptake can be observed in patients with macronodules.

Adrenal (131)I-6ß-iodomethylnorcholesterol scintigraphy in choosing the side for adrenalectomy in bilateral adrenal tumors with subclinical hypercortisolemia.

PURPOSE: Adrenal scintigraphy with 131I-6ß-iodomethylnorcholesterol is considered by several authors the gold standard for assessing tumors with subclinical hypercortisolemia. However, most of the described series consist mainly of cases with unilateral lesions. The aim of our study was to assess whether scintigraphy is useful in choosing the adrenalectomy side in the case of bilateral adrenal tumors with subclinical hypercortisolemia. METHODS: The study focused on 15 consecutive patients with benign bilateral adrenal tumors and subclinical hypercortisolemia. The scintigraphy with 131I-6ß-iodomethylnorcholesterol was performed. Fourteen patients underwent unilateral adrenalectomy; the gland with predominant uptake on scintigraphy was removed. Cortisol and ACTH concentrations were measured one and six months after surgery. Post-dexamethasone cortisolemia was assessed six months after surgery. To date, the patients have been under postoperative observation for 1-4 years. RESULTS: Four patients showed unilateral uptake of radiotracer, and nine patients showed predominant accumulation of radiotracer in one of the adrenal glands. The smaller tumor was predominant in 2 cases. Percentage of activity on the predominant side correlates positively with the difference between tumors' diameters. Unilateral uptake of radiotracer predicts long-lasting postoperative insufficiency of the second adrenal gland. Excision of predominating tumor led to cessation of hypercortisolemia in all patients. CONCLUSIONS: The corticoadrenal scintigraphy is useful in choosing the side for operation in the case of bilateral adrenal tumors with subclinical hypercortisolemia.

Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors.

Subclinical Cushing's syndrome (SCS) is characterized by subtle autonomous cortisol secretion from adrenal tumors without specific signs and symptoms of hypercortisolism. Patients with SCS have a high prevalence of "lifestyle-related diseases," such as hypertension, diabetes mellitus, dyslipidemia, and osteoporosis. Long-term follow-up of SCS patients is reportedly indispensable for establishing indications for surgical treatment of SCS. We performed a follow-up survey of 27 patients with SCS (median: 5.3 years) and compared those who had undergone surgical treatment (n=15) with those who had not (n=12). The mean diameter of tumors was 31 mm; 16 (59%) patients had unilateral lesions and 11 (41%) carried bilateral ones. In 67% and 60% of the treatment group, respectively, hypertension and diabetes mellitus improved. We also noticed that eight of 11 (73%) SCS patients with bilateral adrenal tumors had extra-adrenal malignancies in various tissues. Interestingly, among nine SCS patients who had malignancies, eight showed bilateral adrenal uptake in ¹³¹I-aldosterol scintigraphy. The results imply that surgical treatment can reduce cardiovascular risks in SCS patients. Screening for malignancy may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

Prognostic value of semiquantification NP-59 SPECT/CT in primary aldosteronism patients after adrenalectomy.

PURPOSE: Primary aldosteronism (PA), characterized by an excessive production of aldosterone, affects 5-13 % of patients with hypertension. Accurate strategies are needed for the timely diagnosis of PA to allow curability and prevention of excessive cardiovascular events and related damage. This study aimed to evaluate the usefulness of semiquantification of (131)I-6ß-iodomethyl-norcholesterol (NP-59) single photon emission computed tomography (SPECT)/CT in differentiating aldosterone-producing adenoma (APA) from idiopathic adrenal hyperplasia (IAH) and in predicting clinical outcomes after adrenalectomy. METHODS: We retrospectively reviewed 49 PA patients who had undergone adrenalectomy after NP-59 SPECT/CT within 1 year. A conventional visual scale (VS) and two semiquantitative parameters generated from SPECT/CT, adrenal to liver ratio (ALR) and lesion to contralateral ratio of bilateral adrenal glands (CON), with cutoff values calculated by receiver-operating characteristic (ROC) analysis, were compared with pathology results and postsurgical outcomes to determine the accuracy. RESULTS: An ALR cutoff of 1.84 and a CON cutoff of 1.15 showed an ability to distinguish adenoma from hyperplasia similar to VS (p = 0.2592 and 0.1908, respectively). An ALR cutoff of 2.28 and a CON cutoff of 1.11 yielded the highest sensitivity and specificity to predict postsurgical outcomes, and an ALR of 2.28 had an ability superior to VS (p = 0.0215), while a CON of 1.11 did not (p = 0.1015). Patients with either ALR or CON greater than the cutoff had a high probability of positive postsurgical outcomes (n = 36/38), while patients with both ALR and CON less than the cutoff had a low probability of positive postsurgical outcomes (n = 2/11). CONCLUSION: Semiquantification of NP-59 scintigraphy has an ability similar to VS in differentiating APA from IAH, but an excellent ability to predict postsurgical outcomes of adrenalectomy. An ALR or CON greater than the cutoff strongly suggests benefits from adrenalectomy, and both ALR and CON less than the cutoff implies a reduced chance of improvement in postsurgical outcome.

NP-59 SPECT/CT imaging in stage 1 hypertensive and atypical primary aldosteronism: a 5-year retrospective analysis of clinicolaboratory and imaging features.

OBJECTIVE: We retrospectively analyzed all primary aldosteronism (PA) patients undergoing NP-59 SPECT/CT imaging with regard to their clinicolaboratory and imaging features, investigation, and outcomes. MATERIAL AND METHODS: 11 PA patients who presented to our hospital for NP-59 SPECT/CT imaging between April 2007 and March 2012 and managed here were analyzed. RESULTS: Among 11 PA patients, eight (73%) had stage 1 hypertension, three (27%) stage 2 hypertension, four (36%) normal plasma aldosterone concentration, nine (82%) nonsuppressed plasma renin activity (PRA), six (55%) normal aldosterone-renin-ratio (ARR), eight (73%) serum potassium ≧3 mEq/L, seven (64%) subclinical presentation, seven (64%) negative confirmatory testing, and four (36%) inconclusive results on CT scan and seven (64%) on planar NP-59 scan. All 11 (100%) patients had positive results on NP-59 SPECT/CT scan. Two (18%) met typical triad and nine (82%) atypical triad. Among nine atypical PA patients, three (33%) had clinical presentation, six (67%) subclinical presentation, six (67%) negative confirmatory testing, and four (44%) inconclusive results on CT scan and six (67%) on planar NP-59 scan. All patients had improved outcomes. Significant differences between typical and atypical PA existed in PRA and ARR. CONCLUSIONS: NP-59 SPECT/CT may provide diagnostic potential in stage 1 hypertensive and atypical PA.

Is there a role for Nuclear Medicine in diagnosis and management of patients with primary aldosteronism?

Primary aldosteronism (PA) is the most common cause of secondary hypertension. The diagnosis of PA is of clinical importance for choosing the appropriate treatment, meaning, surgery for the unilateral disease, and inclusion of aldosterone antagonists in the antihypertensive treatment for the bilateral disease. Current diagnostic approaches showed that the prevalence of PA is much higher than previously estimated. There is still controversy regarding the true prevalence of PA in hypertensive patients. The gold standard for differentiating between unilateral and bilateral disease is the adrenal vein sampling (AVS), a method that is invasive and is performed accurately in only few dedicated centers. Non invasive methods (imaging) for discriminating the two entities are: the CT scan, MRI and iodocholesterol (NP-59) scintigraphy performed under dexamethasone suppression. But the accuracy of imaging compared to AVS is suboptimal and can result in wrong therapeutic decisions. NP-59 scintigraphy is a non-invasive functional imaging technique that reveals the adrenal cortical autonomic function and could have of incremental value over anatomical imaging. In conclusion, in previous years NP-59 scintigraphy was used infrequently, but recently with the advent of hybrid single photon emission tomography (SPET/CT) systems the interest in NP-59 scintigraphy has been renewed. Studies comparing NP-59 SPET/CT imaging with AVS are warranted in order to establish its diagnostic accuracy.

Diagnosis of primary aldosteronism in chronic kidney disease by I-131 NP-59 SPECT/CT imaging.

Primary aldosteronism (PA) may be missed in patients with chronic kidney disease (CKD), because CKD may disturb the renin-angiotensin-aldosterone system. Adrenal vein sampling has increased risks in patients with CKD. We report the case of a 58-year-old man with CKD and suspected PA. Left adrenal aldosteronism was diagnosed by NP-59 SPECT/CT. Left adrenalectomy demonstrated adrenocortical nodular hyperplasia. Plasma aldosterone normalized and blood pressure stabilized after surgery. NP-59 SPECT/CT may be a helpful diagnostic tool for detecting and lateralizing PA in CKD patients.

Diagnostic value of I-131 NP-59 SPECT/CT scintigraphy in patients with subclinical or atypical features of primary aldosteronism.

Accumulating evidence has shown the adverse effect of long-term hyperaldosteronism on cardiovascular morbidity that is independent of blood pressure. However, the diagnosis of primary aldosteronism (PA) remains a challenge for patients who present with subtle or atypical features or have chronic kidney disease (CKD). SPECT/CT has proven valuable in the diagnosis of a number of conditions. The aim of this study was to determine the usefulness of I-131 NP-59 SPECT/CT in patients with atypical presentations of PA and in those with CKD. The records of 15 patients with PA were retrospectively analyzed. NP-59 SPECT/CT was able to identify adrenal lesion(s) in CKD patients with suspected PA. Patients using NP-59 SPECT/CT imaging, compared with those not performing this procedure, significantly featured nearly normal serum potassium levels, normal aldosterone-renin ratio, and smaller adrenal size on CT and pathological examination and tended to feature stage 1 hypertension and non-suppressed plasma renin activity. These findings show that noninvasive NP-59 SPECT/CT is a useful tool for diagnosis in patients with subclinical or atypical features of PA and those with CKD.