A Nationwide Study on Primary Aldosteronism in Iceland. From Detection to Immunohistochemistry and Genetic Testing.

Abstract

Introduction Primary aldosteronism (PA) is the most common cause of secondary hypertension (HT), accounting for up to 29% of cases of resistant HT and 14% in general practice. Familial hyperaldosteronism (FH) is a rare cause of PA. The most common presentation of PA is HT with normal potassium levels. PA is widely underdiagnosed, and diagnostic delay reduces treatment efficacy. Early detection and specialized treatment are crucial as PA carries significantly higher cardiovascular risk than essential HT. Adrenal venous sampling (AVS) is the gold standard method to differentiate between unilateral and bilateral PA. Adrenalectomy is potentially curative for the unilateral group, while bilateral disease is managed with mineralocorticoid receptor antagonists (MRA). Immunohistochemistry (IHC) has advanced the histopathological diagnosis of unilateral PA and shown potential in predicting outcomes. Standardized methods for outcome evaluation were introduced recently. The aims of this thesis were to investigate the incidence of PA in Iceland during the study period and assess whether it is underdiagnosed. Additionally, to compare results from screening and confirmatory tests between AVS subgroups and evaluate treatment outcomes. Another objective was to assess long-term outcomes and follow-up needs by classifying patients based on IHC. Finally, we aimed to explore the role of the posture test (PT) and screen the appropriate patients for FH. Methods In 2007, an evidence-based PA work-up protocol was introduced in Landspítali National University Hospital of Iceland. The study cohort consisted of all adults diagnosed with PA during the 10-year period 2007–2016. Screening was performed by measuring morning serum aldosterone, direct renin concentration and 24-hour urinary excretion of aldosterone (UEA). PA was confirmed through the recumbent saline infusion test. All patients underwent adrenal computed tomography (CT) and a 4-hour PT. AVS was used for subtyping. Unilateral PA was treated with laparoscopic adrenalectomy and bilateral PA was managed with MRA. During follow-up visits, blood pressure (BP) was measured, need for potassium supplementation evaluated, and antihypertensive treatment assessed. Outcomes were evaluated based on the alterations in BP, count of antihypertensives, and need for potassium supplementation. Clinical outcomes were further assessed using the Primary Aldosterone Surgical Outcome criteria and the Primary Aldosteronism Medical Outcome criteria. IHC was performed to reevaluate routinely stained tissue samples and histopathological diagnoses using The International Histopathology Consensus for Unilateral Primary Aldosteronism (HISTALDO). Outcomes v were compared between HISTALDO subgroups and the need for follow-up was evaluated. First-degree relatives within the study cohort were screened for FH. Results Between 2007 and 2016, the incidence of confirmed PA in Iceland was 58 cases, 47% (n = 27) had unilateral disease and 53% (n = 31) bilateral. All patients had hypokalaemia at case detection or during work-up. Compared to the bilateral group, the unilateral group had a significantly higher UEA (33,9 vs. 24,6 μg, p < 0,001), post- infusion aldosterone levels (385 vs. 251 pmol/l, p = 0,01), and a higher frequency of adrenal nodules (19/27 vs. 10/31, p = 0,008). The bilateral group was significantly more responsive to posture (206% vs. 56%, p = 0,002). The PT had 81% sensitivity and 45% specificity for detecting bilateral PA. The combination of CT and PT was 96% specific and 32% sensitive for detecting unilateral PA. The AVS success rate was 86% (57/66), with 7/9 failed AVS performed on women (p = 0,08). Following IHC, classical histopathology was identified in 85% (22/26) of the unilateral group, with 23% (6/26) alteration of histopathological diagnoses. During follow-up, both the unilateral and bilateral group experienced significant reductions in systolic BP (p < 0,001, both groups), antihypertensive use (p = 0,002, p = 0,04, respectively), and potassium supplementation needs (p < 0,001, both groups). All patients with classical histopathology who achieved complete clinical success at 12 months (n = 5) remained normotensive without antihypertensives throughout the follow-up period (4–10 years). FH screening among brothers (n = 2) within the cohort yielded negative results. Conclusions This study highlights the underdiagnosis of PA in Iceland as the incidence was low and all patients in the cohort had hypokalaemia. Most cases presented with severe PA, emphasizing the need for increased awareness and broader screening indications at earlier stages of the disease. Unilateral PA was associated with more severe disease at presentation and a more significant reduction in antihypertensive use during follow-up, indicating better treatment response. The combination of PT and CT was highly specific for detecting unilateral PA. IHC improved histopathological diagnosis and was essential for accurate diagnosis. Additionally, follow-up could be individualized based on IHC results, though further research is needed to confirm this. Overall, our study underlines the need for improved screening, a simpler work-up, and personalized treatment and follow-up strategies to optimize PA care.

Frumkomið aldósterónheilkenni (FA) er algengasta orsök afleidds háþrýstings. Allt að 29% lyfjaþolins háþrýstings og 14% háþrýstings í heilsugæsluþýði orsakast af sjúkdómnum. Arfgeng form FA eru sjaldgæf. Algengasta birtingarmynd sjúkdómsins er háþrýstingur með eðlilegu blóðkalíumgildi. FA er víða vangreint og greiningartöf dregur úr meðferðarárangri. Snemmgreining og sérhæfð meðferð skipta sköpum því sjúkdómnum fylgir aukin hættu á hjarta- og æðaáföllum samanborið við frumkominn háþrýsting. Nýrnahettubláæðaþræðing (NHBÞ) er áreiðanlegasta aðferðin til mats á því hvort FA er í annarri eða báðum nýrnahettum (einhliða eða tvíhliða). Nýrnahettubrottnám getur veitt lækningu ef einhliða en tvíhliða sjúkdómur er meðhöndlaður með aldósterón-viðtakahindrum. Sértæk mótefni hafa bætt vefjagreiningu í einhliða FA. Staðlaðar aðferðir við mat á meðferðarárangri komu fram nýlega. Markmið rannsóknarinnar voru að kanna nýgengi FA á rannsóknartímabilinu og meta hvort sjúkdómurinn sé vangreindur á Íslandi. Ennfremur að gera samanburð á niðurstöðum úr skimun og frekari uppvinnslu á milli undirhópa og meta meðferðarsvörun. Einnig að meta áreiðanleika stöðuprófs og vægi sértækrar mótefnalitunar með tilliti til áreiðanleika greiningar og þarfar á eftirfylgd. Loks var kannað hvort arfgeng form FA fyndust innan þýðisins.