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BACKGROUND: Diagnosis of primary aldosteronism (PA) is complicated by the need to withdraw antihypertensive medications that interfere with test results, particularly renin. This study examined whether machine learning-based steroid-probability scores offer a renin measurement-independent approach for testing less prone to interference than the aldosterone-to-renin ratio (ARR). METHODS: This prospective multicenter cohort study involved the use of plasma steroidomics and the ARR in 839 patients tested for PA, including 190 with and 578 without PA (71 indeterminate). Receiver operating characteristic curves for steroid-probability scores and the ARR were examined with and without interfering medications. Impacts of individual medications on plasma aldosterone, 18-oxocortisol, 18-hydroxycortisol, steroid-probability scores, renin, and ARRs were examined by multivariable and paired analyses in patients with and without PA. RESULTS: Receiver operating characteristic curves indicated a significant impact of interfering antihypertensive medications on the diagnostic performance of the ARR and minimal impact on steroid-probability scores. Mineralocorticoid receptor antagonists increased plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol in patients without PA and resulted in false-positive test results for steroid-probability scores and false-negative results for the ARR. Diuretics increased aldosterone, 18-oxocortisol, and steroid-probability scores in patients without PA, whereas angiotensin-converting enzyme inhibitors decreased aldosterone, steroid-probability scores, and ARRs. Beta-adrenoceptor blockers, dihydropyridine calcium channel blockers, and angiotensin receptor blockers had negligible impact on mineralocorticoids and steroid-probability scores. CONCLUSIONS: Among antihypertensive drugs that impact plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol, mineralocorticoid receptor antagonists stood out as a cause of false-positive results for derived steroid-probability scores. Other antihypertensives have minimal or no impact, an advantage for use of steroid-probability scores over the ARR when those medications cannot be withdrawn. REGISTRATION: URL: https://drks.de/; Unique identifier: DRKS00017084.
RÉSUMÉ
Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.
Sujet(s)
Tumeurs de la surrénale , Cortisone , Syndrome de Cushing , Diabète , Hypertension artérielle , Paragangliome , Phéochromocytome , Femelle , Humains , Adulte d'âge moyen , Mâle , Hydrocortisone/métabolisme , Études rétrospectives , Syndrome de Cushing/complications , Stéroïdes , Tumeurs de la surrénale/complications , Hypertension artérielle/complications , Phéochromocytome/complications , Paragangliome/complications , Catécholamines , DéhydroépiandrostéroneRÉSUMÉ
BACKGROUND: Measurements of aldosterone by mass spectrometry are more accurate and less prone to interferences than immunoassay measurements, and may produce a more accurate aldosterone:renin ratio (ARR) when screening for primary aldosteronism (PA). METHODS: Differences in diagnostic performance of the ARR using mass spectrometry vs immunoassay measurements of aldosterone were examined in 710 patients screened for PA. PA was confirmed in 153 patients and excluded in 451 others. Disease classifications were not achieved in 106 patients. Areas under receiver-operating characteristic curves (AUROC) and other measures were used to compare diagnostic performance. RESULTS: Mass spectrometry-based measurements yielded lower plasma aldosterone concentrations than immunoassay measurements. For the ARR based on immunoassay measurements of aldosterone, AUROCs were slightly lower (P = 0.018) than those using mass spectrometry measurements (0.895 vs 0.906). The cutoff for the ARR to reach a sensitivity of 95% was 30 and 21.5â pmol/mU by respective immunoassay and mass spectrometry-based measurements, which corresponded to specificities of 57% for both. With data restricted to patients with unilateral PA, diagnostic sensitivities of 94% with specificities >81% could be achieved at cutoffs of 68 and 52â pmol/mU for respective immunoassay and mass spectrometry measurements. CONCLUSIONS: Mass spectrometry-based measurements of aldosterone for the ARR provide no clear diagnostic advantage over immunoassay-based measurements. Both approaches offer limited diagnostic accuracy for the ARR as a screening test. One solution is to employ the higher cutoffs to triage patients likely to have unilateral PA for further tests and possible adrenalectomy, while using the lower cutoffs to identify others for targeted medical therapy.German Clinical Trials Register ID: DRKS00017084.
Sujet(s)
Aldostérone , Hyperaldostéronisme , Spectrométrie de masse , Humains , Hyperaldostéronisme/diagnostic , Hyperaldostéronisme/sang , Aldostérone/sang , Dosage immunologique/méthodes , Mâle , Femelle , Adulte d'âge moyen , Études prospectives , Spectrométrie de masse/méthodes , Sensibilité et spécificité , Courbe ROC , Adulte , Rénine/sang , Sujet âgé , Dépistage de masse/méthodesRÉSUMÉ
Hypokalemia plays an important role in the diagnosis and management of primary aldosteronism (PA). While the hypokalemic variant of the disease accounts for about one third of all cases, little is known about the incidence of PA in hypokalemic populations. The IPAHK+ study is an epidemiological, cross-sectional trial to provide evidence on the incidence of PA in hypokalemic patients from a university hospital outpatient population. Recruitment of outpatients with hypokalemia≤3 mmol/l is carried out on a continuous referral-basis through an automated data delivery system. Up to an interim data closure, 66 patients underwent the study protocol. The mean age of the participants was 52.9±1.5 years with an equal sex ratio of 1:1 women to men, a mean potassium value of 2.78±0.31 mmol/l [1.8;3.0] and a prevalence of arterial hypertension of 72.7%. PA was diagnosed in 46.6% of all participants, all of whom had a history of hypertension. Incidence of PA increased continuously with decreasing potassium levels with proportions of 26.7%, 50% and 57.1% in the subgroups of 3.0 mmol/l (n=15), 2.8-2.9 mmol/l (n=22) and≤2.7 mmol/l (n=21), respectively. Prior to testing, 59.1% of all patients presented at least with one plausible other cause of hypokalemia. The incidence of PA in the investigated outpatient population was more than 4 out of 10 and inversely correlated with baseline potassium levels. Moderate or severe hypokalemia, regardless of its cause, should therefore prompt evaluation for PA in hypertensive individuals. Normotensive hypokalemic PA was not observed in this cohort.
Sujet(s)
Hyperaldostéronisme , Hypertension artérielle , Hypokaliémie , Mâle , Humains , Femelle , Adulte d'âge moyen , Hypokaliémie/complications , Hypokaliémie/épidémiologie , Incidence , Études transversales , Hyperaldostéronisme/complications , Hyperaldostéronisme/épidémiologie , Hyperaldostéronisme/diagnostic , Potassium , Hypertension artérielle/complications , Hypertension artérielle/épidémiologie , AldostéroneRÉSUMÉ
OBJECTIVE: Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. DESIGN: In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. RESULTS: We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. CONCLUSIONS: Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.
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Hyperaldostéronisme , Hypertension artérielle , Humains , Aldostérone , Rénine , Hypertension artérielle/diagnostic , Hypertension artérielle/étiologie , Enquêtes et questionnairesRÉSUMÉ
CONTEXT: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. OBJECTIVE: We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. METHODS: Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. RESULTS: Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL. CONCLUSION: Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results.
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Tumeurs de la surrénale , Paragangliome , Phéochromocytome , Tumeurs de la surrénale/anatomopathologie , Humains , Patients hospitalisés , Métanéphrine , Normétanéphrine , Patients en consultation externe , Paragangliome/anatomopathologie , Phéochromocytome/anatomopathologie , Sensibilité et spécificitéRÉSUMÉ
CONTEXT: Diagnosis of primary aldosteronism (PA) for many patients depends on positive results for the saline infusion test (SIT). Plasma aldosterone is often measured by immunoassays, which can return inaccurate results. OBJECTIVE: This study aimed to establish whether differences in aldosterone measurements by immunoassay versus mass spectrometry (MS) might impact confirmatory testing for PA. METHODS: This study, involving 240 patients tested using the SIT at 5 tertiary care centers, assessed discordance between immunoassay and MS-based measurements of plasma aldosterone. RESULTS: Plasma aldosterone measured by Liaison and iSYS immunoassays were respectively 86% and 58% higher than determined by MS. With an immunoassay-based SIT cutoff for aldosterone of 170 pmol/L, 78 and 162 patients had, respectivel, negative and positive results. All former patients had MS-based measurements of aldosteroneâ <â 117 pmol/L, below MS-based cutoffs of 162 pmol/L. Among the 162 patients with pathogenic SIT results, MS returned nonpathologic results in 62, including 32 under 117 pmol/L. Repeat measurements by an independent MS method confirmed nonpathogenic results in 53 patients with discordant results. Patients with discordant results showed a higher (Pâ <â 0.0001) prevalence of nonlateralized than lateralized adrenal aldosterone production than patients with concordant results (83% vs 28%). Among patients with nonlateralized aldosterone production, 66% had discordant results. Discordance was more prevalent for the Liaison than iSYS immunoassay (32% vs 16%; Pâ =â 0.0065) and was eliminated by plasma purification to remove interferents. CONCLUSION: These findings raise concerns about the validity of immunoassay-based diagnosis of PA in over 60% of patients with presumed bilateral disease. We provide a simple solution to minimize immunoassay inaccuracy-associated misdiagnosis of PA.
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Aldostérone , Hyperaldostéronisme , Humains , Hyperaldostéronisme/diagnostic , Dosage immunologique/méthodes , Spectrométrie de masse , Rénine , Solution physiologique saléeRÉSUMÉ
Hypokalemia plays a central role for case finding, course, treatment decision, and prognosis of patients with primary aldosteronism. However, to date there is a lack of high-level evidence about the incidence of primary aldosteronism in hypokalemic patients. The IPAHK+study is an epidemiological, cross-sectional, monocentric study to provide evidence on the incidence of PA in a hypokalemic population. The aim of the current analysis was to describe the baseline characteristics of the first 100 patients eligible for study inclusion. The recruitment of patients with hypokalemia (≤3 mmol/l) is carried out continuously on a referral-basis by the central laboratory of the University Hospital Zurich through an automated suitability testing and data delivery system. The careful evaluation of the first 100 reported patients was based on the available reporting system. Out of 28 140 screened patients, 222 (0.79%) were identified with a serum potassium value of≤3 mmol/l (mean 2.89±0.02 mmol/l). Mean potassium levels were slightly lower in non-hypertensive subjects compared to hypertensive subjects (mean difference 0.07 mmol/l, p=0.033), while no significant difference was found between the sexes and patients with and without the diagnosis of primary aldosteronism, atrial fibrillation, or the use of diuretics. The incidence of PA was 4% in the total population studied and 7.5% in the subgroup of hypertensive patients. In conclusion, the continuous enrollment of patients from the IPHAK+hypokalemia registry into the IPAHK+trial will provide evidence about the actual incidence of primary aldosteronism in a hypokalemic outpatient population.
Sujet(s)
Hyperaldostéronisme/sang , Hypokaliémie/sang , Hypokaliémie/complications , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Études transversales , Femelle , Humains , Hyperaldostéronisme/épidémiologie , Hyperaldostéronisme/étiologie , Hyperaldostéronisme/mortalité , Hypokaliémie/mortalité , Incidence , Mâle , Adulte d'âge moyen , Potassium/sang , Enregistrements , Plan de recherche , Suisse/épidémiologie , Jeune adulteRÉSUMÉ
Hypokalemia is closely linked with the pathophysiology of primary aldosteronism (PA). Although hypokalemic PA is less common than the normokalemic course of the disease, hypokalemia is of particular importance for the manifestation and development of comorbidities. Specifically, a growing body of evidence demonstrates that hypokalemia in PA patients is associated with a more severe disease course regarding cardiovascular and metabolic morbidity and mortality. It is also well appreciated that low potassium levels per se can promote or exacerbate hypertension. The spectrum of hypokalemia-related symptoms ranges from asymptomatic courses to life-threatening conditions. Hypokalemia is found in 9-37% of all cases of PA with a predominance in patients with aldosterone producing adenoma. Conversely, hypokalemia resolves in almost 100% of cases after both, specific medical or surgical treatment of the disease. However, to date, high-level evidence about the prevalence of primary aldosteronism in a hypokalemic population is missing. Epidemiological data are expected from the recently launched IPAHK+study ("Incidence of Primary Aldosteronism in Patients with Hypokalemia").
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Hyperaldostéronisme/épidémiologie , Hypokaliémie , Tumeurs corticosurrénaliennes/complications , Tumeurs corticosurrénaliennes/épidémiologie , Tumeurs corticosurrénaliennes/métabolisme , Tumeurs corticosurrénaliennes/anatomopathologie , Adénome corticosurrénalien/complications , Adénome corticosurrénalien/épidémiologie , Adénome corticosurrénalien/métabolisme , Adénome corticosurrénalien/anatomopathologie , Aldostérone/métabolisme , Évolution de la maladie , Humains , Hyperaldostéronisme/étiologie , Hyperaldostéronisme/anatomopathologie , Hypertension artérielle/complications , Hypertension artérielle/épidémiologie , Hypertension artérielle/anatomopathologie , Hypokaliémie/complications , Hypokaliémie/épidémiologie , Hypokaliémie/anatomopathologie , Prévalence , Indice de gravité de la maladieRÉSUMÉ
BACKGROUND: Tissue inflammation in inflammatory bowel diseases [IBD] is associated with local acidification. Genetic variants in the pH-sensing G protein-coupled receptor 65, also known as T cell death-associated gene 8 [TDAG8], have been implicated in IBD and other autoimmune diseases. Since the role of TDAG8 in intestinal inflammation remains unclear, we investigated the function of TDAG8 using murine colitis models. METHODS: The effects of TDAG8 deficiency were assessed in dextran sodium sulphate [DSS], IL-10-/-, and T cell transfer colitis murine models. RNA sequencing of acidosis-activated TDAG8-/- and wild-type [WT] peritoneal macrophages [MΦs] was performed. RESULTS: mRNA expression of IFN-γ, TNF, IL-6, and iNOS in TDAG8-/- mice increased significantly in colonic lymphoid patches and in colonic tissue in acute and chronic DSS colitis, respectively. In transfer colitis, there was a trend towards increased IFN-γ, iNOS, and IL-6 expression in mice receiving TDAG8-/- T cells. However, absence of TDAG8 did not lead to changes in clinical scores in the models tested. Increased numbers of infiltrating MΦs and neutrophils, but not CD3+ T cells, were observed in DSS-treated TDAG8-/- mice. No differences in infiltrating CD3+ T cells were observed between mice receiving TDAG8-/- or WT naïve T cells in transfer colitis. RNA sequencing showed that acidosis activation of TDAG8 in MΦs modulated the expression of immune response genes. CONCLUSIONS: TDAG8 deficiency triggers colonic MΦ and neutrophil infiltration, and expression of pro-inflammatory mediators in DSS colitis models. In transfer colitis, mice receiving TDAG8-/- T cells presented a significantly higher spleen weight and a tendency towards increased expression of pro-inflammatory markers of monocyte/MΦ activity.
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Maladies inflammatoires intestinales/métabolisme , Macrophages/métabolisme , Animaux , Modèles animaux de maladie humaine , Maladies inflammatoires intestinales/anatomopathologie , Interféron gamma/métabolisme , Interleukine-6 , Macrophages/anatomopathologie , Souris , Souris de lignée C57BL , Souris knockout , Nitric oxide synthase type II/métabolisme , Récepteurs couplés aux protéines G/métabolisme , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
BACKGROUND AND AIMS: During active inflammation, intraluminal intestinal pH is decreased in patients with inflammatory bowel disease [IBD]. Acidic pH may play a role in IBD pathophysiology. Recently, proton-sensing G-protein coupled receptors were identified, including GPR4, OGR1 [GPR68], and TDAG8 [GPR65]. We investigated whether GPR4 is involved in intestinal inflammation. METHODS: The role of GPR4 was assessed in murine colitis models by chronic dextran sulphate sodium [DSS] administration and by cross-breeding into an IL-10 deficient background for development of spontaneous colitis. Colitis severity was assessed by body weight, colonoscopy, colon length, histological score, cytokine mRNA expression, and myeloperoxidase [MPO] activity. In the spontaneous Il-10-/- colitis model, the incidence of rectal prolapse and characteristics of lamina propria leukocytes [LPLs] were analysed. RESULTS: Gpr4-/- mice showed reduced body weight loss and histology score after induction of chronic DSS colitis. In Gpr4-/-/Il-10-/- double knock-outs, the onset and progression of rectal prolapse were significantly delayed and mitigated compared with Gpr4+/+/Il-10-/- mice. Double knock-out mice showed lower histology scores, MPO activity, CD4+ T helper cell infiltration, IFN-γ, iNOS, MCP-1 [CCL2], CXCL1, and CXCL2 expression compared with controls. In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle cells, and some macrophages. CONCLUSIONS: Absence of GPR4 ameliorates colitis in IBD animal models, indicating an important regulatory role in mucosal inflammation, thus providing a new link between tissue pH and the immune system. Therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD.
Sujet(s)
Colite/métabolisme , Récepteurs couplés aux protéines G/génétique , Récepteurs couplés aux protéines G/métabolisme , Prolapsus rectal/étiologie , Animaux , Chimiokine CCL2/métabolisme , Chimiokine CXCL1/métabolisme , Chimiokine CXCL2/métabolisme , Colite/induit chimiquement , Colite/complications , Colite/anatomopathologie , Sulfate dextran , Cellules endothéliales/métabolisme , Femelle , Concentration en ions d'hydrogène , Interféron gamma/métabolisme , Interleukine-10/génétique , Muqueuse intestinale/anatomopathologie , Macrophages/métabolisme , Mâle , Souris , Souris knockout , Myocytes du muscle lisse/métabolisme , Nitric oxide synthase type II/métabolisme , Myeloperoxidase/métabolisme , Protons , ARN messager/métabolisme , Prolapsus rectal/génétique , Lymphocytes T auxiliaires/anatomopathologieRÉSUMÉ
BACKGROUND: In vitro and in vivo data have shown that retinoid treatment promotes an anti-inflammatory milieu with few adverse effects toward the gastrointestinal tract. The in vivo studies reported here further evaluate retinoid effects in 2 mouse models of inflammatory bowel disease. METHOD: Chronic dextran sulfate sodium colitis was induced in age- and weight-matched C57Bl/6 mice by 4 cycles of dextran sulfate sodium administration (6-8 animals/group). At cycle 4, animals were administered 13-cis-retinoic acid (isotretinoin, 30 mg/kg) or vehicle (oral gavage) or 4-oxo-13-cis-retinoic acid (15 mg/kg, intraperitoneal) daily. T-cell transfer colitis was induced in CB17 SCID mice by transfer of naive CD4CD62L T cells and treated by transfer of regulatory CD4CD25 T cells (4-6 animals/group); isolated from BALB/c mice after treatment with isotretinoin or vehicle, as above, for 2 weeks. Assessments included endoscopic and histological scores, myeloperoxidase activity, serum cytokines, and plasma isotretinoin levels. RESULTS: Retinoid-treated animals with colitis showed comparable changes in myeloperoxidase activity, and endoscopic and histological scores, versus untreated animals with colitis. Modest and comparable changes were seen in body weight and colon length in animals injected with naive T cells from isotretinoin-treated donors versus those injected with T cells from vehicle-treated donors. Retinoid treatment was consistently associated with lower interleukin-12 levels, which, after the transfer of naive T cells from isotretinoin-treated donors, supported isotretinoin-mediated predisposition of naive T cells toward reduced proinflammatory cytokine expression. Colitis had no effect on isotretinoin exposure. CONCLUSIONS: Retinoids attenuate the proinflammatory cytokine response in vivo, with only modest effects on body weight and parameters of gastrointestinal morphology.