ΜΟΝΗΡΕΣ ΕIΤΕ ΠΟΛΛΑΠΛΑ ΑΔΕΝΩΜΑΤΑ

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1 Hyperaldsternism Intrductin Scintigram btained by using idine-131-6β-idmethylnrchlesterl (NP-59) in a 59- year-ld man with hypertensin shws fairly intense radinuclide uptake in the right adrenal tumr (same patient as in Image 7 in Multimedia). At surgery, a Cnn tumr was cnfirmed. Backgrund 1 Η ΑΝΑΦΟΡΑ 1955 : ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ ΥΠΕΡΕΚΚΡΙΝΩΝ ΑΛΔΟΣΤΕΡΟΝΗ 1 Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ = ΣΥΝΔΡΟΜΟ Cnn : [ ΥΠΕΡΤΑΣΗ ΥΠΟΚΑΛΙΑΙΜΙΑ ] ΣΠΑΝΙΟ ΑΙΤΙΟ ΥΠΕΡΤΑΣΗΣ % ΩΣΤΟΣΟ ΕΙΝΑΙ ΣΗΜΑΝΤΙΚΗ Η ΑΝΕΥΡΕΣΗ ΤΟΥ ΑΦΟΥ ΠΡΟΚΕΙΤΑΙ ΓΙΑ ΜΙΑ ΑΠΟ ΤΙΣ ΕΛΑΧΙΣΤΕΣ ΘΕΡΑΠΕΥΣΙΜΕΣ ΜΟΡΦΕΣ ΥΠΕΡΤΑΣΗΣ ΤΟ ΣΥΧΝΟΤΕΡΟ ΑΙΤΙΟ ΕΙΝΑΙ ΕΝΑ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ ΑΛΛΑ ΔΕΝ ΠΡΕΠΕΙ ΝΑ ΑΠΟΚΛΕΙΕΤΑΙ Η ΔΙΑΧΥΤΗ ΕΠΙΝΕΦΡΙΔΙΚΗ ΥΠΕΡΠΛΑΣΙΑ ΤΟ ΕΠΙΝΕΦΡΙΔΙΚΟ ΝΕΟΠΛΑΣΜΑ ΑΠΟΤΕΛΕΙ ΠΟΛΥ ΣΠΑΝΙΑ ΑΙΤΙΑ Η ΕΚΤΟΜΗ ΑΝΕΥΡΕΘΕΝΤΟΣ ΜΟΝΗΡΟΥΣ ΕΠΙΝΕΦΡΙΔΙΚΟΥ ΑΔΕΝΩΜΑΤΟΣ ΕΚΚΡΙΝΟΝΤΟΣ ΑΛΔΟΣΤΕΡΟΝΗ ΟΜΑΛΟΠΟΙΕΙ ΤΗΝ ΑΡΤΗΡΙΑΚΗ ΠΙΕΣΗ ΣΤΟ 75-90% Pathphysilgy ΚΛΙΝΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ : ΟΦΕΙΛΟΝΤΑΙ ΣΕ ΠΕΡΙΣΣΕΙΑ ΑΛΔΟΣΤΕΡΟΝΗΣ ΣΤΟ ΝΕΦΡΙΚΟ ΣΩΛΗΝΑΡΙΟ Η ΟΠΟΙΑ ΠΡΟΑΓΕΙ ΤΗΝ ΣΥΝΤΗΡΗΣΗ / ΚΑΤΑΚΡΑΤΗΣΗ ΝΑΤΡΙΟΥ κ ΤΗΝ ΑΠΕΚΚΡΙΣΗ ΚΑΛΙΟΥ. Η ΚΑΤΑΚΡΑΤΗΣΗ ΝΑΤΡΙΟΥ ΠΑΡΑΚΡΑΤΑ ΥΔΩΡ ΟΠΟΤΕ ΑΥΞΑΝΕΤΑΙ Ο ΕΝΔΑΓΓΕΙΑΚΟΣ ΟΓΚΟΣ, ΑΥΞΑΝΕΤΑΙ Η ΑΡΤΗΡΙΑΚΗ ΠΙΕΣΗ κ ΚΑΤΑΣΤΕΛΕΤΑΙ Η ΕΚΚΡΙΣΗ ΡΕΝΙΝΗΣ ΥΠΟΚΑΛΙΑΙΜΙΑ : [ ΑΛΚΑΛΩΣΗ ΕΚΓ ΕΥΡΗΜΑΤΑ ΜΥΙΚΗ ΑΔΥΝΑΜΙΑ / ΤΕΤΑΝΙΑ ] Axial enhanced CT scan in a 32-year-ld wman wh presented with hypertensin shws a lw-attenuating 2.8-cm suprarenal mass (A) (same patient as in Image 1 in Multimedia). Histlgic results btained after surgery cnfirmed a tumr due t Cnn syndrme. Lngitudinal sngram thrugh the left kidney in a 32-year-ld wman wh presented with hypertensin shws a 3-cm hypechic but slid mass superir t the upper ple f the kidney. Initially, the mass was regarded as a nnfunctining adenma unrelated t the patient's hypertensin. Subsequently, mild hypkalemia develped. Surgical resectin cnfirmed a tumr due t Cnn syndrme. ΜΟΝΗΡΕΣ ΕIΤΕ ΠΟΛΛΑΠΛΑ ΑΔΕΝΩΜΑΤΑ : (APAs) 65-89% ΜΟΝΗΡΕΣ ΑΔΕΝΩΜΑ : 65-70% ΠΟΛΛΑΠΛΟ ΑΔΕΝΩΜΑ : 13% ΜΙΚΡΟΑΔΕΝΩΜΑΤΩΣΗ : 6% ΕΠΙΝΕΦΡΙΔΙΚΟ ΝΕΟΠΛΑΣΜΑ : 1 % - ΟΙ ΔΙΑΣΤΑΣΕΙΣ ΤΟΥ ΟΓΚΟΥ ΕΙΝΑΙ : [average size f 1.7 cm (range, cm), the left adrenal gland is affected mre ften, and the tumrs are bilateral in 6% f patients ] ΣΥΧΝΑ ΕΚΚΡΙΝΕΙ ΑΛΔΟΣΤΕΡΟΝΗ κ ΓΛΥΚΟΚΟΡΤΙΚΟΕΙΔΗ ΟΠΟΤΕ ΑΝΑΜΕΝΕΤΑΙ ΚΛΙΝΙΚΗ ΕΙΚΟΝΑ ΥΠΕΡΤΑΣΗΣ Η/κ Cushing syndrme ΔΙΑΓΝΩΣΗ = ΕΡΓΑΣΤΗΡΙΑΚΗ ΤΕΚΜΗΡΙΩΣΗ ΩΣΤΟΣΟ ΔΕΝ ΔΙΕΥΚΡΙΝΙΖΕΤΑΙ ΕΝΑ ΠΡΟΚΕΙΤΑΙ ΓΙΑ 1 Ο ΠΑΘΗ Η ΓΙΑ 2 Ο ΠΑΘΗ ΜΟΡΦΗ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΥ : [ ΧΑΜΗΛΟ ΚΑΛΙΟ ΥΨΗΛΟ ΝΑΤΡΙΟ ΧΑΜΗΛΟ ΜΑΓΝΗΣΙΟ Μ ΑΛΚΑΛΩΣΗ [ΥΨΗΛΑ ΔΙΤΤΑΝΘΡΑΚΙΚΑ ph ΧΑΜΗΛΟ ] ΥΨΗΛΗ ΑΛΔΟΣΤΕΡΟΝΗ ΟΡΟΥ κ ΟΥΡΩΝ ] ΘΑ ΠΡΕΠΕΙ ΝΑ ΑΠΟΔΕΙΧΘΕΙ ΟΤΙ ΕΙΝΑΙ ΣΕ ΚΑΤΑΣΤΟΛΗ Η ΠΑΡΑΓΩΓΗ ΡΕΝΙΝΗΣ, ΜΕ ΔΟΚΙΜΑΣΙΑ ΥΠΕΡΦΟΡΤΩΣΗΣ ΣΕ ΧΛΩΡΙΟΥΧΟ ΝΑΤΡΙΟ Χ 3 24ΩΡΑ Η ΟΠΟΙΑ ΘΑ ΕΠΙΦΕΡΕΙ : [ % ΥΠΟΚΑΛΙΑΙΜΙΑ ΕΑΝ ΠΡΑΓΜΑΤΙ ΥΠΑΡΧΕΙ 1 Ο ΠΑΘΗΣ ΝΟΣΟΣ ΜΥΙΚΗ ΑΔΥΝΑΜΙΑ ΑΡΡΥΘΜΙΕΣ ΔΥΣΑΝΕΞΙΑ ΥΔΑΤΑΝΘΡΑΚΩΝ ΝΕΦΡΟΓΕΝΗ ΑΠΟΙΟ ΔΙΑΒΗΤΗ ΥΠΕΡΤΑΣΗ ΚΑΤΑ ΚΑΝΟΝΑ ΜΕΤΡΙΑ ΣΠΑΝΙΩΣ ΚΑΚΟΗΘΗΣ ]

2 ΕΠΙΝΕΦΡΙΔΙΚΟ ΜΥΕΛΟΛΙΠΩΜΑ : ΚΑΛΟΗΘΗΣ, ΛΙΠΩΔΗΣ ΜΑΖΑ ΜΕ ΑΥΤΟΝΟΜΙΑ, ΑΛΛΑ ΠΟΛΥ ΣΠΑΝΙΑ ΜΕ ΔΥΝΑΤΟΤΗΤΑ ΝΑ ΠΡΟΚΑΛΕΣΕΙ ΛΕΙΤΟΥΡΓΙΚΗ κ ΚΛΙΝΙΚΗ ΕΠΙΝΕΦΡΙΔΙΚΗ ΔΙΑΤΑΡΑΧΗ.Jung and clleagues reprted a case f bilateral adrenal myellipmas assciated 5 with primary hyperaldsternism. Frequency United States In % f patients with hypertensin, the cnditin is caused by primary aldsternism. Mrtality/Mrbidity In 75-90% f patients with a slitary APA, surgical adrenalectmy crrects hypertensin and hypkalemia. Mst ther patients have idipathic hyperaldsternism assciated with bilateral adrenal hyperplasia; in these patients, surgery rarely cures hypertensin. Sex The male-t-female rati is 1:2. Age Primary aldsternism ccurs in patients aged years. Anatmy ΑΠΟΛΥΤΗ ΕΝΔΕΙΞΗ ΕΧΟΥΝ Η ΑΞΟΝΙΚΗ κ Ο ΥΠΕΡΗΧΟΣ Preferred Examinatin The wrkup in patients in whm primary aldsternism is suspected usually starts with apprpriate bichemical analysis, after which, thincllimatin CT scanning is perfrmed. 1,6 If CT scan findings are equivcal, radinuclide studies and MRI shuld be perfrmed. 8 If dubt cncerning the diagnsis remains and if CT scans d nt shw a mass in the adrenal glands, adrenal venus sampling is recmmended. Plain radigraphs have n significant rle. Ultrasngraphy has little t cntribute unless the adrenal tumr is large, which is seldm the case. Hwever, ultrasngraphy is an excellent mdality fr the investigatin f hypertensin. Limitatins f Techniques Hypersecreting adrenal glands may appear t be nrmal in size n images, because the size f the adrenal gland may be cmpared t a nrmal measurement and because the healthy adrenal gland varies cnsiderably in size. The adrenal glands als vary in size and weight as a result f illness r stress. This size discrepancy is a particular prblem with APAs, because they are ften small and difficult t detect. In ne series, the average diameter f an APA was 18 mm, and 20% f tumrs were smaller than 1 cm. In earlier generatins f CT scanners, the sensitivity fr detecting APAs was 50-70%. In current CT scanners, the sensitivity has been imprved t 82-88%. Diagnsis by using CT scans is hampered by the detectin f ipsilateral r cntralateral, nnfunctining adenmas, which leads t a false-psitive diagnsis f adrenal hyperplasia. CT scanning is nt reliable in distinguishing between hyperplasia and adenma in patients with multiple, bilateral ndules. 6,7,12,13 Differential Diagnses Other Prblems t Be Cnsidered ΕΠΙΝΕΦΡΙΔΙΟ = ΔΙΠΛΟ, ΠΤΥΧΩΤΟ ΜΟΡΦΩΜΑ ΠΡΟΣΘΙΟΜΕΣΟ ΔΑΚΤΥΛΙΟ κ 2 ΟΠΙΣΘΙΑ Η ΟΠΙΣΘΙΟΜΕΣΑ ΣΚΕΛΗ. ΤΑ ΣΚΕΛΗ ΔΙKΗΝ ΠΤΕΡΩΜΑΤΟΣ ΒΡΙΣΚΟΝΤΑΙ ΣΥΝΕΔΕΜΕΝΑ ΜΕΤΑΞΥ ΤΟΥΣ ΣΤΗΝ ΑΝΩ ΑΠΟΨΗ ΤΟΥ ΜΟΡΦΩΜΑΤΟΣ ΣΤΟΝ ΑΝΩ ΠΟΛΟ ΤΟΥ ΝΕΦΡΟΥ. ΑΠΟ ΕΜΠΡΟΣ ΤΑ 2 ΣΚΕΛΗ ΕΝΑΓΚΑΛΙΖΟΥΝ ΤΟΝ ΑΝΩ ΝΕΦΡΙΚΟ ΠΟΛΟ. ΣΤΗΝ ΠΛΕΟΝ ΚΕΦΑΛΙΚΗ ΤΟΜΗ ΤΗΣ ΑΞΟΝΙΚΗΣ ΤΟ ΕΠΙΝΕΦΡΙΔΙΟ ΟΡΙΖΕΤΑΙ ΩΣ ΓΡΑΜΜΟΕΙΔΕΣ ΜΟΡΦΩΜΑ ΜΕ ΠΡΟΣΘΙΟΠΙΣΘΙΟ ΠΡΟΣΑΝΑΤΟΛΙΣΜΟ Η ΠΡΟΣΘΙΟ ΟΠΙΣΘΙΟΠΛΑΓΙΟ ΜΗ ΛΕΙΤΟΥΡΓΙΚΟ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ + ΠΕΡΙΣΤΑΣΙΑΚΗ ΥΠΕΡΤΑΣΗ 2 Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ + ΜΗ ΛΕΙΤΟΥΡΓΙΚΟ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ ΙΔΙΟΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΨΕΥΔΟΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΤΥΠΟΣ Ι = ΣΥΝΔΡΟΜΟ Liddle ΨΕΥΔΟΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΤΥΠΟΣ ΙΙ = ΣΥΝΔΡΟΜΟ Grdn [familial hypertensive hyperkalemia ] The midsectins f the gland present a Y -shaped cnfiguratin. Occasinally, the antermedial ridge is small r nt well develped, resulting in an inverted, V -shaped gland. The nrmal adrenal limbs measure 3-6 mm in thickness, 4-6 cm in length, and 2-3 cm in width. The variatin in size explains why sme hyperfunctining glands are seen t be nrmal in size n images and at surgery. Presentatin 2 Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΟΦΕΙΛΟΜΕΝΟΣ ΣΕ ΕΞΩΕΠΙΝΕΦΡΙΔΙΚΟ ΜΟΡΦΩΜΑ ΥΠΕΡΕΚΚΡΙΝΩΝ ΡΕΝΙΝΗ : [ adrenal embrylgic rest neplasms in a kidney r vary ] 1 Ο ΠΑΘΗΣ ΝΟΣΟΣ : [ ΥΠΕΡΤΑΣΗ ΧΩΡΙΣ ΟΙΔΗΜΑ ΧΑΜΗΛΟ ΚΑΛΙΟ ΜΕΤΑΒΟΛΙΚΗ ΑΛΚΑΛΩΣΗ ΥΨΗΛΗ ΑΛΔΟΣΤΕΡΟΝΗ ΠΟΥ ΔΕΝ ΟΜΑΛΟΠΟΙΕΙΤΑΙ ΕΠΙ ΑΥΞΗΜΕΝΟΥ ΕΝΔΑΓΓΕΙΑΚΟΥ ΟΓΚΟΥ ΧΑΜΗΛΗ / ΚΑΤΗΡΓΗΜΕΝΗ ΔΡΑΣΤΗΡΙΟΤΗΤΑ ΣΥΣΤΗΜΑΤΟΣ ΡΕΝΙΝΗΣ ] [ ΠΟΛΥΔΙΨΙΑ ΜΥΙΚΗ ΑΔΥΝΑΜΙΑ ΝΥΧΤΟΥΡΙΑ ΠΑΡΑΙΣΘΗΣΙΕΣ ΤΕΤΑΝΙΑ ΚΕΦΑΛΑΓΙΕΣ ΕΚΓ ΕΥΡΗΜΑΤΑ ] [ ΟΡΘΟΣΤΑΤΙΚΗ ΥΠΟΤΑΣΗ ΥΠΑΡΑχνοειδης αιμορραγια ΒΡΑΔΥΚΑΡΔΙΑ ] [ ΣΕ ΝΕΟΓΝΑ : ΛΕΙΤΟΥΡΓΙΚΑ ΓΕΣ ΣΗΜΕΙΑ ΟΦΕΙΛΟΜΕΝΑ ΣΕ ΣΥΝΔΥΑΣΜΟ ΥΠΟΚΑΛΙΑΙΜΙΑ κ ΥΠΕΡΤΑΣΗΣ ]

3 Hyperaldsternism Sterid bisynthetic pathway Intrductin Backgrund Aldsterne = ΤΟ ΚΥΡΙΟ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΕΣ ΣΤΟΝ ΑΝΘΡΩΠΟ, ΠΑΡΑΓΩΜΕΝΟ ΣΤΗ ΣΠΕΙΡΟΕΙΔΗ ΖΩΝΗ ΤΟΥ ΕΠΙΝΕΦΡΙΔΙΚΟΥ ΦΛΟΙΟΥ. ΟΙ ΚΥΡΙΟΙ ΡΥΘΜΙΣΤΕΣ ΓΙΑ ΤΗ ΣΥΝΘΕΣΗ ΤΗΣ ΕΙΝΑΙ : [ ΣΥΣΤΗΜΑ ΡΕΝΙΝΗΣ ΑΓΓΕΙΟΤΕΝΣΙΝΗΣ ΣΥΓΚΕΝΤΡΩΣΗ ΚΑΛΙΟΥ ] ΛΟΙΠΟΙ ΡΥΘΜΣΤΕΣ : [ACTH - atrial natriuretic peptide frm the heart lcal adrenal secretin f dpamine ] ΠΡΟΔΡΟΜΕΣ ΟΥΣΙΕΣ : [dexycrticsterne and 18-hydrxycrticsterne ] ΔΥΝΑΤΟ ΝΑ ΔΩΣΟΥΝ ΠΑΡΟΜΟΙΑ ΚΛΙΝΙΚΗ ΝΟΣΟ ΕΑΝ Η ΣΥΓΚΕΝΤΡΩΣΗ ΤΟΥΣ ΕΙΝΑΙ ΥΨΗΛΗ Η ΑΛΔΟΣΤΕΡΟΝΗ ΕΧΕΙ ΔΡΑΣΗ ΣΕ : [ ΓΕΣ ΙΔΡΩΤΟΠΟΙΟΥΣ ΑΔΕΝΕΣ ] ΑΛΛΑ Η ΚΥΡΙΑ ΔΡΑΣΗ ΤΗΣ ΕΙΝΑΙ ΣΤΟ ΑΠΩ ΣΩΛΗΝΑΡΙΟ : [ ΚΑΤΑΚΡΑΤΗΣΗ ΝΑΤΡΙΟΥ ΑΠΟΒΟΛΗ ΚΑΛΙΟΥ κ ΥΔΡΟΓΟΝΟΚΑΤΙΟΝΤΩΝ ] Pathphysilgy Aldsterne Secretin and Its Regulatin Ο ΜΗΧΑΝΙΣΜΟΣ ΕΚΚΡΙΣΗΣ ΤΗΣ ΑΛΔΟΣΤΕΡΟΝΗΣ ΕΙΝΑΙ ΠΟΛΥΠΛΟΚΟΣ : [ ΣΠΕΙΡΟΕΙΔΗΣ ΖΩΝΗ ΕΠΙΝΕΦΡΙΔΙΟΥ ΠΑΡΑΣΠΕΙΡΑΜΑΤΙΚΗ ΣΥΣΚΕΥΗ ΜΥΟΚΑΡΔΙΟ ΠΝΕΥΜΟΝΑΣ ΑΥΤΟΝΟΜΟ ΝΣ ΗΠΑΡ ] ΑΔΡΑ : ΕΝΕΡΓΟΠΟΙΗΣΗ ΕΚΚΡΙΣΗΣ : [ ΥΠΕΡΚΑΛΙΑΙΜΙΑ ΤΑΣΕΟΥΠΟΔΟΧΕΙΣ ΣΕ ΕΛΕΙΜΜΑ ΚΥΚΛΟΦΟΡΟΥΝΤΟΣ ΟΓΚΟΥ ] ΚΑΤΑΣΤΟΛΗ ΕΚΚΡΙΣΗΣ : [ ΥΠΕΡΚΑΛΙΑΙΜΙΑ ΥΠΕΡΦΟΡΤΩΣΗ ΣΕ ΥΓΡΑ ] The majr factrs stimulating aldsterne prductin and release by the zna glmerulsa are angitensin II and the serum ptassium cncentratin. ACTH stimulates aldsterne secretin in an acute and transient fashin but des nt appear t play a significant rle in the lng-term regulatin f mineralcrticid secretin. The majr inhibitrs f the zna glmerulsa include circulating atrial natriuretic peptide (ANP) and, lcally, dpamine. Althugh ANP levels are clearly increased in hyperaldsternism, neither ANP nr dpamine has been implicated as a primary cause f clinically disrdered aldsterne secretin. Metclpramide has been shwn t increase aldsterne secretin, suggesting that dpamine may tnically inhibit aldsterne release. The physilgic rles f adrenmedullin and vasactive intestinal peptide (VIP) n aldsterne secretin remain t be clarified, althugh bth f these neurpeptides are prduced in rat zna glmerulsa. The juxtaglmerular apparatus is the principal site f regulatin f angitensin II prductin (see Media file 1). The synthesis f prrennin, its cnversin t renin, and its systemic secretin are stimulated by bld vlume cntractin detected by stretch receptrs, beta-adrenergic stimulatin f the sympathetic nervus system, and prstaglandins I2 and E 2. These prcesses are inhibited by vlume expansin and ANP. Renin cnverts angitensingen, a prenzyme synthesized in the liver, int the decapeptide angitensin I, which is then cnverted in the lungs int an ctapeptide, angitensin II, by angitensincnverting enzyme. Angitensin II is bth a stimulatr f aldsterne secretin and a ptent vaspressr. Angitensin II is metablized t angitensin III, a heptapeptide that is als a stimulatr f aldsterne secretin.

4 The synthesis and secretin f prstaglandins I2 and E2 and the nrmal functin f the stretch receptrs are dependent upn intracellular inized calcium cncentratin. Renal prstaglandin secretin is stimulated by catechlamines and angitensin II. The cmplex regulatin f aldsterne synthesis and secretin prvides several pints at which disturbance in the regulatin f aldsterne secretin may ccur. Aldsterne bisynthesis Aldsterne is synthesized frm chlesterl in a series f 6 bisynthetic steps (see Media file 2). can result in a number f disrders f aldsterne synthesis that are discussed belw (see Differentials). Aldsterne receptrs ΟΡΓΑΝΑ ΣΤΟΧΟΙ : [ ΑΠΩ ΝΕΦΡΙΚΟ ΣΩΛΗΝΑΡΙΟ ΙΔΡΩΤΟΠΟΙΟΙ ΣΙΕΛΟΓΟΝΟΙ ΕΠΙΘΗΛΙΟ ΠΑΧΕΟΣ ΕΝΤΕΡΟΥ ] Ο ΥΠΟΔΟΧΕΑΣ ΕΧΕΙ ΠΑΡΟΜΟΙΑ ΣΥΓΓΕΝΕΙΑ ΓΙΑ ΤΑ ΑΛΑΤΟ- κ ΤΑ ΓΛΥΚΟ- ΚΟΡΤΙΚΟΕΙΔΗ. Ο ΥΠΟΔΟΧΕΑΣ ΠΡΟΣΤΑΤΕΥΕΤΑΙ ΑΠΟ ΤΗΝ ΚΟΡΤΙΖΟΛΗ ΑΠΟ ΕΝΑ ΕΝΖΥΜΟ : 11beta-hydrxysterid dehydrgenase type 2, ΤΟ ΟΠΟΙΟ ΜΕΤΑΤΡΕΠΕΙ ΤΗΝ ΚΟΡΤΙΖΟΛΗ ΣΕ ΑΔΡΑΝΗ ΜΟΡΦΗ Primary Aldsternism 99% ΑΔΕΝΩΜΑ ΠΟΥ ΕΚΚΡΙΝΕΙ ΑΛΔΟΣΤΕΡΟΝΗ : [ 40% aldsterneprducing adenma (APA) 60% idipathic hyperaldsternism (IHA) ] ΑΜΙΓΩΣ ΑΛΔΟΣΤΕΡΟΝΗ ΕΚΚΡΙΝΩΝ ΕΠΙΝΕΦΡΙΔΙΚΟ ΝΕΟΠΛΑΣΜΑ = ΠΟΛΥ ΣΠΑΝΙΟ κ ΕΥΜΕΓΕΘΕΣ ΚΑΤΑ ΤΗ ΔΙΑΓΝΩΣΗ ΑΜΦΟ ΕΠΙΝΕΦΡΙΔΙΚΗ ΥΠΕΡΠΛΑΣΙΑ = ΠΟΛΥ ΣΠΑΝΙΑ Ο 1 Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΕΙΝΑΙ ΝΟΣΟΣ ΤΗΣ 4 ΗΣ 6 ΗΣ ΔΕΚΑΕΤΙΑΣ. ΤΟ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ ΚΑΤΑ ΚΑΝΟΝΑ ΜΕ ΚΑΨΑ ΜΙΚΡΟΤΕΡΟ ΑΠΟ 2 ΕΚΑΤΟΣΤΑ, ΣΥΝΗΘΩΣ ΕΙΝΑΙ ΜΟΝΗΡΕΣ. ΣΤΟ 1/3 ΥΠΑΡΧΟΥΝ ΠΟΛΛΑΠΛΑ ΟΖΙΔΙΑ ΣΤΟ ΙΔΙΟ ΕΠΙΝΕΦΡΙΔΙΟ κ ΑΥΤΟ ΔΥΝΑΤΟ ΝΑ ΣΗΜΑΙΝΕΙ ΟΤΙ ΤΟ ΕΠΙΝΕΦΡΙΔΙΟ ΗΤΑΝ ΥΠΕΡΠΛΑΣΤΙΚΟ ΠΡΙΝ ΤΗΝ ΑΝΑΠΤΥΞΗ ΤΟΥ ΑΔΕΝΩΜΑΤΟΣ ΔΙΑΧΥΤΗ ΥΕΡΠΛΑΣΙΑ ΕΠΙΝΕΦΡΙΔΙΩΝ = ΑΜΦΟ ΜΕ ΠΑΧΥΝΣΗ ΤΟΥ ΦΛΟΙΟΥ κ ΠΟΛΑΠΛΑ ΟΖΙΔΙΑ. ΓΙΑ ΜΑΚΡΑ ΧΡΟΝΙΚΗ ΠΕΡΙΟΔΟ ΔΥΝΑΤΟ ΝΑ ΥΠΑΡΧΕΙ ΜΟΝΟ ΗΠΙΑ ΥΠΕΡΤΑΣΗ ΧΩΡΙΣ ΥΠΟΚΑΛΙΑΙΜΙΑ Physilgic regulatin f the renin-angitensin-aldsterne axis. Only the last 2 steps are specific t aldsterne synthesis, the first 4 are cmmn t the crtisl synthesis by the zna fasciculata. Cnsequently, a defect in ne f the specific aldsterne synthetic enzymes des nt lead t hypercrtislism and secndary ACTHmediated adrenal hyperplasia. The enzyme aldsterne synthase is encded by the gene CYP11B2 and has 11beta-hydrxylase, 18- hydrxylase, and 18-hydrxydehydrgenase activity. This gene is lcated n human chrmsme arm 8q24.3-tel, clse t the gene CYP11B1 that encdes 11beta-hydrxylase, the enzyme that catalyzes the final step f crtisl synthesis. Mutatins in these genes Patients with IHA have bilateral thickening and variable ndularity f their adrenal crtex. A wide spectrum f severity exists fr this disrder, which may g undetected fr a lng perid with n hypkalemia and nly mild hypertensin. A prpsal is that IHA arises as a result f an undetected adrenal crtical stimulating factr. Pssibly, this disrder may arise as a result f an activating mutatin in an adrenal crtex specific gene, althugh neither hypthesis has been prven. ΤΑ ΚΛΗΡΟΝΟΜΙΚΑ ΑΙΤΙΑ ΤΗΣ ΝΟΣΟΥ ΕΜΦΑΝΙΖΟΝΤΑΙ ΜΕ ΥΠΕΡΤΑΣΗ ΣΕ ΠΑΙΔΙΚΗ ΗΛΙΚΙΑ κ ΑΦΟΡΟΥΝ ΤΟ 1% ΤΗΣ ΑΙΤΙΟΛΟΓΙΑΣ [familial hyperaldsternism types I and II ]

5 Familial hyperaldsternism type I (gluccrticid-remediable aldsternism) Familial hyperaldsternism type I (FH-I) represents abut 1% f cases f primary hyperaldsternism. It may be detected in asymptmatic individuals when screening the ffspring f affected individuals, r patients may present in infancy with hypertensin, weakness, and failure t thrive due t hypkalemia. It is inherited in an autsmal dminant manner and has a lw frequency f new mutatins. The first clinical descriptin f gluccrticid-remediable aldsternism (GRA) was in 1966, with the genetic mechanism discvered in It arises as a result f unequal crssing ver f CYP11B1 (11beta-hydrxylase gene) and CYP11B2 (aldsterne synthase gene) during meisis, prducing a fusin prduct that cuples the ACTH-sensitive prmter f CYP11B1 t the CYP11B2 gene. The result is ACTH-dependent aldsterne prductin and prductin f 17-hydrxylated analgs f 18-hydrxycrtisl under ACTH regulatin frm ectpic enzyme expressin in the zna fasciculata. Bilateral hyperplasia f the zna fasciculata ccurs and high levels f nvel 18-hydrxysterids appear in the urine. Adenma frmatin is rare, but patients d have a significant increase in incidence f cerebrvascular aneurysms, fr which they require screening. Familial hyperaldsternism type II Familial hyperaldsternism type II (FH-II) is a familial nngluccrticid-suppressible inherited frm f hyperaldsternism that was recgnized as a distinct entity by Grdn et al, althugh cases had previusly been described in the 1980s. Similar t FH-I, it is als inherited in an autsmal dminant manner. The mechanism and gene lcus have nt yet been identified, althugh CYP11B2, the renin and angitensin II receptr genes, have been excluded. Current analysis suggests that this is nt a single disrder. Unlike FH-I, sme kindreds with FH-II exhibit a high rate f adenma frmatin. Secndary Hyperaldsternism This represents a diverse grup f disrders characterized by physilgic activatin f the renin-angitensin-aldsterne (R-A-A) axis as a hmestatic mechanism designed t maintain serum electrlyte cncentratins r fluid vlume. In the presence f nrmal renal functin, it may lead t hypkalemia. Secndary hyperaldsternism can be divided int 2 categries depending n whether assciated hypertensin is present. Hyperreninemia and secndary aldsternism have als been reprted in patients with phechrmcytma, apparently as a result f functinal renal artery stensis. Renin-prducing tumrs are very rare, and very high levels f PRA (up t 50 ng/ml/h) are nted, frequently with an increased prrennin-trenin rati. The tumrs are generally f renal rigin and include Wilms tumrs and renal cell carcinmas. Hyperkalemia due t chrnic renal failure als causes secndary hyperaldsternism. Lw sdium-tptassium ratis can be measured in saliva and stl. Cyclsprin-induced hypertensin in slid rgan transplant patients may als invlve a cmpnent f hyperaldsternism. Secndary hyperaldsternism in the absence f hypertensin ccurs as a result f hmestatic attempts t maintain sdium r circulatry vlume r t reduce ptassium. Clinical situatins where this may ccur include the presence f diarrhea, excessive sweating, lw cardiac utput states, and hypalbuminemia due t liver r renal disease r nephrtic syndrme. As utlined belw, this als ccurs develpmentally in newbrn infants. Increased mineralcrticid dependency in the yung The mineralcrticid dependency f sdium reabsrptin is increased during infancy and childhd, with its peak in the nenatal perid befre decreasing prgressively with advancing age. This arises because the reabsrptin f sdium and water by the prximal tubule is least efficient in early life, resulting in an increased sdium and water lad at the level f the distal renal tubule. The frmer categry includes renvascular hypertensin, which results frm renal ischemia and hypperfusin leading t activatin f the R-A-A axis. The mst cmmn causes f renal artery stensis in children are fibrmuscular hyperplasia and neurfibrmatsis. Hypkalemia may ccur in as many as 20% f patients. Plasma renin activity (PRA) levels are ften in the reference range, but elevated levels f PRA may be detected after prvcatin with a single dse f captpril 1 mg/kg. Renal ischemia is als thught t underlie the secndary hyperaldsternism bserved in malignant hypertensin. Because sdium and water resrptin frm the distal tubule is mediated by the R-A-A axis, the PRA f a newbrn infant is apprximately 10-fld t 20-fld higher than that f an adult. This results in relative increases in aldsterne prductin rates (>300 mcg/m 2 /d in a newbrn infant cmpared with 50 mcg/m 2 /d in an adult) and plasma aldsterne cncentratins (80 pg/dl versus 16 pg/dl, respectively) in the nenate. This increased mineralcrticid dependency in early life explains why yung infants exhibit prfund clinical symptms f hypaldsternism that gradually imprve with advancing age.

6 Frequency Internatinal Primary hyperaldsternism is a rare cnditin in children. The yungest child reprted with an aldsterne-secreting adenma was aged 3 years. Earlier use f hypkalemia as a diagnstic requirement, as advcated by sme authrities, may have led t underrecgnitin f the cntributin f primary aldsternism t hypertensin. A study that used saline infusin as a screening test fr primary aldsternism reprted a frequency f 2.2% f primary aldsternism amng 1036 unselected adults with hypertensin. 1 A smaller study that used the aldsterne-t-pra rati in plasma suggested that primary aldsternism might accunt fr an even greater prprtin f cases f hypertensin. 2 Hypkalemia is mre frequently bserved in patients with adenmas, althugh it shuld nt be cnsidered a diagnstic feature f primary hyperaldsternism, as was nce thught. Patients with adenmas are mre likely t develp this cmplicatin, as are patients wh have milder disease but receive treatment with diuretics fr their hypertensin, befre the hyperaldsternism is diagnsed. Mst hyperaldsternism bserved in the general ppulatin is spradic, with mst cases due t bilateral adrenal hyperplasia. APAs are likely t be diagnsed earlier than IHA because they are mre likely than IHA t prduce early symptmatic hypertensin and hypkalemia. APAs accunt fr 40% f cases f primary hyperaldsternism. Pssibly, the distinctin between adenma and hyperplasia is nt as clear as was nce thught because, in ne third f cases, assciated hyperplasia r ndules f the adjacent zna glmerulsa is present, implying that the adenma may have arisen in previusly hyperplastic tissue. Inherited frms f primary hyperaldsternism (ie, FH-1 [GRA] and FH- II and a very rare frm FH-III) accunt fr apprximately 1% f cases f primary aldsternism, althugh they are mre likely than ther causes f primary hyperaldsternism t ccur during childhd and adlescent years. Studies f secndary hyperaldsternism have fund that apprximately 15% f adults wh attend hypertensin clinics have elevated PRA. Reliable figures fr children are nt readily available. Mrtality/Mrbidity Primary hyperaldsternism can result in a significant increase in mrbidity and mrtality as a result f hypertensive vascular (hypertrphy then sclersis f intimal smth muscle), renal (sclersis), and cardiac (hypertrphy then dilatatin) cmplicatins. Thrugh early recgnitin and treatment f hypertensin, these cmplicatins can be avided in children. Patients with GRA [=??Gluccrticid remedial Aldsternism ] must underg assessment f their cerebral circulatin because this disrder is assciated with a significant risk f cerebral vascular aneurysms. Prvided that hypertensin is well treated, mrbidity and mrtality are nt increased significantly. Hypkalemic patients may experience neurmuscular symptms such as weakness r paralysis, cnstipatin, and plyuria and plydipsia because f an assciated renal cncentrating defect. Hypkalemia als impairs insulin secretin and can prmte the develpment f diabetes mellitus. Althugh cardiac fibrsis has been reprted in adults with primary aldsternism, n such reprts exist in children, pssibly because f their shrter duratin f disease at the time f diagnsis. Cardiac fibrsis has als been reprted in rats treated with excess mineralcrticids, especially if hyperglycemia is als present. This effect can be amelirated with amilride. The rle f aldsterne in diabetic heart disease has been questined, and trials f mineralcrticid antagnists in this cnditin have been initiated. Race The literature n adults demnstrates that blacks are at significantly greater risk f hypertensin-related mrbidity and mrtality than whites. They are als mre likely t develp lw-renin hypertensin, althugh n studies indicate that the prevalence f primary hyperaldsternism is significantly higher in blacks. Sex Data n adults suggest that hyperaldsternism has a female prepnderance. Equivalent infrmatin is nt available fr children, where primary hyperaldsternism due t inherited syndrmes is likely t represent a greater prprtin f cases.

7 Age Because the 2 causes that accunt fr abut 99% f cases f primary hyperaldsternism have a peak age f nset in adulthd, the less cmmn causes accunt fr a larger percentage f children with hyperaldsternism. Fr this reasn, children with apparent hyperaldsternism shuld be evaluated fr evidence f cngenital defects f the R-A-A axis and inherited frms f hypermineralcrticidism. Clinical Histry Primary hyperaldsternism may be asymptmatic, particularly in its early stages. When present, symptms are related t hypertensin (if severe), hypkalemia, r bth. The spectrum f hypertensin-related symptms includes the fllwing: Headaches Facial flushing If severe, weakness, visual impairment, impaired cnsciusness, and seizures (hypertensive encephalpathy) Hypkalemia can be precipitated by nn ptassium-sparing diuretics r sdium lading. Symptms f hypkalemia include the fllwing: Cnstipatin Plyuria and plydipsia (because f impaired renal cncentrating ability) Weakness If lw enugh, paralysis and disturbances f cardiac rhythm 3 Hyperglycemia r frank diabetes mellitus is pssible because insulin secretin is a ptassium-dependent prcess that may be impaired by hypkalemia. Fr patients in whm secndary hyperaldsternism is suggested, questins shuld be specifically directed at ptential causes (eg, the presence and duratin f swelling, the child's exercise tlerance). Infrmatin shuld be sught abut a family histry f essential hypertensin and familial syndrmes that include the fllwing: Neurfibrmatsis (assciated with renal artery stensis and phechrmcytma) Multiple endcrine neplasia (MEN) type 2 MEN 2A - Parathyrid adenma, medullary thyrid carcinma (MTC), phechrmcytma MEN 2B - Mucsal neurmas f eyelids, lips, and tngue with lng thin face, phechrmcytma, and MTC vn Hippel-Lindau syndrme - Cerebellar hemangiblastma; renal and pancreatic cysts and carcinma; hemangimas f the retina, liver, and adrenal glands; phechrmcytmas Physical ΑΠΑΙΤΕΙΤΑΙ ΠΛΗΡΗΣ ΕΛΕΓΧΟΣ ΠΑΙΔΩΝ ΕΦΗΒΩΝ ΜΕ ΥΠΕΡΤΑΣΗ ΑΥΞΗΜΕΝΗ ΣΥΓΚΕΝΤΡΩΣΗ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ ΠΡΕΠΕΙ ΝΑ ΔΙΕΡΕΥΝΑΤΑΙ ΣΕ ΥΠΟΚΑΛΙΑΙΜΙΑ ΑΛΛΑ Η ΥΠΟΚΑΛΙΑΙΜΙΑ ΔΕΝ ΕΙΝΑΙ ΠΑΝΤΟΤΡΕ ΠΑΡΟΥΣΑ ΔΥΣΜΟΡΦΙΕΣ : [ ΜΕΝ 2 ΝΕΥΡΟΙΝΟΜΑΤΩΣΗ ΤΥΠΟΣ Ι [café-aulait lesins, axillary freckling, shrt stature, and evidence f disease in parents) ] ΣΥΝΔΡΟΜΟ CUSHING [besity, shrt stature, striae, and hirsutism] ] ΨΗΛΑΦΗΤΑ ΜΟΡΦΩΜΑΤΑ ΤΡΑΧΗΛΟΥ / ΘΥΡΕΟΕΙΔΟΥΣ : assciated with MEN 2) If secndary hyperaldsternism is suspected as the cause f hypertensin, histry shuld include questins abut flushing, diaphresis, anxiety attacks, and headaches (phechrmcytma) and abut hematuria and abdminal fullness (Wilms tumr r ther renal tumr), in additin t the abve symptms. ΚΥΚΟΛΟΦΡΙΚΟ : [ ΑΡΙΣΤΕΡΑ ΜΕΓΑΛΟΚΑΡΔΙΑ ΣΤΕΝΩΣΗ ΑΟΡΤΗΣ ΦΥΣΗΜΑΤΑ ΚΟΙΛΙΑΚΑ ΦΥΣΗΜΑΤΑ ΕΠΙ ΣΤΕΝΩΣΗΣ ΝΕΦΡΙΚΗΣ ΑΡΤΗΡΙΑΣ ΠΕΡΙΦΕΡΙΚΟ ΟΙΔΗΜΑ ΣΕ 2 Ο ΠΑΘΗ ΜΟΡΦΗ ΤΗΣ ΝΟΣΟΥ ] ΚΟΙΛΙΑ = [ ΜΑΖΕΣ (Wilms tumr) - ΗΠΑΤΟΜΕΓΑΛΙΑ [ ΣΚΑ Η ΗΠΑΤΙΚΗ ΝΟΣΟΣ ] ΣΠΛΗΝΟΜΕΓΑΛΙΑ ΑΣΚΙΤΗΣ ]

8 ΟΦΘΑΛΜΟΛΟΓΙΚΗ ΕΞΕΤΑΣΗ : [ ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΙΚΑ ΑΓΓΕΙΩΜΑΤΑ vn Hippel-Lindau syndrme ΣΤΕΝΩΣΗ ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΙΚΩΝ ΑΡΤΗΡΙΩΝ ΒΑΜΒΑΚΟΕΙΔΕΙΣ ΚΗΛΙΔΕΣ ΟΙΔΗΜΑ ΘΗΛΗΣ Lisch ndules f the iris (neurfibrmatsis type 1) ] ΑΞΙΟΛΟΓΗΣΗ ΜΥΙΚΗΣ ΑΔΥΝΑΜΙΑΣ ΑΠΕΙΚΟΝΙΣΕΙΣ ΠΡΟΣ ΑΠΟΚΛΕΙΣΜΟ ΕΓΚΕΦΑΛΙΚΟΥ ΕΜΦΡΑΚΤΟΥ Η ΑΙΜΟΡΡΑΓΙΑΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ + ΔΕΡΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ = ΥΠΟΝΟΙΑ ΓΙΑ NF-1 Causes ΑΙΤΙΑ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΥ κ ΚΑΤΑΣΤΑΣΕΩΝ ΠΟΥ ΜΙΜΟΥΝΤΑΙ ΑΥΤΟΝ 1 Ο ΠΑΘΕΣ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ (APA) [High aldsterne, lw plasma renin activity (PRA) ] ΙΔΙΟΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ = (IHA) (bilateral adrenal hyperplasia) Gluccrticid remediable aldsternism (GRA) - Sustained suppressin f aldsterne (<4 ng/dl) with dexamethasne Familial hyperaldsternism type II (FH-II) - Familial (prbably autsmal dminant) Cnditins that mimic aldsterne excess Cngenital adrenal hyperplasia (11beta-hydrxylase deficiency, 17alpha-hydrxlyase deficiency) - Lw aldsterne, lw PRA, elevated sterid intermediates Primary gluccrticid resistance - High gluccrticid secretin unsuppressed by dexamethasne Dexycrticsterne-secreting tumrs - Elevated dexycrticsterne levels Syndrme f apparent mineralcrticid excess Liddle syndrme Licrice ingestin Carbenxlne The fllwing is a discussin f causes f hypkalemia: ΠΡΟΔΙΑΘΕΤΙΚΟΙ ΠΑΡΑΓΟΝΤΕΣ ΓΙΑ ΥΠΟΚΑΛΙΑΙΜΙΑ : [ ΔΙΑΤΡΟΦΗ ΠΛΟΥΣΙΑ ΣΕ ΝΑΤΡΙΟ ΔΙΟΥΡΗΤΙΚΑ carbenxlne ] ΦΑΙΝΟΜΕΝΙΚΑ ΑΥΞΗΜΕΝΗ ΣΥΓΚΕΝΤΡΩΣΗ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ = ΚΑΤΑΣΤΑΣΕΙΣ ΜΕ ΑΥΞΗΜΕΝΗ ΚΟΡΤΙΖΟΛΗ ΣΤΙΣ ΟΠΟΙΕΣ Ο ΙΣΤΙΚΟΣ ΥΠΟΔΟΧΕΑΣ ΤΗΣ ΑΛΔΟΣΤΕΡΟΝΗΣ ΔΕΝ ΛΕΙΤΟΥΡΓΕΙ ΚΑΛΑ. Carbenxlne Η ΚΑΤΑΝΑΛΩΣΗ ΓΛΥΚΟΡΙΖΑΣ ΜΠΡΟΚΑΡΟΥΝ ΤΟ ΙΣΤΙΚΟ ΕΝΖΥΜΟ ΤΟ ΟΠΟΙΟ ΠΡΟΣΤΑΤΕΥΕΙ ΤΟΝ ΥΠΟΔΟΧΕΑ ΤΗΣ ΑΛΔΟΣΤΕΡΟΝΗΣ ΑΠΟ ΤΗΝ ΥΨΗΛΗ ΚΥΚΛΟΦΟΡΙΑ ΚΟΡΤΙΖΟΛΗΣ Differential Diagnses Cngenital Adrenal Hyperplasia Other Prblems t Be Cnsidered 2 Ο ΠΑΘΗΣ : [ ΟΙΔΗΜΑ ΚΑ ΝΕΦΡΩΣΙΚΟ ΣΥΝΔΡΟΜΟ ] High aldsterne, nnsuppressed plasma renin activity (>2 ng/ml) ΝΕΦΡΑΓΓΕΙΑΚΗ ΥΠΕΡΤΑΣΗ ΟΓΚΟΙ ΠΟΥ ΠΑΡΑΓΟΥΝ ΡΕΝΙΝΗ Secndary hyperaldsternism Apparent mineralcrticid excess (types I and II) Liddle syndrme Gluccrticid resistance Exgenus mineralcrticid excess Drug-induced apparent mineralcrticid excess ΕΓΚΥΜΟΣΥΝΗ

9 Saline infusin test Wrkup Labratry Studies 1 Ο ΒΗΜΑ : ΤΕΚΜΗΡΙΩΣΗ ΥΠΕΡΤΑΣΗΣ + ΥΠΟΚΑΛΙΑΙΜΙΑΣ 2 Ο ΒΗΜΑ : ΤΕΚΜΗΡΙΩΣΗ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟ κ ΕΑΝ ΔΕΝ ΥΦΙΣΤΑΤΑΙ, ΔΔ ΚΑΤΑΣΤΑΣΕΩΝ ΠΟΥ ΔΙΔΟΥΝ ΤΗΝ ΩΣ ΑΝΩ ΚΛΙΝΙΚΗ ΕΙΚΟΝΑ 3 Ο ΒΗΜΑ : ΔΔ 1 Ο ΠΑΘΟΥΣ ΑΠΟ 2 Ο ΠΑΘΗ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟ Aldsterne-t-renin rati Η ΜΕΤΡΗΣΗ ΕΙΝΑΙ ΠΙΟ ΑΞΙΟΠΙΣΤΗ ΟΤΑΝ ΕΧΕΙ ΠΡΟΗΓΗΘΕΙ ΟΡΘΙΑ ΣΤΑΣΗ ΕΠΙ ΔΥΩΡΟ Ο ΑΣΘΕΝΗΣ ΝΑ ΕΙΝΑΙ ΝΟΡΜΟΚΑΛΙΑΙΜΙΚΟΣ ΑΦΟΥ Η ΥΠΟΚΑΛΙΑΙΜΙΑ ΚΑΤΑΣΤΕΛΛΕΙ ΤΗΝ ΠΑΡΑΓΩΓΗ ΑΛΔΟΣΤΕΡΟΝΗΣ ΑΛΔΟΣΤΕΡΟΝΗ ΡΕΝΙΝΗ > 20 κ ΤΙΜΗ ΑΛΔΟΣΤΕΡΟΝΗΣ>15 ng/dl : διαγνωση 1 ο παθους νοσου Spirnlactne, an aldsterne receptr antagnist, can raise plasma renin levels. Spirnlactne and diuretics shuld be withheld fr 6 weeks, and beta-blckers and dihydrpyridine calcium antagnists shuld be withheld fr 5-7 days befre testing. Patients' hypertensin can be cntrlled with diltiazem and alpha-blckers when testing fr primary aldsternism. Renal impairment can lead t a high aldsterne-t-renin rati in patients withut primary aldsternism because fluid retentin suppresses PRA and hyperkalemia stimulates aldsterne secretin. ΕΔΩ ΘΑ ΠΡΕΠΕΙ ΝΑ ΑΠΟΔΕΙΧΘΕΙ ΟΤΙ ΥΠΑΡΧΕΙ ΑΥΤΟΝΟΜΟ ΑΔΕΝΩΜΑ, ΣΕ 1% ΕΝΔΕΧΕΤΑΙ ΝΑ ΟΦΕΙΛΕΤΑΙ Η ΕΙΚΟΝΑ ΤΟΥ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΥ ΣΕ ΠΕΡΙΣΕΙΑ ΚΟΡΤΙΖΟΛΗΣ The saline infusin test can cnfirm autnmus aldsterne secretin. Other tests described include the measurement f urine aldsterne excretin during ral salt lading r the fludrcrtisne suppressin test. All tests rely n the principle that a lack f suppressin f aldsterne excretin with intravascular expansin is indicative f aldsterne prductin. The saline infusin test is perfrmed by infusing 1140 ml/m 2 bdy surface area (BSA) f 0.9% saline ver 4 hurs. Plasma aldsterne and crtisl are measured befre and at the end f infusin. Thse withut primary aldsternism shuld have a fall in plasma aldsterne levels t less than 10 ng/dl. Plasma aldsterne values greater than 10 ng/dl cnfirm primary aldsternism, and levels frm 5-10 may be cnsidered brderline. Crtisl levels are taken t exclude an adrencrtictrpic hrmne (ACTH)-mediated rise in aldsterne. Cnsider the risks f fluid expansin r hypkalemia in susceptible patients. Oral salt lading The ral salt lading test cnsists f administering 12 g/1.7m 2 BSA f sdium chlride tablets and ad libitum diet fr 3 days fllwed by a 24-hur urinary aldsterne measurement. Urinary aldsterne values greater than mcg/d with a urine sdium excretin greater than 250 nml/d are cnsidered diagnstic f primary aldsternism. Captpril test The captpril test has als been used fr screening. Its use is based n the principle that inhibitin f angitensin II prductin shuld nt affect autnmus secretin f aldsterne in primary aldsternism. Applicatin f the 60-minute aldsterne-t-renin rati after 25 mg f ral captpril yielded a sensitivity f 100% and specificity f 83% fr diagnsis f primary aldsternism, but the test was nly marginally better than baseline values. Smewhat lwer sensitivity was nted in a larger study using aldsterne and PRA 90 minutes after a 50-mg dse f captpril.

10 Fludrcrtisne suppressin test: The fludrcrtisne suppressin test uses fludrcrtisne (0.1 mg q6h) and salt lading. It is less frequently used and was described by Grdn et al in ,6 Tests t differentiate between an APA and ther frms f primary aldsternism Pstural testing: Pstural testing is best perfrmed after vernight recumbency. An intravenus catheter is inserted at 7 am, and baseline aldsterne, crtisl, and PRA are btained at 8 am. After 2 hurs f ambulatin, repeat aldsterne, crtisl, and PRA are btained. Typically, APAs are angitensin II unrespnsive, and a fall in aldsterne ver 2 hurs is bserved in parallel with reduced circadian ACTH and crtisl release. A rise in aldsterne is bserved in IHA. Crtisl levels are used t validate the test, and a rise in crtisl release suggests an ACTH surge, which invalidates the test. Diagnstic accuracy f 85% is reprted. 18-Hydrxycrticsterne: Levels f 18- hydrxycrticsterne are typically elevated (>100 ng/dl) in APA and are significantly lwer in patients with IHA. Althugh a diagnstic accuracy f 82% is reprted, 18-hydrxycrticsterne levels have been nted t parallel the severity f aldsternism, and levels f aldsterne and clinical severity are greater in APA than IHA. Dexamethasne suppressin In cases f bilateral aldsterne secretin r when the diagnsis is suspected n the basis f family histry, GRA can be excluded with a 4-day dexamethasne suppressin test (0.5 mg q6h). The aldsterne and renin levels can be measured befre testing, at 2 days, and at 4 days f suppressin testing. The typical respnse in patients withut GRA is fr the aldsterne levels t fall by apprximately 50% and return t the reference range by the end f testing; hwever, persistent suppressin f aldsterne levels t less than 4 ng/dl are reprted in GRA. The test achieves a sensitivity f 92% and a specificity f 100% fr the diagnsis f GRA cmpared with direct genetic testing. Bichemically unique, markedly elevated levels f 18- xcrtisl and 18-hydrxycrtisl (>100 nml/d) are als bserved in GRA. Mutatin analysis fr the hybrid gene that gives rise t GRA is nw available by Suthern bltting r a lng plymerase chain reactin (PCR) technique. This is likely t supersede the time-intensive dexamethasne suppressin test. Imaging Studies CT scanning f the adrenal glands Adrenal CT scanning is 70% sensitive in detecting APAs. Mean APA size was 1.8 cm in ne large series; hwever, 19% f these tumrs were less than 1 cm. Adrenal incidentalmas are very uncmmn in children, meaning that in the presence f hyperaldsternism, a psitive finding n adrenal CT scanning makes the diagnsis f an adenma very likely. Aldsternmas are typically lipid-rich and cmmnly appear as hmgeneus lesins with a lw Hunsfield number cnsistent with this high lipid cntent. Adrenal scintigraphy has insufficient diagnstic accuracy fr rutine use in diagnsing adrenal adenmas. Prcedures Adrenal venus sampling Adrenal venus sampling requires cnsiderable skill. It can be perfrmed as an utpatient prcedure, althugh yunger children may need general anesthesia. Infusin f ACTH int a peripheral vein (50 mcg/h, starting 30 min befre sampling) masks the effects f cnfunding ACTH peaks during sampling. Vengraphy is avided t reduce the risk f adrenal hemrrhage. With cmparisn f simultaneus aldsterne, crtisl ratis in the adrenal veins and the inferir vena cava allw detectin f unilateral r bilateral surces f aldsterne hypersecretin. Althugh the cut-ff fr lateralizatin is cntrversial, bth 5:1 and 10:1 have been advcated. Nevertheless, adrenal venus sampling is the criterin standard fr the differential diagnsis f primary aldsternism.

11 Histlgic Findings APA IHA Unlike crtisl-prducing adrencrtical tumrs, in which the remaining ipsilateral and cntralateral glands are cmmnly atrphic, the nntumrus crtex may shw hyperplasia f the zna glmerulsa, frming either a brad zne lcally r thickening f the entire crtex, with tngues f glmerulsalike crtex extending inward frm the subcapsular regin. This appearance has been reprted in up t ne third f patients with aldsternma and suggests that the tumr has arisen frm within an area that was hyperplastic, althugh neither an external stimulus nr an intrinsic defect has been fund t date. IHA is a disease f the zna glmerulsa with a variable macrscpic appearance that can range frm hyperplasia with micrndules and macrndules, hyperplasia withut ndules, and nrmal appearing zna glmerulsa with micrndules. The glands may be nrmal in weight r heavy. The nrmal micrscpic appearance f the zna glmerulsa is f small discntinuus subcapsular nests f cells. In hyperplasia, the zna glmerulsa may frm cntinuus bands f cells that may be visibly thickened, as either a cntinuus sheet r fcally extending as tngues int the adjacent crtex. This prcess may be fcal r diffuse and may vary frm ne part f the gland t anther, requiring multiple sectins. Gluccrticid remediable hyperaldsternism (FH-I): This disrder is the result f frmatin f a hybrid gene that leads t ACTH-mediated mineralcrticid synthesis by the zna fasciculata. Histlgically, evidence suggests hyperplasia f this zne in additin t the zna glmerulsa. Nngluccrticid remediable hyperaldsternism (FH-II and III): This autsmal dminant disrder (FH-II) has been linked t a lcus n chrmsme 7p22. Histlgically, evidence suggests adrencrtical hyperplasia and/r hypertrphy and the presence f adenmas. Treatment Medical Care Surgical excisin f the affected adrenal gland is recmmended fr all patients with hyperaldsternism wh have a prven aldsterne-prducing adenma (APA). Ensuring gd cntrl f bld pressure and replenishment f ptassium levels preperatively is imprtant. The literature n adults indicates that remval f an APA by unilateral adrenalectmy results in nrmtensin in apprximately 70% f cases and imprves bld pressure cntrl and restres nrmkalemia in mst f the remainder. These rates are likely t be even better in children wh have fewer independent factrs that predispse t hypertensin. Persistent hypertensin despite cntrl f hyperaldsternism may be the result f cexistent essential hypertensin, hypertensive vascular damage secndary t the hyperaldsternism, r, rarely, anther cause f secndary hypertensin. Phechrmcytma and renal artery stensis have been reprted in assciatin with APA. Pstperative hypaldsternism is cmmn. Ptassium replacement may prduce hyperkalemia in this perid. Patients may need supplementatin with mineralcrticids fr several mnths after successful surgery. Immediate pstperative declines in bld pressure may nt be sustained. Medical care fr idipathic hyperaldsternism (IHA) is as fllws: Althugh bilateral adrenalectmy crrects hypkalemia in patients with IHA, it has nt been shwn t be effective at cntrlling bld pressure. This may be because this cnditin is typically insidius in its nset, allwing time fr chrnic hypertensin t cause secndary damage. Furthermre, bilateral adrenalectmy cmmits the patient t lifelng replacement therapy with gluccrticids and mineralcrticids.

12 Cntrl f hypkalemia and hypertensin in IHA can be achieved with sdium restrictin (t <2 g/d) and spirnlactne r amilride, but additinal antihypertensives are ften needed t achieve gd cntrl in this patient grup. Pediatric drug dses are utlined in the table belw. Althugh spirnlactne is an effective aldsterne antagnist, it antagnizes teststerne synthesis and actin and can cause hypgnadism with gynecmastia and reductin in libid and erectile dysfunctin in pubertal and adult males. Menstrual irregularities are als cmmn in females. Fr this reasn, it shuld be used with cautin in peripubertal children. Newer alternatives are being prduced with better specificity fr the mineralcrticid receptr. Amilride and triamterene may be used instead f spirnlactne. They have a direct effect n the renal tubule t impair sdium reabsrptin in exchange fr ptassium and hydrgen. Drugs Used in the Management f Hyperaldsternism Spirnlactne Aldsterne antagnist Ptassium canrenate Amilride Triamterene Nifedipine Aldsterne antagnist Ptassiumsparing diuretic Ptassiumsparing diuretic Dihydrpyridine calcium channel antagnist 0-10 kg: 6.25 mg/dse PO q12h kg: 12.5 mg/dse PO q12h kg: 25 mg/dse PO q12h >40 kg: 25 mg PO q8h 3-8 mg/kg IV qd; nt t exceed 400 mg 0.2 mg/kg q12h 2 mg/kg/dse q8-24h mg/kg PO q6-8h Amldipine Calcium channel antagnist mg/d PO Dxazsin Alpha1-specific adrenergic antagnist mg/d; nt t exceed 4 mg Prazsin Alpha1-specific adrenergic antagnist mg/kg test dse, then mg/kg/dse q6h; nt t exceed 0.5 mg/dse Table Drug Class Pediatric Dse Gluccrticid-remediable hyperaldsternism (GRA) treatment includes the fllwing: In adult patients with gluccrticidremediable aldsternism (GRA), cntrl f hypertensin can be achieved by treatment

13 with physilgic dses f dexamethasne. Hwever, in children, aviding dexamethasne is best because f its adverse effects n grwth and bne density. Hydrcrtisne is a better chice because f its shrt half-life (typical dse is mg/m 2 ), but it is nt as efficient at reducing mineralcrticid levels. Children receiving lng-term treatment with gluccrticids require cnsultatin by a pediatric endcrinlgist. GRA is assciated with intracranial aneurysm and hemrrhagic strke, and screening fr intracranial aneurysms in patients with prven GRA is recmmended. Amilride and spirnlactne have als been used as mntherapy fr treating GRA. Familial hyperaldsternism type II (FH-II) treatment Surgical Care includes the fllwing: Patients with FH-II shuld be regularly bserved, and treatment shuld be started when they develp hypertensin. Treatment is with the same agents as fr IHA. In the event that patients develp an adenma, adrenal venus sampling shuld be cnsidered t cnfirm lateralizatin f aldsterne hypersecretin befre surgical remval. In cases where gradient is lacking, medical treatment is recmmended, with regular mnitring. Because patients with FH-II are nt at increased risk f carcinma, nnsurgical management may be wrth cnsidering. Laparscpic adrenalectmy significantly reduces perative mrbidity with a substantially shrter hspital stay and reduced bld lss cmpared with an pen apprach. A limited number f cases f islated adenmectmy with preservatin f the remaining nrmal adrenal tissue have been reprted. Transcatheter arterial ablatin with high-cncentratin ethanl injectin f APA has been reprted. Cnsultatins Endcrinlgy: Once screening indicates a pssible diagnsis f hyperaldsternism, referral t an endcrinlgist is recmmended fr further assessment and management because numerus Diet causes f primary aldsternism in children and adlescents can be managed medically. 7 Cardilgy: Patients with severe r lng-standing hypertensin may require assessment by a cardilgist because hyperaldsternism may lead t mycardial fibrsis. This prblem is mre likely t ccur in adults in whm the duratin f disease is much greater. Patients being evaluated fr hyperaldsternism shuld be receiving a high-sdium intake as described abve. Adult recmmendatins are fr a sdium intake f 10 g/d r mre. This amunt can be reduced prprtinately fr children, depending n their size. Regular mnitring f ptassium is imprtant when increasing sdium in patients with suspected hyperaldsternism because this may unmask hypkalemia. Medical management f patients with established hyperaldsternism shuld include salt restrictin. This shuld include nt adding salt t cking and nt having salt n the table. Ideally, patients shuld receive fewer than 2 g f sdium chlride a day. Prblems with cmpliance may ccur because this degree f restrictin is ften unpalatable t children. Activity Patients with significant hypertensin shuld be advised t avid strenuus activity until bld pressure is under cntrl because strenuus activity may further exacerbate their prblem. The type f surgery that has been perfrmed gverns pstperative activity. Patients shuld avid bathing r wetting their wunds until they have healed. Patients wh have undergne lapartmy must avid heavy lifting fr 6 weeks after their peratin. Patients wh have undergne laparscpic adrenalectmy need nly restrict their activity while they are sre r the wund has nt healed. Medicatin Aldsterne antagnists These agents are used t : lwer the bld pressure, nrmalize serum ptassium, and minimize pstperative hypaldsternism.

14 Spirnlactne (Aldactne) Mst cmmnly used t treat hyperaldsternism because it directly antagnizes aldsterne effect at the distal tubule. Adult mg/d PO Ptassium-sparing diuretics Management f hypkalemia assciated with hyperaldsternism when spirnlactne is cntraindicated. Amilride ΚΑΛΙΟΠΡΟΣΤΑΤΕΥΤΙΚΟ ΕΛΑΤΤΩΝΕΙ ΜΕΤΑΞΥ ΑΛΛΩΝ ΤΗΝ ΑΠΕΚΚΡΙΣΗ ΜΑΓΝΗΣΙΟΥ Η ΟΠΟΙΑ ΛΑΜΒΑΝΕΙ ΧΩΡΑ ΣΕ ΜΟΝΟΘΕΡΑΠΕΙΑ ΜΕ ΔΙΟΥΡΗΤΙΚΟ ΑΓΚΥΛΗΣ Η ΘΕΙΑΖΙΔΙΚΟ Adult 5 mg/d PO initially; increasing stepwise t 20 mg/d with clse mnitring f ptassium Precautins ΑΠΟΦΥΓΗ ΣΕ ΝΑ ΗΑ Triamterene (Dyrenium) Inhibits reabsrptin f sdium ins in exchange fr ptassium and hydrgen ins at the segment f the distal tubule under cntrl f adrenal mineralcrticids (especially aldsterne). This activity is nt directly related t aldsterne secretin r antagnism, and it is a result f a direct effect n the renal tubule. Antihypertensive agents ΣΤΟΧΟΙ : ΕΛΑΤΤΩΣΗ ΑΡΤΗΡΙΑΚΗΣ ΠΙΕΣΗΣ ΑΠΟΦΥΓΗ ΥΠΕΡΛΙΠΙΔΑΙΜΙΑΣ ΑΠΟΦΥΓΗ ΔΥΣΑΝΕΞΙΑΣ ΣΤΗ ΓΛΥΚΟΖΗ ΑΠΟΦΥΓΗ ΑΡΙΣΤΕΡΑΣ ΥΠΕΡΤΡΟΦΙΑΣ The fractin f filtered sdium reaching this distal tubular exchange site is relatively small, and the amunt that is exchanged depends n the level f mineralcrticid activity; thus, the degree f natriuresis and diuresis prduced by inhibitin f the exchange mechanism is necessarily limited. Increasing the amunt f available sdium and the level f mineralcrticid activity by the use f mre prximally acting diuretics increases the degree f diuresis and ptassium cnservatin. May ccasinally cause increases in serum ptassium, which can result in hyperkalemia. It des nt prduce alkalsis because it des nt cause excessive excretin f titratable acid and ammnium. Adult mg PO bid initially; increase as required; nt t exceed 300 mg/d Precautins Cautin in severe hepatic encephalpathy, diabetes, renal dysfunctin, and histry f renal stnes Nifedipine (Adalat, Prcardia) Calcium channel blcking agent prducing vasdilatr with antianginal and antihypertensive effects. It acts by blcking the pstexcitatin release f calcium ins int cardiac and vascular smth muscle, thereby inhibiting the activatin f ATPase n myfibril cntractin. The verall effect is reduced intracellular calcium levels in cardiac and smth muscle cells f the crnary and peripheral vasculature, resulting in dilatatin f crnary and peripheral arteries. Available as shrt-acting and SR preparatins. Adult mg IR cap PO tid; nt t exceed mg/d mg SR tab PO qd; nt t exceed mg/d Precautins ΟΤΙ ΙΣΧΥΕΙ ΣΤΗΝ ΑΜΛΟΔΙΠΙΝΗ ΕΧΕΙ ΑΝΑΦΕΡΘΕΙ ΘΕΤΙΚΗ ΑΜΕΣΗ COOMBS ΜΕ Η ΧΩΡΙΣ ΣΥΝΟΔΟ ΑΙΜΟΛΥΤΙΚΗ ΑΝΑΙΜΙΑ

15 Amldipine (Nrvasc) Adult 2.5 mg/d PO if adding t ther drugs r 5 mg/d PO; nt t exceed 10 mg/d Precautins ΑΝΑΠΡΟΣΑΡΜΟΓΗ ΔΟΣΗΣ ΣΕ ΝΑ, ΗΑ ΥΠΟΤΑΣΗ ΣΤΗΝ ΕΝΑΡΞΗ ΤΗΣ ΑΓΩΓΗΣ ΟΙΔΗΜΑ ΚΑΤΩ ΑΚΡΩΝ ΑΛΛΕΡΓΙΚΗ ΗΠΑΤΙΚΗ ΑΝΤΙΔΡΑΣΗ, ΣΠΑΝΙΩΣ Dxazsin (Cardura) Alpha1-adrenergic antagnist. Adult 1 mg PO qd; may increase t 2 mg qd thereafter and titrate t higher dses Precautins ΕΝΑΡΞΗ ΣΕ ΧΑΜΗΛΗ ΔΟΣΗ ΠΡΟΣ ΑΠΟΦΥΓΗ ΥΠΟΤΑΣΗΣ ΠΡΟΣΟΧΗ ΣΕ ΝΑ Prazsin (Minipress) ΜΕΤΑΣΥΝΑΠΤΙΚΟΣ α1 ΑΝΤΑΓΩΝΙΣΤΗΣ ΕΛΑΤΤΩΝΕΙ ΤΗΝ ΑΡΤΗΡΙΑΚΗ ΠΙΕΣΗ ΜΕ ΧΑΜΗΛΟ ΚΙΝΔΥΝΟ ΑΝΤΑΝΑΚΛΑΣΤΙΚΗΣ ΤΑΧΥΚΑΡΔΙΑΣ Adult Initial: 1 mg PO bid/tid Maintenance: 6-15 mg/d PO bid/tid