Hyperaldosteronism                                                                      Scintigram obtained by using iodin...
ΕΠΙΝΕΦΡΙΔΙΚΟ ΜΥΕΛΟΛΙΠΩΜΑ : ΚΑΛΟΗΘΗΣ, ΛΙΠΩΔΗΣ ΜΑΖΑ ΜΕ                      Preferred Examination
Hyperaldosteronism                                                       Steroid biosynthetic pathway


The synthesis and secretion of prostaglandins I 2 and E 2 and the          can result in a number of disorders of aldoster...
Familial hyperaldosteronism type I (glucocorticoid-remediable                   Hyperreninemia and secondary aldosteronism...
Frequency                                                                 Hypokalemia is more frequently observed in patie...

Because the 2 causes that account for about 99% of cases of primary     •   For patients in whom secondary hyperaldos...
ΟΦΘΑΛΜΟΛΟΓΙΚΗ ΕΞΕΤΑΣΗ : [ ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΙΚΑ ΑΓΓΕΙΩΜΑΤΑ               Conditions that mimic aldosterone excess
von Hippel-L...
Saline infusion test

                                                                     o    The saline infusion test c...
likely to supersede the time-intensive dexamethasone
Histologic Findings                                                  Treatment

    •   APA                               ...
o   Control of hypokalemia and hypertension in                                                       0-10 kg: 6.25
with physiologic doses of dexamethasone.                     causes of primary aldosteronism in children and
Spironolactone (Aldactone)                                                  Amiloride

Most commonly used to treat hyperal...
Amlodipine (Norvasc)


2.5 mg/d PO if adding to other drugs or 5 mg/d PO; not to
exceed 10 mg/d


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  1. 1. Hyperaldosteronism Scintigram obtained by using iodine-131-6β-iodomethylnorcholesterol (NP-59) in a 59- year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor (same patient as in Image 7 in Multimedia). At surgery, a Conn tumor was confirmed. Introduction Background 1Η ΑΝΑΦΟΡΑ 1955 : ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ ΥΠΕΡΕΚΚΡΙΝΩΝ ΑΛΔΟΣΤΕΡΟΝΗ 1Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ = ΣΥΝΔΡΟΜΟ Conn : [ ΥΠΕΡΤΑΣΗ – ΥΠΟΚΑΛΙΑΙΜΙΑ ] – ΣΠΑΝΙΟ ΑΙΤΙΟ ΥΠΕΡΤΑΣΗΣ 0.05-2% 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% Pathophysiology 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 ] o ΜΟΝΗΡΕΣ ΕIΤΕ ΠΟΛΛΑΠΛΑ ΑΔΕΝΩΜΑΤΑ : (APAs) 65-89% o ΜΟΝΗΡΕΣ ΑΔΕΝΩΜΑ : 65-70% Axial enhanced CT scan in a 32-year-old woman who presented with hypertension o ΠΟΛΛΑΠΛΟ ΑΔΕΝΩΜΑ : 13% shows a low-attenuating 2.8-cm suprarenal mass (A) (same patient as in Image 1 in o ΜΙΚΡΟΑΔΕΝΩΜΑΤΩΣΗ : 6% Multimedia). Histologic results obtained after surgery confirmed a tumor due to Conn syndrome. ΕΠΙΝΕΦΡΙΔΙΚΟ ΝΕΟΠΛΑΣΜΑ : 1 % - ΟΙ ΔΙΑΣΤΑΣΕΙΣ ΤΟΥ ΟΓΚΟΥ ΕΙΝΑΙ : [average size of 1.7 cm (range, 0.5-3.5 cm), the left adrenal gland is affected more often, and the tumors are bilateral in 6% Longitudinal sonogram through the left kidney in a 32-year-old woman who presented with hypertension shows a 3-cm hypoechoic but solid mass superior to the upper pole of patients ] – ΣΥΧΝΑ ΕΚΚΡΙΝΕΙ ΑΛΔΟΣΤΕΡΟΝΗ κ of the kidney. Initially, the mass was regarded as a nonfunctioning adenoma unrelated ΓΛΥΚΟΚΟΡΤΙΚΟΕΙΔΗ ΟΠΟΤΕ ΑΝΑΜΕΝΕΤΑΙ ΚΛΙΝΙΚΗ ΕΙΚΟΝΑ to the patient's hypertension. Subsequently, mild hypokalemia developed. Surgical ΥΠΕΡΤΑΣΗΣ ‘Η/κ Cushing syndrome resection confirmed a tumor due to Conn syndrome. ΔΙΑΓΝΩΣΗ = ΕΡΓΑΣΤΗΡΙΑΚΗ ΤΕΚΜΗΡΙΩΣΗ – ΩΣΤΟΣΟ ΔΕΝ ΔΙΕΥΚΡΙΝΙΖΕΤΑΙ ΕΝΑ ΠΡΟΚΕΙΤΑΙ ΓΙΑ 1Ο ΠΑΘΗ ‘Η ΓΙΑ 2Ο 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 : [ 80 – 90 % ΥΠΟΚΑΛΙΑΙΜΙΑ ΕΑΝ ΠΡΑΓΜΑΤΙ ΥΠΑΡΧΕΙ 1Ο ΠΑΘΗΣ ΝΟΣΟΣ – ΜΥΙΚΗ ΑΔΥΝΑΜΙΑ – ΑΡΡΥΘΜΙΕΣ – ΔΥΣΑΝΕΞΙΑ ΥΔΑΤΑΝΘΡΑΚΩΝ – ΝΕΦΡΟΓΕΝΗ ΑΠΟΙΟ ΔΙΑΒΗΤΗ – ΥΠΕΡΤΑΣΗ ΚΑΤΑ ΚΑΝΟΝΑ ΜΕΤΡΙΑ ΣΠΑΝΙΩΣ ΚΑΚΟΗΘΗΣ ]
  2. 2. ΕΠΙΝΕΦΡΙΔΙΚΟ ΜΥΕΛΟΛΙΠΩΜΑ : ΚΑΛΟΗΘΗΣ, ΛΙΠΩΔΗΣ ΜΑΖΑ ΜΕ Preferred Examination ΑΥΤΟΝΟΜΙΑ , ΑΛΛΑ ΠΟΛΥ ΣΠΑΝΙΑ ΜΕ ΔΥΝΑΤΟΤΗΤΑ ΝΑ ΠΡΟΚΑΛΕΣΕΙ ΛΕΙΤΟΥΡΓΙΚΗ κ ΚΛΙΝΙΚΗ ΕΠΙΝΕΦΡΙΔΙΚΗ ΔΙΑΤΑΡΑΧΗ.Jung and The workup in patients in whom primary aldosteronism is suspected colleagues reported a case of bilateral adrenal myelolipomas associated usually starts with appropriate biochemical analysis, after which, thin- 5 collimation CT scanning is performed.1,6 If CT scan findings are equivocal, with primary hyperaldosteronism. radionuclide studies and MRI should be performed.8 If doubt concerning the diagnosis remains and if CT scans do not show a mass in the adrenal glands, adrenal venous sampling is recommended. Frequency United States In 0.05-2% of patients with hypertension, the condition is caused Plain radiographs have no significant role. Ultrasonography has little to by primary aldosteronism. contribute unless the adrenal tumor is large, which is seldom the case. However, ultrasonography is an excellent modality for the investigation of Mortality/Morbidity hypertension. Limitations of Techniques • In 75-90% of patients with a solitary APA, surgical adrenalectomy corrects hypertension and hypokalemia. • Most other patients have idiopathic hyperaldosteronism Hypersecreting adrenal glands may appear to be normal in size on images, because the size of the adrenal gland may be compared to a normal associated with bilateral adrenal hyperplasia; in these measurement and because the healthy adrenal gland varies considerably in patients, surgery rarely cures hypertension. size. The adrenal glands also vary in size and weight as a result of illness or stress. This size discrepancy is a particular problem with APAs, because they are often small and difficult to detect. In one series, the average Sex diameter of an APA was 18 mm, and 20% of tumors were smaller than 1 cm. In earlier generations of CT scanners, the sensitivity for detecting APAs The male-to-female ratio is 1:2. was 50-70%. In current CT scanners, the sensitivity has been improved to 82-88%. Diagnosis by using CT scans is hampered by the detection of ipsilateral or contralateral, nonfunctioning adenomas, which leads to a Age false-positive diagnosis of adrenal hyperplasia. CT scanning is not reliable in distinguishing between hyperplasia and adenoma in patients with 6,7,12,13 multiple, bilateral nodules. Primary aldosteronism occurs in patients aged 30-50 years. Anatomy Differential Diagnoses Other Problems to Be Considered ΑΠΟΛΥΤΗ ΕΝΔΕΙΞΗ ΕΧΟΥΝ Η ΑΞΟΝΙΚΗ κ Ο ΥΠΕΡΗΧΟΣ ΜΗ ΛΕΙΤΟΥΡΓΙΚΟ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ + ΠΕΡΙΣΤΑΣΙΑΚΗ ΕΠΙΝΕΦΡΙΔΙΟ = ΔΙΠΛΟ, ΠΤΥΧΩΤΟ ΜΟΡΦΩΜΑ ΠΡΟΣΘΙΟΜΕΣΟ o ΥΠΕΡΤΑΣΗ ΔΑΚΤΥΛΙΟ κ 2 ΟΠΙΣΘΙΑ ‘Η ΟΠΙΣΘΙΟΜΕΣΑ ΣΚΕΛΗ. ΤΑ ΣΚΕΛΗ ΔΙKΗΝ o 2Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ + ΜΗ ΛΕΙΤΟΥΡΓΙΚΟ ΠΤΕΡΩΜΑΤΟΣ ΒΡΙΣΚΟΝΤΑΙ ΣΥΝΕΔΕΜΕΝΑ ΜΕΤΑΞΥ ΤΟΥΣ ΣΤΗΝ ΑΝΩ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ ΑΠΟΨΗ ΤΟΥ ΜΟΡΦΩΜΑΤΟΣ ΣΤΟΝ ΑΝΩ ΠΟΛΟ ΤΟΥ ΝΕΦΡΟΥ. ΑΠΟ o ΙΔΙΟΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΕΜΠΡΟΣ ΤΑ 2 ΣΚΕΛΗ ΕΝΑΓΚΑΛΙΖΟΥΝ ΤΟΝ ΑΝΩ ΝΕΦΡΙΚΟ ΠΟΛΟ. ΣΤΗΝ ΠΛΕΟΝ ΚΕΦΑΛΙΚΗ ΤΟΜΗ ΤΗΣ ΑΞΟΝΙΚΗΣ ΤΟ ΕΠΙΝΕΦΡΙΔΙΟ ΟΡΙΖΕΤΑΙ ΩΣ ΨΕΥΔΟΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΤΥΠΟΣ Ι = ΣΥΝΔΡΟΜΟ Liddle ΓΡΑΜΜΟΕΙΔΕΣ ΜΟΡΦΩΜΑ ΜΕ ΠΡΟΣΘΙΟΠΙΣΘΙΟ ΠΡΟΣΑΝΑΤΟΛΙΣΜΟ ‘Η ΠΡΟΣΘΙΟ – ΟΠΙΣΘΙΟΠΛΑΓΙΟ o ΨΕΥΔΟΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΤΥΠΟΣ ΙΙ = ΣΥΝΔΡΟΜΟ Gordon [familial hypertensive hyperkalemia ] The midsections of the gland present a Y -shaped configuration. Occasionally, the anteromedial ridge is small or not well Ο developed, resulting in an inverted, V -shaped gland. The normal 2 ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΟΦΕΙΛΟΜΕΝΟΣ adrenal limbs measure 3-6 mm in thickness, 4-6 cm in length, ΣΕ ΕΞΩΕΠΙΝΕΦΡΙΔΙΚΟ ΜΟΡΦΩΜΑ ΥΠΕΡΕΚΚΡΙΝΩΝ ΡΕΝΙΝΗ : and 2-3 cm in width. The variation in size explains why some [adrenal embryologic rest neoplasms in a kidney or ovary ] hyperfunctioning glands are seen to be normal in size on images and at surgery. __________________________________ Presentation Ο 1 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. 3. Hyperaldosteronism Steroid biosynthetic pathway Introduction Background Aldosterone = 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 from the heart – local adrenal secretion of dopamine ] ΠΡΟΔΡΟΜΕΣ ΟΥΣΙΕΣ : [deoxycorticosterone and 18-hydroxycorticosterone ] 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 ] Pathophysiology – Aldosterone Secretion and Its Regulation Ο ΜΗΧΑΝΙΣΜΟΣ ΕΚΚΡΙΣΗΣ ΤΗΣ ΑΛΔΟΣΤΕΡΟΝΗΣ ΕΙΝΑΙ ΠΟΛΥΠΛΟΚΟΣ : [ ΣΠΕΙΡΟΕΙΔΗΣ ΖΩΝΗ ΕΠΙΝΕΦΡΙΔΙΟΥ – ΠΑΡΑΣΠΕΙΡΑΜΑΤΙΚΗ ΣΥΣΚΕΥΗ – The major factors stimulating aldosterone production and release by the zona ΜΥΟΚΑΡΔΙΟ – ΠΝΕΥΜΟΝΑΣ – ΑΥΤΟΝΟΜΟ ΝΣ – ΗΠΑΡ ] glomerulosa are angiotensin II and the serum potassium concentration. ΑΔΡΑ : ΕΝΕΡΓΟΠΟΙΗΣΗ ΕΚΚΡΙΣΗΣ : [ ΥΠΕΡΚΑΛΙΑΙΜΙΑ – ΤΑΣΕΟΥΠΟΔΟΧΕΙΣ ACTH stimulates aldosterone secretion in an acute and transient ΣΕ ΕΛΕΙΜΜΑ ΚΥΚΛΟΦΟΡΟΥΝΤΟΣ ΟΓΚΟΥ ] fashion but does not appear to play a significant role in the long-term regulation of mineralocorticoid secretion. The major inhibitors of the zona glomerulosa include circulating atrial natriuretic peptide (ANP) ΚΑΤΑΣΤΟΛΗ ΕΚΚΡΙΣΗΣ : [ ΥΠΕΡΚΑΛΙΑΙΜΙΑ – ΥΠΕΡΦΟΡΤΩΣΗ ΣΕ ΥΓΡΑ ] and, locally, dopamine. Although ANP levels are clearly increased in hyperaldosteronism, neither ANP nor dopamine has been implicated as a primary cause of clinically disordered aldosterone secretion. Metoclopramide has been shown to increase aldosterone secretion, suggesting that dopamine may tonically inhibit aldosterone release. The physiologic roles of adrenomedullin and vasoactive intestinal peptide (VIP) on aldosterone secretion remain to be clarified, although both of these neuropeptides are produced in rat zona glomerulosa. The juxtaglomerular apparatus is the principal site of regulation of angiotensin II production (see Media file 1). The synthesis of prorennin, its conversion to renin, and its systemic secretion are stimulated by blood volume contraction detected by stretch receptors, beta-adrenergic stimulation of the sympathetic nervous system, and prostaglandins I 2 and E 2 . These processes are inhibited by volume expansion and ANP. Renin converts angiotensinogen, a proenzyme synthesized in the liver, into the decapeptide angiotensin I, which is then converted in the lungs into an octapeptide, angiotensin II, by angiotensin- converting enzyme. Angiotensin II is both a stimulator of aldosterone secretion and a potent vasopressor. Angiotensin II is metabolized to angiotensin III, a heptapeptide that is also a stimulator of aldosterone secretion.
  4. 4. The synthesis and secretion of prostaglandins I 2 and E 2 and the can result in a number of disorders of aldosterone synthesis that are normal function of the stretch receptors are dependent upon discussed below (see Differentials). intracellular ionized calcium concentration. Renal prostaglandin secretion is stimulated by catecholamines and angiotensin II. The complex regulation of aldosterone synthesis and secretion provides Aldosterone receptors several points at which disturbance in the regulation of aldosterone secretion may occur. ΟΡΓΑΝΑ ΣΤΟΧΟΙ : [ ΑΠΩ ΝΕΦΡΙΚΟ ΣΩΛΗΝΑΡΙΟ – ΙΔΡΩΤΟΠΟΙΟΙ – ΣΙΕΛΟΓΟΝΟΙ – ΕΠΙΘΗΛΙΟ ΠΑΧΕΟΣ ΕΝΤΕΡΟΥ ] Aldosterone biosynthesis Ο ΥΠΟΔΟΧΕΑΣ ΕΧΕΙ ΠΑΡΟΜΟΙΑ ΣΥΓΓΕΝΕΙΑ ΓΙΑ ΤΑ ΑΛΑΤΟ- κ ΤΑ ΓΛΥΚΟ- Aldosterone is synthesized from cholesterol in a series of 6 ΚΟΡΤΙΚΟΕΙΔΗ. biosynthetic steps (see Media file 2). Ο ΥΠΟΔΟΧΕΑΣ ΠΡΟΣΤΑΤΕΥΕΤΑΙ ΑΠΟ ΤΗΝ ΚΟΡΤΙΖΟΛΗ ΑΠΟ ΕΝΑ ΕΝΖΥΜΟ : 11beta-hydroxysteroid dehydrogenase type 2, ΤΟ ΟΠΟΙΟ ΜΕΤΑΤΡΕΠΕΙ ΤΗΝ ΚΟΡΤΙΖΟΛΗ ΣΕ ΑΔΡΑΝΗ ΜΟΡΦΗ Primary Aldosteronism 99% ΑΔΕΝΩΜΑ ΠΟΥ ΕΚΚΡΙΝΕΙ ΑΛΔΟΣΤΕΡΟΝΗ : [ 40% aldosterone- ] producing adenoma (APA) – 60% idiopathic hyperaldosteronism (IHA) ΑΜΙΓΩΣ ΑΛΔΟΣΤΕΡΟΝΗ ΕΚΚΡΙΝΩΝ ΕΠΙΝΕΦΡΙΔΙΚΟ ΝΕΟΠΛΑΣΜΑ = ΠΟΛΥ ΣΠΑΝΙΟ κ ΕΥΜΕΓΕΘΕΣ ΚΑΤΑ ΤΗ ΔΙΑΓΝΩΣΗ ΑΜΦΟ ΕΠΙΝΕΦΡΙΔΙΚΗ ΥΠΕΡΠΛΑΣΙΑ = ΠΟΛΥ ΣΠΑΝΙΑ Ο 1Ο ΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ ΕΙΝΑΙ ΝΟΣΟΣ ΤΗΣ 4ΗΣ – 6ΗΣ 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 Patients with IHA have bilateral thickening and variable nodularity of their adrenal cortex. A wide spectrum of severity exists for this disorder, which may go undetected for a long period with no hypokalemia and only mild hypertension. A proposal is that IHA arises as a result of an undetected adrenal cortical–stimulating factor. Possibly, this disorder may arise as a result of an activating mutation in an adrenal cortex– Physiologic regulation of the renin-angiotensin-aldosterone axis. specific gene, although neither hypothesis has been proven. Only the last 2 steps are specific to aldosterone synthesis, the first ΤΑ ΚΛΗΡΟΝΟΜΙΚΑ ΑΙΤΙΑ ΤΗΣ ΝΟΣΟΥ ΕΜΦΑΝΙΖΟΝΤΑΙ ΜΕ 4 are common to the cortisol synthesis by the zona fasciculata. ΥΠΕΡΤΑΣΗ ΣΕ ΠΑΙΔΙΚΗ ΗΛΙΚΙΑ κ ΑΦΟΡΟΥΝ ΤΟ 1% ΤΗΣ Consequently, a defect in one of the specific aldosterone synthetic ΑΙΤΙΟΛΟΓΙΑΣ [familial hyperaldosteronism types I and II ] enzymes does not lead to hypercortisolism and secondary ACTH- mediated adrenal hyperplasia. The enzyme aldosterone synthase is encoded by the gene CYP11B2 and has 11beta-hydroxylase, 18- hydroxylase, and 18-hydroxydehydrogenase activity. This gene is located on human chromosome arm 8q24.3-tel, close to the gene CYP11B1 that encodes 11beta-hydroxylase, the enzyme that catalyzes the final step of cortisol synthesis. Mutations in these genes
  5. 5. Familial hyperaldosteronism type I (glucocorticoid-remediable Hyperreninemia and secondary aldosteronism have also been aldosteronism) reported in patients with pheochromocytoma, apparently as a result of functional renal artery stenosis. Familial hyperaldosteronism type I (FH-I) represents about 1% of cases of primary hyperaldosteronism. It may be detected in asymptomatic individuals when screening the offspring of affected individuals, or patients may present in infancy with hypertension, weakness, Renin-producing tumors are very rare, and very high levels of PRA (up and failure to thrive due to hypokalemia. It is inherited in an to 50 ng/mL/h) are noted, frequently with an increased prorennin-to- autosomal dominant manner and has a low frequency of new renin ratio. The tumors are generally of renal origin and include Wilms mutations. The first clinical description of glucocorticoid-remediable tumors and renal cell carcinomas. Hyperkalemia due to chronic renal aldosteronism (GRA) was in 1966, with the genetic mechanism failure also causes secondary hyperaldosteronism. Low sodium-to- discovered in 1992. It arises as a result of unequal crossing over potassium ratios can be measured in saliva and stool. of CYP11B1 (11beta-hydroxylase gene) and CYP11B2 (aldosterone synthase gene) during meiosis, producing a fusion product that couples the ACTH-sensitive promoter of CYP11B1 to the CYP11B2 gene. Cyclosporin-induced hypertension in solid organ transplant patients may also involve a component of hyperaldosteronism. The result is ACTH-dependent aldosterone production and production of 17-hydroxylated analogs of 18-hydroxycortisol under ACTH regulation from ectopic enzyme expression in the zona fasciculata. Bilateral hyperplasia of the zona fasciculata occurs and high levels of novel 18-hydroxysteroids appear in the urine. Adenoma Secondary hyperaldosteronism in the absence of hypertension formation is rare, but patients do have a significant increase in occurs as a result of homeostatic attempts to maintain sodium or incidence of cerebrovascular aneurysms, for which they require circulatory volume or to reduce potassium. Clinical situations where screening. this may occur include the presence of diarrhea, excessive sweating, low cardiac output states, and hypoalbuminemia due to liver or renal Familial hyperaldosteronism type II disease or nephrotic syndrome. As outlined below, this also occurs developmentally in newborn infants. Familial hyperaldosteronism type II (FH-II) is a familial nonglucocorticoid-suppressible inherited form of hyperaldosteronism that was recognized as a distinct entity by Gordon et al, although cases had previously been described in the 1980s. Similar to FH-I, it is also inherited in an autosomal dominant manner. The mechanism and gene locus have not yet been identified, although CYP11B2, the renin and angiotensin II receptor genes, have been excluded. Current analysis suggests that this is not a single disorder. Unlike FH-I, Increased mineralocorticoid dependency in the young some kindreds with FH-II exhibit a high rate of adenoma formation. The mineralocorticoid dependency of sodium reabsorption is increased during infancy and childhood, with its peak in the neonatal Secondary Hyperaldosteronism period before decreasing progressively with advancing age. This arises because the reabsorption of sodium and water by the This represents a diverse group of disorders characterized by physiologic proximal tubule is least efficient in early life, resulting in an activation of the renin-angiotensin-aldosterone (R-A-A) axis as a homeostatic mechanism designed to maintain serum electrolyte concentrations or fluid increased sodium and water load at the level of the distal renal volume. In the presence of normal renal function, it may lead to hypokalemia. tubule. Secondary hyperaldosteronism can be divided into 2 categories depending on whether associated hypertension is present. The former category includes renovascular hypertension, which results from renal ischemia and hypoperfusion leading to activation of the R-A-A axis. The Because sodium and water resorption from the distal tubule most common causes of renal artery stenosis in children are fibromuscular is mediated by the R-A-A axis, the PRA of a newborn infant is hyperplasia and neurofibromatosis. Hypokalemia may occur in as many as 20% approximately 10-fold to 20-fold higher than that of an of patients. adult. Plasma renin activity (PRA) levels are often in the reference range, This results in relative increases in aldosterone production but elevated levels of PRA may be detected after provocation with a rates (>300 mcg/m2/d in a newborn infant compared with 50 single dose of captopril 1 mg/kg. Renal ischemia is also thought to mcg/m2/d in an adult) and plasma aldosterone concentrations underlie the secondary hyperaldosteronism observed in malignant (80 pg/dL versus 16 pg/dL, respectively) in the neonate. This hypertension. increased mineralocorticoid dependency in early life explains why young infants exhibit profound clinical symptoms of hypoaldosteronism that gradually improve with advancing age.
  6. 6. Frequency Hypokalemia is more frequently observed in patients with adenomas, although it should not be considered International a diagnostic feature of primary hyperaldosteronism, Primary hyperaldosteronism is a rare condition in children. The as was once thought. youngest child reported with an aldosterone-secreting adenoma was aged 3 years. Earlier use of hypokalemia as a diagnostic requirement, as advocated by some authorities, may have led to Patients with adenomas are more likely to underrecognition of the contribution of primary aldosteronism to develop this complication, as are patients who hypertension. A study that used saline infusion as a screening test for primary aldosteronism reported a frequency of 2.2% of primary have milder disease but receive treatment with 1 aldosteronism among 1036 unselected adults with hypertension. A diuretics for their hypertension, before the smaller study that used the aldosterone-to-PRA ratio in plasma suggested that primary aldosteronism might account for an hyperaldosteronism is diagnosed. even greater proportion of cases of hypertension.2 Hypokalemic patients may experience neuromuscular symptoms such as weakness or paralysis, constipation, and polyuria and Most hyperaldosteronism observed in the general polydipsia because of an associated renal concentrating defect. population is sporadic, with most cases due to bilateral Hypokalemia also impairs insulin secretion and can promote the adrenal hyperplasia. APAs are likely to be diagnosed earlier development of diabetes mellitus. than IHA because they are more likely than IHA to produce early symptomatic hypertension and hypokalemia. Although cardiac fibrosis has been reported in adults with primary aldosteronism, no such reports exist in children, possibly because of APAs account for 40% of cases of primary hyperaldosteronism. their shorter duration of disease at the time of diagnosis. Cardiac Possibly, the distinction between adenoma and hyperplasia is not as fibrosis has also been reported in rats treated with excess clear as was once thought because, in one third of cases, associated mineralocorticoids, especially if hyperglycemia is also present. This hyperplasia or nodules of the adjacent zona glomerulosa is present, implying that the adenoma may have arisen in previously effect can be ameliorated with amiloride. hyperplastic tissue. The role of aldosterone in diabetic heart disease has Inherited forms of primary hyperaldosteronism (ie, FH-1 [GRA] and FH- II and a very rare form FH-III) account for approximately 1% of cases been questioned, and trials of mineralocorticoid of primary aldosteronism, although they are more likely than other antagonists in this condition have been initiated. causes of primary hyperaldosteronism to occur during childhood and adolescent years. Race Studies of secondary hyperaldosteronism have found that approximately 15% of adults who attend hypertension clinics have The literature on adults demonstrates that blacks are at significantly elevated PRA. Reliable figures for children are not readily available. greater risk of hypertension-related morbidity and mortality than whites. They are also more likely to develop low-renin hypertension, Mortality/Morbidity although no studies indicate that the prevalence of primary hyperaldosteronism is significantly higher in blacks. Primary hyperaldosteronism can result in a significant increase in morbidity and mortality as a result of hypertensive vascular Sex (hypertrophy then sclerosis of intimal smooth muscle), renal (sclerosis), and cardiac (hypertrophy then dilatation) complications. Data on adults suggest that hyperaldosteronism has a female Through early recognition and treatment of hypertension, these preponderance. Equivalent information is not available for children, complications can be avoided in children. where primary hyperaldosteronism due to inherited syndromes is likely to represent a greater proportion of cases. Patients with GRA [=??Glucocorticoid remedial Aldosteronism ] must undergo assessment of their cerebral circulation because this disorder is associated with a significant risk of cerebral vascular aneurysms. Provided that hypertension is well treated, morbidity and mortality are not increased significantly.
  7. 7. Age Because the 2 causes that account for about 99% of cases of primary • For patients in whom secondary hyperaldosteronism is hyperaldosteronism have a peak age of onset in adulthood, the less suggested, questions should be specifically directed at potential common causes account for a larger percentage of children with causes (eg, the presence and duration of swelling, the child's hyperaldosteronism. For this reason, children with apparent exercise tolerance). hyperaldosteronism should be evaluated for evidence of congenital defects of the R-A-A axis and inherited forms of hypermineralocorticoidism. Clinical Information should be sought about a family history of essential hypertension and familial syndromes that include the following: History o Neurofibromatosis (associated with renal artery Primary hyperaldosteronism may be stenosis and pheochromocytoma) asymptomatic, particularly in its early stages. o Multiple endocrine neoplasia (MEN) type 2 When present, symptoms are related to o MEN 2A - Parathyroid adenoma, medullary hypertension (if severe), hypokalemia, or both. thyroid carcinoma (MTC), pheochromocytoma o MEN 2B - Mucosal neuromas of eyelids, lips, The spectrum of hypertension-related symptoms includes the and tongue with long thin face, following: pheochromocytoma, and MTC o von Hippel-Lindau syndrome - Cerebellar o Headaches hemangioblastoma; renal and pancreatic cysts and o Facial flushing carcinoma; hemangiomas of the retina, liver, and o If severe, weakness, visual impairment, impaired adrenal glands; pheochromocytomas consciousness, and seizures (hypertensive encephalopathy) Physical Hypokalemia can be precipitated by non–potassium-sparing diuretics or sodium loading. Symptoms of hypokalemia include the following: ΑΠΑΙΤΕΙΤΑΙ ΠΛΗΡΗΣ ΕΛΕΓΧΟΣ ΠΑΙΔΩΝ ΕΦΗΒΩΝ ΜΕ ΥΠΕΡΤΑΣΗ o Constipation ΑΥΞΗΜΕΝΗ ΣΥΓΚΕΝΤΡΩΣΗ ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ o Polyuria and polydipsia (because of impaired renal ΠΡΕΠΕΙ ΝΑ ΔΙΕΡΕΥΝΑΤΑΙ ΣΕ ΥΠΟΚΑΛΙΑΙΜΙΑ ΑΛΛΑ Η concentrating ability) o Weakness ΥΠΟΚΑΛΙΑΙΜΙΑ ΔΕΝ ΕΙΝΑΙ ΠΑΝΤΟΤΡΕ ΠΑΡΟΥΣΑ o If low enough, paralysis and disturbances of cardiac rhythm3 ΔΥΣΜΟΡΦΙΕΣ : [ ΜΕΝ 2 – ΝΕΥΡΟΙΝΟΜΑΤΩΣΗ ΤΥΠΟΣ Ι [café-au- lait lesions, axillary freckling, short stature, and evidence of disease in parents) ] – ΣΥΝΔΡΟΜΟ CUSHING [obesity, short stature, striae, and hirsutism] ] • Hyperglycemia or frank diabetes mellitus is possible because insulin secretion is a potassium-dependent process that may be ΨΗΛΑΦΗΤΑ ΜΟΡΦΩΜΑΤΑ ΤΡΑΧΗΛΟΥ / ΘΥΡΕΟΕΙΔΟΥΣ : impaired by hypokalemia. associated with MEN 2) ΚΥΚΟΛΟΦΡΙΚΟ : [ ΑΡΙΣΤΕΡΑ ΜΕΓΑΛΟΚΑΡΔΙΑ – ΣΤΕΝΩΣΗ ΑΟΡΤΗΣ – ΦΥΣΗΜΑΤΑ – ΚΟΙΛΙΑΚΑ ΦΥΣΗΜΑΤΑ ΕΠΙ ΣΤΕΝΩΣΗΣ ΝΕΦΡΙΚΗΣ ΑΡΤΗΡΙΑΣ – ΠΕΡΙΦΕΡΙΚΟ ΟΙΔΗΜΑ ΣΕ 2Ο ΠΑΘΗ ΜΟΡΦΗ ΤΗΣ ΝΟΣΟΥ ] • If secondary hyperaldosteronism is suspected as the cause of hypertension, history should include questions about flushing, diaphoresis, anxiety attacks, and headaches ΚΟΙΛΙΑ = [ ΜΑΖΕΣ (Wilms tumor) - ΗΠΑΤΟΜΕΓΑΛΙΑ [ ΣΚΑ ‘Η ΗΠΑΤΙΚΗ (pheochromocytoma) and about hematuria and abdominal ΝΟΣΟΣ ] ΣΠΛΗΝΟΜΕΓΑΛΙΑ – ΑΣΚΙΤΗΣ ] fullness (Wilms tumor or other renal tumor), in addition to the above symptoms.
  8. 8. ΟΦΘΑΛΜΟΛΟΓΙΚΗ ΕΞΕΤΑΣΗ : [ ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΙΚΑ ΑΓΓΕΙΩΜΑΤΑ Conditions that mimic aldosterone excess von Hippel-Lindau syndrome – ΣΤΕΝΩΣΗ ΑΜΦΙΒΛΗΣΤΡΟΕΙΔΙΚΩΝ ΑΡΤΗΡΙΩΝ – ΒΑΜΒΑΚΟΕΙΔΕΙΣ ΚΗΛΙΔΕΣ – ΟΙΔΗΜΑ ΘΗΛΗΣ – Lisch nodules of the iris o Congenital adrenal hyperplasia (11beta-hydroxylase (neurofibromatosis type 1) ] deficiency, 17alpha-hydroxlyase deficiency) - Low aldosterone, low PRA, elevated steroid intermediates ΑΞΙΟΛΟΓΗΣΗ ΜΥΙΚΗΣ ΑΔΥΝΑΜΙΑΣ – ΑΠΕΙΚΟΝΙΣΕΙΣ ΠΡΟΣ o Primary glucocorticoid resistance - High glucocorticoid ΑΠΟΚΛΕΙΣΜΟ ΕΓΚΕΦΑΛΙΚΟΥ ΕΜΦΡΑΚΤΟΥ ‘Η secretion unsuppressed by dexamethasone ΑΙΜΟΡΡΑΓΙΑΣ o Deoxycorticosterone-secreting tumors - Elevated deoxycorticosterone levels o Syndrome of apparent mineralocorticoid excess ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ + ΔΕΡΜΑΤΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ = o Liddle syndrome ΥΠΟΝΟΙΑ ΓΙΑ NF-1 o Licorice ingestion o Carbenoxolone The following is a discussion of causes of hypokalemia: Causes ΠΡΟΔΙΑΘΕΤΙΚΟΙ ΠΑΡΑΓΟΝΤΕΣ ΓΙΑ ΥΠΟΚΑΛΙΑΙΜΙΑ : [ ΔΙΑΤΡΟΦΗ ΑΙΤΙΑ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΥ κ ΚΑΤΑΣΤΑΣΕΩΝ ΠΟΥ ΠΛΟΥΣΙΑ ΣΕ ΝΑΤΡΙΟ – ΔΙΟΥΡΗΤΙΚΑ – carbenoxolone ] ΜΙΜΟΥΝΤΑΙ ΑΥΤΟΝ ΦΑΙΝΟΜΕΝΙΚΑ ΑΥΞΗΜΕΝΗ ΣΥΓΚΕΝΤΡΩΣΗ 1Ο ΠΑΘΕΣ ΕΠΙΝΕΦΡΙΔΙΚΟ ΑΔΕΝΩΜΑ (APA) [High aldosterone, low ΑΛΑΤΟΚΟΡΤΙΚΟΕΙΔΩΝ = ΚΑΤΑΣΤΑΣΕΙΣ ΜΕ ΑΥΞΗΜΕΝΗ plasma renin activity (PRA) ] ΚΟΡΤΙΖΟΛΗ ΣΤΙΣ ΟΠΟΙΕΣ Ο ΙΣΤΙΚΟΣ ΥΠΟΔΟΧΕΑΣ ΤΗΣ ΑΛΔΟΣΤΕΡΟΝΗΣ ΔΕΝ ΛΕΙΤΟΥΡΓΕΙ ΚΑΛΑ. Carbenoxolone ‘Η ΙΔΙΟΠΑΘΗΣ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΣ = (IHA) (bilateral adrenal ΚΑΤΑΝΑΛΩΣΗ ΓΛΥΚΟΡΙΖΑΣ ΜΠΡΟΚΑΡΟΥΝ ΤΟ ΙΣΤΙΚΟ ΕΝΖΥΜΟ hyperplasia) ΤΟ ΟΠΟΙΟ ΠΡΟΣΤΑΤΕΥΕΙ ΤΟΝ ΥΠΟΔΟΧΕΑ ΤΗΣ ΑΛΔΟΣΤΕΡΟΝΗΣ ΑΠΟ ΤΗΝ ΥΨΗΛΗ ΚΥΚΛΟΦΟΡΙΑ ΚΟΡΤΙΖΟΛΗΣ Glucocorticoid remediable aldosteronism (GRA) - Sustained suppression of aldosterone (<4 ng/dL) with dexamethasone Familial hyperaldosteronism type II (FH-II) - Familial (probably autosomal dominant) Differential Diagnoses Congenital Adrenal Hyperplasia Other Problems to Be Considered 2Ο ΠΑΘΗΣ : o Secondary hyperaldosteronism o Apparent mineralocorticoid excess (types I and II) [ ΟΙΔΗΜΑ – ΚΑ – ΝΕΦΡΩΣΙΚΟ ΣΥΝΔΡΟΜΟ ] High aldosterone, o Liddle syndrome nonsuppressed plasma renin activity (>2 ng/mL) o Glucocorticoid resistance o Exogenous mineralocorticoid excess ΝΕΦΡΑΓΓΕΙΑΚΗ ΥΠΕΡΤΑΣΗ o Drug-induced apparent mineralocorticoid excess ΟΓΚΟΙ ΠΟΥ ΠΑΡΑΓΟΥΝ ΡΕΝΙΝΗ ΕΓΚΥΜΟΣΥΝΗ
  9. 9. Saline infusion test o The saline infusion test can confirm autonomous aldosterone secretion. Other tests described Workup include the measurement of urine aldosterone excretion during oral salt loading or the Laboratory Studies fludrocortisone suppression test. All tests rely on the principle that a lack of suppression of 1Ο ΒΗΜΑ : ΤΕΚΜΗΡΙΩΣΗ ΥΠΕΡΤΑΣΗΣ + ΥΠΟΚΑΛΙΑΙΜΙΑΣ aldosterone excretion with intravascular expansion is indicative of aldosterone production. 2Ο ΒΗΜΑ : ΤΕΚΜΗΡΙΩΣΗ ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟ κ ΕΑΝ ΔΕΝ o The saline infusion test is performed by infusing ΥΦΙΣΤΑΤΑΙ, ΔΔ ΚΑΤΑΣΤΑΣΕΩΝ ΠΟΥ ΔΙΔΟΥΝ ΤΗΝ ΩΣ ΑΝΩ 1140 mL/m2 body surface area (BSA) of 0.9% saline ΚΛΙΝΙΚΗ ΕΙΚΟΝΑ over 4 hours. Plasma aldosterone and cortisol are measured before and at the end of infusion. Those 3Ο ΒΗΜΑ : ΔΔ 1Ο ΠΑΘΟΥΣ ΑΠΟ 2Ο ΠΑΘΗ without primary aldosteronism should have a fall in ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟ plasma aldosterone levels to less than 10 ng/dL. Plasma aldosterone values greater than 10 ng/dL confirm primary aldosteronism, and levels from 5- 10 may be considered borderline. o Cortisol levels are taken to exclude an Aldosterone-to-renin ratio adrenocorticotropic hormone (ACTH)-mediated rise in aldosterone. Η ΜΕΤΡΗΣΗ ΕΙΝΑΙ ΠΙΟ ΑΞΙΟΠΙΣΤΗ ΟΤΑΝ ΕΧΕΙ ΠΡΟΗΓΗΘΕΙ o Consider the risks of fluid expansion or ΟΡΘΙΑ ΣΤΑΣΗ ΕΠΙ ΔΥΩΡΟ – Ο ΑΣΘΕΝΗΣ ΝΑ ΕΙΝΑΙ hypokalemia in susceptible patients. ΝΟΡΜΟΚΑΛΙΑΙΜΙΚΟΣ ΑΦΟΥ Η ΥΠΟΚΑΛΙΑΙΜΙΑ ΚΑΤΑΣΤΕΛΛΕΙ ΤΗΝ ΠΑΡΑΓΩΓΗ ΑΛΔΟΣΤΕΡΟΝΗΣ Oral salt loading ΑΛΔΟΣΤΕΡΟΝΗ ¨ΡΕΝΙΝΗ > 20 – κ ΤΙΜΗ ΑΛΔΟΣΤΕΡΟΝΗΣ>15 o The oral salt loading test consists of administering 12 ng/Dl : διαγνωση 1ο παθους νοσου g/1.7m2 BSA of sodium chloride tablets and ad libitum diet for 3 days followed by a 24-hour urinary Spironolactone, an aldosterone receptor antagonist, can aldosterone measurement. raise plasma renin levels. Spironolactone and diuretics o Urinary aldosterone values greater than 10-14 mcg/d should be withheld for 6 weeks, and beta-blockers and with a urine sodium excretion greater than 250 nmol/d dihydropyridine calcium antagonists should be withheld for are considered diagnostic of primary aldosteronism. 5-7 days before testing. Patients' hypertension can be controlled with diltiazem and alpha-blockers when testing for primary aldosteronism. Renal impairment can lead to a high aldosterone-to-renin ratio in patients without primary Captopril test aldosteronism because fluid retention suppresses PRA and hyperkalemia stimulates aldosterone secretion. o The captopril test has also been used for screening. Its use is based on the principle that inhibition of angiotensin II production should not affect autonomous secretion of aldosterone in primary aldosteronism. o Application of the 60-minute aldosterone-to-renin ratio after 25 mg of oral captopril yielded a sensitivity of 100% and specificity of 83% for diagnosis of primary ΕΔΩ ΘΑ ΠΡΕΠΕΙ ΝΑ ΑΠΟΔΕΙΧΘΕΙ ΟΤΙ ΥΠΑΡΧΕΙ ΑΥΤΟΝΟΜΟ aldosteronism, but the test was only marginally better ΑΔΕΝΩΜΑ, ΣΕ 1% ΕΝΔΕΧΕΤΑΙ ΝΑ ΟΦΕΙΛΕΤΑΙ Η ΕΙΚΟΝΑ ΤΟΥ than baseline values. Somewhat lower sensitivity was ΥΠΕΡΑΛΔΟΣΤΕΡΟΝΙΣΜΟΥ ΣΕ ΠΕΡΙΣΕΙΑ ΚΟΡΤΙΖΟΛΗΣ noted in a larger study using aldosterone and PRA 90 minutes after a 50-mg dose of captopril.
  10. 10. likely to supersede the time-intensive dexamethasone suppression test. Fludrocortisone suppression test: The fludrocortisone suppression test uses fludrocortisone (0.1 mg q6h) and salt Imaging Studies loading. It is less frequently used and was described by Gordon et al in 1995.5,6 CT scanning of the adrenal glands o Tests to differentiate between an APA and other forms o Adrenal CT scanning is 70% sensitive in detecting APAs. of primary aldosteronism Mean APA size was 1.8 cm in one large series; however, 19% o Postural testing: Postural testing is best performed of these tumors were less than 1 cm. after overnight recumbency. An intravenous catheter is o Adrenal incidentalomas are very uncommon in children, inserted at 7 am, and baseline aldosterone, cortisol, meaning that in the presence of hyperaldosteronism, a and PRA are obtained at 8 am. After 2 hours of positive finding on adrenal CT scanning makes the diagnosis ambulation, repeat aldosterone, cortisol, and PRA are of an adenoma very likely. obtained. Typically, APAs are angiotensin II o Aldosteronomas are typically lipid-rich and commonly unresponsive, and a fall in aldosterone over 2 hours is appear as homogeneous lesions with a low Hounsfield observed in parallel with reduced circadian ACTH and number consistent with this high lipid content. cortisol release. A rise in aldosterone is observed in IHA. Cortisol levels are used to validate the test, and a • Adrenal scintigraphy has insufficient diagnostic accuracy for rise in cortisol release suggests an ACTH surge, which routine use in diagnosing adrenal adenomas. invalidates the test. Diagnostic accuracy of 85% is reported. o 18-Hydroxycorticosterone: Levels of 18- Procedures hydroxycorticosterone are typically elevated (>100 ng/dL) in APA and are significantly lower in patients • Adrenal venous sampling with IHA. Although a diagnostic accuracy of 82% is o Adrenal venous sampling requires reported, 18-hydroxycorticosterone levels have been considerable skill. It can be performed as an noted to parallel the severity of aldosteronism, and outpatient procedure, although younger levels of aldosterone and clinical severity are greater in children may need general anesthesia. APA than IHA. o Infusion of ACTH into a peripheral vein (50 o Dexamethasone suppression mcg/h, starting 30 min before sampling) masks o In cases of bilateral aldosterone secretion or when the the effects of confounding ACTH peaks during diagnosis is suspected on the basis of family history, sampling. GRA can be excluded with a 4-day dexamethasone o Venography is avoided to reduce the risk of suppression test (0.5 mg q6h). adrenal hemorrhage. o The aldosterone and renin levels can be measured o With comparison of simultaneous aldosterone, before testing, at 2 days, and at 4 days of suppression cortisol ratios in the adrenal veins and the testing. The typical response in patients without GRA is inferior vena cava allow detection of unilateral for the aldosterone levels to fall by approximately 50% or bilateral sources of aldosterone and return to the reference range by the end of hypersecretion. testing; however, persistent suppression of o Although the cut-off for lateralization is aldosterone levels to less than 4 ng/dL are reported in controversial, both 5:1 and 10:1 have been GRA. advocated. Nevertheless, adrenal venous o The test achieves a sensitivity of 92% and a specificity of sampling is the criterion standard for the 100% for the diagnosis of GRA compared with direct differential diagnosis of primary genetic testing. aldosteronism. o Biochemically unique, markedly elevated levels of 18- oxocortisol and 18-hydroxycortisol (>100 nmol/d) are also observed in GRA. o Mutation analysis for the hybrid gene that gives rise to GRA is now available by Southern blotting or a long– polymerase chain reaction (PCR) technique. This is
  11. 11. Histologic Findings Treatment • APA Medical Care o Unlike cortisol-producing adrenocortical tumors, in which the remaining ipsilateral and • Surgical excision of the affected adrenal gland is contralateral glands are commonly atrophic, recommended for all patients with hyperaldosteronism the nontumorous cortex may show who have a proven aldosterone-producing adenoma hyperplasia of the zona glomerulosa, forming (APA). either a broad zone locally or thickening of the o Ensuring good control of blood pressure and entire cortex, with tongues of glomerulosalike replenishment of potassium levels cortex extending inward from the subcapsular preoperatively is important. The literature on region. adults indicates that removal of an APA by o This appearance has been reported in up to unilateral adrenalectomy results in one third of patients with aldosteronoma and normotension in approximately 70% of cases suggests that the tumor has arisen from within and improves blood pressure control and an area that was hyperplastic, although restores normokalemia in most of the neither an external stimulus nor an intrinsic remainder. These rates are likely to be even defect has been found to date. better in children who have fewer • IHA independent factors that predispose to o IHA is a disease of the zona glomerulosa with a hypertension. variable macroscopic appearance that can o Persistent hypertension despite control of range from hyperplasia with micronodules and hyperaldosteronism may be the result of macronodules, hyperplasia without nodules, coexistent essential hypertension, and normal appearing zona glomerulosa with hypertensive vascular damage secondary to micronodules. The glands may be normal in the hyperaldosteronism, or, rarely, another weight or heavy. cause of secondary hypertension. o The normal microscopic appearance of the Pheochromocytoma and renal artery stenosis zona glomerulosa is of small discontinuous have been reported in association with APA. subcapsular nests of cells. In hyperplasia, the • Postoperative hypoaldosteronism is common. zona glomerulosa may form continuous bands o Potassium replacement may produce of cells that may be visibly thickened, as either hyperkalemia in this period. a continuous sheet or focally extending as o Patients may need supplementation with tongues into the adjacent cortex. This process mineralocorticoids for several months after may be focal or diffuse and may vary from one successful surgery. part of the gland to another, requiring multiple o Immediate postoperative declines in blood sections. pressure may not be sustained. • Glucocorticoid remediable hyperaldosteronism (FH-I): • Medical care for idiopathic hyperaldosteronism (IHA) is This disorder is the result of formation of a hybrid gene as follows: that leads to ACTH-mediated mineralocorticoid o Although bilateral adrenalectomy corrects synthesis by the zona fasciculata. Histologically, hypokalemia in patients with IHA, it has not evidence suggests hyperplasia of this zone in addition been shown to be effective at controlling to the zona glomerulosa. blood pressure. This may be because this • Nonglucocorticoid remediable hyperaldosteronism condition is typically insidious in its onset, (FH-II and III): This autosomal dominant disorder (FH-II) allowing time for chronic hypertension to has been linked to a locus on chromosome 7p22. cause secondary damage. Furthermore, Histologically, evidence suggests adrenocortical bilateral adrenalectomy commits the patient hyperplasia and/or hypertrophy and the presence of to lifelong replacement therapy with adenomas. glucocorticoids and mineralocorticoids.
  12. 12. o Control of hypokalemia and hypertension in 0-10 kg: 6.25 IHA can be achieved with sodium restriction mg/dose PO (to <2 g/d) and spironolactone or amiloride, q12h but additional antihypertensives are often 11-20 kg: 12.5 needed to achieve good control in this patient mg/dose PO group. Pediatric drug doses are outlined in the Aldosterone Spironolactone q12h table below. Although spironolactone is an antagonist 21-40 kg: 25 effective aldosterone antagonist, it mg/dose PO antagonizes testosterone synthesis and action q12h and can cause hypogonadism with >40 kg: 25 mg gynecomastia and reduction in libido and PO q8h erectile dysfunction in pubertal and adult males. Menstrual irregularities are also 3-8 mg/kg IV qd; common in females. For this reason, it should Potassium Aldosterone not to exceed be used with caution in peripubertal children. canrenoate antagonist 400 mg o Newer alternatives are being produced with better specificity for the mineralocorticoid receptor. Amiloride and triamterene may be Potassium- Amiloride 0.2 mg/kg q12h used instead of spironolactone. They have a sparing diuretic direct effect on the renal tubule to impair sodium reabsorption in exchange for Potassium- 2 mg/kg/dose Triamterene potassium and hydrogen. Drugs Used in the sparing diuretic q8-24h Management of Hyperaldosteronism Dihydropyridine 0.25-0.5 mg/kg Nifedipine calcium channel PO q6-8h antagonist Calcium channel 0.05-0.2 mg/d Amlodipine antagonist PO Alpha1-specific 0.02-0.1 mg/d; Doxazosin adrenergic not to exceed 4 antagonist mg 0.005 mg/kg test dose, then Alpha1-specific 0.025-0.1 Prazosin adrenergic mg/kg/dose q6h; antagonist not to exceed 0.5 mg/dose • Glucocorticoid-remediable hyperaldosteronism (GRA) treatment includes the following: Table o In adult patients with glucocorticoid- Drug Class Pediatric Dose remediable aldosteronism (GRA), control of hypertension can be achieved by treatment
  13. 13. with physiologic doses of dexamethasone. causes of primary aldosteronism in children and However, in children, avoiding dexamethasone adolescents can be managed medically.7 is best because of its adverse effects on • Cardiology: Patients with severe or long-standing growth and bone density. Hydrocortisone is a hypertension may require assessment by a cardiologist better choice because of its short half-life because hyperaldosteronism may lead to myocardial (typical dose is 10-12 mg/m2), but it is not as fibrosis. This problem is more likely to occur in adults in efficient at reducing mineralocorticoid levels. whom the duration of disease is much greater. o Children receiving long-term treatment with glucocorticoids require consultation by a Diet pediatric endocrinologist. GRA is associated with intracranial aneurysm and hemorrhagic • Patients being evaluated for hyperaldosteronism stroke, and screening for intracranial should be receiving a high-sodium intake as described aneurysms in patients with proven GRA is above. Adult recommendations are for a sodium intake recommended. Amiloride and spironolactone of 10 g/d or more. This amount can be reduced have also been used as monotherapy for proportionately for children, depending on their size. treating GRA. Regular monitoring of potassium is important when • Familial hyperaldosteronism type II (FH-II) treatment increasing sodium in patients with suspected includes the following: hyperaldosteronism because this may unmask o Patients with FH-II should be regularly hypokalemia. observed, and treatment should be started • Medical management of patients with established when they develop hypertension. Treatment is hyperaldosteronism should include salt restriction. This with the same agents as for IHA. In the event should include not adding salt to cooking and not that patients develop an adenoma, adrenal having salt on the table. Ideally, patients should receive venous sampling should be considered to fewer than 2 g of sodium chloride a day. Problems with confirm lateralization of aldosterone compliance may occur because this degree of hypersecretion before surgical removal. restriction is often unpalatable to children. o In cases where gradient is lacking, medical treatment is recommended, with regular monitoring. Because patients with FH-II are Activity not at increased risk of carcinoma, nonsurgical management may be worth considering. • Patients with significant hypertension should be advised to avoid strenuous activity until blood pressure Surgical Care is under control because strenuous activity may further exacerbate their problem. • The type of surgery that has been performed governs • Laparoscopic adrenalectomy significantly reduces postoperative activity. Patients should avoid bathing or operative morbidity with a substantially shorter wetting their wounds until they have healed. Patients hospital stay and reduced blood loss compared with an who have undergone laparotomy must avoid heavy open approach. lifting for 6 weeks after their operation. Patients who • A limited number of cases of isolated adenomectomy have undergone laparoscopic adrenalectomy need only with preservation of the remaining normal adrenal restrict their activity while they are sore or the wound tissue have been reported. has not healed. • Transcatheter arterial ablation with high-concentration ethanol injection of APA has been reported. Medication Consultations Aldosterone antagonists • Endocrinology: Once screening indicates a possible These agents are used to : diagnosis of hyperaldosteronism, referral to an endocrinologist is recommended for further o lower the blood pressure, assessment and management because numerous o normalize serum potassium, and o minimize postoperative hypoaldosteronism.
  14. 14. Spironolactone (Aldactone) Amiloride Most commonly used to treat hyperaldosteronism because it ΚΑΛΙΟΠΡΟΣΤΑΤΕΥΤΙΚΟ directly antagonizes aldosterone effect at the distal tubule. ΕΛΑΤΤΩΝΕΙ ΜΕΤΑΞΥ ΑΛΛΩΝ ΤΗΝ ΑΠΕΚΚΡΙΣΗ ΜΑΓΝΗΣΙΟΥ Η Adult ΟΠΟΙΑ ΛΑΜΒΑΝΕΙ ΧΩΡΑ ΣΕ ΜΟΝΟΘΕΡΑΠΕΙΑ ΜΕ ΔΙΟΥΡΗΤΙΚΟ ΑΓΚΥΛΗΣ ‘Η ΘΕΙΑΖΙΔΙΚΟ 100-400 mg/d PO Adult Potassium-sparing diuretics 5 mg/d PO initially; increasing stepwise to 20 mg/d with close Management of hypokalemia associated with monitoring of potassium hyperaldosteronism when spironolactone is contraindicated. Precautions ΑΠΟΦΥΓΗ ΣΕ ΝΑ – ΗΑ Triamterene (Dyrenium) Antihypertensive agents Inhibits reabsorption of sodium ions in exchange for potassium and ΣΤΟΧΟΙ : ΕΛΑΤΤΩΣΗ ΑΡΤΗΡΙΑΚΗΣ ΠΙΕΣΗΣ – ΑΠΟΦΥΓΗ hydrogen ions at the segment of the distal tubule under control of ΥΠΕΡΛΙΠΙΔΑΙΜΙΑΣ – ΑΠΟΦΥΓΗ ΔΥΣΑΝΕΞΙΑΣ ΣΤΗ ΓΛΥΚΟΖΗ – adrenal mineralocorticoids (especially aldosterone). This activity is not directly related to aldosterone secretion or antagonism, and it is a ΑΠΟΦΥΓΗ ΑΡΙΣΤΕΡΑΣ ΥΠΕΡΤΡΟΦΙΑΣ result of a direct effect on the renal tubule. The fraction of filtered sodium reaching this distal tubular exchange site is relatively small, and the amount that is exchanged depends on the level of mineralocorticoid activity; Nifedipine (Adalat, Procardia) thus, the degree of natriuresis and diuresis produced by inhibition of the exchange mechanism is necessarily limited. Calcium channel–blocking agent producing vasodilator with Increasing the amount of available sodium and the level of antianginal and antihypertensive effects. It acts by blocking mineralocorticoid activity by the use of more proximally acting the postexcitation release of calcium ions into cardiac and diuretics increases the degree of diuresis and potassium vascular smooth muscle, thereby inhibiting the activation of conservation. May occasionally cause increases in serum ATPase on myofibril contraction. The overall effect is reduced intracellular calcium levels in cardiac and smooth muscle potassium, which can result in hyperkalemia. It does not cells of the coronary and peripheral vasculature, resulting in produce alkalosis because it does not cause excessive excretion dilatation of coronary and peripheral arteries. Available as of titratable acid and ammonium. short-acting and SR preparations. Adult Adult 50-100 mg PO bid initially; increase as required; not to exceed 10-30 mg IR cap PO tid; not to exceed 120-180 mg/d 300 mg/d 30-60 mg SR tab PO qd; not to exceed 90-120 mg/d Precautions Precautions Caution in severe hepatic encephalopathy, diabetes, renal ΟΤΙ ΙΣΧΥΕΙ ΣΤΗΝ ΑΜΛΟΔΙΠΙΝΗ – ΕΧΕΙ ΑΝΑΦΕΡΘΕΙ ΘΕΤΙΚΗ dysfunction, and history of renal stones ΑΜΕΣΗ COOMBS ΜΕ ‘Η ΧΩΡΙΣ ΣΥΝΟΔΟ ΑΙΜΟΛΥΤΙΚΗ ΑΝΑΙΜΙΑ
  15. 15. Amlodipine (Norvasc) Adult 2.5 mg/d PO if adding to other drugs or 5 mg/d PO; not to exceed 10 mg/d Precautions ΑΝΑΠΡΟΣΑΡΜΟΓΗ ΔΟΣΗΣ ΣΕ ΝΑ, ΗΑ – ΥΠΟΤΑΣΗ ΣΤΗΝ ΕΝΑΡΞΗ ΤΗΣ ΑΓΩΓΗΣ – ΟΙΔΗΜΑ ΚΑΤΩ ΑΚΡΩΝ – ΑΛΛΕΡΓΙΚΗ ΗΠΑΤΙΚΗ ΑΝΤΙΔΡΑΣΗ, ΣΠΑΝΙΩΣ Doxazosin (Cardura) Alpha1-adrenergic antagonist. Adult 1 mg PO qd; may increase to 2 mg qd thereafter and titrate to higher doses Precautions ΕΝΑΡΞΗ ΣΕ ΧΑΜΗΛΗ ΔΟΣΗ ΠΡΟΣ ΑΠΟΦΥΓΗ ΥΠΟΤΑΣΗΣ – ΠΡΟΣΟΧΗ ΣΕ ΝΑ Prazosin (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