CT scan is part of the diagnostic workup in case there is biochemical confirmation.

A 58-year-old male with a history of arterial hypertension of 6 years of evolution, who consults for poor control of blood pressure figures despite receiving treatment with an angiotensin-converting enzyme inhibitor, a diuretic and a calcium antagonist. On consultation she presented with blood pressure of 149/100 mmHg. Laboratory tests: creatinine 1.2 mg/dl, potassium 2.2 mEq/l and compensated metabolic alkalosis; the rest of the biochemical study, blood count, coagulation and urinary sediment were normal. Mark the correct statement:

The origin of hypertension in this case is excessive aldosterone secretion caused by autonomic hyperfunction of the adrenal medulla.

In most cases the anatomical substrate is bilateral hyperplasia of the adrenal cortex.

CT scan is part of the diagnostic study in case of biochemical confirmation.

Spironolactone is contraindicated in the management of this pathology.

Hypokalemia induced myopathy as first manifestation of primary hyperaldosteronism - an elderly patient with unilateral adrenal hyperplasia: a case report.

Primary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia. A 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland. This report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia.

[Primary aldosteronism and pregnancy: report of 2 cases].

Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism.

Diagnosis and management of primary aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment.

[High doses of aldosterone antagonist is a condition of sufficient blood pressure control in bilateral adrenal hyperplasia].

Primary aldosteronism occurs in 1-10% of hypertensive patients and is classified in adenomas or bilateral adrenal hyperplasia. Computed tomography (CT) or magnetic resonance imaging can be used to discriminate these subtypes and in guiding treatment selection. This case report describes a 65-year-old man with hypertension and hypokalaemia during 25 years. Bilateral adrenal hyperplasia was diagnosed based on a CT, and an oral sodium-loading test with measurement of renin and aldosterone confirmed the diagnosis. Blood pressure and potassium in plasma was normalized during treatment with the mineralocorticoid receptor antagonist eplerenon.

[Reninoma: a rare but curable cause of high blood pressure, a case report].

We report a case of a renin secreting tumor, which is a very rare cause of secondary high blood pressure. A 22-year-old woman was hospitalised for exploration of high blood pressure (160/110 mmHg) with severe hypokaliemia (2,7 mmol/l) and secondary hyperaldosteronism. Physical examination was normal except the high blood pressure. Bioassays show increased kaliuresis (66 mmol/24h), plasma renin (89 pg/ml in clinostastism--108 pg/ml in orthostatism), pro-renin (1207 pg/ml in clinostastism--1412 pg/ml in orthostatism) and aldosterone (210 pg/ml in clinostastism--566 pg/ml in orthostatism). The rest of the endocrine tests were normal (cortisol and ACTH at 8:00 am, urinary free cortisol, overnight 1 mg dexamethasone suppression test). Doppler ultrasound method, performed by an experienced radiologist, did not show renal artery stenosis. Abdominal computerized tomography showed a nodular formation at the upper pole of the right kidney, isodense to renal medullary. The size tumor was 15 mm. The renal vein sampling shows high values of renin on both sides whereas, for the pro-renin, the values were higher on the tumor side. In spite of treatment with CEI (Converting Enzyme Inhibitors) and calcium antagonists, the blood pressure was not controlled. Hypokaliemia persisted (3 mmol/l) in spite of high daily potassium intake (64 mmol/l of potassium chloride). After tumor resection, reninoma was diagnosed by the pathology examination and blood pressure, plasma rennin, plasma aldosterone level returned to normal.

[Clinical characteristics and surgery outcomes of unilateral nodular adrenal hyperplasia in primary aldosteronism: study of 145 cases].

To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P < 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P < 0.05 and P < 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P > 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients.

[Modern pharmacological aspects of hyperaldosteronism therapy].

The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls.

Diagnosis Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. Treatment The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide.

[Chronic kidney disease after adrenalectomy in a patient with primary aldosteronism].

We report one case of estimated glomerular filtration rate (eGFR) decline after taking unilateral adrenalectomy due to aldosterone adenoma. A 60-year-old male with 23-year history of hypertension was reported to the endocrinologist due to hypokalemia (serum potassium 3.01 mmol/L). Urine microalbumin/creatinine (ALB/CR) was 70.15 mg/g, serum creatinine was 82 μmol/L and eGFR was 89.79 mL/(min·1.73 m<sup2</sup). Random serum aldosterone was 172.2-203.5 ng/L, and random plasma rennin activity was 0-0.17 μg/(L·h). His captopril challenge test suggested that his aldosterone le-vels were suppressed by 8% (< 30%) and the adrenal enhanced computed tomography scan revealed a left adrenal tumor. The patient was diagnosed with primary hyperaldosteronism (PA), aldosterone adenoma and underwent left laparoscopic adrenalectomy. Histological examination confirmed adrenal cortical adenoma. One week after the operation, his serum creatinine was increased to 127 μmol/L compared with preoperative level; eGFR was 32.34 mL/(min·1.73 m<sup2</sup). His systolic blood pressure (SBP) was 110 mmHg and diastolic blood pressure (DBP) was 60 mmHg (hypotensive drugs discontinued), and serum potassium level was 5.22 mmol/L. At the end of the 2-year follow up, the serum creatinine of this patient remained at 109-158 μmol/L and eGFR fluctuated from 63.28-40.12 mL/(min·1.73 m<sup2</sup). PA is one of the most common causes of secondary hypertension. Several studies have reported renal function deterioration of PA patients after unilateral adrenalectomy, like the patient in this article. Age, preoperative plasma aldosterone concentration, albuminuria and preoperative potassium level might be significant predictors of a decrease in the eGFR. Growing evidence suggests that aldosterone could contribute to structural kidney damage, arterial injury and hemodynamic disorder. At the same time, patients with PA exhibit glomerular hyperfiltration and glomerular vascular hypertension, leading to the misinterpretation of renal function in PA patients as subtle kidney damage may be masked by the glomerular hyperfiltration before treatment. After a unilateral adrenalectomy, glomerular hyperfiltration by aldosterone excess is resolved and renal damage can be unmasked. In conclusion, kidney function deterioration after adrenalectomy can be detected in some patients with PA. Thus, accurate evaluation of kidney function in patients with PA may be essential, especially for those with preoperative risk factors for postoperative renal impairment. After unilateral adrenalectomy, close monitoring of renal function and adequate management are required for PA patients.

[Primary hyperaldosteronism. Apropos of 2 cases].

Primary hyperaldosteronism (PHA) represents less than 1 to 2% of all causes of hypertension (HT). We report 2 cases of primary hyperaldosteronism which emphasize the difficulty of distinguishing neoplastic PHA from idiopathic PHA, observed in a 60-year-old woman and a 42-year old woman, respectively. In both cases, the diagnosis of PHA was suggested by marked hypokalaemia with inappropriate potassium excretion and was confirmed by hyperaldosteronaemia and low and poorly stimulated renin activity. In the first case, computed tomography showed nodular hyperplasia of the 2 adrenal glands. The patient was treated with spironolactone and calcium channel blockers which controlled blood pressure and serum potassium. In the second case, computed tomography and magnetic resonance imaging revealed an adrenocortical adenoma confirmed by pathological examination after the operation. The diagnosis of primary hyperaldosteronism is based on three steps: detection, positive diagnosis and aetiological diagnosis. Detection is essentially based on demonstration of hypokalaemia. Positive diagnosis is based on demonstration of elevated aldosterone secretion with inhibited renin secretion. The aetiological diagnosis is dominated by the differentiation between Conn's adenoma and bilateral adrenal hyperplasia, which has therapeutic implications.

Pseudohyperaldosteronism

Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma

Conn's syndrome and bilateral renal artery stenosis in the presence of multiple renal arteries.

We report the case of a 42-year-old male who was admitted to our hospital after an acute hypertensive crisis despite four-way anti-hypertensive therapy. The renal scintigraphy, the excretory urogram and the biochemical profile performed two years before were unremarkable, except for slightly elevated serum creatinine and plasma aldosterone, in presence of normal aldosterone/renin ratio. The renal arterial angiography that was performed despite a second unremarkable scintigraphy revealed high-grade bilateral arterial stenosis in the presence of multiple renal arteries. Following dilatation of the left stenosis, the aldosterone/renin ratio was pathologic. Recumbent and orthostatic aldosterone values were 830 pg/ml and 1824 pg/ml, respectively, and recumbent and orthostatic renin values were 0.82 and 1.21 ng angiotensin I/ml/h, respectively. The abdominal computed tomography performed to investigate a possible concomitant Conn's syndrome resulted in the detection of a left adrenal tumor. After resection of the lesion, plasma-aldosterone levels normalized and a pronounced rise in serum potassium levels was observed. Following angioplasty of the right renal artery stenosis, blood pressure could easily be managed with combined beta and calcium channel blocker therapy. Particularly in cases of bilateral (but also in the presence of unilateral) renal artery stenosis in association with Conn's syndrome, all the available screening methods for these disorders can fail. In cases of poor response to combination hypertensive therapies, renal arteriography and a fludrocortisone-suppression test should be performed in order to rule out both renal arterial stenosis and Conn's syndrome, even in the absence of clinical and biochemical findings suspicious for either disorder.

[Primay hyperaldosteronism--diagnostic and treatment].

Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as "Conn-Trias" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary.

[Primary hyperaldosteronism--12 clinical cases].

To show clinical, biochemical, and morphological data of 12 patients with primary hyperaldosteronism: eight with an aldosterone-producing adenoma and four with adrenal hyperplasia. To compare clinical and biochemical parameters of the patients with adenoma and hyperplasia. For those with adenoma, to verify clinical and biochemical modifications after adrenalectomy. In the 12 patients with hyperaldosteronism, retrospective analysis of clinical (age, sex, blood pressure), biochemical (plasmatic and urinary potassium, plasmatic aldosterone, plasma renin activity, and plasmatic aldosterone/renin activity ratio), and morphological (computed tomography, magnetic resonance, and norcholesterol scintigraphy) data was performed. 1--In the 12 patients with hyperaldosteronism (seven female), the age was 51.0 +/- 10.2 years (mean +/- standard deviation), the systolic pressure 200.9 +/- 34.5 mm Hg and the diastolic pressure 120.0 +/- 12.3 mm Hg. Hypertension was diagnosed 12.0 +/- 10.1 years before. As biochemical evidence, we found kalaemia of 3.06 +/- 0.28 and urinary potassium of 63.4 +/- 16.5 mEq/l, renin activity 0.98 +/- 1.02 ng/ml/h, plasmatic aldosterone of 49.4 +/- 36.0 ng/dl, aldosterone/renin activity > 30 in 83% of the cases. As morphological evidence, computed tomography allowed diagnosis in nine patients, suggested it in two, being doubtful in one. Performed on four patients, resonance confirmed the tomography in three and was not contributive in one. The scintigraphy performed in four patients visualized two adenomas, was negative in one adenoma and in one hyperplasia. 2--In the eight patients with adenoma (six female), the youngest age and the highest diastolic pressure compared with patients with hyperplasia were statistically significant (p < 0.01 and 0.05). In the adenomas, the biochemical changes were more pronounced, but not statistically significant. The plasmatic aldosterone/renin activity ratio was also higher in the adenoma cases. 3--After the adrenalectomy, blood pressure became normal in five patients and was more easily therapeutically controlled in three. The average systolic and diastolic pressures decreased and the biochemical parameters became normal in all patients. The pre/post surgical modification of these parameters had statistical significance (systolic pressure decrease, p < 0.01; diastolic pressure decrease, p < 0.01; kalaemia increase, p < 0.001; renin activity increase, p < 0.01; aldosterone decrease, p < 0.02). The plasmatic aldosterone/renine activity ratio normalized in all patients. In diagnosing primary hyperaldosteronism, biochemical (kalaemia, urinary potassium, plasmatic aldosterone, renin activity, aldosterone plasmatic/renin activity) and tomography studies were important. On comparing the patients with hyperplasia with those with adenoma, we found that the latter are younger and exhibit higher diastolic pressure, both findings with statistical significance. After adenoma surgery, blood pressure became normal in five patients and improved in three, these findings, and the improvement of the kalaemia, plasmatic aldosterone, and renin activity parameters were statistically significant.

A case of normoreninemic, normotensive primary aldosteronism associated with essential hypertension and nephrocalcinosis.

A 36-year-old female case of normotensive normoreninemic primary aldosteronism with persistent hypokalemia and nephrocalcinosis is reported. She was referred to us for episodes of sudden muscle weakness during 8 years prior to admission. On the first day of admission, her blood pressure was 174/104 mmHg. On the second day of admission blood pressure normalized to 120/80 mmHg. Both of her parents were hypertensive. Arterial blood gas analysis showed metabolic alkalosis. Except an impaired urine concentration ability, renal functions were normal. Intravenous pyelogram showed numerous granular calcifications. Basal plasma renin activity was 1.0 approximately 1.5 ng/ml/hr and increased by sodium depletion. Plasma aldosterone concentration was 70 approximately 80 ng/dl and did not respond to various stimulations. Blood pressure was dependent on sodium balance. It fell on salt restriction and rose on salt loading. Blood pressure responses to vasoactive hormones were normal. Circulating plasma volume was within normal range. After removal of an adrenal adenoma, there was mild fall of blood pressure, serum potassium returned to normal level and plasma renin activity increased slightly. Histologically, there was renal tubular calcifications, and juxtaglomerular apparatus was normal. Blood pressure was elevated to 160/100 mmHg when patient was followed at out-patient clinic after discharge. We concluded that she had essential hypertension associated with primary aldosteronism. Although sodium loss and an increase in urinary kallikrein were found, they did not seem to be the cause of normoreninemic normotensive state of this patient, and the pathogenesis remains to be elucidated.

Hyperaldosteronism

Primary Primary aldosteronism (hyporeninemic hyperaldosteronism) was previously thought to be most commonly caused by an adrenal adenoma, termed Conn's syndrome. However, recent studies have shown that bilateral idiopathic adrenal hyperplasia is the cause in up to 70% of cases. Differentiating between the two is important, as this determines treatment. Also, see congenital adrenal hyperplasia. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Two familial forms have been identified: type I (dexamethasone suppressible), and type II, which has been linked to the 7p22 gene. Features Hypertension Hypokalemia (e.g., may cause muscle weakness) Alkalosis Investigations High serum aldosterone Low serum renin High-resolution CT abdomen Management Adrenal adenoma: surgery Bilateral adrenocortical hyperplasia: aldosterone antagonist, e.g., spironolactone

InternalMed_Harrison

In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed

Primary aldosteronism

Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk, while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. To determine the underlying cause, medical imaging is carried out.

Hyperaldosteronism

Hyperaldosteronism is a medical condition wherein too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). This cause of mineralocorticoid excess is primary hyperaldosteronism reflecting excess production of aldosterone by adrenal zona glomerulosa. Bilateral micronodular hyperplasia is more common than unilateral adrenal adenoma. Signs and symptoms It can be asymptomatic, but these symptoms may be present: Fatigue Headache High blood pressure Hypokalemia Hypernatraemia Hypomagnesemia Intermittent or temporary paralysis Muscle spasms Muscle weakness Numbness Polyuria Polydipsia Tingling Metabolic alkalosis Nocturia Blurry Vision Dizziness/Vertigo

Antihypertensive drug

Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly used for the quick, temporary reduction of blood pressure in emergencies (such as malignant hypertension or aortic dissection). Hydralazine and its derivatives are also used in the treatment of severe hypertension, although they should be avoided in emergencies. They are no longer indicated as first-line therapy for high blood pressure due to side effects and safety concerns, but hydralazine remains a drug of choice in gestational hypertension. Renin inhibitors Renin comes one level higher than angiotensin converting enzyme (ACE) in the renin–angiotensin system. Renin inhibitors can therefore effectively reduce hypertension. Aliskiren (developed by Novartis) is a renin inhibitor which has been approved by the U.S. FDA for the treatment of hypertension. Aldosterone receptor antagonist Aldosterone receptor antagonists: eplerenone spironolactone

Secondary hypertension

11β-hydroxylase deficiency, aka apparent mineralocorticoid excess syndrome, involves a defect in the gene for 11β-hydroxysteroid dehydrogenase, an enzyme that normally inactivates circulating cortisol to the less-active metabolite cortisone. At high concentrations cortisol can cross-react and activate the mineralocorticoid receptor, leading to aldosterone-like effects in the kidney, causing hypertension. This effect can also be produced by prolonged ingestion of liquorice (which can be of potent strength in liquorice candy), by causing inhibition of the 11β-hydroxysteroid dehydrogenase enzyme and likewise leading to secondary apparent mineralocorticoid excess syndrome. Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present. Cortisol induced hypertension cannot be completely explained by the activity of Cortisol on Aldosterone receptors. Experiments show that treatment with Spironolactone (an inhibitor of the aldosterone

InternalMed_Harrison

Diagnosis Diagnostic screening for mineralocorticoid excess is not currently recommended for all patients with hypertension, but should be restricted to those who exhibit hypertension associated with drug resistance, hypokalemia, an adrenal mass, or onset of disease before the age of 40 years (Fig. 406-12). The accepted screening test is concurrent measurement of plasma renin and aldosterone with subsequent calculation of the aldosterone-renin ratio (ARR) (Fig. 406-12); serum potassium needs to be normalized prior to testing. Stopping antihypertensive medication can be cumbersome, particularly in patients with severe hypertension. Thus, for practical purposes, in the first instance the patient can remain on the usual antihypertensive medications, with the exception that mineralocorticoid receptor antagonists need to be ceased at least 4 weeks prior to ARR measurement. The remaining antihypertensive 2319 drugs usually do not affect the outcome of ARR testing, except that beta blocker

Long-term results of surgical and conservative treatment of patients with primary aldosteronism.

The long-term results of surgical and specific drug therapy were compared in a group of 57 patients with primary aldosteronism (PA) (46 with aldosterone-producing adenoma (APA), 11 with idiopathic hyperaldosteronism (IHA) and bilateral adrenal hyperplasia). Unilateral adrenalectomy completely normalized blood pressure (BP) in 77.1% of surgically treated APA, evidently improving hypertension in remaining 22.9%. No recurrence of the adenoma in the remaining adrenal was seen in any of the surgical APA cases. In 19 of the non-surgical patients (11 with APA, 8 with IHA) monotherapy with spironolactone reduced blood pressure in 73%, though total BP normalization was an exception. The treatment normalized hypokalemia, low total exchangeable potassium, tendency to hypernatremia, and high total exchangeable sodium. Surgical as well as conservative therapy increased to normal or above-normal levels plasma renin activity suppressed prior to treatment. Pre-operatively high urine and plasma aldosterone levels normalized in all adrenalectomized patients, but remained above the normal range during spironolactone therapy in spite of a small decline in its absolute values. The disturbances of maximum renal concentrating capacity due to impaired nephron responsiveness to sufficiently high endogenous vasopressin concentrations were completely eliminated after kaliopenic nephropathy had been repaired. The other renal functions remained within normal values. Echocardiographically diagnosed left ventricular hypertrophy was seen less often than in the other types of arterial hypertension, tending to regress after APA management. Our longitudinal study (2-16 years) showed primary aldosteronism as a well curable, albeit rare, cause of hypertension. As regards BP and laboratory tests normalization, better results were achieved in surgical APA cases than in patients treated with spironolactone. Older age, longer history of hypertension and more frequent incidence of obesity, nephrosclerosis and pyelonephritis may be responsible for hypertension persisting after surgical treatment.

Liddle's syndrome

Diagnosis Evaluation of a child with persistent high blood pressure usually involves analysis of blood electrolytes and an aldosterone level, as well as other tests. In Liddle's disease, the serum sodium is typically elevated, the serum potassium is reduced, and the serum bicarbonate is elevated. These findings are also found in hyperaldosteronism, another rare cause of hypertension in children. Primary hyperaldosteronism (also known as Conn's syndrome), is due to an aldosterone-secreting adrenal tumor (adenoma) or adrenal hyperplasia. Aldosterone levels are high in hyperaldosteronism, whereas they are low to normal in Liddle syndrome. A genetic study of the ENaC sequences can be requested to detect mutations (deletions, insertions, missense mutations) and get a diagnosis.

Pseudohyperaldosteronism

Treatment Specific treatment of pseudohyperaldosteronism depends on the inciting cause. General management focuses on countering the effects of excess mineralocorticoid activity to achieve adequate blood pressure control and avoid end-organ damage and cardiovascular mortality. In some cases, specific antihypertensive medications may be recommended. In Liddle's syndrome, ENaC-binding potassium-sparing diuretics (e.g. amiloride or triamterene) are used to counter the excess ENaC activity. In AME, the mineralocorticoid receptor-binding potassium-sparing diuretics (e.g. spironolactone or eplerenone) are used to limit aldosterone receptor activity. Other medications such as glucocorticoids are added in AME and CAH to inhibit ACTH and further cortisol production. Lifestyle changes such as a low sodium diet are also used for managing hypertension, and cessation of licorice intake is recommended in cases of licorice overconsumption.

Aldosterone

Associated clinical conditions Hyperaldosteronism is abnormally increased levels of aldosterone, while hypoaldosteronism is abnormally decreased levels of aldosterone. A measurement of aldosterone in blood may be termed a plasma aldosterone concentration (PAC), which may be compared to plasma renin activity (PRA) as an aldosterone-to-renin ratio. Hyperaldosteronism Primary aldosteronism, also known as primary hyperaldosteronism, is characterized by the overproduction of aldosterone by the adrenal glands, when not a result of excessive renin secretion. It leads to arterial hypertension (high blood pressure) associated with hypokalemia, usually a diagnostic clue. Secondary hyperaldosteronism, on the other hand, is due to overactivity of the renin–angiotensin system. Conn's syndrome is primary hyperaldosteronism caused by an aldosterone-producing adenoma.

Mineralocorticoid hypertension.

Hypertension affects about 10 - 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism - Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy.

[Primary hyperaldosteronism in a population of hypertensive patients].

The diagnosis of primary hyperaldosteronism (PHPA) has progressively increased over the last years and some authors consider it as the main cause of secondary hypertension. We studied the prevalence of PHPA in hypertensive patients followed at the Hypertension Unit from July 1999 to July 2017. A total of 2500 patients were included and diagnosis of PHPA was done in 79 of them (3.2%). It was more frequent in women (55.7%) with an increased incidence in the elderly, as compared to previous studies (27.8%). Initial diagnosis was suspected upon the presence of inappropriate kaliuria and metabolic alkalosis, associated to an aldosterone/plasma renin activity ratio > 30 (ng/dl)/(ng/ml/h). After confirmation of the presence of PA, imaging techniques to determine the etiology were performed. In this way, 29 cases (36.8%) of aldosterone-producing adenoma and 5 cases of bilateral adrenal hyperplasia with nodules were identified. Computed tomography identified the adenomas and hyperplasias with bilateral cortical nodules in all patients. Adrenalectomy and/or antialdosteronics were efficient in controlling blood pressure in 69.9% of cases. Of note in this series was the remission of stage 3 chronic renal failure in two cases, the high prevalence of hypercalciuric urinary lithiasis and a case of breast carcinoma after prolonged treatment with spironolactone.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency

The adrenal cortex is hyperplastic and overstimulated, with no impairment of the mineralocorticoid pathway. Consequently, levels of DOC, corticosterone, and 18-hydroxycorticosterone are elevated. Although these precursors of aldosterone are weaker mineralocorticoids, the extreme elevations usually provide enough volume expansion, blood pressure elevation, and potassium depletion to suppress renin and aldosterone production. Some persons with 17α-hydroxylase deficiency develop hypertension in infancy, and nearly 90% do so by late childhood. The low-renin hypertension is often accompanied by hypokalemia due to urinary potassium wasting and metabolic alkalosis. These features of mineralocorticoid excess are the major clinical clue distinguishing the more complete 17α-hydroxylase deficiency from the 17,20-lyase deficiency, which only affects the sex steroids. Treatment with glucocorticoid suppresses ACTH, returns mineralocorticoid production toward normal, and lowers blood pressure.

[Primary hyperaldosteronism. Diagnostic procedure useful in hospital routine].

Personal experience in the management of three cases of primary hyperaldosteronism, in which a cure was obtained by surgical removal of an adrenocortical adenoma, is was used in the elaboration of a diagnostic procedure requiring hospitalisation for 12 days. During 6 days, the patient is kept on a diet containing 100 mEq Na and K, and blood potassium values are repeatedly determined. Other causes of hypertension are ruled out. On the 6th day, baselines for blood renin and urinary aldosterone are calculated. Next, a hyposodic diet is given for 4 days, and a diuretic is administered on the last of these days, after which renin is determined "in response to stimulation". Lastly, two days of i.v. NaCl loading are followed by the determination of urinary aldosterone "during inhibition". If the picture is positive for hyperaldosteronism, the patient is discharged and followed during treatment with spironolactone, and eventually subjected to renal and adrenal arteriography to determine the site of the adenoma. Division of the procedure into increasingly complex steps enables the examination to be halted at any point when evidence in support of the suspected diagnosis fails to appear. This feature, coupled with the simplicity of the procedures adopted, enables all young subjects admitted for unexplained hypertension to be screened for hyperaldosteronism, with the assurance of obtaining certain diagnosis without an excessively long stay in hospital.

[Physiopathological and functional semeiologic considerations in a case of primary normoaldosteronemic hyperaldosteronism].

Among the atypical pictures of primary aldosteronism, sometimes, normal blood and urine concentration of aldosterone have been observed in association with an adrenal aldosterone-producing adenoma. Here we report a case of atypical primary aldosteronism so characterized: -- the patient had the typical clinical findings of aldosteronism (hypertension, hypokalemic alkalosis, polyuria, etc). -- the patient exhibted all the biochemical abnormalities of primary aldosteronism: increase of exchangeable Na and of plasma volume, decrease of exchangeable K, etc. -- the patient had normal blood and urine levels of aldosterone. -- the patient's blood and urine aldosterone concentration increased following sodium depletion and K administration. Such increase was comparable with that obtained in normal subjects after the same tests. However, at the end of these tests, the patient was still in potassium depletion and sodium repletion. Therefore, it was concluded that the secretion of aldosterone, although normal in absolute values, was inappropriate to the metabolic status of the patient, since such "normal" values were found in association with conditions that should have produced an inhibition of aldosterone production. The catheterization of adrenal veins demonstrated the existence of a right adrenal adenoma. The blood pressure and the biochemical parameters of the patients have been normalized by right adrenalectomy.

Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy.

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed. Learning points: Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels. The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing's syndrome, Liddle's syndrome and 11-deoxycorticosterone-producing tumours. DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase. The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.