Endocrine Hypertension Essential hypertension92-94% Secondary hypertension6-8% Renal4-5% Miscellaneous~2% Endocrine 1-2% Primary hyperaldosteronism % Cushing’s syndrome <0.1% Pheochromocytoma <0.1%

Endocrine Hypertension Mineralocorticoid excess Cushing’s syn. Pheochromocytoma

Sympathetic Nervous System

CA Synthesis & Metabolism Epinephrine Norepinephrine Metanephrine Normetanephrine COMT MAO Vanylmandelic Acid (VMA) APUD cells Tyrosine Hydroxylase AADC Dopamine β Hydroxylase PNMT

Pheochromocytoma ~ 0.1% or less of hypertension Extraadrenal- Paraganglioma “10% Tumor” Bilateral Extra-adrenal Familial(? ~20%) Malignant

Pheochromocytoma Symptoms During paroxysm: Between attacks: Headache Sweating Sweating Cold hands & feet Palpitations Weight loss Tremor Constipation Chest pain Abdominal pain Nausea, vomiting

Pheochromocytoma Signs:   Increased blood pressure   Orthostatic hypotension   Tachycardia

Pheochromocytoma Syndromic- Multiple Endocrine Neoplasia Type 2 (A & B) Multiple Endocrine Neoplasia Type 1 (rarely) von Hippel-Lindau disease Neurocutaneous syndromes (NF1) Non- syndromic SDHB, C, D; TEM127 Familial forms: (germ-line mutations autosomal dominant )

When to Suspect a Pheochromocytoma?  Episodic HTN accompanied by the classical triad  Refractory HTN  Labile HTN  Severe pressor response to surgery etc.  Familial Hx associated with Pheo  Incidental adrenal mass  HTN at a young age  Takotsubo cardiomyopathy

MEN2  MEN 2A  MEN 2B  Familial Medullary Thyroid Carcinoma (FMTC) 10-20% היפרפרהטירוידיזם 40-50% קרצינומה מדולארית של בלוטת התריס 90% פאוכרומוציטומה 40-50% 100% 90%

MEN2b מראה מרפנואידי נוירומות בריריות

Von-Hippel Lindau Disease  Renal cell carcinoma  Retinal angioma  Cerebellar or spinal hemangioblastoma hemangioblastoma  Pheochromocytoma-7-19%.

 24 hour urine collection for free CATs  epinephrine and norepinephrine  Sensitivity ~70%  24 hour urine collection for CAT metabolites (METS)  metanephrine, normetanephrine and acid  More specific, sensitivity >90%  Urinary CATS + METS  Sensitivity > 95%  Plasma free metanephrines.  Highest sensitivity > 95% Pheochromocytoma- Biochemical Diagnosis

Only after the Dx of pheo is biochemically confirmed!!  CT  MRI  I 123 MIBG  PET- 18 FDG  Octreoscan or 68 Ga-DOTATATE-PET Pheochromocytoma imaging

Malignant pheo- 68 Ga-DOTATATE Scan

Pheochromocytoma- Therapy Surgical resection of tumor-   If localized to adrenal- laparoscopic adrenalectomy Prior to surgery-   Hypertension: α-blockade (phenoxybenzamine, doxasocin, phentolamine)   Tachycardia- β-blockade (only after α blockade)

Mineralocorticoid excess

Biosynthesis and action of Aldosterone Glomerulosa ANDROSTENDIONE cortisol cortisone 11 β HSD type 2 Kidney

Renin-Angiotensin- Aldosterone Regulatory System ↑ACTH Sympathetic stimulation

Mineralocorticoid Excess HyperaldosteronismPrimarySecondary Apparent MC excess ↓PRA and ↓ PAC ↓PRA and ↓ PAC

Hyperaldosteronism DD: Primary-  PRA Secondary-  PRA 1. Renal Artery Stenosis (atherosclerosis, fibromuscular dysplasia). 1. Renal Artery Stenosis (atherosclerosis, fibromuscular dysplasia). 2. Primary tumor of the JGA 2. Primary tumor of the JGA

Primary Aldosteronism Described by Conn in 1955.Described by Conn in Hypertension, hypokalemia, metabolic alkalosis.Hypertension, hypokalemia, metabolic alkalosis. Prevalence: 5-15% of patients with hypertension.Prevalence: 5-15% of patients with hypertension.

Causes of Primary Aldosteronism Aldosterone Producing Adenoma (APA) ~30% Idiopathic/hyperplasia (IHA) ~ 70% Adrenocortical Carcinoma rare

Clinical Presentation Hypertension Moderate to severe (APA>hyperplasia) Moderate to severe (APA>hyperplasia) Refractory to medications Refractory to medications  K on low dose diuretics  K on low dose diuretics End-organ damage (aldosterone, HTN) LVH LVH Micro and macro vascular disease Micro and macro vascular disease

Clinical Presentation  Laboratory  K, ↔K  K, ↔K Metabolic alkalosis Metabolic alkalosis Mild  Na Mild  Na  Symptoms related to hypokalemia Neuromuscular Neuromuscular Nephrogenic DI (polyuria & nocturia) Nephrogenic DI (polyuria & nocturia)

Screening for Primary Hyperaldosteronism  Hypertension and hypokalemia (including patients treated with low dose diuretics).  Severe, resistant, or relatively acute hypertension, age<30.  An adrenal incidentaloma

Diagnosis: Screening testScreening test Confirmatory testingConfirmatory testing Determine the subtypeDetermine the subtype

Screening Tests for Primary Aldosteronism: PAC/PRA (PAC >20 ng/dl, PRA 20 ng/dl, PRA<1 ng/ml/h)  >30 suggestive; >50 diagnostic  Morning, ambulatory, paired, random PAC and PRA.  Serum K levels should be normalized  Not under beta blockers and spironolactone (preferably also w/o ACE inhibitors).

Diagnosis  Confirmatory tests : Saline infusion test- non suppressed aldo. Saline infusion test- non suppressed aldo. 24 hour urinary aldosterone 24 hour urinary aldosterone  Determining subtype: Posture test- Posture test- normal response: elevation of Aldo normal response: elevation of Aldo IHA- normal response IHA- normal response APA- no elevation APA- no elevation

Imaging Only after biochemical Dx (2-10% nonfunctioning adenomas on CT).Only after biochemical Dx (2-10% nonfunctioning adenomas on CT). Abdominal spiral CTAbdominal spiral CT In patients > 40 years of age- Selective adrenal venous samplingIn patients > 40 years of age- Selective adrenal venous sampling

Treatment  APA- Unilateral total adrenalectomy  IHA- Medical management (aldactone, amiloride, aplerenone) (aldactone, amiloride, aplerenone)

> 30

Other Causes for Endocrine HTN  Hypothyroidism –diastolic HTN  Hyperthyroidism- systolic HTN  Acromegaly- salt retention  Hyperparathyroidism