Endocrine HypertensionEndocrine HypertensionEssential hypertension 92-94%

Secondary hypertension 6-8%Renal 4-5%Miscellaneous ~2%

Endocrine 1-2%

Primary hyperaldosteronism 0.3-15% Cushing’s syndrome <0.1%

Pheochromocytoma <0.1%

Endocrine HypertensionEndocrine Hypertension

Mineralocorticoid excessMineralocorticoid excess

CushingCushing’’s syn.s syn.

PheochromocytomaPheochromocytoma

Sympathetic Nervous Sympathetic Nervous SystemSystem

CA Synthesis & MetabolismCA Synthesis & Metabolism

Epinephrine Norepinephrine

Metanephrine Normetanephrine

COMT

MAO

Vanylmandelic Acid (VMA)

APUD cells

Tyrosine Hydroxylase

AADC

Dopamine β Hydroxylase

PNMT

PheochromocytomaPheochromocytoma

• ~ 0.1% or less of hypertension• Extraadrenal- Paraganglioma

“10% Tumor” BilateralExtra-adrenalFamilial(? ~20%)Malignant

PheochromocytomaPheochromocytomaSymptoms

During paroxysm: Between attacks:Headache SweatingSweating Cold hands & feetPalpitations Weight lossTremor ConstipationChest painAbdominal painNausea, vomiting

PheochromocytomaPheochromocytoma

Signs: Increased blood pressure Orthostatic hypotension Tachycardia

PheochromocytomaPheochromocytoma

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: Familial forms: (germ-line mutations autosomal dominant(germ-line mutations autosomal dominant))

When to Suspect a When to Suspect a Pheochromocytoma?Pheochromocytoma?

Episodic HTN accompanied by the Episodic HTN accompanied by the classical triadclassical triad

Refractory HTNRefractory HTN Labile HTNLabile HTN Severe pressor response to surgery etc.Severe pressor response to surgery etc. Familial Hx associated with PheoFamilial Hx associated with Pheo Incidental adrenal massIncidental adrenal mass HTN at a young age HTN at a young age Takotsubo cardiomyopathyTakotsubo cardiomyopathy

MEN2MEN2

MEN 2AMEN 2A

MEN 2BMEN 2B

Familial Medullary Thyroid Familial Medullary Thyroid Carcinoma Carcinoma (FMTC)(FMTC)

10-20%

היפרפרהטירוידיזם

40-50%

קרצינומה מדולארית של בלוטת התריס

90%

פאוכרומוציטומה

40-50%

100%

90%

MEN2bMEN2b

נוירומות נוירומות מראה מרפנואידימראה מרפנואידיבריריותבריריות

Von-Hippel Lindau Von-Hippel Lindau DiseaseDisease

Renal cell carcinomaRenal cell carcinoma

Retinal angiomaRetinal angioma

Cerebellar or spinal Cerebellar or spinal

hemangioblashemangioblasttomaoma

Pheochromocytoma-7-19%.Pheochromocytoma-7-19%.

24 hour urine collection for free CATs 24 hour urine collection for free CATs epinephrine and norepinephrineepinephrine and norepinephrine Sensitivity ~70%Sensitivity ~70%

24 hour urine collection for CAT metabolites (METS)24 hour urine collection for CAT metabolites (METS) metanephrine, normetanephrine and acidmetanephrine, normetanephrine and acid More specific, sensitivity >90%More specific, sensitivity >90%

Urinary CATS + METSUrinary CATS + METS Sensitivity > 95%Sensitivity > 95%

Plasma free metanephrines.Plasma free metanephrines. Highest sensitivity > 95%Highest sensitivity > 95%

Pheochromocytoma-Pheochromocytoma-Biochemical DiagnosisBiochemical Diagnosis

Only after the Dx of pheo is biochemically Only after the Dx of pheo is biochemically confirmed!!confirmed!!

CTCT MRIMRI II123123MIBGMIBG PET-PET-1818FDGFDG Octreoscan or Octreoscan or 6868Ga-DOTATATE-PETGa-DOTATATE-PET

Pheochromocytoma imagingPheochromocytoma imaging

Malignant pheo- Malignant pheo- 6868Ga-DOTATATE ScanGa-DOTATATE Scan

Pheochromocytoma- Pheochromocytoma- TherapyTherapy

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 Mineralocorticoid excessexcess

Biosynthesis and action of Biosynthesis and action of AldosteroneAldosterone

Glomerulosa

ANDROSTENDIONE

cortisol cortisone11 β HSD type 2

Kidney

Renin-Angiotensin- Aldosterone Renin-Angiotensin- Aldosterone Regulatory SystemRegulatory System

↑ACTH

Sympathetic stimulation

Mineralocorticoid ExcessMineralocorticoid Excess

HyperaldosteronismHyperaldosteronismPrimaryPrimarySecondarySecondary

Apparent MC excessApparent MC excess ↓ ↓PRA and ↓ PACPRA and ↓ PAC

Hyperaldosteronism DD:Hyperaldosteronism DD:

Primary-Primary- PRAPRA

Secondary- Secondary- PRAPRA 1. Renal Artery Stenosis 1. Renal Artery Stenosis

(atherosclerosis, fibromuscular dysplasia).(atherosclerosis, fibromuscular dysplasia).

2. Primary tumor of the JGA2. Primary tumor of the JGA

Primary AldosteronismPrimary Aldosteronism

• Described by Conn in 1955.Described by Conn in 1955.

• Hypertension, hypokalemia, Hypertension, hypokalemia, metabolic alkalosis.metabolic alkalosis.

• Prevalence: Prevalence: 5-15% of patients with 5-15% of patients with hypertension. hypertension.

Causes of Primary Causes of Primary AldosteronismAldosteronism

Aldosterone Producing Aldosterone Producing

Adenoma (APA) Adenoma (APA) ~30%~30%

Idiopathic/hyperplasia (IHA) Idiopathic/hyperplasia (IHA) ~ 70% ~ 70%

Adrenocortical Carcinoma Adrenocortical Carcinoma rarerare

Clinical PresentationClinical Presentation

HypertensionHypertension Moderate to severe (APA>hyperplasia)Moderate to severe (APA>hyperplasia) Refractory to medicationsRefractory to medications K on low dose diuretics K on low dose diuretics

End-organ damageEnd-organ damage (aldosterone, HTN)(aldosterone, HTN)

LVHLVH Micro and macro vascular diseaseMicro and macro vascular disease

Clinical PresentationClinical Presentation

LaboratoryLaboratory KK, ↔K, ↔K Metabolic alkalosis Metabolic alkalosis Mild Mild NaNa

Symptoms related to hypokalemiaSymptoms related to hypokalemia NeuromuscularNeuromuscular Nephrogenic DI Nephrogenic DI (polyuria & nocturia)(polyuria & nocturia)

Screening for Primary Screening for Primary HyperaldosteronismHyperaldosteronism

Hypertension and hypokalemia Hypertension and hypokalemia (including patients treated with low dose (including patients treated with low dose diuretics).diuretics).

Severe, resistant, or relatively acute Severe, resistant, or relatively acute hypertension, age<30.hypertension, age<30.

An adrenal incidentalomaAn adrenal incidentaloma

Diagnosis:Diagnosis:• Screening testScreening test

• Confirmatory testingConfirmatory testing

• Determine the subtypeDetermine the subtype

Screening Tests for Primary Screening Tests for Primary Aldosteronism:Aldosteronism:

PAC/PRAPAC/PRA (PAC >20 ng/dl, PRA<1 ng/ml/h)(PAC >20 ng/dl, PRA<1 ng/ml/h)

>30 suggestive; >50 diagnostic>30 suggestive; >50 diagnostic

Morning, ambulatory, paired, random PAC and Morning, ambulatory, paired, random PAC and PRA.PRA.

Serum K levels should be normalizedSerum K levels should be normalized

Not under beta blockers and spironolactone Not under beta blockers and spironolactone (preferably also w/o ACE inhibitors).(preferably also w/o ACE inhibitors).

DiagnosisDiagnosis Confirmatory testsConfirmatory tests::

Saline infusion test-Saline infusion test- non suppressed aldonon suppressed aldo..

24 hour urinary aldosterone24 hour urinary aldosterone

Determining subtype:Determining subtype: Posture test-Posture test- normal response: elevation of Aldonormal response: elevation of Aldo IHA- normal response IHA- normal response APA- no elevation APA- no elevation

Imaging Imaging

• Only after biochemical Dx Only after biochemical Dx (2-10% (2-10% nonfunctioning adenomas on CT).nonfunctioning adenomas on CT).

• Abdominal spiral CT Abdominal spiral CT

• In patients > 40 years of age-In patients > 40 years of age-Selective adrenal venous sampling Selective adrenal venous sampling

TreatmentTreatment APA- Unilateral total adrenalectomyAPA- Unilateral total adrenalectomy IHA- Medical management IHA- Medical management

(aldactone, amiloride, aplerenone)(aldactone, amiloride, aplerenone)

>30

Other Causes for Other Causes for Endocrine HTNEndocrine HTN

Hypothyroidism –diastolic HTNHypothyroidism –diastolic HTN

Hyperthyroidism- systolic HTNHyperthyroidism- systolic HTN

Acromegaly- salt retentionAcromegaly- salt retention

HyperparathyroidismHyperparathyroidism