clinical approach to hypertension in the young

Approach for diagnosis Primary Aldosteronism

• Case detection

• Screening test

– Plasma aldosterone concentration/ plasma renin activity (PAC/PRA) ratio

(or Aldosterone to renin ratio : ARR)

• Confirmation test

– Fludrocortisone suppression test

– IV saline loading

– Oral sodium load

– Captopril suppression test

• Subtype classification

Case Detection

• Recommend in patient groups with relatively high prevalence of PA• Moderate-severe HT (Stage 2 or 3)

• Resistant HT

• HT + spontaneous or diuretic-induced hypokalemia

• HT + family Hx of early onset HT

• HT + family Hx stroke at a young age (<40 yrs)

• Hypertensive 1st degree relatives of pts with PA

• HT + adrenal incidentaloma

• Recommend to use aldosterone-to-renin ratio (ARR) to detect cases of PA in these pt groups.

An Endocrine Society Clinical Practice Guideline, 2008

Measurement of ARR: A Suggested Approach

A: Preparation for aldosterone-renin ratio (ARR) measurement:

Correct hypokalemia

Liberal salt intake

Withdraw agents that markedly afftect ARR at least 4 wks.

• Spironolactone, eplerenone, amiloride, and triamterene

• Potassium-wasting diuretics

• Products derived from licorice root

Withdrawn agents that markedly affect ARR for 2 wks.

• β-blockers, central α2-agonists (Clonidine, alpha-methyldopa)

• NSAIDs

• ACEIs, ARBs, DRI, DHP-CCBs (Amlodipine)

Measurement of ARR: A Suggested Approach

If necessary to maintain HT control, other anti-HT that have lesser effects on the ARR.

– Slow-release verapamil

– Hydralazine

– Prazosin, doxazosin, terazosin

Establish OC and HRT status, because estrogen-containing medications may lower DRC.

Do not withdraw OC unless confident of alternative effective contraception.

SUKOR. Brunei Int Med J. 2013

B: Conditions for collection of blood.

1. Collect blood mid-morning, after upright for ≥ 2 hrs and seated for 5-15 minutes.

2. Collect blood carefully, avoiding stasis and hemolysis.

3. Maintain sample at room temperature.

Measurement of ARR: A Suggested Approach

ARR Interpretations

PAC/PRA

PAC > 15

PRA

ARR > 30

Primary hyperaldosteronism

•Conn’s syndrome •IHA •GRA

Secondaryhyperaldosteronism

•RAS •Reninoma•Ineffective circulatory vol.

Other mineralocorticoid

excess

Cushing syn. CAH (11 OH def 17 OH def)

Confirmation test for PAType of test Methods Criteria for

confirmation

Fludrocortisonesuppression test

-0.1 mg oral fludrocortisone every 6 hrs for 4 days-slow-release NaCl supplements maintain urinary Na excretion rate ≥ 3mmol/kg- KCL supplementationto maintain normokalaemia- D4 plasma aldosterone and PRA measured at 10 a.m. with the in seated posture, and plasma cortisol is measured at 7 a.m. and 10 a.m.

-Upright PA > 6 ng/dl ( 166 pmol/l) at 10a.m. on day 4- Provided upright PRA < 1.0 ng/ml/h- lower cortisol level at 10 a.m. than 7 a.m.

Saline infusion test Intravenous infusion of 0.9% NaCl 2000 ml within 4 hrs

- PAC after infusion > 10 ng/dL

Type of test Methods Criteria for confirmation

Oral sodium load -sodium intake > 200 mmol)day x 3 days- and potassiumsupplementation to maintain normokalaemia

- 24-hr urine aldo > 12-14 mcg/dl (D3 - D4)

Captoprilsuppression test

Measurement of ARR 2 h after oral 25-50 mg captopril

- Post-captopril ARR > 12 (ng/dl) /(ng/ml/h)- Or 40 (pmol/L)/(mU/L) -AND PA > 12 ng/dL(330 pmol/L)

Confirmation test for PA

Subtypes of Primary Aldosteronism

• Adrenal adenoma

• Bilateral adrenal hyperplasia

• Glucocorticoid-remediable hyperaldosteronism: very rare

Subtype evaluation of PA

• Adrenal CT scan

• Adrenal venous sampling

• Posture stimulation test

Adrenal CT scan

• Initial study in subtype testing, and to exclude large masses that may represent adrenocorticalcarcinoma.

• Finding:– Unilateral macroadenoma (>1 cm)– Unilateral microadenomas (<1 cm)– APA small hypodense nodules (usually <2) on CT– Aldosterone-producing adrenal carcinomas almost

always >4 cm.– Bilateral adrenal hyperplasia increase in size both

adreanal glands

Adrenal CT scan

a) CT scan showing a9-mm left adrenal aldosteroneproducing adenoma (arrow)

b) b) left adrenocortical carcinoma

Adrenal venous sampling

• AVS is the gold standard test to differentiate unilateral from bilateral disease in PA.

SUBTYPE TESTING, AND TREATMENT OF PA

Conduct confirmatory testing

Adrenal CT

If surgerynot desired If surgery desired

AVS

Bilateral Unilateral

Treat with MR antagonist Treat with laparoscopic ADX

Approach for diagnosis Pheochromocytoma

• Clinical suspicious

• Diagnostic investigation of pheochromocytomaBiochemical diagnosis • Plasma normetanephrine/metanephrine• 24-hour urine normetanephrine/metanephrine• 24-hour urine vanillylmandelic acid (VMA)

Localization

• CT/MRI adrenal protocol • Functioning imaging : ¹²³I or ¹³¹I-MIBG scintingraphy

18F-FDG PET scan

J Clin Endocrinol Metab, 2003, 88(10):4533–4539Pancreas 2010;39: 775-783

Biochemical Diagnosis for PheochromocytomaTest Sensitivity Specificity

Plasma

Normetanephrine/ metanephrine 96-100 85-89

Catecholamine 84 81

Urinary

Normetanephrine/ metanephrine 86-97 84-95

catecholamine 86 88

VMA 64-90 80-95Herbert C,pancreas,2010;39:775-783 Lenders

JW,JAMA,2002;287:1427-34

Medications may cause falsely elevated test results for plasma and urinary metanephrines

• Acetaminophen

• Labetalol

• Sotalol

• Methyldopa

• Tricyclicantidepressants

• Buspirone

• Phenoxybenzamine

• MAO-inhibitors

• Sympathomimetics

• Cocaine

• Sulphasalazine

• Levodopa

J Clin Endocrinol Metab, June 2014, 99(6):1915–1942

Biochemical diagnosis

Clinical suspicious of Pheochromocytoma

24-hour urine VMA 24-hour urine meta/normetanephrine

Recheck during spell

Normal: investigates other causes of spell

> 2-fold elevation above upper normal limit in urine

Localization

24-hour urine VMA

High Low

Normal

Normal

Localization of Pheochromocytoma

• Characteristics:– Pheochromocytomas are typically large tumors (2 - 5 cm in

diameter) and may contain areas of hemorrhage or necrosis.– 90% of tumors are intraabdominal lesions

• CT abdomen– Adrenal pheochromocytoma sensitivity 93-100%– Extra-adrenal pheo sensitivity 90%– Suggest rather than MRI as first choice imaging

• MRI– Recommend I in metastatic PPGL for detection of skull base and

neck paragangliomas– Absolute indication for pregnancy, children, contrast allergy

CT scan showing a right adrenal phaeochromocytoma (box)

Functioning Localization

¹²³I or ¹³¹I-MIBG scintingraphy

• Radiopharmaceutical agent accumulates preferentially in catecholamine producing tumors

• I-MIBG scintingraphy is indicated

Large size of primary tumor (esp.>10 cm)

Paraganglioma

Multifocal or recurrent disease

18F-FDG PET scan• Suggest in pts with metastatic disease

Genetic test

• Genetic testing should be considered if a patient has one or more of the following: • Bilateral pheochromocytoma

• Unilateral pheochromocytoma with family history pheochromocytoma/paraganglioma

• Unilateral pheochromocytoma with age < 45 years

• Paraganglioma

• Other clinical finding suggestive of syndromicdisorders

• Malignant pheochromocytoma/paraganglioma

Approach for diagnosis Cushing’s syndrome

Steps of work up Cushing’s syndrome

• Cushing's syndrome?

–Clinical suspicion

• ACTH-dependent or independent

–Laboratory confirmation

• Determining the source of the ACTH–Localization

Cushing’s syndrome?Clinical suspicion Cushing’s Syndrome

- 24 hours UFC (2 measurements) Late night - salivary cortisol (2 measurements) 1 mg - overnight dexamethasone suppression test- Standard low dose dexamethasone suppression test

Normal

Cushing’s syndrome unlikely

l

Abnormal

Exclude physiologic causes of hypercortisolism

Cushing’s syndrome

Morbid obesity,Alcoholism, Depression,Pregnancy

Exclude exogenous steroid (serum morning cortisol)

Special consideration

• Pregnancy : UFC, diurnal variation

• Epilepsy : UFC

• Renal failure : DST

• Cyclical CS : UFC, salivary cortisol

• Adrenal incidentaloma : 1 mg DST

ACTH-dependent or independent

Confirmed Cushing’s Syndrome

ACTH(2 measurements)

< 10 pg/mlACTH independent

5-10 pg/mlCRH test to

differnziate the two form

> 10 pg/mlACTH dependent

CT adrenal gland

Pituitary adenomaEctopic ACTH orCRH producing

tumors

วธีิการทดสอบเพือ่หาสาเหตุของ Cushing’s syndrome

Test Method SuspectedCushing’s disease

8 mg ODST

•Serum cortisol at 8.00-9.00 น.• รบัประทาน Dexamethasone 8 mg ชว่ง 23.00–24.00 น. ในวนัทีต่รวจ cortisol• Serum cortisol วนัรุง่ขึน้เวลา 8.00-9.00 น.

Morning cortisol ลดลง > 50% เทยีบกบัก่อนรบัประทานยา

HDDST •Serum cortisol at 8.00-9.00 น.•Dexamethasone 2 mg oral q 6 hrx 48 hr•Serum cortisol at 8.00-9.00 น. การเจาะเลอืดตอ้งเจาะหา่งจากยาเมด็สดุทา้ยอยา่งน้อย 4-6 พ

Morning cortisol ลดลง > 50% เทยีบกบัก่อนรบัประทานยา

ACTH dependent CS

Determining the source of the ACTHin ACTH-dependent CS

MRI Pituitary

Positive Negative

Pituitary Surgery Evaluate ectopic ACTH secretion

BIPSS Positive Cushing’s disease

Diagnosis approach toRenovascular Hypertension

• When Should RVH be Suspected?

Unexplained renal failure (B)

Multivessel CAD (B)

Unexplained CHF or refractory angina (C)

Abdominal bruit – diastole, lateralized

Diagnostic Methods for RVH: Screening

• Class I1. Duplex US

2. CT angiography

3. MR angiography

• Class III (NOT RECOMMENDED)

1. Captopril renal scintigraphy

2. Selective renal vein renin measurements

3. Plasma renin activity4. Captopril test (PRA after captopril)

Indications for Catheter-directedDiagnostic Angiography

• Noninvasive vascular imaging suggests significant RAS

• A very high clinical suspicion of RAS (noninvasive screening can be bypassed)

Screening and confirmatory tests for evaluating young hypertension

Diseases Screening tests Confirmatory tests

Primary aldosteronism ARR Any one of four tests :FST, SST, OLT, CCT

Phaeochromocytoma Plasma/urine metanephrines CT adrenals123I-MIBG

Cushing’s syndrome Any one of four tests:•UFC –2 measurements•Late night salivary cortisol -2measurements•1-mg DST•Longer low-dose DST (2 mg/d for 48h)

Dexamethasone-CRH testMidnight serum cortisolAdrenal CT/MRI pituitary

Renal parenchymal disease Renal profile, Urinalysis Renal biopsy, Renal imaging

Renal artery stenosis Captopril testDoppler ultrasonography

Renal angiography

Obstructive sleep apnea Symptoms (snoring, daytimehypersomnolence)

Sleep study

SLE FBC, ANA, CRP, urinalysis ds-DNA, Renal/skin biopsy

Coarctation of aorta Symptoms and signs( BP in arm > leg, ischaemic symptomsin lower extremities, systolic murmur in thorax)

AortographyTEE