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Withdrawn agents that markedly affect ARR for 2 wks.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