Ipertensione endocrina: solo la punta dell’iceberg? · Roma, 7-9 novembre 2014 Ipertensione...

Roma, 7-9 novembre 2014

Ipertensione endocrina: solo la punta dell’iceberg?

Gli esami di I livello e di conferma

Mauro Maccario Dipartimento di Scienze Mediche

Università di Torino

13°Congresso Nazionale AME, Roma, 6-9 novembre 2014


Ipertensione endocrina: solo la punta dell’iceberg?

Gli esami di primo livello e di conferma •  Iperaldosteronismo primario •  Feocromocitoma/Paraganglioma •  Ipercorticosurrenalismo

13°Congresso Nazionale AME, Roma, 6-9 novembre 2014


Il workup diagnostico dell’ipertensione endocrina: considerazioni generali

•  sensitivity and specificity have not been clearly determined for many of the screening tests used to evaluate for endocrine hypertension.

•  lack of an established “gold-standard” used across studies to define the presence of the disease

•  negative results of screening tests are less well studied than positive results in the medical literature. This is because of a reluctance to perform confirmation testing in persons with a negative screening test result. Thus, the false-negative rates for screening tests are often underestimated

•  case-control designs for establishing the accuracy of diagnostic tests overestimate their accuracy.

•  there is variable information available regarding prevalence of disease in various clinical contexts which influences the ability to estimate the predictive value of screening tests under all circumstances


Iperaldosteronismo primario (IAP). La LG dell’ES

1.0.CASE DETECTION … 1.2. We recommend use of the plasma aldosterone-renin ratio (ARR) to detect cases of PA in these patient groups. 2.0.CASE CONFIRMATION 2.1. Instead of proceeding directly to subtype classification, we recommend that patients with a positive aldosterone-renin ratio (ARR) undergo testing, by any of four confirmatory tests, to definitively confirm or exclude the diagnosis.

Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008, 93(9): 3266–3281

2 step: -  basale -  dinamico


Diagnosi di Iperaldosteronismo primario (IAP): ARR

1.0.CASE DETECTION … 1.2. We recommend use of the plasma aldosterone-renin ratio (ARR) to detect cases of PA in these patient groups. 2.0.CASE CONFIRMATION 2.1. Instead of proceeding directly to subtype classification, we recommend that patients with a positive aldosterone-renin ratio (ARR) undergo testing, by any of four confirmatory tests, to definitively confirm or exclude the diagnosis.


Aldosterone Attività reninica


Iperaldosteronismo Primario: ARR

!  blood samples for testing renin and aldosterone levels should be obtained during mid-morning after the patient has been awake for more than 2 hours and sitting for at least 15 minutes

!  costs are $56.02 for PAC and $30.24 for PRA

•  although there is no established threshold for an abnormal result, an ARR greater than 30 when PAC exceeds 15ng/dL is most commonly used.

•  low renin levels increase the likelihood of a falsely positive elevated ARR •  potassium should be supplemented if needed •  liberalize sodium intake •  medications that interfere with the renin-angiotensin-aldosterone system

must be withheld for at least 2 weeks and abstain from products derived from licorice root

JAMA July 9, 2014 Volume 312, Number 2, pp. 184-185


Iperaldosteronismo Primario: confondenti l'ARR

JAMA July 9, 2014 Volume 312, Number 2, pp. 184-185

Il controllo degli elettroliti è fondamentale!


Iperaldosteronismo Primario: farmaci interferenti su ARR

JAMA 2014, 312:184-185


Iperaldosteronismo Primario: farmaci interferenti su ARR

JAMA 2014, 312:184-185

ND-CCB

αB


Iperaldosteronismo Primario: Raccomandazioni per ARR

•  Overnight fast •  Not smoking •  Unrestricted salt intake •  Hypokalemia corrected •  Withdrawal of eplerenone,

spironolactone, triamterene, aliskiren for 4 weeks

•  2 measurements

Horm Metab Res 2010; 42:382-391


Most groups … use cut-offs of 20 to 40 µg/dl / ng/ml/h when testing is performed in the morning on a seated ambulatory patient.

IAP: ARR, quale cut-off?

Suggested cut-point values for the ARR range from 15-100... The most commonly used cut-point values for a positive ARR are 20-30... In certain clinical settings (e.g., hypertension with spontaneous hypokalemia associated with renal potassium wasting), a very high value of the ARR by itself could be considered diagnostic for PA without the need for further confirmatory testing.


Schwartz GL. Endocrinol Metab Clin North Am. 2011; 40(2): 279–294


IAP: Bassa accuratezza diagnostica di ARR

Schwartz GL. Endocrinol Metab Clin North Am. 2011; 40(2): 279–294

The reference standard used for diagnosis of PA was 24-hour urine aldosterone excretion ≥12 µg following 4 days of dietary sodium loading with >200 mEq sodium in the 24-hour urine collection. The overall prevalence of biochemical PA in the study sample was 13%


IAP: Aggiungere valutazione dei valori assoluti di PRA e ALDO?

William F. Young Primary aldosteronism: renaissance of a syndrome Clinical Endocrinology (2007) 66, 607-618


IAP – test di conferma


Four testing procedures: •  oral sodium loading, •  saline infusion, •  fludrocortisone suppression •  captopril challenge are in common use, and there is currently insufficient direct evidence to recommend one over the others. While it is acknowledged that these tests may differ in terms of sensitivity, specificity, and reliability, the choice of confirmatory test is commonly determined by considerations of cost, patient compliance, laboratory routine, and local expertise (Table 6).

6 g di sale per 3gg

→ aldoU > 12 µg/24h 2l NaCl 0.9% in 4 h

→ aldo > 5-10 µg/dl

fludro 0.1mg ogni6h x 4gg

→ aldo > 6 µg/dl

captopril 25-50 mg

NN→aldo scende>30%


IAP - Test di conferma: Fludrocortisone o NaCl J Clin Endocrinol Metab 91: 2618–2623, 2006

100 hypertensive patients referred to hypertension units with suspected PA after the screening test. A correct diagnosis with SLT was obtained in 88% of patients compared with FST


IAP - Test NaCl: quale cutoff?

J Clin Endocrinol Metab 91: 2618–2623, 2006

massima specificità = ALDO post NaCl 8 ng/dl


IAP: è necessario un test di conferma dopo l’ARR? C’è chi dice no…

Surg Clin N Am 94 (2014) 643–656

The author’s center stopped performing confirmatory tests after ARR case detection in 2005. The protocol directs patients with elevated ARR who are appropriate surgical candidates and who accept further work-up to have an adrenal protocol CT and adrenal venous sampling (AVS) performed (Fig. 1). The ARR is set relatively low (>550 PAC pmol/L: PRA ng/mL/hour) to maximize sensitivity and avoid missing patients with potentially correctable disease. This protocol has not shown an increase in proportion of nonlateralized disease, which would be expected if the false-positive rate of ARR were unacceptably high


Feocromocitoma/Paraganglioma LG Endocrine Society 2014

Recommendation 1.1 We recommend that initial biochemical testing for PPGLs should include measurements of plasma free metanephrines or urinary fractionated metanephrines. (1ØØØØ)

Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab, June 2014, 99(6):1915–1942


Feocromocitoma/Paraganglioma metanefrine plasmatiche o urinarie?

Table 2. Relative merits and demerits of measurements of urinary fractionated and plasma-free metanephrines for the diagnosis of pheochromocytoma Urinary Fractionated Metanephrines Plasma-Free Metanephrines

Well-established, widely available test Relatively new test with limited availability

Urinary concentrations (200–2,000 nmol) make analysis relatively easy

Plasma concentrations (0.1–0.5 nmol) can make analysis difficult

Easy for clinicians to implement with minimal expenditure of time and effort

Blood collections require some time and effort by medical staff

Twenty-four-hour collections can be inconvenient for patients

Blood sampling relatively more convenient for patients

Problems with reliability of incomplete timed urine collections

Collection and handling of blood samples can be better regulated

Difficult to control dietary and daily life influences on sympathoadrenal function

Influences of diet and sympathoadrenal function more easily controlled

In children 24-h collections are difficult and results are difficult to interpret without age-appropriate reference intervals

In children blood sampling may be stressful, but results are more easily interpreted without age-appropriate reference intervals

Urine collections may be inappropriate in patients with renal failure

Test is applicable in patients with renal failure

Ann N Y Acad Sci. 2006 1073:332-47. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Grossman , Pacak K, Sawka A, Lenders JW, Harlander D, Peaston RT, Reznek R, Sisson J, Eisenhofer G.


Feocromocitoma/Paraganglioma Metanefrine - pitfalls in diagnosis

Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline

J Clin Endocrinol Metab, 2014, 99:1915–1942

•  Prelievo ematico in clinostatismo •  Metodica di dosaggio •  Interferenza farmacologica •  Frequenti Falsi Positivi



Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab, 2014, 99:1915–1942

•  Clinostatismo per metanefrine plasmatiche •  Interferenza farmacologica •  Alti Falsi Positivi

"  upper cutoffs of reference intervals determined from blood collected in the seated position … are up to 2-fold higher than those determined in the supine position

"  use of upper limits of reference intervals determined from samples collected in the seated instead of the supine position would result in a drop in diagnostic sensitivity associated with a 3-fold increase in false-negative results

"  when blood taken in the seated position yields a positive result, the test should be repeated in the supine position




•  Metodica di dosaggio •  Recumbent position •  Interferenza farmacologica •  Alti Falsi Positivi

Both plasma and urinary metanephrines are often measured by high pressure liquid chromatography with electrochemical detection (HPLC-EC). More recently methods using gas chromatography with mass spectrometry (GS-MS) or liquid chromatography with tandem mass spectrometry (LC-MS/MS) are being employed. These newer methods of analysis are preferred because they are less susceptible to medication interference and nonspecific binding and, thus, are associated with higher diagnostic accuracy .

Schwartz GL. Endocrinol Metab Clin North Am. 2011 40(2): 279–294.


Feocromocitoma/Paraganglioma

Metanefrine - pitfalls in diagnosis

Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2014, 99:1915–1942

•  Interferenza farmacologica

Attenzione a:

–  β-bloccanti –  antidepressivi –  simpatomimetici




The usually less than 1% pretest prevalence of PPGLs combined with suboptimal diagnostic specificity means that false-positive results far outnumber true-positive results.

•  Numerosi Falsi Positivi


Feocromocitoma e Paraganglioma

Metanefrine - pitfalls in diagnosis

•  Alti Falsi Positivi SS > 0,9 SP tra 0,8 e 0,98 Likelihood Ratio + 10-50

Alta probabilità di malattia: Ptp 25% VPP 80% – 95%

Bassa probabilità di malattia: Ptp 1% VPP 7% – 40%

Bassissima probabilità di malattia: Ptp 0,01% VPP 0,7% – 5%

test metanefrine

VPP


Feocromocitoma/Paraganglioma pitfalls in diagnosis

Test gravato da molti Falsi Positivi in setting di pazienti a bassa probabilità di malattia. Che fare?

- Considerare la probabilità di malattia! Lo screening Lo screening nell’iperteso asintomatico non è raccomandabile

- positività contemporanea di meta e normeta - 3 volte il limite superiore della normalità - metanefrine urinarie se valutate plasmatiche o viceversa - cromogranina A - test alla clonidina (non validato) NB: follow up dei supposti falsi positivi


Diagnosi di Ipercorticosurrenalismo: il primo step

•  Urinary Free Cortisol •  Late-night salivary

cortisol •  1-mg overnight DST •  Longer low-dose DST

(2 mg/d for 48 h)

Figure 1. Algorithm for testing patients suspected of having Cushing’s syndrome (CS)…. Diagnostic criteria that suggest Cushing’s syndrome are UFC greater than the normal range for the assay, serum cortisol greater than 1.8 µg/dl (50 nmol/liter) after 1 mg dexamethasone (1-mg DST), and late-night

salivary cortisol greater than 145 ng/dl (4 nmol/liter).

The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93: 1526–1540, 2008

we recommend that at least two measurements of urine or salivary cortisol be obtained


I test basali per la diagnosi di ipercorticosurrenalismo

Late-night salivary cortisol greater than 145 µg/dl

•  Biologically active free cortisol in the blood is in equilibrium with cortisol in the saliva, and the concentration of salivary cortisol does not appear to be affected by the rate of saliva production

•  Normal subjects usually have salivary cortisol levels at bedtime, or between 2300 and 2400 h, of less than 145 ng/dl (4 nmol/liter).

Urinary free cortisol above the normal range

•  It is important to ensure that patients provide a complete 24-h urine collection with appropriate total volume and urinary creatinine levels

•  Don’t drink a lot •  2 collections



I test di inibizione con Dex per la diagnosi di ipercorticosurrenalismo

•  The overnight test is a simple outpatient test...1 mg dexamethasone is usually given between 2300 and 2400 h, and cortisol is measured between 0800 and 0900 h the following morning.

Cortisol after 48-h, 2 mg/d Dex Suppression Test greater than 1.8 µg/dl

•  Dexamethasone is given in doses of 0.5 mg for 48 h, beginning at 0900 h on d 1, at 6-h intervals, i.e. at 0900, 1500, 2100, and 0300 h. Serum cortisol is measured at 0900 h, 6 h after the last dose of dexamethasone.

•  A different protocol: administering 48 h of dexamethasone at 6-h intervals but beginning at 1200 h and obtaining serum cortisol at 0800 h, exactly 2 h (rather than 6 h as in the usual protocol) after the last

dexamethasone dose.

Cortisol after single dose 1 mg Dex Suppression Test greater than 1.8 µg/dl



I test per la diagnosi di Ipercorticosurrenalismo

•  Assay variability.. •  Normal ranges vary substantially, depending on the

method used… •  Cross-reactivity with cortisol metabolites and synthetic

glucocorticoids.. •  Drugs (carbamazepine and fenofibrate) may interfere

with some of chromatographic methods.. •  Estrogens increase the cortisol-binding globulin

concentration… •  Variable absorption and metabolism of dexamethasone

may influence the result of both the overnight 1-mg DST and the 48-h, 2 mg/d test…

•  High fluid intake (³5 liters/d) significantly increases UFC •  A falsely low UFC can occur when creatinine clearance

falls less than 60 ml/min, and UFC levels fall linearly with more severe renal failure

•  Circadian rhythm is blunted in many patients with depressive illness and in shift workers

REMARKS FOR ALL TESTS The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93: 1526–1540, 2008


Diagnosi di Ipercorticosurrenalismo: valutazioni successive


1°test+ → 2°test

2 test neg → STOP

DEX+CRH? AVP?


Diagnosi di Ipercorticosurrenalismo: valutazioni successive


2 test pos → diagnosi di localizzazione

Follow-up dei negativi e discordanti

Ipertensione endocrina: solo la punta dell’iceberg? · Roma, 7-9 novembre 2014 Ipertensione...

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