Ahmed Al Nahari Pediatric Endocrinology Fellow March 11,2016

Transcription

1 Ahmed Al Nahari Pediatric Endocrinology Fellow March 11,2016

2 Scholar: Review the literature in an evidenced based manner to determine the difference in our clinical setting. Advocate: Develop a better understanding of the difference and uses of different doses of ACTH stimulation test in the diagnoses of adrenal insufficiency and advocate for pediatric patients who could benefit from it.

3 11 y old boy Dizziness - Fatigue Nausea BA since age of 2-3 y On advir and flovent

4 Hypoglycemia Morning cortisol 67 nmol/l

5 The clinical presentation of adrenal insufficiency is variable

6 Patients presenting with Addison's disease need not be pigmented. Barnett AH, Espiner EA, Donald RA(1982)

7 ACTH Circulating levels of cortisol levels cause stimulation of ACTH levels cause dec. release of ACTH

8 Undiagnosed hypoadrenalism can be lifethreatening in patients stressed by intercurrent illness or surgery.

9 Confirmation of the clinical diagnosis of adrenal insufficiency is a three-stage process: low cortisol secretion Determining whether the cortisol deficiency is dependent on or independent of corticotropin (ACTH) deficiency and evaluating mineralocorticoid secretion in patients without ACTH deficiency Etiology

10 The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial.

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12 Serum cortisol concentration Most tests use total serum cortisol as the diagnostic measurement. Cortisol assays are not standardized Salivary or serum free cortisol have been suggested as alternatives but are not widely available, and criteria for response have not been developed.

13 In normal subjects, serum cortisol concentrations are higher in the early morning (about 6 AM), ranging from 10 to 20 mcg/dl (275 to 555 nmol/l), than at other times of the day. Finucane FM,(2008)

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15 UpTodate

16 Dynamic testing is performed to establish the diagnosis in patients with equivocal serum cortisol values in whom hypoadrenalism is suspected.

17 Insulin-induced hypoglycemia test The insulin tolerance test (ITT) has been used as a reference method for assessing the reactivity of the hypothalamic pituitary adrenal (HPA) axis since it was first introduced in the 1960s Enwood et al., 1966;

18 Metyrapone tests In patient S/E

19 Ovine corticotropin-releasing hormone (CRH) stimulation test (1 mcg/kg over 1 min) A lack of a 2-fold increase in serum adrenocorticotropic hormone (ACTH) concentration indicates pituitary dysfunction. Ovine CRH is difficult to obtain, and this test is mainly performed for research purposes. Kronenberg HM;(2008)

20 The test is costly, requires frequent blood sampling and its value in differentiating hypothalamic from pituitary causes of ACTH failure is unclear Taylor & Fishman, (1988)

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22 ACTH STIMULATION TESTS The agent used is synthetic ACTH (1-24) (cosyntropin), which has the full biologic potency of native ACTH (1-39). Short (one hour or less) tests involve administration of a single. Both tests result in supraphysiological plasma ACTH concentrations: about 60,000 pg/ml (1320 pmol/l) after the standard high-dose ACTH test and about 1900 pg/ml (41.8 pmol/l) after the low-dose test Tordjman et al. (1998)

23 Standard high-dose ACTH stimulation test Measuring serum cortisol immediately before and 30 and 60 minutes after intravenous (IV) or intramuscular (IM) injection of 250 mcg (85 nmol, or 40 international units) of cosyntropin The advantage of the high-dose test is that the cosyntropin can be injected IM as well as IV, because pharmacologic plasma ACTH concentrations are still achieved Landon et al., 1967

24 Low-dose ACTH stimulation test Measuring serum cortisol immediately before and 30 minutes after IV injection of cosyntropin in a dose either of 1 mcg (160 milli-international units) or of 0.5 mcg (80 milli- international units) per 1.73 m2. Crowley S,1991

25 Indications Screening procedure for Adrenal Insufficiency. Diagnostic procedure for adrenal biosynthetic defects (e.g. CAH). Monitoring recovery of adrenal function after cure from Cushing s syndrome or glucocorticoid withdrawal.

26 The rationale for using the LDST is based on a number of investigations that have shown that in healthy individuals a dose-dependent rise in plasma cortisol occurs with doses of ACTH ranging from 0.03 μg/1.73 m2 to 1.0 μg/1.73 m2, after which a plateau is reached L. Patel and P.E. Clayton (1999)

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28 Low doses of ACTH have been reported to be sufficient to cause a release of cortisol reflecting the reactivity of the hypothalamic pituitary adrenal axis. The dose of 500 ng ACTH/1.73 m2 has thus been suggested to satisfy the criteria of the standard ACTH test Crowley et al., (1991).

29 Synopsis of the Dynamic Tests Available to Assess Adrenal Function Salvatori, R. JAMA 2005;294: Copyright restrictions may apply.

30 M. Kõrnap et al. 2001

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32 S. Rasmuson et al. (1995)

33 The standard dose of ACTH used in SDT is at least 1000 times higher for maximal adrenal stimulation (Landon et al., 1967). It has been suggested that 1 mg ACTH test is more sensitive than a 250 mg ACTH test in the assessment of HPA axis underactivation (Tordjman et al., 1995; DoE kmetas et al. 2000).

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35 WEINTROB ET AL 1998

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38 Differences in responses between patients treated with two inhaled glucocorticoids, beclomethasone and budesonide, were observed with LDST (0.5 μg/1.73 m2) but not the SDST. CrowleyS(1992)

39 Review of studies assessing HPA function suggests that the LDST (1 μg) has high sensitivity (94-100%), specificity (88-100%) and likelihood ratios compared to insulin and metyrapone tests. The SDST was found to have a lower sensitivity (30-88%) but comparable specificity (91-100%). ThalerL.M.(1998)

40 Peak cortisol responses ranging from 390 to 770 nmol/l (median 565, interquartile range ) and increments ranging from 85 to 410 nmol/l (median 290, interquartile range ) with the LDST (0.5 μg/1.73 m2) in healthy children. However, all normal children had either a peak cortisol of >500 nmol/l and/or an increment from basal to peak level of >200 nmol/l. L. Patel and P.E. Clayton (1999)

41 Cemeroglu et al. 2011

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43 AP Cemeroglu et al. 2011

44 AP Cemeroglu et al In previous studies, peak cortisol response to LD cosyntropin occurred at +20 or +30 min. In our study the peak cortisol response occurred at +30 min in 18 patients (95%) in group A and all group B patients. Only one patient peaked at +20 min in group A and none in group B did.

45 With HD cosyntropin stimulation testing, the peak cortisol response occurred at +150 min (60 min after administration) in 16 patients in group A (84%), and in 16 patients (94%) in group B.

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48 S. Rasmuson et al The reliability of the low dose ACTH test should be increased by defining the peak timepoint. In our study the peak cortisol level was obtained between 30 and 40 minutes after 1 g of ACTH in almost all cases.

49 L. Patel and P.E. Clayton The cortisol response during the insulin tolerance test is helpful in determining the normality of the stress response (19). However, it can be hazardous and is not recommended in adults with cardiovascular dis- ease or epilepsy and children.

50 We feel that there is now compelling evidence that the LDST is an appropriate investigation in patients suspected of adrenal dysfunction. In our paediatric practice, we have been reassured that the LDST will identify those asymptomatic children who have a mild adrenal disorder that could put them at risk under stress.

51 WEINTROB ET AL indeed, the low-dose 1- g ACTH test proved even more efficient in detecting secondary adrenal insufficiency than the standard 250- g test in patients receiving long-term sys- temic corticosteroid therapy

52 Research has suggested (32, 33) that dehydroepiandrosterone sulfate (DHEA-S) blood levels might also help with assessing the HPA axis, particularly when the results of the LDCT are close to either of the two threshold values.

53 There is no consensus among pediatric endocrinologists in using low-dose (LD) versus high-dose (HD) cosyntropin to test for secondary/tertiary adrenal insufficiency.

54 AP Cemeroglu et al Peak cortisol concentrations should be used rather than incremental increases in cortisol concentration from baseline value, because baseline cor- tisol levels may be elevated due to stress surrounding the testing procedure, especially in children. The incremental increase over baseline may not be considered sufficient, but the peak cortisol concentration may be high enough to consider the child as having a normal cortisol response.1 3 In patients with a recent onset of central hypoadrenalism, the cosyntropin stimulation test may be normal for four weeks after pituitary surgery and testing should be postponed.

55 Home However, the high-dose test performs well when it is performed at least four months after surgery, or nine months after radiation therapy. In one report, only 2 of 137 patients with 30-minute cortisol values between 18.2 and 22.7 mcg/dl (510 and 635 nmol/l) subsequently developed adrenal insufficiency Agha A, Tomlinson JW 2006

56 THANK YOU