The ICET-A Survey on Current Criteria Used by Clinicians for the Assessment of Central Adrenal Insufficiency in Thalassemia: Analysis of Results and Recommendations
Vincenzo De Sanctis1, Ashraf T. Soliman2, Heba Elsedfy3, Alice Albu4 , Soad Al Jaouni5; Saif AL Yaarubi6, Salvatore Anastasi7, Duran Canatan8, Massimo Di Maio9, Salvatore Di Maio10, Mohamed El Kholy3, Mehran Karimi11, Doaa Khater12, Yurdanur Kilinc13, Su Han Lum14, Nicos Skordis15, Praveen Sobti16, Iva Stoeva17, Ploutarchos Tzoulis18, Yasser Wali19 and Christos Kattamis20
1 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
2 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital Doha, Qatar and Department of Pediatrics, Division of Endocrinology, Alexandria University Children's Hospital, Alexandria, Egypt.
3 Department of Pediatrics, Ain Shams University, Cairo, Egypt.
4 Endocrinology and Diabetes Department of Elias Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
5 Head Division of Pediatric Hematology Oncology, Deputy Chair of Hematology & Head Section of Hematology Research Lab, King Fahd Medical Research Center Department of Hematology Faculty of Medicine, King Abdulaziz University Jeddah, Kingdom of Saudi Arabia.
6 Head of Pediatric Endocrine Unit, Department of Child Health, Sultan Qaboos University Hospital, Al-Khoud, Sultanate of Oman.
7 Thalassemia Unit, Maternal and Child Department, Garibaldi Hospital, Catania, Italy.
8 Director of Thalassemia Diagnosis Center of Mediterranean Blood Diseases Foundation Antalya, Turkey.
9 Department of Oncology, University of Turin, Mauriziano Hospital , Turin, Italy.
10 Emeritus Director in Pediatrics, Children’s Hospital “Santobono-Pausilipon”, Naples,Italy.
11 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz,Iran.
12 Department of Pediatrics, Endocrinology Unit, Alexandria University Children's Hospital, Egypt and Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman.
13 Çukurova University, Medical Faculty, Department of Pediatric Hematology, Adana,Turkey.
14 Department of Paediatrics, University Malaya Medical Center, Malaysia.
15 Division of Pediatric and Adolescent Endocrinology, Paedi Center for Specialized Pediatrics, St. George's University Medical School at the University of Nicosia, Cyprus.
16 Professor Pediatric Hemato-Oncology, Christian Medical College and Hospital, Ludhiana Punjab,India.
17 Paediatric Endocrinologist,“Screening and Functional Endocrine Diagnostics” SBALDB “Professor Ivan Mitev”, Medical University Sofia, Bulgaria.
18 Department of Endocrinology, Whittington Hospital, University College London , London, UK.
19 Pediatric Hematology Unit, Child Health Department, Sultan Qaboos University Hospital, Muscat, Oman and Department of Pediatrics, Alexandria University Children's Hospital, Egypt.
20 First Department of Paediatrics, University of Athens, Athens, Greece.
Received: May 22, 2016
Accepted: June 14, 2016
Mediterr J Hematol Infect Dis 2016, 8(1): e2016034, DOI 10.4084/MJHID.2016.034
This article is available on PDF format at:
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: In March 2015, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) implemented a two-step survey on central adrenal insufficiency (CAI) assessment in TM patients and after analysis of the collected data, recommendations for the assessment of hypothalamic-pituitary- adrenal (HPA) axis in clinical practice were defined.
Methods: To ascertain the current practice for assessment of CAI in thalassemia, the Coordinator of ICET-A sent two questionnaires by email: i) The first to evaluate the current interpretation of basal serum cortisol level (first step) and ii) The second to assess the current usage of ACTH test and the variability in practice" (second step). Based on the surveys the core ICET-A group prepared the recommendations for the assessment of suspected CAI in thalassemia (third step).
Results: A total of 19 thalassemologists/endocrinologists have participated in the first survey and 35 specialists participated in the second step questionnaire. The study demonstrated a considerable variability in almost all aspects of relevant current criteria used for the diagnosis of CAI. An ROC analysis using peak value > 20 μg/dl (> 550 nmol/L), after ACTH stimulation test, was performed with the aim of identifying the optimal basal serum cortisol cut-off. The optimal threshold that maximizes sensitivity plus specificity for morning basal cortisol against peak post- ACTH value >20 μg/dl (>550 nmol/L) was 10 μg/dl (275 nmol/L). Furthermore, the values associated with the highest negative predictive value (NPV) and highest, positive predictive value (PPV) were 4.20 (115 nmol/L) and 18.45 μg/dl (510 nmol/L), respectively.
Surprisingly, 20 specialists in thalassemia working in blood bank, thalassemia centres (day hospital), internal medicine, hematology and onco-hematology had poor knowledge and experience in testing for CAI and stopped filling the questionnaire after the second question. In contrast, 9 endocrinologists (8 pediatricians) and 6 hematologists working in collaboration with endocrinologists completed the questionnaire.
Conclusions: While waiting for more extensive adequately powered and targeted studies, physicians should adopt an acceptable policy for accurate assessment of HPA in TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are also recommended. The ICET-A recommendations are reported in order to facilitate for interested physicians the approach to a successful assessment of adrenal function in thalassemia.
Accurate assessment of the hypothalamic-pituitary- adrenal (HPA)
axis is essential for the management of patients with potential or
suspected pituitary or hypothalamic disease that is frequent in
patients with thalassemia major (TM). The diagnosis of adrenal
insufficiency (AI) is relatively simple when glucocorticoid secretion
is profoundly depressed. However, AI can present a difficult diagnostic
challenge, especially when adrenal insufficiency is partial. This is a
particularly important issue as acute crises may occur during stress
periods in undiagnosed patients.
Recently, several studies reported a significant prevalence of “biochemical” central adrenal insufficiency (CAI), ranging from 15% to 53.6 %,[1-5] in children, adolescent and adults with TM. In one study the youngest patient reported with “biochemical” CAI was 9 years old. The age of patients varied from 12 and 20 years, 8 to 26 years, 10.2 ± 3.7 years (ranges are not available), 3 to 18 years and 18 to 50 years.
The prevalence of CAI was higher in adult TM patients (32.1%; age range 18–50 years, median 30).[1–4] Extreme variability in the prevalence of CAI has been attributed to the variable duration of regular transfusion (p=0.016, 95% CI: -28.5/- 3.24), iron overload status and the use of different tests for assessing adrenal function as well as different cut-off values for diagnosing AI among the various centres.[1-5]
The pathophysiological basis of “biochemical” AI in TM has not yet been well-defined. Chronic transfusions induce iron overload in several organs, including adrenal and pituitary glands.[1-5] Therefore, it is possible that pituitary iron deposition might reduce ACTH secretion leading to CAI. Furthermore, the adrenal glands might also be directly affected by iron toxicity. In two studies, patients with TM had higher baseline adrenocorticotrophic hormone (ACTH) levels than do controls, suggesting primary impairment of adrenocortical function.[2,5]
There are two methods to differentiate between primary and secondary AI. First is done by measuring plasma ACTH concentration in the basal fasting AM blood sample. If it is higher than normal, the patient has primary AI, whereas if it is low, the diagnosis of secondary or tertiary AI should be considered. The second method assesses the serum cortisol values in response to exogenous corticotropin (ACTH) stimulation or insulin tolerance test (ITT). The agent most commonly used is synthetic ACTH [1-24] (cosyntropin), which has the full biologic potency of native ACTH [1-39]. The text is useful for the diagnosis of AI but not for the differential diagnosis between peripheral and central forms. Therefore, a prolonged corticotropin administration may become helpful in the differential diagnosis. Unfortunately, this diagnostic approach has not been validated in patients with TM.
In March 2015, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a two-steps survey on the assessment CAI in TM patients among Endocrinologists and Hematologists working with thalassemia patients in different countries. After collecting and analysing the data, the ICET-A group prepared relevant clinical and practical recommendations for the assessment of HPA axis in these patients. The results of the ICET-A project are presented in this paper.
To ascertain the current practice for assessment of CAI in
thalassemia, the Coordinator (VDS) of ICET-A sent by email two
questionnaires: i) “to evaluate the current interpretation of basal
serum cortisol level” to 19 thalassemologists/ endocrinologists members
of ICET-A (first step) and ii) a copy of modified questionnaire survey used by Elder et al
”to evaluate the current usage of ACTH test and the variability in
practice” among other 20 additional specialists taking care of TM
patients (second step). A total of 35 specialists participated in the second step questionnaire.
Based on the surveys the core ICET-A group prepared the recommendations for the assessment of suspected CAI (third step). The recommendations were based on published, peer- reviewed scientific evidence, expert opinion, and accumulated professional knowledge and experience. Recommendations from published guidelines were used when available and appropriate. The ICET-A Network also issued expert consensus opinions on topics for which limited or low level evidence is available in the literature. Since not all published references were based on randomised controlled trials, the recommendations have been scored according to the following criteria:
A. High confidence indicates that further research is unlikely to change the confidence in the estimate of effect (●●●)
B. Moderate confidence indicates that further research may change the confidence in the estimate of effect (●●○)
C. Low confidence indicates that further research would likely have a significant impact on the confidence in the estimate of effect (●○○)
D. Insufficient indicates that the evidence is unavailable or does not permit a conclusion (○○○)
A ROC analysis using peak value >20 μg/dl (>550 nmol/L) after ACTH stimulation test as the classification variable and basal value as the continuous predictor variable was performed using the data from the literature.[2-4] and the personal experience, in 80 TM patients (aged 3-50 years) with the aim of identifying the optimal basal cut-off. The optimal cutoff was determined by the Youden Index, which is defined as Sensitivity plus Specificity-1. All analyses and calculations were done using R version 3.3.0, with the open-source package “pROC”. 
First step: Answered questionnaire was received from 15 out of 19 ICET-A members (78.9% response rate). Responders, who are collectively following 1895 TM patients, were asked to report their position on the lowest basal cortisol threshold used to diagnose CAI and the highest basal threshold excluding CAI. The results are summarized in table 1.
|Table 1. Criteria used for the interpretation of basal cortisol levels (expressed in μg/dl) in 15 Centres taking care of 1895 thalassemia major patients.|
In the survey, the lowest basal cortisol threshold reported
was ≤3 μg/dl (88 nmol/l) to exclude CAI and the highest threshold was
≤7 μg/dl (<190 nmol/l) to diagnose CAI. Values greater than 20 μg/dl
(550 nmol/l) were reported to predict best normal HPA axis.
The results of the ROC analysis are shown in table 2 and figure 1. Using the Youden index, the optimal threshold that maximizes sensitivity plus specificity for morning basal cortisol against peak post-ACTH value >20 μg/dl (>550nmol/L) was 10 μg/dl (275 nmol/L). Three chemilumininescent assays (one Beckman Coulter and two Immulite 1000 kits) and one competitive enzyme-linked immunoassay were used for cortisol measurements (AccuBind kit). Furthermore, the values associated with the highest negative predictive value (NPV) and highest positive predictive value (PPV) were 4.20 (115 nmol/L) and 18.45 μg/dl (510 nmol/L), respectively.
|Table 2. ROC analysis ruling out CAI showing sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for different basal serum cortisol levels.|
|Figure 1. ROC curve using peak post-ACTH values of > 20 µg/dl ( >550 nmol/L) as outcome|
Second step: Thirty five centres following a total of 3433 TM patients shared the second questionnaire. Taking into consideration that several protocols have been used to assess the response to ACTH test, the aim of the survey was to collect 5 pieces of information regarding: a) How many patients are you regularly following in your hospital? b) Does your centre carry out? Synacthen testing? Are you familiar with the indication and interpretation of Synacthen test, c) What dose of Synacthen does your Unit use? d) At what age you screen your patients by measuring serum cortisol? e) What cut off point you accept for diagnosing normal and abnormal adrenal function? f) For a normal result what do you require? (Table 3).
|Table 3. Results of Synacthen test questionnaire completed by 15 Centres.|
Surprisingly, 20 specialists working in blood banks,
thalassemia centres (day hospital), internal medicine, hematology and
onco-hematology had poor knowledge about the test and stopped filling
the questionnaire after the second question. On the contrary 9
endocrinologists (8 were pediatricians) and 6 hematologists working in
collaboration with endocrinologists completed the survey (Table 3).
9/15 (60%) of responding centres employed a standard-dose (SDT)
corticotropin stimulation test (Synacthen test: 250 µg intravenously)
and 2/15 (26.6%) a low dose (LDT) stimulation test (Synacthen test: 1
µg intravenously). There was a variation in the timing of cortisol
sampling. 60% collected blood samples at 0', and at 30' and 60' minutes
after ACTH injection. The maximum number of samples per test was 3. The
diagnostic cut-off values used by different centres are reported in table 3.
Peak cortisol level was used on its own as the diagnostic criteria in
60% of centres and in association with cortisol rise from baseline
in 26.6% of centres. Peak cortisol value >18-20 µg/dl (200- 550
nmol/l) was diagnostic for normal adrenal function in 10/15 centres
(66.6%) while 5/15 centres (33.3%) required values > 20 µg/dl (550
nmol/l). Rise from baseline, defined as >7 µg/dl (> 200
nmol/l) or 2-3 fold from baseline was required for diagnosing normal
adrenocotical function by 40% of the centres.
LDT were performed in 6/15 centres diluting one vial of 250 microgram ACTH into 250 mL sterile normal saline. 1 mL (=1 microgram ACTH) of the solution was then injected as an intravenous bolus.
survey demonstrated a considerable variability in the utilization of
the current criteria used for the diagnosis of AI. These included serum
basal cortisol level, ACTH dose, the timing of cortisol sampling and
cut-offs for AI. In our study, the optimal threshold that maximizes
sensitivity plus specificity for morning basal cortisol against peak
post-ACTH value >20 μg/dl (>550 nmol/L) was 10 μg/dl (275 nmol/L).
Furthermore, the values associated with highest negative predictive value (NPV) and highest positive predictive value (PPV) were 4.20 (115 nmol/L) and 18.45 μg/dl (510 nmol/L), respectively.
The lower cut-off is in line with the published data while the upper cut-off is markedly lower than the one reported in the meta-analysis. In fact, in a meta-analysis of 12 studies on adults (635 subjects without thalassemia), a basal cortisol less than 5 μg/dl (< 138 nmol/l) strongly predicted CAI, while values greater than 13 μg/dl (365 nmol/l) a normal HPA axis.
The lack of uniformity in cut-off levels could in part be attributed to differences in study populations, the variability of dynamic tests, different serum cortisol assays used, the cut-off of peak serum cortisol that was deemed indicative of a normal HPA axis response, and the clinical context in which the studies were done. Therefore, additional studies are required to further elucidate these differences.
Dynamic testing is performed to establish the diagnosis in patients with equivocal cortisol levels in whom hypoadrenalism is suspected. Several protocols have been used to assess the response to exogenous corticotrophin (ACTH). The agent used is synthetic ACTH [1-24] (cosyntropin), which has the full biologic potency of native ACTH [1-39]. There is controversy whether the low-dose test (LDT) is superior to the high-dose ACTH stimulation test (HDT).
The existing controversies in the literature about the use of different Synachten stimulation tests in the assessments of the HPA axis are thought to be related to the use of inappropriate cut-off values.[1-5,10-14] Conventionally, adrenal insufficiency is likely if serum cortisol level is less than 18-20 μg/dL (500-550 nmol/L) at 30-60 minutes after administration of ACTH and or an increments of less than 7 μg/dl (200 nmol/L) above basal cortisol, a criterion described by Crowley et al for LDT. Olkers et al suggested the importance of using different cut-off points for HDT and LDT. A raised cut-off of 22 μg/dl (600 nmo/l) could result in higher sensitivity for the diagnosis.
Mayenknecht et al. established normal ranges for cortisol responses in the LDT (0.5 mg/m2 tetracosactin injection) and HDT in 35 endocrinologically normal healthy subjects. Mean responses minus 2 standard deviations were used as the cut-off point. The result for the LDT at 30 min after injection was 20 μg/dL (550 nmol/L); for the HDT at 30 min after injection: 22 μg/dL (600 nmol/L) and at 60 min: 26 μg/dL (715 nmol/L).
The authors concluded that it was crucial to use different cut-off points in the HDT and LDT tests.
It is possible that TM patients with mild/ partial or recent-onset pituitary ACTH or hypothalamic corticotropin-releasing hormone (CRH) deficiency may have a normal response to 250 μg of Synacthen because the adrenal glands have not undergone significant atrophy and still responds to very high concentrations of ACTH.[13,14] This is an especially important issue because acute crisis may occur during stress periods in undiagnosed patients.
A meta-analysis including 30 studies (1209 adults and 228 children) compared the results of high- and low-dose ACTH stimulation tests using different peak serum cortisol cut-offs. The analysis showed that both tests had similar diagnostic accuracy in adults and children. In general, both tests had low sensitivity and high specificity resulting in reasonable likelihood ratios for a positive test, but a relatively suboptimal likelihood ratio for a negative test. Another survey, published in 2016, supports that there is no clear evidence to indicate that one test is superior to another. This report conflicts with earlier studies with a small number of patients, suggesting that the low-dose test was more sensitive.[17-21]
In patients with TM, an AI was demonstrated in 30 of 56 patients (53.6%) after an LDT. To assess more precisely the adrenal function, the insulin tolerance test (ITT) was performed in 26 of 30 TM patients (86.7%) who had peak total cortisol less than 16 µg/dl (440 nmol/l), after ACTH test. The remaining four patients declined the testing. The time interval between the 1 µg ACTH test and ITT was approximately 4–5 wk. Five of 26 patients (19.2%) had peak total cortisol after an ITT of 20 µg/dl or greater. Therefore, about one fifth of patients who failed the 1 µg ACTH test had normal peak total cortisol levels after an ITT. Thus, by using an ITT, the estimated frequency of adrenal insufficiency in the entire patient group was reduced by approximately 20%.
Soliman et al. using the apparently more “physiologic” LDT and a normal peak total cortisol cut-off level of 20 μg/dl (550 nmol/L) and increment >7 µd/dl (>200 nmol/l), diagnosed a prevalence of CAI in 8 out of 23 (34.7%) in TM patients (6 adolescents and 2 children). Using the HDT and the same cut-off levels diagnosed AI in 8.7% (2/23) of these adolescents. Therefore, about 75% of patients who failed the LDT had normal peak total cortisol levels after the HDT. Similar results were reported by Pang et al. in 6/8 TM patients.
In conclusion, further studies and more normative data are urgently needed because neither over diagnosis nor under diagnosis of HPA insufficiency should be acceptable in patients who potentially may be treated with steroids unnecessarily or who may have impaired cortisol in times of stress and are in need of steroids.[2,22]
Twenty specialists working in blood bank, thalassemia centres (day hospital), internal medicine, hematology, and onco-hematology had poor knowledge of the test and stopped to fill the questionnaire after the second question. On the contrary, 9 endocrinologists and 6 hematologists working in collaboration with endocrinologists completed the survey questionnaire.
Therefore, a collaborative working arrangement between professionals is needed to meet all the required comprehensive care to patients. We believe that one of the near future ICET-A tasks is to set up a collaborative enterprise to identify and address the underlying factors that lead to barrier inter-professional team work and thereby to facilitate inter-professional collaboration.
The lack of treatment guidelines and published research often leave hematologists and internists with hesitant to approach TM patients presenting uncommon endocrine complications. Therefore, as a third step, we thought worth to prepare clinical practice recommendations for all those taking care of TM patients on current criteria for the assessment of CAI (Table 4). The recommendations provide helpful information on laboratory parameters and their interpretation, as well as adrenal hormone replacement dosages and management strategies. The guidelines emphasize that clinicians need to suspect AI earlier in TM patients with risk factors, such as advanced age, severe iron overload and/or poor compliance to therapy, and with multiple endocrine complications.
|Table 4. Practical recommendations for the assessment of suspected adrenal insufficiency (AI) in thalassemia.|
If corticotropin testing is not feasible, a combination of a morning plasma ACTH and cortisol levels (less than 4.2 µg/dL=115 nmo/L) can be used as an initial screening; based on the results, a confirmatory testing with corticotropin stimulation is strongly recommended. Because tests are not perfect, there is still an important role for clinical judgment, especially regarding the use of glucocorticoid supplementation during extreme stress, such as surgery.[2,22]
In summary, our survey provides a better understanding of current physician clinical practices and beliefs in the assessment of the hypothalamic-pituitary-adrenal axis in TM patients. While waiting for more extensive, adequately powered and targeted studies, physicians should adopt an applicable, common sense policy for accurate assessment of HPA in TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are also recommended.
We wish to thank dr CE Elder, University of Sheffield, Academic Unit of Child Health, Stephenson Wing, Sheffield Children's Hospital, Western Bank, Sheffield for giving us the opportunity to use a copy of the ACTH test questionnaire used in her publication.
- Elsedfy HH, El Kholy M, Tarif R, Hamed A, Elalfy M. Adrenal function in thalassemia major adolescents. Pediatr Endocrinol Rev. 2011;8 (Suppl 2):295–299 PMid:21705981
- Soliman AT, Yassin M, Majuid NM, Sabt A, Abdulrahman MO, De Sanctis V. Cortisol response to low dose versus standard dose (back-to-back) adrenocorticotrophic stimulation tests in children and young adults with thalassemia major. Indian J Endocrinol Metab. 201317:1046-1052. http://dx.doi.org/10.4103/2230- 8210.122620
- Poomthavorn P, Isaradisaikul B, Chuansumrit A, Khlairit P, Sriphrapradang A, Mahachoklertwattana P. High prevalence of "biochemical" adrenal insufficiency in thalassemics: Is it a matter of different testings or decreased cortisol binding globulin? J Clin Endocrinol Metab. 2010;95:4609–4615 http://dx.doi.org/10.1210/jc.2010-0205 PMid:20660038
- Pang GSW, Lee CY, Ling ASC, LeungWC,Yau HC. Adrenal Insufficiency in Paediatric Transfusion Dependent Thalassaemia Major in Hong Kong: A Pilot Study. HK J Paediatr (New Series) 2015;20:137-144
- Scacchi M, Danesi L, Cattaneo A, Valassi E, Pecori Giraldi F, Radaelli P, Ambrogio A, D'Angelo E, Mirra N, Zanaboni L, Cappellini MD, Cavagnini F. The pituitary-adrenal axis in adult thalassaemic patients. Eur J Endocrinol. 2010;162:43-48. http://dx.doi.org/10.1530/EJE-09-0646 PMid:19820036
- Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383:2152-2167. http://dx.doi.org/10.1016/S0140-6736(13)61684-0
- Elder CJ, Sachdev P, Wright NP. The short Synacthen test: a questionnaire survey of current usage. Arch Dis Child. 2012;97:870-873 http://dx.doi.org/10.1136/archdischild-2012-301713 PMid:22789438
- Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011 Mar 17;12:77. doi: 10.1186/1471-2105-12-77. http://dx.doi.org/10.1186/1471-2105-12-77
- Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi CH, Clayton RN, Courtney CH, Gonc EN, Maghnie M, Rose SR, Soule SG, Tordjman K; Consortium for Evaluation of Corticotropin Test in Hypothalamic-Pituitary Adrenal Insufficiency.Corticotropin tests for Hypothalamic- Pituitary-Adrenal Insuffciency: A Metaanalysis. J Clin Endocrinol Metab. 2008;93:4245-4253. http://dx.doi.org/10.1210/jc.2008-0710 PMid:18697868
- Crowley S, Hindmarsh PC, Holownia P, Honour JW, Brook CGD. The use of low dose of ACTH in the investigation of adrenal function in man. J.Endocrinol. 1991;130:475-479 http://dx.doi.org/10.1677/joe.0.1300475
- Oelkers W. The role of high- and low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency. Eur J Endocrinol. 1998;139:567-570 http://dx.doi.org/10.1530/eje.0.1390567 PMid:9916857
- Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab. 1998;83:1558-1562. http://dx.doi.org/10.1210/jcem.83.5.4831 PMid:9589655
- Halperin Rabinovich I, Obiols Alfonso G, Soto Moreno A, Torres Vela E, Tortosa Henzi F, Català Bauset M, Gilsanz Peral A, Girbés Borràs J, Moreno Esteban B, Picó Alfonso A, Del Pozo Picó C, Zugasti Murillo A, Lucas Morante T, Páramo Fernández C, Varela da Sousa C, Villabona Artero C. Clinical practice guideline for hypotalamic-pituitary disturbances in pregnancy and the postpartum period. Endocrinol Nutr.2008;55:29-43. http://dx.doi.org/10.1016/S1575-0922(08)70633-8
- Dickstein G, Arad E, Schechner C. Low dose ACTH stimulation test. Endocrinologist 1997;7:285-293. http://dx.doi.org/10.1097/00019616-199707050-00002
- Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH.ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta- Analysis. Clin Endocrinol Metab. 2016;101:427-34. http://dx.doi.org/10.1210/jc.2015-1700 PMid:26649617
- Ng SM, Agwu JC, Dwan K. A systematic review and meta-analysis of Synacthen tests for assessing hypothalamic-pituitary-adrenal insufficiency in children. Arch Dis Child. 2016 Mar 7. pii: archdischild-2015-308925. doi: http://dx.doi.org/10.1136/archdischild-2015-308925 [Epub ahead of print]
- Tordjman K, Jaffe A, Grazas N, Apter C, Stern N. The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab. 1995;80:1301-1305. PMid:7714104
- Dickstein G. Commentary to the article: comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab. 1998;83:4531-4533. http://dx.doi.org/10.1210/jcem.83.12.5322-5 PMid:9851808
- Zarkovic M, Ciric J, Stojanovic M, Penezic Z, Trbojevic B, Drezgic M, Nesovic M. Optimizing the diagnostic criteria for standard (250-microg) and low dose (1-microg) adrenocorticotropin tests in the assessment of adrenal function.J Clin Endocrinol Metab. 1999;84:3170-3173. PMid:10487682
- Abdu TA, Elhadd TA, Neary R, Clayton RN. Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab. 1999;84:838-843. PMid:10084558
- Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab. 1998;83:1558-1562. http://dx.doi.org/10.1210/jcem.83.5.4831 PMid:9589655
- Banani SA, Omrani GH. Cortisol and adrenocorticotropic hormone response to surgical stress (splenectomy) in thalassemic patients. Pediatr Surg Int. 2000; 16:400–403. http://dx.doi.org/10.1007/s003830000401
- Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf). 1987;26:221-226. http://dx.doi.org/10.1111/j.1365-2265.1987.tb00780.x
- Yip CE, Stewart SA, Imran F, Clarke DB, Mokashi A, Kaiser SM, Imran SA. The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis. Clin Invest Med. 2013;36 :E216-222. PMid:23906493
- Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenal insufficiency: Evaluation of the corticotropinreleasing hormone test and Basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. J Clin Endocrinol Metab. 2003;88:4193-4198. http://dx.doi.org/10.1210/jc.2002-021897 PMid:12970286
- Le Roux CW, Meeran K, Alaghband-Zadeh J. Is a 0900-h serum cortisol useful prior to a short synacthen test in outpatient assessment? Ann Clin Biochem. 2002;39:148-150. http://dx.doi.org/10.1258/0004563021901919 PMid:11930947
- Reimondo G, Bovio S, Allasino B, Terzolo A. Secondary hypoadrenalism. Pituitary. 2008;11:147-154. http://dx.doi.org/10.1007/s11102-008-0108-4 PMid:18418713
- Huang KE, Mittelman SD, Coates TD, Geffner ME, Wood JC. A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing. J Pediatr Hematol Oncol. 2015;37:54-59. http://dx.doi.org/10.1097/MPH.0000000000000199 PMid:24942024 PMCid:PMC4393555
- De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Soliman NA, Karimi M, Elalaily R. The Diagnostic Approach to Central Adrenocortical Insufficiency (CAI) in Thalassemia. Mediterr J Hematol Infect Dis. 2016 May 1;8(1):e2016026. eCollection 2016. http://dx.doi.org/10.4084/mjhid.2016.026
- Dorin R, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003;139:194-204. http://dx.doi.org/10.7326/0003-4819-139-3-200308050-00017 PMid:12899587