M. Pura et al. (Lubochna and Prague) with the title : “The low dose (1 μg) Cosyntropin test (LDT) for Primary Adrenocortical Insufficiency: Defining the normal cortisol response and report on first patients with Addison Disease confirmed with LDT” (ECED 2010; 118: 151–157)

Dear Sirs,

I would have thought that the Low Dose tetracosactin Test (LDT) is dead, but now and then transient resurrections do occur. In 1998 we compared normal plasma cortisol responses to 1 μg and 250 μg tetracosactin (Synacthen^®, Cosyntropin^®) in 35 healthy subjects. We found 19.4 μg/dl (535 nmol/l) to be the lower cutoff response (mean minus 2 standard deviations) for the LDT and 22.5 μg/dl (621 nmol/l) for the 250 μg-test (high dose test – HDT) 30 min after tetracosactin injection. The responses 60 min after injection are markedly different between the tests, because serum cortisol decreases after 30 min in the LDT, but further rises in the HDT [1]. In the same paper we compared the two tests with the results of insulin hypoglycaemia tests or metyrapone tests in 40 patients with pituitary disease with regard to the presence or absence of secondary adrenal insufficiency. By using the different lower cutoff points of the two tetracosactin tests we found that both provided exactly the same information, and both tests were unable to detect mild forms of secondary adrenal insufficiency. Using our original data and the ROC method of analysis, Dorin et al. confirmed our results and conclusions [2].

Why then should the LDT be used to confirm the suspicion of primary adrenal insufficiency (PAI) ? In PAI serum cortisol is low or normal, and ACTH is increased. In 1988 we have shown that the adrenal cortex is maximally stimulated, when plasma ACTH 1-39 reaches a level of approximately 80 pg/ml [3]. In >95% of patients wit PAI, ACTH levels are much higher, and serum cortisol does not respond in the HDT [4]. It could be expected without testing that cortisol would not respond in these patients to lower dosages, as shown in fig. 4 of the paper by Pura et al.

It is well known that the 250 μg dose used for the HDT is much higher than needed for maximal stimulation of the adrenal cortex. Plasma tetracosactin levels after injection of this dose initially rise to more than 10 000 pg/ml, and even 60 min after injection the level is still slightly higher than 100 pg/ml [1]. Thus the dose of 250 μg is very high, although not “too high”, because it is not harmful to the patient tested, and lower dose tests do not provide better diagnostic information.

The only reason for using a lower dose of tetracosactin could be an economic one. In Germany, a 250 μg ampoule of Synacthen^® costs about 23 Euro, 10 ampoules cost about 130 Euro. Theoretically, one can perform more than 200 LDTs with the content of one ampoule. However, dilution, freezing and storage of tetracosactin in sterile containers (if possible siliconized) can be critical. In addition, while it is without effect on the result of the HDT if you spill 90% of the volume of a 1 ml ampoule, one has to inject the exact 1 μg dose for the LDT, since loss of dose dinminishes the cortisol response 30 min after injection. This test is, therefore, not robust enough for clinical routine. I have discussed this problem previously in short reviews [5] [6]. Thus, if one considers to use a low dose test, I would recommend to inject 10 or 20 μg of tetracosactin, and to use the same lower serum or plasma cortisol cutoff level 30 min after injection as with the standard HDT. This cutoff level has to be established for each special cortisol assay-kit [7.]

References

• 1 Mayenknecht J, Diederich S, Bähr V. et al . Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease.  J Clin Endocrinol Metab. 1998;  83 1558-1562
• 2 Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency.  Ann Intern Med. 2003;  139 194-204
• 3 Oelkers W, Boelke T, Bähr V. Dose-response relationships between plasma adrenocorticotropin, cortisol, aldosterone and 18-OH- corticosterone after injection of ACTH 1-39 or human CRH in man.  J Clin Endocrinol Metab. 1988;  66 181-186
• 4 Oelkers W, Diederich S, Bähr V. Diagnosis and therapy surveillance in Addison';s disease: Rapid adrenocorticotropin test, and measurement of plasma ACTH, renin activity and aldosterone.  J Clin Endocrinol Metab. 1992;  75 259-264
• 5 Oelkers W. Dose-response-aspects in the clinical assessment of the hypothalamo-pituitary-adrenal axis , and the low-dose adrenocorticotropin test.  Eur J Endocrinol. 1996;  135 27-33
• 6 Oelkers W. The role of high- and low-dose corticotrophin tests in the diagnosis of secondary adrenal insufficiency.  Eur J Endocrinol. 1998;  139 567-570
• 7 Clark PM, Neylon I, Raggatt PR. et al . Defining the normal cortisol response to short Synacthen test: Implications for the investigation of hypothalamic-pituitary disorders.  Clin Endocrinol. 1998;  49 287-292

Correspondence