Endocrine Abstracts

Background: Potentially fatal adrenal crises (AC) still occur in educated patients with adrenal insufficiency (AI). Identifying predisposing factors is necessary for prevention in this patient population.

Objectives: Investigating clinical and biochemical fingerprints of increased susceptibility to AC.

Material and methods: Our study population included 260 patients with chronic AI, classified as high and low risk according to the frequency of experienced AC per patient-years. Besides classical clinical and biochemical data, following parameters were assessed: 24 h urinary cortisol, salivary cortisol day profile, steroid profile in serum, plasma and urinary catecholamines, polymorphisms (SNPs) of the glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), HSD11B1, HSD11B2 and FKBP5, information on therapy adjustments and patient education.

Results: 27% (n=71) of the patients were classified as having a high risk for AC. This group was treated with higher glucocorticoid replacement doses (12 ±4 vs 11±4 mg hydrocortisone-equivalent /m²/day, P=0.03) and displayed significantly higher salivary cortisol levels in the morning (pre-dose) and at noon compared to the low risk group (morning 0.034 (0.034-0.23) vs 0.038 (0.034-1.6) µg/dl, P=0.02, noon: 0.36 (0.03-5.5) vs 0.7 (0.03-3.4), P=0.04). Plasma metanephrine levels were significantly lower in the high risk group (17±12 vs 22±12 ng/, P<0.01). Overall, prevalence of risk genotypes of the analysed SNPs was low. Several NR3C1, NR3C2 und HSD11B1 SNPs related to impaired steroid sensitivity were significantly associated with AC frequency. Analysis of dose adjustments performed by patients themselves in case of AC revealed a significantly higher frequency of self-injected hydrocortisone in high risk patients (56% vs 19%, P=0.021), whereas low risk patients increased their oral doSemore often (81% vs 52%, P=0.06). Frequency of prophylactic stress dose adjustments (eg for intense physical activity) over a period of 6 months was also significantly higher in high risk compared to low risk patients (100% vs 73%, P<0.01).

Conclusion: The higher glucocorticoid replacement dose and higher frequency of prophylactic dose adjustments seen in high risk patients fit to previous observations and might simply reflect increased caution but could also be regarded as an indicator of increased vulnerability, as also suggested by lower plasma metanephrine levels. The association between the risk for AC and SNPs of both glucocorticoid and mineralocorticoid receptor as well as HSD11B1 also implies a genetic susceptibility to AC. These observations require validation in prospective studies.