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Free access

Ulf Elbelt, Stefanie Hahner and Bruno Allolio

Objective

Current glucocorticoid replacement regimens fail to fully mimic physiologic cortisol secretion in patients with primary adrenal insufficiency. This may lead to changes in insulin requirement in patients with primary adrenal insufficiency and type 1 diabetes. Therefore, we assessed insulin requirement in patients with autoimmune polyendocrine syndrome type 2 (APS-2).

Design and subjects

Ten females with primary adrenal insufficiency and type 1 diabetes (mean duration of type 1 diabetes 13±11 years and of primary adrenal insufficiency 11±9 years) were retrospectively assessed regarding insulin regimen and insulin dose adjustment. Data were compared with control patients matched for age, sex and duration of diabetes drawn from all patients with type 1 diabetes attending the diabetes outpatient clinics at the University Hospital Wuerzburg for a scheduled consultation.

Results

Glycaemia was well controlled in both groups (mean HbA1c 6.99±0.81% in APS-2 patients versus 6.69±1.03% in control patients). The mean weight-adjusted daily dose of insulin was non-significantly higher in patients with APS-2 compared with control patients (0.69±0.35 IU/kg body weight versus 0.51±0.17 respectively). The mean insulin (IU)/carbohydrate-ratio for 10 g of carbohydrate in the morning was 1.9±1.0 and 1.4±0.5 respectively. However, the insulin/carbohydrate-ratios were significantly higher in the APS-2 patients both at noon (mean ratio 2.0±0.9 vs 1.1±0.5 in control patients) and in the evening (mean ratio 2.1±1.1 vs 1.3±0.5 respectively; P<0.05).

Conclusions

Glucocorticoid replacement therapy in patients with primary adrenal insufficiency and type 1 diabetes leads to significant changes in insulin requirement compared with patients with type 1 diabetes only.

Free access

Stefanie Hahner, Stephanie Burger-Stritt and Bruno Allolio

Objective

Evaluation of the pharmacokinetics and safety of s.c. hydrocortisone injection for use in adrenal emergency.

Design

Single-center, open-label, sequence-randomized, crossover study in a tertiary care center.

Patients and methods

Twelve patients with chronic Addison's disease. Comparison of hydrocortisone pharmacokinetics after s.c. and i.m. injection (100 mg) and after s.c. administration of sodium chloride (0.9%) respectively at three different visits.

Main outcome measure: maximum serum cortisol (Cmax), time to Cmax (tmax), and time to serum cortisol >36 μg/dl (tserum cortisol >36 μg/dl) after s.c. administration compared with i.m. administration, safety, and patient preference.

Results

Serum cortisol increased rapidly and substantially after both i.m. and s.c. injections (Cmax: 110±29 vs 97±28 μg/dl, P=0.27, tmax: 66±51 vs 91±34 min, P=0.17, and tserum cortisol >36 μg/dl: 11±5 vs 22±11 min, P=0.004 respectively). Both i.m. and s.c. injections were well tolerated. Eleven (91.7%) patients preferred s.c. injection, whereas one patient did not have any preference.

Conclusions

S.c. administration of 100 mg hydrocortisone shows excellent pharmacokinetics for emergency use with only a short delay in cortisol increase compared with i.m. injection. It has a good safety profile and is preferred by patients over i.m. injection.

Free access

Sebastian Wortmann, Marcus Quinkler, Christian Ritter, Matthias Kroiss, Sarah Johanssen, Stefanie Hahner, Bruno Allolio and Martin Fassnacht

Objective

No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC.

Methods

Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab (5 mg/kg body weight i.v. every 21 days) and oral capecitabine (950 mg/m2 twice daily for 14 days followed by 7 days of rest) in 2006–2008. Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks.

Results

Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I–II). Median survival after treatment initiation was 124 days.

Conclusions

Bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.

Free access

Benjamin Bleicken, Stefanie Hahner, Melanie Loeffler, Manfred Ventz, Bruno Allolio and Marcus Quinkler

Context

Recent studies have suggested that current glucocorticoid replacement therapies fail to fully restore well-being in patients with adrenal insufficiency (AI).

Objective

To investigate the effect of different glucocorticoid preparations used for replacement therapy on subjective health status (SHS) in AI.

Design and patients

In a cross-sectional study, primary and secondary AI patients were contacted by mail. Individual glucocorticoid replacement regimens, underlying diagnoses and comorbidities were verified by questionnaires and review of medical records. Patients were asked to complete three validated self-assessment questionnaires (Short Form 36 (SF-36), Giessen Complaint List (GBB-24), and Hospital Anxiety and Depression Scale). Results were compared with sex- and age-matched controls drawn from the questionnaire-specific reference cohort.

Results

Of the 883 patients identified, 526 agreed to participate in the study. Completed questionnaire sets were available from 427 patients (primary AI n=232; secondary AI n=195). AI patients showed significantly impaired SHS compared with controls irrespective of the glucocorticoid used for replacement. The only difference in SHS between patients on prednisolone (PR) and hydrocortisone (all patients and sub-analysis for primary AI) was significant higher bodily pain (lower Z-score in SF-36) in patients on PR (P<0.05, P<0.01 respectively). In patients with secondary AI, the PR group showed significantly (P<0.05) less heart complaints (lower Z-score) in the GBB questionnaire compared with the cortisone acetate group.

Conclusions

Glucocorticoid replacement therapy with PR seems to be equivalent to hydrocortisone regarding SHS in patients with AI. However, SHS remains impaired in all patient groups suggesting a need for further improved glucocorticoid replacement strategies.

Free access

Stefanie Hahner, Martin Fassnacht, Fabian Hammer, Markus Schammann, Dirk Weismann, Immo Alex Hansen and Bruno Allolio

Objective: A serine protease from rat adrenal cortex was recently characterized and named adrenal secretory protease (AsP). AsP is expressed in the adrenal cortex and is capable of cleaving pro-γ-melanocyte-stimulating hormone (1-76 N-terminus of pro-opiomelanocortin) into fragments that act as adrenal mitogens. AsP may therefore play a crucial role in adrenal growth and tumourigenesis. The aim of this study was to further characterize the human homologue of AsP and its possible role in adrenal tumourigenesis.

Methods and results: Starting with the rat cDNA sequence of AsP we detected high homology to the catalytic C-terminus of the human airway trypsin-like protease (HAT). Further analysis revealed that the HAT gene is the human homologue of a long splice variant of AsP, which we recently described as rat airway trypsin-like serine protease 1. In contrast to rodents, no short isoform of HAT was found in humans due to a stop codon in exon 6 which prevents the expression of a short isoform. While high expression of HAT mRNA was found in the trachea and in the gastrointestinal tract, expression in the adrenal was only very weak. RT-PCR and real-time PCR analysis revealed a complex tissue expression pattern of HAT, indicating a role for this protease in multiple tissues. We further investigated HAT expression in five normal adrenal glands, 15 adrenocortical adenomas (five hormonally inactive adenomas, five aldosterone-producing adenomas and five cortisol-producing adenomas), nine adrenocortical carcinomas, five phaeochromocytomas and two adrenal hyperplasias. Weak HAT expression was detectable in only two out of five normal adrenal glands, in one out of twenty-four adrenocortical tumours and four out of five phaeochromocytomas. However, the expression in the adrenal tissue was several orders of magnitude lower than in the trachea. In addition, we could not detect any HAT transcripts in a sample of fetal adrenal.

Conclusion: Gene structure and tissue distribution of HAT, the human homologue of the rat adrenal secretory protease AsP, reveal major interspecies differences. The observation of very low expression levels in normal adrenal tissue and adrenocortical tumours casts doubt about a role for HAT in the physiological and pathological growth of adrenocortical cells.

Free access

Nicole Reisch, Marina Willige, Denise Kohn, Hans-Peter Schwarz, Bruno Allolio, Martin Reincke, Marcus Quinkler, Stefanie Hahner and Felix Beuschlein

Objective

To study adrenal crisis (AC) in patients with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (21-OHD). AC was defined as an acute state of health impairment requiring i.v. glucocorticoid administration and hospital admission.

Design and methods

In a cross-sectional study with detailed retrospective assessment, AC was studied following two approaches: i) questionnaire based: 122 adult 21-OHD patients (50 men, 72 women, median age 35 years, range 18–69 years) completed a disease-specific questionnaire; and ii) patient chart based: charts of 67 21-OHD patients (32 males, 35 females, median age 31 years, range 20–66 years) were analyzed from diagnosis to last follow-up with regard to frequency and causes of AC since diagnosis.

Results

Evaluation of questionnaires revealed 257 ACs in 4456 patient years (py; frequency 5.8 crises/100 py), while patient charts documented 106 ACs in 2181 py (4.9 crises/100 py). The chart-based evaluation showed that gastrointestinal infections (29%) and salt-wasting crisis (18%) were the main causes of AC. In 14%, the cause remained uncertain. There was no difference in the overall frequency of AC in males and females. AC mostly occurred during childhood, with more than 70% of AC in the first 10 years of life and one-third of AC in the first year of life. Still, 20% of cases of AC were observed in adults (>18 years).

Conclusion

Our data demonstrate a significant risk of AC in patients with 21-OHD over lifetime. Specific age-adapted and repeated crisis prevention training may help to reduce morbidity due to AC in 21-OHD.

Free access

Stefanie Hahner, Melanie Loeffler, Benjamin Bleicken, Christiane Drechsler, Danijela Milovanovic, Martin Fassnacht, Manfred Ventz, Marcus Quinkler and Bruno Allolio

Objective

Adrenal crisis (AC) is a life-threatening complication of adrenal insufficiency (AI). Here, we evaluated frequency, causes and risk factors of AC in patients with chronic AI.

Methods

In a cross-sectional study, 883 patients with AI were contacted by mail. Five-hundred and twenty-six patients agreed to participate and received a disease-specific questionnaire.

Results

Four-hundred and forty-four datasets were available for analysis (primary AI (PAI), n=254; secondary AI (SAI), n=190). Forty-two percent (PAI 47% and SAI 35%) reported at least one crisis. Three hundred and eighty-four AC in 6092 patient years were documented (frequency of 6.3 crises/100 patient years). Precipitating causes were mainly gastrointestinal infection and fever (45%) but also other stressful events (e.g. major pain, surgery, psychic distress, heat and pregnancy). Sudden onset of apparently unexplained AC was also reported (PAI 6.6% and SAI 12.7%). Patients with PAI reported more frequent emergency glucocorticoid administration (42.5 vs 28.4%, P=0.003). Crisis incidence was not influenced by educational status, body mass index, glucocorticoid dose, DHEA treatment, age at diagnosis, hypogonadism, hypothyroidism or GH deficiency. In PAI, patients with concomitant non-endocrine disease were at higher risk of crisis (odds ratio (OR)=2.02, 95% confidence interval (CI) 1.05–3.89, P=0.036). In SAI, female sex (OR=2.18, 95% CI 1.06–4.5, P=0.035) and diabetes insipidus (OR=2.71, 95% CI 1.22–5.99, P=0.014) were associated with higher crisis incidence.

Conclusion

AC occurs in a substantial proportion of patients with chronic AI, mainly triggered by infectious disease. Only a limited number of risk factors suitable for targeting prevention of AC were identified. These findings indicate the need for new concepts of crisis prevention in patients with AI.

Restricted access

Sophie Schweitzer, Meik Kunz, Max Kurlbaum, Johannes Vey, Sabine Kendl, Timo Deutschbein, Stefanie Hahner, Martin Fassnacht, Thomas Dandekar and Matthias Kroiss

Objective

Current workup for the pre-operative distinction between frequent adrenocortical adenomas (ACAs) and rare but aggressive adrenocortical carcinomas (ACCs) combines imaging and biochemical testing. We here investigated the potential of plasma steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) for the diagnosis of malignancy in adrenocortical tumors.

Design

Retrospective cohort study of prospectively collected EDTA-plasma samples in a single tertiary reference center.

Methods

Steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) in random plasma samples and logistic regression modeling.

Results

Fifteen steroid hormones were quantified in 66 ACAs (29 males; M) and 42 ACC (15 M) plasma samples. Significantly higher abundances in ACC vs ACA were observed for 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, DHEAS and estradiol (all P < 0.05). Maximal areas under the curve (AUC) for discrimination between ACA and ACC for single analytes were only 0.76 (estradiol) and 0.77 (progesterone), respectively. Logistic regression modeling enabled the discovery of diagnostic signatures composed of six specific steroids for male and female patients with AUC of 0.95 and 0.94, respectively. Positive predictive values in males and females were 92 and 96%, negative predictive values 90 and 86%, respectively.

Conclusion

This study in a large adrenal tumor patient cohort demonstrates the value of plasma steroid hormone profiling for diagnosis of ACC. Application of LC-MS/MS analysis and of our model may facilitate diagnosis of malignancy in non-expert centers. We propose to continuously evaluate and improve diagnostic accuracy of LC-MS/MS profiling by applying machine-learning algorithms to prospectively obtained steroid hormone profiles.

Restricted access

Andrea Osswald, Timo Deutschbein, Christina M Berr, Eva Plomer, Anne Mickisch, Katrin Ritzel, Jochen Schopohl, Felix Beuschlein, Martin Fassnacht, Stefanie Hahner and Martin Reincke

Objective

Aim of our study was to analyze long-term outcome of patients with the ectopic Cushing’s syndrome (ECS) compared to patients with Cushing’s disease (CD) regarding cardiovascular, metabolic, musculoskeletal and psychiatric comorbidities.

Design

Cross-sectional study in patients with ECS and CD in two German academic tertiary care centers.

Methods

Standardized clinical follow-up examination was performed including health-related quality of life (QoL) in 21 ECS patients in long-term remission (≥18 months since successful surgery). Fifty-nine patients with CD in remission served as controls.

Results

Time from first symptoms to diagnosis of Cushing’s syndrome (CS) was shorter in ECS than in CD (8.5 (IQR: 30.3) vs 25 (IQR: 39.0) months, P = 0.050). ECS patients had lower self-reported psychiatric morbidity compared to CD (19% vs 43%, P = 0.050) at follow-up. Moreover, female ECS patients reported favorable scores for QoL in the SF-36 questionnaire (mental health: 92 (IQR: 30) vs 64 (IQR: 32) in CD, P = 0.010) and a Cushing-specific QoL questionnaire (73 (IQR: 18) vs 59 (IQR: 36) in CD, P = 0.030). In a pooled analysis of ECS and CD patients, QoL correlated with time from first symptoms until diagnosis of CS, but not with urinary free cortisol levels or serum cortisol after dexamethasone at the time of diagnosis. Long-term outcomes regarding hypertension, metabolic parameters, bone mineral density and grip strength were comparable in ECS and CD.

Conclusions

Our data support the concept that time of exposure to glucocorticoid excess appears to be a better predictor than peak serum cortisol levels at the time of diagnosis regarding long-term psychiatric morbidity and QoL.

Free access

Britta Heinze, Leonie J M Herrmann, Martin Fassnacht, Cristina L Ronchi, Holger S Willenberg, Marcus Quinkler, Nicole Reisch, Martina Zink, Bruno Allolio and Stefanie Hahner

Context

The Li–Fraumeni tumor syndrome is strongly associated with adrenocortical carcinoma (ACC) and is caused by germline mutations in TP53 in 70% of cases. Also, TP53 polymorphisms have been shown to influence both cancer risk and clinical outcome in several tumor entities. We, therefore, investigated TP53 polymorphisms in a cohort of adult patients with ACC.

Objective

Evaluation of the role of TP53 polymorphisms in adult patients with ACC.

Subjects and methods

Peripheral blood for DNA extraction was collected from 72 ACC patients. Polymorphism analysis was carried out by amplification and sequencing of exons and adjacent intron sections of TP53. Results were correlated with clinical data and the distribution of the polymorphisms was compared with published Caucasian control groups.

Results

Compared with control groups, genotype frequencies of analyzed TP53 polymorphisms among ACC patients were significantly different in three out of four polymorphisms: IVS2+38G>C (G/G, P=0.0248), IVS3ins16 (NoIns/NoIns, P<0.0001; NoIns/Ins, P<0.0001), and IVS6+62A>G (G/G, P<0.0001; G/A, P<0.0001). Overall, the survival of ACC patients, which harbored at least one of the less frequent genotype variants of four analyzed polymorphisms (n=23), was significantly inferior (median survival: 81.0 months in patients with the common homozygous genotypes vs 20.0 months in patients with the less frequent genotypes, HR 2.56, 95% CI 1.66–7.07; P=0.001). These results were confirmed by multivariable regression analysis (HR 2.84, 95% CI 1.52–7.17; P=0.037).

Conclusion

Some TP53 polymorphisms seem to influence overall survival in ACC patients. This effect was observed for a combination of polymorphic changes rather than for single polymorphisms.