Manfred Ventz

Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies

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.

Influence of hydrocortisone dosage scheme on health‐related quality of life in patients with adrenal insufficiency

Context  Recent studies suggest that current glucocorticoid replacement therapies fail to completely restore well‐being in patients with adrenal insufficiency (AI).

Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma

CONTEXT Adrenal and extra-adrenal phaeochromocytoma are chromaffin cell-derived tumours that are discovered due to classical symptom triad with headache, sweating and palpitations combined with persistent or paroxysmal hypertension. However, an increasing proportion of phaeochromocytoma seems to be discovered incidentally upon abdominal imaging. OBJECTIVE To specify the exact circumstances of discovery of adrenal and extra-adrenal phaeochromocytoma. DESIGN AND PATIENTS Four German endocrine centres participated in this retrospective study. MEDICAL: records of 201 patients with adrenal and extra-adrenal phaeochromocytoma who were diagnosed between 1973 and 2007 were analyzed. RESULTS The typical triad of symptoms was found only in 10% of cases. Ten percent of patients presented were without clinical symptoms and 6.1% were normotensive. Documented blood pressure peaks occurred in 44.1% of cases. In 24 patients (12.2%), phaeochromocytoma was malignant. Before 1985, <10% of cases were incidentally discovered, whereas thereafter the frequency was >25% (29.4% of the total study population). Patients with incidentally detected phaeochromocytoma were significantly older (53.1+/-1.9 vs 47.0+/-1.3 years; P<0.05) and often had less blood pressure peaks (37.0 vs 70.7%; P<0.001) than patients in whom the diagnosis was suspected on clinical grounds. Of phaeochromocytomas 94.4% were intra-adrenal tumours, of which 12.9% were bilateral. Bilateral tumours were significantly smaller than unilateral tumours (36.6+/-14.7 vs 52.5+/-34.3 mm; P<0.05), whereas extra-adrenal tumours had a mean diameter of 52.6+/-28.7 mm. CONCLUSIONS Owing to better availability and accessibility of imaging procedures, the number of incidentally discovered phaeochromocytoma is increasing and reaches nearly 30% in our study population. Every adrenal incidentaloma should be investigated for the presence of phaeochromocytoma.

Bone Mineral Density Is Not Significantly Reduced in Adult Patients on Low-Dose Glucocorticoid Replacement Therapy

CONTEXT Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive glucocorticoid replacement therapy, which might cause osteoporosis. OBJECTIVES Questions addressed by this study were: 1) Is bone mineral density (BMD) reduced in PAI and CAH on lower glucocorticoid doses than previously reported? 2) Is BMD in PAI influenced by the type of glucocorticoid used? and 3) Does DHEA treatment affect BMD in PAI women? DESIGN AND PATIENTS We conducted a prospective, cross-sectional study including 81 PAI patients and 41 CAH patients. MAIN OUTCOME MEASURES BMD was measured by dual-energy x-ray absorptiometry. Serum levels of bone turnover markers, minerals, vitamins, hormones, and urinary crosslinks were measured. RESULTS PAI and CAH patients received average daily hydrocortisone doses of 12.0 ± 2.7 mg/m(2) (range, 4.9-19.1) and 15.5 ± 7.8 mg/m(2) (range, 5.7-33.7), respectively. BMD varied within the normal reference range (-2 to +2) in both cohorts. However, lower Z-scores for femoral neck and Wards region were found in CAH compared to PAI women, but not in men. Prednisolone treatment showed significant lower osteocalcin levels and lower Z-scores for lumbar spine and femoral neck compared to PAI patients on hydrocortisone. PAI women treated with DHEA had significantly lower urinary collagen crosslinks and bone alkaline phosphatase, and significantly higher Z-scores in lumbar spine and femoral Wards region compared to non-DHEA-treated women. CONCLUSIONS Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addisons women.

Delayed Diagnosis of Adrenal Insufficiency Is Common: A Cross-Sectional Study in 216 Patients

Introduction:Little information is available on patients with adrenal insufficiency (AI) in regard to complaints before diagnosis, time until correct diagnosis, false diagnosis, and professional changes due to the diagnosis. Objective:We retrospectively evaluated circumstances before and at diagnosis of AI in patients with primary and secondary AI by using established Hospital Anxiety and Depression Scale, Short Form-36 and Giessen Complaint List (GBB-24) questionnaires, and a self-established general registration form. Methods:In this cross-sectional study, questionnaire sets were available from 216 patients (primary AI, n = 99; secondary AI, n = 117). Time duration before treatment, underlying diagnoses, and disease symptoms were verified by questionnaires and review of medical records. Results regarding subjective health status (SHS) were compared with sex- and age-matched controls drawn from questionnaire-specific reference cohorts. Results:Less than 30% of woman and 50% of men with AI were diagnosed within the first 6 months after onset of symptoms. Twenty percent of patients suffered >5 years before being diagnosed. More than 67% of patients consulted at least 3 physicians, and 68% were primarily false diagnosed. The most common false diagnoses were of psychiatric and gastrointestinal origin. Overall, patients with AI showed an impaired SHS compared with controls, and patients who were diagnosed correctly within 3 months showed a significantly better SHS. Conclusions:Because of the unspecific symptoms, diagnosis is often delayed, not recognized by physicians or diagnosed falsely. An early diagnosis is necessary and might positively influence SHS in patients with AI.

Impaired subjective health status in chronic adrenal insufficiency: impact of different glucocorticoid replacement regimens.

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.

Long-term management in five cases of TSH-secreting pituitary adenomas: a single center study and review of the literature

OBJECTIVE TSH-secreting pituitary tumors (TSH-omas) are a rare cause of hyperthyroidism and account for <1% of all pituitary adenomas. Failure to recognize the presence of a TSH-oma may result in dramatic consequences such as thyroid ablation that may cause further growth in pituitary tumor. The primary goal of the treatment of TSH-omas is to remove the pituitary tumor. Medical treatment includes dopaminergic agonists or somatostatin analogs. METHODS AND RESULTS We report five cases of TSH-oma diagnosed between 1997 and 2006 and review the literature. All the patients are females with an age range from 54 to 65 years at diagnosis. Four of the five patients had at least one event of thyroid surgery due to goiter or nodule of unknown dignity. Three of the five patients had a stroke before the diagnosis of TSH-oma, probably due to hypertension, or smoking and contraceptive treatment. One patient with invasive tumor growth received stereotactic radiotherapy (and developed panhypopituitarism after operation), another patient received somatostatin analogs preoperatively and successfully underwent transsphenoidal operation. Three of the five patients received dopaminergic agonists (bromocriptine 5 mg daily or cabergoline 0.5-0.75 mg per week), because they refused surgical therapy or the tumor was stable under dopaminergic therapy. All patients have been followed-up for 2.5-8 years. A normalization of circulating thyroid hormone levels was achieved in all patients. The patient who underwent operation shows no recurrence of the disease. The other patients have a stable pituitary mass without signs of growth. CONCLUSION We report the successful long-term treatment of TSH-omas with different therapies.

Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency

OBJECTIVE Patients with adrenal insufficiency (AI) have impaired health-related quality of life (HRQoL), which is thought to be in part due to unphysiological glucocorticoid replacement therapy. The aim was to compare once-daily hydrocortisone (HC) dual-release tablet (modified-release) with conventional HC therapy regarding clinical data and HRQoL. DESIGN AND METHODS We conducted an open, prospective trial at one endocrine center. There were 15 of 26 patients with primary AI, nine of 18 patients with secondary AI, and six congenital adrenal hyperplasia patients switched to modified-release HC therapy by their own decision. We evaluated clinical outcome and disease-specific HRQoL by using AddiQoL questionnaire at baseline and at follow-up (median 202 days (85-498)). RESULTS Patients on modified-release HC (n=30) showed significant decreases in BMI (26.0±0.75-25.6±0.71, P for change=0.006) and HbA1c (6.04±0.29-5.86±0.28, P for change=0.005), whereas patients remaining on conventional HC (n=20) showed no change in these parameters (P for interaction=0.029 and 0.017 respectively). No significant change in AddiQoL score were found in the modified-release HC group (83.8 baseline and 84.9 at follow-up; P for change=0.629). In the conventional HC group, there was a significant decrease in scores (84.0 baseline and 80.9 at follow-up; P for change=0.016), with a between-treatment P for interaction of 0.066. The fatigue subscore of AddiQoL showed the same pattern with a significant decrease (P for change=0.024) in patients on conventional HC therapy (P for interaction=0.116). CONCLUSIONS Modified-release HC decreases BMI and HbA1c compared with conventional HC treatment. In addition, it seems to stabilize HRQoL over time.

Quality of life is less impaired in adults with congenital adrenal hyperplasia because of 21-hydroxylase deficiency than in patients with primary adrenal insufficiency

Objective  Current replacement regimens fail to restore well‐being in patients with primary adrenal insufficiency (PAI). Data on health‐related quality of life (HRQoL) in patients with congenital adrenal hyperplasia (CAH) are scarce, inconsistent and largely restricted to women. The objective of the study therefore was to study HRQoL in CAH because of 21‐hydroxylase deficiency in comparison with PAI and healthy controls.

Modified-release prednisone decreases complaints and fatigue compared to standard prednisolone in patients with adrenal insufficiency.

Patients with adrenal insufficiency (AI) receive first glucocorticoid replacement dose after waking, resulting in a 3-5 h delay compared to physiological secretion. Impaired quality of life (QoL) and fatigue might be due to this delayed dose scheme. Modified-release glucocorticoid preparations might have therapeutic advantages. Exploratory pilot study including 14 patients with AI was conducted in a single university center. Patients on morning dose prednisolone (5 mg) were included, switched to modified-release prednisone (5 mg) at 10 PM for 3 months, and then switched back on standard prednisolone. 3 standardized questionnaires (GBB-24, MFI, and AddiQoL) investigating complaints and fatigue were completed at baseline, after 3, and 6 months. Data regarding clinical and hormonal parameters were assessed. Modified-release prednisone showed significant improvement in one of 4 scales of GBB-24 and positive trends to better scores in 3 of 4 scales. The global score of discomfort improved significantly. The MFI showed also significant improvement in 3 of 5 scales and positive trend to better scores in 2 scales. Significant changes to better scores were seen in 4 out of 30 items of the AddiQoL. Modified-release prednisone showed decreased complaints and fatigue compared to standard prednisolone indicating importance of glucocorticoid increase in early morning hours before waking.