Screening and Stimulation Testing for Residual Secretion of Adrenal Steroid Hormones in Autoimmune Addison's Disease
- Conditions
- Primary Adrenal Insufficiency
- Interventions
- Diagnostic Test: Baseline blood testsDevice: 30-hour ambulatory sampling of intestinal fluidDiagnostic Test: Cosyntropin stimulation testOther: Blood test
- Registration Number
- NCT03793114
- Lead Sponsor
- University of Bergen
- Brief Summary
In autoimmune adrenal insufficiency, or Addison's disease (AD), the immune system attacks the adrenal cortex. As a result, the adrenal cells producing hormones such as cortisol and aldosterone are destroyed, leaving the body with insufficient levels to meet its needs. The common perception is that upon diagnosis of Addison's disease, basically all adrenal hormone production has ceased.
There have, however, been found a few individuals who preserve some residual secretion of cortisol even years after diagnosis. The objectives of this study is to find out how common it is, and to explore if residual function have impact on patient outcome. That is, do patients with and without residual function differ when it comes to quality of life, working ability, medication dosages, and risk of adrenal crisis?
- Detailed Description
Autoimmune destruction of the adrenal cortex is the main cause of primary adrenal insufficiency (Addison's disease, AD). Autoimmune AD (AAD) becomes clinically manifest when 90 % of cortex of adrenal gland is destroyed. Current dogma says that adrenal insufficiency ultimately is complete, that is the adrenal cortex stops producing steroids altogether. However, several case reports indicate that there might be a subgroup of patients that retain some steroid production, even years after the diagnosis. This ability could be beneficial as it could protect against adrenal crises, ease medication, and leave the patient with better quality of life.
The objective of the study is to systematically assess to what extent patients with AAD have residual adrenocortical function, and to characterize this subgroup.
The study will be an open non-randomized three-stage multicenter clinical trial comprising patients from the Norwegian Registry for organ-specific autoimmune disease (ROAS), the Swedish Addison registry, and Germany. In stage 1, patients will be asked to fill out questionnaires and deliver medication-fasting samples for analyses of adrenal steroids. In addition, patients with congenital adrenal hyperplasia (CAH) and bilaterally adrenalectomized will serve as negative controls for adrenal steroids. In stage 2, AAD patients with residual steroid production will be invited to a cosyntropin stimulation test to estimate the maximum steroid output from the adrenal glands. Twenty patients with no sign of residual function will also be tested as a control group. In stage 3, AAD patients with confirmed residual function will be invited to go through a 30-hour ambulatory sampling of interstitial fluid for investigation of diurnal variation in adrenocortical hormone levels. Also, newly diagnosed AAD patients will be invited to repeated cosyntropin testing as a means of delineating the natural progression of adrenocortical failure.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 200
- Men and women with AAD, age 18-70 years old. This requires documented adrenal insufficiency and a positive test for 21-hydroxylase autoantibodies (biomarker for autoimmune cause) on at least one occasion.
- Provided written informed consent
- In case of concomitant endocrine/autoimmune diseases, the patients should be on stable adequate treatment at least the last 3 months prior to the study period.
- For Norwegian AD patients: enrolled in ROAS
- For Swedish AD patients: enrolled in the Swedish Addison registry
- Antihypertensive treatment, with the exception of doxazosin, verapamil, and moxonidine.
- Active malignant disease, severe heart, kidney or liver failure.
- Diabetes mellitus type 1.
- Pregnancy or breast feeding.
- Pharmacological treatment with glucocorticoids (except their usual cortisone or hydrocortisone replacement therapy) or drugs that interfere with cortisol and catecholamine metabolism (antiepileptics, rifampicin, St. Johns wart).
- Use of other glucocorticoid replacement medication than cortisone acetate or hydrocortisone.
- Intake of grapefruit, grapefruit juice, or and liquorice juice the last week before or during the study period.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Bilaterally adrenalectomized control group Baseline blood tests Mapping adrenal steroid profile in patients who are bilaterally adrenalectomized. Diurnal variation in residual adrenocortical hormone levels 30-hour ambulatory sampling of intestinal fluid Patients with detectable serum levels of adrenal hormones will go through a 30-hour ambulatory sampling of interstitial fluid for mapping of any diurnal variation in endogenous adrenocortical secretion. Detectable levels of adrenal hormones Cosyntropin stimulation test Patients with detectable serum levels of adrenal hormones will go through cosyntropin stimulation testing. Controls with undetectable hormone levels Cosyntropin stimulation test Twenty patients without detectable serum levels of adrenal hormones will serve as controls in cosyntropin stimulation testing. Congenital adrenal hyperplasia (CAH) control group Baseline blood tests Mapping adrenal steroid profile in patients with congenital adrenal hyperplasia (CAH) with confirmed total deficiency of 21-hydroxylase. Repeated cosyntropin testing in newly diagnosed patients Cosyntropin stimulation test Newly diagnosed patients will be invited to go through repeated cosyntropin testing to delineate the natural progression of adrenocortical failure. Cardiovascular and inflammatory biomarkers Blood test Compare cardiovascular and inflammatory biomarker profiles in patients with and without residual production of adrenocortical steroids
- Primary Outcome Measures
Name Time Method The percentage of included patients with residual secretion of cortisol and aldosterone. 1 day Percentage of included patients with detectable levels of adrenal steroid hormones.
- Secondary Outcome Measures
Name Time Method Medication-fasting basal levels of cortisol 1 day Levels in hair samples
Medication-fasting basal levels of ACTH in patients with and without residual function. 1 day Levels in urine samples
Medication-fasting basal levels of renin in patients with and without residual function. 1 day Levels in urine samples
Medication-fasting basal levels of cortisol precursors 1 day Levels in hair samples
Medication-fasting basal levels of cortisol metabolites 1 day Levels in hair samples
Medication-fasting basal levels of aldosterone precursors 1 day Levels in urine samples
Medication-fasting basal levels of aldosterone metabolites 1 day Levels in urine samples
Medication-fasting ACTH-stimulated levels of aldosterone metabolites 1 day Levels in blood samples
In patients with and without residual function, generic health-related quality of life by the Short Form (36) Health Survey 1 day The Short Form (36) Health Survey is a generic tool comprising 36 items evaluating patient reported quality of life concerning eight domains (physical functioning, role functioning physical, bodily pain, general health perception, vitality, social functioning, role functioning emotional, and mental health and general perception of change in health). Scores are expressed on a 0-100 scale with higher scores associated with better quality of life. The result of each domain is presented separately.
Medication-fasting ACTH-stimulated levels of cortisol 1 day Levels in blood samples
Medication-fasting ACTH-stimulated levels of cortisol metabolites 1 day Levels in blood samples
In patients with and without residual function: disease-specific quality-of-life 1 day Total score ranging from 30 to 120 in disease-specific quality-of-life questionnaire, Addison Quality of Life (AddiQoL). For every question, scoring is translated in points (1 = 1 point, 2 and 3 = 2 points, 4 and 5 = 3 points, 6 = 4 points) and the algebraic sum of points is calculated. A higher score reflects better health-related quality-of-life.
Medication-fasting basal levels of aldosterone 1 day Levels in urine samples
Medication-fasting ACTH-stimulated levels of aldosterone precursors 1 day Levels in blood samples
Medication-fasting adrenocorticotropic hormone (ACTH)-stimulated levels of metanephrines 1 day Levels in blood samples
Cortisol stress doses in patients with and without residual function. 1 day No. stress doses the last week
Fludrocortisone replacement doses in patients with and without residual function. 1 day Total daily dosage.
Number of adrenal crises pr. 100 patient years 1 day Number of crises pr. 100 patient years for all included patients as well as in patients with versus without residual adrenal function
Medication-fasting basal levels of metanephrines in patients with and without residual function 1 day Levels in urine samples
Medication-fasting ACTH-stimulated levels of cortisol precursors 1 day Levels in blood samples
Medication-fasting ACTH-stimulated levels of aldosterone 1 day Levels in blood samples
Cortisol replacement doses, including stress doses in patients with and without residual function. 1 day Total daily dosage
Trial Locations
- Locations (3)
Karolinska Institutet
🇸🇪Stockholm, Sweden
Haukeland University Hospital
🇳🇴Bergen, Norway
Endokrinologie in Charlottenburg
🇩🇪Berlin, Germany