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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Residual adrenocortical function in patients with autoimmune Addison`s disease

Alternative title: Bevart restproduksjon av binyrebarkhormoner ved autoimmun Addisons sykdom

Awarded: NOK 9.6 mill.

rimary adrenocortical insufficiency (Addison's disease) is a rare, but potentially lethal endocrine disorder. In spite best practice treatment, many patients experience reduced health and quality of life. Addison's disease is usually caused by autoimmune destruction of the adrenal cortex, and it has been assumed that the patients' ability to produce adrenocortical hormones is abolished once the diagnosis is made. However, we and others have discovered individuals with detectable residual adrenocortical function, even years after clinical diagnosis. How common is residual adrenocortical function in autoimmune Addison's disease (AAD)? To answer this, we have conducted a clinical study on 192 patients with AAD in Norway, Sweden, and Germany. We defined residual function as measurable levels of cortisol and/or aldosterone in addition to their respective precursor hormones in medication fasting morning blood samples. We were surprised to find that residual function was present in one third even years after the diagnosis. Residual function was more common, but not limited to patients with shorter disease duration. There was a clear male preponderance of patients with residual production, even though women constituted the majority of the study cohort. We did not, however, find any statistically significant associations between residual function and medication dosages, quality of life, or frequency of adrenal crises. The study was published in May 2020 in Journal of Clinical Endocrinology Metabolism. We then investigated the possible clinical and physiological consequences of the residual function. Both cortisol from the adrenal cortex and catecholamine from the adrenal medulla are important stress hormones, and normally these hormones influence each other's production and function. The adrenal medulla is usually preserved in Addison's disease, and we therefore investigated whether there are differences in the stress response of the adrenal medulla in patients with and without residual function. We did this by measuring the level of catecholamine in serum in 50 patients with and 20 patients without residual function before and after a stimulation test of the adrenal cortex (synacthen test). We found that even low levels of self-produced cortisol affected the level of catecholamines in Addison's disease, but that the stimulation test did not lead to a further increase. The study was published in spring 2023 in the Journal of Clinical Medicine. Furthermore, we have mapped differences in 177 biomarkers for cardiovascular disease and inflammation in Addison's patients with and without residual function compared to healthy controls. It is known that the patient group has poorer metabolic health, a higher incidence of heart disease such as myocardial infarction and a generally increased need for drugs associated with cardiovascular diseases, but little is known about the possible pathomechanisms. We identified 19 biomarkers with significantly changed levels in patients compared to healthy controls. However, there was no difference in biomarker profile between patients with and without residual production. One marker (receptor for advanced glycosylated end products) was associated with the occurrence of adrenal crises and quality of life in the patients. In patients without residual production of cortisol, the level of two biomarkers (programmed cell death ligand 2 and leptin) fell after a stimulation test of the adrenal cortex with ACTH, and thus perceived as a direct effect of ACTH and independent of cortisol. The study is under peer review in the European Journal of Endocrinology (revised version submitted). Moreover, to estimate the total cortisol exposure we have collected hair samples from patients. The cortisol content of hair reflects the total cortisol exposure over time. In a few selected patients, we have sampled subcutanous fluid continuously throughout two consecutive days, the first day with and the second day without replacement medication. This technique enables us to map the pulsatile secretion of adrenocortical hormones compared to healthy individuals. Preliminary data suggest that the secretion of cortisol follows the same pattern in patients with residual function as in healthy, including a clear early morning rise evident before any replacement medication was taken In addition to the clinical studies, we have established patient specific urine derived stem cell lines and are working on a protocol to differentiate them into adrenocortical-like cells. Steroidogenic genes are upregulated in differentiated cells compared to undifferentiated cells. In parallel, we are expanding autoreactive autoreactive lymphocytes from the same patients to establish an innovative co-culture model with differentiated adrenocortical-like cells.

Studier fra England tyder på at restproduksjon kan være forutsetning for å lykkes med regenerativ behandling: understreker nytten av å kartlegge forekomsten. Resultatene peker på den heterogene utviklinga av Addisons sykdom, også etter diagnosen er satt og behandling startet De siste årene har flere studier meldt om kjønnsspesifikke forskjeller i binyrebark-anatomi og -fysiologi, men også risiko for og forløp ved sykdommer i binyrebarken. Dette prosjektet har bidratt med data som understøtter dette: signifikant overvekt av menn med restfunksjon, og avvikende biomarkør-profil hos kun kvinner med Addison sammenlignet med kvinnelige kontroller og ingen forskjell mellom menn med Addison og mannlige kontroller Prosjektet har også identifisert mulige kliniske og fysiologiske konsekvenser av restproduksjon ved å vise at selv lave nivåer av egenprodusert kortisol påvirker katekolaminnivåene hos pasienter med Addison Styrket forskningssamarbeid nasjonalt og internasjonalt: en viktig forutsetning for å lykkes med forskning på sjelden sykdom

Autoimmune Addison’s disease (AAD) is caused by destruction of the adrenal glands by the body’s immune system. AAD is rare (about 200 per million inhabitants), more common in women than in men, and also affects children. Despite best practice replacement therapy with corticosteroids many patients experience reduced health-related quality of life (HRQoL) and increased mortality and morbidity. It is assumed that all adrenocortical tissue is destroyed by autoreactive immune cells, leaving replacement therapy with steroids as the only viable treatment option. However, anecdotal reports and our own observations indicate that a subgroup of patients retain a certain residual steroid producing capacity. Furthermore, emerging evidence suggest that adrenal stem cells located under the adrenocortical capsule have the ability to differentiate into new steroid-producing cells. Building on these observations, our aim is to investigate the frequency of residual adrenocortical steroid production using ultra-sensitive mass spectrometry methods. The clinical implications of residual steroid production will be mapped in terms of medication, HRQoL and complications (adrenal crises, infections, cardiovascular morbidity, and bone health) in close collaboration with patient representatives. In parallel the genetic and immunological variants of those with and without residual function will be defined to generate clues as to the etio-pathogenic mechanisms involved in AAD and to define biomarkers of residual function. Finally we will perform an exploratory trial combining trophic stimulation by adrenocorticotrophic hormone (ACTH) and immunomodulation (e.g. by rituximab) to revive adrenal function. The results of the project will not only help patients with this rare disorder, but will also increase our understanding of the pathogenesis of autoimmune diseases in general and could potentially lead to novel therapeutic strategies for treating common autoimmune disorders.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering