Cortisol Excess and Insufficiency

E. Arvat, A. Falorni, E., Arvat, A., Falorni, Federica Guaraldi, Giovanni Corona, Federica, Guaraldi, Giovanni, Corona

• Publisher: S. Karger
• Year: 2016
• Print ISBN: 9783318058390
• eBook ISBN: 9783318058406
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Disorders associated with cortisol excess and insufficiency, although rare, deserve the attention of the entire medical community because of high associated morbidity and mortality. Both diagnosis and management of hypo- and hypercortisolism are challenging, and disease presentation, at both clinical and laboratory level is not always definite. New tools are available for non-invasive and early diagnosis, and the choice of treatment should be tailored to each patient to improve quality of life through the regulation of the levels and rhythm of hormonal secretion, while limiting complications associated with the disease and therapies. In this new volume, top experts have contributed chapters on the pathognomonic, epidemiological, clinical, radiological, and laboratory aspects of the various disorders associated with altered cortisol secretion. They also present information on still debated standpoints on management. Cortisol Excess and Insufficiency is a valuable reference book for those wishing to have a reasoned and broad overview of the pathophysiology and management of disorders associated with hypo- and hypercortisolism.

Arvat E, Falorni A (eds): Cortisol Excess and Insufficiency.
Front Horm Res. Basel, Karger, 2016, vol 46, pp 115-132 (DOI: 10.1159/000443871)

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From Genetic Predisposition to Molecular Mechanisms of Autoimmune Primary Adrenal Insufficiency

Alberto Falorni^a · Annalisa Brozzetti^a · Roberto Perniola^b

^aSection of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, University of Perugia, Perugia, and ^bDepartment of Pediatrics - Neonatal Intensive Care, V. Fazzi Regional Hospital, Lecce, Italy

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Abstract

Autoimmune Addison's disease (AAD) is a complex disease that results from the interaction of a predisposing genetic background with still unknown environmental factors. Pathogenic variants in the autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrine syndrome type 1, of which AAD is a major disease component. Among the genetic factors for isolated AAD and autoimmune polyendocrine syndrome type 2, a key role is played by HLA class II genes: HLA-DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 are positively, and DRB1*0403 is negatively, associated with genetic risk for AAD. The MHC class I chain-related gene A (MICA) allele 5.1 is strongly and positively associated with AAD. Other gene polymorphisms contribute to the genetic risk for AAD, including CIITA (MHC class II transactivator), the master regulator of MHC class II expression, cytotoxic T-lymphocyte antigen-4 (CTLA-4), PTPN22, STAT4, PD-L1, NALP1, FCRL3, GPR174, GATA3, NFATC1, CYP27B1 and the vitamin D receptor.

© 2016 S. Karger AG, Basel

In Western countries and Japan, an autoimmune process is responsible for the destruction of the adrenocortical cells and clinical manifestations of primary adrenocortical insufficiency (PAI) in around 80-90% of cases [1]. Autoimmune PAI is also known as autoimmune Addison's disease (AAD), after the name of the physician who in 1855 described the disease and attributed it to a pathology of the adrenal glands. In AAD, autoimmune adrenalitis determines a destructive process of all three layers of the adrenal cortex, with subsequent concomitant deficiency of glucocorticoids, mineralocorticoids and adrenal androgens.

Table 1. Risk of AAD in different populations

Population	Overall risk	References
General adult population	1/7,000–1/7,500	1, 11, 12
First-degree relatives of AAD patients	1/300–1/400	1, 6–8
Patients with thyroid autoimmune diseases or T1DM	1/300–1/400	1, 6–8
Patients with POI or primary hypoparathyroidism	1/10–1/20	1, 13

The autoimmune process responsible for AAD is characterized by the appearance of circulating adrenal cortex autoantibodies (ACA), detected by indirect immunofluorescence on cryostatic tissue sections. The major adrenocortical autoantigen is the cytochrome-P450 (CYP) enzyme steroid 21-hydroxylase (21-OH): the related autoantibodies (21-OH-Ab) are present in approximately 70-80% of patients with AAD and in 85-90% of patients with autoimmune polyendocrine syndrome type 1 (APS1). Although autoantibodies to adrenocortical targets do not seem to be pathogenic, detection of 21-OH-Ab by radioimmunological or radiobinding assays is currently the gold standard marker for identifying AAD in patients with clinical signs of PAI [2, 3]. 21-OH-Ab have a high diagnostic sensitivity and specificity for AAD [4] and have been included in a comprehensive flowchart of immunological, biochemical and imaging data for accurate etiological classification of PAI cases [5].

The appearance of 21-OH-Ab in the serum of patients with other autoimmune diseases but no clinical signs of PAI configures a preclinical AAD [6-8]. It is estimated that around 1-1.5% of patients with autoimmune thyroid diseases (ATD), 1-1.5% of patients with type-1 diabetes mellitus (T1DM) and 4-5% of women with premature primary ovarian insufficiency (POI) are positive for 21-OH-Ab. In these cases, an ACTH stimulation test identifies the patients undergoing an irreversible process of organ damage that ultimately leads to overt AAD: statistically, more than 50% of the subjects with a normal response to the test will exhibit spontaneous remission of preclinical AAD, while an impaired response predicts AAD onset within a few years in 80-95% of cases [6-8].

The concomitant presence of two or more autoimmune endocrine diseases configures the autoimmune polyendocrine syndromes, which are classified according to the disease components [1]. Biochemical or clinical signs of another autoimmune disease are present in more than 60% of AAD patients, and AAD is a major component of both APS1 and autoimmune polyendocrine syndrome type 2 (APS2). APS1 is a rare, inherited disease caused by pathogenic variants in the autoimmune regulator (AIRE) gene [9]. Although no association was initially established between APS1 and genes other than AIRE, subsequent studies have shown that some disease components, AAD included, recognize specific HLA class II alleles as determinants [10]. APS2 occurs in adult subjects and is characterized by the association of AAD with ATD, T1DM or both [1]. APS2 and isolated AAD share a common predisposition with other autoimmune endocrine diseases, with a major contribution of HLA genes.

Lastly, population studies suggest a familial and individual susceptibility to AAD (table 1): disease risk is 1/7,500 in the general population [11, 12], but rises to 1/400 in first-degree relatives of AAD patients and in patients with ATD or T1DM. In women with autoimmune POI, the risk for (preclinical or clinical) AAD is 1/10-1/20 [13].

AIRE and Autoimmune Addison's Disease

As indicated, APS1 is a monogenic disease with autosomal recessive inheritance, caused by pathogenic variants in the AIRE gene, which is located on chromosome 21 and encodes for the homonymous protein, AIRE [9]. The syndrome is also known by the acronym APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) to better depict the main types of clinical manifestations [14]. Major components of APS1 are chronic mucocutaneous candidiasis, hypoparathyroidism and AAD. Clinical diagnosis requires the coexistence of two major components; only one major component is sufficient if a first-degree relative of the patient was already diagnosed with APS1 [14]. AAD occurs in about three quarters of APS1 patients, with no gender preponderance. Onset of AAD-related symptoms is usually observed at the beginning of the second decade of life. Various other endocrine and non-endocrine diseases, which include autoimmune POI in the female sex, atrophic gastritis with pernicious anaemia, ATD, T1DM, malabsorption and autoimmune hepatitis, may be observed. Dystrophies of the ectodermal tissues, such as alopecia, vitiligo, interstitial keratitis, nail dystrophy and calcifications of the tympanic membrane, complete the clinical picture [14]. Typically, sera from APS1 patients test positive for many autoantibody specificities, including those to two further adrenocortical/gonadal autoantigens, namely CYP enzymes 17α-hydroxylase and side-chain cleavage [15]. More recent studies have shown that almost all APS1 patients exhibit positivity for autoantibodies to type-1 interferons (IFN), mainly IFNα₂ and IFNω [16]. Because of their sensitivity and early appearance, it has been suggested that assay of such autoantibodies should be used in a diagnostic flowchart to identify atypical forms of APS1 [16]. In addition, autoantibodies to interleukins (IL) produced by T-helper-17 cells, such as IL-17A, IL-17F and IL-22, have been documented in APS1 patients [17].

AIRE acts as a regulator, especially activator, of gene transcription. The biophysical and biochemical properties of AIRE are connected with the domains that compose the amino-acid chain [18]. At the N-terminal end of the molecule, the homogeneously staining region or caspase-recruitment domain is responsible for the intracellular compartmentalization of AIRE, mediates its homomerization and is presumably implied in proapoptotic activity. The middle SAND domain contains several amino-acid basic groups, which could be engaged in electrostatic interaction wi...

Table of contents

• Cover Page
• Front Matter
• Pseudo-Cushing - A Clinical Challenge?
• Cushing's Syndrome: Where and How to Find It
• Subclinical Hypercortisolism: How to Deal with It?
• Etiopathogeny of Primary Adrenal Hypercortisolism
• Metabolic Alterations and Cardiovascular Outcomes of Cortisol Excess
• Skeletal Fragility in Endogenous Hypercortisolism
• Cortisol Excess and the Brain
• Update on Hypercortisolism Therapy
• Is Adrenal Insufficiency a Rare Disease?
• From Genetic Predisposition to Molecular Mechanisms of Autoimmune Primary Adrenal Insufficiency
• From Appearance of Adrenal Autoantibodies to Clinical Symptoms of Addison's Disease: Natural History
• Is Diagnosis and Subclassification of Adrenal Insufficiency as Easy as It Looks?
• Secondary Adrenal Insufficiency: Where Is It Hidden and What Does It Look Like?
• Quality of Life and Life Expectancy in Patients with Adrenal Insufficiency: What Is True and What Is Urban Myth?
• Congenital Adrenal Hyperplasia: Unresolved Issues
• Adrenal Insufficiency Therapy: How to Keep the Balance between Good Quality of Life and Low Risk for Long-Term Side Effects?
• Author Index
• Subject Index