**6.2 Pathogenesis**

Genetically predisposed individuals develop autoantibodies toward the 21-hydroxylase enzyme and eventually lose the ability to produce cortisol. Autoantibodies against 21 hydroxylase are present in the majority of recently diagnosed patients. Susceptibility is conferred through the genes encoding the class II Major Histocompatibility Complex. Similarly as for type 1 diabetes mellitus, there is a strong association with the DR3 haplotype. The highest risk genotype, occurring in 30% of patients with Addison's disease, is represented by DR3/4, DQ2/DQ8 and the DRB1\*0404 /DQ8-DRB1\*0301/DQ2 genotype occurs at an increased frequency in individuals with isolated AD and in those with AD and type 1 diabetes mellitus (El Fassi et al., 2007).

#### **6.3 Diagnosis**

Addison's disease is preceded by a long prodromic, asymptomatic period, followed by subtle clinical manifestations up to adrenal insufficiency. Main symptoms are persistent vomiting, anorexia, hypoglycemia, unexplained weight loss, malaise, ill-defined fatigue, muscular weakness, hypotension, and craving for salt. The most specific sign of primary adrenal insufficiency is generalized hyperpigmentation of the skin and mucosal surfaces, as a consequence of high plasma concentrations of melanocyte stimulating activity of βlipotropin, which origins from the same precursor as ACTH. Laboratory tests can aid in the diagnosis: hypoglycemia, hyponatriemia, hyperkaliemia, acidosis, high levels of ACTH and a deficiency of cortisol. Furthermore, adrenal antibodies represent a useful marker, with a higher predictive value in younger than in adult patient, being present in more than 90% of patients with autoimmune Addison disease. Antibodies are directed against steroidogenic enzymes (CYP21A2 and 21 hydroxylase) or adrenal cortex (Adrenal cortex autoantibodies, ACA). In addition, hypocorticism may cause frequent hypoglycemic events (Van den Driessche et al 2009). We recommend screening patients with type 1A diabetes, hypoparathyroidism, and polyendocrine autoimmunity for 21-hydroxylase autoantibodies. If present, yearly monitoring with an ACTH stimulation test is performed to allow early diagnosis and prevent an adrenal crisis (Aaron et al., 2008).

#### **6.4 Treatment**

Addison's disease treatment consists of urgent lifelong glucocorticoids replacement, with clear counseling about the need for stress dose steroids for illnesses and prior to surgical procedures (Aaron et al., 2008). In some cases supplementation with mineralcorticoids in mandatory.

#### **6.5 Addison's disease and type 1 diabetes**

18 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

In 1849 Thomas Addison firstly described a group of patients characterized by anemia and disease of adrenal glands. Addison's disease is an insidious, chronic disorder of the adrenal cortex resulting in decreased production of glucocorticoids, mineralocorticoids, and androgens. There is a concomitant increased secretion of ACTH from the pituitary gland aimed to stimulate the adrenal gland. In developed countries an autoimmune process is recognized as the most common etiological factor of adrenal gland insufficiency (70-90%); the second cause is tuberculosis of the adrenal gland (10 to 20%). Three clinical forms of adrenal insufficiency are recognized: Addison disease within syndromes characterized by autoimmune involvement of several organs and named Autoimmune Polyendocrine

Genetically predisposed individuals develop autoantibodies toward the 21-hydroxylase enzyme and eventually lose the ability to produce cortisol. Autoantibodies against 21 hydroxylase are present in the majority of recently diagnosed patients. Susceptibility is conferred through the genes encoding the class II Major Histocompatibility Complex. Similarly as for type 1 diabetes mellitus, there is a strong association with the DR3 haplotype. The highest risk genotype, occurring in 30% of patients with Addison's disease, is represented by DR3/4, DQ2/DQ8 and the DRB1\*0404 /DQ8-DRB1\*0301/DQ2 genotype occurs at an increased frequency in individuals with isolated AD and in those with AD and

Addison's disease is preceded by a long prodromic, asymptomatic period, followed by subtle clinical manifestations up to adrenal insufficiency. Main symptoms are persistent vomiting, anorexia, hypoglycemia, unexplained weight loss, malaise, ill-defined fatigue, muscular weakness, hypotension, and craving for salt. The most specific sign of primary adrenal insufficiency is generalized hyperpigmentation of the skin and mucosal surfaces, as a consequence of high plasma concentrations of melanocyte stimulating activity of βlipotropin, which origins from the same precursor as ACTH. Laboratory tests can aid in the diagnosis: hypoglycemia, hyponatriemia, hyperkaliemia, acidosis, high levels of ACTH and a deficiency of cortisol. Furthermore, adrenal antibodies represent a useful marker, with a higher predictive value in younger than in adult patient, being present in more than 90% of patients with autoimmune Addison disease. Antibodies are directed against steroidogenic enzymes (CYP21A2 and 21 hydroxylase) or adrenal cortex (Adrenal cortex autoantibodies, ACA). In addition, hypocorticism may cause frequent hypoglycemic events (Van den Driessche et al 2009). We recommend screening patients with type 1A diabetes, hypoparathyroidism, and polyendocrine autoimmunity for 21-hydroxylase autoantibodies. If present, yearly monitoring with an ACTH stimulation test is performed to allow early

Addison's disease treatment consists of urgent lifelong glucocorticoids replacement, with clear counseling about the need for stress dose steroids for illnesses and prior to surgical

Syndromes (APS-1 and APS-2), and Addison disease as an isolated condition.

**6. Addison's disease** 

**6.1 Background** 

**6.2 Pathogenesis** 

**6.3 Diagnosis** 

**6.4 Treatment** 

type 1 diabetes mellitus (El Fassi et al., 2007).

diagnosis and prevent an adrenal crisis (Aaron et al., 2008).

In adolescents with type 1 diabetes Addison's disease is rarely encountered, and symptoms are sometimes aspecific. Addison's disease usually follows type 1 diabetes diagnosis, being more frequently observed within the Autoimmune Polyendocrine Syndrome type 1 and type 2 (Kordonouri et al., 2009). Correct diagnosis of Addison's disease requires a high degree of clinical suspicion and since the disease is a life-threatening condition, several investigators recommend periodical screening of Addison's disease in all young patients since type 1 diabetes diagnosis (Brewer et al., 1997). In an adolescent with type 1 diabetes, Addison's disease should be suspected in case of recurrent hypoglycemic episodes, unexplained decrease of insulin requirement and improvement of metabolic control, fatigue, weight loss, hyponatriemia and hyperkaliemia. Diagnosis confirmation requires low cortisol levels after ACTH stimulation test. Screening procedures allow to detect asymptomatic children and adolescents with positive adrenal antibodies; where raised ACTH levels suggest the presence of adrenal insufficiency. Risk factors for Addison's disease in patients with type 1 diabetes include a history of other autoimmune conditions, in particular thyroid disease, and a positive family history for autoimmunity, as reported in a case series of 4 adolescents with pre-existing type 1 diabetes who developed Addison disease (Thomas et al., 2004). Three out of 4 patients showed unexplained hypoglycemia and the other one showed unawareness hypoglycemia; all cases reported unexplained improvement in diabetes control. Two out of 4 patients reported skin hyperpigmentation. In all 4 patients a positive personal and family history of other autoimmune conditions has been reported, in particular celiac and/or thyroid autoimmune diseases and Autoimmune Polyendocrine Syndrome type 2. A more recent study in 491 newly diagnosed children with type 1 diabetes aimed to define the prevalence of additional autoimmune conditions reported 1% positivity of antibodies to 21-hydroxylase, while overt Addison's disease was found only in 20% of the positive patients (Triolo et al.; 2011). Noteworthy, all young patients with type 1 diabetes and adrenal autoantibodies develop Addison's disease during the follow-up period, with a progression to overt adrenal failure much more rapid than in adults, indicating that different autoimmune responses may be evoked at different age periods (Betterle et al., 1997).

### **7. The Autoimmune Polyglandular Syndromes (APS)**

From the time of Addison's original description of his disease onwards, it has been apparent that multiple autoimmune endocrine disease can affect individual patients and their families in recognizable clinical clusters.

Twenty years ago, the autoimmune polyglandular syndromes (APS) were classified into three basic types based on the patient's age at onset, their clinical associations with specific endocrinopathies and HLA typing.

**Type I APS**, called also APECED (Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy) is a rare autosomal recessive disorder originally identified through the typical association of mucocutaneous candidiasis with Addison's disease and hypoparathyroidism. These symptoms usually constitute the first manifestation of the

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 21

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disease in early childhood; other endocrine and non-endocrine disorders can be associated: thyroiditis, autoimmune hypogonadism, hypophysitis, chronic active hepatitis, atrophic gastritis, pernicious anemia, alopecia, vitiligo and ectodermal dystrophy (Mazza et al., 2011). The disease results from the inheritance of recessive genes (AIRE gene) mapping to 21q22.3 and it is not linked to genes within the HLA-DR/DQ genetic region of chromosome 6.

**Type II APS** is more common than type 1 APS, the prevalence is 1/20,000 with a female preponderance (male/female ratio = 1/3) and has a peak incidence between the ages of 20 and 60 years, mostly in the third or fourth decade (Van den Driessche et al., 2009). It is defined by the association of Addison's disease with thyroid autoimmunity, type 1 diabetes and sometimes pernicious anemia, vitiligo and hypogonadism. Type II APS is HLAassociated (DQB1\*0302/0201), while Hashimoto's thyroiditis itself is associated with HLA-DQB1\*0301. Multiple antigens have now been identified for the component disease of type II APS ie: thyroperoxydase and thyroglobulin in Hashimoto's thyroiditis; TSH receptors I Graves' disease; insulin, GAD and IA-2 and IA-2B in type 1 diabetes mellitus; 21 hydroxylase in Addison's disease; 17 hydroxylase and SCC (all p450 enzymes) in hypogonadism; tyrosine in vitiligo; H+K+ATPase an intrinsic factor in pernicious anemia and the calcium sensing receptor (CaSR) in hypoparathyroidism. Indeed the autoantibody that reacts to CaSR does so through its external domain, suggesting that the respective autoimmunity (hypoparathyroidism) may be antibody dependent. In mice, such immune responses proceeded through a T cell helper-2 (Th2) pathway; whereas those that results in cell mediated pancreatic β-cell loss are though to occur through a Th1 pathway. It could be that APS I results from an inherited defective Th1 responsiveness resulting in uninhibited Th2 overactivity. On the other hand, APSII/III appears to results from Th1 autoimmunity, perhaps explaining why APS-I does not co-exist with APS-II or III.

CD4+ T helper (Th) cells play important roles in regulating immune responses including that of immunological tolerance to self. When these regulatory processes go away, one or more organ-specific autoimmune disease may develop. One prevailing theory developed in the mice is that immunoresponsiveness follows at least two polarized pathways. While one track (Th1) promotes cellular immune responses, the other (Th2) pathway favours antibody or allergic immunoresponsiveness. Such differentiated Th cells can be distinguished based upon their cytokine phenotypes.
