What is Autoimmune Polyglandular Syndrome (APS)?

From the Guidelines

Autoimmune polyglandular syndrome (APS) is a group of disorders that requires immediate attention to prevent life-threatening complications, and treatment should focus on hormone replacement therapy for each affected gland, with hydrocortisone and fludrocortisone being essential for patients with adrenal insufficiency, as recommended by the consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency 1.

Diagnosis and Treatment

The diagnosis of APS involves identifying the specific endocrine glands affected and the underlying cause of the disorder. According to the consensus statement, the aetiology of primary adrenal insufficiency (PAI) should be ascertained starting with the measurement of serum 21-hydroxylase (anti-adrenal) autoantibodies 1.

• Treatment of APS focuses on replacing the deficient hormones, with the goal of restoring normal endocrine function and preventing long-term complications.
• Patients with adrenal insufficiency require hydrocortisone (typically 15-25 mg daily in divided doses) and sometimes fludrocortisone (0.05-0.2 mg daily) for mineralocorticoid replacement, as recommended by the consensus statement 1.
• Hypothyroidism is treated with levothyroxine (typically starting at 1.6 mcg/kg/day).
• Type 1 diabetes requires insulin therapy tailored to the individual.
• Hypoparathyroidism is managed with calcium supplements and active vitamin D (calcitriol 0.25-2 mcg daily).

Monitoring and Education

Regular monitoring of hormone levels is essential to ensure that the treatment is effective and to prevent long-term complications.

• Patients should wear medical alert identification and carry emergency medications, such as hydrocortisone, in case of an adrenal crisis.
• Patients need education about stress dosing of steroids during illness, as well as how to manage their condition and prevent complications, as emphasized by the consensus statement 1.

Underlying Cause

The underlying cause of APS involves genetic predisposition leading to T-cell-mediated autoimmunity against specific antigens in endocrine tissues.

• Early diagnosis is crucial as untreated endocrine deficiencies can be life-threatening, particularly adrenal crisis which requires immediate treatment with hydrocortisone 100 mg IV and fluid resuscitation, as recommended by the consensus statement 1.
• The diagnosis of APS-1 should be considered in children and young persons presenting with PAI and other diagnostic clinical manifestations, such as hypoparathyroidism and candidiasis, and can be confirmed by the presence of anti-interferon omega antibodies or mutational analysis of the AIRE gene 1.

From the Research

Definition and Diagnosis of Autoimmune Polyglandular Syndrome

• Autoimmune polyglandular syndrome (APS) is a rare disorder characterized by the simultaneous or sequential dysfunction of multiple endocrine or non-endocrine glands 2.
• APS type 1 (APS-1) is defined by the presence of at least two of the following conditions: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency 2, 3.
• A clinical diagnosis of APS-1 is typically based on the presence of these criteria, while genetic testing can also be used to confirm the diagnosis 3.

Clinical Features and Management

• APS-1 is associated with a wide range of chronic and debilitating complications, making early diagnosis and management challenging 2.
• Managing APS-1 is difficult due to its complexity, especially the intricate relationships within manifestations and genetic mutations 2.
• Treatment for APS-1 typically involves oral calcium and calcitriol for hypoparathyroidism, and oral hydrocortisone and fludrocortisone for Addison's disease 3.
• Hormonal induction of secondary sexual characteristics may also be necessary for patients with hypogonadism 3.

Autoimmune Polyglandular Diseases

• Autoimmune polyglandular diseases (APD) are defined as the presence of two autoimmune-induced endocrine failures 4.
• Regular screening for subclinical endocrinopathies is necessary to detect APD at an early stage, reducing the risk of complications and improving prognosis 4.
• Familial clustering is high in patients with APD, and first-degree relatives should be regularly screened for autoimmune endocrinopathies 4.

Types of Autoimmune Polyglandular Syndrome

• APS type 2 (APS-2) is characterized by the combination of autoimmune adrenal insufficiency and autoimmune thyroid disease and/or type 1 diabetes mellitus 5.
• APS-2 has a different pathogenic mechanism than APS-1, involving alleles of human leukocyte antigens (HLAs) that determine the targeting of specific tissues by autoreactive T cells 6.
• IPEX syndrome is a rare disorder characterized by mutations in the forkhead box P3 (FOXP3) gene, leading to severe autoimmunity and immune deficiency 6.