Autoimmune polyendocrine syndrome type 2 (APS-2) is more common than APS-1, predominantly affecting adults, with a higher prevalence in females compared to males. It often shows familial aggregation. Unlike APS-1, APS-2 is primarily characterized by primary adrenal insufficiency, autoimmune thyroiditis, autoimmune type 1 diabetes, and primary gonadal insufficiency. In addition, a small number of patients may also develop lymphocytic hypophysitis, myasthenia gravis, or active hepatitis.
Pathogenesis
The pathogenesis of APS-2 remains unclear, with genetic susceptibility and environmental factors playing important roles. The genetic characteristics of APS-2 are closely associated with human leukocyte antigen (HLA). The HLA genes, primarily located on the short arm of chromosome 6, are involved in immune function, with approximately 40% of the genes in this region linked to immunity. Mutations in HLA-related genes trigger organ-specific autoimmunity, mediating autoimmune inflammatory responses in multiple endocrine glands and organs, leading to glandular and cellular dysfunction.
In recent years, studies have indicated that immune checkpoint inhibitors (ICPis) may act as new triggers for APS. In cancer patients undergoing immune therapy targeting "cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)" or "programmed cell death protein-1 (PD-1)," ICPi-associated immune endocrine disorders such as hypophysitis, hypothyroidism, primary adrenal insufficiency, and diabetes have been reported.
Clinical Manifestations
Similar to APS-1, APS-2 also involves autoimmune inflammatory responses in multiple endocrine glands or non-endocrine tissues. However, unlike APS-1, APS-2 frequently manifests as autoimmune thyroiditis, primary adrenal insufficiency (Addison's disease), and autoimmune type 1 diabetes.
Autoimmune Thyroiditis
Autoimmune thyroiditis is the most common autoimmune disorder associated with APS-2, especially in adult female patients. Thyroid autoantibodies can often be detected in the serum. Chronic lymphocytic thyroiditis is the predominant subtype and typically progresses to hypothyroidism. A smaller proportion of cases present as Graves' disease, which is characterized by clinical symptoms of hyperthyroidism such as palpitations, tremors, sweating, and goiter. Some patients may also experience ocular myasthenia gravis.
Primary Adrenal Insufficiency
Similar to APS-1, APS-2 is commonly accompanied by primary adrenal insufficiency (Addison's disease). Glucocorticoid deficiency is the primary clinical manifestation, with a smaller proportion of cases involving aldosterone deficiency. Specific autoantibodies, such as anti-21-hydroxylase antibodies and anti-steroidogenic enzyme antibodies, can often be detected in the serum.
Type 1 Diabetes
Type 1 diabetes is a frequent autoimmune endocrine disorder associated with APS-2. Multiple islet cell autoantibodies, including glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase-like protein antibodies (IA-2A), and zinc transporter 8 antibodies (ZnT8A), can be found in patients. Pathological findings often reveal significant immune cell infiltration within islet cells.
Other Autoimmune Diseases
APS-2 patients may also have a variety of other autoimmune diseases, including lymphocytic hypophysitis, inflammatory bowel disease, and dermatitis herpetiformis.
Laboratory Tests and Diagnosis
The laboratory evaluation and diagnosis of APS-2 primarily rely on medical history, hormone level measurements, and autoantibody detection. Long-term follow-up is often necessary for APS-2 patients with no clear diagnosis.
Hormone Measurement
Hormone level measurement and functional evaluation of affected endocrine glands are critical for diagnosing and classifying APS-2. For APS-2 patients with multiple endocrine gland dysfunctions, hormone measurements are valuable for assessing treatment efficacy and prognosis.
Autoantibody Detection
Specific autoantibodies often emerge prior to the clinical symptoms or signs. Monitoring specific autoantibodies in plasma and glandular tissue, along with their dynamic changes, holds clinical significance for assessing glandular function, predicting potential glandular insufficiencies, and aiding in diagnosis.
Treatment
The treatment strategies for APS-2 are similar to those for APS-1 and include symptomatic management, hormone suppression (in conditions like Graves' disease with hyperfunction), and hormone replacement therapy. Most endocrine glands affected in APS-2 exhibit functional decline, necessitating timely hormone replacement therapy.