APS-2 (OMIM 269200) is more common than APS-1 with a prevalence of 1 in 100,000. It has a gender bias and occurs more often in female patients with a ratio of at least 3:1 compared to male patients. In contrast to APS-1, APS-2 often has its onset in adulthood with a peak incidence between 20 and 60 years of age. It shows a familial, multigenerational heritage (Table 409-2). The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2: primary adrenal insufficiency (Addison’s disease; 50–70%), Graves’ disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism. Frequently associated autoimmune conditions include celiac disease (3–15%), myasthenia gravis, vitiligo, alopecia, serositis, and pernicious anemia. These conditions occur with increased frequency in affected patients but are also are found in their family members (Table 409-3).
The overwhelming risk factor for APS-2 has been localized to the genes in the human lymphocyte antigen complex on chromosome 6. Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both HLA-DR3 and HLA-DR4. Other class I and class II genes and alleles, such as HLA-B8, HLA-DQ2 and HLA-DQ8, and HLA-DR subtype such as DRB1*0404, appear to contribute to organ-specific disease susceptibility (Table 409-4). HLA-B8- and HLA-DR3-associated illnesses include selective IgA deficiency, juvenile dermatomyositis, dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenia purpura, hypophysitis, metaphyseal osteopenia, and serositis.
TABLE 409-4APS-2 and Other Polyendocrine Disorder Associations ||Download (.pdf) TABLE 409-4 APS-2 and Other Polyendocrine Disorder Associations
|Disease ||HLA Association ||Initiating Factor ||Mechanism ||Autoantigen |
|Graves’ Disease ||DR3 || |
|Antibody ||TSH receptor |
|Myasthenia gravis ||DR3, DR7 || |
|Antibody ||Acetylcholine receptor |
|Anti-insulin receptor ||? ||SLE or other autoimmune disease ||Antibody ||Insulin receptor |
|Hypoparathyroidism ||? ||? ||Antibody ||Cell surface inhibitor |
|Insulin autoimmune syndrome ||DR4, DRB1*0406 || |
|Antibody ||Insulin |
|Celiac disease ||DQ2/DQ8 ||Gluten diet ||T cell ||Transglutaminase |
|Type 1 diabetes || |
|T cell ||Insulin, GAD65, IA-2, ZnT8, IGRP |
|Addison’s disease || |
|Unknown ||T cell || |
|Thyroiditis || |
|T cell || |
|Pernicious anemia ||? ||? ||T cell || |
|Vitiligo ||? || |
|? ||Melanocyte |
|Chromosome dysgenesis–trisomy 21 and Turner’s syndrome ||DQA1*0301 ||? ||? ||Thyroid, islet, transglutaminase |
|Hypophysitis ||? ||Pit-1, TDRD6 ||? ||Pituitary, Pit-1 |
| || || || || |
Several other immune genes have been proposed to be associated with Addison’s disease and therefore with APS-2 (Table 409-3). The “5.1” allele of a major histocompatibility complex (MHC) gene is an atypical class I HLA molecule MIC-A. The MIC-A5.1 allele has a very strong association with Addison’s disease that is not accounted for by linkage disequilibrium with DR3 or DR4. Its role is complicated because certain HLA class I genes can offset this effect. PTPN22 codes for a polymorphism in a protein tyrosine phosphatase, which acts on intracellular signaling pathways in both T and B lymphocytes. It has been implicated in T1D, Addison’s disease, and other autoimmune conditions. CTLA4 is a receptor on the T cell surface that modulates the activation state of the cell as part of the signal 2 pathway. Polymorphisms of this gene appear to cause downregulation of the cell surface expression of the receptor, leading to decreased T cell activation and proliferation. This appears to contribute to disease in Addison’s disease and potentially other components of APS-2. Allelic variants of the IL-2Rα are linked to development of T1D and autoimmune thyroid disease and could contribute to the phenotype of APS-2 in certain individuals.
When one of the component disorders is present, a second associated disorder occurs more commonly than in the general population (Table 409-3). There is controversy as to which tests to use and how often to screen individuals for disease. A strong family history of autoimmunity should raise suspicion in an individual with an initial component diagnosis. The development of a rarer form of autoimmunity, such as Addison’s disease, should prompt more extensive screening for other linked disorders compared to the diagnosis of autoimmune thyroid disease, which is relatively common.
Circulating autoantibodies, as previously discussed, can precede the development of disease by many years but would allow the clinician to follow the patient and identify the disease onset at its earliest time point (Tables 409-3 and 409-4). For each of the endocrine components of the disorder, appropriate autoantibody assays are listed and, if positive, should prompt physiologic testing to diagnose clinical or subclinical disease. For Addison’s disease, antibodies to 21-hydroxylase antibodies are highly diagnostic for risk of adrenal insufficiency. However, individuals may take many years to develop overt hypoadrenalism. Screening of 21-hydroxylase antibody–positive patients can be performed measuring morning ACTH and cortisol on a yearly basis. Rising ACTH values over time or low morning cortisol in association with signs or symptoms of adrenal insufficiency should prompt testing via the cosyntropin stimulation test (Chap. 406). T1D can be screened for by measuring autoantibodies including anti-insulin, anti-GAD65, anti-IA-2, and anti-ZnT8. Risk for progression to disease can be based on the number of antibodies, and in some cases the titer (insulin autoantibody), as well as other metabolic factors (impaired oral glucose tolerance test). National Institutes of Health–sponsored trial groups such as Type 1 Diabetes TrialNet are screening first- and second-degree family members for these autoantibodies and identifying prediabetic individuals who may qualify for intervention trials to change the course of the disease prior to onset.
Screening tests for thyroid disease can include anti–thyroid peroxidase (TPO) or anti-thyroglobulin autoantibodies or anti-TSH receptor antibodies for Graves’ disease. Yearly measurements of TSH can then be used to follow these individuals. Celiac disease can be screened for using the anti–tissue transglutaminase (tTg) antibody test. For those <20 years of age, testing every 1–2 years should be performed, whereas less frequent testing is indicated after the age of 20 because the majority of individuals who develop celiac disease have the antibody earlier in life. Positive tTg antibody test results should be confirmed on repeat testing, followed by small-bowel biopsy to document pathologic changes of celiac disease. Many patients have asymptomatic celiac disease that is nevertheless associated with osteopenia and impaired growth. If left untreated, symptomatic celiac disease has been reported to be associated with an increased risk of gastrointestinal malignancy, especially lymphoma.
The knowledge of the particular disease associations should guide other autoantibody or laboratory testing. A complete history and physical examination should be performed every 1–3 years including CBC, metabolic panel, TSH, and vitamin B12 levels to screen for most of the possible abnormalities. More specific tests should be based on specific findings from the history and physical.
With the exception of Graves’ disease, the management of each of the endocrine components of APS-2 involves hormone replacement and is covered in detail in the chapters on adrenal (Chap. 406), thyroid (Chap. 405), gonadal (Chaps. 411 and 412), and parathyroid disease (Chap. 424). As noted for APS-1, adrenal insufficiency can be masked by primary hypothyroidism and should be considered and treated as discussed above. In patients with T1D, decreasing insulin requirements or hypoglycemia, without obvious secondary causes, may indicate the emergence of adrenal insufficiency. Hypocalcemia in APS-2 patients is more likely due to malabsorption than hypoparathyroidism.
Immunotherapy for autoimmune endocrine disease has been reserved for T1D, for the most part, reflecting the lifetime burden of the disease for the individual patient and society. Although several immunotherapies (e.g., modified anti-CD3, rituximab, abatacept) can prolong the honeymoon phase of T1D, none has achieved long-term success. Active research using new approaches and combination therapy may change the treatment of this disease or other autoimmune conditions that share similar pathways. Furthermore, treatment of subclinical disease diagnosed by the presence of autoantibodies may provide a mechanism to preempt the development of overt disease and is the subject of active basic and clinical research.