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 30-2). 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 30-3).
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 30-4). 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 30-4APS-2 AND OTHER POLYENDOCRINE DISORDER ASSOCIATIONS ||Download (.pdf) TABLE 30-4 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 30-3). 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 30-3). 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 30-3 and 30-4). 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. 8). 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. 8), thyroid (Chap. 7), gonadal (Chaps. 11 and 13), and parathyroid disease (Chap. 34). 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.
Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked disease (IPEX; OMIM 304790) is a rare X-linked recessive disorder. The disease onset is in infancy and is characterized by severe enteropathy, T1D, and skin disease, as well as variable association with several other autoimmune disorders. Many infants die within the first days of life, but the course is variable, with some children surviving for 12–15 years. Early onset of T1D, often at birth, is highly suggestive of the diagnosis because nearly 80% of IPEX patients develop T1D. Although treatment of the individual disorders can temporarily improve the situation, treatment of the underlying immune deficiency is required and includes immunosuppressive therapy generally followed by hematopoietic stem cell transplantation. Transplantation is the only life-saving form of therapy and can be fully curative by normalizing the imbalanced immune system found in this disorder.
IPEX is caused by mutations in the FOXP3 gene, which is also mutated in the Scurfy mouse, an animal model that shares much of the phenotype of IPEX patients. The FOXP3 transcription factor is expressed in regulatory T cells designated CD4+CD25+FOXP3+ (Treg). Lack of this factor causes a profound deficiency of this Treg population and results in rampant autoimmunity due to the lack of peripheral tolerance normally provided by these cells. Certain mutations may lead to varying forms of expression of the full syndrome, and there are rare cases where the FOXP3 gene is intact but other genes involved in this pathway (e.g., CD25, IL-2Rα) may be causative.
Thymomas and thymic hyperplasia are associated with several autoimmune diseases, with the most common being myasthenia gravis (44%) and red cell aplasia (20%). Graves’ disease, T1D, and Addison’s disease may also be associated with thymic tumors. Patients with myasthenia gravis and thymoma may have unique anti–acetylcholine receptor autoantibodies. Many thymomas lack AIRE expression within the thymoma, and this could be a potential factor in the development of autoimmunity. In support of this concept, thymoma is the one other disease with “frequent” development of anticytokine antibodies and mucocutaneous candidiasis in adults. The majority of tumors are malignant, and temporary remissions of the autoimmune condition can occur with resection of the tumor.
ANTI-INSULIN RECEPTOR ANTIBODIES
This is a very rare disorder where severe insulin resistance (type B) is caused by the presence of anti-insulin receptor antibodies. It is associated with acanthosis nigricans, which can also be associated with other forms of less severe insulin resistance. About one-third of patients have an associated autoimmune illness such as systemic lupus erythematosus or Sjögren’s syndrome. Therefore, the presence of antinuclear antibodies, elevated erythrocyte sedimentation rate, hyperglobulinemia, leukopenia, and hypocomplementemia may accompany the presentation. The presence of anti-insulin receptor autoantibodies leads to marked insulin resistance, requiring more than 100,000 units of insulin to be given daily with only partial control of hyperglycemia. Patients can also have severe hypoglycemia due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several patients have had spontaneous remissions. Therapy targeting B lymphocytes including rituximab, cyclophosphamide, and pulse steroids can induce remission of the disease.
INSULIN AUTOIMMUNE SYNDROME (HIRATA’S SYNDROME)
The insulin autoimmune syndrome, associated with Graves’ disease and methimazole therapy (or other sulfhydryl-containing medications), is of particular interest due to a remarkably strong association with a specific HLA haplotype. Such patients with elevated titers of anti-insulin autoantibodies frequently present with hypoglycemia. In Japan, the disease is restricted to HLA-DR4-positive individuals with DRB1*0406. Curiously, a recent report demonstrated that five out of six Caucasian patients taking lipoic acid (sulfhydryl group) who developed insulin autoimmune syndrome were primarily DRB1*0403 (which is related to DRB1*0406); the sixth was DRB1*0406. In Hirata’s syndrome the anti-insulin autoantibodies are often polyclonal. Discontinuation of the medication generally leads to resolution of the syndrome over time.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; also known as Crow-Fukase syndrome; OMIM 192240) patients usually present with a progressive sensorimotor polyneuropathy, diabetes mellitus (50%), primary gonadal failure (70%), and a plasma cell dyscrasia with sclerotic bony lesions. Associated findings can be hepatosplenomegaly, lymphadenopathy, and hyperpigmentation. Patients often present in the fifth to sixth decade of life and have a median survival after diagnosis of less than 3 years. The syndrome is assumed to be secondary to circulating immunoglobulins, but patients have excess vascular endothelial growth factor as well as elevated levels of other inflammatory cytokines such as IL1-β, IL-6, and tumor necrosis factor α. A small series of patients have been treated with thalidomide, leading to a decrease in vascular endothelial growth factor. Hyperglycemia responds to small, subcutaneous doses of insulin. The hypogonadism is due to primary gonadal disease with elevated plasma levels of follicle-stimulating hormone and luteinizing hormone. Temporary resolution of the features of POEMS, including normalization of blood glucose, may occur after radiotherapy for localized plasma cell lesions of bone or after chemotherapy, thalidomide, plasmapheresis, autologous stem cell transplantation, or treatment with all-trans-retinoic acid.
Other diseases can exhibit polyendocrine deficiencies, including Kearns-Sayre syndrome, DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, progressive bilateral optic atrophy, and sensorineural deafness; also termed Wolfram’s syndrome), Down’s syndrome or trisomy 21 (OMIM 190685), Turner’s syndrome (monosomy X, 45,X), and congenital rubella.
Kearns-Sayre syndrome (OMIM 530000) is a rare mitochondrial DNA disorder characterized by myopathic abnormalities leading to ophthalmoplegia and progressive weakness in association with several endocrine abnormalities, including hypoparathyroidism, primary gonadal failure, diabetes mellitus, and hypopituitarism. Crystalline mitochondrial inclusions are found in muscle biopsy specimens, and such inclusions have also been observed in the cerebellum. Antiparathyroid antibodies have not been described; however, antibodies to the anterior pituitary gland and striated muscle have been identified, and the disease may have autoimmune components. These mitochondrial DNA mutations occur sporadically and do not appear to be associated with a familial syndrome.
Wolfram’s syndrome (OMIM 222300, chromosome 4; OMIM 598500, mitochondrial) is a rare autosomal recessive disease that is also called DIDMOAD. Neurologic and psychiatric disturbances are prominent in most patients and can cause severe disability. The disease is caused by defects in wolframin, a 100-kDa transmembrane protein that has been localized to the endoplasmic reticulum and is found in neuronal and neuroendocrine tissue. Its expression induces ion channel activity with a resultant increase in intracellular calcium and may play an important role in intracellular calcium homeostasis. Wolfram’s syndrome appears to be a slowly progressive neurodegenerative process, and there is nonautoimmune selective destruction of the pancreatic beta cells. Diabetes mellitus with an onset in childhood is usually the first manifestation. Diabetes mellitus and optic atrophy are present in all reported cases, but expression of the other features is variable.
Down’s syndrome, or trisomy 21 (OMIM 190685), is associated with the development of T1D, thyroiditis, and celiac disease. Patients with Turner’s syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease. It is recommended to screen patients with trisomy 21 and Turner’s syndrome for associated autoimmune diseases on a regular basis.