Polyglandular autoimmune syndrome (PAS) is made up of a group of autoimmune disorders of the endocrine glands.[1] The syndrome results in failure of the glands to produce their hormones. Glandular abnormalities of the endocrine system tend to occur together; consequently, up to a quarter of patients with evidence of hypofunction in one gland have evidence of other endocrine diseases. Continue to consider other glandular hypofunction when evaluating patients with any type of endocrine hypofunction, because the risk of multiple glandular involvement is quite significant.
The concept of polyglandular failure is not new, having achieved recognition as early as in the 19th century. In 1853, Thomas Addison first described the clinical and pathological features of adrenocortical failure in patients who also appeared to have pernicious anemia (PA). In 1908, Claude and Gougerot suggested a common pathogenesis for these conditions in an article titled "Insufficance pluriglandulaire endocrinnienne." In 1926, Schmidt documented the association between adrenocortical failure and thyroiditis. Carpenter, in 1964, expanded the syndrome described by Schmidt to include insulin-dependent diabetes mellitus.
In 1980, Neufeld and Blizzard developed the first classification of polyglandular failure.[2] Neufeld and Blizzard's classification distinguishes 2 broad categories, PAS type I and PAS type II (PAS I and PAS II). An additional group, PAS type III (PAS III), was subsequently described. PAS III, in contrast to PAS I and II, does not involve the adrenal cortex. In PAS III, autoimmune thyroiditis occurs with another organ-specific autoimmune disease, but the syndrome cannot be classified as PAS I or II.
PAS III is the most common PAS in the pediatric population. In the context of PAS III, the autoimmune diseases that most frequently cluster with autoimmune thyroiditis are immune-mediated diabetes mellitus and celiac disease.[3] PAS III can be further classified into the following three subcategories:
PAS III is associated with the following diseases:
Cases of PAS III associated with a different immunological or genetic disorders have been sporadically reported. The association of PAS III with common variable immunodeficiency (CVID) in a 24-year-old patient was described by Bahceci and colleagues.[4] This patient had PAS III due to the presence of autoimmune thyroiditis, hypergonadotropic hypogonadism, and growth hormone deficiency, without adrenal or parathyroid disease. Such coexistence of PAS III and CVID may be due to autoimmunity and the association of both conditions with human leukocyte antigen (HLA).
A rare case of PAS III in monozygotic twins, in which one of the twins also had autoimmune leukopenia, was also reported,[5] as was a case of PAS III with autoimmune leukopenia.[6] In addition, a case of PAS III complicated with autoimmune hepatitis was reported from Japan.[7] Another report from Japan described a 61-year-old woman with slowly progressive type 1 diabetes mellitus associated with chronic thyroiditis, pernicious anemia, and idiopathic thrombocytopenic purpura.[8] This patient had DQA1 0102, 0103 and DQB1 0602, 0601 that were considered as type 1 diabetes–protective HLA alleles. A case reported from Poland described acquired von Willebrand syndrome in a patient with severe primary hypothyroidism associated with myasthenia gravis in the course of PAS III.[9] PAS IIIC in 12-year-old boy with generalized vitiligo, alopecia universalis, and Hashimoto thyroiditis was recently reported from Turkey, and the patient was the youngest of previously reported cases.[10]
While it is rare, growth hormone deficiency may be a component of all PAS. It has been reported more often with PSA I and PSA II. Recently, an occurrence of growth hormone deficiency was reported in an 8-year-old child who has type 1 diabetes mellitus and received iodine I 131 ablation at age 5 years for hyperthyroidism, suggesting that it could also be a component of PAS III.[11] Adult growth hormone deficiency is also reported to coexist with PAS III.[12] Ulcerative colitis and primary sclerosing cholangitis have also recently been reported as part of PSA III.[13] Association between PAS III and myasthenia gravis has been reported with both generalized myasthenia[14] and seronegative ocular myasthenia.[15] A complex case of PAS III, characterized by the association of Graves disease, autoimmune leukopenia, latent autoimmune diabetes of the adult (LADA), autoimmune gastritis, ulcerative colitis, Sjögren syndrome, and antiphospholipid syndrome was reported in 2014.[16] The prevalence of PAS III is found to be about 34% among patients with spontaneous 46XX primary ovarian insufficiency.[17] A rare coexistence of PAS IIIA and pulmonary arterial hypertension has been reported in a Japanese woman.[18]
Autoimmunity, environmental factors, and genetic factors are the 3 major factors that should be considered in the pathophysiology of PAS III.
Autoimmune disease affecting a single endocrine gland is frequently followed by impairment of other glands, resulting in multiple endocrine failure. The autoimmune pathogenesis of these disorders began to emerge in the mid-20th century. In 1956, Roitt and colleagues discovered circulating precipitating autoantibodies to thyroglobulin in patients with Hashimoto thyroiditis.
The identification of circulating organ-specific autoantibodies provided the earliest and strongest evidence for the autoimmune pathogenesis of polyglandular failure syndromes. Endocrine autoimmunities are associated with autoantibodies that react to specific antigens, whereas patients with collagen diseases synthesize immunoglobulins that recognize nonorgan-specific cellular targets, such as nucleoproteins and nucleic acids.
Cellular autoimmunity is also important in the pathogenesis of polyglandular failure syndromes. Histologic examination of the affected glands (eg, thyroid, parathyroid, ovaries, pancreatic islets, gastric mucosa) has demonstrated similar results, that is, mononuclear infiltrate composed mainly of lymphocytes, macrophages, natural killer (NK) cells, and plasma cells. The striking feature is the sparing of adjacent nontarget tissue. As the disease progresses, atrophy and fibrosis predominate.
Experimental animal models of PAS III have been described. In BioBreeding/Worcester (BB/W) rats, the frequency of chronic lymphocytic thyroiditis was remarkably increased in diabetic insulin-treated BB/W rats.[19]
Animal models have provided many of the insights into endocrine immunities. Polyglandular immunity, including gastritis, oophoritis, orchitis, and thyroiditis, could be induced in genetically susceptible mice by depleting T lymphocytes permanently or transiently. By using the model of neonatal thymectomy, it has been demonstrated that early interactions between the lymphoid system and target organs are important in the pathogenesis of autoimmunity. Furthermore, it also was demonstrated that CD4+ splenocytes from adult (but not neonatal mice) contain regulatory populations that can prevent the transfer of autoimmune endocrinopathies.
An autoimmune attack of a target organ often begins in individuals who have a genetic predisposition after an unknown precipitating event. The early process manifests by provoking autoantibody production, and it may arrest at this stage. Progressive disease is associated with secondary responses against antigens released by damaged tissue. Disease initially is detectable by observing minimal biochemical abnormalities such as elevation of trophic hormones. Organ function loss may plateau before the threshold of critical organ mass is reached, or it may progress to clinically overt disease. Early hormone replacement therapy may decelerate the destruction of surviving tissue; but, at the late stage, complete organ atrophy is inevitable.
Some authorities postulate that environmental precipitators of autoimmunity might play a role in polyglandular autoimmunity. Viral infection may exaggerate the ongoing immune response and precipitate glandular failure, although no human epidemiological studies show infection triggering polyglandular autoimmunity.
The links between congenital rubella infection, type 1 diabetes mellitus, and hypothyroidism are well known. Reovirus type I infection in susceptible mice causes type 1 diabetes mellitus and growth failure.
International comparisons show a positive correlation between type 1 diabetes mellitus prevalence and ingestion of cow milk. Circulating autoantibodies against a peptide with homology to bovine serum albumin and human islet cell surface protein have been observed in patients with IMD.
Development of PAS III after interferon-alpha therapy for hepatitis C has been described, raising the possibility of interferon-enhanced major histocompatibility complex expression, which in turn initiated the onset of organo-specific autoantibodies and the clinical manifestations of autoimmune diseases.
PAS III, as well as PAS II, is associated with HLA class II genes with apparently distinctive HLA alleles for each. The underlying non-HLA genes of PAS III remain to be further defined genetically. PAS III is often observed in individuals in the same family, suggesting that its inheritance could be an autosomal dominant trait with incomplete penetrance.[20, 21, 22, 23]
HLA-DRB1*04/DQA1*0301/DQB1*0302 is the predominant HLA haplotype associated with susceptibility in IMD. Interestingly, the HLA-DQB1*0602 allele protects against IMD, even if the HLA-DQB1*0301 or DQB1*0302 susceptibility gene is present. HLA-DQB1*0301 is the HLA haplotype frequently associated with autoimmune thyroiditis. HLA-DRB1*13 is associated with vitiligo. Alopecia areata is strongly associated with DQB1*03 and DRB1*1104, which appear to be markers of general susceptibility to alopecia areata. In addition, the frequency of HLA-DRB1*0401 and DQB1*0301 is remarkably increased among patients with alopecia totalis and those with alopecia universalis, the most extensive form of the condition.
Multigenetic involvement in the development of the individual components of PAS III has been proved. For example, IMD is linked to several loci in non-HLA genomic regions. Furthermore, autoimmune thyroiditis also is polygenic.
Family and population studies showed that the PAS IIIA has a strong genetic background. Several gene variations present in both autoimmune thyroiditis and IMD have been identified by whole genome and candidate gene approaches. The most important susceptibility genes are human leucocyte antigen (chromosome 6), cytotoxic T-lymphocyte–associated antigen 4 (chromosome 2), protein tyrosine phosphatase nonreceptor type 22 (chromosome 1), forkhead box P3 (X chromosome), and the interleukin 2 receptor alpha/CD25 gene region (chromosome 10).[24]
United States
The exact prevalence of PAS III in the United States is unknown.
International
The exact international prevalence of PAS III is unknown.
The morbidity and mortality of PAS III is determined by the individual components of the syndrome.
No racial or ethnic difference in frequency of PAS III has been reported.
PAS III is more common in females than in males.
PAS III typically is observed in middle-aged women but can occur in persons of any age.
Prognosis of PAS III depends on the individual glandular failures involved.
No systematic studies of long-term prognosis of patients with PAS III have been conducted.
Education on diet, blood glucose monitoring, insulin injections, awareness of hypoglycemic symptoms and appropriate action, and use of glucagon kits is of paramount importance in managing type 1 diabetes mellitus (see Diabetes Mellitus, Type 1).
The need for continuous monitoring and adjustment of therapy should be stressed when educating patients with IMD, autoimmune thyroiditis, and PA.
Instruct patients to watch for the symptoms of failure of other endocrine glands.
For patient education resources, see Anatomy of the Endocrine System.
The hallmark of polyglandular autoimmune syndrome (PAS) III is the absence of adrenal insufficiency. In fact, PAS III is PAS II without adrenocortical involvement (see Neufeld and Blizzard's classification in Background). Once adrenocortical insufficiency develops, such patients are reclassified as having PAS II. The involvement of multiple glands may be apparent at the time of initial presentation, but, more commonly, individual glandular failure develops sequentially. No specific sequence exists by which the individual glandular failures develop.
The clinical symptoms of PAS III are a constellation of manifestations of endocrine gland failures that comprise the syndrome.
Autoimmune thyroiditis is the characteristic of all subcategories of PAS III.
The presenting symptoms are goiter, those due to hypothyroidism, or both. Occasionally, destruction of the gland early in the process gives rise to the release of thyroid hormones, creating a transient hyperthyroid state (ie, Hashitoxicosis). When this process is complete, hypothyroidism becomes apparent.
Fatigue and depression are leading symptoms in many patients with autoimmune thyroiditis. Weight gain, cold intolerance, constipation, dry hair, sluggishness, somnolence, hoarseness, and menorrhagia also are major clinical symptoms.
Although some patients report a sensation of tightness in the neck, pain is usually not a prominent symptom. Patients may have a history of other autoimmune conditions such as inflammatory bowel disease, celiac disease, gonadal dysgenesis (Turner syndrome), and hepatitis C.
Classic symptoms of IMD are polyuria, polydipsia, and polyphagia. Polyuria is secondary to osmotic diuresis caused by hyperglycemia. Polydipsia is secondary to hyperosmolality. Polyphagia is probably secondary to deficient glucose utilization in the cells of the hypothalamic ventromedial nuclei.
Weight loss despite polyphagia is characteristic.
Blurred vision is common and also is secondary to hyperosmolality.
Paresthesia in the extremities may be present at presentation, although it is usually reversible with better glycemic control. Paresthesia is thought to be secondary to transient impairment of peripheral sensory nerve function caused by hyperglycemia.
Rapid development of insulin deficiency, usually precipitated by infection or other forms of stress, could result in diabetic ketoacidosis (DKA) as the initial presentation of type 1 diabetes mellitus. Abdominal pain, nausea, and vomiting are common in DKA, along with above symptoms. Altered mental status and rapid breathing are symptoms associated with severe DKA.
Usual presenting features include insidious onset of fatigue, weakness, lightheadedness, headache, vertigo, tinnitus, and palpitations secondary to anemia.
Vague gastrointestinal symptoms, such as anorexia or diarrhea, may be present. Sore tongue, numbness and tingling in the extremities, and difficulty with balancing may be present at onset or may develop later in the course.
Neuropsychiatric manifestations may not parallel symptoms of anemia. In addition to the above neurological symptoms, irritability, memory loss, depression, hallucinations, agitation, suicidal ideation, and sphincter disturbances are recognized manifestations.
Vitiligo is associated with many autoimmune endocrinopathies. Patients with an early age of onset are less likely to have PAS II or other endocrinopathies.
Loss of skin pigmentation in vitiligo has been linked to autoimmune destruction of melanocytes by antityrosinase and antimelanocyte antibodies. The leading symptom is loss of skin pigmentation, which is more noticeable around the mouth, eyes, nose, nipples, umbilicus, or anus. Trauma to the skin results in further loss of pigmentation (Koebner phenomenon).
Autoimmune alopecia (alopecia areata) ranges in severity from (1) small round patches of hair loss that regrow spontaneously to (2) persistent extensive patchy involvement to (3) the loss of all scalp hair (alopecia totalis) or all scalp and body hair including eyelashes, eyebrows, underarm hair, and pubic hair (alopecia universalis).
In the latter, absence of eyebrows results in perspiration trickling into the eyes; absence of eyelashes results in little protection from dust and glare. Absence of nasal hairs results in lack of protection in the nostrils or sinuses from foreign particles in the air. Spontaneous remission and recurrence are common.
Physical findings in autoimmune thyroiditis are goiter, hypothyroidism, or both. The thyroid gland is palpably enlarged in classic goitrous autoimmune thyroiditis (Hashimoto disease). The entire thyroid gland is diffusely enlarged and is firm. The surface of the thyroid gland often is bosselated, that is, characterized by numerous bosses or rounded protuberances.
Extrathyroidal signs of autoimmune thyroiditis and hypothyroidism include facial pallor; bradycardia; hypertension; delayed relaxation of deep-tendon reflexes; and nonpitting edema (myxedema) of the skin of the hands, feet, and eyelids.
Dry skin and mucous membranes may be observed secondary to fluid loss associated with osmotic diuresis.
Severe dehydration or severe DKA may lead to hypotension.
The most striking physical sign of PA is pallor.
Mild scleral icterus may be present secondary to indirect hyperbilirubinemia caused by intramedullary hemolysis.
The tongue usually is smooth, raw, and beefy.
Systolic flow murmur and tachycardia may be present secondary to anemia.
Neurological signs may vary from diminished vibration and joint position sense to gross motor, sensory, and cognitive deficits.
A marked discordance may be present between the severity of neurological signs and the degree of anemia (see History).
Vitiligo is characterized by symmetric areas of complete pigment loss, particularly affecting the periorificial areas and bony prominences.
The hairs within the patches of vitiligo often remain pigmented. However, in older lesions, the hairs also become white. Wood-lamp examination reveals more apparent chalky-white areas.
Alopecia areata causes different patterns of hair loss.
These include a localized patch of hair loss, a netlike pattern of hair loss, a serpentine pattern of hair loss that covers the periphery of the scalp similar to a serpent forming a turban over the edges of the scalp, and a diffuse form that affects the whole scalp without distinct patches.
Complications of PAS III include a constellation of complications associated with each glandular failure.
Laboratory studies to diagnose polyglandular autoimmune syndrome (PAS) III include (1) serological tests for autoantibodies, (2) assessment of end-organ function, and (3) genetic tests.
Some experts argue that measurement of levels of circulating antibodies may not be very useful, because many individuals have these antibodies without clinical manifestations. In a study by Hunger-Battefeld et al involving 139 patients with IMD, 63% of the patients were found to have 1 or more pathologically increased antibody titers associated with an autoimmune endocrine disease other than diabetes; however, only 31% of the patients presented with symptoms of this additional disease. In the study, thyropathy was the most prevalent autoimmune disease accompanying IMD. The authors recommended that patients with IMD be screened for other autoimmune endocrine diseases.[26]
Serological tests may be helpful in the following circumstances:
Some autoantibodies appear to predict the development of glandular failure. This may allow the initiation of immunomodulatory treatment before the development of overt disease.
The following list delineates autoantibodies detected in each glandular disease:
Autoimmune thyroiditis
Immune-mediated diabetes
Pernicious anemia
Mutations in the HLAD gene should be analyzed in patients with PAS III and in siblings with symptoms of component glandular diseases. HLA-DR oligotyping and HLA-DQ oligotyping by polymerase chain reaction are commercially available through Associated Regional and University Pathologists Laboratories. HLA-DR typing of loci 1 and loci 2 also is available through Specialty Laboratories.
Perform fine-needle aspiration biopsy of the thyroid gland to exclude malignancy if a suggestive nodule (ie, dominant nodule) is present or if the goiter is growing rapidly.
Histopathology of involved endocrine glands in PAS III demonstrates lymphocytic infiltration. For autoimmune thyroiditis, clumps of oxyphilic thyroid follicular cells surrounded by lymphocytes (struma lymphomatosa) are present. For vitiligo, melanocytes are absent and mild lymphocytic infiltrate is present.
Medical care of patients with polyglandular autoimmune syndrome (PAS) III includes monitoring of glandular functions for early detection of glandular failure, lifelong hormone replacement therapy for established glandular failure or failures, and familial screening. Details of different approaches of treating each component disease are beyond the scope of this article. Monitoring of glandular functions is discussed in Lab Studies.
Patients with hypothyroidism need lifelong thyroxine therapy. Thyrotropin levels should be monitored by using highly sensitive assays to maintain a euthyroid state.
Overreplacement with thyroxine may result in osteoporosis and increased risk of atrial fibrillation.
The mainstay of immune-mediated diabetes (IMD) treatment is lifelong replacement therapy with exogenous insulin injections. Monitor the progress of disease by periodic retina examination, foot examination, and measurement of glycosylated hemoglobin level and the ratio of urine microalbumin to creatinine.
The late 20th-century development of recombinant human insulin was a major breakthrough in the treatment of IMD. Intensive insulin therapy has improved the long-term outcome of the disease at the expense of frequent hypoglycemia.
Pancreatic transplantation is becoming an option but usually is reserved for patients with end-stage renal disease who already require renal transplantation.
Specific therapies aimed at suppressing the immune response of the pancreatic islet cells are being researched.
The mainstay of PA treatment is lifelong replacement therapy with parenteral hydroxocobalamin. Within 48-72 hours of the first injection, serum potassium levels drop precipitously because of rapid regeneration of red blood cells.
Hypokalemia may be severe enough to necessitate replacement therapy. Serum iron levels also drop precipitously for the same reason.
If the patient initially has a marginal iron reserve, this may halt the recovery of anemia. Some experts suggest giving a small dose of iron supplements concurrently to prevent this phenomenon.
Psychological counseling is an essential component of treatment because the disease can negatively impact self-esteem and self-image. Many treatment options are available, but results are rather disappointing.
Refer to the Medscape Reference topic Vitiligo for details of different treatment approaches, which are beyond the scope of this article.
Treatment of alopecia areata depends on the patient's age and the severity of the condition.
Refer to the Medscape Reference topic Alopecia Areata for details of different treatment approaches, which are beyond the scope of this article.
Patients with IMD require individualized dietary prescriptions to achieve therapeutic goals. Details of dietary management of IMD are beyond the scope of this article and are not discussed.
Individuals with PAS III can continue to participate in all regular activities, although individual component glandular diseases, such as IMD, can dramatically alter a patient's life.
Many approaches are being tested for prevention of each component of glandular disease. Prevention trials currently are assessing the efficacy of inducing antigen-specific immune tolerance through the intravenous or subcutaneous administration of insulin in persons at risk who have evidence of decreased beta cell mass.
Relatives of patients with IMD who are at risk for the disease can be identified. Screening of the general population for each glandular failure is associated with high false-positive rates that preclude intervention studies. Some experts propose that periodic screening for another glandular failure should be performed in patients already diagnosed with PAS III.
Patients with polyglandular autoimmune syndrome (PAS) III must undergo lifelong monitoring of hormones and/or vitamin replacement therapy to avoid the development of new glandular failures.
The goals of pharmacotherapy are to correct hormone deficiencies, prevent complications, and reduce morbidity.
Clinical Context: Rapidly inhibits the release of thyroid hormones via a direct effect on the thyroid gland and inhibits the synthesis of thyroid hormones. Iodide also appears to attenuate the cAMP-mediated effects of thyrotropin. In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.
These agents are administered for replacement of thyroid hormone in hypothyroidism.
Clinical Context: Stimulates proper use of glucose by cells and reduces blood sugar levels. Multiple forms of insulin with different time constants for activity, from very rapid onset and activity to very long sustained activity, can be used to provide glucose control.
Clinical Context: Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 synthesized by microbes but not humans or plants.
Vitamins are essential for normal DNA synthesis and for replacement therapy with vitamin B-12 in PA.