Type II Polyglandular Autoimmune Syndrome 

Updated: Mar 26, 2018
Author: Surendra Sivarajah, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

Polyglandular autoimmune syndrome type II (PGA-II) is the most common of the immunoendocrinopathy syndromes. It is characterized by the obligatory occurrence of autoimmune Addison disease in combination with thyroid autoimmune diseases and/or type 1 diabetes mellitus (also known as insulin-dependent diabetes mellitus, or IDDM). Primary hypogonadism, myasthenia gravis, and celiac disease also are commonly observed in this syndrome.

The definition of the syndrome depends on the fact that if one of the component disorders is present, an associated disorder occurs more commonly than in the general population. The most frequent clinical combination association is Addison disease and Hashimoto thyroiditis (Schmidt syndrome), while the least frequent clinical combination is Addison disease, Graves disease, and type 1 diabetes mellitus. The complete triglandular syndrome is sometimes referred to as Carpenter syndrome.

PGA-II occurs primarily in adulthood, usually around the third and fourth decades of life. Middle-aged women have shown an increased prevalence of PGA-II. It is associated with HLA-DR3 and/or HLA-DR4 haplotypes, and the pattern of inheritance is autosomal dominant with variable expressivity.[1, 2]

Two other related autoimmune endocrinopathies exist, namely type I and type III. The former is rare and presents in childhood. It usually consists of mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (presenting in that order). PGA-I usually is inherited in an autosomal recessive pattern, with variable inheritance; it has no HLA association and, unlike PGA-II, has an equal sex incidence. Type 1 diabetes mellitus is rare in children with PGA-I.

Type III, although ill defined, is the co-occurrence of autoimmune thyroid disease with 2 other autoimmune disorders, including diabetes mellitus type 1, pernicious anemia, or a nonendocrine, organ-specific autoimmune disorder in the absence of Addison disease.[3]

Pathophysiology

The pathogenesis of polyglandular autoimmune syndrome type II (PGA-II) is poorly understood.[4, 5] The following steps have been postulated:

  • Some degree of genetic susceptibility must exist in the individual.[6]

  • The individual is then exposed to the autoimmune trigger, which could be an environmental or intrinsic factor. The trigger mimics the molecular structure of a self-antigen. An alternative explanation is that a breakdown in normal immunologic tolerogenesis occurs.

  • Next, a subclinical phase of active production of organ-specific autoantibodies occurs.

  • This phase is followed by autoimmune activity in the respective organ, in which there is progressive glandular destruction. The individual is still asymptomatic.

  • Overt clinical disease subsequently develops when extensive organ damage, caused by the aforementioned autoimmune activity, has occurred. Evidence of this autoimmune phenomenon that may be responsible for this syndrome is based on whether the affected organs demonstrate a chronic inflammatory infiltrate composed of lymphocytes (mainly).

Some of the component diseases are associated with immune-response genes encoded by the class II HLA complex.[1] The syndrome is replete with autoantibodies reacting to target tissue-specific antigens.

Epidemiology

Frequency

United States

Approximately 14-20 people per million population are affected by polyglandular autoimmune syndrome type II. Observations have revealed, however, that the disease is much more prevalent if subclinical forms are included.

Mortality/Morbidity

To date, the mortality and morbidity rates of polyglandular autoimmune syndrome type II (PGA-II) have not been clinically estimated. The mortality and morbidity of PGA-II are believed to equal the mortality and morbidity of the individual component disorders.

Sex

The female-to-male ratio of polyglandular autoimmune syndrome type II is 3-4:1.[7]

Age

Polyglandular autoimmune syndrome type II occurs in the third or fourth decade of life.

 

Presentation

History

Polyglandular autoimmune syndrome type II ( PGA-II) consists of Addison disease plus either an autoimmune thyroid disease or type 1 diabetes mellitus associated with hypogonadism, pernicious anemia, celiac disease, and recent primary biliary cirrhosis.[8] The clinical features consist of a constellation of the individual endocrinopathies.

For type 1 diabetes mellitus, some of these clinical features closely mimic those of primary adrenal insufficiency. Note the following:

  • Symptoms - Polyuria, polydipsia, polyphagia, unexplained weight loss, intermittent blurred vision, and lethargy (may present initially with diabetic ketoacidosis and coma)

  • Signs - Depend on the severity; consist of poor skin turgor, orthostasis, and hypotension

For Hashimoto thyroiditis (chronic lymphocytic thyroiditis), note the following:

  • Symptoms - Usually nonspecific and include cold intolerance, fatigue, somnolence, poor memory, constipation, menorrhagia, myalgias, and hoarseness

  • Signs - Slow tendon reflexes, bradycardia, facial and periorbital edema, dry skin and nonpitting edema, carpal tunnel syndromes, deafness, and pericardial or pleural effusions

For Graves disease, note the following:

  • Symptoms - Heat intolerance, weight loss, weakness, palpitations, oligomenorrhea, and anxiety

  • Signs - Brisk tendon reflexes, fine tremor, proximal weakness, stare and eyelid lag, exophthalmos, atrial fibrillation, and sinus tachycardia

For Addison disease (primary adrenal insufficiency), note the following:

  • Symptoms - Anorexia, nausea, vomiting, weight loss, weakness, and fatigue

  • Signs - Chronic hyperpigmentation of creases and scars, as well as orthostatic hypotension

For celiac disease, symptoms are weight loss, steatorrhea, bloating, cramping, and malnutrition.

For pernicious anemia, symptoms are pallor, jaundice, ataxia, glossitis, impaired cognition, impaired vibratory and position sense, and impaired cognition.

Other disorders associated with PGA-II include the following:

  • Hypogonadism (usually autoimmune oophoritis) and hypopituitarism

  • Idiopathic thrombocytopenic purpura

  • Myasthenia gravis

  • Parkinson disease

  • Vitiligo

  • Alopecia

  • Seronegative arthritis

Physical

See History.

Causes

The etiology of polyglandular autoimmune syndrome type II (PGA-II) is very poorly understood. Note the following:

  • Some association has been seen between diabetes or hypothyroidism and congenital rubella infection.

  • Immune stimulation by certain dietary proteins is a possible etiologic factor.

  • Additional possibilities include genetic susceptibility and idiopathic immunopathologic dysfunction.

  • Animal models have demonstrated that cytomegalovirus-infected mice may develop PGA-II with lymphocytic infiltration of the thyroid, liver, myocardium, adrenals, pancreatic islets, and salivary glands. At this time, however, no infectious agents or noticeable immunodeficiency states have been associated with human PGA-II.

 

DDx

Diagnostic Considerations

Chromosomal disorder (45,O; trisomy 21)

Congenital rubella

Kearns-Sayre syndrome - Possibly occurring with myopathic disease with hypoparathyroidism, primary hypogonadism, type 1 diabetes mellitus, and hypopituitarism, with or without cardiac conduction defects

Myotonic dystrophy - Hypogonadism and occasionally diabetes

Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS), usually occurring in Japanese patients

Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness [DIDMOAD])

Thymoma - As many as 50% of cases occur in people older than 40 years; malignant more frequently than benign and associated with myasthenia gravis; possibly associated with Cushing disease, Graves disease, or Addison disease

Endocrine deficiency

Thyrogastric autoimmunity

Differential Diagnoses

 

Workup

Laboratory Studies

The time course of the development of organ-specific autoimmunity makes it necessary to repeatedly reevaluate patients and their families over time. Provocative and suppressive testing frequently is necessary.[9, 10]

Among patients with type 1 diabetes mellitus, thyroid autoimmunity and celiac disease coexist with sufficient frequency to justify screening. Measuring annual thyrotropin levels in individuals with type 1 diabetes mellitus is recommended as cost-effective.

Clinical history and examination suggesting evidence of more than 1 endocrine deficiency should prompt testing, to include serum autoantibody screening and an evaluation of end-organ function.

Serum autoantibodies screen - This helps to verify the autoimmune etiology of the disease and to identify persons who may later develop multi-endocrine deficiency. This test also is useful in screening asymptomatic family members who may develop autoimmune endocrine disease in the future. The screening panel includes autoantibodies to the following:

  • 21-hydroxylase

  • 17-hydroxylase

  • Thyroid peroxidase (TPO) - The antibodies may be present without the progression to overt disease. If they are positive in a patient who is hypothyroid, they are diagnostic of Hashimoto's thyroiditis. Thyroid-stimulating immunoglobulins (TSI) in patients with signs of hyperthyroidism are diagnostic of Graves disease.

  • Glutamic acid decarboxylase-65 and islet cells - The antibodies are used to screen for type 1 diabetes mellitus.

  • Antitissue transglutaminase antibodies - These are used because 2-3% of patients with type 1 diabetes mellitus have celiac disease. Other antibodies for celiac disease include immunoglobulin-A (IgA) endomysial antibodies and antigliadin antibodies.

  • Parietal cell and anti-intrinsic factor antibodies - These are used to screen for pernicious anemia.

Evaluation of end-organ function is necessary to confirm the diagnosis in patients with positive autoantibodies. Even if these antibodies are negative, still perform testing if clinical suspicion is high, because the sensitivity of these assays is not perfect. Testing—some of which certain authorities advocate be performed annually, because not all diseases manifest at the time of the initial diagnosis—is recommended as follows:

  • Gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]), and appropriate sex hormones (testosterone, estradiol) (In females who have regular menses, gonadotropins and estradiol are not necessary.)

  • TSH, free thyroxine (T4), and free triiodothyronine (T3) if necessary

  • Adrenocorticotropic hormone (ACTH) plasma cortisol level and Cortrosyn-stimulation test

  • Plasma renin activity and serum electrolytes

  • Calcium, phosphorus, magnesium, and albumin

  • Fasting blood glucose

  • Complete blood count (CBC) with mean cell volume (MCV) and vitamin B-12 levels

Imaging Studies

Perform a computed tomography (CT) scan of the adrenal glands to exclude hemorrhage and fungal infections as the cause of primary adrenal insufficiency.[5]

Perform a magnetic resonance imaging (MRI) scan of the pituitary if hypopituitarism (autoimmune hypophysitis vs other causes) is a possibility (rare).

Perform thyroid imaging (uptake and/or scan) only in patients who are hyperthyroid; in Graves disease, it shows uniform distribution and high uptake.

Procedures

If antitissue transglutaminase antibodies are present, perform a small-bowel biopsy to rule out celiac disease. The majority of patients with high levels of antitissue transglutaminase are asymptomatic.

Histologic Findings

The biopsy findings range from villi atrophy (with numerous plasma cells within the lamina propria) to almost complete disappearance of villi. These findings are not specific, but they are suggestive of celiac disease.

 

Treatment

Medical Care

Currently, the treatment of the polyendocrine autoimmune syndromes is dictated by the individual disorders. With the exception of celiac disease and Graves disease, the mainstay of treatment is primarily hormonal replacement therapy.[5] Succinct organ-specific therapies exist to treat the associated diseases, but general therapeutic considerations that are specifically related to polyglandular autoimmune syndrome type II (PGA-II) must be addressed as well.

Most of the component disorders of this syndrome have long prodromal phases that express organ-specific autoantibodies before overt disease develops.[11] Considering this, several experimental attempts have been made to intervene during this prodromal phase in an effort to forestall overt disease. Studies evaluating the use of cyclosporin A for immunosuppression in new onset type 1 diabetes mellitus have shown preservation of some residual insulin secretion. Unfortunately, the extent of beta-cell damage at diagnosis precluded long-term remission of diabetes, not to mention the multiple adverse effects of the long-term use of the drug.

Another approach currently under investigation is isohormonal therapy, a form of immunomodulatory therapy that uses the hormonal product of the affected organ to influence autoimmune activity. Such therapies are believed to cause a bystander suppression of the prevailing autoimmune activity and/or induction of immunologic tolerance to the relevant hormone, while simultaneous negative feedback of the target organ occurs.

T4 therapy can precipitate life-threatening adrenal insufficiency. However, before thyroid replacement therapy can be instituted in patients who are hypothyroid, assess adrenal function. This situation arises due to the action of thyroxine in enhancing hepatic corticosteroid metabolism. If immediate thyroid replacement is indicated, coverage with glucocorticoids can be provided and the status assessed later. A patient with both deficiencies who has glucocorticoid replacement initially may see an improvement in his/her thyroid function.

A decreasing insulin requirement in patients with type 1 diabetes mellitus can be one of the earliest indications of adrenal insufficiency or renal dysfunction. This can occur before the development of hyperpigmentation or electrolyte abnormalities.

For Hashimoto thyroiditis (Hashimoto disease), note the following:

  • Approximately 90% of hypothyroidism cases are due to Hashimoto disease.

  • Treatment of hypothyroidism remains independent of its cause. The aim is to achieve euthyroidism.

  • Comorbidity (cardiac disease and advanced age) necessitates smaller initial doses, usually 12.5-25 mcg/d. This view has been questioned by some.

  • States such as pregnancy and younger healthy people require maintenance doses, approximately 75-125 mcg/d (1.6 mcg/kg/d). Thyroid hormone requirement increases during pregnancy by about 30% from prepregnancy replacement dose.

  • Much higher doses are required in patients who are on drugs that increase the metabolism of T4 and in those who have undergone thyroidectomy secondary to thyroid cancer in an attempt to reduce potential tumorigenesis.

  • Thyroid-stimulating hormone (TSH) is used to assess the level of euthyroidism. After 6 weeks of therapy, measure plasma TSH. Adjust the dose in increments of 12-25 mcg at intervals of 6-8 weeks until TSH is normal. Thereafter, annual measurements can be taken to ensure compliance and prevent overtreatment.

For type 1 diabetes mellitus (see Diabetes Mellitus, Type 1), note the following:

  • It requires lifelong treatment with exogenous insulin.

  • A roughly estimated dose for otherwise healthy individuals is approximately 0.6-1.2 U/kg/d (35-50 U/d in adults).

  • Basal needs (insulin needed to maintain glycemic control between meals and during sleep) are estimated at around 40-50% of the dosage figure. The dietary requirement is devoted to controlling glucose after meals and accounts for the remaining percentage.

  • Various dosage regimens and types of insulin exist. The ultimate goal of treatment is to achieve persistent normoglycemia with a minimum of hypoglycemic complications.

  • The most important aspect of management is educating the patient with diabetes. Without this, the goals can never be achieved.

For pernicious anemia, note the following:

  • Replacement with cyanocobalamin is the goal of therapy.

  • A typical schedule is 1 mg IM once a day for 7 days, and then weekly for 1-2 months or until the hemoglobin is normalized. Long-term therapy is 1 mg/mo.

  • Symptomatic hypokalemia may occur within 48 hours of initiating therapy, and supplemental potassium may be needed.

  • With therapy, the reticulocytosis should rise and peak in 1 week, followed by a rising hemoglobin level in the next 6-8 weeks.

For Graves disease, note the following:

  • Antithyroid medications usually are the first line of treatment in older patients (>60 y) or in those with underlying heart disease. When euthyroidism is achieved, radioactive iodine is then administered.

  • Ablation by radioactive iodine administration is the therapy of choice by most patients (young and healthy). It is simple, highly effective, and causes no life-threatening complications.

  • Thyroidectomy is less common and can occasionally cause complications, including recurrent laryngeal nerve damage and hypoparathyroidism. In addition, the intrinsic risks of general anesthesia and surgery exist. Surgery is much safer in experienced hands.

  • The restoration of euthyroidism using antithyroid drugs takes several months. Patients are evaluated at 6-week intervals by assessing the clinical findings and serum free T4 and free T3. There is no agreement on the optimal duration of therapy, but 1-2 years is the common range.

For Addison disease, note the following:

  • Adrenal insufficiency requires replacement therapy with hydrocortisone and fludrocortisone.[12]

  • Adjust the hydrocortisone dose depending on patient's symptoms. Monitor the activity levels of plasma renin to assess the efficacy of treatment with fludrocortisone and serum electrolytes.

  • In case of concurrent illness, increase the doses of hydrocortisone.

  • In the presence of coexisting diabetes, occasionally seen in polyglandular autoimmune syndrome type I, the daily dose usually should not exceed 30 mg/d because this necessitates higher doses of insulin, and on many occasions, there is difficulty in controlling glucose levels.

  • Adrenal gland transplants have been successful in experimental rodents and humans.

  • In addition to these, vitamin and mineral replacement occasionally is needed to complement hormonal replacement.

For celiac disease, note the following:

  • Place patients on a gluten-free diet.

  • Depending on the degree of malabsorption, patients also may require iron, folate, calcium, or vitamin supplementation.

  • In patients whose conditions are severe or refractory, a trial of prednisone (10-20 mg) may be effective.

  • If symptoms persist despite this therapy, consider dietary indiscretion or the possibility of small-bowel lymphoma, and perform the appropriate radiologic examination.

Consultations

The following consultations may be helpful:

  • Endocrinologist

  • Hematologist - Pernicious anemia

  • Gastroenterologist - Celiac disease

Diet

Dietary guidelines for polyglandular autoimmune syndrome type II depend on its presentation. Such guidelines include the following:

  • If the patient is diabetic and underweight, institute a 2000-calorie (minimum) diabetic diet.

  • If the patient is overweight, institute an 1800-calorie diabetic diet, preferably with low salt, low cholesterol, and low saturated fat.

  • If Addison disease is present, institute a high-sodium, low-potassium diet until electrolytes are controlled with mineralocorticoid therapy.

  • If the patient has celiac disease, consult a dietician for a gluten-free diet.

Activity

Patients with polyglandular autoimmune syndrome type II can participate in all of their regular activities. However, inform patients that their disease could unpredictably alter their life, depending on the severity of the presentation.

In type 1 diabetes mellitus, muscular exertion reduces the requirement for insulin, and either a snack must be provided or less insulin taken before the exercise. Where possible, consistency of diet and exercise will make control more consistent.

 

Medication

Medication Summary

With the exception of antithyroid drugs for Graves disease, most medications listed here are essentially for replacement therapy.

Glucocorticoids

Class Summary

Glucocorticoids are used in the replacement therapy associated with adrenal failure. Significant trauma can acutely increase the need for such treatment.

Hydrocortisone (Hydrocortone, Hydrocort, Cortef, Hydro-Tex)

Useful in treatment of diverse group of diseases, especially autoimmune and inflammatory diseases. Used for primary adrenal failure. Has weak mineralocorticoid activity. Individualize dosing.

Thyroid hormones

Class Summary

These agents are used for thyroid replacement in hypothyroidism.

Levothyroxine (Synthroid, Levoxyl, Levothroid, Unithroid, Tirosint)

DOC due to stability, cost, lack of foreign-protein allergens, and long half-life (qd dosing). T4 converted to T3 intracellularly, and T4 administration produces both hormones. In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.

Infants and children require more T4/kg than do adults.

Dosing depends on age and comorbidity.

Antithyroid agents

Class Summary

These drugs act by inhibiting TPO-catalyzed reactions to block iodine organification and by inhibiting peripheral deiodination of T4/T3. (The last effect is seen only by propylthiouracil [PTU].)

Propylthiouracil (PTU)

Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby inhibiting thyroid hormone synthesis; inhibits T4 to T3 conversion (advantage over other agents). Ten times less active than methimazole.

Relatively safe in pregnancy and breastfeeding due to tight bond to plasma proteins.

Methimazole (Tapazole)

Inhibits thyroid hormone by blocking oxidation of iodine in thyroid gland. However, not known to inhibit peripheral conversion of thyroid hormone. Taper gradually to the minimum dose required to keep the patient clinically euthyroid and to avoid fetal hypothyroidism. Cases of fetal aplasia cutis are reported.

Antidiabetic agents

Class Summary

These agents are used for type 1 diabetes mellitus replacement.

Insulin regular human (Humulin, Novolin), NPH Insulin (Humulin, Novolin), Long-acting basal insulin analogs (detemir, glargine), Fast-acting prandial insulin analogs (lispro, aspart, glulisine).

Stimulates proper utilization of glucose by the cells and reduces blood sugar levels. Wide variety derived from pork, beef, and synthetic human derivatives. Various preparations with variable onsets of actions; shortest and quickest is lispro insulin, and longest acting is ultralente insulin. Not administered PO because becomes denatured by acid and intestinal peptidases. Can be administered IV/IM/SC. Nasal administration may be available soon, depending on required preparation.

Dosing individualized based on lifestyle, dietary compliance, infections, and surgeries.

Mineralocorticoids

Class Summary

These are employed in partial replacement therapy for primary and secondary adrenocortical insufficiency.

Fludrocortisone (Florinef)

Mineralocorticoid required for conservation of Na and renal loss of K. Maintains blood pressure and intravascular/extracellular volume.

Vitamins

Class Summary

Vitamin B-12 replacement in pernicious anemia. Megaloblastic anemia must be further evaluated to differentiate folate deficiency from vitamin B-12 deficiency, because the latter requires life-long treatment. When cyanocobalamin is deficient mainly due to malabsorption, it must be replaced via the NG route. Hydroxocobalamin is the more potent vitamin B-12 variant, because it forms a tight bond with plasma proteins and stays in circulation longer. Hydroxocobalamin may be a good complexing agent for cyanide poisoning. Possible effective antidote.

Cyanocobalamin (Crystamine, Cyomin, Crysti 1000, Nascobal)

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 is synthesized by microbes but not by humans or plants. Vitamin B-12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum.

 

Follow-up

Further Inpatient Care

Continuously screen patients who have had fewer than all 3 diseases every 1-2 years, until they are aged 50 years. This detects new disorders before overt clinical features develop. Screening should include an assessment of autoantibodies, electrolytes, thyroid function tests, liver function tests, vitamin B-12 levels, Cortrosyn-stimulation test, fasting blood glucose, plasma renin activity, CBCs, gonadotropins, and testosterone/estradiol. In females who have regular menses, gonadotropins and estradiol are not necessary.

Evaluate patients for asplenia, and administer pneumococcal and flu vaccinations.

Family members should be strongly considered for genetic counseling and should undergo necessary screening for autoimmune diseases.

All patients with adrenal insufficiency should wear emergency identification bracelets, because adrenal crises are a significant cause of preventable mortality in these individuals. Bracelets should indicate whether the patient also has diabetes, because the coexistence of adrenal failure increases the risk of hypoglycemia.

Patients committed to the lifelong use of minerals, vitamins, blood work, and hormonal replacement therapy require psychosocial support.

The mortality and morbidity rates associated with polyglandular autoimmune syndrome type II (PGA-II) are assumed to be identical to those of the component diseases when these disorders occur in isolation.

Inpatient & Outpatient Medications

Administer specific hormone replacement as necessary (eg, T4, corticosteroids, sex steroids, insulin), depending on which endocrine end-organ failures have occurred.

Complications

Complications are related to the underlying endocrine organ failure, ie, complications of diabetes in autoimmune insulitis/diabetes.

Prognosis

See Further Inpatient Care.

Patient Education

If autoimmune destruction of the pancreas occurs, provide extensive diabetes education for the patient. The same is true for the thyroid and other aspects.

The genetic predisposition of polyglandular autoimmune syndrome type II (PGA-II) requires educating other family members regarding testing.

For patient education resources, see the Endocrine System Center; Diabetes Center; Esophagus, Stomach, and Intestine Center; and Blood and Lymphatic System Center, as well as Thyroid Problems, Diabetes, Celiac Sprue, and Anemia.