eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

Polyglandular Autoimmune Syndrome, Type I

Saleh A Aldasouqi, MD, FACP, FACE, Assistant Professor of Medicine, Associate Program Director, Department of Medicine, Division of Endocrinology, Michigan State University College of Human Medicine
Olakunle PA Akinsoto, MD, MB, BCh, Consulting Staff, Family Health Center, Jacksonville Medical Center; Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University

Updated: Jan 7, 2009

Introduction

Background

Polyglandular autoimmune (PGA) syndromes (otherwise known as polyglandular failure syndromes) are constellations of multiple endocrine gland insufficiencies. Other descriptive terminologies, such as autoimmune polyendocrine syndrome (APS), also are used in the literature. In the classification of these syndromes, Roman numerals (eg, I and II) and Arabic numbers (eg, 1 and 2) have been variably used in the literature. For the purpose of consistency in this article, the term PGA and Roman numerals will be used.

Essentially, 2 types of PGA exist, type I and the more common type II, also known as Schmidt syndrome. A third type (type III), which occurs in adults, has been described. Type III does not involve the adrenal cortex, but it includes 2 of the following: thyroid deficiency, pernicious anemia, type 1A diabetes mellitus, vitiligo, and alopecia. Other disorders also have been described in association with the PGA syndromes; pulmonary hypertension in association with PGA syndrome type II (PGA-II) is one example.¹

Historically, the interest in these syndromes began in the 19th century and essentially focused on the adrenal cortex. In 1849, Thomas Addison first described the clinical and pathologic features of adrenocortical failure in patients who also appeared to have coexisting pernicious anemia. Between 1849 and 1980, geneticists, immunologists, and endocrinologists generated a wealth of new information concerning the pathogenesis of the PGA syndromes and their component disorders.

In 1929, Thorpe and Handley recognized the association of mucocutaneous candidiasis with glandular failure, and case reports and case series have since appeared in the international literature. In 1981, Neufeld and colleagues distinguished 2 major PGA syndromes, and other authors subsequently began to add to our knowledge of these conditions.² In 2004, Eisenbarth and Gottlieb extended the discussion on the classification of these syndromes.³ While they acknowledged the system that was adopted by the so-called splitters, dividing the syndromes into 4 subtypes (I, II, III, IV), Eisenbarth and Gottlieb recommended the system adapted by the "lumpers." The latter system "lumps" the syndromes into just 2 types, I and II. Finally, according to Eisenbarth and Gottlieb, the term polyendocrine is a misnomer, because these syndromes include a number of nonendocrine disorders.

PGA-I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or as Whitaker syndrome, is associated with candidiasis, hypoparathyroidism, and adrenal failure⁴ (although PGA-I without mucocutaneous candidiasis has been reported in an adolescent⁵ ). A syndrome with these features was first described in 1946. It is a rare disorder, with sporadic autosomal recessive inheritance.

Pathophysiology

The 3 main types of autoantibodies are directed to the surface receptor molecules, intracellular enzymes, and secreted proteins, such as hormones. Their pathogenic relevance is still unclear, and even measuring levels of these autoantibodies against endocrine glands or their components does not appear to be useful, because such antibodies may persist for years without the patient developing endocrine failure. Their primary function is to differentiate autoimmune causes and infectious/iatrogenic causes of endocrine insufficiency.

With regard to genetic susceptibility, PGA-I is unique among autoimmune endocrine disorders, because it has no HLA antigen association. However, an increased frequency of HLA-A28 and HLA-A3 has been documented in PGA-I, more so than in normal controls. The genetic locus responsible for the disease has been localized to the short arm of chromosome 21 near markers D21s49 and D21s171 on band 21p22.3. A Finnish study concluded that the mutation R257X is responsible for 82% of cases.⁶

A monogenic mutation of AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs, is believed to be the likely pathogenic paradigm for PGA-I.⁷

Studies on young, thymectomized mice have contributed significantly to the understanding of the pathophysiology of PGA-I, as neatly illustrated by Eisenbarth and Gottlieb in a 2004 review article.³

Frequency

United States

In North America, polyglandular autoimmune (PGA) syndrome, type I, is extremely rare, and only scattered US case reports have been published. Most of the published literature has come from Europe, where the disease clusters in certain populations (see International frequency, below). Frequency, therefore, is not well documented in the United States; the mixed ethnic makeup of the US population may explain the low rate of case clustering. The 2 largest case series from North America were published by Neufeld and colleagues in 1981 and by Heino and coauthors in 1999.^2,8 In the latter report, 16 patients were described, including 13 white patients, 1 Hispanic individual, 1 Middle Eastern patient, and 1 Asian person.

International

Polyglandular autoimmune (PGA) syndrome, type I, is a very rare disorder; it clusters in certain homogeneous ethnic populations due to consanguineous marriages and/or clustering of descendants of common family founders. These populations include special groups of Finns, Sardinians, and Iranian Jews. Less frequent clustering has been reported from northern Italy, northern Britain, Norway, and Germany. Scattered case reports from various countries around the world have been published. The highest number of patient groups has notably been reported in Finland, in successive case series over the last few decades. The prevalence of PGA-I in Finland has been estimated to be 1 case per 25,000.⁶ Known frequencies in other ethnic groups include 1 case per 14,400 in Sardinians and 1 case per 9,000 in Iranian Jews.^9,10

Mortality/Morbidity

The mortality and morbidity associated with polyglandular autoimmune (PGA) syndrome, type I, appear to be equivalent to the individual components of the syndrome. Certainly morbidity and mortality can be reduced with improved case findings in relatives of index cases. In individual cases, early detection of life-threatening complications, such as adrenal crisis, hypocalcemia, and sepsis, is prudent.

Race

As discussed in Frequency, ethnic clustering of polyglandular autoimmune (PGA) syndrome, type I, has been observed in certain ethnic populations. Sporadic cases reported around the world have most likely been caused by various isolated mutations, many of which have been identified.

Sex

The female-to-male ratio for polyglandular autoimmune (PGA) syndrome, type I, ranges from 0.8:1 to 1.5:1, as reported in earlier case series. Figures from 2003 indicate that this ratio is between 0.8:1 and 2.4:1, indicating some tendency toward female preponderance.¹¹ A sporadic report from Italy, by Iannello and colleagues, showed a rather exclusive female preponderance in an X-linked inheritance fashion.¹²  In reports from around the world, however, autosomal recessive inheritance has been found to be the genetic mode of transmission in most families.

Age

Polyglandular autoimmune (PGA) syndrome, type I, usually occurs in children aged 3-5 years or in early adolescence, but it always occurs by the early part of the third decade of life. A general trend has been noted in the order of appearance of the 3 major systemic manifestations, eg, candidiasis, hypoparathyroidism, and Addison disease. However, that is not always the case, and decades may pass before the appearance of newer syndromic components. Therefore, lifelong follow-up is prudent for early detection of additional components. This cannot be overemphasized, because unrecognized hypoparathyroidism or adrenal insufficiency can be life-threatening.

Clinical

History

• Overview of clinical features
  • The 3 major components of polyglandular autoimmune (PGA) syndrome, type I, are (1) chronic mucocutaneous candidiasis, (2) hypoparathyroidism, and (3) autoimmune adrenal insufficiency.
  • The presence of all 3 components is not required to make a diagnosis; at least 2 components have to be present in an individual. Additional manifestations, including, among others, type 1A diabetes (documented autoimmune etiology), hypogonadism, pernicious anemia, malabsorption, alopecia, and vitiligo, may be present as well.
  • The first manifestation usually occurs in childhood, and the complete evolution of the 3 main diseases takes place within the first 20 years of life. Accompanying diseases continue to appear at least until the fifth decade of life.
  • Candidiasis usually is the first clinical manifestation, most often presenting in people younger than 5 years. Hypoparathyroidism occurs next, usually in people younger than 10 years. Lastly, Addison disease occurs in people younger than 15 years.
  • Overall, the 3 components occur in fairly precise chronological order, and they are present in roughly 40% of cases. As mentioned earlier, however, careful follow-up is mandatory to watch for the more dreadful manifestations, eg, adrenal insufficiency, regardless of the reportedly expected pattern of appearance.
  • The probability that multiple components of the disease will occur depends on how early the symptoms appear.
  • In a case of PGA-I reported by Bhansali and colleagues, no candidiasis was noted in an East Indian boy aged 16 years.⁵
• Mucocutaneous candidiasis
  • This condition usually occurs earliest and is the most common of the 3 main diseases of PGA-I.
  • Assess any young person with moniliasis for a possible state of T-cell deficiency and PGA-I.
  • Between 50 and 100% of patients with PGA-I develop a recurrent monilial infection. Most of the lesions are limited to the skin (usually <5% of surface area), nails, and oral and anal mucosa.¹³ Esophageal involvement may be complicated by strictures and stenosis.
  • Even though the presence of candidiasis is consistent with a T-cell defect, no increased frequency of other opportunistic infections exists.
  • Because these patients have a normal B-cell response to candidal antigens, they are spared from developing disseminated candidiasis.
• Hypoparathyroidism⁴
  • This is the first endocrine disease to occur during the course of PGA-I, usually developing after candidiasis and before Addison disease.
  • Antiparathyroid antibodies have been reported in 10-40% of patients with hypoparathyroidism; however, whether these are being confused with mitochondrial autoantibodies is still under debate. The pathologic significance of these antibodies is not clear.
  • Other disease states presenting with neonatal hypocalcemia (DiGeorge syndrome or congenital absence or malformation of the parathyroid) must be differentiated from PGA-I. DiGeorge syndrome results from a congenital defective disorder of the branchial clefts. It manifests as hypoparathyroidism and cutaneous candidiasis; unlike PGA-I, DiGeorge syndrome does not involve the adrenal glands.
  • More than 75% of patients develop hypoparathyroidism, which usually presents in persons younger than 10 years.
  • Clinical features may include, among others, (1) tetanic clinical symptoms, such as carpopedal spasm and paresthesias of the lips, fingers, and feet; (2) seizures; (3) laryngospasm; (4) leg cramps; (5) diffuse mild encephalopathy; (6) cataracts; and (7) papilledema. Electrocardiography may show a prolonged QT interval.
• Adrenocortical failure (Addison disease)
  • Addison disease typically occurs in people aged 10-30 years (mean, 12-13 y); it usually is the third disease to appear in PGA-I.
  • Mineralocorticoid and glucocorticoid deficiencies usually arise simultaneously, but their onset can be dissociated by up to 3 years.
  • CYP21 appears to be the major autoantigen in isolated Addison disease and Addison disease associated with PGA-II. Autoantibodies to CYP17 and a side-chain cleavage enzyme (CYP11A1) have been associated with Addison disease in PGA-I.
  • Early symptoms include weakness, fatigue, and orthostatic hypotension.
  • Pigmentation usually is increased and may serve as a differentiating point from secondary hypoadrenalism (primary pituitary failure).
  • Anorexia, nausea, vomiting, diarrhea, and cold intolerance often occur.
  • Late symptoms include weight loss, dehydration, hypotension, and a small-sized heart.
• Less common clinical manifestations
  • Hypergonadotropic hypogonadism
  • Type 1 diabetes mellitus
  • Autoimmune thyroid disease (not including Graves disease)
  • Pernicious anemia
  • Chronic atrophic gastritis
  • Chronic active hepatitis
  • Enamel hypoplasia, which occasionally precedes the onset of hypoparathyroidism
  • Asplenia
  • Keratoconjunctivitis
  • Cholelithiasis
  • Malabsorption
  • Alopecia
  • Vitiligo
  • Interstitial nephritis

Physical

Physical findings in polyglandular autoimmune (PGA) syndrome, type I, are dependent on the components of the syndrome that are clinically manifested at the time of examination.

Causes

• Genetic
  • HLA alleles are not seen in polyglandular autoimmune (PGA) syndrome, type I.
  • The postulated genetic locus is described in Pathophysiology.
• Environmental
  • Precipitators of autoimmunity exist, but they continue to be elusive.
  • Postulations include the association between congenital rubella infections and type 1 diabetes mellitus or hypoparathyroidism.

Differential Diagnoses

Other Problems to Be Considered

Chromosomal disorder (45,O; trisomy 21)
Congenital rubella
Hemochromatosis
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 - Malignant more frequently than benign and associated with myasthenia gravis; as many as 50% of cases occur in people older than 40 years; possibly associated with Cushing, Graves, or Addison disease

Other conditions that may give rise to any of the components of the syndrome if solely present

Workup

Laboratory Studies

In diagnosing polyglandular autoimmune (PGA) syndrome, type I, a clinical history and examination that suggest evidence of more than 1 endocrine deficiency should prompt the use of the following tests:

• Serum endocrine autoantibody screen^14,15
  • This helps to verify the autoimmune etiology of the disease and to identify patients who may later develop multi-endocrine deficiency.
  • It is useful for screening family members who may develop autoimmune endocrine disease in the future.
  • The screening panel may include autoantibodies to 21-hydroxylase, 17-hydroxylase, thyroid peroxidase (TPO) and thyroid-stimulating immunoglobulins (TSI), glutamic acid decarboxylase and islet cell antibodies, and parietal cell enzyme (H⁺/K⁺ -ATPase) antibodies.
  • Not all patients have positive antibodies; therefore, the absence of these antibodies does not exclude PGA-I.
• End-organ function tests are necessary to confirm the diagnosis.
  • Test testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in males.
  • In females who have regular menses, no laboratory assessment of the gonadotropin axis is necessary. If menses are irregular or absent, obtain estradiol, FSH, LH, and prolactin levels.
  • TSH and, if necessary, free thyroxine (T4) and free triiodothyronine (T3) - TSH may be elevated, and free T4 and T3 may be low.
  • Adrenocorticotropic hormone (ACTH) and cosyntropin (Cortrosyn) stimulation test - ACTH may be elevated with an abnormal Cortrosyn test, which consists of a low cortisol level found 30 minutes after administering Cortrosyn.
  • Plasma renin activity - High renin activity may be noted.
  • Electrolytes; calcium, phosphorus, magnesium, and albumin; and fasting blood glucose: Hyponatremia, hyperkalemia, mild metabolic acidosis, and azotemia may occur with dehydration. The values for calcium, phosphorus, and magnesium vary, depending on the extravascular status of the patient and the severity and duration of illness. These also depend on the severity of hypoparathyroidism, which causes low calcium, an elevated phosphorus, and low magnesium.
  • Fungal skin scrapings - These may be positive for candidiasis.
  • Complete blood count (CBC) with mean cell volume (MCV) and vitamin B-12 levels - These may show lymphocytosis, neutropenia, and anemia. If coexisting pernicious anemia exists, the MCV is elevated and the vitamin B-12 levels are low.
  • CD4 counts and possibly human immunodeficiency virus (HIV) testing - Both of these are performed to exclude the differential diagnosis of HIV.
  • Some authorities have recommended that some of these tests be performed on an annual basis, because not all diseases manifest at the time of the initial diagnosis.
• Depending on the presentation, liver function tests along with antibodies to the liver, kidney, and spleen (autoimmune hepatitis) may be considered because of their occasional association with PGA-I.
• Malabsorption and atrophic gastritis occasionally are associated with PGA-I, and patients with suggestive clinical features may require endoscopic biopsies to prove the diagnosis.

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.
• Other imaging studies depend on the syndrome components or other associated disorders present at the time of the evaluation.

Other Tests

Other tests depend on the syndrome components or other associated disorders present at the time of the evaluation.

Procedures

• Endoscopies with biopsies of the stomach and small bowel are used to rule out atrophic gastritis and celiac disease.
• Other procedures depend on the syndrome components or other associated disorders present at the time of the evaluation.

Histologic Findings

Histology depends on the organ that has been affected. There usually is chronic inflammatory cell infiltration of the affected organs. Examples are as follows:

• Adrenal gland - May be anything ranging from cellular infiltration (lymphocytic and plasma cells) to extensive fibrosis of the adrenal cortex
• Gastric atrophy - Lymphocytic/plasma cell infiltration of the lamina propria, with a progression of parietal cells and eventual atrophy with only mucous glands

Treatment

Medical Care

The treatment for polyglandular autoimmune (PGA) syndrome, type I, is targeted at whatever organ is affected. It is always best to identify and treat the respective autoimmunity before any significant morbidity can develop.

For the most part, replacement therapy and patient education about the chronic diseases are integral to treatment success. The educational aspect is extremely important, because it helps the patient with the early detection of any new autoimmune states and aids in the adequate treatment of this chronic syndrome.

• Mucocutaneous candidiasis
  • This condition is treated with oral fluconazole and ketoconazole.
  • Absorption of ketoconazole may be compromised if coexistent atrophic gastritis exists. Ketoconazole may also inhibit adrenal and gonadal synthesis, which could worsen the coexistent Addison disease and cause hepatitis.
  • Fluconazole is preferred, because it does not inhibit steroidogenesis and is less frequently associated with the development of hepatitis. It is, however, an expensive medication.
• Hypoparathyroidism
  • This disorder usually is gradual and permanent, and oral calcium and vitamin D usually are adequate therapy. Doses of vitamin D range from 50,000-100,000 U/d. Calcitriol (1,25-dihydroxy D) is a better choice physiologically, but it is more expensive. Other vitamin D synthetic analogues also are suitable for replacement, but cost again must be considered.
  • In cases in which there is coexisting malabsorption, tetany may occur and IV calcium gluconate and magnesium may be necessary.
  • The hypocalcemia seen in PGA-I also has been reported to result from pancreatic insufficiency, giardiasis (which occurs with increased frequency in PGA-I), and lymphangiectasia. Each of these requires specific therapy.
• Adrenal insufficiency (Addison disease)
  • The treatment of adrenal failure depends mainly on 2 factors.
    • Treatment is influenced by the question of whether or not the patient is in crisis with hypotension and consequently requires IV fluids and IV steroids. Otherwise, treatment is influenced by the question of whether or not chronic and otherwise stable oral steroids, eg, prednisone, can be used with or without fludrocortisone.
    • Another factor influencing treatment is whether or not a confident diagnosis of adrenal failure can be made based on the information at hand when the patient is seen. This may determine what kind of IV steroid is used. If the diagnosis is not clear, then the physician may opt to use dexamethasone IV, because it does not interfere with subsequent cortisol measurements required for the diagnosis of Addison disease. However, if sufficient clinical evidence exists in favor of Addison disease, then using hydrocortisone is better because of its additional mineralocorticoid benefit, as an aldosterone defect also is seen. Most of the time, a mineralocorticoid (eg, fludrocortisone) also is added to the regimen.
  • The glucocorticoid dose is changed according to the patient's symptoms. Monitor electrolytes and the activity levels of plasma renin to assess the efficacy of treatment with fludrocortisone.
  • In cases of intercurrent illness, increase the doses of hydrocortisone.
  • In the presence of coexisting diabetes, which is occasionally seen with PGA-I, the daily dose usually should not exceed 30 mg/d, unless the need for a larger dosage is confirmed. This necessitates higher doses of insulin; on many occasions, this results in difficulty controlling glucose levels.
  • Other deficiencies seen in association with diabetes and pernicious anemia, eg, hypothyroidism, can be corrected by replacement therapy.
  • Adrenal gland transplants have been successful in experimental rodents and in humans.
  • Vitamin and mineral replacement occasionally is needed to complement hormonal replacement.

Surgical Care

No specific surgical interventions exist that are unique to the management of polyglandular autoimmune (PGA) syndrome, type I. However, complications from a component of the syndrome may require therapeutic procedures or surgical interventions, as for example, in the case of a patient requiring intubation and other critical care therapeutic interventions after going into adrenal crisis culminating in septic/hypovolemic shock.

Consultations

• Endocrinology - Complex interactions exist that may affect the replacement of adrenal, thyroid, and parathyroid hormones; these are best handled by an endocrinologist.
• Infectious diseases - To help with recurrent candidiasis
• Gastroenterology - If bowel or hepatic involvement is noted
• Rheumatology - If necessary because of the autoimmune nature of the disease, especially when considering immunosuppressive therapy
• Other consultations may be needed according to the clinical situation.

Diet

• A high-salt diet is beneficial to patients with adrenal insufficiency.
• If coexisting diabetes is present, institute a diabetic diet.

Activity

As tolerated

Medication

The drugs listed here are used primarily for the replacement of deficient hormones and electrolytes (except for ketoconazole). The medications detailed in this list are the major, well-established drugs available for each category. However, newer agents, especially in the antifungal category, have been introduced; these may be administered by qualified physicians, especially to critically ill patients in the ICU.

Corticosteroids

These are used for adrenocortical insufficiency replacement. Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

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

DOC because of mineralocorticoid activity and glucocorticoid effects. Useful for treatment of many diseases, especially autoimmune and inflammatory diseases. Used in PGA-I for primary adrenal failure.

Dosing

Adult

Range: 20-240 mg PO
Usual: 15-20 mg PO am and 5-10 mg pm (cortisol) to mimic circadian rhythm
Acute adrenal failure: 100 mg IV q6-8h

Pediatric

0.56 mg/kg/d PO qd or in divided doses

Interactions

Clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in tuberculosis, latent amebiasis, hyperthyroidism, hypothyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, myasthenia gravis, renal insufficiency, hypertension, and fresh bowel anastomosis

Fludrocortisone (Florinef)

Partial replacement therapy for primary and secondary adrenocortical insufficiency. Most commonly prescribed synthetic mineralocorticoid. Possesses glucocorticoid qualities. Encourages sodium reabsorption at distal renal tubules, GI mucosa, and the sweat and salivary glands.

Dosing

Adult

0.05-0.2 mg PO qd; often necessary to reduce initial dose to 0.05 mg qod due to ankle edema; patient will adjust but may need higher doses; adjustment is based on activity levels of plasma renin, BP, and potassium

Pediatric

Not established

Interactions

Enhanced hypokalemia with amphotericin B, furosemide, ethacrynic acid, and benzothiadiazides; increased risk of arrhythmias or digoxin toxicity with digitalis glycosides; decreased PT times with oral anticoagulants; diminishes effects of antidiabetic drugs; decreases salicylate levels but increases ulcerogenic effect; metabolic clearance increased with barbiturates, phenytoin, and rifampin; lack of antibody responses to vaccines

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Taper dose gradually; caution in Addison disease, potassium loss, and sodium retention; adverse reactions occur from prolonged use or too rapid withdrawal; like glucocorticoids, increase doses with stress if used for 1 y; caution in latent peptic ulcer, fresh bowel anastomosis, nonspecific ulcerative colitis, renal insufficiency, hypertension, osteoporosis, myasthenia gravis, and diverticulosis

Antifungals

These drugs treat mucocutaneous candidiasis. Their mechanism of action may involve an alteration of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Ketoconazole (Nizoral)

First azole used in clinical practice. Imidazole broad-spectrum antifungal agent that inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death. Also acts on several P450 enzymes including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. May inhibit ACTH secretion when used at therapeutic doses. Possess narrow therapeutic index.

Dosing

Adult

200-600 mg PO qd

Pediatric

Not established

Interactions

Isoniazid may decrease bioavailability of ketoconazole; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels; coadministration with cisapride or astemizole may cause serious cardiac effects; potentiates effects of triazolam, midazolam, and oral hypoglycemics; caution with hepatically metabolized drugs

Contraindications

Documented hypersensitivity; fungal meningitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (side effects avoided with dose of 200-400 mg/d); administer antacid, anticholinergics, or H2 blockers at least 2 h after taking ketoconazole; caution in severe Addison disease; achlorhydria may impair absorption

Fluconazole (Diflucan)

Fungistatic activity. Synthetic oral antifungal (broad-spectrum bis-triazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Dosing

Adult

200 mg d 1, then 100 mg qd for at least 2 wk; may need to treat up to 4 wk and may need up to 400 mg/d in resistant cases

Pediatric

6 mg/kg d 1, then 3 mg/kg for at least 2 wk; may need to treat up to 4 wk and may need up to 12 mg/kg/d in resistant cases

Interactions

Levels may increase with hydrochlorothiazides; fluconazole levels may decrease with chronic coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose for renal insufficiency; monitor closely if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS or malignancy) and while taking multiple concomitant medications; not recommended for breastfeeding women

Vitamins and mineral salts

These are used as nutritional supplements.

Calcitriol (Calcijex, Rocaltrol)

Active metabolite of vitamin D synthesized from precursor in the kidney under influence of PTH. Increases calcium levels by promoting absorption of calcium in intestines and retention in kidneys. Low in absence of PTH or hypoparathyroidism.

Dosing

Adult

0.25-2 mcg/d PO; increase as necessary to maintain normal range

Pediatric

Not established

Interactions

Cholestyramine and colestipol decrease absorption; magnesium-containing antacids and thiazide diuretics can increase effects

Contraindications

Documented hypersensitivity; hypercalcemia, hypervitaminosis D, malabsorption syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in breastfeeding women; adequate response depends on adequate dietary calcium intake; maintain adequate fluid intake

Ergocalciferol (Calciferol, Drisdol)

Stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood. Precursor of active form of vitamin D (calcitriol). Because it is a precursor, a significant delay between dose administration and effect exists. Liver must be intact for intermediate to be formed (calcidiol, 25-hydroxy vitamin D). Many drugs may affect this step. Has lipid storage, so overdoses may cause prolonged hypercalcemia.
Measure of efficacy is serum calcium concentration.

Dosing

Adult

50,000-150,000 U/d PO

Pediatric

Not established

Interactions

Colestipol, mineral oil, and cholestyramine may decrease absorption of ergocalciferol from small intestine; thiazide diuretics may increase effects of vitamin D

Contraindications

Documented hypersensitivity; hypercalcemia; hypervitaminosis D; malabsorption syndrome

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in breastfeeding women, impaired renal function, renal stones, heart disease, or arteriosclerosis

Calcium carbonate (Oystercal, Caltrate)

Calcium moderates nerve and muscle performance by regulating action potential excitation threshold. For hypoparathyroidism, use a supplementation of at least 2 g of elemental calcium/d.

Dosing

Adult

1-4 g elemental calcium PO qd

Pediatric

Not established

Interactions

May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; IV administration antagonizes effects of verapamil; large intakes of dietary fiber may decrease calcium absorption and levels

Contraindications

Renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; patients with digitalis toxicity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Hypercalcemia or hypercalciuria may occur when therapeutic amounts are given; caution in breastfeeding women, hyperparathyroidism, patients who are digitalized, respiratory failure, and acidosis

Follow-up

Further Inpatient Care

If evidence of hypothyroidism is present, perform an adrenal evaluation before any thyroid replacement. If replacement of thyroid hormones is urgent, draw blood for later adrenal evaluation, and administer steroids before starting thyroid replacement dosing.

Further Outpatient Care

• The patient's diet should be high in calcium, fresh fruits, and vegetables and low in simple carbohydrates.
• In addition to any other stress management techniques, encourage moderate exercise. This is mainly relevant for patients with adrenal insufficiency.
• Patients may need a dual-energy radiographic absorptiometry (DEXA) scan to assess any degree of osteoporosis due to long-term steroid use.
• Inform patients about the symptoms of an acute exacerbation, such as dizziness, lightheadedness, abdominal pain, and nausea and vomiting.
• In addition, make patients aware of the signs and symptoms of hypoparathyroidism, including muscle cramps or spasms.
• If evidence of hypothyroidism exists, perform an adrenal evaluation before any thyroid replacement. If replacement of thyroid hormones is urgent or emergent, draw blood for later adrenal evaluation, and administer steroids before starting thyroid replacement dosing.

Inpatient & Outpatient Medications

These medications depend on the components present in individual patients and range from agents used for hormone replacement to medications employed to manage fungal infections and other complications/deficiencies.

Deterrence/Prevention

• Strongly advise patients to wear medical alert bracelets indicating that they have adrenal insufficiency.
• Provide patients with increased steroid coverage before surgeries or periods of stress (for example, in the case of a febrile illness).

Complications

• Hypoparathyroidism
  • Cataracts
  • Laryngospasm
  • Basal ganglial calcification
  • Ventricular arrhythmias
  • Renal stones may arise from vitamin D use due to possible excessive urine Ca⁺⁺ excretion. Urine calcium excretion may be monitored in these patients.
• Addison disease
  • Arrhythmias secondary to electrolyte imbalance
  • Loss of libido
  • Psychotic illnesses
  • Hypoglycemic spells
  • Gastrointestinal complaints
  • Complications from treatment, such as osteoporosis or gastrointestinal ulceration with concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs)
• Other complications include the following:
  • Neuropathies and anemia (pernicious anemia)
  • Malabsorption (celiac disease)

Prognosis

The prognosis is variable, depending on how organs are affected and the severity of the disease.

Patient Education

• Outpatient management should include patient education on the various components of polyglandular autoimmune (PGA) syndrome, type I, and the need to screen close relatives as appropriate. An important aspect of patient education is the provision of information about adrenal deficiency; subtle deficiency that goes unnoticed in normal, daily-life situations may become life-threatening in stressful situations.
• See Further Outpatient Care.

Miscellaneous

Medicolegal Pitfalls

• Failure to refer the patient to a specialist (usually an endocrinologist)
• Failure to provide proper follow-up care
  • Polyglandular autoimmune (PGA) syndrome, type I, can have multiple pathologies.
  • It has an unpredictable outcome, because each pathology can occur anytime during the course of the disease.
  • Failure to see these patients as frequently as possible can result in missing the onset of a potentially fatal pathology.
• Failure to provide appropriate genetic counseling

Special Concerns

When evidence of a second autoimmunity is present, consider that the patient may have polyglandular autoimmune (PGA) syndrome, type I, or PGA-II, because of the different prognoses in these syndromes.

References

1. Garcia-Hernandez FJ, Ocana-Medina C, Gonzalez-Leon R, et al. Autoimmune polyglandular syndrome and pulmonary arterial hypertension. Eur Respir J. Mar 2006;27(3):657-8. [Medline]. [Full Text].

2. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). Sep 1981;60(5):355-62. [Medline].

3. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. May 13 2004;350(20):2068-79. [Medline].

4. Alimohammadi M, Bjorklund P, Hallgren A, et al. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. Mar 6 2008;358(10):1018-28. [Medline]. [Full Text].

5. Bhansali A, Kotwal N, Suresh V, et al. Polyglandular autoimmune syndrome type 1 without chronic mucocutaneous candidiasis in a 16 year-old male. J Pediatr Endocrinol Metab. Jan 2003;16(1):103-5. [Medline].

6. Bjorses P, Halonen M, Palvimo JJ, et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am J Hum Genet. Feb 2000;66(2):378-92. [Medline]. [Full Text].

7. Org T, Chignola F, Hetenyi C, et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. Apr 2008;9(4):370-6. [Medline]. [Full Text].

8. Heino M, Scott HS, Chen Q, et al. Mutation analyses of North American APS-1 patients. Hum Mutat. 1999;13(1):69-74. [Medline].

9. Rosatelli MC, Meloni A, Meloni A, et al. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum Genet. Oct 1998;103(4):428-34. [Medline].

10. Zlotogora J, Shapiro MS. Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet. Nov 1992;29(11):824-6. [Medline]. [Full Text].

11. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. Jul 2003;88(7):2983-92. [Medline]. [Full Text].

12. Iannello S, Campanile E, Cipolli D, et al. [A rare case of juvenile diabetes mellitus associated with APECED (autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy) with strong X-linked familial inheritance]. Minerva Endocrinol. Jun 1997;22(2):51-9. [Medline].

13. LeBoeuf N, Garg A, Worobec S. The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Pediatr Dermatol. Sep-Oct 2007;24(5):529-33. [Medline].

14. Meloni A, Furcas M, Cetani F, et al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. Nov 2008;93(11):4389-97. [Medline].

15. Oftedal BE, Wolff AS, Bratland E, et al. Radioimmunoassay for autoantibodies against interferon omega; its use in the diagnosis of autoimmune polyendocrine syndrome type I. Clin Immunol. Oct 2008;129(1):163-9. [Medline].

16. Ahonen P, Myllarniemi S, Sipila I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. Jun 28 1990;322(26):1829-36. [Medline].

17. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. Dec 1997;17(4):399-403. [Medline].

18. Katzung BG, ed. Basic and Clinical Pharmacology. 7^th ed. Stamford, Conn: Appleton & Lange; 1998:635-52, 706-22.

19. Betterle C, Greggio NA, Volpato M. Clinical review 93: autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. Apr 1998;83(4):1049-55. [Medline]. [Full Text].

20. Eisenbarth GS, Gottlieb PA. The immunoendocrinopathy syndromes. In: Larsen PR, Kronenberg HM, Melmed S, et al, eds. Williams Textbook of Endocrinology. 10^th ed. Philadelphia, Pa: Saunders; 2003:1763-76.

21. Halonen M, Eskelin P, Myhre AG, et al. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab. Jun 2002;87(6):2568-74. [Medline]. [Full Text].

22. Hannigan NR, Jabs K, Perez-Atayde AR, et al. Autoimmune interstitial nephritis and hepatitis in polyglandular autoimmune syndrome. Pediatr Nephrol. Aug 1996;10(4):511-4. [Medline].

23. Hogenauer C, Meyer RL, Netto GJ, et al. Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I. N Engl J Med. Jan 25 2001;344(4):270-4. [Medline].

24. Muir A, Schatz DA, Maclaren NK. Polyglandular failure syndromes. In: DeGroot LJ, et al, eds. Endocrinology. 3^rd ed. Philadelphia, Pa: Saunders; 1995:3013-22.

25. Myhre AG, Halonen M, Eskelin P, et al. Autoimmune polyendocrine syndrome type 1 (APS I) in Norway. Clin Endocrinol (Oxf). Feb 2001;54(2):211-7. [Medline].

26. Nieman LK. Causes of primary adrenal insufficiency (Addison's disease). www.uptodate.com. Available at http://www.utdol.com/utd/content/topic.do?topicKey=adrenal/7188&view. Accessed May, 10, 2006.

27. Obermayer-Straub P, Manns MP. Autoimmune polyglandular syndromes. Baillieres Clin Gastroenterol. Jun 1998;12(2):293-315. [Medline].

28. Rybojad M, Abimelec P, Feuilhade M, et al. [Familial chronic mucocutaneous candidiasis associated with autoimmune polyendocrinopathy. Treatment with fluconazole: 3 cases]. Ann Dermatol Venereol. Jan 1999;126(1):54-6. [Medline].

29. Soderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. Feb 2004;89(2):557-62. [Medline]. [Full Text].

30. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17^th ed. Whitehouse Station, NJ: Merck; 1999:119-20.

31. Toonkel R, Levine M, Gardner L. Erythropoietin-deficient anemia associated with autoimmune polyglandular syndrome type I. Am J Hematol. Feb 2004;75(2):84-8. [Medline].

Keywords

polyglandular autoimmune syndrome, autoimmune, adrenal, autoimmune diseases, adrenal glands, Addison's disease, autoimmune disorders, adrenal gland, autoimmune disease, autoimmune disorder, candidiasis, Addison disease, auto immune, polyglandular autoimmune syndrome type I, polyglandular autoimmune syndrome type 1, autoimmune polyendocrine syndromes, APS, autoimmune polyendocrinopathy, autoimmune polyglandular syndrome, candidiasis ectodermal dysplasia, immunoendocrinopathy syndromes, PGA syndromes, polyglandular failure syndromes, endocrine gland insufficiency, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED, Whitaker syndrome, PGA syndrome type I, PGA-I

Contributor Information and Disclosures

Author

Saleh A Aldasouqi, MD, FACP, FACE, Assistant Professor of Medicine, Associate Program Director, Department of Medicine, Division of Endocrinology, Michigan State University College of Human Medicine
Saleh A Aldasouqi, MD, FACP, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists and American College of Physicians
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching; Amylin Grant/research funds Clinical Trial

Coauthor(s)

Olakunle PA Akinsoto, MD, MB, BCh, Consulting Staff, Family Health Center, Jacksonville Medical Center
Olakunle PA Akinsoto, MD, MB, BCh is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Medical Association
Disclosure: Nothing to disclose.

Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University
Serge A Jabbour, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Thyroid Association, Endocrine Society, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Ghassem Pourmotabbed, MD†, Former Associate Professor, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Tennessee School of Medicine and Health Science Center
Ghassem Pourmotabbed, MD† is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

I would like to thank Jinie Shirey at the Department of Medicine, College of Human Medicine, Michigan State University, East Lansing for manuscript assistance and preparation, and Laura Smith at the Medical Library, Sparrow Hospital, Lansing, Michigan, for assistance in reference retrieval.

Related eMedicine topics:
Addison Disease [Dermatology]
Addison Disease [Endocrinology]
Adrenal Insufficiency
Adrenal Insufficiency and Adrenal Crisis
Candidiasis, Chronic Mucocutaneous
Hypoparathyroidism [Emergency Medicine]
Hypoparathyroidism [Endocrinology]
Hypoparathyroidism [Pediatrics: General Medicine]
Polyglandular Autoimmune Syndrome, Type II
Polyglandular Autoimmune Syndrome, Type III

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)