Type I Polyglandular Autoimmune Syndrome 

Updated: Nov 11, 2021
Author: Saleh A Aldasouqi, MD, FACE, ECNU; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

Type I polyglandular autoimmune syndrome (PGA-I) is a rare disorder with sporadic autosomal recessive inheritance. The three major components of PGA-I are as follows:

  • Chronic mucocutaneous candidiasis
  • Hypoparathyroidism
  • Autoimmune adrenal insufficiency

Signs and symptoms

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), primary hypogonadism, pernicious anemia, malabsorption, autoimmune hepatitis, ovarian failure, pure red cell aplasia, 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.

See Presentation for more detail.

Diagnosis

Laboratory studies

In diagnosing PGA-I, clinical history and examination findings that suggest evidence of more than 1 endocrine deficiency should prompt the use of serum endocrine autoantibody screening tests. End-organ function tests are necessary to confirm 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.

See Workup for more detail.

Management

The treatment for PGA-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.

See Treatment and Medication for more detail.

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 failure[4] (although PGA-I without mucocutaneous candidiasis has been reported in an adolescent).[5] A syndrome with these features was first described in 1946.

Pathophysiology

The evidence supporting the autoimmune etiology of polyglandular autoimmune (PGA) syndrome, type I, is based on the presence of chronic inflammatory infiltrates composed mainly of lymphocytes in the affected organs and on the presence of autoantibodies reacting to target tissue – specific antigens. The antibodies are believed to occur as a result of a breakdown in normal immunologic tolerogenesis or as a consequence of immunization with an environmental agent that has a similar antigenic molecular structure to a self-antigen.

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.

Another immunological feature is the presence of circulating neutralizing antibodies to cytokines in the peripheral blood of APECED patients. Neutralizing Abs to Th (T helper) cytokines are present in the peripheral blood of patients causing defective antifungal response, contributing to the development of mucocutaneous candidiasis.[6]  Virtually all the of patients with PGA-1 have been found to express autoantibodies reacting with interferon-omega and the great majority express autoantibodies reacting with interferon alpha.[7]

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.[8]

A monogenic mutation of AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs, is very strongly linked to PGA-I.[9]  In autoimmune disorders such as Addison's disease, patients without the PGA-1 syndrome, do not show AIRE mutations suggesting that the gene alterations are not involved in these more common diseases, but unique to PGA-1.

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]

Etiology

Genetic

HLA alleles are not seen in polyglandular autoimmune (PGA) syndrome, type I. The postulated genetic locus is described in Pathophysiology, with most notably being mutation of the AIRE gene.

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.

Epidemiology

United States statistics

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, 10] In the latter report, 16 patients were described, including 13 white patients, 1 Hispanic individual, 1 Middle Eastern patient, and 1 Asian person.

International statistics

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.[8] Known frequencies in other ethnic groups include 1 case per 14,400 in Sardinians and 1 case per 9,000 in Iranian Jews.[11, 12]  Approximately 400 cases have been reported worldwide.[13]

Race-, sex-, and age-related demographics

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.

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.[14] A sporadic report from Italy, by Iannello and colleagues, showed a rather exclusive female preponderance in an X-linked inheritance fashion.[15] In reports from around the world, however, autosomal recessive inheritance has been found to be the genetic mode of transmission in most families.

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.

Prognosis

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

Morbidity/mortality

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.

Complications

The following are complications of 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.

The following are complications of 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)

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.

 

Presentation

History and Physical Examination

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), primary hypogonadism, pernicious anemia, malabsorption, autoimmune hepatitis, ovarian failure, pure red cell aplasia, 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.[16]  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.

Hypoparathyroidism

Hypoparathyroidism is the first endocrine disease to occur during the course of PGA-I, usually developing after candidiasis and before Addison disease.[4]  In the case of a 50-year-old man with PGA-I reported by Lima Ferreira et al, the first and only manifestation for decades was hypoparathyroidism.[13]

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

Less common clinical manifestations include the following:

  • Hypergonadotropic hypogonadism (primary 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

  • Pure red cell aplasia

Physical examination

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.

 

DDx

Diagnostic Considerations

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

Differential Diagnoses

 

Workup

Laboratory Studies

The diagnosis of polyglandular autoimmune (PGA) syndrome, type I is usually made with two or three of the following conditions: mucocutaneous candidiasis, hypoparathyroidism and/or adrenal insufficiency. In diagnosing PGA-1, 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[7, 17]

  • 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, CYP450c21, 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.

Since the different components of this disease develop over years to decades, once there is clinical suspicion, surveillance is essential for other associated autoimmune disorders.

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.

  • Thyroid-stimulating hormone (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 (see Fungal Culture).

  • 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.

  • Treatment of oral candidiasis is indicated in order to prevent the late complication of epithelial carcinoma.

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/day. 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

See the list below:

  • 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

Medication Summary

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

Class Summary

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, A-Hydrocort, Solu-Cortef)

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.

Fludrocortisone

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.

Antifungals

Class Summary

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

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.

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.

Vitamins and mineral salts

Class Summary

These are used as nutritional supplements.

Calcitriol (Vectical, Rocaltrol)

Active metabolite of vitamin D that binds to and activates the vitamin D receptor in kidney, parathyroid gland, intestine, and bone. The active form of vitamin D stimulates intestinal calcium transport and absorption. This medication is essential in individuals with hypoparathyroidism.

Ergocalciferol (Calciferol, Drisdol, Calcidol)

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.

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.

 

Follow-up

Further Outpatient Care

Apart from the usual medications, enforce the following measures:

  • 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, as will need stress dosing of the chosen glucocorticoid therapy.

  • 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.

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.

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).