PGMCET 2012 review- Schmidt's syndrome

POLYGLANDULAR AUTOIMMUNE SYNDROME'S

When immune dysfunction affects two or more endocrine glands and other nonendocrine immune disorders are present, the polyglandular autoimmune (PGA) syndromes should be considered. The PGA syndromes are classified as two main types: 

the type I syndrome starts in childhood and is characterized by mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency; 

the type II, or Schmidt syndrome is more likely to present in adults and most commonly includes adrenal insufficiency, thyroiditis, or type 1 diabetes mellitus. Some authors have attempted to subdivide PGA II on the basis of association with some autoimmune disorders but not others (i.e., type II and type III). 

The type III syndrome is heterogeneous and may consist of autoimmune thyroid disease along with a variety of other autoimmune endocrine disorders . However, little information is gained by making this subdivision in terms of understanding pathogenesis or prevention of future endocrine complications in individual patients or in the affected families.

Features of Polyglandular Autoimmune (Pga) Syndromes

PGA I PGA II Epidemiology Autosomal recessive Polygenic inheritance Mutations in APECED gene HLA-DR3 and HLA-DR4 associated Childhood onset Adult onset Equal male:female ratio Female predominance Disease Associations Mucocutaneous candidiasis Adrenal insufficiency Hypoparathyroidism Hypothyroidism Adrenal insufficiency Graves' disease Hypogonadism Type 1 diabetes Alopecia Hypogonadism Hypothyroidism Hypophysitis Dental enamel hypoplasia Myasthenia gravis Malabsorption Vitiligo Chronic active hepatitis Alopecia Vitiligo Pernicious anemia Pernicious anemia Celiac disease

Abbreviation: APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Polyglandular Autoimmune Syndrome Type I

PGA type I usually is recognized in the first decade of life and requires two of three components for diagnosis: mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Mucocutaneous candidiasis and hypoparathyroidism present with similar high frequency (100% and 79–96%, respectively). Adrenal insufficiency is observed in 60–72% of patients. Mineralocorticoids and glucocorticoids may be lost simultaneously or sequentially. 

PGA type 1 also is called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Other endocrine defects can include gonadal failure (60% female, 14% male), hypothyroidism (5%), and destruction of the beta cells of the pancreatic islets and development of insulin-dependent (type 1) diabetes mellitus (14% lifetime risk). Additional features include hypoplasia of the dental enamel, nail dystrophy, tympanic membrane sclerosis, vitiligo, keratopathy, and gastric parietal cell dysfunction resulting in pernicious anemia (13%). Some patients develop autoimmune hepatitis (12%), malabsorption (variably attributed to intestinal lymphangiectasia, bacterial overgrowth, or hypoparathyroidism), asplenism, achalasia, and cholelithiasis . At the outset, only one organ may be involved, but the number increases with time so that patients eventually manifest two to five components of the syndrome.

Most patients initially present with oral candidiasis in childhood; it is poorly responsive to treatment  and relapses frequently. Chronic hypoparathyroidism usually occurs before adrenal insufficiency develops. More than 60% of postpubertal women develop premature hypogonadism. The endocrine components, including adrenal insufficiency and hypoparathyroidism, may not develop until the fourth decade, making continued surveillance necessary.

Type I PGA syndrome is not associated with a particular HLA type and usually is inherited as an autosomal recessive trait. It may occur sporadically. The responsible gene, designated as either APECED or AIRE, encodes a transcription factor that is expressed in thymus and lymph nodes; a variety of different mutations have been reported. The mechanism by which these mutations lead to the diverse manifestations of type I PGA is unknown.

Polyglandular Autoimmune Syndrome Type II:

PGA type II is characterized by two or more of the endocrinopathies listed above. Most often these endocrinopathies include primary adrenal insufficiency, Graves' disease or autoimmune hypothyroidism, type 1 diabetes mellitus, and primary hypogonadism. Because adrenal insufficiency is relatively rare, it is used frequently to define the presence of the syndrome. Among patients with adrenal insufficiency, type 1 diabetes mellitus coexists in 52% and autoimmune thyroid disease occurs in 69%. However, many patients with antimicrosomal and antithyroglobulin antibodies never develop abnormalities of thyroid function. Thus, increased antibody titers alone are poor predictors of future disease. Other associated conditions include hypophysitis, celiac disease (2–3%), atrophic gastritis, and pernicious anemia (13%). Vitiligo, which is caused by antibodies against the melanocyte, and alopecia are less common than in the type I syndrome. Mucocutaneous candidiasis does not occur. A few patients develop a late-onset, usually transient hypoparathyroidism caused by antibodies that compete with PTH for binding to the PTH receptor. Up to 25% of patients with myasthenia gravis and an even higher percentage who have myasthenia and a thymoma have PGA type II.

The type II syndrome is familial in nature, often transmitted as an autosomal dominant trait with incomplete penetrance. As in many of the individual autoimmune endocrinopathies, certain HL-DR3 and -DR4 alleles increase disease susceptibility; several different genes probably contribute to the expression of this syndrome.

A variety of autoantibodies are seen in PGA type II, including antibodies directed against 

(1) thyroid antigens such as thyroid peroxidase, thyroglobulin, and the thyroid-stimulating hormone (TSH) receptor; 

(2) adrenal side chain cleavage enzyme, steroid 21-hydroxylase, or ACTH receptor; and 

(3) pancreatic islet glutamic acid decarboxylase or the insulin receptor, among others. 

The roles of cytokines such as interferon and cell-mediated immunity are unclear.

Diagnosis:

The clinical manifestations of adrenal insufficiency often develop slowly, may be difficult to detect, and can be fatal if not diagnosed and treated appropriately. Thus, prospective screening should be performed routinely in all patients and family members at risk for PGA types I and II. The most effective screening test for adrenal disease is a cosyntropin stimulation test . A fasting blood glucose level can be obtained to screen for hyperglycemia. Additional screening tests should include measurements of TSH, luteinizing hormone, follicle-stimulating hormone, and, in men, testosterone levels. In families with suspected type I PGA syndrome, calcium and phosphorus levels should be measured. These screening studies should be performed every 1–2 years up to about age 50 in families with PGA type II syndrome and until about age 40 in patients with type I syndrome. Screening measurements of autoantibodies against potentially affected endocrine organs are of uncertain prognostic value. 

The differential diagnosis of PGA syndrome should include the 

-DiGeorge syndrome (hypoparathyroidism due to glandular agenesis and mucocutaneous candidiasis) 

-Kearns-Sayre syndrome (hypoparathyroidism, primary hypogonadism, type 1 diabetes mellitus, and panhypopituitarism)

-Wolfram's syndrome (congenital diabetes insipidus and diabetes mellitus)

-IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, X-linked)

-congenital rubella (type 1 diabetes mellitus and hypothyroidism).

Treatment: Polyglandular Autoimmune Syndrome

With the exception of Graves' disease, the management of each of the endocrine components of the disease involves hormone replacement.  Some aspects of therapy merit special emphasis. 

Primary hypothyroidism can mask adrenal insufficiency by prolonging the half-life of cortisol; consequently, administration of thyroid hormone to a patient with unsuspected adrenal insufficiency can precipitate adrenal crisis. Thus, all patients with hypothyroidism in the context of PGA syndrome should be screened for adrenal disease and, if it is present, treated with glucocorticoids before or concurrently with thyroid hormone therapy. 

Hypoglycemia or decreasing insulin requirements in a patient with diabetes mellitus type 1 may be the earliest symptom of adrenal insufficiency. Consequently, such patients should be screened for adrenal disease. 

Treatment of mucocutaneous candidiasis with ketoconazole may induce adrenal insufficiency. This drug also may elevate liver enzymes, making the diagnosis of autoimmune hepatitis more difficult. 

Hypocalcemia in PGA type II is more commonly due to malabsorption associated with celiac disease than to hypoparathyroidism.