Autoimmune Polyendocrine Syndrome Type 2

In most cases, adrenal insufficiency manifests before dysfunction of other endocrine glands cause clinical symptoms. Consequently, patients presenting with SS often show unspecific symptoms corresponding to Addison's disease upon the first presentation. They usually claim fatigue, weakness, nausea, vomiting, diarrhea, constipation and abdominal pain. Patients tend to lose their appetite and weight, but they may report cravings for salt. Hypotension is often registered. During the physical examination of skin and mucous membranes, hyperpigmented areas of may be recognized, particularly in skin folds and oral cavity. On the other hand, vitiligo may be noted. Vitiligo is considered a comorbidity and a possible marker of autoimmune processes, not a consequence of Addison's disease.

SS develop thyroid disorders and/or diabetes mellitus type 1 either simultaneously or in a delayed manner. Autoimmune thyroiditis and subsequent hypothyroidism are more frequently observed than Graves disease and is associated with fatigue, weakness, intolerance to cold, dry skin, myxedema, constipation and weight gain. Alopecia may be observed in some patients. Graves disease, in contrast, is characterized by symptoms of hyperthyroidism, i.e., restlessness, anxiety, intolerance to heat, arrhythmias, hypertension, diarrhea and weight loss. In some cases, thyroid disorders may manifest before adrenal insufficiency is diagnosed.

Diabetes mellitus type 1 may lead to polydipsia and polyuria.

Additional symptoms may affect parathyroid glands, pituitary gland and gonads, gastrointestinal tract and musculature [9].

• Hypoparathyroidism and hypocalcemic tetany have been reported in SS [1].
• Hypophysitis has been described in SS patients [2].
• A minor share of women suffering from SS claims amenorrhea due to ovarian failure.
• Celiac disease is often observed.
• Myasthenia gravis may be related to SS.
• Pernicious anemia may aggravate fatigue and weakness, cause tachycardia and dyspnea.

Due to SS being a genetic disorder, it is important to query the patient regarding a familial history of endocrine disorders.

Generally, laboratory analyses of blood samples yield multiple alterations that may be ascribed to the distinct components of this polyendocrinopathy.

• Addison's disease causes hypoglycemia, hyponatremia, hyperkalemia and acidosis.
• Thyroid disorders cause decreased levels of triiodothyronine (T3) and thyroxine (T4) despite high concentrations of thyroid-stimulating hormone (TSH) or vice versa in hypothyroidism and hyperthyroidism, respectively.
• Diabetes mellitus type 1 is associated with insulin-dependent hyperglycemia.

Additional findings may point at the involvement of other organs. Further diagnostic measures don't differ from those applied to determine single endocrinopathies and should be taken if the results of blood sample analyses imply a certain entity. An ACTH stimulation test is recommended to confirm primary adrenal insufficiency. Thyroid function tests, for instance, are indicated if the clinical presentation and serum levels of T3, T4, and TSH suggest hypothyroidism or Graves disease.

Measurement of organ-specific autoantibodies is a sensitive method that allows for an early detection of endocrinopathies before tissue damage suffices to cause symptoms [10].

A patient may be diagnosed with SS if they present symptoms of Addison's disease and thyroid disorders or diabetes mellitus type 1, and if autoantibodies are detected that support the tentative diagnosis of an autoimmune disease.

Patients diagnosed with SS (and possibly even those only suffering from Addison's disease) should undergo regular follow-ups in order to identify comorbidities before severe symptoms manifest. Such follow-ups should comprise blood sample analyses and thyroid function tests.

Treatment regimes correspond to those described for the individual endocrinopathies that form part of SS. Before initiation of treatment, a complete workup needs to be performed. Patients suffering from multiple endocrinopathies may present with adverse events to otherwise well-tolerated drugs. Substitution of thyroid hormones, for instance, may trigger an Addisonian crisis in people suffering from concurrent adrenal insufficiency.

The following drugs are the mainstays of SS therapy:

• So as to compensate for adrenal insufficiency, patients receive hydrocortisone and fludrocortisone to replace glucocorticoids and mineralocorticoids.
• Levothyroxine is the drug of choice in case of hypothyroidism.
• In contrast, anti-thyroid drugs are required by patients presenting with Graves disease. Radiolabeled iodine and surgery constitute therapeutic alternatives.
• Diabetes mellitus type 1 is treated with insulin.

SS patients require life-long treatment. They need to understand that compliance with drug therapy significantly improves their prognosis.

There is no causative treatment for SS; components of this syndrome have to be treated individually and symptomatically. In general, hormone deficits can be compensated for by means of drug therapy and patients are able to lead a relatively normal life. However, Addisonian crisis, thyrotoxic crisis, and diabetic ketoacidosis are life-threatening complications of decompensated endocrinopathies and it is of utmost importance that patients are aware of those risks. Additionally, significant morbidity may arise from long-term decompensation of serum hormone levels, e.g., peripheral neuropathy, nephropathy, and retinopathy in the case of hyperglycemia due to diabetes mellitus type 1.

SS is an autoimmune disorder presumably caused by determined gene patterns. Rather than being triggered by a single mutation, polygenic inheritance seems to lead to this polyendocrinopathy. Consequently, precise inheritance patterns cannot be defined; some genes that contribute to a predisposition for SS may be inherited as an autosomal dominant trait, others in an autosomal recessive manner. Sex chromosomes don't seem to be involved in SS inheritance.

It has been suggested that certain HLA haplotypes may predispose for SS. This hypothesis originates from studies conducted with patients suffering from Addison's disease, a main component of SS. Here, haplotypes comprising HLA-DR3, HLA-DR4, HLA-DQ2, and HLA-DQ8 are associated with a high risk for adrenal insufficiency [3]. Further research is required to confirm that these findings are also applicable to SS.

Of note, SS may also be diagnosed in patients whose family has no medical history of autoimmune disorders. It is not yet clear whether these sporadic cases correspond to recombination, de novo mutation or diseases triggered by environmental factors in a given genetic background.

Little is known about the autoimmune response that causes symptom onset. It has been proposed that SS may manifest in patients who suffered from congenital rubella syndrome. The latter has been related to adult-onset hypothyroidism, diabetes mellitus, growth hormone deficiency and autoimmune disorders [4]. Dietary factors may also alter the individual susceptibility for SS.

In developed countries, the overall incidence of SS has been estimated to be less than 5 per 100,000 inhabitants [5]. The risk of developing SS may be increased 50-fold in people who inherited one of the aforementioned HLA haplotypes and is highest in those patients previously diagnosed with Addison's disease. These estimates are based on the following observations:

• Addison's disease is the most frequently observed initial manifestation of SS.
• The overall incidence of Addison's disease is 10 per 100,000 inhabitants and 500 per 100,000 carriers of determined HLA haplotypes [3].
• People suffering from an autoimmune disease are more prone to develop another, similar disorder than their healthy peers [6]. In the case of Addison's disease, up to 50% of affected individuals will develop another autoimmune disorder, e.g., thyroid disorders or diabetes mellitus [7].

With regards to SS, women are affected about three times as often as men. Symptom onset typically occurs during the third or fourth decade of life, but this type of polyendocrinopathy has also been diagnosed in pediatric and elder patients [5].

The pathogenesis of SS is poorly understood and only general statements can be made regarding the pathophysiological events leading to dysfunction of multiple endocrine glands and other organs in this pathology.

As has been indicated above, SS is primarily considered a genetic disorder. With regards to HLA haplotypes and polymorphisms related to SS, penetrance and expressivity seem to vary widely. Symptom onset rarely occurs in childhood and the patient's immune system works just fine until well into adulthood. Thus, environmental, dietary or intrinsic factors are assumed to trigger an autoimmune response in patients predisposed to this type of polyendocrinopathy. In this context, SS may likely be classified as a multifactorial disease.

The nature of SS trigger(s) is not clear; they induce an autoimmune response and production of distinct, organ-specific autoantibodies. Their target structures, namely adrenal glands, thyroid cells and the endocrine pancreas, are progressively destroyed by the patient's own immune system. Symptom onset does not occur until considerable shares of hormone-producing cells are destructed.

Histopathological analysis of affected glands shows focal or generalized infiltration with lymphocytes and extensive tissue damage [8].

Medical bracelets may identify SS patients in case of emergency and guide their treatment.

First degree relatives of SS patients should undergo genetic testing to diagnose this autoimmune disorder before symptom onset. Additionally, affected families may benefit from genetic counseling.

Despite being the most common polyendocrinopathy, Schmidt syndrome (SS) is a rare disorder. Alternative denominations for that same disease are autoimmune polyendocrine syndrome type 2 or polyglandular autoimmune syndrome type 2.

SS is considered a genetic disorder, but the disease has not been related to determined polymorphisms or mutations. According to current knowledge, polygenic inheritance and environmental factors contribute to predisposition and symptom onset. First symptoms typically manifest in adulthood, but patients pertaining to all age groups may be affected. Women are affected significantly more often than men.

As per definition, SS may be diagnosed if a patient presents with Addison's disease and thyroid disorders and/or diabetes mellitus type 1. With regards to thyroid dysfunction, both primary hypothyroidism and Graves disease may be associated with SS, but the former is more common. Additionally, parathyroid glands, pituitary gland, and gonads may be compromised by the autoimmune response occurring in SS patients [1] [2]. Celiac disease, myasthenia gravis, pernicious anemia and vitiligo may also be observed.

Of note, the diagnosis of autoimmune polyendocrine syndromes is based on the presence or absence of certain symptoms. Types 1, 3 and 4 are defined as follows:

• Type 1 is characterized by hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis. It is typically diagnosed in childhood; two out of three symptoms are required for diagnosis.
• Type 3 is marked by those symptoms described for SS except for adrenal insufficiency.
• Type 4 is a polyendocrinopathy that does not fulfill the criteria for either types 1, 2 or 3.

Schmidt syndrome (SS) is a rare autoimmune disorder characterized by multiple endocrinopathies. The disease may also be referred to as autoimmune polyendocrine syndrome type 2.

Causes

SS is a genetic disorder, i.e., inheritance of certain genomic pattern predisposes patients for this disease. However, penetrance and expressivity vary largely and neither do all patients that carry those patterns develop SS nor do all SS patients present the same symptoms.

Symptom onset usually occurs in adulthood and is caused by the induction of an autoimmune response. Here, the body's immune system produces antibodies against its adrenal and thyroid glands, against the pancreas that secretes insulin and sometimes also against other endocrine glands.

Symptoms

SS patients suffer from Addison's disease and thyroid disorders and/or diabetes mellitus type 1. Commonly observed symptoms may be ascribed to those endocrinopathies and may comprise the following:

• Fatigue, weakness
• Loss of appetite, nausea, vomiting, diarrhea, constipation and abdominal pain
• Weight fluctuations
• Hyperpigmented skin and mucous membranes
• Altered blood pressure
• Vitiligo
• Intolerance to cold or heat
• Excessive thirst and frequent urination

Diagnosis

Clinical examination and laboratory analyses of blood samples allow for a tentative diagnosis of polyendocrinopathy. Special tests have to be carried out to confirm adrenal insufficiency, thyroid malfunction or diabetes mellitus, though.

Measurement of autoantibodies is required to proof that observed symptoms are provoked by an autoimmune response.

Treatment

Treatment mainly consists in the substitution of lacking hormones. Lifelong therapy is required.

Glucocorticoids and mineralocorticoids are prescribed in case of Addison's disease; levothyroxine is required if SS patients suffer from hypothyroidism. In the case of Graves disease - a form of hyperthyroidism - excess production of thyroid hormones needs to be limited by means of medication, radiolabeled iodine or surgery. Diabetes mellitus type 1 is treated with insulin.

Compliance with drug therapy significantly affects the patient's prognosis since decompensation of hormonal levels may cause the Addisonian crisis, thyrotoxic crisis or diabetic ketoacidosis, which are life-threatening events.

1. Dutta D, Maisnam I, Ghosh S, Dasgupta R, Mukhopadhyay S, Chowdhury S. Tetany due to hypoparathyroidism as the initial manifestation of autoimmune polyendocrine syndrome type-2: A case report. Indian J Endocrinol Metab. 2012; 16(Suppl 2):S495-497.
2. Hrubiskova K, Jackuliak P, Vanuga P, Pura M, Payer J. [Autoimmune polyendocrine syndrome type 2 associated with autoimmune hypophysitis and coeliac disease]. Vnitr Lek. 2010; 56(11):1169-1176.
3. Robles DT, Fain PR, Gottlieb PA, Eisenbarth GS. The genetics of autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am. 2002; 31(2):353-368, vi-vii.
4. Forrest JM, Turnbull FM, Sholler GF, et al. Gregg's congenital rubella patients 60 years later. Med J Aust. 2002; 177(11-12):664-667.
5. Metwalley KA, Farghaly HS. Hepatitis C virus infection in a child with autoimmune polyendocrine syndrome type 2: a case report. J Med Case Rep. 2012; 6:221.
6. Cojocaru M, Cojocaru IM, Silosi I. Multiple autoimmune syndrome. Maedica (Buchar). 2010; 5(2):132-134.
7. Meyer G, Neumann K, Badenhoop K, Linder R. Increasing prevalence of Addison's disease in German females: health insurance data 2008-2012. Eur J Endocrinol. 2014; 170(3):367-373.
8. Kahaly GJ. Polyglandular autoimmune syndrome type II. Presse Med. 2012; 41(12 P 2):e663-670.
9. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004; 137(2):225-233.
10. Falorni A, Laureti S, Santeusanio F. Autoantibodies in autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am. 2002; 31(2):369-389, vii.

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