Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, clusters of endocrine abnormalities is a rare autoimmune disorder in which there is a steep drop in the production of several essential hormones by the glands that secrete these hormones and lymphocytic infiltration causing organ-specific damage with immune dysregulation and that permits treatment and anticipation of associated systemic or other hormonal deficiencies. When first described, this disorder was thought to involve only adrenal insufficiency (Addison’s disease) and thyroid insufficiency (Hashimoto’s thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. Polyglandular autoimmune syndrome type 2 (PAS-2) is an autoimmune disease with polygenic inheritance. It is also called Schmidt syndrome and Carpenter syndrome. The clustering of multiple endocrine diseases in a single patient was documented well before the classification of PAS came into existence.
These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically. Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse.
Most cases of this disorder are sporadic although some clinical researchers believe that there is a familial or hereditary trait associated with AIPS-II. If so, it may involve a complex interaction among many genes.
Causes
The exact cause of AIPS-II is not known, but it is thought to result from one or more abnormal immune responses. Autoimmune reactions occur when, for reasons not quite clear, the body mistakenly reacts to a normal antibody as if it were a foreign one.
PAS-2 is an autoimmune disease affecting multiple endocrine organs.
PAS-2 is a polygenic disease, with significant heterogeneity due to multiple genetic loci and environmental factors responsible for organ-specific damage. Major histocompatibility complex (MHC) genes located on chromosome 6 have been implicated in organ-specific damage in PAS-2.[1] It appears that HLA-DR3 and HLA-DR4 haplotypes and the class 2 HLA alleles DQ2 and DQ8 increase predisposition to PAS-2.[rx][rx]
Non-HLA genes can also predispose to PAS-2 and include CD25-interleukin-2 receptor, cytotoxic T-lymphocyte protein 4 (CTLA-4), and protein tyrosine-protein phosphatase, non-receptor type 22 (PTPN22).[rx]
Symptoms
Many conditions and symptoms are associated with this disorder. The symptoms may vary greatly among affected individuals.
Addison’s disease is a rare disorder characterized by chronic and insufficient functioning of the outer layer of the adrenal gland (adrenal cortex). Patients with Addison’s disease have a deficiency in the production of glucocorticoid hormones which are manufactured by the adrenal gland. These hormones (especially cortisol and aldosterone) are involved in carbohydrates, fat and protein metabolism, carbohydrate and blood sugar storage, and they fight inflammation and suppress the immune response. The deficiency in glucocorticoids causes an increased release of sodium and decreased release of potassium in the urine, sweat, saliva, stomach, and intestines. These changes can cause low blood pressure and increased water excretion which can lead to severe dehydration.
PAS-2 patients may present with vague symptoms of weight loss, fatigue, nausea, vomiting, generalized weakness, anorexia, abdominal pain, diarrhea, polyuria, and polydipsia. Common signs in these patients may include mucosal and cutaneous hyperpigmentation low blood glucose levels and orthostatic hypotension if Addison disease is the diagnosis or polyuria and polydipsia with hyperglycemia if T1DM is present. Hypothyroidism can present with bradycardia, and delayed tendon reflexes.
Hypothyroidism (underactive thyroid) is a disorder that can be genetic or acquired and may occur alone or as a symptom of another illness. Major symptoms may include the development of an enlarged thyroid gland in the neck, a dull facial expression, puffiness and swelling around the eyes, drooping eyelids, thinning hair which is coarse and dry, and poor memory. Hypothyroidism can be caused by disorders of the hypothalamus or pituitary centers in the brain, disorders that affect control of the thyroid hormone, blockage in the metabolic process of transporting thyroid, or iodine in the thyroid gland itself, or the result of a hereditary disorder called Hashimoto’s thyroiditis. Hashimoto’s thyroiditis is an autoimmune disorder in which the body’s natural defenses against invading organisms (i.e., antibodies, lymphocytes, etc.) suddenly begin to attack healthy tissue. (For more information on these disorders chooses “Hypothyroidism” and “Hashimoto” as your search terms in the Rare Disease Database).
Some (but not all) of the following additional findings may be present in patients with autoimmune polyendocrine type II :
Diabetes mellitus: This type of diabetes generally starts during childhood or adolescence. The starches and sugars (carbohydrates) in the foods we eat are normally processed by digestive juices into glucose. The glucose circulates in the blood as a major energy source for body functions. A hormone produced by the pancreas (insulin) regulates the body’s use of glucose. In diabetes mellitus, the pancreas does not manufacture the correct amount of insulin needed to metabolize sugar. As a result, the patient needs daily injections of insulin to regulate blood sugar levels. Symptoms of this disorder may be frequent urination, extreme thirst, constant hunger, weight loss, itching of the skin, vision changes, slow healing of cuts and bruises, and in children there is a failure to grow and develop normally. (For more information on this disorder choose “Insulin-Dependent Diabetes” as your search term in the Rare Disease Database).
Hypoparathyroidism: This disorder causes lower than normal levels of calcium in the blood due to insufficient levels of parathyroid hormones. This condition can be inherited, associated with other disorders, or the result of a neck injury. Symptoms of hypoparathyroidism may be a weakness, muscle cramps, abnormal sensations of the hands such as burning and numbness, excessive nervousness, loss of memory, headaches, cramping of wrists and feet, and spasms in facial muscles. (For more information on this disorder choose “Hypoparathyroidism” as your search term in the Rare Disease Database).
Gonadal failure: This refers to the failure of the organ that produces sex cells (gonads-or testes in the male, and ovaries in the female) to function properly causing an absence of secondary sex characteristics.
Pernicious anemia: This is a blood disorder resulting from impaired absorption of vitamin B-12. This vitamin is used in the production of red blood cells. Healthy individuals absorb sufficient amounts of vitamin B-12 in their normal diet with the help of a substance secreted by the stomach called intrinsic factor. Patients with pernicious anemia generally lack intrinsic factors and can not absorb sufficient amounts of vitamin B-12. Symptoms of vitamin B-12 deficiency usually appear years after absorption of the vitamin ceases because B-12 is stored in large quantities in the liver. Symptoms of this disorder may be shortness of breath, fatigue, weakness, rapid heartbeat, angina, anorexia, abdominal pain, indigestion, and possibly intermittent constipation and diarrhea. (For more information on this disorder choose “Pernicious Anemia” as your search term in the Rare Disease Database).
Vitiligo: This is a skin condition in which there is an absence of pigment-producing cells (melanocytes) causing decreased pigmentation of the skin. These “white spots” on the skin appear most often on the face, neck, hands, abdomen, and thighs although they may appear on all parts of the skin. Vitiligo is sometimes familial, but the exact model of heredity is not yet understood. (For more information on this disorder choose “Vitiligo” as your search term in the Rare Disease Database).
Celiac sprue: This chronic hereditary intestinal malabsorption disorder is caused by intolerance to gluten. The most common symptoms of this disorder are weight loss, chronic diarrhea, abdominal cramping and bloating intestinal gas and abdominal distention, and muscle wasting. Celiac sprue is a hereditary congenital disorder. Gluten is a protein that is present in wheat, oats, barley, rye, and probably millet. Patients with celiac sprue cannot properly absorb a part of gluten called gliadin. This causes intestinal abnormalities as well as physiological deficiencies. Although the disorder begins in infancy, it is sometimes not diagnosed until the patient reaches adulthood. (For more information on this disorder choose “Celiac Sprue” as your search term in the Rare Disease Database).
Myasthenia gravis: Sometimes this disorder can be associated with autoimmune polyendocrine syndrome type II. Myasthenia gravis is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. (For more information on this disorder choose “Myasthenia Gravis” as your search term in the Rare Disease Database).
Grave’s disease: This is a disorder that affects the thyroid gland. It is thought to occur as a result of an imbalance in the immune system. This disorder causes increased thyroid secretion (hyperthyroidism), enlargement of the thyroid gland, and protrusion of the eyeballs. The exact cause of this disorder is not known. It is thought to be inherited as an autosomal recessive trait.
Diagnosis
The diagnosis of PAS-2 is often delayed, and this can sometimes cause significant complications. Usually, these patients present with isolated endocrine dysfunction and later develop other endocrine and non-endocrine diseases.
Manuela Dittmar et al. followed 151 out of 360 PAS-2 patients for 13 years and found that autoimmune thyroid disease was most prevalent in 99 patients (65.6%), and out of these, 50 patients (33.1%) were found to have Graves’ disease, and 49 patients (32.5%) had Hashimoto’s thyroiditis. T1DM was found in 92 patients (60.9%), and Addison disease was found in 28 patients (18.5%). T1DM occurred early in life with a mean age of 27.5 years while other diseases manifested around age 36.5 to 40 years. The coexistence of T1DM and thyroid disease was most common while the coexistence of Addison and thyroid disease was less common.[rx]
PAS-2 patients may present with vague symptoms of weight loss, fatigue, nausea, vomiting, generalized weakness, anorexia, abdominal pain, diarrhea, polyuria, and polydipsia. Common signs in these patients may include mucosal and cutaneous hyperpigmentation low blood glucose levels and orthostatic hypotension if Addison disease is the diagnosis or polyuria and polydipsia with hyperglycemia if T1DM is present. Hypothyroidism can present with bradycardia, and delayed tendon reflexes.
Patients with Addison disease may present with shock-like features including hypotension, tachycardia, and altered mental status suggestive of adrenal crisis.
There is a 2.5-fold increase risk of adrenal crisis in patients who have Addison disease due to the autoimmune polyendocrine syndrome.[rx]
PAS-2 is diagnosed by occurrence in the same patient of at least 2 out of 3 manifestations including primary adrenal insufficiency (Addison disease), autoimmune thyroid disease-causing Grave disease or hypothyroidism, and T1DM. Other endocrine and non-endocrine manifestations of PAS-2 are primary hypogonadism, myasthenia gravis, celiac disease, alopecia, vitiligo, pernicious anemia, and idiopathic heart block, Stiff-man syndrome, Parkinson’s disease, IgA deficiency, serositis, dermatitis herpetiformis, idiopathic thrombocytopenia, and hypophysitis.[rx]
Diagnosis of Addison disease or primary adrenal insufficiency is based on a morning serum cortisol level less than 6.0 mcg/dl or a serum cortisol less than 18 mcg/dl at 60 minutes after ACTH stimulation test using a 250-mcg intravenous or intramuscular bolus of cosyntropin. The presence of 21-hydroxylase or 17-hydroxylase autoantibodies can confirm autoimmune adrenalitis.[rx] Patients with positive 21-hydroxylase or 17-hydroxylase antibodies should have annual monitoring of morning cortisol and ACTH and cosyntropin stimulation test if suspicion is high.
Diagnosis of hypothyroidism due to Hashimoto’s thyroiditis or hyperthyroidism due to Graves’ disease can be made by evaluation of TSH and T4 for the former and TSH, T4, and T3 for the latter. In euthyroid patients, the presence of anti-thyroglobulin antibodies, thyroid microsomal antibodies, and thyrotropin receptor antibodies (Graves’ disease) can detect patients at risk of thyroid disease in the future.
Diagnosis of T1DM can be made with classic symptoms of polyuria, polydipsia, and polyphagia associated with elevated serum glucose level (fasting greater than 125 mg/dl and random over 200 mg/dl and or elevated HbA1c, greater than 6.4%). Standard guidelines should be used for the diagnosis of individual organ dysfunction. These patients can be tested for anti-glutamic acid decarboxylase antibodies (GAD), anti-islet cell antigen 2, and anti-Zn transporter 8 antibodies. Also following a challenge with glucagon (1 mg) the plasma C-Peptide is less than 0.6 ng/ml.
A timely diagnosis of PAS-2 requires knowledge of the complete spectrum of this disease. A complete history and thorough physical exam may give important clues. In many cases, the diagnosis of PAS-2 may be delayed due to the heterogeneous presentation. It is uncommon for these patients to have dysfunction of all 3 major endocrine organs simultaneously and there is usually a latent phase between the endocrinopathies.
Patients with PAS-2 and their family members should be monitored long-term due to the risk of development of organ-specific dysfunction over time. Family members who are not affected by PAS-2 should watch for symptoms related to adrenal, thyroid, and endocrine pancreatic dysfunction. Asymptomatic carriers should be followed on an annual basis.
Organ-specific antibodies like 21-hydroxylase antibody for Addison disease, an antibody against GAD 65 for type 1 diabetes, thyrotropin receptor antibody, and TPO antibody for autoimmune thyroid disease can be assayed for making a diagnosis. Transglutaminase antibodies are useful for the diagnosis of Celiac disease. However, the presence of autoantibodies in the thyroid, adrenal, and islets does not predict glandular failure.
PAS-2 can be differentiated from PAS-1 due to late-onset on clinical manifestation mostly after age 20, different patterns of disease combination with no mucocutaneous candidiasis, and polygenic inheritance versus monogenic.
Delay in diagnosis can cause significant morbidity and mortality in these patients due to the risk of severe hypothyroidism, adrenal crisis, and diabetic ketoacidosis. Thyroid ultrasound is an excellent noninvasive tool to evaluate thyroid disease. The diffuse or multifocal hypoechoic pattern is commonly seen in autoimmune thyroid disease.
CT scan and MRI of the adrenal gland are often normal, but sometimes there is a decrease in the volume of the gland suggestive of atrophy. Unfortunately, there is no reliable imaging technique that can indicate endocrine pancreatic disease.
Treatment
Replacement with appropriate hormones is the key. These patients should be followed up by an interprofessional team led by an endocrinologist. Patients should be followed at least every 6 months with appropriate blood work to avoid over and under-treatment. These patients are at risk of adrenal crisis, hypoglycemia, and diabetic ketoacidosis, among others. The treating physician should be proactive to diagnose these conditions and possible manifestations expected to occur over time without delay to avoid complications.
Care should be taken to treat patients with thyroxine as this can precipitate a life-threatening Addisonian crisis if the patient has undiagnosed adrenal insufficiency. In these patients, testing for adrenal insufficiency should be done before treating hypothyroidism with levothyroxine.[rx] Hydrocortisone replacement should precede thyroxine therapy by about a week.
Family members at risk for developing PAS-2 can be identified by checking organ-specific antibodies.
Due to the autoimmune nature of this disease, multiple immunosuppressants and immune-modulators have been tested, but none of these agents are being used on a regular basis due to the potential risk of side effects.
References
