Polyglandular Autoimmune Syndrome Type 2

A 39-year-old Hispanic woman presented to the outpatient clinic with complaints of loss of appetite, weight loss, dizziness, fatigue, loose stools, and increasing pigmentation of her skin of 4 months’ duration. She had a prior history of hypothyroidism secondary to Hashimoto’s thyroiditis, which was controlled with thyroxine. She had long-standing amenorrhea secondary to premature ovarian failure. She denied use of any exogenous steroids. She was afebrile. Physical examination revealed blood pressure of 86/50 mm Hg with orthostasis; heart rate of 108 beats/min; and hyperpigmented gums, palate, tongue, palms, and soles. She was sent to the emergency department for further evaluation.

Blood tests showed normal white blood cell count, blood glucose of 62 mg/dL, serum sodium of 117 mmol/L (normal, 136-145 mmol/L), and serum potassium of 7.4 mmol/L (normal, 3.5-5.1 mmol/L). An ECG did not reveal any abnormality. She was admitted to the medical ICU and treated for hyperkalemia and hypotension.

There was no evidence of any ongoing infection. Her morning cortisol level was 0.6 μg/dL (normal, 6-21 μg/dL) and adrenocorticotropic hormone (ACTH) level was 628 pg/mL (normal, 10-58 pg/mL). Parathyroid hormone and thyroid-stimulating hormone levels were normal. CT of the abdomen did not demonstrate any adrenal mass or hemorrhage. Treatment with hydrocortisone and aggressive hydration was started, with marked improvement in hemodynamic status and electrolytes. An assay for 21-hydroxylase antibody was positive.

On the basis of these parameters, a diagnosis of polyglandular autoimmune syndrome type 2 (PAS-2) was made. She was discharged on a regimen of oral prednisone. She followed up 2 months later and was found to be hemodynamically stable with normal electrolyte levels. Her skin lesions had resolved. Cyclic estrogen and progesterone therapy for premature ovarian failure was started.

Discussion

Polyglandular autoimmune syndromes (PAS) are heterogeneous disorders characterized by the involvement of at least 2 glandular organs in autoimmune-mediated diseases that result in organ hypofunction. There are 4 types of PAS: type 1 consisting of Addison disease (AD), hypoparathyoidism, and chronic mucocutaneous candidiasis; type 2 comprising adrenal failure and autoimmune thyroiditis; type 3 with features of autoimmune thyroiditis and other autoimmune diseases such as type 1 diabetes mellitus (T1DM), but excluding adrenal failure; and, type 4 which includes other autoimmune endocrine disorders.¹

Presentation

AD is a prominent component of PAS types 1 and 2. Each has a strong genetic component with type 1 syndrome seen in siblings and type 2 syndrome occurring in multiple generations. PAS-2 is defined by the presence of autoimmune AD with either T1DM, autoimmune thyroiditis, or both. PAS-2 with adrenal insufficiency and autoimmune hypothyroidism was previously referred to as “Schmidt” or “Carpenter” syndrome. The prevalence of PAS-2 is 1 in 20,000.² It is more frequently encountered in women, with a male to female ratio of 1:3.³ The majority of cases are seen in patients between ages 20 and 40 years. AD is present in all cases of PAS-2, thyroiditis in 66%, and T1DM in 61%.⁴

Workup

Patients with T1DM represent an important cohort for screening for other autoimmune disorders. Islet cell and glutamic acid decarboxylase 65 antibodies are detected in T1DM. Patients with T1DM require lifelong insulin therapy and strict glycemic control. They run the risk of developing chronic complications due to diabetes mellitus such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. They can also have fluctuating glucose levels, making them susceptible to hypoglycemia and neuroglycopenic symptoms on one hand and diabetic ketoacidosis on the other. PAS-2 may also be associated with diabetes insipidus and premature ovarian failure (POF). POF is defined as amenorrhea for at least 4 months in women before 40 years of age along with hypogonadotropic hypogonadism without prior history of surgery, irradiation, or medications known to cause ovarian dysfunction.⁵ Autoimmune POF may be associated with AD or may be isolated. Steroid-producing cell antibodies (StCA) are markers of primary ovarian failure, particularly in patients with AD.⁵

In women with PAS-1, POF usually develops after the onset of AD, whereas in those with PAS-2, it develops before the occurrence of AD, as in this patient. Hence, patients with autoimmune thyroiditis and POF or T1DM should be tested for 21-hydroxylase antibodies to assess the risk of potential AD, and for StCA or steroidogenic enzyme antibodies to confirm autoimmune POF. Thyroid autoimmunity is also a common feature of PAS-2. Its expressions include thyroid atrophy, hypertrophic goiter related to Hashimoto thyroiditis, Graves disease, and asymptomatic autoimmune thyroiditis. Thyroid peroxidase and thyroglobulin autoantibodies are found in patients with Hashimoto thyroiditis. The degree of ensuing hyperthyroidism or hypothyroidism may adversely affect the course of associated endocrine disorders and thus need to be managed aggressively.

Non-endocrine associations include vitiligo, alopecia, immune thrombocytopenic purpura, connective-tissue disorders such as rheumatoid arthritis and Sjogren syndrome, myasthenia gravis, chronic atrophic gastritis, chronic autoimmune hepatitis, hypophysitis, and rarely reversible cardiomyopathy.

Clues in autoantibodies

Autoantibodies not only help to establish the autoimmune nature but also to identify asymptomatic individuals at risk for developing other components of the disease. In the present case, the patient had a history of autoimmune disease (hypothyroidism secondary to Hashimoto thyroiditis) and would have benefitted from screening for AD. This could have prevented her eventual adrenal crisis. The presence of 21-hydroxylase autoantibodies is highly specific for autoimmune AD. Symptoms of AD are the result of corticosteroid and mineralocorticoid hormone deficiencies. Common manifestations include weight loss, cutaneous and mucosal pigmentation, hypotension, and hypoglycemia. Laboratory features include hyponatremia, hyperkalemia, low basal levels of cortisol, elevated ACTH level, and a suboptimal response of cortisol to a cosyntropin stimulation test. These patients need lifelong corticosteroid therapy to avoid these complications, which may be life-threatening. Although AD is seen in all patients with PAS-2, it may not be the first presentation and patients may have a diagnosis of hypothyroidism, T1DM, or hypogonadism long before the diagnosis of adrenal insufficiency.

Early diagnosis of PAS may be challenging. There are no consensus guidelines on screening recommendations for patients in whom PAS is suspected. Certain patients, however, may be at greater risk for the condition than others. Patients with evidence of at least 2 autoimmune endocrinopathies and first-degree relatives of patients with PAS should be considered high risk and would benefit from screening for the presence of PAS. Patients with a confirmed diagnosis of PAS should be screened for other components of the syndrome because there may be a temporal delay in manifestation.

Primary care physicians should maintain a high index of suspicion for these syndromes when confronted with an autoimmune process involving an endocrine or nonendocrine organ, and particularly in a female patient.

Take-home Points

1. Polyglandular autoimmune syndromes are a heterogeneous group comprising many different endocrinopathies. Patients with evidence of 2 or more autoimmune endocrinopathies should be considered to be at high risk for PAS and may be considered for screening.

2. Patients with an established diagnosis of PAS should be screened for other components of the disease, since there may be a temporal delay in appearance of different manifestations.

3. Addison disease is an important component of PAS-2 and its early recognition and treatment may prevent patients from developing life-threatening adrenal crisis.

References:

1. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981;60:355–362.

2. Ten S, New M, Maclaren N. Clinical review 130: Addison's disease 2001. J Clin EndocrinolMetab. 2001;86:2909-2922.

3. Förster G, Krummenauer F, Kühn I, et al. Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation [in German]. Dtsch Med Wochenschr. 1999;124:1476-1481.

4. Wémeau JL, Proust-Lemoine E, Ryndak A, Vanhove L. Thyroid autoimmunity and polyglandular endocrine syndromes. Hormones (Athens). 2013;12:39-45.

5. Reato G, Morlin L, Chen S, et al. Premature ovarian failure in patients with autoimmune Addison's disease: clinical, genetic, and immunological evaluation. J Clin Endocrinol Metab. 2011;96:E1255-E1261.