Continuing Education Activity
Polyglandular autoimmune syndrome type 2 (PAS-2) is an autoimmune syndrome which leads to lymphocytic infiltration causing organ-specific damage. PAS-2 is diagnosed when at least 2 out of 3 of the following are present: primary adrenal insufficiency (Addison disease), autoimmune thyroid disease-causing Grave's disease or hypothyroidism, and type 1 diabetes mellitus (T1DM). Carpenter syndrome is a type of PAS-2 that includes the triad of Addison disease, autoimmune thyroid disease, and T1DM. This activity reviews the diagnosis and management of the Carpenter syndrome variant of PAS-2 and highlights the role of the interprofessional team in the early detection and management of this condition.
Objectives:
- Distinguish Carpenter's syndrome from other types of polyglandular autoimmune syndrome type 2.
- Explain signs and symptoms that should prompt consideration of polyglandular autoimmune syndrome type 2.
- Describe the management of Carpenter's syndrome.
- Explain how coordination of interprofessional teams can lead to earlier diagnosis of polyglandular autoimmune syndrome type 2, allowing for treatment aimed at minimizing comorbidities, leading to better patient outcomes.
Introduction
Polyglandular autoimmune syndrome (PAS) is a clustering of at least 2 or more endocrine diseases in a single patient. Common autoimmune polyglandular syndromes are PAS-1, PAS-2 and X-linked immune dysregulation polyendocrinopathy and enteropathy (IPEX).[1] Recently, a new category has emerged. It is iatrogenic polyendocrinopathy due to use of immunoregulatory agents in patients with cancer.[2] Ipilimumab which is used to treat metastatic cancer can cause hypophysitis. 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. In 1926, Schmidt published 2 cases of Addison disease and chronic lymphocytic thyroiditis known as Schmidt syndrome.[3] Five years later, in 1931, Rowntree and Snell reported the first case of Addison disease with hyperthyroidism and type 1 diabetes mellitus (T1DM).[3]. Beaven et al. reviewed 66 cases, and Solomon et al. reviewed 113 cases of Addison disease and diabetes mellitus.[3] Post-mortem investigation showed lymphocytic infiltration in the glands in the majority of these cases, confirming that it was an autoimmune disease. Carpenter confirmed the association of diabetes mellitus with Schmidt syndrome in a review of 142 cases of Schmidt syndrome and coined the term Carpenter syndrome, which is a triad of Addison disease, autoimmune thyroid disease, and TIDM.[4] This review focuses on the diagnosis and management of PAS-2 defined by the cluster of T1DM, auto-immune thyroid disease, and Addison disease.
Etiology
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 the 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.[2][4]
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).[1]
Epidemiology
PAS-2 is the commonest PAS. There is significant variability in reported prevalence ranging from 1:1000 to 1:20,000 in the general population.[1] It is around 3 times more common in women.[5] Typical age of onset is between 20 to 40 years.[2]
Pathophysiology
Polyglandular autoimmune syndrome type 2 is an autoimmune syndrome which leads to lymphocytic infiltration causing organ-specific damage.
History and Physical
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 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.[6]
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.[7]
Evaluation
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 and celiac disease, alopecia, vitiligo, pernicious anemia, idiopathic heart block, Stiff-man syndrome, Parkinson disease, IgA deficiency, serositis, dermatitis herpetiformis, idiopathic thrombocytopenia, and hypophysitis.[1][2][8]
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 250-mcg intravenous or intramuscular bolus of cosyntropin.[6] The presence of 21-hydroxylase or 17-hydroxylase autoantibodies can confirm autoimmune adrenalitis.[9] 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 with PAS-2 should watch for symptoms related to adrenal, thyroid and endocrine pancreatic dysfunction. Asymptomatic carriers should be followed on an annual basis.[1]
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 to 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 is often normal, but sometimes there is a decrease in the volume of the gland suggestive of atrophy.
Unfortunately, there is no reliable imaging technique which can indicate endocrine pancreatic disease.
Treatment / Management
Replacement with appropriate hormones is the key. These patients should be followed up by an interprofessional team lead 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, 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 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.[10] 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.
Enhancing Healthcare Team Outcomes
Patients affected with PAS-2 can face multiple challenges and may feel a significant burden due to the complexity of this disease. An interprofessional team approach for care and follow up of PAS-2 patients should be used because of the involvement of multiple endocrine and non-endocrine organs, and this team should be led by an endocrinologist. Interprofessional communications between different physicians taking care of the PAS-2 patient can be significantly improved by involving a case coordinator who can improve the quality of care. This can also prevent overtreatment and undertreatment. Treatment of autoimmune polyendocrine syndrome in an interprofessional setting can improve outcomes.[11] (Level III)
Polyglandular Autoimmune Syndrome Type II