Polyglandular Autoimmune Syndrome, Type II (Carpenters, Schmidt)


Article Author:
Gurdeep Singh


Article Editor:
Ishwarlal Jialal


Editors In Chief:
Jon Parham
Abigail Frank
Jon Sivoravong


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
4/2/2019 4:38:19 PM

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 immunodysregulation polyendocrinopathy and enteropathy (IPEX).[1] Recently, a new category has emerged. It is iatrogenic polyendocrinopathy due to use of immunoregulatory agents in cancer patients.[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. 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

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 mean age 27.5 years while other diseases manifested around age 36.5 to 40 years. 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 2.5-fold increase risk 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] 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, presence of anti-thyroglobulin antibodies, thyroid microsomal antibodies and thyrotropin receptor antibodies (Graves' disease) can detect patients at risk of thyroid disease in 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 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.

Timely diagnosis of PAS-2  requires knowledge of the complete spectrum of this disease. Complete history and thorough physical exam may give important clues. In many cases, 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 pattern 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. 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 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 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 outcome.[11] (Level III)


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Polyglandular Autoimmune Syndrome, Type II (Carpenters, Schmidt) - Questions

Take a quiz of the questions on this article.

Take Quiz
Which of the following presents with concurrent coronal, sagittal, and lambdoid craniosynostosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 32-year-old white male with previous history of diabetes mellitus type 1 has been having symptoms of fatigue, nausea, weight loss and darkening of the skin. His provider ordered thyroid function tests and found that he has hypothyroidism due to Hashimoto thyroiditis with TSH 25 mIU/L (reference range 0.5-5 mIU/L), T4 free 0.6 ng/dl (reference range 0.8-1.8 ng/dl, thyroid peroxidase antibodies greater 1300 IU/ml (reference range less than 2 IU/ml). He was started on levothyroxine 100 mcg daily. He is at risk of which complication?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which genetic mutation is not seen in autoimmune polyglandular syndrome type 2?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 40-year-old woman with the diagnosis of autoimmune polyendocrine syndrome type 2 is worried that 1-year old daughter who is healthy and recently had normal physical exam may also develop autoimmune polyendocrine syndrome type 2. What is the typical age of presentation of autoimmune polyglandular syndrome type 2?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following statement is not true about autoimmune polyendocrine syndrome type 2?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not a feature to diagnose autoimmune polyendocrine syndrome (APS) type 2?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Polyglandular Autoimmune Syndrome, Type II (Carpenters, Schmidt) - References

References

Husebye ES,Anderson MS,Kämpe O, Autoimmune Polyendocrine Syndromes. The New England journal of medicine. 2018 Mar 22     [PubMed]
Sperling M,Yau M, Autoimmune Polyglandular Syndromes null. 2000     [PubMed]
Betterle C,Lazzarotto F,Presotto F, Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clinical and experimental immunology. 2004 Aug     [PubMed]
CARPENTER CC,SOLOMON N,SILVERBERG SG,BLEDSOE T,NORTHCUTT RC,KLINENBERG JR,BENNETT IL Jr,HARVEY AM, SCHMIDT'S SYNDROME (THYROID AND ADRENAL INSUFFICIENCY). A REVIEW OF THE LITERATURE AND A REPORT OF FIFTEEN NEW CASES INCLUDING TEN INSTANCES OF COEXISTENT DIABETES MELLITUS. Medicine. 1964 Mar     [PubMed]
Förster G,Krummenauer F,Kühn I,Beyer J,Kahaly G, [Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation]. Deutsche medizinische Wochenschrift (1946). 1999 Dec 10     [PubMed]
Cutolo M, Autoimmune polyendocrine syndromes. Autoimmunity reviews. 2014 Feb     [PubMed]
Brandão Neto RA,de Carvalho JF, Diagnosis and classification of Addison's disease (autoimmune adrenalitis). Autoimmunity reviews. 2014 Apr-May     [PubMed]
Dittmar M,Kahaly GJ, Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. The Journal of clinical endocrinology and metabolism. 2003 Jul     [PubMed]
Wang X,Ping F,Qi C,Xiao X, Delayed diagnosis with autoimmune polyglandular syndrome type 2 causing acute adrenal crisis: A case report. Medicine. 2016 Oct     [PubMed]
Meyer G,Badenhoop K,Linder R, Addison's disease with polyglandular autoimmunity carries a more than 2·5-fold risk for adrenal crises: German Health insurance data 2010-2013. Clinical endocrinology. 2016 Sep     [PubMed]
Gouda MR,Al-Amin A,Grabsch H,Donnellan C, A multidisciplinary approach to management of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). BMJ case reports. 2013 Jan 30     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Family Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Family Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Family Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Family Medicine. When it is time for the Family Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Family Medicine.