DEFINITION

• Schmidt syndrome refers to the combination of autoimmune primary adrenal insufficiency (Addison’s disease) with autoimmune hypothyroidism and/or type 1 diabetes mellitus (T1DM), and is part of a larger syndrome known as autoimmune polyendocrine syndrome type 2 (APS-2) or polyglandular autoimmune syndrome type II (PAS II).
• In 1926, Schmidt M.B. described 2 patients with non-tuberculous Addison’s disease and thyroiditis, in both organs lymphocytic infiltration was found. Schmidt syndrome was initially reported as a biglandular disease. Later in 1964, Carpenter C.C. confirmed that T1DM was part of this syndrome.[14]
• The term Schmidt syndrome is sometimes used interchangeably with APS-2 or PAS II.
• APS-2 is a polygenic disorder, which may include autoimmune thyroid disease (hypothyroidism or hyperthyroidism), T1DM, Addison’s disease, primary hypogonadism, and less commonly hypoparathyroidism or hypopituitarism.[7]
• Associated non-endocrine autoimmune conditions may be present including vitiligo, celiac disease, alopecia, pernicious anemia, myasthenia gravis, idiopathic thrombocytopenic purpura, Sjogren’s syndrome, and rheumatoid arthritis.[7]
• Further classifying APS-2 into subtypes (i.e APS-3 and APS-4) has been suggested by some authors who consider a specific genetic (HLA) background in each group.[3]Other authors consider that there is not strong evidence supporting different causes in these subtypes.[2]

EPIDEMIOLOGY

• APS-2 is the most common autoimmune polyendocrine syndrome.[6]It has a prevalence of 1:20,000 in the general population, an annual incidence of 1-2:100,000 and a 3:1 ratio of females to males affected.[3]
• Peak incidence: 3rd - 4th decade of life.
• APS-2 has familial clustering with multiple family members often affected.
• In patients with APS-2, autoimmune thyroid disease is present in 70-75%, T1DM in 40-60% and Addison’s disease in 40-50% [3]
• The mode of inheritance is complex as it is a polygenic disorder with autosomal dominant inheritance and incomplete penetrance.[7][2]
• Associated with genes coding for protein that regulate the adaptive and innate immune system, mainly HLA genes. HLA-DR3, HLA-DR4, and non HLA genes, MICA5.1, CTLA-4, PTPN22, BACH, VTNR and the CD25-IL-2 receptor have been associated. Environmental risk factors may also contribute. [7][3][2][13]
• Among patients with T1DM, < 1% of patients have Addison’s disease, whereas 2-5% have autoimmune thyroid disease (mainly hypothyroidism) and up to 5% have celiac disease.[12]Up to 33% may have thyroid autoantibodies and 12% have transglutaminase autoantibodies.[10]
• Type 1 diabetes patients who developed autoimmune thyroid disease had an interval of 13.3 +/- 11.8 years between first and second endocrinopathies with variable interval seen in development of other autoimmune conditions.[11]

DIAGNOSIS

• Currently there are no specific test to detect APS-2.[2] Antibody screening identifies patients at risk.
• The diagnosis of component disorders of APS-2 is the same as that of the individual disorders.
• Diagnosis of T1DM and celiac disease are reviewed elsewhere.
• Diagnosis of Addison’s disease (primary adrenal insufficiency due to autoimmune adrenalitis) is based on the following: 1) early morning (i.e. 7-9 am) serum cortisol < 3 mcg/dL or a serum cortisol less than 18 mcg/dL 30 to 60 minutes after an IV bolus of cosyntropin (ACTH), strongly suggests adrenal insufficiency (AI), (the cutoffs can vary, they are assay-specific); 2) elevated basal serum ACTH level, supports a primary AI; and 3) antibodies to 21-hydroxylase aid in diagnosing of autoimmune primary AI.[5][4]
• In APS-2, the titers of antibodies to 21-hydroxylase decrease as the disease progresses, therefore the diagnostic value is highest early in the course.[15]Interestingly, in asymptomatic patients with positive antibodies the development of clinical Addison’s disease in APS-2 takes longer than in APS-1.[1]
• Diagnosis of primary hypothyroidism is based on: 1) an elevated serum TSH and low (or normal in subclinical disease) serum free T4 level, whereas hyperthyroidism is diagnosed based on a low TSH with elevated (or normal in subclinical disease) serum free T4 and/or total T3; and 2) the presence of antithyroid antibodies (e.g. anti-thyroid peroxidase (formerly anti-microsomal antibodies), anti-thyroglobulin antibodies, thyroid stimulating immunoglobulins) can be useful for confirming autoimmune etiology (see thyroid function tests module ).

SIGNS AND SYMPTOMS

• In a patient with T1DM, Addison’s disease may present as hypoglycemia and fatigue, which can be intermittent and/or severe. Decreased insulin requirements, hypotension, weight loss, hyperpigmentation, and vitiligo may be present.
• Other symptoms consistent with adrenal insufficiency include dizziness and orthostasis, anorexia, weakness, nausea, emesis and abdominal pain, salt craving.[5][4]
• Hypothyroidism in a patient with type I diabetes may also present with fatigue, decreased insulin requirements, and hypoglycemia, whereas hyperthyroidism is associated with increased insulin requirements and hyperglycemia.
• Associated laboratory findings in Addison’s disease include hyponatremia, hyperkalemia, hypoglycemia, anemia, eosinophilia, elevated thyrotropin (TSH). In hypothyroidism hyponatremia, hypoglycemia, anemia, hyperlipidemia can be present. Signs and symptoms of related autoimmune conditions (e.g. alopecia, celiac disease) may be present.

CLINICAL TREATMENT

• Treatment of the component disorders of APS-2 is the same as that of the individual disorders.
• Treatment of primary hypothyroidism: physiologic thyroid hormone replacement with levothyroxine. Typical replacement dose is 1.6 mcg/kg per day (lower doses in elderly and those with cardiac disease) and adjusted every 4-6 weeks initially to maintain TSH and thyroxine levels in the mid normal range.
• Chronic treatment of Addison’s disease: physiologic glucocorticoid and mineralocorticoid replacement. Initial glucocorticoid regimen can be hydrocortisone 15-25 mg per day given in 2-3 divided doses and adjusted to relieve symptoms of glucocorticoid deficiency and avoid manifestations of glucocorticoid excess. Usual initial mineralocorticoid regimen is fludrocortisone 0.1 mg/day, adjusted as necessary with monitoring of blood pressure, volume status, weight, plasma renin activity, sodium, and potassium.
• Treatment of Addison’s disease in acute illness or surgery requires increased dosing of glucocorticoid therapy according to the degree of stress.
• Patients should be given medical alert bracelet and prescribed hydrocortisone self-injection emergency kit.

FOLLOW UP

• Antibody screening may help identify patients at risk for developing autoimmune gland failure. Those with Addison’s should be screened for antibodies against IA-2, insulin, GAD65 to test for type I diabetes predisposition, anti-thyroid peroxidase to assess for hypothyroidism risk, and tissue transglutaminase autoantibodies to screen for celiac disease. However, an evidence based approach to antibody screening is lacking and optimal screening interval is unknown[10]
• Those with PAS-II should be provided information about other associated autoimmune conditions and asked to monitor for particular symptoms.

EXPERT COMMENTS

• Recommend screening of children with T1DM at diagnosis for hypothyroidism (by measuring serum TSH and anti-thyroid peroxidase antibody) and celiac disease (by measuring tissue transglutaminase antibodies), and in all persons with T1DM whenever symptoms are present.
• In the absence of symptoms, routine screening for Addison’s disease or other associated PAS II autoimmune conditions is not recommended.
• Caution: In a patient with coexisting hypothyroidism and Addison’s disease, starting thyroid hormone therapy prior to replacement of glucocorticoids can precipitate acute adrenal insufficiency and crisis.
• Immune therapies are in development, and may be useful for prevention and to moderate progression of disease.

References

1. Naletto L, Frigo A, Ceccato F, et al. THE NATURAL HISTORY OF AUTOIMMUNE ADDISON'S DISEASE FROM THE DETECTION OF AUTOANTIBODIES TO DEVELOPMENT OF THE DISEASE: A LONG FOLLOW-UP STUDY ON 143 PATIENTS. Eur J Endocrinol. 2019.  [PMID:30608902]
2. Husebye ES, Anderson MS, Kämpe O. Autoimmune Polyendocrine Syndromes. N Engl J Med. 2018;378(12):1132-1141.  [PMID:29562162]
3. Kahaly GJ, Frommer L. Polyglandular autoimmune syndromes. J Endocrinol Invest. 2018;41(1):91-98.  [PMID:28819917]
4. Bancos I, Hahner S, Tomlinson J, et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216-26.  [PMID:25098712]
5. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-67.  [PMID:24503135]
6. Cutolo M. Autoimmune polyendocrine syndromes. Autoimmun Rev. 2014;13(2):85-9.  [PMID:24055063]
7. Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol. 2010;6(5):270-7.  [PMID:20309000]
8. Owen CJ, Cheetham TD. Diagnosis and management of polyendocrinopathy syndromes. Endocrinol Metab Clin North Am. 2009;38(2):419-36, x.  [PMID:19328420]
9. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009;161(1):11-20.  [PMID:19411300]
10. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350(20):2068-79.  [PMID:15141045]
11. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. 2003;88(7):2983-92.  [PMID:12843130]
12. Förster G, Krummenauer F, Kühn I, et al. [Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation]. Dtsch Med Wochenschr. 1999;124(49):1476-81.  [PMID:10629665]
13. Eisenbarth G, Wilson P, Ward F, et al. HLA type and occurrence of disease in familial polyglandular failure. N Engl J Med. 1978;298(2):92-4.  [PMID:619238]
14. CARPENTER CC, SOLOMON N, SILVERBERG SG, et al. 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 (Baltimore). 1964;43:153-80.  [PMID:14132718]
15. Peterson P, Husebye ES. The Autoimmune Diseases. Chapter 43: Polyendocrine Syndromes. 5th ed. Rose NR, Mackay IR, editors. Academic Press; 2014. 605-618 p