Johns Hopkins Diabetes GuideComplications and ComorbiditiesEndocrine

Schmidt Syndrome

Amin Sabet, M.D., Reshmi Srinath, M.D.

DEFINITION

  • Schmidt syndrome refers to the combination of autoimmune 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 II or polyglandular autoimmune syndrome type II (PAS II).
  • The term Schmidt syndrome is sometimes used interchangeably with PAS II.
  • PAS II 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. More common than other polyglandular autoimmune disorders [5].
  • 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.

EPIDEMIOLOGY

  • Schmidt Syndrome: 1:20,000 prevalence in general population with 3:1 ratio of females to males affected [4]
  • Peak incidence: 3rd - 4th decade of life
  • Familial clustering with multiple family members often affected
  • Autosomal dominant inheritance with variable penetrance. Associated with certain HLA antigens HLA-DR3, HLA-DR4, non HLA gene M-ICA and CTLA-4 [5] [1].
  • 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 [4]. Up to 33% may have thyroid autoantibodies and 12% have transglutaminase autoantibodies [3]
  • 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 [8].

DIAGNOSIS

  • Diagnosis of component disorders of PAS II 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 60 minutes after a 250 mcg IV bolus of cosyntropin (ACTH), is strongly suggestive; 2) elevated basal serum ACTH level; 3) early morning 8 AM salivary cortisol < 5 nmol/L (testing only recommended if high suspicion for falsely low serum cortisol due to low cortisol binding globulins); 4) Antibodies to 21-hydroxylase may aid in making the diagnosis if detectable. Abdominal CT to evaluate for other causes of adrenal insufficiency (infection, hemorrhage, metastases) is recommended 5) presence of other autoimmune disorders [2].
  • Diagnosis of primary hypothyroidism is based on an elevated serum TSH and low (or normal in subclinical disease) serum T4 level, whereas hyperthyroidism is diagnosed based on a low TSH with elevated (or normal in subclinical disease) serum T4 and/or T3. The presence of antithyroid antibodies (e.g. anti-thyroglobulin antibodies, anti-microsomal 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 intermittent, severe hypoglycemia and intermittent, severe fatigue. 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 [2].
  • 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 lab findings include hyponatremia, hyperkalemia, hypoglycemia, anemia, eosinophilia, elevated thyrotropin and low thyroxine.
  • Signs and symptoms of related autoimmune conditions (e.g. alopecia, celiac disease) may be present.

CLINICAL TREATMENT

  • Treatment of the component disorders of PAS II is the same as that of the individual disorders.
  • Treatment of primary hypothyroidism: physiologic thyroid hormone replacement with levothyroxine. Typical initial dose is 1.6 mcg/kg per day (lower dose in elderly and those with cardiac disease) and adjusted every 4-6 weeks to maintain TSH and thyroxine in 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 fludorcortisone 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 physiologic 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, GAD 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 [3].
  • 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. Eisenbarth G et al: HLA type and occurrence of disease in familial polyglandular failure. N Engl J Med 298:92, 1978  [PMID:619238]

    Comment: Association of HLA antigens with PAS.

  2. Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet 383:2152, 2014  [PMID:24503135]
  3. Eisenbarth GS, Gottlieb PA: Autoimmune polyendocrine syndromes. N Engl J Med 350:2068, 2004  [PMID:15141045]
  4. Förster G et al: [Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation]. Dtsch Med Wochenschr 124:1476, 1999  [PMID:10629665]

    Comment: Reviews epidemiology of PAS II.

  5. Michels AW, Gottlieb PA: Autoimmune polyglandular syndromes. Nat Rev Endocrinol 6:270, 2010  [PMID:20309000]
  6. Kahaly GJ: Polyglandular autoimmune syndromes. Eur J Endocrinol 161:11, 2009  [PMID:19411300]

    Comment: Provides review of the pathophysiology and role of genetic testing in PAS.

  7. Owen CJ, Cheetham TD: Diagnosis and management of polyendocrinopathy syndromes. Endocrinol Metab Clin North Am 38:419, 2009  [PMID:19328420]

    Comment: Reviews diagnosis and management of polyendocrinopathy syndromes.

  8. Dittmar M, Kahaly GJ: Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab 88:2983, 2003  [PMID:12843130]

    Comment: Type 1 diabetes patients who developed autoimmune thyroid disease had an interval of 13.3 +/- 11.8 years between first and second endocrinopathies.

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Last updated: February 26, 2015