Addisonian Crisis Precipitated by Thyroxine Therapy: A Complication of Type 2 Autoimmune Polyglandular Syndrome

Leland Graves III, MD, Robert M. Klein, PHD, Anne D. Walling, MD


South Med J. 2003;96(8) 

In This Article


The original description by Schmidt in 1926 of autoimmune disease affecting more than one endocrine organ concerned a patient with thyroiditis and hypoadrenalism.[1,2] The syndrome is now defined as autoimmune adrenal disease associated with autoimmune thyroid disease and/or type 1 diabetes and is referred to as APS2. The most common combination (around 75% of cases) is of thyroid and adrenal failure, and either organ may fail first.[3] In those patients who have a combination of type 1 diabetes and adrenal failure, the diabetes typically occurs first,[4] and an unexpected fall in insulin requirements may be the earliest indication of impending adrenal failure.[5] About 10% of cases have all three of the major conditions[3] (type 1 diabetes mellitus plus autoimmune adrenal and thyroid disease). Other autoimmune diseases, especially of the skin, stomach, and gonads, occur with increased frequency in patients with APS2 ( Table 1 ).

APS2 is one of a group of autoimmune polyendocrinopasyndromes ( Table 2 ),[6] but new findings in molecular biology and genetics[7,8] may lead to changes in classification. The traditional concept of distinct autoimmune endocrine diseases (such as Addison's and Hashimoto's diseases), each resulting in damage to a specific end organ, is being expanded to include appreciation of autoimmune attack on multiple endocrine organs. The autoimmune process is increasingly recognized as directed against enzymes.[9] It is now estimated that 40 to 50% of autoimmune adrenocortical failure (classical Addison's disease) are due to APS2.[10] Patients with one autoimmune endocrinopathy should be considered at risk of failure of other endocrine organs regardless of classification or original diagnosis. The prevalence of APS2 is estimated to be 1.5 to 4.5/100,000 population.[3] The condition is most common in middle-aged women, with average age of onset between 35 and 40 years and a female/male ratio of around 4:1.[3]

The destructive process in APS2 is believed to be a cell-mediated immune response and a loss of self-tolerance (Fig 1). Although the genetic basis of the condition has not been clearly defined, it is strongly linked to various alleles within the HLA-DR3-carrying haplotype or related genes.[7] As HLA molecules largely determine T-cell responses to antigens, both an external antigen stimulus and a genetic susceptibility may be required to initiate the autoimmune destructive process. The wide range of endocrine-related autoantibodies reported in APS2 indicates that B cells are activated and contribute to the pathologic process (Fig. 1).[8] Extensive tissue destruction must occur before the process becomes clinically apparent; one report estimated that 80 to 90% of adrenal tissue must be destroyed before symptoms of Addison's disease occur.[11]

Schematic of involvement of both B-cell and T-cell responses in polyglandular autoimmunity. (IFN- , interferon- ; IL-2, interleukin 2; CTL, cytotoxic T lymphocytes; Ab,antibody; MHC, major histocompatability complex.)

The highest risk for polyglandular failure exists in patients with autoimmune adrenal failure and individuals with a family history of polyglandular failure. Approximately half of patients with APS2 report a family history of polyglandular failure. Several modes of inheritance have been suggested, including autosomal recessive, autosomal dominant, and polygenic.[3,8] The index of suspicion should also be elevated in patients with autoimmune adrenal insufficiency as at least half of these patients have one or more additional autoimmune endocrine disorders.[12] Patients with Addison's disease should be evaluated for thyroid dysfunction, type 1 diabetes mellitus, and pernicious anemia. In addition to thorough history and physical examination, laboratory assessment of autoantibodies to thyroid, adrenal, and parietal cell tissues may reveal potential endocrine failure. Associated conditions such as vitiligo, myasthenia gravis, thrombocytopenic purpura, Sjögren's syndrome, rheumatoid arthritis, and primary antiphospholipid syndrome should be considered in patients with APS2. In some cases, these conditions may be the initial indication of APS2.

In contrast to patients who present with Addison's disease, less than 1% of patients with autoimmune thyroid disease or type 1 diabetes develop adrenal insufficiency. Screening for adrenal insufficiency is not indicated unless there is a suggestive family history or clinical suspicion (including detection of one of the associated conditions listed above). Assessment of thyroid function is recommended in patients with type 1 diabetes. Unexplained reduction in insulin requirements should prompt a search for thyroid and/or adrenal insufficiency.

Laboratory confirmation of thyroid dysfunction is best achieved with serum free thyroxine and thyrotropin-secreting hormone assessments. Adrenal insufficiency is more difficult to document owing to the variable secretion of cortisol and broad range of normal values. The two patients presented had profound adrenal failure. Patients with partial or compensated adrenal failure may have normal basal cortisol levels but be unable to produce a stress response. If the clinical suspicion is high but cortisol levels are normal, an ACTH stimulation test provides the best assessment of adrenal function. In this test, serum cortisol is measured before IV administration of 250 µg of ACTH and 30 and 60 minutes after injection. A cortisol level of 20 µg/dl or greater at any point during the test indicates normal adrenal function.

Patients with adrenal failure may show multiple abnormalities of blood chemistry depending on the degree of destruction of the affected endocrine organs. Hyponatremia is reported in 90% of patients, hyperkalemia in 65%, and hypercalcemia in 6 to 66% of patients. Eosinophilia is reported in 20% of cases.[13]

The management of APS2 is based on individualized, lifelong replacement therapy for the affected endocrine organs plus monitoring for development of insufficiency in other organs or the associated conditions listed in Table 1 . Patients must be monitored regularly with history, physical examination, and appropriate laboratory evaluation. Medi-alert and other measures should be taken to ensure that adrenal function is taken into consideration during illness, surgery, or emergency situations. Family members should also be made aware of the increased risk of endocrine disease, especially of APS2.

The great danger in APS2 (as illustrated by these cases) is treatment of a presenting hypothyroid state without recognition of concomitant hypoadrenalism. This may precipitate Addisonian crisis through two mechanisms. First, hypothyroidism reduces cortisol clearance. The addition of thyroid hormone replacement increases cortisol clearance, thus decreasing circulating cortisol availability. Second, hypothyroidism reduces the metabolic rate thereby reducing the need for cortisol. The increased metabolic rate accompanying thyroxine replacement increases the cortisol requirements that cannot be provided by the failing adrenals. Patients may die from ensuing Addisonian crisis.


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