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


Physicians should be alert to the potential for additional endocrine conditions, particularly adrenal failure, in all patients with autoimmune endocrine diseases, especially those with insulin-dependent diabetes and autoimmune thyroid conditions.

South Med J 96(8) 2003


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


Abstract and Introduction


Hypothyroidism is a common condition. Rarely, it may occur in combination with autoimmune failure of other endocrine glands (autoimmune polyendocrinopathy syndrome type 2, previously known as Schmidt's syndrome). In such cases, restoring normal thyroid function may precipitate adrenal failure. Clinicians should have a high index of suspicion for this condition in patients with Addison's disease, those with a family history of autoimmune endocrine gland failure, patients with one autoimmune endocrine disease who develop nonspecific or serious illness, and patients with type 1 diabetes mellitus whose insulin requirements drop without obvious explanation.



Both autoimmune thyroid disease and type 1 diabetes mellitus are common conditions. Rarely, one or both of these conditions is the presenting feature of potentially fatal auto-immune failure of several endocrine organs known as auto-immune polyendocrinopathy syndrome type 2 (APS2). A high index of suspicion for adrenal failure should be maintained when patients with autoimmune thyroid disease or type 1 diabetes mellitus develop nonspecific but serious illness.


Case Reports

Patient 1

A 44-year-old white woman consulted her primary care physician because of fatigue increasing over several months. Additional symptoms of numbness of her hands and feet, change in skin condition from oily to dry, and recent onset of breathlessness on exertion were elicited by detailed questioning. The patient appeared unusually well and was coping with a busy schedule as a day-care provider as well as being responsible for her own four children plus two elderly relatives. Her pulse rate of 60 beats/min and blood pressure of 90/60 mm Hg were not significantly different from previous readings, but a weight loss of approximately 10 pounds had occurred during the previous 18 months. Family history and physical examination revealed no significant new information. On initial testing, her thyrotropin was 230 ?IU/ml (normal range 0.35-5.5 ?IU/ml) with a decreased free thyroxine index. Microsomal antibodies were significantly increased at 2,966 IU/ml (normal range, 0-99 IU/ml). A diagnosis of autoimmune hypothyroidism was made, and she quickly improved both clinically and by laboratory evaluation with thyroid replacement therapy. Approximately 4 months later, the patient reported return of fatigue and had lost an additional 2 pounds in weight. In spite of being euthyroid by clinical and laboratory examination, her pulse and blood pressure remained low, and she appeared unusually tanned. PM serum cortisol measured 1.2 ?g/dl (normal range, 3.0 -15.0 ?g/dl) with an adrenocorticotropin (ACTH) of 1,462 pg/ml (normal range, 9-52 pg/ml). The patient was treated for impending Addisonian crisis and has remained well on thyroid and adrenal replacement therapy with regular monitoring for associated conditions.


Patient 2

A 25-year-old white man consulted his primary care physician because of inability to continue his aggressive physical fitness program owing to progressive fatigue, weakness, and unintentional weight loss of 15 pounds during a 4-month period. He had previously been in excellent health and participated in endurance sports. Family history was significant for hypothyroidism in his maternal grandfather and two aunts. On physical examination he appeared healthy, with a blood pressure of 110/70 mm Hg and a resting pulse of 60 beats/min. His skin was mildly dry, but no other significant features were noted. Laboratory testing confirmed hypothyroidism with an elevated thyrotropin of 68 ?IU/ml, and a deceased thyroxine. Thyroid replacement therapy was initiated.


Two weeks later, the patient reported increasing fatigue and weakness to the extent of being unable to carry out daily activities. He also reported dizziness on standing and recent onset of nausea and vomiting. On examination, he appeared acutely ill, with tachycardia (120 beats/min). His supine blood pressure of 90/60 mm Hg fell to 80/50 mm Hg on sitting, and he was unable to stand because of dizziness. His skin was universally tanned, with excessive pigmentation in the palmar creases. The diagnosis of Addison's disease was confirmed by laboratory testing. Electrolyte studies showed a decrease in serum sodium and bicarbonate with an elevation of potassium, a decreased serum cortisol of 2.2 ?g/dl, and elevated ACTH of 639 pg/ml (normal range, 9-52 pg/ml), all consistent with Addison's disease. Antimicrosomal, antithyroglobulin, and antiparietal cell antibodies were all significantly elevated. After initial inpatient management of Addisonian crisis, the patient has remained well on treatment with hydrocortisone and levothyroxine. He has not developed other manifestations of endocrine failure.



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]





Figure 1. 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, Sj?gren'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 ?g of ACTH and 30 and 60 minutes after injection. A cortisol level of 20 ?g/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.



The autoimmune destruction of several endocrine organs in APS2 results in clinical adrenal failure plus autoimmune thyroid disease or type 1 diabetes mellitus. Research indicates that autoimmune processes commonly attack multiple endocrine organs, although this may not result in sufficient damage to produce clinical symptoms. Physicians should be alert to the potential for additional endocrine conditions, particularly adrenal failure, in all patients with autoimmune endocrine diseases, especially those with insulin-dependent diabetes and autoimmune thyroid conditions.


Reprint Address


Reprint requests to Leland Graves III, MD, Division of Endocrinology, Metabolism, and Genetics, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Email: lgraves@kumc.edu


Leland Graves III, MD, Robert M. Klein, PHD, and Anne D. Walling, MD, Division of Metabolism, Endocrinology and Genetics, Departments of Internal Medicine and Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, and the Department of Family and Community Medicine, University of Kansas School of Medicine - Wichita, Wichita, Kansas


South Med J 96(8):824-827, 2003. ? 2003 Lippincott Williams & Wilkins

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