Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome.Abstract: Hypothyroidism hypothyroidism: see thyroid gland. 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 adrenal /ad·re·nal/ (ah-dre´n'l)
2. adrenal gland.
3. pertaining to an adrenal gland.
1. failure. Clinicians should have a high index of suspicion index of suspicion Medtalk A phrase broadly used to indicate how seriously a particular disease is being entertained as a diagnosis; as an example, there is a high IOS that rapid and unexplained weight loss in an elderly Pt is due to pancreas CA, and a low IOS that 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 nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.
2. not directed against a particular agent, but rather having a general effect.
1. or serious illness, and patients with type 1 diabetes mellitus type 1 diabetes mellitus Brittle DM, insulin-dependent DM, juvenile-onset DM Endocrinology A severe form of DM caused by ↓ endogenous insulin production by the pancreas, which comprises +– 10% of DM Clinical Extreme hyperglycemia, lability of glucose whose insulin requirements drop without obvious explanation.
* The autoimmune destruction of several endocrine organs in autoimmune polyendocrinopathy syndrome type 2 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.
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 thyrotropin (thī'rätrō`pĭn) or thyroid-stimulating hormone (TSH), hormone released by the anterior pituitary gland that stimulates the thyroid gland to release thyroxine. was 230 [micro]IU/ml (normal range 0.35-5.5 [micro]IU/ml) with a decreased free thyroxine index free thyroxine index FT4I, T7 assay, T12 assay Endocrinology A lab value for T3 uptake combined with total T4; FTI is a clinical parameter measured by RIA, used to evaluate thyroid function, calculated by T4 x %T . Microsomal microsomal
pertaining to or emanating from microsome. 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 Euthyroid
Having the right amount of thyroxin stimulation.
Mentioned in: Goiter
having a normally functioning thyroid gland. by clinical and laboratory examination, her pulse and blood pressure remained low, and she appeared unusually tanned. PM serum cortisol cortisol (kôr`tĭsôl') or hydrocortisone, steroid hormone that in humans is the major circulating hormone of the cortex, or outer layer, of the adrenal gland. measured 1.2 [micro]g/dl (normal range, 3.0-15.0/ [micro]g/dl) withan adrenocorticotropin adrenocorticotropin /adre·no·cor·ti·co·trop·in/ (-kor?ti-ko-tro´pin) corticotropin.
ad·re·no·cor·ti·co·trop·in or ad·re·no·cor·ti·co·troph·in
See ACTH. (ACTH ACTH: see adrenocorticotropic hormone.
in full adrenocorticotropic hormone
Polypeptide hormone made in the pituitary gland. ) of 1,462 pg/ml (normal range, 9-52 pg/ml). The patient was treated for impending im·pend
intr.v. im·pend·ed, im·pend·ing, im·pends
1. To be about to occur: Her retirement is impending.
2. Addisonian crisis and has remained well on thyroid and adrenal replacement therapy with regular monitoring for associated conditions.
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 [micro]IU/ml, and a deceased thyroxine. Thyroid replacement therapy was initiated.
Two weeks later, the patient reported increasing fatigue and weakness to the extent &being unable to carry out daily activities. He also reported dizziness on standing and recent onset of nausea and vomiting Nausea and Vomiting Definition
Nausea is the sensation of being about to vomit. Vomiting, or emesis, is the expelling of undigested food through the mouth. . 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 pigmentation, name for the coloring matter found in certain plant and animal cells and for the color produced thereby. Pigmentation occurs in nearly all living organisms. 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 [micro]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. Alter initial inpatient management of Addisonian crisis, the patient has remained well on treatment with hydrocortisone hydrocortisone (hī'drəkôr`tĭzōn'), another name for the steroid hormone cortisol, more especially used to refer to preparations of this hormone used medicinally. and levothyroxine. He has not developed other manifestations of endocrine failure.
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 autoimmune failure of several endocrine organs known as autoimmune 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.
The original description by Schmidt in 1926 of autoimmune disease affecting more than one endocrine organ concerned a patient with thyroiditis Thyroiditis Definition
Thyroiditis is inflammation of the thyroid gland, a butterfly-shaped organ next to the windpipe.
The thyroid is the largest gland in the neck. and hypoadrenalism. (1,2) The syndrome is now defined as autoimmune adrenal disease associated with autoimmune thyroid disease and/or type 1 diabetes type 1 diabetes
See diabetes mellitus. 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 polyendocrinopathy syndromes (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 adrenocortical /adre·no·cor·ti·cal/ (-kor´ti-k'l) pertaining to or arising from the adrenal cortex.
Of, relating to, or derived from the adrenal cortex. 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 The age of onset is a medical term referring to the age at which an individual acquires, develops, or first experiences a condition or symptoms of a disease or disorder.
Diseases are often categorized by their ages of onset as congenital, infantile, juvenile, or adult. 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 cell-mediated immune response
The immune response produced when sensitized T cells attack foreign antigens and secrete lymphokines that initiate the body's humoral 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 haplotype /hap·lo·type/ (-tip) the group of alleles of linked genes, e.g., the HLA complex, contributed by either parent; the haploid genetic constitution contributed by either parent.
n. or related genes. (7) As HLA HLA human leukocyte antigens.
human leukocyte antigen
HLA (human leuckocyte antigen) 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 OMITTED]
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 polygenic /poly·gen·ic/ (pol?e-jen´ik) pertaining to or determined by several different genes.
adj. . (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 vitiligo
Skin disorder manifested by smooth, white spots on various parts of the body. Though the pigment-making cells of the skin, or melanocytes, are structurally intact, they have lost the ability to synthesize the pigment. , myasthenia gravis myasthenia gravis (mīəsthē`nēə grä`vĭs), chronic disorder of the muscles characterized by weakness and a tendency to tire easily. , thrombocytopenic purpura, Sjogren'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 [micro]g of ACTH and 30 and 60 minutes after injection. A cortisol level of 20 [micro]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 Hyponatremia Definition
The normal concentration of sodium in the blood plasma is 136-145 mM. Hyponatremia occurs when sodium falls below 130 mM. Plasma sodium levels of 125 mM or less are dangerous and can result in seizures and coma. is reported in 90% of patients, hyperkalemia Hyperkalemia Definition
The normal concentration of potassium in the serum is in the range of 3.5 to 5.0 mM. Hyperkalemia refers to serum or plasma levels of potassium ions above 5.0 mM. in 65%, and hypercalcemia Hypercalcemia Definition
Hypercalcemia is an abnormally high level of calcium in the blood, usually more than 10.5 milligrams per deciliter of blood. in 6 to 66% of patients. Eosinophilia eosinophilia /eo·sin·o·phil·ia/ (e?o-sin?o-fil´e-ah) abnormally increased eosinophils in the blood.
An increase in the number of eosinophils in the blood. 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. Medialert 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 Hypothyroid
Having too little thyroxin stimulation.
Mentioned in: Goiter
hypothyroid adjective Referring to hypothyroidism, see there 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.
Table 1. Clinical components of Schmidt's syndrome (APS2) (a) Disorder Prevalence Addison's Disease 100% Autoimnmne thyroid disease (b) 70-80% Type 1 Diabetes Mellitus 30-50% Hypogonadal conditions 5-50 Atrophic gastritis 10 Vitiligo 10 Pernicious anemia 5 Chronic hepatitis 4 Increased Incidence [less than or equal to] 1 Hypophysitis Alopecia Sjogren's syndrome Myasthenia gravis Thrombocytopenic purpura Rheumatoid arthritis (a) Data from References 1-3, 7, and 8. (b) May include Graves' disease, Hashimoto's, and other conditions. Table 2. Autoimmune polyendocrinopathy syndromes (a) Type 1 Endocrine abnormality Type 1 Chronic candidiasis Hypoparathyroidism Autoimmune Addition's disease High prevalence other conditions; e.g., pernicious anemia, hypogonadism, hepatitis, malabsorption Type 2 Autoimmune Addison's disease Autoimmune thyroid disease [+ or -] Type 1 diabetes mellitus Type 3 Autoimmune thyroid disease Other autoimmune disease excluding autoimmune adrenal or parathyroid Type 4 Two or more endocrine autoimmune conditions not classifiable as types 1, 2, or 3. Type 1 Clinical setting Type 1 Childhood onset: both sexes Rare, except in selected populations (Finland and Sardinia) Type 2 Middle-aged women Type 3 Patients may progress to type 2 Type 4 (a) Based on References l, 2, and 5.
(1.) Schmidt MB. Eine biglanduloma Erkrankung (Nebennieren und Schilddruse) bei Morbus Addisonii. Verh Dtsch Ges Pathol 1926;21:212-221.
(2.) Graber MA, Freed HA. Polyglandular autoimmune syndrome polyglandular autoimmune syndrome Either of 2, often overlapping endocrinopathies, characterized by gonadal failure, possibly 2º to hypothalamic defects with vitiligo and autoimmune adrenal insufficiency–80% have autoantibodies. : A cause of multiple and sequential endocrine emergencies. Am J Emerg Med 1992;10:130-132.
(3.) Betterle C, Dal Pra C, Greggio N, et al. Autoimmunity in isolated Addison's disease and in polyglandular autoimmune diseases type 1, 2, and 4. Ann Endocrinol 2001;62:193-201.
(4.) Riley WJ. Autoimmune polyglandular syndromes. Horm Res 1992;38: 9-15.
(5.) Khalil S, Evers ML. Case report: Autoimmune polyglandular syndrome. N J Med 1995;92:671-674.
(6.) Neufeld M, Blizzard RM. Polyglandular autoimmune diseases, in Pinchera A, Doniach D, Fenzi GF, Baschieri L (eds): Symposium on Autoimmune Aspects of Endocrine Disorders. New York, Academic Press, 1980, pp 357-365.
(7.) Vaidya vaidya /vai·dya/ (vi´dyah) [Sanskrit "one who knows"] in ayurveda, a physician. B, Pearce S, Kendall-Taylor P. Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure. Clin Endocrinol 2000;53:403-418.
(8.) Peterson P, Uibo R, Krohn KJ. Adrenal autoimmunity: Results and developments. Trends Endocrinol Metab 2000;11:285-290.
(9.) Muir A, Maclaren NK. Autoimmune diseases of the adrenal glands, parathyroid glands, gonads and hypothalamic-pituitary axis. Endocrinol Metab Clin North Am 1991;20:619-645.
(10.) Werbel SS, Ober KP. Acute adrenal insufficiency. Endocrinol Metab Clin North Am 1993;22:303-328.
(11.) Davenport J, Kellerman C, Reiss D, et al. Addison's disease. Am Fam Physician 1991;43:1338-1342.
(12.) Zelissen PM, Bast Bast, in Egyptian religion
Bast (băst), ancient Egyptian cat goddess. At first a goddess of the home, she later became known as a goddess of war. The center of her cult was at Bubastis. Her name also appears as Ubast. EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun 1995;8:121-130.
(13.) Chung AD, English JC. Cutaneous hyperpigmentation Hyperpigmentation Definition
Hyperpigmentation is the increase in the natural color of the skin.
Melanin, a brown pigment manufactured by certain cells in the skin called melanocytes, is responsible for skin color. and polyglandular autoimmune syndrome type II. Cutis cutis /cu·tis/ (ku´tis) the skin.
cutis anseri´na transitory elevation of the hair follicles due to contraction of the arrectores pilorum muscles; a reflection of sympathetic nerve discharge. 1997;59:77-80.
From the Division of Metabolism, Endocrinology and Genetics, Departments of Internal Medicine and Anatomy and Cell Biology, University of Kansas The University of Kansas (often referred to as KU or just Kansas) is an institution of higher learning in Lawrence, Kansas. The main campus resides atop Mount Oread. Medical Center, Kansas City, Kansas Kansas City, Kansas (KCK) is the third largest city in the U.S. state of Kansas and the county seat of Wyandotte County (WyCo); it is part of the "Unified Government" which also includes the cities of Bonner Springs and Edwardsville. , and the Department of Family and Community Medicine, University of Kansas School of Medicine--Wichita, Wichita, Kansas.
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: firstname.lastname@example.org
Accepted August 12, 2002.