Autoimmune polyglandular syndrome II: clinical syndrome and treatment

Endocrinol Metab Clin N Am 31 (2002) 339–352

Autoimmune polyglandular syndrome II: clinical syndrome and treatment Desmond A. Schatz, MDa,*, William E. Winter, MDa,b a

Department of Pediatrics, Box 100296, JHMCH, University of Florida, Gainesville, FL 32610, USA b Department of Pathology, Immunology, and Laboratory Medicine, Box 100275, JHMCH, University of Florida, Gainesville, FL 32610, USA

The autoimmune polyglandular syndromes (APSs) are recognizable patterns of coexistent autoimmune endocrine disorders (e.g., immunoendocrinopathies). Nonendocrine autoimmune disorders can also serve as integral components of the APS. These conditions are uncommon in the general population; APS Type II (APS II) is however more common than APS Type I (APS I). In 1849, Thomas Addison’s first described clinical and pathological features of adrenocortical failure in patients who likely also had pernicious anemia [1]. In 1908, Claude and Gourgerot implicated a common pathogenetic mechanism for polyglandular insufficiencies (adrenal, gonadal, islet, thyroid, anterior pituitary) [2]. Shortly afterwards, Parkinson described the association of diabetes with pernicious anemia [3]. In 1912, Hashimoto was the first to describe mononuclear infiltration of a goitrous thyroid gland [4]. In 1926, Schmidt described the occurrence of lymphocytic infiltrates of both the thyroid and adrenal glands in autopsies of two patients dying from addisonian crisis (Schmidt syndrome) [5]. Von Myenburg described a similar histopathologic lesion of the pancreatic islets, termed insulitis, in 1940 [6]. In 1959, Beaven et al. and Carpenter et al. 5 years later subsequently described the association between Schmidt Syndrome and Type 1 diabetes (Carpenter syndrome) [7,8]. The identification by Roitt et al. in 1956 of autoantibodies to thyroglobulin in patients with Hashimoto thyroiditis was followed by the identification of autoantibodies to the adrenal cortex, gastric parietal cells, islet cells, and steroid-producing gonadal cells and appreciation of a

Supported in part by grant RR00082 from the GCRC. * Corresponding author. E-mail address: [email protected]fl.edu (D.A. Schatz). 0889-8529/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 8 9 - 8 5 2 9 ( 0 1 ) 0 0 0 1 2 - 3

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common autoimmune basis for these immunoendocrine disease associations [9,10]. In 1980, Neufeld et al. classified the autoimmune polyglandular syndromes into two distinct syndromes, APS I and II [11,12]. APS II (Table 1) is defined by the coexistence of autoimmune adrenocortical insufficiency (AAI), or serologic evidence of adrenalitis with either autoimmune thyroid disease (AITD), or Type I diabetes mellitus (T1DM) [11–17]. Adrenal failure or autoantibodies plus autoimmune thyroiditis is termed Schmidt syndrome. Adrenal failure or autoantibodies plus AITD and T1DM constitute Carpenter syndrome. AITD encompasses a spectrum of thyroid disorders, including atrophic thyroiditis, euthyroid thyroid-autoantibody-positive goiter, and Graves’ disease. The presence of AITD without adrenal disease but associated with either T1DM, pernicious anemia, vitiligo, or alopecia has been referred to as APS III. Alternatively, and most commonly, investigators refer to these latter associations by name exclusive of the APS nomenclature. For example, instead of APS III, coexistent AITD and autoimmune pernicious anemia are termed thyrogastric autoimmunity.

Clinical aspects APS II Unlike APS I, APS II usually has its onset in adulthood, particularly during the third or fourth decades, although APS II may occur at any age. APS II is at least three times more common in females than males. In approxiTable 1 APS I and II

Comparative frequency Onset Heredity Gender Genetics Hypoparathyoidism Mucocutaneous candidiasis Ectodermal dysplasia Addison’s disease Type 1 diabetes Autoimmune thyroid disease Pernicious anemia Gonadal failure Females Males Vitiligo Alopecia Autoimmune hepatitis Malabsorption

APS I (%)

APS II (%)

Less common Infancy/early childhood Autosomal recessive Males ¼ females AIRE gene; no HLA association 77–89 73–100 77 60–86 4–18 8–10 12–15

More common Late childhood, adulthood Polygenic Female predominance HLA associated; DR/DQ None None None 70–100 41–52 70 2–25

30–60 7–17 4–13 27 10–15 10–18

3.5–10 5 4–5 2 Rare Rare

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mately 50% of APS II cases, adrenocortical failure is the initial endocrine abnormality. Several of the disease components may be present at diagnosis, and thus the clinician should be alerted to the possibility of a second major endocrine disorder once one component of the syndrome is diagnosed. When a patient presents with Addison’s disease, T1DM and AITD are found to coexist, respectively, about one-fifth and two-thirds of the time. Therefore, the diagnosis of both T1DM mellitus and AITD should be vigorously sought when Addison’s disease is first diagnosed. Coexistent AITD is more common in females. AITD occurs in 80–90% of females with APS II. AITD is the single most common component of APS II that occurs as an isolated condition [17]. Ovarian failure, seen as either primary or secondary amenorrhea, is present in approximately 10% of women with APS II under 40 years of age. Among females with biopsy-proven lymphocytic oophoritis, adrenocortical failure or subclinical AAI is often present [18]. Progression to gonadal failure is very rare among males with Addison’s disease, even in the presence of the high-risk steroidal cell autoantibodies. Pituitary involvement is occasionally seen in APS II [19–22]. Hypophysitis and empty sella syndrome have been described leading to isolated failure of secretion of GH, ACTH, TSH, FSH, or LH. Several nonendocrinological conditions have been reported in association with APS II. These include ulcerative colitis, primary biliary cirrhosis, sarcoidosis, achalasia, myositis, and neuropathy [23–27]. AITD (autoimmune thyroid disease) without Addison’s In isolation, AITD has an increased incidence during the teen years, with a peak appearing in the fifth and sixth decades. Hashimoto disease (chronic lymphocytic thyroiditis) is the most common form of AITD, although Graves’ disease and postpartum thyroiditis are not uncommon. Pancreatic islet autoimmunity or overt T1DM coexists in 3–8% of cases [28,29]. About 1% of patients with isolated AITD display serological evidence of adrenal autoimmunity. Polyglandular involvement is thus infrequent in patients with AITD. AITD, or a family history of AITD, however, is common in patients with pernicious anemia, vitiligo, alopecia, myasthenia gravis, and Sjo¨gren syndrome, and the diagnosis of AITD should be sought in all such patients [30–34]. Although a higher percentage of patients with APS I than APS II have vitiligo, most patients with vitiligo and another autoimmune disease have APS II, since APS I is far less common than APS II. Twenty to forty percent of vitiligo patients have another autoimmune disorder with thyrogastric autoimmunity being most common [31,34]. Many of the patients with vitiligo are asymptomatic, and evidence for autoimmunity can only be ascertained by antibody screening. Vitiligo limited to dermatomal regions (segmental vitiligo) is not associated with autoimmunity [35]. Up to 15%

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of patients with alopecia (areata, totalis, universalis) and 5% of their first-degree relatives, and nearly 30% of myasthenia gravis patients, have AITD [32]. Typically, subjects with AITD are more likely to have a milder expression of their myasthenia gravis and a lower incidence of thymic disease or autoantibodies to the acetylcholine receptor a-chain than AITDnegative patients. The proportion of ocular myasthenia is higher in patients with Graves’ disease. TIDM (Type I diabetes) without Addison’s A gender discrepancy is not present in patients with isolated T1DM; however, a female predominance occurs in APS II patients. This difference is almost certainly related to the coexistence of AITD. AITD (often asymptomatic), detected by the presence of circulating thyroid microsomal (thyroid peroxidase) or thyroglobulin autoantibodies, is present in about 20% of patients with T1DM, with females significantly outnumbering males [9,36]. Likewise, a female disproportion is found in patients with T1DM and gastric parietal cell autoimmunity, again likely reflecting the coexistence of AITD. Gastric parietal cell autoantibodies (PCA) occur in approximately 10% of females and 5% of males with T1DM [37]. Progression to overt pernicious anemia rarely occurs in younger patients. The disease typically affects women usually after the fifth decade. Atrophic gastritis may lead to megaloblastic anemia due to the absence of intrinsic factor, and thus an inability to absorb vitamin B12. Iron deficiency anemia has also been reported in adolescents and adults. It results from decreased acid production (e.g., hypochlorhydria or achlorhydria), which leads to poor iron absorption. AAI (autoimmune adrenal insufficiency) is much less frequent among patients with T1DM, with serological evidence reported in 0.4–2.7% of cases [38– 40]. Celiac disease occurs in 2–3% of patients with T1DM and should be suspected in patients with unexplained diarrhea, weight loss, a failure to gain weight, or failure to thrive [41]. Transglutaminase or endomysial autoantibodies are used to screen for celiac disease [42].

Diagnostic approach and follow-up The diagnosis of APS rests upon clinical or laboratory (e.g., autoantibody) identification of two or more key component diseases. The diagnosis of APS II is established when an individual is diagnosed with adrenalitis plus AITD or insulitis. Adrenalitis is defined as Addison’s disease or adrenal autoantibodies. AITD is defined as clinical thyroid disease or thyroid autoantibodies. Insulitis is defined as clinical T1DM or by the presence of islet cell autoimmune markers. Once APS is suspected, a full assessment of endocrine function is required in patients with autoantibodies, as well as in those who may be antibody negative but in whom disease is suspected (Tables 2 and 3). There is a clear

AITD

X

X

X

X

X

X

X

X X X

X

X X X

X X

X

X

X

X X

X X

b

X

X

b

X X

X X

P450c21A

Adrenal autoimmun ACA

Autoimmune

Enteropathy Hepatitis

Gluten

X

X X

X

X X

X

X X

X

X X

X

X

X

X

X

X

SCA 3-HSDA Endomysial SMA LKM1

Autoimmunity

Gonadal

Abbreviations: Autoantibodies. ACA, Adrenal cortical cytoplasmic; CA512A, Insulinoma-associated 2; GADA, Glutamic acid decarboxylase; GPCA, Gastric parietal cell cytoplasmic; IAA, Insulin; ICA, Islet cell cytoplasmic; LKM1, Liver/kidney microsome type 1; P450c21A, P450 21-hydroxylase; SCA, Steroid cell cytoplasmic; SMA, Smooth muscle cell; TGA, Thyroglobulin; TMA, Thyroid microsomal; TPO, Thyroperoxidase. a GPCAI, gastric purietal cell autoimmunity. b If either AITD or GPCAI are detected.

APS I APS II X Isolated disorders Mucocutaneous candidiasis Hypoparathyroidism Addison disease Autoimmune thyroid disease Type 1 diabetes X Pernicious anemia Premature ovarian failure Celiac disease Autoimmune hepatitis

a

GPCAI

ICA IAA GADA ICA512A TMA/TPO TGA GPCA

b-cell autoimmunity

Pancreatic

Table 2 Autoantibodies indicated for diagnosis (bold) or screening for autoimmune endocrinopathies and associated disorders

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X X

— SMA LKM1

GPCA

X

[X]

IA-2A

X

[X] [X]

X X X

[X]

[X] X

TPO/TMA TGA ICA IAA GADA

[X]

X X





X X X X

Hct, RBC indices, ferritin, Intestinal AST, Vit B12 biopsy ALT

[X] indicates testing because of associated disease; indicates for research purposes only. Abbreviations: FPGA, fasting plasma glucose; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test. a If increased, do Testosterone or Estradiol. b If abnormal, do PTH.

Gluten enteropathy Autoimmune hepatitis

Pernicious anemia

Autoimmune thyroid disease Type 1 diabetes

Gonaditis

3-HSDA SCA

X X

[X]

P450c21A SCA

Addison’s disease

[X]

Addison’s disease

X

X

ACA

Autoimmune disease Autoantibody

Adrenal cortical cytoplasmic P450 21-hydroxylase Steroidal cell cytoplasmic 3-hydroxysteroid dehydrogenase Steroidal cell cytoplasmic Thyroperoxidase Thyroglobulin Islet cell cytoplasmic Insulin Glutamic acid decarboxylase Insulinomaassociated Gastric parietal cell cytoplasmic Endomysial Smooth muscle cell Liver/kidney microsome

FSH, LHa Cortisol Supine (if incr.: Ca, T4 OGIT Abbreviation postcortrosyn renin T or E2) PO4b TSH FFG IVGTT

Table 3 Annual functional assessment in autoantibody positive subjects

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link between the presence of organ-specific autoantibodies and either the presence of pre-existing disease or subsequent progression to disease. Because the number of associated disorders that will develop and their age of appearance are clinically unpredictable in APS II, long-term clinical follow-up is necessary in both autoantibody positive and negative subjects. Recognition of multiorgan autoimmune diseases before their symptomatic phases is the best way to minimize their associated morbidity and mortality. A thorough history and physical examination should always be performed and a high index of suspicion should be maintained. Another clue to the identification of asymptomatic polyglandular disease may come from the history of a relative who has either a different component disease than the proband or has typical multiorgan disease. Any patient with suspected APS should be tested with a panel of autoantibodies. These include adrenal cortex autoantibodies or antibodies directed against 21 hydroxylase, (markers for autoimmune Addison’s disease), GADA (glutamic acid decarboxylase autoantibodies), IA-2A (insulinoma associated antigen), IAA (insulin autoantibodies), and ICA (cytoplasmic islet cell antibodies) (for T1DM), thyroid microsomal/peroxidase and thyroglobulin antibodies (for AITD), steroidal cell antibodies (for ovarian failure), and endomyceal or transglutaminase antibodies (for celiac disease). All patients with a single autoimmune disease must be considered at risk for other autoimmune diseases. Whether and when to screen for other autoantibodies is based on the likelihood of finding another autoimmune disease, cost effectiveness and the likelihood that screening will prevent morbidity and mortality from other diseases such as diabetic ketoacidosis, addisonian crisis, and hypocalcemia. Because of the high incidence of AITD with T1DM, we recommend that such patients have thyroid microsomal/peroxidase and thyroglobulin autoantibodies measured biannually. This approach is preferred to assessing thyrotropin levels, because autoantibody seroconversion is a much earlier event in the evolution of thyroid disease. In addition, measurement of both thyroid microsomal/peroxidase and thyroglobulin antibodies has close to 90% sensitivity. In those subjects who are have thyroid autoantibodies thyrotropin (TSH) levels are measured annually. The current third-generation thyrotropin assays are preferred and achieve a lower limit of detection of at least 0.01 uIU/ mL. In patients with confirmed Addison’s disease, in place of biannual thyroid autoantibody screening, some clinicians prefer to measure TSH annually. Delayed diagnoses and even preventable deaths, unfortunately, still occur in patients with undiagnosed adrenocortical failure. As mentioned previously, signs and symptoms are often vague and nonspecific until an addisonian crisis ensues. In individuals with T1DM, unexplained hypoglycemia or spontaneous improvement in blood glucose control can serve as clues to the diagnosis of Addison’s disease. Declining blood glucose levels may represent the loss of anti-insulin activity that is associated with glucocorticoid deficiency.

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Most patients with isolated Hashimoto thyroiditis will not subsequently develop additional endocrine autoimmune diseases. If patients with Hashimoto thyroiditis are affected by additional autoimmune endocrinopathies, the thyroid disease has usually (but not always) been preceded by the overt failure of another gland. Therefore, testing for APS II is not recommended in isolated instances of Hashimoto thyroiditis unless other problems are clinically suspected. For patients with confirmed APS, however, before the start of thyroid hormone replacement therapy, evidence for AAI must be sought, because thyroid hormone replacement can precipitate an adrenal crisis in a patient with marginal adrenocortical function, by increasing catabolism of steroid hormones. Because chronic lymphocytic gastritis is commonly associated with AITD, patients with AITD should be tested for gastric parietal cell autoantibodies. Testing for APS II-associated disorders should also be performed in women with primary amenorrhea, secondary amenorrhea, or frank premature ovarian failure, or young patients with vitiligo. Assessment of end-organ function in individuals with endocrine autoantibodies annually is recommended (Table 3). A fasting plasma glucose and/ or oral glucose tolerance testing and measurement of serum calcium, phosphate (if diagnosis of APS I versus APS II is not certain), and TSH levels can effectively assess pancreatic islet, parathyroid, and thyroid function in asymptomatic individuals. If hypocalcemia and hyperphosphatemia are recognized, a parathyroid hormone (PTH) level should then be measured to diagnose hypoparathyroidism. Gonadal failure can be diagnosed by the finding of elevated FSH and LH levels with concomitant low serum concentrations of sex steroids. Obtaining a hemoglobin and hematocrit together with red blood cell indices can assess progression to atrophic gastritis in patients with gastric parietal cell autoimmunity. The findings of a megaloblastic anemia with an elevated red blood cell mean corpuscular volume (MCV) suggest vitamin B12 deficiency while a microcytic hypochromic anemia suggests iron deficiency. If the vitamin B12 level is less than 100 pg/mL, vitamin B12 deficiency is confirmed. The additional presence of gastric parietal cell autoantibodies confirms the diagnosis of chronic lymphocytic gastritis and pernicious anemia. In cases where the vitamin B12 level is 100 pg/mL but <300 pg/mL and the diagnosis of vitamin B12 deficiency is equivocal, finding an elevated methylmalonic acid level in either blood or urine confirms vitamin B12 deficiency. Confirmation of iron deficiency is achieved when the iron profile displays depressed concentrations of serum ferritin, elevated total iron binding capacity, elevated transferrin, low serum iron, and low transferrin saturation. A new test for iron status involves the measurement of circulating transferrin receptors. In iron deficient states, elevated levels of transferrin receptors are detected. Neurologic symptoms of pernicious anemia can be present in the absence of anemia or other hematologic changes. Therefore, vitamin B12 and studies of methylmalonic acid (if needed) should be vigorously pursued if suspected.

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Patients testing positive for endomysial or transglutaminase antibodies should have an intestinal biopsy to confirm the diagnosis of celiac disease. Low morning cortisol levels, electrolyte abnormalities (hyponatremia/ hyperkalemia), hypoglycemia, and Type IV renal tubular acidosis represent late changes occurring at or just before the onset of clinically significant adrenal insufficiency. Hyperpigmentation due to elevated ACTH levels may be observed. Just as the natural history of pre-T1DM has now been well described, there are now data to predict the subsequent development of adrenocortical insufficiency. During the development of adrenocortical insufficiency in adrenocortical autoantibody positive subjects, increased plasma renin activity with normal to low aldosterone may be an early manifestation. A decreased cortisol response to exogenous ACTH administration usually precedes an elevated basal ACTH. A low morning cortisol value occurs later [39,40,43,44]. In practice, in those individuals with adrenocortical antibodies, we suggest testing with midafternoon or late ACTH levels, or a b 1-24 coticotropinstimulation test together with measurement of supine renin activity. Because individual autoimmune endocrinopathies and APS display familial tendencies or are frankly Mendelian in their inheritance (e.g. APS I), family members should also be examined for associated endocrine autoantibodies (Table 4).

Treatment Hormone replacement or other therapies for the component diseases of APS II are similar whether the ailments occur in isolation or in association Table 4 Autoantibody testing in relatives of probands with autoimmune endocrinopathies Autoimmune disease/syndrome APS II

Relatives to be screened

Appropriate autoantibody screening

ACA, 21-hydroxylase autoantibodies, ICA, IAA, GADA, IA-2A, TMA/TPO, TGA APS I Siblings (AIRE screening ACA, 21-hydroxylase can identify affected sibs) autoantibodies, SCA, SMA, Mitochondrial autoantibodies AITDa First-degree relatives TMA or TPO TGA and of proband PCAb Type 1 diabetes mellitus First-degree relatives ICA, IAA (children), GADA, of probandc IA-2A Autoimmune Addison’s disease First-degree relatives ACA, 21-hydroxylase (excluding APS I) of proband autoantibodies a b c

First-degree relatives of proband

Hashimoto thyroiditis, atrophic thyroiditis, and Graves’ disease. Chronic lymphocytic gastritis and AITD very commonly affect family members. For research purposes only.

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with other conditions. Investigation into the pathogenesis of these disorders provides hope for the development of specific therapeutic measures to block their pathologic basis. Because coexistent endocrine end-organ failures may be present, a missed diagnosis may lead to morbidity and mortality. The commencement of thyroid hormone replacement can precipitate life threatening addisonian crisis in a patient with unsuspected adrenal insufficiency. A decreasing insulin requirement may be one of the earliest features of adrenal insufficiency in a subject with Type I diabetes. This may also occur as an early sign of hypothyridism. Whenever acute adrenal insufficiency is strongly suspected, therapy should not be delayed awaiting laboratory results or diagnostic testing. In patients with addisonian crises, the initial goal is to reverse hypotension and electrolyte abnormalities. Fluids (normal saline with 5% dextrose) are infused at a rate of twice maintenance. If the patient is in shock, a bolus of normal saline (10–20 cc/kg) should be infused in the first hour of treatment. Hydrocortisone (100 mg for older childen and adults, 50 mg for for small children, should be given as a bolus intravenously. The dose should be repeated every 6 hours for the first 24 hours. Some clinicians prefer dexamethasone sodium phosphate (2–4 mg depending on age) because the effects last 12–24 hours and the analogs do not affect steroid measurement during subsequent ACTH testing. Unless there is an ongoing complicating illness, the dose of glucocorticoids can be tapered over 3 days to maintenance (12–14 mg/m2 hydrocortisone orally). Mineralocorticoid (Florinef 0.1 mg) replacement can be commenced at that time. It takes several days for the sodium retaining effects to occur and adequate sodium replacement can be achieved through intravenous saline administration. Glucocorticoids may be administered in the form of hydrocortisone divided thrice daily, prednisone twice daily, or dexamethasone at bedtime. Education of the patient and family is critical to successful management. Instruction must be given about the need for tripling glucocorticoid doses during minor febrile illnesses or stress. The need for immediately contacting a physician and the use of injectable hydrocortisone or dexamethasone during severe illnesses or trauma cannot be overemphasized. A medical alert bracelet or necklace is advised identifying the subject as steroid-dependent or adrenal insufficient. T1DM management alone or in the context of APS II is similar. Because diabetes management is complex, a multidisciplinary medical team, including a diabetologist or endocrinologist, certified diabetes nurse educator, nutritionist, psychologist, and social worker, is essential to optimizing management. The Diabetes Control and Complications Trial (DCCT) demonstrated a strong relationship between good metabolic controls and the rate and progression of microvascular and neuropathic complications. Although tight glycemic control should be sought for all patients, a balance must be achieved between the patient’s medical needs (e.g., insulin, nutrition, exercise, blood glucose testing, hemoglobin A1c, lipids, complication surveillance) and the lifestyle demands and desires of the patient. Each

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patient needs individualized therapy based on age, schedule, social environment, and capabilities. A detailed description of the mechanics of achieving tight metabolic control is beyond the scope of this chapter. Because the onset of T1DM can be fairly reliably predicted using a combination of immunologic (islet-related autoantibodies), genetic (susceptible and protective HLA genotypes), and metabolic parameters (oral glucose tolerance testing and first phase insulin responses), efforts are underway worldwide to both prevent and ameliorate T1DM. Hypothyoidism, as previously mentioned, is far more common than Graves’ disease. Na–L-thyroxine (levothyroxine) is the mainstay of therapy and is indicated for patients with overt and compensated hypothyroidism. The initial dose depends on the degree of hypothyoidism, the age, and the general health of the patient. For example, healthy young individuals can be started on a complete replacement dose, whereas more elderly patients who may have concomitant heart disease must be given extremely small doses of L-thyroxine initially. Free thyroxine and TSH levels should be measured approximately 3 months after commencing therapy. Interestingly, in patients with hypothyroidism and adrenal insufficiency, an improvement in thyroid function has been reported after glucocorticoid therapy [45]. Likewise, ovulatory menstrual periods have also been reported to resume with thyroid hormone replacement [46]. A detailed discussion of the therapy of Graves’ disease is beyond the scope of this chapter. Either antithyoid medications (the thiocarbamides—propylthiouracil or methimazole) or 131 I ablation is used at our institution as first line therapy depending on clinical circumstances. When a diagnosis of autoimmune gonadal failure is made, hormonal substitution is begun. In affected adolescent females, treatment should be initiated at least by 13–14 years of age. Several different hormonal replacement regimens are available. We prefer initial therapy with either ethinyl estradiol (5 lg orally) or a conjugated estrogen (0.3 mg) for 6 months. After 6 months, or sooner if breakthrough bleeding occurs, cyclic estrogen/progesterone therapy is begun. Estrogen is given for the first 21 days of the month with medroxyprogesterone acetate (5 mg daily) given from days 12–21. Over the next 1–2 years, the dose of estrogen is increased. Conjugated estrogens are increased to 0.6–1.25 mg per day or ethinyl estradiol is increased to 10–20 lg per day. Oral contraceptive agents containing estogen and progesterone may also be used. Pernicious anemia with confirmed vitamin B12 deficiency must be treated with adequate amounts of vitamin B12. Adults with pernicious anemia can usually be maintained on 100 lg per month of intramucularly-injected cyanocobalamin. If nervous system involvement was present, clinical disease progression can be halted and, where death of nerve cells has not occurred, may be reversed. If pernicious anemia is untreated or inadequately treated, the risk of carcinoma of the stomach is increased. Following remission induced by injectable vitamin B12, the drug may be given intranasally once

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a week. Vitamin B12 levels should be monitored every 6–12 months to insure that the vitamin B12 level is 300 pg/mL or greater. Iron deficiency is relieved by the administration of iron given orally. Ferritin can be monitored every 6–12 months to insure that iron stores are adequate. Celiac disease should be treated with complete removal of dietary gluten. Together with the provision of adequate calories, avoidance of dietary gluten leads to quick improvement in those patients in whom the disease is clinically manifest. Most experts consider that gluten exclusion should be life long because of the increase risk of malignancy, especially involving intestinal lymphoma as well as carcinoma of the small and large bowel. Summary A high index of suspicion should be maintained whenever one organspecific autoimmune disorder is diagnosed in order to prevent morbidity and mortality from the index disease as well as associated diseases. Further definition of susceptibility genes and autoantigens, and understanding of immune tolerance and the induction and propagation of autoimmune reactions should prove to be the best path to improved diagnostic and therapeutic modalities in the care of these patients.

Acknowledgments The authors would particularly like to thank Dr. Arlan Rosenbloom for his advice and editorial review.

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