Autoimmune Endocrine Diseases


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Autoimmune Endocrine Diseases

  1. 1. Autoimmune Diseases Autoimmune Endocrine Diseases JMAJ 47(9): 419–424, 2004 Hiroki SHIMURA* and Tetsuro KOBAYASHI** *Lecturer, **Professor, Third Department of Internal Medicine, School of Medicine, University of Yamanashi Abstract: Autoimmune endocrine diseases occur most frequently among various autoimmune diseases. Among autoimmune endocrine diseases, Graves’ disease, Hashimoto’s disease, type 1 diabetes mellitus, and Addison’s disease are especially frequent in daily clinical practice. Graves’ disease produces thyro- toxicosis due to the effects of the anti-TSH receptor antibody upon the thyroid gland and diverse symptoms due to its effects on extrathyroid tissues. Hashimoto’s disease is the most frequently encountered autoimmune disorder, and cellular immunity is thought to be involved. Guidelines for the diagnosis of these thyroid diseases have been provided by the Japan Thyroid Association. Autoimmune mechanisms are involved in many cases of type 1 diabetes mellitus. Type 1 diabetes mellitus has a wide spectrum of clinical disease states ranging from the rapid onset form, which develops diabetes mellitus within several days, to SPIDDM, which slowly progresses over years. Addison’s disease is also an autoimmune disorder in many cases and may present polyglandular autoimmune syndrome with compli- cations by other organ-specific autoimmune disorders. Key words: Graves’ disease; Hashimoto’s disease; Type 1 diabetes mellitus; Addison’s disease several organs. Introduction This paper presents brief accounts of Graves’ It is generally recognized that endocrine disease, Hashimoto’s disease, type 1 diabetes organs may contract various organ-specific mellitus, and Addison’s disease, which are fre- autoimmune diseases, which, except for Base- quently seen autoimmune endocrine diseases dow’s disease (Graves’ disease) in which auto- in daily clinical practice. antibodies possess endocrine gland-stimulating activity, present diverse clinical features due to Graves’ Disease endocrine hypofunction through autoimmune mechanisms. Widely known among these disor- 1. Pathophysiology ders is polyglandular autoimmune syndrome The disease is characterized by the presence involving autoimmune endocrine diseases of of an autoantibody that recognizes the TSH This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129, No. 7, 2003, pages 917–920). JMAJ, September 2004—Vol. 47, No. 9 419
  2. 2. H. SHIMURA and T. KOBAYASHI receptor and stimulates the thyroid gland (i.e., Table 1 Guidelines for the Diagnosis of Graves’ Disease anti-TSH receptor antibody), goiter, and signs a) Clinical findings of thyrotoxicosis. Exophthalmos and pretibial 1. Signs of thyrotoxicosis such as tachycardia, myxedema, which are also characteristic fea- weight loss, finger tremor, and sweating tures of Graves’ disease, cannot be explained 2. Diffuse enlargement of the thyroid gland by excess thyroid hormones and currently are 3. Exophthalmos and/or specific ophthalmopathy considered to be ascribable to the reactions of b) Laboratory findings 1. Elevation in serum free thyroxine (FT4) level antibody to TSH receptors in adipocytes, etc.1) 2. Suppression of serum thyroid stimulating hormone (TSH): less than 0.1 U/ml 2. Clinical features and physical findings 3. Positive for anti-TSH receptor antibody (TRAb or Merseburg’s triad (palpitations, struma, and TBII) or thyroid stimulating antibody (TSAb) 4. Elevated radioactive iodine (or 99m TcO4 ) uptake exophthalmos) is important as symptoms and to the thyroid gland findings in Graves’ disease. Other major symp- 1) A patient shall be said to have Graves’ disease if he/she toms include weight loss (with an associated has satisfied at least one of the clinical findings and all 4 increase in appetite), fatiguability, shortness of laboratory findings. breath, hyperidrosis, finger tremors, diarrhea, 2) A patient shall be said probably to have Graves’ disease if he/she has satisfied at least one of the clinical findings periodic paralysis (male), and muscle weakness. and 3 laboratory findings 1 through 3. Physical findings include (1) diffuse struma 3) A patient is suspected to have Graves’ disease if he/she (vascular murmurs audible); (2) ocular symp- has satisfied at least one of the clinical findings and 2 laboratory findings 1 and 2. Elevation in serum FT4 have toms exophthalmos, lid lag and Graefe’s sign; usually been present for at least 3 months. (3) tachycardia and atrial fibrillation; (4) warm Notes moist skin; (5) tremors; and (6) pretibial 1. Decrease of serum cholesterol and increase of serum alkaline phosphatase are often observed. myxedema. 2. There are rare cases with free triiodothyronine (FT3) elevation alone and normal FT4. 3. A patient shall be said to have “euthyroid Graves’ disease” or 3. Laboratory findings “euthyroid ophthalmopathy”, if he/she has ophthalmopathy and is positive for TRAb or TSAb, but shows normal FT4 and TSH. (1) Routine examination: Elevation in serum 4. In an elderly patient, clinical symptoms and signs including an ALP (bone type isozyme), a slight increase in enlargement of the thyroid gland, may not be clear. 5. In children, decreased scholastic ability, accelerated growth, AST/ALT, low serum cholesterol level, and a restlessness and other symptoms are observed. slight increase in blood glucose are noted. (2) Endocrine tests: Low serum TSH level and elevations in free T3 and free T4 in serum are observed. Patients show elevated radio- thyroid with low internal echo level. Enhanced active iodine uptake (30% or more). internal blood flow is noted on Doppler (3) Immunological tests: Patients are posi- ultrasonography. tive for anti-TSH receptor antibody. For serum anti-TSH receptor antibody determination, two 4. Essentials of diagnosis different assay methods are currently avail- Guidelines for the diagnosis of thyroid dis- able: 1) measurement of the degree of inhibi- eases (the sixth draft) have been provided by tion of binding to labeled TSH receptor (TBII, the Japan Thyroid Association.2) The associ- TRAb) and 2) measurement of cAMP produc- ation’s guidelines for the diagnosis of Graves’ tion in cultured thyroid cells (TSAb). Usually, disease are cited in Table 1. These guidelines one or the other of the tests is performed first, are available at the Japan Thyroid Association’s and if the test is found negative, then the other website ( test is undertaken. (4) Imaging diagnosis: Ultrasonographic 5. Treatment examination reveals diffuse enlargement of the (1) Antithyroid drugs: These drugs are 420 JMAJ, September 2004—Vol. 47, No. 9
  3. 3. AUTOIMMUNE ENDOCRINE DISEASES often used as drugs of first choice for the Table 2 Guidelines for the Diagnosis of Chronic Thyroiditis (Hashimoto’s Disease) treatment of Graves’ disease in Japan. Usually, methimazole (MMI) with a slightly higher a) Clinical findings potency is instituted at a dosage level of 15– 1. Diffuse swelling of the thyroid gland without any other cause (such as Graves’ disease) 30 mg/day, followed by a gradual dose reduc- tion over several years. In case of any adverse b) Laboratory findings 1. Positive for anti-thyroid microsomal antibody or reaction occurring (except for agranulocytosis) anti-thyroid peroxidase (TPO) antibody or during lactation, the drug is replaced with 2. Positive for anti-thyroglobulin antibody propylthiouracil (PTU). Antithyroid drugs are 3. Lymphocytic infiltration in the thyroid gland drugs of first choice for pregnant women. confirmed with cytological examination (2) Radioactive iodine therapy: Patients in 1) A patient shall be said to have chronic thyroiditis if he/ whom antithyroid drugs cannot be used and she has satisfied clinical criterion and any one laboratory criterion. middle-aged and older patients who respond Notes poorly to the therapy regimens are better indi- 1. A patient shall be suspected to have chronic thyroiditis, if he/she cated for the use of radioiodine. At present, has primary hypothyroidism without any other cause to induce hypothyroidism. the therapy is feasible at outpatient services. 2. A patient shall be suspected to have chronic thyroiditis, if he/she has anti-thyroid microsomal antibody and/or anti-thyroglobulin Therapeutic effects become evident about 6 antibody without thyroid dysfunction nor goiter formation. months after the start of medication, with sub- 3. If a patient with thyroid neoplasm has anti-thyroid antibody by chance, he or she should be considered to have chronic thyroiditis. sequent development of late hypothyroidism 4. A patient is possible to have chronic thyroiditis if hypoechoic in many cases. and/or inhomogeneous pattern was observed in thyroid ultrasonography. (3) Subtotal thyroidectomy: This is pre- ferred for refractory juvenile cases of Graves’ disease with notable enlargement of the thyroid. 3. Laboratory findings (1) Routine examination: Increased ESR, Hashimoto’s Disease elevation in serum -globulin (increased ZTT 1. Pathophysiology and TTT values), elevations in CPK and LDH, This disease occurs in nearly one out of and high serum cholesterol level are noted. every ten middle-aged women and is an organ- (2) Endocrine tests: Free T3 and free T4 in specific autoimmune disorder with the highest serum are lowered and TSH is elevated. Latent prevalence. The etiology remains unclear, hypothyroidism with a normal thyroid hormone although cellular immunity and antibody- level and with elevation in TSH alone is also dependent cytotoxicity are generally thought frequently observed. to be involved. (3) Immunological tests: Patients are posi- tive for anti-thyroid peroxidase (TPO) antibody 2. Clinical features and physical findings and for anti-thyroglobulin (Tg) antibody. Firm diffuse enlargement of the thyroid is the only finding if thyroid hypofunction is not 4. Essentials of diagnosis present. The disease progresses into hypothy- The diagnosis guidelines (the sixth draft) roidism to produce generalized edema, weight provided by the Japan Thyroid Association2) gain, subjective symptoms such as fatiguability, are shown in Table 2. Occasionally, patients sensitivity to the cold and diarrhea, and physi- may present transient symptoms of thyro- cal findings such as hoarseness, dry skin, falling toxicosis, which is called painless thyroiditis. of the lateral one-third of both eyebrows, bra- dycardia, and a prolonged relaxation phase of 5. Treatment the Achilles tendon reflex. Replacement therapy with T4 preparations is JMAJ, September 2004—Vol. 47, No. 9 421
  4. 4. H. SHIMURA and T. KOBAYASHI performed in patients with hypothyroidism. It ing a fatal clinical course. is a common practice to use a low dose level for initiating T4 drug therapy, with subsequent 2. Clinical features and physical findings gradual dosage increase until serum TSH level There are no symptoms/findings specific to becomes normalized. The therapy should be type 1 diabetes mellitus. Most patients are non- started at a dose level of 12.5 g/day especially obese, with more severe symptoms of weight in elderly patients and severe cases because loss, polyuria and thirst due to marked hyper- of the potential risk of angina pectoris or car- glycemia, and are prone to diabetic coma. In diac failure. fulminant type 1 diabetes mellitus, about 70% of patients develop common cold-like symp- toms such as upper abdominal pain, fever, and Type 1 Diabetes Mellitus headache before the onset of diabetes mellitus. 1. Pathophysiology The diagnostic criteria and classification of 3. Laboratory findings diabetes mellitus into two types depicting (1) Routine examination: A diagnosis of disease states — insulin-dependent diabetes diabetes mellitus can be established according mellitus (IDDM) and non-insulin-dependent to the diagnostic criteria for diabetes mellitus. diabetes mellitus (NIDDM) — were revised HbA1c is usually elevated but this parameter in 1999 to those classifying the disease into remains at normal to a slight elevation in cases four types based on etiology, i.e., types 1 and of the fulminant form of type 1B disease. Exo- 2, other particular mechanisms or disorders crine pancreatic enzymes such as elastase I and (inclusive of genetic abnormalities), and ges- amylase are elevated in the fulminant form. tational diabetes. Acidosis is often present among cases of type 1 Type 1 diabetes denotes diabetes mellitus, disease other than SPIDDM. which develops due to destruction of pan- (2) Endocrine tests: The fasting serum C creatic cells. The disease under this category peptide level ( 0.5 ng/ml) and urinary C pep- is further classified into type 1A, which arises tide output ( 10 g/day) are lowered due to through autoimmune mechanisms, and type depressed insulin secretory function. These are 1B, which is of non-autoimmune nature. not the case with SPIDDM. Type 1A disease of autoimmune etiology (3) Immunological tests: Patients with type includes the slow-progressing insulin-dependent 1A disease are positive for anti-glutamic acid diabetes mellitus (SPIDDM) besides the rapid- decarboxylase (GAD) antibody being anti-islet onset type, which is typical of conventional autoantibody, islet cell antibody (ICA), anti- IDDM. SPIDDM is a disease form that pre- insulin autoantibody (IAA), and IA-2 antibody.3) sents clinical features close to type 2 diabetes Patients with the fulminant form of type 1 dia- mellitus but progresses over several years with betes are negative for these autoantibodies. depression of pancreatic cell function and Of human leukocyte antigens, patients often ultimately into an insulin-dependent status. In possess HLA-DR4 or -DR9 and are negative both these forms of type 1A, the anti-islet auto- for HLA-DR2. antibody (to be described below) is detected. The anti-islet autoantibody is not demonstrated 4. Essentials of diagnosis in cases of type 1B disease. Anti-GAD antibody can be measured rou- Recently, attention has been focused on the tinely and must be determined positively when presence of fulminant type 1 diabetes mellitus type 1 diabetes mellitus is suspected. In the in which ketoacidosis develops in a period of fulminant form, common cold-like symptoms several days (mean: 4 days), occasionally tak- frequently precede the onset of the disease, 422 JMAJ, September 2004—Vol. 47, No. 9
  5. 5. AUTOIMMUNE ENDOCRINE DISEASES so urine tests for glucose (and ketones) are (1) Routine examination: Hypoglycemia, essential in patients with colds complaining hyponatremia, hyperkalemia, and peripheral of lassitude. blood eosinophilia are present. (2) Endocrine tests: Diagnostic findings 5. Treatment include elevated plasma ACTH, low plasma and Usually, an intensive insulin therapy regimen urine cortisol levels, low plasma aldosterone consisting of a dose of a regular (or rapid- level, low plasma DHEA-S value, decrease in acting) insulin is undertaken before every meal urinary 17-OHCS/17-KS, and no or low plasma and a dose of an intermediate-acting (or long- cortisol in the rapid ACTH test. acting) insulin at bedtime. If the blood glucose (3) Immunological tests: Autoantibodies level is still poorly controlled with this regimen, recognizing steroid-synthesizing enzymes are then continuous subcutaneous insulin infusion detected but these laboratory tests have not (CSII) is performed. It has been shown that been generally adopted to date. low-dose insulin provides a protective effect for pancreatic cells, and replacement with 4. Essentials of diagnosis insulin therapy is required in patients with When there are diverse nonspecific symp- SPIDDM receiving sufonylureas. toms, the disease must be deduced from skin pigmentation and routine laboratory test data. Caution must be exercised because if the dis- Addison’s Disease ease is left undiagnosed and without adequate 1. Pathophysiology steroid substitution therapy, some types of stress Addison’s disease is caused by destruction may precipitate adrenal crisis (acute adrenal of the adrenal cortices resulting in chronic insufficiency) with a fatal outcome. adrenocortical insufficiency. Leading causes are autoimmune destruction, termed idiopathic, 5. Treatment and tuberculosis. In the idiopathic entity, the Replacement therapy with hydrocortisone disease may present polyglandular autoimmune at 20 mg/day is a common practice. A divided syndrome involving complications by other dose in the morning may be greater than the organ-specific autoimmune disorders (i.e., type one given in the early evening to be in harmony 1 diabetes mellitus, Hashimoto’s disease, idio- with circadian rhythm in cortisol secretion. The pathic hypoparathyroidism, gonadal hypofunc- dose of hydrocortisone should be raised 2- to tion, mucocutaneous candidiasis, and pernicious 3-fold the usual dose (40–60 mg/day) in case of anemia). These are classified into type I caused common cold with pyrexia or other infections, by juvenile-onset autoimmune regulator (AIRE) trauma, or surgery. gene abnormality, type II, being an adult-onset disease without associated non-endocrine dis- Conclusions order, and type III, which does not involve Addison’s disease.4) Endocrine diseases in which autoimmune mechanisms are considered to be involved, 2. Clinical features and physical findings besides the four above-mentioned diseases, Hyperpigmentation due to increased secre- include lymphocytic adenohypophysitis, lym- tion of ACTH is a characteristic clinical feature. phocytic infundibuloneurohypophysitis, and Aldosterone-cortisol-adrenal androgen deficit idiopathic hypoparathyroidism. Autoimmune symptoms are also noted. endocrine disorders are most frequent among various autoimmune diseases, so it is of impor- 3. Laboratory findings tance to always keep this fact in mind in daily JMAJ, September 2004—Vol. 47, No. 9 423
  6. 6. H. SHIMURA and T. KOBAYASHI clinical practice to achieve diagnosis and treat- Basedow’s disease, hypothyroidism, indolent ment in such cases. thyroiditis/chronic thyroiditis (Hashimoto’s disease) and subacute thyroiditis. Horumon- to-Rinsho 2002; 50: 643–653. (in Japanese) REFERENCES 3) Kobayashi, T.: Pathophysiology and immune systems in type 1 diabetes mellitus. Karadano- 1) Endo, T.: Approaches to thyroid disorders.— kagaku 2001; Special Issue (Diabetes Mellitus The pathogenetic mechanisms of Graves’ dis- 2001): 54–57. (in Japanese) ease and basic strategies for pharmacotherapy 4) Kudo, J. and Shimizu, N.: Genetic autoimmune and management. Medical Practice 2002; 19: disorder (APECED): Polyglandular auto- 196–202. (in Japanese) immune endocrinopathy type I. Naibunpitsu- 2) Mitsuma, T., Shishiba, Y., Uchimura, H. et al.: Tonyobyoka 1999; 9: 527–533. (in Japanese) Guidelines for the diagnosis of thyroid diseases: 424 JMAJ, September 2004—Vol. 47, No. 9