Immunogenic hyperthyroidism E05.0

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Autoimmune hyperthyroidism; Grave`s disease; Graves' disease; Graves' hyperthyroidism; Graves' Syndrome; Hyperthyroidism immunogenic; Immunohyperthyroidism; Immunothyroidism of the Graves' disease type

History
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Graves' Day 1840

Definition
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Immunothyroidism of Graves' disease type, is an autoimmune disease with thyroid (struma diffusa, hyperthyroidism) and extrathyroid manifestations (endocrine orbitopathy, pretibial myxoedema, acropathy), which may be associated with other autoimmune diseases. Thyroid stimulating immunoglobulins (TSH-R-Ak) are specific for Graves' disease. The diagnosis can be made reliably and economically by anamnesis, physical examination, few laboratory tests and complementary imaging procedures (Menconi F et al. 2014).

Classification
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  • Hyperthyroidism without goiter
  • Hyperthyroidism with diffuse struma
  • Hyperthyroidism with nodular goiter

Occurrence/Epidemiology
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The incidence in Central Europe is 50/100,000 persons/year; w:m=5:1

Etiopathogenesis
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Hyperthyroidism is caused by the TSH receptor antibody(T-R-A-K) . This antibody has a stimulating effect on the thyroid parenchyma.

A complex, multifactorial event is present; in addition to an ethnically-bound genetic predisposition (Li H et al.2013), where the tissue antigens HLA-B8, -DR3 and -DQA1*0501 are pathogenetically significant in Caucasians, multiple immunological mechanisms as well as psychosocial factors and environmental influences play a major role. There is evidence of "molecular mimicry" between thyroid autoantigens, antigens in extrathyroid tissues (orbita, subcutis of the pretibial region), certain stress proteins, viral and bacterial antigens (e.g. yersinia enterocolitica proteins) and superantigens. Presumably, an immune response is triggered against bacterial/viral antigens that show similarities to antigens of the thyroid gland, e.g. the human TSH receptor. The consequence of the antigen-antibody reaction that takes place is the infiltration of the thyroid tissue by activated autoreactive lymphocytes (CD4+ and CD8+ T lymphocytes, B lymphocytes), whereby probably different types of antigens are present. Adhesion molecules (ICAM-1 and -2, E-selectin, VCAM-1, LFA-1, LFA-3, CD44) probably play a pathogenetic role. Activated T-lymphocytes induce a humoral immune response via cytokines and signalling substances that are formed, which leads to the maturation of specific plasma cells via antigen-specific stimulation of B-lymphocytes in thyroid and extrathyroid lymphatic tissue and thus stimulates the formation of antibodies against TSH-R, thyroid peroxidase, thyroglobulin.

Antibodies directed against the human TSH receptor (TSH-R-Ak) are specific for type MB immune hyperthyroidism. These do not represent a uniform population, but represent a heterogeneous spectrum of polyclonal immunoglobulins which bind to the different regions of the TSH receptor and stimulate or block it to varying degrees depending on the binding affinity. By binding to the TSH-R, they activate various intracellular signalling pathways (especially the formation of cAMP and IP3) and stimulate, in addition to iodine uptake and thyroid growth, the formation and release of thyroid hormones. Furthermore, the TSH-R-Ak, in addition to their functionally stimulating effect, also possess immunomodulating properties, which are also mediated via the TSH-R.

Manifestation
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In 2/3 of the patients an MB manifests itself after the age of 35; women are affected about 5 times more often than men. In women, the time of realisation of immunogenic hyperthyroidism mainly affects the stages of life with significant endocrinological changes such as puberty, peripartum and climacteric.

Clinical features
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In most cases, immunogenic hyperthyroidism manifests itself with the "classic" clinical constellation of symptoms of the "Merseburg Triad": goiter (70% of cases; in the case of strong vascularization, a buzzing over the thyroid parenchyma is detectable), sinus tachycardia and exophthalmos.

Further clinical symptoms of hyperthyroidism are: weight loss with increased appetite (ravenous hunger), possibly hyperglycaemia (due to increased metabolism with mobilization of fat and glycogen depots), tendency to sweat, heat intolerance, insomnia, inner restlessness, breathing difficulties during physical exertion, increased fatigue, nervousness, fine finger tremor of the outstretched fingers, muscle cramps, diarrhea.

Endocrine orbidopathy (conspicuous by exophthalmus, lid edema, foreign body sensation, conjunctivitis, photophobia, lid retraction, retrobulbar pressure sensation) occurs in 40% of patients in addition to hyperthyroidism.

Furthermore pretibial myxedema (5% of cases, rarer localizations of myxedema are forearms or shoulder regions) (Menconi F et al. 2014). Occasionally acropacia (hypertrophy of the long tubular bones, distal bone ends and skin of the extremities with drumstick fingers can occur in EO and pretibial myxedema (Krützfeld J et al. 2017). Possible signs of osteoporosis (negative calcium balance, hypercalzuria, increased alkaline phosphatase).

In older patients with immunohyperthyroidism of type MB, oligosymptomatic forms of the disease dominate with uncharacteristic symptoms such as anorexia, weakness, fatigue or sensitivity to cold, symptoms which are often misinterpreted as "signs of ageing" or neuropsychiatric clinical pictures.

Monosymptomatic forms with cardiac arrhythmias (sinus tachycardia, atrial fibrillation) are also common in old age (Caution: the use of iodine-containing contrast media can lead to critical hyperthyroid states).

Regarding skin changes see below. Thyroid gland diseases, skin changes.

Imaging
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Sonography: Sonographically, volume, internal structure and echogenicity of the thyroid gland can be assessed and documented. In about 75% of patients, the thyroid gland is presented sonographically as a symmetrical, diffuse struma with rounded thyroid lobes, increased depth and a conspicuously low internal echo pattern.

Scintigraphy: Scintigraphically, a diffuse, homogeneous increased storage in a symmetrically enlarged thyroid gland with increased total technetium uptake (5 to 20 percent) is shown. In areas with endemic iodine deficiency and increased prevalence of a nodular goiter, signs of functional autonomy can be demonstrated sonographically and scintigraphically simultaneously in about 10% of patients with MB (Marine-Lenhart Syndrome). In hyperthyroid autonomy there is unifocal, multifocal or dissmenated radionuclide accumulation.

Laboratory
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TSH-R-Ak (=TRAK) The measurement of TSH-R-Ak in >95% increased, anti-TPO-Ak in 70% increased. (the conventional TSH-R-Ak assay detects all the TSH-R-Ak present, but does not distinguish their functional activities - stimulation or blockage of the TSH receptor).

TSH basally decreased (=screening test); free triiodothyronine(fT3) almost always increased, free thyroxine fT4 increased in 90%.

A normal basal TSH serum level(0.4 to 4.0 mU/liter) very probably excludes a hyperthyroid functional situation (exceptions: TSH-producing pituitary tumor, partial thyroid hormone resistance). Apparently without clinical relevance is the detection of ANA (175%), anti-Ro/SS-A in 2.5%; anti-RNP 2.5%, anti-La/SS-B in 1.9% (Nisihara R et al. 2018).

Diagnosis
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Medical history (yodexposure, symptoms of hyperthyroidism), clinical history (whirring struma diffusa, wet skin, resting tachycardia, tremor, symmetric hyperreflexia, endocrine orbidopathy)

Pioneering laboratory constellation

Sonography: diffuse echo deficiency

Scintigraphy: homogeneous intensive radionuclide enrichment

Differential diagnosis
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The differential diagnosis for sonographically echo deficient thyroid glands is, above all, an immune thyroid disease of the Hashimoto type (chronic insidious course, only rarely a merely transient hyperthyroidism (Hashitoxicose see below chronic lymphocytic thyroiditis - Hashimoto); TPO-Ak and Tg-Ak positive) (Krützfeld J et al. 2017).

Acute thyroiditis: Bacterial (streptococci, staphylococci) inflammation of the hypertrophied and enlarged thyroid gland in immunologically weakened patients with considerable feeling of illness, pain in swallowing.

Subacute thyroiditis de Quervain (acutely occurring painful, diffuse multinodular thyroid gland).

Invasive fibrosing thyroiditis(Riedel's goiter). Very rare, "so-called ice-hard goiter", chronic course.

Functional autonomy of the thyroid gland (syn.: autonomous adenoma): sign of hyperthyroidism, usually older age. Scintigraphic and sonographic evidence of the autonomous adenomas. In disseminated autonomy, in the absence of an EO, the initial determination of TSH-R-Ak (TRAK assay) is helpful for the classification of hyperthyroidism as immunohyperthyroidism of type MB. A TSH-R-Ak-negative immunohyperthyreopathy of type MB without clinical signs of EO is rare (about 5%) (Krützfeld J et al. 2017).

Exclusion of thyroid tumours (adenomas, carcinomas of the thyroid gland).

Therapy
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Interdisciplinary cooperation (general practitioner, endocrinologist, nuclear medicine specialist, surgeon, ophthalmologist) is an essential prerequisite for optimal individual patient care and long-term therapeutic success.

The treatment of immunohyperthyroidism type MB is traditionally (in Anglo-American countries, subtotal or total thyroidectomy is preferred as primary therapy: Genovese BM et al. 2013) primarily with thyrostatic drugs that inhibit the synthesis of thyroid hormones. The drugs of choice are thiamizole, carbimazole and propylthiouracil.

Initial therapy 10 - 30 mg thiamazol (15 to 30 mg carbimazol), if necessary in combination with a beta-receptor blocker (e.g. propranolol 3x 20 to 40 mg/day). Control intervals initially every 2-4 weeks, after reaching an euthyroid metabolic state every 2-3 months. Controls are necessary to ensure an optimal setting (TSH level between 0.4 and 1.0 mU/l) with sufficient control of hyperthyroidism (fT3, fT4). Maintenance therapy is continuously adjusted according to clinical findings. A lower dosage (thiamazole 2.5 to 10 mg/day, carbimazole 5 to 15mg) should be aimed for. The TRAK value also plays a role in therapy control (at values >10IU/l after 6-month therapy, a remission is unlikely).

After 1 year the therapy is discontinued. A sustained remission is only expected in about 50% of patients. Smoking increases the recurrence rate! The TRAk level after 6 months of therapy has prognostic significance. With values > 10IU/l a remission is unlikely. Definitive rehabilitation (surgery, radioiodine therapy) should be aimed for.

Long-term antithyroid therapy over several years seems to reduce the high risk of recurrence somewhat, but involves risks of side effects and compliance problems.

In juvenile patients with immunohyperthyroidism type MB the success rate is significantly lower, so that in >50% of these patients a definitive therapy (radioiodine therapy or surgical therapy) should be carried out in the long term.

Treatment of the recurrence of hyperthyroidism

In case of recurrence of hyperthyroidism (in 50% of the cases), which occurs after one year of continuous thyrostatic therapy, a definitive follow-up treatment (radioiodine therapy or surgery) is preferred.

If there are contraindications or a justified indication for an alternative treatment, a new drug therapy with an antithyroid substance can be tried for another year. At the latest, however, after the second recurrence of hyperthyroidism, a definitive cure should be given.

Patients with EO whose hyperthyroidism is not sufficiently controlled or recurs under consistent antithyroid medication should be immediately given definitive therapy (surgery; RJT under glucocorticosteroid protection).

In elderly or multimorbid patients, where both procedures are used in different types of patients, the use of the same technique is recommended. For elderly or multimorbid patients where both procedures are not feasible for various reasons, a long-term therapy with antithyroid drugs is recommended.

Supplementary drug therapy: In case of tachycardia beta-blockers, e.g. propanol, which inhibits the conversion of T4 to T3.

Therapy of the thyrotoxic crisis: in-patient intensive care unit (Thiamizol 80mg i.v. every 8 hours). Otherwise symptomatic therapy (fluid, electrolyte and calorie replacement).

Radioiodine therapy (RJT)

For radioiodine therapy immunohyperthyroidism type MB, hearth doses of 150 to 200 Gy are used. With this radiation dose, hyperthyroidism is usually safely eliminated. Pronounced hyperthyroidism must be corrected with medication before the radioactive iodine is applied. However, low-dose antithyroid therapy does not have to be discontinued before RJT is performed. To avoid hypothyroidism, which has an unfavourable effect on the course of EO, substitution with LT4 (50 to 75 µg per day) should be carried out early on following ablative RJT. The substitution is necessary for life.

In total, more than 50% of patients after RJT are expected to develop latent or manifest hypothyroidism. This can only occur years after the end of RJT therapy as so-called late hypothyroidism. In patients with immunohyperthyroidism of type MB and EO, RJT should only be carried out under passive glucocorticosteroid protection (e.g. 30 to 40 milligrams of prednisone per day for two weeks, followed by gradual dosage) because of the unfavourable antigen release for the course of EO.

Operative therapie
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The main goal of surgery for a Graves' struma is to avoid a relapse of hyperthyroidism. The aim is to leave a low thyroid volume of about 3-5g. The procedure can be performed as a bilateral almost total thyroidectomy or as a unilateral hemithyroidectomy with a subtotal resection of the contralateral thyroid lobe. Noteworthy complications are secondary bleeding (about 5%), passagonal and permanent recurrent paresis (1-4%) and passagonal or permanent hypoparathyroidism (1-10%). Preoperatively an euthyroid metabolic state can be induced by treatment with antithyroid substances.

Note(s)
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Immunohyperthyroidism of type MB with associated diseases:

Immunohyperthyroidism type MB + primary biliary cirrhosis (Shetty S et al. 2014)

Immunohyperthyroidism type MB + Immunoglobulin A nephropathy (Shetty S et al. 2014)

S.a. Thyroid gland diseases and skin changes.

Literature
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  1. Classen M et al (2004) In: Classen M et al (Hrsg) Endocrine disorders. Urban § Fischer publishing house Munich,Jena p.319-343
  2. Genovese BM et al (2013) What is the best definitive treatment for Graves' disease? A systematic review of the existing literature. Ann Surg Oncol 20:660-667.
  3. Khan I et al (2015) Grave's disease associated with immunoglobulin A nephropathy: A rare association. Indian J Nephrol 25:248-250.
  4. Krützfeld J et al. (2017) Thyroid diseases. In: E.Battegay (Hrsg)Differential diagnosis of internal diseases. Georg Thieme Publishing House. Stuttgart New York S 1251-1264
  5. Li H et al.(2013) Genetic susceptibility to Grave's disease. Front Biosci (Landmark Ed) 18:1080-1087.
  6. Menconi F et al (2014) Diagnosis and classification of Graves' disease. Autoimmune Rev 13:398-402.
  7. Nisihara R et al (2018) Rheumatic Disease Autoantibodies in Patients with Autoimmune Thyroid Diseases. Med Princ Pract doi: 10.1159/000490569.
  8. Shetty S et al (2014) Grave's Disease and Primary Biliary Cirrhosis-An Unusual and Challenging Association. J Clin Exp Hepatol: 4: 66-67.

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Last updated on: 29.10.2020