Immunogenic hyperthyroidism E05.0

Graves' Day 1840

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).

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

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

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.

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.

In most cases, immunogenic hyperthyroidism manifests itself with the "classic" clinical symptom constellation of the "Merseburg triad": goiter (70% of cases; in the case of severe vascularization, a buzzing above the thyroid parenchyma is detectable), sinus tachycardia and exophthalmos.

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

Endocrine orbidopathy (noticeable due to exophthalmos, eyelid oedema, foreign body sensation, conjunctivitis, photophobia, eyelid retraction, retrobulbar pressure sensation) occurs in 40% of patients in addition to hyperthyroidism.

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

Older patients with MB-type immune hyperthyroidism are dominated by oligosymptomatic forms with uncharacteristic symptoms such as anorexia, weakness, fatigue or sensitivity to cold, symptoms that are often misjudged as "signs of ageing" or neuropsychiatric disorders.

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

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

Sonography: The volume, internal structure and echogenicity of the thyroid gland can be assessed and documented by sonography. In about 75% of patients, the thyroid gland presents sonographically as a symmetrical, diffuse goiter with rounded thyroid lobes, increased depth and a conspicuously hypoechoic internal pattern.

Scintigraphy: Scintigraphy shows a diffuse, homogeneous multiple storage in a symmetrically enlarged thyroid gland with increased total technetium uptake (5 to 20 percent). In areas with endemic iodine deficiency and an increased prevalence of nodular goiter, about 10% of patients with MB show sonographic and scintigraphic signs of functional autonomy at the same time (Marine-Lenhart syndrome). Hypertyroid autonomy is characterized by unifocal, multifocal or disseminated radionuclide accumulation.

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).

Medical history (iodine exposure, symptoms of hyperthyroidism), clinic (buzzing diffuse goiter, moist skin, resting tachycardia, tremor, symmetrical hyperreflexia, endocrine orbidopathy)

Pioneering laboratory constellation

Sonography: diffuse hypoechoicity

Scintigraphy: homogeneous intense radionuclide accumulation

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).

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

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

Initial therapy 10 - 30 mg thiamazole (15 to 30 mg carbimazole), 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 a euthyroid metabolic state every 2-3 months. Check-ups 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 depending on the clinical findings. A lower dosage should be aimed for (thiamazole 2.5 to 10 mg/day, carbimazole 5 to 15 mg). The TRAK value also plays a role in therapy monitoring (if the value is >10IU/l after 6 months of therapy, remission is unlikely).

Therapy is discontinued after 1 year. A sustained remission can only be expected in around 50% of patients. Smoking increases the recurrence rate! The TRAk level after 6 months of therapy is of prognostic significance. Remission is unlikely with values > 10IU/l. Definitive treatment (surgery, radioiodine therapy) should be sought.

Although long-term antithyroid therapy over several years appears to reduce the high risk of recurrence somewhat, it carries the risk of side effects and compliance problems.

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

Treatment of recurrent hyperthyroidism

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

If there are contraindications or a justified indication for an alternative treatment, a new attempt at drug therapy with an antithyroid substance can be made for a further year. However, definitive treatment should take place at the latest after the second recurrence of hyperthyroidism.

In patients with EO whose hyperthyroidism is not sufficiently controlled under consistent antithyroid medication or relapses, definitive therapy (surgery; RJT under glucocorticosteroid protection) should be carried out immediately.

In elderly or multimorbid patients in whom both procedures are not feasible for various reasons. Long-term therapy with antithyroid medication is recommended for older or multimorbid patients in whom both procedures are not feasible for various reasons.

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

Therapy of thyrotoxic crisis: inpatient intensive care unit (thiamizole 80mg i.v. every 8 hours). Otherwise symptomatic therapy (fluid, electrolyte and calorie replacement).

Radioiodine therapy (RJT): In radioiodine therapy for MB-type immunohyperthyroidism, focal doses of 150 to 200 Gy are used. This radiation dose usually safely eliminates the hyperthyroidism. Pronounced hyperthyroidism must be corrected with medication before the radioactive iodine is applied. On the other hand, low-dose antithyroid therapy does not have to be discontinued before RJT is carried out. To avoid hypothyroidism, which has an unfavorable effect on the course of EO, substitution with LT4 (50 to 75 µg per day) should take place early on following ablative RJT. Substitution is necessary for the rest of the patient's life.

Overall, the development of latent or manifest hypothyroidism must be expected in more than 50% of patients after RJT. This can occur years after the end of RJ therapy as so-called late hypothyroidism. In patients with MB and EO-type immune hyperthyroidism, RJT should only be carried out under temporary glucocorticosteroid protection (e.g. 30 to 40 milligrams of prednisone/day for two weeks, followed by a tapered dosage) due to the unfavorable antigen release for the course of EO.

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.

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.

1. Classen M et al. (2004) In: Classen M et al (eds) Endocrine diseases. Urban § Fischer Verlag Munich,Jena pp.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 (ed)Differential diagnosis of internal diseases. Georg Thieme Publishers. 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.