Graves-Basedow disease is a form of thyroiditis, an autoimmune disorder that stimulates the thyroid gland, being the most common cause of hyperthyroidism (overactivity of the thyroid). Also known in the English-speaking world simply as Graves’ disease, it occurs most frequently in women (8:1 compared to men) of middle age. Symptoms include fatigue, weight loss and rapid heart beat. Because similar antibodies to those stimulating the thyroid also affect the eye, eye symptoms are also commonly reported. Treatment is with medication that reduces the production of thyroid hormone (thyroxin), or with radioactive iodine if refractory.

Signs and symptoms
Graves-Basedow disease is a disorder characterized by a triad of hyperthyroidism, goitre, and exophthalmos (bulging eyeballs).

Due to the many physiological actions of thyroid hormone, many symptoms and signs are linked to Graves’ disease:

Cardiac: cardiac arrhythmias (especially atrial fibrillation), tachycardia (increased heart rate), collapsing pulse and widened pulse pressure (difference between systolic and diastolic BP) and congestive cardiac failure with peripheral edema, ascites, anasarca.
Endocrine: weight loss in the presence of increased appetite, intolerance to heat, elevated basal metabolic rate
Dermatological: profuse sweating, thyroid acropachy (clubbing) of the fingernails, onycholysis (fingernail destruction), palmar erythema, pretibial myxedema (3 to 5% of Graves’ patients, not to be confused with the myxedema of hypothyroidism)
Neurological: tremor (especially noticeable on extending the arms), apprehension, weakness, headache, proximal myopathy (difficulty rising from a chair or squatting position) and hyperactive deep tendon reflexes
Gastrointestinal: diarrhea (common), vomiting (rare)
Ophthalmological: thyroid eye disease (TED) characteristic of Graves disease include lid retraction (Dalrymple sign) above the superior corneoscleral limbus, lid lag (von Graefe’s sign), proptosis or forward displacement of the globes, periorbital swelling and chemosis.
Extremely manifested disease that can sometimes be life-threatening is called the thyroid storm.

On the basis of the signs and symptoms, thyroid hormone (T4) and thyroid-stimulating hormone (TSH) are determined in the medical laboratory. T4 is markedly elevated, while TSH is suppressed due to negative feedback. An elevated protein-bound iodine level may be detected. A large goiter is sometimes seen on X-rays.

Thyroid-stimulating antibodies may be detected serologically.

Most features are due to the production of autoantibodies that bind to the TSH receptor, which is present on the follicular cells of the thyroid (the cells that produce thryoid hormone). These antibodies activate the cells in the same fashion as TSH itself, leading to an elevated production of thyroid hormone.

The infiltrative opthalmopathy (thyroid eye disease) that is frequently encountered has been explained by the expression of the TSH receptor on retroorbital tissue.

The exact cause of antibody production is not known. Viral infection may trigger antibodies against its epitopes, which cross-react with the human TSH receptor. There appears to be a genetic predisposition for Graves’ disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.

Medical treatment of Graves disease includes antithyroid drugs, radioactive iodine and thyroidectomy (surgical excision of the gland).

Antithyroid drugs
The main antithyroid drugs are methimazole (US), carbimazole (UK) and propylthiouracil (PTU). These drugs block the binding of ioding and coupling of iodotyrosines. The most dangerous side-effect is agranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which does not stop on cessation of drug). Others include granulocytopenia (dose dependant, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should stop the medication and see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk.

This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are: failed medical therapy or surgery and where medical or surgical therapy are contraindicated.

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative- it can aggravate thyroid eye disease), solitary nodules. Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring hormone suppletion. It acts slowly and has a relapse rate that depends on the dose administered.

This modality is suitable for young patients and pregnant patients. Indications are: a large goitre (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid) and patients with opthalmopathy.

Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on 1 side and partial lobectomy on other side) are possible.

Advantages are: immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea) and scarring.

Eye disease
For mild disease – artificial tears, steroid eyedrops, oral steroids (to reducechemosis)
For moderate disease – lateral tarsorrhaphy
For severe disease – orbital decompression or retro-orbital radiation

If left untreated
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, and in extreme cases, death. Graves-Basedow disease is often accompanied by an increase in heart rate, which may lead to further heart complications.

There is female predominance (ratio 8:1), and onset is commonly in the third to fifth decades of life. There is a marked family preponderance, which has led to speculation that there may be a genetic cause. To date, no clear genetic defect has been found that would point at a monogenic cause.

Ljunggren (1983) suggests that the Persian physician Sayyid Ismail Al-Jurjani should be credited with recognising the disease, having noted the association of goitre and exophthalmos, in “Thesaurus of the Shah of Khwarazm”, the most famous of his five books, and the major medical dictionary of its time.

Caleb Hillier Parry (1755-1822) first noted the clinical picture in 1786, and it is reported in his posthumous collection of unpublished writings in 1825. It was also described by the Italians Giuseppe Flajani (1741-1808) in 1802 and Antonio Giuseppe Testa (1756-1814) in 1810. Robert James Graves (1797-1853) of Ireland in 1835, and Karl Adolph von Basedow of Germany. in 1840, independently reported the constellation of symptoms. On the European Continent the term Basedow’s disease is the more common, while it is known as Graves’ disease in the English-speaking world.

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