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Graves-Basedow disease

Graves-Basedow disease, also known simply as Graves disease, is a medical disorder that may manifest several different conditions, includinggoitre and hyperthyroidism (over-activity of thyroid hormone production), infiltrativeexophthalmos (protuberance of one or both eyes and associated problems) and infiltrative dermopathy (a skin condition usually of the lower extremities). This disorder is the most common cause of hyperthyroidism. It is known to be related to an antibody mediated type of auto-immunity, but the trigger for the reaction is unknown.

Incidence and epidemiology

Also known in the English-speaking world simply as Graves' disease, the disease occurs most frequently in women (8:1 compared to men). It occurs most often in middle age (most commonly in the third to fifth decades of life), but is not uncommon in adolescents, during pregnancy, at the time of menopause and in people over age 50. There is a marked family preponderance, which has led to speculation that there may be a genetic component. To date, no clear genetic defect has been found that would point at amonogenic cause.

Etiology

The cause of this disease are unknown, but it is generally felt that genetic and environmental factors contribute to its development.^[1] With this being an autoimmune disease which appears suddenly, often quite late in life, a cross reaction by the body to a viral disease is one suspected cause (this is a similar mechanism to that postulated for some cases of type Idiabetes).

One possible candidate is infection with yersinia enterocolitica (a cousin of the plague bacteria), but whilst there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited.[1] Yersinia seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.^[2] It has also been suggested that yersinia enterocolitica infection is not thecause of auto-immune thyroid disease, but rather is only anassociated condition; with both having a shared inherited susceptibility.^[3] More recently the role for yersinia enterocolitica has been disputed.^[4]

Signs and symptoms

Graves-Basedow disease is a disorder characterized by a triad ofhyperthyroidism,goitre, andexophthalmos (bulging eyeballs).

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

• Cardiac:cardiac arrhythmias (especiallyatrial fibrillation),tachycardia (increasedheart rate), collapsingpulse and widened pulse pressure (difference between systolic and diastolic BP) andcongestive cardiac failure with peripheraledema,ascites,anasarca.
• Endocrine:weight loss in the presence of increasedappetite, intolerance to heat, elevatedbasal metabolic rate. In premenopausal women, there may be a reduction in the amount of menses (oligomenorrhea).
• Dermatological: profusesweating, thyroid acropachy (clubbing) of the fingernails,onycholysis (fingernail destruction),palmar erythema, pretibialmyxedema (3 to 5% of Graves' patients, not to be confused with the myxedema ofhypothyroidism)
• Neurological:tremor (especially noticeable on extending the arms), apprehension,weakness,headache, proximalmyopathy (difficulty rising from a chair or squatting position), restlessness, and hyperactivedeep 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),exophthalmos (forward displacement of the globes), periorbital swelling andchemosis. Visual field defects may be present if periorbital swelling puts pressure on theoptic nerve. The patient may complain ofdry eye due to incomplete lid closure.
• Stomatological: multipledental caries, parodontitis (rare).

Graves disease can lead to extreme hyperthyroidism which is life-threatening. This is calledthyroid storm.

Because similarantibodies to those stimulating the thyroid may also react with the eye muscles, patients may develop an enlargement of the ocular muscles with resultant forward movement of the eyeball (proptosis, also called exopthalmos) and inflammation of the tissues around the eye. Enlargement of the eye muscles may result in difficulty with proper movement and coordination of the eyes, and cause double vision and an obvious disparity in the relative position of both eyes. Difficulty in closing the eyelids may lead to eye dryness and occasionally corneal ulceration.

The ocular manifestations of Graves-Basedow disease are more common in smokers and tend to worsen (or develop for the first time) following radioiodine treatment of the thyroid condition. Thus, they are not caused by hyperthyroidism per se; this common misperception may result from the fact that hyperthyroidism from other causes may cause eyelid retraction or eyelid lag (so-called hyperthyroid stare) which can be confused with the general appearance of proptosis/exopthalmos, despite the fact that the globes do not actually protrude in other causes of hyperthyroidism. Also, both conditions may exist at the same time in the hyperthyroid patient with Graves-Basedow disease.

Diagnosis

On the basis of the signs and symptoms,thyroid hormone (thyroxine or T4, triiodothyronine or T3) andthyroid-stimulating hormone (TSH) are determined in themedical laboratory. Free T4 and Free T3 is markedly elevated, while TSH is suppressed due tonegative feedback. An elevated protein-boundiodine level may be detected. A large goiter is sometimes seen onX-rays.

Thyroid-stimulating antibodies may be detectedserologically.

Pathophysiology

Grave's disease is an example of atype II hypersensitivity autoimmune disorder. Most features are due to the production ofautoantibodies 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 itsepitopes, which cross-react with the human TSH receptor. There appears to be agenetic 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.

Treatment

Medical treatment of Graves' disease includes antithyroid drugs, radioactiveiodine andthyroidectomy (surgical excision of the gland).

Treatment of the hyperthyroidism of Graves-Basedow disease may be with medications such as methimazole or propylthiouracil (PTU), which reduce the production ofthyroid hormone, or withradioactive iodine. Surgical removal of the thyroid is another option, but still requires preoperative treatment with methimazole or PTU. This is done to render the patient "euthyroid" (i.e. normothyroid) before the surgery since operating on a frankly hyperthyroid patient is dangerous. Therapy with radioactive iodine (I-131) is the most common treatment in the United States and in many other parts of the world. Thyroid blocking drugs and/or surgical thyroid removal is used more often than radioactive iodine as definitive treatment in Japan, perhaps because of general fear of radioactivity among many Japanese.

The development of radioactive iodine (I-131) in the early 1940s and its widespread adoption as treatment for Graves' Disease has led to a progressive reduction in the use of surgical thyroidectomy for this problem. In general, RAI therapy is effective, less expensive, and avoids the small but definite risks of surgery. Treatment with antithyroid medications must be given for six months to two years, in order to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells.

Antithyroid drugs

The main antithyroid drugs aremethimazole (US),carbimazole (UK) andpropylthiouracil (PTU). These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side-effect isagranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which does not stop on cessation of drug). Others includegranulocytopenia (dose dependent, which improves on cessation of the drug) andaplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross theplacenta and are secreted in breast milk.

Radioiodine

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

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

Surgery

This modality is suitable for young patients and pregnant patients. Indications are: a large goitre (especially when compressing thetrachea), suspicious nodules or suspectedcancer (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 ofcarcinoma. Its risks are injury of therecurrent laryngeal nerve,hypoparathyroidism (due to removal of theparathyroid glands),hematoma (which can be life-threatening if it compresses thetrachea) andscarring.

Eye disease

• For mild disease -artificial tears, steroid eyedrops, oral steroids (to reduce chemosis)
• For moderate disease - lateraltarsorrhaphy
• For severe disease - orbital decompression or retro-orbital radiation

If left untreated

If left untreated, more seriouscomplications could result, includingbirth defects in pregnancy, increased risk of amiscarriage, and in extreme cases, death. Graves-Basedow disease is often accompanied by an increase in heart rate, which may lead to further heart complications. If the eyes are proptotic (bulging) severely enough that the lids do not close completely at night, severe dryness will occur with a very high risk of a secondary corneal infection which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss as well.

 

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