Graves' disease

Graves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones (a serious metabolic imbalance known as hyperthyroidism and thyrotoxicosis). This is caused by autoantibodies (TSHR-Ab) that activate the TSH-receptor (TSHR), thereby stimulating thyroid hormone synthesis and secretion, and thyroid growth (causing a diffusely enlarged goiter). The resulting state of hyperthyroidism can cause a dramatic constellation of neuropsychological and physical signs and symptoms.

Graves' disease is the most common cause of hyperthyroidism in children and adolescents, and usually presents itself during early adolescence. It has a powerful hereditary component, affects up to 2% of the female population, and is between five and ten times as common in females as in males. Graves’ disease is also the most common cause of severe hyperthyroidism, which is accompanied by more clinical signs and symptoms and laboratory abnormalities as compared with milder forms of hyperthyroidism. About 25-30% of people with Graves' disease will also suffer from Graves' ophthalmopathy (a protrusion of one or both eyes), caused by inflammation of the eye muscles by attacking autoantibodies.

Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be useful. However, Graves’ thyrotoxicosis often gradually affects the life of the patients, usually for many months, but sometimes years, prior to the diagnosis. This is partially because symptoms can develop so insidiously that they go unnoticed; when they do get reported, they are often confused with other health problems. Thus, diagnosing thyroid disease clinically can be challenging. Nevertheless, patients can experience a wide range of symptoms and suffer major impairment in most areas of health-related quality of life.

There is no cure for Graves’ disease. There are, however, treatments for its consequences: hyperthyroidism, ophthalmopathy and mental symptoms. The Graves’ disease itself - as defined, for example, by high serum TSHR-Ab concentrations or ophthalmopathy - often persists after its hyperthyroidism has been successfully treated. Further signs that may be seen on physical examination are mainly a diffusely enlarged (usually symmetric) nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart such as sinus tachycardia, atrial fibrillation and premature ventricular contractions, as well as hypertension. It has also been suggested that Y. enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility. More recently the role for Y. enterocolitica has been disputed.

Some of the eye symptoms of hyperthyroidism are believed to result from heightened sensitivity of receptors to sympathetic nervous system activity, possibly mediated by increased alpha-adrenergic receptors in some tissues.

Some people may have a genetic predisposition to develop TSH receptor autoantibodies. HLADR (especially DR3) appears to play a significant role.

Neuropsychological manifestations

Hyperthyroidism plays a major role in psychiatric morbidity in Graves' disease, and is associated with long-term mood disturbances. Although hyperthyroidism has been considered to induce psychiatric symptoms by enhancement of the sensitivity and turnover in catecholaminergic neurotransmission, the precise mechanism of cognitive and behavioral dysfunction in hyperthyroidism is not known. According to Gonen, the direct influence of thyroid hormones on brain functions stems from the presence of wide distribution of T3 receptors throughout the brain. Improvement of some clinical features (attention and concentration) with beta-blocker therapy suggests a role for a hyperthyroid-induced hyperactivity of the adrenergic nervous system, possibly disrupting the adrenergic pathways between the locus ceruleus and frontal lobe that subserve attention and vigilance, and thereby accounting for many physical and mental symptoms. Others propose that hyperthyroidism may produce oxidative stress, producing neuronal injury and hastening a presentation of degenerative or vascular dementia. A study of 2002 suggests another possible mechanism, involving activational and translational regulation of functional proteins in the brain. This is underscored by recent studies, who document a thyroid hormone effect on the neurotransmitters serotonin and norepinephrine, with changes in neurotransmitter synthesis and receptor sensitivity being noted. De Groot points out that, in spite of the fact that epinephrine levels and catecholamine excretion are actually not elevated, propranolol (presumably acting by inhibition of alpha-adrenergic sympathetic activity) certainly reduces anxiety and tremor in a very useful manner, indicating that some of the central nervous system irritability is a manifestation of elevated sensitivity to circulating epinephrine (though this has not been proved).

A study by Singh et al. showed for the first time that differential thyroidal status induces apoptosis in adult cerebral cortex. T3 acts directly on cerebral cortex mitochondria and induces release of cytochrome c to induce apoptosis. They note that adult cerebellum seems to be less responsive to changes in thyroidal status. Protein formation and destruction are both accelerated in hyperthyroidism. The absorption of vitamin A is increased and conversion of carotene to vitamin A is accelerated (the requirements of the body are likewise increased, and low blood concentrations of vitamin A may be found). Requirements for thiamine and vitamin B6 and B12 are increased. Lack of the B vitamins has been implicated as a cause of liver damage in thyrotoxicosis. Also, parathyroid hormone (PTH) levels tend to be suppressed in hyperthyroidism, possibly in response to elevated calcium levels.

Diagnosis

The onset of Graves' disease symptoms is often insidious: the intensity of symptoms can increase gradually for a long time before the patient is correctly diagnosed with Graves’ disease, which may take months or years.) One study puts the average time for diagnosis at 2.9 years, having observed a range from 3 months to 20 years in their sample population. A 1996 study offers a partial explanation for this generally late diagnosis, suggesting that the psychiatric symptoms (due to the hyperthyroidism) appeared to result in delays in seeking treatment as well as delays in receiving appropriate diagnosis. The results of overlooking the thyroid can however be very serious. Also noteworthy and problematic, is that in a 1996 survey study respondents reported a significant decline in memory, attention, planning, and overall productivity from the period 2 years prior to Graves' symptoms onset to the period when hyperthyroid.

The resulting hyperthyroidism in Graves' disease causes a wide variety of symptoms. The two signs that are truly 'diagnostic' of Graves' disease (i.e., not seen in other hyperthyroid conditions) are exophthalmos (protuberance of one or both eyes) and pretibial myxedema, a rare skin disorder with an occurrence rate of 1-4%, that causes lumpy, reddish skin on the lower legs. Graves' disease also causes goitre (an enlargement of the thyroid gland) that is of the diffuse type (i.e., spread throughout the gland). This phenomenon also occurs with other causes of hyperthyroidism, though Graves' disease is the most common cause of diffuse goitre. A large goitre will be visible to the naked eye, but a smaller goitre (very mild enlargement of the gland) may be detectable only by physical exam. Occasionally, goitre is not clinically detectable but may be seen only with CT or ultrasound examination of the thyroid.

A highly suggestive symptom of hyperthyroidism, is a change in reaction to external temperature. A hyperthyroid person will usually develop a preference for cold weather, a desire for less clothing and less bed covering, and a decreased ability to tolerate hot weather.

Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by a blood test. Elevated blood levels of the principal thyroid hormones (i.e. free T3 and T4), and a suppressed thyroid-stimulating hormone (low due to negative feedback from the elevated T3 and T4), point to hyperthyroidism. However, a 2007 study makes clear that diagnosis depends to a considerable extent on the position of the patient’s unique set point for T4 and T3 within the laboratory reference range (an important issue which is further elaborated below).

Differentiating Graves' hyperthyroidism from the other causes of hyperthyroidism (thyroiditis, toxic multinodular goiter, toxic thyroid nodule, and excess thyroid hormone supplementation) is important to determine proper treatment. Thus, when hyperthyroidism is confirmed, or when blood results are inconclusive, thyroid antibodies should be measured. Measurement of thyroid stimulating immunoglobulin (TSI) is the most accurate measure of thyroid antibodies. They will be positive in 60 to 90% of children with Graves' disease. If TSI is not elevated, then a radioactive iodine uptake should be performed; an elevated result with a diffuse pattern is typical of Graves' disease. Biopsy to obtain histological testing is not normally required but may be obtained if thyroidectomy is performed.

Treatment

It is yet unknown how to interrupt the autoimmune processes of Graves' disease, which means treatment has to be indirect. The link that is targeted is the thyroid gland, via three different methods (which have not changed fundamentally since the introduction of antithyroid drugs and radioactive iodine in the 1940s). These are the use of antithyroid drugs (which reduce the production of thyroid hormone), partial or complete destruction of the thyroid gland by ingestion of radioactive iodine (radioiodine), and partial or complete surgical removal of the thyroid gland (thyroidectomy).

There is no standard choice for treating Graves' hyperthyroidism; it is not straightforward and often involves complex decision making. The physician must weigh the advantages and disadvantages of the different treatment options and help the patient arrive at an individualized therapeutic strategy that is appropriate and cost-effective. Kaplan summarizes that "the choice of therapy varies according to nonbiological factors - physicians' training and personal experience; local and national practice patterns; patient, physician, and societal attitudes toward radiation exposure; and biological factors including age, reproductive status, and severity of the disease". Therapy with radioiodine is the most common treatment in the United States, whilst antithyroid drugs and/or thyroidectomy is used more often in Europe, Japan, and most of the rest of the world. However, due to the varying success of every treatment option, patients are often subjected to more than one of these, when the first attempted treatment didn't prove entirely successful.

In the short term, treatment of hyperthyroidism usually produces a parallel decrease in endocrine symptoms and in psychiatric symptoms. When prolonged treatment normalizes thyroid function, some psychiatric symptoms and somatic complaints may persist (as has been thoroughly clarified above). Patients who do not have a spontaneous remission with the use of antithyroid drugs, become lifelong thyroid patients.

Symptomatic

therapy.]]

Beta blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of rapid heart rate and nausea until such time as antithyroid treatments start to take effect.

Antithyroid drugs

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. The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side-effect is agranulocytosis. Others include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic anemia, and for propylthiouracil severe, fulminant liver failure. Patients on these medications should see a doctor if they develop sore throat or fever.

A randomized control trial testing single dose treatment for Graves' found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil. But generally both drugs are considered equivalent.

If treatment with antithyroid drugs fails to induce remission, RAI or surgery must be considered.

Radioiodine

Radioiodine (radioactive iodine-131, abbreviated as RAI) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for RAI 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), and solitary thyoid nodules.

The radio-iodine treatment acts slowly (over months to years) to partially or completely destroy the thyroid gland (depending on the administered dose). Patients must therefore be monitored regularly with thyroid blood tests to ensure that they don't evolve to hypothyroidism (incidence rate of 80%), in which case they will become lifelong thyroid patients. For some patients, finding the correct thyroid replacement hormone and the correct dosage may take many years and may be in itself a much more difficult task than is commonly understood.

Graves' disease-associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the administered dose of radioiodine.

Surgery

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 ophthalmopathy. As operating on a frankly hyperthyroid patient is dangerous, prior to thyroidectomy preoperative treatment with antithyroid drugs is given to render the patient "euthyroid" (i.e. normothyroid). Preoperative administration of (not radioactive) iodine, usually by Lugol's iodine solution, decreases intraoperative blood loss during thyroidectomy in patients with Grave's disease. However, it appears ineffective in patients who are already euthyroid due to treatment with anti-thyroid drugs and T4.

Doctors can opt for partial or total removal of the thyroid gland (subtotal thyroidectomy vs total thyroidectomy). A total removal excludes the difficulty in determining how much thyroid tissue must be removed. More aggressive surgery has a higher likelihood of inducing hypothyroidism; less aggressive surgery has a higher likelihood of recurrent hyperthyroidism. Around 10–15% of patients who had a subtotal thyrodectomy will develop underactive thyroids many years after their operation. This is not counting those who develop underactive thyroids immediately after the operation (within 6 weeks). Thyroid remnants smaller than 4 grams are associated with postoperative hypothyroidism in 27 to 99 percent of patients. Patients who have thyroid remnants of 7 to 8 g become euthyroid, but may have subclinical hyperthyroidism. In addition, 9 to 12 percent develop recurrent overt hyperthyroidism. As repeat surgery is associated with a high risk of complications, further permanent treatment should be with radioiodine..]]

In a study of 380 patients undergoing subtotal thyroidectomy, the complications were as followed:

Transient vocal cord paralysis in 3%

Prolonged postoperative hypocalcemia in 3%

Permanent hypoparathyroidism in 1% (due to removal of one or more parathyroid glands)

Recurrent hyperthyroidism in 2%

A scar is created across the neck just above the collar bone line. However, the scar is very thin, and eventually recedes to appear as nothing more than a crease in the neck. Patients may spend one or more nights in hospital after the surgery, and endure the effects of general anesthesia (i.e., vomiting), as well as a sore throat, a raspy voice, and a cough from having an endotracheal tube inserted in the trachea during surgery.

Removal of the gland enables complete biopsy to be performed to have definite evidence of thyroid cancer, since needle biopsies are not as accurate at predicting a benign state of the thyroid. No further treatment of the thyroid is required, unless cancer is detected. Radioiodine treatment may be done after surgery, to ensure that all remaining (potentially cancerous) thyroid cells are destroyed (i.e., those near the nerves to the vocal cords, which cannot be surgically removed without damage to those vocal cords). Besides this, the only remaining treatment will be thyroid replacement pills (to be taken for the rest of the patient's life), if the surgery results in hypothyroidism.

Thyroid hormones

Many Graves' disease patients will become lifelong thyroid patients, due to the surgical removal or radioactive destruction of their thyroid. In effect, they are then hypothyroid patients, requiring perpetual intake of artificial thyroid hormones. Given the one-week plasma half life of levothyroxine (T4), it takes about five-six weeks (half-lives) before a steady state is attained after the dosage is initiated or changed. After the optimal thyroxine dose has been defined, long-term monitoring of patients with an annual clinical evaluation and serum TSH measurement is appropriate. Being treated with too much or too little thyroid hormone can lead to a chronic state of (possibly subclinical) hypo- or hyperthyroidism. Several studies show that this is not an uncommon occurrence.

Neuropsychiatric symptoms

A substantial proportion of patients have an altered mental state, even after successful treatment of hyperthyroidism. When psychiatric disorders remain after restoration of euthyroidism and after treatment with beta blockers, specific treatment for the psychiatric symptoms, especially psychotropic drugs, may be needed. German research of 2004 reported that 35 percent of treated Graves' disease patients (with normal thyroid tests for at least six months after treatment), suffered from psychological distress, and had high levels of anxiety. Almost all these patients had clear-cut depression.

Eye disease

Mild cases are treated with lubricant eye drops or non steroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).

Eyelid muscles can become tight with Graves, making it impossible to completely close the eyes. Difficulty closing the eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full sleep. Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves' on the eyelids. Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms.

Orbital decompression can be performed to enable bulging eyes to be retracted again. In this procedure, bone is removed from the skull behind the eyes, and space is made for the enlarged muscles and fatty tissue to be moved back into the skull.

General measurements

Graves' disease patients are nutritionally depleted in proportion to the duration and severity of their illness. Until metabolism is restored to normal, and for some time afterward, caloric and protein requirements may be well above normal. Specific deficiencies may exist, and multivitamin supplementation is indicated. The intake of calcium should be above normal. All in all, the physician should pay heed to the patient's emotional needs, as well as to his or her requirements for rest, nutrition, and specific (anti)thyroid medication.

Remission and relapses

A literature study in 2006 found that patients who have residual mental symptoms have a significantly higher chance of relapse of hyperthyroidism. Patients with recurrent Graves’ hyperthyroidism, compared with patients in remission and healthy subjects, had significantly higher scores on scales related to depression and anxiety, as well as less tolerance of stress.

Mental impairment

A literature review in 2006, whilst noting methodology issues in the consistency of Graves' disease diagnostic criteria, found many reports about residual complaints in patients who were euthyroid after treatment with a high prevalence of anxiety disorders and bipolar disorder, as well as elevated scores on scales of anxiety, depression and psychological distress. In rare cases, patients will experience psychosis-like symptoms only after they have been treated for hypo- or hyperthyroidism, due to a rapid normalisation of thyroid hormone levels in a patient who has partly adapted to abnormal values. Given the sometimes dramatic impact and long duration of the disease and its treatment, identifying and maintaining emotional support systems (which are frequently affected) can help patients and their families cope. Because emotional lability of the thyrotoxic patient may create interpersonal problems (often producing significant marital stress and conflict), thorough explanation of the disease can be invaluable.

However, many patients indicate they are not getting the information they need from the general medical community, and are concerned that they have not obtained a full understanding of their condition. De Groot et al. feel that sympathetic discussion by the physician, possibly together with assistance in environmental manipulation, is an important part of the general attack on Graves' disease. In a statistical study of symptoms and signs of 184 thyrotoxic patients (52 men, 132 women), the male patients were somewhat older than the females, and there were more severe cases among men than among women. Cardiac symptoms were more common in women, even though the men were older and more often had a severe form of the disease; palpitations and dyspnea were more common and severe in women.

History

Graves' disease owes its name to the Irish doctor Robert James Graves, who described a case of goitre with exophthalmos in 1835. However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, the term Basedow's syndrome/disease is more common on the European continent than Graves' disease. It has also been called exophthalmic goitre. Less commonly, it has been known as Parry's disease, Begbie's disease, Flajani's disease, Flajani-Basedow syndrome, and Marsh's disease, in honor of other pioneer investigators of the disorder, whose earlier reports were not widely circulated: Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century, first noted the condition in 1786. This case was not published until 1825, but still 10 years ahead of Graves.

However, fair credit for the first description of Graves' disease goes to the 12th century Persian physician Sayyid Ismail al-Jurjani, who noted the association of goitre and exophthalmos in his "Thesaurus of the Shah of Khwarazm", the major medical dictionary of its time.

One of the first reports of the adverse effects of hyperthyroidism on the skeleton dates from 1891, when von Recklinghausen described the "worm eaten" appearance of the long bones of a young woman who died from hyperthyroidism.

Notable cases

used his bulging eyes, caused by Graves disease, to good effect in his work as a comedian.]] John Adams, Second President of the United States (possible case) Ayaka, Japanese singer/songwriter George H. W. Bush, U.S. president, developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease, and treated with radioactive iodine. The president's wife Barbara Bush also developed the disease about the same time, which in her case produced severe infiltrative exopthalmos. Scientists said that the odds of both George and Barbara Bush having Graves’ disease might be 1 in 100,000 or as low as 1 in 3,000,000, presuming that the disease was independently caused. Maggie Cheung Ho-Yee, Hong Kong actress Toni Childs, American singer/songwriter Gail Devers, Athletic champion Marty Feldman, British comedian Diane Finley, Canadian cabinet minister Faith Ford, American actress Sia Furler, Australian singer Sammy "The Bull" Gravano, Former Gambino Family Underboss Herbert Norman Howells, British Composer Nadezhda Krupskaya, the wife of Lenin Barbara Leigh, an American former actress and fashion model, now spokeswomen for the National Graves' Disease Foundation Yūko Miyamura, Japanese voice actress Christopher Monckton, 3rd Viscount Monckton of Brenchley Claire Rayner, UK Nurse, Agony Aunt and Broadcaster Christina Georgina Rossetti, British Victorian Poet Cecil Spring-Rice, British Ambassador to the USA from 1912 to 1918 Mary Webb, English author and poet, descendant of Sir Walter Scott

See also

Hashitoxicosis

Myxedema

Neuroendocrinology

Thyroidologist

Thyrotoxic myopathy

Notes

External links

Graves' Disease Foundation Conducts research about Graves' disease, and provides support via the largest internet forum on Graves' disease

Thyroid Disease Manager Contains several very specialised chapters on Graves' disease, and related issues

Patient information: Antithyroid drugs Article at UpToDate

Drug Therapy: Antithyroid drugs Elaborate article published in 2005 in the medical magazine Medicina Interna

Category:Autoimmune diseases Category:Thyroid disease