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 to the TSH-receptor (TSHR-Ab) that activate that 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, which can severely compromise the patients’ ability to maintain jobs and relationships.^[1]

It is the most common cause of hyperthyroidism in children and adolescents, and usually presents itself during early adolescence.^[2] It has a powerful hereditary component, affects up to 2% of the female population, and has a female:male incidence of 5:1 to 10:1.^[3] 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.^[4] About 20-25% 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.^[5] However, Graves’ thyrotoxicosis often gradually affects the life of the patients, usually for many months, but sometimes years, prior to the diagnosis.^[6] 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.^[7] Nevertheless, patients can experience a wide range of symptoms and suffer major impairment in most areas of health-related quality of life.^[8]

There is no treatment for Graves’ disease. There are, however, treatments for its consequences: hyperthyroidism, ophthalmopathy and mental symptoms.^[9] 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.^[9]

Symptoms and signs

Except for Graves' ophthalmopathy, goitre and pretibial myxedema (which all result from the autoimmune processes of Graves' disease), virtually all signs and symptoms result from the direct and indirect effects of hyperthyroidism. These clinical manifestations are dramatic and involve virtually every system in the body. The mechanisms that mediate these effects are not well-understood. The severity of the symptoms and signs of hyperthyroidism is related to the duration of the disease, the magnitude of the thyroid hormone excess, and the patient's age. There is also significant variability in the individual response to hyperthyroidism and individual sensitivity to thyroid hormone fluctuations generally.^[10] It should also be noted that Graves' disease patients can also undergo periods of hypothyroidism (for further information, see symptoms of hypothyroidism). This is usually due to the fact that finding the right dosage of thyroid hormone suppression and/or supplementation during treatment can be difficult and takes time. The body's need for thyroid hormone can also change over time, e.g. the first months after radioactive iodine treatment (RAI). Also, thyroid autoimmune diseases are sometimes volatile, and hyperthyroidism can interchange with hypothyroidism and euthyroidism.^[11]

• Goitre (enlarged thyroid). If the thyroid grows large enough, it may compress the recurrent laryngeal nerve, producing vocal cord paralysis, dysphonia, and even respiratory stridor. A Horner's syndrome may also result from compression of the sympathetic chain.
• Graves' ophthalmopathy (protrusion of eyes)
• Pretibial myxedema (lumpy, reddish skin of the lower legs)

• Cardiovascular features may include hypertension (the systolic blood pressure is frequently elevated, while the diastolic blood pressure is characteristically decreased),^[3] and heart rate that may be rapid or irregular in character; these may be perceived as palpitations.^[3] Less common findings include left ventricular hypertrophy, premature atrial and ventricular contractions, atrial fibrillation, congestive heart failure, angina, myocardial infarction, systemic embolization, death from cardiovascular collapse and resistance to some drug effects (digoxin, coumadin).^[3]
• Hyperreflexia, with a rapid relaxation phase.^[3]
• A distinctly excessive reaction to all sorts of stimuli.^[3]
• Hyperactivity/increased energy. Patients remark that they are impelled to incessant activity, which, however, causes great fatigue.^[3]
• A marked increase in fatigability, or asthenia, is often prominent. This increased weariness may be combined with hyperactivity.^[3]
• Insomnia
• Tremor (usually fine shaking; tremor of the outstretched fingers). In a small study of newly diagnosed hyperthyroid patients, tremor was observed in 76%. Some studies lay the cause for hyperthyroid tremor with a heightened beta-adrenergic state, others suggest an increased metabolism of dopamine.
• Weight loss despite normal or increased appetite.
• Increased appetite. The effect of this increase is to offset, in part (sometimes completely), the loss of weight that might be expected from the increased catabolism in hyperthyroidism.^[3]
• Some patients (especially younger ones) gain weight due to excessive appetite stimulation, that exceeds the weigh loss effect of hyperthyroidism.
• Weakness or muscle weakness (especially in the large muscles of the arms and legs) occurs in 60 to 80 percent of patients with untreated hyperthyroidism. However, it is uncommon for a patient with hyperthyroidism to present with muscle weakness as the chief complaint. The likelihood and degree of muscle weakness is correlated with the duration and severity of the hyperthyroid state, and becomes more likely after the age of 40. Muscle strength returns gradually over several months after the hyperthyroidism has been treated.
• Muscle degeneration
• Shortness of breath^[3]
• Increased sweating
• Heat intolerance
• Warm and moist skin
• Thin and fine hair
• Redness of the elbows is frequently present. It is probably the result of the combination of increased activity, an exposed part, and a hyperirritable vasomotor system.^[3]
• Chronic sinus infections
• Brittle nails
• Plummer's nail (nail in which there is onycholysis, or separation of the nail from the nail bed, particularly affecting the ring and little fingers).^[12]
• Abnormal breast enlargement in men
• Gastrointestinal symptoms including increased bowel movements, but malabsorption is unusual.^[3]
• Augmented calcium levels in the blood (by as much as 25% - known as hypercalcaemia) can cause stomach upset, excessive urination, and impaired kidney function.^[13]
• Diabetes may be activated or intensified, and its control is worsened. The diabetes is ameliorated or may disappear when the thyrotoxicosis is treated.^[3]
• Evidence of mild or severe liver disease may be found.^[3]
• Reproductive symptoms in men may include reduced free testosterone (due to the elevation of testosterone-estrogen binding globulin level),^[3] diminished libido, erectile dysfunction and reversible impaired sperm production with lower mean sperm density, a high incidence of sperm abnormalities, and reduced motility of the sperm cells.^[3] Women may experience infrequent menstruation or irregular and scant menstrual flow along with difficulty conceiving, infertility and recurrent miscarriage.
• Neurologically seizures may occur, neuropathy from nerve entrapment by lesions of pretibial myxedema, and hypokalemic periodic paralysis.^[3] Rarely a thyrotoxic neuropathy may occur, corticospinal tract disease with pyramidal tract damage, and abnormal movements of chorea and athetoid movements.^[3] Very rarely there may be an acute thyrotoxic encephalopathy.^[3]

Effects on skeleton

Overt hyperthyroidism is associated with accelerated bone remodeling (resulting in increased porosity of cortical bone and reduced volume of trabecular bone), a generally reduced bone density, osteoporosis, and an increase in fracture rate. The changes in bone metabolism are connected with negative calcium balance, an increased excretion of calcium and phosphorus in the urine (hypercalciuria) and stool, and, rarely, hypercalcemia.^[13] In hyperthyroidism, the normal cycle duration of bone resorption of approximately 200 days is halved, and each cycle is associated with a 9.6 percent loss of mineralized bone. In hypothyroidism, cycle length approximates 700 days and is associated with a 17 percent increase in mineralized bone.

The extent of the reduction in bone density in most studies is 10-20%. The clinical manifestations on bone differ depending on the age of the patient. Postmenopausal woman are most sensitive to accelerated bone loss from thyrotoxicosis. Accelerated bone growth in growing children can increase ossification in the short term, but generally results in short-stature adults compared with the predicted heights.

With the introduction of antithyroid drugs and radioiodine in the 1940s, clinically apparent hyperthyroid bone disease became less common. However, bone density measurements have demonstrated that bone loss is common in patients with overt hyperthyroidism and, to a lesser extent, in those with subclinical hyperthyroidism. A history of overt hyperthyroidism is a risk factor for hip fracture later in life, which in turn is one of the causes of excess late mortality in previously hyperthyroid patients. It is therefore reasonable to assume that in some hyperthyroid patients bone density does not completely return to normal after antithyroid treatment.

However, if the thyrotoxicosis is treated early, bone loss can be minimized.^[13] The level of calcium in the blood can be determined by a simple blood test, and a bone density scan can document the amount of bone loss. There are many medications that can help to rebuild bone mass and to prevent further bone loss.^[13] Risedronate treatment has been demonstrated to help restore bone mass in osteopenia/osteoporosis associated with Graves’ disease.^[14] Nevertheless, weight-bearing exercises, a balanced diet, calcium intake of about 1500 mg a day and enough vitamin D, are of course elementary foundations.^[13]

Eye symptoms

Hyperthyroidism almost always causes general eye symptoms like dryness and irritation, regardless of what the cause of the hyperthyroid state is. However, these need to be distuingished from Graves' ophthalmopathy, which can only occur in patients who have Graves' disease. (It may also, rarely, be seen in Hashimoto's thyroiditis, primary hypothyroidism, and thyroid cancer).

About 20-25% of patients with Graves' disease will suffer from clinically obvious Graves' ophthalmopathy, and not just from the eye signs of hyperthyroidism. Only 3 to 5% will develop severe ophthalmopathy.^[15] However, when subjected to closer inspection (e.g. by magnetic resonance imaging of the orbits) many more patients have evidence of ophthalmopathy (primarily enlargement of retroocular muscles). It is estimated that for every 100,000 persons, 16 women and 3 men have Graves' ophthalmopathy every year.

Although it is true that in most patients ophthalmopathy, goiter, and symptoms of thyrotoxicosis appear more or less coincidentally, it is also true that in certain cases eye signs may appear long before thyrotoxicosis is evident, or become worse when the thyrotoxicosis is subsiding or has been controlled by treatment.^[3] In approximately 20% of ophthalmopathy patients, ophthalmopathy appears before the onset of hyperthyroidism, in about 40% concurrently, and in about 20% in the six months after diagnosis. In the remainder, the eye disease first becomes apparent after treatment of the hyperthyroidism, more often in patients treated with radioiodine.

It can sometimes be difficult to distinguish between eye symptoms due to hyperthyroidism and those due to Graves' antibodies, not in the least because the two often occur coincidently. What can make things particularly difficult, is that many patients with hyperthyroidism have lid retraction, which leads to stare and lid lag (due to contraction of the levator palpebrae muscles of the eyelids). This stare may then give the appearance of protruding eyeballs (proptosis), when none in fact exists. This subsides when the hyperthyroidism is treated.

Due to Graves' ophthalmopathy

Graves' ophthalmopathy is characterized by inflammation of the extraocular muscles, orbital fat and connective tissue. It results in the following symptoms, which can be extremely distressing to the patient:^[3]

• Most frequent are symptoms due to conjunctival or corneal irritation: burning, photophobia, tearing, pain, and a gritty or sandy sensation.^[3]
• Protruding eyeballs (known as proptosis and exophthalmos).
• Diplopia (double vision) is common.^[3]
• Limitation of eye movement (due to impairment of eye muscle function).
• Periorbital and conjunctival edema (accumulation of fluid beneath the skin around the eyes).
• Infiltrative dermopathy (pretibial myxedema).
• In severe cases, the optic nerve may be compressed and acuity of vision impaired.^[16]
• Occasionally loss of vision.

Due to hyperthyroidism

In the absence of Graves' ophthalmopathy, patients may demonstrate other ophthalmic signs due to hyperthyroidism:

• Dry eyes (due to loss of corneal moisture).^[16]
• A sense of irritation, discomfort, or pain in the eyes.
• A tingling sensation behind the eyes or the feeling of grit or sand in the eyes.
• Excessive tearing that is often made worse by exposure to cold air, wind, or bright lights.
• Swelling or redness of the eyes.
• Stare
• Lid lag (Von Graefe's sign)
• Sensitivity to light.
• Blurring of vision.
• Widened palpebral fissures.
• Infrequent blinking.
• The appearance of lid retraction.

Neuropsychological manifestations

Several studies have suggested a high prevalence of neuropsychiatric disorders and mental symptoms in Graves' disease (and thyroid disease in general), which are similar to those in patients with organic brain disease.^{[9][17][18][19][20]} These manifestations are diverse, affecting the central and peripheral nervous systems. The vast majority of patients with hyperthyroidism meet criteria for some psychiatric disorders,^[9] and those with milder presentations are probably not entirely free of mental symptoms such as emotional lability, tension, depression and anxiety.^[9] A study of 2006 failed to confirm a link between thyroid dysfunction and depression or anxiety.^[21]

In one study on hospitalised elderly patients, over half had cognitive impairment with either dementia or confusion.^[22] However, a controlled study on 31 Graves' disease patients found that while patients had subjective reports of cognitive deficits in the toxic phase of Graves' thyrotoxicosis, formal testing found no cognitive impairment and suggested the reported symptoms may reflect the affective and somatic manifestations of hyperthyroidism.^[23]

Treatment of hyperthyroidism typically leads to improvement in cognitive and behavioral impairments.^[23] Agitation, inattention, and frontal lobe impairment may improve more rapidly than other cognitive functions. However, several studies confirm that a substantial proportion of patients with hyperthyroidism have psychiatric disorders or mental symptoms and decreased quality of life even after successful treatment of their hyperthyroidism.^[18]

Several studies point out that the severity of psychiatric symptoms could easily result in an inappropriate referral to a psychiatrist prior to the diagnosis of hyperthyroidism.^[24][25] Consequently, undiagnosed hyperthyroidism sometimes results in inappropriate use of psychotropic medications; prompt recognition of hyperthyroidism (or hypothyroidism) through thyroid function screening is therefore recommended in the evaluation of patients with psychiatric symptoms.^[25][26] Naturally, the management of patients would be improved by collaboration between a psychiatrist and an endocrinologist.^[27]

Reported symptoms vary from mild to severe aspects of anxiety or depression, and may include psychotic and behavioural disturbances:

• Varying degrees of anxiety,^[18] such as a very active mind,^[3]irritability,^[18] hyperactivity, agitation, restlessness, nervousness, distractible overactivity^[28] and panic attacks.^[29] In addition patients may experience vivid dreams and, occasionally, nightmares.
• Depressive features of mental impairment, memory lapses,^[18] diminished attention span,^[18] fluctuating depression^[28][30]
• Emotional lability and in some patients, the emotional pattern is that of hypomania,^[31] or pathologic well-being (euphoria) or the hyperactivity may produce a state of exhaustion, and profound fatigue or asthenia chiefly characterizes the picture.^[3]
• Erratic behaviour may include intermittent rage disorder, mild attention deficit disorder^[32] and some patients become hyperirritable and combative, which can precipitate accidents or even assaultive behaviour.^[3]
• In more extreme cases features of psychosis,^[33] with delusions of persecution or delusions of reference.^[34] pressure of speech Rarely, patients develop visual or auditory hallucinations or a frank psychosis,^[3] and may appear schizophrenic, lose touch with reality and become delirious,^[11] or hallucinate.^[28] Such psychotic symptoms may not completely clear up after the hyperthyroidism has been treated.^[3] Paranoia and paranoid-hallucionary psychosis in hyperthyroidism usually have a manick disposition and it is therefore often not clear if the patient is experiencing a paranoid psychosis with depressive streaks, or a depression that has paranoid streaks.^[11]

Effects on pre-existing psychiatric disorders

Patients with pre-existing psychiatric disorders, will experience a worsening of their usual symptoms, as observed by several studies. A study of 1999 found that Graves' disease exacerbated the symptoms of Tourette's disorder and attention-deficit hyperactivity disorder (ADHD), and points out that the lack of diagnosis of the Graves' disease compromised the efficacy of the treatment of Tourette's disorder and ADHD.^[35] Patients who are known to have a convulsive disorder may become more difficult to control with the usual medications, and seizures may appear in patients who have never previously manifested such symptoms.^[3]

Subclinical hyperthyroidism

In subclinical hyperthyroidism, serum TSH is abnormally low, but T4- and T3-levels fall within laboratory reference ranges.^[36] It primarily affects the skeleton and the cardiovascular system (abnormalities in other systems have also been reported), in a similar but less severe and less frequent way than overt hyperthyroidism does. It can alter cardiac function, with increased heart rate, increased left ventricular mass index, increased cardiac contractility, diastolic dysfunction, and induction of ectopic atrial beats. Long-term mild excess of thyroid hormone can thus cause impaired cardiac reserve and exercise capacity.^[3]

In a large population-based study of 2008, the odds of having poorer cognitive function were greater for subclinical hyperthyroidism than for stroke, diabetes mellitus, and Parkinson's disease.^[37] However, while clinical hyperthyroidism is associated with frank neuropsychological and affective alterations, the occurrence of these alterations and their treatment in mild and subclinical hyperthyroidism remains a controversial issue.^[38] But regardless of the inconsistent findings, a 2007 study by Andersen et al. states that the distinction between subclinical and overt thyroid disease is in any case somewhat arbitrary.^[39] Sublicnical hyperthyroidism has been reported in 63% of euthyroid patients with Graves' ophthalmopathy.

Children and adolescents

Hyperthyroidism has unique effects in children on growth and pubertal development, e.g. causing epiphyseal maturation. In growing children, accelerated bone growth from hyperthyroidism can increase osteogenesis in the short term, but generally results in short-stature adults compared with the predicted heights. Pubertal development tends to be delayed, or slowed. Girls who have undergone menarche may develop secondary amenorrhea. Hyperthyroidism is associated with high sex hormone-binding globulin (SHBG), which may result in high serum estradiol levels in girls and testosterone levels in boys. However, unbound or free levels of these hormones are decreased. Hyperthyroidism before the age of four may cause neurodevelopmental delay. A study by Segni et al. suggests that permanent brain damage can occur as a result of the illness.^[3][40]

Ophthalmopatic findings are more common but less severe in children (severe infiltrative exophthalmos is virtually unknown before mid-adolescence), but besides that, many of the typical clinical features of hyperthyroidism in children and adolescents are similar to those in adults.^[3] An important difference between children and adults with Graves' disease, is that children have not yet developed like adults have (psychological and physiological), and that they are a lot more dependent on their environment. The encephalopathy will have profound effects on children's developing personalities and developing relationship with their environment. Disturbments in bodily development further complicates matters. The consequences for the development and the somatic and psychological wellbeing of the child can be very radical and sometimes irreversible. The earlier a person is affected by thyroid disease, the less (s)he has been able to develop himself or herself, and the more the development of personality is affected and the bigger the delay from their potential development level. The child gets behind in its cognitive, emotional and sexual growth, which, by itself, also influences its processing abilities of the endocrine disease.^[11]

Children with hyperthyroidism tend to have greater mood swings and disturbances of behavior, as compared with adults. Their attention span decreases, they are usually hyperactive and distractable, they sleep poorly, and their school performance deteriorates. Because devastating personality and emotional changes often appear in the child or adolescent with Graves' disease, many hyperthyroid children are (similar to many adults) referred to a developmental specialist or child psychiatrist to evaluate emotional and behavioral symptoms before the presence of hyperthyroidism is suspected.^[3]

Older patients

In older patients, emotional instability may be less evident, or depression may occur, and the symptoms and signs are manifestly circulatory. In many, the thyroid is not readily palpable.^[3] Symptoms such as rapid heart rate, shortness of breath on exertion, and edema may predominate. Older patients also tend to have more weight loss and less of an increase in appetite. Thus anorexia in this group is fairly frequent, as is constipation.^[3]

Elderly patients may have what is called "apathetic thyrotoxicosis", a state in which they have less and less severe symptoms, except for weakness, depression and lethargy (making it even more prone to escape diagnosis).

Graves' disease and work

Considering the many signs and symptoms, the generally delayed diagnosis, and the possibility of residual complaints after treatment, it is little wonder that a significant number of people with Graves' disease have difficulty keeping their job. One study found that of 303 patients successfully treated for hyperthyroidism (77% had Graves’ disease) 53% dealt with lack of energy. About one-third were unable to resume their customary work, mainly due to persistent mental problems.^[9][41] In their 1986 study of 26 patients (10 years after successful treatment of hyperthyroidism), Perrild et al. note that four patients had been granted disability pensions on the basis of intellectual dysfunction.^[42] Between 2006 and 2008, Ponto et al. surveyed 250 Graves' disease patients. Of these, 36% were written of sick and 5% even had to take early retirement. In the same study, 34% of 400 questioned physicians reported treating patients with fully impaired earning capacity.^[43]

A 2008 meta-article by De groot states that the patient with Graves' disease should have time away from normal duties to help in reestablishing his or her psychic and physiologic equilibria. Patients can and do recover with appropriate therapy while continuing to work, but more rapid and certain progress is made if a period away from the usual occupation can be provided.^[14]

Cause

The trigger for autoantibody production is unknown.

Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I diabetes). One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacterium and the human thyrotropin receptor, direct causative evidence is limited.^[44] 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.^[45] 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.^[46] More recently the role for Y. enterocolitica has been disputed.^[47]

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 autoantibodies. HLADR (especially DR3) appears to play a significant role.^[44]

Neuropsychological manifestations

Hyperthyroidism plays a major role in psychiatric morbidity in Graves' disease, and is associated with long-term mood disturbances.^[31][48] 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.^[49] 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.^[50] 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.^[51] 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.^[49] Whatever the precise mechanisms, it is clear that thyroid hormones influence adult brain functioning, and may interact with mood regulation via targets in specific brain circuits.^[48] Singh et al. formulate that "differential thyroidal status is known to cause decrease in cell number and induces irreversible morphometric changes in adult brain resulting in different neuronal abnormalities".^[52] 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.^[53] 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).^[3] Thompson mentions that T3 can increase the activity of serotonin in the brain, while serotonin has been shown to inhibit thyroid function. Thus, although a complex system of interaction between thyroid hormone and neurotransmitters has been recognized and examined, no clear-cut explanation for the effect of thyroid hormone on depression has emerged.^[53]

A literature study of 2006 mentions that ophtalmopathy may also contribute to psychiatric morbidity, probably through the psychosocial consequences of changed appearance.^[9] However, the observation that a substantial proportion of patients have an altered mental state even after successful treatment of hyperthyroidism, has led some researchers to suggest that the automimmune process itself may play a role in the presentation of mental symptoms and psychiatric disorders in Graves’ disease, whether or not ophtalmopathy is present.^[9] Persistent stimulation of TSH-Rs may be involved. In Graves’ disease, the TSH-R gives rise to antibodies and in some patients these antibodies persist after restoration of euthyroidism. The cerebral cortex and hippocampus are rich in TSH-Rs. Antibody stimulation of these brain receptors may result in increased local production of T3.^[9]

Thus, despite ongoing research, a full understanding of the causes of mental disability in Graves’ disease awaits a full description of the effects on neural tissue of thyroid hormones as well as of the underlying autoimmune process.^[31]

Pathophysiology

Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSHR). (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.) These antibodies (TSHR-Ab) bind to the TSH receptors, which are located on the cells that produce thyroid hormone in the thyroid gland (follicular cells), and chronically stimulate them, resulting in an abnormally high production of T3 and T4. This causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland (visible as goitre).

The infiltrative exophthalmos that is frequently encountered, has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball. The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

There are 3 types of autoantibodies to the TSH receptor currently recognized:

• TSI, Thyroid stimulating immunoglobulins: these antibodies (mainly Immunoglobulin G) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than the normal thyroid-stimulating hormone (TSH), leading to an elevated production of thyroid hormone.

• TGI, Thyroid growth immunoglobulins: these antibodies bind directly to the TSH-receptor and have been implicated in the growth of thyroid follicles.

• TBII, Thyrotropin Binding-Inhibiting Immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor.

In their study of thyrotoxic patients, Sensenbach et al. found the cerebral blood flow to be increased, the cerebral vascular resistance decreased, arteriovenous oxygen difference decreased, and oxygen consumption unchanged. They found that during treatment, brain size was shown to decrease significantly, and ventricular size increased. The cause of this remarkable change is unknown, but may involve osmotic regulation.^[54]

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.^[55]

Hyperthyroidism causes lower levels of apolipoprotein (A), HDL, and ratio of total/HDL cholesterol.^[3] The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones in almost all tissues.^[56] 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.^[3] Hyperthryoidism can also augment calcium levels in the blood by as much as 25% (known as hypercalcaemia). An increased excretion of calcium and phosphorus in the urine and stool can result in bone loss from osteoporosis.^[13]

Diagnosis

Graves' disease Symptoms

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.^[6] (Not only Graves' disease, but most endocrinological diseases have an insidious, subclinical onset.^[57]) 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.^[31] 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.^[18] Also, earlier symptoms of nervousness, hyperactivity, and a decline in school performance, may easily be attributed to other causes. Many symptoms may occasionally be noted, at times, in otherwise healthy individuals who do not have thyroid disease (e.g., everyone feels anxiety and tension to some degree), and many thyroid symptoms are similar to those of other diseases.^[10] Thus, clinical findings may be full blown and unmistakable or insidious and easily confused with other disorders.^[58] The results of overlooking the thyroid can however be very serious.^[28] 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.^[18] A large 2002 study found "no statistical association between thyroid dysfunction, and the presence of depression or anxiety disorder."^[21]

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.^[3] When thyroid disease runs in the family, the physician should be particularly wary: studies of twins suggest that the genetic factors account for 79% of the liability to the development of Graves’ disease (whereas environmental factors account presumably for the remainder).^[3] Other nearly pathognomonic signs of hyperthyroidism are excessive sweating, high pulse during sleep, and a pattern of weight loss with increased appetite (although this may also occur in diabetes mellitus and malabsorption or intestinal parasitism).^[3][11]

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).^[39]

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 bloodresults 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).^[31]

A 2009 study shows that in spite of modern therapeutic modalities, Graves' disease is accompanied by seriously impaired quality of life. Several recent studies stress the importance of early prevention, speedy rehabilitation, and a thorough follow-up of hyperthyroid patients.^[59] Patients who do not have a spontaneous remission with the use of antithyroid drugs, become lifelong thyroid patients.

Symptomatic

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

Scan of affected thyroid before and after radioiodine therapy.

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 (1/250, more in PTU); this is an idiosyncratic reaction which does not stop on cessation of drug. Others include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic 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 the placenta and are secreted in breast milk. Lugol's iodine is used to block hormone synthesis before surgery.

A randomized control trial testing single dose treatment for Graves' found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).^[60] But generally both drugs are considered equivalent.

A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However two markers were found that can help predict the risk of recurrence. These two markers are an elevated level of thyroid stimulating hormone receptor antibodies (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.^[61]

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

Scar in the neck, ten weeks after a total thyroidectomy. Current surgical techniques typically leave a smaller scar.

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.^[62] However, it appears ineffective in patients who are already euthyroid due to treatment with anti-thyroid drugs and T4.^[63]

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).^[64] 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 a breathing tube stuck down the windpipe during surgery.

Removal of the gland enables complete biopsy to be performed to have definite evidence of thyroid cancer, since needle biopsies are not so 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 chords, which cannot be surgically removed without damage to those vocal chords). 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.^[65] 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.^[65] However, the difficulty lies in determining and controlling the proper dosage for a particular patient, which can be an intricate process. Because levothyroxine has a very narrow therapeutic index, the margin between overdosing and underdosing can be quite small.^[66] 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.^[7][67][68]

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.^[9] A literature study concluded in 2006, found that, after being diagnosed with Graves’ hyperthyroidism, approximately one-third of patients are prescribed psychotropic drugs. Sometimes these drugs are given to treat mental symptoms of hyperthyroidism, sometimes to treat mental symptoms remaining after amelioration of hyperthyroidism, and sometimes when the diagnosis of Graves’ hyperthyroidism has been missed and the patient is treated as having a primary psychiatric disorder. There are no systematic data on the general efficacy of psychotropic drugs in the treatment of mental symptoms in patients with hyperthyroidism, although many reports describe the use of individual agents.^[9] De Groot mentions that a mild sedative or tranquilizer is often helpful.^[14]

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.^[14]

Prognosis

The disease typically begins gradually, and is progressive unless treated.^[3] If left untreated, more serious complications could result, including bone loss and fractures, inanition, birth defects in pregnancy, increased risk of a miscarriage.^[3] Graves disease is often accompanied by an increase in heart rate, which may lead to cardiovascular damage and further heart complications including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke.^[3] If the eyes are 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. In severe thyrotoxicosis, a condition frequently referred to as thyroid storm, the neurologic presentations are more fulminant, progressing if untreated through an agitated delirium to somnolence and ultimately to coma. All in all, untreated Graves' disease can lead to significant morbidity, disability and even death. However, the long-term history also includes spontaneous remission in some cases and eventual spontaneous development of hypothyroidism if autoimmune thyroiditis coexists and destroys the thyroid gland.^[3]

When effective thyroid treatment is begun, the general response is quite favorable: physicial symptoms resolve, vitality returns and the mental processes become efficient again.^[28] However, symptom relief is usually not immediate and is achieved over time as the treatments take effect and thyroid levels reach stability. In addition, not all symptoms may resolve at the same time. Prognosis also depends on the duration and severity of the disease before treatment.

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.^[9][48] According to a 2010 publication, a total thyroidectomy offers the best chance of preventing recurrent hyperthyroidism.^[69]

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.^[9] Bunevicius et al. point out that this "substantial mental disability" is more severe in patients with residual hyperthyroidism but is present even in euthyroid patients.^[31] Delay in therapy markedly worsens the prognosis for recovery, but complications can be prevented by early treatment.^[70] 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.^[11]

Thyroid replacement treatment after thyroidectomy or radioiodine

Several studies point out a a high frequency of TSH level abnormalities in patients who take thyroid hormone supplemenation, and stress the importance of periodic assessment of serum TSH.^[67][68]

Coping with Graves' disease & the patient-physician relationship

Mentally, Graves' disease can be very disturbing. Mood swings, thinking impairment and other mental symptoms can be difficult to handle, and make it appear that the patient is suffering from a severe mental disorder. There have even been cases where patients have been placed in mental institutions.^[1][10] 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.^[14][18] 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.^[14][18] In Graves' disease, the accent should lie on written information, as a host of mental problems, such as decreased attention span and memory problems, can impair a patient’s ability to absorb details of doctor visits. In a complicated and difficult illness like Graves' disease, physicians should therefore furnish patients with educational materials or resources such as handouts, website links and community support groups.^[71]

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.^[1][72] 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.^[14] Patient education is the "drug of choice" for prevention and treatment of every medical condition, and open communication with health care professionals can be highly beneficial in maximizing health and outlook on life.^[14][71] During the initial and subsequent interviews, the physician must determine the level of the psychic and physical stresses. Frequently, major emotional problems come to light after the patient recognizes the sincere interest of the physician. Personal problems can strongly affect therapy by interfering with rest or by causing economic hardship.^[14] It is therefore recommended that physicians implement a social questionnaire as part of the initial intake, allowing the patient to communicate essential, non-medical information about their lives.^[71]

The communication and health management skills of Graves' disease patients can be seriously impaired. This is something physicians should be conscious of while dealing with these patients, as mounting evidence demonstrates that the effectiveness of the patient-physician relationship directly relates to health outcomes. The report of a large 2003 summit of physicians and patients notes a number of barriers to achieving desired patient-centered outcomes. It mentions insufficient or unreliable clinical information, lack of communication or inability to communicate effectively, lack of trust between patient and physician, lack of appropriate coordination of care, lack of physician cooperation, and the need to work with too many caregivers, all of which can be very relevant to Graves' disease.^[71]

Epidemiology

Recent studies in England put the incidence of Graves' disease at 1 to 2 cases per 1,000 population per year (in England). It occurs much more frequently in women than in men. The disease frequently presents itself during early adolescence or begins gradually in adult women, often after childbirth, and is progressive until treatment. It has a powerful hereditary component.^[3]

Graves' disease tends to be more severe in men, even though it is rarer. It appears less likely to go into permanent remission and the eye disease tends to be more severe, but men are less likely to have large goitres.^[73] 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.^[3]

Cigarette smoking, which is associated with many autoimmune diseases, raises the incidence of Graves' ophthalmopathy 7.7-fold.^[74]

History

Graves' disease owes its name to the Irish doctor Robert James Graves, who described a case of goitre with exophthalmos in 1835.^[75][76] However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840.^[77][78] As a result, the term Basedow's syndrome/disease is more common on the European continent than Graves' disease.^[79][80] It has also been called exophthalmic goitre.^[81] 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.^[79][81] For example, cases of goitre with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively.^[82][83][84] Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century, first noted the condition in 1786.^[85][86] This case was not published until 1825, but still 10 years ahead of Graves.^[87]

However, fair credit for the first description of Graves' disease goes to the 12th century Persian physician Sayyid Ismail al-Jurjani,^[88] who noted the association of goitre and exophthalmos in his "Thesaurus of the Shah of Khwarazm", the major medical dictionary of its time.^[79][89][90]

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

• Ayaka, Japanese singer/songwriter^[91]
• 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.^[92]
• Maggie Cheung Ho-Yee, Hong Kong actress^[93]
• Toni Childs, American singer/songwriter^[94]
• Gail Devers, Athletic champion^[95]
• Marty Feldman, British comedian^[96]
• Diane Finley, Canadian cabinet minister^[97]
• Faith Ford, American actress^[98]
• Sia Furler, Australian singer ^[99]
• Sammy "The Bull" Gravano, Former Gambino Family Underboss
• Nadezhda Krupskaya, the wife of Lenin^[100]
• Barbara Leigh, an American former actress and fashion model, now spokeswomen for the National Graves' Disease Foundation ^[101]
• Yūko Miyamura, Japanese voice actress^[102]
• Christopher Monckton, 3rd Viscount Monckton of Brenchley^[103]
• Christina Georgina Rossetti, British Victorian Poet^[104]
• Cecil Spring-Rice, British Ambassador to the USA from 1912 to 1918^[105]
• Mary Webb, English author and poet, descendant of Sir Walter Scott^[106]

Notes

See also

• Hashitoxicosis
• Myxedema
• Thyroidologist
• Neuroendocrinology

External links

• Graves' Disease Foundation Conducts research about Graves' disease, and provides support via the largest internet forum on Graves' disease
• Wrong Diagnosis entry for 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
• MedPix: Coronal CT Graves' Disease Pictures