Graves' disease | Understanding and definition of 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.

The symptoms and signs of Grave's disease virtually always result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves' ophthalmopathy, goitre and pretibial myxedema (which all result from the autoimmune processes of Graves' disease). Symptoms of the resultant hyperthyroidism are mainly: nervousness, insomnia, irritability, hand tremor, hyperactivity, excessive sweating, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, muscle weakness and skin being warm and moist. 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.

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 (not the same as 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. 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. 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.

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. 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. 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". 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). 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.

A literature study of 2006 mentions that ophtalmopathy may also contribute to psychiatric morbidity, probably through the psychosocial consequences of changed appearance. 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. 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.

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.

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. This swelling has also been postulated to be the consequence of mucopolysacharide deposition posterior to the eyes, a symptom tangentially related to Graves'. 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.

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.

Hyperthyroidism causes lower levels of apolipoprotein (A), HDL, and ratio of total/HDL cholesterol. The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones in almost all tissues. 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. 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. Also, parathyroid hormone (PTH) levels tend to be suppressed in hyperthyroidism, possibly in response to elevated calcium levels.

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. (Not only Graves' disease, but most endocrinological diseases have an insidious, subclinical onset.) 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. 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. Thus, clinical findings may be full blown and unmistakable or insidious and easily confused with other disorders. 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. Also, hypersensitivity of the central nervous system to low-grade hyperthyroidism can result in an anxiety disorder before other Graves’ disease symptoms emerge. E.g., panic disorder has been reported to precede Graves’ hyperthyroidism by 4 to 5 years in some cases, although it is not known how frequently this occurs.

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. 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). 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).

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.

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).

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. Patients who do not have a spontaneous remission with the use of antithyroid drugs, become lifelong thyroid patients.

The disease typically begins gradually, and is progressive unless treated. If left untreated, more serious complications could result, including bone loss and fractures, inanition, birth defects in pregnancy, increased risk of a miscarriage. 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. 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.

When effective thyroid treatment is begun, the general response is quite favorable: physical symptoms resolve, vitality returns and the mental processes become efficient again. 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. Swedish research of 2005 reports a lower quality of life for 14 to 21 years after treatment of Graves' disease, with lower mood and lower vitality, regardless of the choice of treatment.

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. 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. 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.

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. 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. 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. 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.

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.

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.

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. 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.