Graves-Basedow disease
Encyclopedia
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 thyroid 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, 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. Graves’ thyrotoxicosis frequently builds over an extended period, sometimes reaching years, before being diagnosed. 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.
, with main exceptions being Graves' ophthalmopathy, goitre
and pretibial myxedema
(which are caused by the autoimmune processes of Graves' disease). Symptoms of the resultant hyperthyroidism are mainly insomnia
, hand tremor
, hyperactivity, hair loss, excessive sweating
, heat intolerance, weight loss
despite increased appetite, diarrhea
, frequent defecation
, palpitation
s, muscle weakness
and skin being warm and moist. Further signs that may be seen on physical examination
are most commonly 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 contraction
s, as well as hypertension
. It is important to note that thyrotoxic patients may experience behavioral and personality changes, such as psychosis
, agitation
, and depression
. In milder hyperthyroidism, patients will rather experience less overt manifestations like anxiety
, restlessness, irritability
, and emotional lability.
production is unknown.
Some people may have a genetic predisposition
to develop TSH receptor autoantibodies (HLA
DR, especially DR3, appears to play a significant role. 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.
, 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 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.
Another possibility is that hyperthyroidism may cause oxidative stress
, resulting in 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 (it is presumed, acting by inhibition of alpha-adrenergic sympathetic activity) 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 ophthalmopathy may also contribute to psychiatric morbidity, it is presumed through the psychosocial consequences of a 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 ophthalmopathy 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 complete 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.
disorder, in which the body produces antibodies
to the receptor for thyroid-stimulating hormone (TSHR). (Antibodies to thyroglobulin
and to the thyroid hormone
s 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
that 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:
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 cause 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 may be detectable only by a physical exam. On occasion, 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, it is presumed, account 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 that 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 (almost all patients with Graves' hyperthyroidism have detectable TSHR-Ab). 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.
), 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; the risk of relapse or subsequent hypothyroidism is substantial.
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.
Beta blocker
s (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.
(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.
Treatment with antithyroid medications must be given for six months to two years, in order to be effective. Success rates vary from 34% to 64%, but even then the hyperthyroid state may recur, sometimes upon cessation of the drugs, somtimes months or years later. If treatment with antithyroid drugs fails to induce remission, RAI or surgery must be considered.
, 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 doctors prefer to use it mainly for older patients. Indications for RAI are failed medical therapy or surgery, or 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 do not evolve to hypothyroidism
(incidence rate of 80%), in which case they will become lifelong thyroid patients. 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.
), 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". 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 versus 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 a 98% subtotal thyroidectomy, the complications were as followed:
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 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.
(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. 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. 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.
or tranquilizer
is often helpful. 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.
or nonsteroidal 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, making it impossible to completely close the eyes. This 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' disease on the eyelids. This surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. The muscle then becomes 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.
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.
unless treated. If left untreated, more serious complications could result, including bone loss
and fractures
, inanition, birth defects in pregnancy, and 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 cornea
l 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.
and anxiety
, as well as less tolerance of stress
. According to a 2010 publication, a total thyroidectomy
offers the best chance of preventing recurrent hyperthyroidism.
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. 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. Delay in therapy markedly worsens the prognosis for recovery, but complications can be prevented by early treatment. 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.
level abnormalities in patients who take thyroid hormone supplementation for long periods of time, and stress the importance of periodic assessment of serum TSH
.
, 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.
, 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 goitre
s. 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.
Cigarette smoking, which is associated with many autoimmune diseases, raises the incidence of Graves' ophthalmopathy 7.7-fold.
, 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. It has been known less commonly 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. For example, cases of goitre with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. 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.
With Graves Disease affecting the immune system the body also has potential to be affected by Pneumocystis carinii pneumonia
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
is overactive, producing an excessive amount of thyroid hormones (a serious metabolic imbalance known as hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
and thyrotoxicosis). This is caused by thyroid autoantibodies (TSHR-Ab) that activate the TSH
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
-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, 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. Graves’ thyrotoxicosis frequently builds over an extended period, sometimes reaching years, before being diagnosed. 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.
Symptoms and signs
The symptoms and signs of Graves' disease virtually all result from the direct and indirect effects of hyperthyroidismHyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
, with main exceptions being Graves' ophthalmopathy, goitre
Goitre
A goitre or goiter , is a swelling in the thyroid gland, which can lead to a swelling of the neck or larynx...
and pretibial myxedema
Pretibial myxedema
Pretibial myxedema is an infiltrative dermopathy, resulting as a rare complication of Graves' disease, with an incidence rate of about 1-4% in patients.-Presentation:...
(which are caused by the autoimmune processes of Graves' disease). Symptoms of the resultant hyperthyroidism are mainly insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, hand tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, hyperactivity, hair loss, excessive sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, heat intolerance, weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
despite increased appetite, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, frequent defecation
Defecation
Defecation is the final act of digestion by which organisms eliminate solid, semisolid or liquid waste material from the digestive tract via the anus. Waves of muscular contraction known as peristalsis in the walls of the colon move fecal matter through the digestive tract towards the rectum...
, palpitation
Palpitation
A palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s, muscle weakness
Muscle weakness
Muscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
and skin being warm and moist. Further signs that may be seen on physical examination
Physical examination
Physical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...
are most commonly a diffusely enlarged (usually symmetric) nontender thyroid, lid lag, excessive lacrimation
Tears
Tears are secretions that clean and lubricate the eyes. Lacrimation or lachrymation is the production or shedding of tears....
due to Graves' ophthalmopathy, arrhythmias of the heart such as sinus tachycardia
Sinus tachycardia
Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
, atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
and premature ventricular contraction
Premature ventricular contraction
A premature ventricular contraction , also known as a premature ventricular complex, ventricular premature contraction , ventricular premature beat , or extrasystole, is a relatively common event where the heartbeat is initiated by the heart ventricles rather than by the sinoatrial node, the...
s, as well as hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. It is important to note that thyrotoxic patients may experience behavioral and personality changes, such as psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, agitation
Agitation
Agitation may refer to:* Agitation , putting into motion by shaking or stirring* Emotional state of excitement or restlessness** Psychomotor agitation, an extreme form of the above, which can be a side effect of antipsychotic medication...
, and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
. In milder hyperthyroidism, patients will rather experience less overt manifestations like anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, restlessness, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, and emotional lability.
Cause
The trigger for autoantibodyAutoantibody
An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
production is unknown.
Some people may have a genetic predisposition
Genetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
to develop TSH receptor autoantibodies (HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
DR, especially DR3, appears to play a significant role. Some of the eye symptoms of hyperthyroidism are believed to result from heightened sensitivity of receptors to sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
activity, possibly mediated by increased alpha-adrenergic receptors in some tissues.
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 neurotransmissionNeurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
, 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 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
Locus ceruleus
The locus coeruleus , is a nucleus in the brainstem involved with physiological responses to stress and panic. It was discovered in the 18th century by Félix Vicq-d'Azyr....
and frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
that subserve attention and vigilance, and thereby accounting for many physical and mental symptoms.
Another possibility is that hyperthyroidism may cause oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, resulting in neuronal injury and hastening a presentation of degenerative or vascular dementia. A study of 2002 suggests another possible mechanism, involving activational and translational regulation
Translational regulation
Translational regulation refers to the control of the levels of protein synthesized from its mRNA. The corresponding mechanisms are primarily targeted on the control of ribosome recruitment on the initiation codon, but can also involve modulation of the elongation or termination of protein synthesis...
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
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, with changes in neurotransmitter synthesis and receptor sensitivity being noted. De Groot points out that, in spite of the fact that epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
levels and catecholamine excretion are actually not elevated, propranolol (it is presumed, acting by inhibition of alpha-adrenergic sympathetic activity) reduces anxiety and tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
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
Triiodothyronine
Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....
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 ophthalmopathy may also contribute to psychiatric morbidity, it is presumed through the psychosocial consequences of a 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 ophthalmopathy 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
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
are rich in TSH-Rs. Antibody stimulation of these brain receptors may result in increased local production of T3
Triiodothyronine
Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....
.
Thus, despite ongoing research, a complete 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.
Pathophysiology
Graves' disease is an autoimmuneAutoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
disorder, in which the body produces antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
to the receptor for thyroid-stimulating hormone (TSHR). (Antibodies to thyroglobulin
Thyroglobulin
Thyroglobulin is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. In earlier literature, Tg was referred to as colloid....
and to the thyroid hormone
Thyroid hormone
The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,...
s 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
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
stimulate them, resulting in an abnormally high production of T3 and T4. This causes the clinical symptoms of hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
, and the enlargement of the thyroid gland (visible as goitre
Goitre
A goitre or goiter , is a swelling in the thyroid gland, which can lead to a swelling of the neck or larynx...
).
The infiltrative exophthalmos
Exophthalmos
Exophthalmos is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral or unilateral . Measurement of the degree of exophthalmos is performed using an exophthalmometer...
that is frequently encountered, has been explained by postulating that the thyroid gland and the extraocular muscles
Extraocular muscles
The extraocular muscles are the six muscles that control the movements of the eye . The actions of the extraocular muscles depend on the position of the eye at the time of muscle contraction.-List of muscles:-Importance:...
share a common antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
that 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 GImmunoglobulin GImmunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
) 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
Cerebral blood flow
Cerebral blood flow, or CBF, is the blood supply to the brain in a given time. In an adult, CBF is typically 750 millitres per minute or 15% of the cardiac output. This equates to 50 to 54 millilitres of blood per 100 grams of brain tissue per minute. CBF is tightly regulated to meet the brain's...
to be increased, the cerebral vascular resistance decreased, arteriovenous oxygen difference
Arteriovenous oxygen difference
The arteriovenous oxygen difference, or a-vO2 diff, is the difference in the oxygen content of the blood between the arterial blood and the venous blood. It is an indication of how much oxygen is removed from the blood in capillaries as the blood circulates in the body...
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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in adult cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
. T3
T3
T3 or T-3 may refer to:* SPARC_T3, a CPU introduced by Sun Microsystems in 2010* Digital Signal 3 or T3 line, a type of telecommunications service* Fletcher's Ice Island or T-3, an iceberg discovered by U.S. Air Force Colonel Joseph O...
acts directly on cerebral cortex mitochondria and induces release of cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
to induce apoptosis. They note that adult cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
seems to be less responsive to changes in thyroidal status.
Hyperthyroidism causes lower levels of apolipoprotein
Apolipoprotein
Apolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....
(A), HDL
HDL
HDL may refer to one of the following:* Hardware description language* High-density lipoprotein, so-called "good cholesterol".* Hong Kong Disneyland, in China.* Les Hurlements d'Léo, an alternative rock band from France.* GE HDL diesel engine...
, and ratio of total/HDL cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. 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
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
is increased and conversion of carotene
Carotene
The term carotene is used for several related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but cannot be made by animals. Carotene is an orange photosynthetic pigment important for photosynthesis. Carotenes are all coloured to the human eye...
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
Thiamine
Thiamine or thiamin or vitamin B1 , named as the "thio-vitamine" is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate derivatives are...
and vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
and B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
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
Hypercalcaemia
Hypercalcaemia is an elevated calcium level in the blood. . It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a workup should be undertaken if it persists...
). An increased excretion of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and phosphorus
Phosphorus
Phosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...
in the urine and stool can result in bone loss from osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. Also, parathyroid hormone (PTH) levels tend to be suppressed in hyperthyroidism, possibly in response to elevated calcium levels.
Diagnosis
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
to low-grade hyperthyroidism can result in an anxiety disorder
Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
before other Graves’ disease symptoms emerge. E.g., panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
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
Exophthalmos
Exophthalmos is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral or unilateral . Measurement of the degree of exophthalmos is performed using an exophthalmometer...
(protuberance of one or both eyes) and pretibial myxedema
Pretibial myxedema
Pretibial myxedema is an infiltrative dermopathy, resulting as a rare complication of Graves' disease, with an incidence rate of about 1-4% in patients.-Presentation:...
, 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
Goitre
A goitre or goiter , is a swelling in the thyroid gland, which can lead to a swelling of the neck or larynx...
(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 may be detectable only by a physical exam. On occasion, goitre is not clinically detectable but may be seen only with CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
or ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
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, it is presumed, account for the remainder). Other nearly pathognomonic
Pathognomonic
Pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...
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
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
or intestinal parasitism
Intestinal parasite
Intestinal parasites are parasites that populate the gastro-intestinal tract in humans and other animals. They can live throughout the body, but most prefer the intestinal wall. Means of exposure include: ingestion of undercooked meat, drinking infected water, and skin absorption...
).
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
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
(low due to negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
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 that is further elaborated below).
Differentiating Graves' hyperthyroidism from the other causes of hyperthyroidism (thyroiditis
Thyroiditis
Thyroiditis is the inflammation of the thyroid gland. The thyroid gland is located on the front of the neck below the laryngeal prominence, and makes hormones that control metabolism.-Classification:...
, 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 (almost all patients with Graves' hyperthyroidism have detectable TSHR-Ab). 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
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
to obtain histological testing is not normally required but may be obtained if thyroidectomy
Thyroidectomy
A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. Surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland...
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 1940s). These are the use of antithyroid drugs (which reduce the production of thyroid hormoneThyroid hormone
The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,...
), 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
Thyroidectomy
A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. Surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland...
).
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
Thyroidectomy
A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. Surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland...
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; the risk of relapse or subsequent hypothyroidism is substantial.
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.
Symptomatic
Beta blocker
Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
s (such as propranolol) may be used to inhibit the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
symptoms of rapid heart rate
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
and nausea until such time as antithyroid treatments start to take effect.
Antithyroid drugs
The main antithyroid drugs are carbimazoleCarbimazole
Carbimazole is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents the thyroid peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the...
(in the UK), methimazole
Methimazole
Methimazole is an antithyroid drug, and part of the thioamide group.-Indications:...
(in the US), and propylthiouracil
Propylthiouracil
Propylthiouracil or 6-n-Propylthiouracil is a thioamide drug used to treat hyperthyroidism by decreasing the amount of thyroid hormone produced by the thyroid gland...
/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side-effect is agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
. Others include granulocytopenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
(dose dependent, which improves on cessation of the drug) and aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
, and for propylthiouracil
Propylthiouracil
Propylthiouracil or 6-n-Propylthiouracil is a thioamide drug used to treat hyperthyroidism by decreasing the amount of thyroid hormone produced by the thyroid gland...
severe, fulminant liver failure. Patients on these medications should see a doctor if they develop sore throat or fever.
Treatment with antithyroid medications must be given for six months to two years, in order to be effective. Success rates vary from 34% to 64%, but even then the hyperthyroid state may recur, sometimes upon cessation of the drugs, somtimes months or years later. If treatment with antithyroid drugs fails to induce remission, RAI or surgery must be considered.
Radioiodine
Radioiodine (radioactive iodine-131Iodine-131
Iodine-131 , also called radioiodine , is an important radioisotope of iodine. It has a radioactive decay half-life of about eight days. Its uses are mostly medical and pharmaceutical...
, abbreviated as RAI) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center
Mallinckrodt General Clinical Research Center
The Mallinckrodt MGH General Clinical Research Center is a research center at Massachusetts General Hospital. It is located in Boston, Massachusetts, with satellites in Cambridge, MA and Charlestown, MA. It is supported by a GCRC grant through the National Institutes of Health.-History:The MGH...
. This modality is suitable for most patients, although some doctors prefer to use it mainly for older patients. Indications for RAI are failed medical therapy or surgery, or where medical or surgical therapy are contraindicated. Contraindications to RAI are pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
(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 do not evolve to hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
(incidence rate of 80%), in which case they will become lifelong thyroid patients. 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 tracheaVertebrate trachea
In tetrapod anatomy the trachea, or windpipe, is a tube that connects the pharynx or larynx to the lungs, allowing the passage of air. It is lined with pseudostratified ciliated columnar epithelium cells with goblet cells that produce mucus...
), suspicious nodules or suspected cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
(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". Preoperative administration of (not radioactive) iodine, usually by Lugol's iodine
Lugol's iodine
Lugol's iodine, also known as Lugol's solution, first made in 1829, is a solution of elemental iodine and potassium iodide in water, named after the French physician J.G.A. Lugol. Lugol's iodine solution is often used as an antiseptic and disinfectant, for emergency disinfection of drinking water,...
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
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
.
Doctors can opt for partial or total removal of the thyroid gland (subtotal thyroidectomy versus 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
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
; less aggressive surgery has a higher likelihood of recurrent hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
. 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.
- Transient vocal cord paralysis in 3%
- Prolonged postoperative hypocalcemia in 3%
- Permanent hypoparathyroidismHypoparathyroidismHypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
in 1% (due to removal of one or more parathyroid glands) - Recurrent hyperthyroidismHyperthyroidismHyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
in 2%
A scar
Scar
Scars are areas of fibrous tissue that replace normal skin after injury. A scar results from the biological process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in...
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
General anaesthesia
General anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...
(i.e., vomiting), as well as a sore throat, a raspy voice, and a cough from having an endotracheal tube inserted in the trachea
Vertebrate trachea
In tetrapod anatomy the trachea, or windpipe, is a tube that connects the pharynx or larynx to the lungs, allowing the passage of air. It is lined with pseudostratified ciliated columnar epithelium cells with goblet cells that produce mucus...
during surgery.
Removal of the gland enables complete biopsy to be performed to have definite evidence of thyroid cancer
Thyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...
, 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 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 levothyroxineLevothyroxine
Levothyroxine, also L-thyroxine, synthetic T4, or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine , used as a hormone replacement for patients with thyroid problems. The natural hormone is chemically in the chiral L-form, as is the pharmaceutical agent...
(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. 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. 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. 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. De Groot mentions that a mild sedativeSedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
or tranquilizer
Tranquilizer
A tranquilizer, or tranquilliser , is a drug that induces tranquility in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...
is often helpful. 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 dropsEye Drops
Eye Drops was a television program on TechTV that showcased short computer animation movies and clips made using off the shelf 3D animation software. The show claimed to showcase all different types of animation, but only a very small number of shorts featured non-CG animation...
or nonsteroidal anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
drops. Severe cases threatening vision (corneal exposure or optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
compression) are treated with steroids or orbital decompression. In all cases cessation of smoking
Smoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
is essential. Double vision
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
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, making it impossible to completely close the eyes. This 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' disease on the eyelids. This surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. The muscle then becomes 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 metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
is restored to normal, and for some time afterward, caloric
Food energy
Food energy is the amount of energy obtained from food that is available through cellular respiration.Food energy is expressed in food calories or kilojoules...
and protein requirements may be well above normal. Specific deficiencies may exist, and multivitamin
Multivitamin
A multivitamin is a preparation intended to supplement a human diet with vitamins, dietary minerals, and other nutritional elements. Such preparations are available in the form of tablets, capsules, pastilles, powders, liquids, and injectable formulations...
supplementation is indicated. The intake of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
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
Nutrition
Nutrition is the provision, to cells and organisms, of the materials necessary to support life. Many common health problems can be prevented or alleviated with a healthy diet....
, and specific (anti)thyroid medication.
Prognosis
The disease typically begins gradually, and is progressiveProgressive illness
The term progressive illness describes the course of an illness that gradually progresses and changes mode, generally to the worse. In contrast, non-progressive or chronic illnesses are relatively constant.-Examples:...
unless treated. If left untreated, more serious complications could result, including bone loss
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
and fractures
Bone fracture
A bone fracture is a medical condition in which there is a break in the continuity of the bone...
, inanition, birth defects in pregnancy, and increased risk of a miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
. Graves disease is often accompanied by an increase in heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
, which may lead to cardiovascular damage and further heart complications including loss of the normal heart rhythm (atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
), which may lead to stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. 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 cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
l infection, which could lead to blindness
Blindness
Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...
. Pressure on the optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
behind the globe can lead to visual field
Visual field
The term visual field is sometimes used as a synonym to field of view, though they do not designate the same thing. The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments", while 'field of view' "refers to the physical...
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
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
to somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
and ultimately to coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
. All in all, untreated Graves' disease can lead to significant morbidity, disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...
and even death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
. However, the long-term history also includes spontaneous remission
Spontaneous remission
Spontaneous healing, also called spontaneous remission or spontaneous regression, means an unexpected improvement or cure from a disease which usually is taking a different course. Both terms are mainly used for unexpected transient or final improvements in cancer. Spontaneous remissions concern...
in some cases and eventual spontaneous development of hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
if autoimmune thyroiditis
Autoimmune thyroiditis
Autoimmune thyroiditis is a form of thyroiditis associated with an autoimmune disease where the body treats the thyroid gland and sometimes the hormones it produces as foreign bodies, therefore rejecting and attacking both.-Treatment:...
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.
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 depressionDepression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, as well as less tolerance of stress
Stress (biology)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
. According to a 2010 publication, a total thyroidectomy
Thyroidectomy
A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. Surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland...
offers the best chance of preventing recurrent hyperthyroidism.
Mental impairment
A literature review in 2006, whilst noting methodologyMethodology
Methodology is generally a guideline for solving a problem, with specificcomponents such as phases, tasks, methods, techniques and tools . It can be defined also as follows:...
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
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, as well as elevated scores on scales of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
and psychological distress. 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. Delay in therapy markedly worsens the prognosis for recovery, but complications can be prevented by early treatment. In rare cases, patients will experience psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
-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.
Thyroid replacement treatment after thyroidectomy or radioiodine
Several studies find a high frequency of TSHTSH
TSH may refer to:* Tanzanian shilling, the currency of Tanzania* Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells* Tshiuetin Rail Transportation, a Canadian railway between Labrador and Quebec...
level abnormalities in patients who take thyroid hormone supplementation for long periods of time, and stress the importance of periodic assessment of serum TSH
TSH
TSH may refer to:* Tanzanian shilling, the currency of Tanzania* Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells* Tshiuetin Rail Transportation, a Canadian railway between Labrador and Quebec...
.
Coping with Graves' disease & the patient-physician relationship
Mentally, Graves' disease can be very disturbing. Mood swingsMood Swings
Mood Swings is an album by Koby Israelite released in 2005 on Tzadik.- Track listing :# "Dror Ikra" - 3:03# "Return of the Idiots" - 2:19# "It Is Not a War Here" - 7:05# "Ethnometalogy" - 5:08# "Europa?" - 2:49# "Hiriya On My Mind" - 4:53...
, 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
Peer support
Peer support occurs when people provide knowledge, experience, emotional, social or practical help to each other. It commonly refers to an initiative consisting of trained supporters, and can take a number of forms such as peer mentoring, listening, or counseling...
(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
Patient education
Patient education is the process by which health professionals and others impart information to patients that will alter their health behaviors or improve their health status...
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
Attention span
Attention span is the amount of time that a person can concentrate on a task without becoming distracted. Most educators and psychologists agree that the ability to focus one's attention on a task is crucial for the achievement of one's goals....
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
Patient education
Patient education is the process by which health professionals and others impart information to patients that will alter their health behaviors or improve their health status...
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
Questionnaire
A questionnaire is a research instrument consisting of a series of questions and other prompts for the purpose of gathering information from respondents. Although they are often designed for statistical analysis of the responses, this is not always the case...
as part of the initial intake, allowing the patient to communicate essential, non-medical information about their lives.
The communication
Communication
Communication is the activity of conveying meaningful information. Communication requires a sender, a message, and an intended recipient, although the receiver need not be present or aware of the sender's intent to communicate at the time of communication; thus communication can occur across vast...
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.
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 childbirthChildbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
, 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 goitre
Goitre
A goitre or goiter , is a swelling in the thyroid gland, which can lead to a swelling of the neck or larynx...
s. 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
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
were more common and severe in women.
Cigarette smoking, which is associated with many autoimmune diseases, raises the incidence of Graves' ophthalmopathy 7.7-fold.
History
Graves' disease owes its name to the Irish doctor Robert James GravesRobert James Graves
Robert James Graves, M.D., F.R.C.S. was an eminent Irish surgeon after whom Graves' disease takes its name. He was President of the Royal College of Physicians of Ireland, Fellow of the Royal Society of London and the founder of the Dublin Journal of Medical Science...
, who described a case of goitre with exophthalmos in 1835. However, the German Karl Adolph von Basedow
Karl Adolph von Basedow
Carl Adolph von Basedow was a German physician most famous for reporting the symptoms of what could later be dubbed Graves-Basedow disease, now technically known as exophthalmic goiter.-Biography:...
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. It has been known less commonly 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
James Begbie
James Begbie FRSE FRCPE FRCSE was a Scottish medical doctor who served as president of the Medico-Chirurgical Society of Edinburgh and as president of the Royal College of Physicians of Edinburgh .He was among the first physicians to give a detailed description of exophthalmic goitre, currently...
, Giuseppe Flajani, and Henry Marsh. For example, cases of goitre with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. 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
Islamic medicine
In the history of medicine, Islamic medicine, Arabic medicine or Arabian medicine refers to medicine developed in the Islamic Golden Age, and written in Arabic, the lingua franca of Islamic civilization....
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
Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen was a German pathologist who practiced medicine in Würzburg and Strassburg . Born in Gütersloh, Westphalia, he was the father of physiologist Heinrich von Recklinghausen ....
described the "worm eaten" appearance of the long bones of a young woman who died from hyperthyroidism.
With Graves Disease affecting the immune system the body also has potential to be affected by Pneumocystis carinii pneumonia
Notable cases
- John AdamsJohn AdamsJohn Adams was an American lawyer, statesman, diplomat and political theorist. A leading champion of independence in 1776, he was the second President of the United States...
, Second President of the United States (possible case) - AyakaAyakais a Japanese female singer formerly signed to Warner Music Japan. Born in Osaka, she moved to Tokyo to pursue a singing career. She married actor Hiro Mizushima on February 22, 2009.-2006:...
, Japanese singer/songwriter - George H. W. BushGeorge H. W. BushGeorge Herbert Walker Bush is an American politician who served as the 41st President of the United States . He had previously served as the 43rd Vice President of the United States , a congressman, an ambassador, and Director of Central Intelligence.Bush was born in Milton, Massachusetts, to...
, 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 BushBarbara BushBarbara Pierce Bush is the wife of the 41st President of the United States George H. W. Bush, and served as First Lady of the United States from 1989 to 1993. She is the mother of the 43rd President George W. Bush and of the 43rd Governor of Florida Jeb Bush...
also developed the disease about the same time, which in her case produced severe infiltrative exophthalmosExophthalmosExophthalmos is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral or unilateral . Measurement of the degree of exophthalmos is performed using an exophthalmometer...
. 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 ChildsToni ChildsToni Childs is an American singer-songwriter from Orange, California. She has released four studio albums and is best known for her songs "Don't Walk Away" , "I've Got To Go Now", a Top 5 hit in Australia in 1991, and the Emmy-winning "Because You're Beautiful" Toni Childs (born October 29, 1957)...
, American singer/songwriter - Gail DeversGail DeversYolanda Gail Devers is a retired three-time Olympic champion in track and field for the US Olympic Team. Devers was born in Seattle, Washington, and grew up near National City, California and graduated from Sweetwater High School in 1984...
, Athletic champion - Melissa Arnette "Missy" Elliott, American songwriter, producer and recording artist
- Marty FeldmanMarty FeldmanMartin Alan "Marty" Feldman was an English comedy writer, comedian and actor who starred in a series of British television comedy shows, including At Last the 1948 Show, and Marty, which won two BAFTA awards and was the first Saturn Award winner for Best Supporting Actor for his role in Young...
, British comedian - Diane FinleyDiane FinleyDiane Finley, PC, MP is a Canadian politician. She serves as Minister of Human Resources and Skills Development in the cabinet of Prime Minister Stephen Harper. Of the 12 MPs in the Priorities and Planning Committee of cabinet , known as the inner cabinet, she is the only woman...
, Canadian cabinet minister - Faith FordFaith FordFaith Ford is an American television and film actress, known for having played the roles of Corky Sherwood on Murphy Brown and Hope Fairfield-Shanowski on Hope & Faith.-Early life:...
, American actress - Sia FurlerSia FurlerSia Kate Isobelle Furler or simply Sia, is an Australian pop, downtempo, and jazz singer and songwriter. In 2000, her single, "Taken for Granted" was a top 10 hit in the United Kingdom. Her 2008 album, Some People Have Real Problems peaked in the top 30 on the Billboard 200...
, Australian singer - Sammy "The Bull" Gravano, Former Gambino Family Underboss
- Herbert Norman Howells, British Composer
- Nadezhda Krupskaya, the wife of Lenin
- Barbara LeighBarbara LeighBarbara Leigh is an American former actress and fashion model. In 1972 she appeared in the film Junior Bonner with former boyfriend Steve McQueen....
, an American former actress and fashion model, now spokeswomen for the National Graves' Disease Foundation - Yūko MiyamuraYuko Miyamura' is a Japanese voice actress, actress, J-pop singer and director of audiography. Her married name is ', although she still works under her maiden name. Miyamura was born in Kobe, and graduated from the theater division of the Tōhō Gakuen College of Drama and Music. Her pet name is '...
, Japanese voice actress - Christopher Monckton, 3rd Viscount Monckton of BrenchleyChristopher Monckton, 3rd Viscount Monckton of BrenchleyChristopher Walter Monckton, 3rd Viscount Monckton of Brenchley is a British politician, public speaker, former newspaper editor and hereditary peer. Formerly a member of the Conservative Party, Monckton has been the Head of the Policy Unit for the UK Independence Party since November 2010. He was...
- Claire RaynerClaire RaynerClaire Berenice Rayner OBE was an English nurse, journalist, broadcaster and novelist, best known for her role for many years as an agony aunt.-Early life:...
, UK Nurse, Agony Aunt and Broadcaster - Christina Georgina Rossetti, British Victorian Poet
- Cecil Spring-RiceCecil Spring-RiceSir Cecil Arthur Spring-Rice GCMG GCVO , was a British diplomat who served as British Ambassador to the United States from 1912 to 1918.-Early life:...
, British Ambassador to the USA from 1912 to 1918 - Mary WebbMary WebbMary Webb , was an English romantic novelist and poet of the early 20th century, whose work is set chiefly in the Shropshire countryside and among Shropshire characters and people which she knew. Her novels have been successfully dramatized, most notably the film Gone to Earth in 1950 by Michael...
, English author and poet, descendant of Sir Walter Scott
See also
- HashitoxicosisHashitoxicosisHashitoxicosis, which can be abbreviated "Htx", is a transient hyperthyroidism caused by inflammation associated with Hashimoto's thyroiditis disturbing the thyroid follicles, resulting in excess release of thyroid hormone.-Symptoms:...
- MyxedemaMyxedemaMyxedema describes a specific form of cutaneous and dermal edema secondary to increased deposition of connective tissue components in subcutaneous tissue as seen in various forms of hypothyroidism and Graves' disease. It is more common in women than in men...
- NeuroendocrinologyNeuroendocrinologyNeuroendocrinology is the study of the extensive interactions between the nervous system and the endocrine system, including the biological features of the cells that participate, and how they functionally communicate...
- ThyroidologistThyroidologistA thyroidologist is a medical practitioner specializing in the thyroid and related areas.In the United States it refers to a board certified endocrinologist physician, who is either a full time academician with multiple responsibilities beside thyroid patient care, or a clinical thyroidologist...
- Thyrotoxic myopathyThyrotoxic MyopathyThyrotoxic myopathy is a neuromuscular disorder that develops due to the overproduction of the thyroid hormone thyroxine. Also known as hyperthyroid myopathy, TM is one of many myopathies that lead to muscle weakness and muscle tissue breakdown. Evidence indicates the onset of TM may be caused by...
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 UpToDateUpToDateUpToDate is an evidence based, peer reviewed medical information resource published by a medical company called UpToDate, Inc. It is available both via the Internet and offline on personal computers or a PDA. An update is published every four months....
- Drug Therapy: Antithyroid drugs Elaborate article published in 2005 in the medical magazine Medicina Interna