signs and symptoms of graves' disease signs and symptoms of graves' disease the signs and symptoms of graves' disease generally result from the direct and indirect effects of hyperthyroidism; sometimes they are caused by thyroidal conditions, such as graves' ophthalmopathy, goitre and pretibial myxedema. these clinical manifestations can involve virtually every system in the body. the mechanisms that mediate these effects are not well understood. the severity of the signs and symptoms of hyperthyroidism is related to the duration of the disease, the magnitude of the thyroid hormone excess, and the patient's age. although the vast majority of patients enjoy significant improvement and remission after proper medical care, health care providers should be aware of variability in the individual response to hyperthyroidism and individual sensitivity to thyroid hormone fluctuations generally. graves' disease patients can also undergo periods of hypothyroidism (inadequate production of thyroid hormone; see symptoms of hypothyroidism), due to the challenges of finding the right dosage of thyroid hormone suppression and/or supplementation. the body's need for thyroid hormone can also change over time, such as in the first months after radioactive iodine treatment (rai). thyroid autoimmune diseases can also be volatile: hyperthyroidism can interchange with hypothyroidism and euthyroidism. general symptoms goitre (enlarged thyroid). if the thyroid grows large enough, it may compress the recurrent laryngeal nerve, producing vocal cord paralysis, dysphonia, and even respiratory stridor. compression of the sympathetic chain may result in horner's syndrome. graves' ophthalmopathy (protrusion of one or both eyes) pretibial myxedema cardiovascular features may include hypertension, and heart rate that may be rapid or irregular in character; these may be perceived as palpitations. less common findings include high-output heart failure, left ventricular hypertrophy, premature atrial and ventricular contractions, atrial fibrillation, congestive heart failure, angina, myocardial infarction, systemic embolization, death from cardiovascular collapse and resistance to some drug effects (digoxin, coumadin). hyperreflexia, with a rapid relaxation phase. a distinctly excessive reaction to all sorts of stimuli. a marked increase in fatigability, or asthenia, is often prominent. this increased weariness may be combined with hyperactivity; patients remark that they are impelled to incessant activity, which, however, causes great fatigue. insomnia tremor (usually fine shaking; tremor of the outstretched fingers). in a small study of newly diagnosed hyperthyroid patients, tremor was observed in 76% of them. some studies lay the cause for hyperthyroid tremor with a heightened beta-adrenergic state, others suggest an increased metabolism of dopamine. weight loss despite normal or increased appetite. some patients (especially younger ones) gain weight due to excessive appetite stimulation that exceeds the weight loss effect. increased appetite. weakness or muscle weakness (especially in the large muscles of the arms and legs). this latter occurs in 60 to 80 percent of patients with untreated hyperthyroidism. muscle weakness is rarely the chief complaint. the likelihood and degree of muscle weakness is correlated with the duration and severity of the hyperthyroid state, and becomes more likely after the age of 40. muscle strength returns gradually over several months after the hyperthyroidism has been treated. muscle degeneration shortness of breath increased sweating heat intolerance warm and moist skin thin and fine hair redness of the elbows is frequently present. it is probably the result of the combination of increased activity, an exposed part, and a hyperirritable vasomotor system. chronic sinus infections brittle nails plummer's nail abnormal breast enlargement in men gastrointestinal symptoms. this includes increased bowel movements, but malabsorption is unusual. augmented calcium levels in the blood (by as much as 25% – known as hypercalcaemia). this can cause stomach upset, excessive urination, and impaired kidney function. diabetes may be activated or intensified, and its control worsened. the diabetes is ameliorated or may disappear when the thyrotoxicosis is treated. evidence of mild or severe liver disease may be found. reproductive symptoms in men may include reduced free testosterone (due to the elevation of testosterone-estrogen binding globulin level), diminished libido, erectile dysfunction and (reversible) impaired sperm production with lower mean sperm density, a high incidence of sperm abnormalities, and reduced mobility of the sperm cells. women may experience infrequent menstruation or irregular and scant menstrual flow along with difficulty conceiving, infertility and recurrent miscarriage. neurological seizures, neuropathy from nerve entrapment by lesions of pretibial myxedema, and hypokalemic periodic paralysis may occur. athetoid, choreia, and corticospinal tract damage, are rare. an acute thyrotoxic encephalopathy is very rare. effects on the skeleton overt hyperthyroidism caused by grave's disease is associated with accelerated bone remodeling (resulting in increased porosity of cortical bone and reduced volume of trabecular bone). this can lead to reduced bone density and eventually osteoporosis as well as increased fracture rates. the increased hip fracture rates later in life in turn cause excess late mortality. the changes in bone metabolism are connected with negative calcium balance, an increased excretion of calcium and phosphorus in the urine (hypercalciuria) and stool, and, rarely, hypercalcemia. in hyperthyroidism, the normal cycle duration of bone resorption of approximately 200 days is halved, and each cycle is associated with a 9.6 percent loss of mineralized bone. in hypothyroidism, cycle length approximates 700 days and is associated with a 17 percent increase in mineralized bone. the extent of the reduction in bone density in most studies is 10–20%. the clinical manifestations on bone differ depending on the age of the patient. postmenopausal woman are most sensitive to accelerated bone loss from thyrotoxicosis. accelerated bone growth in growing children can increase ossification in the short term, but generally results in short-stature adults compared with the predicted heights. if thyrotoxicosis is treated early, bone loss can be minimized. the level of calcium in the blood can be determined by a simple blood test, and a dual energy x-ray absorptiometry scan can help determine patient bone density relative to the rest of the population. there are many medications that can help to rebuild bone mass and to prevent further bone loss, such as bisphosphonates. risedronate treatment has been demonstrated to help restore bone mass in osteopenia/osteoporosis associated with graves' disease. nevertheless, weight-bearing exercises, a balanced diet, calcium intake of about 1500 mg a day and enough vitamin d, are of course elementary foundations. eye symptoms hyperthyroidism almost always causes general eye symptoms like dryness and irritation, regardless of what the cause of the hyperthyroid state is. however, these need to be distinguished from graves' ophthalmopathy, which can only occur in patients who have graves' disease. (it may also, rarely, be seen in hashimoto's thyroiditis, primary hypothyroidism, and thyroid cancer). about 20–25% of patients with graves' disease will suffer from clinically obvious graves' ophthalmopathy, and not just from the eye signs of hyperthyroidism. only 3 to 5% will develop severe ophthalmopathy. however, when subjected to closer inspection (e.g. by magnetic resonance imaging of the orbits) many more patients have evidence of ophthalmopathy. it is estimated that for every 100,000 persons, 16 women and 3 men have graves' ophthalmopathy every year. although it is true that in most patients ophthalmopathy, goiter, and symptoms of thyrotoxicosis appear more or less coincidentally, it is also true that in certain cases eye signs may appear long before thyrotoxicosis is evident, or become worse when the thyrotoxicosis is subsiding or has been controlled by treatment. in approximately 20% of ophthalmopathy patients, ophthalmopathy appears before the onset of hyperthyroidism, in about 40% concurrently, and in about 20% in the six months after diagnosis. in the remainder, the eye disease first becomes apparent after treatment of the hyperthyroidism, more often in patients treated with radioiodine. it can sometimes be difficult to distinguish between eye symptoms due to hyperthyroidism and those due to graves' antibodies, because the two often occur coincidentally. what can make things particularly difficult, is that many patients with hyperthyroidism have lid retraction, which leads to stare and lid lag (due to contraction of the levator palpebrae muscles of the eyelids). this stare may then give the appearance of protruding eyeballs (proptosis), when none in fact exists. this subsides when the hyperthyroidism is treated. due to graves' ophthalmopathy main article: graves' ophthalmopathyphoto showing the classic finding of proptosis and lid retraction in graves' disease graves' ophthalmopathy is characterized by inflammation of the extraocular muscles, orbital fat and connective tissue. it results in the following signs, which can be extremely distressing to the patient: most frequent are symptoms due to conjunctival or corneal irritation: burning, photophobia, tearing, pain, and a gritty or sandy sensation. protruding eyeballs (known as proptosis and exophthalmos). diplopia (double vision) is common. limitation of eye movement (due to impairment of eye muscle function). periorbital and conjunctival edema (accumulation of fluid beneath the skin around the eyes). in severe cases, the optic nerve may be compressed and acuity of vision impaired. occasionally loss of vision. due to hyperthyroidism in the absence of graves' ophthalmopathy, patients may demonstrate other ophthalmic symptoms and signs due to hyperthyroidism: dry eyes (due to loss of corneal moisture). a sense of irritation, discomfort, or pain in the eyes. a tingling sensation behind the eyes or the feeling of grit or sand in the eyes. excessive tearing that is often made worse by exposure to cold air, wind, or bright lights. swelling or redness of the eyes. stare lid lag (von graefe's sign) sensitivity to light blurring of vision widened palpebral fissures infrequent blinking the appearance of lid retraction. neuropsychological manifestations several studies have suggested a high prevalence of neuropsychiatric disorders and mental disorder symptoms in graves' disease (and thyroid disease in general), which are similar to those in patients with organic brain disease. these manifestations are diverse, affecting the central and peripheral nervous systems. the vast majority of patients with hyperthyroidism meet criteria for some psychiatric disorders, and those with milder presentations are probably not entirely free of mental symptoms such as emotional lability, tension, depression and anxiety. anxiety syndromes related to hyperthyroidism are typically complicated by major depression and cognitive decline, such as in memory and attention. some studies contradict the psychological findings. for example, a large 2002 study found "no statistical association between thyroid dysfunction, and the presence of depression or anxiety disorder." in one study on hospitalised elderly patients, over half had cognitive impairment with either dementia or confusion. however, a controlled study on 31 graves' disease patients found that while patients had subjective reports of cognitive deficits in the toxic phase of graves' thyrotoxicosis, formal testing found no cognitive impairment and suggested the reported symptoms may reflect the affective and somatic manifestations of hyperthyroidism. notably, a literature review of 2006 notes methodology issues in the consistency of graves' disease diagnostic criteria, which might explain the apparently contradicting findings. these researchers found many reports about residual complaints in patients who were euthyroid after treatment, with a high prevalence of anxiety disorders and bipolar disorder, as well as elevated scores on scales of anxiety, depression and psychological distress. in a 1992 study, a significant proportion of the 137 questioned patients with graves' disease reported – among other things – increased crying (55%), being easily startled (53%), being tired all the time (47%), a significant decrease in social activity (46%), feelings of being out of control (45%), feelings of hopelessness (43%), loss of sense of humor (41%), loss of interest in things they formerly enjoyed (39%), not being able to 'connect' with others (34%). several studies point out that the severity of psychiatric symptoms could easily result in an inappropriate referral to a psychiatrist prior to the diagnosis of hyperthyroidism. consequently, undiagnosed hyperthyroidism sometimes results in inappropriate use of psychotropic medications; prompt recognition of hyperthyroidism (or hypothyroidism) through thyroid function screening is therefore recommended in the evaluation of patients with psychiatric symptoms. naturally, the management of patients would be improved by collaboration between an endocrinologist and a psychiatrist. overall, reported symptoms vary from mild to severe aspects of anxiety or depression, and may include psychotic and behavioral disturbances: varying degrees of anxiety, such as a very active mind, irritability, hyperactivity, agitation, restlessness, nervousness, distractible hyperactivity and panic attacks. in addition patients may experience vivid dreams and, occasionally, nightmares. depressive features of mental impairment, memory lapses, diminished attention span, fluctuating depression. emotional lability and in some patients hypomania. the pathological well-being (euphoria) or hyperactivity may produce a state of exhaustion, and profound fatigue or asthenia chiefly characterizes the picture. erratic behaviour may include intermittent rage disorder and mild attention deficit disorder. some patients become