3.3.1 Clinical assessment and systemic manifestations of thyrotoxicosis

The term thyrotoxicosis refers to the clinical syndrome that results when the serum concentrations of free thyroxine, free triiodothyronine, or both, are high. The term hyperthyroidism is used to mean sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland; Graves’ disease is the most common example of this. Occasionally, thyrotoxicosis may be due to other causes such as destructive thyroiditis, excessive ingestion of thyroid hormones, or excessive secretion of thyroid hormones from ectopic sites; in these cases there is no overproduction of hormone by thyrocytes and, strictly speaking, no hyperthyroidism. The various causes of thyrotoxicosis are listed in Chapter 3.3.5. The clinical features depend on the severity and the duration of the disease, the age of the patient, the presence or absence of extrathyroidal manifestations, and the specific disorder producing the thyrotoxicosis. Older patients have fewer symptoms and signs of sympathetic activation, such as tremor, hyperactivity, and anxiety, and more symptoms and signs of cardiovascular dysfunction, such as atrial fibrillation and dyspnoea. Rarely a patient with ‘apathetic’ hyperthyroidism will lack almost all of the usual clinical manifestations of thyrotoxicosis (1).

Almost all organ systems in the body are affected by thyroid hormone excess, and the high levels of circulating thyroid hormones are responsible for most of the systemic effects observed in these patients (Table 3.3.1.1). However, some of the signs and symptoms prominent in Graves’ disease reflect extrathyroidal immunological processes rather than the excessive levels of thyroid hormones produced by the thyroid gland (Table 3.3.1.2).

Thyrotoxicosis is accompanied by cutaneous alterations that reflect the basic pathophysiological process and by various manifestations that may have practical diagnostic significance. Cutaneous changes occur whenever there is an increase in the metabolic rate and heat production. The skin has a smooth and silky texture. The typical thyrotoxic patient’s skin is usually moist and warm because of vasodilatation, which represents a homeostatic mechanism for dissipating the heat being generated in the body (2). Temperature elevation and erythema are consequences of increased dermal blood flow. The patient may complain of cutaneous flushing, perspiration at rest, and sweaty palms. As a consequence of excessive perspiration found in about one-half of thyrotoxic patients, miliaria, caused by poral occlusion and intracutaneous sweat retention, may be present. Pigmentation may be increased and is often diffuse, although a spectrum of abnormalities may be seen ranging from localized to diffuse hyperpigmentation particularly in such areas as the knuckles and skin creases. Vitiligo of variable extent occurs in a substantial number of patients with Graves’ disease and Hashimoto’s thyroiditis as a marker of autoimmune disease (3, 4). Among the less frequently reported cutaneous changes in thyrotoxicosis are dermographism, urticaria, purpura, and ill-defined generalized erythematous eruptions. Pruritus may be the chief complaint in a few cases. The epidermal changes are rapidly reversed after restoration of euthyroidism.

The hair may be fine and soft, and hair loss can be excessive. Alopecia areata and loss of axillary, pubic, body, and eyebrow hairs have been noted since the initial description by von Basedow, but are uncommon. The severity of hair loss is not directly related to the severity of the endocrine abnormality.

Localizing nonpitting oedema is a clinical finding that can be the tip-off to establish the diagnosis of Graves’ disease. Although this manifestation occurs along the shins (so-called pretibial myxoedema), it can occur elsewhere, generally on extensor surfaces (Fig. 3.3.1.1) (4). The lesion reflects the deposition of increased amounts of glycosaminoglycans in the subcutaneous connective tissue. The lesion is elevated above the surrounding tissue and is often finely dimpled and hyperpigmented, or pruritic and red.

The nails become shiny and may be soft and friable. The rate of nail growth is increased, and longitudinal striations associated with a flattening of the surface contour result in a scoop-shovel appearance. In many patients the nail is separated prematurely from the nail bed (onycholysis). Onycholysis is not specific to thyrotoxicosis, but when it occurs in this setting it usually begins under the distal central portion of the fourth fingernail. Such nail changes are less common in thyrotoxic patients over 60 years of age.

Retraction of the upper eyelid, evident as the presence of a rim of sclera between the lid and the limbus, is frequent in all forms of thyrotoxicosis, and is responsible for the bright-eyed ‘stare’ or ‘fish eyes’ of the patient with thyrotoxicosis (Fig. 3.3.1.2). Lid lag is caused by the fact that the upper lid lags behind the globe when the patient is asked to gaze downward; globe lag occurs when the globe lags behind the upper lid when the patient gazes slowly upward. In severe cases the movements of the lids are jerky and spasmodic, and a fine tremor of the lightly closed lids can be observed. These ocular manifestations appear to be the result of increased adrenergic activity. It is important to differentiate these ocular manifestations from those of infiltrative ophthalmopathy, characteristic of Graves’ disease (5, 6) (see Chapter 3.3.10).

Thyrotoxicosis due to nodular goitre or Graves’ disease is usually associated with an enlargement of the thyroid (Fig. 3.3.1.3a); excessive ingestion of thyroid hormones is not associated with goitre unless superimposed on a pre-existing thyroid enlargement. An asymmetrical thyroid gland is generally found in patients with toxic adenoma or multinodular goitre (Fig. 3.3.1.3b), but such a gland can also be observed in Graves’ disease. The thyroid gland in a typical patient with Graves’ disease is diffusely enlarged and visible, although a retrosternal gland or a low-lying nodule may be clinically inapparent. The size is related, but not closely, to the severity of the disease. The pyramidal lobe should always be searched for, since enlargement indicates the presence of diffuse disease of the thyroid. The marked increase in the blood flow to the thyroid gland in Graves’ disease is reflected clinically by the presence of a bruit or a thrill. The bruit is usually continuous but sometimes heard only in systole and is most readily detected at the upper or lower poles. Either the bruit or a thrill is highly suggestive, but not pathognomonic, of thyrotoxicosis. If local examination of a goitre discloses either of these signs, even though other evidence of hyperfunction may be lacking, a careful investigation of thyroid function is indicated. Both thrill and bruits decrease in intensity as thyrotoxicosis subsides. Colour flow Doppler sonography shows hypervascularity and increased peak systolic velocity (7). Dysphagia and the sensation of a lump in the neck may be produced by goitre.

Respiratory changes occurring in thyrotoxicosis are reported in Box 3.3.1.1. There are not many detailed studies of the effects of thyrotoxicosis on the lung. The frequency and the relative relevance of these changes is uncertain because available data are scarce and often conflicting. The increased metabolic rate stresses the lung, requiring a more rapid net rate of gas exchange to accommodate the increased oxygen consumption and carbon dioxide production. Dyspnoea is present in a large majority of severely affected thyrotoxic patients (8) and several factors may contribute to this condition, such as respiratory muscle weakness, reduction of vital capacity, decreased pulmonary compliance, and increase in respiratory dead space ventilation.

A decrease of residual volume, vital capacity, and total lung capacity have been reported in early studies in one-quarter of patients (8). In more recent studies no significant differences in the mean baseline vital capacity, total lung capacity, residual volume, static compliance, or pressure–volume curves between patients and controls have been observed (9). In some studies, the residual volume is increased and the total lung capacity is decreased, suggesting muscle weakness, but in other reports the results are contradictory. These heterogeneous findings may reflect either inclusion of patients with underlying lung diseases or the fact that thyrotoxicosis may cause several types of changes in the lungs, which may variably occur in different patients. For example, the weakness of respiratory muscles resulting from chronic thyrotoxic myopathy probably occurs only in some patients. Arterial blood gas partial pressures and oxygen–haemoglobin and carbon dioxide–haemoglobin dissociation curves are usually normal. Although the total amount of oxygen extracted by the peripheral tissues is increased, the efficiency of oxygen extraction is decreased.

Lung compliance may be altered by changes in the elastic properties or by vascular engorgement. It is calculated from the static pressure–volume curve of the lung, with measurement of the intrathoracic pressure using an oesophageal balloon manometer. In some cases it is difficult to separate patients with pure respiratory muscle weakness from patients who have only decreased lung compliance. Manifestations of respiratory muscle dysfunction include rapid, shallow respirations, respiratory dyskinesis, hypoventilation, respiratory acidosis, and easy fatigability (10). Most thyrotoxic patients with overt thyrotoxicosis have diminished proximal muscle strength. Chronic thyrotoxic myopathy affects the diaphragm and other respiratory muscles in up to one-half of severely affected thyrotoxic patients, causing loss of maximal respiratory muscle power.

Thyrotoxicosis may affect the central regulatory response to a blood gas perturbation, which can be assessed by evaluating the increase of ventilation while breathing either a hyperoxic hypercapnic or a hypoxic isocapnic gas mixture. Both these responses are increased in most thyrotoxic patients. These changes are independent of the β-adrenergic effects of catecholamines, and their mechanisms are not completely understood. Thyrotoxicosis, by increasing the ventilatory drive superimposed on underlying lung disease, may worsen dyspnoea and cause respiratory failure.

Resting heart rate, cardiac output, respiratory rate, and minute ventilation are increased (9). The amount of oxygen required to perform any work load is increased. Both minute ventilation and cardiac output for a given level of oxygen consumption are elevated at all levels of oxygen consumption. Pulmonary artery pressures of thyrotoxic patients may rise more than usual with exercise, but this has not been evaluated carefully. Exercise normally decreases the mixed venous oxygen saturation and the dead space/tidal volume ratio; the converse occurs in thyrotoxicosis.

Cardiac changes of thyrotoxicosis may affect the lungs in two ways, either by pulmonary artery dilatation or by high-output cardiac failure (11). The pulmonary artery may appear dilated on plain chest radiographs. The findings of an accentuated pulmonary second heart sound and a right ventricular heave suggest pulmonary hypertension. Mild increases of resting pulmonary artery pressure are common with thyrotoxicosis, and the pressure frequently rises significantly during exercise. A physical sign of thyrotoxicosis is the Means–Lerman sign, a scratchy coarse systolic ejection rub or murmur that is heard best along the left sternal border at the base of the heart. This sign has been attributed to rubbing of the dilated aorta or pulmonary artery against other mediastinal structures or to turbulent pulmonary artery blood flow. The precise origin and the physiological significance of this sign are unknown.

Most of the renal effects in thyrotoxic patients produce no symptoms except mild polyuria (12).

Thyrotoxicosis is associated with an increase in renal plasma flow and glomerular filtration rate, probably because of the increase in cardiac output and decrease in peripheral resistance. Intrarenal vasodilatation also occurs. The mean 24-h urine creatinine excretion is significantly lower in thyrotoxic patients as compared to normal subjects. The latter finding has been attributed to loss of muscle mass and it occurs despite an increase in urea clearance (12). These changes are normalized when the eumetabolic state is restored. Renal tubular mass is increased, and the morphological changes that occur in renal tubules are accompanied by an increased renal tubular capacity for transport. An activation of the renin–angiotensin system contributes to cardiac hypertrophy in patients with thyrotoxicosis (13).

Thyrotoxic patients rarely have abnormalities in water metabolism. Serum electrolytes are usually normal. Some thyrotoxic patients have polydipsia, with 24-h urine volumes up to 3–4 litres. Polyuria in these patients is due to increased thirst, as in primary polydipsia, and could be secondary to an increase of plasma angiotensin II concentration. Polydipsia and polyuria revert to normal after treatment of thyrotoxicosis.

Plasma atrial natriuretic hormone levels and plasma renin activity are increased in thyrotoxicosis; these changes seem to have no clinical consequences except for mild oedema. The total amount of exchangeable potassium is decreased, but the amount of exchangeable sodium tends to be increased. Despite these changes, serum sodium, potassium, and chloride concentrations are normal. The level of exchangeable magnesium concentration is often decreased, and urinary magnesium excretion is increased.

Renal tubular acidosis occasionally occurs in association with thyrotoxicosis. In this condition there is a failure to achieve maximal urinary acidification. This rarely results from hypercalcaemia and hypercalciuria, which can cause nephrocalcinosis, tubular damage, and impairment of renal acidification. Renal tubular acidosis may occur in association with thyrotoxicosis caused by Graves’ disease, also in the absence of nephrocalcinosis, and may persist after restoration of the euthyroid state. This condition may have an autoimmune basis (14).

Patients with thyrotoxicosis may develop pitting oedema involving the legs, hands, ankles, and sacrum. Oedema results from renal salt and water retention in response to the reduction in effective arterial volume, and this retention contributes to an increase in blood volume and venous pressure. The oedema that develops under these circumstances does not necessarily imply the presence of congestive heart failure. Severe thyrotoxic patients also may have protein-calorie malnutrition and hypoalbuminaemia leading to an expansion of plasma volume and oedema.

The classic gastrointestinal manifestations of thyrotoxicosis are rapid intestinal transit, increased frequency of semiformed stools, and weight loss from increased caloric requirement or malabsorption (15). These changes are not necessarily frequent. An increase in appetite, both at mealtimes and between meals, is a common symptom, but it is usually not seen in patients with mild disease. In severe disease, the increased intake of food is usually inadequate to meet the increased caloric requirements, and weight is lost at a variable rate. Anorexia, rather than hyperphagia, sometimes accompanies severe thyrotoxicosis. It occurs in about one-third of elderly patients and contributes to the picture of ‘apathetic’ thyrotoxicosis.

Frequent bowel movements are significantly more common in patients with thyrotoxicosis than in normal controls. Diarrhoea is rare (16). When constipation was present before the development of thyrotoxicosis, bowel function may become normal. More often stools are less well formed, and the frequency of bowel movements is increased. Anorexia, nausea, and vomiting are rare, but may occur with severe disease. Gastric emptying and intestinal motility are increased, and these changes appear to be responsible for slight malabsorption of fat. Steatorrhoea is common in severe thyrotoxicosis. The mechanism underlying the gastrointestinal hypermotility has not been elucidated, but hypermotility disappears when euthyroidism is restored. Coeliac disease and Graves’ disease may coexist more frequently than can be accounted for by chance; both have an autoimmune origin.

Hepatic function may be altered, particularly when the disease is severe (17); hypoproteinaemia and increased serum alkaline phosphatase and transaminase levels may be present. In severe cases hepatomegaly and jaundice may be found. Graves’ disease and autoimmune hepatitis coexist more often than can be expected by chance. Because of the alterations in hepatic function, the metabolism of various drugs may be affected.

Hyperactivity, emotional lability, distractibility, and anxiety observed in thyrotoxicosis may reflect changes in the nervous system, but the pathogenetic mechanisms remain obscure (18). The hyperactivity is characteristic: movements are quick, jerky, and exaggerated. Examination reveals a fine rhythmic tremor of the hands, tongue, or slightly closed eyelids. Emotional lability causes patients to lose their tempers easily and to have episodes of crying without apparent reason. Crying may be evoked by merely questioning the patient about the symptom. In rare cases mental disturbance may be severe. Anxiety is characterized by restlessness, shortness of attention span, and a compulsion to be moving around, despite a feeling of fatigue. Fatigue is due both to muscle weakness or to insomnia which is frequently present.

Persistent fine tremor is the most prominent finding. It most commonly involves the hands, but may also affect the feet, chin, lips, and tongue. The tremor may sometimes mimic that of parkinsonism, and a pre-existing parkinsonian tremor can be accentuated. Chorea seldom appears as a manifestation of thyrotoxicosis (19). Chronic atrial fibrillation is associated with an increased risk of embolic stroke. The neurological manifestation of thyrotoxic crisis (20) may rarely include coma and status epilepticus (21). In patients with convulsive disorders, the frequency of seizures is increased.

The electroencephalogram of most thyrotoxic patients reveals increased fast-wave activity. The basal metabolic rate tends to correlate with the frequency of brain waves, but at the extremes of thyroid abnormality the correlation is frequently poor.

Muscle weakness and fatigue are frequent (22). In most instances they are not accompanied by objective evidence of local disease of muscle except for the generalized wasting associated with weight loss. Weakness is often most prominent in the proximal muscles of the limbs, causing difficulties in climbing stairs or in maintaining the leg in an extended position. Occasionally, in severe untreated cases, muscle wasting occurs as a predominant symptom (thyrotoxic myopathy). In extreme forms, the patient may be unable to rise from a sitting or lying position and may be virtually unable to walk.

Muscle manifestations affect men with thyrotoxicosis more commonly than women and may overshadow other manifestations of the syndrome. In severe forms, the myopathy involves mainly distal muscles and extremities and the muscles of the trunk and face. The involvement of ocular muscles may mimic myasthenia gravis. Graves’ disease occurs in about 3–5% of patients with myasthenia gravis, and about 1% of patients with Graves’ disease develop myasthenia gravis (23). Myasthenia gravis associated with Graves’ disease has a mild expression characterized by preferential involvement of the eye muscles (23). Another myopathy sometimes observed in association with thyrotoxicosis is hypokalaemic periodic paralysis (24). It is characterized by sporadic attacks (which may last from minutes to many hours), most commonly involving flaccidity and paralysis of either legs, arms, or trunk, even though any muscle can be involved. Episodes can occur spontaneously, after carbohydrate ingestion, or after exercise. Hypokalaemic periodic paralysis is most frequent in Asian populations (see Chapter 3.3.2).

Thyrotoxicosis is associated with an increase of bone turnover and eventually bone loss, especially in postmenopausal women (25). Patients with a longstanding history of thyrotoxicosis may have overt osteoporosis and an increased risk of fractures (26).

Bone turnover is increased, but the increase in bone resorption is relatively greater than that of bone formation, so the urinary excretion of calcium, phosphorus, and hydroxyproline is increased (26, 27). As a consequence of this acceleration in bone resorption, hypercalcaemia may occur in a significant proportion of patients with thyrotoxicosis. Total serum calcium may be slightly increased in as many as 27% of patients and ionized serum calcium level in 47%. However, patients are rarely symptomatic due to hypercalcaemia. The concentrations of alkaline phosphatase and osteocalcin are also frequently increased (28). These findings are reminiscent of those of primary hyperparathyroidism. Parathyroid hormone and 1,25-dihydroxyvitamin D₃ levels tend to be low as a result of the increased calcium released from bone. True primary hyperparathyroidism and thyrotoxicosis may sometimes coexist. The alterations in bone metabolism in thyrotoxicosis are reversed when the eumetabolic state is restored (28, 29).

Excretion of calcium in the faeces is also increased in thyrotoxic patients. The secretions of the gastrointestinal tract are altered in thyrotoxicosis and the transit time of calcium in the intestine is shortened.

Thyrotoxicosis is one of the well-known risk factors for osteoporosis (26). In thyrotoxicosis there is an increase in osteoid, the unmineralized bone matrix. The microscopic appearance of the bone is similar to that of osteomalacia. The direct effect of thyroid hormone on osteoblasts accounts for the increased circulating levels of alkaline phosphatase and osteocalcin frequently present in thyrotoxic patients. Despite the increased mineralization rate and osteoblastic activity, the increased bone formation cannot compensate for increments in bone resorption, and bone mass may be decreased. The pathological changes are variable and may include osteoporosis, osteomalacia, and osteitis fibrosa. Individuals with a history of thyrotoxicosis have a slightly increased risk of fracture, and sustain fractures at an earlier age than individuals who have never been thyrotoxic. As the thyrotoxicosis is treated, bone density may return to predisease levels in premenopausal patients (29, 30). Postmenopausal women, however, may have a permanent reduction in bone density that may require treatment with agents that increase bone mass.

The skeletal effects of thyroid hormone replacement are unclear. Recently, some reports suggested that patients receiving chronic l-thyroxine treatment, particularly those treated with doses that suppress thyroid-stimulating hormone (TSH) secretion (suppressive doses), may have a reduced bone mass (31). Recently, other studies (32, 33) suggested that l-thyroxine suppressive therapy, if carried out carefully and monitored, using the smallest dose necessary to suppress TSH secretion, has no significant effect on bone metabolism or bone mass, at least in premenopausal women and in men, whereas in postmenopausal women some degree of bone loss can be observed.

Thyroid acropachy occurs in approximately 1% of patients with Graves’ disease, and is always associated with exophthalmos and pretibial myxoedema (34). It frequently develops after treatment of thyrotoxicosis. This condition affects the peripheral skeleton and consist of clubbing, periostitis, and swelling.

In most patients with thyrotoxicosis, red blood cells are usually normal, but the red blood cell mass is increased. The increase in erythropoiesis appears to be due both to a direct effect of thyroid hormones on the erythroid marrow and to an increased production of erythropoietin. A parallel increase in plasma volume also occurs, and therefore the haematocrit value is normal.

The most common red blood cell morphological abnormality is microcytosis, which is found in at least 37% of patients. The cause of this change is unclear. Iron deficiency is occasionally reported in thyrotoxic states. Microcytosis usually resolves with the restoration of euthyroidism. Some patients with severe thyrotoxicosis may develop a normocytic anaemia. Defective iron use has been shown to occur in thyrotoxic patients and may be responsible for the development of anaemia.

Approximately 3% of patients with Graves’ disease have pernicious anaemia, and a further 3% have antibodies to intrinsic factor but normal absorption of vitamin B₁₂. Autoantibodies against gastric parietal cells are present in about one-third of the patients with Graves’ disease, and the requirements for vitamin B₁₂ and folic acid appear to be increased.

The total white blood cell count is often low because of a decrease in the number of neutrophils. The absolute lymphocyte count is normal or increased, leading to a relative lymphocytosis. The numbers of monocytes and eosinophils may also be increased. A generalized lymphadenopathy may be present, and the spleen, although not often palpable on physical examination, has been shown to be enlarged in 10% of patients with thyrotoxicosis due to Graves’ disease.

Blood platelets and the intrinsic clotting mechanism are normal. However, the concentration of factor VIII is often increased and returns to normal when thyrotoxicosis is treated. Furthermore, there is an enhanced sensitivity to coumarin anticoagulants because of an accelerated clearance of vitamin K-dependent clotting factors. A hypercoagulable state has been described in hyperthyroid patients (35).

The cardiovascular manifestations of thyrotoxicosis constitute some of the most profound and characteristic symptoms and signs of the disorder (Box 3.3.1.2) (36, 37). Tissue blood flow is increased in response to accelerated metabolism and increased oxygen consumption. Haemodynamic changes in thyrotoxic patients are characterized by an elevated cardiac output and a decreased peripheral vascular resistance. The mechanism responsible for the reduced vascular resistance is unclear. Thyroid hormone itself may be involved directly through its action on the smooth muscle of blood vessels (38). Moreover, the finding in thyrotoxic patients of elevated levels of plasma adrenomedullin and proadrenomedullin-N-terminal 20-peptide, which have a potent vasodilatory activity, raises the possibility that these substances might also be involved in the decrease of vascular resistance in these patients (39).

Clinically, nearly all patients have tachycardia and a bounding pulse; the widened pulse pressure reflects both the increase in cardiac output and the decrease in peripheral vascular resistance. The common complaint of palpitations usually indicates a resting tachycardia. The heart rate is also elevated during sleep; this helps to distinguish tachycardia of thyrotoxic origin from that of psychogenic origin. Other common cardiovascular symptoms include exercise intolerance and dyspnoea on exertion. The latter is usually present with sustained activity, but may also arise with activity as limited as climbing a flight of stairs. Because of the diffuse and forceful nature of the apex beat, the heart may be enlarged, but echocardiography is usually normal. In elderly thyrotoxic patients the cardiovascular manifestations of thyrotoxicosis may be limited to resting tachycardia; (40) other classic thyrotoxic symptoms may be absent, possibly due to the relative paucity of adrenergic activity (41).

Thyrotoxic patients may have chest pain similar in almost all respects to angina pectoris, probably caused by either relative myocardial ischaemia or coronary artery spasm. In elderly patients, however, the increased myocardial oxygen demand due to thyrotoxicosis may unmask coronary artery disease. The plasma level of homocysteine, an independent risk factor for cardiovascular disease, in thyrotoxic patients did not differ significantly from that of controls (42). On the contrary, hyperhomocysteinaemia has been found in hypothyroid patients and, in association with lipid abnormalities, may contribute to the increased risk of coronary artery disease (43).

In patients with thyrotoxicosis, tachycardia is the most common of all abnormal findings. The heart rate is increased, with bounding pulses in the larger arteries due to widened pulse pressure. Systolic blood pressure is elevated and diastolic blood pressure is decreased (44); the mean blood pressure is usually normal. An exaggerated increase in systolic blood pressure may be present in older patients due to the loss of elasticity of the larger arteries (44); the mean blood pressure in these patients may also be high. The first heart sound may be sharp and audible. Auscultation may reveal a systolic ejection murmur and a gallop rhythm caused by rapid flow of blood through the aortic outflow tract. Systolic murmurs may arise from valve prolapse, left ventricular dilatation, or dysfunction of the mitral valve apparatus. A systolic ‘scratch’ is heard in the pulmonary area corresponding to contact between the pleural and pericardial surfaces during cardiac contraction. Mild oedema not uncommonly occurs in the absence of heart failure. Heart failure rarely occurs in thyrotoxic patients, unless an underlying cardiac disease is also present (41).

Sinus tachycardia is present on routine electrocardiographic tracings in the majority of thyrotoxic patients (37). Cardiac arrhythmias are almost invariably supraventricular. Approximately 10% of patients with thyrotoxicosis have atrial fibrillation, and a similar percentage of patients with otherwise unexplained atrial fibrillation are thyrotoxic (41). This manifestation may be the presenting symptom of thyrotoxicosis, particularly in older people. Most patients with atrial fibrillation have arrhythmia for less than 4–8 weeks before the diagnosis of thyrotoxicosis, and a spontaneous reversion often occurs. In elderly patients with subclinical thyrotoxicosis the risk of developing persistent atrial fibrillation is approximately 3 times that of normal subjects (41, 45). Paroxysmal supraventricular tachycardia may be demonstrable or may be suggested by the history. Ventricular premature contractions are rare. Angina pectoris and myocardial infarction may rarely occur in the absence of coronary artery disease. Nonspecific electrocardiographic changes may occur in thyrotoxicosis. A shortening of the P–R interval is common, secondary to the increased rate of conduction through the atrioventricular node.

Thyrotoxicosis alone may determine heart failure in elderly and, much less often, in young patients (44). In large clinical studies of thyrotoxic patients with heart failure, patients were generally old and, therefore, at risk of underlying heart disease, and had chronic thyrotoxicosis. Elderly patients with rhythm disturbances, including atrial fibrillation, have the greatest risk of heart failure (40, 46); in the absence of atrial fibrillation, heart failure is rare. In young patients, or in the absence of underlying heart disease, the heart failure is thought to be ‘high output’. High-output heart failure may not be a true heart failure but a circulatory congestion caused by fluid retention. In thyrotoxicosis, cardiac output is potentially near to maximal at rest and cannot increase in response to exercise, stress, surgery, or pregnancy (36, 47). As a consequence, atrial filling pressures rise, leading to pulmonary and peripheral oedema. This situation may be worse if atrial fibrillation is present. Left ventricular function is impaired because the persistent tachyarrhythmia alters this function. Sustained tachycardia causes abnormal ventricular systolic and diastolic function, which resolves when arrhythmia is treated. β-adrenergic receptor blockade-mediated slowing of the heart rate can rapidly reverse even severe degrees of left ventricular dysfunction in thyrotoxic patients.

Thyrotoxicosis affects the secretion of most pituitary hormones, in particular the secretion of growth hormone, prolactin, adrenocorticotropin (ACTH), follicle-stimulating hormone, and luteinizing hormone. Children with thyrotoxicosis grow more rapidly than normal children (48). The height and bone ages are accelerated, but their relationship remains normal. Growth acceleration in thyrotoxicosis suggests that growth hormone secretion might be greater than normal. Serum growth hormone concentrations, however, are lower in thyrotoxic patients than normal subjects. This decrease is probably due to the increased metabolic clearance rate. Serum insulin-like growth factor-1 concentration is higher in thyrotoxic patients and returns to normal values after restoration of the euthyroid state. Basal secretion of prolactin and its response to thyrotropin-releasing hormone may also be decreased. No physiological or clinical consequences of these abnormalities are known.

Thyrotoxicosis has several effects on adrenocortical function and adrenocortical hormone metabolism, with an increased clearance of the latter (49). The half-life of cortisol is shortened, but both the number of bursts of ACTH and the resulting burst of cortisol secretion are increased and maintain serum cortisol levels (50). A subtle impairment of adrenocortical reserve has been reported in thyrotoxicosis (50). The plasma concentration of corticosteroid-binding globulin is normal. The urinary excretion of the free cortisol and 17-hydroxycorticosteroids is normal or slightly increased, whereas the urinary excretion of 17-ketosteroids may be reduced (51). The turnover rate of aldosterone is increased, but its plasma concentration is normal. Plasma renin activity is increased, and sensitivity to angiotensin II is reduced.

β-adrenergic receptor blockade ameliorates most of the cardiovascular manifestations of thyrotoxicosis. This suggests that catecholamines play a role in their genesis, but the secretion rate and plasma levels of adrenaline and noradrenaline are normal in thyrotoxic patients (52). Indeed, the apparent sympathetic hyperactivity appears to be the consequence of a direct effect of thyroid hormones on peripheral tissues. Some effects induced by thyroid hormones are also reminiscent of those of the carcinoid syndrome, but plasma serotonin levels, urinary 5-hydroxyindoleacetic acid excretion, and platelet monoamine oxidase activity are normal. Thyrotoxicosis in early life may cause delayed sexual maturation, although physical development is normal and skeletal growth may be accelerated.

Thyrotoxicosis, after puberty, influences the reproductive function (53), especially in women. An increase in libido occurs in both genders. The intermenstrual interval may be prolonged or shortened, and menstrual flow initially diminishes and ultimately ceases. Fertility may be reduced. In some women, menstrual cycles are predominantly anovulatory with oligomenorrhoea, but in most, ovulation occurs. It is unclear whether these changes are due to a direct action of thyroid hormones on the ovary and uterus, or on the pituitary and hypothalamus, or both. The effects of thyroid hormones on fertility are less well established, although the disturbances in menstrual cycles will obviously disturb fertility. With treatment, menstrual cycles return to their regular pattern. Thyrotoxicosis in prepubertal girls may result in slightly delayed menarche. In premenopausal women with thyrotoxicosis, basal plasma concentrations of luteinizing hormone and follicle-stimulating hormone are normal but may display an enhanced responsiveness to luteinizing hormone-releasing hormone (54).

An increase in libido has also been reported in men (54), An increase in sex hormone-binding globulin is a prominent feature of thyrotoxicosis and is responsible for many of the alterations in steroid metabolism (55). Because of the increase in sex hormone-binding globulin, the metabolic clearance rates of testosterone and, to some extent, of oestradiol are decreased. Testosterone levels are elevated because of the increased concentration of sex hormone-binding globulin. Free testosterone levels tend to be normal. The metabolic clearance rate of oestradiol is normal, suggesting that tissue metabolism of the hormone is increased. Conversion rates of androstenedione to testosterone, oestrone, and oestradiol, and of testosterone to dihydrotestosterone are increased. Extragonadal conversion of androgens to oestrogens is increased and this could be the mechanism responsible for gynaecomastia observed in a consistent minority of thyrotoxic men. Abnormalities in sperm motility which are reversible after restoration of euthyroidism have been described in male hyperthyroid patients (56).

One of the most prominent symptoms in the hyperthyroid patient is heat intolerance. The symptom reflects an increase in the basal metabolism of many substrates (57). The increase in metabolic activity results in increased consumption of ATP and oxygen. The consequent thermogenesis is responsible for heat intolerance. Despite the increased food intake, a state of chronic caloric inadequacy often ensues, depending on the degree of increased metabolism, and becomes more pronounced with age. In addition to losing fat stores, there is often a loss of muscle mass as well, making weakness a common complaint. Both synthesis and degradation of proteins are increased, the latter to a greater extent than the former, so that there is a net decrease in tissue protein content.

Both glucose absorption and glucose production are increased (58). The oral glucose tolerance test is often abnormal. The most common abnormality is a faster rise in plasma glucose after glucose ingestion, but some patients have a delayed peak plasma glucose or a peak value that is higher than in normal subjects (59). These abnormalities may reflect changes in glucose absorption rather than metabolism (60), since many patients who have abnormal oral glucose tolerance have normal responses to intravenous glucose administration. Pre-existing diabetes mellitus is aggravated by thyrotoxicosis, one cause being increased degradation of insulin.

Both synthesis and clearance of cholesterol and triglycerides are increased, but the latter effect predominates, so that serum levels are generally low (60). Plasma phospholipid and low-density lipoprotein (LDL) cholesterol concentrations fall, while high-density lipoprotein (HDL) cholesterol levels increase. Malnutrition and weight loss, commonly present in thyrotoxic patients, may account for part of the cholesterol-lowering action of thyroid hormones. In addition, hypermetabolism may also lower serum lipid levels. Finally, thyroid hormones may influence cholesterol metabolism by increasing its conversion to bile acid and its clearance through the membrane surface LDL receptors (61). In this regard, experimental evidence using HepG2 cells indicates that triiodothyronine increases LDL receptor promoter activity and surface LDL receptor protein (61).

Although fatty acid synthesis is increased in both adipose tissue and liver, degradation of most lipids appears to be stimulated out of proportion to synthesis; body lipid deposits consequently become depleted and plasma concentrations of various lipid components fall. Rates of fatty acid oxidation and free fatty acid release from adipose tissue are increased in both human and experimental thyrotoxicosis, and the enhanced rate of cholesterol synthesis is counterbalanced by a concomitant increase in the rate of cholesterol degradation and excretion (62).

Several studies have investigated the relationship between leptin level and thyroid status. With the exception of two reports suggesting a relative hypoleptinaemia, most clinical studies have found no effect of thyrotoxicosis on leptin levels (63).

Thyrotoxicosis can influence the metabolism of vitamin A in different ways. Vitamin A concentrations tend to be low and a minor impairment of dark adaptation has been detected in some patients. Alterations in calcium metabolism and vitamin D are also present in thyrotoxicosis. Serum parathyroid hormone levels are low and the conversion of 25-hydroxyvitamin D to 1,25-hydroxyvitamin D is diminished, resulting in lowered serum concentrations of the latter (64). Calcium balance is negative as a result of decreased intestinal absorption and increased urinary calcium loss. The serum concentration of vitamin E tends to be reduced in thyrotoxicosis. This reduction may be secondary to generalized disturbances in lipid metabolism, because serum concentrations of HDL and LDL, in which vitamin E is incorporated, are decreased (65).

Several features of thyrotoxicosis are common to other disorders and may confuse the diagnosis. The condition that most frequently simulates thyrotoxicosis is an anxiety state characterized by nervous irritability, fatigue, and insomnia. Fatigue is pronounced and differs from that in thyrotoxicosis because it is not accompanied by a desire to be active. Tachycardia is common during examination but, in contrast to thyrotoxicosis, the sleeping pulse rate is normal. Hyperreflexia is present in both disorders.

Phaeochromocytoma may closely resemble thyrotoxicosis. Tachycardia and hypermetabolism are common to both conditions. The patient may have weight loss despite a good appetite and may have hyperglycaemia with glycosuria. In the patient with phaeochromocytoma, goitre is absent and serum thyroid hormones are normal.

Myeloproliferative disorders may mimic thyrotoxicosis because patients with these diseases have increased sweating, weight loss, and tachycardia, especially if anaemia is present. Goitre is absent and the laboratory indices are normal. In diabetes mellitus, weight loss despite a good appetite, muscle wasting, and occasionally diarrhoea may suggest thyrotoxicosis.