Overview of the clinical manifestations of hyperthyroidism in adults

INTRODUCTION — The clinical manifestations of hyperthyroidism are largely independent of its cause. However, the disorder that causes hyperthyroidism may have other effects. In particular, Graves' disease, the most common cause of hyperthyroidism, causes unique problems that are not related to the high serum thyroid hormone concentrations. These include Graves' orbitopathy and infiltrative dermopathy (localized or pretibial myxedema). Most patients with Graves' hyperthyroidism have a diffuse goiter, but so do patients with other, less common causes of hyperthyroidism such as painless thyroiditis and thyroid-stimulating hormone (TSH)-secreting pituitary tumors.

The major clinical manifestations of hyperthyroidism (thyrotoxicosis) and its effects on specific organ systems will be reviewed here. More detailed discussions of its causes, as well as the diagnostic approach to patients with hyperthyroidism, are discussed separately. (See "Disorders that cause hyperthyroidism" and "Diagnosis of hyperthyroidism".)

CLASSIC SYMPTOMS — Most patients with overt hyperthyroidism have a dramatic constellation of symptoms. The classic symptoms of hyperthyroidism include heat intolerance, tremor, palpitations, anxiety, weight loss despite a normal or increased appetite, increased frequency of bowel movements, and shortness of breath. Goiter is commonly found on physical examination. Patients with mild hyperthyroidism and older patients often have symptoms that are referable to one or only a few organ systems. (See "Diagnosis of hyperthyroidism", section on 'Symptoms'.)

SPECIFIC ORGAN SYSTEMS

Skin — The skin is warm (and may rarely be erythematous) in hyperthyroidism due to increased blood flow; it is also smooth because of a decrease in the keratin layer [1]. Other changes include:

●Sweating, which increases due to increased calorigenesis; this is often associated with heat intolerance

●Onycholysis (loosening of the nails from the nail bed, Plummer's nails) and softening of the nails

●Hyperpigmentation, which can occur in severe cases; it appears to be mediated by accelerated cortisol metabolism, leading to increased corticotropin (ACTH) secretion [2]

●Pruritus and hives, which are occasional findings, primarily in patients with Graves' hyperthyroidism [3]

●Vitiligo and alopecia areata, which can occur in association with autoimmune disorders

●Thinning of the hair

Infiltrative dermopathy occurs only in patients with Graves' hyperthyroidism. The most common site is the skin overlying the shins, where it presents as raised, hyperpigmented, violaceous, orange-peel-textured papules. (See "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)

Eyes — Stare and lid lag occur in all patients with hyperthyroidism. They are due to sympathetic overactivity, possibly mediated by increased alpha-adrenergic receptors in some tissues [4]. Lid lag is evaluated by having the patient follow the examiner's finger as it is moved up and down. The patient has lid lag if sclera can be seen above the iris as the patient looks downward.

As noted above, only patients with Graves' disease have orbitopathy. It is characterized by inflammation of the extraocular muscles and orbital fat and connective tissue, which results in proptosis (exophthalmos), impairment of eye muscle function, and periorbital and conjunctival edema. Risk factors for developing Graves' orbitopathy include cigarette smoking, advancing age, and male sex [5]. (See "Clinical features and diagnosis of thyroid eye disease".)

Patients with orbitopathy may have gritty feeling or pain in their eyes, and they may have diplopia due to extraocular muscle dysfunction. Corneal ulceration can occur as a result of proptosis and lid retraction, and severe proptosis can cause optic neuropathy and even blindness.

Cardiovascular — Patients with hyperthyroidism have an increase in cardiac output, due both to increased peripheral oxygen needs and increased cardiac contractility. Heart rate is increased, pulse pressure is widened, and peripheral vascular resistance is decreased [6]. Systolic hypertension is common [7]. The left ventricular ejection fraction does not increase appropriately during exercise, suggesting the presence of a true cardiomyopathy [8]. High- or normal-output congestive heart failure can occur in patients with severe hyperthyroidism, and congestive heart failure worsens in patients who already have it. (See "Cardiovascular effects of hyperthyroidism".)

Atrial fibrillation occurs in 10 to 20 percent of patients with hyperthyroidism, and it is more common in older patients. In one study, 8 percent of all patients and 15 percent of patients between ages 70 to 79 developed atrial fibrillation within 30 days of the diagnosis of hyperthyroidism [9]. Even subclinical hyperthyroidism is associated with an increased rate of atrial ectopy and a threefold increased risk of atrial fibrillation (figure 1) [10].

In 60 percent of hyperthyroid patients with atrial fibrillation, the rhythm converts spontaneously to sinus rhythm when the hyperthyroidism is treated; in one study, all who spontaneously converted did so within four months after becoming euthyroid [11]. Among those who do not convert spontaneously to sinus rhythm and who undergo successful electrical cardioversion, the two-year risk of recurrent atrial fibrillation was 59 percent compared with 83 percent of patients whose atrial fibrillation was not associated with hyperthyroidism [12].

Anticoagulation should be considered in hyperthyroid patients with atrial fibrillation. In several studies, 10 to 40 percent of patients with hyperthyroidism and atrial fibrillation had an arterial embolus [13]. Left atrial enlargement, which is a risk factor for thrombus formation, is present in approximately 90 percent of hyperthyroid patients with atrial fibrillation and 2 percent of hyperthyroid patients with sinus rhythm. Based on these results, we usually anticoagulate hyperthyroid patients with atrial fibrillation. The role of anticoagulant therapy in patients with hyperthyroidism and atrial fibrillation is reviewed in detail separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)

Other abnormalities, including mitral valve prolapse, mitral regurgitation, and an increase in left ventricular mass index have also been reported. (See "Cardiovascular effects of hyperthyroidism".)

Metabolic/Endocrine

Bone — Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone [14]. The loss in cortical bone density is greater than that of trabecular bone. Serum alkaline phosphatase and osteocalcin concentrations are high, indicative of increased bone turnover. The increase in bone resorption may lead to an increase in serum calcium concentrations, thereby inhibiting parathyroid hormone secretion and the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol (1,25-dihydroxyvitamin D). In addition, the metabolic clearance rate of calcitriol is increased. These changes can result in impaired calcium absorption and an increase in urinary calcium excretion. The net effect is osteoporosis and an increased fracture risk in patients with chronic hyperthyroidism [15]. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)

Graves' disease may also be associated with thyroid acropachy, with clubbing and periosteal new bone formation in the metacarpal bones or phalanges. Patients with thyroid acropachy commonly present with asymptomatic clubbing, severe ophthalmopathy, and dermopathy; a high percentage are cigarette smokers [16].

Serum lipids — Patients with hyperthyroidism tend to have low serum total and high-density lipoprotein (HDL) cholesterol concentrations and a low total cholesterol/HDL cholesterol ratio. These values increase after treatment [17].

Hyperglycemia — Although thyroxine (T4) is not a counterregulatory hormone, hyperthyroidism can interfere with glucose metabolism. It is associated with both increased sensitivity of pancreatic beta cells to glucose, resulting in increased insulin secretion, and antagonism to the peripheral action of insulin [18]. The latter effect usually predominates, leading to impaired glucose tolerance in untreated patients [19].

Adrenal function — Interpretation of the cortisol response to corticotropin (ACTH) stimulation testing may be misleading in patients with hyperthyroidism because corticosteroid-binding globulin (CBG) levels decrease, resulting in lower total serum cortisol concentrations. In one report of 49 hyperthyroid patients undergoing ACTH testing, 35 percent had subnormal total serum cortisol values (<18 mcg/dL), while only 11 percent had a subnormal free cortisol index (ratio of serum total cortisol to CBG) [20].

Respiratory — Dyspnea and dyspnea on exertion may occur for many reasons in hyperthyroidism (see "Respiratory function in thyroid disease"):

●Oxygen consumption and carbon dioxide production increase. These changes result in hypoxemia and hypercapnia, respectively, both of which stimulate ventilation.

●Respiratory muscle weakness is an important cause of dyspnea [21], and reduced exercise capacity may be largely due to respiratory muscle weakness and decreased lung volume [22].

●There may be tracheal obstruction from a large goiter.

●Hyperthyroidism may exacerbate underlying asthma.

●Pulmonary arterial systolic pressure is increased [23].

Gastrointestinal — Weight loss is due primarily to increased metabolic rate (hypermetabolism) and secondarily to increased gut motility and the associated hyperdefecation and malabsorption; rare patients have steatorrhea. Celiac disease is also more prevalent in patients with Graves' disease [24]. Most patients have hyperphagia, but an occasional patient with mild hyperthyroidism may have sufficient appetite stimulation that weight is gained (more commonly in younger patients) [25]. Anorexia may be prominent in older hyperthyroid patients [26].

Other changes that may occur include:

●Vomiting [27] and abdominal pain, rarely.

●Dysphagia due to goiter.

●Abnormalities in liver function tests, particularly high serum alkaline phosphatase concentrations and, rarely, cholestasis. In a meta-analysis, alanine transaminase (ALT) and aspartate transaminase (AST) were elevated in 33 and 23 percent of patients presenting with hyperthyroidism, respectively, while alkaline phosphatase was elevated in 44 percent of patients [28].

Thymic enlargement — In patients with Graves' disease, thymic enlargement due to hyperplasia has been reported [29-31]. Thymic enlargement is usually discovered incidentally during the evaluation of other symptoms, such as dyspnea. The pathogenetic mechanism is unclear, but it is not a feature of hyperthyroidism due to causes other than Graves' disease. Potential mechanisms include autoimmune mediated (thyroid-stimulating immunoglobulins from patients with Graves' disease bind to the thyroid-stimulating hormone [TSH] receptor in the human thymus and cause thymocyte proliferation) and hyperthyroidism mediated (hyperthyroidism-induced angiogenesis) [29,32]. Causes of thymic enlargement other than Graves' disease should be considered. (See "Approach to the adult patient with a mediastinal mass".)

In most patients, treatment of Graves' disease with antithyroid medications, radioiodine, or thyroidectomy results in involution of thymic hyperplasia over 4 to 25 months [31]. However, coexisting malignancies have been reported, and therefore, repeat imaging three to four months after initiation of therapy is warranted to ensure regression.

Hematologic — The red blood cell mass is increased in hyperthyroidism, but the plasma volume is increased more, resulting in a normochromic, normocytic anemia [33]. Serum ferritin concentrations may be high.

Graves' hyperthyroidism may be associated with autoimmune hematologic disorders such as immune thrombocytopenia (ITP) and pernicious anemia, and some patients have antineutrophil antibodies. In a meta-analysis, 10 percent of patients presenting with Graves' hyperthyroidism had neutropenia [34].

Hyperthyroidism may also be prothrombotic [35,36]. As an example, in a meta-analysis of 51 studies evaluating the effect of thyroid hormone excess (exogenous or endogenous) on the coagulation system, excess thyroid hormone was associated with a rise in prothrombotic factors, including factors VIII, IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1 [36]. Similar findings were noted in patients with either overt or subclinical hyperthyroidism.

Genitourinary — Urinary frequency and nocturia are common in hyperthyroidism, although the mechanism is uncertain. Possible causes include primary polydipsia [37] and hypercalciuria. Enuresis is common in children.

In women, serum sex hormone-binding globulin (SHBG) concentrations are high, which results in high serum estradiol concentrations and low-normal serum free (unbound) estradiol concentrations, high serum luteinizing hormone (LH) concentrations, a reduced mid-cycle surge in LH secretion, oligomenorrhea, and anovulatory infertility [38,39]. Amenorrhea can occur in women with severe hyperthyroidism.

In men, the increase in serum SHBG concentrations results in high serum total testosterone concentrations, but serum free (unbound) testosterone concentrations are normal or low [40,41]. Serum LH concentrations may be slightly high. Extragonadal conversion of testosterone to estradiol is increased, so that serum estradiol concentrations are high. These changes can cause gynecomastia, reduced libido, and erectile dysfunction [38,42]. Spermatogenesis is often decreased or abnormal, eg, more spermatozoa are abnormal or nonmotile [41].

Neuropsychiatric — Patients with thyrotoxicosis may experience behavioral and personality changes, such as psychosis, agitation, and depression. Less overt manifestations that are more common in less severe thyrotoxicosis include anxiety, restlessness, irritability, and emotional lability [43]. Insomnia is also common. Symptoms often worsen in patients with preexisting psychiatric disorders.

These behavioral manifestations are accompanied by cognitive impairments, particularly impaired concentration, confusion, poor orientation and immediate recall, amnesia, and constructional difficulties. Other neurologic manifestations are discussed separately. (See "Neurologic manifestations of hyperthyroidism and Graves' disease".)

THYROTOXIC PERIODIC PARALYSIS — A rare presentation of thyrotoxicosis from any cause is periodic paralysis, marked muscle weakness associated with hypokalemia, frequently precipitated by exercise, fasting, or a high carbohydrate meal, and seen most frequently in East Asian males. (See "Thyrotoxic periodic paralysis".)

GERIATRIC HYPERTHYROIDISM — Hyperthyroidism in older patients may be apathetic, rather than having hyperactivity, tremor, and other symptoms of sympathetic overactivity [44]. However, two-thirds of such patients have symptoms similar to those in younger patients [45]. In cross-sectional studies of patients with hyperthyroidism, older patients had a reduced risk for the presence of several classical symptoms (ie, heat intolerance, tremor, nervousness) but a higher prevalence of weight loss and shortness of breath compared with younger patients [45,46]. Older patients also had a higher rate of atrial fibrillation and moderate to severe ophthalmopathy [46].

Older patients with Graves' hyperthyroidism are less likely to have a goiter. Toxic multinodular goiter is more common in older patients, although the majority of hyperthyroid patients at any age have Graves' hyperthyroidism. In addition, older patients often have persistent constipation. Tachycardia of 100 beats per minute is absent in 40 percent of older hyperthyroid patients, due primarily to coexistent conduction system disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)")

●Beyond the Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")

SUMMARY

●Classic symptoms – The classic symptoms of hyperthyroidism include weight loss, heat intolerance, tremor, palpitations, anxiety, increased frequency of bowel movements, and shortness of breath. Goiter is commonly found on physical examination. (See 'Classic symptoms' above.)

●Mild hyperthyroidism – Patients with mild hyperthyroidism and older patients often have symptoms that are referable to one or only a few organ systems. (See 'Specific organ systems' above.)

●Symptoms in older patients – Older patients may have fewer classical manifestations of hyperthyroidism. However, weight loss, shortness of breath, and atrial fibrillation occur more commonly in older than younger patients. (See 'Geriatric hyperthyroidism' above.)

●Findings unique to Graves' disease – Although the clinical manifestations of hyperthyroidism are largely independent of its cause, Graves' disease causes unique problems that are not related to the high serum thyroid hormone concentrations. These include Graves' orbitopathy and infiltrative dermopathy (localized or pretibial myxedema). (See "Clinical features and diagnosis of thyroid eye disease" and "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)