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Clinical manifestations of hypothyroidism

Clinical manifestations of hypothyroidism
Author:
Martin I Surks, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jan 2024.
This topic last updated: Aug 29, 2022.

INTRODUCTION — Whether hypothyroidism results from hypothalamic-pituitary disease or primary thyroid disease, symptoms and signs of the disease vary in relation to the magnitude of the thyroid hormone deficiency and the acuteness with which the deficiency develops. Hypothyroidism is less prominent clinically and better tolerated when there is a gradual loss of thyroid function (as in most cases of primary hypothyroidism) than when it develops acutely after thyroidectomy or abrupt withdrawal of exogenous thyroid hormone.

The typical clinical manifestations of hypothyroidism may be modified by factors such as coexisting nonthyroidal illness. Furthermore, when hypothyroidism is caused by hypothalamic-pituitary disease, the manifestations of associated endocrine deficiencies such as hypogonadism and adrenal insufficiency may mask the manifestations of hypothyroidism. Finally, when hypothyroidism follows treatment of Graves' hyperthyroidism, some manifestations of Graves' disease, such as ophthalmopathy and vitiligo, may persist throughout the patient's life.

This topic will review the major clinical manifestations of hypothyroidism. The diagnosis and treatment of hypothyroidism, subclinical hypothyroidism, and goiter are discussed separately. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Treatment of primary hypothyroidism in adults" and "Subclinical hypothyroidism in nonpregnant adults" and "Clinical presentation and evaluation of goiter in adults".)

CLINICAL MANIFESTATIONS — Many of the manifestations of hypothyroidism reflect one of two changes induced by lack of thyroid hormone (table 1):

A generalized slowing of metabolic processes. This can lead to abnormalities such as fatigue, slow movement and slow speech, cold intolerance, constipation, weight gain (but not class III obesity), delayed relaxation of deep tendon reflexes, and bradycardia.

Accumulation of matrix glycosaminoglycans in the interstitial spaces of many tissues [1]. This can lead to coarse hair and skin, puffy facies, enlargement of the tongue, and hoarseness. These changes are often more easily recognized in young patients, and they may be attributed to aging in older patients.

Skin — The skin is cool and pale in patients with hypothyroidism because of decreased blood flow. The epidermis has an atrophied cellular layer and hyperkeratosis that results in the characteristic dry roughness of the skin [2].

The following skin changes may also occur:

Sweating is decreased because of decreases in calorigenesis and acinar gland secretion.

Skin discoloration may occur. A yellowish tinge may be present if the patient has carotenemia, while hyperpigmentation may be seen when primary hypothyroidism is associated with primary adrenal failure.

Hair may be coarse, hair loss is common, and the nails become brittle.

Nonpitting edema (myxedema) occurs in severe hypothyroidism and may be generalized. It results from infiltration of the skin with glycosaminoglycans with associated water retention [1].

Vitiligo and alopecia areata may be present in patients with hypothyroidism after treatment of Graves' hyperthyroidism.

Eyes — Periorbital edema often presents as a manifestation of generalized nonpitting edema. In addition, as previously mentioned, Graves' ophthalmopathy may persist when hypothyroidism develops after treatment of Graves' hyperthyroidism. Thus, periorbital edema may also be a manifestation of ophthalmopathy, in which case the patient may also have variable degrees of stare, protrusion of the eyes, and extraocular muscle weakness.

Hematologic — A systematic review of 36 studies reported that patients with hypothyroidism appear to be at increased risk of bleeding due to a hypothyroidism-associated hypocoagulable state [3], caused by an acquired von Willebrand's syndrome type 1 [4]. (See "Acquired von Willebrand syndrome", section on 'Hypothyroidism'.)

Anemia — Patients with hypothyroidism have a decrease in red blood cell mass and a normochromic, normocytic hypoproliferative anemia [5]. Pernicious anemia occurs in 10 percent of patients with hypothyroidism caused by chronic autoimmune thyroiditis. Such patients present with a macrocytic anemia with marrow megaloblastosis. However, occasional patients without anemia may display macrocytosis without marrow megaloblastosis [6]. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies" and "Macrocytosis/Macrocytic anemia".)

Women in the childbearing years may develop iron deficiency anemia, secondary to menorrhagia (see 'Reproductive abnormalities' below). In patients with iron deficiency anemia and hypothyroidism, combined therapy with levothyroxine and oral iron supplements results in correction of the anemia, which may be refractory to treatment with iron alone [7]. Of note, levothyroxine and iron supplements should be taken at separate times as oral iron may interfere with absorption of thyroid hormone. (See "Drug interactions with thyroid hormones", section on 'Drugs that affect gastrointestinal absorption of thyroid hormone'.)

Cardiovascular system — The systemic hypometabolism that is associated with hypothyroidism results in a decrease in cardiac output that is mediated by reductions in heart rate and contractility [8,9]. Thyroid hormone regulation of genes coding for specific myocardial enzymes involved in myocardial contractility and relaxation is responsible for the decrease in contractility [10]. The mechanism underlying the decrease in heart rate is unknown. (See "Cardiovascular effects of hypothyroidism".)

Reduced cardiac output probably contributes to decreased exercise capacity and shortness of breath during exercise, two common complaints in patients with hypothyroidism. However, symptoms and signs of congestive heart failure are usually absent in patients who have no other cardiac disease. By contrast, heart failure or angina may worsen when hypothyroidism develops in patients with heart disease. In such patients, T4 (levothyroxine) replacement should be administered cautiously, beginning with a low initial dose (eg, 25 mcg) and then increasing in small increments every one or two months. (See "Treatment of primary hypothyroidism in adults".)

Other abnormalities contributing to cardiovascular disease that may occur in hypothyroid patients are:

Pericardial effusion, which only rarely compromises ventricular function.

Hypertension, because of an increase in peripheral vascular resistance. In normotensive patients, blood pressure increases are small (eg, maximal blood pressure less than 150/100 mmHg). The blood pressure of patients with established hypertension, however, may increase further with the development of hypothyroidism.

Hypercholesterolemia, which is caused by a decrease in the rate of cholesterol metabolism [11,12]. (See 'Metabolic abnormalities' below.)

Hyperhomocysteinemia [13]. (See 'Metabolic abnormalities' below.)

Coronary artery revascularization is occasionally necessary in patients with hypothyroidism. Studies have shown that it is safe to operate without T4 replacement [14]. T4 raises myocardial and peripheral oxygen consumption, requiring increased cardiac output and cardiac work. These changes can exacerbate established coronary artery disease. (See "Treatment of primary hypothyroidism in adults".)

Respiratory system — Fatigue, shortness of breath on exertion, rhinitis, and decreased exercise capacity may result from impaired respiratory function, as well as cardiovascular disease. Hypoventilation occurs because of respiratory muscle weakness [15,16] and reduced pulmonary responses to hypoxia and hypercapnia [17]. Although respiratory muscle function is restored by T4 replacement, normalization of gas exchange may not occur, particularly in patients with obesity. (See "Respiratory function in thyroid disease" and "Control of ventilation".)

Sleep apnea occurs in some patients with hypothyroidism, mostly as a result of macroglossia. Treatment of the hypothyroidism will usually reverse the sleep apnea, but some patients require treatment with continuous positive airway pressure (CPAP) [18]. (See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome".)

The prevalence of hypothyroidism is high among patients with idiopathic pulmonary arterial hypertension, although hypothyroidism is not currently believed to be a risk factor for the condition [19,20]. The basis of the observed association of the two disorders is unclear. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

Gastrointestinal disorders — Decreased gut motility results in constipation, one of the most common complaints of patients with hypothyroidism. When euthyroid patients who already have constipation become hypothyroid, their constipation worsens [21]. In occasional patients, marked ileus may be confused with intestinal obstruction. Small intestinal bacterial overgrowth may also contribute to gastrointestinal symptoms [22].

Other gastrointestinal problems that can occur in hypothyroidism are:

Decreased taste sensation.

Gastric atrophy due to the presence of antiparietal cell antibodies. Pernicious anemia occurs in 10 percent of patients with hypothyroidism caused by chronic autoimmune thyroiditis.

Celiac disease is four times more common in hypothyroid patients compared with the general population [23].

Nonalcoholic fatty liver disease [24].

A modest weight gain due to decreased metabolic rate and accumulation of fluid (nonpitting edema) that is rich in glycosaminoglycans is a frequent finding. However, marked obesity is not characteristic of hypothyroidism.

Ascites is a rare finding.

Reproductive abnormalities — Women with hypothyroidism may have either oligo- or amenorrhea or hypermenorrhea-menorrhagia. In a study of 171 premenopausal women with hypothyroidism, 77 percent had normal cycles, 16 percent had oligo- or amenorrhea, and 7 percent had hypermenorrhea-menorrhagia; the respective frequencies in 214 normal women were 92 percent, 7 percent, and 1 percent [25]. Among the women with hypothyroidism who had abnormal cycles, the abnormalities persisted despite T4 therapy in almost half.

These menstrual changes result in decreased fertility. If pregnancy does occur, there is an increased likelihood for early abortion [26]. Hyperprolactinemia may occur and is occasionally sufficiently severe to cause amenorrhea or galactorrhea [27].

The serum sex hormone-binding globulin concentration may be low in hypothyroidism. This will lower serum total but not free sex hormone concentrations, a change that can be misleading in the evaluation of gonadal function. However, some men with hypothyroidism have low serum free testosterone concentrations but normal serum luteinizing hormone concentrations, suggesting a direct effect of hypothyroidism on the hypothalamus or pituitary [28]; their serum free testosterone concentrations rise with T4 treatment.

Decreased libido, erectile dysfunction, and delayed ejaculation are found in 64 percent of hypothyroid men [29]. In one report, sperm morphology was abnormal in 64 percent of hypothyroid men before treatment and 24 percent after T4 therapy [30].

Neurologic dysfunction — The neurologic manifestations of hypothyroidism are both common and protean, affecting both the central and peripheral nervous system. While usually occurring in the setting of other clinical manifestations of hypothyroidism, they may be the presenting feature and can cause significant disability. Most of these complications are partially or fully responsive to thyroid replacement. The more common disorders are discussed in detail separately. (See "Neurologic manifestations of hypothyroidism" and "Hypothyroid myopathy".)

Hashimoto encephalopathy — Hashimoto encephalopathy is an uncommon syndrome thought to be an autoimmune vasculitis. It is believed to be an immune-mediated disorder rather than representing the direct effect of an altered thyroid state on the central nervous system; positive thyroid peroxidase antibodies are likely a surrogate marker for autoimmunity in these patients. It is most often characterized by a subacute onset of confusion, with altered level of consciousness, seizures, and myoclonus. This topic is discussed separately. (See "Hashimoto encephalopathy".)

Myxedema coma — Myxedema coma may occur when severe hypothyroidism is complicated by trauma, infection, cold exposure, or inadvertent administration of hypnotics or opiates. The diagnosis should be suspected in comatose patients who are hypothermic, hypercapnic, and hyponatremic. (See "Myxedema coma".)

Carpal tunnel — Carpal tunnel syndrome is a common complication of hypothyroidism and is often reversible with thyroid hormone therapy. (See "Neurologic manifestations of hypothyroidism", section on 'Carpal tunnel syndrome'.)

Musculoskeletal symptoms — Muscle involvement in adults with hypothyroidism is common. Symptoms may include weakness, cramps, and myalgias. Serum creatine kinase (CK) is frequently elevated, and the degree of CK elevation does not clearly correlate with the severity of other clinical manifestations of muscle disease.

Joint pains, aches, and stiffness may also occur in patients with hypothyroidism, although they are not a common presentation. (See "Evaluation of the adult with polyarticular pain".)

An increased prevalence of hyperuricemia and gout has been reported in hypothyroid patients compared with the general population, probably secondary to decreased renal plasma flow and impaired glomerular filtration [31].

Metabolic abnormalities — A variety of metabolic abnormalities can occur in hypothyroidism:

Hyponatremia may result from a reduction in free water clearance. Hypothyroidism must be excluded in any hyponatremic patient before making the diagnosis of the syndrome of inappropriate antidiuretic hormone secretion. (See "Causes of hypotonic hyponatremia in adults", section on 'Hypothyroidism'.)

Reversible increases in serum creatinine occur in 20 to 90 percent of hypothyroid patients [32].

As previously mentioned, lipid clearance may be decreased, resulting in an elevation in the serum concentrations of free fatty acids and total and low-density lipoprotein cholesterol [11,12]. Furthermore, hypothyroidism is not an infrequent cause of hyperlipidemia in the general population. In one study of 1509 consecutive patients referred for evaluation of hyperlipidemia, 4.2 percent had hypothyroidism, approximately twice the incidence in the general population [12]. Only those patients with a serum thyroid-stimulating hormone (TSH) concentration above 10 mU/L had a significant reduction in the serum cholesterol concentration during thyroid hormone replacement. This observation suggests that minimal thyroid hormone deficiency may not adversely affect lipid metabolism, which is compatible with the inconsistent findings in patients with subclinical hypothyroidism. (See "Subclinical hypothyroidism in nonpregnant adults" and "Lipid abnormalities in thyroid disease".)

A variety of lipid abnormalities have been described in overt hypothyroidism. A report from the Mayo Clinic, for example, evaluated 295 patients with hypothyroidism [11]. Hypercholesterolemia was present in 56 percent, hypercholesterolemia and hypertriglyceridemia in 34 percent, and hypertriglyceridemia in 1.5 percent; only 8.5 percent had a normal lipid profile. (See "Lipid abnormalities in thyroid disease".)

Plasma homocysteine concentrations are increased in some hypothyroid patients, including some with recent-onset hypothyroidism, and return to normal after treatment with T4 [13].

Drug clearance — The clearance of many drugs, including antiseizure, anticoagulant, hypnotic, and opioid drugs, is decreased in hypothyroidism. Thus, drug toxicity may occur if drug dose is not reduced. In addition, drugs that are administered at effective doses in patients who are hypothyroid may become less effective during T4 replacement.

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: Hypothyroidism".)

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 5th to 6th 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 10th to 12th 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: Hypothyroidism (underactive thyroid) (The Basics)")

Beyond the Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (Beyond the Basics)")

SUMMARY

Clinical manifestations – Whether hypothyroidism results from hypothalamic-pituitary disease or primary thyroid disease, the symptoms and signs of hypothyroidism vary in relation to the magnitude of the thyroid hormone deficiency and the acuteness with which the deficiency develops.

Many of the manifestations of hypothyroidism reflect one of two changes induced by lack of thyroid hormone: a generalized slowing of metabolic processes and accumulation of matrix glycosaminoglycans in the interstitial spaces of many tissues (table 1). Other symptoms and signs include depression, decreased hearing, diastolic hypertension, and pleural and pericardial effusions. (See 'Clinical manifestations' above.)

The clinical manifestations of central hypothyroidism are similar to those of primary hypothyroidism. When hypothyroidism is caused by hypothalamic-pituitary disease, the manifestations of associated endocrine deficiencies such as hypogonadism and adrenal insufficiency may mask the manifestations of hypothyroidism. (See "Central hypothyroidism" and "Diagnostic testing for hypopituitarism".)

Metabolic abnormalities – A variety of metabolic abnormalities can occur in hypothyroidism, including hyponatremia, hyperlipidemia, anemia, and high serum muscle enzyme concentrations. (See 'Metabolic abnormalities' above and 'Musculoskeletal symptoms' above.)

Drug clearance – The clearance of many drugs, including antiseizure, anticoagulant, hypnotic, and opioid drugs, is decreased in hypothyroidism. (See 'Drug clearance' above.)

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