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Clinical manifestations of hypothyroidism

Author: Martin I Surks, MD
Section Editor: Douglas S Ross, MD
Deputy Editor: Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2023. | 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
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Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These
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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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REFERENCES

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3. Squizzato A, Romualdi E, Büller HR, Gerdes VE. Clinical review: Thyroid dysfunction and effects on
coagulation and fibrinolysis: a systematic review. J Clin Endocrinol Metab 2007; 92:2415.

4. Manfredi E, van Zaane B, Gerdes VE, et al. Hypothyroidism and acquired von Willebrand's
syndrome: a systematic review. Haemophilia 2008; 14:423.
5. Green ST, Ng JP. Hypothyroidism and anaemia. Biomed Pharmacother 1986; 40:326.

6. Colon-Otero G, Menke D, Hook CC. A practical approach to the differential diagnosis and
evaluation of the adult patient with macrocytic anemia. Med Clin North Am 1992; 76:581.

7. Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-

deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin
Endocrinol Metab 2009; 94:151.

8. Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992; 327:94.
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10. Dillmann WH. Biochemical basis of thyroid hormone action in the heart. Am J Med 1990; 88:626.

11. O'Brien T, Dinneen SF, O'Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and
secondary hypothyroidism. Mayo Clin Proc 1993; 68:860.
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in a large cohort of patients referred for dyslipidemia. Arch Intern Med 1995; 155:1490.

13. Hussein WI, Green R, Jacobsen DW, Faiman C. Normalization of hyperhomocysteinemia with L-
thyroxine in hypothyroidism. Ann Intern Med 1999; 131:348.

14. Becker C. Hypothyroidism and atherosclerotic heart disease: pathogenesis, medical management,
and the role of coronary artery bypass surgery. Endocr Rev 1985; 6:432.

15. Laroche CM, Cairns T, Moxham J, Green M. Hypothyroidism presenting with respiratory muscle
weakness. Am Rev Respir Dis 1988; 138:472.
 16. Siafakas NM, Salesiotou V, Filaditaki V, et al. Respiratory muscle strength in hypothyroidism. Chest
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17. Ladenson PW, Goldenheim PD, Ridgway EC. Prediction and reversal of blunted ventilatory
responsiveness in patients with hypothyroidism. Am J Med 1988; 84:877.

18. Rosenow F, McCarthy V, Caruso AC. Sleep apnoea in endocrine diseases. J Sleep Res 1998; 7:3.

19. Curnock AL, Dweik RA, Higgins BH, et al. High prevalence of hypothyroidism in patients with
primary pulmonary hypertension. Am J Med Sci 1999; 318:289.

20. Peacock AJ. Primary pulmonary hypertension. Thorax 1999; 54:1107.

21. Shafer RB, Prentiss RA, Bond JH. Gastrointestinal transit in thyroid disease. Gastroenterology 1984;
86:852.

22. Lauritano EC, Bilotta AL, Gabrielli M, et al. Association between hypothyroidism and small
intestinal bacterial overgrowth. J Clin Endocrinol Metab 2007; 92:4180.
23. Elfström P, Montgomery SM, Kämpe O, et al. Risk of thyroid disease in individuals with celiac
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24. Mantovani A, Nascimbeni F, Lonardo A, et al. Association Between Primary Hypothyroidism and
Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Thyroid 2018; 28:1270.

25. Krassas GE, Pontikides N, Kaltsas T, et al. Disturbances of menstruation in hypothyroidism. Clin
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26. Burrow G. Thyroid diseases. In: Medical complications during pregnancy, 2nd, Burrow GN, Ferris T
F (Eds), WB Saunders, Philadelphia 1982. p.187.

27. Honbo KS, van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism.
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28. Donnelly P, White C. Testicular dysfunction in men with primary hypothyroidism; reversal of
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29. Carani C, Isidori AM, Granata A, et al. Multicenter study on the prevalence of sexual symptoms in
male hypo- and hyperthyroid patients. J Clin Endocrinol Metab 2005; 90:6472.

30. Krassas GE, Papadopoulou F, Tziomalos K, et al. Hypothyroidism has an adverse effect on human
spermatogenesis: a prospective, controlled study. Thyroid 2008; 18:1255.

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Topic 7846 Version 19.0
GRAPHICS

Major symptoms and signs of hypothyroidism

Mechanism Symptoms Signs

Slowing of metabolic processes Fatigue and weakness Slow movement and slow speech

Cold intolerance Delayed relaxation of tendon

reflexes
Dyspnea on exertion
Bradycardia
Weight gain
Carotenemia
Cognitive dysfunction

Intellectual disability (infantile

onset)

Constipation

Growth failure

Accumulation of matrix Dry skin Coarse skin

substances
Hoarseness Puffy facies and loss of eyebrows

Edema Periorbital edema

Enlargement of the tongue

Other Decreased hearing Diastolic hypertension

Myalgia and paresthesia Pleural and pericardial effusions

Depression Ascites

Menorrhagia Galactorrhea

Arthralgia

Pubertal delay

Graphic 62676 Version 5.0

Contributor Disclosures
Martin I Surks, MD No relevant financial relationship(s) with ineligible companies to disclose. Douglas S Ross,
MD Consultant/Advisory Boards: Arbor Pharmaceuticals [Hypothyroidism];IBSA Pharma Inc
[Hypothyroidism];Medullary Thyroid Cancer Registry Consortium [Thyroid cancer];Spectrix Therapeutics, LLC
[Hypothyroidism]. All of the relevant financial relationships listed have been mitigated. Jean E Mulder, MD No
relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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