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Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. It usually is a primary process in which the thyroid gland produces insufficient amounts of thyroid hormone. It can also be secondary, that is lack of thyroid hormone secretion due to the failure of either adequate thyrotropin (ie, thyroid-stimulating hormone [TSH]) secretion from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus (secondary or tertiary hypothyroidism). The patient's presentation may vary from asymptomatic to, rarely, coma with multisystem organ failure (myxedema coma). The most common cause in the Unites States is autoimmune thyroid disease (Hashimoto thyroiditis).
Cretinism refers to congenital hypothyroidism, which affects 1 per 4000 newborns.
Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum free T4 levels with slightly high serum TSH concentration.


Localized disease of the thyroid gland that results in decreased thyroid hormone production is the most common cause of hypothyroidism. Under normal circumstances, the thyroid releases 100-125 nmol of thyroxine (T4) daily and only small amounts of triiodothyronine (T3). The half-life of T4 is approximately 7-10 days. T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5’-deiodination. Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and thyroid T4-5'-deiodinase activity. This, in turn, causes the thyroid to release more T3.

Because all metabolically active cells require thyroid hormone, the effects of hormone deficiency vary. Systemic effects are either due to derangements in metabolic processes or direct effects by myxedematous infiltration, that is accumulation of glucosaminoglycans in the tissues. 
The myxedematous changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. In the GI tract, achlorhydria and decreased intestinal transit with gastric stasis can occur. Delayed puberty, anovulation, menstrual irregularities, and infertility are common. Decreased thyroid hormone effect can cause increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and a possible change in high-density lipoprotein (HDL) cholesterol due to a change in  metabolic clearance. In addition, hypothyroidism may result in an increase in insulin resistance.


United States

The Third National Health and Nutrition Examination Survey (NHANES III) of 17,353 individuals reflecting the US population reported hypothyroidism (defined as elevated TSH levels) in 4.6% of the population (0.3% overt and 4.3% subclinical).1 It is more common in women with small body size at birth and low body mass index during childhood.2


Iodine deficiency as a cause of hypothyroidism is more common internationally. The prevalence is reported as 2-5% depending on the study, increasing to 15% by age 75 years.


In developed countries, death caused by hypothyroidism is uncommon.


NHANES III reported that the prevalence of hypothyroidism (including subclinical) was higher in whites (5.1%) than in people of Hispanic descent (4.1%) or African Americans (1.7%). African Americans tend to have lower TSH values.1


Community studies use slightly different criteria for determining hypothyroidism; therefore, female-to-male ratios vary. Generally, thyroid disease is much more common in females than in males, with reports of prevalence 2-8 times higher in females.


The frequency of hypothyroidism, goiters, and thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2% to as much as 20% of older age groups having some form of hypothyroidism. In the Framingham study, thyroid function was assessed in adults older than 60 years. The study found hypothyroidism (TSH >10 mIU/L) in 5.9% of women and 2.4% of men.



Hypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs of this disease are often subtle and neither sensitive nor specific. Classic signs and symptoms such as cold intolerance, puffiness, decreased sweating, and coarse skin previously reported in 90-97% of patients may actually occur in only 50-64% of younger patients. Many of the more common symptoms are nonspecific and difficult to attribute to a specific cause. Individuals can also present with obstructive sleep apnea (secondary to macroglossia) or carpal tunnel syndrome. Women can present with galactorrhea and menstrual disturbances. Consequently, the diagnosis of hypothyroidism is based on clinical suspicion and confirmed by laboratory testing.
 Myxedema coma is a severe form of hypothyroidism that results in an altered mental status, hypothermia, bradycardia, hypercarbia, and hyponatremia. Cardiomegaly, pericardial effusion, cardiogenic shock, and ascites may be present. Myxedema coma most commonly occurs in individuals with undiagnosed or untreated hypothyroidism that are subjected to an external stress such as cold exposure, surgery, infection, hypnotics, or other medical interventions.
 The following are symptoms of hypothyroidism:   

  • Fatigue, loss of energy, lethargy
  • Weight gain
  • Decreased appetite
  • Cold intolerance
  • Dry skin
  • Hair loss
  • Sleepiness 
  • Muscle pain, joint pain, weakness in the extremities
  • Depression
  • Emotional lability, mental impairment
  • Forgetfulness, impaired memory, inability to concentrate
  • Constipation
  • Menstrual disturbances, impaired fertility
  • Decreased perspiration
  • Paresthesia and nerve entrapment syndromes
  • Blurred vision
  • Decreased hearing
  • Fullness in the throat, hoarseness
The following are symptoms more specific to Hashimoto thyroiditis:

  • Feeling of fullness in the throat
  • Painless thyroid enlargement
  • Exhaustion
  • Neck pain, sore throat, or both
  • Low-grade fever



Signs found in hypothyroidism are usually subtle and require a careful physical examination. Often, many signs are dismissed as part of aging; however, consider a diagnosis of hypothyroidism when such signs are present.
Physical signs of hypothyroidism include the following:

  • Hypothermia
  • Weight gain
  • Slowed speech and movements
  • Dry skin
  • Jaundice
  • Pallor
  • Coarse, brittle, strawlike hair
  • Loss of scalp hair, axillary hair, pubic hair, or a combination
  • Dull facial expression
  • Coarse facial features
  • Periorbital puffiness
  • Macroglossia,
  • Goiter
  • Hoarseness
  • Decreased systolic blood pressure and increased diastolic blood pressure
  • Bradycardia
  • Pericardial effusion
  • Abdominal distension, ascites is uncommon.
  • Nonpitting edema (myxedema)
  • Pitting edema of lower extremities
  • Hyporeflexia with delayed relaxation, ataxia, or both
Additional signs specific to different causes of hypothyroidism, such as diffuse or nodular goiter or pituitary tumor, can occur.
Metabolic abnormalities associated with hypothyroidism include anemia, dilutional hyponatremia, hyperlipidemia, and reversible increase in creatinine.3




Worldwide, iodine deficiency remains the foremost cause of hypothyroidism. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease is most common. The prevalence of antibodies is higher in women, and increases with age.

Primary hypothyroidism 

  • Autoimmune: The most frequent cause of acquired hypothyroidism is autoimmune thyroiditis (Hashimoto thyroiditis). The body recognizes the thyroid antigens as foreign, and a chronic immune reaction ensues, resulting in lymphocytic infiltration of the gland and progressive destruction of functional thyroid tissue. Up to 95% of affected individuals have circulating antibodies to thyroid tissue. Antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies are found more commonly than antithyroglobulin antibodies (95% vs 60%). These antibodies may not be present early in the disease process and usually disappear over time.  
  • Postpartum thyroiditis: Up to 10% of postpartum women may develop lymphocytic thyroiditis in the 2-10 months after delivery. The frequency may be as high as 25% in women with type 1 diabetes mellitus. The condition is usually transient (2-4 mo) and can require a short course of treatment with levothyroxine (LT4), but postpartum patients with lymphocytic thyroiditis are at increased risk of permanent hypothyroidism. The hypothyroid state can be preceded by a short thyrotoxic state. High titers of anti-TPO antibodies during pregnancy have been reported to be 97% sensitive and 91% specific for postpartum autoimmune thyroid disease.
  • Subacute granulomatous thyroiditis: Inflammatory conditions or viral syndromes may be associated with transient hyperthyroidism followed by transient hypothyroidism (de Quervain or painful thyroiditis, subacute thyroiditis). These are often associated with fever, malaise, and a painful and tender gland.  
  • Drugs: Medicationssuch as amiodarone, interferon alpha, thalidomide, lithium, and stavudine have also been associated with primary hypothyroidism.
  • Iatrogenic
    • Use of radioactive iodine for treatment of Graves disease generally results in permanent hypothyroidism within one year of therapy. The frequency is much lower in patients with toxic nodular goiters and those with autonomously functioning thyroid nodules. Patients treated with radioiodine should be monitored for clinical and biochemical evidence of hypothyroidism.
    • Thyroidectomy
    • External neck irradiation (for head and neck neoplasms, breast cancer, or Hodgkin disease) may result in hypothyroidism and require monitoring. 
  • Rare: Rare causes include inborn errors of thyroid hormone synthesis.
  • Iodine deficiency or excess: Worldwide Iodine deficiency is the most common cause of hypothyroidism. Excess iodine, as in radiocontrast dyes, amiodarone, health tonics, and seaweed, inhibits iodide organification and thyroid hormone synthesis. Most healthy individuals have a physiologic escape from this effect; however those with abnormal thyroid glands may not. These include patients with autoimmune thyroiditis, surgically treated Graves hyperthyroidism (subtotal thyroidectomy) and prior radioiodine therapy.4

Central hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. Various causes should be considered.

  • Pituitary adenoma
  • Tumors impinging on the hypothalamus
  • History of brain irradiation
  •  Drugs (eg, dopamine, lithium)
  • Differential Diagnoses

    Addison Disease
    Infectious Mononucleosis
    Apnea, Sleep
    Infertility, Male
    Autoimmune Thyroid Disease and Pregnancy
    Iodine Deficiency
    Cardiac Tamponade
    Lithium Nephropathy
    Chronic Fatigue Syndrome
    Lymphomas, Endocrine, Mesenchymal, and Other Rare Tumors of the Mediastinum
    Megacolon, Chronic
    De Quervain Thyroiditis
    Myxedema Coma or Crisis
    Ovarian Insufficiency
    Pericardial Effusion
    Eosinophilia-Myalgia Syndrome
    Pituitary Macroadenomas
    Erectile Dysfunction
    Polyglandular Autoimmune Syndrome, Type I
    Euthyroid Sick Syndrome
    Polyglandular Autoimmune Syndrome, Type II
    Polyglandular Autoimmune Syndrome, Type III
    Prolactin Deficiency
    Goiter, Lithium-Induced
    Riedel Thyroiditis
    Goiter, Nontoxic
    Sleep Disorder, Geriatric
    Hypercholesterolemia, Familial
    Sleep Disorders
    Hypercholesterolemia, Polygenic
    Syndrome of Inappropriate Secretion of Antidiuretic Hormone
    Thyroid Lymphoma
    Thyroiditis, Subacute
    Hypopituitarism (Panhypopituitarism)
    Thyroxine-Binding Globulin Deficiency

    Other Problems to Be Considered

    The list of differential diagnoses for hypothyroidism is long because the most frequent presenting symptoms are nonspecific.


    Laboratory Studies

    Third-generation TSH assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism. 
    Generally accepted normal reference range for serum TSH is 0.40-4.2 mIU/L. Data from the NHANES III database reveals that, of the 17,353 people evaluated, 80.8% had a serum TSH below 2.5 mIU/L.1 
    TSH levels peak in the evening and are lowest in the afternoon, with marked variations due to physiologic conditions such as illness, psychiatric disorders, and low energy intake.
    If TSH levels are above the reference range, the next step would be to measure total T4 with a measure of binding proteins. Thyroxine is highly protein bound (99.97%) with approximately 85% bound to thyroid-binding globulin (TBG), approximately 10% bound to transthyretin or thyroid-binding prealbumin, and the remainder bound loosely to albumin.

    The levels of these binding proteins could vary by hormonal status, inheritance, and in various disease states. Hence, free T4 assays are becoming popular as they measure unbound (ie, free hormone). However, free T4 assays can be unreliable in the setting of severe illness. No currently available kit actually measures unbound T4 directly. A free thyroxine index (FTI) serves as a surrogate of the free hormone level. Free thyroid hormone levels can be estimated by calculating the percentage of available thyroid hormone-binding sites (T3 resin uptake) or by measuring the concentration of thyroxine-binding globulin (TBG). The FTI is the product of the T3 resin uptake and total T4 levels. 
    Patients with primary hypothyroidism have elevated TSH levels and decreased free hormone levels. Patients with elevated TSH levels but normal free hormone levels or estimates are considered to have mild or subclinical hypothyroidism.
    Primary hypothyroidism is virtually the only disease that is characterized by sustained, rising TSH levels. As the TSH level increases early in the disease, an increased conversion of T4 to T3 occur, this maintains T3 levels. In early hypothyroidism, TSH levels are increased, T4 levels are normal to low, and T3 levels are normal.
    Evaluation of the presence of thyroid autoantibodies (antimicrosomal or anti-TPO antibodies) and antithyroglobulin (anti-Tg) may be helpful in determining the etiology of hypothyroidism or in predicting future hypothyroidism. Anti-TPO antibodies have been associated with a higher risk of infertility and miscarriage.
    In patients with nonthyroid disease who are severely ill, TSH secretion is normal or decreased, total T4 levels are decreased, and total T3 levels are markedly decreased. This can be confused with secondary hypothyroidism. In these patients, the primary abnormality is the decreased peripheral production of T3 from T4. They have an increased reverse T3, which can be measured. Other abnormalities seen in patients who are critically ill include decreased TBG levels and abnormalities in the hypothalamic-pituitary axis. During recovery, some patients have transient elevations in serum TSH concentrations (up to 20 mIU/L). Hence, thyroid function should not be evaluated in a critically ill person unless thyroid dysfunction is strongly suspected, and, if so, screening with TSH alone is insufficient.
    In patients with hypothalamic or pituitary dysfunction, TSH levels do not increase in appropriate relation to the low free T4 levels. The absolute levels may be in the normal or even slightly elevated range but inappropriately low for the severity of the hypothyroid state. Hence, when secondary or tertiary hypothyroidism is suspected, a serum TSH measurement alone is inadequate; a free T4 should be measured.

    The TRH stimulation test is rarely needed now because of improved TSH assays.

    Imaging Studies

    Ultrasound of the neck and thyroid can be used to detect nodules and infiltrative disease. It has little use in hypothyroidism per se unless a secondary anatomic lesion in the gland is of clinical concern. Hashimoto thyroiditis is usually associated with a heterogeneous image by ultrasound. It can be rarely associated with lymphoma of the thyroid. Serial images with fine-needle aspiration of suspicious nodules may be useful. 
    Radioactive iodine uptake (RAIU) and thyroid scanning are not useful in hypothyroidism because these tests require some level of endogenous function in the hypofunctioning gland to provide information. Patients with Hashimoto thyroiditis may have relatively high early uptake (after 4 h) but do not have the usual doubling of uptake at 24 hours consistent with an organification defect.


    Fine-needle aspiration biopsy
    Thyroid nodules are often found incidentally during physical examination, chest radiograph, CT scan, or MRI. Thyroid nodules can be found in patients who are hypothyroid, euthyroid, or hyperthyroid. Fine-needle aspiration (FNA) biopsy is the procedure of choice to evaluate suspicious nodules.
    About 5-6% of solitary nodules are malignant. Suspicious nodules are those that are larger than 1 cm in diameter or those with suspicious features found on a sonogram (eg, irregular margins, intranodular vascular spots, microcalcifications).
    Risk factors for thyroid nodules include age greater than 60 years, history of head or neck irradiation, or family history of thyroid cancer.

    Histologic Findings

    Autoimmune thyroiditis causes a decrease in intrathyroidal iodine stores, an increased iodine turnover, and defective organification. Chronic inflammation of the gland causes progressive destruction of the functional tissue with widespread infiltration by lymphocytes and plasma cells with epithelial cell abnormalities. In time, dense fibrosis and atrophic thyroid follicles replace the initial lymphocytic hyperplasia and vacuoles. Functional tissue destruction and infiltration may also be caused by previous administration of radioiodine, surgical fibrosis, metastasis, lymphomatous changes, sarcoidosis, tuberculosis, amyloidosis, cystinosis, thalassemia, and Riedel thyroiditis.

    Source -

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