AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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.

Pathophysiology

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.

Frequency

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

International

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.

Mortality/Morbidity

In developed countries, death caused by hypothyroidism is uncommon.

Race

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

Sex

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.

Age

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.
 

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

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

Physical

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

Causes

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: Medications such 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)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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.

Procedures

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment goals for hypothyroidism are the reversal of clinical progression and the corrections of metabolic derangements as evidenced by normal blood levels of TSH and free T4. Thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4).
 
Clinical benefits begin in 3-5 days and level off after 4-6 weeks. Anticipated full replacement doses may be initiated in individuals who are otherwise young and healthy. In elderly patients or those with known ischemic heart disease, treatment should begin with one fourth to one half the expected dose, and the dose should be adjusted in small increments no sooner than 4-6 weeks.
 
Achieving a TSH level within the reference range may be slowed because of delay of hypothalamic-pituitary axis readaptation and may take several months. After dose stabilization, patients can be monitored with annual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of over treatment, which include tachycardia, palpitations, nervousness, tiredness, headache, increased excitability, sleeplessness, tremors, and possible angina. 

A recent metaanalysis of randomized controlled trials of thyroxine-triiodothyronine combination therapy (T4 + T3) versus thyroxine monotherapy (T4) for treatment of clinical hypothyroidism found no difference in the effectiveness of the combination vs monotherapy in bodily pain, depression, fatigue, body weight, anxiety, quality of life, total cholesterol, LDL-C, HDL-C and triglyceride levels. Hence, T4 monotherapy remains the treatment of choice.⁵
 
Pregnancy
 
Hypothyroidism in pregnancy is associated with preeclampsia, anemia, postpartum hemorrhage, cardiac ventricular dysfunction, spontaneous abortion, low birth weight, impaired cognitive development, and fetal mortality. Even mild disease may be associated with adverse affects for offspring.
 
Increased dosage requirements should be anticipated during pregnancy, especially in the first and second trimesters. Recent studies have suggested that patients with hypothyroidism should augment the LT4 dose by 30% at the confirmation of pregnancy, followed by adjustments according to TSH levels. For previously diagnosed women serum TSH should be measured every 3-4 weeks during the first half of pregnancy and every 6 weeks thereafter.  LT4 dose should be adjusted to maintain a serum TSH less than 2.5 mIU/L. TSH and free T4 levels should be measured every 3-4 weeks after every dosage adjustment.⁶
 
Autoimmune thyroid disease without overt hypothyroidism has been associated with a higher miscarriage rate. In a recent study, Negro et al show that euthyroid Caucasian women with positive anti-TPO antibodies treated with levothyroxine during the first trimester had lower miscarriage rates when compared to those who were not treated. They also had lower incidence of premature delivery, comparable to women without thyroid antibodies.⁷ This will need to be confirmed by other studies, and, if confirmed, there will be an indication to treat euthyroid pregnant women with thyroid antibodies.
 
Levothyroxine should not be taken with prenatal vitamins with iron and calcium supplements. After delivery, LT4 can be reduced to the prepregnancy dose and TSH should be checked in 6 weeks.
             
Subclinical hypothyroidism
    
Significant controversy persists regarding the treatment of patients with mild hypothyroidism. Some have argued that treatment of these patients improves symptoms, prevents progression to overt hypothyroidism, and may have cardioprotective benefits. Recent reviews by the American Medical Association and US Preventive Services Task Force have found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L.
 
Following subclinical hypothyroidism and treating on a case-by-case basis is reasonable. Treatment of subclinical hypothyroidism has been shown to reduce total cholesterol, LDL-C, and non HDL-C.⁸
 
American Association of Clinical Endocrinologists (AACE) guidelines state that treatment is indicated in patients with TSH levels more than 10 mIU/mL or in patients with TSH levels between 5 and 10 mIU/mL in conjunction with goiter or positive antithyroid peroxidase antibodies or both, as these patients have the highest rates of progression to overt hypothyroidism. An initial dose of LT4 25-50 mcg/d can be used and titrated every 6-8 weeks to achieve a target TSH between 0.3 and 3 mIU/mL.⁹

Myxedema coma
 
An effective approach is to use intravenous LT4 at a dose of 4 mcg/kg of lean body weight, or approximately 200-250 mcg as a bolus in a single or divided dose, depending on the patient's risk of cardiac disease followed by 100 mcg 24 hours later and then 50 mcg daily IV or PO along with stress doses of intravenous glucocorticoids. Adjustment of the dose can then be made based on clinical and laboratory along with stress doses of intravenous glucocorticoids. Use of intravenous triiodothyronine is controversial and based on expert opinion. It has a higher frequency of adverse cardiac events and is generally reserved for patients who are not improving clinically on LT4. LT3 can be given initially as a 10 mcg IV bolus and repeated every 8-12 hours until the patient can take maintenance oral doses of T4. Advanced age, high dose T4 therapy, and cardiac complications had the highest associations with mortality.¹⁰

Surgical Care

Surgery is indicated for large goiters that compromise tracheoesophageal function; surgery is rarely needed in patients with hypothyroidism and is more common in the treatment of hyperthyroidism.

Consultations

Patients with a nodular thyroid, suspicious thyroid nodules, or compressive symptoms such as dysphagia; pregnant women; patients with underlying cardiac disorders or other endocrine disorders; persons younger than 18 years; and those unresponsive to treatment should be referred to an endocrinologist.
 
Some patients with thyroiditis can develop hyperthyroidism (or symptoms consistent with hyperthyroidism) before developing hypothyroidism and may benefit from consultation with an endocrinologist.
 
Suspected myxedema coma is a medical emergency with a high risk of mortality that requires initiation of parenteral (intravenous) LT4 and glucocorticoids prior to laboratory confirmation. An urgent endocrinology consultation should be obtained.
 
Rarely an increase in size of a goiter in a patient with autoimmune thyroid disease could be a lymphoma and should be evaluated by an endocrinologist.

Diet

No specific diets are required for hypothyroidism.

Subclinical hypothyroidism has been seen in increased frequency in patients with greater iodine intake. The World Health Organization recommends a daily dietary iodine intake of 150 mcg for adults, 200 mcg for pregnant and lactating women, and 50-120 mcg for children.

Activity

Patients who have hypothyroidism have generalized hypotonia and may be at risk for ligamental injury, particularly from excessive force across joints. Thus, patients should exercise caution with certain activities, such as contact sports or heavy physical labor.
 
Patients with uncontrolled hypothyroidism may have difficulty maintaining concentration in low-stimulus activities and may have slowed reaction times. Patients should use caution if an activity has a risk of injury (eg, operating presses or heavy equipment, driving).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Thyroid hormone replacement

Levothyroxine is generally considered to be the treatment of choice for patients with hypothyroidism.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Most patients can be treated in an ambulatory care setting.
• Patients with severe hypothyroidism, myxedema, require aggressive management in an inpatient setting.
• Overreplacement with LT4 may precipitate tachyarrhythmias or, rarely, thyroid storm, which may require hospitalization. Risk is higher with T3.
• Patients who require long-term continuous tube feeding require IV LT4 replacement, as the absorption of oral agents is impaired by contents of tube feeds.

Further Outpatient Care

• Once appropriate therapeutic dose is obtained, patients can be monitored annually or semiannually with laboratory evaluation and physical examination.
• Patients should take thyroid hormone as a single dose in the morning to avoid insomnia. Thyroid hormone is better absorbed in the small bowel; therefore, absorption can be affected by malabsorptive states, small bowel disease, and the patient's age. Many drugs (eg, iron, calcium carbonate, aluminum hydroxide, sucralfate [Carafate]) can interfere with absorption. Emphasize proper compliance at each visit.
• In addition, monitor patients for signs of excess dosing (eg, nervousness, palpitations, diarrhea, excessive sweating, heat intolerance, chest pain). Monitor pulse rate, blood pressure, and vital signs. In children, sleeping pulse rate and basal temperature can be used as guides to adequate clinical response to treatment.

Deterrence/Prevention

No universal screening recommendations exist for thyroid disease for adults. All neonates should be screened for thyroid disease.
   
The American Thyroid Association recommends screening at age 35 years and every 5 years thereafter, with closer attention to patients who are at high risk (eg, pregnant women, women >60 y, patients with type 1 diabetes or other autoimmune disease, patients with history of neck irradiation).¹¹ 
 
The American College of Physicians recommends screening all women older than 50 years who have one or more clinical features of disease.^{12, 13}
  
The American Association of Clinical Endocrinologists recommends TSH measurements of all women of childbearing age before pregnancy or during the first trimester.⁹
 
 
The US Preventive Task Force concludes that the evidence is insufficient to recommend for or against routine screening for thyroid disease in adults (grade I recommendation).¹⁴
             
Because screening prevents a delay in recognition and treatment of cretinism, governmental bodies frequently mandate screening of neonates.

Complications

• Thyroid hormone replacement can precipitate adrenal crises in patients with untreated adrenal insufficiency. If suspected, the presence of adrenal insufficiency should be confirmed or ruled out and should be treated prior to treatment of hypothyroidism.
• Aggressive replacement of thyroid hormone may compromise cardiac function in patients with existing cardiac disease. In these patients, administer smaller initial doses of LT4 with small incremental increases.
• Subclinical hyperthyroidism, which can result from treatment with L-thyroxine, is more common, but its relationship to osteoporosis and fracture is unclear. Previously, osteoporosis was thought to be a risk of TSH suppression below the normal range; however, more recent studies have not consistently confirmed this hypothesis except in postmenopausal women.¹⁵  Nonetheless, patients at risk for osteoporosis (eg, women who are estrogen deficient) and individuals receiving a long-term suppressive of LT4 (eg, patients with differentiated thyroid cancer) should be closely monitored. Note that patients with thyroid cancer are usually on a higher dose of LT4. Desired TSH depends on the staging of their thyroid cancer. In patients with stage IV thyroid cancer, it is desirable to keep their TSH below 0.1 mIU/L.
• Advise patients that vision may temporarily worsen when starting hormone therapy. Rarely, pseudotumor cerebri occurs.
• Patients with depression may develop mania, and psychosis may be exacerbated in patients with severe psychological illness.
• Because most brain growth occurs in the first 2 years of life, untreated hypothyroidism in infants can cause irreversible mental retardation. Older infants are spared nervous system damage but continue to have slowed physical and linear bone growth. They also have delayed dental development.

Prognosis

• Undertreatment leads to disease progression with gradual worsening of symptoms and further metabolic derangements.
• Fortunately, in most patients older than 3 years, the signs and symptoms of hypothyroidism are reversed with thyroid hormone treatment.
• With treatment, circulating lipid levels should improve to a mild degree. This may result in a decrease of coronary artery disease (CAD).

Patient Education

• Clearly discuss the life-long nature of hypothyroidism, the need for life-long therapy, the proper way to take medicine, and the minimum need for annual TSH testing.
• For excellent patient education resources, visit eMedicine's Endocrine System Center and Muscle Disorders Center. Also, see eMedicine's patient education articles Thyroid Problems and Chronic Fatigue Syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Aggressive treatment in the presence or suggestion of cardiac disease may raise the risk of mortality.
• A delay in the diagnosis and treatment of hypothyroidism in an infant with cretinism may lead to irreversible CNS damage. Legally mandated screening of neonates confers additional legal requirements on institutions, laboratories, and other nonphysician entities for compliance with, quality of, and follow-up for abnormal screening.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, et al. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J . Clin Endocrinol Metab. Feb 2002;87(2):489-499. [Medline].
2. Kajantie E, Phillips DI, Osmond C, Barker DJ, Forsen T, Eriksson JG. Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab. Dec 2006;91(12:4953-4956. [Medline].
3. Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med. 159(1);Jan 11 1999:79-82. [Medline].
4. Woeber KA. Iodine and thyroid disease. Med Clin North Am. Jan 1991;75(1):169-178. [Medline].
5. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006/07;91(7):2592-2599. [Medline].
6. LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am. Mar 2006;35(1):117-136, vii. [Medline].
7. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab. Jul 2006;91(7):2587-2591. [Medline].
8. Ito M, Arishima T, Kudo T, Nishihara E, Ohye H, Kubota S, et al. Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients. J Clin Endocrinol Metab. Feb 2007;92(2):608-611. [Medline].
9. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. Nov-Dec 2002;8(6):457-469. [Medline].
10. Wartofsky L. Myxedema coma. Endocrinol Metab Clin North Am. Dec 2006;35(4):687-698, vii-viii. [Medline].
11. Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG, et al. American Thyroid Association Guidelines For Detection Of Thyroid Dysfunction. Arch Internal Med. 2000;160:1573-75. [Medline].
12. American College of Physicians. Clinical guideline, part 1. Screening for thyroid disease. Ann Intern Med. 1998;129(2):141-3. [Medline].
13. Helfand M, Redfern CC. Clinical guideline, part 2. Screening for thyroid disease: an update. American College of Physicians. Ann Intern Med. Jul 15 1998;129(2):144-58. [Medline].
14. US Preventative Services Task Force. Screening for thyroid disease: recommendation statement. Ann Intern Med. Jan 20 2004;140(2):125-7. [Medline].
15. Morris MS. The association between serum thyroid-stimulating hormone in its reference range and bone status in postmenopausal American women. Bone. Apr 2007;40(4):1128-1134. [Medline].
16. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. Jul 15 2004;351(3):241-9. [Medline].
17. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. Feb 11 1999;340(6):424-9. [Medline].
18. Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. Dec 10 2003;290(22):2952-8. [Medline].
19. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. Feb 2006;16(2):109-142. [Medline].
20. Glinoer D. Management of hypo- and hyperthyroidism during pregnancy. Growth Horm IGF Res. Aug 2003;13 Suppl A:S45-54. [Medline].
21. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. Aug 19 1999;341(8):549-55. [Medline].
22. Helfand M. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. Jan 20 2004;140(2):128-41. [Medline].
23. Kita M, Goulis DG, Avramides A. Post-partum thyroiditis in a mediterranean population: a prospective study of a large cohort of thyroid antibody positive women at the time of delivery. J Endocrinol Invest. Jun 2002;25(6):513-9. [Medline].
24. Ladenson PW. Recognition and management of cardiovascular disease related to thyroid dysfunction. Am J Med. Jun 1990;88(6):638-41. [Medline].
25. Ladenson PW. Diagnosis of hypothyroidism. In: Werner and Ingbar's The Thyroid. 7^th ed. New York: Lippencott-Raven Publishers; 1996:880.
26. Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocri. June 2004;150(6):751-5. [Medline].
27. Roberts CG, Ladenson PW. Hypothyroidism. Lancet. Mar 6 2004;363(9411):793-803. [Medline].
28. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med. Aug 1985;145(8):1386-8. [Medline].
29. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. Jan 14 2004;291(2):228-38. [Medline].

Article Last Updated: Oct 12, 2007