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					Hypothyroidism

Article Last Updated: Oct 12, 2007

AUTHOR AND EDITOR INFORMATION

Section 1 of 10

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


Author: Shikha Bharaktiya, MD, Clinical Fellow, Department of Internal Medicine, Division of
Endocrinology and Metabolism, University of Texas Medical School at Houston

Coauthor(s): Philip R Orlander, MD, Director of Endocrinology and Metabolism Fellowship,
Director and Professor, Department of Medicine, Division of Endocrinology, University of Texas
Health Science Center at Houston; Walter R Woodhouse, MD, MSA, Program Director of
Transitional Year Program, St Vincent Mercy Medical Center; Associate Professor, Department of
Family Practice, Medical College of Ohio; Anu Bhalla Davis, MD, Assistant Professor,
Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University
of Texas Health Science Center at Houston

Editors: Frederick H Ziel, MD, Chief of Endocrinology, Kaiser Permanente Woodland Hills,
Associate Professor, Department of Internal Medicine, Division of Diabetes and Endocrinology,
University of California at Los Angeles; Francisco Talavera, PharmD, PhD, Senior Pharmacy
Editor, eMedicine; Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Affiliate Research
Professor, School of Computational Sciences; Principal, Bioinformatics and Computational
Biology Program, C/A Informatics, LLC; Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes &
Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University;
George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis
University

Author and Editor Disclosure

Synonyms and related keywords: thyroiditis, myxedema coma, cretinism, hypothyrosis,
hypothyroidea, thyrotropin, TSH, tertiary hypothyroidism, thyrotropin releasing-hormone, TRH,
thyroxine, T4, triiodothyronine, T3, Hashimoto disease, Hashimoto thyroiditis, primary
hypothyroidism, secondary hypothyroidism, congenital hypothyroidism, cold intolerance, weight
gain, menstrual disturbances, periorbital puffiness, goiter, autoimmune thyroiditis, iodine
deficiency, de Quervain thyroiditis, subacute thyroiditis, postpartum autoimmune thyroid disease,
amiodarone, interferon alpha, thalidomide, stavudine, central hypothyroidism, subclinical
hypothyroidism
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
                                                 1
the population (0.3% overt and 4.3% subclinical). It is more common in women with small body
                                                        2
size at birth and low body mass index during childhood.

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
                                          1
Americans tend to have lower TSH values.

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

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
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

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,
                                                       3
hyperlipidemia, and reversible increase in creatinine.

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
             
             o 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.
             o Thyroidectomy
             o 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
                                                                                                4
        treated Graves hyperthyroidism (subtotal thyroidectomy) and prior radioiodine therapy.

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


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

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
                 1
below 2.5 mIU/L.

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
                                                                                 5
triglyceride levels. Hence, T4 monotherapy remains the treatment of choice.

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
                                                           6
measured every 3-4 weeks after every dosage adjustment.

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
                                                                           7
of premature delivery, comparable to women without thyroid antibodies. 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
            8
non HDL-C.

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
               9
and 3 mIU/mL.

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
                                                           10
complications had the highest associations with mortality.

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.

                      Levothyroxine (Synthroid, Levoxyl, Levothroid,
    Drug Name
                      Unithroid)
                      In active form, influences growth and maturation
                      of tissues. Involved in normal growth, metabolism,
                      and development. Produces stable levels of T3
                      and T4. Administered as a single dose in the
                      morning on an empty stomach. May be
                      administered PO/IV/IM. Has long half-life (7-10 d),
    Description       and parenteral dosing is rarely needed (except
                      when PO is unavailable, patient is on continuous
                      enteral feeds, or in emergency, such as
                      myxedema coma). Initial subtherapeutic doses are
                      recommended to avoid the stress of rapid
                      metabolic change in elderly patients and in those
                      with coronary artery disease or severe COPD.
                      1.6 mcg/kg/d PO; higher doses may be required in
                      pregnancy; in elderly and those with coronary
                      disease or severe COPD, start at 25-50 mcg/d
                      PO, increase by 25-50 mcg/d q4-8wk until desired
                      response achieved
                      Maintenance: 50-200 mcg PO qam
                      Subclinical hypothyroidism: If treated an initial
                      dose of LT4 25-50 mcg/d can be used and titrated
    Adult Dose        q6-8wk to achieve a target TSH between 0.3 and
                      3 mIU/mL
                      Myxedema coma: 200-250 mcg IV bolus, followed
                      by 100 mcg the next day and then 50 mcg/d PO or
                      IV along with T3; use smaller doses in patients
                      with cardiovascular disease; patients should first
                      receive stress dose steroids in case they have
                      concomitant primary or secondary adrenal
                      insufficiency (see above)
                      Neonate to 6 months: 25-50 mcg/d PO
                      6-12 months: 50-75 mcg/d PO
  Pediatric Dose      1-5 years: 75-100 mcg/d PO
                      6-12 years: 100-150 mcg/d PO
                      >12 years: 150 mcg/d PO
                   Documented hypersensitivity, uncorrected adrenal
 Contraindications insufficiency; acute MI uncomplicated by
                   hypothyroidism; untreated thyrotoxicosis
                      Hepatic enzyme inducers (phenytoin) may
    Interactions
                      increase degradation of, antidiabetic agents,
                   theophylline, adrenocorticoids, digoxin, and
                   anticoagulants, which may need dose
                   adjustments; IV phenytoin may release thyroid
                   hormone from thyroglobulin; effects of TCAs and
                   sympathomimetics may be increased;
                   cholestyramine, sucralfate, iron may decrease
                   absorption; estrogens may decrease response to
                   thyroid hormone therapy in patients with
                   nonfunctioning thyroid glands; activity of some
                   beta-blockers may decrease when patient with
                   hypothyroidism is converted to a euthyroid state;
                   beta-blockers may decrease conversion of T3 to
                   T4
                   A - Fetal risk not revealed in controlled studies in
   Pregnancy
                   humans
                   Caution in elderly patients and patients with renal
                   insufficiency, hypertension, ischemia, angina, and
                   other cardiovascular diseases; periodically
                   monitor thyroid status; because of the risk of
  Precautions
                   adrenal crisis, T4 should not be administered
                   without corticosteroids in any patient with
                   suspected adrenal insufficiency, either primary or
                   secondary
   Drug Name       Liothyronine (Cytomel, Triostat)
                   Synthetic form of the natural thyroid hormone T3
                   converted from T4. Used when a rapid effect is
                   desired perioperatively or for nuclear medicine
                   studies. Not intended as sole maintenance
                   therapy. Can be used in combination with
                   levothyroxine in small doses (5-15 mcg/d).
                   Duration of activity is short (half-life is 12-24 h)
   Description     and allows for quick dosage adjustments in event
                   of overdosage. May be preferred when GI
                   absorption is impaired (95% absorbed compared
                   to 50-80% of T4) or if peripheral conversion is
                   impaired.
                   Dosage recommendations are for short-term use
                   in special circumstances (see above) with the
                   guidance of an endocrinologist.
                   Initial: 25 mcg/d PO in divided bid; increase by
                   12.5-25 mcg/d PO q1-2wk until desired response
                   achieved
                   Maintenance: 50-100 mcg/d PO
                   Myxedema coma: 10 mcg IV and repeated q8 -
   Adult Dose
                   12h until patient can take PO maintenance oral
                   dose of T4 (see above)
                   Elderly patients or patients with suspected or
                   known coronary disease: Avoid because of high
                   risk of cardiovascular manifestations
                   5 mcg/d PO; increase by 5 mcg q3d until desired
 Pediatric Dose
                   response achieved
Contraindications Documented hypersensitivity; uncorrected adrenal
                   insufficiency; acute MI uncomplicated by
                   hypothyroidism; untreated thyrotoxicosis; cardiac
                   arrhythmias; suspected or known coronary
                   disease
                   Hepatic enzyme inducers (phenytoin) may
                   increase degradation; of antidiabetic agents,
                   theophylline, adrenocorticoids, digoxin, and
                   anticoagulants, these may need dose
                   adjustments; IV phenytoin may release thyroid
                   hormone from thyroglobulin; effects of TCAs and
                   sympathomimetics may be increased;
  Interactions
                   cholestyramine may decrease absorption;
                   estrogens may decrease response to thyroid
                   hormone therapy in patients with nonfunctioning
                   thyroid glands; activity of some beta-blockers may
                   decrease when hypothyroid patient converted to
                   euthyroid state; beta-blockers may decrease
                   conversion of T3 to T4
                   A - Fetal risk not revealed in controlled studies in
   Pregnancy
                   humans
                   Caution in elderly patients and patients with renal
                   insufficiency, hypertension, ischemia, angina, and
                   other cardiovascular diseases; periodically
                   monitor thyroid status; because of risk of adrenal
  Precautions
                   crisis, liothyronine should not be administered
                   without corticosteroids in any patient with
                   suspected adrenal insufficiency, either primary or
                   secondary
   Drug Name       Desiccated thyroid (Armour Thyroid)
                   Derived from extract of bovine or porcine thyroid
                   glands. Some manufacturers standardize based
                   on bioassays; others use iodine content.
                   Desiccated thyroid is referred to as natural thyroid
                   and generally contains T3 and T4 in a 1:4 ratio. It
                   is made in the following strengths 1/8, 1/4, 1/2, 1,
   Description
                   2, and 3 grain as well as 4 and 5 grain tabs. One
                   grain (60 mg) contains about 38 mcg of T4 and 9
                   mcg of T3. Because these preparations contain
                   variable quantities of T3, they should not be
                   prescribed for patients with known or suspected
                   cardiac disease (see above).
                   Initial: 30 mg/d PO; increase by 15-30 mg/d PO
   Adult Dose      q4wk until desired response achieved
                   Maintenance: 60-180 mg/d PO
                   Neonate to 6 months: 15-30 mg/d PO
                   6-12 months: 30-45 mg/d PO
 Pediatric Dose    1-5 years: 45-60 mg/d PO
                   6-12 years: 60-90 mg/d PO
                   >12 years: 60-180 mg/d PO
                  Documented hypersensitivity; uncorrected adrenal
Contraindications insufficiency; acute MI uncomplicated by
                  hypothyroidism; untreated thyrotoxicosis; known
                     or suspected cardiac disease
                     Hepatic enzyme inducers (phenytoin) may
                     increase degradation of antidiabetic agents,
                     theophylline, adrenocorticoids, digoxin, and
                     anticoagulants, which may need dose
                     adjustments; IV phenytoin may release thyroid
                     hormone from thyroglobulin; effects of TCAs and
                     sympathomimetics may be increased;
    Interactions
                     cholestyramine, sucralfate, iron may decrease
                     absorption; estrogens may decrease response to
                     thyroid hormone therapy in patients with
                     nonfunctioning thyroid glands; activity of some
                     beta-blockers may decrease when hypothyroid
                     patient is converted to a euthyroid state; beta-
                     blockers may decrease the conversion of T3 to T4
                     A - Fetal risk not revealed in controlled studies in
    Pregnancy
                     humans
                     Caution in elderly patients and patients with renal
                     insufficiency, hypertension, ischemia, angina, and
                     other cardiovascular diseases; monitor thyroid
                     status periodically; because of the risk of adrenal
    Precautions
                     crisis, thyroid hormone replacement should not be
                     administered without corticosteroids in any patient
                     with suspected adrenal insufficiency, either
                     primary or secondary

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
              11
irradiation).

The American College of Physicians recommends screening all women older than 50 years who
                                               12, 13
have one or more clinical features of disease.

The American Association of Clinical Endocrinologists recommends TSH measurements of all
                                                                          9
women of childbearing age before pregnancy or during the first trimester.


The US Preventive Task Force concludes that the evidence is insufficient to recommend for or
                                                                                  14
against routine screening for thyroid disease in adults (grade I recommendation).

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
                                   15
        postmenopausal women. 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

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Hypothyroidism excerpt

Article Last Updated: Oct 12, 2007