Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
E t i o l o g y, D i a g n o s i s ,
a n d Ma n a g e m e n t
Jaime P. Almandoz,
MB, BCh
a,b
, Hossein Gharib,
b,
KEYWORDS
Hypothyroidism Thyroid-stimulating hormone
Subclinical hypothyroidism Thyrotropin-releasing hormone
Hypothyroidism is the result of inadequate production of thyroid hormone or inadequate action of thyroid hormone in target tissues. Hypothyroidism is commonly
seen in outpatient practice, and improvements in assays and increased awareness
of the condition has led to the evaluation of more patients. The wide array of symptoms of hypothyroidism indicates an effect on metabolism and dysfunction in multiple
organ systems. Primary hypothyroidism is the principal manifestation of hypothyroidism, but other causes include central deficiency of thyrotropin-releasing hormone
(TRH) or thyroid-stimulating hormone (TSH), or consumptive hypothyroidism from
excessive inactivation of thyroid hormone. Subclinical hypothyroidism (SCH) is
present when there is laboratory evidence of primary hypothyroidism with an elevated
TSH but a normal free thyroxine (FT4) level. Treatment in most cases involves oral
administration of exogenous synthetic thyroid hormone.
This review presents an update on the etiology and types of hypothyroidism,
including subclinical disease; drugs and thyroid function; and diagnosis and treatment
of hypothyroidism, with a glance at some controversial issues.
EPIDEMIOLOGY
Mayo School of Graduate Medical Education, College of Medicine, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905, USA
b
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, USA
* Corresponding author. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905.
E-mail address: gharib.hossein@mayo.edu
Med Clin N Am 96 (2012) 203221
doi:10.1016/j.mcna.2012.01.005
medical.theclinics.com
0025-7125/12/$ see front matter 2012 Elsevier Inc. All rights reserved.
204
United States, Europe, and Japan have reported the prevalence of hypothyroidism to
be between 0.6 and 12 per 1000 in women and between 1.3 and 4.0 per 1000 in men.1
The National Health and Nutrition Examination Survey III data estimate the prevalence
of overt hypothyroidism (OH) in the American population at 0.3% and prevalence of
SCH at 4.3%.2 The Colorado Thyroid Disease Prevalence Survey revealed a similar
prevalence of hypothyroidism of 0.4% in a self-selected group not taking thyroid
hormone, but a much higher prevalence of SCH at 8.5%.3 The Colorado survey
involved individuals voluntarily seeking screening, so the estimated prevalence might
be expected to be higher. In the Wickham cohort, 20-year survivor follow-up data indicate the mean annual incidence of hypothyroidism to be 3.5 per 1000 in women and
0.6 per 1000 in men.4 The odds ratio of developing hypothyroidism were increased
from 8 in women and 44 in men with an elevated TSH, to 38 in women and 173 in
men for those that had both an elevation in TSH and positive antibodies.4
ETIOLOGY
Hypothyroidism can arise as primary from the thyroid gland, when there is a defect in
thyroid hormone synthesis and release; or centrally from the hypothalamic-pituitarythyroid axis, when there is a defect in either TRH or TSH signaling to the thyroid
(Table 1). The condition may also be transient or permanent.
Primary Hypothyroidism
Chronic autoimmune (Hashimoto) thyroiditis is the most common cause of hypothyroidism in iodine-sufficient areas. It is characterized by diffuse lymphocytic infiltration
of the thyroid gland associated primarily with circulating antithyroid peroxidase (TPO)
Table 1
Causes of hypothyroidism
Primary (Thyroid)
Secondary (Pituitary)
Autoimmune
Surgery
Iatrogenic
Lymphocytic hypophysitis
Thyroidectomy/thyroid surgery
Infection
Medications
Antithyroid medications
Miscellaneous
Tertiary (hypothalamus)
Medications
Medications
Radiation exposure
Systemic illness (usually moderate
or severe)
Thyroid agenesis
Defective hormone synthesis
Thyroid hormone resistance
Hypothyroidism
antibodies; antibodies may also be present against other aspects of the thyroid (thyroglobulin [Tg], TSH receptor, TSH-blocking antibodies).57 This process seems to be
due to an inherited defect in immune surveillance that leads to dysregulation and
subsequent destruction of the thyroid gland.8 As such, patients may present with or
without a goiter.
Detecting serum thyroid autoantibodies is a vital component in diagnosing autoimmune thyroid disease. Positive serum autoantibodies in the absence of abnormalities
in the testing of thyroid function should be interpreted with caution, as more than 20%
of women older than 50 years in the general population have positive TPO antibodies,
and thus antibody positivity does not equal clinical disease,2 although these individuals are more likely than antibody-negative individuals to develop thyroid dysfunction.
Iodine deficiency remains the most common cause of hypothyroidism worldwide,
but is uncommon in North America because of the widespread use of iodized table
salt and other fortified foods.9 A study of bread and cows milk in the Boston area
revealed that the average slice of bread contained 10 mg of iodine, whereas some
brands provided more than 300 mg per slice. This study also showed that all cows
milk samples contained at least 88 mg per 250 mL.10 As recently at 1990, 28.9% of
the worlds population was at risk for iodine deficiency. The recommended daily intake
for iodine is 150 mg for the general population and 225 to 350 mg during pregnancy and
lactation.11 Radioactive iodine (131I) therapy is the most common treatment modality
for hyperthyroidism in the United States. It is also used for treatment of thyroid
remnant ablation following thyroidectomy and treatment of iodine-avid thyroid
cancers. The principal side effect of 131I is hypothyroidism, requiring lifelong thyroid
hormone replacement therapy.12
Excess exposure to iodine can lead to transient hypothyroidism, referred to as the
Wolff-Chaikoff effect.13 This effect is sometimes used in preparing patients with
Graves disease for surgery or treating thyroid storm. Patients with underlying organification defects, for example, Hashimoto thyroiditis, or following 131I therapy can
suffer from prolonged hypothyroidism when exposed to excess iodide.14,15 This situation also occurs in patients on amiodarone therapy and is likely caused by a failure to
escape the Wolff-Chaikoff effect.16 Escape or adaptation to the Wolff-Chaikoff effect
occurs approximately 2 days after initial iodine exposure, and in rats has been shown
to be due to a transcriptional decrease in sodium/iodide symporter messenger RNA
and protein expression, which results in decreased iodide transport into the thyroid.17
External radiation exposure from treatment of nonthyroid cancer increases the
chances of hypothyroidism. The prevalence of hypothyroidism following radiation
for head and neck cancer ranges between 10% and 45% in the literature.18 A recent
systematic review looking at risk factors for developing hypothyroidism after radiation
therapy identified female sex, white race, and concomitant thyroid or neck surgery as
notable factors.19 Considerable variation was seen between studies, but there was
a radiationdose response relationship, with a 50% risk of hypothyroidism with
a dose of 45 Gy. Chemotherapy and age were not associated with an increased risk
of hypothyroidism.
Tyrosine kinase inhibitors have been shown to cause hypothyroidism in 36% to 71%
of patients in prospective data.20 This class of medication has also been shown to
increase the requirement of levothyroxine replacement in those already on thyroid
hormone replacement, by an average dose of 50 mg per day in one study looking at vandetanib.21 It has been suggested by several investigators that this increase in thyroid
hormone requirement is attributable to an induction in type 3 deiodinase activity.22,23
The evidence linking low-dose environmental radiation exposure to autoimmune
thyroid disease and hypothyroidism is inconclusive.24 The Japanese Adult Health
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206
Survey, when examining 50-year survivors of the Hiroshima and Nagasaki atomic
bombs, found an increase in spontaneous OH with a prevalence of 5.6%.25 There
does not appear to be a link between radiation exposure and positive antithyroid antibody status or antibody-positive hypothyroidism in this cohort. The Hanford Thyroid
Disease Study also failed to find an association between hypothyroidism, autoimmune
thyroiditis, and prolonged 131I exposure in infancy and childhood.26
Infiltrative processes can lead to primary hypothyroidism, and causes include
hemochromatosis, lymphoma, sarcoidosis, and Riedel thyroiditis.2730 Infections of
the thyroid with pathogens such as Pneumocystis jiroveci can cause inadequate
production of thyroid hormone if enough of the gland is damaged. However, infections
of the thyroid are rare because of its encapsulation, high iodide content, and lymphatic
drainage.30
Inflammatory destruction of the thyroid as occurs in thyroiditis leads to transient
thyrotoxicosis by release of thyroid hormone from the injured gland. As hormone
stores are depleted, a transient hypothyroid phase follows until the inflammation
has subsided. Postpartum thyroiditis (PPT) is caused by lymphocytic infiltration and
may occur in 5% to 7% of women worldwide. PPT is more common in women with
thyroid autoantibodies, and those with positive TPO antibodies early in pregnancy
have a 30% to 52% chance of developing PPT. Other autoimmune conditions
increase the incidence of PPT, which is at least 15% in women with type 1 diabetes
mellitus.31 It is widely believed that most women with PPT will recover before the
end of the first postpartum year.32 A recent large-scale prospective study of women
in southern Italy challenged this, showing that 1 in 25 developed the condition and
that 54% had persistent hypothyroidism at the end of the first postpartum year.33
Consumptive hypothyroidism results from excessive production of type 3 deiodinase by vascular endothelium, resulting in conversion of thyroxine (T4) to reverse triiodothyronine (T3) and T3 to diiodothyronine. This rare condition is usually associated
with hemangiomas, and surgical resection is curative.34
Medications
SCH is used to describe an asymptomatic patient who has an elevated serum TSH
and a normal serum FT4 level. This description is only accurate if the hypothalamicpituitary-thyroid axis is intact, there is no ongoing or recent severe illness, and the
pattern is reproducible through time. It suggests a compensated early state of primary
thyroid failure whereby an increased level of TSH is required to maintain levels of
thyroid hormone within the normal range. SCH can occur in the setting of Hashimoto
thyroiditis, prior thyroid surgery, radioiodine therapy, or external beam radiation. Transient SCH has also been reported following an episode of thyroiditis.39
Hypothyroidism
DIAGNOSIS
Symptoms and Presentations
The symptoms of hypothyroidism are often very subjective, and vary according to the
degree of biochemical hypothyroidism. Symptoms typically include fatigue, cold intolerance, dry skin, constipation, vocal changes, and muscle aches. These symptoms,
including proposed scoring systems for the diagnosis of hypothyroidism, have poor
sensitivity and specificity for the condition.40 On physical examination prolonged
ankle-jerk reflex time appears to correlate best with the degree of hypothyroidism;
however, much of the clinical evaluation in current clinical practice has been overshadowed by the use of sensitive assays.40,41
The decrease in circulating thyroid hormones has a negative effect on basal metabolic rate, which has a negative effect on multiple organ systems. The accumulation of
glycosaminoglycans from increased synthesis of hyaluronic acid along with the
decreased metabolic rate can explain many of the presenting features of the affected
patient.
Lipid Metabolism
Some investigators recommend that thyroid function be measured in all patients with
lipid abnormalities, as more than 90% of patients with OH will have abnormal serum
lipid values.42 OH is characterized by increased low-density lipoproteins (LDL) and
apolipoprotein B because of reduced hepatic clearance from a decreased number
of hepatic LDL receptors. A decrease in cholesterylester transfer protein can increase
the levels of high-density lipoproteins (HDL) in hypothyroidism.43 Although there is
a tendency toward elevated cholesterol in hypothyroidism, it seems to arise from an
increase in large-LDL and large-HDL subtypes, which are thought to be less
atherogenic.44
Cardiovascular and Other Changes
207
208
Box 1
Medications that contribute to hypothyroidism
Certain agents may have more than 1 mechanism.
Medications decreasing TSH secretion
Glucocorticoids
Opiates
Dopamine
Bromocriptine
Phentolamine
Octreotide
Growth hormone
Drugs affecting thyroid hormone synthesis and secretion
Iodine
Amiodarone
Thionamides
Thiocyanate
Aminogluthemide
Perchlorate
Lithium
Cytokines (IFN-g, IL-2, GM-CSF)
Drugs altering thyroid hormone metabolism
Rifampicin
Phenytoin
Carbamazepine
Barbiturates
Tyrosine kinase inhibitors
Growth hormone
Glucocorticoids
Propylthiouracil
b-Blockers
Iodinated contrast agents
Clomipramine
Drugs that increase thyroxine-binding globulin
Estrogen
SERMs
Opiates
Mitotane
Clofibrate
Perphenazine
5-Fluorouracil
Hypothyroidism
Laboratory testing is required for the diagnosis of hypothyroidism because the symptoms and examination findings lack sensitivity and specificity. Accordingly, clinical
scoring systems correlate poorly with hypothyroidism and should not be used for
diagnosis. Nonthyroid serum testing such as elevated creatine kinase, hyperlipidemia,
and physical findings such as basal metabolic rate should not be used to diagnose
thyroid dysfunction, but should prompt more specific thyroid testing.
Primary hypothyroidism is manifested by an elevated serum TSH with a low serum
FT4. SCH is present when there is an elevation in TSH but the FT4 is within the normal
reference range. In secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the
FT4 is low and the TSH is not appropriately elevated. Imaging of the hypothalamus and
pituitary gland should be performed on patients in whom central hypothyroidism is
suspected.
TSH is widely measured using a third-generation chemiluminometric assay. There is
controversy regarding the appropriate upper limit of normal for the reference range.
The authors laboratory currently uses a reference range of 0.3 to 5.0 mIU/L. A
209
210
Universal screening of the general population is controversial, and there is disagreement between professional societies about who should be screened for thyroid hypofunction and when. The United States Preventive Services Task Force does not
recommend routine screening for thyroid disease in adults,63 whereas the American
Thyroid Association (ATA) recommends screening for adults beginning at age 35 years
and every 5 years thereafter.64 The American Association of Clinical Endocrinologists
(AACE) recommends screening in older patients of an unspecified age, particularly if
female.65
Because of the lack of data supporting screening on a population-based level,
a consensus group of representatives from the Endocrine Society, ATA, and AACE
Hypothyroidism
recommended aggressive case finding in pregnant women, those older than 60 years,
and people at risk for thyroid dysfunction. Patients thought to be at risk included those
with a family history of thyroid dysfunction or a personal history of autoimmune
disease.66 Other patients who could fall into the at-risk group include those on medications that affect thyroid function, those with presence of a goiter, those who have
had prior neck surgery, or those with a history of radiation exposure.
Treatment
211
212
Hypothyroidism
213
214
Universal screening for congenital hypothyroidism (CH) is performed in most industrialized countries within the first few days of life. The purpose of this population-based
screening is to prevent intellectual disability in those affected, previously estimated at
1 in 4000 live births in iodine-sufficient regions.110 There are several screening strategies including an initial T4 with a reflex TSH for those below a defined T4 threshold,
a TSH-only test, and a combined TSH and T4 test. Congenital central hypothyroidism
can be missed by TSH-only screening methods, and the estimated birth prevalence of
this disorder is approximately 1 in 29,000.111
Thyroid dysgenesis accounts for 85% of the cases of CH, and of those, two-thirds
are caused by an ectopic thyroid gland, followed by agenesis and hypoplasia. Most of
these cases are sporadic and only 2% of cases are found to have known genetic
mutations. Thyroid dyshormonogenesis is responsible for almost 15% of CH cases
and includes defects in functional thyroid peroxidase, the sodium/iodide symporter.
Transient CH is associated with conditions such as maternal iodine insufficiency or
acute ingestion, and maternal TSH-blocking antibodies.112
In 2007, an article by Harris and Pass113 raised concern that the birth prevalence of
CH had doubled over the previous 2 decades. A 20-year retrospective study from
Quebec determined that their stated increase in birth prevalence of CH was attributable to a lowering of the upper limit of normal in the confirmatory test, from 15 mIU/L to
5 mIU/L. The lowering of this diagnostic threshold identified an additional 49 cases
Hypothyroidism
that would not otherwise have been detected, out of a total of 620 cases. Although
these additional cases were considered to be mild, 86% had permanent hypothyroidism.114 There are no randomized controlled studies demonstrating a therapeutic
benefit in these milder cases of CH, which would have been previously missed, but
it would seem prudent to treat them.
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