Hypothyroidism: diagnostic criteria, complications, and treatment.
Thyroiditis: classification, diagnostic criteria, treatment.
Cancer of the thyroid gland.
Iodine deficiency disorders.
Hypothyroidism: diagnostic criteria, complications, and treatment.
It is the characteristic reaction to thyroid hormone deficiency. The spectrum of hormone ranges from a few non – specific symptoms to overt hormone, to myxedema coma. Hypothyroidism occurs in 3 to 6 for the adult population, but is symptomatic only in a minor of them. It occurs 8 to 10 times more often in woman than in men and usually develops after the age of 30.
Classification
1.Congetial.
2. Acquired: 1. Primary (thyroid gland disturbances).
2. Secondary (due to pituitary disease).
3.Tertiary (due to hypothalamic disease).
4.Peripheral.
Etiology
A cause is usually evident from the history and physical examination.
1.Primary (thyroidal) hypothyroidism.
1) environmental iodine deficiency is the most common cause of hypothyroidism on a worldwide basis.
2) autoimmune processes (hypothyroidism usually occurring as a sequel to Hashimoto’s thyroiditis and results in shrunken fibroid thyroid gland with a little or no function and infiltrative diseases (tuberculosis, actynomycosis). Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) is the most common cause of hypothyroidism in areas of iodine sufficiency. Autoimmune thyroid diseases (AITDs) have been estimated to be 5-10 times more common in women than in men.
Distinct genetic syndromes with multiple autoimmune endocrinopathies have been described, with some overlapping clinical features. The presence of two of the three major characteristics is required to diagnose the syndrome of multiple autoimmune endocrinopathies (MAEs). The defining major characteristics for type 1 MAE and type 2 MAE are as follows:
o Type 1 MAE: Hypoparathyroidism, Addison’s disease, and mucocutaneous candidiasis caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein (51). Autoimmune thyroiditis is present in about 10%-15%.
o Type 2 MAE: Addison’s disease, autoimmune thyroiditis, and type 1 diabetes known as Schmidt’s syndrome;
3) surgical removal, total thyroidectomy of thyroid carcinoma, subtotal thyroidectomy (hypothyroidism occurs from 25 to 75 of patients in different series);
4) irradiation (hypothyroidism results from external neck irradiation therapy in doses 2000 rads or more such as are used in the treatment of malignant lymphoma and laryngeal carcinoma); I131 therapy for hyperthyroidism (it results in hyperthyroidism in 20 % to 60 % of patients within the first year after therapy and in 1 % to2 % each year there after);
5) during or after therapy with propylthyouracil, methimazole, iodides;
6) medications such as amiodarone, interferon alpha, thalidomide, lithium, and stavudine have also been associated with primary hypothyroidism.
7) trauma.
2.Secondary and tertiary hypothyroidism
It occurs due to either deficient secretion of TSH from the pituitary or lack of secretion of TRH from the hypothalamus. Secondary hypothyroidism accounts for less than 5% or 10% of hypothyroidism cases. Tertiary hypothyroidism accounts for less than 5% of hypothyroidism cases.
1. hypothalamic tumors (including craniopharyngiomas)
2. inflammatory (lymphocytic or granulomatous hypophysitis)
3. infiltrative diseases
4. hemorrhagic necrosis (Sheehan’s syndrome)
5. surgical and radiation treatment for pituitary or hypothalamic disease
6. drugs (reserpin, parlodel).
3. Peripheral hypothyroidism:
– peripheral tissue resistance to thyroid hormones;
– decreasing of T4 peripheral transformation into T3 (in liver or in kidneys) ;
– production of antibodies to thyroid hormones.
Congenital:
– Maldevelopment –hypoplasia or aplasia;
– Inborn deficiencies of biosynthesis or action of thyroid hormone;
– Atypical localization of thyroid gland;
Classification. (cont.)
B. 1. Laboratory (subclinical) hypothyroidism.
2. Clinical hypothyroidism, which can be divided on stages of severity: mild, moderate, severe.
C. 1. Compensation.
2. Subcompensation.
3. Decompensation.
D. 1. Without complications.
2. With complications (myopathy, polyneuroparhy, encephalopathy, coma).
Clinical features
The major symptoms and signs of hypothyroidism reflect showing of physiologic function. Virtually every organ system can be affected. The onset of symptoms may be rapid or gradual, severity varies considerably and correlates poorly with biochemical changes. Because many manifestations of hypothyroidism are non-specific, the diagnosis is particularly likely to be overlooked in patients with other chronic illnesses and elderly.
Nervous system
Most of hypothyroid patients complain of fatigue, loss of energy, lethargy, forgetfulness, reduced memory. Their level of physical activity decreases, and they may speak and move slowly. Mental activity declines and there is inattentiveness, decreased intellectual function, and sometimes may be depression.
Neurological symptoms include also hearing loss, parasthesias, objective neuropathy, particularly the carpal tunnel syndrome, ataxia.
Tendon reflex shows slowed or hung-up relaxation.
Skin and hair.
Hypothyroidism results in dry, thick and silk skin, which is often cool and pale. Glycosoamynoglicanes, mainly hyaluronic acid accumulate in skin and subcutaneous tissues retaining sodium and water. So, there is nonpitting oedema of the hands, feet and periorbital regions (myxedema). Pitting oedema also may be present. The faces are puffy and features are coarse. Skin may be orange due to accumulation of carotene. Hair may become course and brittle, hair growth slows and hair loss may occur. Lateral eyebrows thin out and body hair is scanty.
Cardiovascular system.
There may be bradycardia, reduced cardiac output, quiet heart sounds, a flabby myocardium, pericardial effusion (see pict.), cardiac wall is thick, it is increased by interstitial oedema. (These findings, along with peripheral edema, may simulate congestive heart failure). Increased peripheral resistance may result in hypertension. The ECG may show low voltage and/or non-specific ST segment and T wave changes. Hypercholesterolaemia is common. Whether or not these is an increased prevalence of ischemic heart disease is controversial. Angina symptoms, when present, characteristically occur less often after the onset of hypothyroidism, probably because of decreased activity.
Gastrointestinal system.
Hypothyroidism does not cause obesity, but modest weight gain from fluid retention and fat deposition often occurs. Gastrointestinal motility is decreased loading to constipation and abdominal distension. Abdominal distension may be caused by ascities as well. Ascitic fluid, like other serous effusions in myxedema, has high protein content. Achlorhydria occurs, often associated with pernicious anemia.
Renal system.
Reduced excretion of a water load may be associated with hyponatriemia. Renal blood flow and glomerular filtration rate are reduced, but serum creatinine is normal. May be mild proteinuria and infections of urinary tract.
Respiratory system.
Dyspnea of effort is common. This complaint may be caused by enlargement of the tongue and larynx, causing upper airway obstruction, or by respiratory muscle weakness, interstitial edema of the lungs, and for pleural effusions which have high protein content. Hoarseness from vocal curt enlargement often occurs.
Musculoskeletal system.
Muscle and joint aches, pains and stiffness are common. Objective myopathy and joint swelling or effusions are less often present. The relaxation phase of the tendon reflexes is prolonged. Serum creatine phosphokinase and alanine aminotransferase activities are often increased, probably as much to slowed enzyme degradation as to increased release from muscle.
Hemopoetic system.
Anemia, usually normocytic, caused by decreased red blood cell production, may occur. It is probably from decreased need of peripheral oxygen delivery rather than hematopoetic defect. Megaloblastic anemia suggests coexistent pernicious anemia. Most patients have no evidence iron, folic acid or cyancobalamin deficiency.
Endocrine system.
There may be menorrhagia (from anovulatory cycles), secondary amenorrhea, infertility and rarely galactorrhea. Hyperprolactinemia occurs because of the absence of the inhibitory effect of thyroid hormone on prolactine secretion (and causes galactorrhea and amenorrhea or Van – Vik – Cheness – Ross’s syndrome).
Pituitary-adrenal function is usually normal. Pituitary enlargement from hyperplasia of the thyrotropes occurs rarely in patients with primary hypothyroidism –such enlargement also may be caused by a primary pituitary tumor, which resulting TSH deficiency.
Enlargement of thyroid gland in young children with hypothyroidism suggests a biosynthetic defect. Hypothyroidism in adults is caused by Hashimoto thyroiditis.
Secretion of growth hormone is deficient because thyroid hormone is necessary for synthesis of growth hormone. Growth and development of children are retarded. Epiphyses remain open.
Metabolic changes.
Hypothermia is common. Hyperlipidemia with increase of serum cholesterol and trigliceride occurs because of reduced lipoprotein lipase activity.
Subclinical (laboratory) hypothyroidism.
It is an asymptomatic state in which serum T4 and free T4 are normal, but serum TSH is elevated. ). This designation is only applicable when thyroid function has been stable for weeks or more, the hypothalamic-pituitary-thyroid axis is normal, and there is no recent or ongoing severe illness. It is a state in which we can’t find clinical features of hypothyroidism and euthyroidism is reached by compensatory increasing of TSH secretion and that’s why synthesis and secretion of such level of thyroid hormone that will be enough for organism.
An elevated TSH, usually above 10 mIU/L, in combination with a subnormal free T4 characterizes overt hypothyroidism. The presence of elevated TPOAb titers in patients with subclinical hypothyroidism helps to predict progression to overt hypothyroidism—4.3% per year with TPOAb vs. 2.6% per year without elevated TPOAb titers. The higher risk of developing overt hypothyroidism in TPOAb-positive patients is the reason that several professional societies and many clinical endocrinologists endorse measurement of TPOAbs in those with subclinical hypothyroidism.The therapy may provide the patient with more energy, a feeling of well being, desirable weight reduction, improved bowel function or other signs of better health even though the patient is not aware of these symptoms before therapy.
Peculiarities of congenital hypothyroidism
• Children are born with increased weight
• Subcutaneous edema
• Hypotermia
• Prolonged jaundice
• Physical (dwarfism) and mental retardation (cretinism
Diagnostic of hypothyroidism is based on:
1) history;
2) clinical features;
3) blood analysis: anemia; hypercholesterolemia;
4) levels of thyroid hormone: both serum T4 and T3 are decreased (but in 25% of patients with primary hypothyroidism may be normal circulating levels of T3);
5) ECG;
6) examination of tendon reflexes;
7) ultrasonic examination;
Measurement of serum TSH is the primary screening test for thyroid dysfunction, for evaluation of thyroid hormone replacement in patients with primary hypothyroidism, and for assessment of suppressive therapy in patients with follicular cell-derived thyroid cancer. TSH levels vary diurnally by up to approximately 50% of mean values. TSH secretion is exquisitely sensitive to both minor increases and decreases in serum free T4, and abnormal TSH levels occur during developing hypothyroidism and hyperthyroidism before free T4 abnormalities are detectable. According to NHANES III, a disease-free population, which excludes those who self-reported thyroid disease or goiter or who were taking thyroid medications, the upper normal of serum TSH levels is 4.5 mIU/L.
Recommendations of Six Organizations Regarding Screening of
Asymptomatic Adults for Thyroid Dysfunction
|
Organization |
Screening recommendations |
|
American Thyroid Association |
Women and men >35 years of age should be screened every 5 years. |
|
American Association of Clinical Endocrinologists |
Older patients, especially women, should be screened. |
|
|
Patients ≥60 years of age should be screened. |
|
American College of Physicians |
Women ≥50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated. |
|
|
Insufficient evidence for or against screening |
|
|
Screening of the healthy adult population unjustified |
Differential diagnosis of primary and secondary hypothyroidism:
1) clinical features:
Secondary hypothyroidism is not common, but it often involves other endocrine organs affected by the hypothalamic – pituitary axis. The clue to secondary hypothyroidism is a history of amenorrhea rather than menorrhagia in a woman with known hypothyroidism.
In secondary hypothyroidism, the skin and hair are dry but not as coarse; skin depigmentation is ofteoted; macroglossia is not prominent; breasts are atrophic; the heart is small without accumulation of the serous effusions in the pericardial sac; blood pressure is low, and hypoglycemia is often found because of concomitant adrenal insufficiency or growth hormone deficiency.
2) laboratory evaluation:
shows a low level of circulating TSH in secondary hypothyroidism, whereas in primary hypothyroidism there is no feedback inhibition of the intact pituitary and serum levels of TSH are very high. The serum TSH is the most simple and sensitive test for the diagnosis of pituitary hypothyroidism.
Serum cholesterol is generally low in secondary hypothyroidism, but high in pituitary hypothyroidism.
Other pituitary hormones and their corresponding target tissue hormones may be low in secondary hypothyroidism.
The TSH test is useful in distinguishing between secondary and tertiary hypothyroidism in the former; TSH is not released in response to TRH; whereas in the later, TSH is released.
Treatment of hypothyroidism.
1. No specific diets are required for hypothyroidism.
2. Regimen is not restricted.
3. 1) replacement therapy:
– desiccated animal thyroid (this is an extract of pig and cattle thyroid glands, which standardized based on its iodine content but they are too variable in potency to be reliable and should be avoided);
– synthetic preparations of :
T4 (l-thyroxine)
– T4 is preparation of choice, because it produces stable serum levels of both T4 and T3.
– Absorption is fairly constant 90 to 95% of the dose. T3 is generated from T4 by the liver.
– The initial dosage can be 1.6 mkg/kg of ideal weight or 12.5-25 mkg in older patients and 25-50 mkg in young adult. Patients who are athyreotic (after total thyroidectomy and/or radioiodine therapy) and those with central hypothyroidism may require higher doses, while patients with subclinical hypothyroidism or after treatment for Graves’ disease may require less. However, patients with subclinical hypothyroidism do not require full replacement doses. Doses of 25-75 μg daily are usually sufficient for achieving euthyroid levels, with larger doses usually required for those presenting with higher TSH values. Moreover, although elderly patients absorb L-thyroxine less efficiently they often require 20-25% less per kilogram daily than younger patients, due to decreased lean body mass
– Young healthy adults may be started on full replacement dosage, which is also preferred after planned (in preparation for thyroid cancer imaging and therapy) or short-term inadvertent lapses in therapy. Starting with full replacement versus low dosages leads to more rapid normalization of serum TSH but similar time to symptom resolution.
– The dosage can be increased in 25-50 mkg increments at 4 to 6 week intervals until clinical and biochemical euthyroidism is achieved. In older patients more gradual increments are indicated. Cautious replacement is particularly warranted in patients with ischemic heart disease, because angina pectoris or cardiac arrhythmia may be precipitated by T4 therapy.
Patients older than 50-60 years, without evidence of coronary heart disease (CHD) may be started on doses of 50 μg daily. Among those with known CHD, the usual starting dose is reduced to 12.5-25 μg/day. Clinical monitoring for the onset of anginal symptoms is essential. Anginal symptoms may limit the attainment of euthyroidism. However, optimal medical management of arteriosclerotic cardiovascular disease (ASCVD) should generally allow for sufficient treatment with L-thyroxine to both reduce the serum TSH and maintain the patient angina-free.
– The average maintenance dosage is 100 to 150 mkg/day orally, only rarely is a larger dosage required. In general, the maintenance dose may decrease in the elderly and may increase in pregnancy.
– The dosage should be minimum that restores TSH levels to normal (though this criterion cannot be used in patients with secondary hypothyroidism). The most reliable therapeutic endpoint for the treatment of primary hypothyroidism is the serum TSH value. Confirmatory total T4, free T4, and T3 levels do not have sufficient specificity to serve as therapeutic endpoints by themselves, nor do clinical criteria. Moreover, when serum TSH is within the normal range, free T4 will also be in the normal range. On the other hand, T3 levels may be in the lower reference range and occasionally mildly subnormal.
– Patients being treated for established primary hypothyroidism should have serum TSH measurements done at 4-8 weeks after initiating treatment or after a change in dose. Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise.
– In patients with central hypothyroidism, assessment of free T4 or free T4 index, not TSH, should be done to diagnose and guide treatment of hypothyroidism.
– Patient takes the whole dose of T4 once a day (in the morning), in the summer the dose may be decreased and in the winter should be increased.
– When a woman with hypothyroidism becomes pregnant, the dosage of L-thyroxine should be increased as soon as possible to ensure that serum TSH is <2.5 mIU/L and that serum total T4 is in the normal reference range for pregnancy. Moreover, when a patient with a positive TPOAb test becomes pregnant, serum TSH should be measured as soon as possible and if >2.5 mIU/L, T4 treatment should be initiated. Serum TSH and total T4 measurements should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation to ensure that the requirement for L-thyroxine has not changed.
T3 (liothyronine sodium) should not be used alone for long-term replacement because its rapid turnover requires that it be taken. T3 is occasionally used mainly in starting therapy because the rapid excretion is useful in the initial titration of a patient with longstanding hypothyroidism in whom cardiac arrhythmia may occur early in replacement therapy. The risk of jatrogenic hyperthyroidism is therefore greater in patients receiving these preparations.
In addition, administering standard replacement amounts of T3 (25 to 50 mkg/day) results in rapidly increasing serum T3 levels to between 300 and 1000 mkg within 2 to 4 h, these levels return to normal by 24 h. Therefore, when assessing serum T3 levels in patients on this particular regimen, it is important for the physician to be aware of the time of prior administration of the hormone. Additionally, patients receiving T3 are chemically hyperthyroid for at least several hours a day and thus are exposed to greater cardiac risks. Similar patterns of serum T3 concentrations are seen when mixtures of T3 and T4 are taken orally, although the peak levels of T3 are somewhat lower. Replacement regimes with synthetic preparations of T4 reflect a different pattern of serum T3 response increases in serum T3 occur gradually over weeks, finally reaching a normal value about 8 wk. after starting therapy.
Synthetic T3 and T4 combinations (liotrix, thyreocomb). These preparations were developed before it was appreciated that T4 is converted to T3 outside of the thyroid. These preparations should not be used.
2) Symptomatic therapy:
– beta-blockers (should be used in patients with tachycardia and hypertension);
– hypolypidemic agents;
– vitamins (A, B, E);
– diuretics and others.
Subclinical hypothyroidism
However, there are virtually no clinical outcome data to support treating patients with subclinical hypothyroidism with TSH levels between 2.5 and 4.5 mIU/L. The possible exception to this statement is pregnancy because the rate of pregnancy loss, including spontaneous miscarriage before 20 weeks gestation and stillbirth after 20 weeks, have been reported to be increased in anti-thyroid antibody-negative women with TSH values between 2.5 and 5.0
Many endocrinologists would treat such patients with T4, especially if hypercholesterolemia were present. Even in the absence of hyperlipidemia, a trial of therapy might be varianted to determine if the patient experiences improvement presumably the normal serum T4 concentrations before therapy did not reflect adequate tissue effects of thyroid hormones in such patients. Unfortunately, it is also reasonable to follow these patients without T4 therapy by surveying thyroid function at 4-to 6 months intervals to determine whether thyroid failure has occurred, as indicated by the serum T4 falling to subnormal levels along with a greater increase in serum TSH and the appearance of clear symptoms.
Reviews by the US Preventive Services Task Force and an independent expert panel found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L. The Endocrine Society recommends thyroxine replacement in pregnant women with subclinical hypothyroidism; the
Amiodarone-induced hypothyroidism
Amiodarone-induced hypothyroidism (AIH) is believed to result from the inability of the thyroid to escape from the Wolff-Chaikoff effect. Thyroid hormone biosynthesis is impaired because of the persistent block in intrathyroidal iodine organification, as evident by the positive perchlorate discharge test in patients with AIH. This may arise from an underlying thyroid abnormality, such as autoimmune thyroiditis. As many as 40% of patients who develop hypothyroidism after amiodarone administration have positive thyroid antibodies, suggesting that iodide excess could unmask some pre-existent subclinical thyroid disease to produce overt thyroid failure.
The reported incidence of AIH varies widely, ranging from 6% in countries with low iodine intake to 13% in countries with a high dietary iodine intake. The risk of developing hypothyroidism is independent of the daily or cumulative dose of amiodarone. However, the risk is greater in the elderly and in female patients, probably as a result of a higher prevalence of underlying thyroid abnormality. The relative risk of developing AIH was found to be 13-fold higher in female patients with positive thyroid microsomal or thyroglobulin antibodies, as compared with men without thyroid antibodies. AIH may be transient or persistent, the latter is almost always associated with an underlying thyroid disorder. Unlike thyrotoxicosis, which may occur anytime during therapy or even after discontinuation of therapy, hypothyroidism is usually an early event and it is uncommon after the first 18 months of amiodarone treatment.
Clinical features and diagnosis
The clinical features of hypothyroidism are usually vague. Fatigue, lethargy, intolerance of cold, and dry skin are commonly reported; goitre is uncommon. The diagnosis is confirmed by a raised serum TSH concentration (usually > 20 mU/l) in combination with low serum levels of free T4. Serum T3 concentration is an unreliable indicator as it can be low in euthyroid patients, whereas hypothyroid patients may have T3 levels within the normal range. In spite of the large iodine load during amiodarone treatment, the majority of patients with AIH have inappropriately elevated thyroid radioactive iodine uptake (RAIU) results.
Treatment
AIH may be managed by either discontinuation of amiodarone therapy or thyroid hormone replacement. Discontinuation of amiodarone may not be feasible because of the underlying indication for its use, especially in the treatment of difficult ventricular tachyarrhythmias. A safer and more reliable option is to institute thyroid hormone replacement therapy, starting with 25–50 μg laevothyroxine daily and increasing at intervals of 4–6 weeks until the symptoms have resolved and the target serum T4 level is achieved.The goal of treatment is to bring serum T4 levels to the upper end of its normal range, as often seen in euthyroid patients who are receiving amiodarone. It is important to realise that patients on amiodarone can have mildly elevated serum TSH levels despite adequate thyroid hormone replacement. Over-replacement will undermine the anti-arrhythmic effect of amiodarone, believed to be mediated via an intracellular state of hypothyroidism within the cardiac tissues. In general, patients should be monitored at 6 weeks and then every 3 months.
In small studies, perchlorate treatment has been shown to restore normal thyroid function rapidly in patients with AIH. The drug relieves iodine-induced inhibition of thyroid hormone synthesis by its ability to discharge inorganic iodine and to block further entry of iodide into the thyroid. As perchlorate toxicity can result from either prolonged use or high dosages (>
In the absence of hypothyroid symptoms or thyroid antibodies, patients with moderately raised serum TSH (< 20 mU/l) but high-normal or raised serum free T4 concentrations may reflect amiodarone-induced alteration in thyroid function parameters or subclinical hypothyroidism. Close monitoring may be all that is necessary in these subjects.
Myxedema coma.
Myxedema coma is an uncommon presentation of severe hypothyroidism that is potentially fatal. Published mortality rates exceed 60%, and even with early detection and appropriate treatment, death occurs in up to 30% of individuals. The term myxedema coma is a misnomer, as myxedema and coma are neither diagnostic criteria nor common presenting findings. A more proper description would be critical hypothyroidism. Because of its lethal nature and nonspecific features, the actual prevalence of myxedema coma is unknown. However, this syndrome is extensively cited in the literature and is not uncommon in clinical practice.
Myxedema coma, or critical hypothyroidism, occurs most often in patients with long-standing, preexisting hypothyroidism. Hypothyroidism is 4 times more common in women than in men, and 80% of cases of myxedema coma occur in females. It occurs almost exclusively in persons 60 years or older. There are approximately 300 cases of myxedema coma reported in the literature. Most cases occur during the winter, when thermoregulatory stressors are high. It can develop from all causes of hypothyroidism, including autoimmune thyroiditis, secondary hypothyroidism, and drug-induced hypothyroidism (eg, caused by lithium or amiodarone).
Clinical Manifestation and Diagnosis
Precipitating factors include:
– exposure to cold;
– infection;
– trauma;
– drugs that suppress the CNS.
Cardiac events (myocardial infarction, congestive heart failure), cerebral infarction, trauma, hemorrhage, hypothermia, hypoglycemia, and respiratory depression secondary to anesthetics or sedatives have also been implicated.
Clinical findings in myxedema coma are similar to those encountered with hypothyroidism, but they are typically seen in greater magnitude. In short, it is a state of profound decreased metabolic activity. Cardinal features include impaired thermoregulation (hypothermia), hypotension, bradycardia, and mental status depression. Mental status depression is a common clinical feature and may progress to stupor, obtundation, or frank coma. The hypometabolic state and mental status depression may result in centrally mediated hypoventilation and hypercapnic respiratory failure. Concomitant endocrinopathies are commonly encountered, most notably adrenal insufficiency, which may contribute to the electrolyte, thermoregulatory, and cardiovascular derangements commonly seen. Hyponatremia resulting from an increased release of antidiuretic hormone and hypoglycemia caused by decreased gluconeogenesis, infection, or adrenal insufficiency are common features. Myxedema is characterized by generalized skin and soft tissue swelling, periorbital edema, ptosis, macroglossia, and the presence of cool, dry skin. Despite the name of the condition, clinically significant myxedema is infrequently identified and is not a diagnostic criteria.
Unlike thyroid storm, most patients with myxedema coma have a prior diagnosis of hypothyroidism. Although it is necessary to confirm the diagnosis, thyroid function testing can be confusing. The diagnosis is suspected clinically and confirmed with TFT. Treatment should not be delayed for laboratory confirmation. Hypothyroidism is diagnosed in individuals with elevated TSH levels and low levels of free T4 and T3. In myxedema coma, T3 and T4 levels may be profoundly diminished or even undetectable. The degree of TFT abnormalities does not distinguish hypothyroidism from myxedema coma. Rather, the distinction is based on clinical findings. Abnormal TFT can be seen in other acute illnesses and does not necessarily reflect myxedema coma or even hypothyroidism. It is important for the clinician to be able to differentiate hypothyroidism from euthyroid sick syndrome, in which patients have a reduction in both TSH and thyroid hormone levels. Given the common association with adrenal insufficiency, a cosyntropin stimulation test should be considered, especially in those with hemodynamic instability.
Treatment of myxedema coma.
The treatment of myxedema coma involves rapid replacement of thyroid hormone, treatment of the precipitating cause, and general supportive measures.
It is treated with large doses of T4 (250-500 mkg I/v bolus 3 – 4 times a day) or T3 if available (40 – 100 mkg I/v bolus 3 times a day), because TBG must be saturated before any free hormone is available for response. The maintenance dose for T4 is 50 mkg/day I/v and for T3 10-20 mkg/day I/v until the hormone can be given orally.
Ventilatory support, passive external rewarming, and correction of underlying electrolyte abnormalities are commonly required. The patient should not be rewarmed rapidly because of the threat of cardiac arrhythmia. Hypoxemia is common, so PaO2 should be measured at the outset of treatment. If alveolar ventilation is compromised, immediate mechanical ventilatory assistance is required.
Glucose and steroid replacement should also be considered until recovery. Given the strong association with infectious causes, antimicrobial therapy should be considered.
Thyroiditis: classification, diagnostic criteria, treatment.
The various types of thyroiditis encompass a heterogeneous group of inflammatory disorders of diverse etiologies and clinical features. With all forms of thyroiditis, destruction of the normal architecture of the thyroid follicular occurs, yet each disorder has distinctive histologic characteristics. For the purposes of understanding the clinical manifestations, thyroiditis is classified according to either the severity or duration of illness using the following scheme:
1. Acute thyroiditis.
2. Subacute thyroiditis:
– subacute granulamatous thyroiditis;
– subacute lymphocytous thyroiditis.
3. Chronic thyroiditis:
– Hashimoto thyroiditis;
– Ridel struma.
4. Specific thyroiditis.
5. Thyroiditis caused by mechanical or physical factors.
Types of Thyroiditis
|
Type |
Cause |
Time course |
Thyroid function |
RAIU at 24 hours |
Anti-TPO antibodies |
Prevalence or incidence |
|
|
Painful |
|||||||
|
Subacute granulomatous |
Infection (viral) |
Subacute |
Hyper, hypo, or both, theormal |
< 5 percent |
Low or absent titer |
Four to five cases per 100,000 persons |
|
|
Suppurative |
Infection (nonviral) |
Acute (nonbacterial may be subacute) |
Normal |
Normal |
Absent |
Undetermined but very rare |
|
|
Radiation or trauma |
Destruction of thyroid parenchyma |
Acute |
Hyper, hypo, or normal |
< 5 percent |
Absent* |
1 percent of those receiving131I for Graves’ disease |
|
|
Painless |
|||||||
|
Hashimoto’s disease |
Autoimmune |
Chronic |
Normal or hypo |
Normal or low |
High titer, persistent |
5 to 10 percent |
|
|
Postpartum |
Autoimmune |
Subacute |
Hyper, hypo, or both, theormal |
< 5 percent |
High titer, persistent |
5 to 7 percent of postpartum women |
|
|
Subacute lymphocytic |
Autoimmune |
Subacute |
Hyper, hypo, or both, theormal |
< 5 percent |
Present, persistent |
10 to 15 cases per 100,000 persons |
|
|
Drug-induced |
|||||||
|
|
Amiodarone (Cordarone) |
Inflammation |
Acute or subacute |
Hyper or hypo |
Low |
Absent |
10 percent |
|
|
Interferon-alfa (Infergen; Intron A, Roferon-A, Rebetron combination therapy) |
Inflammation |
Acute or subacute |
Hyper or hypo |
Low |
5 to 10 percent positive |
10 to 15 percent |
|
|
Interleukin-2 |
Inflammation |
Acute or subacute |
Hyper or hypo |
Low |
< 10 percent positive |
Undetermined |
|
|
Lithium |
Autoimmune |
Acute or subacute |
Hyper theormal, or low |
Low |
33 percent positive |
13 cases per 100,000 persons |
|
Riedel’s |
Fibrosis |
Chronic |
Normal or low |
Normal or low |
Present |
Undetermined |
|
RAIU = radioactive iodine uptake; TPO = thyroid peroxidase; hyper = hyperthyroidism; hypo = hypothyroidism.
*—May be present if patient has underlying Graves’ disease.
Source: Thyroiditis. ARCHANA BINDRA, M.D., and GLENN D. BRAUNSTEIN, M.D., Cedars-Sinai Medical Center, Los Angeles, California // Am Fam Physician. 2006 May 15;73(10):1769-1776.
Acute thyroiditis
Etiology
Acute thyroiditis it is an acute bacterial inflammation due to a bacterial pathogen, most commonly staphylococcus aureus, streptococcus hemolytica,streptococcus pneumonie, of anaerobic streptococcal organisms. Infection due to other bacterial pathogens, such as salmonella and escherichia coli have been reported, as well as fungal infections such as coccidiodomycosis. Infection occurs either secondary to hematogenous or lymphatic spread, or as a result of direct introduction of an infective agent by trauma. This disorder is rare because of the inherent resistance of the thyroid gland to infection. Microbial inflammatory thyroiditis occurs most often in women 20 to 40 years of age. Most patients have a preexisting thyroid disorder, usually nodular goiter.
Clinical features
Fever, chills and other systemic signs or symptoms of abscess formation are present. Anterior neck pain and swelling are usual, with pain occasionally radiating to the ear or mandible.
The physical examination suggests the presence of an abscess, with erythema of the skin, marked tenderness to palpation, and at times fluctuance.
Laboratory tests
Leucocytosis with a left shift, increased ESR are usually present. Thyroid hormone concentrations in blood are normal, although hyperthyroxinemia has been reported. RAIU may be normal or show cold nodules in areas of abscess formation. The cause of infection is first determined by culture and sensitivity of samples obtained through fine-needle aspiration.
Treatment
Patient should be treated at surgical department. Parental antibiotics should be administered according to the specific pathogen identified. If fluctuance is present, incision and drainage might be required. Bacterial thyroiditis must be treated early and aggressively, since abscess formation can occasionally dissect downward into the mediastinum. Heat, rest and aspirin provide symptomatic relief; steroids may offer additional benefit. The disease is usually self-limited, lasting weeks to months.Recurrences of the disorder are very rare. (Duration of the treatment must be nearly 1,5-2 month).
Subacute granulomatous thyroiditis (giant cell thyroiditis) SAT.
Etiology
Subacute granulomatous thyroiditis is the most common cause of a painful thyroid gland. It is most likely caused by a viral infection and is generally preceded by an upper respiratory tract infection. Numerous etiologic agents have been implicated, including mumps virus, echovirus, coxsackievirus, Epstein-Barr virus, influenza and adenovirus. A genetic predisposition is likely because of the association of HLA-BW 35 histocompatibility antigens.
Epidemiology
Women are three to five times more likely to be affected than men. The average age of onset is 30 to 50 years. The disorder tends to be geographical and seasonal, occurring most often in the summer and fall.
Clinical features
The most common symptom is unilateral anterior neck pain, often associated with unilateral radiation of pain to the ear or mandible. Pain is often proceeded by a few weeks prodrome of myalgias, low-grade fever, malaise and sore throat. Dysphagia is also common. Symptoms of hyperthyroidism (such as tachycardia, weight loss, nervousness, and diaphoresis occur in up to 50% of patients as the disorder processes, pain can migrate to the contralateral side.
Physical examination discloses an exquisitely tender, very hard, nodular enlargement, which is most often unilateral. Tenderness is often so extreme that palpation is limited. Bilateral tenderness and goiter can occur as well. Tachycardia, a widened pulse pressure, warm skin and diaphoresis are also observed when hyperthyroidism is present.
Laboratory findings.
Early in the disease we can find an increase in T4, a decrease in RAI uptake (often 0) and a high ESR. A normal ESR essentially rules out the diagnosis of subacute granulomatous thyroiditis. The leukocyte count is normal or slightly elevated. Thyrotoxicosis is present in 50 percent of patients in the acute phase, and the serum T4 concentration is disproportionately elevated relative to the T3 level. Serum TSH concentrations are low to undetectable. Thyroglobulin is elevated. A normal thyroglobulin level essentially rules out the diagnosis of subacute granulomatous thyroiditis. The RAIU is notably low, often less than 2 percent at 24 hours. In summary, the physical examination, an elevated ESR, an elevated thyroglobulin level and a depressed RAIU confirm the diagnosis.
After a several weeks, the T4, is decreased and the RAI uptake remains low. Full recovery is the rule; rarely, patients may become hypothyroid.
Treatment
The natural history of subacute granulomatous thyroiditis involves four phases that generally unfold over four to six months. The acute phase of thyroid pain and thyrotoxicosis may last three to six weeks or longer. Transient asymptomatic euthyroidism follows. Hypothyroidism often ensues and may last weeks to months or may be permanent (in up to 5 percent of patients). The final phase is a recovery period, during which thyroid function tests normalize.
Therapy with antithyroid drugs is not indicated in patients with subacute granulomatous thyroiditis because this disorder is caused by the release of preformed thyroid hormone rather than synthesis of new T3 and T4. Therapy with beta blockers may be indicated for the symptomatic treatment of thyrotoxicosis. Nonsteroidal anti-inflammatory drugs are generally effective in reducing thyroid pain in patients with mild cases. Patients with more severe disease require a tapering dosage of prednisone (20 to 40 mg per day) given over two to four weeks. Up to 20 percent of patients experience the recurrence of thyroid pain on discontinuation of prednisone.RAIU can assist clinicians in determining patients at high risk for relapse. Low RAIU uptake implies ongoing inflammation, and steroid therapy should be continued.
Following the acute phase euthyroidism is restored, and the thyroid becomes depleted of stored hormone. Patients can either remain euthyroid or progress to hypothyroid phase. It rarely lasts longer than 2-3 months, and during this phase thyroid hormone replacement in the form of levothyroxine 0,10-0,15 mg/day should be given. After several months of treatment T4 can be discontinued.
Following the hypothyroid phase recovery occurs, and the normal histologic features and secretory capacity of the thyroid are restored.
Subacute lymphocytic thyroiditis (silent thyroiditis)
Subacute lymphocytic thyroiditis occurs most often in the postpartum period but may also occur sporadically. Therefore, it is subdivided into two groups, postpartum thyroiditis and sporadic painless thyroiditis. Antimicrosomal antibodies are present in 50 to 80 percent of patients, while antithyroid peroxidase antibodies are present iearly all patients. Subacute lymphocytic thyroiditis starts with an initial hyperthyroid phase, followed by subsequent hypothyroidism and, finally, a return to the euthyroid state. In the postpartum patient, thyrotoxicosis usually develops in the first three months following delivery and lasts for one or two months. Then the patient returns to a euthyroid state or hyperthyroidism ensues for several months. Patients with an initial episode of postpartum subacute lymphocytic thyroiditis have a notably high risk of recurrence in subsequent pregnancies. Serum TSH testing is indicated in symptomatic patients.
EPIDEMIOLOGY
Subacute lymphocytic thyroiditis comprises 29 to 50 percent of all cases of thyroiditis and occurs most often in women between 30 and 50 years of age. There is a higher incidence of antimicrosomal antibodies in the postpartum form (80 percent) of the disease than in the sporadic form (50 percent). A family history of autoimmune thyroid disease is found in 50 percent of patients with the postpartum form of thyroiditis. The severity of the hypothyroid phase correlates directly with the antimicrosomal antibody titer. A titer of 1:1,600 or greater early in pregnancy is associated with a high risk of postpartum hypothyroidism. Approximately 6 percent of patients who have the postpartum form develop chronic hypothyroidism.
Etiology
Recent evidence suggests on:
1) autoimmune component (because of autoantibodies observed);
2) genetic predisposition (this is a significant prevalence of HLA-DRW3 and HLA-DRW5 histocompatibility agents);
3) viral etiology (viral antibody titers are rarely elevated);
Clinical features.
Hyperthyroid symptoms are frequent and vary from mild to normal. (Postpartum thyroiditis occur 6 weeks to 3 months after delivery).
Physical examination usually discloses a mildly enlarged, diffuse, firm, nontender goiter it has been reported that up to 50 % of patients do not have goiter.
Laboratory findings
The ESR and white blood cell count are normal. T4 and triiodothyronine (T3) levels are initially elevated, with a disproportionate increase in T4 compared with T3. RAIU is decreased in the hyperthyroid phase of the disease and is almost always less than 3 percent. This situation contrasts markedly with the elevated RAIU found in patients with Graves’ disease. Biopsies reveal lymphocytic infiltration as seen in Hashimotos thyroiditis.
Thyroid autoantibodies are positive in greater than 50 % of patients.
Treatment
Hyperthyroid phase lasts from 6 weeks to 3 month. Treatment is conservative, usually requiring only B-adrenergic blockers (propranolol). Antithyroid drugs, which inhibit the production of new T4, are not indicated in the management of patients with hyperthyroidism because symptoms are caused by the release of preformed T3 and T4 from the damaged gland.
Euthyroid interval lasts for 3-6 weeks.
Replacement of thyroid hormone in the hypothyroid phase is indicated if the patient’s symptoms are severe or of long duration. During hypothyroid period (it usually lasts no longer than 2-3 months) thyroid hormone supplementation with T4 0,10-0,15 mg/day may be required. Following the hypothyroid phase patients usually remain clinically euthyroid. If the hypothyroid phase lasts longer than six months, permanent hypothyroidism is likely.
Hashimoto thyroiditis (chronic lymphocytic thyroiditis)
Etiology
HT is an organ – specific autoimmune disorder, a chronic inflammation of the thyroid with lymphocytic infiltration of the gland generally thought to be caused by autoimmune factors.
It is more prevalent (8:1) in woman than men and is most frequent between the ages of 30 and 50 . A family history of thyroid disorders is common, and incidence is increased in patients with chromosomal disorders, including Turners, Down and Klinefelters syndromes. Histologic studies reveal extensive infiltration of lymphocytes in the thyroid.
The basic defect underlying this disease suggests an abnormality in suppressor T lymphocytes that allows helper T lymphocytes to interact with specific antigens directed against the thyroid cell. A genetic predisposition is suggested because of the frequent occurrence of the HLA- DR5 histocompatibility antigen in patients with HT.
A genetic predisposition to thyroid auto-immunity exists; it is inherited as a dominant trait. Hashimoto’s disease has been linked to other autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, diabetes mellitus and Sjögren’s syndrome. A rare but serious complication of chronic autoimmune thyroiditis is thyroid lymphoma. These lymphomas, generally the B-cell, non-Hodgkin’s type, tend to occur in women 50 to 80 years of age and are usually limited to the thyroid gland.
Pict. Interstitial lymfoid infiltrate (HASH)
Pict. Low power view of a case of Hashimoto’s thyroiditis.
Notice lymphoid follicles
Pict. High power view of a case of Hashimoto’s thyroiditis
showing lymphoid follicles within thyroid tissue.
Clinical features
HT is characterized by a wide spectrum of clinical features, ranging from no symptoms and the presence of small goiter to frank myxedema. At the time of diagnosis, symptoms of hypothyroidism are present in 20 percent of patients.
Occasionally patients complain of a vague sensation of tightness in the area of the anterior neck or mild dysphagia, however, neck pain and tenderness are rare. In general, however, thyroid enlargement is insidious and asymptomatic. Symptoms of hypothyroidism may or may not be present, depending on the presence or absence of biochemical hypothyroidism.
Physical examination usually discloses a symmetrically enlarged, very firm goiter, a smooth or knobby consistency is common. Occasionally patients present with a single thyroid nodule.
A small group of patients have a form of HT termed primary idiopathic hypothyroidism, goiter is usually absent in this group.(atrophic form of HT).
Yet a small subset of patients(probably 2-4%) present with hyperthyroidism and have so-called hashitoxicosis (hypertrophy from of HT).
Laboratory findings
1) The erythrocyte sedimentation rate (ESR) and white blood cell count are normal.
2) The definitive indicator of chronic lymphocytic thyroiditis is the presence of thyroid-specific autoantibodies in the serum. The three main targets for thyroid antibodies are thyroglobulin (a protein carrier for thyroid hormones), thyroid microsomal antigen (also called thyroid peroxidase) and the thyroid-stimulating hormone (TSH) receptor. Low levels of circulating antibodies are common in other thyroid diseases, such as multinodular goiter and thyroid malignancy. Antithyroid microsomal antibodies in titers greater than 1:6,400 or antithyroid peroxidase antibodies in excess of 200 IU per mL, however, are strongly suggestive of chronic autoimmune thyroiditis. Testing of thyroid autoantibodies and measurement of serum thyroglobulin levels will confirm the diagnosis.
3) early in the disease a normal T4. Late in the disease, the patient develops hypothyroidism with a decreased in T4 and antibodies in this stage are usually no longer detectable;
4) the thyroid scan typically shows a irregular pattern of iodine uptake; Radioactive iodine uptake (RAIU) is variable and can be depressed, normal or increased, depending on the extent of follicular destruction.
5) Ultrasonography shows an enlarged gland with a diffusely hypoechogenic pattern in most patients.
6) fine-needle biopsy of the nodule or enlarging area should be done to rule out a coexistent neoplasm.
Treatment
1) treatment of HT requires lifelong replacement with thyroid hormone to correct and prevent hypothyroidism. The average oral replacement dose with l-thyroxine is 100 to 150 mkg/day;
2) glucocorticoids have been reported to be effective in HT when true is a rapidly enlarging goiter associating with pressure symptoms;
3) symptomatic therapy
Ridel thyroiditis
Etiology
This extremely rare inflammatory disorder is of uncertain etiology, and earlier suggestions that it might be a fibroid variant of HT have not been substained.
Clinical features
Clinically, Ridel thyroiditis presents with pressure symptoms, and on examination an extremely hard , immobile thyroid gland is palpated The thyroid can be uniformly enlarged, or only one lobe might be affected. The disorder can be associated with other focal sclerosing symptoms, including retroperitoneal and mediastenal fibrosis and ascending cholecystitis.
Laboratory findings
1. Thyroid function tests show hypothyroidism in approximately 25 % of patients.
2. Thyroid antibodies are usually negative.
3. The thyroid scan shows decreased uptake in involved areas.
Treatment
– is surgical for those patients in whom symptoms of obstruction occur.
– Thyroid hormone is required for treatment of hypothyroidism, but thyroid hormone alone will not result in goiter shrinkage.
Clinical Manifestations of Thyroiditis Subtypes
|
Subtype |
Etiology |
Neck pain |
RAIU |
TSH |
T4 |
Thyroid autoantibodies |
|
Chronic lymphocytic (Hashimoto’s disease) |
Autoimmune |
No |
Variable |
Variable |
Variable |
Present |
|
Subacute granulomatous |
Viral |
Yes |
Decreased |
Decreased |
Increased |
Absent |
|
Subacute lymphocytic |
Autoimmune |
No |
Decreased |
Decreased |
Increased |
Present |
|
Microbial inflammatory |
Bacterial, fungal, parasitic |
Yes |
Variable |
Normal |
Normal |
Absent |
|
Hashitoxicosis |
Autoimmune |
No |
Decreased |
Decreased |
Increased |
Present |
|
Invasive fibrous |
Unknown |
No |
Variable |
Normal |
Normal |
Variable |
– RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone; T4 = thyroxine.
Differentiating Thyroiditis
Source: Thyroiditis: Differential Diagnosis and Management JOHN SLATOSKY, D.O., BENJAMIN SHIPTON, D.O., and HANEY WAHBA, M.D., Mercy Hospital, Pittsburgh, Pennsylvania. Am Fam Physician. 2000 Feb 15;61(4):1047-1052.
RADIATION-INDUCED THYROIDITIS
Approximately 1 percent of patients who have radioactive iodine therapy for hyperthyroidism develop radiation thyroiditis between five and 10 days after the procedure. The rapid destruction of the thyroid parenchyma results in pain, tenderness, and an exacerbation of hyperthyroidism from the release of stored T4 and T3. A brief course of NSAIDs or, rarely, prednisone in dosages of 40 to 60 mg per day may be used to alleviate pain; a beta blocker often is required to block the peripheral effects of the thyroid hormone. The gland eventually undergoes extensive fibrosis in approximately six to 18 weeks.
Thyroiditis also may develop from radiation therapy for lymphoma or head and neck cancers. The major risk factors for developing thyroid damage after external irradiation are high-dose irradiation, younger age, female sex, and preexisting hypothyroidism.
TRAUMA-INDUCED THYROIDITIS
Transient thyroiditis with pain and tenderness has beeoted on rare occasions following physical trauma to the thyroid. Low RAIU with normal or elevated T4 levels and normal or suppressed TSH levels may be found; however, these findings add little practical information to the clinical history and, because the effects of trauma are self-limited, work-up is not necessary.
DRUG – INDUCED THYROIDITIS
Amiodarone (Cordarone), interferonalfa (Infergen; Intron A, Roferon-A, Rebetron combination therapy), interleukin-2, and lithium may cause a destructive thyroiditis with hyperthyroidism or hypothyroidism, low RAIU, and variable presence of antithyroid peroxidase antibodies. Treatment is similar to that of subacute granulomatous or lymphocytic thyroiditis. The thyroid abnormalities usually resolve with discontinuation of the drug responsible.
Amiodarone-induced thyrotoxicosis
Amiodarone is a class III antiarrhythmic drug used in the treatment of recurrent severe ventricular arrhythmias, paroxysmal atrial tachycardia, atrial fibrillation and maintenance of sinus rhythm after cardioversion of atrial fibrillation. Amiodarone-induced thyrotoxicosis (AIT) develops in 3% of amiodarone-treated patients in
The thyrotoxicosis is mediated by amiodarone’s iodine content. In each 200 mg tablet, there is 75 mg of iodine; approximately 10% of the iodine is released as free iodide daily. Amiodarone is very lipophilic and accumulates in adipose tissue, cardiac and skeletal muscle, and the thyroid. With long-term treatment, there is a 40-fold increase in plasma and urinary iodide levels, and an elimination half-life of 50 to 100 days. The pharmacological concentration of iodide associated with amiodarone treatment causes inhibition of thyroidal T4 and T3 production and release within the first two weeks of treatment (the Wolff-Chaikoff effect). Amiodarone also inhibits type 1 5′-deiodinase activity in peripheral tissue. Amiodarone and its metabolites demonstrate direct toxicity to cultured thyroid cells exposed to media with concentrations above those normally found in patients.
The effects of amiodarone on the thyroid can be seen as early as a few weeks after starting treatment and/or up to several months after its discontinuation. Because thyroid dysfunction is relatively common in amiodarone therapy, all patients should have free thyroxine and thyroid-stimulating hormone (TSH) levels measured before starting therapy, at three- to four-month intervals during treatment and for at least one year after the amiodarone is discontinued. A diagnosis of AIT can also be considered at any time in a patient who develops clinical signs of thyrotoxicosis. Cardiac manifestations may be absent due to amiodarone’s effect on the heart. Any patient who is taking amiodarone or has discontinued it within the previous year should be evaluated for AIT if they develop cardiac decompensation such as ventricular tachycardia.
The differential diagnoses of AIT are classified as type 1 and type 2. Type 1 AIT occurs in patients with an underlying thyroid pathology such as autonomous nodular goiter or Graves’ disease. In these patients, there is accelerated thyroid hormone synthesis secondary to the iodide load from the amiodarone therapy (the Jod-Basedow phenomenon). In type 2 AIT, the thyrotoxicosis is a destructive thyroiditis that results in excess release of preformed T4 and T3 into the circulation. It typically occurs in patients without underlying thyroid disease, and is caused by a direct toxic effect of amiodarone on thyroid follicular cells. The thyrotoxic phase may last several weeks to several months, and it is often followed by a hypothyroid phase with eventual recovery in most patients. For unclear reasons, the toxic effects of amiodarone may take two to three years to manifest. The majority of cases of AIT in
DIFFERENTIATING BETWEEN TYPE 1 AND TYPE 2 AIT
Differentiating type 1 from type 2 is important because it has therapeutic implications. However, this may be difficult because many patients have a mixture of both mechanisms. Thyroid function tests are not helpful in differentiating type 1 from type 2 AIT. Evaluation should include a careful history and physical examination to determine whether the patient has a pre-existing thyroid condition. Physical examination may reveal a goiter or exophthalmos. Ultrasonography of the thyroid may show an enlarged gland or a nodular goiter.
The iodine-131 uptake test can help differentiate type 1 from type 2 AIT. The uptake is typically normal or high in type 1 AIT, whereas in type 2, there is very little or no uptake of the iodine due to destruction or damage to the thyroid tissue. However, some patients with type 1 AIT may have uptake values below 3% because the uptake of radioiodine tracer is inhibited by high intrathyroidal iodine concentrations, even with accelerated thyroid activity. This is common in iodine-sufficient areas and can lead to a misdiagnosis of patients with type 1 AIT.
Biochemical markers to detect destruction of the thyroid gland can provide further information but may not assist with the diagnosis. For example, serum thyroglobulin levels may be elevated in both type 1 and type 2 AIT. Elevation in type 2 AIT is due to thyroid gland destruction, whereas in type 1, it may simply be due to the goiter, regardless of whether there is hyperthyroidism or autoimmunity. The presence of thyrotropin receptor antibodies suggests Graves’ disease. Interleukin-6 (IL-6) is thought to be a better marker because it has been found to be normal or mildly elevated in patients with type 1 AIT and significantly elevated in patients with type 2 AIT. IL-6 may be elevated in patients with other coexisting illnesses such as heart failure, nonthyroidal conditions and other thyroid conditions such as Graves’ disease. Additionally, some patients with type 2 AIT have been reported to have unexpectedly low IL-6 levels, which may be related to the commercial assay used. Overall, it is believed that IL-6 testing should be used to follow patients with type 2 AIT who present with significantly elevated levels of IL-6, or have exacerbations during weaning of treatment and in cases of type 1 AIT that recur or fail to respond to treatment.
A tool that is considered to be the best for rapid and early diagnosis of type 1 and 2 AIT is CFDS. This test determines the amount of blood flow within the thyroid and provides information about the morphology of the thyroid. Eighty per cent of patients can be classified as having type 1 or 2 AIT by CFDS.
MANAGEMENT
Treatment of AIT is difficult, especially when the type is uncertain. Factors complicating the treatment decision include the importance of amiodarone in the management of the patient’s arrhythmia. Additionally, amiodarone’s long drug elimination half-life and the large total-body iodine stores indicate that the thyrotoxicosis may not resolve for months.
Overall, mild AIT resolves spontaneously in approximately 20% of cases. Type 1 AIT is treated with a thionamide because it is caused by increased hormonal synthesis. Higher than average doses are often required (eg, propylthiouracil 450 mg to 600 mg daily, or methimazole 30 mg to 40 mg daily). The dose is gradually tapered to a low maintenance dose. If the amiodarone is stopped, the thionamide can be discontinued after six to 18 months, when the urine iodide level returns to normal; however, if amiodarone is continued and the thyrotoxicosis is thought to be secondary to the iodide load, the patient should remain on the thionamide.
Another therapy for type 1 AIT is potassium perchlorate, which minimizes intrathyroidal iodine content by competitively inhibiting thyroidal iodine intake. Potassium perchlorate must be used with caution, because high doses are associated with aplastic anemia. It is recommended that daily doses be less than 1000 mg, or dosages be tapered or stopped after 30 days. Perchlorate is also not currently available in
Type 2 AIT is treated with glucocorticoids for anti-inflammatory and membrane-stabilizing effects. Prednisone is started at 40 mg to 60 mg daily and tapered over two to three months. During the taper, exacerbations can occur, which should be treated by increasing the steroid dose again. Patients may develop transient hypothyroidism when the thyrotoxicosis resolves and may benefit from thyroid hormone replacement therapy. Lithium has also been used in patients with type 2 AIT. It is believed that lithium inhibits thyroid hormone secretion.
For patients who fail to respond to therapy, total thyroidectomy should be considered. Often, the risk of surgery under careful cardiovascular monitoring is less than the risk of several months of uncontrolled thyrotoxicosis. The use of plasmapheresis has only been described in case reports.
Cancer of the thyroid gland
The thyroid consists predominantly of follicular epithelial cells, which incorporate iodine into thyroid hormone to be stored in follicles, and of smaller numbers of parafollicular cells, which produce calcitonin (CT). Malignant transformation of either type of cell may occur, but the parafollicular malignancy (medullary carcinoma of the thyroid [MCT]) is much less common than cancers derived from follicular epithelial cells. Malignancies originating from follicular epithelial cells are designated according to their microscopic appearance and include papillary, follicular, and anaplastic carcinomas
Papillary carcinoma and its variants comprise approximately 60-80% of thyroid cancers, whereas follicular carcinoma makes up approximately 15-30% of primary thyroid malignancies. These two forms are frequently referred to as the differentiated thyroid carcinomas (DTCs). MCT accounts for 2-10% of thyroid carcinomas, whereas anaplastic forms of thyroid carcinoma account for 1-10%.
Papillary and follicular carcinomas are histologically distinct. Papillary carcinoma is generally an unencapsulated tumor marked by enlarged cells with dense cytoplasm and overlapping nuclei that have granular, powdery chromatin, nucleoli, and pseudonuclear inclusion bodies (often called “Orphan Annie eyes”), all arranged in papillary fronds. Follicular carcinoma is generally characterized by atypical-appearing thyroid cells with dense, uniform, overlapping nuclei, and a disorganized microfollicular architecture.
Papillary and follicular carcinomas behave as clinically distinct entities. Most endocrinologists consider follicular carcinoma to be the more aggressive of the differentiated cancers, with a higher rate of metastases, more frequent recurrence after therapy, and an exaggerated mortality rate compared with the relatively indolent papillary carcinoma. This view is not universal. Some authors believe that the sharp dichotomy between the clinical courses of papillary and follicular carcinomas is artificial and attribute the apparent aggressiveness of follicular carcinoma to its occurrence in an older population; they argue that when cases are controlled for age, outcomes of patients with either form of DTC are comparable.
Papillary carcinoma usually presents as a painless nodule within the thyroid gland or cervical lymphatics. The primary tumor is rarely encapsulated (4-22% in most series) but is less aggressive if a capsule is present. Papillary carcinoma is more commonly multifocal within the thyroid than is follicular carcinoma; 20-80% of glands have multiple lesions at resection. Extrathyroidal invasion through the capsule of the thyroid occurs in 5-16% of cases. Compared with other malignancies, papillary carcinoma is relatively indolent. Cancer-related death occurs in only 4-12% of patients during 20-year follow-up. Prognostic factors at the time of diagnosis that augur a poor outcome include male sex, age > 40 years, extrathyroidal invasion, distant metastases, and large primary tumor (>
Follicular carcinoma usually presents as an asymptomatic nodule within the thyroid, but unlike papillary carcinoma, it may present as an isolated metastatic pulmonary or osseous focus without a palpable thyroid lesion. Very rarely metastatic foci of follicular carcinoma retain hormonal synthetic capability and overproduce thyroid hormones, causing thyrotoxicosis. The tumor is nearly always encapsulated, and the degree of vascular or capsular invasiveness (minimal to extensive) is indicative of malignant potential. Follicular carcinoma is usually unifocal (< 10% multifocal). Death due to follicular carcinoma occurs in 13-59% of patients followed for 20 years. Prognostic factors at the time of initial therapy that portend a poor outcome include age greater than 50 years, male sex (in some settings), marked degree of vascular invasion, and distant metastases.
Treatment of DTCs
Patients with large or aggressive tumors, metastatic disease evident during surgery, or extrathyroidal lesions visible on postsurgical whole-body scans usually receive 100-200 mCi of 131I in an attempt to eradicate the malignancy. These “large” doses of radioiodine have traditionally been administered only in an approved inpatient facility under the auspices of the Nuclear Regulatory Commission (NRC). Patients remain isolated until ambient levels of radioactivity fall to acceptable levels. Radionuclide is excreted renally, but significant amounts are also present in saliva and sweat. Such wastes must be disposed of appropriately. Recently, the NRC has lifted the absolute requirement for inpatient administration of high-dose 131I, and it is now performed in some centers on an outpatient basis.
Late complications of high-dose radioiodine therapy may include gonadal dysfunction and predisposition to nonthyroidal malignancies. Some studies have demonstrated reduced sperm counts in male patients proportional to the administered dose of 131I. Older women may experience temporary amenorrhea and reduced fertility. Two deaths from bladder cancer and three deaths from leukemia have been reported among patients treated with lifetime cumulative doses of radioiodine exceeding 1000 mCi. Most studies suggest that cumulative doses of 131I less than 700-800 mCi, given in increments of 100-200 mCi separated by 6-12 months, are not leukemogenic.
Following surgery and radioiodine therapy, all patients are placed on a large enough dose of exogenous thyroid hormone to render serum TSH levels low or undetectable. Most endocrinologists recommend detecting recurrent disease in the asymptomatic patient by annual neck palpation and serum thyroglobulin measurement. This protein, manufactured only by normal or malignant thyroid cells, should be undetectable in the serum of a patient who has undergone complete surgical and radioiodine ablation. Sensitivity of thyroglobulin measurement is enhanced if the patient is withdrawn from exogenous thyroid hormone or stimulated with recombinant TSH
1. Papillary and follicular carcinomas comprise the DTCs. Mortality rates are low.
2. DTC is diagnosed by fine needle aspiration (FNA) of a thyroid nodule.
3. Therapy of DTC is based on surgical resection of the primary tumor and removal of all remaining thyroid tissue (bed).
4. Orally administered radioactive iodine is accumulated by thyroid tissue, ablating the thyroid bed and metastatic foci.
5. Thyroglobulin is the most sensitive tumor marker for DTC.
6. Elimination of TSH, a DTC growth factor, by suppressive doses of levothyroxine is the most important therapeutic intervention
The type of histologic variant does not appear to affect outcome; prognosis is dismal in most cases. Surgical extirpation has been combined with external beam irradiation (4500-6000 cGy) or chemotherapy (usually doxorubicin or paclitaxel) in an attempt to eradicate the malignancy. Despite vigorous therapy, average survival is approximately 6-8 months.
Iodine deficiency pathology
Iodine deficiency is considered to be the most common endocrinopathy and most preventable cause of mental retardation globally. In 1998, one-third of the world’s population lived in iodine-deficient areas. Although the primary recognized manifestation of iodine deficiency is endemic goiter, it is only the most visible and well-documented sign of a deficiency. There are several manifestations of iodine deficiency now termed iodine deficiency disorders. The majority of these manifest in infants and children as a result of maternal iodine deficiency. Hearing loss, learning deficits, brain damage, and myelination disorders can occur due to fetal or perinatal hypothyroidism. Infant mortality rates have decreased 65 percent in communities where iodine deficiencies have been eliminated. Maternal iodine deficiency manifests as low thyroxine, elevated thyroid stimulating hormone (TSH), and subclinical thyroid enlargement (subclinical goiter). As pregnancy and lactation increase iodine loss, the risk for goiter continues, and even after lactation ceases it may manifest as multinodular goiter and hyperthyroidism. Iodine deficiency in women can lead to overt hypothyroidism and consequent anovulation, infertility, gestational hypertension, spontaneous first-trimester abortion, and stillbirth. Iodine deficiency is also associated with increased risk for thyroid carcinoma in animal models and humans.
In mild deficiencies, euthyroid (normal thyroid hormone levels) states may occur but at the expense of thyroid enlargement, neck compression, and thyroid nodules with possible development of hyperthyroid – ism. 11 Mild hypothyroidism in pregnant women secondary to iodine deficiency is associated with lower IQ and cognitive deficits in their children. In an area of endemic goiter, iodine administra – tion to infants was shown to normalize delayed immunity using skin testing with tetanus toxoid, suggesting a role of iodine sufficiency iormal delayed immunity. Dietary Levels of Iodine: The Japanese Phenomenon Japanese populations have historically consumed significant amounts of dietary iodine from sea – weed intake, possibly consuming a minimum of 7,000 mcg iodine daily from kombu alone. Estimates of the average daily Japanese iodine consumption vary from 5,280 mcg to 13,800 mcg; by comparison the aver – age U.S. daily consumption is 167 mcg. The Japanese, therefore, consume dietary iodine approximately 5-14 times above the upper safety limit of 1 mg by U.S. standards. Mean urinary iodine levels in Japanese populations are approximately twice the levels found in the U.S. NHANES 2001-2002 data. These higher levels, however, appear to have no suppressive effect on thyroid function as indicated by thyroid volume measurements, the accepted standard for assessing thyroid enlargement. A study comparing urine iodine and thyroid volume in Japanese children showed 16 percent of those tested excreted over 1,000 mcg/L. Elevated levels of urinary iodine did not predict increased thyroid gland volume, as might be expected from data in studies of Chinese populations associating excess levels of iodine with autoimmune thyroiditis and hypothyroidism. Japanese women who consume a traditional high-seaweed diet also have a low incidence of benign and malignant breast disease.
Elevated levels of urinary iodine did not predict increased thyroid gland volume, as might be expected from data in studies of Chinese populations associating excess levels of iodine with autoimmune thyroiditis and hypothyroidism. Japanese women who consume a traditional high-seaweed diet also have a low incidence of benign and malignant breast disease. Japanese women who consume a Western diet low in seaweed or who emi grate to the United States lose this protective advantage and gain the same risk for fibrocystic breast disease and breast cancer as their Western counterparts. Japan also has a low incidence of iodine-deficiency goiter and autoimmune thyroiditis. It has been hypothesized the amount of iodine in the Japanese diet has a protective effect for breast and thyroid disease.
The Role of Iodine in the Human Body
Iodine is found iature in various forms: inorganic sodium and potassium salts (iodides and iodates), inorganic diatomic iodine (molecular iodine or I2 ), and organic monoatomic iodine. Sea – weeds, such as wakame, nori or mekabu (used in sushi, soups, salads, and in powdered form as a condiment) and widely consumed in Asian cultures, contain high quantities of iodine in several chemical forms, including iodine in the molecular form (I2 ) and iodine organified to proteins. These forms of iodine are absorbed through the intestinal tract via two different mechanisms. Molecular iodine (I2) is transported by facilitated diffusion. Iodides (I -) are absorbed via a transport protein in the gastric mucosa called the sodium-iodide symporter, a molecule found in a variety of tissues in the body that utilize and concentrate iodine – the thyroid, mammary tissue, salivary gland, and cervix.
In order to produce concentrated iodine-based hormones, the thyroid tissue sodium-iodide symporter protein, a critical plasma membrane protein in the thyroid follicular cells, sequesters iodide from the extracellular fluid. The iodide molecule then moves across the apical membrane to the cell-colloid surface where it is oxidized by thyroid peroxidase (TPO). In this form it is bound to tyrosine residues in the thyroglobulin molecule and these mono- and diiodotyrosines become the precursors to commonly known thyroid hormones T 3 and T 4.
Iodine accounts for 65 percent of the molecular weight of T 4 and 59 percent of the molecular weight of T 3. In an adult with sufficient iodine intake, approximately 15-20 mg iodine is concentrated in the tissues of the thyroid gland. However, only 30 percent of the body’s iodine is concentrated in the thyroid tissue and thyroid hormones. The remaining nonhormonal iodine is found in a variety of tissues, including mammary tissue, eye, gastric mucosa, cervix, and salivary glands. With the exception of mammary tissue, the function of iodine in these tissues is largely unknown. Mammary tissue’s role in sequestering and concentrating iodine is related to fetal and neonatal development and is largely evolutionary, as detailed below. However, iodine’s role in mammary and other tissues has also been shown to have an antioxidant function. Iodide can act as an electron donor in the presence of hydrogen peroxide, peroxidase, and some polyunsaturated fatty acids, decreasing damage by free oxygen radicals. Iodine- deficient glands contain increased amounts of malondialdehyde, a product of lipid peroxidation that can occur as a result of inadequate iodine stores.
Concentrations of iodine as low as 15 micromolar (achievable in human serum) have the same antioxidant activity as ascorbic acid. This antioxidant effect of iodine may explain the therapeutic effects of seaweed baths or iodine-rich solutions known as thalassotherapy used historically to treat ocular diseases, thyroid disease, diabetes, cardiac and respiratory disease, and arteriosclerosis. Animal studies have shown iodine normalizes elevated adrenal corticosteroid hormone secretion related to the stress response and reverses the effect of hypothyroidism on the ovaries, testicles, and thymus in thyroidectomized rats.
Iodine may also have a role in immune function; when placed in a medium containing 10 -6 M iodide, human leukocytes synthesize thyroxine. Testing Iodine Levels More than 90 percent of dietary iodine is excreted in the urine. Single random urine sampling is the standard accepted method of measuring body stores of iodine.
The World Health Organization has deter – mined 50-99 mcg/L indicates mild deficiency, 20-49 mcg/L indicates moderate deficiency, and less than 20 indicates severe deficiency. Because random urine samples have been found to be adequate for population screening, there is little advantage in calculating urine iodine: creatinine ratios. For individual measurements, however, multiple spot urine iodine measurements or 24-hour urine iodine evaluations are more precise.
Iodine Toxicity
The U.S. recommended daily intake (RDI) for dietary iodine is 150 mcg for adults, 220 mcg for pregnancy, and 270 mcg during lactation. The safe up – per limit has been set at 1,000 mcg (1 mg) as a result of studies assessing TSH levels with supplementation. Iodine supplementation over this limit has been shown to potentially contribute to an underlying thyroid pathology in those with Hashimoto’s thyroiditis, Graves’ disease, or exacerbation of nodularities in euthyroid individuals if intake exceeds 20 mg iodine or iodide. In addition to pre-existing thyroid pathologies exacerbated with iodine supplementation, excessive ingestion of iodine in medication (amiodarone) or water contamination may contribute to goiter, hypothyroidism, elevated TSH levels, and ocular damage. Selenium is required for the production of deiodinase selenoenzymes. Clinical investigators in selenium- and iodine-deficient populations conclude the coexisting deficiencies cause increased TSH levels and contribute to goiter development. One French study found an inverse relationship between selenium status and thyroid volume. Co-existing deficiencies become problematic in areas where iodine supplementation is promoted on a population-wide basis. Selenium supplementation may be necessary to prevent potential thyroid damage from iodide supplementation in selenium- deficient individuals.
The iodine deficiency disorders
Recommended iodine intake
UNICEF, ICCIDD, and WHO recommend that the daily intake of iodine should be as follows:
• 90 μg for preschool children (0 to 59 months);
• 120 μg for schoolchildren (6 to 12 years);
• 150 μg for adolescents (above 12 years) and adults;
• 250 μg for pregnant and lactating women.
The iodine deficiency disorders
Iodine deficiency occurs when iodine intake falls below recommended levels. It is a natural ecological phenomenon that occurs in many parts of the world. The erosion of soils in riverine areas due to loss of vegetation from clearing for agricultural production, overgrazing by livestock, and tree-cutting for firewood results in a continued and increasing loss of iodine from the soil. Groundwater and foods grown locally in these areas lack iodine.
When iodine intake falls below recommended levels, the thyroid may no longer be able to synthesize sufficient amounts of thyroid hormone. The resulting low level of thyroid hormones in the blood (hypothyroidism) is the principal factor responsible for damage to the developing brain and other harmful effects known collectively as “iodine deficiency disorders” . The adoption of this term emphasizes that the problem extends far beyond simply goitre and cretinism.
The most critical period is from the second trimester of pregnancy to the third year after birth. Normal levels of thyroid hormones are required for optimal development of the brain. In areas of iodine deficiency, where thyroid hormone levels are low, brain development is impaired. In its most extreme form, this results in cretinism, but of much greater public health importance are the more subtle degrees of brain damage and reduced cognitive capacity which affects the entire population. As a result, the mental ability of ostensibly normal children an adults living in areas of iodine deficiency is reduced compared to what it would be otherwise. Thus, the potential of a whole community is reduced by iodine deficiency. Indeed, in an iodine deficient population, everybody may seem to be slow and rather sleepy. The quality of life is poor, ambition is blunted, and the community becomes trapped in a self-perpetuating cycle. Even the domestic animals, such as village dogs, are affected. Livestock productivity is also dramatically reduced.
Diagnostic procedures
Urinary iodine
Most iodine absorbed in the body eventually appears in the urine. Therefore, urinary iodine excretion is a good marker of very recent dietary iodine intake. In individuals, urinary iodine excretion can vary somewhat from day to day and even within a given day. However, this variation tends to even out among populations. Studies have convincingly demonstrated that a profile of iodine concentrations in morning or other casual urine specimens (child or adult) provides an adequate assessment of a population’s iodine nutrition, provided a sufficient number of specimens are collected. Round the clock urine samples are difficult to obtain and are not necessary. Relating urinary iodine to creatinine, as has been done in the past, is cumbersome, expensive, and unnecessary. Indeed, urinary iodine/ creatinine ratios are unreliable, particularly when protein intake – and consequently creatinine excretion – is low. Interpretation
Simple modern methods make it feasible to process large numbers of samples at a low cost and to characterize the distribution according to different cut-off points and intervals.
The median value for the sampled population is the most commonly assessed indicator. Urinary iodine values from populations are usually not normally distributed. Therefore, the median rather than the mean should be used as the measure of central tendency. Likewise, percentiles rather than standard deviations should be used as measures of spread. Frequency distribution curves can also be very useful for full interpretation, particularly if there is salt iodine level data available for the same population.
In children and non-pregnant women, median urinary iodine concentrations of between 100 μg/l and 299 μg/l define a population which has no iodine deficiency. In addition, not more than 20% of samples should be below 50 μg/l. Ion-pregnant, non-lactating women, a urinary iodine concentration of 100 μg/l corresponds roughly to a daily iodine intake of about 150 μg under steady-state conditions. During pregnancy, median urinary iodine concentrations of between 150 μg/l and 249 μg/l define a population which has no iodine deficiency.
Establishing the ideal range of values for urinary iodine is difficult. Historically, schoolchildren were assessed by palpation, establishing a pre-intervention baseline for the prevalence of IDD. This population was also sampled for urinary iodine, thus establishing a normal range.
This normal range has been extrapolated to the full population. It may be more logical to sample women of reproductive age, or adolescent girls – thus providing more information on populations that may include those with or on the verge of greater need. The upper limit of the recommended range for these populations refl ects concern about the risk of hyperthyroidism when high levels are introduced to a previously endemic population.
Recent data have suggested that the normal range for pregnant and lactating women should refl ect their additional need and the risk that these needs may not be met if population levels are too low. However, this leaves a relatively narrow range for a median UI level that will both meet the needs for pregnant/lactating women, and not be excessive forthe remainder of the population. This guide provides the best current estimates for the optimal values to meet the overall populatioeeds. Urinary iodine concentration is currently the most practical biochemical marker for iodine nutrition when carried out with appropriate technology and sampling. This approach assesses iodine nutrition only at the time of measurement, whereas thyroid size refl ects iodine nutrition over months or years. Therefore, even though populations may have attained iodine sufficiency on the basis of median urinary iodine concentration, goitre may persist, even in children. Tolerance to high doses of iodine is quite variable, and many individuals ingest amounts of several milligrams or more per day without apparent problems. The major epidemiological consequence of iodine excess is iodine-induced hyperthyroidism (IIH). This occurs more commonly in older subjects with preexisting nodular goitres, and may occur even when iodine intake is within the normal range.
Iodine intakes above 300 μg/l per day should generally be discouraged, particularly in areas where iodine deficiency has previously existed. In these situations, more individuals may be vulnerable to adverse health consequences, including iodine-induced hyperthyroidism and autoimmune thyroid diseases.
In populations characterized by long-standing iodine defi ciency and a rapid increase in iodine intake, median values for urinary iodine above 200 μg/l (and in pregnant women, above 250 μg/l) are not recommended because of the possible risk of iodine-induced hyperthyroidism. This adverse condition can occur during the 5 to 10 years following the introduction of iodized salt. Beyond this period of time, median values up to 300 μg/l have not demonstrated side-effects, at least not in populations with adequately iodized salt. In schoolchildren, urinary iodine concentrations >500 μg/l are associated with increasing thyroid volume, which refl ects the adverse effects of chronic iodine excess.
Thyroid size
The traditional method for determining thyroid size is inspection and palpation. Ultrasonography provides a more precise and objective method. Both methods are described below. Issues common to palpation and ultrasound are not repeated in the section on ultrasound.
Thyroid size by palpation The size of the thyroid gland changes inversely in response to alterations in iodine intake, with a lag interval that varies from a few months to several years, depending on many factors. These include the severity and duration of iodine defi ciency, the type and effectiveness of iodine supplementation, age, sex, and possible additional goitrogenic factors. The term “goitre” refers to a thyroid gland that is enlarged. The statement that “a thyroid gland each of whose lobes have a volume greater than the terminal phalanges of the thumb of the person examined will be considered goitrous” is empiric, but has been used in most epidemiological studies of endemic goitre and is still recommended.
Feasibility Palpation of the thyroid is particularly useful in assessing goitre prevalence before the introduction of any intervention to control IDD, but much less so in determining impact. Costs are associated with mounting a survey, which is relatively easy to conduct, and training of personnel. These costs will vary depending upon the availability of health care personnel, accessibility of the population, and sample size. Feasibility and performance vary according to target groups, as follows:
Neonates: It is neither feasible nor practical to assess goitre among neonates, whether by palpation or ultrasound. Performance is poor.
School-age children (6–12 years): This is the preferred group, as it is usually easily accessible. However, the highest prevalence of goitre occurs during puberty and childbearing age. Some studies have focused on children 8 to 10 years of age. There is a practical reason for not measuring very young age groups. The smaller the child, the smaller the thyroid, and the more diffi cult it is to perform palpation. If the proportion of children attending school is low, schoolchildren may not be representative. In these cases, spot surveys should be conducted among those who attend school and those who do not, to ascertain if there is any significant difference between the two. Alternatively, children can be surveyed in households. For further discussion, see Chapter 5 on survey methods.
Adults: Pregnant and lactating women are of particular concern. Pregnant women are a prime target group for IDD control activities because they are especially sensitive to marginal iodine deficiency. Often they are relatively accessible given their participation in antenatal clinics. Women of childbearing age – 15 to 44 years – may be surveyed in households.
Technique
The subject to be examined stands in front of the examiner, who looks carefully at the neck for any sign of visible thyroid enlargement. The subject is then asked to look up and thereby to fully extend the neck. This pushes the thyroid forward and makes any enlargement more obvious.
Finally, the examiner palpates the thyroid by gently sliding their own thumb along the side of the trachea (wind-pipe) between the cricoid cartilage and the top of the sternum. Both sides of the trachea are checked. The size and consistency of the thyroid gland are carefully noted.
If necessary, the subject is asked to swallow (e.g. some water) when being examined – the thyroid moves up on swallowing. The size of each lobe of the thyroid is compared to the size of the tip (terminal phalanx) of the thumb of the subject being examined.
Blood constituents
Two blood constituents, TSH and Tg, can serve as surveillance indicators. In a population survey, blood spots on fi lter paper or serum samples can be used to measure TSH and/or Tg.
Determining serum concentrations of the thyroid hormones, thyroxin (T4) and triiodothyronine (T3), is usually not recommended for monitoring iodine nutrition, because these tests are more cumbersome, more expensive, and less sensitive indicators. In iodine defi ciency, the serum T4 is typically lower and the serum T3 higher than iormal populations. However, the overlap is large enough to make these tests impractical for ordinary epidemiological purposes.
Thyroid stimulating hormone (TSH)
Biological features
Iodine deficiency lowers circulating T4 and raises the serum TSH, so iodine-deficient populations generally have higher serum TSH concentrations than do iodine-sufficient groups.
However, the difference is not great and much overlap occurs between individual TSH values. Therefore, the blood TSH concentration in school-age children and adults is not a practical marker for iodine deficiency, and its routine use in school-based surveys is not recommended. In contrast, TSH ieonates is a valuable indicator for iodine deficiency. The neonatal thyroid has a low iodine content compared to that of the adult, and hence iodine turnover is much higher. This high turnover, which is exaggerated in iodine deficiency, requires increased stimulation by TSH. Hence, TSH levels are increased in iodine-deficient populations for the first few weeks of life – this phenomenon is called transient hyperthyrotopinemia.
The prevalence of neonates with elevated TSH levels is therefore a valuable indicator of the severity of iodine deficiency in a given population. It has the additional advantage of highlighting the fact that iodine deficiency directly affects the developing brain. In iodine-sufficient populations, about one in 4000 neonates has congenital hypothyroidism, usually because of thyroid dysplasia. Prompt correction with thyroid hormone is essential to avoid permanent mental retardation.
Thyroid hormone affects proper development of the central nervous system, particularly its myelination; a process that is very active in the perinatal period. To detect congenital hypothyroidism and initiate rapid treatment, most developed countries conduct universal screening of neonates with bloodspot TSH taken on fi lter papers, or occasionally with blood spot T4 followed by TSH.
While screening in developed countries is directed at detectingneonates with TSH elevations which are 20 mIU/l whole blood or higher, the availability of TSH assays sensitive to 5 mlU/l permits detection of mild elevations above normal. This permits detection of transient hyperthyrotopinemia. To be broadly applicable in a population, the screening must be universal, and not omit children born in remote or impoverished areas. For countries and regions that already have a system of universal neonatal screening with a sensitive TSH assay in place, the data can be examined and transient iodine defi ciency recognized, usually without further surveying.
Interpretation
Permanent sporadic congenital hypothyroidism, with extremely elevated neonatal TSH, occurs in approximately one of 4000 births in iodinesuffi cient countries. Other than infrequent cases of goitrogen exposure, iodine defi ciency is the only signifi cant factor to increase this incidence. The increase in the number of neonates with moderately elevated TSH concentrations (above 5 mlU/l whole blood) is proportional to the degree of iodine defi ciency during pregnancy. It may be higher than 40% in severe endemic areas. When a sensitive TSH assay is used on samples collected three to four days after birth, a <3% frequency of TSH values >5 mlU/l indicates iodine suffi ciency in a population. Interpretation is complicated when antiseptics containing betaiodine, such as povidone iodine, are used for cleaning the perineum prior to delivery or even the umbilical area of the baby. Betaiodine increases TSH levels in the neonate in both cord blood and heel prick specimens.
Thyroglobulin (Tg)
Tg is a thyroid protein that is a precursor in the synthesis of thyroid hormone, and small amounts of Tg can be detected in the blood of all healthy individuals. The thyroid hyperplasia and goitre characteristic of iodine deficiency increases serum Tg levels, and in this setting serum Tg reflects iodine nutrition over a period of months or years. This contrasts to urinary iodine concentration, which assesses more immediate iodine intake. A serum Tg assay has recently been adapted for use on dried whole blood spots (DBS). The assay makes sampling practical even in remote areas. Measurement of DBS Tg in school-age children is a sensitive indicator of iodine status in a population and can be used to monitor improving thyroid function after iodine repletion. Interpretation Standard reference material for the DBS Tg assay is now available from WHO. It is stable when stored for up to one year at temperatures ≤ -20 °C. An international reference range for DBS Tg has been established in iodine-sufficient five to 14 year-old children that can be used for monitoring iodine nutrition. The DBS Tg reference interval for iodinesuffi cient school-age children is 4–40 μg/l.
Correction of iodine deficiency
Iodine Replacement
Iodine replacement should be based on the recommendations of WHO. In an adult, 150 mcg/day is sufficient for normal thyroid function. Replacement of iodine is most easily achieved by requesting that the patient use iodized salt in his or her cooking and at the table or an iodine-containing daily multiple vitamin. Other dietary sources of iodine include milk, egg yolks, and saltwater fish. Not all daily or prenatal multiple vitamins contain iodine, but those that do, typically contain 150 mcg of iodine per tablet.
Universal salt iodization (USI)
In 1994, a special session of the WHO and UNICEF Joint Committee on Health Policy recommended USI as a safe, cost-effective, and sustainable strategy to ensure suffi cient intake of iodine by all individuals. Iearly all countries where iodine defi ciency occurs, it is now well recognized that the most effective way to achieve the virtual elimination of IDD is through USI. USI involves the iodization of all human and livestock salt, including salt used in the food industry. Adequate iodization of all salt will deliver iodine in the required quantities to the population on a continuous and self-sustaining basis. The additional cost of iodine fortification in the process of salt production should eventually be borne by the consumer, but is negligible. This will greatly assist sustainability. National salt iodization programmes are now implemented worldwide and have followed a common pattern of evolution.
Iodine supplementation
In some countries and areas with insufficient access to iodized salt for vulnerable groups of the population, additional temporary strategies need to be considered to ensure optimal iodine nutrition for these groups while strengthening the salt iodization programmes to reach universal coverage. In particular, each country should assess the current situation of its salt iodization programme to identify national or subnational problems and to update its strategies and action plans. The most vulnerable groups, pregnant and lactating women, should be considered for supplementation with iodine until the salt iodization programme is scaled up. For children seven to 24 months of age, either supplementation or use of iodine-fortified complementary foods may be a possible temporary public health measure.
Treatment of Nontoxic Goiters Caused by Iodine Deficiency
Long-term dietary iodine replacement at levels recommended by IOM and WHO may decrease the size of iodine-deficient goiters in very young children and pregnant women and is indicated for all patients with iodine deficiency. Generally, long-standing goiters associated with iodine deficiency disorder respond with only small amounts of shrinkage after iodine supplementation, and patients are at risk for developing hyperthyroidism. Patients do not routinely require specific therapy unless the goiter is large enough to cause compressive symptoms (eg, tracheal obstruction, thoracic inlet occlusion, hoarseness).
Levothyroxine
Exogenous levothyroxine (L-T4) can also be used to decrease goiter size but generally is not effective in adults and older children. Supplemental L-T4, when added to the T3 and T4 secretion by the autonomous nodules in the endemic goiter, may cause thyrotoxicosis. Long-term L-T4 therapy that results in the suppression of the TSH level to below-normal levels may have deleterious effects on cardiac and bone health; therefore, L-T4 therapy is no longer routinely administered to patients with goiter.
Radioactive iodine
Radioactive iodine (iodine-131 [131 I]) has been used, primarily in Europe, to decrease thyroid volume in patients with euthyroid goiters (40-60% volume reduction). In the United States,131 I is the most common treatment for toxic multinodular goiters associated with hyperthyroidism. Risks associated with131 I therapy include permanent hypothyroidism.
Surgery
The standard of care for large goiter associated with obstructive symptoms such as dough, stridor, and dysphagia is thyroidectomy. If the goiter extends into the anterior mediastinum, surgery is the recommend treatment even without obstructive symptoms. After the surgery, the patient need levothyroxine replacement therapy.
Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer, November 2009
DIFFERENTIATED THYROID CANCER: INITIAL MANAGEMENT GUIDELINES
Differentiated thyroid cancer, arising from thyroid follicular epithelial cells, accounts for the vast majority of thyroid cancers. Of the differentiated cancers, papillary cancer comprises about 85% of cases compared to about 10% that have follicular histology, and 3% that are Hürthle cell or oxyphil tumors (110). In general, stage for stage, the prognoses of PTC and follicular cancer are similar (107,110). Certain histologic subtypes of PTC have a worse prognosis (tall cell variant, columnar cell variant, diffuse sclerosing variant), as do more highly invasive variants of follicular cancer. These are characterized by extensive vascular invasion and invasion into extrathyroidal tissues or extensive tumor necrosis and/or mitoses. Other poorly differentiated aggressive tumor histologies include trabecular, insular, and solid subtypes (111). In contrast, minimally invasive follicular thyroid cancer, is characterized histologically by microscopic penetration of the tumor capsule without vascular invasion, and carries no excess mortality (112–115).
[B2] Goals of initial therapy of DTC
The goals of initial therapy of DTC are follows:
1. To remove the primary tumor, disease that has extended beyond the thyroid capsule, and involved cervical lymph nodes. Completeness of surgical resection is an important determinant of outcome, while residual metastatic lymph nodes represent the most common site of disease persistence/recurrence (116–118).
2. To minimize treatment-related morbidity. The extent of surgery and the experience of the surgeon both play important roles in determining the risk of surgical complications (119,120)
3. To permit accurate staging of the disease. Because disease staging can assist with initial prognostication, disease management, and follow-up strategies, accurate postoperative staging is a crucial element in the management of patients with DTC (121,122).
4. To facilitate postoperative treatment with radioactive iodine, where appropriate. For patients undergoing RAI remnant ablation, or RAI treatment of residual or metastatic disease, removal of all normal thyroid tissue is an important element of initial surgery (123). Near total or total thyroidectomy also may reduce the risk for recurrence within the contralateral lobe (124).
5. To permit accurate long-term surveillance for disease recurrence. Both RAI whole-body scanning (WBS) and measurement of serum Tg are affected by residual normal thyroid tissue. Where these approaches are utilized for long-term monitoring, near-total or total-thyroidectomy is required (125).
6. To minimize the risk of disease recurrence and metastatic spread. Adequate surgery is the most important treatment variable influencing prognosis, while radioactive iodine treatment, TSH suppression, and external beam irradiation each play adjunctive roles in at least some patients (125–128).
[B3] What is the role of preoperative staging with diagnostic imaging and laboratory tests?
[B4] Neck imaging. Differentiated thyroid carcinoma (particularly papillary carcinoma) involves cervical lymph nodes in 20–50% of patients in most series using standard pathologic techniques (45,129–132), and may be present even when the primary tumor is small and intrathyroidal (133). The frequency of micrometastases may approach 90%, depending on the sensitivity of the detection method (134,135). However, the clinical implications of micrometastases are likely less significant compared to macrometastases. Preoperative US identifies suspicious cervical adenopathy in 20–31% of cases, potentially altering the surgical approach (136,137) in as many as 20% of patients (138,139). However, preoperative US identifies only half of the lymph nodes found at surgery, due to the presence of the overlying thyroid gland (140).
Sonographic features suggestive of abnormal metastatic lymph nodes include loss of the fatty hilus, a rounded rather than oval shape, hypoechogenicity, cystic change, calcifications, and peripheral vascularity. No single sonographic feature is adequately sensitive for detection of lymph nodes with metastatic thyroid cancer. A recent study correlated the sonographic features acquired 4 days preoperatively directly with the histology of 56 cervical lymph nodes. Some of the most specific criteria were short axis >
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FIG. 2. Lymph node compartments separated into levels and sublevels. Level VI contains the thyroid gland, and the adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic) artery, and laterally on each side by the carotid sheaths. The level II, III, and IV nodes are arrayed along the jugular veins on each side, bordered anteromedially by level VI and laterally by the posterior border of the sternocleidomastoid muscle. The level III nodes are bounded superiorly by the level of the hyoid bone, and inferiorly by the cricoid cartilage; levels II and IV are above and below level III, respectively. The level I node compartment includes the submental and submandibular nodes, above the hyoid bone, and anterior to the posterior edge of the submandibular gland. Finally, the level V nodes are in the posterior triangle, lateral to the lateral edge of the sternocleidomastoid muscle. Levels I, II, and V can be further subdivided as noted in the figure. The inferior extent of level VI is defined as the suprasternal notch. Many authors also include the pretracheal and paratracheal superior mediastinal lymph nodes above the level of the innominate artery (sometimes referred to as level VII) in central neck dissection (166). |
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Confirmation of malignancy in lymph nodes with a suspicious sonographic appearance is achieved by US-guided FNA aspiration for cytology and/or measurement of Tg in the needle washout. This FNA measurement of Tg is valid even in patients with circulating Tg autoantibodies (143,144).
Accurate staging is important in determining the prognosis and tailoring treatment for patients with DTC. However, unlike many tumor types, the presence of metastatic disease does not obviate the need for surgical excision of the primary tumor in DTC (145). Because metastatic disease may respond to RAI therapy, removal of the thyroid as well as the primary tumor and accessible locoregional disease remains an important component of initial treatment even in metastatic disease.
As US evaluation is uniquely operator dependent, alternative imaging procedures may be preferable in some clinical settings, though the sensitivities of CT, MRI, and PET for the detection of cervical lymph node metastases are all relatively low (30–40%) (146). These alternative imaging modalities, as well as laryngoscopy and endoscopy, may also be useful in the assessment of large, rapidly growing, or retrosternal or invasive tumors to assess the involvement of extrathyroidal tissues (147,148).
- RECOMMENDATION 21
Preoperative neck US for the contralateral lobe and cervical (central and especially lateral neck compartments) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant cytologic findings on biopsy. US-guided FNA of sonographically suspicious lymph nodes should be performed to confirm malignancy if this would change management. Recommendation rating: B
- RECOMMENDATION 22
Routine preoperative use of other imaging studies (CT, MRI, PET) is not recommended. Recommendation rating: E
[B5] Measurement of serum Tg. There is limited evidence that high preoperative concentrations of serum Tg may predict a higher sensitivity for postoperative surveillance with serum Tg (149). Evidence that this impacts patient management or outcomes is not yet available.
- RECOMMENDATION 23
Routine preoperative measurement of serum Tg is not recommended. Recommendation rating: E
[B6] What is the appropriate operation for indeterminate thyroid nodules and DTC? The goals of thyroid surgery can include provision of a diagnosis after a nondiagnostic or indeterminate biopsy, removal of the thyroid cancer, staging, and preparation for radioactive ablation and serum Tg monitoring. Surgical options to address the primary tumor should be limited to hemithyroidectomy with or without isthmusectomy, near-total thyroidectomy (removal of all grossly visible thyroid tissue, leaving only a small amount [<1 g] of tissue adjacent to the recurrent laryngeal nerve near the ligament of Berry), and total thyroidectomy (removal of all grossly visible thyroid tissue). Subtotal thyroidectomy, leaving >
[B7] Surgery for a nondiagnostic biopsy, a biopsy suspicious for papillary cancer or suggestive of “follicular neoplasm” (including special consideration for patients with other risk factors). Amongst solitary thyroid nodules with an indeterminate (“follicular neoplasm” or Hürthle cell neoplasm) biopsy, the risk of malignancy is approximately 20% (151–153). The risk is higher with large tumors (>
- RECOMMENDATION 24
For patients with an isolated indeterminate solitary nodule who prefer a more limited surgical procedure, thyroid lobectomy is the recommended initial surgical approach. Recommendation rating: C
- RECOMMENDATION 25
a. Because of an increased risk for malignancy, total thyroidectomy is indicated in patients with indeterminate nodules who have large tumors (>4 cm), when marked atypia is seen on biopsy, when the biopsy reading is “suspicious for papillary carcinoma,” in patients with a family history of thyroid carcinoma, and in patients with a history of radiation exposure. Recommendation rating: A
b. Patients with indeterminate nodules who have bilateral nodular disease, or those who prefer to undergo bilateral thyroidectomy to avoid the possibility of requiring a future surgery on the contralateral lobe, should also undergo total or near-total thyroidectomy. Recommendation rating: C
[B8] Surgery for a biopsy diagnostic for malignancy. Near-total or total thyroidectomy is recommended if the primary thyroid carcinoma is >
- RECOMMENDATION 26
For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy unless there are contraindications to this surgery. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases. Recommendation rating: A
[B9] Lymph node dissection. Regional lymph node metastases are present at the time of diagnosis in 20–90% of patients with papillary carcinoma and a lesser proportion of patients with other histotypes (129,139). Although PTC lymph node metastases are reported by some to have no clinically important effect on outcome in low risk patients, a study of the Surveillance, Epidemiology, and End Results (SEER) database found, among 9904 patients with PTC, that lymph node metastases, age >45 years, distant metastasis, and large tumor size significantly predicted poor outcome on multivariate analysis (163). All-cause survival at 14 years was 82% for PTC without lymph node and 79% with lymph node metastases (p < 0.05). Another recent SEER registry study concluded that cervical lymph node metastases conferred an independent risk of decreased survival, but only in patients with follicular cancer and patients with papillary cancer over age 45 years (164). Also, the risk of regional recurrence is higher in patients with lymph node metastases, especially in those patients with multiple metastases and/or extracapsular nodal extension (165).
In many patients, lymph node metastases in the central compartment (166) do not appear abnormal preoperatively with imaging (138) or by inspection at the time of surgery. Central compartment dissection (therapeutic or prophylactic) can be achieved with low morbidity in experienced hands (167–171), and may convert some patients from clinical N0 to pathologic N1a, upstaging patients over age 45 from American Joint Committee on Cancer (AJCC) stage I to III (172). A recent consensus conference statement discusses the relevant anatomy of the central neck compartment, delineates the nodal subgroups within the central compartment commonly involved with thyroid cancer, and defines the terminology relevant to central compartment neck dissection (173).
Comprehensive bilateral central compartment node dissection may improve survival compared to historic controls and reduce risk for nodal recurrence (174). In addition, selective unilateral paratracheal central compartment node dissection increases the proportion of patients who appear disease free with unmeasureable Tg levels 6 months after surgery (175). Other studies of central compartment dissection have demonstrated higher morbidity, primarily recurrent laryngeal nerve injury and transient hypoparathyroidism, with no reduction in recurrence (176,177). In another study, comprehensive (bilateral) central compartment dissection demonstrated higher rates of transient hypoparathyroidism compared to selective (unilateral) dissection with no reduction in rates of undetectable or low Tg levels (178). Although some lymph node metastases may be treated with radioactive iodine, several treatments may be necessary, depending upon the histology, size, and number of metastases (179).
- RECOMMENDATION 27*
a. Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. Recommendation rating: B
b. Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4). Recommendation rating: C
c. Near-total or total thyroidectomy without prophylactic central neck dissection may be appropriate for small (T1 or T2), noninvasive, clinically node-negative PTCs and most follicular cancer. Recommendation rating: C
These recommendations (R27a–c) should be interpreted in light of available surgical expertise. For patients with small, noninvasive, apparently node-negative tumors, the balance of risk and benefit may favor simple near-total thyroidectomy with close intraoperative inspection of the central compartment with compartmental dissection only in the presence of obviously involved lymph nodes. This approach may increase the chance of future locoregional recurrence, but overall this approach may be safer in less experienced surgical hands.
Lymph nodes in the lateral neck (compartments II–V), level VII (anterior mediastinum), and rarely in Level I may also be involved by thyroid cancer (129,180). For those patients in whom nodal disease is evident clinically, on preoperative US and nodal FNA or Tg measurement, or at the time of surgery, surgical resection may reduce the risk of recurrence and possibly mortality (56,139,181). Functional compartmental en-bloc neck dissection is favored over isolated lymphadenectomy (“berry picking”) with limited data suggesting improved mortality (118,182–184).
- RECOMMENDATION 28*
Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. Recommendation rating: B
[B10] Completion thyroidectomy. Completion thyroidectomy may be necessary when the diagnosis of malignancy is made following lobectomy for an indeterminate or nondiagnostic biopsy. Some patients with malignancy may require completion thyroidectomy to provide complete resection of multicentric disease (185), and to allow RAI therapy. Most (186,187) but not all (185) studies of papillary cancer have observed a higher rate of cancer in the opposite lobe when multifocal (two or more foci), as opposed to unifocal, disease is present in the ipsilateral lobe. The surgical risks of two-stage thyroidectomy (lobectomy followed by completion thyroidectomy) are similar to those of a near-total or total thyroidectomy (188).
- RECOMMENDATION 29
Completion thyroidectomy should be offered to those patients for whom a near-total or total thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. This includes all patients with thyroid cancer except those with small (<1 cm), unifocal, intrathyroidal, node-negative, low-risk tumors. Therapeutic central neck lymph node dissection should be included if the lymph nodes are clinically involved. Recommendation rating: B
- RECOMMENDATION 30
Ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy (189). It is unknown whether this approach results in similar long-term outcomes. Consequently, routine radioactive iodine ablation in lieu of completion thyroidectomy is not recommended. Recommendation rating: D
[B11] What is the role of postoperative staging systems and which should be used?
[B12] The role of postoperative staging. Postoperative staging for thyroid cancer, as for other cancer types, is used: 1) to permit prognostication for an individual patient with DTC; 2) to tailor decisions regarding postoperative adjunctive therapy, including RAI therapy and TSH suppression, to assess the patient’s risk for disease recurrence and mortality; 3) to make decisions regarding the frequency and intensity of follow-up, directing more intensive follow-up towards patients at highest risk; and 4) to enable accurate communication regarding a patient among health care professionals. Staging systems also allow evaluation of differing therapeutic strategies applied to comparable groups of patients in clinical studies.
[B13] AJCC/UICC TNM staging. Application of the AJCC/International Union against Cancer (AJCC/UICC) classification system based on pTNM parameters and age is recommended for tumors of all types, including thyroid cancer (121,190), because it provides a useful shorthand method to describe the extent of the tumor (191) (Table 4). This classification is also used for hospital cancer registries and epidemiologic studies. In thyroid cancer, the AJCC/UICC stage does not take account of several additional independent prognostic variables and may risk misclassification of some patients. Numerous other schemes have been developed in an effort to achieve more accurate risk factor stratification, including CAEORTC, AGES, AMES, U of C, MACIS, OSU, MSKCC, and NTCTCS systems. (107,116,122,159,192–195). These schemes take into account a number of factors identified as prognostic for outcome in multivariate analysis of retrospective studies, with the most predictive factors generally being regarded as the presence of distant metastases, the age of the patient, and the extent of the tumor. These and other risk factors are weighted differently among these systems according to their importance in predicting outcome, but no scheme has demonstrated clear superiority (195). Each of the schemes allows accurate identification of the majority (70–85%) of patients at low-risk of mortality (T1–3, M0 patients), allowing the follow-up and management of these patients to be less intensive than the higher-risk minority (T4 and M1 patients), who may benefit from a more aggressive management strategy (195). Nonetheless, none of the examined staging classifications is able to account for more than a small proportion of the uncertainty in either short-term, disease-specific mortality or the likelihood of remaining disease free (121,195,196). AJCC/IUCC staging was developed to predict risk for death, not recurrence. For assessment of risk of recurrence, a three-level stratification can be used:
- Low-risk patients have the following characteristics: 1) no local or distant metastases; 2) all macroscopic tumor has been resected; 3) there is no tumor invasion of locoregional tissues or structures; 4) the tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma) or vascular invasion; 5) and, if 131Iis given, there is no 131I uptake outside the thyroid bed on the first posttreatment whole-body RAI scan (RxWBS) (197–199).
- Intermediate-risk patients have any of the following: 1) microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery; 2) cervical lymph node metastases or 131I uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation (200,201); or 3) tumor with aggressive histology or vascular invasion (202–204).
- High-risk patients have 1) macroscopic tumor invasion, 2) incomplete tumor resection, 3) distant metastases, and possibly 4) thyroglobulinemia out of proportion to what is seen on the posttreatment scan (205).
Since initial staging is based on clinico-pathologic factors that are available shortly after diagnosis and initial therapy, the AJCC stage of the patient does not change over time. However, depending on the clinical course of the disease and response to therapy, the risk of recurrence and the risk of death may change over time. Appropriate management requires an ongoing reassessment of the risk of recurrence and the risk of disease-specific mortality as new data are obtained during follow-up (206).
TABLE 4. TNM CLASSIFICATION SYSTEM FOR DIFFERENTIATED THYROID CARCINOMA
|
|
Definition |
|
|
T1 |
Tumor diameter 2 cm or smaller |
|
|
T2 |
Primary tumor diameter >2 to 4 cm |
|
|
T3 |
Primary tumor diameter >4 cm limited to the thyroid or with minimal extrathyroidal extension |
|
|
T4a |
Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve |
|
|
T4b |
Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels |
|
|
TX |
Primary tumor size unknown, but without extrathyroidal invasion |
|
|
N0 |
No metastatic nodes |
|
|
N1a |
Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) |
|
|
N1b |
Metastasis to unilateral, bilateral, contralateral cervical or superior mediastinal nodes |
|
|
NX |
Nodes not assessed at surgery |
|
|
M0 |
No distant metastases |
|
|
M1 |
Distant metastases |
|
|
MX |
Distant metastases not assessed |
|
|
Stages |
|
|
|
|
Patient age <45 years |
Patient age 45 years or older |
|
Stage I |
Any T, any N, M0 |
T1, N0, M0 |
|
Stage II |
Any T, any N, M1 |
T2, N0, M0 |
|
Stage III |
|
T3, N0, M0 |
|
|
|
T1, N1a, M0 |
|
|
|
T2, N1a, M0 |
|
|
|
T3, N1a, M0 |
|
Stage IVA |
|
T4a, N0, M0 |
|
|
|
T4a, N1a, M0 |
|
|
|
T1, N1b, M0 |
|
|
|
T2, N1b, M0 |
|
|
|
T3, N1b, N0 |
|
|
|
T4a, N1b, M0 |
|
Stage IVB |
|
T4b, Any N, M0 |
|
Stage IVC |
|
Any T, Any N, M1 |
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (435).
RECOMMENDATION 31
Because of its utility in predicting disease mortality, and its requirement for cancer registries, AJCC/UICC staging is recommended for all patients with DTC. The use of postoperative clinico-pathologic staging systems is also recommended to improve prognostication and to plan follow-up for patients with DTC. Recommendation rating: B
[B14] What is the role of postoperative RAI remnant ablation? Postoperative RAI remnant ablation is increasingly being used to eliminate the postsurgical thyroid remnant (122). Ablation of the small amount of residual normal thyroid remaining after total thyroidectomy may facilitate the early detection of recurrence based on serum Tg measurement and/or RAI WBS. Additionally, the posttherapy scan obtained at the time of remnant ablation may facilitate initial staging by identifying previously undiagnosed disease, especially in the lateral neck. Furthermore, from a theoretical point of view, this first dose of RAI may also be considered adjuvant therapy because of the potential tumoricidal effect on persistent thyroid cancer cells remaining after appropriate surgery in patients at risk for recurrence or disease specific mortality. Depending on the risk stratification of the individual patient, the primary goal of the first dose of RAI after total thyroidectomy may be 1) remnant ablation (to facilitate detection of recurrent disease and initial staging), 2) adjuvant therapy (to decrease risk of recurrence and disease specific mortality by destroying suspected, but unproven metastatic disease), or 3) RAI therapy (to treat known persistent disease). While these three goals are closely interrelated, a clearer understanding of the specific indications for treatment will improve our ability to select patients most likely to benefit from RAI after total thyroidectomy, and will also influence our recommendations regarding choice of administered activity for individual patients. Supporting the use of RAI as adjuvant therapy, a number of large, retrospective studies show a significant reduction in the rates of disease recurrence (107,159,160,207) and cause-specific mortality (159,160,207–209). However, other similar studies show no such benefit, at least among the majority of patients with PTC, who are at the lowest risk for mortality (110,122,162,209–212). In those studies that show benefit, the advantage appears to be restricted to patients with tumors >
TABLE 5. MAJOR FACTORS IMPACTING DECISION MAKING IN RADIOIODINE REMNANT ABLATION
|
|
|
Expected benefit |
|
|
||
|
Factors |
Description |
Decreased risk of death |
Decreased risk of recurrence |
May facilitate initial staging and follow-up |
RAI ablation usually recommended |
Strength of evidence |
|
T1 |
1 cm or less, intrathyroidal or microscopic multifocal |
No |
No |
Yes |
No |
E |
|
|
1–2 cm, intrathyroidal |
No |
Conflicting dataa |
Yes |
Selective usea |
I |
|
T2 |
>2–4 cm, intrathyroidal |
No |
Conflicting dataa |
Yes |
Selective usea |
C |
|
T3 |
>4 cm |
|
|
|
|
|
|
|
<45 years old |
No |
Conflicting dataa |
Yes |
Yes |
B |
|
|
≥45 years old |
Yes |
Yes |
Yes |
Yes |
B |
|
|
Any size, any age, minimal extrathyroidal extension |
No |
Inadequate dataa |
Yes |
Selective usea |
I |
|
T4 |
Any size with gross extrathyroidal extension |
Yes |
Yes |
Yes |
Yes |
B |
|
Nx,N0 |
No metastatic nodes documented |
No |
No |
Yes |
No |
I |
|
N1 |
<45 years old |
No |
Conflicting dataa |
Yes |
Selective usea |
C |
|
|
>45 years old |
Conflicting data |
Conflicting dataa |
Yes |
Selective usea |
C |
|
M1 |
Distant metastasis present |
Yes |
Yes |
Yes |
Yes |
A |
aBecause of either conflicting or inadequate data, we cannot recommend either for or against RAI ablation for this entire subgroup. However, selected patients within this subgroup with higher risk features may benefit from RAI ablation (see modifying factors in the text).
In addition to the major factors listed in Table 5, several other histological features may place the patient at higher risk of local recurrence or metastases than would have been predicted by the AJCC staging system. These include worrisome histologic subtypes (such as tall cell, columnar, insular, and solid variants, as well as poorly differentiated thyroid cancer), the presence of intrathyroidal vascular invasion, or the finding of gross or microscopic multifocal disease. While many of these features have been associated with increased risk, there are inadequate data to determine whether RAI ablation has a benefit based on specific histologic findings, independent of tumor size, lymph node status, and the age of the patient. Therefore, while RAI ablation is not recommended for all patients with these higher risk histologic features, the presence of these features in combination with size of the tumor, lymph node status, and patient age may increase the risk of recurrence or metastatic spread to a degree that is high enough to warrant RAI ablation in selected patients. However, in the absence of data for most of these factors, clinical judgment must prevail in the decision-making process. For microscopic multifocal papillary cancer, when all foci are <
Nonpapillary histologies (such as follicular thyroid cancer and Hürthle cell cancer) are generally regarded as higher risk tumors. Expert opinion supports the use of RAI in almost all of these cases. However, because of the excellent prognosis associated with surgical resection alone in small follicular thyroid cancers manifesting only capsular invasion (without vascular invasion (so-called “minimally invasive follicular cancer”), RAI ablation may not be required for all patients with this histological diagnosis (112).
- RECOMMENDATION 32
a. RAI ablation is recommended for all patients with known distant metastases, gross extrathyroidal extension of the tumor regardless of tumor size, or primary tumor size >
b. RAI ablation is recommended for selected patients with 1–4 cm thyroid cancers confined to the thyroid, who have documented lymph node metastases, or other higher risk features (see preceding paragraphs) when the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer (see Table 5 for strength of evidence for individual features). Recommendation rating: C (for selective use in higher risk patients)
c. RAI ablation is not recommended for patients with unifocal cancer <1 cm without other higher risk features (see preceding paragraphs). Recommendation rating: E
d. RAI ablation is not recommended for patients with multifocal cancer when all foci are <1 cm in the absence other higher risk features (see preceding paragraphs). Recommendation rating: E
[B15] How should patients be prepared for RAI ablation? (see Fig. 3) Remnant ablation requires TSH stimulation. No controlled studies have been performed to assess adequate levels of endogenous TSH for optimal ablation therapy or follow-up testing. Noncontrolled studies suggest that a TSH of >30 mU/L is associated with increased RAI uptake in tumors (218), while studies using single dose exogenous TSH suggest maximal thyrocyte stimulation at TSH levels between 51 and 82 mU/L (219, 220). However, the total area under the TSH curve, and not simply the peak serum TSH concentration, is also potentially important for optimal RAI uptake by thyroid follicular cells. Endogenous TSH elevation can be achieved by two basic approaches to thyroid hormone withdrawal, stopping LT4 and switching to LT3 for 2–4 weeks followed by withdrawal of LT3 for 2 weeks, or discontinuation of LT4 for 3 weeks without use of LT3. Both methods of preparation can achieve serum TSH levels >30 mU/Lin >90% of patients (220–229). These two approaches have not been directly compared for efficiency of patient preparation (efficacy of ablation, iodine uptake, Tg levels, disease detection), although a recent prospective study showed no difference in hypothyroid symptoms between these two approaches (230). Other preparative methods have been proposed, but have not been validated by other investigators (231,232). Children with thyroid cancer achieve adequate TSH elevation within 14 days of LT4 withdrawal (233). A low serum Tg level at the time of ablation has excellent negative predictive value for absence of residual disease, and the risk of persistent disease increases with higher stimulated Tg levels (198,205,234).
FIG. 3. Algorithm for initial follow-up of patients with differentiated thyroid carcinoma.
aEBRT, external beam radiotherapy. The usual indication for EBRT is macroscopic unresectable tumor in a patient older than 45 years; it is not usually recommended for children and adults less than age 45.
bNeck ultrasonography of operated cervical compartments is often compromised for several months after surgery.
cTg, thyroglobulin with anti-thyroglobulin antibody measurement; serum Tg is usually measured by immunometric assay and may be falsely elevated for several weeks by injury from surgery or by heterophile antibodies, although a very high serum Tg level after surgery usually indicates residual disease.
dSome clinicians suspect residual disease when malignant lymph nodes, or tumors with aggressive histologies (as defined in the text) have been resected, or when there is a microscopically positive margin of resection.
erhTSH is recombinant human TSH and is administered as follows: 0.9mg rhTSH i.m. on two consecutive days, followed by 131I therapy on the third day.
fTHW is levothyroxine and=or triiodothyronine withdrawal.
gSee text for exceptions regarding remnant ablation. The smallest amount of 131I necessary to ablate normal thyroid remnant tissue should be used. DxWBS (diagnostic whole-body scintigraphy) is not usually necessary at this point, but may be performed if the outcome will change the decision to treat with radioiodine and=or the amount of administered activity.
hRxWBS is posttreatment whole-body scan done 5 to 8 days after therapeutic 131I administration.
iUptake in the thyroid bed may indicate normal remnant tissue or residual central neck nodal metastases.
- RECOMMENDATION 33
Patients undergoing RAI therapy or diagnostic testing can be prepared by LT4 withdrawal for at least 2–3 weeks or LT3 treatment for 2–4 weeks and LT3 withdrawal for 2 weeks with measurement of serum TSH to determine timing of testing or therapy (TSH >30 mU/L). Thyroxine therapy (with or without LT3 for 7–10 days) may be resumed on the second or third day after RAI administration. Recommendation rating: B
[B16] Can rhTSH (Thyrogen™) be used in lieu of thyroxine withdrawal for remnant ablation? For most patients, including those unable to tolerate hypothyroidism or unable to generate an elevated TSH, remnant ablation can be achieved with rhTSH (235,236). A prospective randomized study found that thyroid hormone withdrawal and rhTSH stimulation were equally effective in preparing patients for 131I remnant ablation with 100 mCi with significantly improved quality of life (237). Another randomized study using rhTSH showed that ablation rates were comparable with 50 mCi compared to 100 mCi with a significant decrease (33%) in whole-body irradiation (238). Finally, a recent study has shown that ablation rates were similar with either withdrawal or preparation with rhTSH using 50 mCi of 131I (239). In addition, short-term recurrence rates have been found to be similar in patients prepared with thyroid hormone withdrawal or rhTSH (240). Recombinant human TSH is approved for remnant ablation in the United States, Europe, and many other countries around the world.
- RECOMMENDATION 34
Remnant ablation can be performed following thyroxine withdrawal or rhTSH stimulation. Recommendation rating: A
[B17] Should RAI scanning be performed before RAI ablation? RAI WBS provides information on the presence of io-dine-avid thyroid tissue, which may represent the normal thyroid remnant or the presence of residual disease in the postoperative setting. In the presence of a large thyroid remnant, the scan is dominated by uptake within the remnant, potentially masking the presence of extrathyroidal disease within locoregional lymph nodes, the upper mediastinum, or even at distant sites, reducing the sensitivity of disease detection (241). Furthermore, there is an increasing trend to avoid pretherapy RAI scans altogether because of its low impact on the decision to ablate, and because of concerns over 131Iinduced stunning of normal thyroid remnants (242) and distant metastases from thyroid cancer (243). Stunning is defined as a reduction in uptake of the 131I therapy dose induced by a pretreatment diagnostic activity. Stunning occurs most prominently with higher activities (5–10 mCi) of 131I (244), with increasing time between the diagnostic dose and therapy (245), and does not occur if the treatment dose is given within 72 hours of the scanning dose (246). However, the accuracy of low-activity 131I scans has been questioned, and some research has reported quantitatively the presence of stunning below the threshold of visual detection (247). Although comparison studies show excellent concordance between 123I and 131I for tumor detection, optimal 123I activity and time to scan after 123I administration are not known (248). Furthermore, 123I is expensive, is not universally available, its short half life (t½ = 13 hours) makes handling this isotope logistically more difficult (249), and stunning may also occur though to a lesser degree than with 131I (245). Furthermore, a recent study showed no difference in ablation rates between patients that had pre-therapy scans with 123I (81%) compared to those who had received diagnostic scans using 2 mCi of 131I (74%, p > 0.05) (250). Alternatively, determination of the thyroid bed uptake, without scanning, can be achieved using 10–100 µCi 131I.
- RECOMMENDATION 35
Pretherapy scans and/or measurement of thyroid bed uptake may be useful when the extent of the thyroid remnant cannot be accurately ascertained from the surgical report or neck ultrasonography, or when the results would alter either the decision to treat or the activity of RAI that is administered. If performed, pretherapy scans should utilize 123I (1.5–3 mCi) or low-activity 131I (1–3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity. Recommendation rating: C
[B18] What activity of 131I should be used for remnant ablation? Successful remnant ablation is usually defined as an absence of visible RAI uptake on a subsequent diagnostic RAI scan or an undetectable stimulated serum Tg. Activities between 30 and 100 mCi of 131I generally show similar rates of successful remnant ablation (251–254) and recurrence rates (213). Although there is a trend toward higher ablation rates with higher activities (255,256), a recent prospective randomized study found no significant difference in the remnant ablation rate using 30 or 100 mCi of 131I (257). Furthermore, there are data showing that 30 mCi is effective in ablating the remnant with rhTSH preparation (258). In pediatric patients, it is preferable to adjust the ablation activity according to the patient’s body weight (259) or surface area (260).
- RECOMMENDATION 36
The minimum activity (30–100 mCi) necessary to achieve successful remnant ablation should be utilized, particularly for low-risk patients. Recommendation rating: B
- RECOMMENDATION 37
If residual microscopic disease is suspected or documented, or if there is a more aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma), then higher activities (100–200 mCi) may be appropriate. Recommendation rating: C
[B19] Is a low-iodine diet necessary before remnant ablation? The efficacy of radioactive iodine depends on the radiation dose delivered to the thyroid tissue (261). Low-iodine diets (<50 µg/d of dietary iodine) and simple recommendations to avoid iodine contamination have been recommended prior to RAI therapy (261–263) to increase the effective radiation dose. A history of possible iodine exposure (e.g., intravenous contrast, amiodarone use) should be sought. Measurement of iodine excretion with a spot urinary iodine determination may be a useful way to identify patients whose iodine intake could interfere with RAI remnant ablation (263). Information about low-iodine diets can be obtained at the Thyroid Cancer Survivors Association website (www. thyca.org).
- RECOMMENDATION 38
A low-iodine diet for 1–2 weeks is recommended for patients undergoing RAI remnant ablation, particularly for those patients with high iodine intake. Recommendation rating: B
[B20] Should a posttherapy scan be performed following remnant ablation? Posttherapy whole-body iodine scanning is typically conducted approximately 1 week after RAI therapy to visualize metastases. Additional metastatic foci have been reported in 10–26% of patients scanned following high-dose RAI treatment compared with the diagnostic scan (264,265). The new abnormal uptake was found most often in the neck, lungs, and mediastinum, and the newly discovered disease altered the disease stage in approximately 10% of the patients, affecting clinical management in 9–15% (264–266). Iodine 131 single photon emission computed tomography (SPECT)/CT fusion imaging may provide superior lesion localization after remnant ablation, but it is still a relatively new imaging modality (267).
- RECOMMENDATION 39
A posttherapy scan is recommended following RAI remnant ablation. This is typically done 2–10 days after the therapeutic dose is administered, although published data supporting this time interval are lacking. Recommendation rating: B
[B21] Postsurgery and RAI therapy early management of DTC
[B22] What is the role of TSH suppression therapy? DTC expresses the TSH receptor on the cell membrane and responds to TSH stimulation by increasing the expression of several thyroid specific proteins (Tg, sodium-iodide symporter) and by increasing the rates of cell growth (268). Suppression of TSH, using supra-physiologic doses of LT4, is used commonly to treat patients with thyroid cancer in an effort to decrease the risk of recurrence (127,214,269). A meta-analysis supported the efficacy of TSH suppression therapy in preventing major adverse clinical events (RR = 0.73; CI = 0.60–0.88; p < 0.05) (269).
[B23] What is the appropriate degree of initial TSH suppression? Retrospective and prospective studies have demonstrated that TSH suppression to below 0.1 mU/Lmay improve outcomes in high-risk thyroid cancer patients (127,270), though no such evidence of benefit has been documented in low-risk patients. A prospective cohort study (214) of 2936 patients found that overall survival improved significantly when the TSH was suppressed to undetectable levels in patients with NTCTCSG stage III or IV disease and suppressed to the subnormal to undetectable range in patients with NTCTCSG stage II disease; however, in the latter group there was no incremental benefit from suppressing TSH to undetectable levels. Suppression of TSH was not beneficial in patients with stage I disease. In another study, there was a positive association between serum TSH levels and the risk for recurrent disease and cancer-related mortality (271). Adverse effects of TSH suppression may include the known consequences of subclinical thyrotoxicosis, including exacerbation of angina in patients with ischemic heart disease, increased risk for atrial fibrillation in older patients (272), and increased risk of osteoporosis in postmenopausal women (273).
- RECOMMENDATION 40
Initial TSH suppression to below 0.1 mU/L is recommended for high-risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly below the lower limit of normal (0.1–0.5 mU/L) is appropriate for low-risk patients. Similar recommendations apply to low-risk patients who have not undergone remnant ablation, i.e., serum TSH 0.1–0.5 mU/L. Recommendation rating: B
[B24] Is there a role for adjunctive external beam irradiation or chemotherapy?
[B25] External beam irradiation. External beam irradiation is used infrequently in the management of thyroid cancer except as a palliative treatment for locally advanced, otherwise unresectable disease (274). There are reports of responses among patients with locally advanced disease (275,276) and improved relapse-free and cause-specific survival in patients over age 60 with extrathyroidal extension but no gross residual disease (277). It remains unknown whether external beam radiation might reduce the risk for recurrence in the neck following adequate primary surgery and/or RAI treatment in patients with aggressive histologic subtypes (278).
- RECOMMENDATION 41
The use of external beam irradiation to treat the primary tumor should be considered in patients over age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective. The sequence of external beam irradiation and RAI therapy depends on the volume of gross residual disease and the likelihood of the tumor being RAI responsive. Recommendation rating: B
[B26] Chemotherapy. There are no data to support the use of adjunctive chemotherapy in the management of DTC. Doxorubicin may act as a radiation sensitizer in some tumors of thyroid origin (279), and could be considered for patients with locally advanced disease undergoing external beam radiation.
- RECOMMENDATION 42
There is no role for the routine adjunctive use of chemotherapy in patients with DTC. Recommendation rating: F
References for Guidelines: http://thyroidguidelines.net/revised/references
References.
А. Main
Davidson’s Principles and Practice of Medicine (1st Edition) / Edited by N. R. Colledge, B. R. Walker, S. H. Ralston. – Philadelphia : Churchill Livingstone, 2010. – 1376 p.
Harrison’s Principles of Internal Medicine (18th edition) / D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J. Loscalzo,. – New York : McGraw-Hill Education – Europe, 2011. – 4012 p.
Kumar and Clark’s Clinical Medicine (8th Revised edition) (With studenrconsult Online Access) / P. KumarM. L. Clark . – London : Elsevier Health Sciences, 2012. – 1304 p.
B. Additional
1. Greenspan’s Basic and Clinical Endocrinology (9th Revised edition) / David G. Gardner, Dolores M. Shoback. – New York : McGraw-Hill Education – Europe, 2011. – 880 p.
2. Oxford Textbook of Endocrinology and Diabetes2nd Revised edition / John A. H. WassPaul StewartStephanie A. AmielMelanie J. Davies. – Oxford : Oxford University Press, 2011. – 2160 p.
Web-sites:
· http://emedicine.medscape.com/endocrinology
· http://www.endo–society.org/
· https://www.aace.com/ ATA/AACE Guidelines CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS
