Thyroid Functionand DiseaseSponsored byACCESS Medical GroupDepartment of Continuing Medical Education

Funded by an unrestricted educational grant from Abbott Laboratories.

The Thyroid Gland and Thyroid Hormones

Anatomy of the Thyroid Gland

Follicles: the Functional Units of the Thyroid GlandFollicles Are the Sites Where Key Thyroid Elements Function: Thyroglobulin (Tg) Tyrosine Iodine Thyroxine (T4) Triiodotyrosine (T3)

The Thyroid Produces and Secretes 2 Metabolic HormonesTwo principal hormonesThyroxine (T4 ) and triiodothyronine (T3)Required for homeostasis of all cellsInfluence cell differentiation, growth, and metabolismConsidered the major metabolic hormones because they target virtually every tissue

Thyroid-Stimulating Hormone (TSH)Regulates thyroid hormone production, secretion, and growthIs regulated by the negative feedback action of T4 and T3

Hypothalamic-Pituitary-Thyroid AxisNegative Feedback Mechanism

Biosynthesis of T4 and T3The process includesDietary iodine (I) ingestionActive transport and uptake of iodide (I-) by thyroid glandOxidation of I- and iodination of thyroglobulin (Tg) tyrosine residues Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3 Proteolysis of Tg with release of T4 and T3 into the circulation

Iodine SourcesAvailable through certain foods (eg, seafood, bread, dairy products), iodized salt, or dietary supplements, as a trace mineralThe recommended minimum intake is 150 g/day

Active Transport and I- Uptake by the Thyroid

Dietary iodine reaches the circulation as iodide anion (I-)The thyroid gland transports I- to the sites of hormone synthesisI- accumulation in the thyroid is an active transport process that is stimulated by TSH

Iodide Active Transport is Mediated by the Sodium-Iodide Symporter (NIS)NIS is a membrane protein that mediates active iodide uptake by the thyroidIt functions as a I- concentrating mechanism that enables I- to enter the thyroid for hormone biosynthesisNIS confers basal cell membranes of thyroid follicular cells with the ability to effect iodide trapping by an active transport mechanismSpecialized system assures that adequate dietary I- accumulates in the follicles and becomes available for T4 and T3 biosynthesis

Oxidation of I- and Iodination of Thyroglobulin (Tg) Tyrosyl ResiduesI- must be oxidized to be able to iodinate tyrosyl residues of TgIodination of the tyrosyl residues then forms monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are then coupled to form either T3 or T4Both reactions are catalyzed by TPO

Thyroperoxidase (TPO)TPO catalyzes the oxidation steps involved in I- activation, iodination of Tg tyrosyl residues, and coupling of iodotyrosyl residues TPO has binding sites for I- and tyrosine TPO uses H2O2 as the oxidant to activate I- to hypoiodate (OI-), the iodinating species

Proteolysis of Tg With Release ofT4 and T3T4 and T3 are synthesized and stored within the Tg moleculeProteolysis is an essential step for releasing the hormonesTo liberate T4 and T3, Tg is resorbed into the follicular cells in the form of colloid droplets, which fuse with lysosomes to form phagolysosomesTg is then hydrolyzed to T4 and T3, which are then secreted into the circulation

Conversion of T4 to T3 in Peripheral Tissues

Production of T4 and T3 T4 is the primary secretory product of the thyroid gland, which is the only source of T4 The thyroid secretes approximately 70-90 g of T4 per dayT3 is derived from 2 processesThe total daily production rate of T3 is about 15-30 gAbout 80% of circulating T3 comes from deiodination of T4 in peripheral tissuesAbout 20% comes from direct thyroid secretion

T4: A Prohormone for T3T4 is biologically inactive in target tissues until converted to T3Activation occurs with 5' iodination of the outer ring of T4T3 then becomes the biologically active hormone responsible for the majority of thyroid hormone effects

Sites of T4 ConversionThe liver is the major extrathyroidal T4 conversion site for production of T3Some T4 to T3 conversion also occurs in the kidney and other tissues

T4 DispositionNormal disposition of T4About 41% is converted to T3 38% is converted to reverse T3 (rT3), which is metabolically inactive 21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bileNormal circulating concentrations T4 4.5-11 g/dLT3 60-180 ng/dL (~100-fold less than T4)

Hormonal Transport

Carriers for Circulating Thyroid HormonesMore than 99% of circulating T4 and T3 is bound to plasma carrier proteinsThyroxine-binding globulin (TBG), binds about 75%Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA), binds about 10%-15%Albumin binds about 7%High-density lipoproteins (HDL), binds about 3%Carrier proteins can be affected by physiologic changes, drugs, and disease

Free Hormone ConceptOnly unbound (free) hormone has metabolic activity and physiologic effects Free hormone is a tiny percentage of total hormone in plasma (about 0.03% T4; 0.3% T3)Total hormone concentration Normally is kept proportional to the concentration of carrier proteins Is kept appropriate to maintain a constant free hormone level

Changes in TBG Concentration Determine Binding and Influence T4 and T3 LevelsIncreased TBG Total serum T4 and T3 levels increase Free T4 (FT4), and free T3 (FT3) concentrations remain unchangedDecreased TBGTotal serum T4 and T3 levels decrease FT4 and FT3 levels remain unchanged

Drugs and Conditions That Increase Serum T4 and T3 Levels by Increasing TBGDrugs that increase TBGOral contraceptives and other sources of estrogenMethadoneClofibrate5-FluorouracilHeroinTamoxifen

Conditions that increase TBGPregnancyInfectious/chronic active hepatitisHIV infectionBiliary cirrhosisAcute intermittent porphyriaGenetic factors

Drugs and Conditions That Decrease Serum T4 and T3 by Decreasing TBG Levels or Binding of Hormone to TBGDrugs that decrease serum T4 and T3 GlucocorticoidsAndrogensL-AsparaginaseSalicylatesMefenamic acidAntiseizure medications, eg, phenytoin, carbama-zepineFurosemideConditions that decrease serum T4 and T3 Genetic factorsAcute and chronic illness

Thyroid Hormone Action

Thyroid Hormone Plays a Major Role in Growth and DevelopmentThyroid hormone initiates or sustains differentiation and growthStimulates formation of proteins, which exert trophic effects on tissuesIs essential for normal brain developmentEssential for childhood growthUntreated congenital hypothyroidism or chronic hypothyroidism during childhood can result in incomplete development and mental retardation

Thyroid Hormones and the Central Nervous System (CNS)Thyroid hormones are essential for neural development and maturation and function of the CNSDecreased thyroid hormone concentrations may lead to alterations in cognitive functionPatients with hypothyroidism may develop impairment of attention, slowed motor function, and poor memoryThyroid-replacement therapy may improve cognitive function when hypothyroidism is present

Thyroid Hormone Influences Cardiovascular HemodynamicsThyroid hormoneMediated Thermogenesis(Peripheral Tissues)Release Metabolic EndproductsLocal VasodilitationDecreased Systemic Vascular ResistanceDecreased Diastolic Blood PressureCardiac Chronotropy and InotropyIncreased Cardiac OutputElevated Blood VolumeT3

Laragh JH, et al. Endocrine Mechanisms in Hypertension. Vol. 2. New York, NY: Raven Press;1989.

Thyroid Hormone Influences the Female Reproductive SystemNormal thyroid hormone function is important for reproductive functionHypothyroidism may be associated with menstrual disorders, infertility, risk of miscarriage, and other complications of pregnancyDoufas AG, et al. Ann N Y Acad Sci. 2000;900:65-76. Glinoer D. Trends Endocrinol Metab. 1998; 9:403-411.Glinoer D. Endocr Rev. 1997;18:404-433.

Thyroid Hormone is Critical for Normal Bone Growth and DevelopmentT3 is an important regulator of skeletal maturation at the growth plateT3 regulates the expression of factors and other contributors to linear growth directly in the growth plateT3 also may participate in osteoblast differentiation and proliferation, and chondrocyte maturation leading to bone ossification

Thyroid Hormone Regulates Mitochondrial ActivityT3 is considered the major regulator of mitochondrial activityA potent T3-dependent transcription factor of the mitochondrial genome induces early stimulation of transcription and increases transcription factor (TFA) expressionT3 stimulates oxygen consumption by the mitochondria

Thyroid Hormones Stimulate Metabolic Activities in Most TissuesThyroid hormones (specifically T3) regulate rate of overall body metabolismT3 increases basal metabolic rateCalorigenic effectsT3 increases oxygen consumption by most peripheral tissuesIncreases body heat production

Metabolic Effects of T3Stimulates lipolysis and release of free fatty acids and glycerolInduces expression of lipogenic enzymesEffects cholesterol metabolismStimulates metabolism of cholesterol to bile acidsFacilitates rapid removal of LDL from plasmaGenerally stimulates all aspects of carbohydrate metabolism and the pathway for protein degradation

Thyroid Disorders

Overview of Thyroid Disease States

Hypothyroidism

Hyperthyroidism

HypothyroidismHypothyroidism is a disorder with multiplecauses in which the thyroid fails to secrete an adequate amount of thyroid hormoneThe most common thyroid disorder Usually caused by primary thyroid gland failureAlso may result from diminished stimulation of the thyroid gland by TSH

HyperthyroidismHyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues

Typical Thyroid Hormone Levels in Thyroid Disease TSHT4 T3Hypothyroidism HighLow LowHyperthyroidism LowHigh High

9.5% of subjects had elevated TSH; most of them had subclinical hypothyroidism (normal T4 with TSH >5.1 IU/mL)Among the subjects already taking thyroid medication (almost 6% of study population), 40% had abnormal TSH levels, reflecting inadequate treatmentAmong those not taking thyroid medication, 9.9% had a thyroid abnormality that was unrecognizedThere may be in excess of 13 million cases of undetected thyroid failure nationwide The Colorado StudyCanaris GJ, et al. Arch Intern Med. 2000;160:523-534.Prevalence of Thyroid DiseaseAt a statewide health fair in Colorado (N=25 862), participants were tested for TSH and total T4 levels

Prevalence of Thyroid Disease by Age

Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.

Elevated TSH, %(Age in Years)18253545556575Male34.53.55610.516Female456.5913.51521The incidence of thyroid disease increases with age

Prevalence of Thyroid Disease by GenderStudies conducted in various communities over the past 30 years have consistently concluded that thyroid disease is more prevalent in women than in menThe Whickham survey, conducted in the 1970s and later followed-up in 1995, showed the prevalence of undiagnosed thyrotoxicosis was 4.7 per 1000 women and 1.6 to 2.3 per 1000 menThe Framingham study data showed the incidence of thyroid deficiency in women was 5.9% and in men, 2.3%The Colorado study concluded that the proportion of subjects with an elevated TSH level is greater among women than among men

Increasing Prevalence of Thyroid Disease in the US PopulationNational Health and Nutrition Examination Surveys (NHANES I and III)Monitored the status of thyroid function in a sample of individuals representing the ethnic and geographic distribution of the US populationNHANES III measured serum TSH, total serum T4, and thyroid antibodies to thyroglobulin (TgAb) and to thyroperoxidase (TPOAb)Hypothyroidism was found in 4.6%; of those, 4.3% had mild thyroid failureHyperthyroidism was found in 1.3%

Hypothyroidism: TypesPrimary hypothyroidismFrom thyroid destructionCentral or secondary hypothyroidismFrom deficient TSH secretion, generally due to sellar lesions such as pituitary tumor or craniopharyngiomaInfrequently is congenitalCentral or tertiary hypothyroidismFrom deficient TSH stimulation above level of pituitaryie, lesions of pituitary stalk or hypothalamus Is much less common than secondary hypothyroidismBravernan LE, Utiger RE, eds. Werner & Ingbar's The Thyroid. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000.Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635.

Primary Hypothyroidism: Underlying CausesCongenital hypothyroidismAgenesis of thyroidDefective thyroid hormone biosynthesis due to enzymatic defectThyroid tissue destruction as a result ofChronic autoimmune (Hashimoto) thyroiditisRadiation (usually radioactive iodine treatment for thyrotoxicosis)ThyroidectomyOther infiltrative diseases of thyroid (eg, hemochromatosis)Drugs with antithyroid actions (eg, lithium, iodine, iodine-containing drugs, radiographic contrast agents, interferon alpha)In the US, hypothyroidism is usually due to chronic autoimmune (Hashimoto) thyroiditis

Clinical Features of HypothyroidismTirednessForgetfulness/Slower ThinkingMoodiness/ IrritabilityDepressionInability to ConcentrateThinning Hair/Hair LossLoss of Body HairDry, Patchy SkinWeight GainCold IntoleranceElevated CholesterolFamily History of Thyroid Disease or DiabetesMuscle Weakness/ CrampsConstipationInfertilityMenstrual Irregularities/ Heavy PeriodSlower HeartbeatDifficulty SwallowingPersistent Dry or Sore ThroatHoarseness/ Deepening of VoiceEnlarged Thyroid (Goiter)Puffy Eyes

Mild Thyroid Failure

Definition of Mild Thyroid FailureElevated TSH level (>4.0 IU/mL)Normal total or free serum T4 and T3 levelsFew or no signs or symptoms of hypothyroidismMcDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000;1001.

Causes of Mild Thyroid FailureExogenous factorsLevothyroxine underreplacementMedications, such as lithium, cytokines, or iodine-containing agents (eg, amiodarone)Antithyroid medications131I therapy or thyroidectomyEndogenous factorsPrevious subacute or silent thyroiditis Hashimoto thyroiditisBiondi B, et al. Ann Intern Med. 2002;137:904-914.

Prevalence and Incidence of Mild Thyroid FailurePrevalence4% to 10% in large population screening surveysIncreases with increasing ageIs more common in women than in menIncidence2.1% to 3.8% per year in thyroid antibody-positive patients0.3% per year in thyroid antibody-negative patients McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.Biondi B, et al. Ann Intern Med. 2002;137:904-914.

Populations at Risk for Mild Thyroid FailureWomenPrior history of Graves disease or postpartum thyroid dysfunctionElderlyOther autoimmune diseaseFamily history of Thyroid diseasePernicious anemiaType 1 Diabetes mellitusCaraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.Carmel R, et al. Arch Intern Med. 1982;142:1465-1469.Perros P, et al. Diabetes Med. 1995;12:622-627.

Mild Thyroid Failure Affects Cardiac FunctionCardiac function is subtly impaired in patients with mild thyroid failureAbnormalities can include Subtle abnormalities in systolic time intervals and myocardial contractilityDiastolic dysfunction at rest or with exerciseReduction of exercise-related stroke volume, cardiac index, and maximal aortic flow velocityThe clinical significance of the changes is unclearMcDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:1004.

Mild Thyroid Failure May Increase Cardiovascular Disease RiskMild thyroid failure has been evaluated as a cardiovascular risk factor associated withIncreased serum levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) levelsReduced high-density lipoprotein cholesterol (HDL-C) levelsIncreased prevalence of aortic atherosclerosisIncreased incidence of myocardial infarction

The Rotterdam Study Design and ObjectivesA population-based cross-sectional cohort study conducted in a district of Rotterdam, the NetherlandsCohort included 3105 men and 4878 women aged 55 and olderThyroid status was determined from a random sample of 1149 elderly women (mean age 69 7.5 years) selected from the studyThe study's objective was to investigate whether mild thyroid failure and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction

Mild Thyroid Failure Increases Risk of Myocardial Infarction (MI)Findings from the Rotterdam StudyMild thyroid failure contributed to 60% of MI cases in patients with diagnosed mild thyroid failure, and 14% of all MI instances in the study populationMild thyroid failure appeared to be a strong indicator of risk for aortic atherosclerosis and MI in older womenThyroid autoimmunity by itself was not associated with aortic atherosclerosis or MIHak AE, et al. Ann Intern Med. 2000;132:270-278.

Mild Thyroid Failure Associated With Aortic AtherosclerosisPresence of Aortic AtherosclerosisHak AE, et al. Ann Intern Med. 2000;132:270-278.Women With Mild Thyroid FailureEuthyroidWomenWomen With Mild Thyroid Failure and Antibodies to Thyroid PeroxidaseEuthyroid Women Without Antibodies to Thyroid Peroxidase050100Patients, %Condition PresentCondition Absent

Relationship Between Thyroid Hormone and LDL ReceptorsLow-density lipoprotein (LDL) specifically binds and transports

Colorado Study Cholesterol End PointsTreating mild thyroid failure may aid in the treatment of hyperlipidemia and prevent associated cardiovascular morbidityAs TSH levels rise, cholesterol levels rise concomitantlyCanaris GJ, et al. Arch Intern Med.2000;160:526-534.Mean Total Cholesterol (mg/dL)TSH (IU/mL)Mean Cholesterol by TSHEuthyroidAbnormal TSH2092292382392232702672162262002102202302402502602702805.1-10>10-15>15-20>20-40>40-60>60-80>80

Four Stages in the Development of Hypothyroidism Consensus Stage FT4 FT3 for Treatment Earliest Normal Within population None reference range

Second Normal High Controversial(5-10 IU/mL)Third Normal High Treat with(>10 IU/mL) LT4*Fourth LowHighUniform: (>10 IU/mL) Treat with LT4Chu J, et al. J Clin Endocrinol Metab. 2001;86:4591-4599.* Treat if patient falls into predefined categories.

The Rate of Progression of Mild Thyroid Failure to Overt HypothyroidismMild thyroid failure is a common disorder that frequently progresses to overt hypothyroidismProgression has been reported in about 3% to 18% of affected patients per yearProgression may take years or may rapidly occurThe rate is greater if TSH is higher or if there are positive antithyroid antibodiesThe rate may also be greater in patients who were previously treated with radioiodine or surgery

Disorders Characterized by Hyperthyroidism

Signs and Symptoms of HyperthyroidismNervousness/TremorMental Disturbances/ IrritabilityDifficulty SleepingBulging Eyes/Unblinking Stare/ Vision ChangesEnlarged Thyroid (Goiter)Menstrual Irregularities/ Light PeriodFrequent Bowel MovementsWarm, Moist Palms

First-Trimester Miscarriage/Excessive Vomiting in PregnancyHoarseness/ Deepening of VoicePersistent Dry or Sore ThroatDifficulty SwallowingPalpitations/ Tachycardia Impaired FertilityWeight Loss or GainHeat IntoleranceIncreased SweatingFamily History of Thyroid Disease or DiabetesSudden Paralysis

Hyperthyroidism Underlying CausesSigns and symptoms can be caused by any disorder that results in an increase in circulation of thyroid hormone Toxic diffuse goiter (Graves disease)Toxic uninodular or multinodular goiterPainful subacute thyroiditisSilent thyroiditisToxic adenomaIodine and iodine-containing drugs and radiographic contrast agentsTrophoblastic disease, including hydatidiform moleExogenous thyroid hormone ingestion

Graves Disease(Toxic Diffuse Goiter) The most common cause of hyperthyroidism Accounts for 60% to 90% of casesIncidence in the United States estimated at 0.02% to 0.4% of the populationAffects more females than males, especially in the reproductive age rangeGraves disease is an autoimmune disorder possibly related to a defect in immune tolerance

Chronic Autoimmune Thyroiditis(Hashimoto Thyroiditis)Occurs when there is a severe defect in thyroid hormone synthesis Is a chronic inflammatory autoimmune disease characterized by destruction of the thyroid gland by autoantibodies against thyroglobulin, thyroperoxidase, and other thyroid tissue componentsPatients present with hypothyroidism, painless goiter, and other overt signsPersons with autoimmune thyroid disease may have other concomitant autoimmune disordersMost commonly associated with type 1 diabetes mellitus

Thyroid Nodular DiseaseThyroid gland nodules are common in the general population Palpable nodules occur in approximately 5% of the US population, mainly in womenMost thyroid nodules are benign Less than 5% are malignantOnly 8% to 10% of patients with thyroid nodules have thyroid cancer

Multinodular Goiter (MNG)MNG is an enlarged thyroid gland containing multiple nodulesThe thyroid gland becomes more nodular with increasing ageIn MNG, nodules typically vary in sizeMost MNGs are asymptomaticMNG may be toxic or nontoxicToxic MNG occurs when multiple sites of autonomous nodule hyperfunction develop, resulting in thyrotoxicosisToxic MNG is more common in the elderly

Thyroid CarcinomaIncidenceThyroid carcinoma occurs relatively infrequently compared to the common occurrence of benign thyroid diseaseThyroid cancers account for only 0.74% of cancers among men, and 2.3% of cancers in women in the USThe annual rate has increased nearly 50% since 1973 to approximately 18 000 casesThyroid carcinomas (percentage of all US cases)Papillary (80%)Follicular (about 10%)Medullary thyroid (5%-10%)Anaplastic carcinoma (1%-2%)Primary thyroid lymphomas (rare)Metastatic from other primary sites (rare)

Association Between Goiters, Thyroid Nodules, and Thyroid CarcinomaRisk factors for carcinoma associated with presence of thyroid nodulesSolitary thyroid nodules in patients >60 or 5.1 IU/mL. Included was a group of people who were already on thyroid medication. Study results show that 40% of those undergoing thyroid hormone-replacement therapy still had abnormal TSH levels. Among patients not taking thyroid medication, almost 10% exhibited a thyroid abnormality that had not been detected previously by a physician. This landmark study concluded that there may be more than 13 million cases of undetected thyroid gland failure in the United States. Results from the Colorado Study also revealed the large number of patients who take thyroid hormones, but are not within the therapeutic range, suggesting that physicians should consider more frequent monitoring of patients receiving thyroid replacement therapy.Reference1. Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.Prevalence of Thyroid Disease by Age.Findings from the Colorado Study showed that the incidence of thyroid disease increases dramatically with age.1 The chart indicates that over the course of 6 decades, prevalence of thyroid disease in men increases from 3% to 16%, and in women from 4% to 21%.1 The number of subjects with elevated TSH increased with advancing age.1 In spite of the high incidence of thyroid dysfunction in the elderly, there may be delay and difficulty in diagnosis because symptoms are not always obvious and may be attributed to normal aging.2References Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Mohandas, R, et al. Postgrad Med. 2003;113:54-56, 65-68,100.

Prevalence of Thyroid Disease by Gender.The prevalence of thyroid disorders was evaluated in a number of studies. Among them, the Whickham survey, a large cross-sectional study of a mixed urban and rural area of England, was first conducted in the 1970s with a follow-up study 20 years later.1 The data showed that the prevalence of undiagnosed thyrotoxicosis was 4.7 per 1000 women and 1.6 to 2.3 per 1000 men.1 In the Framingham study, an epidemiological study conducted in Massachusetts, women (5.9%) had thyroid deficiency more often than men (2.3%).2 Nearly all studies reported a higher prevalence of hypothyroidism in women and with age.3 From data from the Colorado study, which tested attendees at a state fair for thyroid disease, it was concluded that the proportion of subjects with an elevated TSH level is greater among women and that it increases with age.3References Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:467-468. Sawin CT, et al. Arch Intern Med. 1985;145:1386-1388. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.Increasing Prevalence of Thyroid Disease in the US Population.The NHANES surveys were designed to give national standardized estimates of the health and nutritional status of the US civilian, noninstitutionalized population.1 The sample of 17 353 individuals surveyed represented the geographic and ethnic distribution of the US population aged 12 years. In the 20 years between NHANES I (1971-1974) and NHANES III (1988-1994), the mean urinary iodine concentration decreased from 320 g/L to 145 g/L. NHANES III also measured serum TSH, total serum T4, and antibodies to Tg (TgAb) and to TPO (TPOAb) in "disease-free" people who did not report thyroid disease, goiter, or taking thyroid medications. These data provided a reference for other studies of these analytes in the US. Hypothyroidism was found in 4.6% of the US population. Of these, 0.3% had clinical hypothyroidism, and 4.3% had subclinical or mild hypothyroidism. Hyperthyroidism was found in 1.3% of the population (0.5% clinical and 0.7% subclinical). Higher TSH values and the prevalence of antithyroid antibodies were greater in females, increased with age, and were greater in whites and Mexican Americans than in African Americans. It was concluded that a large proportion of the US population unknowingly have laboratory evidence of thyroid disease, adding further credence to the usefulness of screening thyroid function for early detection of thyroid disease.1Reference1. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.Hypothyroidism: Types.Primary hypothyroidism is most often caused by a disorder of the thyroid gland that leads to a decrease in thyroidal production and secretion of T4 and T3.1 Primary hypothyroidism is usually accompanied by increased TSH secretion.1 Less frequently, hypothyroidism is caused by decreased thyroidal stimulation by TSH, which is referred to as central, hypothyrotropic, or secondary hypothyroidism.1 This condition can be the consequence of an anatomic or functional disorder of the pituitary gland, the hypothalamus, or both. Formerly, the term secondary referred to a pituitary origin for the TSH deficiency, and tertiary referred to hypothyroidism of hypothalamic origin.1Central hypothyroidism (CH) results from impaired stimulation by TSH of an otherwise normal thyroid gland.2 Large lesions of the intrasellar or parasellar regions account for most of the sporadic cases of acquired CH, since the secretion of TSH molecules with reduced bioactivity is a common occurrence in patients with hypothalamic-pituitary lesions.2References1. Braverman LE, Utiger RE, eds. Werner & Ingbars The Thyroid. 8th ed. Philadelphia, Pa; Lippincott Williams & Wilkins. 2000:719.2. Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635Primary Hypothyroidism: Underlying Causes.The underlying causes of hypothyroidism are listed in this slide.1 In 70% to 80% of cases of congenital thyroid disorder, some form of developmental abnormality is involved.1 Primary hypothyroidism may also be caused by diseases or treatments that destroy gland tissue, such as atrophic and goitrous forms of chronic autoimmune thyroiditis, radiation from 131I therapy for thyrotoxicosis or radiotherapy to the head and neck for nonthyroid malignant disease, total and subtotal thyroidectomy, and infiltrative diseases of the thyroid including amyloidosis, and scleroderma.1In a small percentage of cases, primary hypothyroidism results from actions that interfere with thyroid hormone biosynthesis, including iodine deficiency.1Primary hypothyroidism has also been implicated as a side effect of a number of drugs (eg, lithium, antithyroid drugs used to treat hyperthyroidism, iodine-containing drugs, some radiographic contrast agents, and interferon alpha).1 Worldwide, iodine deficiency is the most common cause of hypothyroidism. In the US, it is commonly caused by autoimmune thyroiditis (Hashimoto disease).2References1. Braverman LE, Utiger RD, eds. Werner & Ingbar's The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000: 719.2. Endocr Pract. 2002; 8:458-469.

Clinical Features of Hypothyroidism.As shown in this slide, hypothyroidism can cause a wide range of symptoms. Symptoms include puffy eyes and problems in the throat (goiter, hoarseness, sore throat and difficulty swallowing). These occur because the thyroid becomes strained and swollen. The heart can slow down. Many women also experience menstrual irregularities and infertility. Constipation and myalgia are frequent. Other signs include: tiredness, forgetfulness, irritability, depression, poor concentration, and cold intolerance. Some additional visible clues are hair loss, dry skin, and weight gain. Elevated cholesterol and hyperlipidemia can be caused by hypothyroidism. A family history of thyroid disease or diabetes increases the chances of developing one or both diseases. The symptoms are generally related to the duration and severity of hypothyroidism, the speed with which hypothyroidism occurs, and the psychological characteristics of the patient. Other symptoms of hypothyroidism include reflex delay, ataxia, mental impairment, bradycardia, myxedema fluid tissue infiltration, and yellow skin.1 Reference 1. Endocr Pract. 2002;8:458-469.Definition of Mild Thyroid Failure.Mild thyroid failure, also known as subclinical hypothyroidism, is defined as an elevated serum TSH level (>4.0 IU/mL) that occurs with normal total or free serum thyroxine (T4) and triiodothyronine (T3) levels1 and that is associated with few or no signs or symptoms of hypothyroidism.2References1. McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.2. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000;1001.

Causes of Mild Thyroid Failure.There are several exogenous and endogenous factors that can cause mild thyroid failure.1 Exogenous factors that can cause mild thyroid failure include levothyroxine (LT4) underreplacement in patients with hypothyroidism, medications containing lithium, cytokines, or iodine, antithyroid medications, iodine 131 therapy, or a thyroidectomy.1Endogenous factors for mild thyroid failure include previous subacute or silent thyroiditis or Hashimoto thyroiditis (HT).1 Persons with HT have high titers of thyroid peroxidase or thyroglobulin antibodies, elevated TSH in the absence of medications, and/or a positive history or examination.2 Goitrous hypothyroidism occurs in HT and when there is a severe defect in thyroid hormone production.3 References1. Biondi B, et al. Ann Intern Med. 2002;137:904-914.2. McCanlies E, et al. J Clin Endocrinol Metab. 1998;83:1548-1551.3. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394.Prevalence and Incidence of Mild Thyroid Failure. The overall prevalence of mild thyroid failure has been reported to range from 4% to 10% in large general population screening surveys and from 7% to 26% in studies of the elderly.1 The prevalence is higher in women than in men and increases with age.2Study reviews have found that the incidence of mild thyroid failure ranges from 2.1% to 3.8% per year in thyroid antibodypositive patients, and is approximately 0.3% per year in thyroid antibodynegative patients.3References1. McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.2. Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.3. Biondi B, et al. Ann Intern Med. 2002;137:904-914.

Populations at Risk for Mild Thyroid Failure.Certain patient populations are at a higher risk for developing mild thyroid failure.Women are at a higher risk than men for developing mild thyroid failure.1 The risk of developing mild thyroid failure increases with age, often reaching a peak of 21% in women and 16% in men over 74 years of age.1Patients with a family history of thyroid disease, pernicious anemia, and diabetes mellitus also are at risk for developing mild thyroid failure.2,3References1. Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.2. Carmel R, et al. Arch Intern Med. 1982;142:1465-1469.3. Perros P, et al. Diabetes Med. 1995;12:622-627.

Mild Thyroid Failure Affects Cardiac Function.Myocardial function has been reported in multiple studies to be subtly impaired in patients with mild thyroid failure.1 Studies designed to evaluate changes in systolic time intervals and cardiac contractility in patients with mild thyroid failure have shown different results. It can be concluded that some patients with mild thyroid failure have subtle abnormalities in systolic time intervals and myocardial contractility that improve during treatment.2 Other functional abnormalities include diastolic dysfunction at rest or with exercise, and significant impairment of exercise-related stroke volume, cardiac index, and maximal aortic flow velocity. Pulmonary testing in the same patients showed decreased vital capacity, reduced anaerobic thresholds, and decreased oxygen uptake at the anaerobic threshold.1 Myocardial texture in patients with mild thyroid failure was also shown to be abnormal by videodensitometric analysis.1References1. McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.2. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:1004.

Mild Thyroid Failure May Increase Cardiovascular Disease Risk.Mild thyroid failure has been extensively evaluated as a cardiovascular risk factor and found to be associated with coronary artery disease risk.1 In most studies, mild thyroid failure has been associated with increased serum levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C). Some studies have shown a reduction in high-density lipoprotein cholesterol (HDL-C). Some reports suggested that even high-normal serum TSH values may adversely affect serum lipid and lipoprotein levels. The relationship between TSH and LDL-C appears to be most significant in individuals who have underlying insulin resistance. Patients with mild thyroid failure or even high-normal TSH values have evidence of endothelial dysfunction. A case-control study showed an association with peripheral vascular disease in elderly women. The Rotterdam study concluded that patients with mild thyroid failure have a significantly increased prevalence of aortic atherosclerosis and myocardial infarction (MI).Reference1. McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.

The Rotterdam Study. Design and Objectives.Overt hypothyroidism, accompanied by hypercholesterolemia and hypertension, is known to be associated with cardiovascular disease. Subclinical hypothyroidism or mild thyroid failure, an asymptomatic state characterized by normal serum concentrations of FT4 and elevated serum TSH, is highly prevalent in elderly women. Before the Rotterdam study, the association of mild thyroid failure as a risk factor for cardiovascular disease had not been confirmed by consistent study findings. Thyroid autoimmunity was also in question as a cardiovascular risk factor.The Rotterdam study was a population-based cross-sectional cohort study, conducted in a district of Rotterdam, the Netherlands, to assess the occurrence and clarify the determinants of chronic diseases in an aging population.1 Its objective was to investigate whether mild thyroid failure and thyroid autoimmunity are associated with aortic atherosclerosis and MI in postmenopausal women. The cohort included 3105 men and 4878 women 55 years of age. Thyroid status was determined from a random sample of 1149 elderly women, with a mean age of 69 7.5 years, who were selected from the study. Reference1. Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Mild Thyroid Failure Increases Risk of Myocardial Infarction (MI).Of the participants in the Rotterdam study, 10.8% had mild thyroid failure. The presence of myocardial infarction (MI) was assessed by self report and electrocardiogram analysis. The authors calculated an attributable risk of 60% and a population attributable risk of 14% for mild thyroid failure associated with MI.1 These findings suggested that mild thyroid failure contributed to 60% of MI cases among women who had mild thyroid failure, and it was involved in the pathogenesis of 14% of all MIs in the study sample.Mild thyroid failure was associated with a greater age-adjusted prevalence of aortic atherosclerosis and MI. Associations were slightly stronger in women who had mild thyroid failure and antibodies to thyroid peroxidase. No separate association was found between thyroid autoimmunity and cardiovascular disease.Reference1. Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Mild Thyroid Failure Associated With Aortic Atherosclerosis. In the Rotterdam study, the investigators measured the occurrence of aortic atherosclerosis in women with mild thyroid failure.1 Aortic atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta. The authors found that mild thyroid failure was associated with a greater prevalence of aortic atherosclerosis. In addition, the authors found that women with mild thyroid failure and antibodies to thyroid peroxidase had a greater prevalence of aortic atherosclerosis than euthyroid women without antibodies to thyroid peroxidase.However, no association was found between aortic atherosclerosis and history of MI when thyroid status was not altered.Reference1. Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Relationship Between Thyroid Hormone and LDL Receptors.A small fraction (3%) of T4 is bound to plasma lipoproteins, primarily HDL,1 and 10 IU/mL on repeated measurement, those who have clinical symptoms or signs associated with thyroid failure, a strong family history of thyroid disease, or severe hyperlipidemia being treated with statins or fibric acid drugs, or patients who are pregnant.1,2References1. Chu J, et al. J Clin Endocrinol Metab. 2001; 86:4591-4599.2. Glueck CJ, et al. Cur Atheroscler Rep. 2003;5:73-77.The Rate of Progression of Mild Thyroid Failure to Overt Hypothyroidism.Mild thyroid failure represents an early stage of thyroid disease that commonly progresses to overt hypothyroidism.1 In the 20-year follow-up survey of the Whickham study, an estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time showed an increase with age and antithyroid antibodies in hypothyroidism.2 Progression to overt hypothyroidism has been reported to occur in 3%-18% per year of patients with mild thyroid failure.1 Strong predictors of progression are the presence of antithyroid antibodies, serum TSH values >20 IU/mL, a history of radioiodine ablation for Graves disease, a history of external radiation therapy for nonthyroid malignancies, and chronic lithium treatment.1 Progression may take years or may occur quickly.3References1. McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.2. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.3. Smallridge RC. Postgrad Med. 2000;107:143-52.Signs and Symptoms of Hyperthyroidism.This slide shows systems of the body that are affected by hyperthyroidism. The throat region is strained with hoarseness, dryness, goiter, and difficulty swallowing.1 Rapid heartbeat occurs. There are gynecological problems: infertility, menstrual irregularities and first-trimester miscarriage, as well as excessive vomiting in pregnancy. There is sweating, heat intolerance, and frequent bowel movements. The patient may also be nervous, cranky, and sleepless. The eyes appear bulging and staring. In addition, patients with hyperthyroidism may have tremors, weight loss or gain, and alterations in appetite, changes in vision, fatigue and muscle weakness, and exertional intolerance and dyspnea. Reference1. Endocr Pract. 2002; 8:458-467.

Hyperthyroidism. Underlying Causes.The signs and symptoms of hyperthyroidism are caused by excessive thyroid hormone in the circulation.1 A number of disorders cause the increase in circulating thyroid hormone including toxic diffuse goiter (Graves disease), which is the most common cause;2,3 toxic uninodular and multinodular goiter;2,3 painful subacute thyroiditis, silent thyroiditis;2 toxic adenomas;3 iodine and iodine-containing drugs and radiographic contrast agents,3 trophoblastic disease including hydatidiform mole;3,4,5 and exogenous thyroid hormone ingestion.3

References1. Endocr Pract. 2002;8:458-467.2. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394.3. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:515-516,688-689.4. Yoshimura M, et al. J Endocrinol Metab. 1994;78:862-866.5. Mestman JH. Endocrinol Metab Clin North Am. 1998; 27:127-149.

Graves Disease (Toxic Diffuse Goiter).Graves disease (also called toxic diffuse goiter) is the most common cause of high radioactive iodine uptake (RAIU) thyrotoxicosis.1 Its prevalence ranges from 60% to 90% of the RAIU cases, depending upon age and geographic region. Women are affected by Graves disease to a greater extent than men, and though the disease can occur at any age, it is more common between the ages of 20 and 50.1 Graves disease is an autoimmune disorder characterized by hyperthyroidism1 (elevated levels of thyroid hormone, suppressed levels of TSH, and increased RAIU),2 diffuse (uniformly enlarged) goiter, and IgG antibodies that bind and activate the TSH receptor (TSH-R).1 By binding to the TSH-R, these antibodies stimulate thyroid function, thus elevating concentrations of circulating free thyroid hormones.3 The eyes show characteristic exophthalmos, which is considered to be an autoimmune-mediated inflammation of the periorbital connective tissue and extraocular muscle.1,3 The production of excessive heat, increased motor activity, and increased activity of the sympathetic nervous system causes the skin to become warm, moist, and flushed, the muscles weak and trembling, and the heart rate rapid with a forceful beat.1 Although appetite increases, there may be weight loss, insomnia, anxiety, and apprehension, heat intolerance, and increased bowel movement frequency. Older patients may experience angina, heart failure, and arrhythmias.1 Thyroid nodules are frequently seen in patients with Graves disease.4References Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394. Sklar C, et al. J Clin Endocrinol Metab. 2000;85:3227-3232. Weetman AP, et al. Endocr Rev. 1994;15:788-830. Mishra A, et al. J Postgrad Med. 2001;47:244-247.Chronic Autoimmune Thyroiditis (Hashimoto Thyroiditis).Hashimoto thyroiditis (HT), also called chronic autoimmune thyroiditis or chronic goitrous thyroiditis,1 is characterized by hypothyroidism with autoantibodies directed against thyroglobulin and thyroperoxidase, as well as other components of thyroid tissue.1 When severe, HT is associated with multiple symptoms that affect the appearance and mental activity of the patient.2 The face is pale, puffy, and without expression.2 The skin is cold and dry, and the patient may complain of cold intolerance. The scalp is scaly, hair and fingernails brittle, and subcutaneous tissue appears thickened and edematous.2 The patient is lethargic, with a husky voice and slow speech, and depression may be present, along with poor appetite and diminished gastrointestinal activity.2 The coexistence of 2 or more autoimmune endocrine diseases is common1 and autoimmune thyroiditis is commonly associated with insulin-dependent (IDDM) (Type 1) diabetes mellitus,3 another autoimmune endocrine disease.4 References Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:721.2. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1394.3. McCanlies E, et al. J Clin Endocrinol Metab. 1998;83:1548-1551.4. Matejkova-Behanova M. Endocr Reg. 2001;35:167-172.Thyroid Nodular Disease.Thyroid nodules are the most common endocrine disorder.1,2 Although thyroid nodules commonly occur and their presence raises questions about malignancy, fewer than 5% are found to be malignant3 and only 8%-10% of patients with thyroid nodules have thyroid cancer.2 The prevalence of thyroid nodules is about 4%-7% in iodine-sufficient areas and much higher in iodine-deficient countries.2,4 Thyroid nodular disease is very common in the US, with palpable nodules occurring in approximately 5% of adults, especially women.5 The frequency of thyroid nodular disease increases throughout adult life.2 Nodules can be detected in an otherwise normal gland, but are especially prevalent in iodine-deficient areas in the form of multiple nodules in an enlarged thyroid gland (multinodular goiter).1 Toxic uninodular or multinodular goiter accounts for 10% to 40% of cases of hyperthyroidism and is more common in older patients.2 Thyroid nodules can be divided into 2 types: "hot" or autonomously functioning thyroid nodules (AFTN), and nonfunctioning or "cold" thyroid nodules (CTN).6 AFTN are characterized by nonautoimmune hyperthyroidism and nodular proliferation. CTN are without function and are less differentiated.6 A defect in the expression or structure of the NIS gene is thought to cause impaired iodide trapping in nonfunctioning CTN.1

References Tonacchera M, et al. J Clin Endocrinol Metab. 2002;87:352-357.2. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1396.3. Bennedbaek FN, et al. J Clin Endocrinol Metab. 2000;85:2493-2498.4. Tonacchera M, et al. J Clin Endocrinol Metab. 1999;84:4155-4158.5. Singer PA. Otolaryngol Clin North Am. 1996; 29:577-591.6. Eszlinger M, et al. J Clin Endocrinol Metab. 2001;86:4834-4842

Multinodular Goiter (MNG).The thyroid gland becomes more nodular with age.1 MNG develops in an enlarged thyroid gland and is especially prevalent in populations in iodine-deficient areas.2 Thyroid enlargement may have progressed from a simple nontoxic goiter or have been associated with Hashimoto disease.3 MNG usually results from a low-grade, probably intermittent stimulus to the thyroid gland from iodine deficiency, goitrogens (foods that induce hypothyroidism and goiter in the diet such as cabbage, broccoli, cauliflower, and brussels sprouts),4 decreased thyroid hormone production, or an autoimmune disease, which causes multiplication and growth of small groups of thyroid cells.3 After Graves disease, toxic multinodular goiter (TMG) is the most common cause of hyperthyroidism5 and thyrotoxicosis in the elderly.6 TMG occurs most often in patients aged 50 or older and mainly in women, when the nodules in a nontoxic MNG become autonomous5 and function independent of TSH stimulation.7 It is very prevalent in geographic regions with iodine deficiency and rarely occurs in places where iodine intake is sufficient. Thyroid autonomy is most frequently found in TMGs.7 Patients are often asymptomatic or very mildly toxic, and have a goiter, and lab findings that indicate suppressed TSH with normal FT4 and T3 levels.5References1. Hurley DL, et al. Geriatrics. 1995;50:24-26,29-31.2. Tonacchera M, et al. J Clin Endocrinol Metab. 2002;87:352-367.3. Bayliss RIS, Tunbridge WMG. Thyroid Disease: the Facts. 3rd ed. Oxford, UK: Oxford University Press; 1998:121.4. Stoewsand GS. Food Chem Toxicol. 1995;33:537-543.5. Fisher JN. South Med J. 2002;95:493-505.6. Vitti P, et al. J Endocrinol Invest. 2002;25(10 Suppl):16-18.7. Krohn K, et al. J Clin Endocrinol Metab. 2001;86:3336-3345.Thyroid Carcinoma.The annual rate of thyroid cancer in the United States has risen nearly 50% since 1973, striking approximately 18 000 people.1 Thyroid cancers account for about 90% of newly diagnosed endocrine malignancies and cause about 1200 deaths each year.1,2 Thyroid carcinoma is 3 times more common in women than in men.3 Thyroid cancer mortality rates fell significantly (20%) in the US between 1973 and 1996, most likely because of early diagnosis and effective treatment of the common forms of thyroid cancer.1 The decline in mortality was seen only in women, possibly because they undergo routine medical examinations more frequently than men.1 Thyroid cancers comprise 4 carcinoma and 2 miscellaneous types (percentage of thyroid neoplasms in the US): papillary (80%), follicular (about 10%), medullary (5%-10%), and anaplastic carcinomas (1%- 2%); plus primary thyroid lymphoma and sarcoma (rare).3 Anaplastic thyroid carcinomas are invasive and almost always fatal.2 Papillary and follicular thyroid cancers are referred to as differentiated thyroid cancer (DTC), which is usually curable when discovered at an early stage.1 DTC comprises 90% of thyroid cancers and 70% of thyroid cancer deaths.1 A known cause of thyroid carcinoma is low-dose radiation exposure.4 The risk is increased in women, who have a 40% higher rate of radiation-induced thyroid cancer than men, and if radiation exposure occurs before15 years of age.4 Ninety percent of radiation-induced thyroid cancers are papillary thyroid carcinoma; the remaining 9%-10% are follicular carcinomas. Anaplastic or medullary carcinomas are rare.4References1. Mazzaferri E, et al. J Clin Endocrinol Metab. 2001;86:1447-1463.2. Heaney AT, et al. J Clin Endocrinol Metab. 2001;86:5025-5032.3. Sharma PK, Johns MM. Thyroid cancer. [eMedicine Specialties Web site]. September 14, 2001. Available at http://www.emedicine.com/ent/topic646.htm. Accessed July 2, 2003. 4. Yeung S-CJ. Endocr Rev. 1998;19:144-172.

Association Between Goiters, Thyroid Nodules, and Thyroid Carcinoma.Thyroid carcinoma is often preceded by other thyroid abnormalities, including endemic and sporadic goiter, benign thyroid nodules, lymphocytic thyroiditis, and Graves disease.1 Data remain inconclusive regarding whether patients with these conditions should be considered at greater risk for developing thyroid carcinoma.1 Cumulative data suggest that a history of goiter or benign thyroid nodules is a thyroid carcinoma risk factor.1 Pain or tenderness in a nodule not caused by thyroiditis increases the chance of malignancy.1 Rapid enlargement of a lesion, especially in patients over 65 years of age, may indicate a malignancy.1 Nodules that continue to enlarge while the patient is receiving thyroid hormone are more likely to be malignant, as is a nodule in a man, although benign and malignant lesions are more common in women.1 The peak age for developing papillary carcinoma is about 30 years, and for follicular cancer, 45 years.1 A thyroid nodule in a very old or very young patient is more likely to contain a carcinoma.1 In one study, clinical criteria (ie, solitary versus multiple nodules, nodule size) did not verify the risk of malignancy; however, solitary nodules presented a higher but not significantly increased risk of cancer when compared to nodules within multinodular goiters.2 References Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:881,898. Papini E, et al. J Clin Endocrinol Metab. 2002;87:1941-1946.