APS ART AST ATA ATD ATP AVP bid BMD BMI BNP Draznin_Prelims.indd xxviii 4/2/2011 6:51:24 PM DETAILED CONTENTS xxix SYMBOLS AND ABBREVIATIONS BP CaE CAH CBC CBG CD CHF CHD CK CKD CMV CNS CPA CPK CRF CRH CSF CSII CST CSW CT CTLA-4 CVD CVP DA DCCT DDAVP DEX DHEA DHEAS DHT DI DIDMOAD blood pressure calcium excretion congenital adrenal hyperplasia complete blood count cortis ol-binding globulin Cushing \200\231s disease congestive heart failure coronary heart disea se creatinine kinase chronic kidney disease cytomegalovirus central nervous system cyproter one acetate creatine phosphokinase chronic renal failure corticotropin-releasing hormone ce rebrospinal \202 uid continuous subcutaneous insulin infusion cortrosyn stimulating test cerebral salt wasting syndrome computed tomography cytotoxic T-lymphocyte antigen 4 cardiov ascular disease central venous pressure dopamine agonist Diabetes Control and Complications Trial desamino-D-arginine vasopressin dexamethasone dihydroepiandrosterone DHEA sulfate di hydrotestosterone diabetes insipidus d iabetes i nsipidus, DM , o ptic a trophy + sensorine ural d eafness (Wolfram \200\231s syndrome) deciliter diabetes mellitus deoxycortisterone d isorders of sex development dexamethasone suppression test differentiated thyroid carcinoma deep vein thrombosis dL DM DOC DSD DST DTC DVT Draznin_Prelims.indd xxix 4/2/2011 6:51:24 PM xxx SYMBOLS AND ABBREVIATIONS DETAILED CONTENTS DXA EBRT ED EE2 ENT ESR ESRF ESS ETDRS FAI FBC FCHL FDB FDG FFM FH FHH FIHP FMTC FNAC FSH F T 4 FTC g GAD GC GCT GFR GH GHBH GHD GHRH GI GIFT GIP GLP-1 GNRH GRA GRTH h HAART dual energy X-ray absorptiometry external beam radiation therapy erectile dysfunction ethin ylestradiol ear, nose, throat erythrocyte sedimentation rate end-stage renal failure empty sella syndrome Early Treatment of Diabetic Retinopathy Study free androgen index full blood count familial combined hyperlipidemia familial defective apolipoprotein B-100 [18F] \202 uorodeoxyglucose fat free mass familial hypercholesterolemia familial hypocalciuric hyperc alcemia familial isolated hyperparathyroidism familial medullary thyroid carcinoma \201 n e needle aspiration cytology follicle stimulating hormone free T 4 follicular thyroid carci noma gram(s) glutamic acid decarboxylase glucocorticoids germ cell tumor glomerular \201 ltation rate growth hormone growth hormone \200\223binding hormone growth hormone de \201 ciency growth hormone \200\223releasing hormone gastrointestinal gamete intrafallopian tran sfer gastric inhibitory peptide glucogen-like polypeptide 1 gonadotropin-releasing hormone glucocorticoid remedial aldosteronism generalized resistance to thyroid hormone hour(s) hig hly active antiretroviral therapy Draznin_Prelims.indd xxx 4/2/2011 6:51:24 PM DETAILED CONTENTS xxxi SYMBOLS AND ABBREVIATIONS HC hCG HDL HERS 5HIAA HLA hMG HMG CoA HNF HP HPA HPT-JP HPV HRT HSG HZV ICSI ID IDDM IDL IF G IGF-1 IGFPT IGT IHD IHH IM IPSS IRMA ITT IU IUD IUGR IUI IV IVF KS L LCAT LCCSCT LDL hydrocortisone human chorionic gonadotrophin high-density lipoprotein Heart and Estrogen-Pr ogestin Replacement Study 5-hydroxyindole acetic acid human leukocyte antigen human menopau sal gonadotropin 3-hydroxy-3-methylglutaryl coenzyme A hepatic nuclear factor hypothalamus \200\223pituitary hypothalmic \200\223pituitary \200\223adrenal (axis) hyperparathyroidism \200\223jaw tumor syndrome human papillomavirus hormone replacement therapy hysterosalpingo graphy herpes zoster virus intracytoplasmic sperm injection intradermal insulin-dependent d iabetes mellitus (type 1) intermediate-density lipoprotein impaired fasting hyperglycemia i nsulin-like growth factor 1 insulin-like growth factor binding protein impaired glucose tol erance ischemic heart disease idiopathic hypogonadotrophic hypogonadism intramuscular infer ior petrosal sinus sampling intraretinal microvascular abnormalities insulin tolerance test international units intrauterine device intrauterine growth retardation intrauterine insem ination intravenous in vitro fertilization Kaposi sarcoma liter(s) lecithin:cholesterol acy ltransferase large-cell calcifying Sertoli cell tumor low-density lipoprotein Draznin_Prelims.indd xxxi 4/2/2011 6:51:24 PM SYMBOLS AND ABBREVIATIONS DETAILED CONTENTS xxxii LFT LH LHRH MC mcg MEN MHC MI MIBG MIS mL MODY MPH MRI MRSA MTC NASH NF NFA NG NGF NICE NIC H NIDDM NOF NSAID NVD NVE OCP od OGTT 25OHD 17OHP OHSS PAI PCOS PCT PDE PET PHP liver function test luteinizing hormone luteinizing hormone \200\223releasing hormone miner alocorticoid microgram(s) multiple endocrine neoplasia major histocompatibility complex myo cardial infarct 123 iodine-metaiodobenzylguanidine M llerian inhibitory substance millilit er(s) maturity-onset diabetes of the young mid-parental height magnetic resonance imaging m ethicillin-resistant Staphylococcus aureus medullary thyroid cancer nonalcoholic steatohepa titis neuro \201 bromatosis nonfunctioning pituitary adenoma nasogastric nerve growth fact or National Institute for Health and Clinical Excellence non \200\223islet cell hypoglycemi a non \200\223insulin-dependent diabetes mellitus (type 2) National Osteoporosis Foundation nonsteroidal anti-in \202 ammatory drug new vessels on the disc (diabetic retinopathy) ne w vessels elsewhere (diabetic retinopathy) oral contraceptive pill omni die (once a day) or al glucose tolerance test 25-hydroxy vitamin D 17-hydroxyprogesterone ovarian hyperstimulat ion syndrome platelet activator inhibitor polycystic ovary syndrome postcoital test phospho diesterase positron emission spectrography primary hyperparathyroidism Draznin_Prelims.indd xxxii 4/2/2011 6:51:24 PM DETAILED CONTENTS xxxiii SYMBOLS AND ABBREVIATIONS PI PID PIH PMC PNMT PO POEMS protease inhibitor pelvic in \202 ammatory disease pregnancy-induced hypertension papillar y microcarcinoma of the thyroid phenylethanolamine- N -methyl transferase per os (by mouth) progressive polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes premature ovarian failure premature ovary insuf \201 ciency pro-opiomelanocortin p rogesterone-only pill pancreatic polypeptide plasma renin activity postprandial reactive hy poglycemia proton pump inhibitor prolactin pituitary resistance to thyroid hormones prostat ic-speci \201 c antigen papillary thyroid carcinoma parathyroid hormone parathyroid hormon e \200\223related peptide propylthiouracil every (q2h: every 2 hours) quality of life radio active iodine therapy renal cysts and diabetes Rathke \200\231s cleft cyst radiofrequency a blation recombinant human GH reverse T 3 thyroid hormone resistance subcutaneous subcutaneo us insulin infusion standard deviation selective estrogen replacement modulator small for g estational age sex hormone binding globulin systemic lupus erythematosus single-fraction ra diosurgery POF POI POMC POP PP PRA PRH PPI PRL PRTH PSA PTC PTH PTHrP PTU q QoL RAI RCAD RCC RFA rhGH rT 3 RTH SC SCII SD SERM SGA SHBG SLE SRS Draznin_Prelims.indd xxxiii 4/2/2011 6:51:25 PM SYMBOLS AND ABBREVIATIONS DETAILED CONTENTS xxxiv SSRI T t T 3 T 4 TB TBG TBI TBPA TC TCA TFT Tg TG TGF tid TNF TPO TPP TR TRH TSAb TSH TS H-RAB TSS TTR U&Es UFC UKPDS US VEGF VHL VIP VLDL VMA WBS WHI WHO XRT ZE selective serotonin reuptake inhibitor testosterone half-life tri-iodothyronine thyroxine t uberculosis thyroxine-binding globulin; thyroid-binding globulin traumatic brain injury T 4 -binding prealbumin total cholesterol tricyclic antidepressant thyroid function test thyro globulin triglycerides transforming growth factor three times a day tumor necrosis factor t hyroid peroxidase thyrotoxic periodic paralysis thyroid hormone receptor thyrotropin-releas ing hormone TSH-stimulating antibodies thyroid-stimulating hormone TSH receptor antibodies transsphenoidal surgery transthyretin urea and electolytes urinary free cortisol UK Prospec tive Diabetes Study ultrasound vascular endothelial growth factor von Hippel \200\223Lindau disease vasoactive intestinal peptide very high \200\223density lipoprotein vanillylmandel ic acid whole body scan Women \200\231s Health Initiative World Health Organization radioth erapy Zollinger Ellison syndrome Draznin_Prelims.indd xxxiv 4/2/2011 6:51:25 PM Part 1 Thyroid Caroline Messer, Rachel Pessah, and Dina Green 1 Anatomy and physiology of the thyroid 2 Thyroid investigations 3 Thyrotoxicosis 4 Graves \200\231 ophthalmopathy, dermopathy, 2 7 17 and acropachy 39 44 49 53 62 66 5 Multinodular goiter and solitary adenomas 6 Thyroiditis 7 Hypothyroidism 8 Amiodarone and thyroid function 9 Thyroid cancer 01-Draznin-Chap01.indd 1 3/31/2011 2:33:38 PM CHAPTER 1 Anatomy and physiology of the thyroid 2 Anatomy and physiology of the thyroid Anatomy The thyroid gland comprises \200 A midline isthmus lying horizontally just below the cricoid cartilage. \200 Two lateral lobes that extend upward over the lower half of t he thyroid cartilage. The gland lies deep to the strap muscles of the neck, enclosed in the pre- tracheal fascia, which anchors it to the trachea, so that the thyroid moves up on swallowing. Histology Fibrous septa divide the gland into pseudolobules. Pseudolobules are com- posed o f vesicles called follicles or acini, surrounded by a capillary network. The follicle walls are lined by cuboidal epithelium. The lumen is \201 lled with a proteinaceous colloid, which contains the unique protein th yroglobulin. The peptide sequences of thyroxine (T 4 ) and tri-iodothyronine (T 3 ) are syn thesized and stored as a component of thyroglobulin. Development The thyroid develops from the endoderm of the \202 oor of the pharynx with so me contribution from the lateral pharyngeal pouches. Descent of the mid- line thyroid anlag e gives rise to the thyroglossal duct, which extends from the foramen caecum near the base of the tongue to the isthmus of the thyroid. During development, the posterior aspect of th e thyroid becomes asso- ciated with the parathyroid gland and the parafollicular C cells, d erived from the ultimobranchial body, which become incorporated into its sub- stance. The C cells are the source of calcitonin and give rise to medullary thyroid carcinoma when they undergo malignant transformation. The fetal thyroid begins to concentrate and organify iodine at about 10 \200\22312 weeks gestation. Maternal thyrotropin-releasing hormone (TRH) readily crosses the pla- centa; maternal thyroid-stimulating (TSH) and T 4 do not. T 4 from the fetal thyroid is the major thyroid hormone available to the fetus. The fetal h ypothalamic \200\223pituitary \200\223thyroid axis is a functional unit dis- tinct from tha t of the mother \200\224active at 18 \200\22320 weeks. 01-Draznin-Chap01.indd 2 3/31/2011 2:33:38 PM ANATOMY 3 Thyroid examination Inspection \200 Look at the neck from the front. If a goiter (enlarged thyroid gland) is present, the patient should be asked to swallow a mouthful of water. The thyroid moves up w ith swallowing. Watch for appearance of any nodule not visible before swallowing; e.g., in an elderly patie nt with kyphosis, the thyroid may be partially retrosternal. Palpation \200 Is the thyroid gland tender to touch? \200 With the index and middle \201 ngers feel below the thyroid cartilage where the isthmus of the thyroid gland lies over the trachea. Palpate the two lobes of the thyroid, which extend laterally behind the sternocleidomastoid muscle. Ask the patient to swallow again while you continue to palpate the thyroid. Assess size: soft, \201 rm, or hard? Assess texture: nodular or diffusely enlarged? Assess whether it moves readily on swallowing. Palpate along the medial edge of the sternocleidomastoid muscle on either side to look for a pyramidal lobe. Palpate for lymph nodes in the neck. Percussion \200 Percuss upper mediastinum for retrosternal goiter. Auscultation \200 Au scultate to identify bruits, consistent with Graves \200\231 disease. \200 Occasionally, inspiratory stridor can be heard with a large or retrosternal goiter causing tracheal compression ( b see Pemberton \200\231s sign, p. 45). Assess thyroid status \200 Observe for signs of thyroid disease \200\224exophthalmos, pro ptosis, thyroid acropachy, pretibial myxedema, hyperactivity, restlessness, or immobility and disin terest. Take pulse; note the presence or absence of tachycardia, bradycardia, or atrial \201 brillation. Feel palms \200\224assess if they are warm and sweaty or cold. \200 Look for tremor in ou tstretched hands. \200 Examine eyes for exophthalmos (forward protrusion of the eyes \200 \224 proptosis), lid retraction, sclera visible above cornea, lid lag, conjuctival injection or edema (cheimosis), periorbital edema, or loss of full-range movement. 01-Draznin-Chap01.indd 3 3/31/2011 2:33:39 PM CHAPTER 1 Anatomy and physiology of the thyroid 4 Physiology Thyroid hormone contains iodine. Iodine enters the thyroid in the form of inorga nic or ionic iodide, which is organized by the thyroid peroxidase enzyme at the cell \200 \223colloid interface. Subsequent reactions result in the formation of iodothyronines. The thyroid is the only source of T 4 . The thyroid secretes 20% of cir- culating T 3 ; the remainder is generated in extraglandular tissues by the conversion of T 4 to T 3 by deiodi nases (largely in the liver and kidneys). Synthesis of the thyroid hormones can be inhibited by a variety of agents termed goitrogens. \200 Perchlorate and thiocyanate inhibit iodide transportation. \200 Thioureas and mercaptoimidazole inhibit the initial oxidation of iodide and coupling of iodothyronines. In large doses, iodine blocks organic binding and coupling reactions. \200 Lithium has se veral inhibitory effects on intrathyroidal iodine metabolism. In the blood, T 4 and T 3 are almost entirely bound to plasma proteins. T 4 is bound in d o rder of af \201 nity to T 4 -binding globulin (TBG), transthyretin (TTR), and albumin. T 3 is bound 10 \200\22320 times less avidly by TBG and not signi \201 cantly by TTR. Only the free or unbound hormone is available to tissues. The meta- bolic state correlates more closely with the free than the total hormone concentration in the plasma. The relative ly weak binding of T 3 accounts for its more rapid onset and offset of action. Table 1.1 summarizes states associated with primary alterations in the concentration of TBG . When there is primarily an alteration in the con- centration of thyroid hormones, the con centration of TBG changes mini- mally (Table 1.2). The concentration of free hormones does not necessarily vary directly with that of the tota l hormones; e.g., while the total T 4 level rises in preg- nancy, the free T 4 (FT 4 ) leve l remains normal. Table 1.1 Disordered thyroid hormone \200\223protein interactions Serum total T 4 and T 3 Free T 4 and T 3 Primary abnormality in TBG i Concentration d Concentration Primary disorder of thyroid func tion i d Normal Normal i d i d Hyperthyroidism Hypothyroidism 01-Draznin-Chap01.indd 4 3/31/2011 2:33:39 PM PHYSIOLOGY 5 Table 1.2 Circumstances associated with altered concentration of TBG i TBG d TBG Pregnancy Androgens Newborn state Large doses of glucocorticoids; Cushing \200\231s syndrome OCP and other sources of estrogens Chronic liver disease Tamoxifen Severe systemic illness Hepatitis A; chronic active hepatitis Active acromegaly Biliary cirrhosis Nephrotic syndrome Acute intermittent porphyria Genetically determined Genetically determined Drugs, e.g., phenytoin OCP, oral contraceptive pill. The levels of thyroid hormone in the blood are tightly controlled by feedback mechanisms in volved in the hypothalamic \200\223pituitary \200\223thyroid axis. \200 TSH secreted by t he pituitary stimulates the thyroid to secrete principally T 4 and also T 3 . TRH stimulates the synthesis and secretion of TSH. T 4 and T 3 inhibit TSH synthesis and secretion directly. \200 T 4 and T 3 are bound to TBG, TTR, and albumin. The remaining free hormones inhibit synthesis and release of TRH and TSH to in \202 uence growth and metabolism. T 4 is converted peripherally to the metabolically active T 3 or the inactive reverse T 3 (rT 3 ). T 4 and T 3 are metabolized in the liver by conjugation with glucuronate and sulfate. Enzym e inducers such as phenobarbital, carbamazepine, and phenytoin increase the metabolic clear ance of the hormones without decreasing the proportion of free hormone in the blood. Molecular action of thyroid hormone T 3 is the active form of thyroid hormone. It binds to thyroid hormone receptors (TRs), of which there are several isoforms and which are mem- ber s of the nuclear hormone receptor superfamily. TR/T 3 complexes elicit action by binding to response elements in the DNA of gene promoters. Recruitment of co-activators alters the ch romatin con \201 guration, allow- ing gene transcription to proceed, whereas co-repressors cause the oppo- site effect. Abnormalities of development Remnants of the thyroglossal duct may be found in any position along the course of the tract of its descent: \200 In the tongue, it is referred to as l ingual thyroid . \200 Thyroglossal cysts may be visible as midline swellings in the neck. 01-Draznin-Chap01.indd 5 3/31/2011 2:33:39 PM CHAPTER 1 Anatomy and physiology of the thyroid 6 Thyroglossal \201 stula develops as an opening in the middle of the neck. \200 Thyroglo ssal nodules or \200 The pyramidal lobe , a structure contiguous with the thyroid isthmus , which extends upward. The gland can descend too far down to reach the anterior mediastinum. Congenital hypothyroidism results from failure of the thyroid to develop (agenesis). More c ommonly, however, congenital hypothyroidism re \202 ects enzyme defects impairing hormone synthesis. 01-Draznin-Chap01.indd 6 3/31/2011 2:33:39 PM TESTS OF HOMEOSTATIC CONTROL 7 Thyroid investigations Tests of hormone concentration Highly speci \201 c and sensitive chemiluminescent and radi oimmunoassays are used to measure serum T 4 and T 3 concentrations. Free hormone con- centr ations usually correlate better with the metabolic state than do total hormone concentratio ns because they are unaffected by changes in bind- ing protein concentration or af \201 ni ty. Tests of homeostatic control b See Table 2.1. Serum TSH concentration is used as \201 rst line in the diagnosis of primary hypothyroidi sm and hyperthyroidism. The test is misleading in patients with secondary thyroid dysfuncti on re \202 ecting hypothalamic or pituitary disease. The TRH stimulation test, which can be used to assess the functional state of the TSH secre tory mechanism, is now rarely used to diagnose primary thyroid disease, since it has been s uperseded by sensitive TSH assays. Its main use is in the differential diagnosis of elevate d TSH in the setting of elevated thyroid hormone levels and in the differential diagnosis o f resistance to thyroid hormone and a TSH-secreting pituitary adenoma (Table 2.3). In interpreting results of thyroid function tests (TFTs), the effects of drugs that the pat ient might be on should be considered. Table 2.2 lists the in \202 uence of drugs on TFTs. Table 2.3 gives some examples of a typical TFT panel. Box 2.1 Thyroid hormone resistance (RTH) \200 This syndrome is characterized by reduced r esponsiveness to elevated circulating levels of free T 4 and free T 3 , normal or elevated serum TSH, and in tact TSH responsiveness to TRH. Clinical features apart from goiter are usually absent but may include short stature, hyperactivity disorders, and attention de \201 cits with mental or learning disabilities. The etiology is a mutation in the thyroid hormone receptor. \200 Differential diagnosis i ncludes TSH-secreting pituitary tumor. \200 Most cases require no treatment. If therapy i s needed, B-adrenergic blockers may be used to ameliorate the tissue effects of raised thyr oid hormone levels. 02-Draznin-Chap02.indd 7 3/31/2011 2:34:03 PM CHAPTER 2 Thyroid investigations 8 Table 2.1 Thyroid hormone concentrations in thyroid: various abnormalities Condition TSH Free T 4 ii Normal Free T 3 i ii Normal i Primary hyperthyroidism Undetectable T 3 toxicosis Subclinical hyperthyroidism Undetectable d i or normal Normal i Secondary hyperthyroidism (TSHoma) i or normal i i d or normal i d Normal d i d or normal Normal d or normal Thyroid hormone resistance Primary hypothyroidism Subclinical hypothyroidism Secondary hypothyroidism Table 2.2 In \202 uence of drugs on thyroid function tests i d Metabolic process TSH secretion Amiodarone (transiently increases: normalizes after 2 \200\2233 months) Sertraline St John \200\231s wort Glucocorticoids, dopamine agonists, phenytoin, dopamine T 4 synthesis/release Binding proteins Iodide Iodide, lithium Estrogen, clo \201 brate, heroin Glucocorticoids, androgens, phenytoin, carbamazepine T 4 metabolism Inhibition of T 4 binding to TBG (TSH normal) Anticonvulsants; rifampin Salicylates, furosemide, mefenamic acid 02-Draznin-Chap02.indd 8 3/31/2011 2:34:03 PM TESTS OF HOMEOSTATIC CONTROL 9 Table 2.3 Atypical thyroid function tests Test Possible cause Suppressed TSH and elevated free T 3 , normal free T 4 Suppressed TSH and normal free T 4 a nd free T 3 T 3 toxicosis (approximately 5% of thyrotoxicosis) Subclinical thyrotoxicosis Recovery from thyrotoxicosis Excess thyroxine replacement Sick e uthyroidism Detectable TSH and elevated free T 4 and free T 3 TSH-secreting pituitary tumor Thyroid hormone resistance Heterophile antibodies leading to spurious measurements of free T 4 and free T 3 Amiodarone Elevated free T 4 and low \200\223normal free T 3 , normal TSH 02-Draznin-Chap02.indd 9 3/31/2011 2:34:03 PM CHAPTER 2 Thyroid investigations 10 Antibody screen High titers of antithyroid peroxidase (anti-TPO) antibodies or antithy- rog lobulin antibodies are found in patients with autoimmune thyroid dis- ease (Hashimoto \200 \231s thyroiditis, Graves \200\231 disease, and, sometimes, euthyroid individuals). b See T able 2.4. The American Thyroid Association recommends that adults be screened for thyroid dysfunction with serum TSH measurement, beginning at age 35 years and every 5 years thereafter. 1 Screening for thyroid disease 2 The following categories of patients are at risk for thyroi d disease and screening should be considered: \200 Patients with atrial \201 brillation or hyperlipidemia \200 Periodic (within every 6 months) assessment in patients receiving medications such as amiodarone hydrochloride and lithium carbonate. \200 Annual check of thyroid function in annual review of diabetic patients \200 Women with type 1 diabetes in the \201 rst trimester of pregnancy and post-delivery (3-fold increase in incidence of p ostpartum thyroid dysfunction in such patients) Women with a past history of postpartum thyroiditis \200 Previous thyroid dysfunction or goiter \200 History of surgery or radiotherapy affecting the thyroid gland \200 Vitilig o \200 Pernicious anemia \200 Consider annual check of thyroid function in people with Down syndrome, Turner syndrome, and primary adrenal insuf \201 ciency (Addison \200\231s diseas e) in light of the high prevalence of hypothyroidism in such patients. Women with thyroid autoantibodies have 8 \227 risk of developing hypothyroidism over 20 years compared to antibody-negative controls Women with thyroid autoantibodies and isolated elevated TSH have 38 \227 risk of developin g hypothyroidism, with 4% annual risk of overt hypothyroidism. Table 2.4 Antithyroid antibodies and thyroid disease TSH receptor antibody Condition Anti-TPO Antithyroglobulin Graves \200\231 disease 70 \200\22380% 30 \200\22350% 70 \200\223100% (stimulating) Autoimmune hypothyroidism 95% 60% 10 \200\22320% (blocking) Note: TSH receptor antibodies may be stimulatory or inhibitory. Heterophile antibodies pres ent in patient sera may cause abnormal interference, causing abnormally low or high values of free T 4 and free T 3 , and can be removed with absorption tubes. 1 Ladenson PW, et al. (2000). American Thyroid Association Guidelines for detection of thyr oid dysfunction. Arch Intern Med 160:1573 \200\2231575. 2 Tunbridge WM, Vanderpump MP (2000 ). Population screening for autoimmune thyroid disease. Endocrinol Metab Clin North Am 29(2 ):239 \200\223253. 02-Draznin-Chap02.indd 10 3/31/2011 2:34:03 PM SCINTISCANNING 11 Scintiscanning This scanning enables localization of sites of accumulation of radioiodine o r sodium pertechnetate [ 99m Tc], which gives information about the activ- ity of the iodin e trap (Table 2.5). This can be used \200 To de \201 ne areas of hyper- or hypofunction within the thyroid (Table 2.6). It can be useful to differentiate among causes of thyrotoxicosis (i.e., Graves \200\231 dis ease vs. toxic nodular goiter vs. thyroiditis). Provide information about the size and shape of the thyroid gland (detect retrosternal goiter; ectopic thyroid tissue). The scan may be altered by \200 Agents that in \202 uence thyroid uptake: high-iodine fo ods and supplements, such as kelp (seaweed) Drugs containing iodine, such as amiodarone \200 Recent use of radiographic contrast dyes , which can potentially interfere with the interpretation of the scan Table 2.5 Radioisotope scans 99 Technitium pertechnetate 123 Iodine Half-life Short Short Advantage Low emission of radiation. Has higher energy photons, hence useful for imaging a toxic goit er with a substernal component Maximum thyroid uptake within 30 min of administration. Can be used in breast- feeding wome n (discontinue feeding for 24 hours) Disadvantage Technetium is only trapped by the thyroid without being organi \201 ed. Use Functional assessment of the thyroid Rapid scanning 02-Draznin-Chap02.indd 11 3/31/2011 2:34:03 PM CHAPTER 2 Thyroid investigations 12 Table 2.6 Radionuclide scanning (scintigram) in thyroid disease Condition Scan appearance Graves \200\231 hyperthyroidism Enlarged gland Intense and homogeneous radionucleotide uptake Thyroiditis (e.g., de Quervain syndrome) Low or absent uptake Toxic nodule A solitary area of high uptake with suppression of extranodular tissue Thyrotoxicosis factitia Depressed thyroid uptake Successful 131 I uptake by tumor tissue requires an adequate level of TSH, achieved by stop ping T 3 replacement 10 days before scanning, withholding levothyroxine until TSH is >30 uU /mL, or giving recombinant TSH injection. Thyroid cancer 02-Draznin-Chap02.indd 12 3/31/2011 2:34:04 PM ULTRASOUND (US) SCANNING 13 Ultrasound (US) scanning Ultrasound provides an accurate indication of thyroid size and is useful for differentiating cystic nodules from solid ones, but it cannot be used to disting uish between benign and malignant disease de \201 nitively. Please see the Revised America n Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Different iated Thyroid Cancer (2009) for further details. Diagnostic features \200 Microcalci \201 cation within nodules favors the diagnosis of m alignancy; microcalci \201 cations <2 mm in diameter are observed in 60% of malignant nod ules, but in <2% of benign lesions. Calci \201 cation is a prominent feature of medullary carcinoma of the thyroid. US can detect whether a nodule is solitary or part of a multinodular process. Irregular nodule capsule is more common in malignancy. Uses \200 Sequential scanning can be employed to assess changes in size of thyroid over time. Assess neck lymph nodes in thyroid cancer patients Note: Neither scintigraphy nor US is routinely indicated in a patient with goiter. 02-Draznin-Chap02.indd 13 3/31/2011 2:34:04 PM CHAPTER 2 Thyroid investigations 14 Fine needle aspiration (FNAC) cytology FNAC is now considered the most accurate test for di agnosis of thyroid nodules. It is performed in an outpatient setting. One to two aspirations are drawn with a 23- to 27-gauge needle, inserted into different sit es of each nodule; aspiration is carried out at different sites for each nodule. Cytologica l \201 ndings are satisfactory or diagnostic in approximately 85% of specimens and nondia gnostic in the remainder. In experienced hands, FNAC is an excellent diagnostic technique, as shown in Table 2.7. Repeat FNAC after 3 \200\2236 months further reduces the proportion of false negatives. FNA C cannot be used to differentiate between benign and malignant follicular neoplasm. Surgical excision of a follicular neoplasm is always indicated. b See Table 2.8 for diagnos tic categories from FNAC. Table 2.7 Diagnostic features of FNAC Feature Range (%) Mean value (%) Accuracy 85 \200\223100 95 Speci \201 city 72 \200\223100 92 Sensitivity 65 \200\22398 83 False negative 1 \200\22311 5 Table 2.8 Diagnostic categories for FNA 1. Nondiagnostic 2. Malignant 3. Indeterminate/Suspicious for neoplasm 4. Benign Taken from American Thyroid Association Management Guidelines for Patients with Thyroid Nod ules in Differentiation Thyroid Cancer Computed tomography (CT) CT is useful in evaluation of retrosternal and retrotracheal exten sion of an enlarged thyroid. Compression of the trachea and displacement of the major vessels can be identi \201 ed with CT of the superior mediastinum. CT can demonstrate the extent of intrathoracic extension of thyroid malignancy and in \201 ltration of adjacent structures, such as the carotid artery, internal jugular vein, trache a, esophagus, and regional lymph nodes. Use of CT imaging with iodine-containing radiocontrast dye interferes with further radioiod ine imaging and treatment for at least 6 weeks. Urinary iodine testing can be useful to hel p determine when further radio- iodine imaging and treatment can be performed. 02-Draznin-Chap02.indd 14 3/31/2011 2:34:04 PM SICK EUTHYROID SYNDROME 15 Additional laboratory investigations Hematological tests Long-standing thyrotoxicosis may be associated with a normochromic anem ia and, occasionally, mild neutropenia, lymphocytosis, and, rarely, thrombocytopenia . In hypothyroidism, a macrocytosis is typical, although concurrent vita- min B 12 de \201 ciency should be considered. There may also be a microcytic anemia due to menorrhagia and impaired iron utilization. Biochemical tests Alkaline phosphatase may be elevated in thyrotoxicosis. Mild hypercalcemia may occur in thyrotoxicosis and re \202 ects i bone resorption. Hypercalciuria is more common. In a hypothyroid patient, hyponatremia may be due to an inability to suppress antidiuretic hormone (ADH) and/or reduced renal tubular water loss, resulting in retention of ingested w ater. Less commonly, it may be due to coexisting cortisol de \201 ciency. In hypothyroidism, creatine kinase is often raised and the lipid pro \201 le altered with i low-density lipoprotein (LDL) cholesterol. Endocrine tests In untreated hypothyroidism, there may be inadequate responses to provocati ve testing of the hypothalamic \200\223pituitary \200\223adrenal (HPA) axis. In hypothyroid ism, serum prolactin may be elevated as a result of i TRH. In thyrotoxicosis there is an increase in sex hormone binding globulin (SHBG) and a complex interaction with sex steroid hormone metabolism, resulting in changes in the levels of and rogens and estrogens. The net physiological result is an increase in estrogenic activity, w ith gynecomastia and a decrease in libido and erectile dysfunction in males. Sick euthyroid syndrome (non-thyroidal illness syndrome) \200 Biochemistry: Low T 4 and T 3 \200 Inappropriately normal/suppressed TSH Tissue thyroid hormone concentrations are very low. \200 Clinical context \200\224starvat ion Severe illness, e.g., severe infections, renal failure, cardiac failure, liver failure, end-stage malignancy Thyroxine replacement is not indicated because there is no clear evidence that treatment is effective. 02-Draznin-Chap02.indd 15 3/31/2011 2:34:04 PM CHAPTER 2 Thyroid investigations 16 Atypical clinical situations \200 Thyrotoxicosis factitia No thyroid enlargement \200 Elevated free T 4 and suppressed TSH \200 Depressed thyroid uptake on scintigraphy \200 Low thyroglobulin differentiates from thyroiditis (which sho ws depressed uptake on scintigraphy but i thyroglobulin) and all other causes of elevated thyr oid hormones. Struma ovarii (ovarian teratoma containing hyperfunctioning thyroid tissue) \200 No thyroid enlargement \200 Depressed thyroid uptake on scintigraphy \200 A body scan after radioiodine con \201 rms diagnosis. Trophoblast tumors: human chorionic gonadotropin (hCG) has structural homology with TSH and leads to thyroid gland stimulation, and usually mild thyro toxicosis. Hyperemesis gravidarum: Thyroid function tests may be abnormal with a suppressed TSH ( b se e Chapter 3, p. 31, and Chapter 62, p. 348). \200 Choriocarcinoma of the testes may be as sociated with gynecomastia and thyrotoxicosis \200\224measure hCG. 02-Draznin-Chap02.indd 16 3/31/2011 2:34:04 PM ETIOLOGY 17 Thyrotoxicosis Etiology Epidemiology Graves \200\231 autoimmune thyroid disease is 5 x more common in women than in men. Annual incidence is 0.5 cases per 1000. De \201 nition of thyrotoxicosis and hyperthyroidism The term thyrotoxicosis denotes the c linical, physiological, and biochemical \201 ndings that result when the tissues are expo sed to excess thyroid hor- mone. It can arise in a variety of ways (Table 3.1). It is essen tial to establish a speci \201 c diagnosis as this determines therapy choices and provides impor- tant information for the patient regarding prognosis. The term hyperthyroidism should be used to denote conditions in which hyperfunction of the thyroid leads to thyrotoxicosis. Genetics of autoimmune thyroid disease (AITD) AITD consists of Graves \200\231 disease, Has himoto \200\231s thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis, a nd thyroid-associ- ated ophthalmopathy \200\224conditions that appear to share a common gen etic predisposition. There is a female preponderance. Twin studies show a concordance for Graves \200\231 disease and autoimmune hypothyroidism in monozygotic compared to dizygotic twins. It is estimated that genetic factors account for 79% of the susceptibil- ity for Graves \200\231 disease. Sibling studies indicate that sisters and children of women with Graves \200\231 disease have a 5 \200\2238% risk of developing Graves \200\231 disease or autoimmu ne hypothyroidism. On the background of a genetic predisposition, environmental factors are thought to contrib ute to the development of disease. A number of interacting susceptibility genes are thought to play a role in the develop- ment of disease. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is associated with Graves \200\231 disease in Cau casian populations. Speci \201 cally, the CT60 allele has a preva- lence of 60% in the gen eral population, but is also the allele most highly associated with Graves \200\231 disease , indicating the complex nature of genetic susceptibility and interplay of environmental fa ctors. Association of major histocompatibility complex (MHC) loci with Graves \200\231 disease has been demonstrated in some populations, but not others. HLA- DR3 is associated with Graves \200\231 disease in whites. HLA-DQA1*0501 is associated in some populations, especially for men. However, the overall contribution of MHC genes to Graves \200\231 disease has been es timated to be only 10 \200\22320% of the inherited susceptibility. 03-Draznin-Chap03.indd 17 4/1/2011 5:27:35 PM CHAPTER 3 Thyrotoxicosis 18 Table 3.1 Classi \201 cation of the etiologies of thyrotoxicosis Associated with hyperthyroidism Excessive thyroid stimulation Graves \200\231 disease, Hashitoxicosis Pituitary thyrotrope adenoma Pituitary thyroid horm one resistance syndrome (excess TSH) Trophoblastic tumors producing hCG with thyrotrophic a ctivity Thyroid nodules with autonomous function Toxic solitary nodule, toxic multinodular goiter Thyroid cancer (rare occurrence) Not associated with hyperthyroidism Thyroid in \202 ammation Silent and postpartum thyroiditis, subacute (de Quervain \200\231s) thyroiditis Drug-induce d thyroiditis (amiodarone) Exogenous thyroid hormones Overtreatment with thyroid hormone Thyrotoxicosis factitia (thyroxine use in nonthyroidal d isease) Ectopic thyroid tissue Metastatic thyroid carcinoma Struma ovarii, teratoma containing functional thyroid tissue, results in mild features of thyrotoxicosis (mildly elevated serum free T 4 and T 3 ; suppre ssed TSH) 03-Draznin-Chap03.indd 18 4/1/2011 5:27:35 PM MANIFESTATIONS OF HYPERTHYROIDISM 19 Manifestations of hyperthyroidism Investigation of thyrotoxicosis \200 Thyroid function tests reveal elevated FT 4 and supp ressed TSH (elevated free T 3 [FT 3 ] in T 3 toxicosis). Thyroid antibodies \200\224 b see Table 2.4 (p. 10) \200 Radionucleotide thyroid scan if necessary to con \201 rm Graves \200\230 hyperthyroidism and exclude other causes (i.e., painless thyroiditis) ( b see p. 169) Manifestations of Graves \200\231 disease (in addition to those in Box 3.1 ) \200 Diffuse goiter \200 Ophthalmopathy ( b see Graves \200\231 ophthalmopathy, p. 39) A feeling of grittiness and discomfort in the eye \200 Retrobulbar pressure or pain, eyel id lag or retraction \200 Periorbital edema, chemosis,* scleral injection* \200 Exophth almos (proptosis)* \200 Extraocular muscle dysfunction* \200 Exposure keratitis* \200 Optic neuropathy* Box 3.1 Manifestations of hyperthyroidism (all forms) Symptoms \200 Hyperactivity, irritability, altered mood, insomnia \200 Heat intolerance , sweating \200 Palpitations \200 Fatigue, weakness \200 Dyspnea \200 Weight loss w ith increased appetite (weight gain in 10% of patients) \200 Pruritus \200 Increased st ool frequency \200 Thirst and polyuria \200 Oligomenorrhea or amenorrhea; loss of libid o Signs \200 Sinus tachycardia, atrial \201 brillation \200 Fine tremor, hyperkinesia, hyperre \202 exia \200 Warm, moist skin \200 Palmar erythema, onycholysis \200 Hair loss \200 Muscle weakness and wasting \200 Congestive (high-output) heart failure, chor ea, periodic paralysis (primarily in Asian males), psychosis (rare) A combination of these suggests congestive ophthalmopathy. Urgent action is necessary if th ere is corneal ulceration, congestive ophthalmopathy, or optic neuropathy ( b see Graves \200\231 ophthal- mopathy, p. 39). 03-Draznin-Chap03.indd 19 4/1/2011 5:27:35 PM CHAPTER 3 Thyrotoxicosis 20 Localized dermopathy (pretibial myxedema, b see Graves \200\231 dermopathy, p. 43) \200 Lymphoid hyperplasia \200 Thyroid acropachy ( b see Thyroid acr opathy, p. 43) Conditions associated with Graves \200\231 disease \200 Type 1 diabetes mellitus \200 A ddison \200\231s disease \200 Vitiligo \200 Pernicious anemia \200 Alopecia areata \200 Myasthenia gravis \200 Celiac disease (4.5%) \200 Other autoimmune disorders asso ciated with the HLA-DR3 haplotype 03-Draznin-Chap03.indd 20 4/1/2011 5:27:35 PM TREATMENT 21 Treatment Medical treatment In general, the standard policy in Europe is to offer a course of antithy - roid drugs (ATD) \201 rst. In the United States, radioiodine is more likely to be offer ed as \201 rst-line treatment. See the American Thyroid Association (ATA) Treatment Guide lines for Patients with Hyperthyroidism and Hypothyroidism (1995) for further details.