Patients almost inevitably have Graves \200\231 ophthalmopathy or pretibial myxedema. If not, an alternative cause of clubbing should be looked for. There is no effective treatment. Further reading European Group on Graves \200\231 Orbitopathy (2006). Clinical assessment o f patients with Graves \200\231 orbitopathy: recommendations to generalists, specialists an d clinical researchers. Eur J Endocrinol 155(3):387 \200\223389. Schwartz KM, Fatourechi V, Ahmed DD, et al. (2992). Dermopathy of Graves \200\231 disease ( pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 87(2):438 \200\223446. Tellez M, Cooper J, Edmonds C (1992). Graves \200\231 ophthalmopathy in relation to cigaret te smoking and ethnic origin. Clin Endocrinol 36:291 \200\223294. 04-Draznin-Chap04.indd 43 3/31/2011 2:35:17 PM CHAPTER 5 Multinodular goiter 44 Multinodular goiter and solitary adenomas Background Nodular thyroid disease denotes the presence of single or multiple palpa- ble or nonpalpable nodules within the thyroid gland. Prevalence rates range from 5 to 50% depending on the population studied and sensitivity of detection methods. Prevalence increases linearly with age and exposure to ionizing radiati on and iodine de \201 ciency. Clinically apparent thyroid nodules are evident in 4 \200\2237% of the U.S. population. Inc idence of thyroid nodules is about 4 \227 more common in women. Thyroid nodules always raise the concern of cancer, although <5% are cancerous. Nodules are more likely to be malignant in patients <20 or >60 years of age. Thyroid nodule s are more common in women but approximately 4 \227 more likely to be malignant in men. 05-Draznin-Chap05.indd 44 3/31/2011 2:35:41 PM CLINICAL EVALUATION 45 Clinical evaluation An asymptomatic thyroid mass may be discovered either by a clinician on routine neck palpation or by the patient during self-examination. History should concentrate on the following: An enlarging thyroid mass \200 A previous history of radiation, especially childhood head and neck irradiation A family history of thyroid cancer \200 Development of hoarseness or dysphagia Physical \201 ndings suggestive of malignancy include a \201 rm or hard non- tender nod ule, a recent history of enlargement, \201 xation to adjacent tissue, and the presence of regional lymphadenopathy. Pemberton \200\231s sign is facial erythema and jugular venous distension upon raising the arms. It is a sign of superior venacaval obstruction caused by a substernal mass. A hot nodule on a radioisotope scan makes malignancy less likely. See Table 5.1 for the eti ology of thyroid nodules. Clinical features raising suspicion of thyroid malignancy \200 Age (<20 or >60 years) \200 Rapidly enlarging nodule \200 Local symptoms including dysphagia, stridor, or hoars eness \200 Previous exposure to radiation \200 Positive family history of thyroid cance r or multiple endocrone neoplasia (MEN) syndrome Table 5.1 Etiology of thyroid nodules Common causes \200 Colloid nodule \200 Cyst \200 Lymphocytic thyroiditis Uncommon causes \200 Granulomatous thyroiditis \200 Infections \200 Malignancy \200 Medullary \200 Anaplastic \200 Metastatic \200 Lymphoma Benign neoplasms \200 Hurthle cell \200 Follicular \200 Malignancy \200 Papillary \200 Follicular 05-Draznin-Chap05.indd 45 3/31/2011 2:35:41 PM CHAPTER 5 Multinodular goiter 46 Gardner \200\231s syndrome (familial large intestinal polyposis) \200 Familial polyposis coli \200 Cowden syndrome (autosomal dominantly inherited hamartoma syndrome) Lymphadenopathy \200 History of Hashimoto \200\231s disease (Increased incidence of lymph oma) Studies \200 FNA (see p. 14) \200 Serum TSH concentration. If TSH is suppressed, a radi oisotope thyroid scan should be performed. Serum calcitonin if there is a family history of medullary carcinoma or MEN 2A or 2B Respiratory \202 ow loop, especially for a large goiter possibly causing tracheal obstruction CT scan or MRI if there are concerns about retrosternal goiter or tracheal compression 05-Draznin-Chap05.indd 46 3/31/2011 2:35:41 PM TREATMENT 47 Treatment Toxic multinodular goiter or nodule ATDs ATDs are effective in controlling the hyperthyroidism but are not cura- tive. As the h ot nodules are autonomous, the condition will recur after stopping the drugs. Methimazole and propylthiouracil are useful treatments to gain control of the disease in pr eparation for surgery or radioiodine treatment or as long-term treatment in those patients unwilling to accept radioiodine or surgery. Radioiodine This form of treatment is often considered the \201 rst choice for de \201 n i- tive treatment. 131 I is preferentially accumulated in hot nodules but not in normal thy roid tissue, which, because of the thyrotoxic state, is nonfunctioning. Radioiodine treatment commonly induces a euthyroid state as the hot nodules are destroyed a nd the previously nonfunctioning follicles gradually resume normal function. A dose of 14 \200\22316 mCi for small to medium goiters and 16 \200\22322 mCi for medium to large goiter s is recommended. Surgery The aim of surgery is to remove as much of the nodular tissue as pos- sible and, if the goiter is large, to relieve local symptoms. Postoperative follow-up should involve che cks of thyroid function. Goiter recurrence, although rare, does occasionally occur. Nontoxic multinodular goiter or nodule Surgery This is the preferred treatment for patients with the following: \200 Local compression symptoms \200 Cosmetic dis \201 gurement \200 Solitary nodule with FNA suspicious for malignancy Radioiodine This may be indicated in elderly patients for whom surgery is not appro- priate . It may require admission. Up to 50% shrinkage of goiter mass has been reported in recent studies. Hypothyroidism following radioiodine is relatively low but is still recognized. Box 5.1 Etiology of goiter \200 Autoimmune thyroid disease \200 Sporadic \200 Endemic (iodine de \201 ciency, dietary origins) \200 Pregnancy \200 Drug induced (ATDs, lith ium, amiodarone) \200 Thyroiditis syndromes 05-Draznin-Chap05.indd 47 3/31/2011 2:35:41 PM CHAPTER 5 Multinodular goiter 48 Medical treatment Use of T 4 to suppress TSH is associated with a risk of cardiac arrhythmi as and bone loss. T 4 is useful only if TSH is detectable but is not generally indicated. Pathology Thyroid nodules may be described as adenomas if the follicular cell dif- ferentia tion is enclosed within a capsule, and as adenomatous when the lesions are circumscribed bu t not encapsulated. Thyroid nodules in pregnant mothers \200 Increase in size during gestation \200 Increas e in number \200 Need FNA as higher risk of malignancy \200 Can be operated on in secon d trimester or postpartum 05-Draznin-Chap05.indd 48 3/31/2011 2:35:41 PM BACKGROUND 49 Thyroiditis Background The term thyroiditis refers to a varied group of disorders all characterized by some form of thyroid in \202 ammation (Table 6.1). It includes conditions characterized by thyroid pain and tenderness (i.e., subacute granuloma- tous, infectious, traumatic, and ra diation-induced thyroiditis) and those characterized primarily by thyroid dysfunction or go iter without pain (i.e., painless, postpartum, drug-induced and \201 brous thyroiditis, c hronic lym- phocytic thyroiditis [Hashimoto \200\231s]). In \202 ammation of the thyroid gland often leads to a transient thyrotoxico- sis followed by hypothyroidism (Table 6.2). Table 6.1 Causes and characteristics of thyroiditis Cause Characteristic features Chronic lymphocytic thyroiditis (Hashimoto \200\231s) Grossly lymphocytic and \201 brotic thyrotoxicosis or hypothyroidism Postpartum thyroiditis Lymphocytic thyroditis, transient thyrotoxicosis or hypothyroidism Drug induced Particularly with amiodarone Subacute granulomatous (de Quervain) Thought to be viral in origin, multinuclear giant cells Riedel thyroiditis Extensive \201 brosis of the thyroid Radiation thyroiditis Radiation injury, transient thyrotoxicosis Pyogenic Staph. aureus , streptococci, E. coli , tuberculosis, fungal 06-Draznin-Chap06.indd 49 3/31/2011 2:33:07 PM CHAPTER 6 Thyroiditis 50 Table 6.2 Clinical presentation of thyroiditis Form of thyroiditis Clinical presentation Thyroid function Suppurative (acute) Painful, tender thyroid, fever Usually normal Subacute granulomatous (de Quervain) Painful anterior neck, arthralgia, antecedent upper respiratory tract infection; generalize d malaise. Early thyrotoxicosis, occasionally late hypothyroidism Chronic autoimmune Hashimoto \200\231s: goiter Atrophic: no goiter Usually hypothyroid Sometimes euthyroid Rarely early thyrotoxicosis Riedel Hard woody consistency of thyroid Usually normal Chronic autoimmune thyroiditis See Tables 6.1 and 6.2. Hashimoto \200\231s thyroiditis This is characterized by a painless, variably sized goiter with rubbery con- sistency and an irregular surface. The normal follicular structure of the gland is extensively replaced by lymphocytic and plasma cell in \201 ltrates with formati on of lymphoid germinal centers. The patient may have normal thyroid function, or subclinical, or overt hypothyroidism. Occa sional patients present with thyrotoxicosis in asso- ciation with a thyroid gland that is u nusually \201 rm and with high titers of circulating antithyroid antibodies. Atrophic thyroiditis This probably indicates end-stage thyroid disease. These patients do n ot have goiter and are antibody positive. Biochemically, the picture is that of frank hypot hyroidism. Studies \200 Thyroid function tests \200 Thyroid antibodies (antithyroglobulin antibodi es positive in 20 \200\22325%, and antithyroperoxidase antibodies in >90%). FNA to exclude malignancy in patients who present with a goiter and dominant nodule Prognosis The long-term prognosis of patients with chronic thyroiditis is good, because hyp othyroidism can easily be corrected with T 4 and the goiter is not usually of suf \201 cie nt size to cause local symptoms. In the atypical situation where Hashimoto \200\231s thyroiditis presents with rapidly enlar ging goiter and pain, a short course of prednisone at a dose of 40 mg daily may prove helpf ul. 06-Draznin-Chap06.indd 50 3/31/2011 2:33:07 PM OTHER TYPES OF THYROIDITIS 51 Other types of thyroiditis Silent thyroiditis This is associated with transient thyrotoxicosis or hypothyroidism. A si g- ni \201 cant percentage of patients have a personal or family history of autoim- mune t hyroid disease. It may progress to permanent hypothyroidism. Postpartum thyroiditis Also see p. 34. Thyroid dysfunction occurs within the \201 rst 6 m onths post- partum. Prevalence ranges from 5 to 7%. Postpartum thyroiditis devel- ops in 30 \200\22352% of women who have positive thyroid peroxidase (TPO) antibodies. Most patients have a complete remission but some may progress to permanent hypothyroidism. It is three times as common in patients with type I diabetes mellitus. Chronic \201 brosing (Riedel \200\231s) thyroiditis This rare disorder is characterized b y intense \201 brosis of the thyroid gland and surrounding structures, leading to indurat ion of the tissues of the neck. It may be associated with mediastinal and retroperitoneal \201 brosis, salivary gland \201 brosis, sclerosing cholangitis, lachrymal gland \201 brosis, and parathyroid gland \201 brosis leading to hypoparathyroidism. Patients are usually euthyroid. The main differential diagnosis is thyroid neoplasia. Management Corticosteroids are usually ineffective. Surgery may be needed to relieve obstru ction and to exclude malignancy. Tamoxifen may be of bene \201 t. Pyogenic thyroiditis This disorder is rare; it is usually preceded by a pyogenic infection else- where. It is characterized by tenderness and swelling of the thyroid gland, redness a nd warmth of the overlying skin, and constitutional signs of infection. Piriform sinus should be excluded. Excision of the tract is preferable to incision and drainage. Treatment consists of antibiotic therapy and incision and drainage if a \202 uctuant area within the thyroid should occur. Subacute thyroiditis (granulomatous or de Quervain thyroiditis) This condition is most like ly viral in origin. Symptoms include pronounced asthenia, malaise, pain over the thyroid, o r pain referred to the lower jaw, ear, or occiput. Less commonly, the onset is acute with f ever, pain over the thyroid, and symptoms of thyrotoxicosis. Characteristic signs include exquisite tenderness and nodularity of the thy- roid gland. Th ere is often an elevated erythrocyte sedimentation rate (ESR) and depressed radionuclide up take. Biochemically, the patient may be initially thyrotoxic, though later the patient may become hypothyroid (15%). 06-Draznin-Chap06.indd 51 3/31/2011 2:33:07 PM CHAPTER 6 Thyroiditis 52 In mild cases, nonsteroidal anti-in \202 ammatory agents offer symptomatic relief. In seve re cases, glucocorticoids (prednisone 20 \200\22340 mg/day) are effective. Propranolol can be used to control associated thyrotoxicosis. Treatment can be withdrawn when T 4 returns t o normal. T 4 replacement is required if the patient becomes hypothyroid. Treatment with methimazole or propylthiouracil is not indicated. Drug-induced thyroiditis Causes \200 Amiodarone \200 Lithium \200 Interferon-A (15% develop thyroid peroxidase antibodies and or thyroid dysfunction) Interleukin 2 Further reading Lazarus JH, Hall R, Othman S, et al. (1996). The clinical spectrum of postp artum thyroid disease. QJM 89:429 \200\223435. Muller AF, Drexhage HA, Berghout A (2001). Postpartum thyroiditis and autoimmune thyroiditi s in women of child-bearing age: recent insights and consequences for antenatal and postnat al care. Endocr Rev 22:605 \200\223630. Pearce EN, Farwell AP, Braverman LE (2003). Thyroiditis. N Engl J Med 348(26):2646 \200\223 2655. Weetman AP (2000). Autoimmune thyroid disease. In DeGroot LJ, Jameson JL (eds.), Endocrinol ogy, Vol. 2. Philadelphia: WB Saunders. 06-Draznin-Chap06.indd 52 3/31/2011 2:33:08 PM BACKGROUND 53 Hypothyroidism Background Hypothyroidism results from a variety of abnormalities that cause insuf \201 - cient secretion of thyroid hormones (Table 7.1). The most common cause is autoimmune thyroi d disease. Myxedema is severe hypothyroidism in which there is accumulation of hydrophilic mucopolysac charides in the ground substance of the dermis and other tissues leading to thickening of t he facial features and doughy induration of the skin. Subclinical hypothyroidism refers to elevated TSH levels in the presence of normal concentrations of free thyroid hormones. Epidemiology In community surveys, approximately 0.1 \200\2232% of adults have overt hypoth yroidism. In the United States Nation Health and Nutrition Examination Survey (NHANES III), 4.3% of p eople without known thyroid disease had subclini- cal hypothyroidism, and 0.3% had overt hy pothyroidism. Incidence is higher in whites than in Hispanics or African-American populations. Incidence is higher in areas of high iodine intake. An elevated TSH is associated with higher serum lipid concentrations, which may be an additional reason to initiate therapy. 07-Draznin-Chap07.indd 53 3/31/2011 2:36:25 PM CHAPTER 7 Hypothyroidism 54 Table 7.1 Classi \201 cation of the causes of hypothyroidism TSH i Free T 4 d Nongoitrous Postablative (radioiodine, surgery) Congenital development defect Atrophic thyroiditis Postradiation (e.g., for lymphoma) i d Goitrous Chronic thyroiditis (Hashimoto \200\231s thyroiditis) Iodine de \201 ciency Drug elicited (amiodarone, aminosalicylic acid, iodides, lithium aminoglutethimide, interfe ron-A, thalidomide, bexarotene, stavudine \200\224antiretroviral) Heritable biosynthetic de-fects Maternally transmitted (antithyroid agents, iodides) d d Pituitary Panhypopituitarism Isolated TSH de \201 ciency d d Hypothalamic Neoplasm In \201 ltrative (sarcoidosis) Congenital defects Infection (encephalitis) i d Self-limiting Following withdrawal of suppressive thyroid therapy Subacute thyroiditis and chronic thyroiditis with transient hypothyroidism Postpartum thyroiditis 07-Draznin-Chap07.indd 54 3/31/2011 2:36:25 PM CLINICAL PICTURE 55 Clinical picture Adult \200 Insidious nonspeci \201 c onset \200 Fatigue, lethargy \200 Constipation \200 Cold intolerance \200 Muscle stiffness, cramps, carpal tunnel s yndrome \200 Menorrhagia, later oligo- or amenorrhea \200 Slowing of intellectual and m otor activities \200 d Appetite and weight gain \200 Dry skin, hair loss \200 Deep ho arse voice \200 d Visual acuity \200 Obstructive sleep apnea \200 Depression Myxoedema \200 Dull, expressionless face, sparse hair, periorbital puf \201 ness, macroglossia Pale, cool skin that feels rough and doughy \200 Enlarged heart (dilation and pericardial effusion) \200 Megacolon/intestinal obstruction \200 Cerebellar ataxia \200 Prolonge d relaxation phase of deep tendon re \202 exes \200 Peripheral neuropathy. \200 Enceph alopathy \200 Hyperlipidemia \200 Hypercarotenemia (also caused by hyperlipidemia, diab etes mellitus, and porphyria) Psychiatric symptoms, e.g., depression, psychosis Myxedema coma \200 Predisposed to by cold exposure, trauma, infection, administration of central nervous system (CNS) depressants Marked respiratory depression with increased arterial P CO2 \200 Hyponatremia from impair ed water excretion and disordered regulation of vasopressin secretion 07-Draznin-Chap07.indd 55 3/31/2011 2:36:26 PM CHAPTER 7 Hypothyroidism 56 Treatment of hypothyroidism Normal metabolic state should be restored gradually as a rapid increase in metabolic rate may precipitate cardiac arrhythmias. The average replace- ment d ose is 1.6 mcg/kg per day. In younger patients, start levothyroxine at 50 \200\223100 mcg. In the elderly, with a hist ory of ischemic heart disease, an initial dose of levothyroxine 25 \200\22350 mcg can be in creased by 25-mcg increments at 4-week intervals until normal metabolic state is attained. The optimum dosage is determined by clinical criteria, the objective of treatment being to restore serum TSH to the normal range. TSH should be checked only 2 months after any dose change. Once stabilized, TSH should be checked on an annual basis. In patients with secondary hypothyroidism, free T 4 is the most useful parameter to follow. Dose requirements can increase by 25 \200\22350% in pregnancy because of the increase in th yroid-binding globulin (TBG). Recent data have shown that mild maternal hypothyroidism in t he \201 rst trimester is associated with slightly impaired cognitive function in offsprin g. Thus, some now recom- mend a routinely increased levothyroxine dose by 25 mcg in any wom en on replacement therapy when she learns she is pregnant. Combined T 4 and T 3 replacement Some studies have suggested that the additional replacemen t with T 3 and T 4 in combination improves well-being and cognitive function in patients co mpared to treatment with T 4 alone. A recent meta-analysis of double-blind crossover studies showed no bene \201 t of this therapy; thus it is not recommended. 07-Draznin-Chap07.indd 56 3/31/2011 2:36:26 PM TREATMENT OF SUBCLINICAL HYPOTHYROIDISM 57 Treatment of subclinical hypothyroidism Treatment is indicated if the biochemistry is susta ined in patients with a past history of radioiodine treatment for thyrotoxicosis or positiv e thy- roid antibodies. In these situations, progression to overt hypothyroidism is almost inevitable (at least 5% per year of those with positive antithyroid peroxidase antibodies). Two samples should be taken 2 \200\2233 months apart to distinguish from nonthyroidal illness. There is controversy over the advantages of T 4 treatment in patients with negative thyroid antibodies and no previous radioiodine treatment. If treatment is not given, follow-up wit h annual thyroid function tests is important. There is no generally accepted consensus of when patients should receive treatment. Some au thorities suggest treatment when the serum TSH is >10 U/L, because of an increased rate of progression to overt hypothyroidism. Increased incidence of cardiac risk is probably greater if >65 years old. Management Antibody +ve Previous treatment of Graves \200\231 disease Other organ-specific autoimmune disease TSH>10 No Yes Levothyroxine treatment; TSH in normal range 6 \200\22312-monthly TSH measurement; If patient symptomatic, a trial of levothyroxine Fig. 7.1 Algorithm for management of subclinical hypothyroidism. Reprinted from The Lancet , Vol. 349, Lindsay RS and Toft AD, Hypothyroidism, pp. 413 \200\223417, Copyright 1997, wi th permission from Elsevier. 07-Draznin-Chap07.indd 57 3/31/2011 2:36:26 PM CHAPTER 7 Hypothyroidism 58 Management of myxedema coma \200 Identify and treat concurrent precipitating illness. \200 Give antibiotic therapy after blood cultures. \200 Manage hypothermia with passive external rewarming. \200 Manage patient in an intensive treatment unit if they are comato se. \200 Give warm humidi \201 ed oxygen by facemask. Mechanical ventilation is needed if the patient is hypoventilating. Aim for a slow rise in core temperature (0.5 C/h). \200 Use a cardiac monitor for suprav entricular arrhythmias. \200 Correct hyponatremia (mild \202 uid restriction), hypotens ion (cautious volume expansion with crystalloid or whole blood), and hypoglycemia (glucose administration ). Monitor rectal temperature, oxygen saturation, blood pressure (BP), central venous pressure (CVP), and urine output hourly. Take blood samples for thyroid hormones, TSH, and cortisol before starting treatment. If hy pocortisolemic, administer glucocorticoids. On thyroid hormone replacement no consensus has been reached. The following is an accepted regimen: \200 T 4 300 \200\223500 mcg IV or by NG tube as a starting dose followed by 50 \200\223100 mcg daily until oral medication can be taken If no improvement within 24 \200\22348 hours, T 3 10 mcg IV q8h or 25 mcg IV q8h can be given in addition to above. Give hydrocortisone 50 \200\223100 mg q6 \200\2238h in case of cortisol de \201 ciency. Management of persistently elevated TSH despite thyroxine replacement See Fig. 7.2. \200 Elevated TSH despite thyroxine replacement is common, most usually due to lack of compliance. TSH rising/not in normal range Question compliance Lack of compliance \200\224encourage compliance and recheck TSH in 3 months Compliance assured \210\222ve antibodies ? Other malabsorption +ve antibodies ? Malabsorption \200\224check celiac antibodies Confirm diagnosis and treat Consider thyroxine absorption test +/ \210\222 supervised weekly dose administration (singl e dose = 7 x 1.6 mcg/kg) with TSH monitoring monthly. Fig. 7.2 Suggestions for investigations of elevated TSH despite thyroxine replacement thera py to >1.6 mcg/kg/day[N3]. 07-Draznin-Chap07.indd 58 3/31/2011 2:36:26 PM MANAGEMENT OF MYXEDEMA COMA 59 If TSH is still elevated when the levothyroxine dose is at 1.6 mcg/kg/ day or higher, careful questioning of compliance is needed. Consider malabsorption. \200 Consider other drugs that may interfere with levothyroxine a bsorption (Box 7.1). Box 7.1 Interference with absorption of thyroxine \200 Celiac disease \200 Drugs \200 \224colestyramine, aluminum hydroxide, sucralfate, omeprazole, rifampicin, phenytoin, iron, and calcium carbonate \200 Atrophic gastritis in H. pylori infection (d T 4 by 30%) 07-Draznin-Chap07.indd 59 3/31/2011 2:36:26 PM CHAPTER 7 Hypothyroidism 60 Congenital hypothyroidism Incidence is about 1 in 5000 neonates. All neonates should be scr eened. Thyroid agenesis This occurs in 1 in 1800 births. Thyroid hormone dysgenesis This is caused by inborn errors of thyroid metabolism. The disor ders may be autosomal recessive, indicating single protein defects. The disorder can be caused by inactivation of the TSH receptor, abnor- malities of the thyr oid transcription factors TTF1, TTF2, and PAX8, or defects in iodide transportation, organi \201 cation (peroxidase), coupling, deiodi- nase, or thyroglobulin synthesis. In a large proportion of patients with congenital hypothyroidism, the molecular background is unknown. Pendred \200\231s syndrome This is characterized by overt or subclinical hypothyroidism, go iter, and moderate to severe sensorineural hearing impairment. The prevalence varies betwee n 1 in 15,000 and 1 in 100,000. There is a partial iodide organi \201 cation defect detect ed by increased perchlorate discharge. Thyroid hormone synthesis is only mildly impaired and so may not be detected by neonatal thyroid screening. Box 7.2 Clinical features and congenital hypothyroidism The following features are late sequelae of congenital hypothyroidism. With routine screeni ng now available, they should not be seen. \200 Physiological jaundice \200 Goiter \200 Hoarse cry, feeding problems, constipation, somnolence \200 Delay in reaching norma l milestones of development; short stature \200 Coarse features with protruding tongue, b road \202 at nose, wide-set eyes Sparse hair and dry skin, protuberant abdomen with umbilical hernia \200 Impaired mental development, retarded bone age \200 Epiphyseal dysgenesis, delayed dentition Laboratory tests \200 Neonatal screening by measurement of serum TSH \200 Imaging proce dure: ultrasonography or 123 I scintigraphy \200 Measurement of serum thyroglobulin and l ow molecular weight iodopeptides in urine to discriminate between various types of defects \200 Measurement o f neonatal and maternal autoantibodies as an indication of possible transient hypothyroidism 07-Draznin-Chap07.indd 60 3/31/2011 2:36:26 PM CONGENITAL HYPOTHYROIDISM 61 Treatment Irrespective of the cause of congenital hypothyroidism, early treatment is essent ial to prevent cerebral damage. Suf \201 cient T 4 should be given to maintain TSH in the normal range. Further reading Clyde PW, Harari AE, Getka EJ, et al. (2003). Combined levothyroxine plus l iothyronine com- pared with levothyroxine alone in primary hypothyroidism: a randomized con trolled trial. JAMA 290(22):2952 \200\2232958. de Vijlder JJM, Vulsma T (2000). In DeGroot LJ, Jameson JL (ed.), Endocrinology, Vol. 2. Ph iladelphia: WB Saunders. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, et al. (2005). Treatment of h ypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 90(8):4949 \200\2234954. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, et al. (2005). Thyroid hormone re placement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med 142(6):412 \200\223424. Roberts CG, Ladenson PW (2004). Thyroxine adherence in primary hypothyroidism. Lancet 363(9 411):793 \200\223803. 07-Draznin-Chap07.indd 61 3/31/2011 2:36:26 PM CHAPTER 8 Amiodarone and thyroid function 62 Amiodarone and thyroid function Background Amiodarone is a potent antiarrythymic drug used to treat various tach- yarrhythm ias. It is a benzofuranic derivative with a high concentration of iodine, and it bears stru ctural resemblance to thyroxine. Each 200 mg tab- let contains approximately 75 mg of organ ic iodine. Amiodarone is distributed in several tissues from where it is slowly released. In one study , terminal elimination half-life of amiodarone aver- aged 52.6 days with a standard deviati on of 23.7 days. Abnormalities of thyroid function occur in up to 14 \200\22318% of patients 1 (Table 8.1). In the UK and United States, 2% of patients on amiodarone develop thyrotoxicosis and about 13% develop hypothyroidism. Patients residing in areas with high iodine intake develop amiodarone- induced hypothyroidi sm (AIH) more often than amiodarone-induced thy- rotoxicosis (AIT), but AIT occurs more fre quently in regions with low iodine intake. AIT can present several months after discontinui ng the drug because of its long half-life. Hypothyroidism is more common in women and in patients with thy- roid autoantibodies. Thyroid function tests should be monitored initially and then every 6 months in patients taking amiodarone. Table 8.1 Thyroid function tests in clinically euthyroid patients after administration of a miodarone Tests 1 \200\2233 months >3 months Free T 3 Decreased Remains slightly decreased, but within normal range TSH Transient increase Normal Free T 4 Modest increase Slightly increased compared to pretreatment values, may be in normal range or slightly incr eased. Reverse T 3 Increased Increased 1 Gopalan M, Burks J (2009). Thyroid dysfunction induced by amiodarone therapy: differentia l diagnoses and workup, eMedicine July 2, 2009. 08-Draznin-Chap08.indd 62 3/31/2011 2:36:52 PM PATHOGENESIS 63 Pathogenesis The high iodine content of amiodarone may either inhibit thyroid hor- mone syn thesis and release, thus causing AIH (failure to escape the Wolff-Chaikoff effect), or may result in iodine-induced thyrotoxicosis (Jod \200\223Basedow phenomenon). Thyrotoxicosis resulting from iodine excess and therefore increased hormone synthesis is re ferred to as AIT type I . Thyrotoxicosis due to a direct toxic effect of amiodarone is refe rred to as AIT type II (Table 8.2). Drug-induced destructive thyroiditis results in leakage of thyroid hor- mones from damaged follicles into the circulation and, like subacute thyro iditis, can be followed by a transient hypothyroid state before euthy- roidism is restored. Table 8.2 Characteristics of AIT* AIT type I (10%) AIT type II (90%) Etiology Iodine toxicity Thyroiditis Signs of clinical thyroid disease Yes No Goiter Frequent Infrequent Thyroid antibodies Positive Negative Radioiodine uptake Normal Decreased Thyroglobulin Normal or slightly elevated Very elevated Serum IL6 (research test) Normal Very elevated Late hypothyroidism No Possible Vascularity (Doppler) Increased/normal Reduced Some patients have a mixed form and classi \201 cation is not always possible. 08-Draznin-Chap08.indd 63 3/31/2011 2:36:52 PM CHAPTER 8 Amiodarone and thyroid function 64 Diagnosis and treatment See Table 8.3. After chronic administration of amiodarone, a steady state is achieved, typically re \202 ected in mild elevation of free T 4 and reduction in free T 3 . Thus in clinically euthyroid patients on amiodarone, a slightly elevated T 4 is not indicative of hyperthyroidism, nor is a low T 3 indicative of hypothyroidism. Hyperthyroidism is indicated by signi \201 cantly i free T 4 , together with elevated free T 3 and suppressed serum TSH. Hypothyroidism is indicated by elevation of TSH with low serum free T 4 . See Box 8.1 for treatment. Discontinuation of amiodarone does not always control the thyrotoxic state because of its l ong half-life (particularly in the obese) due to its very high volume of distribution and f at solubility. Numerous complex published algorithms exist for management, but since classi \201 cation i nto type I and type II is often dif \201 cult (see Table 8.2), in practice most patients a re treated with ATDs glucocorticoids (see Table 8.4). Table 8.3 Side effects and complications of amiodarone therapy Side effect Incidence (%) Corneal microdeposits 100 Anorexia and nausea 80 Photosensitivity; blue/gray skin discoloration 55 \200\22375 Ataxia, tremors, peripheral neuropathy 48 Deranged liver function tests 25 Abnormal thyroid function tests 14 \200\22318 Interstitial pneumonitis 10 \200\22313 Cardiac arrhythmias 2 \200\2233 Box 8.1 Treatment of amiodarone-induced hypothyroidism Underlying thyroid abnormality (usually Hashimoto \200\231s thyroiditis) \200 Amiodarone therapy can be continued. \200 Add thyroxine replacement therapy. Apparently normal thyroid \200 Discontinue amiodarone if possible and follow up for resto ration of euthyrodism. \200 If amiodarone cannot be withdrawn, start thyroxine replacement therapy. 08-Draznin-Chap08.indd 64 3/31/2011 2:36:52 PM DIAGNOSIS AND TREATMENT 65 Table 8.4 Treatment of amiodarone-induced thyrotoxico-sis Type 1 AIT Type 2 AIT Methimazole up to 40 mg/day or propylthiouracil 400 mg/day. If possible, discontinue amioda rone* Discontinue amidarone if possible* Prednisone 40 mg/day In mixed forms, add methimazole or pro- pylthiouracil as in type 1 AIT Step 1 Aim: restore euthyroidism Step 2: De \201 nitive treatment Radioiodine treatment or thyroidectomy Follow up for possible spontaneous progression to hypothyroidism If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyro idectomy. The \201 rst line of treatment is ATDs (methimazole or propylthiouracil). A combination o f corticosteroids and ATDs may be effective in AIT type II. A high dose of prednisone, 40 \200\22360 mg daily, may be required for 8 \200\22312 weeks; studies where steroids have be en discontinued after 2 \200\2233 weeks have been associated with a high relapse rate. Potassium perchlorate may be of additional bene \201 t, but it is currently not available in the United States Radioiodine is not usually effective because of reduced uptake by the thyroid gland, re \202 ecting the iodine load associated with the drug. Surgery remains a very successful form of treatment, with euthyroidism being restored withi n a matter of days. Achieving preoperative euthy- roidism may be dif \201 cult, however. Cardiac function may be compromised by propranolol used in com- bination with amiodarone, s ince this may produce bradycardia and sinus arrest. Further reading Bartalena L, Brogioni S, Grasso L, et al. (1996). Treatment of amiodarone-i nduced thyrotoxicosis, a dif \201 cult challenge: results of a prospective study. J Clin E ndocrinol Metab 81:2930 \200\2232933. Martino E, Bartalena L, Bogazzi F, et al. (2001). The effects of amiodarone on the thyroid. Endocr Rev 22(2):240 \200\223254. Newman CM, Price A, Davies DW, et al. (1998). Amiodarone and the thyroid. Heart 79:121 \200 \223127. Wiersinga WM (1997) Amiodarone and the thyroid. In Weetman AP, Grossman A (eds.), Pharmacot herapeutics of Thyroid Gland . Berlin: Springer-Verlag, pp. 225 \200\223287. 08-Draznin-Chap08.indd 65 3/31/2011 2:36:52 PM CHAPTER 9 Thyroid cancer 66 Thyroid cancer Epidemiology Clinically detectable thyroid cancer is rare. It accounts for <1% of all can- cer and <0.5% of cancer deaths. Thyroid microcarcinoma (diameter <1 cm) may be found in multinodular goi ters. Thyroid cancers are most common in adults aged 40 \200\22350 and are rare in children and a dolescents. Women are affected more frequently than men. See Table 9.1 for classi \201 cat ion of thyroid cancer and Table 9.2 for a comparison of the various types of carcinoma. Table 9.1 Classi \201 cation of thyroid cancer Cell of origin Tumor type Frequency (%) Papillary Differentiated Papillary Follicular Undifferentiated (anaplastic) >80 10 1 \200\2235 C cells Medullary 5 \200\22310 Lymphocytes Lymphoma 1 \200\2235 Table 9.2 Comparison of papillary, follicular and anaplastic carcinomas of the thyroid Characteristic Papillary Ca Follicular Ca Anaplastic Ca Age at presentation 30 \200\22350 (mean 44) 40 \200\22350 60 \200\22380 Spread Lymphatic Hematogenous Hematogenous Prognosis Good Good Poor Treatment Initially: near total thyroidectomy Postoperative TSH suppression High-risk patient: 131 I remnant ablation Postoperative total body radioiodine scan Initially: near total thyroidectomy Postoperative TSH suppression 131 I remnant ablation Po stoperative total body radioiodine scan Total thyroidectomy with lymph node clearance Chemotherapy with doxorubicin and cisplatin E xternal beam irradiation 09-Draznin-Chap09.indd 66 3/31/2011 2:38:14 PM ETIOLOGY 67 Etiology Irradiation There does not appear to be a threshold dose of external irradiation f or thyroid carcinogenesis; doses of 200 \200\223500 rad seem to produce thyroid cancer at a rate of about 0.5%/year. There is no evidence that therapeutic or diagnostic 131 I administration can induce thyroid cancer, although there is a small increase in death rates from thyroid cancer after 131 I. At present it is unclear whether this is due to an effect of 131 I or part of the natural history of the underlying thyroid disease. External irradiation at an age <20 years is asso ciated with an increased risk of thyroid nodule development and thyroid cancer (most common ly papillary). The radioactive fallout from the Chernobyl nuclear explosion in 1986 resulte d in a 4.7-fold increase in thyroid cancer in the regions of Belarus from 1985 to 1993, inc luding a 34-fold increase in children. Most of these were papillary carcinomas. The risk is greater for women and when irradiation occurs at a younger age. There is a latency of at least 5 years with maximum risk at 20 years following exposure, th ough this was not seen following the Chernobyl disaster. Other environmental factors Most investigators agree that iodine supplementation has result ed in a decrease in the incidence of follicular carcinoma. Genetic syndromes and oncogenes RET/PTC1 proto-oncogene abnormalities in the long arm of ch romosome 10 are associated with some papillary tumors (5 \200\22330%), especially after irr a- diation (60 \200\22380%). It is similar to the abnormality associated with medullary thy roid carcinoma in MEN2A. Two new proto-oncogenes have been have been identi \201 ed: RET/PTC2 and RET/PTC3 TRK (less common). The tumor suppressor gene p53 has been found to be mutated in some de-differentiated cancers. Overexpression of the ras and PTTG oncogenes is found in papillary thyroid cancers. These w ere found to be markers for adverse prognosis. c -myc mRNA expression has been correlated w ith histological markers of papillary cancer aggression. Papillary microcarcinoma of the thyroid (PMC) PMC is de \201 ned by the World Health Organ ization (WHO) as a tumor focus of 1.0 cm or less in diameter. It is detected coincidentally on his- topathological examination of resected thyroid Autopsy studies show the following: \200 Prevalence ranges from 1 to 35.6%. \200 No sig ni \201 cant difference in the prevalence rates of PMC has been demonstrated between the sexes. PMC rarely progresses to clinically apparent thyroid cancer with advancing age. 09-Draznin-Chap09.indd 67 3/31/2011 2:38:14 PM CHAPTER 9 Thyroid cancer 68 PMC can be multifocal. \200 Cervical lymph node metastasis from PMC ranges from 4.3 to 18 .2%. \200 Lymph node metastasis was most often associated with multifocal tumors. Althoug h exposure to irradiation increases the likelihood of developing papillary thyroid cancer, the tumors will usually be >1.0 cm in diameter and thus not PMC. Follow-up studies suggest that PMC is a slow-growing lesion that rarely spreads to distant sites and carries a good prognosis. The recommenda- tions for treatment of PMC vary widely: \200 The low morbidity and long survival mean that collection of randomized, prospective data has never been performed and comparisons of therapies are based on retrospective stud ies. \200 The treatment of PMC should not cause more morbidity than the disease process itself. Surgical treatment recommendations range from simple excision to ipsilateral lobectomy.