TPP is precipitated by carbohydrate intake, insulin, cold, and vigorous exercise. Treatment is with potassium replacement, usually by oral route. However, in treatment of th yrotoxicosis, one needs to avoid overtreat- ment of hypokalemia resulting in hyperkalemia. Symptoms usually improve within 2 \200\2234 hours; full resolution in 24 \200\22348 hours. Nonselective B-blockers, such as propranolol (3 mg/kg), help reverse attacks as well as prevent attacks until a euthyroid state is achieved. 03-Draznin-Chap03.indd 30 4/1/2011 5:27:36 PM THYROTOXICOSIS IN PREGNANCY 31 Thyrotoxicosis in pregnancy b Also see p. 53. Thyrotoxicosis occurs in about 0.2% of pregnancies. Graves \200\231 disease accounts for 90% of cases. Less common causes include toxic adenoma and multinodular goiter. Other causes are gestatio nal hyperthyroidism (hyperemesis gravidarum) and trophoblastic neoplasia. Diagnosis of thyrotoxicosis during pregnancy may be dif \201 cult or delayed due to the no rmal physiological changes of pregnancy, which are similar to those of hyperthyroidism Total T 4 and T 3 are elevated in pregnancy secondary to an elevated level of TBG. Free hor mone assays can be used to better assess thyroid function. Physiological features of normal pregnancy include an increase in basal metabolic rate, car diac stroke volume, palpitations, and heat intolerance. Serum free T 3 concentrations remai n within the normal range in most pregnant women; serum TSH concentration decreases during the \201 rst trimester. Symptoms Hyperemesis gravidarum may cause mild hyperthyroidism, also known as \200\234gest ational thyrotoxicosis. \200\235 Tiredness, palpitations, insomnia, heat intol- erance, pro ximal muscle weakness, shortness of breath, and irritability may be presenting symptoms. Thyrotoxicosis may occasionally be diagnosed when the patient presents with pregnancy-induced hypertension or congestive heart failure. Signs \200 Failure to gain weight despite a good appetite \200 Persistent tachycardia w ith a pulse rate >90 beats/min at rest \200 Other signs of thyrotoxicosis as described pr eviously Natural history of Graves \200\231 disease in pregnancy There is aggravation of symptoms in the \201 rst half of the pregnancy, amel- ioration of symptoms in the second half of the pregnancy, and often recur- rence of symptoms in the postpartum period. Transient hyperthyroidism of gestational hyperthyroidism (hyperemesis gravidarum) The mecha nism is likely due to raised B-hCG level, which activates the TSH receptor. B-hCG, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and TSH are glycoprote in hormones that contain a common A-subunit and a hormone-speci \201 c B-subunit. There is an inverse relationship between the serum levels of TSH and hCG, best seen in early pregna ncy. Structural homology exists between the TSH and hCG receptors. Serum free T 4 concentration may be i and the TSH levels suppressed in women with hyperemesis gravidarum. Thyroid function tests recover after the resolution of hyperemesis. 03-Draznin-Chap03.indd 31 4/1/2011 5:27:36 PM CHAPTER 3 Thyrotoxicosis 32 Pregnant women with gestational hyperthyroidism (hyperemesis gravi- darum), accounting for 2/3 of hyperemesis, are not usually given ATD treatment but managed supportively with \202 uids, antiemetics, and nutri- tional support. There is no i risk of thyrotoxicosis in subsequent pregnancies. This condition can be diffe rentiated from Graves \200\231 disease by the absence of a goiter, antithyroid antibodies, family history of Graves \200\231 disease, history of other autoimmune phenomena, or a prev ious history of ophthalmic Graves \200\231 disease. Management of Graves \200\231 disease in the mother The aim of treatment is alleviation of thyroid symptoms and normaliza- tion of thyroid function tests in the shortest time. Patien ts should be seen every 4 \200\2238 weeks and TFTs performed. Serum free T 4 is the best te st to follow the response to ATDs. Block and replace regimen should not be used, as this wi ll result in fetal hypothyroidism. Both propylthiouracil (250 mg daily in divided doses or less) and methimazole control the d isease in pregnancy; however, given the recent data regarding the risk of fatal hepatotoxic ity with PTU, in an alert issued on 6/4/2009, the FDA recommended that given the risk of fe tal hepatotoxicity, \200\234PTU may be more appropriate for patients with Graves \200\231 disease who are in their \201 rst trimester of pregnancy. \200\235 The choice of antithyr oid agent during pregnancy remains con- troversial. PTU is more bound to plasma proteins an d theoretically less of the drug would be transferred to the fetus than would methimazole. In addition, methimazole has been associated with aplasia cutis. A B-blocker (propranolol 2 0 \200\22340 mg q6 \200\2238h) is effective in controlling the hypermetabolic symptoms but should be used only for a few weeks until symptoms abate. The dosage of ATDs is frequently adjusted during the course of the pregnancy; therefore, th yroid tests should be done at 2- to 4-week inter- vals, with the goal of keeping free thyro id hormone levels in the upper 1/3 of the reference range. Thyroid tests may normalize spontaneously with the progression of a normal pregnancy as a result of immunological changes. The use of iodides and radioiodine is contraindicated in pregnancy because it crosses the placenta and may cause toxicity to the fetal thyroid gland. Surgery is rarely performed in pregnancy. It is reserved for patients not responding to ATD s. It is preferable to perform surgery in the second trimester. Breast-feeding mothers should be treated with the lowest possible dose of propylthiouracil or methimazole. The low levels of ATD in breast milk do not affect the fetal thyroid gland. Pre-pregnancy counseling Hyperthyroid women who want to conceive should attain euthyroidism before conception, since uncontrolled hyperthyroidism is associated with an i risk of cong enital abnormalities (most seriously, stillbirth and cranial synostosis). b See Table 3.3. There is no evidence that radioactive iodine treatment given to the mother 6 months or more before pregnancy has an adverse effect on the fetus or on offspring in later life. 03-Draznin-Chap03.indd 32 4/1/2011 5:27:36 PM THYROTOXICOSIS IN PREGNANCY 33 Antithyroid medication requirements decrease during gestation; in about 50 \200\22360% of p atients, the dose may be discontinued in the last few weeks of gestation. The risk of recurrent hyperthyroidism should be discussed with the patient. The rare occurr ence of fetal and neonatal hyperthyroidism should be included during counseling sessions an d the diagnosis of Graves \200\231 hyper- thyroidism conveyed to the obstetrician and neona tologist. Management of the fetus The hypothalamic \200\223pituitary \200\223thyroid axis is well dev eloped at 12 weeks gestation but remains inactive until 18 \200\22320 weeks. Circulating TS H recep- tor antibodies (TSH-RAb) in the mother can cross the placenta. The risk of hyperth yroidism to the neonate can be assessed by measuring TSH- RAb in the maternal circulation a t the beginning of the third trimester. Antithyroglobulin antibodies and thyroid peroxidase antibodies have no effect on the fetus. Long-term follow-up studies of children whose mothers received either methimazole or propyl thiouracil have not shown an i incidence of any physical or psychological defects. Monitoring of the fetal heart rate and growth rate is the standard means by which fetal thy rotoxicosis may be detected. A rate >160 beats/min is suspicious of fetal thyrotoxicosis in the third trimester. Fetal thyrotoxi- cosis may complicate the latter part of the pregnanc y of women with Graves \200\231 disease even if they have previously been treated with radi oiodine or surgery, since TSH receptor antibodies may persist. If there is evidence of fetal thyrotoxicosis, the dose of ATD should be increased. If this causes maternal hypothyroidism a small dose of T 4 can be added since, unlike methimazole, T 4 crosses the placenta less. A pediatri- cian should be involved to monitor neonatal thyr oid function and detect thyrotoxicosis. Hypothyroidism in the mother should be avoided because of the poten- tial adverse effect on subsequent cognitive function of the neonate; b see Table 3.3. If the mother has been treated with methimazole, the post-delivery levels of T 4 may be low and neonatal levels of T 4 may only rise to the Table 3.3 Potential maternal and fetal complications in uncontrolled hyperthyroidism in pre gnancy Maternal \200 Pregnancy induced hypertension \200 Preterm delivery \200 Congestive he art failure \200 Thyroid storm \200 Miscarriage \200 Abruptio placentae \200 Accide ntal hemorrhage Fetal \200 Hyperthyroidism \200 Neonatal hyperthyroidism \200 Intrauterine growth ret ardation \200 Small-for-gestational age \200 Prematurity \200 Stillbirth \200 Crani al synostosis 03-Draznin-Chap03.indd 33 4/1/2011 5:27:36 PM CHAPTER 3 Thyrotoxicosis 34 thyrotoxic range after a few days. In addition, TSH is usually absent in neonates who subse quently develop thyrotoxicosis. Clinical indicators of neonatal thyrotoxicosis include low birth weight, poor weight gain, tachycardia, and irritability. Methimazole can be given and withdrawn after a few weeks aft er the level of TSH-RAb declines. Postpartum thyroiditis This is de \201 ned as a syndrome of postpartum thyrotoxicosis or h ypothy- roidism in women who were euthyroid during pregnancy. Postpartum thyroid dysfunction, which occurs in women with autoim- mune thyroid disease, is characterized in 1/3 by a thyrotoxic phase in the \201 rst 3 months postpartum, followed by a hypothyroid phase occurring 3 \200\2236 months after delivery, followed by spontaneou s recovery. In the remaining 2/3, a single-phase pattern or the reverse occurs. Approximately 5 to 7% of women develop biochemical evidence of thy- roid dysfunction after delivery. An i incidence is seen in patients with type I diabetes mellitus (25%) and other autoimmune diseases, in the presence of anti-TPO antibodies, and in the presence of a famil y history of thyroid disease. Hyperthyroidism due to Graves \200\231 disease accounts for 10 \200\22315% of all cases of postpartum thyrotoxicosis. In most cases, hyperthyroidism occurs later in the postpartum pe riod (>3 \200\2236 months) and persists. Providing the patient is not breast-feeding, a radioiodine uptake and scan can differentiat e the two principal causes of autoimmune thyrotoxi- cosis by demonstrating i uptake in Grav es \200\231 disease and low uptake in postpartum thyroiditis. Graves \200\231 hyperthyroidism should be treated with ATDs. Propylthiouracil is preferable if the patient is breast-feeding. Thyrotoxic symptoms due to postpartum thyrotoxicosis are managed symptomatically using propranolol. One-third of affected women with postpartum thyroiditis develop symptoms of hypothyroidism and may require LT 4 for 2 \200\2233 months fol- lowed by a trial of 4 \200\2236 weeks off of LT4 and measurement of plasma TSH. There is a suggestion of an i risk of postpartum depr ession in those with hypothyroidism. Histology of the thyroid in the case of postpartum thyroiditis shows lymphocytic in \201 l tration with destructive thyroiditis, predominantly occur- ring at 16 weeks in women with p ositive antimicrosomal antibodies. Subsequent permanent hypothyroidism occurs in 25 \200\22330% of patients with postpartum th yroiditis. Given the increased risk, these patients should be followed up with annual TSH m easurements. 03-Draznin-Chap03.indd 34 4/1/2011 5:27:37 PM HYPERTHYROIDISM IN CHILDREN 35 Hyperthyroidism in children Epidemiology Thyrotoxicosis is rare before the age of 5 years. Although there is a pro- gressive increase in incidence throughout childhood, it is still r are and accounts for <5% of all cases of Graves \200\231 disease. Clinical features Behavioral abnormalities, hyperactivity, and declining school performance may bring the child to medical attention. Features of hyperthyroidism are as described und er Manifestations of hyperthyroidism (p. 19). Accelerated growth rate is common in patients and presents as increas- ing height percentil es on growth charts. The disease may be part of McCune \200\223Albright syndrome, myastheni a gravis, Down syndrome, diabe- tes mellitus, or other associated diseases. Clinical exam should include examination for caf -au-lait pigmentation, precocious puberty, and bony abnormalities. Investigations The primary cause of thyrotoxicosis in children is Graves \200\231 disease ( positive antibodies to thyroid-stimulating antibodies, thyroglobulin, and/or thyroid peroxi dase). Thyroiditis and toxic nodules have been described and a radioiodine scan may be usef ul if the diagnosis is not clear. Hereditary syndromes of thyroid hormone resistance, often misdiag- nosed as Graves \200\231 disease, are now increasingly recognized in children. Treatment ATDs represent the treatment of choice for thyrotoxic children. Therapy is genera lly started with propylthiouracil 6 \200\2238 mg/kg in three divided doses or methimazole ( 0.6 \200\2230.8 mg/kg per day). Since relapse after withdrawal of ATDs is common, these drugs may be continued long term, u ntil education is complete and de \201 nitive treatment with surgery or radioiodine can be offered (if ATDs result in serious side effects or if there is a recurrence after thyroide ctomy). 03-Draznin-Chap03.indd 35 4/1/2011 5:27:37 PM CHAPTER 3 Thyrotoxicosis 36 Secondary hyperthyroidism An elevated serum free T 4 and non-suppressed serum TSH are chara cter- istic of TSH-secreting adenomas or resistance to thyroid hormone These conditions mus t be differentiated (Table 3.4). TSH-secreting pituitary tumors These tumors account for <1% of all pituitary tumors. Charac teristically, there are elevated serum free T 4 and T 3 concentrations and non-suppressed ( inappropriately normal or frankly elevated) serum TSH levels. Among the 280 TSHomas reported in the literature (until 1998), 72% secreted TSH alone; the remainder co-secreted growth hormone (GH) (16%), prolactin (11%), or, rarely, gonadotropins . Approximately 90% were macroadenomas (>1 cm in diameter) and 71% exhibited suprasellar ex tension, invasion, or both into adjacent tissues ( b see p. 131). Patients with pure TSHomas may present with typical symptoms and signs of thyrotoxicosis and the presence of a diffuse goiter. Patients may exhibit features of oversecretion of the other pituitary hor- mones, e.g., mos t commonly, prolactin or growth hormone. Headaches, visual \201 eld defects, menstrual ir regularities, amenorrhea, delayed puberty, and hypogonadotropic hypogonadism have also been reported. Careful establishment of the diagnosis is key to treatment. Inappropriate treatment of such patients with subtotal thyroidectomy or radioiodine administration not only fails to cure the underlying disorder but may also be associated with subsequent pituitary tumor enlargem ent and an i risk of invasiveness into adjacent tissues. Table 3.4 Tests useful in the differential diagnosis of TSHomas, PRTH, and GRTH Test TSHomas PRTH GRTH Clinical thyrotoxicosis Present Present Absent Family history Absent Present Present TSH response to TRH No change Increase In-crease TSH response to T 3 (100 mcg/day + B-blockers) SHBG A-Subunit Pituitary MRI No change Decrease Decrease Normal \200 Elevated \200\22392%* Normal Elevated \200\22365% 2% elevated Tumor \200\22330% micorade-noma \200 Normal Normal Fall in TSH on octreotide LAR 20 mg/month for 2 months 95% No change No change Not usually raised in mixed GH/TSH tumor. \200 Peripheral markers of toxicosis sometimes affected (8% SHBG elevated). \200 The best biochemical test is an elevated A-subunit. 03-Draznin-Chap03.indd 36 4/1/2011 5:27:37 PM SECONDARY HYPERTHYROIDISM 37 Treatment options are as follows: Transphenoidal surgery \200 Pituitary radiotherapy if surgical results are unsatisfactory or surgery is contraindicated or not desired Medical therapy with somatostatin analogs such as octreotide or lanreotide may be useful preoperatively and suppresses TSH secretion in 80% of the cases. Resistance to thyroid hormones Patients with generalized resistance to thyroid hormone (GRT H) may present with mild hyperthyroidism, deaf mutism, delayed bone matura- tion, raised ci rculating thyroid hormone concentrations, non-suppressed TSH, and failure of TSH to decreas e normally upon administration of sup- raphysiological doses of thyroid hormones. Most patients present with goiter or incidentally found abnormal TFTs. Treatment is determined by thyroid status. In selective pituitary resistance to thyroid hormones (PRTH), the thy- roid hormone resista nce is more pronounced in the pituitary. Thus the patient exhibits de \201 nite clinical m anifestations of thyrotoxicosis. About 90% of thyroid hormone resistance syndromes result from muta- tions in the gene encod ing TRB. Mutant receptors have a reduced af \201 nity for T 3 and are functionally de \201 cient. It is usually inherited in an autosomal dominant pattern with the affected indi viduals being heterozygous for the mutation. A subset of RTH receptors has been identi \201 ed that are capable of inhib- iting wild-ty pe receptor action. When coexpressed, the mutant proteins are able to inhibit the function of their wild-type counterparts in a domi- nant negative manner. Common features of patients with thyroid hormone resistance syn- dromes include goiter (mos t commonly) and, less frequently, tachycardia, hyperkinetic behavior, emotional disturbance s, ear, nose, and throat infec- tions, language disabilities, auditory disorders, low body weight, cardiac abnormalities, and subnormal intelligence quotients. Treatment options in RTH are not usually necessary. In PTRH, treatment may be needed, but t his is uncommon. Treatment is with chronic suppression of TSH secretion with LT 4 , triiodo thyroacetic acid, octreotide, or bromocriptine. If this is ineffective, thyroid ablation wi th radioiodine or surgery can be tried, with subsequent close monitor- ing of thyroid hormo ne status and pituitary gland size. Further reading Allahabadia A, Heward JM, Nithiyananthan R, et al. (2001). MHC class II reg ion, CTLA4 gene, and ophthalmopathy in patients with Graves \200\231 disease. Lancet 358(92 86):984 \200\223985. Brent GP (2008). Grave \200\231s disease. N Engl J Med 358:2594 \200\2232605. Brix TH, Kyvik KO, Hegedus L (1998). What is the evidence of genetic factors in the etiolog y of Graves \200\231 disease? A brief review. Thyroid 8 : 727 \200\223734. Franklyn JA, Maisonneuve P, Sheppard MC, et al. (1998). Mortality after the treatment of hy perthy- roidism with radioactive iodine. N Engl J Med 338:712 \200\223718. 03-Draznin-Chap03.indd 37 4/1/2011 5:27:37 PM CHAPTER 3 Thyrotoxicosis 38 Franklyn JA, Maisonneuve P, Sheppard MC, et al. (1999). Cancer incidence and mortality afte r radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet 353:21 11 \200\223 2115. Gunji K, Kubota S, Swanson J, et al. (1998). Role of the eye muscles in t hyroid eye disease: identi \201 cation of the principal autoantigens. Thyroid 8 : 553 \200 \223556 [erratum Thyroid 1998; 8:1079]. Helfgott S, Smith RN (2002). Case records of the Massachusetts General Hospital. Weekly cli nico- pathological exercises: Case 21-2002: a 21-year-old man with arthritis during treatme nt for hyper- thyroidism. N Engl J Med 347(2):122 \200\223130. Parle JV, Maisonneuve P, Sheppard MC, et al. (2001). Prediction of all-cause and cardiovasc ular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort st udy. Lancet 358(9285):861 \200\223865. Panzer C, Beazley R, Braverman L (2004). Rapid preoperative preparation for severe hyperthy roid Graves \200\231 disease. J Clin Endocrinol Metab 89(5):2142 \200\2232144. Pearce SH (2004). Spontaneous reporting of adverse reactions to carbimazole and propylthiou racil in the UK. Clin Endocrinol 61(5):589 \200\223594. Rivkees SA, Sklar C, Freemark M (1998). The management of Graves \200\231s disease in child ren, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 83:3767 \200 \2233776. Ron E, Doody MM, Becker DV, et al. (1998). Cancer mortality following treatment for adult h yper- thyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group. JAMA 280:347 \200\223355. Toft AD (2001). Clinical practice. Subclinical hyperthyroidism N Engl J Med 345(7):512 \200 \223516. Weetman AP (2000). Graves \200\231s disease. N Engl J Med 343(17):1236 \200\2231248. Weetman AP, Pickerill AP, Watson P, et al. (1994). Treatment of Graves \200\231 disease wit h the block- replace regimen of antithyroid drugs: the effect of treatment duration and imm unogenetic suscep- tibility on relapse. QJM 87:337 \200\223341. 03-Draznin-Chap03.indd 38 4/1/2011 5:27:37 PM GRAVES \200\231 OPHTHALMOPATHY 39 Graves \200\231 ophthalmopathy, dermopathy, and acropachy Graves \200\231 ophthalmopathy (cid:2) See European Working Group on Graves \200\231 Ophtha lmopathy at www. EUGOGO.org. This organ-speci \201 c autoimmune disorder is characterized by swelling of the extraocula r muscles, lymphocytic in \201 ltration, late \201 brosis, muscle tethering, and prolife ration of orbital fat and connective tissue. The lesions are due to localized accumulation of glycosaminoglycans. The disorder is clinically evident in 30% of patients. Most have mild disease, but 5% have severe disease that threatens sight. Incidence is higher in women (except for severe disease, for which there is equal sex-incid ence). There is a bimodal age distribution in women, with peak onsets between 40 \200\22344 years and 60 \200\22364 years. In men, a single peak incidence occurs at 65 \200\22369 yea rs. There are two stages in the development of the disease: an active in \202 ammatory (dynami c) stage and a relatively quiescent static stage. 5% of patients with Graves \200\231 ophth almopathy have hypothyroidism and 5% are euthyroid. 75% of patients develop Graves \200\231 disease within a year of devel- oping Graves \200\231 ophthalmopathy. The temporal relationship between the onset of thyroid dysfunction and ophthalmopathy is va riable. In a minority of patients, there is a lag period between the presentation of hypert hyroidism and the appearance of eye \201 ndings. Smoking and hypothyroidism moderately worsen Graves \200\231 ophthalmopa- thy, and current smokers (>20 cigarettes/day) are more likely to develop ophthalmopathy. The endocrinologist should be prepared to identify ocular emergen- cies, such as corneal ul ceration, congestive ophthalmopathy, and optic neuropathy. Clinical features Retraction of eyelids is extremely common in thyroid eye disease. The mar gin of the upper eyelid normally rests about 2 mm below the limbus. Retraction can be suspe cted if the upper eyelid margin is either level with or above the superior limbus, thus all owing the sclera to be visible below the lid. Additionally, the lower lid normally rests at the inferior limbus, and retraction can be suspected when the sclera is visible above the lower eyelid. Proptosis or exopthalmos can result in failure of lid closure, thereby increasing the likel ihood of exposure keratitis and a gritty eye sensation. 04-Draznin-Chap04.indd 39 3/31/2011 2:35:17 PM CHAPTER 4 Graves \200\231 ophthalmopathy 40 Damage to the eye can be con \201 rmed with a \202 uorescein or rose Bengal stain. Fundoscopy should be performed to rule out papilledema. Proptosis may result in periorbital edema and chemosis because the displaced orbit results in less ef \201 cient orbital drai nage. Persistent visual blurring may indicate an optic neuropathy requiring urgent treatment. Sev ere conjunctival pain may indicate corneal ulceration requiring urgent referral. Features are unilateral in approximately 15% of cases. Investigation of proptosis The NOSPECS classi \201 cation is not universally accepted; for detailed classi- \201 cation see (cid:2) www.EUGOGO.org and The European Group on Graves \200\231 Orbitopathy. 1 Documentation using a Hertel exophthalmometer The feet of the apparatus are placed against the lateral orbital margin as de \201 ned by the zygomatic bones. The distance between the lateral angle of the bony orbit and an imaginary line tangent to the most anterior aspect of the cornea is recorded. A normal result is considered <20 mm (<18 mm in Asians, <22 in Afro- Carribeans). A reading of 21 mm or more is abnormal, and a difference of 2 mm between the eyes is suspicious. Soft tissue involvement Soft-tissue signs and symptoms include conjunctival hyperemia, chem osis, and foreign-body sensation. CT or MRI scan of the orbit This demonstrates enlargement of the extraocular muscles, which can be useful in cases of diagnostic dif \201 culty. This is also more accurate for dem- onstration of proptosis. Examining for possible ophthalmoplegia Patients may complain of diplopia due to ocular musc le dysfunction caused by either edema during the early active phase or \201 brosis during the later phase. Assessment using a Hess chart may be helpful. Intraoptic pressure may increase on upgaze and result in compression of the globe by a \201 brotic inferior rectus muscle. Ocular mobility may be restricted by edema during the a ctive in \202 ammatory phase or by \201 brosis during the \201 brotic stage. The two most common \201 ndings are defective eye elevation caused by \201 brotic contr action of the inferior rectus muscle, and a convergence defect caused by \201 brotic cont raction of the medial rectus. Disorders of the medial rectus, superior rectus, and lateral rectus muscle produce typi- cal signs of defective adduction, depression, and abduction, re spectively. 1 The European Group on Graves \200\231 Orbitopathy (2006). Clinical assessment of patients with Graves \200\231 orbitopathy: recommendations to generalists, specialists and clinical researchers. Eur J Endocrinol 155(3):387 \200\223389. 04-Draznin-Chap04.indd 40 3/31/2011 2:35:17 PM GRAVES \200\231 OPHTHALMOPATHY 41 Examining for possible optic neuropathy History of poor vision, a recent or rapid change in vision, and poor color vision are reasons for prompt referral. A visual acuity of <6/18 wa rrants referral to an ophthalmologist. For color vision, each eye should be evaluated using a simple 15-plate Ishihara color visio n test. Color vision is a subtle indicator of optic nerve function. Failure to identify >2 of the plates with either eye is an indication for referral. This is unhelpful in the 8% of men who may be color blind. Marcus Gunn pupil: The \200\234swinging \202 ashlight \200\235 test detects the presence of an afferent pupillary defect. Medical treatment See Box 4.1. Lid retraction Most patients do not require any treatment, as clinical signs usually improv e with treatment of hyperthyroidism or spontaneously with time (40%). \200 Sunglasses hel p with photophobia and excess tears. \200 In patients with signi \201 cant lid retractio n and exposure keratopathy, topical lubricants improve symptoms (surgery to reduce the vertical lid \201 ssures can b e considered). Botulinum toxin injection may reduce upper lid retraction. \200 Head elevation during sle ep and diuretics may help congestion. \200 Tape eyelids at night to avoid corneal damage Active ophthalmopathy threatening sight \200 Glucocorticoids at high doses (e.g., prednis one 60 \200\22380 mg/day) improve ophthalmopathy in 60 \200\22375% of cases. Effectiveness of glucocorticoids is more likely in those with diplopia at neutral gaze and an in \202 ammatory component to ophthalmoplegia. \200 Treatment should be given for 2 w eeks and then tapered gradually. \200 Urgent referral to an ophthalmologist is indicated for any suspicion of optic neuropathy or corneal ulceration. Orbital radiotherapy \200 Indications for lens-sparing orbital radiotherapy are similar t o those for high-dose glucocorticoids. Radiotherapy probably works by reducing the activity and number of activated T lymphocytes in the retrobulbar tissues. 20 Gray administered in 10 doses of 2 Gray over 2 weeks \200 Treatment with both radiothe rapy and glucocorticoids is more effective than either alone. Effectiveness in 60% of patients <40 years of age Other medical therapies \200 Other immunosuppressive regimens have no proven place in the general management of Graves \200\231 ophthalmopathy. Use of depot octreotide has been shown to be of no bene \201 t in management. 04-Draznin-Chap04.indd 41 3/31/2011 2:35:17 PM CHAPTER 4 Graves \200\231 ophthalmopathy 42 Box 4.1 Treatment of Graves \200\231 ophthalmopathy General measures \200 Smoking cessation \200 Dark glasses, with eye protection \200 C ontrol of thyroid function Speci \201 c measures Problem Grittiness Eyelid retraction Treatment Arti \201 cial tears and simple eye ointment Tape eyelids at night to avoid corneal damage. Surgery if risk of exposure keratopathy Head elevation during sleep Diuretics Systemic ster oids Radiotherapy Orbital decompression Systemic steroids Radiotherapy Orbital decompressio n Prisms in lenses in the acute phase Orbital decompression Orbital muscle surgery Proptosis Optic neuropathy Ophthalmoplegia Surgical treatment See Box 4.1. Surgery for decompression \200 Orbital decompression may be indicated for urgent treatmen t of optic neuropathy. Posteromedial wall of orbit is usually removed. \200 Complications include dysmotility of the eye, blindness, orbital cellulitis, cerebrospinal \202 uid (CSF) leak, cerebral hema toma, obstruction to nasolacrimal \202 ow, and anosmia. Surgery for strabismus \200 Should be performed after any necessary orbital decompression \200 Aims are to allow correct binocular vision \200 Performed when eyes are in a quie scent phase for at least 6 months after active disease Involves alteration, loosening or tightening of eye muscles, often over several operations, to improve binocular vision. Eyelid surgery This is the \201 nal stage of any surgical approach. The aims are to adjus t the upper and lower eyelid position to improve comfort and appearance. 04-Draznin-Chap04.indd 42 3/31/2011 2:35:17 PM THYROID ACROPACHY 43 Graves \200\231 dermopathy This is a rare complication of Graves \200\231 thyrotoxicosis (0 .5%). It is usually pretibial in location (99%) and hence called pretibial myxedema. It is associ- ated with ophthalmopathy (97%) and acropachy (18%). Typically, raised, discolored, and indurated lesions are on the front or back of the legs o r on the dorsum of the feet. Occasionally, these have been described in other areas, includ ing the hands and face. Lesions are due to localized accumulation of glycosaminoglycans. It is now recognized that there is a lymphocytic in \201 ltrate. Lesions are char- acteristically asymptomatic, but they can also be pruritic, tender, and dis \201 guring. Treatment This condition is usually not treated. Potent topical \202 uorinated steroids s uch as \202 uocinolone acetonide may be effective (4 \200\2238 weeks) for treatment of lo calized pain and tenderness and occasionally may result in resolution of the visible skin s igns. Surgery may worsen the condition. One-fourth of cases remit completely; 50% are chronic on no therapy. The effect of topical steroids on remission rates is unclear. Thyroid acropachy This is the rarest manifestation of Graves \200\231 disease. It presents as painless clubbing of the digits and subperiosteal new bone formation. The soft- tissue s welling is similar to that seen in localized myxedema and consists of glycosaminoglycan acc umulation. 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)