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. Aims and principles of medical treatment \200 To induce remission in Graves \200\231 dise ase \200 Monitor for relapse off treatment initially every 6 \200\2238 weeks for 6 months, then every 6 months for 2 years, and then annually thereafter or sooner if symptoms return. For patients who relapse, consider de \201 nitive treatment such as radioiodine or surgery. A second course of ATD rarely results in remission. Choice of drugs \200\224thionamides Methimazole has a longer duration of action and can be given as a single dose. Carbimazole, the drug of choice in the UK, is converted to methima- zole by cleavage of a carboxyl side chain on \201 rst liver passage. Methimazole and pro pylthiouracil are used widely in the United States and elsewhere in the world. Propylthiour acil is limited by tid dosing. During pregnancy and lactation propylthiouracil (PTU) is the drug of choice given the assoc iation between PTU and fatal hepatotoxicity, PTU may be the drug of choice during the \201 rst trimester, however this remains an area of controversy. Methimazole is often recom mended for second and third trimester although does have associated risks, such as aplasia cutis. Action of thionamides Thyroid hormone synthesis is inhibited by blockade of the action of t hy- roid peroxidase. Thionomides are especially actively accumulated in thy- rotoxic tissue . Propylthiouracil also inhibits extrathyroidal conversion of T 4 to T 3 by type 1 deiodinase , and thus may have advantages when given at high doses in severe thyrotoxicosis. Dose and effectiveness A does of 5 mg of carbimazole is roughly equivalent to 50 mg of pro- pylthiouracil. Carbimazole dosing is 740% higher than methimazole. Propylthiouracil has a theoretical advantage of inhibiting the conversion of T 4 to T 3 , and T 3 levels decline m ore rapidly after starting the drug. According to the ATA, initial daily doses of methimazole range from 10 \200\22340 mg daily and for PTU 100 \200\223600 mg daily. Most ATDs as primary therapy are given for 6 months to 2 years, as there is no established standard for duration of therapy with ATDs. From 30 to 40% of patients treated with an ATD remain euthyroid 10 years after discontinuat ion of therapy. If hyperthyroidism recurs after treatment with an ATD, there is little chan ce that a second course of treatment will result in permanent remission. Young patients, sm okers, 03-Draznin-Chap03.indd 21 4/1/2011 5:27:35 PM CHAPTER 3 Thyrotoxicosis 22 and those with large goiters, ophthalmopathy, or high serum concentra- tions of thyrotropin receptor antibody at the time of diagnosis are unlikely to have a permanent remission. B-A drenergic antagonists Propranolol 10 \200\22340 mg up to four times daily or longer-acting B-blockers can be used to control symptoms such as anxiety, tremor, and palpita- tions. Rel ief may be appreciated in the initial 4 \200\2238 weeks of treatment. Atrial \201 brillation (AF) AF should convert to sinus rhythm \200\224otherwise, cardiove rt after 4 months euthyroid. Side effects ATDs are generally well tolerated. Uncommonly, patients may complain of gastro intestinal (GI) symptoms or changes in sense of taste and smell. Agranulocytosis represents a potentially fatal but rare side effect of ATD occurring in 0.1 \200\2230.5% of patients. Because cross-reactivity between ATDs has been reported, and may be idiosyncratic and dose dependent, it is not recommended to switch from one ATD if agranulocytosis has developed t o another. It is controversial whether agranulocytosis is more frequent with methimazole or propylthiouracil. Agranulocytosis usually occurs within the \201 rst 3 months after initiation of therapy ( 97% within the \201 rst 6 months, especially on higher doses). Although rare, it is impor tant to be aware of the documented cases, which have occurred a long time after starting tr eatment. As agranulocytosis occurs very suddenly and is potentially fatal, routine monitoring of com plete blood count (CBC) is thought to be of little use. Patients typically present with fev er and evidence of infection, usually in the oropharynx, and each patient should therefore receive written instruc- tions to discontinue antithyroid drug therapy and contact their do ctor for a CBC should a severe sore throat and fever arise. Neutrophil dyscrasias occur more frequently in males; however these are more often fatal in the elderly. Allergic-type reactions are more common in the form of rash, urticaria, and arthralgia, whi ch occur in 1 \200\2235% of patients taking these drugs. These side effects are often mild and do not usually necessitate drug withdrawal, although one ATD may be substituted for ano ther in the expectation that the second agent may be taken without side effects. Thionamides may cause cholestatic jaundice; elevated serum ami- notransaminases and fulmina nt hepatic failure have also been reported. However, hepatic necrosis due to PTU and choles tatic jaundice due to methimazole is rare enough that routine liver function tests monitori ng is unnecessary, according to the American Thyroid Association. 1 All patients should be given written and verbal warnings about the potential side effects of thionamides. Rarely, antineutrophil cytoplasmic antibody (ANCA)-positive vascu- litis develops with prop ylthiouracil therapy, manifesting as arthralgias, 1 Singer PA, Cooper DS, Levy EG, et al. (1995). Treatment guidelines for patients with hype rthy- roidism and hypothyroidism. JAMA 273:808 \200\223812. 03-Draznin-Chap03.indd 22 4/1/2011 5:27:36 PM TREATMENT 23 skin lesions, glomerulonephritis, fever, and/or alveolar hemorrhage. Skin lesions include u lcers. Biopsy reveals vasculitis. Treatment is discontinu- ation of propylthiouracil and in itiation of steroids if needed. Treatment regimen Two alternative regimens are practiced for Graves \200\231 disease: dose titration and block and replace. Dose titration regime The primary aim is to achieve a euthyroid state with relatively high drug doses and then to maintain euthyroidism with a low stable dose. The dose of methimazole or propylthiouracil is titrated according to the thyroid function t ests performed every 4 \200\2238 weeks, aiming for a serum free T 4 in the normal range and a detectable TSH. High serum TSH indicates the need for a dose reduction. TSH may remain s uppressed for weeks or months. The typical starting dose of methimazole is 10 \200\22320 mg/day. Higher initial doses (40 mg) may be indicated in severe hyperthyroidism. When the plasma FT 4 level returns to normal, the dose should be adjusted to maintain norma l FT 4 levels. No consensus exists on the optimal duration of therapy, although 12 months t o 24 months is most common. Relapses are most likely to occur within the \201 rst year an d may be more likely in the presence of a large goiter and high T 4 level at the time of di agnosis, or the presence of TSH-receptor antibodies at the end of treat- ment ( b see p. 33 .) Patients with multinodular goiters and thyrotoxicosis frequently relapse on cessation of an tithyroid medication, and de \201 nitive treatment with radioiodine or surgery is usually advised. Long-term low-dose thionamide therapy is also an option. Block and replace regimen After achieving an euthyroid state on methimazole or PTU alone, T 4 at a dose of 100 mcg can be prescribed. The patient can be continued on the combination of antithyroid drug and T 4 for an additional 12 \200\22324 months. If the size of the glan d returns to normal or the former time period is reached, the drugs are discontinued. The m ain advantages of this regimen are fewer hos- pital visits for checks of thyroid function a nd shorter duration of treatment. Most patients achieve an euthyroid state within 4 \200 \2236 weeks of carbima- zole therapy. During treatment, FT 4 values are measured 4 weeks after starting thy- roxine and the dose of thyroxine is altered, if necessary, in 25 mcg incre- ments to maintain FT 4 in the norma l range. Most patients do not require any dose adjustment. The originally reported higher remission rate was not con \201 rmed in a large, prospectiv e, multicenter European trial when combination treat- ment was compared to carbimazole alon e, but side effects were more common. 2 Relapses are most likely to occur within the \201 rst year. 2 Reinwein D, Benker G, Lazarus JH, et al. (1993). A prospective randomized trial of antith yroid drug dose in Graves \200\231 disease therapy. European Multicenter Study Group on Ant ithyroid Drug Treatment. J Clin Endocrinol Metab 76:1516 \200\2231521. 03-Draznin-Chap03.indd 23 4/1/2011 5:27:36 PM CHAPTER 3 Thyrotoxicosis 24 Table 3.2 Recommended activity of radioiodine Etiology Comments \200 First presentation; no signi \201 cant eye disease \200 Moderate goiter (40 \200\22350 g) Mild heart failure; atrial \201 brillation or other concomitant disease , e.g., cancer Guide dose (MBq) 8 \200\22316 mCi (400 \200\223600 MBq) Graves \200\231 disease Toxic multinodular goiter in older person 13.5 \200\22321.6 mCi (500 \200\223800 MBq) Toxic adenoma Usually mild hyperthyroidism 13.5 mCi (500 MBq) Postpone radioiodine until Severe Graves \200\231 disease with thyroid eye disease 13.5 \200\22321.6 mCi (500 \200\223800 MBq) eye disease is stable. Prednisone 40 mg daily to be administered at same time as radioiodine and for further 4 \200\2236 weeks (see below) \200 Severe accompanying medical condition such as heart fail ure, atrial \201 brillation, or other concurrent medical disorders (e.g., psy-chosis) 13.5 \200\22321.6 mCi (500 \200\223800 MBq) Ablation therapy Reprinted with permission from Weetman AP (2007), Radioiodine treatment for benign thyroid diseases. Clin Endocrinol 66(6):757 \200\223764. Radioiodine treatment \200\224radioiodine therapy b See Table 3.2. Indications \200 De \201 nitive treatment of multinodular goiter or adenoma \200 Relapsed Graves \200\231 dis ease Contraindications \200 Young children, because of the potential risk of thyroid carcinoge nesis \200 Pregnant and lactating women \200 Situations where it is clear that the safe ty of other people cannot be guaranteed Graves \200\231 ophthalmopathy There is some evidence that Graves \200\231 ophthalmopathy m ay worsen after the administration of radioactive iodine, especially in smokers. In cases o f moderate to severe ophthalmopathy, radioiodine may be avoided. Alternatively, steroid cover in a dose of 40 mg prednisone daily should be given on the day of administering radioiodine, with taper over the next 1 \200\2232 months following radioi odine treatment. It is essential that euthy- roidism be closely maintained following radioi odine to avoid worsening of ophthalmopathy. 03-Draznin-Chap03.indd 24 4/1/2011 5:27:36 PM TREATMENT 25 Caveats \200 The control of disease may not occur for a period of weeks or a few months. More than one treatment may be needed in some patients, depending on the dose given; 15% re quire a second dose and a few patients require a third dose. The second dose should only be considered at least 6 months after the \201 rst dose. Compounds that contain iodine, such as amiodarone, block iodine uptake for a period of several months following cessation of therapy. Iodine uptake measure ments may be helpful in this instance in determining the activity required and the timing o f radioiodine therapy. \200 Women of childbearing age should avoid pregnancy for a minimu m of 6 months following radioactive iodine ablation. The prevalence of hypothyroidism is about 50% at 10 years and continues to increase thereafter. Side effects are rare \200 Anterior neck pain caused by radiation-induced thyroiditis \200 Transient rise (72 hours) in plasma T 4 may occur within the \201 rst 2 weeks after therapy, which may exacerbate heart failure if present. Hypothyroidism after radioiodine After radioiodine administration, ATDs may be restarted. T he ATDs should be withdrawn gradually, guided by TFTs every 6 \200\2238 weeks. Early post-r adioiodine hypothyroidism may be transient. TSH should be moni- tored initially, then annua lly after radioiodine therapy to determine late- onset hypothyroidism. In patients treated for autonomous toxic nodules, the incidence of hypothyroidism is lower since the toxic nodule takes up the radioac- tive iodine; the surrounding tissue will recov er normal function once the hyperthyroidism is controlled, though this is disputed by some experts. Cancer risk after radioiodine therapy In a recent large series, no overall excess risk of c ancer was found. It is unclear whether the risk of death from thyroid cancer is slightly hi gher. Clinical guidelines The goal is to administer enough radioiodine to achieve euthyroidism wi th the acceptance of a moderate rate of hypothyroidism, e.g., 15 \200\22320% at 2 years. Instructions to patients before treatment Discontinue ATDs 2 \200\2237 days before radioiod ine administration, since their effects last for 24 hours or more, though PTU has a prolong ed radiopro- tective effect. ATDs may be restarted 3 \200\2237 days after radioiodine admin is- tration without signi \201 cantly affecting the delivered radiation dose. Administration of radioiodine (Table 3.2) \200 Radioactive iodine-131 is administered ora lly as a capsule or a drink. \200 No universal agreement exists regarding optimal dose. D osing according to size alone is not successful in 90% of cases. 03-Draznin-Chap03.indd 25 4/1/2011 5:27:36 PM CHAPTER 3 Thyrotoxicosis 26 A dose of 10 \200\22321.6 mCi (400 \200\223800 MBq) should be suf \201 cient to cure hyperthyroidism in 90%. Most patients are treated with 10 \200\22316 mCi (400 \200\223600 MBq) as the \201 rst dose. It is contraindicated in women who are pregnant and/or breast- feeding. For precaution, b see Table 3.3. Outcomes of radioiodine treatment In general, 50 \200\22370% of patients have restored norm al thyroid function within 6 \200\2238 weeks of receiving radioiodine. Shrinkage of goiter occurs but is slower. Surgery Thyroidectomy is rarely recommended for patients with Graves \200\231 disease. Indi cations for subtotal or total thyroidectomy include patients with very large, multinodular goiters causing obstruction of the airway, or those who cannot tolerate or are noncompliant with antithyroid drugs. Pregnant women with severe Graves \200\231 disease allergic to ant ithyroid therapy may be advised to undergo surgery. There is disagreement regarding which operation to perform. Often patients require LT4 following thyroidectomy. See Box 3.2. Indications \200 Documented suspicious or malignant thyroid nodule by FNAC \200 Pregnan t mothers who are not adequately controlled by ATDs or in whom serious allergic reactions develop while being treated medically. Thyroidectomy is usu ally performed in the second trimester. Thyroidectomy is also indicated in the following patients: \200 Those who reject or fear exposure to radiation \200 Those with poor compliance to medical treatment \200 Those i n whom a rapid control of symptoms is desired Box 3.2 Complications of thyroidectomy Immediate \200 Recurrent laryngeal nerve damage \200 Hypoparathyroidism \200 Thyroid crisis \200 Local hemorrhage, causing laryngeal edema \200 Wound infection Late \200 Hypothyroidism \200 Keloid formation 1 Royal College of Physicians of London Working Group (2007). Radioiodine in the management of benign thyroid disease. London: Royal College of Physicians of London[JH2]. 03-Draznin-Chap03.indd 26 4/1/2011 5:27:36 PM TREATMENT 27 Those with severe manifestations of Graves \200\231 ophthalmopathy, since total and subtotal thyroidectomy does not worsen eye manifestations Those with relapsed Graves \200\231 disease \200 Those with local compressive symptoms th at may not improve rapidly with radioiodine. Operation removes these symptoms in most patients. Those with large thyroid glands and relatively low radioiodine uptake Preparation of patien ts for surgery ATDs should be used preoperatively to achieve euthyroidism (approxi- mately 6 weeks). B-blockers can be added as preparation for surgery, especially in those patients where surg ery must be performed sooner than achieving euthy- roid state. Potassium iodide, 5 drops twice daily, can be used during the preop- erative period (for 7 \200\22310 days) to reduce the vascularity of the gland. Operating later than this can be a ssociated with exacerbation of thyro- toxicosis as the thyroid escapes from the inhibitory effect of the iodide. In practice, it is rarely needed, as good control of thyrotoxicosis c an be achieved with ATDs in the majority of patients. In patients who are noncompliant with ATDs and thyrotoxic prior to surgery, hospital inpati ent admission may be necessary for supervised administration of high-dose ATDs, together wi th B-blockade, and meas- urement of FT 4 and FT 3 twice weekly. There is a risk of thyroid crisis, or storm, if a patient undergoes operation when thyrotoxic. Most patients can be rendered euthyroid within 2 \200\2234 weeks and potas- sium iodide can be administered as above to coincide with the timing of surgery. Additional measures are as for thyroid storm. 03-Draznin-Chap03.indd 27 4/1/2011 5:27:36 PM CHAPTER 3 Thyrotoxicosis 28 Thyroid crisis (storm) Thyroid crisis represents a rare but life-threatening exacerbation o f the manifestations of thyrotoxicosis. It should be promptly recognized since the conditio n is associated with a signi \201 cant mortality; see Box 3.3. Thyroid crisis develops in uncontrolled hyperthyroid patients who \200 Have a complicating acute infection. \200 U ndergo thyroidal or non-thyroidal surgery or (rarely) radioiodine treatment. Thyroid crisis should be considered in a very sick patient if there is \200 Recent histor y suggestive of thyrotoxicosis. \200 Acute stressful precipitating factor such as surgery . \200 History of previous thyroid treatment. Laboratory investigations \200 Routine hematology may indicate a leukocytosis, which is w ell recognized in thyrotoxicosis even in the absence of infection. The biochemical screen may reveal a raised alkaline phosphatase and mild hypercalcaemia. Thyroid function tests and thyroid antibodies should be requested, although treatment should not be delayed while awaiting the results. \200 Thyroid hormone levels will be raised but may not be grossly elevated and are usually within the range of uncomplicated thyrotoxicosis. Treatment General supportive therapy The patient is best managed in an intensive care unit where close attention can be paid to cardiorespiratory status, \202 uid balance, and cool ing. Standard antiarrhythmic drugs may need to be used, including digoxin (usually in higher than normal dose) after correction for hypokalemia. Broad-spectrum antib iotics should be given if infection is suspected. Speci \201 c treatment The aim is to inhibit thyroid hormone synthesis completely. \200 Antithyroid drugs in large doses (propylthiouracil or methimazole) i.e., PTU 200 \200\22330 0 mg every 6 hours via nasogastric (NG) tube if necessary. Propylthiouracil is preferred be cause of its ability to block T 4 -to-T 3 conversion in peripheral tissues. Alternatively, methimaole 60 mg every 24 hours can be given. ATDs should be started \201 rst and quickly . Box 3.3 Clinical signs suggestive of a thyroid storm \200 Alteration in mental status \200 High fever \200 Tachycardia or tachyarrhythmias \200 Severe clinical signs of hyp erthyroidism \200 Vomiting, jaundice, and diarrhea \200 Multisystem decompensation: car diac failure, respiratory distress, congestive hepatomegaly, dehydration, and renal failure 03-Draznin-Chap03.indd 28 4/1/2011 5:27:36 PM THYROID CRISIS (STORM) 29 Potassium iodide 10 drops, twice daily, after starting antithyroid drugs, will inhibit thyroid hormone release. B-Adrenergic blocking agents are essential in management to control tachycardia, tremor, and other adrenergic manifestations. \200 Propranolol 160 \200\22348 0 mg/day in divided doses or as an infusion at a rate of 2 \200\2235 mg/h. Calcium channel blockers can be tried in patients with known bronchospastic disease or severe heart failure when B-blockade is contraindicated. High doses of glucocorticoids are capable of blocking T 4 -to-T 3 conversion: prednisone 60 mg daily or hydrocortisone 50 mg IV every 6 hours. Plasmapheresis and peritoneal dialysis may be effective in cases resistant to the usual pharmacological measures in order to remove high levels of circulati ng thyroid hormones. Colestyramine (3 g tid) reduces the enterohepatic circulation of thyroid hormones and may help improve thyrotoxicosis. Subclinical hyperthyroidism Values of thyroid hormones should be repeated to exclude nonthy roidal illness. Subclinical hyperthyroidism is de \201 ned as undetectable thyrotropin (TSH) concentration in patients with normal levels of T 4 and T 3 . Subtle symptoms and signs of thyrotoxicosi s may be present. It may be classi \201 ed as endogenous in patients with thyroid hormone production associa ted with nodular thyroid disease or underlying Graves \200\231 disease, and as exogenous in those with undetectable serum thyrotropin concentrations as a result of treatment with lev othyroxine. Subclinical hyperthyroidism is a risk factor for development of atrial \201 brillation or osteoporosis. 1 The increased risk of fracture reported in older women taking thyroid hormone disappears wh en those with a history of hyperthyroidism are excluded. In many patients with endogeneous subclinical hyperthyroidism who do not have nodular thyro id disease or complications of excess thyroid hormone, treatment is unnecessary, but TFTs s hould be performed every 6 months. In older patients with atrial \201 brillation or osteoporosis that could have been caused or exacerbated by mild excess of thyroid hormone, ablative therapy with 131 I is the best initial option. In patients with exogeneous subclinical hyperthyroidism, the dose of levothyroxine should b e reduced, excluding those with prior thyroid can- cer in whom thyrotropin suppression may be required. The dose of lev- othyroxine used for treating hypothyroidism may also be reduc ed if the patient develops the following: 1 Parle JV, Maisonneuve P, Sheppard MC, et al. (2001). Prediction of all-cause and cardiova scular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 358(9285):861 \200\223865. 03-Draznin-Chap03.indd 29 4/1/2011 5:27:36 PM CHAPTER 3 Thyrotoxicosis 30 New-onset atrial \201 brillation, angina, or cardiac failure \200 Accelerated bone loss \200 Borderline high serum T 3 concentration Thyrotoxic periodic paralysis (TPP) TTP is more common in Asians (5 \200\22310% of all with thyrotoxicosis due to Graves \200\231 disease or multinodular goiter) (0.1 \200\2230.2% of non-Asian Europeans/ North Americans). The etiology is probably disordered function of ion channels in muscle cell membranes. TPP is the most common form of acquired periodic paralysis. The usual age of onset is 20 \200\22340 years and it occurs mostly in men. There are recurrent episodes of painless muscle weakness lasting min- utes to days. Flaccid paralysis occurs, usually spreading from the legs proxi- mally, with depressed or absent d eep tendon re \202 exes. Clinical manifestations of thyrotoxicosis may be few, thus TSH should be checked in anyone presenting with periodic paralysis The condition improves as thyrotoxicosis is treated. Serum potassium is low during attacks. Creatine phosphokinase (CPK) is i during the recovery phase. 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.