Management of Hyperthyroidism

• TNG:
  • Generally causes milder symptoms than Graves’ disease
• In the absence of contraindications:
  • Beta-blockers may be used for symptomatic relief:
    • While awaiting results of definitive treatment
  • Beta-blockers may also be appropriate for patients with:
    • Atrial fibrillation and rapid ventricular response
  • Propranolol has been widely used to block T4 to T3 conversion:
    • A theoretic benefit
  • A selective beta-blocker:
    • Such as atenolol:
      • May be used in patients who cannot tolerate propranolol
  • If beta-blockers are contraindicated:
    • A calcium channel blocker may be useful
• Definitive Treatment:
  • Toxic Nodular Goiter:
    • RAI therapy (with ¹³¹I) and surgery:
      • Are effective options for the definitive treatment for TNG
    • The long-term use of thionamide antithyroid drugs (ATDs):
      • Is not favored:
        • Unless either ¹³¹I therapy or surgery is contraindicated
    • Thionamides, however, may be used before surgery:
      • Especially in older patients:
        • Until euthyroidism is restored
    • Radioactive iodine:
      • The clinical utility of RAI therapy in the management of TNG:
        • Is well established
      • If radioactive iodine uptake (RAIU) is adequate and the patient is not a good surgical candidate:
        • RAI is the treatment of choice 
      • Although the dose of ¹³¹I may be calculated on the basis of uptake determinations and gland weight:
        • TNGs are relatively resistant to ¹³¹I:
          • Because of their larger size and relatively lower uptake of iodine:
            • For these reasons, some clinicians increase the standard dose:
              • By 20% to 50%
      • Frequently, RAI doses between:
        • 15 and 50 mCi (555 and 1850 MBq) are administered
      • In a report from Mayo Clinic, Jensen et al:
        • Treated their patients with a mean dose of 37 mCi (1370 MBq) (range, 6.3 to 150 mCi [233 to 5550 MBq]):
          • After 1 year of follow-up:
            • 16% of patients were hypothyroid
      • Danaci et al. treated TNGs with a fixed dose of 16.6 mCi (631 MBq) ¹³¹I and reported:
        • A cumulative relapse rate of:
          • 39% at 5 years
        • Cumulative incidence of hypothyroidism of:
          • 24% at 5 years
      • In a large prospective study involving 130 consecutive patients with TNGs and a mean follow-up of 6 years:
        • 92% of patients were cured after one or two treatments with ¹³¹I
        • Thyroid volume was reduced by a mean of 43%, and adverse effects were few
        • Patients were treated with a median dose of 10 mCi (370 MBq)

• Generally, after RAI most patients are euthyroid within 2 to 4 months:
  • Although sometimes achieving euthyroidism may take longer
• Although most patients treated with RAI achieve long-term euthyroidism:
  • 10% to 24% of these patients eventually become hypothyroid:
    • Regardless of the dose used
  • RAI is associated with a 20% chance of recurrence:
    • In which case patients may receive a second dose of ¹³¹I or opt for thyroidectomy
    • These patients should not be given iodide preoperatively:
      • Because of the risk of exacerbating thyrotoxicosis
• Surgery:
  • Total thyroidectomy:
    • Is recommended for patients with:
      • Large goiters causing obstructive symptoms such as:
        • Choking
        • Dyspnea
        • Dysphagia:
          • Hoarsness
    • For those who refuse RAI therapy
    • Surgery may also be indicated when a suspicious cold or growing nodule is identified in a TNG
    • Surgery is an excellent option for patients who:
      • Decline RAI therapy and also for pregnant women 
  • Two issues with the operation:
    • The extent of thyroidectomy remains somewhat controversial
    • In the past, some clinics have preferred subtotal thyroidectomy to minimize complications such as:
      • Recurrent laryngeal nerve damage and hypoparathyroidism
    • In current practice, most surgeons perform:
      • A total thyroidectomy for bilateral benign nodular goiters:
        • This is what I recommend
    • Also, the trend in recent decades:
      • Suggests that RAI is being increasingly considered as:
        • An attractive, effective alternative to surgery in TNG
      • For example, a study from Mayo Clinic showed that between 1950 and 1974:
        • 83% of patients had surgical treatment
        • 17% had RAI treatment
      • Between 1990 and 1999, the figures were:
        • 53% for surgery and 47% for RAI
• Thionamide antithyroid drugs:
  • Thionamide antithyroid drugs are the preferred transient treatment:
    • During pregnancyuntil delivery
  • They should also be considered for patients who are not candidates for or who decline definitive treatment
  • Treatment is generally indefinite with thionamide ATDs:
    • Generally because permanent remission is never achieved in TNG
• Graves’ Disease:
  • In the management of Graves’ disease:
    • Treatment preferences vary substantially by geographic region
  • This was suggested by the outcome of an international survey of endocrinologists from the United States, Europe, and Japan:
    • Among physicians in the United States:
      • Thionamide ATDs were selected as the primary form of therapy for a “typical 43-year-old healthy woman” by only approximately 30%, whereas 69% chose RAI treatment and 1% opted for surgery
    • By contrast, 77% of European physicians and 88% of Japanese physicians selected thionamide ATDs as the preferred primary treatment, with RAI therapy as the second choice.
  • Thionamide antithyroid drugs:
    • Thionamide ATDs inhibit biosynthesis of thyroid hormones:
      • Biochemical euthyroidism is usually achieved within 6 to 8 weeks after initiation of therapy
    • Currently, three thionamide ATDs are available: 
      • Methimazole
        • Available in the United States
        • Half-life of methimazole in plasma is:
          • 3 to 5 hours
      • Propylthiouracil 
        • Available in the United States
        • Half-life of  in plasma of propylthiouracil is 1 to 2 hours
      • Carbimazole:
        • Which is metabolized to methimazole:
          • Is sometimes used in Europe and Asia
    • Methimazole has a longer duration of action:
      • Although both drugs are effective for more than 5 hours because they accumulate in thyroid cells
    • Initial daily doses range from:
      • 10 mg to 40 mg of methimazole usually once daily
      • 100 to 150 mg of propylthiouracil every 6 to 8 hours daily
      • 15 to 45 mg daily of carbimazole usually in one dose up to three divided doses
    • The decision to use methimazole / carbimazole or propylthiouracil:
      • Is a matter of physician preference:
        • Because both agents are equally effective
      • However, observations over several decadeshave shown that methimazole and its prodrug carbimazole are better than propylthiouracil in controlling more severe hyperthyroidism;
        • But propylthiouracil should not be routinely used because of potential fatal hepatotoxicity
    • This has led to the recommendation that methimazole / carbimazole:
      • Be the first-line drug when ATD therapy is initiated:
        • Either for primary treatment or to prepare a patient for RAI therapy or surgery
      • An exception to this rule has been pregnancy:
        • During which propylthiouracil has been preferred:
          • Because of rare reports of birth defects associated with methimazole
        • Propylthiouracil has also been used in patients with:
          • Minor reactions to methimazole but who, nonetheless, prefer to continue ATD therapy 
        • Propylthiouracil may also be preferable in patients with:
          • Life-threatening thyrotoxicosis:
            • Because of its additional inhibition of T4 to T3 conversion
    • It is crucial to evaluate patients clinically and biochemically (with serum T4 and TSH measurements) regularly:
      • From 6 to 8 weeks after the initiation of ATD treatment:
        • Until the patient is biochemically euthyroid and every 8 to 12 weeks thereafter
      • Once the patient is euthyroid, the ATD dose may be reduced
    • Some clinicians favor adding levothyroxine to the ATD regimen as part of a block-replacement regimen:
      • Without reducing the original ATD dose:
        • To minimize the number of patient visits and maintain a more normal stable TSH:
          • This addition to the regimen causes no difference in the remission outcome compared with titration of ATD alone
        • The concern about compliance and the advantages of ATD alone have ensured that combination treatment (thyroxine and ATD) has not been widely adopted
    • It has been determined from various reports that treatment with thionamide ATDs for 12 to 18 months is optimal:
      • Resulting in long-term remission in 40% to 60% of patients with Graves’ disease:
        • With higher remission rates in women than in men
      • The likelihood of sustained remission:
        • Is greater in patients with:
          • Mild hyperthyroidism
          • Small goiter
          • Low or undetectable TSHR-Ab titers:
            • Than in those with moderate to severe hyperthyroidism or T3 toxicosis, large goiter, and high TSHR-Ab titers
      • If hyperthyroidism recurs:
        • Other modes of therapy (RAI or surgery) are considered
      • Most relapses following cessation of thionamide ATDs;
        • Occur shortly after the ATDs are discontinued:
          • Generally within the first few months:
            • Although they may occur several years later:
              • Therefore, clinical and biochemical evaluation is necessary 2 months after ATD withdrawal and periodically at regular intervals thereafter
    • As with all other drugs, thionamide ATDs may cause adverse effects:
      • As early as 2 weeks after initiation of therapy or later in the course of therapy:
        • It is essential to instruct patients on how to deal with these adverse reactions
    • The most serious and rare complication:
      • Agranulocytosis:
        • Should be ruled out:
          • By obtaining white blood cell and differential counts:
            • If fever and signs of infection such as sore throat occur while the patient is on thionamide ATD therapy

Adverse Effect	Propylthiouracil (100 to 150 mg/day)	Methimazole (10 to 40 mg/day)
Minor reactions
—Fever, rash, arthralgia	5% to 20%	5% to 20% (dose related)
Major reactions
—Agranulocytosis	0.2%-0.5% (not clearly dose related)	0.2%-0.5% (dose related)
—Hepatotoxicity (hepatitis)	30% (< 1% severe)	Cholestatic (usually reversible, with few deaths reported)
—Vasculitis	ANCA +	Rare
ANCA, antineutrophil cytoplasmic antibody

• Inorganic Iodine:
  • Iodine given in pharmacologic doses (as Lugol solution or as a saturated solution of potassium iodide):
    • Inhibits the release of thyroid hormones for a few days or weeks:
      • After which its antithyroid action is lost
    • For this reason it is not used routinely:
      • But short-term iodine therapy is useful in:
        • The preparation of patients for surgery
        • After RAI therapy to hasten the fall in serum T3 and T4 concentrations to normal:
          • Although this is not a routine indication
      • In the treatment of thyrotoxic crisis
    • The usual dose of Lugol solution (5% iodine and 10% potassium iodide in water) is:
      • 0.1 to 0.3 mL three times daily
    • The usual dose of potassium iodide is:
      • 60 mg (1 drop) three times daily
• Radioactive iodine therapy:
  • In use for more than 60 years:
    • RAI therapy is established as an effective, relatively inexpensive, and safe treatment option for Graves’ disease
  • The objective of RAI therapy is to:
    • Destroy sufficient thyroid tissue to cure hyperthyroidism
  • The goal of treatment is to:
    • Render the patient either euthyroid or hypothyroid:
      • Depending on the willingness of the physician to risk the possibility of persistent hyperthyroidism
  • Much attention has focused on achieving euthyroidism:
    • By adjusting the RAI dose:
      • But there is little consensus regarding the most appropriate dose schedule
  • The regimens used include the traditional method of:
    • Repeated low doses (2 mCi)
    • Fixed doses
    • Doses calculated on the basis of:
      • The size of the thyroid
      • The RAIU
      • The turnover of ¹³¹I
  • Because it has proved impossible to titrate doses for individual patients accurately to guarantee a euthyroid state:
    • The majority of physicians in the United States:
      • Prefer to administer a single, relatively large dose:
        • 10 to 20 mCi initially with the intent of:
          • Inducing thyroid ablation and the development of hypothyroidism
      • Thyroid function is then assessed 6 to 8 weeks after RAI administration and possibly every month thereafter:
        • To monitor the development of hypothyroidism:
          • Especially during the first 6 months after RAI treatment
      • When hypothyroidism is detected by TSH elevations:
        • Levothyroxine treatment should be initiated:
          • To maintain the TSH level in the normal range (0.5 to 3 mIU/L)
      • However, if hyperthyroidism persists:
        • Another RAI dose may be delivered:
          • But should not be given until at least 6 months after the first dose
  • Before RAI treatment is started:
    • Patients should be informed of the precautions needed after RAI
    • Rarely patients may experience:
      • Mild anterior neck pain after RAI
      • A short-lived exacerbation of hyperthyroid symptoms:
        • Caused by the leakage of preformed thyroid hormones from a damaged thyroid gland
      • Worsening of Graves’ ophthalmopathy:
        • Especially among smokers:
          • May be observed after ¹³¹I treatment
        • Risk is reduced by:
          • Cessation of smoking and the administration of glucocorticoids, namely, prednisone:
            • Different regimens are available, but most agree on the regimen of oral prednisone:
              • Administration 1 to 3 days after RAI treatment at 0.3 to 0.5 mg/kg daily, and the dose is tapered until withdrawal about 3 months later
  • Whether to pretreat patients with thionamide ATDs:
    • Until they are euthyroid before ¹³¹I administration is a matter of debate:
      • Retrospective studies have shown that the efficacy of treatment with ¹³¹I:
        • Is decreased after propylthiouracil:
          • It is best to discontinue ATDs a few days before RAI is given
    • Previously RAI was reserved for adults because of the lack of long-term data in children and adolescents:
      • More recently, in properly administered doses, data have shown that RAI is the ideal form of therapy for Graves’ disease in children
    • It remains absolutely contraindicated:
      • During pregnancy and lactation
• Surgery:
  • Because of the higher relapse rates seen with subtotal thyroidectomy, or near-total thyroidectomy:
    • Total thyroidectomy:
      • Is the recommended surgical procedure for the treatment of Graves’ hyperthyroidism
  • It usually results in postoperative hypothyroidism:
    • Requiring lifelong levothyroxine replacement
  • Thyroidectomy is preferred in patients with:
    • Large goiters:
      • Especially those with tracheoesophageal compression symptoms)
    • Coincidental suspicious thyroid nodules
    • Contraindications to ¹³¹I or ATDs
    • In those who refuse RAI treatment or are pregnant when hyperthyroidism is difficult to control
  • Surgical morbidity, including:
    • Permanent hypoparathyroidism
    • Vocal cord dysfunction caused by recurrent laryngeal nerve injury,
    • Infection
    • Hematoma
      • Is low in experienced centers
  • Any patient with hyperthyroidism scheduled to undergo surgery:
    • Should be treated with thionamide ATDs:
      • To restore euthyroidism
  • Alternative methods of preoperative therapy include:
    • Thionamide ATDs combined with beta-blockers:
      • Propranolol:
        • 40 to 80 mg three times a day or
      • A longer-acting beta-adrenergic antagonist:
        • Atenolol, 50 mg/day
    • Potassium iodide:
      • 40 mg three times a day for 10 days
    • Potassium iodide (several drops per day for 10 days) in combination with propranolol (40 to 120 mg per day):
      • May be another alternative:
        • Any of these regimens virtually eliminates the risk of postoperative thyrotoxic crisis
  • Indefinite follow-up is essential after thyroidectomy:
    • With an adequate replacement dose of levothyroxine that maintains TSH within the range of normal
• Pregnancy:
  • Appropriate management of hyperthyroidism during pregnancy is important for the mother’s health and for the course of the pregnancy
  • Moreover, the quality of management may have considerable impact on the progeny:
    • Both in fetal and in neonatal life and on the long-term health of the child
  • The most common form of hyperthyroidism during pregnancy:
    • Is mostly the result of Graves’ disease:
      • Its adequate control is essential
  • Pregnant hyperthyroid women should be treated with:
    • Thionamide ATDs:
      • Most clinicians prefer propylthiouracil:
        • Although both propylthiouracil and methimazole:
          • Are shown to cross the placenta equally
      • As noted previously, rare reports of birth defects associated with methimazole exist
      • The minimum dose of ATD that keeps maternal thyroid function around or slightly above the upper limit of normal should be used:
        • To avoid fetal hypothyroidism and fetal goiter:
          • Therefore, frequent monitoring of the mother and the fetus is necessary
      • Mothers may experience:
        • Exacerbation of thyrotoxicosis after delivery
      • Newborns may have:
        • Transient thyroid dysfunction when exposed to ATDs or may develop transient neonatal hyperthyroidism resulting from the passage of TSHR antibodies through the placenta
  • Postpartum propylthiouracil:
    • Is also preferred for nursing mothers:
      • Because less drug appears in breast milk than with methimazole
  • Surgical thyroidectomy:
    • In the second trimester of a pregnant woman with Graves’ disease:
      • Is performed only in the case of uncontrollable hyperthyroidism:
        • That threatens the health of the woman or when ATDs are not tolerated
    • If thyroidectomy is performed, this should be followed by a systematic and a careful follow-up evaluation of the thyroid state of the fetus

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