1998/11/01 by Scott A. Rivkees, Charles A. Sklar, Michael Freemark · 3 citations
Medicine · #Thyroid Disorders and Treatments #Thyroid Cancer Diagnosis and Treatment #Restraint-Related Deaths
paper · pdf · doi:10.1210/jcem.83.11.5239
openalex publication_date 1998/11/01 · openalex created_date 2016/06/24 · openalex updated_date 2026/07/31
The most common cause of thyrotoxicosis in children and adults is Graves’ disease, an autoimmune disorder characterized by diffuse goiter, hyperthyroidism and ophthalmopathy (1–4). Thyrotoxicosis can be also seen in children with T4 ingestion and acute or subacute thyroiditis, and occasionally in patients with chronic lymphocytic thyroiditis (4). However, the hyperthyroid state is transient in these conditions, whereas thyrotoxicosis is persistent in Graves’ disease (4). Toxic adenomas and multinodular goiters may also cause long-standing hyperthyroidism in children (4). These conditions, however, are uncommon causes of thyrotoxicosis in children and may be distinguished from Graves’ disease by palpation of the thyroid gland and/or diagnostic imaging (4). In Graves’ disease, the spontaneous development of antibodies (TSAbs) that mimic TSH action leads to the excessive production and release of thyroid hormone, resulting in thyrotoxicosis. Untreated, thyrotoxicosis can have pernicious physical and behavioral effects on growing children and adolescents (1–4) and is commonly associated with weight loss, polyuria and polydipsia, palpitations, impaired skeletal mineralization, behavioral disturbances, and poor academic performance (1–4). Because Graves’ disease is a protracted disorder that only rarely spontaneously resolves (1–4), treatment of hyperthyroidism is essential for the well-being of the child and adolescent. Few subjects raise greater controversy than the treatment of Graves’ disease in children. There is no specific cure for the illness, and potential complications are associated with each therapeutic option. Antithyroid drug therapy with thioamides is associated with side-effects and a high relapse rate even after prolonged therapy (2, 5–8). Thyroidectomy achieves high rates of remission, yet is a complex surgical procedure that can result in hypoparathyroidism or dysphonia due to damage to the recurrent laryngeal nerves (9). Radioiodine therapy achieves high rates of remission (8, 10–16), yet the long term safety of iodine-131 in children and adolescents has been evaluated in fewer than 1000 individuals (6, 15, 17–23). Concerns also linger about the oncogenic potential of radioiodine and the potential risks of genetic damage to any offspring after iodine-131 treatment (24–28). In this report, we review information about the risks and benefits of current treatments for hyperthyroidism in adult and childhood Graves’ disease with special emphasis on children and the safety of iodine-131 therapy in the pediatric population. Drug therapy of Graves’ disease was introduced in the early 1940s by Astwood (10). Current mainstays of antithyroid therapy include the thioamide derivatives propylthiouracil (PTU), methimazole (MMI), and carbimazole that reduce thyroid hormone synthesis by inhibiting the oxidation and organic binding of thyroid iodide (7, 29, 30). PTU has a short-half life (4–6 h) and requires administration several times each day (7, 29, 30). In contrast, MMI is 10-fold more potent on a weight basis than PTU and has a longer half-life (12–16 h) (7, 29, 30). To control the hyperthyroid state, PTU is typically given every 8 h, whereas MMI can be administered once or twice daily after thyrotoxicosis is controlled (31). Recommended doses for initial therapy are about 5–10 mg/kg·day for PTU and 0.5–1.0 mg/kg·day for MMI (32). However, even lower doses of PTU or MMI may be effective for induction or maintenance therapy. Maximal clinical responses to medications occur after about 4–6 weeks of therapy. Before that time the signs and symptoms of hyperthyroidism may be controlled with β-blockers such as atenolol or propranolol (7). Biochemical thyrotoxicosis can be controlled more rapidly using solutions of saturated potassium iodide (or Lugol’s solution) (7). Iodides block the release of thyroid hormones and reduce the vascularity of the thyroid gland, making them particularly useful for preparing a thyrotoxic patient for surgery (7). Previous studies of adult patients reported remission rates of 40–50% after prolonged therapy (7). However, rates of remission after drug therapy have fallen considerably over the past few decades (33), possibly due to the well documented increase in mean dietary iodine intake (34). Remission rates also appear to be similar whether patients are treated with or without levo-T4 during antithyroid drug therapy (35). In children, long term remission rates are at best 50–60% after several years of drug therapy (2, 5) and are usually less than 30–40% (2, 6, 8, 36–39). Furthermore, when responses to medical therapy among prepubertal and pubertal children are compared, 1-yr remission rates are considerably less in prepubertal (17%) than in pubertal children (30%) (39). Increasing evidence shows that the efficacy of the antithyroid drugs is inversely related to serum levels of TSAb (40, 41). After several years of antithyroid therapy, remission rates in adults range from 15% in individuals with high levels of TSAb at the time of diagnosis to 50% in individuals with low pretreatment TSAb levels (40). It has also been suggested that the long term remission rate can be predicted from the response to short term (∼4–6 months) antithyroid drug therapy (42, 43). Long term remission is less likely if high levels of TSAb are present or if hyperthyroidism persists after short term drug treatment (40, 42, 43). Side-effects of antithyroid drugs are more common in children than adults (32, 44) and may be either idiosyncratic or dose related. Rarely, side-effects may be very serious and even fatal (4, 6) (Table 1). To date, 36 serious complications and 2 deaths in children caused by antithyroid drug therapy have been reported to the FDA MedWatch Program, which is prone to underreporting of drug side-effects (Malozowski, S., personal communication). Published studies including children (2, 6, 8, 36–38), show that 20–30% of patients will develop complications of drug therapy (Table 1). In one third to one fourth of these patients, complications require discontinuation of all thioamide drugs. In the remaining patients, complications may resolve after switching to an alternative thioamide drug. Complications of antithyroid drug therapy in more than 500 children (2, 4, 5, 6, 37, 38 ) May respond favorably to substitution of an alternative thioamide drug. Necessitate discontinuation of all thioamide drugs. Complications of antithyroid drug therapy in more than 500 children (2, 4, 5, 6, 37, 38 ) May respond favorably to substitution of an alternative thioamide drug. Necessitate discontinuation of all thioamide drugs. Mild leukopenia (white blood cell count <4000/mm3) is a common complication of hyperthyroidism and may be exacerbated by treatment with thioamide drugs (45, 46). In most cases, the leukopenia is transient and is not associated with an increased risk of infection (46). Severe leukopenia (total white blood cell count<2500/mm3) or granulocytopenia (<1000/mm3) can be associated with serious opportunistic infections (46) and should prompt discontinuation of thioamide therapy. Mild increases in liver enzyme levels may accompany hyperthyroidism (7, 47, 48). However, 28% of patients with normal liver function tests at therapy onset will have mild and transient elevations of liver enzymes during therapy with PTU (45, 47, 49). Patients may also develop overt drug-induced hepatitis, which is accompanied by marked elevations in liver enzymes and hepatic necrosis and may be fatal (6, 47, 49, 50). Hepatitis may develop anytime during therapy, but usually occurs within the first 2–3 months (47, 49, 50). MMI characteristically causes cholestatic hepatitis, whereas PTU usually induces cytotoxic hepatitis (47, 49, 50). In such cases, thioamide therapy be and may to thioamides may include and and of the may also occur The resolves if thioamide drug is for the and can be treated with and may also occur during treatment with thioamides Rarely, patients may develop with and antibodies In such may and serious effects of thioamide drugs include and The development of any of these complications requires discontinuation of drug therapy. The of thyroid in is in for and in for show that patients with Graves’ disease have a of thyroid than normal subjects or patients with of thyroid disease in patients with Graves’ disease may also be more than in individuals without Graves’ disease The Thyrotoxicosis that the of thyroid over of is in adults with Graves’ disease treated with thioamide drugs than in patients treated with iodine-131 in and than in patients treated in of thyroid adenomas also and times among the adults treated with antithyroid drugs in than in patients treated with iodine-131 in or surgery in than a for medical therapy in the of thyroid these may the of more thyroid in patients treated with drugs than in individuals treated with radioiodine or is the of therapy for Graves’ disease, with the to in for in this (7). was in years for children and adults is to reduce the risk of recurrent hyperthyroidism and are surgical and the of complications and the rates of of hyperthyroidism in on the and of the to with in thyroid surgery is (4, After of hyperthyroidism is in about of children and and in about of individuals in about of patients after In hyperthyroidism in less than of children and adults and is rates are or The most of the complications of thyroid surgery was on of thyroid on adults and children in (9). These to one third of the that in the (9). rates for adults and in about for children (9). The most complications and transient (9). may of the blood to the and/or of by common include and (9). studies complications of thyroid surgery in children fewer subjects but similar rates of complications (Table Complications of in more than children ) Complications of in more than children ) are of a more the of complications and deaths after thyroid with in and is that complication rates have However, with of less thyroid surgery is and fewer are to develop and than in the past Radioiodine therapy for Graves’ disease was introduced at that more than 2 individuals have iodine-131 for Graves’ disease, making this therapy one of the most therapeutic of a administered After administration of iodine-131 to patients with Graves’ disease, the of is in the thyroid gland and and of is the result of from iodine-131 have a of and will iodine-131 and in the after radioiodine treatment include and and The acute is by of the gland The of iodine-131 by the thyroid gland the of the thyroid gland and the of the of radioiodine administered to the patient are gland and iodine using of of thyroid thyroid radioiodine (7, if a dose of thyroid is for a patient with a thyroid gland and a 50% radioiodine at h, the administered dose will be can be to the of a normal thyroid gland of for or more by However, even when gland and effective iodine-131 are and a high of of dose is the is due to in the of the thyroid to radioiodine clinical of thyroid is usually when the radioiodine It has been suggested that doses to the thyroid are to the thyroid gland However, doses to the thyroid are more commonly and may result in or of the thyroid thyroid doses of doses of to the thyroid to the and will be about and The will be about The effective half-life of iodine-131 is at weeks after less than of the administered in the thyroid after iodine-131 levels of thyroid hormones may as thyroid hormone is from of hyperthyroidism during this time can be controlled using β-blockers potassium iodide or Lugol’s will hyperthyroidism during this and not the of radioiodine therapy to 8 weeks after the thyroid gland and which can be (7, In to of patients, hyperthyroidism will 2 months of a dose of radioiodine is for these patients (7, In a dose of radioiodine is not given months after the initial therapy. The of iodine-131 therapy for childhood Graves’ disease have been reported in several studies (6, 15, 17–23). Patients as as of have been treated with iodine-131 The reported iodine-131 doses in children and adolescents have from thyroid (6, 15, 17–23). Long term cure rates are in patients treated with than in given of radioiodine (7). There is in rates of and among using the administered In adult patients treated with low doses of iodine-131 hyperthyroidism persists in after therapy The of hyperthyroidism The of in patients treated with lower doses from at and increases with time In after treatment with iodine-131 doses only of patients are hyperthyroid at and (7, In children treated with thyroid of patients are hyperthyroid several years after therapy In in children treated with a dose of hyperthyroidism persists in of patients, and of patients The of radioiodine therapy is by the of the thyroid gland and possibly by levels of TSAb to iodine-131 therapy are lower in patients with very and high TSAb levels than in patients with surgical may be associated with cure rates than radioiodine therapy for There is also evidence that responses to radioiodine are less after treatment with antithyroid drugs complications of iodine-131 therapy have been but the is low and not well (7, (Table In children, very few acute responses to iodine-131 therapy of Graves’ disease have been (6, 15, 17–23). Complications of therapy in adults ) Complications of therapy in adults ) In transient has been reported after radioiodine and mild over the thyroid gland, thyroiditis, may develop after a therapeutic dose (7, These side-effects are and respond to treatment with (7, Severe and have been reported rarely in patients with very goiters after iodine-131 administration and can be controlled with doses of after radioiodine treatment typically occurs with doses greater than such doses are for therapy occurs very rarely has been reported to develop after iodine-131 treatment in a very of patients complication is and no reported among patients treated with iodine-131 at one (10). Patients with thyrotoxicosis and very goiters may be at risk for thyroid In this antithyroid drugs can be administered for several weeks radioiodine therapy to that the thyroid has been of hormones radioiodine therapy (7, are the administration of radioiodine (7, have on the of iodine-131 therapy of Graves’ disease with the development or of ophthalmopathy studies have no effects of iodine-131 therapy on the clinical of disease whereas of disease after therapy of adults of ophthalmopathy in 15% of patients with Graves’ disease months after treatment with iodine-131 In of these patients, in and and at after disease was in of patients In disease in of patients treated with methimazole and high dose for of patients treated with radioiodine and of patients treated with methimazole may to the development or of ophthalmopathy after radioiodine therapy, including high pretreatment levels of and high serum of TSH from using radioiodine in patients with particularly if Because high pretreatment levels of are a risk for disease after iodine-131 pretreatment with antithyroid drugs may reduce the risk of an of ophthalmopathy After radioiodine therapy, thyroid hormone and TSH levels should be and T4 at early to reduce the risk of ophthalmopathy in one suggested that the development and of ophthalmopathy are by treatment with for months after radioiodine therapy However, therapy is not for most children long term of ophthalmopathy occurs and after radioiodine treatment administration is also associated with weight and in children. the may be useful after radioiodine therapy for patients with In to children rarely develop ophthalmopathy is and children treated with iodine-131 for Graves’ disease, signs in of children, not in and in after treatment In children with ophthalmopathy at the onset of disease in and in after or more of drug therapy After in children, disease in In contrast, disease was in children after surgical disease in only a of children after or surgical therapy of Graves’ iodine-131 treatment of Graves’ disease, the are to Radioiodine therapy has been associated with the development of transient hypoparathyroidism in a few individuals complication is and is typically transient may to the development of as in has also been reported in several patients treated with iodine-131 for thyroid or Graves’ disease of serum levels every has been for patients treated with iodine-131 for Graves’ disease The only of patients with Graves’ disease and however, not an increased of The increased risk of thyroid after thyroid in childhood has been for a of iodine-131 therapy to the risks of thyroid and this has been the of several long term studies more than patients of the effects of diagnostic iodine-131 and radioiodine and have also the risks of and thyroid These studies show that the risk of thyroid is increased with to low or levels of In contrast, thyroid risks are lower after high that in thyroid cell or of to a dose of iodine-131 in the of to the thyroid gland in adults There is no evidence of an increased risk of thyroid or after this to iodine-131 no risk of thyroid or has been among in of high in In contrast, when the thyroid gland is to of is an increased risk of thyroid risk of thyroid has been reported within of to or The mean time for development of in patients is with the time to than of are of are and of are or of the in an increased of thyroid after acute from from to iodine-131 and in the after in thyroid gland at for adults and for children These associated with to 10-fold increases in the rates of and thyroid However, the of iodine-131 to thyroid risk not be and was very personal communication). The also in an increased rate of thyroid in children less than of In to the long reported in studies after thyroid thyroid seen as early as after the These may in a of iodine of the resulting in the early of and of iodine-131 and associated with the The in these individuals was The of the patients in the and the studies have information about the risks after iodine-131 therapy. After treatment of Graves’ disease in adults with which the thyroid gland to high levels of rates of thyroid and thyroid not increased children in the that thyroid adenomas in of the patients treated in one with low doses of iodine-131 to result in thyroid of in the children treated with doses of iodine-131 the of thyroid was not increased after iodine-131 treatment of children and adolescents with hyperthyroidism have been reported for 1000 individuals in (6, 15, 17–23). The of in these studies from less than to with only subjects for more than These studies have not an increased risk of thyroid There are several of the of radioiodine on in After iodine-131 treatment for the risk of not from control increases in the risk of after iodine-131 therapy have been these increases are not and the have not been reported rates of the a but increase in in adults studies have not after iodine-131 therapy children, a of risks has yet to be The risk of thyroid after thyroid is in children than in children or adults After the at the of of thyroid in less than of at the time of the patients of at the time of thyroid After of thyroid adenomas more than and the of of thyroid of However, is not whether iodine-131 a to the of thyroid show that when occurs after of the risk of thyroid is not increased when occurs of thyroid rates are at show that thyroid risks are and for and more than at the time of personal communication). individuals to and thyroid risks and when and of personal communication). However, even after of thyroid occur children are more to risks after thyroid we not if children to the doses of iodine-131 for treatment of Graves’ disease are at increased risk for thyroid Radioiodine therapy will most of the thyroid gland, which will or studies have that after iodine-131 therapy, thyroid is to in most patients and cell after the of thyroid will are of long term studies that have the of thyroid that after iodine-131 therapy in children. In the that thyroid after iodine-131 is a risk that remaining may However, as doses are and marked in thyroid are thyroid risks will be considerably less after radioiodine therapy than after the of children to thyroid after we that is a risk of a increase in the rate of thyroid after iodine-131 therapy during potential risk will be in children treated of and lower in children treated 5–10 and of the that childhood radioiodine therapy is not associated with or increases in thyroid we are of only reported of thyroid in children treated with iodine-131 of at treatment with of at treatment with of at treatment with and of at treatment with of these individuals treated with low doses of and one patient was treated with a dose of low doses of iodine-131 are associated with an increased of thyroid and the risk of iodine-131 therapy is associated with a rate of about is that the child treated with iodine-131 will about will be in the that including the and However, increases in risk associated with such low doses will be very even if very of children are and any increases in the of are likely to be very of the during iodine-131 therapy which is to the from a or an The on 500 offspring to subjects treated with iodine-131 for hyperthyroidism during childhood and (6, 15, The of reported among the offspring of patients treated with radioiodine not from the in the population. In was no increased risk of in the offspring of patients treated in childhood with iodine-131 Furthermore, was no evidence of an increased rate of in of the and to levels of of the than are associated with radioiodine therapy studies show that increased of TSH the thyroid gland to (8, has been suggested that doses of levo-T4 be administered to patients to elevations in TSH and we not the long term efficacy of this in show that patients with Graves’ disease have a of thyroid than patients with of thyroid disease or the normal of thyroid may be in patients with Graves’ disease treated with drugs than in treated with radioiodine or surgery of the thyroid is essential for all patients with a of Graves’ or surgical of is to whether a Because thyroid more typically appear after long term the pediatric years is In thyroid in about in patients during a to after radioiodine therapy in the The most common after thyroid is which is a growing treated by and iodine-131 therapy The of in children is and from occur rarely in the that thyroid after childhood radioiodine therapy, the should be of complication and long term remission each treatment for Graves’ disease therapy in children is associated with long term remission rates of less than 30–40% and a 20–30% of that may rarely be serious or fatal (2, 5, 6, 8, Drug therapy is a first therapy in and is useful when TSAb levels are low and the thyroid gland is (40, 41). treatment is also useful for hyperthyroidism more of therapy are or the child is for radioiodine drugs may also be to radioiodine in children with In to drug therapy, surgery has more cure rates and the hyperthyroid state is a complex surgical procedure with surgical including in about in 1000 in children (9). is the that the of thyroid has over the past several decades radioiodine therapy is not surgery is useful for the patient complications or not remission with drug may be when the thyroid gland is very should also be when is ophthalmopathy and remission be with thioamides Radioiodine is associated with high cure rates that are typically greater than therapy is the and treatment for Graves’ disease and rarely is accompanied by acute side-effects complications include an of ophthalmopathy in a of patients, particularly of children with Graves’ disease treated with doses of iodine-131 have not an increased risk of thyroid (6, 15, 17–23). However, as only several children have been treated with iodine-131 and not all have been long is only to that radioiodine is not associated with or increases in the of thyroid long term of is to the of thyroid in children treated with as as of have been treated with iodine-131 for Graves’ disease we not whether is an which high dose iodine-131 therapy should be of thyroid after are in children less than of and with if is thyroid after radioiodine may be a increase in the of thyroid in children treated with may be to radioiodine therapy in children less than of in the that thyroid after childhood iodine-131 therapy, should be associated with an The of doses of iodine-131 thyroid to the thyroid gland will also the risks of and is to lower dose therapy in children. of a treatment for the child with Graves’ disease is a and personal The risk of an increase in the rate of thyroid after radioiodine therapy to be the complications of drug therapy or of the and risks of each therapeutic by the is essential to the patient and a treatment option. the that Graves’ disease is a serious with risks of therapy should not be Radioiodine is a and effective therapy for childhood Graves’ The efficacy of iodine-131 therapy is dose related. After administered of long term cure rates of hyperthyroidism are or In of patients, a dose of iodine-131 is to cure Patients with Graves’ disease are at risk for thyroid than the normal population. risk may be in patients treated with antithyroid drugs than in treated with radioiodine or may the of more thyroid after drug therapy than after iodine-131 treatment or The risk of thyroid in children treated with iodine-131 is the increase in the risk of thyroid in children to we that may be a increase in the risk of thyroid in children treated with risk is in children treated with iodine the of and lower in treated at 5–10 and 5) should doses of iodine-131 to thyroid and After radioiodine therapy, levo-T4 therapy should be to and elevations of serum 6) There is no evidence of an increased rate of in offspring of patients treated with radioiodine or to levels of therapy of childhood Graves’ disease is typically associated with long term remission rates less than 30–40% after prolonged therapy and a 20–30% of a of which may be serious or long term responses to drug therapy are seen in patients with low levels of and remission after short term therapy. The of surgical therapy is by an thyroid in childhood is associated with cure a of and a rate patients with very thyroid cure rates may be after than after drug or radioiodine therapy. is for all patients treated for Graves’ disease and should include of the thyroid gland once a thyroid should be or after is most commonly which is on and has an are to and at the for at the FDA is for MedWatch also at the at and at of at at the of at of and at of for this and and for this from the drug and of the