Rev Esp Endocrinol Pediatr

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Rev Esp Endocrinol Pediatr 2013;4 Suppl(1):7-14 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2013.Mar.169
Graves Disease (GD) in childhood and adolescence: current concepts and controversies

Sent for review: 27 Mar. 2013 | Accepted: 27 Mar. 2013  | Published: 2 May. 2013
Rosalind S Brown
Division of Endocrinology. Boston Children’s Hospital Boston and Harvard Medical School. Boston, Massachusetts (United States of America)
Correspondence:Rosalind S Brown, Division of Endocrinology, Boston Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts, United States of America
E-mail: Rosalind.Brown@childrens.harvard.edu
Table 1 - Susceptibility Genes implicated in GD*
Table 2 - Representative Costs of Diagnostic Tests for Graves’ Disease*
Figure 1 - Causes of an elevated T4 concentration in childhood
Abstract

Graves disease is the most common cause of hyperthyroidism in childhood but frequently needs to be distinguished from chronic lymphocytic thyroiditis and from other, rarer, causes of thyrotoxicosis. Thyrotropin receptor antibodies are present in a majority of patients, whether measured by binding assay or bioassay, and form the basis of diagnosis. However, sensitivity in different assays varies. Optimal treatment is controversial and needs to be individualized. Therapy with antithyroid drugs is the initial approach used by most pediatric endocrinologists, but children,  particularly prepubertal ones and those < 5 years of age, tend to have more persistent disease than adults, so there is a higher risk of relapse when treatment is withdrawn, especially  if treatment is continued for < 2 years.  Antithyroid drugs are also rarely associated with serious adverse effects, including agranulocytosis. This has led some pediatric endocrinologists to favor permanent thyroid ablation with radioactive iodine as the initial approach to therapy, although the longterm safety of this approach, especially in younger children is unknown.  Surgery remains an option, but only if an experienced surgeon is available. It is hoped that a better understanding of the underlying etiology will permit the development of safer, more specific therapy in the future.

Key Words: Graves’ disease, pediatrics, hyperthyroidism, TSH receptor Abs, radioactive iodine Palabras clave:

Introduction

Graves Disease (GD) accounts for >95% of cases of hyperthyroidism in childhood and adolescence and is much more common in females, even prior to puberty. Like chronic lymphocytic thyroiditis (CLT) the other major autoimmune thyroid disease with which it is closely associated and from which it must frequently be distinguished, GD is a complex genetic disorder that requires both a genetic predisposition and an environmental trigger for disease expression. A unique feature of GD in childhood is its persistence, particularly in prepubertal children1 and those <5 years of age2. Despite advances in our knowledge about the genetic contribution of GD and improved methods of measuring thyrotropin (TSH) receptor antibodies (Abs), optimal treatment remains elusive and controversial. In this talk, current concepts and controversies about GD in childhood will be reviewed, with a particular emphasis upon advances in our understanding about the etiology of GD, measurement of TSH receptor Abs and the benefits and risks of each of the three major forms of therapy-antithyroid drugs (ATDs), radioactive iodine (RAI) and surgery.

Etiology of Graves Disease

GD is caused by Abs that bind to the TSH receptor, and stimulate adenylyl cyclase, thereby  leading to increased thyroid hormonogenesis and growth3, 4. Other TSH receptor Ab populations may also be present in serum, including those that block TSH-induced thyroid stimulation and growth, and those without a discernible effect on thyroid function (neutral Abs). In any one patient there may exist multiple TSH receptor Abs each with different specificities and functional activities. Both stimulatory and blocking TSH receptor Abs bind to the extracellular domain of the receptor and recognize apparently discrete but overlapping  linear epitopes in the context of a three-dimensional structure4.  Based on concordance studies in twins, it has been estimated that up to 80% of susceptibility in GD is genetic, the rest being attributable to environmental factors5.  However individual genes appear to play a relatively minor role, and, like in other complex immune diseases, polymorphisms in multiple genes have been identified. Table 1 summarizes 6 such genes as well as their postulated role in contributing to susceptibility in GD6, 7. Four of these genes affect key aspects of immune regulation and have been implicated in other autoimmune diseases as well. These include human leukocyte antigens (HLA), cytotoxic T-lymphocyte antigen (CTLA)-4, CD40,l, and protein tyrosine phosphatase  (PTPN)-228.  The two other genes are thyroid-specific (thyroglobulin, Tg ,and the TSH receptor).

Diagnosis of Graves disease

Causes of an elevated serum thyroxine (T4) concentration are summarized in Figure 1. Thyrotoxicosis , defined as an elevated serum concentration of T4 and/or triiodothyronine (T3) associated with a suppressed TSH concentration, may be due to hyperthyroidism, i.e.,thyroid overactivity, or can result from the leakage of preformed  thyroid hormone into the circulation after tissue injury, a temporary condition that does not require specific therapy . Patients with GD also frequently have an increased  serum T3 concentration out of proportion to the T4. This occurs both because of increased thyroidal secretion of T3 and because TSH receptor Abs, like TSH, stimulate the peripheral conversion of T4 to T3.

The most cost effective method to confirm the diagnosis of GD is the demonstration of TSH receptor Abs in serum (Table 2). An elevated serum concentration of thyroid peroxidase (TPO) Abs or Tg Abs , advocated by some, is not useful in distinguishing GD from CLT and in one study in children, these Abs were present in only 71% of affected patients9. Other approaches that have been used are helpful when the level of TSH receptor Abs is borderline but are more costly and need not be done as a first line approach in all patients. For example, the finding of an elevated 123I uptake and/or a diffusely enlarged hypervascular thyroid gland on ultrasound may be of assistance in distinguishing true hyperthyroidism (increased uptake) from thyroiditis (decreased uptake/heterogeneous echogenicity). An additional disadvantage of  scintiscan is unnecessary irradiation.

Assays for TSH Receptor Abs

The availability of commercial kits, and the development of both molecularly engineered cells, and a stimulating human anti-TSH receptor monoclonal Ab have greatly improved the performance of TSH receptor Ab assays available both clinically and in a research setting(10). Both radioreceptor assay and,, more recently, enzyme-linked immunosorbent assay [ELISA], take advantage of the ability of these Abs to inhibit the binding of TSH to either porcine thyroid membranes or to recombinant human TSH receptor transfected into Chinese hamster ovary (CHO) cells. When measured by binding assay, TSH receptor Abs are referred to as TBII (TSH binding-inhibitory Immunoglobulins) or TRAbs (TSH receptor Abs). The ELISA  is more sensitive than the radioreceptor assay and is usually expressed as U/mL rather than % inhibition. In the third generation assay when enzyme-linked monoclonal TSH receptor Ab is substituted for TSH as ligand, the assay is positive in up to 99% of adults with GD11. It is important to note that the results in different clinical assays for TSH receptor Abs are not interchangeable12.

Benefits of current binding assays for TSH receptor Abs in the diagnosis of GD include their sensitivity, specificity, relatively low cost and rapidity of performance. They can also be of use in distinguishing a relapse from non compliance. However, they do not provide any information as to the biological activity of the Abs. For this reason, some endocrinologists prefer to employ a bioassay that demonstrates stimulation of thyroid cell function directly. Bioassays take advantage of the property of TSH and TSH receptor Abs of stimulating adenyl cyclase. Stimulatory TSH receptor Abs detected by bioassay are termed thyroid-stimulating immunoglobulins (TSI) or thyroid-stimulating Abs (TSAbs). Bioassays are extremely sensitive and specific for TSI when performed in a research setting but results are much more variable in the clinical arena.  For example, in one study, TSI were present in 91% of children and adolescents with newly diagnosed GD in a research laboratory9. In contrast, results were positive in only 51% and 56% of affected children13, 14, respectively, in 2 other recent studies and were just modestly elevated in a third when measured commercially15.  We recently confirmed this low sensitivity in 31 children with newly diagnosed GD and positive TSH receptor Abs by binding assay. When the TSI bioassay in routine use in our hospital was employed only 15 /31 (48 %) of patients had elevated TSI . In contrast  all 31 samples were positive when the same sera were reevaluated by a newly developed clinical kit that utilizes a luminescence method and either wild type human or chimeric (Mc4) TSH receptor. These results emphasize the importance to clinicians of knowing the bioassay for TSI that is utilized in their hospital or referral laboratory and of the wide variability in sensitivity. Properly performed, bioassays are the most definitive and sensitive method to document that the hyperthyroidism is due to stimulatory TSH receptor Abs16, but the newer, improved methods are more expensive and so have not been universally adopted to date.

Treatment

Controversy continues to surround the optimal treatment of GD in children and adolescents. Treatment is aimed at either pharmacological blockade of thyroid hormone synthesis with ATDs  or permanent thyroid ablation with either RAI  or surgery, approaches that have not changed in >60 years. Each therapeutic strategy has its advantages and disadvantages so therapy should be individualized.      

Medical Therapy

Medical therapy continues to be the initial choice of most pediatric endocrinologists. The thiouracil compounds propyl thiouracil (PTU), methimazole (MMI) and carbimazole exert their antithyroid effect by inhibiting the organification of iodine and the coupling of iodotyrosine residues on the Tg molecule to T3 and T4. MMI (or carbimazole) is preferred in most pediatric patients because of the risk of PTU-induced hepatotoxicity (discussed in further detail below). MMI also has a longer half life than PTU and is associated with more rapid correction of the hyperthyroidism17. An exception is the use of PTU during the first trimester of pregnancy because of potential MMI teratogenicity18. The initial dosage of MMI is 0.5-0.7 mg/kg/day given every 12 hours with a maximum daily dose of 30 mg and of PTU is 5-7.5 mg/kg/day given every 8 hours with a maximal dose of 300 mg daily. In severe cases, a beta-adrenergic blocker (atenolol, 25 to 50 mg daily or twice daily) can be added to control the cardiovascular overactivity until a euthyroid state is obtained. Patients should be followed every 4 to 6 weeks until the serum concentration of T4 (or free  T4) and total T3 normalizes.  Once the T4/free T4 and T3 have normalized, one can either decrease the dosage of thioamide drug by 30% to 50% or, alternatively, wait until the TSH begins to rise and add a small, supplementary dose of  L-thyroxine (block-replace regimen). The TSH concentration may take several months to normalize and so should not be used as a guide to therapy initially. Monotherapy has the advantage that disease activity can be assessed and a smaller drug dosage is used,  an advantage since toxic reactions to MMI appear to be dose-related. Maintenance doses of MMI may be administered once daily. PTU is given twice daily. Usually patients can be followed every 4 months once thyroid function has normalized.

Toxic drug reactions (erythematous rashes, urticaria, arthralgias, transient granulocytopenia (<1500 granulocytes/mm3), have been reported in 5% to 14% of children. Most reactions are mild and do not contraindicate continued use. The most feared complication is agranulocytosis, (<500 granulocytes/mm3), which can occur after both MMI and PTU. In one recent study of 50,385 patients in Japan, the risk of agranulocytosis was 0.1% and the median time of onset was 69 days after the initiation of therapy, with a range of 11 to 233 days19. However, agranulocytosis can occur at any time. The risk of severe fulminant hepatic failure appears to be limited to PTU and is an idiosyncratic drug reaction that is not predicted by routine monitoring of liver function or transaminase levels. Another rare complication of PTU is antineutrophil cytoplasmic antibody (ANCA) positive vasculitis and lupus-like syndromes17. In contrast, MMI has been associated with cholestasis but not with significant hepatocellular damage20. It is important to caution all patients to stop their medication immediately and consult their physician should they develop unexplained fever, sore throat, gingival sores or jaundice.

In most children and adolescents, circulating thyroid hormone levels can be normalized readily with ATDs, as long as compliance is not a problem. However, as a group, younger children, particularly prior to puberty, tend to have more persistent disease than adults and there is a higher risk of relapse when ATDs are withdrawn. Therefore, treatment guidelines developed for older individuals should not be applied to the young. In one retrospective study, TSH receptor Abs disappeared from the circulation in <20% of patients after 13-24 months of medical therapy21 in contrast to adults in most of whom TSH receptor Abs normalize by 6 months22, 23. Taken together, the results from numerous retrospective studies suggest a remission rate of only 25- 30% of children after 2 years of therapy, with a median time to remission of 3 to 4 years24, 25.  Lippe et al demonstrated  an additional 25% remission rate with every 2 years of medical therapy up to a total 6 years25. A similar beneficial effect of prolonged therapy (up to ten years) was recently reported in a large prospective study of 154 pediatric patients from France26.

In children as well as adults, an increased risk of relapse has been related in some but not other studies to both the severity of the initial hyperthyroidism12, 26 and TRAb concentration  (>4X upper limited of normal)26. Other predictors include younger age at diagnosis (<12 years1 and especially < 5 years)2 and shorter duration of ATD therapy (<2 years)26. In one recent prospective study of 51 children, normalization of thyroid function within 3 months was the best predictor of those who achieved a remission after 2 years of therapy12. We recently conducted a prospective study of 23 pediatric patients with GD diagnosed by the presence of elevated TSH receptor Abs Although patients with the highest TSH receptor Ab concentration (>35%) were significantly more likely to have persistently elevated TSH receptor Abs at 13-24 months, the best predictor of an immunological response to therapy was a fall in TSH receptor Abs at 6 months. Similar results have been reported in adults.

The goals of ATD therapy include achievement of a permanent remission or simply a bridge to future definitive therapy at an age when it will be safer and/or better tolerated.  Some children and adolescents who relapse off therapy can be maintained indefinitely on a low, once daily dosage of MMI without any adverse effects. On the other hand, should a continued high dose of ATDs be required, permanent thyroid ablation should be considered.

Radioactive Iodine

Definitive therapy with either medical (RAI) or surgical thyroid ablation is usually reserved  for patients who have failed drug therapy, developed a toxic drug reaction, or are non compliant. In recent years, however, RAI is being favored increasingly by some pediatric endocrinologists, even as the initial therapy27. The advantages are the relative ease of administration, the reduced need for medical follow up and short-term safety. RAI should not be used in patients with a large goiter because the response to 131I therapy may be poor and should be used with caution if significant opthalmopathy is present and in children <10 years of age, but evidence is lacking as to what exactly constitutes a safe age. RAI is also contraindicated in pregnancy. A dose of 200 to 300 μCi of 131I/estimated gram of thyroid tissue is recommended in order to completely ablate the thyroid gland and thereby reduce the risk of future neoplasia. Alternately a standard amount (12 to 15 mCi) may be prescribed . Children <10 years of age should receive <10 mCi because in them the same absolute  dose of 131I results in a higher total body exposure to irradiation. Pretreatment with ATDs prior to RAI therapy is advisable if the hyperthyroidism is severe and/or the goiter is large in order to prevent the rare complication of thyroid storm. To enhance the efficacy of RAI, ATDs may be discontinued 5-7 days before and not restarted until a week after radioablation. One usually sees a therapeutic effect within 6 weeks to 3 months.

The major theoretic concern about the use of RAI in the pediatric age range relates to the well-documented increased susceptibility of the young thyroid gland to the proliferative effects of ionizing radiation28, a sensitivity demonstrated most strikingly in recent times by the consequences of the Chernobyl nuclear disaster29, 30. In 1200 children with GD treated with RAI and followed for 5 to >20 years, there was no evidence of an increased rate of leukemia, thyroid cancer or congenital anomalies in offspring31 but only a few children were < 12 years of age and even fewer were <5 years of age, the population of patients who are most at risk. Given the rarity of thyroid cancer in children (1 in a million) and adults (1 in 100,000) as well as the long latency period, small increases would not be detectable in such a  small series and long term, adequately powered, collaborative studies are needed to more reliably determine the long term risk of RAI therapy in young children.

Surgery

Surgery, the third therapeutic modality, is performed less frequently now than in the past. An advantage of this form of therapy is the rapid resolution of the hyperthyroidism. Near-total thyroidectomy is the procedure of choice  if an experienced surgeon is available in order to minimize the risk of recurrence. Surgery usually is reserved for patients who have failed medical management, who have a markedly enlarged thyroid, who refuse RAI therapy, and for patients requiring definitive therapy in whom RAI therapy is contraindicated e.g., because of significant ophthalmopathy or young age. Prior to surgery, it is important to treat with ATDs in order to render the child euthyroid and prevent thyroid storm. Iodides are added for 7 to 14 days prior to surgery in order to decrease the vascularity of the gland. The most common potential complication is transient hypocalcemia which occurs in up to 10% of patients. Other, less common potential complications are keloid formation , recurrent laryngeal nerve paralysis , and hypoparathyroidism , but these complications are rare with an experienced surgeon and when modern methods of anesthesia and pain control are used32.

Future Directions

The application of molecular biological tools and techniques has led to significant progress in our understanding of the genes predisposing to GD and to improvements in our ability to measure TSH receptor Abs. It is hoped that these advances will also be translated into safer, more targeted therapy  in the near future  as well.  Indeed, already novel reagents have been developed that specifically inhibit the binding of stimulatory TSH receptor Abs to their receptor33, 34. Hopefully we can look forward to specific therapy that modulates the underlying disease process rather than blocking thyroid hormone production as well in the not too distant future.

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