Myopathy Associated with Acute Hypothyroidism following Radioiodine Therapy for Graves Disease in an Adolescent

We describe acute myopathy following I-131 treatment for hyperthyroidism due to Graves Disease (GD) in an adolescent. A 15 year-old diagnosed with GD required treatment with radioactive iodine (I-131) therapy. Six weeks post I-131, he developed generalized muscle cramps. The CK was 19.800 U/L, the total thyroxine was 2.3 mcg/dL (29.6 nmol/L SI) and the estimated free thyroxine (EFT) was 0.5 ng/dL (6.4 pmol/L SI). The ALT was 112 U/L and AST was 364 U/L (normal <35 U/L). The muscle cramps and CK elevation normalized five months after initiation of thyroid replacement therapy. This observation shows that acute myopathy can rarely occur in pediatric patients with GD following treatment with I-131.


Introduction
Graves Disease (GD) is uncommon in children with an estimated incidence of 1 per 10,000 [1]. GD accounts for 95% of the cases of hyperthyroidism in children and is more frequent in those with a familial history of autoimmune thyroid disease [2]. Although pharmacological therapy with antithyroid drugs (ATDs) is the first-line therapy in pediatric GD, long-term remission rates of GD in children are less than 25% [3]. Thus, definitive treatment with radioactive iodine (RAI, I-131) or surgery is required for the majority of individuals with GD [3,4]. When I-131 is used, the treatment goal is hypothyroidism which typically occurs 2-4 months after the administered dose [5,6].
Acute myopathy with onset during the acute hypothyroidism following treatment of GD is rare in adults [16]. Severe rhabdomyolysis, a more severe state where elevation of muscle enzymes is additionally associated with myoglobinuria, elevated creatinine, and renal failure, has also been observed in this setting [17,18]. In children, myopathy with hypothyroidism is rare [19], and we are unaware of reports of acute myopathy following 131-I treatment in the pediatric population. We now describe acute myopathy following I-131 treatment for hyperthyroidism due to GD in an adolescent.
Six weeks after 131-I treatment, he developed sudden onset of generalized muscle cramps. The CK was 19.800 U/L (normal 24-195 U/L), with an increased CK-MB fraction of 13.9 ng/mL (normal <5 ng/mL). Troponin-I levels and an electrocardiogram were normal. The total T4 was 2.3 mcg/dL (29.6 nmol/L SI), and the EFT was 0.5 ng/dL (6.4 pmol/L SI). The ALT was 112 U/L, and AST was 364 U/L (normal <35 U/L). There was no evidence of myoglobinuria or electrolyte abnormalities. Renal function was normal. He received intravenous hydration and was placed on levothyroxine (125 mcg/day). He continued to have milder muscle cramps which resolved over the next three months. Neurological evaluation did not reveal an intrinsic myopathy. Five months after starting levothyroxine therapy, CK levels normalized (Figure 1).

Discussion
Acute myopathy in GD was initially reported in an adult treated with 131-I, who presented with muscle cramps and CK elevation six weeks after treatment, a condition that resolved with the correction of the hypothyroid state [16]. Severe rhabdomyolysis was reported in a patient with papillary thyroid cancer two weeks after total thyroidectomy [17]. Adults have been reported to have developed either myopathy or rhabdomyolysis following the sudden onset of hypothyroidism [18,20,21]. The magnitude of CK elevations in these individuals was postulated to be related to the degree of hypothyroidism [14]; however, such correlations have not been found by others [22]. Acute myopathy has also been described in individuals undergoing GD treatment with thionamides [15,18,23]. CK elevations during medical treatment of GD, in the absence of a hypothyroid state in two children, have been reported too [19].
The pathogenesis of hypothyroid myopathy is not yet well understood. It has been suggested that thyroxine deficiency leads to an abnormal glycogenolysis [21], metabolic disturbances in mitochondrial oxidative metabolism and triglyceride turnover, which impairs muscle function [24]. Muscle biopsies performed in this setting reveal nonspecific changes, including type II fiber atrophy [25]. It has also been suggested that a reversible, acquired glycogen storage and mitochondrial disorder is a part of hypothyroid myopathy [13,26].
Although a muscle biopsy was not performed, formal neurological evaluation did not reveal a potential for underlying myopathic condition. Following normalization of CK levels, they have remained normal even in the face of rigorous physical activity. Of note, the decline in T4 levels subsequent to 131-I therapy in our patient was also not unusual in comparison with that reported in pediatric patients [5]. Thus, at present, a specific cause for myopathy, other than acute onset hypothyroidism, cannot be discerned.
Over the past two decades of 131-I use in the treatment of GD in pediatric patients at our institution, this is the only individual to have developed this problem. Thus, we estimate the incidence of myopathy following 131-I therapy on GD to be less than 0.5% in children.