Elevated Fluorine-18-FDG Uptake in Skeletal Muscles: A Clue for the Diagnosis of Graves Disease

Transcription

1 Elevated Fluorine-18- Uptake in Skeletal Muscles: A Clue for the Diagnosis of Graves Disease Yen-Kung Chen 1, Yen-Ling Chen 2, Yeh-You Shen 1 1 Department of Nuclear Medicine; 2 Department of Endocrinology and Metabolism, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan A 45-year-old woman complained of weakness, dizziness, tremor and loss of body weight 2 kg within one month. She was underwent a whole-body fluorine fluorodeoxyglucose () positron emission tomography (PET) study for physical check up. There was symmetric diffused high uptake in the skeletal muscles. Results of thyroid function test were as follow: TSH was not measurable, whereas both T4 21 µg/dl and T3 381 ng/dl were increased. The image of thyroid echo was hypoechoic and heterogenous compatible with Graves disease. So that, the increment of muscle uptake may be responsible for the high peripheral glucose utilization seen in Graves disease. Key words: Graves disease, skeletal muscle, positron emission tomography, 18 F- Ann Nucl Med Sci 2003;16:41-45 Introduction Graves hyperthyroidism is caused by these thyroidstimulating antibodies, which bind to and activate the thyrotropin receptor on thyroid cells. The typical symptoms of a hyperthyroid patient are gaunt, restless, talks rapidly, and emotional lability. It is important to note that older patients Received 10/7/2002; revised 10/30/2002; accepted 11/5/2002. For correspondence or reprints contact: Yen-Ling Chen, M.D., Department of Endocrinology and Metabolism, Shin Kong Wu Ho-Su Memorial Hospital. 95 Wen Chang Road, Shih Lin District, Taipei 111, Taiwan. Tel: (886) ext. 2032, Fax: (886) , M004330@ms.skh.org.tw tend to show fewer findings, and rare patients with apathetic hyperthyroidism will lack almost all of the usual clinical manifestations of thyrotoxicosis [1]. Furthermore, patients may have vague symptoms and weight loss with a suspicious malignant disorder. Positron emission tomography (PET) with fluorine-18-2-fluorodeoxyglucose () is a diagnostic modality that provides noninvasive survey of the entire body and sensitively to detect various cancers. The appearance of hyperthyroidism in -PET image is what we want to present. Case Report A 45-year-old housekeeping woman had chief complaints of weakness, dizziness, hand tremor and loss of body weight 2 kg within one month. Our institution offered health check with physical examination, laboratory study, ultrasonography and PET. -PET scan showed a symmetric diffused high uptake in the skeletal muscles, especially in the psoas muscles and limb muscles (Figure 1). The patient has no diabetes mellitus history and the blood sugar was 108 mg/dl before injection of. At the same day, the results of thyroid function test were as follows: TSH was not measurable, whereas both T4 21 µg/dl and T3 381 ng/dl were increased. Reference values of our laboratory for T4 are between 4.5 to 12 µg/dl, and for T3 80 to 180 ng/dl. The image of thyroid echo was hypoechoic and heterogenous compatible with Graves disease. In view of the clinical history, thyroid function test, and thyroid echo, PET scan findings suggest Graves disease. The PET scan was performed with a dedicated PET scanner (Siemens ECAT EXACT HR+, Knoxville, TN).

2 Chen YK et al Figure 1. A series of coronal image using ordered subsets expectation maximization (OSEM) reconstructed PET images of the illustrative case. PET study was performed using an ECAT EXACT HR+ whole-body PET system. PET images showed symmetric diffused increased accumulation of uptake in psoas muscles (SUV=1.64) and skeletal muscles (arm SUV=1.18, thigh SUV=1.91). Patients were required to fast for 8 h before the PET scan was performed. They were scanned in as many sequential images as necessary to include the entire head, thorax, abdomen, and pelvis. Transmission images were obtained for 2 minutes per bed position to correct for photon attenuation using a germanium 68 pin source. After intravenous administration of 370 MBq (10 mci) of, emission images were acquired for 5 minutes per bed position. The uptake period between injection and the beginning of the emission scan was 60 minutes. The images were analyzed semi-quantitatively using the standard uptake value (SUV) in the patient. The SUV was calculated as follows: SUV = (activity in ROI in mci/ml)/(injected dose in mci/patient s weight in kg). Discussion The skeletal muscle mass is quantitatively of major importance in glucose disposal [2]. Energy from monosaccharides is derived by glycolysis during which glucose is degraded to lactic acid. An enhanced glycolysis has been linked to both an increase in the amount of glucose membrane transporters and an increase in the activity of the principal enzymes controlling the glycolytic pathways. Glucose transporter (GLUT) into most tissues occurs through the action of the members of a family of facilitative diffusion glucose transport proteins designated GLUT 1-7. Normal thyroid tissue is reported to express GLUT 1 and 4, but not GLUT 2 and 5. GLUT 3 was also not found in the thyroid. In hyperthyroidism, an increased GLUT 4 expression has been reported in various tissues and the influence of hyperthyroidism on glucose metabolism of various tissues has been studied extensively. Increased expression of muscle glucose transporter proteins may be responsible for the increased peripheral glucose utilization seen in hyperthyroidism [3,4]. is an analogue of glucose and has been used as a tracer of energy substrate metabolism. Because does not enter further enzymatic reactions after being converted into -6-phosphate by hexokinase, it remains effectively trapped in tissue because it is highly negatively charged. In tissues with low concentrations of glucose-6-phosphatase such as heart and brain, the accumulation of -6-PO 4 is proportional to the glycolytic rate. Tissues with high levels of glucose-6-phosphatase such as liver, intestine and resting muscle accumulate smaller amounts of -6-PO 4. Ann Nucl Med Sci 2003;16:41-45 Vol. 16 No. 1 March

3 PET of Graves disease However, active skeletal muscle may show significant accumulation. At rest, skeletal muscle does not show significant accumulation of, but after exercise or if contraction takes place in the uptake period after injection of, the uptake is increased. This relates to increased aerobic glycolysis of active muscle tissue. Examples of increased uptake after exercise include running, which results in increased leg muscle uptake, and walking with crutches, which causes forearm uptake. In general, this type of appearance would not cause diagnostic confusion. Another cause of muscle uptake that is not under voluntary control is stress-induced muscle tension. The characteristic appearance of this is symmetrical increases in uptake in the paraspinal muscles, in the posterior cervical muscles, and frequently in the trapezius muscles across the shoulders. Tissue metabolic activity is enhanced by thyroid hormones and high requirements of glucose have been observed both in human and experimental hyperthyroidism. Hyperthyroidism has augmented blood flow to skeletal muscle during submaximal exercise in rats [5]. Skeletal muscle expresses 2 isoforms of the glucose transporter (GLUT1 and GLUT4) with GLUT4 being quantitatively the predominant form. Weinstein et al reported that T3 increased abundance of GLUT1 protein and mrna levels in a liver derived cell line [6]. Casla et al. indicated that thyroid hormones increase basal glucose uptake in skeletal muscle and this is due to an increase in GLUT4 isoform [4]. The report of Dimitriadis and coworker showed when hyperthyroidism progresses in severity, increases in the sensitivity of glucose transport to insulin and in the activity of hexokinase may also be involved [7]. In addition, hyperthyroidism, which promotes glucose uptake and utilization by skeletal muscle, would be expected to facilitate pyruvate dehydrogenase complex activation and pyruvate oxidation in muscle via the suppression of pyruvate dehydrogenase kinase activity by pyruvate [8]. All together, Graves hyperthyroidism increased uptake in skeletal muscles is associated with an increased glucose metabolism. The image of Graves disease increased uptake in skeletal muscles is more like insulin caused uptake in skeletal muscle. Insulin regulation of glucose transport and phosphorylation in skeletal muscle is overexpression of GLUT4 and hexokinase II [9]. Then, insulin used in hyperglycemia patients may cause marked uptake in cardiac muscles and uneven uptake of in skeletal muscles [10]. In thyroid gland, the free fatty acids are the preferred substrate for energy metabolism [11]. In Graves disease, glucose hypermetabolism of the thyroid as measured by PET is correlated to stimulation of TSH-receptor-autoantibody. In the study of Boerner et al., modeling of glucose metabolism revealed substantial differences in thyroid utilization constants (k 3 values) corresponding to enhanced local metabolic rates in Graves disease. An enhanced uptake of the thyroid was significant in Graves disease [12]. However, uptake of thyroid has overlap in Graves disease and control. Thus say, Graves disease with probable no substantial uptake of in thyroid like this case may due to low TSH-receptor-autoantibody according to the study by Boerner et al. [12]. In conclusion, an increment of muscle uptake may be responsible for the high peripheral glucose utilization seen in Graves disease. The present results demonstrate that thyroid hormone may be an important physiological factor regulating the uptake of in skeletal muscles. References 1. Spaulding SW. Age and the thyroid. Endocrinol Metab Clin North Am 1987;16: DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981;30: Foss MC, Paccola GM, Saad MJ, Pimenta WP, Piccinato CE, Iazigi N. Peripheral glucose metabolism in human hyperthyroidism. J Clin Endocrinol Metab 1990;70: Casla A, Rovira A, Wells JA, Dohm GL. Increased glucose transporter (GLUT4) protein expression in hyperthyroidism. Biochem Biophys Res Commun 1990;171: McAllister RM, Sansone JC Jr, Laughlin MH. Effects of hyperthyroidism on muscle blood flow during exercise in 2002;16:

4 Chen YK et al rats. Am J Physiol 1995;268(1 Pt 2):H Weinstein SP, Watts J, Haber RS. Thyroid hormone increases muscle/fat glucose transporter gene expression in rat skeletal muscle. Endocrinology 1991;129: Dimitriadis G, Parry-Billings M, Bevan S, et al. The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats. Eur J Clin Invest 1997;27: Sugden MC, Lall HS, Harris RA, Holness MJ. Selective modification of the pyruvate dehydrogenase kinase isoform profile in skeletal muscle in hyperthyroidism: implications for the regulatory impact of glucose on fatty acid oxidation. J Endocrinol 2000;167: Kelley DE, Williams KV, Price JC. Insulin regulation of glucose transport and phosphorylation in skeletal muscle assessed by PET. Am J Physiol 1999;277(2 Pt 1):E Huitink JM, Visser FC, van Leeuwen GR, et al. Influence of high and low plasma insulin levels on the uptake of fluorine-18 fluorodeoxyglucose in myocardium and femoral muscle, assessed by planar imaging. Eur J Nucl Med 1995;22: Field JB. Intermediary metabolism of the thyroid. In Greep RO, Astwood EB, eds. Handbook of Physiology Endocrinology III. Washington, 1974, pp Boerner AR, Voth E, Theissen P, Wienhard K, Wagner R, Schicha H. Glucose metabolism of the thyroid in Graves disease measured by F-18-fluoro-deoxyglucose positron emission tomography. Thyroid 1998;8: Ann Nucl Med Sci 2003;16:41-45 Vol. 16 No. 1 March

5 PET of Graves disease () TSH 0.1 U/mL T4 21 g/dl T3 381 ng/dl (Graves disease) ;16: (02) (02) M004330@ms.skh.org.tw 2003;16: