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Introduction  The incidence of clinical hyperthyroidism has been reported as 0.8/1000 women per year, and it is less common in men.1 Causes of thyrotoxicosis include Grave’s disease, toxic multi-nodular goitre, toxic adenoma and thyroiditis. Rarely, thyrotoxicosis can arise as a paraneoplastic syndrome. Systemic symptoms of underlying malignancy may be wrongly attributed to primary hyperthyroidism leading to a delay in diagnosis. Human chorionic gonadotropin (hCG)-induced thyrotoxicosis associated with testicular germ cell tumors is a rare cause of hyperthyroidism. There is no consensus on whether such patients should be treated with antithyroid drugs (ATDs). It is seen in patients suffering from conditions associated with extremely high levels of HCG, such as hyperemesis gravidarum, hydatidiform moles, and germ cell tumors. At very high levels, HCG can stimulate the TSH receptor, causing hyperthyroidism. Germ cell carcinomas comprise the overwhelming majority (98.9%) of adult testicular carcinomas.Testicular cancer is a relatively rare cancer with an estimated 8,290 new cases diagnosed annually in the US. Germ cell tumours are divided into seminomatous or non-seminomatous types. Non-seminomatous germ cell tumours (NSGCT) composed of embryonal carcinoma, teratoma, choriocarcinoma, or yolk sac tumors. Ninety percent of non-seminomatous tumours express either alphafetoprotein or human chorionic gonadotrophin (hCG). We report a rare case of thyrotoxicosis due to metastatic testicular non seminomatous germ cell tumor that highlights the importance of a systematic clinical and biochemical assessment.Key words: Germ cell tumuor; human chorionic gonadotrophin (hCG); thyrotoxicosis, hyperthyroidismCase ReportA 33 year-old man with no known medical illness, presented with one month history of palpitation. There were no other associated symptoms of hyperthyroidism. His free thyroxine level was 95.27 (NR 11.5-22.7) with TSH level < 0.008 mIU/L (NR 0.55-4.78). He was diagnosed as hyperthyroidism, started on Carbimazole 30mg daily and Propranolol 40mg TDS. One month later, he presented again with worsening of breathlessness on exertion, loss of appetite and loss of weight approximately 5 kilograms. He still experienced intermittent palpitation but denied any other symptoms of hyperthyroidism or chest discomfort. Incidentally noted there was painless right scrotal swelling which further questioning revealed a progressive nature of enlargement for the past one year. There were no preceding trauma and he did not seek any medical attention for this. Upon presentation, patient was tachypneic requiring oxygen supplement, hemodynamically unsupported and had low grade temperature. There was no goiter and no sign of thyroid eye disease. Clinically no evidence of heart failure. There were bilateral gynaecomastia present. Lungs and cardiovascular examinations were unremarkable. Scrotal examination revealed an enlarged and hard right testicular swelling. Patient was empirically treated as pneumonia with broad spectrum antibiotic. Blood investigations parameter shows total white count of 18 x 109/L with neutrophils predominant of 79%, normal renal function and  liver function test. His repeated thyroid function test improved (free thyroxine 44.04 pmol/L, TSH 0.013 mIU/L) and hence was not labeled as thyroid storm. His Burch Wartosky score was 15out of 45. Ultrasound of the right testis showed well defined heterogeneous solid lesion with cystic degeneration and calcification measuring 5.7 x 3.1 cm. A chest radio-graph showed diffuse pulmonary nodules with multiple sizes of cannon ball lesions bilateral lungs field. Computed tomography of thorax, abdomen and pelvis showed multiple lungs nodules of varying sized bilaterally, multiple mediastinal and left hilar lymphadenopathy, a heterogeneous mass within the right testis measuring 6.0 x3.3 x 6.6 cm and right hydrocele. Tumor marker related were sent included beta HCG level of 339.8 mIU/ml (NR < 9.5mIU/ml). Other tumor marker included alpha fetoprotein, prostate specific antigen (PSA) and lactate dehydrogenase (LDH)  level were normal ranges.A diagnosis of clinically non- seminomatous germ cell tumor (NSGCT) with diffuse lung metastases was made. Owing to high clinical suspicion on beta HCG induced hyperthyroidism, serum beta HCG was repeated and the result was more than 225 000 mIU/ml after serial dilution. Patient was planned for initiation of urgent chemotherapy with Etoposide and Cisplation by the oncologist. Unfortunately, his condition deteriorated rapidly with worsening of pneumonia needing escalation of antibiotic, invasive ventilator support and maximum inotropic support. He succumbed to his illness prior to initiation of chemotherapy.      Discussion Hyperthyroidism is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid. Appropriate treatment of hyperthyroidism requires an accurate diagnosis. In the United States, the prevalence of hyperthyroidism is approximately 1.2% (0.5% overt and 0.7% subclinical); the most common causes include Graves' disease (GD), toxic multinodular goiter (TMNG), and toxic adenoma (TA).Seminomas account for 50% of all testicular germ cell cancers. The remainder comprise teratomas or non-seminomatous germ cell tumors (NSGCT), with mixed tumors occurring in 10% of cases(3). The very high levels of beta-human Chorionic Gonadotrophin(hCG) in this patient was strongly suggestive of choriocarcinoma histology, which is associated with a very poor prognosis and propensity for advance hematogenous metastases. Our patient had clinically and biochemically evidence of human chorionic gonadotrophin (hCG) induced thyroitoxicosis secondary to a non-seminomatous testicular germ cell tumors(NSGCT). Human chorionic gonadotrophin (hCG) induced thyrotoxicosis commonly occurs in pregnancy, in association with hyperemesis gravidarum. Thyroitoxicosis occurs because of cross-reactivity of hCG and TSH at the thyroid receptor. Human chorionic gonadotrophin (hCG) is a glycoprotein hormones that shares a common alpha subunit with thyroid stimulating hormones (TSH). this cross -stimulation only occurs at very high level of hCG, since hCG is only a weak agonist for the TSH receptor. Therefore, patient with testicular choriocarcinoma presenting with overt thyroitoxicosis may have widely metastatic disease at presentation. In patient with non seminomatous testicular germ cell tumor (NSGCT) with high level serum human chorionic gonadotrophin (hCG), hyperthyroidism has been recognised and is considered to be a paraneoplastic phenomenon. The occurence of human chorionic gonadotrophin(hCG)-induced thyroitoxicosis in men is rare (MEDLINE search 1964-2010). It was first report in 1964, when a man with an embryonal testicular tumor and grossly raised hCG level, died of thyroid storm during chemotherapy. The prevalence of hyperthyroidism in patient presenting with metastasis non seminomatous germ cell tumor is not known. In one small series, Giralt et al reported elevated thyroxine level in 7 of 17 NSGCT patients with hCG level in excess of more than 50,000mIU/ml. However, the data in Malaysia is still not  available. American Thyroid Association (ATA) recommended that treatment of hyperthyroidism due to choriocarcinoma and related tumors involves both treatment directed against the primary tumor and anti thyroid drugs. However, our patient was not able to initiate on chemotherapy. ConclusionThis is a rare case of thyroitoxicosis-induced by human chorionic gonadotrophin(hCG) due to metastases testicular germ cell tumor. Recognition of rare causes of hyperthyroidism especially in patients that did not present with typical symptoms ans signs with no palpable goiter is very important. The presentation was significant in that the presenting clinical features were attributed to hyperthyroidism, but were likely to have been caused by his metastatic tumor. This case highlights the importance of a comprehensive clinical history and examination for all patients presenting with hyperthyroidism, especially in males.Thyroid function should be measured in all patients with serum hCG level more than 50000 IU/ml related testicular tumor and hyperthyroidism should be treated temporarily in symptomatic patient to improve well being and performance, which may result in better tolerability of chemotherapy.  

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