- 1Endocrinology Department, University Hospital Zurich, Zurich, Switzerland
- 2Oncology Department, University Hospital Zurich, Zurich, Switzerland
- Correspondence to Dr Sibylle Kohler,
The authors describe a 31-year-old male with a metastatic germ cell tumour and massively elevated human chorionic gonadotrophin (HCG) levels who presented with hyperthyroidism. As HCG is structurally closely related to thyroid stimulating hormone (TSH), it can activate the TSH receptor; grossly elevated levels may result in hyperthyroidism. After initiation of chemotherapy, HCG levels decreased and hyperthyroidism resolved.
Hyperthyroidism is a common condition, but human chorionic gonadotrophin (HCG)-induced hyperthyroidism is rare. It can occur in patients with hyperemesis gravidarum, hydatidiform moles or germ cell tumours. Patients with HCG-induced hyperthyroidism have suppressed thyroid stimulating hormone (TSH) levels and elevated free thyroid hormones (FT4 and FT3), but typically lack clinical characteristics of Graves’ disease and TSH receptor antibodies. It is important to consider HCG-induced hyperthyroidism in patients presenting with biochemical hyperthyroidism but with an atypical clinical presentation.
A 31-year-old man presented to the emergency department because of a headache of 7 days duration. He reported having coughed up a small amount of blood that day. He had noticed diarrhoea and had vomited once 2 days ago.
On further questioning, the patient stated he had sweated slightly more during the past few days. He denied palpitations, irritability, tremor, visual problems or throat ache. His height was 166 cm and weight 68 kg. He had intentionally lost 10 kg during the past months with daily body building. He reported having felt well and physically fit during the previous weeks. He did not take any drugs and his medical as well as family history were unremarkable.
On examination, he appeared comfortable. Temperature was 36.6°C, blood pressure 120/60 mm Hg, the pulse 100 beats per min and the oxygen saturation 97% while he was breathing ambient air. The abdomen was tender on palpation, the remainder of the examination was normal. The neck was supple with no palpable masses or thyroid enlargement, there were no signs of ophthalmopathy. A radiograph of the chest showed multiple pulmonary nodules. CT of the chest and abdomen showed multiple bilateral pulmonary nodules. There were no pulmonary infiltrates or enlarged lymph nodes. A retroperitoneal mass of 5.7 × 4.3 cm in diameter was visible along the inferior vena cava and seemed to invade the vena cava below the kidneys. The other intraabdominal organs were normal. A CT scan of the brain revealed two nodules, one in the corpus callosum (1 cm) and one in the vermis (2.4 cm).
Blood tests showed normal glucose and electrolytes, a creatinine of 56 umol/l (normal range 62–106 umol/l), an elevated lactate dehydrogenase of 1117 U/l (normal range 240–480 U/l) and a suppressed TSH of < 0.01 mU/l (normal range 0.3–3.18 mU/l). The free thyroid hormones were measured and found to be elevated, FT4 was 94.8 pmol/l (normal range 13.1–21.3 pmol/l) and FT3 was 18.2 pmol/l (normal range 4.1–6.7 pmol/l). HCG was massively elevated at 553 627 U/l (normal range < 2 U/l). Urine pregnancy test was positive. A genital exam, performed after HCG levels were known, did not reveal any testicular masses.
Common endogenous causes of primary hyperthyroidism (suppressed TSH) include Graves’ disease, toxic adenoma, toxic multinodular goitre and thyroiditis (viral or postpartum). Rarely, primary hyperthyroidism is caused by germ cell tumours (e.g, choriocarcinoma producing large amounts of HCG) or hyperemesis gravidarum (vomiting and HCG-induced hyperthyroidism in early pregnancy). Very rarely, struma ovarii (ovarian teratoma containing hyperfunctioning thyroid tissue) may be the cause of hyperthyroidism. Causes of exogenous hyperthyroidism may be contrast agents containing iodine for angiography or CT scans, amiodarone or overtreatment with thyroid hormone.
Treatment, outcome and follow-up
The patient was diagnosed with a metastatic non-seminomatous germ cell tumour on the basis of the massively elevated HCG, the CT scan results and his clinical presentation. A biopsy was not performed. He received the chemotherapy combination BEP (cisplatin, etoposide and bleomycin), to which he responded well. HCG levels dropped from 553 627 U/l on presentation to within normal range 5 months after chemotherapy was started. FT4 fell to within normal range within the first 3 weeks (figure 1).
Germ cell tumours normally occur in the gonads but may be found in extragonadal sites (due to abnormal migration of germ cells during embryogenesis). They are divided into two main classes, seminomatous and non-seminomatous tumours. Non-seminomatous tumours originate from various cell types and can produce substantial amounts of HCG when they contain cytotrophoblasts and syncytiotrophoblasts (choriocarcinoma). Pure choriocarcinoma in men is rare (<1%). Most germ cell tumours originate from the germinal epithelium of the seminiferous tubules (seminomas), which produce excess HCG in only 15–20%. HCG, TSH, follicle-stimulating hormone and luteinising hormone are members of the same glycoprotein hormone family and are composed of an identical α subunit and a hormone-specific β subunit. HCG and TSH have 85% similarity on the first 114 amino acids, so that HCG is able to stimulate the TSH receptor.1 The first case of HCG-induced hyperthyroidism in a male was published in 1964,2 the association between high levels of HCG and hyperthyroidism has been documented repeatedly since then.3 In a recent study from the Netherlands, 144 male patients with metastatic non-seminomatous germ cell cancer in whom thyroid function tests were performed were evaluated.4 Hyperthyroidism, defined as decreased TSH (<0.40 mU/l) and elevated FT4 (>18.2 pmol/l), was found in 50% of patients with serum HCG levels above 50 000 IU/l. Some patients with germ cell tumours and high HCG levels develop hyperthyroidism while others do not. One explanation is that there are different forms of circulating HCG molecules (eg, regarding glycosylation), some of which have higher thyrotropic bioactivity, another is that different TSH receptors exist, some of which are potentially hypersensitive to HCG.5 Mutant TSH receptors have been described as a cause of gestational hyperthyroidism.6
HCG is also produced during normal pregnancy. Hyperemesis gravidarum is characterised by frequent vomiting, weight loss > 5% and frequently associated with particularly high HCG levels and hyperthyroidism. It develops in 0.3 to 1% of all pregnancies.7 Hyperthyroidism is usually of short duration and generally resolves spontaneously with the decline of HCG by the beginning of the second trimester.
HCG driven hyperthyroidism is generally mild, with FT4 rising to around 25–30 pmol/l, and most patients remain asymptomatic. If symptoms develop, β blockers can be given. In pregnant women this is usually unnecessary, whereas patients with germ cell tumours will benefit from chemotherapy.
▶ HCG-induced hyperthyroidism should be considered in patients presenting with intraabdominal masses suggestive of cancer and concomitant hyperthyroidism.
▶ Hyperthyroidism associated with vomiting in the first trimester of pregnancy is suggestive of hyperemesis gravidarum.
▶ HCG-induced hyperthyroidism will generally resolve spontaneously when treatment of the underlying cause is initiated (chemotherapy for germ cell tumour) and by the beginning of the second trimester in pregnancy.