Thyroid storm as an early presentation of hCG-producing metastatic choriocarcinoma: a case report and review of the literature

Abstract

Human chorionic gonadotropin (hCG)-induced hyperthyroidism has been previously reported as a rare paraneoplastic syndrome in non-seminomatous germ cell tumours and usually presents with mild symptoms or subclinical thyrotoxicosis. We present a case of a young adult man who consulted with abdominal pain, nausea and emesis. On admission, he was found to be tachycardic, febrile, anxious and with icteric sclera and tenderness to palpation in the right upper abdomen. A right scrotal mass was also noted. Initial studies revealed transaminitis, hyperbilirubinaemia, suppressed thyroid-stimulating hormone and elevated free T4. Scrotal biopsy confirmed diagnosis of testicular choriocarcinoma with an elevated hCG level of 6074 mIU/mL, which was corrected to 6 760 713 mIU/mL when reassessed with dilution. The clinical scenario reflected hCG-induced thyrotoxicosis concerning for thyroid storm. Euthyroid state was restored after initiation of chemotherapy and a short course of methimazole. Unfortunately, the patient passed away due to progression of his malignant disease. This case suggests that when choriocarcinoma is suspected, the use of iodinated contrast agents should be limited to avoid precipitation of thyroid storm or worsening of hCG-induced hyperthyroidism. Moreover, if the clinical picture does not support a primary aetiology of hyperthyroidism and hCG is not concordantly elevated, reassessment of hCG by dilution should be considered as hCG assays are subject to prozone effect.

Background

Human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH) share the same alpha and structurally similar beta subunits, which can lead to cross-stimulation of the TSH receptor along with direct thyrotropic activity exerted by the hCG molecule.^1–5 Elevated hCG levels can lead to overproduction of thyroid hormones, suppress TSH and present as hyperthyroidism. hCG-induced gestational hyperthyroidism can occur during the first trimester of pregnancy and manifest as hyperemesis gravidarum.⁶ However, hCG-induced hyperthyroidism occurring as paraneoplastic syndrome in hCG-producing malignancies such as non-seminomatous germ cell tumours (NSGCT) has been rarely reported.^{7 8} Previous case reports of hCG-induced hyperthyroidism have primarily been in women who have either been asymptomatic or presented with mild thyrotoxicosis symptoms.^9–11 To the best of our knowledge, this is the second report of hCG-producing choriocarcinoma presenting as thyroid storm.¹² Moreover, this is the first reported case of hCG-induced hyperthyroidism exacerbated by the use of an iodinated contrast agent.

Case presentation

A previously healthy young adult Hispanic man presented to an outside emergency department (ED) with a 1-day history of persistent abdominal pain, intractable nausea, emesis and subjective fever. He was found to have a large palpable right testicular mass which prompted a CT of the abdomen/pelvis, with contrast demonstrating a 5×5 cm testicular lesion with multiple hepatic masses suspicious for malignancy (figure 1). He was treated symptomatically and instructed to pursue outpatient work-up with urology. Nine days after his initial presentation, he returned to the same ED with worsening clinical signs including tachycardia (165 beats per minute), tachypnoea (32 beats per minute), fever (38.2°C) and elevated blood pressure (143/100 mm Hg). Physical examination revealed diaphoresis, anxious demeanour, scleral icterus, tenderness to palpation of right upper abdominal quadrant and persistence of the previously noted right scrotal mass. Laboratory studies showed white blood cells of 12.0 × 10⁹/L (normal range, 4–10.8 × 10⁹/L), aspartate aminotransferase of 428 U/L (normal range, 3–34 U/L), alanine aminotransferase of 176 U/L (normal range, 15–41 U/L), total bilirubin of 6.3 mg/dL (normal range, 0.2–1.3 mg/dL), TSH of <0.005 uIU/mL (normal range, 0.4–4.0 uIU/mL), free T4 (FTH) of 5.02 ng/dL (normal range, 0.7–1.4 ng/dL) and total T3 (TT3) of 365.5 ng/dL (normal range, 60–180 ng/dL). Infectious work-up was unrevealing. His clinical presentation was consistent with thyrotoxicosis concerning for thyroid storm based on 60 points in the Burch-Wartofsky Scale (<25, unlikely to represent thyroid storm; 25–44, impending thyroid storm; and ≥45, highly suggestive of thyroid storm)¹³ and the Japan Thyroid Association criteria (TS1, alternate combination).¹⁴ The patient was transferred to a tertiary care centre (our institution) for further evaluation and management.

Figure 1.

Tomographic findings identified on admission. (A) A 8.3×7.4 cm metastasis near the liver dome (white arrow). (B) Conglomerate nodal masses in the retroperitoneum and the abdomen measuring up to 10.6×6.8 cm (white arrow). (C) A large, heterogeneously enhancing right testicular mass (white arrow).

Investigations

At our institution, work-up included thyroid ultrasound showing increased vascularity without nodularity. His thyroglobulin antibody, thyroid peroxidase antibody, thyrotropin receptor antibody and thyroid-stimulating immunoglobulin were all negative. His thyroxine-binding globulin was minimally elevated at 31.2 µg/mL (normal range, 13–30 µg/mL). His hCG level was 6074 mIU/mL (normal range, 0–3 mIU/mL), alpha-fetoprotein was 229.7 IU/mL (normal range, 0–6.6 IU/mL) and lactate dehyrogenase was 4781 units/L (normal range, 87–241 units/L). Retesting of hCG with dilution was specifically requested given incongruence with clinical presentation, and his initial hCG was corrected to 6 760 713 mIU/mL. Oncological evaluation confirmed diagnosis of non-seminomatous hCG-producing testicular choriocarcinoma complicated by hepatic and pulmonary metastases.

Treatment

On admission, the patient was started on methimazole, propranolol and intravenous corticosteroids (figure 2). On the fourth day of hospitalisation, he received his first cycle of cisplatin/etoposide, which led to a marked and progressive reduction in his hCG level (213 467 mIU/mL). His hCG improvement correlated with improvement in his thyroid function tests (TFTs), leading to complete resolution of his hyperthyroid symptoms, thus enabling methimazole discontinuation on his eighth day of hospitalisation. However, on hospital day 25, his hCG, FT4 and TT3 levels began to uptrend with secondary TSH suppression, requiring reinitiation of methimazole. Subsequently, a second cycle of cisplatin/etoposide was started on day 29 allowing symptomatic control and normalisation of his TFTs by day 38.

Figure 2.

Chronological display of hormone level variation during hospitalisation. X axis represents number of days since admission, and Y axis represents specific hormone levels with their respective measurement units. (A) represents the findings for TSH levels (uIU/mL), (B) represents the findings for TT3 (ng/dL), (C) represents the findings for FT4 (ng/dL), (D) represents the findings for beta-hCG (mIU/mL) and (E) represents the start and end days for each of the therapies used. FT4, free T4; hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone; TT3, total T3.

Outcome and follow-up

The patient’s labile clinical condition precluded orchiectomy, and unfortunately, despite achieving and maintaining successful control of his hyperthyroidism, he succumbed to his extensive and rapidly progressive malignant disease 46 days after admission.

Discussion

hCG is a glycoprotein well known for its fundamental role in human reproductive and developmental processes.¹⁵ hCG and TSH belong to a group of structurally similar glycoproteins that share the same alpha subunit structure but differ on the molecular structure of their beta subunits, which also results in several hCG isoforms with diverse biological effects.^{4 5} hCG exerts thyrotrophic activity through cross-reactivity on other hormone receptors within the same group1 2 16 17 and via intrinsic thyroid-stimulating activity of hCG.^{3 18}

In early pregnancy, mild variations in normal TFTs (increased FT4 and mildly decreased TSH) have been attributed to the effect of hCG on the TSH receptor.^{6 17} However, as thyroid stimulation is dependent on the amplitude and duration of the hCG peak, clinical effect during pregnancy is mostly minor, self-limited and not routinely detected. Previous studies have demonstrated a correlation between decreased TSH, increased FT4 and elevated hCG levels in women with hyperemesis gravidarum compared with pregnant controls.¹⁹ Clinically significant hCG-induced gestational hyperthyroidism has been previously reported but has been limited to the first half of pregnancy.⁶

Very high hCG secretion can lead to overproduction of thyroid hormones and feedback suppression of TSH levels. In addition, hCG-induced hyperthyroidism has been described as a rare paraneoplastic syndrome most commonly seen in women with hCG-secreting germ cell tumours^{7 20} and rarely seen in men with hCG-secreting choriocarcinomas.8 9 11 21 22 Irrespective of the gender and etiology, patients generally present with subclinical hyperthyroidism or mild hyperthyroid symptoms such as tachycardia and anxiety.^{11 16 21} This creates a diagnostic challenge for clinicians as the early signs of thyrotoxicosis could be attributed to infectious or inflammatory aetiologies, as well as worsening of primary malignant disease. Clinically significant thyrotoxicosis due to hCG-producing malignancy is unusual.9 10 23 24 To our knowledge, this is the second case describing hCG-induced thyroid storm in a male with newly diagnosed hCG-secreting metastatic testicular choriocarcinoma.¹² Of note, 40%–60% of testicular choriocarcinoma cases have been reported to have elevated hCG titres.⁹ The vast majority of these patients have normal TFTs,^{7 8} with an estimated 3.5% developing hyperthyroidism as a paraneoplastic process.²⁵ The reason that markedly elevated hCG level does not necessarily cause hyperthyroidism could be explained by the existence of hCG variants with diverse potency and thyrotrophic activity.^{2 6} Although less likely, a TSH receptor gene polymorphism could also increase the sensitivity of thyroid receptor to the hCG molecule.²⁶

Commercially available hCG assays are based on the use of monoclonal antibodies (capture and tracer antibodies) that bind to known epitopes of the hCG molecule, forming a sandwich complex that can be quantified via spectrometry.²⁷ When very high levels of hCG molecules are present (>500 000 mIU/mL), the tracer and receptor antibodies become polysaturated, preventing them from forming the sandwich complex and leading to an inaccurate molecule quantification; this has been described as the prozone (‘Hook-like’) effect.²⁸ In our patient’s initial work-up, the hCG level was found to be 6074 mIU/mL (Roche-Elecsys Free hCG Assay; detection range, 0.1–190 mIU/mL. Levels above the detection range should be measured again with sample dilution),²⁹ which is lower than expected for hCG-induced hyperthyroidism. Conversely, given negative work-up for autoimmune and other causes of thyrotoxicosis, retesting of hCG level with dilution was requested to assess for a level above the detection range and overcome the prozone effect of the assay, which resulted in a corrected level of 6 760 713 mIU/mL, confirming our clinical suspicion for hCG-induced thyrotoxicosis. Of note, hCG assays could indicate false-positive results in the presence of heterophilic antibodies²⁷; thus, if the result does not correlate with the clinical suspicion, retesting with blocking antibodies or with an alternative assay is indicated.

One complicating factor in our patient was the use of CT with iodinated contrast (95 mL of Omni 350). Iodine load can precipitate thyrotoxic symptoms through increased substrate uptake and increased production of circulating thyroid hormones (Jod-Basedow phenomenon) within 2–12 weeks after contrast exposure.³⁰ This patient had mild symptoms attributable to thyrotoxicosis on initial evaluation and returned to the ED with thyroid storm 9 days after receiving CT with iodinated contrast. Although we cannot quantify the degree to which contrast administration contributed to his thyroid storm, it is worth noting that imaging with contrast administration should be used judiciously in patients with suspected hCG-producing malignancies as it can precipitate or worsen thyrotoxicosis.³¹

We observed a direct correlation between hCG peak and TFT abnormalities as seen in prior case reports.^{7 11 21} Our patient’s hCG normalised after chemotherapy initiation with subsequent achievement of biochemical euthyroid state, thus enabling methimazole discontinuation. Recurrence of overt thyrotoxicosis during his hospitalisation was consistent with increasing hCG production, supporting the notion that the thyroid-stimulating role of hCG was likely the main driver of his thyrotoxicosis and his impending thyroid storm.

Most of the previously reported cases of hCG-induced hyperthyroidism have only required symptomatic management with beta adrenergic blockade.²¹ Rarely, temporary use of antithyroid agents has been documented.¹¹ However, given the severity of our patient’s clinical presentation, we implemented a multimodal approach that included intensive care monitoring, beta adrenergic blockade, corticosteroid therapy, and pharmacological and physical hyperthermia control. Methimazole was given during hCG peaks preceding chemotherapy, coinciding with periods of clinically significant thyrotoxicosis. Moreover, the use of iodinated contrast was also avoided to prevent further thyrotoxic stimulus.

In conclusion, although rare, very high hCG levels have been associated with hyperthyroidism in NSGCT. When present, hyperthyroidism is usually subclinical or minimally symptomatic and may require transient symptomatic and antithyroid management while response to oncological directed therapy is achieved. Use of iodinated contrast agents and/or exceptionally high levels of serum hCG may lead to development of thyroid storm, requiring emergent and ongoing aggressive management

Recognising early signs of thyrotoxicosis can be difficult in patients with testicular choriocarcinoma as initial presentation and symptoms could be attributed to worsening burden of primary malignancy. Given the substantial mortality of thyroid storm (10%–30%),^{14 32} a low threshold of suspicion should be maintained for possibility of clinically significant hyperthyroidism. If the clinical picture does not support a primary aetiology of hyperthyroidism and hCG is not concordantly elevated, reassessment of hCG by dilution should be considered to minimise falsely low hCG levels due to ‘Hook-like’ effect. When present, hyperthyroidism or thyroid storm should be actively treated and TFTs closely monitored as patients can experience rapid symptomatic improvement and biochemical normalisation in response to therapy. Finally, imaging studies requiring iodinated contrast should be limited or avoided in these patients to prevent potential worsening of underlying thyrotoxicosis.

Learning points.

• Clinically significant thyrotoxicosis due to human chorionic gonadotropin (hCG)-producing testicular choriocarcinoma in men is rare but can be a manifestation of the disease.

• hCG level could be subject to ‘Hook-like’ effect when using routine assays, thus resulting in falsely low hCG measurement and creating a clinical challenge.

• Use of iodinated contrast agents should be avoided in patients with thyrotoxicosis at risk of thyroid storm.

• Once hCG-induced thyrotoxicosis in the setting of malignancy is identified, it is imperative to implement a timely oncological directed therapy. Transient multimodal treatment targeting symptoms with antithyroidal and other agents may be needed to achieve biochemical euthyroid state.

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