Hypercalcaemia as the initial presentation of Graves’ disease

Abstract

Hypercalcaemia in patients with hyperthyroidism is usually asymptomatic. It occurs due to increased bone turnover and demineralisation. There are only a few case reports where symptomatic hypercalcaemia was the presenting complaint of hyperthyroidism. An Asian man in his 40s presented to us with intractable vomiting for the last 6 months which was not controlled despite multiple antiemetic medications. On routine biochemistry performed at our institute, he was found to have hypercalcaemia and concomitant hyperthyroidism. Classical symptoms suggestive of hyperthyroidism were not present in our patient thus delaying the diagnosis. His symptoms resolved after the correction of hypercalcaemia. Hypercalcaemia did not recur after achieving an euthyroid status on treatment with carbimazole. Other common and more sinister causes for hypercalcaemia like malignancy were ruled out. This case highlights that symptomatic hypercalcaemia could be the initial presentation of hyperthyroidism and amelioration of hyperthyroidism corrects the hypercalcaemia.

Background

Hyperthyroidism commonly presents with classic clinical features such as weight loss, palpitations, heat intolerance and diarrhoea. Some atypical presentations include—myopathy, abdominal pain, osteoporosis, heart failure and pedal oedema.¹ Hypercalcaemia as initial presentation in patients with hyperthyroidism is less common but is reported in a few case reports.^2–4 We report a case of a middle-aged man who presented with recurrent vomiting for the last 6 months and was found to have hypercalcaemia and hyperthyroidism.

Case presentation

An Asian man in his 40s presented with multiple episodes of vomiting and diffuse pain abdomen for the past 6 months. There was also a history of loss of appetite and weight loss of around 30 kg. He was taking medications after consultation with local practitioners but there was no improvement in his symptoms. His medical records showed that he was being prescribed antiemetics. He was also diagnosed with hyperthyroidism based on laboratory tests when his symptoms started and was prescribed carbimazole. He took carbimazole for 1 month and then stopped taking the drug as he did not find any improvement in his symptoms but continued to take antiemetics. He even consulted a gastroenterologist for his symptoms and an upper gastrointestinal (GI) endoscopy was done that was also normal. There was no history of abnormal bowel movements or dark-coloured stools. There was no history of jaundice, chronic fever, chronic cough, abdominal distension or swelling of the feet. He did not have any palpitations, tremors or postural giddiness. He was a non-smoker and non-alcoholic.

When the patient came to our institute, he looked poorly nourished. His body mass index was 17.4 kg/m². He was dehydrated and had resting tachycardia (pulse rate – 114/min). Blood pressure measured in supine position was 130/90 mm Hg and there was no significant postural drop. On examination, he was found to have fine tremors in bilateral hands and left-sided non-tender gynecomastia measuring 4 cm in diameter. There was no pallor, icterus, eye signs, goitre or lymphadenopathy. There was no organomegaly or ascites on abdominal examination. Respiratory and cardiovascular examination was also normal. Genital examination revealed tanner stage 5 pubic hair and adult testicular size (15–20 cm³ bilateral symmetrical) as measured by Prader orchidometer with no testicular masses.

Investigations

Routine blood investigations showed hypercalcaemia and hyperuricaemia. Workup for aetiology of hypercalcaemia revealed parathyroid hormone (PTH)-independent hypercalcaemia (table 1). Thyroid function tests showed primary hyperthyroidism with elevated thyroid-stimulating hormone receptor antibodies confirming Graves’ disease. Technetium (Tc99m) pertechnetate scan was done, which showed increased uptake with a cold thyroid nodule in the right lobe (figure 1). Ultrasound-guided fine-needle aspiration cytology (FNAC) was done from the cold thyroid nodule and was reported as atypia of undetermined clinical significance (Bethesda cytology category III). An ultrasound of both breasts was done that showed bilateral gynecomastia of benign aetiology (Breast Imaging-Reporting and Data System (BIRADS) II). Adrenocorticotropic hormone stimulated cortisol was done to rule out adrenal insufficiency as an aetiology of persistent vomiting but it was normal. CT of the neck, thorax, abdomen and pelvis and tumour markers were done to rule out malignancy as a cause of PTH-independent hypercalcaemia and were normal (table 1). Serum ACE levels were slightly elevated. Peripheral blood smear and bone marrow cytology were normal.

Table 1.

Biochemical investigations of the patient at admission and during follow-up

Test	At admission	3rd day	1 week	1 month	Normal range SI units
Serum calcium (corrected)	3.29 mmol/L	2.79 mmol/L	2.45 mmol/L	2.3 mmol/L	2.12–2.62 mmol/L
Serum phosphorus	0.97 mmol/L				0.81–1.45 mmol/L
Serum 25 OH Vit D	98.34 nmol/L				74.8–125 nmol/L
Serum iPTH	3.3 ng/mL				15–18 ng/mL
Serum FT4	47.87 pmol/L	–	25.23 pmol/L	16.34 pmol/L	11.4–22.6 pmol/L
Serum TSH	0.007 mIU/L			<0.005 mIU/L	0.5–4.5 mIU/L
TSH-R Ab	26.82 IU/L				<1.22 IU/L
Serum uric acid	892.2 µmol/L	731.6 µmol/L	410.41 µmol/L	380.67 µmol/L	209–428.3 µmol/L
Serum creatinine	91.96 umol/L				61.9–104 µmol/L
24-hour urine calcium	4.46 µmol /24 hours				6.16–2.64 µmol/24 hours
Serum CA 125	6.10 U/mL				<35 U/mL
Serum CEA	0.76 µg/L				<5 μg/L
Serum ACE	82 U/L				12–68 U/L
Serum AFP	1.40 µg/L				<10 μg/L
Serum b HCG	<2 IU/L				<2 IU/L
Urine Bence-Jones protein	Negative

ACE, Angiotensin Converting Enzyme; AFP, Alpha fetoprotein; b HCG, beta Human Chorionic Gonadotropin; CEA, Carcinoembryonic antigen; fT4, Free thyroxine; iPTH, Intact Parathyroid hormone; TSH, thyroid-stimulating hormone; TSH-R Ab, TSH receptor antibodies.

Figure 1.

99mTc pertechnetate thyroid scintigraphy scan suggestive of a hypofunctioning thyroid nodule involving right lobe in background of the diffusely enlarged and hyperfunctioning thyroid gland.

Differential diagnosis

Initially, any medication or GI causes were thought of as an underlying cause for chronic vomiting and were ruled out by history, imaging and baseline biochemical tests. For endocrine causes—hypercalcaemia, and adrenal insufficiency were thought of. Routine investigations showed hypercalcaemia that was PTH independent and concomitant hyperthyroidism. As hypercalcaemia in hyperthyroidism is usually mild and asymptomatic, other common causes like sarcoidosis, multiple myeloma and malignancy were ruled out.

Treatment

The patient was started on intravenous hydration for hypercalcaemia and serum calcium levels were monitored twice daily. He was simultaneously also started on antithyroid drugs (carbimazole 10 mg three times a day), beta-blockers for heart rate control and febuxostat for hyperuricaemia. After 2 days of hydration, his calcium levels came to normal range and his vomiting resolved. He was discharged on the same doses of carbimazole, propranolol and febuxostat and followed up 3 weeks later.

Outcome and follow-up

At the follow-up visit in the outpatient department, the patient was asymptomatic and there was no further nausea or vomiting. He was euthyroid on carbimazole and had normal serum calcium levels and uric acid levels. Febuxostat was stopped and uric acid levels were monitored later. Hyperuricaemia and hypercalcaemia did not recur, attributing their aetiology to the underlying uncorrected hyperthyroidism. For the thyroid nodule (Bethesda-III) patient was advised either follow-up or surgical excision. He underwent right hemithyroidectomy and histopathology of the surgical specimen showed papillary thyroid carcinoma measuring 1.8×1.6×1.2 cm (American Thyroid Association (ATA) low-risk category). He is being planned for total thyroidectomy and central compartment neck dissection.

Discussion

We describe an adult male who presented with nausea and vomiting and was found to have PTH-independent hypercalcaemia and underlying Graves’ disease. Hypercalcaemia resolved with hydration and did not recur once the euthyroid state was achieved.

Hypercalcaemia in hyperthyroidism is usually mild in nature and mostly asymptomatic.⁵ The underlying mechanism for hypercalcaemia in hyperthyroidism is increased bone remodelling. Increased interleukin-6 (IL-6) in hyperthyroidism stimulates osteoclastic activity and alters osteoblastic coupling.⁶ Also, tri-iodothyronine (T3) increases the sensitivity of bone to IL-6.⁷ Some authors have proposed that increased adrenergic tone in hyperthyroidism also leads to increased bone turnover.⁸ There is a disproportionate increase in bone resorption over new bone formation that leads to net bone loss and calcium mobilisation.⁷ There is a linear relationship between serum calcium levels and thyroid function which is more evident with older age.⁹ There are only a few case reports in which patients with hyperthyroidism presented with hypercalcaemia symptoms.^{2–4 10} In one study, up to 20% of patients with hyperthyroidism were found to have hypercalcaemia with up to one-third having GI symptoms.¹¹

Hyperparathyroidism and malignancy constitute 80%–90% of the causes of hypercalcaemia. Other endocrine causes include—hyperthyroidism, adrenal insufficiency and pheochromocytoma.¹² Our patient was found to have PTH-independent hypercalcaemia. Since hypercalcaemia in hyperthyroidism is usually asymptomatic and mild in nature, workup for other common causes for PTH-independent hypercalcaemia like malignancy, multiple myeloma and sarcoidosis was done and after excluding those hyperthyroidism was thought of as the underlying cause. Resolution of hypercalcaemia with beta-blockers and carbimazole also supports underlying Graves’ disease as the aetiology for hypercalcaemia in our patient. Iqbal et al and Chen et al also described similar cases of Graves’ disease presenting as hypercalcaemia symptoms where the diagnosis was made after exclusion of other common causes.^{13 14}

Serum ACE levels, a biomarker for sarcoidosis, are also elevated in other non-sarcoidosis conditions, such as hyperthyroidism.^{15 16} Our patient had a mild elevation of serum ACE levels. Chest and abdomen imaging performed did not show any lesions suspicious of sarcoidosis. The elevation of serum ACE levels in our patient could, therefore, be attributed to the underlying hyperthyroidism. Serum alkaline phosphatase(ALP) levels are elevated in most of the patients with hyperthyroidism that normalises with treatment of hyperthyroidism.¹⁷ Our patient had normal serum ALP levels at the presentation.

Hyperuricaemia can be seen with hyperthyroidism because of increased urate production.¹⁸ In an observational study, it was seen that serum uric acid concentration corelates with serum thyroxine concentration, and increased uric acid levels become normal with the achievement of an euthyroid state.¹⁹ More studies are needed to determine whether uric acid lowering medications are required along with antithyroid drugs for the hyperuricaemia accompanying hyperthyroidism. Our patient was started on febuxostat along with antithyroid medications which was tapered down on follow-up visits when serum uric acids were in the normal range. No significant hyperuricaemia was detected thereafter on follow-up visits.

Gynecomastia has been seen in up to 30% of patients with hyperthyroidism and the proposed mechanism is alteration in oestrogen and testosterone metabolism which resolves with normalisation of thyroid hormone levels.²⁰ Gynecomastia seen is mostly bilateral but a few reports of unilateral gynecomastia as the initial presentation of Graves’ disease exist.²¹ Our patient had unilateral gynecomastia on palpation but ultrasound examination confirmed it as bilateral.

Our patient had a cold nodule on thyroid scintigraphy and FNAC showed Bethesda category III with a malignancy risk of 10%–30%. Options were to either follow-up or do molecular testing for further risk assessment. Due to the risk of lost to follow-up and the non-availability of molecular testing he underwent right hemithyroidectomy 2 months later. Histopathology reports suggested papillary thyroid carcinoma with ATA low-risk category. He is planned for completion thyroidectomy with central compartment neck dissection.

Patient’s perspective.

I was not able to eat anything for the last 6 months because of my condition and was not getting any relief from any of the medications prescribed to me. Getting to know the exact cause of my condition and getting treated for that was such a relief for me. I am feeling better and have not experienced any such symptoms again after discharge.

Learning points.

• Symptomatic hypercalcaemia can rarely be a presenting complaint in hyperthyroidism.

• Diagnosis is based on exclusion after ruling out other common etiologies of hypercalcaemia.

• Normal serum calcium levels ensue on follow-up after achieving an euthyroid state.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).