Graves’ Disease Hyperthyroidism Induced Severe Hypercalcemic Crisis in Case Report

While hyperthyroidism affects roughly 0.2 percent to 1.4 percent of people globally and accelerates bone resorption over bone formation, serum calcium concentrations rarely exceed 3.0 mmol/L in hyperthyroidism-induced hypercalcemia. A hypercalcemic crisis, characterized by serum calcium levels exceeding 3.5 mmol/L, represents an exceptionally uncommon clinical manifestation of the condition.

The patient initially sought medical attention at an outpatient gastroenterology clinic after experiencing progressive anorexia, nausea, and vomiting. An upper gastroscopy revealed erosive gastritis, and an electrocardiogram documented sinus tachycardia with a heart rate of 117 beats per minute. Treatment with the proton pump inhibitor rabeprazole failed to relieve her gastrointestinal symptoms, leading her to seek further hospital evaluation where laboratory testing revealed a critical serum calcium elevation of 3.62 mmol/L against a normal reference range of 2.10 to 2.60 mmol/L. Her serum sodium, potassium, phosphorus, and albumin remained within normal ranges.

Due to the critical calcium measurement, the patient was promptly transferred to the emergency department for urgent intervention, receiving 0.9 percent saline solution and furosemide to lower her calcium to 3.40 mmol/L before being admitted for monitoring. On physical examination the following day, her body temperature was 36.6 degrees Celsius, heart rate was 109 beats per minute, blood pressure was 130/80 mmHg, and her body mass index was 21.50 kg/m2. She exhibited bilateral hand tremors and reported an unintentional weight loss of 10 kilograms over the preceding month, accompanied by constipation, thirst, polyuria, and irritability, while showing no signs of exophthalmos, goiter, thyroid tenderness, or heat intolerance.

Extensive diagnostic workup was undertaken to clarify the underlying cause of her severe PTH-independent hypercalcemia. Blood tests revealed a profoundly suppressed serum parathyroid hormone level of 3.85 pg/mL, ruling out primary hyperparathyroidism as the driver of her hypercalcemia. Thyroid profiling showed marked thyrotoxicosis, with elevated free T3 of 13.9 pg/mL, elevated free T4 of 44.7 ng/L, suppressed thyroid stimulating hormone below 0.005 uIU/mL, and positive TSH receptor antibodies at 30.2 IU/L, confirming the diagnosis of Graves’ disease.

To evaluate potential alternative causes of hypercalcemia, clinicians conducted imaging and oncological screenings. Thyroid ultrasonography revealed uniform echogenicity with a cystic nodule on the left lobe categorized as C-TIRADS II. Plain computed tomography scans of the neck, thorax, abdomen, and pelvis, alongside breast ultrasound, were normal and showed no signs of malignancy or bone destruction.

Further laboratory assessments eliminated other systemic hematologic and endocrine disorders. Morning serum cortisol was 8.09 ug/dL, excluding adrenal insufficiency. Immunoglobulin levels of IgA, IgG, and IgM, as well as serum protein electrophoresis and peripheral blood smear, demonstrated no evidence of multiple myeloma, with M protein testing returning negative. Dual-energy X-ray absorptiometry revealed osteopenia, showing T-scores of -1.7 at L1, -2.7 at L2, -2.7 at L3, -2.0 at L4, -2.3 across the total lumbar spine, -1.4 at the femoral neck, and -1.1 across the entire femur.

Initial inpatient management focused on volume rehydration and endocrine stabilization, utilizing 2500 mL of 0.9 percent saline and 20 mg of intravenous furosemide twice daily.

Because the patient continued to endure persistent anorexia, nausea, and vomiting, medical staff administered 10 units of subcutaneous elcatonin and an intravenous infusion of 5 mg zoledronic acid to rapidly suppress osteoclastic activity. By the following day, the serum calcium dropped sharply to 2.70 mmol/L, accompanied by substantial relief of her gastrointestinal distress.

Subsequent outpatient follow-up examinations confirmed sustained clinical remission and stabilization of biochemical parameters. At one week post-discharge, her serum calcium measured 1.91 mmol/L. At one month, calcium was 2.07 mmol/L, free T3 was 2.59 pg/mL, free T4 was 6.49 ng/L, and TRAb was 34.6 IU/L under a daily regimen of 5 mg methimazole. At two months, serum calcium stabilized at 2.29 mmol/L, parathyroid hormone rose to 51.27 pg/mL, free T3 was 4.59 pg/mL, free T4 was 8.23 ng/L, and methimazole was successfully reduced to 5 mg every other day.

Discussing the physiological mechanism, the authors noted that hyperthyroidism stimulates excessive bone turnover with a shortened remodeling cycle, releasing excess calcium into circulation. The patient presented with a mildly elevated serum alkaline phosphatase level of 148.9 U/L, a bone formation marker elevated in roughly 50 percent of hyperthyroid patients complicated by hypercalcemia. While factors such as elevated interleukin-6 and wingless/integrated signaling inhibition by sclerostin have been linked to osteoclastic resorption in research literature, prompt combined intervention with antithyroid medications and bone resorption inhibitors proved vital to resolve the crisis.

A twenty-four-hour urine calcium measurement yielded 3.54 mmol per twenty-four hours, safely within the normal reference range of 2.5 to 7.5 mmol per twenty-four hours. Serum phosphorus remained normal during serial assessments, measuring 1.17 mmol/L during initial screening and 1.05 mmol/L upon admission against a reference span of 0.80 to 1.45 mmol/L. Fasting blood glucose was normal at 5.67 mmol/L compared with the reference range of 3.89 to 6.11 mmol/L, while serum creatinine measured 69.1 μmol/L within the normal limits of 35 to 97 μmol/L. Furthermore, specialized thyroid antibody testing revealed normal concentrations of antithyroid globulin antibodies at 13.9 IU/mL against a reference threshold below 115 IU/mL, and antithyroid peroxidase antibodies at 13.7 IU/mL against a reference limit below 34 IU/mL.

To thoroughly rule out occult malignancies and hematologic neoplasms, the clinical investigators documented detailed serum protein fractions and specific circulating oncologic markers. Serum protein electrophoresis revealed beta-1 globulin at 5.60 percent within the normal range of 4.7 to 7.2 percent, beta-2 globulin at 8.40 percent against the standard span of 3.2 to 6.5 percent, and electrophoretic albumin at 51.30 percent relative to the normal range of 55.8 to 66.1 percent. Alpha-1 globulin measured 4.40 percent across the normal range of 2.9 to 4.9 percent, alpha-2 globulin measured 9.20 percent within reference limits of 7.1 to 11.8 percent, and gamma-globulin stood at 21.10 percent against the reference range of 11.1 to 18.8 percent. Serum immunoglobulin quantification confirmed immunoglobulin A at 3.45 g/L within the interval of 0.7 to 4.0 g/L, immunoglobulin G at 15.8 g/L across the 7.0 to 16.0 g/L range, and immunoglobulin M at 1.25 g/L within the 0.4 to 2.3 g/L boundary. Tumor markers demonstrated reassuring values, with carcinoembryonic antigen at 0.492 μg/L, alpha-fetoprotein at 3.72 ng/mL, carbohydrate antigen 19-9 at 3.84 U/mL, carbohydrate antigen 15-3 at 8.02 g/L, squamous cell carcinoma antigen at 0.706 ng/mL, cytokeratin 19 fragment at 2.9 μg/L, and neuron-specific enolase at 12.4 μg/L.

The clinical course emphasized the pharmacokinetic lag intrinsic to antithyroid drug therapy during acute endocrine emergencies. Because circulating thyroxine has a seven-day plasma half-life and preformed hormones in the thyroid gland require two weeks to deplete, antithyroid medications cannot rapidly clear circulating thyroid hormone. To contextualize this delay, the authors cited prior findings by Montefusco and colleagues involving hyperthyroidism complicated by hypercalcemia, where serum calcium fell from 3.27 mmol/L to below 3.0 mmol/L after one week but required two full weeks to reach normal ranges. In this patient, five days of antithyroid treatment failed to lower calcium levels, while persistent nausea and vomiting caused substantial distress. The medical team therefore administered ten units of subcutaneous elcatonin and five milligrams of intravenous zoledronic acid, achieving a rapid drop in calcium to 2.7 mmol/L by the following morning.

Pathophysiological discussions in the report also highlighted the interplay of adrenergic tone and osteoclastic signaling in thyrotoxic bone loss. Researchers propose that heightened adrenergic stimulation contributes directly to elevated bone turnover in hyperthyroid patients. Additionally, while literature links elevated interleukin-6 to enhanced osteoclastic activity in Graves’ disease, the hospital’s clinical laboratory lacked the capability to measure interleukin-6 levels directly. The authors underscored that because primary hyperparathyroidism remains the most prevalent cause of hypercalcemia in clinical practice, clinicians must maintain high suspicion for Graves’ disease when evaluating severe parathyroid-independent hypercalcemia. Prompt combined intervention targeting both acute bone resorption and thyroid hypersecretion remains essential to reverse life-threatening crises and preserve patient outcomes.

Subject of Research: Hypercalcemic crisis induced by Graves' disease hyperthyroidism

Article Title: Hypercalcemic Crisis Induced by Hyperthyroidism of Graves' Disease: A Case Report

Article References: Wang, S., & Wang, J. (2026). Hypercalcemic Crisis Induced by Hyperthyroidism of Graves' Disease: A Case Report. Clinical Case Reports, 14(11), Article e73882. https://doi.org/10.1002/ccr3.73882

Image Credits: AI Generated

DOI: 10.1002/ccr3.73882

Keywords: Graves' disease, hyperthyroidism, hypercalcemic crisis, hypercalcemia, zoledronic acid, elcatonin, methimazole, bone resorption, Hypercalcemic, Crisis, Induced, Graves'