Thyrotoxicosis and concomitant hypercalcemia

In clinical practice, serum electrolytes of patients with hyperthyroidism are often ignored. The prevalence of hypercalcemia in patients with thyrotoxicosis was 17% to 50% in literatures,1,2 and asymptomatic serum calcium elevation has been documented in up to 20%.1 We described a case of hypercalcemia related to thyrotoxicosis, which had been neglected by the doctors at the first visit. A 35-year old man was admitted to Peking University First Hospital on September 14, 2009 due to hyperthyroidism and hypercalcemia. He had a three-week history of palpitation, diaphoresis and weight loss, and was diagnosed as hyperthyroidism due to thyroid function test. His biochemical tests were calcium 3.16 mmol/L and phosphorus 1.61 mmol/L, but hypercalcemia was neglected at the first visit. He was given methimazole (MMI) 10 milligram (mg) three times per day and bisoprolol 5 mg once per day. Three days later he suddenly presented nausea and vomiting without diarrhea and abdominal pain, and he went to our hospital. There were no special diseases in his past medical history and he denied to have taken any kind of special medicine. Physical examination revealed warm skin. Pulse rate was 82 beats per minute and blood pressure was 110/60 mmHg. There was diffuse goiter and vascular murmur could be heard. Laboratory findings on admission revealed normal liver and renal function, a mild degree of hypercalcemia (Ca 2.94 mmol/L), normal albumin and phosphate, decreased level of intact parathyroid hormone (iPTH) 9.69 pmol/L with a normal fT4, decreased TSH 0 mIU/L and positive anti-TSH receptor antibody (TRAb) 78.62 U/L. Thyroid ultrasound showed a diffuse thyroid change with abundant blood flow. The bone mineral density was normal. All the tumor markers and serum/urine immunofixation electrophoresis (IFE) were negative. His serum angiotensin-converting enzyme (ACE) was mild elevated (85 U/L), but sarcoidosis was excluded since he did not have symptoms like cough, chest tightness, fever and his chest radiograph was normal. Considering that serum iPTH was decreased, a diagnosis of hypercalcemia secondary to thyrotoxicosis was made. He was rehydrated with intravenous isotonic saline, bisoprolol was given orally. His sympathetic symptoms and hypercalcemia were successfully controlled. Since his white blood cell (WBC) and neutrophil decreased gradually, MMI was discontinued and he received radioiodine (RAI) treatment two weeks later. His sympathetic symptoms and serum calcium level were worsened after thyroid ablation therapy. Calcium level increased to 3.13 mmol/L. Calcitonin was injected 50 units twice per day. One week later his serum calcium level normalized to 2.52 mmol/L. After two months of thyroid ablation therapy, the patient became euthyroid without taking any drugs and maintained normal calcium level for the next nine months. We further reviewed the literatures about case reports of thyrotoxicosis complicating with hypercalcemia in English and Chinese from January 1, 1990 to October 31, 2012. We used ‘hyperthyroidism’, ‘thyrotoxicosis’ ‘hyperthyrotoxic’ and ‘hypercalcemia’ ‘high calcium crisis’ as the key words and searched the ‘Pubmed’, ‘Web of Science’, ‘China National Knowledge Infrastructure (CNKI)’ and ‘Wan Fang’ databases (in Chinese). As shown in Table 1, there were 34 case reports of hypercalcemia in thyrotoxic patients. Most of them were adults (22-69 years) and only one was a child. Female (22/34, 64.7%) was predominantly affected. Hypercalcemia caused by thyrotoxicosis per se was about 47.1% (15/34), and not only hyperthyroidism (12/15, 80%) but also transient thyrotoxicosis caused by various thyroiditis (such as Hashimoto's thyroiditis, subacute thyroiditis and factitious thyrotoxicosis) could result in hypercalcemia. Graves' disease (GD) was the main cause of thyrotoxicosis per se induced hypercalcemia (11/15, 73.3%). The other causes combined with thyrotoxicosis were primary hyperparathyroidism (PHP) (11/34); increasing PTH-related peptide (PTHrP) (1/34) induced by thymus enlargement; diabetes insipidus (1/34); toxic multi-nodular goiter (1/34) and glucocorticoid deficiency (6/34). Glucocorticoid deficiency was always caused by hypoadrenalism, such as post operation of adrenalectomy due to Cushing's syndrome or hypopituitarism after treatment of acromegaly and lymphocytic hypophysitis itself.Table 1: Thirty-four case reports of hypercalcemia in thyrotoxic patients during recent yearsAccording to our summary, weight loss (64.7%), nausea and vomiting (both 50%) were the most typical manifestations of these thyrotoxic patients with hypercalcemia. Symptoms of sympathetic stimulation, such as heat intolerance, palpitation, hand tremor and insomnia were less frequent. In most cases (70.5%), hypercalcemia was mild to moderate ranging from 2.65 to 3.50 mmol/L. Calcium level was higher than 3.5 mmol/L only in two kinds of patients, with GD alone or combined with PHP. Hypercalcemic crisis (serum calcium was 4.15 mmol/L) was developed in a GD patient with central diabetes insipidus (DI). Only six out of 34 cases had no symptoms of hypercalcemia. In thyrotoxicosis-induced hypercalcemia, females were affected more frequently than males. It was probable due to the higher prevalence of thyroid diseases in females. The calcium levels in case reports ranged from 2.7 to 3.5 mmol/L and rarely exceeded 2.8-3.0 mmol/L. And it seems that there was no difference in serum calcium levels in patients with or without hypercalcemia symptoms (6/34, 17.6%). The most common cause of hyperthyroidism was GD. Besides, hypercalcemia could also result from transient thyrotoxicosis. The pathogenesis of hypercalcemia in thyrotoxicosis is multi-factorial. It has been reported that increased osteoclast activity most likely accounted for the high concentrations of serum calcium. Nonetheless, other humoral mechanisms, such as a hyperadrenergic state could also contribute to hypercalcemia. Increased sensitivity of beta-adrenergic receptors to catecholamines by thyroid hormone is another possible mechanism. Both PHP and glucocorticoid deficiency combined with thyrotoxicosis could lead to hypercalcemia. In patients with glucocorticoid deficiency, intestinal calcium absorption increased and renal calcium excretion decreased respectively. Furthermore, thyroid hormone-induced bone resorption is inhibited by glucocorticoids. Bone resorption may be synergistically stimulated in thyrotoxic patients with glucocorticoid deficiency. Thus, mild hypercalcemia in thyrotoxic patients may be aggravated when glucocorticoid deficiency coexists. As we all know, thyrotoxicosis present with diversity physiological effects of excessive thyroid hormones. However, signs and symptoms in hypercalcemia per se are weakness, apathy, depression, constipation and even coma, which were quite opposite to the former. Thereby, the clinical manifestations of thyrotoxicosis with hypercalcemia were compounded. Hypercalcemia symptoms, such as constipation, nausea and anorexia, might mask symptoms of thyrotoxicosis, such as diarrhea or an increased appetite. Therefore, serum calcium levels in thyrotoxic patients with nausea and anorexia should be monitored. The laboratory examinations in thyrotoxicosis induced hypercalcemia were usually invariably mild to moderate hypercalcemia (2.6-3.5 mmol/L), low to high levels of phosphorus, high alkaline phosphatase (ALP), and low levels of PTH. The reduced intestinal calcium absorption and enhanced renal loss in thyrotoxicosis help to prevent further increasing of serum calcium level. It might be the reason that hypercalcemia in hyperthyroidism was usually mild to moderate. A positive correlation between thyroid hormone levels and the severity of hypercalcemia has been noted,3 although this relationship was not a consistent finding. Hypercalcemia might be more serious when thyrotoxicosis concomitant with other diseases which can aggravate hypercalcemia per se, such as PHP and glucocorticoid deficiency. For the patients with hypercalcemia and thyrotoxicosis, it was necessary to bring down serum calcium promptly in severe hypercalcemia. Besides the general managements with saline hydration and diuretic, other modalities of treatments could be used in resistant cases. It has been shown that propranolol, calcitonin and pamidronate were effective to control hypercalcemia in thyrotoxic patients. For patients with mild or in high normal range hypercalcemia, the calcium level will return to normal range in euthyroid state. In hyperthyroid adults, the mainstay of treatments on hypercalcemia is to control hyperthyroidism. Since RAI increases thyroid hormone releasing, it should be alert that ablation therapy by radioiodine (RAI) can exacerbate thyrotoxicosis and even hypercalcemia, as illustrated in our case and the other two case reports. Therefore, it must be cautious to choose RAI as the ablation therapy in thyrotoxic patients with hypercalcemia. In all cases with glucocorticoid deficiency, no matter what the causes were, serum calcium level rapidly normalized after administration of glucocorticoids. Considering the high relapse rate of hyperthyroidism treated by antithyroid drug, surgery might be the best choice for patients with severe hypercalcemia. In cases that GD erupted simultaneously with PHP, surgical treatment could correct both diseases at the same time. In summary, the present case highlights that concomitant thyrotoxicosis and hypercalcemia always appears untypical clinical manifestations and laboratory examinations. Physicians should take thyrotoxicosis into consideration in the differential diagnosis of hypercalcemia and pay more attention to the electrolyte status in thyrotoxic patients.