Background

Calcium is the main component of the skeleton; it has major roles on muscle contraction, blood clotting, neuronal transmission and intracellular signaling. Hypercalcemia is a frequent occurrence in everyday medical practice. Although most patients will have mild or moderate hypercalcemia, in some cases hypercalcemia may be severe and life threatening without rapid and efficient treatment.

1 Subjects and Methods

Our study included patients presenting primary hyperparathyroidism with serum calcium levels > 3.5 mmol/l (14 mg/dl).

We reported clinical features, biological results, radiological findings and complications in these patients.

We also reported the symptomatic treatment of hypercalcemia and its effect as well as the etiological treatment of primary hyperparathyroidism and the evolution in the postoperative period.

2 Results

Five patients presenting primary hyperparathyroidism with severe hypercalcemia were reported. There are 3 males and 2 females with a mean age of 48 years. Serum calcium levels varied between 3.5 and 4.5 mmol/l (N: 2.1-2.75). Phosphatemia varied between 0.66 and 0.83 mmol/l (N: 0.83-1.50). Parathormone (PTH) levels varied between 840 and 1631 pg/ml (N: 15-65).

Non-specific symptoms such as anorexia, nausea, vomiting, polyuria, dehydration, abdominal pain, weight loss, fatigue, muscular weakness, pruritus, irritability and lethargy were present in all patients. Bone lesions: fractures or brown tumors were seen in four patients. One patient has oligoanuria and another patient has bilateral nephrocalcinosis. The parathyroid nodule size varied between 20 and 46 mm, it was palpable in three patients.

Because of the severity of hypercalcemia, all patients received symptomatic treatment before surgical ablation of parathyroid tumor. These treatments consisted in rehydration with isotonic saline in all patients, bisphosphonates (zoledronic acid) in three patients, calcitonin in two patients and corticosteroids in one patient. One of our patients required two sessions of hemodialysis.

While biphosphonates allowed normalization of serum calcium levels in all patients, other treatments had mild effect on serum calcium levels, with decrease ranging from 0.25 to 0.50 mmol/l.

All patients were operated on. Histological examination had concluded to carcinomas in two cases and to adenomas in three cases.

In the postoperative period all patients developed hypocalcaemia. The two patients who did not receive preoperative bisphosphonates experienced severe postoperative hypocalcaemia requiring infusion of high doses of calcium.

3 Discussion

Primary hyperparathyroidism which was viewed as relatively rare several decades ago and associated with significant morbidity is now considered a common disorder that is often asymptomatic. Prior to the mid-1970s, most patients were diagnosed when they presented with specific symptoms of hyperparathyroidism, nephrolithiasis or bone lesions. Nowadays, most patients are asymptomatic and are usually diagnosed incidentally when serum calcium is noted to be mildly elevated on a multiphasic chemistry profile (Bilezikian, 2012).

Severe hypercalcemia is rare in primary hyperparathyroidism, it occurs in 1% to 2% of patients with primary hyperparathyroidism (Kebebew and Clark, 1998). We have identified only 5 cases in our practice. Its presence increases the possibility of malignancy, as severe hypercalcemia may be seen in 10 to 38% of parathyroid carcinoma cases, while parathyroid carcinoma represent less than 1% of primary hyperparathyroidism etiologies (Wermers et al., 2006). 40% of our patients had carcinoma.

Clinical manifestations of hypercalcemia depend on the degree of hypercalcemia and the rapidity of its onset. In general, overt symptoms are rare in patients with serum calcium levels below 12 mg/dL, but at concentrations above 14 mg/dL most patients are symptomatic (Bilezikian, 1993). Manifestations of hypercalcemia are depicted in Table 1.

Management of severe hypercalcemia includes medical treatment for rapid lowering of calcium levels and surgical treatment for the underlying etiology of primary hyperparathyroidism (Ariyan and Sosa, 2004).

Emergency treatment of hypercalcemia must first focus on correcting dehydration, restoring intravascular volume, and enhancing renal calcium excretion. Restoration of intravascular volume will enhance urinary calcium excretion by increasing glomerular filtration of calcium and decreasing proximal tubular and loop reabsorption of sodium. Parenteral fluid resuscitation must be administered cautiously in patients with heart or kidney failure. 500 to 1,000 ml of 0.9 % saline should be infused over the first hour, and then 2 to 5 liters are added over the first 24 hours. The goal of this regimen is to achieve a urine output of 200 ml per hour. It usually decreases serum calcium levels by 1-3 mg/dl. The addition of loop diuretics to saline infusion has been advocated to enhance renal calcium leak, but it should be administered after adequate hydration has taken place because diuretic- induced volume contraction can worsen the hypercalcemia. Therefore, diuretics are best reserved for those patients with compromised heart function (LeGrand et al., 2008).

Bisphosphonates are pyrophosphate analogues that are deposited in bone and lower serum calcium levels via multiple effects on osteoclasts, one of which is inhibition of osteoclastic bone resorption. Because of their efficiency in normalizing serum calcium, they should be considered for use early in the course of treatment of severe hypercalcemia. Intravenous bisphosphonates have been successfully used in the treatment of severe hypercalcemia related to parathyroid adenoma or carcinoma as in our patients (Witteveen et al., 2010). The effect of a parenteral bisphosphonate to lower serum calcium is apparent within 2-4 days, with maximal effect within 7-10 days after commencing treatment. The effect can persist for 7-30 days. Zoledronic acid, the bisphosphonates we used in our patients has proven efficacious in the treatment of severe hypercalcemia with a longer duration of action (Sabry and Habib, 2011).

Glucocorticoids have been widely used in the management of severe hypercalcemia, though; they are usually not effective in the treatment of hypercalcemia related to primary hyperparathyroidism. Glucocorticoids lower calcium levels by decreasing intestinal absorption of calcium via decreased synthesis of 1, 25-dihydroxy vitamin D and by increasing urinary calcium excretion (Kristensen et al., 1992).

Calcitonin is another therapeutic option to inhibit osteoclastic resorption. It has a rapid onset of action, causing serum calcium levels to fall within hours of administration. It can be used in conjunction with a bisphosphonates to more rapid reduction of serum calcium levels. It is usually given intramuscularly or subcutaneously. However, the efficacy of calcitonin is transient due to rapidly acquired resistance (Ljunghall, 1989).

Hemodialysis against a low- or zero-calcium dialysate is effective in temporarily reducing the serum calcium level and has been sometimes, successfully used in the treatment of severe hypercalcemia (Wang et al., 2009).

Treatment of the underlying etiology is essential. It is surgical and it consists in a parathyroidectomy. After parathyroidectomy, patients are at risk of rapid and sharp decline of calcium levels in the postoperative period and may require large amounts of calcium infusion as we observed in two of our patients. The risk of postoperative hypocalcemia is attributed to the severity of the disease (Harjit et al., 2007).

4 Conclusions

Severe hypercalcemia is an endocrine emergency that requires rapid action to prevent cardiac, neurological and renal complications. The diagnosis should be considered in any patient with known parathyroid disease who presents with acute clinical picture, we also emphasize on the importance of early diagnosis and treatment of hypercalcemia to improve the prognosis.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to this article.

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