Postoperative Hypocalcemia After Thyroidectomy for Graves' Disease

Introduction

G raves' disease is the most common cause of hyperthyroidism and the most common autoimmune disorder in the United States. As a first-line treatment antithyroid medications or radioactive iodine ablation are generally used, with total thyroidectomy serving as a third-tier approach. However, in pregnant patients or patients with thyroid nodules, total thyroidectomy can serve as a first- or second-line approach. Surgical procedures generally include subtotal thyroidectomy, a near-total thyroidectomy, or total thyroidectomy (1). Risks of permanent recurrent laryngeal nerve palsy and permanent hypoparathyroidism are similar in patients who undergo total thyroidectomy versus those who undergo subtotal thyroidectomy. Total thyroidectomy, however, also allows for elimination of all abnormal tissue in the neck and lower recurrence rates for Graves' disease (2).

Estimates of the percentage of patients who experience transient hypoparathyroidism after all thyroid surgery range from 6.9% (3) to 46% (4,5). It is believed that patients undergoing thyroidectomy for Graves' disease are more likely to experience postoperative hypocalcemia than patients undergoing total thyroidectomy for other indications. However, no study has directly compared these two groups of patients.

The exact mechanisms of postoperative hypocalcemia are unknown and are yet to be elucidated; however, there appear to be significant factors that are associated with this complication: (i) Graves' disease; (ii) female gender; (iii) the extent of manipulation of the parathyroid glands at the time of surgery; and (iv) hungry bone syndrome with rapid skeletal uptake of calcium in patients with osteodystrophy (6). Two surgical groups have investigated hypocalcemia associated with thyroidectomy and their findings are summarized in Table 1.

We sought to determine whether Graves' disease patients are indeed more likely to experience postoperative hypocalcemia and whether the hypocalcemia was more severe than patients who underwent total thyroidectomy for other benign diseases.

Materials and Methods

An institutional review board-approved database was created of all patients who underwent total thyroidectomy from 1998 to 2009 at the Johns Hopkins Hospital. A total of 68 patients with Graves' disease underwent surgery during this period. An additional 55 patients who underwent total thyroidectomy for benign disease during this same period were randomly selected from the database and served as control subjects. Total thyroidectomy was performed by one of three surgeons.

On the basis of literature review of potential covariates involved in the development of postoperative hypocalcemia after thyroid surgery (7 –12), a retrospective review of patient charts was conducted to identify such factors. These included age (greater or less than 50 years), gender, ethnicity, preoperative alkaline phosphatase level, size of the goiter, whether or not parathyroid tissue or glands were present in the specimen, and the season the patient underwent surgery. Specific outcomes examined were calcium levels on postoperative day 1, whether or not patients experienced symptoms of hypocalcemia, whether or not Rocaltrol was started upon discharge due to hypocalcemia, the number of calcium tablets prescribed upon discharge, whether or not postoperative tetany occurred, and calcium levels 1 month after discharge. Number of calcium tablets and not exact dosage was recorded since a range of tablet sizes is available to patients over the counter (200–600 mg calcium per tablet). Consequently, specific dosages were unavailable for this study.

Total calcium or ionized calcium was measured depending upon the attending surgeon's choice. Hypocalcemia was defined as a total calcium level <8.5 mg/dL (normal 8.5–10.5 mg/dL) or an ionized calcium level <1.13 mmol/L (normal 1.13–1.32 mmol/L) on postoperative day 1 and 1 month after discharge. Symptoms of hypocalcemia among patients included perioral numbness, extremity paresthesias or myalgias, and/or positive Chvostek (if documented to be negative preoperatively) or Trousseau sign.

The routine practice of all three surgeons involved checking each patient's calcium level the morning after thyroidectomy. If a patient was normocalcemic, no supplementation was given as an inpatient or upon discharge. If the patient was hypocalcemic, they were administered calcium tablets as an inpatient and given instructions for calcium supplementation upon discharge. If the calcium level after calcium tablet supplementation was not easily stabilized, Rocaltrol was added and prescribed upon discharge. Graves' disease patients and control patients were supplemented identically. After discharge, hypocalcemic patients were followed by a nurse practitioner by phone to clarify quantity and length of calcium supplementation required and to inquire about any additional ongoing symptoms of hypocalcemia. Both normocalcemic and hypocalcemic patients were discharged postoperative day 1 unless calcium levels could not be stabilized. If the patient was symptomatic as an outpatient and the symptoms could not be resolved with additional calcium, serum calcium was checked.

Each outcome (“calcium levels on postoperative day 1,” “whether or not patients experienced symptoms of hypocalcemia,” “whether or not Rocaltrol was started upon discharge due to hypocalcemia,” and “calcium levels one month after discharge”) was analyzed using a logistic regression to obtain odds ratios (OR), 95% confidence intervals (CI), and p-values based on a Chi-square statistic. A Poisson regression was used to model count data for the outcome “number of calcium tablets prescribed upon discharge.” The outcome of “whether or not postoperative tetany occurred” required use of a Fisher exact test. For each potential risk factor, both adjusted for Graves' disease and unadjusted OR are presented where feasible.

Results

An analyses summary of each outcome is provided (Table 2).

Discussion

Prospective multicenter studies have shown that independent risk factors for predicting the development of transient hypocalcemia after thyroidectomy include female gender, the extent of manipulation of the parathyroid glands at the time of surgery, and, more recently, the presence of Graves' disease. The mechanisms suggested include hungry bone syndrome with rapid skeletal uptake of calcium in patients with osteodystrophy, as well as abnormal release of calcitonin by manipulation of the thyroid gland (6). In addition, Graves' disease may be associated with more profuse bleeding and adhesions between the thyroid capsule and parathyroid glands. Adhesions and reduction of visibility during diffuse bleeding from dissected thyroid tissue can more frequently lead to injuries of the parathyroid glands (8). Some studies suggest that the extent of resection and surgical technique have the greatest impact on the incidence of permanent postoperative hypoparathyroidism (7).

In comparison to control patients there was a trend toward Graves' disease patients having a higher prevalence of hypocalcemia on postoperative day 1, symptoms of hypocalcemia as inpatients, having Rocaltrol started upon discharge, and having a higher prevalence of hypocalcemia 1 month after thyroid surgery. The OR was significant for Graves' disease patients and the number of calcium tablets prescribed upon discharge. Further, 6 of 68 patients with Graves' disease and no patient in the control group were readmitted with tetany (p = 0.033). This supports our hypothesis that patients with Graves' disease are at increased odds of signs and symptoms of hypocalcemia after thyroidectomy.

Not surprisingly, the presence of parathyroid gland tissue in the thyroid specimen was predictive of postoperative hypocalcemia. A statistically significant association was found between presence of parathyroid tissue and both incidence of hypocalcemia on postoperative day 1 as well as incidence of starting the patient on Rocaltrol postoperatively. These findings support the work of others in demonstrating the importance of surgical technique in preserving the parathyroid glands during surgery (5). Thomusch et al. found that removal of a single parathyroid gland was not associated with postoperative hypocalcemia, whereas resection of at least two parathyroid glands increased the risk of transient and permanent hypoparathyroidism. We also agree that preservation of the parathyroid glands and their blood supply during thyroidectomy is a recommended surgical strategy to decrease the rate of postoperative hypocalcemia. Future studies are needed to determine whether there is decreased incidence of hypocalcemia after parathyroid reimplantation during thyroid surgery. In our study we did not find that incidental parathyroidectomy occurred more often in our patients with Graves' disease versus control patients undergoing thyroidectomy.

We controlled for multiple patient characteristics that others and we have hypothesized to be potential risk factors for hypocalcemia after thyroidectomy. Yamashita et al. described female sex to be the most important risk factor for tetany, related to the fact that women are more susceptible to calcium and vitamin D deficiency than men (9). Another study showed that seasonal variations in calcium homeostasis had an effect on incidence of postoperative hypocalcemia. Patients with Graves' disease were found to be more susceptible to calcium and vitamin D deficiency during the winter months and thus had a higher incidence of postoperative tetany when thyroidectomy was performed in the winter (11). We did not find this in our study, however. Another study showed that patients with Graves' disease who had vitamin D deficiency with high serum alkaline phosphatase levels were at highest risk for operative tetany (12). They concluded that serum vitamin D and alkaline phosphatase levels should be monitored in patients with Graves' disease undergoing thyroidectomy. Although we were able to examine alkaline phosphatase levels on our patients, vitamin D levels were not available for all patients in our retrospective review. We did not, however, find a significant association between preoperative alkaline phosphatase levels and postoperative hypocalcemia in either control or Graves' disease patients. After completion of this study and reviewing the results of others, we now collect preoperative vitamin D levels on all patients scheduled for thyroidectomy.

Interestingly, our results demonstrated that older age patients had significantly lower odds of experiencing symptoms of hypocalcemia than younger patients when adjusting for Graves' disease (p-value = 0.04). Also, older age patients had significantly lower odds of starting Rocaltrol than younger age patients after adjusting for Graves' disease (p-value = 0.04). Bhattacharyya et al. analyzed data from 517 total thyroidectomy cases and similarly found that younger age was a significant risk factor for hypocalcemia, whereas patient sex, indication for surgery, and parathyroid implantation were not (13). Others, however, refute this association noting that advanced age is a known major risk factor for vitamin D deficiency. Erbil et al. found that age >50 years was associated with an increased risk of postoperative hypocalcemia after total thyroidectomy, thought largely due to low vitamin D concentrations associated with aging in that population (14).

The limitations of this study include the retrospective nature of data analysis. In addition, certain data were not available on all patients, including vitamin D levels. As stated previously, we now collect preoperative vitamin D levels on all patients scheduled for thyroidectomy. Although results were adjusted when possible, we do not believe clinically significant differences in the covariates varied between the two groups.

This study has changed our clinical practice significantly. Each Graves' disease patient who is scheduled for total thyroidectomy is now prescribed calcium supplementation preoperatively until the day of surgery. Calcium levels are now checked both the night of surgery as well as the morning after. Finally, Graves' disease patients are prescribed calcium supplementation empirically upon discharge, even if normocalcemic as an inpatient. Future studies are planned to examine whether this practice will alter the occurrence of signs and symptoms of hypocalcemia in Graves' disease patients after thyroidectomy.

Conclusion

Patients with Graves' disease are more likely to require increased dosages of calcium as well as experience tetany postoperatively than patients undergoing total thyroidectomy for other indications, probably due to alterations in calcium homeostasis as there was a trend for their serum calcium to be lower than patients having thyroidectomy for conditions other than Graves' disease. This suggests that patients operated upon for Graves' disease warrant close follow-up, as both inpatients and outpatients, for signs and symptoms of hypocalcemia.