|Ahead of print publication
Long-term hypocalcemia prediction post thyroidectomy
Deepak Janardhan1, Sandeep Suresh1, PG Balagopal1, Nebu Abraham George1, KM Jagathnath Krishna2
1 Department of Head and Neck Surgery, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
2 Department of Epidemiology and Biostatistics, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
|Date of Submission||06-Dec-2020|
|Date of Acceptance||10-Dec-2020|
|Date of Web Publication||19-Apr-2021|
Nebu Abraham George,
Department of Head and Neck Surgery, Regional Cancer Centre, Thiruvananthapuram - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
Introduction: Hypocalcemia is a common sequela of total thyroidectomy and is usually transient (30%), only a few develop permanent hypoparathyroidism. Till date, no effective risk stratification score to predict hypocalcemia is available that can predict postoperative hypocalcemia.
Materials and Methods: This was a prospective observational study including all patients who underwent total or completion thyroidectomy with initial parathormone (PTH) within the normal range in our institution during a 1 year period. Postoperative 6th h PTH fall was noted in all patients and cutoff point for the prediction of long-term hypocalcemia (LTHP) was determined using a paired t-test.
Results: Postoperatively, calcium supplementation was initiated in 52% of patients. In 7.6% of patients who had a fall in PTH to more than 80% of preoperative value, calcium supplementation could not be tapered even after 3 months postoperatively. About 66% of patients <20 years of age developed hypocalcemia in the postoperative period. Patients who developed delayed hypocalcemia with initial normal calcium levels had fall in PTH of at least 45%. For individuals below 20 years, a PTH fall of 56% or more required calcium supplementation. The various variables studied failed to attain statistical significance.
Conclusions: More than 82% fall in 6th h postoperative PTH predicts long-term hypocalcemia. Post total thyroidectomy, adolescent individuals are at a higher risk of developing hypocalcemia; hence, early calcium supplementation is recommended based on fall in PTH. Weighted score to predict LTHP could not be developed, as none of the risk factors evaluated were statistically significant.
Keywords: Postoperative issues/complications, thyroid cancer, thyroid surgery
|How to cite this URL:|
Janardhan D, Suresh S, Balagopal P G, George NA, Jagathnath Krishna K M. Long-term hypocalcemia prediction post thyroidectomy. Thyroid Res Pract [Epub ahead of print] [cited 2021 Jun 22]. Available from: https://www.thetrp.net/preprintarticle.asp?id=314049
Hypocalcemia is common sequelae of total thyroidectomy and is usually transient (30%), but, however, few develop permanent hypoparathyroidism. Till date, there is no effective risk stratification score to predict postoperative hypocalcemia. Development of such a score would help to initiate calcium supplementation as early as possible and thus avoid prolonged hospital stay and unwarranted prolonged calcium supplementation in selected patients who might not require the same.
| Introduction|| |
All patients who underwent total or completion thyroidectomy for malignancy with parathormone (PTH) within the normal range from April 2015 to May 2016 in our institution were included in the study after ethical committee clearance. This was a prospective observational study done after obtaining clearance from the Ethics Committee. Exclusion criteria were abnormal serum albumin, abnormal preoperative calcium, and/or PTH levels. The main aim of the study was to predict long-term hypocalcemia (LTHP) using preoperative PTH and postoperative 6th h serum PTH fall in patients undergoing thyroidectomy for malignancy so as to device a weighted score after analyzing various clinical and intraoperative variables.
| Materials And Methods|| |
Patients were considered hypocalcemic if the biochemical calcium value was <7.5 on the 1st or 2nd postoperative day (POD) or in presence of signs or symptoms. LTHP was defined as requirement of calcium supplementation for 3 months or more postoperatively. Postoperatively, 6th h PTH fall was noted in all patients and the cutoff point for prediction of LTHP was determined using paired t-test.
Factors such as age of patient, preoperative calcium levels, extent of surgery, central compartment neck dissection, intraoperative parathyroid identification, intraoperative findings such as extracapsular or extra thyroidal spread, fall of PTH level and serum calcium level, and histology were analyzed for statistical significance in predicting hypocalcemia to device perioperative weighted scoring system.
A total of 105 patients were included in the study and among them 73.6% were females. 18% of patients were <20 years of age. Histology was papillary carcinoma in 82% of the patients. 22.6% underwent completion thyroidectomy and 2% underwent revision surgery. Intraoperatively, parathyroids were identified in 82% of cases and parathyroid implantation had to be done in 0.9% of cases. Central compartment neck dissection was done in 24.5% of cases [Table 1]. Preoperative calcium was <8 mg/dl in 4.7% of cases [Table 1].
| Results|| |
Postoperatively, calcium supplementation was initiated for 52% of cases. In majority, the calcium supplementation could be tapered and stopped by 2nd month following surgery. In 7.6% of patients, calcium supplementation could not be tapered even after 3 months, as all of these patients had a fall in PTH to more than 80% of preoperative value.
About 5.7% who had normal calcium on1st Post Operation Day (POD) but developed hypocalcemia after 4th POD requiring re-hospitalization. About 66% of patients <20 years were more prone to postoperative hypocalcemia.
A PTH fall of 45% or more was found to be significant in predicting hypocalcemia that required calcium supplementation for up to 2 months (P < 0.001 using Chi-square test). Furthermore, all patients with initial normal calcium levels who developed delayed hypocalcemia had a fall in PTH to more than 45% of the initial value. In individuals below 20 years, a PTH fall of 56% or more required calcium supplementation with a sensitivity of 83.3%.
The length of hospital stay was <2 days for 68% of patients [Table 1]. The various variables studied to establish LTHP prediction score as in the chart failed to attain statistical significance [Table 2] and [Table 3].
The increased awareness and easy access to diagnostic procedures among people have led to early detection of thyroid malignancies, leading to rise in thyroidectomies all over the world. However, it is not totally free of complications. Of them, hypocalcemia is the most common that adds to morbidity as well as prolongs hospital stay and procedure costs. It is a reasonably acceptable but simultaneously disabling complication as supported by Lam and Kerr who demonstrated increased susceptibility of the parathyroids to surgical trauma by a drop in PTH levels in 83% of total thyroidectomies, 1 h after the procedure.
| Discussion|| |
Postthyroidectomy hypocalcemia occurs in 10%–50% of cases and is usually transient around 8.9%–53% but can be permanent when it does not return to normal within 6 months in up to 25% of cases.,,, However, the projected incidence of hypocalcemia can be misleading due to various reasons. First, the extent of surgery in benign cases is not as radical as in malignancies. Second, the definition of hypocalcemia varies in different studies which is either based on clinical symptoms or biochemical values, which itself causes variation in incidence ranging from 0% to 46%., Finally, long-term follow-up of patients is not available in most studies.
Hypocalcemia following thyroidectomy is due to devascularization of parathyroids during surgery due to intraoperative mechanical or thermal trauma resulting in accidental parathyroidectomy.,,,,, Identification of fewer parathyroid glands during total thyroidectomy has been attributed to gland injury and accidental parathyroidectomy., Other causes include hemodilution, increased urinary calcium excretion due to surgical stress, calcitonin release due to thyroid manipulation, Vitamin D deficiency, hungry bone syndrome and alkalosis which is caused by hyperventilation due to postoperative pain. Impaired PTH production prevents bone resorption and reduces 1,25-dihydroxyvitamin D synthesis in the kidney leading to reduced intestinal absorption of calcium.
Posttotal thyroidectomy hypocalcemia typically manifests at around 24–48 h postoperatively but may be delayed till POD 4, as seen in 5.7% of our patients. Although multifactorial, none of the studies have reached a general consensus on the variables to accurately predict hypocalcemia.,
A marked fall in postoperative calcium levels on POD 1 reliably predicts hypocalcemia. Decrease in intra-operative Parathormone (iPTH) values has been correlated with drop in postoperative calcium to <8 mg/dl.,, iPTH values <10 pg/ml at 4th postoperative hour correlate with serum calcium levels below 8 mg/dl with a positive predictive value of 90%. Although some authors showed high sensitivity, specificity, and positive predictive value of iPTH on POD 1 and serum calcium level on POD 2, it was not reciprocated in other studies. The cost has been considered as a limiting factor for incorporating iPTH as part of routine investigations. Recovery of parathyroid function is a dynamic event that can be predicted with a number of parathyroids preserved intraoperatively and serum calcium levels at 1st month postoperatively.
Risk factors for postoperative hypocalcemia following total thyroidectomy include young age, female gender,,, thyroid gland size, type of thyroid disorder like Graves' disease, and thyroid cancer, extent of surgery, central compartment neck dissection,,, and revision surgery.,,,, Biochemically, larger fall in serum calcium,,, lower postoperative PTH levels,,, larger fall in per-operative, and postoperative PTH,,, low preoperative Vitamin D,, low postoperative magnesium, and high preoperative alkaline phosphatase and bone turnover markers suggesting hungry bone syndrome were predictive factors for postoperative hypocalcemia.
The association between postoperative hypocalcemia and female gender found in the literature and in our study as well [Table 1] and [Table 3] may be due to women being more prone to calcium and vitamin D deficiency than men., An elevated risk of hypocalcemia in younger patients may be due to the increased calcium requirement in growing age groups. The protective effect against hypocalcemia with age is not however universally reported.
It is reported that the transient hypocalcemia after thyroidectomy for cancer ranges from 13.6% to 19.3%[ ]reaching up to 75% and definitive hypoparathyroidism from 3.3% to 5.8%, with cancer being the main predictive factor for the development of these complications. This is in concordance with 56% and 7.6% respectively, noted in our study. Probably, the reason is relative aggressiveness in surgical approach leading to incidental parathyroidectomy.,
Chronic hyperthyroidism can lead to hypocalcemia after total thyroidectomy due to rapid recalcification (”hungry bone”) due to the loss of action of thyroid hormone, which normally increases the rate of bone remodeling and both fecal and urinary excretion of calcium with reabsorption of phosphorus.,,
During revision surgery, there is ten times risk of parathyroid injury with incidence of transient hypocalcemia of 3%–44% and permanent hypocalcemia of 0%–11%: the reasons being inflammation, bleeding, friability of tissues, scarring, or adhesions which hinder the identification of parathyroid glands causing injury to the parathyroid vascular pedicle. Level VI clearance is associated with an increased incidence of postoperative hypoparathyroidism, ranging from 14% to 54.6% (transient) and 4%–17.4% (permanent) and also to a greater incidence of inadvertent resection of the parathyroid., However, no statistical significance could be established in our study [Table 3].
Although parathyroid gland identification has no influence on postoperative hypocalcemia,, some consider it as a risk factor for hypocalcemia.,, Parathyroid autotransplantation and permanent hypoparathyroidism have conflicting literature evidence with some recommending and some not recommending parathyroid autotransplantation.
The classic symptoms of hypocalcemia are associated with neuromuscular excitability, demonstrated by provocation tests such as Chvostek's sign and Trousseau's sign. They vary from numbness and tingling to paresthesias of the upper and lower extremities in the extremities and circumoral region. In severe forms, carpopedal spasm or diffuse tetany can occur, with broncholaryngospasm. Neurological symptoms such as disorientation, seizure, prolonged QT interval, arrhythmias, and heart failure can also occur.
Most authors agree on the biochemical diagnosis hypocalcemia as a total serum calcium concentration <8 mg/dL or 2 mmol/L.,, Other authors define hypocalcemia as serum calcium <1.8 or 1.9 mmol/L. Prediction of postoperative hypocalcemia has been attempted by many authors in different ways. 1- and 6-h postoperative PTH and calcium levels have reported to have high sensitivity and specificity of detecting postoperative hypocalcemia,, while others consider PTH percent change as a predictor for hypocalcemia. A single postoperative 1st-h PTH level of <9 pg/mL requires treatment with calcium and vitamin D and those between 9 and 12 pg/ml are considered as high-risk groups warranting prophylactic supplementation. Those with permanent hypoparathyroidism are at risk of developing renal failure, basal ganglia calcifications, neuropsychiatric derangements, and infections.,
Hypocalcemia is treated with high-dose calcium and Vitamin D supplementation. Although some prefer calcium supplementation for a short duration on a routine basis, postthyroid surgery, many still prefer to wait and supplement only when needed. Rising calcium levels with supplementation at discharge have positive effect on parathyroid recovery, described as “parathyroid splinting,” where the injured parathyroid glands are allowed to rest in a normal or high serum calcium environment. However, calcium levels need to be monitored to avoid hypercalcemia which is also distressing.
Prolonged hospital stay with frequent biochemical analysis to ascertain hypocalcemia initially and regular follow-up assays to avoid hypercalcemia by dose adjustments incur heavy cost. This has motivated many authors to analyze various predicting factors, but most of them tend to lack uniformity; however, its significance cannot be undervalued in the present era of day-care surgeries.
More than 82% fall in 6th-h postoperative PTH predicts long-term hypocalcemia even if late onset as in some of our patients. Posttotal thyroidectomy, adolescent individuals are at a higher risk of developing hypocalcemia wherein a fall of 56% or more in PTH levels advocates calcium supplementation. Weighted score to predict LTHP could not be designed since none of the risk factors evaluated correlated with hypocalcemia attained statistical significance.
| Conclusions|| |
We wish to thank the faculty, fellows, residents, and staff of the department of Head & Neck Surgery, Regional Cancer Centre, Thiruvananthapuram, for their whole-hearted support in successful completion of this study. There was no funding for this research work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]