Normal Parathyroid Hormone Levels Do Not Exclude Permanent Hypoparathyroidism After Thyroidectomy

Abstract

Background:

Permanent hypoparathyroidism has become the most common and the most severe complication after thyroid surgery. In our experience, some patients suffer from permanent hypocalcemia and related symptoms despite normal parathyroid hormone (PTH) values after thyroid surgery. The aim of this work was to present a series of such patients with long-term hypocalcemia and normal PTH values to evaluate to what extent parathyroid function was impaired by thyroidectomy, and determine whether irregularities of bone and calcium metabolism were associated with this phenomenon.

Methods:

We present a series of eight patients with normal PTH and subnormal calcium levels at follow-up 2 months after thyroid surgery. Outcome parameters were intra- and postoperative PTH and calcium kinetics, and the following markers of calcium and bone metabolism at long-term follow-up: serum calcium, total serum albumin, ionized calcium, magnesium, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, urinary calcium, urinary creatinine, osteocalcin, c-terminal telopeptide of type I collagen, and alkaline phosphatase.

Results:

All patients had normal calcium and PTH levels at the start of the operation. The intraoperative decline in PTH was >90%; the trough (3.3% of preoperative value) was reached 3 hours after surgery. Patients underwent complete determination of bone metabolism parameters during long-term follow-up 13.8 ± 2.4 months after surgery. Hypocalcemia was found in all eight patients, as well as PTH levels within the normal range. In three patients (3/8 = 37.5%), none of the other parameters was altered. In the remaining five patients, only isolated abnormalities in bone and calcium metabolism parameters were found (i.e., alterations in urinary calcium, thyrotropin, 25-hydroxyvitamin D, osteocalcin, and c-terminal telopeptide of type I collagen).

Conclusions:

An intraoperative injury to the parathyroid glands or their vascularization is the likely contributing factor to the development of permanent hypocalcemia with normal PTH values after thyroid surgery. The remaining parathyroid tissue is subject to a maximum stimulus by hypocalcemia and, therefore, is able to maintain PTH values in the normal range. These are still too low to re-establish normal serum calcium levels. In these patients, the term “hypoparathyroidism” might be replaced with “parathyroid insufficiency.”

Introduction

T he three most common complications of thyroid surgery are vocal cord palsy, postoperative hemorrhage, and hypocalcemia. Accurate postoperative quality monitoring has demonstrated that permanent hypoparathyroidism has become the most common severe complication after thyroid surgery. Its prevalence is 4% or higher (1). The criteria for the diagnosis of permanent hypoparathyroidism, however, have not been standardized. In one interpretation, the word “hypoparathyroidism” indicates the presence of low parathyroid hormone (PTH) levels. However, permanent hypoparathyroidism after thyroidectomy is often defined on the basis of symptoms and the need for calcium supplementation for 6 months or more, even years after surgery. This practically equates it with permanent hypocalcemia (2,3).

Calcium is known to exert a direct inhibitory feedback on PTH secretion by stimulating the Gq-coupled calcium-sensing receptor (4). However, low postoperative calcium levels often are unable to trigger an appropriate increase in PTH secretion. It has been demonstrated that the secretory capacity of the parathyroid glands (PGs) can become impaired during the course of thyroid surgery (2,5 –7).

In our experience, some patients who suffer from permanent hypocalcemia-related symptoms have normal PTH values at follow-up even 6 or more months after thyroid surgery. It is likely that this is caused by parathyroid injury during thyroid surgery. Accordingly, low serum calcium levels would lead to maximum stimulation of the remaining intact parathyroid tissue, and thereby to serum PTH levels within the normal range. The aim of the present study was to analyze a series of patients with long-term hypocalcemia but with normal serum PTH concentrations.

Materials and Methods

Patient selection

Ten patients with select criteria from a large prospective study (8) on intra- and postoperative PTH kinetics during and after thyroidectomy that evaluated the intraoperative criteria for the development of postoperative permanent hypoparathyroidism were identified. The select criteria were that these patients had normal PTH and subnormal calcium levels on follow-up 2 months after surgery. They had undergone a bilateral thyroid operation during the original study period. Of the 10 patients, 8 required permanent calcium-supplementation 12 months after surgery, and 2 were lost to follow-up after 2 months. There were seven women and one man with a mean age of 53.4 ± 14.3 years at the time of surgery.

Study design and blood sampling protocol

The study design has been published previously (8) and is summarized as follows. A total of 16 blood samples per patient were obtained for perioperative PTH- and calcium kinetics. After anesthesia was induced, blood was drawn from a peripheral vein before skin incision. This was repeated 10 minutes after resection of the first and 10 minutes after resection of the second thyroid lobe. Additional blood samples were obtained 3 hours after the operation and on the first, second, and third postoperative day. After discharge, the first outpatient follow-up examination took place 10–14 days after the operation. Long-term follow-up visits were scheduled for 2 months after surgery and after about 12 months.

As part of the prospective study design, all surgeons had to describe the intraoperative sites of the PGs in detail. Surgical specimens were routinely sectioned completely for histopathologic investigation to determine if inadvertent removal of the PGs had occurred.

The following parameters were chosen to assess calcium metabolism and bone turnover during long-term follow-up: thyrotropin (TSH), serum calcium, total serum albumin and ionized calcium, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, magnesium, and urinary calcium. To rule out factors other than parathyroid insufficiency that could influence calcium metabolism, other tests were performed. These were urinary creatinine to assess renal function with respect to urinary calcium, osteocalcin, c-terminal telopeptide of type I collagen (c-telopeptide), and alkaline phosphatase. At follow-up visits 2 and 12 months after surgery, all patients were studied in a morning fasting state after calcium supplementation had been discontinued for at least 1 day before the examination.

Surgical technique

In thyroid cancer, total thyroidectomy, including central compartment lymphadenectomy, is the minimum surgical procedure, except for papillary microcarcinoma and minimally invasive follicular cancer. In benign disease, our aim was to perform total thyroidectomies for multinodular goiter and Graves' disease when the PGs are at a distance from the resection line. In cases where the PGs were found in an exposed position, we leave a remnant of the thyroid capsule to preserve their blood supply. Thus, in our collective patients, a near-total thyroidectomy indicates that the surgeon left a small tissue remnant to preserve the exposed PGs. The risk for hypoparathyroidism is similar in patients with near-total thyroidectomy and in patients with total thyroidectomy and unexposed PGs. Since we consider it likely that undetected PGs are in a safe position, and at some distance from the resection line, we do not make any efforts to force their dissection.

Laboratory determinations

Serum concentrations of calcium, ionized calcium, alkaline phosphatase, and total albumin were determined by routine methods. The serum level of PTH was measured by Nichols Advantage^® Bio-Intact-PTH (1-84)-assay on a Nichols Advantage^® Speciality System. The serum level of calcium was measured by Flex^® reagent cartridge on Dimension RXL^® (Dade Behring). Serum concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were determined using commercially available RIA kits (Incstar Co.). Serum concentrations of osteocalcin (EIA-2095; DRG) and c-telopeptide (RatLaps™, E04-022-96; IASON) were determined using commercially available ELISA kits according to the manufacturers' protocols. Total calcium in urine was determined by flame photometry (EFOX 5053; Eppendorf). TSH, free thyroxine (fT4), and free triiodothyronine (fT3) were measured using a chemiluminescent microparticle immunoassay (Elecsys 2010; Roche).

Statistical analysis

Variables are described by frequencies and mean ± standard deviation. A Wilcoxon test was performed to test for differences between intra- and postoperative PTH and calcium levels. A p-value <0.05 was considered statistically significant. Statistical analysis was performed in SPSS 15.0.1 for Windows (SPSS Inc., 1989–2006).

Results

Patient characteristics

From the total series including 603 subjects with regular follow-up visits after bilateral thyroid surgery, the following number of patients had laboratory abnormalities in their calcium and/or PTH levels after surgery (from day 1 until 14). Nine patients were hypocalcemic hyoparathyrinemic (1.5%), 7 were hyperparathyrinemic hypocalcemic (1.2%), 16 were normoparathyrinemic hypocalcemic (2.7%), and 37 were hyperparathyrinemic normocalcemic (6.1%). At follow-up 2 months after surgery, 4 patients were hypocalcemic hypoparathyrinemic (0.7%), 2 were hyperparathyrinemic hypocalcemic (0.3%), 10 were normoparathyrinemic hypocalcemic (1.7%), and 6 were hyperparathyrinemic normocalcemic (1.0%). Patients were treated with calcium supplementation when they were found to be hypocalcemic.

Here we report on eight normoparathyrinemic hypocalcemic patients (seven women and one man; mean age, 53.4 ± 14.3 years) who underwent complete long-term follow-up after a mean of 13.8 ± 2.4 months (range, 12–19 months) after total (n = 3) or near-total thyroidectomy (n = 5). Table 1 shows detailed information on patient characteristics and on the intraoperative situs of the PGs. There was no parathyroid tissue found in surgical specimens evaluated by histopathologic investigation in any of these patients.

Table 1.

Patient Characteristics

Patient number	Sex	Age	Underlying thyroid disease	Surgical procedure	Intraoperative situs of the PGs
1	Female	56	Thyroid carcinoma	Total thyroidectomy + central lymph node dissection	4 visualized PGs, 2/4 resected for oncological reasons
2	Female	47	Benign euthyroid nodular goiter	Near-total thyroidectomy	3 visualized PGs, 1/3 slightly discolored
3	Female	64	Benign euthyroid nodular goiter	Near-total thyroidectomy	3 visualized PGs
4	Female	56	Benign euthyroid nodular goiter	Near-total thyroidectomy	4 visualized PGs, 1/4 slightly discolored
5	Female	69	Benign euthyroid nodular goiter	Near-total thyroidectomy	4 visualized PGs, 1/4 slightly discolored
6	Female	19	Grave's disease	Near-total thyroidectomy	3 visualized PGs, 1/3 slightly discolored
7	Female	59	Thyroid carcinoma	Total thyroidectomy + central lymph node dissection	3 visualized PGs
8	Male	57	Benign euthyroid nodular goiter, microcarcinoma	Total thyroidectomy	4 visualized PGs, 1/4 slightly discolored

PG, parathyroid gland.

One patient (number 8) was known to suffer from osteoporosis. He had already been treated with bisphosphonates and calcium-/vitamin-D supplementation before thyroid surgery. None of the other seven patients showed any disturbances of calcium or bone metabolism before surgery.

Calcium and PTH kinetics

All patients had normal calcium and PTH levels at the start of the operation. Intra- and postoperative calcium- and PTH-kinetics are presented in Figure 1. For calcium, an initial mean value of 2.3 ± 0.1 mmol/L was found. After a stable intraoperative course, the mean calcium level declined to a subnormal value of 2.0 ± 0.2 mmol/L (normal range, 2.1–2.7 mmol/L), as early as 3 hours after the operation. After that time, patients did not become normocalcemic and required oral calcium and vitamin D supplementation. At follow-up visits 2 and 12 months after the operation, serum calcium levels below the normal range were found in all patients.

FIG. 1.

Intra- and postoperative parathyroid hormone (PTH) and calcium kinetics. Perioperative blood samples were taken before skin incision (A), 10 minutes after resection of the first (B) and the second thyroid lobe (C), 3 hours after the operation (D), and on the first (1), second (2), and third postoperative day (3). All patients revealed a sharp intraoperative decline in PTH, reaching levels <10% of the initial value at the end of the operation (C). Serum calcium levels below the normal range were found postoperatively. During subsequent follow-up visits calcium remained low, whereas PTH levels recovered gradually.

PTH declined from a preoperative value of 30.2 ± 14.0 pg/mL (normal range, 6–40 pg/mL) to a postoperative level of 1.0 ± 0.8 pg/mL (3.3%, p = 0.003). PTH secretion apparently recovered, and a mean of value 6.4 ± 1.4 pg/mL was seen at follow-up after 2 weeks. From then on, a continuing increase in PTH levels was observed: at follow-up visits at 2 and 12 months after the operation, PTH was within the normal range, with mean levels of 13.9 ± 3.1 and 22.8 ± 14.2 pg/mL, respectively.

Hypocalcemia-related symptoms

Seven of eight (87.5%) patients reported the first hypocalcemia-related symptoms (i.e., paresthesia of the arms, the legs, or the face) within a few hours up to 1 day after the operation. One patient (number 8, see Table 1) became symptomatic 6 days after the operation after having already been discharged from the hospital. All patients were given calcium and vitamin D supplementation based on the presence of symptoms, not on the low calcium levels. Since all patients were symptomatic after having discontinued calcium supplementation for at least 1 day at the 6-month and 1-year follow-up visits, permanent hypocalcemia was diagnosed.

Long-term follow-up: calcium and bone metabolism

All patients underwent complete determination of bone metabolism parameters at long-term follow-up 13.8 ± 2.4 months after surgery. Tables 2 and 3 show the details about calcium metabolism and bone turnover. Hypocalcemia was found for all eight patients, as well as PTH levels within the normal range. For three patients (numbers 1, 4, and 7; 3/8 = 37.5%), none of the other parameters was altered. One patient (number 3) revealed an increased urinary calcium level, which was, however, found to be within the normal range again 8 weeks afterward. A low serum level of TSH was found for patient number 6; hyperthyroidism was confirmed by high levels of fT3 and fT4 (data not shown). One patient (number 5) had an increased serum level of 25-hydroxyvitamin D, as well as a decreased level of osteocalcin. Two other patients (numbers 2 and 6) had slightly decreased osteocalcin levels. For patient number 8, distinctly decreased c-telopeptide and osteocalcin levels were found. No patients had vitamin D deficiency.

Table 2.

Parameters of Calcium Metabolism at Long-Term Follow-Up (≥1 Year After Surgery)

	Serum calcium (mmol/L)	Total serum protein (g/dL)	Ionized calcium (mmol/L)	Serum magnesium (mmol/L)	Intact PTH (pg/mL)	25OH-vitamin D (nmol/L)	1,25(OH)₂-vitamin D (pg/mL)	TSH ( μU/mL)	Venous pH	Urinary calcium (mmol/L)
Patient number	2.1–2.7 ^a	6.0–8.0 ^a	1.1–1.3 ^a	0.7–1.0 ^a	6–40 ^a	50.0–92.0 ^a	25–66 ^a	0.25–4.2 ^a	7.36–7.45 ^a	—
1	1.99	7.3	0.97	0.94	11.6	58.1	39	1.28	7.37	0.50
2	1.94	7.2	1.06	0.73	40.8	53.3	35	4.68	7.36	0.88
3	2.08	6.9	1.19	0.84	48.7	50.4	40	0.35	7.35	3.06
4	1.97	6.1	0.95	0.86	13.8	80.2	27	1.54	7.39	0.91
5	1.89	7.7	1.05	0.76	14.8	109.3	39	2.71	7.40	0.52
6	1.70	8.0	0.92	0.72	15.5	65.4	40	0.01	7.40	1.91
7	1.86	6.7	1.01	0.78	13.1	32.6	33	2.76	7.37	0.93
8	2.00	6.8	1.11	0.92	24.5	84.9	25	0.27	7.29	0.75

Bold values, values outside the normal range.

Normal range.

1,25(OH)₂-vitamin D, 1,25-dihydroxyvitamin D; PTH, parathyroid hormone; TSH, thyrotropin.

Table 3.

Parameters of Bone Turnover at Long-Term Follow-Up (≥1 Year After Surgery)

	c-Telopeptide (ng/mL)	Osteocalcin (ng/mL)	Alkaline phosphatase (U/L)
Patient number	(0.03–0.37) ^a	(11–36) ^a	(50–136) ^a
1	0.04	12.2	61
2	0.06	9.9	55
3	0.27	20.2	62
4	0.25	29.5	93
5	0.06	6.9	70
6	0.06	9.5	84
7	0.18	14.7	72
8	0.01	6.8	87

Normal range.

Discussion

We report on eight patients who suffered from permanent hypocalcemia despite normal sustained PTH values after thyroidectomy. Notably, this was the most common dysregulation of the calcium/PTH metabolism in the 2 months after surgery in our patients. The rate of patients having reactive high serum PTH was low compared to the postoperative courses after surgery for hyperparathyroidism with prevalences of postoperative elevated serum PTH concentrations of up to 43% (9). However, the underlying mechanisms differ. In patients with primary hyperparathyroidism the normal PGs are suppressed by hypercalcemia. After surgery, when calcium levels have normalized, PTH secretion is no longer suppressed. Thus, PGs are activated rapidly and PTH is produced and secreted consecutively, thereby often leading to hyperparathyrinemia. This is not the case when surgical damage has occurred to the PGs in the course of thyroid surgery. In this situation there is not enough functional parathyroid tissue left and compensatory hyperparathyrinemia is uncommon (9). Moreover, we excluded all patients whose serum PTH levels were elevated before thyroid surgery.

When compared to the mean preoperative PTH level of 30 pg/mL, patients 1, 4, 5, 6, and 7 had lower serum PTH levels at long-term follow-up although they were within the normal range. Nonetheless, the finding of normal PTH levels at long-term follow-up may mislead the surgeon into believing that he or she had not caused permanent hypoparathyroidism by injuring the PGs during surgery. However, our intraoperative hormone kinetics demonstrate that intraoperative damage to the PGs or their blood supply can, indeed, occur without the surgeon's being aware of it. In the long-term, the reduction in the mass of parathyroid cells then resulted in a relative parathyroid insufficiency, despite the presence of normal serum PTH levels. In intact PGs, reactive hyperparathyroidism should be expected when hypocalcaemia is present (9).

It is generally assumed that two PGs suffice to maintain normal calcium levels (10). Accordingly, it has been demonstrated that, in patients with impairment of parathyroid function, glands are damaged by surgical manipulation on both sides. Thus, PTH levels decline immediately after resection of the first thyroid lobe. A further decrease to serum PTH levels below the normal range is then found after resection of the second thyroid lobe. One might argue that this phenomenon may be due to vigorous fluid therapy. However, as demonstrated previously, the combination of both decreases in intraoperative PTH kinetics is specific for patients with permanent parathyroid dysfunction and does not occur in other patients. This indicates that all four PGs were damaged during surgery (2). Such intraoperative PTH courses were found for all eight patients reported here. Thus, severe intraoperative damage to the PGs on both sides can be assumed.

All patients had normal serum calcium levels before thyroid surgery. None of them were on calcium supplementation except for one patient (number 8), who had osteoporosis and took oral calcium, vitamin D, and bisphosphonates. All patients became hypocalcemic after the operation and remained in permanent need of calcium supplementation.

The parathyroid cells sense even small changes in the plasma calcium-ion concentration: this process is mediated by the calcium-sensing receptor on the parathyroid cells. A decline in serum calcium leads to the secretion of PTH, which then acts on the two main direct target organs (kidney and bone) to normalize the serum calcium level (11). In the kidney, PTH activates the vitamin D system by accelerating the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active metabolite of vitamin D. In the bone, resorption is enhanced, allowing more calcium to appear in plasma (12). As a result of this mechanism, transient hypocalcemia after bilateral thyroid surgery leads to increased levels of PTH, a kind of reactive hyperparathyroidism (2). The same phenomenon can be seen in patients with chronic kidney disease in whom low serum calcium levels caused by renal calcium loss lead to secondary hyperparathyroidism (13). Accordingly, permanent hypocalcemia should cause an appropriately increased PTH secretion. One would expect PTH levels within the high normal range, or even above, during the parathyroid recovery phase. Obviously, the PTH levels within the lower or middle normal range represent the maximum output of the remaining functioning parathyroid tissue, but do not suffice to normalize serum calcium concentrations. This is likely due to an extensive loss of parathyroid tissue caused by surgical injury to the PGs during thyroid surgery, which can be demonstrated by intraoperative PTH kinetics, as in our patients. In accordance with the nomenclature for hypothyroidism, this may be called overt hypoparathyroidism or parathyroid insufficiency.

However, completely normal calcium and bone metabolism was found at long-term follow-up in only three patients (numbers 1, 4, and 7). Slightly decreased osteocalcin levels were found for patients 2, 5, and 6. It cannot be definitively confirmed whether this change in bone metabolism is related to the development of or caused by permanent hypocalcemia. These patients, however, had normal c-telopeptide levels. Thus, we consider the changes in osteocalcin clinically irrelevant. Likewise, the increased level of 25OH-vitamin D in patient number 5 seems clinically irrelevant, since the 1,25OH-vitamin D was within the normal range; thus, an impaired conversion of 25OH-vitamin D to 1,25OH-vitamin D was not likely. In patient 3 the elevated urinary calcium normalized within 6 weeks.

In the patient (number 8) who had osteoporosis, the clear decrease of osteocalcin and c-telopeptide was probably caused by his intake of oral bisphosphonates, which are known to inhibit bone turnover. c-Telopeptide, a marker of bone resorption, was as low as 0.01 ng/mL, indicating the therapeutic success of the bisphosphonate treatment (14).

In addition, one patient (number 6) had a low TSH serum level, as well as high fT3 and fT4 serum levels, indicating that the dose of thyroid hormone substitution was too high. However, since this was a one-time event, and the subsequent TSH was normal, it is unlikely that this contributed to parathyroid dysfunction.

Parameters of bone turnover and calcium metabolism were not evaluated preoperatively. Thus, it is not known if alterations in calcium and bone metabolism contributed to the permanent hypocalcemia in our series. However, we conclude from the intraoperative PTH kinetics that severe intraoperative injury to the PGs was the cause of permanent hypocalcemia in our series. It is likely that in them only a minimal amount of parathyroid cells remained vital and contributed to PTH production. They were likely subjected to a maximum stimulus by the persistent hypocalcemia, but their maximal output of PTH was not sufficient to re-establish normal serum calcium levels.

In conclusion, in patients with persistent low calcium levels during long-term follow-up after thyroidectomy, even normal PTH values are likely due to an insufficient parathyroid response. In these patients the term “parathyroid insufficiency” is probably better than “hypoparathyroidism.”

Disclosure Statement

The authors declare that no competing financial interests exist.

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