A comparative study of serum ultrafiltrable, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevation in total calcium

Measurement of serum ionized calcium has been shown to be more sensitive a method of diagnosing primary hyperparathyroidism than total calcium in patients with subtle or intermittent elevations of total calcium. The measurement of ionized calcium, however, is technically difficult. The measurement of serum ultrafiltrable calcium would circumvent technical difficulties because atomic absorption spectroscopy would be used to measure the calcium of a filtrate produced by passing serum through a filter which excludes protein-complexed calcium (Worthington ultrafree filter). The normal range for ultrafiltrable calcium (4.7 to 6.8 mg/dl) was determined in 138 patients by nonlinear least-squares analysis and chart review. The serum concentration of ultrafiltrable calcium correlated well with ionized calcium (r = 0.91). Previous studies have demonstrated no benefit in measuring ionized calcium, as opposed to total calcium, in the diagnosis of primary hyperparathyroidism unless there was subtle, intermittent, or no elevation of the total calcium. This comparative study of ultrafiltrable, ionized, and total calcium was, therefore, done in six patients with primary hyperparathyroidism who exhibited intermittent, minimal, or no elevations in serum total calcium. All six patients had symptoms referrable to hyperparathyroidism. All six underwent parathyroid surgery, and a parathyroid adenoma was found in each case. These six patients had a total of 24 concurrent preoperative determinations of ionized, ultrafiltrable, and total calcium levels. The total calcium value was elevated in only 9 of these 24 determinations (38%), ultrafiltrable calcium was elevated in 15 (63%), and ionized calcium was elevated in 23 (96%). The values of ionized calcium were elevated more frequently than both total calcium (p less than 0.0005) and ultrafiltrable calcium (p less than 0.025). The values for ultrafiltrable calcium were more frequently elevated than those for total calcium; this difference, however, was not significant. This study confirms our previous reports showing that ionized calcium is a more sensitive indicator of primary hyperparathyroidism in patients with intermittent or borderline elevation of the total calcium and extends those observations to show that ionized calcium is also a more sensitive indicator of primary hyperparathyroidism than ultrafiltrable calcium in this group of patients.     

Normocalcemic hyperparathyroidism in patients with osteoporosis

BACKGROUND: Diagnosing primary hyperparathyroidism (PHP) in patients with osteoporosis is important because of the benefits of surgery. Screening patients with osteoporosis for PHP with only total serum calcium level will fail to diagnose PHP in patients with intermittent or no elevation of the total calcium level. METHODS: This is a retrospective study of 140 patients who had a preoperative bone density study of the 223 patients who had surgery for PHP from January 1995 to June 1999. Normocalcemic hyperparathyroidism was defined as having all normal total calcium values or only intermittent elevation defined as at least 40% of the total calcium values in the normal range. RESULTS: Osteoporosis was identified in 64 of these 140 patients (46%). Fifteen patients with osteoporosis and PHP had normocalcemic hyperparathyroidism. Six of these patients had all preoperative total calcium values in the normal range, and the remaining 9 patients had intermittent elevation of the total calcium. This group consisted of 12 women and 3 men aged 55 to 79 years. Forty-four concomitant ionized and total calcium values were available in the patients with all normal preoperative total serum calcium values. Forty-two serum ionized calcium values (95%) were elevated. Fifty-one concomitant values were available in the patients with intermittent elevation of the total calcium, and only 20 total calcium values (39%) were elevated and 47 of ionized values (92%) were elevated ( P < .01). Intact parathyroid hormone was also significantly better than total calcium in identifying PHP. Twenty of 23 intact serum parathyroid hormone values (87%) were elevated ( P < .05). CONCLUSIONS: Screening patients with osteoporosis for PHP with only total calcium levels will fail to identify patients with no elevation of total calcium level and many patients with only intermittent elevation of the total calcium level. Ionized calcium and intact parathyroid hormone were comparable and significantly better than total calcium level in the detection of PHP in patients with osteoporosis. Ionized calcium and intact parathyroid hormone should be used to diagnose hyperparathyroidism in patients with osteoporosis and normal serum total calcium levels.     

Nonautonomy of parathyroid hormone and urinary cyclic AMP in primary hyperparathyroidism.

This study demonstrates that appreciable changes in serum parathyroid hormone and urinary cyclic AMP occur during experimentally induced hyper- and hypocalcemia in almost all patients with primary hyperparathyroidism regardless of histology. A single patient with tertiary hyperparathyroidism also demonstrated a significant elevation of serum parathyroid hormone and urinary cyclic AMP in response to EDTA induced reduction in ionized calcium. Thus, total autonomy of hormone secretion was not present in the great majority of the patients with a parathyroid adenoma, parathyroid hyperplasia, or the single patient with tertiary hyperparathyroidism. Therefore, preoperative evaluation of the rsponse of urinary cyclic AMP and serum parapthyroid hormone to EDTA or calcium infusion will not distinguish parathyroid adenomas from hyperplasia on the basis of total autonomy of hormone secretion. If a difference in secretory control is present between parathyroid adenomas and parathyroid hyperplasia, it is more subtle than total autonomy for adenomas and nonautonomy for hyperplasia.     

Total parathyroidectomy for posttransplantation hyperparathyroidism

The acute and short-term clinical course of 19 subjects who underwent total parathyroidectomy and forearm implantation for persistent hyperparathyroidism following successful kidney transplantation (mean [+/- SD] time after transplant 43.7 +/- 29.5 months) is described. Their mean preoperative serum calcium level of 10.8 +/- 0.5 mg% decreased to a nadir of 7.9 +/- 0.9 mg%, 62.5 +/- 27.7 hr after the operation. The lowest serum ionized calcium (1.80 +/- 0.2 mEq/L) was recorded 57 +/- 49 hr postoperatively. After an average of five hospital days, the patients were discharged with a mean serum total calcium concentration of 8.3 +/- 1.0 mg%. Three months following the operation, the mean serum total calcium concentration was 9.5 +/- 0.6 mg%. With an average follow-up of 19 months (range 3-36 months) serum total calcium was 9.6 +/- 0.6 mg%, with only one subject requiring calcium supplementation. Total parathyroidectomy with forearm implantation was associated with normalization of serum-immunoreactive parathyroid hormone concentrations and maintenance of stable allograft function. Our experience suggest that this procedure is an effective modality with a predictable postoperative recovery of parathyroid function when used to treat persistent hyperparathyroidism in the long-term survivor of renal transplantation.     

Unexpected parathyroid disease discovered at thyroidectomy in irradiated patients

Eight of 23 patients undergoing total thyroidectomy for radiation-associated nodular thyroid disease were found to have unsuspected parathyroid hyperplasia or adenoma at operation. The total serum calcium level was normal preoperatively in each patient. Serum ionized calcium and parathyroid hormone levels were measured in five patients preoperatively and were normal in each case. These pathologic findings in normocalcemic patients may represent a preclinical form of hyperparathyroidism, which would be further evidence linking radiation to the pathogenesis of hyperparathyroidism. The parathyroid glands should be evaluated both preoperatively and at operation in all patients who have a history of radiation and require thyroidectomy.     

Primary hyperparathyroidism: what every orthopedic surgeon should know.

The diagnosis of hyperparathyroidism should rarely by missed by the orthopedic surgeon. When a patient presents with a pathologic fracture, routine serum calcium should be obtained. If there is evidence of elevated serum calcium or any of the pathognomonic findings of primary hyperparathyroidism on plain radiographs, total and ionized calcium and an intact parathyroid hormone levels should be obtained to make the diagnosis (Figure 5). When patients require surgical treatment for an orthopedic condition and also need surgery for hyperparathyroidism, the procedures can be safely performed simultaneously. Simultaneous parathyroidectomy corrects the underlying endocrinopathy, thereby improving the outcome of the orthopedic procedure. In addition, these procedures can easily be performed simultaneously under one anesthetic and thereby minimize cost and length of hospitalization.     

Calcium infusion in suspected hyperparathyroidism: changes in parathyroid hormone concentration related to histopathological findings.

Changes in parathormone, total and free calcium concentrations in serum were studied in 27 patients with suspected hyperparathyroidism (25 with normocalcemia judged from CaT). Six patients were classified as normals. In 21 patients neck explorations was performed. Patients with definite pathology in the parathyroid glands had higher parathormone, total and free calcium levels than patients with borderline pathology or normal glands. The mean parathormone concentration fell significantly during calcium infusion in patients with histologically normal parathyroid glands. In patients with definitely pathological glands the parathormone concentration remained unchanged during the calcium infusion.     

Treatment of refractory secondary hyperparathyroidism with ethanol injection: the importance of glandular volume

BACKGROUND: Percutaneous ethanol injection treatment (PEIT) has been proposed as an alternative to surgery for patients with secondary hyperparathyroidism. The present study was undertaken to determine factors that may predict results. METHODS: We performed PEIT in 19 patients with secondary hyperparathyroidism refractory to medical therapy under ultrasonographic guidance in an ambulatory facility with local anesthesia. Biochemical assays were performed immediately before the last dialysis session (basal) and between 1 to 7 days after PEIT (post-PEIT). RESULTS: Serum PTH, calcium, and phosphorus levels decreased significantly after treatment. The percent of change in serum PTH was significantly correlated to total nodular volume (r = 0.73, P = 0.0004), and basal PTH levels (r = 0.48, P = 0.03). Post-PEIT serum phosphate and calcium x phosphate product disclosed negative correlations that were statistically significant with the decrease of PTH levels (r = -0.60, P = 0.009, and r = -0.60, P = 0.01, respectively). The total nodular volume was significantly correlated to the percent change in serum calcium levels (r = 0.60, P = 0.01), in phosphate levels (r = 0.64, P = 0.009), and calcium x phosphate product (r = 0.66, P = 0.01). CONCLUSION: Our findings suggest that patients with uncontrolled secondary hyperparathyroidism may benefit from PEIT if they present with very high basal PTH levels and/or big nodule size.     

Vecuronium-induced neuromuscular blockade in two patients with hyperparathyroidism and a patient with hypoparathyroidism]

Vecuronium-induced neuromuscular blockade was evaluated in two patients with primary hyperparathyroidism and in a patient with hypoparathyroidism. A 39 year old male with typical primary hyperparathyroidism was scheduled for surgical removal of the parathyroid adenoma. Serum levels of calcium and ionized calcium were 15.0 mg.dl-1 and 1.95 mmol.l-1, respectively. A 44 year old female suffering from primary hyperparathyroidism was also scheduled for surgical removal of the adenoma. Serum levels of calcium and ionized calcium were 12.5 mg.dl-1 and 1.51 mmol.l-1, respectively. A 63 year old male, suffering from postoperative secondary hypoparathyroidism and treated with calcium, was scheduled for surgical removal of the recurrent pharyngeal cancer. Serum levels of calcium and ionized calcium were 9.0 mg.dl-1 and 1.15 mmol.l-1, respectively. Anesthesia was induced with thiamylal 4-5 mg.kg-1 and vecuronium 0.08 mg.kg-1 and was maintained with 70% nitrous oxide in oxygen and fentanyl in all three patients. Neuromuscular blockade following the administration of vecuronium was measured by a big toe abduction evoked by supramaximal stimulation of the tibial nerve (Myograph 2000, Biometer, Denmark). In order to evaluate the effect of serum calcium level on vecuronium neuromuscular blockade, ten patients with normal serum levels of calcium, were examined in the same fashion. In only one patient with hyperparathyroidism, whose serum calcium was 15.0 mg.dl-1, the onset and the duration of vecuronium were later and shorter than those of other patients with normal serum levels of calcium. In conclusion, we should pay attention to the antagonistic responses to vecuronium in patients with severely high levels of serum calcium.     

Evidence that factors other than 1,25 dihydroxyvitamin D may play a role in augmenting intestinal calcium absorption in patients with primary hyperparathyroidism

Summary We examined 17 patients with primary hyperparathyroidism for their serum 1,25 dihydroxyvitamin D levels and for their fractional intestinal calcium absorption rates using a whole body counter and calcium-47. As controls, 10 normal volunteers were examined both before and after administration of 1α-hydroxyvitamin D to increase serum 1,25 dihydroxyvitamin D. Values of serum 1,25 dihydroxyvitamin D were 71.6±37.6 pg/ml (mean ±SD) in patients with primary hyperparathyroidism and 75.3±27.7 pg/ml (mean ±SD) in normal volunteers after administration of 1α-hydroxyvitamin D, while values of intestinal calcium absorption rate were 61.5±16.5% (mean ±SD) in patients with primary hyperparathyroidism and 34.1±5.1% (mean ±SD) in normal controls, respectively. There was a positive correlation between values of serum 1,25 dihydroxyvitamin D and intestinal calcium absorption in both groups. However, in patients with primary hyperparathyroidism, intestinal calcium absorption was more increased than that in normal volunteers when compared to their serum values of 1,25 dihydroxyvitamin D. This suggests that another factor than 1,25 dihydroxyvitamin D plays an important role in the intestinal calcium absorption in patients with primary hyperparathyroidism.     

Die parathyreotoxische Krise – ein chirurgischer Notfall

INTRODUCTION: The extremely rare but life-threatening hypercalcemic crisis is caused by an exacerbation of a chronic hyperparathyroidism. The etiologic reasons for this exacerbation are conditions which increase the serum calcium level in addition to the hyperparathyroidism with a complete breakdown of the calcium homeostasis, e. g. malignant tumors, primary and tertiary hyperparathyroidism, vitamin D poisoning or overdoses of calcium, vitamin D and calcium-containing ionizer in patients with renal insufficiency. METHODS: We present the clinical course of five patients with an acute hypercalcemic crisis and discuss the diagnostic procedure and the principles of surgical treatment with regard to the current literature. RESULTS: A hypercalcemic crisis develops if the total serum calcium concentration is over 4 mmol/l and parathormone over 90 pmol/l. The resulting syndrome is manifested by nausea and vomiting, polyuria and consecutive dehydration and hypotonia culminating in lethargy, hallucinations and coma. Hypercalcemia is the single most important diagnostic finding. CONCLUSION: The emergency therapy predominantly consists on the one hand in rehydration and parallel stimulation of diuresis. Urgent surgery is required if conservative therapy is not successful.     

Acute effects of calcium carbonate and citrate on secondary hyperparathyroidism in chronic renal failure.

Two grams of elemental calcium as carbonate or citrate were given after an overnight fast to 14 patients with advanced renal failure (serum creatinine 759 +/- 365 mumol/l, mean +/- SD). The suppressibility of their hyperparathyroidism was confirmed with a calcium infusion test. Both calcium citrate and carbonate increased significantly plasma ionized calcium (6.8 and 4.5%, respectively) and total calcium (9.3 and 6.0%), p less than 0.001. In the majority of the patients, calcium citrate but not carbonate increased plasma calcium sufficiently to induce the suppression of hyperparathyroidism. The decrease of plasma intact parathyroid hormone was 35.9 +/- 24.8% (mean +/- SD); p less than 0.001) after calcium citrate and 9.2 +/- 18.9% (mean +/- SD; NS) after calcium carbonate.     

Secondary hyperparathyroidism in diabetic and nondiabetic patients on long-term continuous ambulatory peritoneal dialysis (CAPD)

Serum values of calcium, phosphate, alkaline phosphatases and parathyroid hormone (PTH) are reported for 24 diabetic and 26 nondiabetic patients treated with continuous ambulatory peritoneal dialysis (CAPD) for a total of 779 months, without the use of vitamin D or calcium supplements. Radiographic data are reported for 25 patients followed on CAPD for at least 12 months. Serum calcium was well maintained and control of hyperphosphataemia acceptable, but phosphate-binding therapy had to be continued in the majority of patients. Diabetic patients had lower serum phosphate levels and higher serum calcium than nondiabetic patients during the first year of CAPD. In nondiabetic patients the institution of CAPD was followed by a fall in PTH, possibly largely reflecting transperitoneal PTH elimination. No patient achieved normalization of serum PTH on CAPD. Although no symptomatic bone disease was observed, radiographic evidence of progressive hyperparathyroid bone disease developed in 3 of the 25 examined patients, all nondiabetic. In summary, long-term CAPD with a dialysate calcium concentration of 1.75 mmol/l seems to be compatible with normocalcaemia and a steady-state situation with regard to secondary hyperparathyroidism in the majority of patients. Despite transperitoneal elimination, serum PTH remains elevated, and definite progression of hyperparathyroidism is observed in some patients, however, probably making a case for vitamin D therapy and/or intraperitoneal or peroral calcium supplementation in these patients.     

Treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the calcimimetic agent cinacalcet

Calcimimetic agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium <10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the calcimimetic agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH <145 pg/ml) with clinical improvement and without any side effect. It seems that this new agent will improve our clinical approach of renal bone disease permitting a more integrated and successful treatment of hyperparathyroidism and its consequences on patients with chronic kidney disease.     

Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery.

Patients with normocalcemic hyperparathyroidism represent a diagnostic and therapeutic challenge. It is unclear to what extent these patients benefit from surgery in terms of correction of their serum chemistry abnormalities and their symptoms. We studied 142 patients: 23 with normocalcemic hyperparathyroidism (serum calcium levels below 2.62 mmol/L), 35 with intermittent hypercalcemia, and 84 with hypercalcemic hyperparathyroidism. Serum chemistry analyses and a standardized questionnaire of symptoms were completed before and after surgery. Overall, patients in the normocalcemic group reported a similar frequency of preoperative symptoms; had a similar reduction in postoperative symptoms; and had a similar normalization of serum calcium, parathormone, and phosphate levels as those in the two control groups. This study indicates that factors other than elevated serum calcium levels are in large part responsible for the symptoms of hyperparathyroidism and that these patients benefit from operation.     

Normocalcemic primary hyperparathyroidism with fractures

Normocalcemic primary hyperparathyroidism is an uncommon condition usually found among patients with urinary stones. To the best of our knowledge, this is the first case of a patient with normocalcemic primary hyperparathyroidism presenting with bilateral femoral neck fracture. A 45-year-old man had pain both hip joints and limping in for several months. Vertical fractures of bilateral femoral necks were found by radiographs. Laboratory findings showed a normal value of total serum calcium but elevated serum ionized calcium. Serum parathyroid hormone and alkaline phosphatase levels were elevated. The patient was treated with subtrochanteric valgus osteotomy fixed with a dynamic hip screw and total parathyroidectomy. Histopathologic examination showed hyperplasia of the parathyroid glands. At 1-year follow-up, the patient was doing well clinically.     

Diagnosis and treatment of primary hyperparathyroidism

Summary The leading symptom of primary hyperparathyroidism is renal lithiasis which was present in 64 of 100 cases, whereas bone disease was noted in 11 per cent only. The diagnosis of primary hyperparathyroidism is generally made on the basis of raised serum levels of calcium and of immunoreactive parathyroid hormone (PTH). With antibodies detecting primarily COOH-terminal fragments of intact PTH-(1-84) there was an almost total discrimination of serum levels of PTH in normal subjects and in patients with primary hyperparathyroidism. Serum PTH was in the upper normal range in only 5 per cent of 128 patients with surgically verified hyperparathyroidism, whereas PTH was normal or undetectable in 35 hypercalcaemic patients with tumours unrelated to the parathyroid glands. A comparable discrimination of patients with primary hyperparathyroidism from normal subjects can be achieved with the measurement of the urinary cyclic adenosine 3, 5-monophosphate excretion, provided it is related to the glomerular filtration rate. With the measurement of the urinary excretion of calcium and phosphate, on the other hand, there is a large overlap in control subjects and in patients with primary hyperparathyroidism.The surgical removal of parathyroid tumours is the treatment of choice of primary hyperparathyroidism. In the routine preoperative evaluation, we do not recommend PTH measurements in the venous effluent of parathyroid tumours, since all parathyroid glands have to be surgically localized. In previously explored patients the interpretation of selective PTH measurements is difficult because of distorsion of the venous drainage from the parathyroid glands.     

Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients.

BACKGROUND: Cinacalcet rapidly normalizes serum calcium and reduces intact parathyroid hormone (PTH) levels in renal transplant patients with hypercalcaemia and persistent hyperparathyroidism. The aim of this study is to evaluate the 6 months efficacy of cinacalcet and the effect of cinacalcet withdrawal on serum calcium and PTH in such patients. Furthermore, the impact of cinacalcet on bone turnover and quality of life was assessed. METHODS: Twelve renal allograft recipients with hypercalcaemia due to persistent hyperparathyroidism were treated with cinacalcet for 26 weeks. Cinacalcet was then withdrawn to check for recurrence of hypercalcaemia. RESULTS: Cinacalcet maintained normocalcaemia in all patients from week 4 to 26, and PTH significantly decreased and remained suppressed. Serum phosphate increased, whereas the serum calcium-phosphate product remained unchanged. The excretion of calcium and phosphate in the 24 h urine had tendency to decrease. After cinacalcet was withdrawn, hypercalcaemia recurred rapidly and PTH increased to baseline values. Renal function remained stable, proteinuria was unchanged and no allograft rejection was observed. During treatment with cinacalcet, total and bone-specific alkaline phosphatase increased, whereas the urinary deoxypyridinoline-creatinine ratio did not change significantly, suggesting enhanced bone formation. Quality of life assessed at weeks 10 and 26 remained unchanged compared with baseline. CONCLUSIONS: In conclusion, continued treatment with cinacalcet is required to maintain long-term normocalcaemia and to suppress the enhanced PTH production in renal transplant recipients with persistent hyperparathyroidism.     

Acute primary hyperparathyroidism: experience of 59 cases

Acute primary hyperparathyroidism is a rare disease with a high mortality rate in some series. Between 1960 and 1986, 1000 patients were treated for primary hyperparathyroidism, among them 59 patients with acute hyperparathyroidism. All these patients were successfully operated on; none of them died before surgery. This study reveals the importance of resuscitation and urgent surgery. It is necessary to rehydrate, to correct electrolyte disorders and to lower serum calcium levels, but it is not necessary to obtain normal serum calcium levels before surgery.     

Parathyroid hormone: before and after parathyroidectomy

The clinical value of measuring serum immunoreactive parathyroid hormone (iPTH) for the diagnosis of primary hyperparathyroidism is sometimes debated, and the clinical significance of an elevated postoperative serum iPTH level is unknown. Therefore we studied 141 consecutive patients with primary hyperparathyroidism before and after parathyroidectomy to determine the clinical value of measuring serum iPTH by a mid-region-specific radioimmunoassay. Eighty-eight percent of the patients with primary hyperparathyroidism had an absolute increase in the level of serum iPTH (greater than 40 microliter Eq/ml) before surgery, and the remaining patients had an inappropriately increased level of serum iPTH for the simultaneous serum calcium level. Preoperative serum iPTH level correlated positively with serum calcium level and parathyroid tumor size. Postoperative elevation of serum iPTH level was common (as high as 40%) and was associated with higher preoperative levels of blood urea nitrogen, serum creatinine, and alkaline phosphatase and larger tumors. An elevated postoperative serum iPTH level without hypercalcemia did not indicate a failed parathyroidectomy, whereas negative parathyroid exploration and postoperative hypercalcemia were the best predictors of persistent hyperparathyroidism. We conclude that preoperative serum iPTH measurement is a very sensitive diagnostic test for primary hyperparathyroidism, but postoperative serum iPTH measurement is not a good predictor for persistent or recurrent hyperparathyroidism.