Department of Medicine, West Los Angeles VA Medical Center and UCLA, Los Angeles, CA
Correspondence and offprint requests to: Arnold J. Felsenfeld, MD, Nephrology Section (111L), West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA.
Keywords: calcium; hypercalcemia; parathyroid hormone; parathyroid infarction; primary hyperparathyroidism
Introduction
On rare occasions, primary hyperparathyroidism has been reported to resolve itself spontaneously as a result of haemorrhage and/or infarction of a parathyroid adenoma and we have identified a limited number of such reports in the literature [127]. We recently treated a patient who presented with severe hyperparathyroidism and marked hypercalcaemia which spontaneously resolved itself without any clinical symptoms or signs suggestive of haemorrhage or infarction. However, after a relatively stable period of several months, a rapid recurrence of marked hypercalcaemia and hyperparathyroidism developed and necessitated an immediate parathyroidectomy. This anecdotal observation may shed light on some issues of parathyroid pathophysiology in secondary hyperparathyroidism as well.
Case report
A 72-year-old male presented in late July to his physician with complaints of polyuria, constipation and weakness of 23 weeks duration. At that time serum calcium, phosphorus and creatinine values were 13.8, 2.8 and 2.7 mg/dl respectively (Table 1). Intact PTH (Nichols Institute, San Juan Capistrano, CA) was 812 pg/ml (normal 1065 pg/ml). Only 4 weeks earlier, the serum calcium was 9.6 mg/dl. He denied any previous neck radiation or surgery but before emigrating to the United States, he had lived in the Ukraine within 40 miles of Chernobyl during the meltdown and the subsequent year. His past medical history was significant for a Dukes stage II adenocarcinoma of the sigmoid colon resected 3 years before his current presentation. After the surgery, he had several colonoscopies with removal of polyps all of which were hyperplastic but without malignant foci. The last colonoscopy done 6 months earlier was normal. CEA levels were measured several times and were always in the normal range. The patient had a history of hypertension managed with diet alone and previous surgery for benign prostatic hypertrophy. There was no family history of hypercalcaemia or cancer and the patient was not taking any medications.
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The patient was managed with oral furosemide supplemented with a high oral intake of sodium and water for 8 weeks while awaiting parathyroidectomy. Before his scheduled surgery in October, laboratory tests revealed a serum calcium of 9 mg/dl with an ionized calcium of 4.76 mg/dl; the PTH level was 177 pg/ml. These results were confirmed by a second set of laboratory tests. He denied any neck pain or discomfort during the 8 week interval in which no laboratory tests were performed. After cancellation of his parathyroidectomy, he was closely followed in an outpatient setting. Serum 1,25 dihydroxyvitamin D (SmithKline Beecham Clinical Laboratories, Van Nuys, CA), measured in late October, was 64 pg/ml (normal 2076 pg/ml). As shown in Table 1 and Figure 1
, from early October to late February, total and ionized serum calcium and PTH values were relatively stable but did slowly increase; serum creatinine values were stable. Between late February and mid-April, severe hypercalcaemia again developed as PTH values increased by approximately 5-fold. Repeat measurements confirmed the severe hypercalcaemia and hyperparathyroidism and the patient was immediately scheduled for parathyroidectomy. An enlarged right upper parathyroid gland was located. Upon removal, the gland measured 2.5x1.5 cm and weighed 1.3 g. The other three glands were visualized and appeared normal; biopsies were taken from these glands. Microscopic examination showed a well-circumscribed parathyroid adenoma surrounded by a rim of normal parathyroid tissue. The adenoma was cellular and composed of monotonous parathyroid chief cells with minimal cytologic variation. No haemorrhage, fibrosis, infarction, calcification or cystic changes were present. Biopsy specimens obtained from the other three parathyroid glands were normal. The thyroid was also biopsied because of the presence of nodularity and microscopic exam showed a multinodular goiter.
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Discussion
We have described a case of primary hyperparathyroidism in which the patient had rapid development and spontaneous resolution of severe hypercalcaemia followed by several months of relative quiescence. During the period of relative quiescence, we believed that the patient had had a spontaneous resolution of hyperparathyroidism due to a silent infarction of a parathyroid adenoma. However, he then had rapid progression of his biochemical alterations. Such a result suggests the rapid growth of parathyroid cells and that the rapidly proliferating cells were relatively insensitive to the increasing serum calcium. It is also possible that some of the increase in PTH could have been due to cell hypertrophy with increased PTH secretion per cell [28]. Another factor which could potentially enhance PTH secretion per cell is increased post-transcriptional stability of PTH mRNA. However, since hypocalcaemia has been shown to result in increased stability [29], it would seem unlikely that hypercalcaemia would have this effect.
Since 25-hydroxyvitamin D was not measured, we cannot completely eliminate the possibility of a vitamin D deficiency. However, we believe that such a possibility is remote because it would not explain the marked decrease in PTH that was associated with the spontaneous resolution of the hypercalcaemia. Moreover, that the patient was a healthy man who resided in a sunny climate (Los Angeles) and the initial presentation of hypercalcaemia occurred in July also make the possibility of a vitamin D deficiency remote.
In 1946, Norris et al. described the first case of a parathyroid adenoma with spontaneous infarction in a patient who presented with tetany and convulsions [1]. Since then a limited number of cases of parathyroid gland infarction have been described [227]. Nylen et al. have suggested that spontaneous parathyroid infarction is characterized by two distinctly different clinical presentations, one with intracapsular and the other with extracapsular haemorrhage [24]. In the former, the patient experiences mild neck pain and tenderness and the hyperparathyroidism resolves with the patient becoming normocalcaemic or even sometimes, hypocalcaemic tetany develops. In the latter, severe neck and/or substernal pain develops because of swelling due to bleeding. Significant respiratory distress, dysphonia and dysphagia are sometimes present [19,24]. Most of these patients require emergency surgery. Our patient denied any symptoms although it is possible that he might have ignored minimal discomfort.
Some reports have suggested that large adenomas are more vulnerable to the occurrence of spontaneous haemorrhage and resolution [2,8,21]; such a possibility suggests that rapidly growing adenomas may outgrow their vascular supply and infarct. Moreover, in many patients who have been reported to have a parathyroid infarction, a hypercalcaemic crisis has often coincided with the infarction [5,20]. Thus, it has been postulated that the infarcting gland may release large amounts of stored PTH causing severe hypercalcaemia.
Our patient had severe hypercalcaemia and very high PTH levels before these values spontaneously decreased. Although the PTH values did not return to normal as the serum calcium values did, the decrease in PTH values was dramatic. During the 5 months after his parathyroid surgery was cancelled, the serum ionized calcium slowly increased and PTH values rose by approximately 2-fold. Shortly thereafter, PTH values rapidly increased by an additional 5-fold in a presentation similar to that of his initial one.
We have found three previous case reports of presumed spontaneous parathyroid infarction in which the hypercalcaemia resolved and reappeared after a period of quiescence [4,15,25]. Gibbs et al. reported a patient with spontaneous resolution of hypercalcaemia and radiographic healing of osteitis fibrosa [25]. Recurrence of hypercalcaemia was detected 90 weeks after the initial episode and led to several unsuccessful parathyroid explorations. The final one, performed 250 weeks after the initial presentation resulted in successful removal of a parathyroid adenoma which was embedded in the thyroid gland; the excised adenoma had no fibrosis or evidence of previous haemorrhage. Wood et al. [15] reported a patient who had a spontaneous and complete resolution of severe hypercalcaemia (>16 mg/dl) for 5 months before severe hypercalcaemia rapidly recurred leading to parathyroidectomy. A parathyroid adenoma was resected and microscopic examination did not show any fibrosis or evidence of previous haemorrhage. Pearl et al. described a patient with hypercalcaemia that resolved after the left lobe and isthmus of the thyroid were resected when an incidental papillary carcinoma was found during surgery [4]. The hypercalcaemia resolved although no parathyroid tissue was present in the resected specimen. Approximately 10 months later, hypercalcaemia recurred and a parathyroid adenoma was removed in an area adjacent to the previous thyroid surgery. Microscopic examination of that adenoma showed the presence of a central area of loose fibrous granulation tissue with small nests of adenoma cells within the granulation tissue. The bulk of the adenomatous tissue surrounded the central mass of granulation tissue. The authors concluded that during the removal of the thyroid cancer, the blood supply to the parathyroid adenoma was interrupted, resulting in parathyroid gland infarction except for a small rim of viable cells. It was presumed that the regrowth of these cells caused the recurrence of the hyperparathyroidism.
It has been suggested that hyperparathyroidism can result from either (i) an alteration in the set point, a situation in which an elevated serum calcium concentration is needed to retard parathyroid cell proliferation or (ii) changes in cell division in which the feedback control of cell proliferation by serum calcium is minimal or lacking [30,31]. The set point control for the parathyroid gland is defined as the serum calcium level which provides the negative feedback to control PTH secretion. An altered set point results in the need for a higher than normal serum calcium value to suppress PTH secretion and to retard cell proliferation. In set point alterations, it has been suggested that patients have smaller parathyroid glands than with mitotic changes and in addition, the parathyroid cells are characterized by having an asymptotic manner of growth that is controlled by a higher serum calcium [30,31]. Conversely, in addition to the larger parathyroid glands with mitotic changes, higher serum calcium values and a continuous manner of growth that is not affected or only minimally affected by elevated serum calcium values are characteristic [30]. The rapidity of development and severity of hypercalcaemia during the initial presentation and subsequent relapse in our patient suggests the presence of a mitotic change.
The clinical course in which our patient rapidly developed severe hypercalcaemia twice would suggest that the parathyroid adenoma had the capacity for rapid growth. The challenge in our patient and in the other three patients described in the literature with a similar clinical course [4,15,25], is to reconcile the clinical and pathological findings. In all four patients, a presumed parathyroid infarction led to resolution of severe hypercalcaemia and after a prolonged period of quiescence, rapid recurrence of the hypercalcaemia developed. In our patient and in two other patients [15,25], an unremarkable parathyroid adenoma was removed at surgery; in the fourth patient, a central area of fibrosis was present in the removed adenoma [4]. Thus, one must resolve why, if an infarction did occur, should pathological evidence not be present in all the cases. Furthermore, it is important to note that the only patient with fibrosis present in the adenoma was the patient in whom the resolution of the hyperparathyroidism was not spontaneous but rather resulted from surgical exploration of the neck [4]. Thus, in none of the three patients in whom the hypercalcaemia resolved spontaneously was evidence of the presumed parathyroid infarction present in the pathological specimen. Consequently, we believe that possibilities other than a complete infarction of the parathyroid adenoma must be entertained.
An attractive hypothesis is the possibility that rapidly growing cells could outgrow their vascular supply to an extent which does not result in infarction but does reduce their capacity to synthesize and secrete hormone. In recent studies on rapidly growing neoplastic tissue, Folkman et al. have shown that inhibition of angiogenesis results in an orderly involution of the rapidly growing tissue without any fibrosis [32,33]. Thus, it may be possible that a vascular event insufficient to produce infarction but sufficient to markedly compromise tissue oxygenation could have a similar effect. During such an event, the diminished blood supply could affect the intercellular signalling that may be critical to coordinate PTH secretion [34,35]. While our explanation is speculative, we have tried to consider a possibility which could integrate the entire clinical course with the pathological findings. Whether such a sequence of events could happen clinically remains to be determined.
A final consideration is that the patient's development of primary hyperparathyroidism could have been related to his radiation exposure during the Chernobyl meltdown. Studies of radiation-induced hyperparathyroidism have reported an increased association of thyroid disease [3639] and our patient had multinodular goiter. Thus, it is possible that radiation exposure may have played a role in the genesis of the parathyroid adenoma and the multinodular goiter. However, our patient's latency period was only 10 years as compared to the average reported latency of 3040 years for the development of parathyroid pathology after the medical use of radiation [37,40]. Whether a particularly high dose of radiation exposure could have resulted in a shorter latency period needs further study [41].
In summary, we have presented an unusual case of primary hyperparathyroidism that during a 10 month period was characterized by the rapid development of severe hypercalcaemia, the spontaneous resolution of the hypercalcaemia, a prolonged period of quiescence, and the rapid recurrence of severe hypercalcaemia. Possible explanations for this patient's unusual course were discussed and comparisons were made with three similar cases in the literature.
References