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Serum immunoreactive parathyroid hormone (IPTH) was measured by radioimmunoassay in 54 patients with primary hyperparathyroidism and in 18 consecutive patients with ectopic hyperparathyroidism due to nonparathyroid cancer without apparent skeletal metastasis. Although serum calcium concentration was higher in the group with ectopic hyperparathyroidism, serum IPTH was lower (rank sum test, P < 0.001) and was undetectable in eight. A second anti-PTH antiserum also differentiated between IPTH in the two groups, although IPTH was undetectable in only 1 of 14 sera. When IPTH values in serial dilutions were plotted, slopes for the two patients with ectopic hyperparathyroidism who had relatively high IPTH were less (P < 0.001) than slopes for standard hyperparathyroid sera. By using differences in either IPTH rank or slope of the dilutional curve of sera, primary hyperparathyroidism could be excluded as a cause of the hypercalcemia in 16 of the 18 patients with ectopic hyperparathyroidism. The data are interpreted as indicating that PTH-like material in the serum of these patients with ectopic hyperparathyroidism is immunologically different from the PTH in the serum of patients with primary hyperparathyroidism.
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BACKGROUND: Parathyroidectomy for primary hyperparathyroidism (PHPT) can cause secondary hyperparathyroidism, with increased serum parathyroid hormone (PTH) and normal or low serum calcium concentrations. METHODS: A prospective study investigated 78 consecutive patients who underwent exploration for PHPT. Serum intact PTH and total calcium concentrations were measured the evening after operation and ionized Ca++ the following morning. These levels were reassayed 1 week later. RESULTS: Before operation, the mean PTH level was 138 +/- 15 pg/mL, total calcium concentration was 11.6 +/- 0.1 mg/dL, and ionized Ca++ concentration was 1.44 +/- 0.02 mmol/L. On the night of the operation, the PTH level was 11 +/- 2 pg/mL, and the total calcium concentration was 8.9 +/- 0.1 mg/dL. Fifty-five patients had hypoparathyroidism, with a PTH level less than 10 pg/mL. The day after the operation, the ionized Ca++ level was 1.14 +/- 0.01 mmol/L. One week later, PTH, ionized Ca++, and total serum calcium concentrations returned to normal levels. In 9 patients (12%), PTH levels were increased (98 +/- 16 pg/mL), although ionized Ca++ concentrations were normal (1.18 +/- 0.02 mmol/L), demonstrating secondary hyperparathyroidism. Risk factors for postoperative secondary hyperparathyroidism included older age, symptomatic hyperparathyroidism, higher preoperative PTH and alakaline phosphatase levels, and lower serum phosphorous levels. In 70% of these patients, PTH levels returned to normal in 3 to 12 months. CONCLUSIONS: Secondary hyperparathyroidism occurs in 12% of patients after surgical treatment of PHPT. It is transient, possibly compensating for relative hypocalcemia.
OBJECTIVE: In general it is thought that recurrence of primary hyperparathyroidism is a rare event. To our knowledge, however, only one large patient series has been reported with a mean of more than 7 years of follow-up. The aim of the present study was to determine the long-term recurrence rate in 785 out of 886 patients operated on for primary hyperparathyroidism and followed-up for a mean of 10.03 years after surgery. DESIGN: Medical records were scrutinised. The patients who were still alive answered a questionnaire and had laboratory tests. METHODS: Follow-up data concerning the state of health, medical treatment, other diagnoses, renal function, and serum calcium and creatinine levels were found in the medical records of 203 patients, and were registered at the start of investigation of 582 patients. Intact parathyroid hormone values were determined in 252 patients. Recurrence rate and 95% confidence interval (C.I.) were calculated. RESULTS: Recurrence rate of hyperparathyroidism with constant or intermittent hypercalcaemia (n=39) was 4.97% (95% C.I.=3.45-6.74%) during a mean of 10 years of follow-up. Nine out of 39 had elevated serum creatinine levels. Recurrence rate of hyperparathyroidism with normal serum creatinine levels, including patients with normocalcaemia, intermittent hypercalcaemia, and constant hypercalcaemia was estimated to be 7-8% during a mean of 10 years of follow-up. CONCLUSIONS: Recurrence rate was determined with reasonable precision in this large patient series, and recurrence of hyperparathyroidism cannot be considered to be extremely rare, but it may occur more than 20 years after treatment in both single and multiple gland disease.
Tthe findings of 150 patients with proven primary hyperparathyroidism are reported. The purpose of the analysis was to find differences between the various clinical manifestations of the disease. Furthermore the occurrence of acute hyperparathyroid crisis in our series as well as in the literature are described. 65.8% of the patients were females, 34.2% were males. The leading symptom in 98 patients (group I) were kidney stones and in 23 patients (group II) cystic bone disease. Both manifestations of the disease occurred in only 7 patients (group III) and no symptoms related to the kidneys or to the bones occurred in 24 patients (group IV). Because of the difference of the clinical manifestations the additional data were analyzed for each group separately and compared with each other. There was no difference in the mean serum calcium levels for all four groups, however, patients of group I were on the average younger, the duration of the disease was longer and the weight of the parathyroid adenoma was lower compared to the other three groups. Data are presented regarding calcium excretion, phosphate clearance and tubular reabsorption of phosphate for each group. At operation single or multiple adenoma formation was present in 133 patients, whereas diffuse hyperplasia was found in 17 and carcinoma in 2 other patients. 46 of the adenomas were found in atypical anatomical localisation. This observation is responsible for the many unsuccessful or second explorations of the neck. The weight of the adenomas varied between 0.1 and 23.5 g. The most difficult diagnosis was that of diffuse hyperplasia. The success of the surgical intervention was usually established in over 80% of the cases within 24 to 48 hours after the operation with a significant fall of serum calcium. There is still no definite explanation for the variability of the clinical manifestations of primary hyperparathyroidism. Parathyroid hormone determinations on larger numbers of patients are not yet published. The assumption, that different hormones or peptide fragments are responsible for the different action on bone and kidney is discussed. In our series of 152 patients acute hyperparathyroid crisis occurred eight times. Our findings are compared to the other well documented cases in the literature. Main symptoms were nausea, vomiting abdominal pain and different states of cerebral dysfunction. Most of the patients had calcium levels over 16 mg/100 ml. Partial renal insufficiency with elevated blood urea and phosphate retention was found in ov er 50% of the cases. Overall mortality of all cases with acute parathyroid crisis is 52.5%. The pathogenesis of acute hyperparathyroidism and the implications of high calcium levels are discussed. According to our own experience hypercalcemia can be controlled with an intensive therapeutic program and emergency operation for acute parathyroid crisis is no longer necessary.
Neonatal severe hyperparathyroidism (NSHPT) is considered an autosomal-recessive disorder, attributable in many cases to homozygous inactivating mutations of the Ca++-sensing receptor (CASR) gene at 3q13.3-21. Most heterozygotes are clinically asymptomatic but manifest as familial (benign) hypocalciuric hypercalcemia (FHH) with a laboratory profile that is variably and sometimes only marginally different from normal. In 5 NSHPT cases from 3 Nova Scotian families, we found homoallelic homozygosity for an insertion mutation in exon 7 of CASR that includes an Alu repeat element with an exceptionally long polyA tract. Four of the 5 NSHPT infants were treated by parathyroidectomy more than a decade ago and are well now. A fifth went undiagnosed until adulthood and has profound musculoskeletal and neurobehavioral deficits. Among 36 identified FHH heterozygotes are 3 individuals with an unexpected degree of hypercalcemia and elevated circulating parathyroid hormone levels consistent with secondary hyperparathyroidism. Two are obligately heterozygous offspring of NSHPT mothers with surgical hypoparathyroidism and variable compliance with vitamin D therapy. The other is an adult with coexistent celiac disease in whom hyperparathyroidism, probably secondary to vitamin D deficiency, led to surgery. In counseling affected families, the heterozygous state should not be considered entirely benign, since FHH heterozygotes, particularly infants, may be prone to secondary hyperparathyroidism and symptomatic hypercalcemia. In such families, molecular diagnosis will allow for unambiguous identification of at-risk individuals.
A patient with myotonic dystrophy and associated primary hyperthyroidism and hyperparathyroidism is described; this association has not been reported previously, to the authors' knowledge. The patient also suffered from hypergonadotropic hypogonadism and hyperinsulinism with insulin resistance. The etiology of hyperthyroidism and hyperparathyroidism is not clear. At surgery, a parathyroid adenoma was extirpated, and a subtotal thyroidectomy was performed. Postoperative course was unremarkable, with consistently normal serum calcium levels but persistently elevated serum parathyroid hormone concentrations. The possibility that the patient had a residual hyperparathyroidism could not be eliminated. Thyroid function was normal. After surgery, the patient reported subjective improvement in his muscle strength. The authors conclude that both diseases-- hyperthyroidism and hyperparathyroidism--exert a negative effect on the myotonic dystrophy and that an early recognition of these two diseases is crucial for the favorable evolution of the patient.
Approximately 70 families with familial isolated hyperparathyroidism (FIHP) have been reported. Whether it is a separate entity or a variant of multiple endocrine neoplasia type 1 (MEN1 at 11q13) or hyperparathyroidism-jaw tumor (HPT-JT or HRPT2 at 1q21-32) syndrome is not known. We describe here 3 unreported families with familial primary hyperparathyroidism and evaluate their clinical, pathological, and genetic profiles. Biochemical and radiological screenings for MEN1 were negative for all families. In 2 families with a total of 10 affected cases and 3 female obligate carriers, there is no evidence of jaw or renal lesions despite careful radiological investigations. In both families the disease was linked to the 1q21-q32 region with the maximum logarithm of the odds (lod) scores of 3.10 and 3.43 for markers D1S222 and D1S249 respectively, at recombination fraction of 0. In 1 family 2 types of parathyroid pathology were found: 3 of chief cell type and 1 of oxyphil/oncocytic cell type. Two chief cell tumors and 1 oxyphil tumor were found to have loss of heterozygosity (LOH) involving loss of the wild-type alleles for chromosome 1q markers. In the third family, with 4 affected siblings, a parathyroid carcinoma and 2 cases of polycystic kidney disease were found. The parathyroid carcinoma also showed loss of heterozygosity in the 1q region. In conclusion, we found that the hyperparathyroidism traits in a subset of FIHP families are linked to the 1q21-32 markers in the HRPT2 region. We describe the spectrum of parathyroid disease in 1q-linked families involving 3 different types of pathology and demonstrate for the first time loss of wild-type alleles in these parathyroid tumors. Taken together, the results suggest that some of the FIHP are a variant of HPT-JT and that the gene involved is a tumor suppressor gene.
Heterotransplantation of adenomatous parathyroid glandular tissue from humans with primary hyperparathyroidism into athymic nude mice creates a unique animal model of this disease. The mice manifest high concentrations of both midregion/C-terminal human parathyroid hormone and biologically active intact human parathyroid hormone relative to either mice with no implants or mice that received normal human parathyroid tissue. Secretion of these substances is maintained in most mice for at least 9 to 13 months after implantation. In addition, animals that have experienced implantation exhibit other characteristics associated with human primary hyperparathyroidism including relative hypercalcemia and increased renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity. We also measured these parameters in a group of nude mice that received transplantation of a similar mass of hyperplastic parathyroid tissue that was obtained from patients with uremic secondary hyperparathyroidism. Although we hypothesized that the level of human parathyroid hormone secretion from these implants would fall over time in response to the normal host environment, hormone levels remained as high as those in recipients of adenomatous heterografts, even after 9 to 13 months. Moreover, similar biologic effect of the excess parathyroid hormone (i.e., relative hypercalcemia, hyperphosphatasemia, and increased 1,25-dihydroxyvitamin D biosynthesis) were detected. These animal models should prove extremely useful in supplementing our understanding of hyperparathyroid disorder in man.
The bone histology of renal osteodystrophy is classified into osteitis fibrosa, osteomalacia, those of mixed, osteoporosis and low turnover bone. Osteitis fibrosa is the most frequent skeletal abnormality and is caused by various degrees of hyperparathyroidism. The main factors inducing hyperparathyroidism which is a well known complication in patients with renal failure include (a) phosphorus retention: 1) hypocalcemia and 2) decreased levels of 1 alpha, 25(OH)2 Vitamin D3, (b) reduced number of 1 alpha, 25(OH)2 Vitamin D3 receptors in parathyroid tissue, (c) skeletal resistance to set-point for calcium-regulated parathyroid hormone secretion. Serum or plasma levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, calcitonin and tartrate resistant acid phosphatase are measured to evaluate hyperparathyroidism and metabolic bone disease. Dietary phosphorus restriction in chronic renal insufficiency prevents secondary hyperparathyroidism and renal osteodystrophy. Other treatment of phosphorus binders, Vitamin D metabolites or analogues, carcitonin and bisphosphonate are useful for the management of renal bone disease.
OBJECTIVE: To examine changes over the past three decades in the indications for, and outcomes of, surgery for primary hyperparathyroidism. DESIGN: Survey of a prospective hospital database. SETTING: Royal North Shore Hospital (a tertiary referral and university teaching hospital), Sydney, New South Wales, January 1962 to December 1996. PATIENTS: All 733 patients who underwent neck exploration for primary hyperparathyroidism. RESULTS: The annual number of parathyroidectomies increased virtually exponentially, from a mean of two in 1962-1969 to 73 in 1996. In the 1960s and 1970s, the most common indication for surgery was the presence of renal calculi (58% and 43%, respectively), but in the 1980s there was a marked increase in presentation of asymptomatic disease after biochemical screening (19%). In the 1990s, low bone mineral density detected by osteodensitometry has become the most common indication for surgery (31%). After initial operation, 11 patients (2%) had persistent hypercalcaemia, with five of these cured by reoperation--an overall failure rate of 1%. CONCLUSIONS: Surgery for primary hyperparathyroidism has become increasingly common, with low bone mineral density replacing renal calculi as the most common indication for surgery. Neck exploration in experienced hands results in an overall cure rate of 99%.
Radioimmunological determination of immunoreactive parathyroid hormone (iPTH) in sera of patients with primary and secondary hyperparathyroidism was carried out using antisera specific for the amino-terminal and the mid-region part of the hormone. In 58 patients with primary hyperparathyroidism and in 29 patients with the secondary form of the disease due to renal failure, there was a linear correlation between the concentration of serum iPTH determined with the two types of antiserum. In all cases the mid-region-specific antiserum measured the highest iPTH concentrations. The molecular forms of serum iPTH were examined after gel filtration of Sephadex G-75 followed by Bio-Gel P-60 in nine patients. Fractions which represented molecular forms equal to or smaller than intact PTH were collected. Using the mid-region-specific antiserum, the predominant immunoreactivity (50-80%) eluted corresponding to one or several large fragments in both forms of the disease. In contrast, iPTH activity co-eluting with the intact hormone represented 2-8% of the total. Similar elution profiles were observed when the amino-terminal-specific radioimmunoassay was used. However, this antiserum showed that in both disease states relatively higher concentrations of iPTH co-eluted with the intact hormone (about 20%). In conclusion, the higher serum iPTH concentrations measured with mid-region-specific antiserum are mainly due to quantitative differences due to the presence of large and intermediate sized fragments. The appearance of higher concentrations of iPTH in secondary hyperparathyroidism may be due to a reduced degradation and/or filtration by the kidney.
In a series of 6 patients out of 47 cases with extrarenal hyperparathyroidism we investigated the clinical, laboratory and ultrastructural peculiarities of acute hyperparathyroidism. It was found that there are characteristic differences between both entities which, however, are fluid. Clinically more severe were neuromuscular psychiatric and mental signs. In the laboratory parameters PTH determined by radioimmunoassay and calcium were higher whereas hemoglobin was lower. The weights of the adenomas did not differ in both groups and this was also true for light microscopy findings. Electron microscopy revealed accelerated hormone extrusion and autodigestion of retrived membrane material in the cases of acute hyperparathyroidism similar to characteristics of parathyroid cells stimulated by hypocalcemia in tissue culture.
Familial isolated hyperparathyroidism (FIHP) can result occasionally from the incomplete expression of a syndromic form of familial hyperparathyroidism (HPT), specifically multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric hypercalcemia, or the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The cause of FIHP has not been identified in the majority of families. We investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT. All families had negative clinical testing for MEN1, hypocalciuric hypercalcemia, and HPT-JT and negative mutational screening of MEN1 and CASR, the gene for the calcium-sensing receptor. Thus, an extended effort was made to exclude each of the principal syndromic causes of FIHP. The families were characterized by young probands (42 +/- 3 yr) and occasionally unusual parathyroid histology, including four families with one case of parathyroid cancer. We had speculated that there was a high frequency of occult mutation in HRPT2 among such carefully screened kindreds. This hypothesis became testable with the recent identification of that gene. Among the 32 FIHP families, only a single one was found to have a mutation in HRPT2 (679insAG); this mutation predicts premature truncation of its gene product, parafibromin, and thus its presumed inactivation. Even accounting for families with one of the three occult syndromes and false negative biochemical or DNA testing, these results indicate that an unexpectedly large fraction of FIHP has currently unrecognized causes.
Surgical treatment offers a definite cure of patients with primary hyperparathyroidism. When making the diagnosis of primary hyperparathyroidism the success of a surgical solution depends on the experience and judgment of the surgeon. Our experience with 222 operations and re-operations convinced us on the preference of a bilateral approach, i.e. exploration of both sides of the neck. The ectopic localization of the parathyroid glands, the limited possibilities of an unequivocal interpretation of the histological examinations but also the frequent incidence of thyropathies leads the surgeon, in our opinion, to the complete exploration of both sides of the neck within the framework of the primary operation for primary hyperparathyroidism. This approach leads most probably to the best results. We use an aimed unilateral approach only in old patients who are in a very bad condition where we anticipate a benefit from a short operation.
In patients with uremia, intact parathyroid hormone (PTH) measurement appears to overestimate the biologically active hormone in circulation. The recent description of the accumulation in these patients of a non-intact PTH form measured by the standard immunometric assays, re-opened the question. In this study we submitted serum samples from 7 patients with primary hyperparathyroidism (PHP) and from 10 patients with hyperparathyroidism secondary to chronic renal failure (SHP) to preparative HPLC in order to discriminate the molecular forms measured by our currently used immunofluorometric assay for intact PTH. The elution profile obtained with the HPLC system showed two clearly defined peaks, the first one corresponding to a lower molecular weight form, and the second to the intact PTH (1-84) form. In patients with SHP the area under the curve for the first peak (mean 29.5%, range 20.6 to 40.4%) was significantly greater than that observed for patients with PHP (mean 15.6%, range 5.6 to 21.9%). This confirms previous studies showing accumulation of molecular forms of slightly lower molecular weight, presumably PTH (7-84), in patients with SHP and, to a lesser extent, in patients with PHP. The real necessity of assays that discriminate between these two molecular forms is debatable.
Cinacalcet is a new drug with antiparathyroid effects that belongs to the class of calcimimetics. It increases the sensitivity of the calcium-sensing receptor (CaSR) to calcium, thus inducing a decrease in plasma parathyroid (PTH) levels. In patients with uncontrolled secondary hyperparathyroidism due to uremia, cinacalcet has been shown to decrease the levels of PTH even in those optimally treated with calcium and 1-ahydroxylated vitamin D. Cinacalcet decreases plasma calcium and plasma PTH levels in patients with primary hyperparathyroidism or parathyroid cancer.