Pseudogout associated with primary hyperparathyroidism: management in the immediate postoperative period for prevention of acute pseudogout attack

Three cases of pseudogout associated with primary hyperparathyroidism are reported. Preoperative radiological studies revealed association of pseudogout. Considering the frequent development of acute pseudogout attack following parathyroidectomy, prevention of a sudden decrease in the serum calcium concentration was attempted using calcium supplement therapy starting on the first postoperative day in all three cases. Serum calcium slowly decreased to the normal range, and the postoperative courses were uneventful. From these experiences, we advocate that calcium supplement therapy is worth trying for the prevention of acute pseudogout attack following parathyroidectomy.     

Clinical and roentgenographic aspects of pseudogout: a study of 50 cases and a review.

Pseudogout, defined as recurrent acute arthritis due to intrasynovial deposition of calcium pyrophosphate dihydrate crystals, is a relatively common arthritic disorder of the elderly. The clinical and roentgenographic aspects of 50 cases of pseudogout in hospitalized patients are reviewed in this paper. Oligoarticular and polyarticular episodes were observed in half of these patients. Antecedent problems included infection, trauma, surgery and vascular events. Consistent with previous reports, most patients had roentgenographic evidence of chondrocalcinosis. A third had asymptomatic capsular or periarticular calcific deposits or both, and a third had pyrophosphate arthropathy, a progressive, destructive, accelerated form of osteoarthritis. An attack of pseudogout may offer a clue to the presence of an unsuspected metabolic disease, such as primary hyperparathyroidism or idiopathic hemochromatosis.     

Two cases of acute pseudogout attack following parathyroidectomy.

Two cases of acute attack of pseudogout associated with primary hyperparathyroidism are reported. Case 1 suffered from acute pain and swelling of the right ankle and dorsal of the right foot. Case 2 suffered from unknown fever and pain of the bilateral jaw, shoulder, elbow, wrist and knee joints. Postoperative radiological studies revealed the association of chondrocalcinosis in both cases. Synovial fluid in case 2 was aspirated and analyzed for calcium pyrophosphate dihydrate crystal by microscopic examination.     

Basal and stimulated calcitonin secretion in primary hyperparathyroidism before and after parathyroidectomy

To investigate calcitonin secretion in primary hyperparathyroidism, basal and stimulated (3 mg Ca++/kg body weight/10 min) immunoreactive calcitonin plasma levels were studied before parathyroidectomy. Plasma calcitonin levels were raised in 50% of patients regardless of sex, but a significant correlation between basal plasma calcium and calcitonin was found only in males. A reduced calcitonin response to calcium infusion was observed in all patients. Parathyroidectomy invariably induced a normalization of calcitonin basal levels. Our findings confirm the existence of a decreased parafollicular cell reserve probably as a consequence of the persistent hypercalcemic state in hyperparathyroid patients and suggest that it is more frequent in females.     

Double-blind trial of oral 1,25-dihydroxy vitamin D3 versus placebo in asymptomatic hyperparathyroidism in patients receiving maintenance haemodialysis.

Fifty-seven patients who had been receiving maintenance haemodialysis for a mean of 4.6 years were given 0.25-0.5 microgram oral 1,25-dihydroxy (1,25-(OH)2) vitamin D3 or a placebo in a double-blind manner for one to two years. In patients with normal radiographs (mean plasma parathyroid hormone concentration 205 microliterEq/ml) 1,25-(OH)2 vitamin D3 prevented the development of the radiological appearances of hyperparathyroidism. In patients with abnormal radiographs (mean plasma parathyroid concentration 709 microliterEq/ml) 1,25-(OH)2 vitamin D3 arrested or reversed the radiological changes of hyperparathyroidism. Nevertheless, the response was slow and the concentration of the hormone remained considerably raised (mean 445 microliterEq/ml). It is concluded from these results that giving 1,25-(OH)2 vitamin D3 to patients receiving maintenance haemodialysis who have normal hand radiographs or minimal erosions is beneficial. In patients with more advanced hyperparathyroidism parathyroidectomy should be considered unless there is a rapid response.     

Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: comparison with sporadic parathyroid adenomas.

A prospective study on the natural course of primary hyperparathyroidism has recently been reported. Since hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is genetically distinct from most forms of sporadic hyperparathyroidism, it is important to know the natural course of hyperparathyroidism in MEN 1 for better clinical management. For this purpose, we retrospectively reviewed clinical parameters of patients with MEN 1 when they were diagnosed as having hyperparathyroidism, and compared them with those of patients with sporadic primary hyperparathyroidism. In patients with MEN 1: 1) levels of intact PTH (i-PTH) gradually increased with age, which accelerated over 40 years; 2) compared to the steep rise in i-PTH levels in aged patients, increase in serum calcium or decrease of serum inorganic phosphate concentration was relatively mild, and 3) the high concentrations of i-PTH in aged patients were not due to renal insufficiency. These features were not observed in patients with sporadic primary parathyroid adenomas. Clinical features of untreated hyperparathyroidism in MEN 1 may be significantly affected by the age of the patient. The effect, if any, of age-dependent deterioration on recurrence rate after subtotal or total parathyroidectomy requires further elucidation.     

Association of Parathyroidectomy With 5-Year Clinically Significant Kidney Stone Events in Patients With Primary Hyperparathyroidism

ObjectivePatients with primary hyperparathyroidism (PHPT) are at increased risk of kidney stones. Guidelines recommend parathyroidectomy in patients with PHPT with a history of stone disease. This study aimed to compare the 5-year incidence of clinically significant kidney stone events in patients with PHPT treated with parathyroidectomy versus nonoperative management.MethodsWe performed a longitudinal cohort study of patients with PHPT in a national commercial insurance claims database (2006-2019). Propensity score inverse probability weighting-adjusted multivariable regression models were calculated.ResultsWe identified 7623 patients aged ≥35 years old with continuous enrollment >1 year before and >5 years after PHPT diagnosis. A total of 2933 patients (38.5%) were treated with parathyroidectomy. The cohort had a mean age of 66.5 years, 5953 (78.1%) were female, and 5520 (72.4%) were White. Over 5 years, the unadjusted incidence of ≥1 kidney stone event was higher in patients who were managed with parathyroidectomy compared with those who were managed nonoperatively overall (5.4% vs 4.1%, respectively) and among those with a history of kidney stones at PHPT diagnosis (17.9% vs 16.4%, respectively). On multivariable analysis, parathyroidectomy was associated with no statistically significant difference in the odds of a 5-year kidney stone event among patients with a history of kidney stones (odds ratio, 1.03; 95% CI, 0.71-1.50) or those without a history of kidney stones (odds ratio, 1.16; 95% CI, 0.84-1.60).ConclusionBased on this claim analysis, there was no difference in the odds of 5-year kidney stone events in patients with PHPT who were treated with parathyroidectomy versus nonoperative management. Time horizon for benefit should be considered when making treatment decisions for PHPT based on the risk of kidney stone events.     

Bone loss in primary hyperparathyroidism

X-ray images of the second metacarpals of 153 hyperparathyroid subjects were measured and an index of cortical bone was derived. Compared with normal standards, the cortical index was above the 50th percentile in only 17.8% of women and 13.6% of men. Comparing the mean index of hyperparathyroid subjects with the normal indices of each 10-year age group, it was found that the differences were highly significant and were the same for all age groups in each sex. In particular, the difference was not greater between older female hyperparathyroid and normal subjects than it was between younger female hyperparathyroid and normal subjects. It appears that bone involvement in the form of excessive cortical thinning is extremely common in hyperparathyroidism and that sex and age do not further influence its incidence or severity.     

Increased potassium permeability in erythrocytes from patients with hyperparathyroidism

Parathyroid hormone (PTH) has been shown to modify Ca2+ and Na+ transport in several epithelia. The molecular mechanisms of these effects are poorly understood. We investigated here whether PTH may modify Na+ and K+ transport across the human red blood cell membrane in vitro and ex vivo. Fourteen patients with severe primary or secondary hyperparathyroidism and hypercalcemia were studied before and 5-7 days after surgical parathyroidectomy. Erythrocyte ouabain-sensitive as well as furosemide-sensitive Na+ efflux rates of the patients were comparable to that of healthy volunteers and remained unchanged after parathyroidectomy. Moreover, erythrocyte Na+ fluxes of control subjects remained unchanged when red blood cells were incubated in the presence of 1.0 IU/ml of bovine PTH (1-85). However, erythrocytes from hyperparathyroid patients showed a significant increase in passive K+ permeability when compared to that of healthy controls (p less than 0.05). This abnormality could be corrected in vivo after parathyroidectomy and in vitro using quinine, respectively. It is concluded that hyperparathyroidism induces a moderate increase in Ca2+ dependent K+ permeability of erythrocytes ("Gardos effect") which is reversible after parathyroidectomy.     

Surgical treatment of primary hyperparathyroidism in the elderly.

Twelve patients aged over 70 with primary hyperparathyroidism (persistent hypercalcaemia and raised serum parathyroid hormone concentrations) underwent parathyroidectomy, which was well tolerated by all. After operation serum calcium concentrations returned to normal and the commonest symptoms before operation (muscle weakness, malaise, and mild to severe dementia), although not related in severity to the degree of hypercalcaemia, improved. Mental function was greatly improved. The findings suggest that primary hyperparathyroidism should be sought in any elderly patient with hypercalcaemia and that more such patients with the diagnosis should be considered for parathyroidectomy irrespective of age.     

The suppression of TSH in the presence of the normal PRL responses to TRH out of 26 patients with primary hyperparathyroidism

The responses of TSH and PRL to intravenous doses of 500 micrograms of TRH were investigated in 26 patients with primary hyperparathyroidism. Fourteen patients (54%) showed low responses of TSH with peak values of less than 5 microU/ml (Group A). Twelve patients showed normal responses of TSH to TRH (Group B). Among the 26, 12 cases belonging to Group A and eight in Group B were reexamined after the correction of serum calcium level by parathyroidectomy. After successful treatment, the responses of TSH to TRH in six of the 12 patients in Group A returned to normal, whereas those in the remaining six were unchanged. The responses in the eight patients in Group B after surgery were not changed when compared to those before treatment. The basal values of PRL and the responses of PRL to TRH were normal in all patients and did not change after treatment. We showed that patients with primary hyperparathyroidism have a high incidence (54%) of suppressed TSH response to TRH. Hypercalcemia was obviously one of the causative factors in inducing this abnormality in six patients. However, persistently suppressed responses of TSH to TRH were observed in the other six patients in Group A even after the correction of the serum calcium level by surgery. This finding suggests a primary failure of the TSH-regulatory mechanism in some cases of primary hyperparathyroidism.     

Ultrasonic examination of the parathyroid glands, bone x-ray and calcium deposits of the eye in diagnosis of secondary hyperparathyroidism in light of 12 observed cases]

Twelve patients with chronic renal failure treated with repeated dialysis underwent subtotal parathyroidectomy. Histologic examination revealed hyperplasia parathyroidal adenoma in all patients. Diagnostic correlation between bone X-ray, ultrasound of parathyroid glands, calcium deposits in cornea and conjunctiva, and histological findings has been analysed. Radiological abnormalities have been noted in 8 patients (66%), parathyroid glands hyperplasia in 9 (75%), and corneal and conjunctival calcium deposits in 10 (83%) patients. These data confirm the value of techniques under study for the diagnosis of the secondary hyperparathyroidism in patients with chronic renal failure.     

Calcium oxalate crystal formation in patients with hyperparathyroidism and hyperthyroidism and related metabolic disturbances

The crystallization of calcium oxalate in the urine of patients with hyperparathyroidism and hyperthyroidism was studied using a mixed suspension mixed product removal (MSMPR) system. In addition, calcium metabolism in hyperthyroidism and its relationship to urolithiasis was investigated. The urines from all the three groups (normal subjects, hyperparathyroid and hyperthyroid patients) showed reduced nucleation rates and increased growth rates in comparison with the control synthetic urine. The nucleation rate was not significantly different between the three human urine groups, while the growth rate was significantly higher in the hyperparathyroid group compared to the normal and hyperthyroid groups. Crystal volume (suspension density) in the hypetparathyroid group was approximately twice that in the other two groups. Serum and ionized calcium levels in hyperparathyroid patients were higher than in normal subjects, while hyperthyroid patients had levels only slightly higher than those in normal subjects. The hyperparathyroid and hyperthyroid groups differed significantly from the normal group in urinary calcium excretion. These two groups also showed significantly higher levels of serum alkaline phosphatase and urinary hydroxyproline than did the normal group. Although hyperthyroid patients have a calcium metabolism similar to hyperparathyroid patients, the incidence of urolithiasis is no different between hyperthyroid and normal subjects. The results of both crystallization and calcium metabolism in hyperparathyroid patients were not significantly different between those with and without urolithiasis. The result of crystallization was also not significantly different between hyperparathyroid patients with and without hypercalciuria. This study suggests that hypercalciuria alone does not produce urinary stones and that urine from hyperparathyroid patients may contain promotors of calcium oxalate crystallization and calcium stone formation.     

The Risk of Peripheral Arterial Disease after Parathyroidectomy in Patients with End-Stage Renal Disease

PurposeThe changes of the risk of peripheral arterial disease (PAD) in patients with end-stage renal disease after parathyroidectomy are scant.MethodsWe used a nationwide health insurance claims database to select all dialysis-dependent patients with end-stage renal disease aged 18 years and older for the study population in 2000 to 2006. Of the patients with end-stage renal disease, we selected 947 patients who had undergone parathyroidectomy as the parathyroidectomy group and frequency matched 3746 patients with end-stage renal disease by sex, age, years since the disease diagnosis, and the year of index date as the non-parathyroidectomy group. We used a multivariate Cox proportional hazards regression analysis with the use of a robust sandwich covariance matrix estimate, accounting for the intra-cluster dependence of hospitals or clinics, to measure the risk of peripheral arterial disease for the parathyroidectomy group compared with the non-parathyroidectomy group after adjusting for sex, age, premium-based income, urbanization, and comorbidity.ResultsThe mean post-op follow-up periods were 5.08 and 4.52 years for the parathyroidectomy and non-parathyroidectomy groups, respectively; the incidence density rate of PAD in the PTX group was 12.26 per 1000 person-years, significantly lower than the data in the non-PTX group (24.09 per 1000 person-years, adjusted HR = 0.66, 95% CI = 0.46–0.94).ConclusionParathyroidectomy is associated with reduced risk of peripheral arterial disease in patients with end-stage renal disease complicated with severe secondary hyperparathyroidism.     

Increase of nocturnal melatonin levels in hemodialyzed patients after parathyroidectomy: a pilot study

In hemodialyzed patients hormonal disturbances are known to occur. However, melatonin levels have not been completely studied. The aim of the study was to find whether changes in calcaemia affect melatonin secretion. For this reason we followed the nocturnal serum concentrations of melatonin and parathyroid hormone (PTH) in 9 hemodialyzed patients (6 women and 3 men, aged 37-65 years) both before and 1-3 months after parathyroidectomy at 6 p.m., 9 p.m., 11 p.m., 2 a.m., 5 a.m. and 7 a.m. At 6 p.m. blood samples to evaluate the levels of calcium and phosphate were also collected. Parathyroidectomy resulted in an increase in nocturnal melatonin levels. As expected, the parathyroidectomy was followed by considerable PTH decrease. PTH showed no nocturnal variation before or after parathyroidectomy. Calcium levels significantly decreased after the operation while phosphate levels increased. In summary, in hemodialyzed patients with hyperparathyroidism, parathyroidectomy significantly increases the nocturnal secretion of melatonin. Relationships between the pineal gland and parathyroid glands have yet to be elucidated.     

Reduction of passive extension and radiographic evidence of degenerative knee joint diseases in cage-raised and free-ranging aged rhesus monkeys (Macaca mulatta)

The knee joints of aged (greater than or equal to 15 years) rhesus macaques raised and maintained in individual cages were compared with those of formerly free-ranging monkeys using radiographs and measures of passive joint flexion and extension. Free-ranging monkeys had a significantly higher prevalence (p less than 0.01) and severity (p less than 0.0003) of degenerative joint diseases (osteoarthritis and/or pseudogout) based on radiographic findings and significantly (p less than 0.02) more restricted passive knee joint extension than caged animals of the same age.     

Inhibition of growth hormone secretion in mild primary hyperparathyroidism

INTRODUCTION: Impairment in growth hormone (GH) secretion has been reported to occur in primary hyperparathyroidism (PHP) with strikingly elevated (>150 pg/ml) plasma PTH and free Ca levels. Patients with these characteristics are relatively few, whereas the great majority of patients with biochemically diagnosed PHP are asymptomatic and show borderline or slightly elevated plasma PTH and Ca levels. We wondered whether also patients in these latter conditions show a defective GH secretory pattern. METHODS: In order to answer this question, 8 female subjects (mean age +/- SE: 44 +/- 1.3 years) were selected at the time of a checkup examination from a larger population of persons in fairly good clinical condition. Inclusion criteria were plasma PTH values slightly above the normal range (up to 50% higher than the maximum limit) with free Ca levels in the upper normal range or slightly higher (experimental group). Normal values in our laboratory are ionized calcium: 1.22-1.42 mmol/ml and plasma PTH: 12-72 pg/ml. A group of 15 age-matched healthy women with plasma PTH and Ca levels in the middle normal range and significantly lower than values found in the experimental group was also selected and used as control. Experimental and control groups were tested with arginine [0.5 mg/kg body weight (BW)] infused intravenously over 30 min and arginine plus GH-releasing hormone (GHRH; 1 microg/kg BW in an intravenous bolus injection). The GH responses to these challenging stimulations were compared between groups. RESULTS: Basal serum GH values were similar in all subjects. Both arginine and arginine plus GHRH induced a significant GH rise in both groups; however, the GH responses were significantly lower in the experimental than in the control group. Mean GH peak was 27.7 and 14.6 times higher than baseline after arginine and 57.5 and 26.6 times higher than baseline after arginine plus GHRH in the control and experimental group, respectively. No significant correlation was observed between PTH or Ca levels and the GH responses to challenging stimuli in any group. CONCLUSION: These data show that impairment in GH secretion is associated with slightly elevated levels of PTH in the presence of serum Ca values in the upper normal range. GH responses to stimulations were reduced by about 50% in our hyperparathyroid subjects. A long-time duration of this relatively small decline of GH secretory activity may be supposed to contribute to age-related catabolic processes in a large number of patients with mild primary hyperparathyroidism.     

A new, vitamin D-based, multidimensional nomogram for the diagnosis of primary hyperparathyroidism

ObjectiveTo refine the diagnostic criteria for primary hyperparathyroidism (1°HPT) to identify atypical patients, in whom serum calcium, parathyroid hormone (PTH), or both are within the “normal” range.MethodsTotal serum calcium, intact PTH, and 25-hydroxyvitamin D [25(OH)D] levels were measured in patients with 1°HPT and healthy patient groups. Multivariate analysis of healthy patient data first identified factors that significantly affected PTH levels and defined a new PTH reference range with a mathematical model. That nomogram was then validated for prediction of atypical 1°HPT in patients with surgically confirmed disease.ResultsOn multivariate analysis, calcium (P = .0002), 25(OH)D (P < .0001), and age (P = .015) independently affected PTH. With these variables, we created a 4-dimensional nomogram that distinguished normal patients from those with hyperparathyroid states. Mathematically, this nomogram predicts 1°HPT when the measured serum PTH value is higher than PTH calculated by the following formula: PTH (pg/mL) = 120-[6 × calcium (mg/dL)]-[0.52 × 25(OH)D (ng/mL)] + [0.26 × patient age (years)]. When applied to our surgical group of patients, this nomogram successfully identified 100% of patients (238 of 238) with classic 1°HPT, 84% (64 of 76) with normocalcemic 1°HPT, and 54% (20 of 37) with 1°HPT and normal PTH.ConclusionThis study uniquely defines a patientspecific upper limit of normal for PTH based on the readily available variables of serum calcium, 25(OH)D, and patient age. Our nomogram may allow for more rapid definitive diagnosis and treatment of 1°HPT in patients with atypical presentations. (Endocr Pract. 2012;18:124-131)     

Significance of Elevated Parathyroid Hormone After Parathyroidectomy

ObjectiveTo review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms.MethodsA Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms “elevated PTH after parathyroidectomy.” All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed.ResultsWithin 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done.ConclusionElevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. (Endocr Pract. 2010;16:112-117)     

Alendronate increases bone mineral density in patients with symptomatic primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is often associated with low bone mineral density (BMD). An open-labeled, prospective trial was conducted to determine whether alendronate (ALN), 10 mg daily, maintains or improves BMD in patients with advanced PHPT. All patients had symptomatic PHPT and met surgical guidelines however refused surgery. Nineteen patients was treated with alendronate for 2 years. The primary outcome index, BMD, was measured at the lumbar spine (LS) and femoral neck (FN) every 6 months by dual-energy x-ray absorptiometry. Serum calcium, phosphorous and PTH, and urinary calcium excretion were monitored every 3 months. Treatment with alendronate over 2 years was associated with a significant (5.3+/-0.4%; p<0.01) increase in LS BMD in comparison with baseline. FN BMD increased significantly at 24 months with alendronate by 2.5%+/-0.7 (p<0.01) from baseline. Serum calcium, phosphorus and PTH, and urine calcium excretion did not change with alendronate therapy. In PHPT, alendronate significantly increases BMD at the LS and FN at 24 months from baseline values with stable serum calcium and PTH levels. Alendronate may be a useful alternative to parathyroidectomy in symptomatic PHPT among those with low BMD, who are candidates for surgery but either decline or for whom surgery is contraindicated.