Clinical aspects of primary hyperparathyroidism: clinical manifestations, diagnosis, and therapy.

Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia. An autonomous overproduction of parathyroid hormone leading to hypercalcemia, which is not downregulated by the calcium-sensing receptor, is the pathophysiological basis of the disease. The classical manifestations of PHPT include a generalized bone disease, kidney stones, and nephrocalcinosis, gastrointestinal, cardiovascular, neuromuscular and neuropsychiatric symptoms. Recently, the clinical presentation of PHPT, however, has changed in Western countries, it occurs oligo-asymptomatic in up to 80 %. Clinical examination, laboratory, and imaging techniques for the characterization of the disease and the localization include the diagnostic procedure. If possible, parathyroidectomy is the treatment of choice for clinically overt PHPT, for asymptomatic PHPT guidelines were developed in order to decide in individual cases between surgical and conservative approach; this consists of monitoring, adequate calcium and vitamin D intake, as well as hydration. Medical therapy includes bisphosphonates and calcimimetics.

Osteitis fibrosa cystica-a forgotten radiological feature of primary hyperparathyroidism.

Although bone disease and stone disease are the universally accepted classical manifestations of primary hyperparathyroidism, clinical parathyroid bone disease is rarely seen today in the United States (<5% of patients) and Western Europe. Nevertheless, in a given patient, classical skeletal involvement can be the first sign of primary hyperparathyroidism, but not recognized because it is not usually included, anymore, in the differential diagnosis of this manifestation of skeletal disease. We describe four cases of primary hyperparathyroidism in which the first clinical manifestation of the disease was a pathological fracture that masqueraded as a malignancy. The presence of large osteolytic lesions gave rise to the initial diagnosis of a primary or metastatic cancer. In none of the reported cases was primary hyperparathyroidism with osteitis fibrosa considered as the diagnosis. It would seem to us that this course is best explained by the fact that in many countries such manifestations of primary hyperparathyroidism have become a rarity. In fact, the incidence of osteitis fibrosa among patients with primary hyperparathyroidism in the US is estimated as so rare, that in majority of medical centers routine x-ray examinations of the bones in these patients is not recommended. The X-ray or computed tomography scan findings of osteitis fibrosa cystica include lytic or multilobular cystic changes. Multiple bony lesions representing brown tumors may be misdiagnosed on computed tomography scan as metastatic carcinoma, bone cysts, osteosarcoma, and especially giant-cell tumor. Distinguishing between primary hyperparathyroidism and malignancy is made readily by the concomitant measurement of parathyroid hormone which in primary hyperparathyroidism, again, will be markedly elevated. In the hypercalcemias of malignancy, such elevations of parathyroid hormone are virtually never seen. CONCLUSION: When radiographic evidence of a lytic lesion and hypercalcemia are present, primary hyperparathyroidism should always be considered in the differential diagnosis.

From mild to severe primary hyperparathyroidism: The Brazilian experience.

Primary hyperparathyroidism often presents as an asymptomatic disorder. In our institution, routine serum calcium measurements have now been used as part of medical examination for 23 years. Out of 124 patients consecutively seen at our institution, 47% presented with no symptoms related to the disease, while 25% presented with severe skeletal involvement and osteitis fibrosa cystica, 25% with renal stone disease without overt bone involvement, and 2% with the typical neuropsychiatric syndrome. This same pattern is seen in the city of São Paulo. In severe disease pathological fractures are frequently seen, especially in long bones of the lower extremities, and also loss of lamina dura of the teeth and salt-and-pepper appearance of the skull. Bone mineral density is extremely low in these patients but usually show remarkable recovery following surgical cure. Serum PTH and bone markers are considerable higher in severely affected patients, who also have a high rate of vitamin D deficiency, and the parathyroid lesion is easier located compared with asymptomatic patients. From pathological specimens 87% had histological confirmation of a single adenoma, 6.4% multiple gland hyperplasia and 3.8% carcinoma.

Musculoskeletal manifestations of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) can be associated with a variety of musculoskeletal complaints, which occasionally can be the leading or presenting manifestation. In this paper, we describe the musculoskeletal manifestations observed in patients with primary hyperparathyroidism. Medical record reviews of a select population of 74 patients with primary hyperparathyroidism are seen in a rheumatology practice. Bone manifestations included back pain in 11 patients (15.2 %), generalized bone pain in 7 patients (9.7 %), rib cage/chest pain in 6 (8.3 %), pseudoclubbing in 3, and a giant cell tumor of the mandible in 2 (2.3 %) patients. Articular manifestations such as chondrocalcinosis with or without apatite deposition disease were seen in 13 (17.7 %), arthralgias in 11 (15.2 %), and non-specific synovitis in 7 (9.7 %). Muscle weakness was observed in six patients (8.3 %) and myalgias in three (4.6 %). Less common manifestations such as Achilles tendon rupture, Jaccoud-like arthropathy, sacral insufficiency fracture, arthritis associated with fever of unknown origin (FUO), meningitis, cervical cord compression, and persistent headache were observed in single patients. Musculoskeletal findings are still a frequent and important presentation in patients with primary hyperparathyroidism seen in rheumatology practice. Some of these manifestations can be quite unusual and may represent diagnostic dilemmas to the practicing rheumatologist and/or endocrinologist.

Multilevel brown tumors of the spine in a patient with severe secondary hyperparathyroidism A case report and review of the literature.

BACKGROUND: The brown tumour is an extreme form of osteitis fibrosa cystica, representing a serious complication of the advanced primary or secondary hyperparathyroidism. It occurs in settings of high levels parathyroid hormone, like in primary or secondary hyperparathyroidism, with a frequency of 3-4% and 1.5-13% respectively, usually affecting young people. CASE REPORT: The authors report a case of a 45 years old woman on long-term hemodialysis, with severe secondary hyperparathyroidism. The main clinical complaints were neck pain, lower thoraco-lumbar back pain, persistent left groin pain, and bilateral lower extremities weakness. The computed tomography scan revealed multiple spine brown tumors affecting the cervical, thoracic and lumbar level. After an initial partial response to the treatment of two years with Cinacalcet, a deterioration of the secondary hyperparathyroidism occurred (hypercalcemia, hyperphosphatemia) and the patient was referred for parathyroidectomy. The patient underwent total parathyroidectomy with auto-transplantation, with a positive postoperative result. CONCLUSIONS: Secondary hyperparathyroidism can lead, during its course, to osteolytic bone lesions called brown tumors. If the medical treatment fails, the surgical removal of the parathyroid glands with autotransplant remains the only treatment of the bone lesions progression. Reviewing the relevant literature in English (until March 2015), we found 24 cases of symptomatic vertebral brown tumors. To the authors' knowledge, this is the first case which describes a multilevel spine involvement (more than two), and the fifth describing a cervical localization. KEY WORDS: Hypocalcaemia, Secondary hyperparathyroidism, Spine brown tumors.

Vitamin D metabolism during recovery from severe osteitis fibrosa cystica of primary hyperparathyroidism.

Serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D] and immunoreactive parathyroid hormone were measured before and for 7 months after the removal of a 15-g parathyroid adenoma from a 44-yr-old woman with primary hyperparathyroidism and severe osteitis fibrosa cystica. Despite the fall in parathyroid hormone levels from preoperative levels of 20 to 1--2 ng/ml after surgery (normal, up to 1.2 ng/ml), serum 1,25-(OH)2D concentrations remained markedly elevated (156 pg/ml) preoperatively; 124 pg/ml 17 weeks postoperative), approaching the normal range (18--56 pg/ml) only after 5 months (65 pg/ml). Hypocalcemia and hypophosphatemia persisted despite oral 1,25-(OH)2D3 (1 and 2 micrograms/day) and large doses of (oral and iv) calcium gluconate (up to 30 g/day). Healing of the skeletal lesions, reversal of the myopathy, and return of 1,25-(OH)2D circulating levels to normal corresponded to the time when serum phosphate became normal. The stimulus for the persistently elevated serum 1,25-(OH)2D levels may have been hypocalcemia per se, low serum phosphate, or an unidentified signal that paralleled serum phosphate, as serum PTH levels remained in the upper normal range throughout the recovery period.

Spontaneous hypercalcemia in patients undergoing dialysis. Etiologic and therapeutic considerations.

Ten dialysis-treated patients with hypercalcemia (11.5 +/- 0.3 mg/dl, mean +/- SE) due to renal osteodystrophy were compared with 30 control dialysis-treated patients who were not hypercalcemic (9.5 +/- 0.1 mg/dl). The hypercalcemic patients were more disabled than the control patients. Fifty percent of the hypercalcemic patients and 37 percent of the control patients had a mineralization defect (p greater than 0.6). In the control group, intact parathyroid hormone level was significantly higher in patients with osteitis fibrosa than in those with osteomalacia (247 +/- 39 pg/ml versus 60 +/- 20 pg/ml, respectively, p less than 0.005) whereas in the hypercalcemic patients, parathyroid hormone measurements did not discriminate between these two types of bone disease. Osteomalacia was more severe and bone aluminum staining was stronger in the hypercalcemic patients than in the control patients (2.02 +/- 0.47 versus 0.35 +/- 0.11 mm/mm2 tissue area, p less than 0.001). The mean serum calcium level fell from 11.2 +/- 0.2 mg/dl to 10.5 +/- 0.3 mg/dl (p less than 0.01) in eight hypercalcemic patients treated with 24,25-dihydroxyvitamin D. It is concluded that hypercalcemia in patients undergoing dialysis is associated with an increase in bone aluminum level, and with more severe osteomalacia. Intact parathyroid hormone levels are useful for predicting bone histomorphometric parameters but only when hypercalcemia is not present. The drug, 24,25-dihydroxyvitamin D, was effective in lowering the serum calcium level.

[Hormonal markers of early-stage osteitis fibrosa in patients on hemodialysis]. / Indici ormonali di osteite fibrosa in fase iniziale nel paziente emodializzato.

The diagnosis of renal osteodystrophy is straightforward when the disease has reached an advanced stage and the pathology is extremely difficult to treat, whereas it is considerably more complex during the early stages. A study was carried out to assess the sensitivity of some biochemical, hormonal and instrumental markers in the early diagnosis of osteitis fibrosa in patients undergoing hemodialysis due to chronic renal insufficiency. Of these markers, the assay of whole molecule PTH appeared to be the most sensitive and specific biological marker.

Dialysate calcium levels, dialysis hours and the healing of osteitis fibrosa.

Unselected patients receiving intermittent haemodialysis at home were examined by hand radiographs to study the progression of osteitis fibrosa. Patients were using Kiil dialysers and Drake-Willock proportioning systems. The calcium phosphorus product was controlled by an adequate dialysis schedule supplemented by aluminum hydroxide gel. Dialysate calcium ranged between 5.7 and 7.3 mg/100 ml depending on the calcium content of local tap water. In 73 percent of patients the osteitis fibrosa improved radiologically and in most patients complete healing occurred. The rate of change was slow. Patients whose bones healed had significantly higher serum and tap water calcium levels than those whose bones deteriorated. There was no significant difference in the serum phosphorus levels in the two groups. Improvement of osteitis fibrosa requires both control of calcium phosphorus product and suppression of the parathyroid gland. Long dialysis hours with a positive calcium balance during dialysis were necessary to achieve the best results.

[Diagnosis of an osseous form of hyperparathyroidism]. / Diagnostika kostnoi formy giperparatireoza

Under observation were 66 (50.3%) of 130 patients with an ossific form of hyperparathyroidism. Fourty five patients showed the classical picture of Recklinghausen disease, and 21-only diffuse osteoporosis. The correct diagnosis would be established 4-5 years following the onset of the disease. During the period of most distinct manifestations pains in bones were noted in 93 per cent of cases. Two thirds of patients showed marked atonia and fatigue. Pathological fractures were multiple and were observed in 45 of 66 patients (totally 125 fractures). Great importance in establishing the diagnosis of the form of hyperparathroidism is attached to roentgenological investigation of all bones and biochemical assay of blood and urine.

Evolution of maxillofacial brown tumors after parathyroidectomy in primary hyperparathyroidism.

BACKGROUND: Brown tumor occasionally affects the facial bones. Clinically, these lesions can be mistaken for a neoplasm. Opinions are divided on the course of management of the bony lesions once parathyroidectomy has been carried out. METHODS: We treated 22 patients with primary hyperparathyroidism and osteitis fibrosa cystica and observed their clinical and biochemical recovery. RESULTS: Fifteen patients (68.2%) had brown tumors in mandible, and 7 (31.8%) in maxilla. After parathyroidectomy, 21 patients had normal total serum calcium values. All brown tumors presented a spontaneous progressive regression; in 18 cases, regression was total, with a mean time period of 10 months. Two patients had partial regression after nearly 2 years. Another 2 patients were lost to follow-up. CONCLUSIONS: After successful parathyroid surgery, the bony lesions tended to regress spontaneously, either partially or completely. However, if the lesion is disfiguring or symptomatic, surgical excision may be indicated.

Biological activity of endogenous and exogenous calcitonin in patients with osteitis fibrosa and chronic renal failure.

Successful treatment of osteitis fibrosa with 1alpha-hydroxycholecalciferol (1alpha-OHD3) in 9 patients with end-stage chronic renal failure was associated with a significant increase in plasma levels of immunoreactive calcitonin (iCT) independently of changes in plasma calcium, and a decrease in levels of parathyroid hormone (iPTH). In 9 further patients whose plasma alkaline phosphatase activity failed to suppress with 1alpha-OHD3, changes in iPTH were associated with proportionate changes in iCT. This suggests that a rise in endogenous calcitonin (CT) secretion contributes to the success of treatment with 1alpha-OHD3. In 13 further patients, injections of salmon CT induced a fall in plasma calcium and phosphate which was proportional to the prevailing level of plasma alkaline phosphatase. These data provide further evidence that bone resorption can be effectively inhibited when CT levels are raised either by exogenous CT or its endogenous stimulation.

Plasma magnesium concentration in primary hyperparathyroidism.

The plasma magnesium concentration has been determined in 73 patients with primary hyperparathyroidism. In most patients it lay within the normal range (1.7-2.3 mg./100 ml.), but in five it was less than 1.6 mg./100 ml. These patients had relatively high urinary magnesium outputs, and one of them, studied in greater detail, failed to retain parenterally administered magnesium. Hence hypomagnesaemia in hyperparathyroidism may be associated with a defect in renal magnesium conservation, which may be reversible.

Postparathyroidectomy hypocalcemia as an accurate indicator of preparathyroidectomy bone histology in the uremic patient.

19 chronic renal failure patients underwent iliac crest bone biopsy prior to total parathyroidectomy with autotransplantation. The preoperative serum calcium concentration did not correlate with the number of osteoclasts/mm2 present on the preparathyroidectomy iliac biopsy. However, the postparathyroidectomy decrement in serum calcium (mg/dl and percent change) and the osteoclasts/mm2 were strongly correlated (p less than 0.001). In addition, the postoperative fall in serum calcium also correlated with the postoperative change in serum alkaline phosphatase (p less than 0.001). The nadir in postparathyroidectomy serum calcium was attained in a mean of 4.4 +/- 2.7 days. Our results indicate that the preoperative serum calcium concentration does not necessarily reflect active bone resorption, but the postoperative decrement in serum calcium provides an accurate index of preoperative histologic activity. The available data do not provide information with respect to the mechanism of postparathyroidectomy hypocalcemia since either the cessation of bone resorption, continued bone deposition, or a combination of both may be operative.

[Osteitis fibrosa cystica von Recklinghausen]. / Osteitis fibrosa cystica von Recklinghausen.

We present the case of a woman with classical osteitis fibrosa cystica generalisata von Recklinghausen, caused by a single adenoma of the left inferior parathyroid gland. After six months with increasing bone pain, pathological fractures and cystic lesions radiologically, hyperparathyroidism was diagnosed by persistent elevated levels of serum calcium, and elevated levels of PTH. Surgical extirpation of the parathyroid adenoma caused a period with severe hypocalcemia followed by complete clinical restitution. The diagnosis should be considered in any case of persistent bone pain and uncharacteristic fatigue.

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia.

The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and compared to those with osteitis fibrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal parathyroid hormone response (+/- SD) (0.39 +/- 0.33 vs. 0.87 +/- 0.53 ng/ml, P less than 0.05) and maximum carboxy terminal parathyroid hormone response (+/- SD) (0.36 +/- 0.20 vs. 0.84 +/- 0.47, P less than 0.02) to hypocalcemia. The decline in plasma calcium was greater in patients with osteomalacia at 90 (P less than 0.05), 120 (P less than 0.01), and 150 min (P less than 0.01). In osteomalacia patients the surface density of histologically detectable trabecular bone aluminum correlated directly with the percent relative osteoid volume (P less than 0.005) and inversely with the maximum amino terminal parathyroid hormone response to hypocalcemia (P less than 0.025). These results suggest that hemodialysis patients with osteomalacia have diminished secretion of parathyroid hormone and a decreased ability to restore plasma calcium homeostasis during hypocalcemia.