Reduced binding of [3H]1,25-dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure

This study examined the hypothesis that altered binding of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) to parathyroid receptors might be involved in the pathogenesis of secondary hyperparathyroidism associated with chronic renal failure. The binding of [3H]1,25-(OH)2D3 to hyperplastic parathyroid glands obtained from seven patients with chronic renal failure was measured. These values were compared with those for binding to hyperplastic parathyroid tissue obtained from six patients who had received renal transplants and for binding to parathyroid adenomas removed from five patients who had primary hyperparathyroidism. We found that Nmax (an estimate of the concentration of 1,25-(OH)2D3 receptors) was reduced (42 +/- 15 fmol per milligram of protein) in patients with chronic renal failure as compared with patients with transplanted kidneys (78 +/- 24 fmol per milligram of protein) and patients with primary hyperparathyroidism (114 +/- 30). Nmax correlated inversely with the severity of renal dysfunction, the serum level of phosphorus, and the logarithm of the serum level of immunoreactive parathyroid hormone. These observations suggest that 1,25-(OH)2D3 binding by parathyroid tissue is reduced in chronic renal failure. This may contribute to the pathogenesis of secondary hyperparathyroidism by reducing the inhibition by 1,25-(OH)2D of parathyroid hormone secretion. The low serum levels of 1,25-(OH)2D in chronic renal failure may accentuate this effect.     

Hyperparathyroidism and bone disease after renal transplantation

Metabolic bone disease is one of the most frequent complications of chronic renal failure. Numerous disorders leading to the metabolic bone disease can be reversed by successful renal transplantation. However, in some patients, in spite of satisfactory renal function, some disorders may persist for months after successful transplantation, e.g. increased parathyroid hormone secretion. Besides, drugs used in immunossuppressive therapy may cause metabolic bone disease or reduction of of bone mass. Therefore, significant loss of mass takes place in the majority of patients during the first six months. Among drugs used in the prevention of bone disease after transplantation of solid organs the most important role have biphosphonates and vitamin D, i.e. calcitriol.     

Ultrasonography methods in the diagnosis of renal osteodystrophy

Bone disease, i.e. renal osteodystrophy, is commonly seen in patients with chronic renal failure. It encompasses all the disorders of mineral and bone metabolism associated with chronic renal insufficiency, i.e. secondary hyperparathyroidism, retention and accumulation of beta 2 microglobulin and aluminum. The most frequent cause of renal osteodystrophy is secondary hyperthyroidism, with a consequence of high turnover bone disease. Secondary hyperparathyroidism, i.e. increased parathyroid hormone (PTH) secretion and parathyroid gland hyperplasia, develops early in the course of chronic renal insufficiency. Hypocalcemia, phosphate retention and deficiency of calcitriol stimulate PTH synthesis and secretion and parathyroid cell proliferation, i.e. hyperplasia. Parathyroid cell proliferation is initially polyclonal (diffuse hyperplasia), and later it is monoclonal or multiclonal (nodular hyperplasia). Calcitriol receptors as well as calcium-sensing receptors are significantly reduced in parathyroid glands in nodular hyperplasia. Patients with such parathyroid gland hyperplasia are often resistant to vitamin D therapy. A specific form of bone disease is beta 2 amyloidosis. Destructive arthropathy, cystic changes and carpal tunnel syndrome are clinical manifestations of dialysis-related amyloidosis, which is one of the major complications in patients on longterm hemodialysis. Aluminum intoxication leads to the low turnover bone disease and consequential osteomalacia or aplastic bone lesions, the cause of which has not yet been fully clarified. Ultrasound can be a useful, economical and noninvasive method in the evaluation of renal osteodystrophy. Ultrasound waves are very important for noninvasive imaging of soft tissue, especially parathyroid glands, pathologic changes of the joints, and for detection of metastatic calcifications. They are also useful in the evaluation of skeletal status in dialysis patients. Ultrasound waves of a frequency above the limit of human hearing are used in the morphological diagnosis of parathyroid gland. Today, because of its simplicity and non-invasiveness, it is a generally accepted method for the detection of enlarged parathyroid gland in patients with secondary hyperparathyroidism, for the monitoring of pathologic changes, and for making decisions on the method of treatment based on the size and number of parathyroid glands. Ultrasound can distinguish nodal from diffuse parathyroid hyperplasia. Under ultrasound guidance it is possible to perform fine needle aspiration biopsy, to confirm ultrasound findings, and percutaneous inactivation of parathyroid gland (PEI) with alcohol. Ultrasound is useful in the diagnosis of pathologic changes of the musculoskeletal system in patients with beta 2 amyloidosis, to assess the process of its spread, especially in the shoulder joint where the changes are most pronounced (rotator cuff thickness, amyloid deposits as hyperechogenic pads, and detection of fluid in the joint), but it can also be used to examine other joints as well as soft tissue in which metastatic calcifications may occur. Standard ultrasound equipment (pulse-echo) and linear probe of 5-13 MHz are used, also serving for ultrasound examination of the neck, joints and soft tissue. Quantitative bone ultrasonometry is based on different physical characteristics of the ultrasound including: transmission, Speed Of Sound (SOS) in meters/sec and Broad Band Attenuation (BUA) in dB/MHz, and different concepts of the apparatus. These parameters depend on the strength and architecture of the bones and describe better the changes in bone structure in dialysis patients by calculation of the Stiffness Index (QUI), better than the standard bone densitometry by dual-energy x-ray absorptiometry, which only measures bone density. Combined ultrasound measurement of the bone in several locations may be successful in monitoring dialysis patients.     

Osteocalcin in chronic hemodialysis patients as an additional parameter in the diagnosis of advanced secondary hyperparathyroidism

Osteocalcin (OC), also called Bone Gla Protein (BGP), is a bone matrix protein of 5800 MW synthesized by osteoblasts. Since OC is mainly metabolized in the kidney, its blood concentration is altered in renal failure. The relationship between OC and the calcium-phosphorus regulating hormones (parathyroid hormone, calcitonin) and the biochemical parameters of bone metabolism (serum calcium, serum phosphorus and serum alkaline phosphatase) was studied in 30 patients on chronic hemodialysis (mean age: 51 years; mean duration of dialysis treatment: 39 months). OC levels were significantly elevated in all patients on chronic hemodialysis (34.7 +/- 31.5 ng/ml) when compared to healthy subjects (6.25 +/- 1.39 ng/ml, p less than 0.001). In 2 patients the OC levels were excessively high (127.54 ng/ml; 148.02 ng/ml), which was associated with severe renal osteodystrophy due to secondary hyperparathyroidism. When divided into 2 groups in the patients with secondary hyperparathyroidism the mean OC value was markedly elevated (50.5 +/- 12.7 ng/ml) compared to the patients without secondary hyperparathyroidism (24.1 +/- 2.8 ng/ml) (p less than 0.05). 70 per cent of the patients on chronic hemodialysis with OC levels greater than 30 ng/ml showed moderate to severe scintigraphic findings of bone disease. In neither of the 2 groups could a correlation between OC and serum alkaline phosphatase be demonstrated. The results indicate, that OC levels could be useful additional parameter in hemodialyzed patients with secondary hyperparathyroidism and OC levels could reflect bone formation in these patients.     

Surgical treatment of mediastinal parathyroid adenoma

Ectopic parathyroid adenoma is a frequent cause of persistent or recurrent hyperparathyroidism after parathyroidectomy in patients with chronic renal failure on dialysis. An unusual anatomic localization of parathyroid adenoma may make the diagnosis and surgery difficult. In a 41-year-old woman with chronic renal failure, increased serum level of parathyroid hormone and symptoms of progressive renal osteodystrophy, mediastinal parathyroid adenoma was detected in the aorticopulmonary window by 99m Tc sesta MIBI scintigraphy and transmission computed tomography. Extirpation of adenoma, sized 3 x 2 cm, was performed through a left thoracotomy. Serum parathormone level returned to normal and the patient steadily recovered.     

甲状旁腺全切加前臂皮下移植术治疗肾性继发性 甲状旁腺功能亢进的研究

继发性甲状旁腺功能亢进是终末性肾脏疾病常见的严重并发症。严重肾衰患者合并存在的低钙血症、高磷血症、稀释性低钠血症、代谢性酸中毒等内稳态失衡,是正常及异位的甲状旁腺组织强烈的生长刺激信号,可引起甲状旁腺组织的弥漫性增生。同时,SHPT又可使患者发生代谢性骨病,动脉粥样硬化等,两种疾病互为因果,又相互促进,严重影响患者的生存质量。2003年,美国肾脏疾病基金会颁布了肾性SHPT的治疗指南,但由于对此疾病的认识,在不同的研究中心还存在不同的观点,SHPT的最佳手术适应症、手术方式等还存在一定的争议,本文就甲状旁腺全切加前臂皮下移植术治疗肾性继发性甲状旁腺功能亢进的研究进展作一综述。     

Sistemic calciphylaxis and thrombotic microangiopathy in a kidney transplant patient: Two mixing fatal syndromes?

Abnormalities in calcium and phosphorus metabolism are common and metabolic bone diseases develop often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions, however, appear to increase the risk of soft tissue and vascular calcification in patients with End Stage Renal Disease (ESRD), so current therapeutic approaches are thus being re-evaluated in an effort to limit these risks. Patients with calciphylaxis have an extremely high mortality rate, diagnosis requires a high degree of clinical suspicion and the role and extent of parathyroidectomy in the management of this condition remain controversial. In some cases renal transplant patients could suffer from a comorbidity in which vascular function is compromised not only by secondary hyperparathyroidism-related calcification but also by other pathological condition as haemolytic uremic syndrome (HUS), leading to a fatal clinical outcome. We postulate that in these cases a secondary hyperparathyroidism not properly diagnosed in an early phase of the renal disease (probably before the kidney transplant) could cause a vascular calcification which, adding to the pre-existing HUS-related vascular compromission, gave rise to catastrophic clinical consequences. In the management of ESRD patients, in particular in the cases of pre-existing angiopathies, could be therefore crucial the early and proper diagnosis of an alteration of calcium-posphorus metabolism and effort of medicine could be oriented in these cases also towards identification of screening methodologies to undoubtedly assess such a diagnosis.     

C-cell hyperplasia in secondary hyperparathyroidism

Calcitonin is a hypocalcaemia producing hormone and is secreted by C-cells of the thyroid. The current study was undertaken on a hypothesis that C-cell hyperplasia may develop in the secondary hyperparathyroidism of chronic renal failure in response to sustained hypercalcaemia. With an immunoperoxidase staining method for calcitonin, C-cell hyperplasia was noted in four of six cases of autosomal dominant polycystic kidney disease and in three of six cases of acquired renal cystic disease, an overall incidence of 58% compared with an incidence of 36% (five of 14) in cases of primary hyperparathyroidism with parathyroid adenoma. Thus, both primary and secondary hyperparathyroidism may trigger C-cell hyperplasia in an attempt to produce a hypocalcaemic effect.     

Hyperphosphatemia in dialysis patients: the therapeutic role of lanthanum carbonate

Phosphate overload is a dramatic consequence in end-stage renal disease (ESRD) patients. Recent studies have well documented that abnormalities in mineral and bone metabolism in these patients are associated with increased cardiovascular morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of secondary hyperparathyroidism and extra-skeletal calcification in dialysis patients. Furthermore, inorganic phosphate may cause vascular calcification directly through a real "ossification" of the tunica media in the vasculature of ESRD patients. The "classical" treatment of secondary hyperparathyroidism and hyperphosphatemia in ESRD patients consists of either calcium- or aluminum-based phosphate binders and calcitriol administration. Unfortunately, this "old generation" therapy is not free of complications. This review paper suggests that new calcium- and aluminum-free phosphate binders, such as lanthanum carbonate, can be used to treat hyperphosphatemia and secondary hyperparathyroidism in ESRD patients.     

A case report of brown tumor in a patient with chronic renal failure and renal cell carcinoma

We report a case of a 72 year old male with hyperparathyroidism secondary to end stage diabetic renal disease and coexisting bilateral chromophobe renal cell carcinomas. The patient presented with back and groin pain, right pelvic hemorrhage, and multiple lytic bone lesions concerning for metastatic renal cell carcinoma. Fine needle aspiration cytology demonstrated benign appearing osteoclasts and spindled cells. A concurrent core biopsy showed foci of spindled cell proliferation populated by osteoclast‐like giant cells with stromal hemorrhage without evidence of metastatic carcinoma. The cytologic and histologic findings, in correlation with the clinical history, radiographic features, markedly increased parathyroid hormone levels and other serologic studies, were diagnostic of the reactive lesion seen in brown tumor of hyperparathyroidism secondary to chronic renal failure.     

Value of plasma chloride concentration and acid-base status in the differential diagnosis of hyperpara-thyroidism from other causes of hypercalcaemia

A study is reported of the estimation of plasma chloride concentration and acid-base status in the differentiation of primary hyperparathyroidism from all other causes of hypercalcaemia. In the two groups of patients studied, all of whom had hypercalcaemia, there was complete separation between the two groups on the basis of plasma chloride concentration and acid-base status. In 16 patients with primary hyperparathyroidism the increase in plasma chloride concentration and associated metabolic acidosis could have been accounted for by the known renal tubular effects of parathyroid hormone. In 13 patients with hypercalcaemia due to various other causes the decrease in plasma chloride concentration and associated metabolic alkalosis could be accounted for either by the known effects of an excess of calcium-ion on the renal tubules, or perhaps by suppression of endogenous parathyroid hormone secretion. In patients with hypercalcaemia and hypophosphataemia of ;pseudohyperparathyroidism' associated with non-endocrine tumours it is postulated that the low plasma chloride concentrations and metabolic alkalosis found in these patients were due either to a differing biological activity of the parathyroid-hormone-like polypeptide secreted by the tumour cells, or possibly to simultaneous secretion by these cells of an ACTH-like polypeptide.     

BsmI polymorphism of the vitamin D receptor gene in hyperparathyroid or hypoparathyroid dialysis patients.

Since bone mineral density may be influenced by the polymorphisms of the vitamin D receptor (VDR) gene, we studied whether VDR genotypes might drive the progression toward hyperparathyroidism or hypoparathyroidism in patients with end-stage renal disease. On the basis of their parathyroid hormone (PTH) levels, we divided 99 patients undergoing dialysis into 2 groups: 56 patients with hypoparathyroidism (PTH < 104 pg/mL [< 11 pmol/L]) and 43 with hyperparathyroidism (PTH > 261 pg/mL [> 27.5 pmol/L]). The BB polymorphism was more frequent in patients with hypoparathyroidism (34%) than in patients with hyperparathyroidism (16%), but the difference did not reach statistical significance. Patients with the B allele and BB genotype had a significantly lower dialytic age and serum PTH and alkaline phosphatase levels than patients with the b allele and bb genotype. These results suggest that in end-stage renal disease, the BB genotype may mark a higher risk of developing hypoparathyroidism and diminished bone turnover.     

Azotaemic renal osteodystrophy: a quantitative study on iliac bone

The histopathology of bone is described in 60 patients with chronic renal failure due to a variety of renal diseases. Changes of azotaemic renal osteodystrophy included osteitis fibrosa, osteomalacia, and osteosclerosis. Quantitative histology using a point-counting technique revealed a significant increase in total bone, mineralized bone, and osteoid in comparison with a control group of 68 individuals. Osteitis fibrosa due to secondary hyperparathyroidism occurred in 93%, osteomalacia in 40%, and osteosclerosis in 30% of patients. Woven bone formation was a characteristic feature and was related to the severity of osteitis fibrosa. There were significant correlations between the weights of parathyroid glands and the number of osteoclasts, amounts of woven bone, and marrow fibrosis in the ilium. Hyperparathyroidism caused degradation of mineralized bone but the loss was balanced or exceeded by the aggradation of woven mineralized bone. Woven bone formation together with excess osteoid gave rise to osteosclerosis. The histological findings indicate that hyperparathyroidism and osteitis fibrosa usually occur early in chronic renal failure and that osteomalacia develops subsequently.     

Klinische Erfahrungen nach operativer Therapie der asymptomatischen,oligosymptomatischen und symptomatischen Nebenschilddrüsenüberfunktion

Summary Depending on their symptomatology 152 cured (i.e., normocalcemic) patients with surgically proven primary hyperparathyroidism (pHPT) showed typical symptoms preoperatively. Besides hypercalcemia and elevated parathyroid hormone levels, 15 patients suffered only from hypertension and/or diffuse osteoporosis and/or complaints caused by the hypercalcemic syndrome (oligosymptomatic patients). Nine patients had no complaints (asymptomatic patients). The long-term clinical course of all patients was analyzed up to 22 years. Although the formation of urinary calculi was stopped in 94% of cases, a deterioration of renal function and hypertension was seen in symptomatic (12.5% and 9.2%, respectively) and oligosymptomatic patients (6.7% and 13.3%, respectively). Renal function and hypertension were unpredictable despite normalization of the hyperactive parathyroid metabolism and were of decisive prognostic significance; 6% died of acute or chronic renal failure, or of the consequences of hypertension. Multiple bone lesions, even large, healed functionally and were of no prognostic significance. In the majority of symptomatic patients gastrointestinal manifestations held postoperatively, but two patients died of acute pancreatitis without gastrointestinal complaints preoperatively. Almost all symptoms of the hypercalcemic syndrome disappeared immediately and permanently in symptomatic and oligosymptomatic patients. No deterioration of renal function and no elevation of blood pressure was observed in cured asymptomatic patients postoperatively. Immediate surgical treatment even in asymptomatic patients may have avoided complications of chronic renal failure or of hypertension. As soon as organic manifestations, even in a mild form, have been established, it seems impossible to predict the course and to prevent an unfavorable clinical outcome.

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Abkürzungsverzeichnis pHPT primärer Hyperparathyreoidismus - PTH Parathormon     

Hypothesis: the case for quaternary hyperparathyroidism

We report the case of a young woman with hyperparathyroidism due to a large parathyroid adenoma associated with severe vitamin D deficiency. The case is noteworthy for the size of the parathyroid adenoma and for the young age at presentation, and is more typical of the presentation of hyperparathyroidism seen in developing countries where the prevalence of vitamin D deficiency is high. Vitamin D is known to have a suppressive effect on parathyroid cell proliferation and parathyroid hormone synthesis. Vitamin D deficiency may result in a compensatory increase in the secretion of parathyroid hormone (secondary hyperparathyroidism) which involves hyperplasia of all four parathyroid glands. Secondary hyperparathyroidism can become autonomous and this has been termed tertiary hyperparathyroidism, the underlying pathology of which has been variably described in the literature as adenoma formation or four gland hyperplasia. The pathogenesis of parathyroid adenoma formation in vitamin D deficiency remains unclear. It is possible that a proportion of cases represent the coincidence of primary hyperparathyroidism in patients with vitamin D deficiency. Alternatively, we hypothesise that autonomous four gland hyperplasia or tertiary hyperparathyroidism may progress to adenoma formation and that this should be termed 'quaternary hyperparathyroidism'.     

Parathyroid hormone immunohistochemistry in dogs with primary and secondary hyperparathyroidism: the question of adenoma and primary hyperplasia

In primary hyperparathyroidism, calcium homeostasis is disrupted by excessive synthesis and secretion of parathyroid hormone (PTH), which is usually caused by a solitary adenoma, or less often by nodular hyperplasia or carcinoma of the parathyroid glands. So far, the distinction between these forms of primary hyperparathyroidism has been made by histological examination. In this report clinical and histological findings, including PTH immunohistochemistry, are described in five dogs with primary hyperparathyroidism, three dogs with secondary hyperparathyroidism due to chronic renal failure, and eight control dogs. In the dogs with primary hyperparathyroidism, nodular adenomatous hyperplasia was found in two animals and parathyroid adenoma in three. The dogs with chronic renal failure had diffuse parathyroid gland hyperplasia. The parathyroid glands of the control dogs and the inactive cells surrounding the hyperplastic nodules showed slight to moderate, localized, paranuclear PTH immunolabelling. In the primary nodular and secondary diffuse hyperplasia, all parathyroid cells had a diffuse cytoplasmic PTH labelling pattern, sometimes in combination with localized paranuclear labelling. In parathyroid adenoma, areas with either paranuclear labelling or diffuse cytoplasmic labelling were observed. As both parathyroid adenoma and primary nodular parathyroid gland hyperplasia have characteristics of intrinsic autonomy (i.e., suppression of the remaining endocrine tissue), there would seem to be no functional difference between the two abnormalities. It is argued that primary (multi)nodular hyperplasia is a multiple form of parathyroid adenoma.     

Effect of parathyroidectomy on bone aluminum accumulation in chronic renal failure

In some patients with chronic renal failure, bone mineralization becomes defective after parathyroidectomy for secondary hyperparathyroidism. Because aluminum deposition in bone is associated with impaired bone formation and osteomalacia, we retrospectively studied bone-biopsy specimens from patients on hemodialysis who were not exposed to dialysate contaminated with aluminum, to determine whether aluminum accumulation on bone surfaces was enhanced by parathyroidectomy. Serial biopsy specimens taken before and after parathyroidectomy revealed an increase in the rate of aluminum deposition on the surface of mineralized bone after parathyroidectomy in each of the six patients studied. The accelerated rate of aluminum accumulation could not be explained by changes in the oral aluminum intake. The mean rate of bone formation (+/- S.E.M.) before parathyroidectomy was higher in the six patients than in six control patients who did not undergo parathyroid surgery (586 +/- 147 vs. 237 +/- 85 micron2 per square millimeter per day; P less than 0.05). After parathyroidectomy, the rate of bone formation fell to levels below normal (148 +/- 32 vs. 311 +/- 29 micron2 per square millimeter per day; P less than 0.05) but was not significantly different from the rate in the control group (319 +/- 126 micron2 per square millimeter per day). We conclude that parathyroidectomy in patients with chronic renal failure is associated with enhanced aluminum deposition on the bone surface, possibly as a result of low bone formation. Patients with secondary hyperparathyroidism who may be candidates for parathyroidectomy should be evaluated for aluminum excess before surgery, so that treatment with aluminum chelation may be considered.     

Secondary hypercalcemic hyperparathyroidism

Summary A search was made for patients with associated secondary hyperparathyroidism and hypercalcemia: 22 such cases were found in the literature and 22 were recorded among 92 patients operated upon because of parathyroid disease. In the remaining 70 patients the effect of the operation on the serum calcium level was investigated: persisting hypercalcemia after the operation was found in 28 per cent of the cases.The patients reporded in the literature possessed severe renal and skeletary changes and light microscopic evidence of parathyroid adenoma (2 cases), hyperplasia (15 cases), or hyperplasia and adenoma (5 cases).The other 22 patients had histories of long-standing renal disease, most often chronic pyelonephritis, of varying severity. Skeletary roentgenograms were often normal. Morphologic examination of the parathyroids showed adenoma (6 cases) or hyperplasia (16 cases). Postoperatively, normal serum calcium level was found in 9 cases and persisting hypercalcemia in 13 (=59 per cent) cases. One patient possessed also a malignant -cell insuloma and Zollinger-Ellison's syndrome.It is suggested that secondary hyperparathyroidism may develop in patients with only slight or moderate impairment of renal function, that hypercalcemia occurs more often than previously believed in secondary hyperparathyroidism, and that some cases of secondary hyperparathyroidism previously, erroneously have been classified as primary hyperparathyroidism.Supported by grants from the Swedish Medical Research Council (Project No. B72-17X-3499-01), the Swedish Cancer Society (Project No. 552-B71-01P), and the Medical Faculty, University of Umeå.     

Pathogenesis of anaemia in hyperparathyroidism

It is suggested that parathyroid hormone (PTH), when in excessive amounts, interferes with normal erythropoiesis by downregulating the erythropoietin receptors on erythroid progenitor cells in the bone marrow. Therefore, physiologic concentrations of EPO can no longer sustain normal red cell counts, so normocytic and normochromic anaemia ensues. In primary hyperparathyroidism (HPT), this effect is observed with very high concentrations of PTH. In secondary HPT during chronic renal failure, this effect is more pronounced because erythropoietin synthesis is impaired.