Parathyroid glands in chronic aluminum intoxication.

In chronic renal failure, aluminum overload may influence parathyroid function. In a study of possible aluminum-induced parathyroid abnormalities, parathyroid glands from nine parathyroidectomized patients on hemodialysis were examined by light and electron microscopy and by X-ray microanalysis. Aluminum overload was assessed by the presence of stainable aluminum (aluminum surface, 23.3% +/- 11% of total surface) in bone biopsy specimens. The mean plasma aluminum concentration was 7.7 +/- 1.9 mumol/L. All patients but one had elevated plasma concentrations of immunoreactive parathyroid hormone as well as osteitis fibrosa. The aluminum concentrations in bone and parathyroid gland from these patients were significantly higher than those in tissue from patients on hemodialysis without stainable bone aluminum. Abundant aluminum deposits were present in parathyroid chief cell cytoplasm in lipoid bodies, lipofuscin granules, and mitochondria. These cells exhibited features of active hormonal synthesis and contained numerous secretory granules. The data show that in the parathyroid glands of these aluminum-intoxicated patients the presence of aluminum deposits neither induced cellular damage or chief cell necrosis nor interfered with the production of parathyroid hormone.

Bone disease in children with homozygous beta-thalassemia.

The histological features of thalassemic bone are imperfectly known, and the roles of bone marrow hyperactivity, iron overload or vitamin D deficiency in the pathogenesis of the disease are not clearly identified. In this study we examined iliac crest biopsies from 17 transfusion-dependent children with homozygous beta-thalassemia and severe radiological skeletal thalassemic changes, including widening of medullary spaces and osteoporosis. Rachitic lesions were not observed. Serum ferritin concentrations were increased in all but one subject. Iron deposits were histochemically detected in bone marrow, at the marrow-bone interface, along cement lines and mineralizing perimeters. Minor changes were present in trabecular bone, and osteomalacia was absent. By contrast, cortical bone exhibited severe changes including fissures and focal mineralization defects. Plasma 25-hydroxyvitamin D (25(OH)D) concentrations measured during the winter (December-May, 6.5 +/- 4.9 ng/ml, mean +/- SD, n = 6) and during the summer (June-November, 13.8 +/- 8.4 ng/ml, n = 9) did not differ from those of age-matched children living in the same country. Seven patients had moderate hypocalcemia but no biological signs suggestive of vitamin D deficiency: all had normal alkaline phosphatase activity, normal or slightly elevated plasma phosphate, only two had low plasma 25(OH)D concentrations and two others supranormal values of plasma immunoreactive parathyroid hormone. These results show that iron overload and vitamin D deficiency do not seem to play an important role in the pathogenesis of thalassemic bone disease, which is characterized by cortical lesions probably related to marrow hyperactivity.

Hyperparathyroidism and abnormal calcitriol metabolism in the spontaneously hypertensive rat.

Abnormalities of calcium metabolism and of its two principal regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3 (calcitriol), have been reported in the spontaneously hypertensive rat (SHR). Reports of abnormal calcitriol metabolism in the SHR by several groups have not provided measurements of tissue calcitriol receptors. Similarly, few data are available as to the parathyroid status of the SHR. In the present study, circulating calcitriol levels and intestinal and parathyroid gland calcitriol receptor status were determined in male SHR and in Wistar-Kyoto (WKY) rats. Parathyroid status was investigated by determination of parathyroid gland mass together with tissue micromorphometry and by quantitative histology of bone as a measure of the biological action of parathyroid hormone. Circulating calcitriol levels were reduced in the 11-week-old SHR compared with the WKY rat (165 +/- 23 vs. 194 +/- 28 pmol/l, p less than 0.01, mean +/- SD). Calcitriol-free ratio was diminished and maximal specific binding capacity for calcitriol was increased in the SHR in parathyroid tissue (172 +/- 4.9 vs. 123 +/- 6.6 fmol/mg protein, p less than 0.01) and in intestinal mucosa with no change of receptor affinity. Plasma ionized calcium (1.29 +/- 0.05 vs. 1.45 +/- 0.35 mmol/l, p less than 0.05) and phosphate (1.5 +/- 0.26 vs. 2.4 +/- 0.03 mmol/l, p less than 0.05) were significantly lower in the SHR. Parathyroid gland mass was increased in the SHR (59 +/- 12 vs. 17 +/- 7 micrograms/100 g body wt, p less than 0.001) as a result of hyperplasia and not hypertrophy. Higher osteoclast numbers were observed in SHR bone (27.6 +/- 0.79 vs. 23.9 +/- 0.66 osteoclasts/mm2, p less than 0.01), suggesting increased parathyroid hormone activity. In summary, in the 11-week-old SHR we observed reduced circulating calcitriol levels together with increased tissue calcitriol receptor numbers, increased parathyroid gland mass, and histological evidence of hyperparathyroidism. It is possible that these abnormalities influence the development of hypertension in the SHR.

Bone modeling in gallium nitrate-treated rats.

Gallium nitrate (GaN) reduces cancer-related hypercalcemia and inhibits bone resorption in vitro. This study investigated the effects of chronic GaN administration on bone, kidney, and parathyroid gland activity of growing rats. Experimental animals received GaN (1.75 mg elemental gallium i.p. QOD X 8, Ga+), and controls received the solvent (Ga-). In the bone of Ga+ rats the number of osteoclasts was increased (Ga+: 70.4 +/- 2.31 osteoclasts/mm2; Ga-: 46.5 +/- 1.61 osteoclasts/mm2, P less than 0.001), and apposition rate and osteoid width were unchanged. Ga was concentrated in bone (2.4 mumol/g cortical bone) and detected by electron microprobe on the surface of a few trabeculae. Alkaline (Alp) and acid (Acp) phosphatase activities were higher in Ga+ than in Ga- calvaria (Ga+: Alp 223 +/- 23.4 U/mg prot, Ga-: Alp 145 +/- 13.3 U/mg prot, P less than 0.02; Ga+: Acp 69.5 +/- 4.7 U/mg prot, Ga-: 57.5 +/- 2.8 U/mg prot, P less than 0.05). Serum iPTH was increased (Ga+: 112.9 +/- 17.6 pg/ml, Ga-: 41.4 +/- 7.4 pg/ml, P less than 0.01), serum calcium was reduced (Ga+: 2.4 +/- 0.02 mmol/l, Ga-: 2.6 +/- 0.03 mmol/l, P less than 0.001); calciuria remained comparable to controls. Relative to the hypocalcemia this suggests renal loss of Ca. The calcemic response to hPTH 1-34 (i.v. 50 micrograms/kg) was decreased 2 hours after injection of the hormone (delta Ca: TPTX Ga+: 0.11 +/- 0.04 mmol/l, Ga-: 0.33 +/- 0.03 mmol/l P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum action on mouse bone cell metabolism and response to PTH and 1,25(OH)2D3.

Aluminum (Al) accumulation in bone is associated with low bone formation and mineralization rates; resorption may also be reduced. The mechanism of these Al-induced changes was investigated using cultured mouse osteoblast-like (OB) and osteoclast-like (OC) cells. The Al effect on bone resorption was measured by the in vitro release of 45Ca and beta-glucuronidase from mouse fetal limb-bones. Al had a biphasic effect. High concentrations (greater than 1.5 X 10(-6) M) of Al inhibited collagen and DNA synthesis, ornithine decarboxylase and alkaline phosphatase activity in OB, and depressed tartrate-resistant acid phosphatase activity in OC. Lower Al concentrations stimulated these cellular activities and 45Ca and beta-glucuronidase release from fetal bones. Al had no effect on basal cAMP levels in OB but inhibited the stimulating effect of bPTH on cAMP content. Al also altered the 1,25(OH)2D3 effects on the ornithine decarboxylase activity of OB cells. These data suggest that: (i) the low bone formation observed in vivo during Al intoxication may be due to the inhibition of collagen synthesis and to depressed cell proliferation; and (ii) Al may indirectly influence bone remodeling by interfering with the actions of bPTH and 1,25(OH)2D3 on bone cells.

Parathyroid response to aluminum in vitro: ultrastructural changes and PTH release.

The endocrine response of porcine parathyroid gland tissue slices in vitro to aluminum was studied by electron microscopy and radioimmunoassay of PTH. Medium aluminum concentrations were 20 to 500 ng/ml covering the range corresponding to concentrations reported in the plasma of aluminum-intoxicated hemodialyzed patients. Aluminum inhibited iPTH-release and caused severe cell alterations. This inhibition was incomplete and there was an aluminum-insensitive iPTH-release capacity. This phenomenon seemed to be due to heterogeneous parathyroid cell population as regards aluminum sensitivity, perhaps linked to the spontaneous asynchronous cyclic parathyroid cell changes. Sensitivity to aluminum was modulated by the extra-cellular calcium concentration. Sensitivity to extra-cellular calcium concentration variations persisted in aluminum intoxicated tissues. The severity of the observed cell lesions induced by high concentrations of aluminum suggested that the recovery of an iPTH-release capacity when parathyroid tissue was withdrawn from a toxic environment and switched to aluminum-free media is more likely to be due to activation of a "less-sensitive to aluminum" cell pool than to a true reversibility of the toxic effect.

Value of the 99mTc-methylene diphosphonate bone scan in renal osteodystrophy.

The value of radionuclide bone scanning in the diagnosis of renal osteodystrophy is still debated. In order to re-examine this issue, 25 uremic patients treated by intermittent hemodialysis underwent 99m-Technetium Methylene Diphosphonate (99mTc-MDP) bone scan. They were subdivided into three groups according to quantitative bone histology. Group 1 (N = 8) had pure dialysis osteomalacia, group 2 (N = 7) mixed lesions, and group 3 (N = 10) pure osteitis fibrosa. The scintigraphic studies were interpreted by means of a five point semi-quantitative scale. Using this quantification, all but one group 1 patients had decreased bone tracer uptake, and all patients of group 3 had an increased uptake (chi square test of Yates, P less than 0.001). Among patients of group 2, bone uptake was decreased in the three patients with clearly reduced mineralization front and moderate osteitis fibrosa, but it was increased in all patients with severe osteitis fibrosa and subnormal mineralization front. A quantitative analysis of regional tracer uptake into bone was performed in two patients: one of group 2 and one of group 3. The results obtained clearly corroborated the semi-quantitative findings. Thus, in hemodialysis patients with symptomatic bone disease, the 99mTc-MDP bone scan provides useful information for the differential diagnosis between dialysis-related osteomalacia and secondary hyperparathyroidism. In patients with mixed lesions, the importance of bone tracer uptake appears to depend on the extent of the mineralization front and on the intensity of osteitis fibrosa.

Mitochondrial calcium and bone mineralization in the rat fetus.

The initial mineralization of the tibial bone collar of 17-day-old rat fetuses has been investigated. Images obtained after glutaraldehyde-paraformaldehyde-OsO4 fixation were compared to those obtained after K-pyroantimonate (PAO) fixation. Ca, P and Sb were identified and Ca/P intensity ratios evaluated by wavelength dispersive X-ray microanalysis. Alkaline phosphatase was detected on decalcified sections. Some osteoblasts showed degenerative changes and free mitochondria could be seen within the osteoid on the prolongation of their cytoplasmic processes. The mitochondria contained mineralized granules and clusters. Similar granules, numerous clusters and few matrix vesicles were observed within osteoid. The Ca/P intensity ratios (PAO fixed sections) of mitochondrial mineral (11.5 +/- 2.54) were different from the ratio of crystalline mineral in matrix vesicles (1.52 +/- 0.07). Alkaline phosphatase was present along plasmalemma of osteoblasts and around mineral deposits. These results show that in the rat fetus osteoblast mitochondria may be extruded from the cells, and that mitochondrial granules may represent the first mineral deposits in osteoid.

Response to parathyroid hormone and 1,25-dihydroxyvitamin D3 of bone-derived cells isolated from normal children and children with abnormalities in skeletal development.

In order to evaluate the role of intrinsic defects in osteoblast function in the pathogenesis of diseases of skeletal development, we developed techniques which permit the evaluation of the metabolic properties of bone-derived cells in vitro. Cells from control children demonstrated a variety of properties classically attributed to osteoblasts (presence of alkaline phosphatase positive cells and synthesis of bone gla protein) and responded to PTH (cAMP production) and to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) ([3H]25-hydroxyvitamin D3 conversion into [3H]24,25-dihydroxyvitamin D3 and bone gla protein secretion). Using these techniques we evaluated the function of cultured bone cells from patients with three rare diseases of skeletal development. Cells from a patient with rickets resistant to 1,25(OH)2D3 were resistant to 1,25(OH)2D3 but responded normally to PTH. Cells from a patient with acroosteolysis with osteoporosis responded normally to PTH and 1,25(OH)2D3. Cells from a patient with hyperphosphatasia with osteoectasia responded normally to 1,25(OH)2D3 but did not respond to PTH. The results demonstrate that bone cell cultures can provide information about the role of osteoblast dysfunction in such diseases.

The role of parathyroid function and parathyroidectomy in the outcome of aluminium-related dialysis encephalopathy.

Aluminium (Al) intoxication in patients with chronic renal failure may lead to osteomalacia, microcytic anaemia, and encephalopathy. It has been suggested that the expression of Al toxicity may be related to the function of the parathyroid glands. The purpose of this study was to determine whether the functional state of the parathyroids influenced the evolution of Al-related encephalopathy in Al-intoxicated haemodialysed patients. The patients were subdivided into two groups according to outcome: group I patients (n = 6) had died with the clinical feature of severe cerebral dysfunction; group II patients (n = 15) had a favourable outcome with partial or complete recovery. The degree of hyperparathyroidism, as evaluated by plasma biochemistry and bone histology, was comparable in both groups. Three patients of group I and five of group II underwent parathyroidectomy. Before the clinical onset of encephalopathy the duration of Al overload in group I was not different from group II, but after its onset patients of group I were intoxicated significantly longer (8 months +/- 6.6) than those of group II (1.5 months +/- 1.9). This study shows that, in uraemic patients with Al-related encephalopathy, parathyroid function and parathyroidectomy do not play an essential role in clinical outcome. The duration of Al intoxication following the first signs of encephalopathy appears to be the major prognostic element.

Hypercalciuria during experimental vitamin K deficiency in the rat.

Vitamin K promotes the formation of gamma-carboxylated glutamate (GLA) in several protein species. GLA residues have a high affinity for the Ca ion. In the present study, we tested the hypothesis that experimental vitamin K deficiency in rats could induce changes in Ca metabolism. Vitamin K depletion, which was associated with a reduction in urinary GLA excretion, induced within 7 days a significant increase in cumulative urinary Ca excretion that persisted throughout the 21 days of study. The hypercalciuria of vitamin K-deficient rats was corrected on vitamin K supplementation. No concomitant changes were observed in intestinal Ca absorption determined by a balance technic or of skeletal resorption and apposition rates determined by bone histomorphometry. Plasma Ca, but not total protein concentration, of vitamin k-depleted rats showed a transient decrease at day 15 that disappeared at day 21. plasma sodium, phosphate and 1,25(OH)2 vitamin D concentration, and urinary phosphate, sodium, and creatinine excretion remained unchanged. In conclusion, vitamin k deficiency in the rat induced hypercalciuria that could be of renal origin. Its possible relationship to vitamin K-dependent renal GLA protein remains to be clarified.

Dialysis osteomalacia: clinical aspects and physiopathological mechanisms.

Dialysis osteomalacia is characterized by distinctive, although not pathognomonic, clinical and biochemical features. Symptoms and signs may include musculoskeletal pain, arthralgias, proximal muscle weakness, and spontaneous fractures. Biochemical characteristics may be hypercalcemia and normal serum alkaline phosphatase activities. Vitamin D administration may induce early severe hypercalcemia. Plasma phosphate and immunoreactive parathyroid hormone concentrations may be at any level. Only bone histology allows to establish the diagnosis of dialysis osteomalacia with certainty. Diphosphonate bone scan, however, enables to distinguish between severe osteitis fibrosa and dialysis osteomalacia. The diagnostic value of desferrioxamine administration with subsequent measurement of plasma aluminium remains to be determined. The complex interactions existing between parathyroid hormone and aluminium are not yet fully understood.

Bone ultrastructure and x-ray microanalysis of aluminum-intoxicated hemodialyzed patients.

In hemodialyzed patients aluminum (Al) intoxication may induce osteomalacic lesions which are mainly observed when plasma immunoreactive parathyroid hormone (iPTH) concentrations are low, and osteitis fibrosa absent. In this study, the bone tissue of eight hemodialyzed patients with elevated plasma and bone Al concentrations was examined by histomorphometry, electron microscopy, and x-ray microanalysis. Five patients (group 1) had osteomalacia and minimal osteitis fibrosa, three patients (group 2) had severe osteitis fibrosa. In group 1, Al was concentrated at the mineralizing front, in hexagonal structures measuring 200 to 1,000 A which also contained phosphorus, but not calcium. Hydroxyapatite needles had a normal aspect. Osteoblasts appeared inactive. In group 2, Al was also present at the mineralizing layer of osteoid, but, in these cases, in small clusters next to abnormal calcium deposits. Osteoblasts appeared very active. Their mitochondria contained calcium and phosphorus granules, or amorphous material, measuring 1,500 to 2,000 A, emitting x-rays characteristic for Al and phosphorus. These results suggest that secondary hyperparathyroidism, by stimulating the cellular activity, may increase the uptake and release of Al by the osteoblasts. The presence of Al within the mitochondria of these cells may be one of the factors inducing the mineralization defect.

[Hyperparathyroidism secondary to renal insufficiency: anatomo-clinical relations and the potential role of an aluminum overload]. / Hyperparathyroïdie secondaire à l'insuffisance rénale: relations anatomo-cliniques et rôle potentiel d'une surcharge aluminique.

Severe secondary hyperparathyroidism is still observed at present in 5-10% of haemodialysis patients. It requires surgical correction. Fifty-eight haemodialysis patients had neck surgery and their 222 parathyroid glands analysed. The individual gland weight was comprised between 22 and 3880 mg (mean +/- SEM, 689 +/- 62 mg). Mean total parathyroid gland weight per patient was comprised between 2 and 3 g. Schematically, 4 types of gland architecture could be distinguished: diffuse hyperplasia alone; diffuse hyperplasia associated with incipient nodule formation; hyperplasia with pronounced nodule formation; and nodule formations alone. Total gland weight was significantly higher for the latter two histological forms than for the former suggesting transformation with time of pure hyperplasia to nodular hyperplasia. Patients with chronic pyelonephritis had a mean gland weight higher than that of patients with chronic glomerulonephritis (3308 +/- 498 mg versus 1824 +/- 358 mg, p less than 0.01). No relation was found between total gland weight and plasma calcium, phosphate or alkaline phosphatases. However, a weak relation existed between total gland weight and plasma immunoreactive parathyroid hormone. In addition, a negative relation was observed between highest prior plasma aluminium and gland weight when considering only patients with a gland weight less than 2000 mg. Parathyroid gland aluminium content was significantly higher in haemodialysis patients than in nonuraemic patients with primary hyperparathyroidism. A direct relation was found between parathyroid gland and bone aluminium. In conclusion, in haemodialysis patients with evolving hyperparathyroidism initially diffuse gland hyperplasia appears to be associated progressively with nodule formation. Circulating immunoreactive parathyroid hormone is positively related to total gland weight.(ABSTRACT TRUNCATED AT 250 WORDS)

[Osteomalacia as a result of aluminum poisoning during chronic hemodialysis]. / Ostéomalacie par intoxication à l'aluminium au cours de l'hémodialyse chronique.

The iliac crest biopsy of an uremic child, suffering from nephronophtisis, and hemodialyzed since the age of 11 1/2 years, was examined by histomorphometry, electron-probe X-ray microanalysis and ion microscopy. The results have been compared with those obtained with the same techniques in the bone tissue of 11 hemodialyzed aluminum-intoxicated adults. In this child, radiology of the skeleton and plasma biochemistry suggested secondary hyperparathyroidism; by contrast, histology showed impaired mineralization, little bone resorption, and aluminum deposits at the limit between osteoid and calcified tissue similar to those observed in the bone tissue of the adults. This observation, and the fact that the child had a high plasma aluminum level, and that dialysis was performed with softened aluminum-rich water, strongly suggests that the severe osteomalacia of this child was due to aluminum toxicity.