[Aetiological spectrum of hyperferritinemia]. / Spectre étiologique des hyperferritinémies.

UNLABELLED: Serum ferritin levels may be increased in many conditions: renal diseases, liver diseases, human immunodeficiency virus infection. The purpose of this study was to assess the aetiological spectrum of high serum ferritin levels in a 1200-bed university hospital, to compare our results with the data already published and to assess a potential association between aetiology and ferritin levels. PATIENTS AND METHODS: Patients with a serum ferritin level higher than 600 microg/l were retrospectively included between 15 November 2003 and 15 January 2004, and their medical records were reviewed. RESULTS: Ninety-eight patients (38 women and 60 men; median age: 59,5 years [19-92]) were recruited in departments of hepatology and gastroenterology (22%), haematology (14%) and internal medicine (18%). Diagnosis performed were: non-HIV systemic infections (23,8%), haematological diseases (16,1%), alcoholism (11,2%) and malignancies (9,8%). Dialysed chronic renal failure, liver diseases, haemochromatosis and systemic inflammatory diseases counted for 4.2 to 5.2% of cases. Serum ferritin level lied between 600 and 1000 microg/l for 50 patients, between 1000 and 1500 microg/l for 24, and over 1500 microg/l for 24. There was no significant difference between the three groups as regards the etiological distribution. DISCUSSION: In our study, chronic renal failure was not a major cause of high ferritin level: this is probably due to the current use of erythropoietin, which has decreased the use of blood transfusions. The two major aetiology of hyperferritinemia were non-HIV infections and malignancies.

A targeted approach significantly increases the identification rate of patients with undiagnosed haemochromatosis.

OBJECTIVE: To determine the optimal means of identifying patients with undiagnosed haemochromatosis. DESIGN: Case-control study where cases are defined by the presence of specific clinical diagnoses or symptoms. SETTING: Primary care patients were recruited from three Oxfordshire practices and secondary care patients were recruited from those patients attending specialist clinics in Amiens University Hospital. SUBJECTS: A total of 569 patients recruited via hospital clinics and 60 primary care patients (recruited from 4022 consultations) presenting with the following haemochromatosis associated conditions, diabetes, arthralgia/chronic fatigue, osteoporosis or arthropathy were studied. The control group, a total of 991 healthy volunteers, were recruited through a Health Appraisal Centre. Patients and controls were included in the study if they or their family members had not previously been diagnosed with hereditary haemochromatosis. MAIN OUTCOME MEASURES: Serum ferritin concentration, transferrin saturation (Tsat) and presence of HFE mutations, C282Y and H63D. The check-up in controls consisted of a questionnaire, clinical examination, biochemical tests and screening for the presence of the C282Y and H63D mutations. RESULTS: Patient groups presenting with unstable diabetes or chronic fatigue and arthralgia together with a raised serum ferritin concentration showed an enrichment in the haemochromatosis-associated genotype HH/YY, odds ratio (OR) = 40.1, confidence interval (CI) = 8.0-202.1 and OR = 103, CI = 22.9-469.7, respectively. CONCLUSION: Patients presenting to hospital clinics with haemochromatosis associated conditions should be screened biochemically for iron overload. Only those with a serum ferritin >300 microg L-1 or Tsat >40% should subsequently go on to be genotyped for HFE mutations. The patients at greatest risk of having undiagnosed haemochromatosis are those presenting with unstable diabetes, or fatigue and/or arthralgia in the absence of any other explanation.

Contrasting effects of excess ferritin expression on the iron-mediated oxidative stress induced by tert-butyl hydroperoxide or ultraviolet-A in human fibroblasts and keratinocytes.

Iron and/or ferritin accumulation are known to occur under pathological conditions in many inflammatory skin diseases or in human skin chronically exposed to UV light. Under such conditions, ferritin is believed to play an effective protective role in accommodating and 'deactivating' excess 'free' iron produced by the inflammatory process or the UV illumination. The present study compares the relationship between ferritin over-expression and effects of an oxidative stress induced chemically by tert-butyl hydroperoxide or photochemically by UV-A radiation. As shown by immunoassay, cultured MRC 5 and HS 68 fibroblasts treated for at least one day with transferrin or overnight with non-toxic concentrations of the ferric nitrilotriacetate complex express up to 10 times more ferritin than untreated cells, whereas a five-fold increase is obtained with NCTC 2544 keratinocytes. In all cases a parallel increase in soluble cellular iron is measured by inductive plasma emission spectroscopy. The superoxide dismutase and catalase activities and total glutathione levels are not modified by the iron treatment, whereas a transient increase in the Se-dependent glutathione peroxidase activity of keratinocytes is observed after a short incubation with the iron complex. In keratinocytes and fibroblasts, ferritin over-expression after iron treatment markedly inhibits lipid peroxidation but, paradoxically, not the mortality induced by tert-butyl hydroperoxide. In contrast, this excess ferritin does not protect cells from both the peroxidation and mortality induced by moderate doses (30 J/cm2) of UV-A radiation. As a consequence, protection against oxidative damage by excess ferritin synthesis clearly depends on the nature of the oxidative stress on cell targets and it seems to be of lesser importance in the case of photochemically induced oxidation.

Renal ostodystrophy during the developing stage of maintenance dialysis in Transylvania. Early development of periarticular calcifications and beta 2 microglobulin amyloidosis in spite of a relatively good prevention of secondary hyperparathyroidism.

BACKGROUND: Dialysis facilities have been introduced only recently in Transylvania with many limitations, in particular a standard high calcium dialysate, Al(OH)3 as phosphate binder and pharmacological doses of native vitamin D2, but neither CaCO3 nor 1 alpha hydroxylated vitamin D. Rheumatological complaints and metastatic calcifications were frequent, leading to suspect either overt hyperparathyroidism, adynamic bone disease or beta 2 microglobulin amyloidosis. AIMS OF THE STUDY: Evaluate the prevalence of radiological osteitis fibrosa, amyloid osteoarthropathy and periarticular calcification and their link with PTH secretion, phophocalcic disorders, acidosis, bone turn over, aluminum and beta 2 microglobulin accumulation in the dialysis population of Sibiu (Transylvania). METHODS: The clinical and radiological rheumatological data of the 49 uremic patients dialyzed in Sibiu since 1990 were reviewed as well as the monthly routine monitoring of their plasma phosphocalcic parameters. Furthermore in July 1994, 36 of them had an X rays of the hands for evaluation of subperiosteal resorption of the phalanges, periarticular calcifications and carpal cysts as well as a determination of plasma concentrations of intact PTH (normal range: 10-55; optimal range: 100-200 pg/ml), osteocalcin, bone alkaline phosphatase, aluminum and 25 OH vitamin D. RESULTS: The prevalence of subperiostal resorption of the phalanges was 8% and that of severe biological hyperparathyroidism (PTH > 400 pg/ml) 22%, whereas that of a relative hypoparathyroidism (PTH < 100 pg/ml) was 31%. Mean plasma concentrations of calcium was 2.07 +/- 0.15; of phosphate 2.50 +/- 0.35; of bicarbonate 15 +/- 2.0 mmol/l, of 25 OHD 30 +/- 20 ng/ml, of aluminum 1.1 +/- 0.5 mumol/l. Plasma PTH concentrations were negatively correlated to dialysis duration, and to plasma concentrations of aluminum, calcium and 25 OH vitamin D but not to those of phosphate and bicarbonate. Multivariate analysis showed however that only duration of dialysis and plasma aluminum concentration were independently and negatively correlated to plasma PTH concentrations. The prevalence of periarticular calcifications (26%) and of carpal cysts suggestive of beta 2 microglobulin amyloidosis (10%) were relatively high considering the young age of the population (42 years) and the short duration of dialysis (2.6 years). Patients with calcifications comparatively to those without calcifications were older, had longer duration on dialysis, higher prevalence of carpal cysts and higher plasma beta 2 microglobulin concentrations, lower plasma PTH (98 versus 313 pg/ml) and higher plasma aluminum concentration (1.3 versus 0.8 mumol/l). Patients with carpal cysts comparatively to those without cyst were older, had a longer duration on dialysis and a higher prevalence of periarticular calcifications. CONCLUSIONS: a) In spite of no use of 1 alpha hydroxylated vitamin D derivatives, and poor control of hyperphosphatemia and acidosis, hyperparathyroidism declined with duration of dialysis due to the use of a high dialysate calcium concentration, Al(OH)3 as sole phosphate binder and high supplement of native vitamin D. b) Considering the relative young age and short duration on dialysis, the prevalence of periarticular calcifications and carpal cysts were high. c) Calcifications were possibly favored by relative hypoparathyroidism and moderate aluminum overload. d) The association of periarticular calcifications and subchondrial cysts suggest a causal relationship.

[Relative depletion in native vitamin D: a potential risk factor in Algerian hemodialysis patients with radiological evidence of hyperparathyroidism and osteomalacia independent of calcitriolemia]. / La déplétion relative en vitamine D native: un facteur de risque potentiel chez l'hémodialysé algérien de lésions radiologiques d'hyperparathyroïdie et d'ostéomalacie indépendant de la calcitriolémie.

Looser striae on the ischio-pubian branches and subperiosteal resorption of the phalanges were looked for in 113 chronic hemodialysis patients at the University Hospital of Annaba (Algeria) and were found in respectively 14 and 48 patients. Comparison of patients with and without radiological complications showed no significant difference in their age, sex ratio, nature of initial kidney disease and duration on dialysis. The patients with Looser striae had lower plasma levels of 25OHD3 than those without striae, whereas all other plasma parameters were similar. The plasma concentrations of intact PTH were higher in patients with resorption; these patients had lower plasma concentrations of calcium, bicarbonate, aluminum and 25OHD3 but similar plasma concentrations of phosphate and 1,25(OH)2D3. Multivariate analysis showed that PTH concentrations were independently linked only to plasma 25OHD3 (negatively) and duration on dialysis (positively). The results of this transversal study are in agreement with the well established pathophysiological roles of PTH hypersecretion, hypocalcemia and acidosis in the appearance of radiological hyperparathyroidism in hemodialysis patients. Furthermore they suggest that a relative native vitamin D deficiency may have a calcitriol independent role in favoring the occurrence of both osteitis fibrosa and osteomalacia.

Glucose-enriched medium enhances cell-mediated low density lipoprotein peroxidation.

A 1 week preculture of endothelial or smooth muscle cells in glucose-enriched (11.2 to 44.8 mM) media resulted in a marked enhancement of the subsequent ability of cells to oxidize low density lipoprotein, as assessed by the lipid peroxidation end product and conjugated diene content of the particle, its relative electrophoretic mobility and its degradation by macrophages. This phenomenon is correlated to a marked stimulation of superoxide anion secretion by cells. Such an effect of elevated glucose concentration on cell-induced LDL oxidative modification could be involved in the increased occurrence of atherosclerotic lesions in diabetes mellitus.

Determination of aluminum in bone in haemodialyzed patients, using inductively coupled argon plasma emission spectrometry.

We propose a new method for measuring aluminium in bone tissue, using argon plasma emission spectrophotometry. The detection limit in the bone nitric digestion liquid was 0.015 mumol/l (corresponding to 0.0075 mumol/g, i.e. 0.2 microgram/g for a tissue sample with 1.0 g wet weight). Within-run CVs were 4.66% and 1.43% for tissues containing 0.15 and 0.64 mumol/g, respectively. Other bone constituents such as calcium, phosphorus, magnesium, sodium, potassium, do not affect aluminum results. Normal values obtained in bone of subjects not suspected of aluminium intoxication were: mean +/- SD; 0.09 +/- 0.044 mumol/g (n = 24). In dialysis patients we found a mean bone aluminium content of 0.75 mumol/g for concentrations ranging between 0.16 and 3.38 mumol/g.

Indirect clinical evidence that 1 alpha OH vitamin D3 increases the intestinal absorption of aluminum.

In a previous study we showed that 1 alpha OH vitamin D3 [1 alpha (OH)3] given to 16 hemodialyzed patients taking Al(OH)3 at a constant dose increased their plasma concentrations of aluminum [Demontis et al. 1986]. In order to choose between 2 possible mechanisms explaining this increase (increased intestinal absorption or decreased tissue storage of aluminum), we gave, in the present study, 1 alpha (OH)3 the same dose (6 micrograms per week) for the same period (4 weeks) to 15 stable hemodialyzed patients after their Al(OH)3 had been discontinued for 6 weeks. Under Al(OH)3 treatment they had a mean plasma aluminum (2.33 +/- 2.36 mumol/l) which was not significantly different from that of the patients in our former study (1.23 +/- 0.25 mumol/l). After Al(OH)3 discontinuation, plasma aluminum (measured by inductively coupled plasma emission spectrometry) decreased significantly as early as the 2nd week of the control period (1.39 mumol/l). The decrease was maintained at a plateau throughout the 5 weeks of the control period (1.38 mumol/l), the 4 weeks of 1 alpha OH vitamin (vit) D3 administration (1.40 mumol/l) and the 8 weeks of the post 1 alpha (OH)3 period (1.22 mumol/l). Plasma calcium and phosphate concentrations increased significantly with 1 alpha (OH)3 and decreased thereafter whereas plasma PTH concentrations decreased during 1 alpha (OH)2 D3 and increased after its discontinuation suggesting biological activity of 1 alpha (OH)3. Since 1 alpha (OH)3 increases plasma aluminum in hemodialyzed patients only when they are simultaneously taking Al(OH)3, it is suggested that this increase is explained by an increase of intestinal absorption of aluminum and not by a tissue redistribution of aluminum.

Magnesium hydroxide as a complementary aluminium-free phosphate binder to moderate doses of oral calcium in uraemic patients on chronic haemodialysis: lack of deleterious effect on bone mineralisation.

To control hyperphosphataemia without hyperaluminaemia, A1(OH)3, which was given in addition to high doses of oral calcium, was replaced by Mg(OH)2 for 6 months in 20 haemodialysed patients and for 20 months in 12. The treatment during the control period was 110 +/- 91 mmol/day of oral calcium element given as CaCO3 and/or Calcium Sorbisterit and 1.05 +/- 1.47 g/day of A1(OH)3. Haemodialysis treatment was 4 h, thrice weekly. To prevent hypermagnesaemia, dialysate magnesium was decreased from 0.75 mmol/l to 0.375 mmol/l. After a control period of 3 months, Mg(OH)2 was given at a mean dose of 2.6 +/- 2 g/day and oral calcium supplements were decreased to 76 mmol/day. Two subsequent bone histomorphometry studies were performed at 8 month intervals in four patients and at 20 month intervals in seven patients. The results show a good control of plasma calcium (mean +/- SD: 2.43 +/- 0.1 mumol/l); phosphate (1.76 +/- 0.4 to 1.66 +/- 0.3 mmol/l); aluminum (1.3 +/- 0.1 mumol/l to 0.6 +/- 0.1 mumol/l); alkaline phosphatase (135 +/- 65 to 125 +/- 40 IU); and PTH fragments (PTH C terminal decreased from 260 +/- 214 to 185 +/- 182 pg/ml, PTH medium from 4185 +/- 5113 to 2270 +/- 4880 pg/ml). Plasma magnesium increased from 0.96 +/- 0.2 to 1.54 +/- 0.2 mmol/l. Bone histomorphometry shows no change in mineralisation, and a borderline decrease of resorption parameters. The main side-effects are (1) diarrhoea, which was well controlled by transient treatment with karaya gum, and (2) an increased need for potassium binders.(ABSTRACT TRUNCATED AT 250 WORDS)

[Indirect evaluation of the effect of 1 alpha-hydroxyvitamin D3 on intestinal absorption of aluminum]. / Evaluation indirecte de l'effet de la 1 alpha OH vitamine D3 sur l'absorption intestinale de l'aluminium.

In a former study we have shown that 1 alpha OH vitamin D3 given to hemodialyzed patients taking A1(OH)3 at a constant dose increased their plasma concentrations of aluminium. Two mechanisms can explain this increase: increased intestinal absorption or decreased tissue storage of aluminium. We have, in the present study, given 1 alpha(OH)3 at the same dose (6 micrograms per week) and during the same duration (4 weeks) to 15 stable hemodialyzed patients after aluminium hydroxide has been discontinued 6 weeks before. Under A1(OH)3 treatment mean plasma aluminium was 2.33 +/- 2.36 mumol/l. After A1(OH)3 discontinuation, plasma aluminium decreased significantly as soon as the 2nd week of the control period (1.39 mumol/l). The decrease was maintained in plateau throughout the 5 weeks of the control period (1.38 mumol/l and, the 4 weeks of 1 OH Vit D3 administration (1.40 mumol/l). After 1 alpha OH D3 discontinuation there has been a non significant transient drop of aluminemia followed by a plateau at a level comparable to the previous plateau. Plasma calcium and phosphate concentrations increased significantly with 1 alpha(OH)3 and decreased thereafter confirming biological activity of 1 alpha(OH)3. Since 1 alpha(OH)3 increases plasma aluminium in hemodialyzed patients only when they are taking simultaneously A1(OH)3, it is suggested that this increase is mainly explained by an increase of the intestinal absorption of aluminium.

Rapid determination of iron in urine, in the presence of deferoxamine, by inductively coupled plasma emission spectrometry.

Using a spectrometer with an argon plasma source coupled to a high-frequency magnetic field, we developed a direct method for determining iron in urine of patients being treated with deferoxamine. The detection limit for iron was 75 nmol/L; added iron was satisfactorily recovered; and we observed no interference from deferoxamine at its most commonly used concentrations. Values for between-run and within-run precision (CV) was less than 5%. Correlation of results with those obtained with a colorimetric method involving bathophenanthroline was good (r = 0.96).

Comparative evaluation of bone aluminum content and bone histology in patients on chronic hemodialysis and hemofiltration.

In order to compare hemofiltration (HF) and hemodialysis (HD) in connection with the risk of aluminum overload and renal osteodystrophy, double bone biopsies after double tetracycline labeling and a desferrioxamine test were performed in 12 patients on HF and 15 patients on HD. The aluminum concentration was low (less than 0.6 mumol/l) both in the dialysate and the substitution fluid. The duration of treatment (about 2 years) and the cumulative doses of Al(OH)3 and CaCO3 were comparable in the two groups. None of the patients was taking 1 alpha-OH-D. The aluminum balance during an HF run ranged from -22 to +1.8 mumol/l, the balance being positive only when the plasma aluminum was less than 0.5 mumol/l. Basal plasma aluminum and its increase induced by desferrioxamine were comparable in the two groups. Bone aluminum content was also comparable, but was about 10 times higher than in 7 nonuremic controls. Bone aluminum content and plasma aluminum increase after desferrioxamine were correlated to the Al(OH)3 cumulative dose. None of the patients had florid osteomalacia with increased osteoid thickness, and only 1 in each group had traces of stainable aluminum. The mineralization front was decreased in 8 of 12 HF and in 9 of 14 HD patients, so that no difference was observed between the means of the two groups. The predominant histological bone picture of the patients was osteitis fibrosa which was present in 10 of 12 HF and in 13 of 15 HD patients. Mean osteoclast count and active resorption surface were comparable in the two groups, but was increased (5-10 times the mean of the controls).(ABSTRACT TRUNCATED AT 250 WORDS)

The desferrioxamine test predicts bone aluminium burden induced by A1(OH)3 in uraemic patients but not mild histological osteomalacia.

Desferrioxamine (DFO), a chelating agent of aluminium was administered to 27 uraemic patients on chronic haemodialysis or haemofiltration with a minimal parenteral exposure to aluminium but taking various amounts of A1(OH)3 for about two years. All these patients had a double bone biopsy for measurement of their aluminium content and histomorphometric evaluation. Bone aluminium of our patients were 10 times greater than in our uraemic controls. Plasma aluminium increase (delta A1) induced by DFO correlated better than basal plasma aluminium with bone aluminium and cumulative dose of A1(OH)3 correlated with bone aluminium and delta A1 DFO. None of the patients had florid osteomalacia and only two had traces of aluminium staining. However 16 had mild mineralisation defect as demonstrated by low mineral appositional rate. The aluminium parameters were not different between the two groups of patients with or without mild mineralisation defect. It is concluded that the DFO test predicts bone aluminium but not mild histological osteomalacia in uraemic patients moderately aluminium over-loaded with phosphate binders.

Influence of biochemical and hormonal factors on the bone histomorphometric features of uraemic patients.

A multidimensional analysis was used to evaluate, the influence on bone histology of various biochemical and hormonal factors in 20 uraemic patients on chronic haemodialysis or haemofiltration. A positive relationship (p less than 0.1) was found between PTH and osteoclastic and osteoblastic surfaces but not with mineral apposition and bone formation rates. The mineral appositional rate which reflects the cellular activity of osteoblasts was positively related to D metabolites 25(OH)D3 and 1,25(OH)2D3 and to phosphate (p less than 0.1). Mineral appositional rate and bone formation rate were negatively related to bone aluminium (p less than 0.05). These data indicate that: 1) PTH simulates bone turnover but has no direct effect on the bone cellular activity of osteoblasts which is mainly dependent on D metabolites and phosphate; 2) mild aluminium overload not severe enough to cause osteomalacia decreases bone formation in uraemic patients. This study evaluates the role of various simultaneously measured biochemical and hormonal factors on bone histological parameters in uraemic patients.