Corticosteroids and bone: a review.
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Biomedical subjects
Publications and source records attributed to P Burckhardt.
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Stone formers are often told to select a drinking water with low Ca content. To see whether this measure has a rational biochemical background, 4 Ca hyperabsorbers were asked to drink, first tap water ad libitum, then 2 liters/day of tap water, then 2 liters/day of a low Ca water (A) and finally 2 liters/day of a high Ca water (B). On A, subjects were normocalciuric but hyperoxaluric; whereas on B, they were markedly hypercalciuric but normooxaluric. Therefore, Ca . Ox concentration products were similar on B and A. However, on A as well as on B, Ca . Ox products were much lower than on tap water ad libitum due to the high fluid intake which had thus been imposed. It is concluded that, in the prevention of the recurrence of nephrolithiasis, 'have a high fluid intake' is probably a more relevant advice than 'select a water with a particularly low Ca content'.
The treatment of tumour-induced hypercalcemia (HCa) by diphosphonates appears to be safe and reliable with very mild side effects. We have tested APD as sole treatment in 14 patients with cancer and symptomatic HCa. APD was given i.v. in a dose of 0.38 +/- 0.03 mg/kg BW/day until two subsequent normal plasma calcium (Ca) levels were obtained (Ca determined daily). The mean duration of treatment was 5.56 +/- 1.9 (4 to 11 days). As expected, there was a significant correlation between initial Ca and duration of therapy (p less than 0.001). Mean Ca fell from 3.38 +/- 0.19 mmol/l before APD to 2.43 +/- 0.09 after 4 days of treatment and remained normal four weeks after the start of treatment. Four patients relapsed 11 to 31 days after the end of treatment during a one-month follow-up. This recurrence did not depend on initial Ca, length of treatment and duration of remission. Two of these patients were treated successfully with a second course of APD, while in the other two no further treatment was undertaken. Both mean UCa and UHydroxyproline decreased significantly when measured seven days after the beginning of the treatment. Plasma PTH values remained in the normal range, while NcAMP rose significantly after a week of treatment from low to normal values. Plasma phosphorus decreased significantly (p less than 0.005) during the treatment while TRP % increased, suggesting a positive phosphorus balance. We conclude that short treatments with APD of tumour-induced HCa are effective and sufficiently sustained, even if they are interrupted as soon as normal Ca is obtained.
The 75% of the renal stone formers have a so-called idiopathic calcium urolithiasis. The majority of these patients, however, do have a detectable biochemical disorder such as hypercalciuria, hyperuricosuria or hyperoxaluria. A high fluid intake unequivocally represents the first step in the therapeutic approach to these patients. Nevertheless, the detection of any type of biochemical disturbance is of great importance since the addition of a specific therapy will then become possible. Patients with absorptive idiopathic hypercalciuria will be advised to decrease their intake of dairy products as a function of the degree of calcium hyperabsorption, and simultaneously the major dietary sources of oxalate such as chocolate, spinach, rhubarb and asparagus will be eliminated; neutral orthophosphates (3-4 times 500 mg/d) or a thiazide, resp. an analogue as chlorthalidone (50 mg/d) are reasonable alternatives. Renal idiopathic hypercalciuria should be treated, according to the authors, with chlorthalidone (50 mg/d), with or without allopurinol (300 mg/d) depending on the presence of concomitant hyperuricosuria. Patients with dietary idiopathic hypercalciuria should be advised to better equilibrate the various components of their dietary intake. Finally, patients with isolated idiopathic hyperuricosuria whose disease would remain active despite a high fluid intake should receive allopurinol (300 mg/d). The treatment of isolated idiopathic hyperoxaluria is not yet well established. Two main arguments favor this so to say "tailored" approach to the idiopathic stone former: first, some metabolic disturbances are causally related to a particularly active and severe urolithiasis, whereas others are less so; second, the lack of efficacy of some types of treatment appears more and more to be due to insufficient screening of the patients before starting a given treatment.
Thirty-one cases of medullary carcinoma of the thyroid have been studied over the past fifteen years at the University Hospital of the Canton of Vaud, Switzerland (CHUV). Twenty cases were of sporadic nature and eleven presented as part of the familial MEN II syndrome (multiple endocrine neoplasia), one of which showed the classical features of the rare MEN IIb type. It is important to distinguish between the familial and sporadic cases, because membership of the former group implies the investigation of associated endocrinopathies (pheochromocytoma, hyperparathyreoidism) and study of the family tree as the syndrome is autosomal dominant. Medullary carcinoma of the thyroid is a constant feature of the MEN II syndrome and is the cause of premature death in these patients. The familial type should be suspected if the carcinoma appears early in life, is located in the superior pole of the thyroid or is bilateral or multicentric, if the histology shows hyperplasia of the C cells and, of course, if there is a history of surgery for pheochromocytoma or hyperparathyroidism. Although total thyroidecomy is the rule for these familial cases, its role is debatable in sporadic medullary carcinoma of the thyroid. Postoperative follow-up of these patients is based on serum calcitonin determination, as this is an extremely sensitive marker. The ten year survival rate is 50%, with the worst prognosis in MEN IIb type.
The analysis of nephrogenous cyclic AMP (NcAMP) has been reported to be a means of estimating parathyroid function with the advantage of being rapidly and easily performed. More specific than the analysis of urinary cyclic AMP (UcAMP), it measures biological activity of the parathyroid hormone. This study tests its use in the diagnosis of primary hyperparathyroidism (HPP) and compares the results of UcAMP with those of NcAMP. Analyses of NcAMP and parathyroid hormone were performed in a group of 21 healthy controls and two groups of hypercalcemic patients, one consisting of 12 patients with HPP and the other of 14 patients with hypercalcemia of non-parathyroid origin (HCa). It was confirmed that NcAMP is a parameter of parathyroid function, analysis of which allows the diagnosis of HPP with the same precision as analysis of the carboxyterminal plasma PTH. It has the added advantage over PTH measurements of detecting low values, thus permitting documentation of parathyroid inhibition in HCa patients.
We measured plasma concentrations of tryptophan (Trp) and the other large neutral amino acids (LNAA) in 6 control and 7 obese subjects before and after they consumed a low-carbohydrate "protein-sparing modified fast" (PSMF) diet; LNAA levels in control subjects were also assessed after supplemental oral Trp. Consumption of the PSMF diet by non-obese subjects, or obesity per se, caused major reductions in the ratio of the plasma Trp concentration to the summed plasma concentrations of the other LNAA (i.e., the "plasma Trp ratio"), and may thus have diminished brain serotonin synthesis. Administration of even 2 g of supplemental Trp did not elevate the plasma Trp ratio beyond the normal range observed previously in subjects consuming carbohydrate-containing meals.
Plasma testosterone (T), androstenedione (A), follicle-stimulating hormone, (FSH), luteinizing hormone (LH), prolactin (PRL), and urinary 17-ketosteroids (17-CS) have been measured in 152 women complaining of acne and/or hirsutism. Mean plasma levels of T, A, LH, PRL, and urinary 17-CS were significantly increased as compared to controls. T and/or A were increased in 59% of the cases. T was higher in women with PRL greater than 16 micrograms/l as compared to women with PRL less than 13 micrograms/l. Hirsutism had markedly decreased in 64% and acne in 84% of patients treated with cyproterone acetate.
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In a 22-year old man plasma calcitonin was normal in the basal state but elevated to 2.6 ng/ml after stimulation with calcium and pentagastrin. Two other family members had had bilateral pheochromocytoma accompanied by medullary carcinoma of the thyroid in one case and by adenomas of the parathyroid glands in the other. The literature of Sipple's syndrome, the value of calcitonin assay and the grounds for screening in affected families are reviewed. Surgery (total thyroidectomy) confirmed the clinical suspicion of C-cell hyperplasia and medullary microcarcinoma of the thyroid gland. Hyperplasia of the parathyroid glands was also found.
Calcium (Ca) metabolism was compared in 2 groups of patients with chronic interstitial nephritis: in 21 patients (AAN-group) nephropathy was due to exposure for 5 to 50 years (mean 21.1) to phenacetin containing analgesics, whereas in 21 other patients (controls) it was due to exposure for 1 to 80 years (mean 21.4) (NS) to other causes. Patients were followed for 2.5 +/- 0.6 and 1.6 +/- 0.6 years respectively (mean +/- SEM) (NS). Blood Ca, P, protein, creatinine, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), together with arterial acid-base status and urinary excretion rate of Ca, P and creatinine were measured serially. For each patient the results were averaged for 2 degrees of renal failure, i.e. for creatinine levels below and above 400 mumol/l (logarithmic mean). Results were included only when P was maintained between 0.7 and 1.9 mmol/l. The range of creatinine levels studied was 95 to 1600 mumol/l. No differences were found between the 2 groups with respect to creatinine clearance, blood, P, protein, arterial pH and urinary excretion rates of Ca and P. There was a trend for blood HCO3 to be lower in the AAN group. Mean plasma Ca was significantly lower, and PTH was significantly higher, in the AAN than in the control group at both degrees of renal failure; mean plasma alkaline phosphatase activity was also significantly higher in the AAN group, but at severe degrees of renal failure only. Significant correlations were observed between individual values of both Ca and PTH (r = -0.747) and PTH and alkaline phosphatase (r = 0.603). The degree of hypocalcemia and of hyperparathyroidism was not related to the plasma level of 25-OH-D. It is concluded that at comparable degrees and duration of renal failure patients with AAN, when compared with patients with interstitial nephritis of other origins, have lower blood Ca and consequently higher PTH levels and alkaline phosphatase activities, suggesting more severe osteodystrophy.
Urinary excretion rate of oxalate was measured in 79 patients with idiopathic calcium (Ca) nephrolithiasis and the results were compared with those obtained in 28 healthy volunteers. The group of stone formers consisted of 20 patients with idiopathic hypercalciuria (IHC) of the absorptive type, 23 patients with IHC of the renal type, 11 patients with hypercalciuria secondary to dietary factors, 1 patient with hyperuricosuria (as an isolated finding) and 24 patients without hypercalciuria nor hyperuricosuria. Classification was based upon the urinary excretion rate of uric acid, as well as that of calcium measured under 3 different dietary conditions (i.e. free diet, free diet supplemented with 3 g Ca/day for 3 days, and diet free of dairy products for 5 days). On a free diet, normal values of oxaluria ranged from 125 to 435 mumol/24 h; an elevated value was observed in 11 (14%) patients, 5 of whom belonged to the subgroup without hypercalciuria nor hyperuricosuria. On a low Ca diet, mild hyperoxaluria occurred in 3 controls and in 19 patients, the tendency to develop hyperoxaluria being particularly marked in the subgroup with absorptive-IHC. Moreover, there was a positive correlation between oxaluria on a low Ca diet and the estimated degree of intestinal absorption of Ca. This study confirms the finding that on a free diet, the incidence of mild hyperoxaluria amongst idiopathic stone formers is rather low. It shows, however, that a significant percentage of patients classically referred to as "without metabolic disorder" have in fact slight hyperoxaluria, an observation with a potential therapeutic impact. Finally, it shows that on a low Ca diet, patients with absorptive-IHC are particularly prone to develop hyperoxaluria: the latter observation renders questionable the relevance of a low Ca diet for patients with absorptive IHC, unless their intake of oxalate is simultaneously reduced.
The MEN IIb syndrome is a rare form of multiple endocrine neoplasia, clearly defined more than 15 years ago, since which time more than 100 cases have been identified. It has a characteristic phenotype appearance which is unique and should permit more frequent diagnosis. The patient who is the subject of this study had passed through several different hospital departments without his very characteristic appearance being recognized or a diagnosis established. The marfanoid aspect of such patient is however very obvious, with kyphosis, skeletal asymmetry and funnel chest. The facial appearance of blunt features and thick lips is even more specific. The tongue and digestive mucosa are covered with small polypoid lesions which are submucosal ganglioneuromas. The visible presence of fine hyperplastic nerve fibres on the cornea is pathognomonic. This syndrome occurs sporadically but is generally transmitted genetically in an autosomal dominant manner. A medullary thyroid carcinoma, followed or preceded by pheochromocytoma (often bilateral), is associated with these dysmorphic signs. The tumours are themselves preceded by C-cell hyperplasia or adrenal medullary hyperplasia. The ganglioneuromas which predominate in the digestive tract exist from birth. The accompanying symptoms may, initially, be mistaken for inflammatory bowel disease. The prognosis is poor, since it relates to the evolution of the medullary thyroid carcinoma which is particularly malignant and presents at an early age. We have been following the course of this unusual disease of the APUD system in a young man, now aged 26 years, for over 2 years.
Only a small number of cases of idiopathic hypoparathyroidism linked to the presence of specific antibodies have been described until now. Serum antiparathyroid antibodies have been frequently discovered in the absence of overt parathyroid disease. This suggests either that this kind of antibody is only a marker of genetic predisposition to immunological disease or more probably that subclinical hypoparathyroidism does exist though we lack the sensitive laboratory tests to prove it.
A 38-year-old woman with hypercalcemia, severe hypertension, and high renin levels was treated with the angiotensin-converting enzyme inhibitor captopril. This therapy, together with spironolactone, normalized blood pressure (BP), but even with three daily administrations of the converting enzyme inhibitor, intermittent rebound hypertension could not be avoided. The administration of only verapamil, an antagonist of calcium transport, did not induce BP control, but when verapamil therapy was combined with administration of captopril and spironolactone, BP could be normalized with only twice-daily administration of the converting enzyme inhibitor. Thus, high plasma calcium levels seem to sensitize the arterioles to the intermittent increase of angiotensin II levels that accompanies captopril therapy.
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