[Hemochromatosis and myocardial disease : beneficial role of iron depletion (author's transl)].
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Biomedical subjects
Publications and source records attributed to P Passa.
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Six normal subjects and six normotensive insulin-dependent diabetics underwent two insulin hypoglycaemia tests after administration for three days of either a placebo or of acebutolol--a cardioselective beta-blocker--at a dose of 400 mg per day. The order in which the tests were performed was decided by random selection. Acebutolol suppressed the tachycardia which occurred as a reaction to hypoglycaemia but did not interfere with other warning symptoms and signs. In both normal subjects and diabetics, acebutolol neither worsened the initial hypoglycaemia nor did it delay a return to normal values. The increase in lactate levels following hypoglycaemia was not reduced by acebutolol but free fatty acid rebound was suppressed. Hormonal responses (glucagon, cortisol, growth hormone) were unaffected by the beta-blocker. If they are confirmed by long term studies, these results would suggest that acebutolol is safer to use than non-cardioselective beta-blockers in the treatment of coronary insufficiency and of hypertension in diabetics exposed to the risk of hypoglycaemia.
HbA1c is the product of a slow, virtually irreversible reaction, occurring continuously throughout the 120 day life-span of the erythrocyte, between HbAo and glucose. It has been shown to represent the time-averaged blood glucose concentration of the preceeding 2 month period, and is independant of day to day fluctuations in the blood glucose concentration. HbA1c therefore acts as a biochemical marker and permits clinicans, by one test, to judge the quality of the diabetic control, in their patients.
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Hepatic insufficiency is responsible for numerous modifications of drug metabolism and pharmacokinetics, because the liver is the most important organ for the transformation and, with the kidney, elimination of drugs. Pharmacokinetics of furosemide, an anthranilic diuretic, was compared in normal subjects and cirrhotics with hepatic insufficiency, after oral administration. In patients, we observed few modifications of the bioavailability. The total elimination of the drug was normal when the urinary excretion compensated a slight reduction in biliary secretion, but when this reduction was important the total clearance of furosemide decreased. In urine, the elimination time was lengthened, but the percentage of excretion was about the same as for normal subjects. The pharmacological effects were also modified for cirrhotics with decrease of sodium and water excretion, for the same blood concentration of drug as in controls. Also, we observed a shift between the salidiuretic effect and the blood concentration in patients, when there was an exact concordance of these times in control subjects. Two hypotheses have been proposed to explain this phenomenon: (1) modifications in hepatic metabolism or, (2) in drug protein binding.
In vivo platelet survival was estimated, in 31 diabetic patients, using 51Cr-labelled autologous platelets. A mathematical analysis attempted to measure the "potential" life span (senescence process) and the degree of a superimposed aleatory destruction (consumption process). The potential platelet life span in diabetics did not differ from normal values. However, excessive consumption was observed in one third of the studied cases, without correlation with the age of the patients, the clinical duration of diabetes, and the degree of vascular impairment. Thus, platelet kinetic studies did not provide presently useful indications, in a particular patient, regarding the prognosis of the vascular disease, and the justification of anti-aggregant therapy.
In the course of familial idiopathic haemochromatosis with diabetes, after stimulation with arginine, the alpha cell responds perfectly to stimulation, in contrast to the case of chronic pancreatic diseases. After an oral glucose load, there is no reduction in plasma glucagon concentrations, and a paradoxal increase is sometimes seen. These results are quite similar to those reported in common diabetes. Secretion of growth hormone after an infusion of arginine and insulin hypoglycaemia seem to be significantly reduced in comparison with normal subjects and those suffering from common diabetes, paired and explored using the same protocol. This may perhaps explain the low degree of severity and slow course of associated vascular disease.
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Forty-eight unrelated patients with idiopathic hemochromatosis were found to have a significantly higher frequency of three HLA antigens (A3, B7 and B14) than 591 healthy controls. A significant association between HLA haplotypes and disease segregations was demonstrated in 14 family studies. A recessive inheritance of a strongly A3-linked disease gene responsible for abnormal iron stores in the heterozygote state is postulated. The lod score value (4.415 for theta = 0.025) is compatible with this hypothesis. However, the excess of HLA-identical pairs of affected sibs does not exclude the possibility of a pseudo-recessiveness due to two codominant genes both HLA-linked. For the first time, a means of screening for high risk subjects is available and therefore offers the possibility of a preventive approach.
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Fourteen selected families containing two or more subjects suffering from idiopathic hemochromatosis and 34 unrelated cases have been studied for their HLA markers. A 3 was present in 75% of the unrelated cases vs 26% in the normal population (p less than 10(-8)). The frequencies of B 7 (38% vs 19%) and B 14 (23% vs 9%) were also increased (p lessthan 0,05). Inevitably, in most cases both antigens in the B locus were associated with A 3. Seven of nine affected sib pairs shared both HLA haplotypes, while two shared only one. Significant association between HLA haplotypes and diseases segregation has been demonstrated in family studies. These facts are consistent with the recessive inheritance of a strongly A 3 linked "disease" gene responsible for abnormal iron stores in the heterozygote state. This hypothesis would account for 64% of our present cases. Most of discordances (26%) were females who are physiologically protected, or children under 17 who might later develop the disease. The remaining 10% of disordant cases could be explained by crossing-over between "disease" gene and HLA loci or by an heterogeneity of the disease. This provides a method for screening for high risk subjects and perhaps an opportunity for anticipatory prevention.
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The aim of the present investigation was to determine in patients with idiopathic haemochromatosis whether diabetes is of the primary type or secondary to pancreatic injury due to iron deposition. For this purpose, plasma glucagon concentrations were determined following arginine infusion or an oral glucose load in eight patients with diabetes and idiopathic haemochromatosis. The enhanced glucagon response to arginine and the nonsuppressibility of glucagon secretion by oral glucose found in these patients were similar to the results found in the same tests performed in our previous series of patients with "idiopathic" diabetes and at variance with those reported by others in patients with chronic pancreatitis.
In patients with idiopathic hemochromatosis, retinopathy was investigated by ophthalmoscopy and fluorescein angiography and was present in eight out of 23; this prevalence is similar to that reported in patients with diabetes aged between 30 and 60 years at onset of diabetes and with the same duration of the disease; in these eight patients retinopathy was of mild degree, with no impairment of visual acuity, fewer than 10 microaneurysms in each fundus, and no other retinal abnormatic islets directly. These studies confirm that anticholinergic drugs may be useful adjuvants in treating these patients.
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As impairment in coagulation and platelet function has been reported following acute administration of somatostatin, a reevaluation of the effects of the cyclic and linear form of the peptide was undertaken. In vitro somatostatin had no effect by itself on platelet aggregation and no effect on ADP- or ristocetin-induced aggregation. In vivo ten healthy men infused with cyclic or linear somatostatin (loading dose of 250 microgram and three hour-infusion with 1,500 microgram) and five control subjects were investigated during the infusion and for three hours after the end of the infusion. With this dose, sufficient in man for maintaining plasma growth hormone and insulin at fasting levels under arginine stimulation, no abnormalities in platelet count, in ADP-induced platelet aggregation and in plasma VIII von Willebrand factor, factor VIII procoagulant activity and factor VIII related antigen levels were observed.