Adrenal endothelin-1 levels are not associated with aldosterone secretion in primary aldosteronism.

BACKGROUND: Endothelin-1 (ET-1) may function as an aldosterone secretagogue and, in turn, aldosterone can upregulate ET-1 expression. Hence, the existence of a feedforward loop involving ETs and aldosterone has been speculated in primary aldosteronism (PA). In the present study, we sought to examine ET-1 secretion from the adrenal glands in patients with PA. DESIGN: We determined ET-1 levels in blood samples obtained during adrenal venous sampling of patients affected by PA (n=17). Furthermore, we examined the mRNA expression of the ET system in tissue samples from aldosterone-producing adenomas (APAs, n=9) and control normal adrenals (n=3). METHODS: Blood ET-1 levels were determined by RIA. Tissue mRNA expression of the ET system was assayed with Affymetrix microarrays. RESULTS: ET-1 levels did not differ between inferior vena cava and adrenal vein blood in both bilateral adrenal hyperplasia and APA patients. Moreover, cortisol-normalized ET-1 levels did not show lateralized adrenal ET-1 secretion in APAs. Through gene expression profiling with microarray performed in a distinct set of APA individuals (n=9), we confirmed the adrenal expression of a complete ET system, but we did not detect a significant upregulation of ET components within the APA tissue compared with normal adrenals. CONCLUSIONS: The present data argue against the hypothesis of increased ET-1 secretion from APAs and do not support a general role for adrenal ET-1 in the vascular pathophysiology of PA.

Cognitive decline and low blood pressure: the other side of the coin.

Low blood pressure has been found to be associated with cognitive decline and dementia in cross-sectional studies. Two mechanisms have been proposed to interpret this association: blood pressure levels decrease during the course of the dementia process, and low blood pressure induces or accelerates cognitive decline by lowering cerebral blood flow. Results of the prospective studies are contradictory. Low blood pressure and orthostatic hypotension have been found to predict cognitive impairment in the elderly population in some studies only. While hypotension may play a protective role in healthy elderly people, low blood pressure levels in frail elderly patients with associated diseases may cause cerebral hypoperfusion and accelerate cognitive decline.

Spontaneous release of interleukin 1 beta from human blood monocytes in thyrotoxic osteodystrophy.

Hyperthyroidism is a well documented cause of impaired bone turnover characterized by increased osteoblastic and osteoclastic activity, resulting in predominance of bone resorption and in decreased bone mass. Thyroid hormones can carry out a direct effect on osteoblasts which express specific receptors on their surface membrane; differently effect on osteoclast seems to be mediated by local factors, cytokynes released by activated osteoblasts or by bone monocytes cells. Interleukin 1 beta is the first purified cytokyne shown to have bone resorbing activity. In ten thyrotoxic female patients IL 1 beta in the cellular medium of the monocytes blood cells culture has been measured, compared to PYD/cr urinary excretion, and FT3, BGP serum levels, before and after thyrostatic treatment. Ten normal females were studied as control group. The results before treatment showed osteopenia in 20% (DEXA densitometry), increased values of FT3, BGP, IL 1 beta and PYD/cr in patients versus controls (p < 0.001). The thyrostatic therapy obtained normalization of IL 1 beta, PYD/cr, BGP, and FT3 levels. Our data demonstrate that increased thyroid hormone levels in vivo are associated to increased secretion of monocytes cytokynes in vitro and suggest that alterations in local production of bone acting cytokyne may underlie to thyrotoxic osteodistrophy.

[Wilson's disease: physiopathology, therapeutic approach and case report]. / Morbo di Wilson. Fisiopatologia, approccio terapeutico e contributo alla casistica.

Wilson's disease is an hereditary recessive autosomal disorder which affects around five people per million inhabitants. The primary defect is localized in the liver and the disease is manifested by the accumulation of copper in tissues. The diminution of ceruloplasmin, which until a few years ago was mistakenly thought to be the pathogenetic cause of Wilson's disease, is an epiphenomenon of the underlying metabolic defect characterized by defective copper biliary excretion. There are four stages in the natural history of the disease: 1) an asymptomatic stage of hepatic copper accumulation; 2) dismission and redistribution of copper leading to hepatocellular necrosis and hemolysis; 3) extrahepatic accumulation of copper leading to the onset of cirrhosis and neurological damage; 4) stage of homeostasis following treatment but with possible irreversible neurological damage. Treatment of Wilson's disease takes the form of pharmacological, dietary and surgical therapy. Through the formation of copper and protein metal complexes D-penicillamine impoverishes copper deposits causing the reduction or disappearance of hepatic and neurological symptoms; a small percentage of patients treated develops a nephrotic syndrome requiring the compulsory suspension of the drug. In this case a valid alternative is triethylenetetramine dichlorohydrate (TETA) which provokes increased blood copper during copper diuresis. The response to pharmacological treatment is better the earlier treatment is started and the more regular its administration. Dietary intake of copper must be reduced in parallel avoiding foods with a high copper content. Liver transplant obviously leads to the "resolution" of the underlying metabolic problem in patients who develop fulminating hepatitis with hypercupremia and hemolysis and, of course, in cases of uncompensated cirrhosis which do not respond to chelating therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Osteodystrophy in thalassemia major]. / Osteodistrofia nella talassemia major.

Subjects with thalassemia major frequently have bone disorders of debatable pathogenesis. We attempt here to analyze the relationships between siderosis and thalassemic osteodystrophy by assessing calcium-phosphorus balance, hormone-vitamin homeostasis, osteoblastic-osteoclastic activity parameters, and bone mineral density (BMD) in 30 patients with thalassemia major (16 males, 14 females, age range 17-30 years). We found a significant increase in ferritin (p < 0.001) and significant decreases in serum i-PTH, 25OHD3, 1.25(OH)2D3, osteocalcin, estradiol, testosterone and FT4 (p < 0.001) in both sexes. In all patients a net decrease of bone mineral density was documented (p < 0.001). These results were then submitted to linear regression analysis: positive correlations between BMD and FT3, testosterone, estradiol (p < 0.01), were documented, and an inverse correlation between osteocalcin and ferritin was confirmed. Our findings suggest that thalassemic osteodystrophy is the result of several inhibitory influences on osteoblastic activity and bone apposition (related to hormone deficits and siderosis) which are aggravated further by anemia, chronic hypoxia and red marrow expansion.

[Paget's disease: the prospects with ipriflavone]. / Morbo di Paget: prospettive con ipriflavone.

Paget's disease is a bone disorder characterized by high rates of bone remodelling. We have evaluated the efficacy of the new drug, ipriflavone, which has a double effect on the inhibition of bone reabsorption and on the activation of bone neodeposition. We studied 20 patients with active Paget's disease: 10 have been treated with 600 mg/die and 10 with 1200 mg/die of ipriflavone, for six months. In pharmacological wash-out, we have measured alkaline phosphatase, plasmatic BGP, the urinary hydroxyproline/creatinine ratio and the urinary calcium (Nordin Test). These valuations have been repeated after three and six months from the beginning of the administration of the drug. We have verified a propitious and speedy effect on pain, independent of dosage, and efficacy of treatment in function of bone turn-over parameter changes, by using no parametric statistical tests. In all subjects favourable effects have been found after three months treatment with 1200 mg/die. These have shown a greater efficacy than the lower dosage. After six months treatment we have not found significant differences as regards the efficacy of both dosages. These results may suggest to start therapy with higher initial doses and to carry-on with lower supporting doses. It's necessary to investigate further confirmation regarding the consolidation and perseverance of obtained favourable results, even after interruption of the treatment.

[Familial Mediterranean fever: a report of 2 cases of Italian origin]. / Febbre mediterranea familiare: descrizione di due casi di origine italiana.

Familial Mediterranean fever is an inherited disease, occurring almost exclusively in Arabs, Jews and Turks. Cases are very rarely described in the USA, USSR, France, and patients are all natives to the Mediterranean area. This paper describes two cases of familial Mediterranean fever in brothers native to Campania, Italy. Both had complained of repeated episodes of fever, with acute abdomen, thoracalgia and arthralgia since the age of about 20. One of them had had pleuritis when he was 6 years old. In the period preceding our first observation, both underwent laparotomy to evaluate abdominal symptoms, with negative results. After ruling out other diseases with similar signs and symptoms, we raised the hypothesis of familial Mediterranean fever, despite the fact that the literature has described very few Italian natives affected by this disease. The diagnostic hypothesis was confirmed by the positivity of the metaraminol provocation test. At the same time we evaluated the presence of amyloidosis by rectal biopsy, with negative results. Treatment with colchicine 1 mg/day per os was established. Dramatic improvement of the symptoms was observed in both patients. The present paper stresses the importance of familial Mediterranean fever, its correct diagnosis in Italy and the fundamental role played by the metaraminol provocation test as a determinant diagnostic tool. It allows establishment of appropriate treatment as soon as possible, so that renal amyloidosis, the most severe complication and major prognostic determinant of familial Mediterranean fever, can be prevented. Inappropriate, useless and potentially harmful surgical diagnostic procedures are also avoided.

An association of primary hyperparathyroidism and non medullary thyroid carcinoma.

A 40-year-old woman was admitted because of long-lasting asymptomatic hypercalcaemia. About 2 years earlier she underwent thyroidectomy and further 131 I therapy because of well-differentiated non medullary thyroid carcinoma. On admission biochemical data and hormonal values (serum calcium, serum phosphorus, i-PTH) were consistent with primary hyperparathyroidism; ultrasonography, computed tomography, thallium-technetium scintiscanning disclosed right paratracheal mass; on surgical procedure a right parathyroid adenoma was removed. The coexistence of non medullary thyroid carcinoma and primary hyperparathyroidism is rare: the prior 131 I therapy might be linked to subsequent development of parathyroid adenoma.

Association of the Budd-Chiari syndrome with lupus anticoagulant. Case report and critical review.

The Budd-Chiari syndrome (BCS) was diagnosed in a 30-year-old male hospitalized with hepatomegaly, abdominal collateral vessels and hepatic veins and inferior vena cava thrombosis (IVC) in 1988. The presence of circulating lupus anticoagulant (LAC) was suspected and demonstrated on this occasion in view of an earlier diagnosis of systemic lupus erythematosus (SLE) and recurrent vein thrombosis dating from 1981. There are sporadic reports of an association of BCS with SLE and other autoimmune diseases. The recent literature also describes associations with hypercoagulability due to LAC. These are reviewed together with the personal case to provide the rationale for correct diagnosis and therapy.

Dopaminergic regulation of aldosterone secretion: assessment in different subtypes of primary aldosteronism and in essential hypertension.

The inhibitory effect of dopamine on aldosterone secretion was investigated in patients with different types of primary aldosteronism, six with idiopathic hyperaldosteronism (IHA) and four with dexamethasone-suppressible hyperaldosteronism (DSH), and in 10 patients with essential hypertension. The effects of 10 mg metoclopramide given intravenously, 10 mg bromocriptine given orally and 100 micrograms adrenocorticotrophic hormone given intravenously on plasma aldosterone and renin activities were investigated in all patients. Metoclopramide induced a rise in plasma aldosterone activity only in patients with IHA and not in those with DSH and essential hypertension. After bromocriptine plasma aldosterone concentrations decreased in patients with IHA only, and after adrenocorticotrophic hormone plasma aldosterone concentrations increased in patients with DSH only. Plasma renin activity was unaffected in all cases. These results provide evidence of increased endogenous dopaminergic inhibition of aldosterone secretion in IHA and of a blunted aldosterone response in both DSH and essential hypertension.

Efficacy of nicardipine slow release (SR) on hypertension, potassium balance and plasma aldosterone in idiopathic aldosteronism.

We evaluated the efficacy and tolerance of a dihydropyridine calcium antagonist, nicardipine slow release, in eight patients with idiopathic aldosternism. Nicardipine (80 mg/day) was given orally for 12 weeks and no dietary restrictions were imposed. During the study measurements were made of supine blood pressure, plasma renin activity, plasma aldosterone concentration, and serum potassium. Nicardipine lowered systolic and diastolic blood pressure to normal, plasma aldosterone was reduced and serum potassium levels were increased. Basal renin concentration was not altered by nicardipine. There were no side effects sufficient to cause withdrawal from the study. These results suggest that nicardipine, for efficacy and tolerance, may represent an alternative among Ca2+ channel blockers, either controlling blood pressure or reducing aldosterone levels in patients with idiopathic aldosteronism.

Two cases of congenital hepatic fibrosis in children of consanguineous marriage.

An association of congenital hepatic fibrosis (CHF), Caroli's disease, medullary sponge kidney, type II interventricular defect with right transposition of the aorta, multiple cervical vertebra malformations, and first sacral vertebra schisis in a 16 year old son of consanguineous parents (consanguinity factor = 1/32), is described. The patient's sister presented asymptomatic CHF and medullary sponge kidney only. Parental consanguinity in this case lends support to the view that CHF, medullary sponge kidney and cardiac malformations are more likely to be manifestation of a single recessive gene, with a varying phenotypic expression, than of different mutant genes.

Hypothalamic pituitary adrenal function in patients with thalassemia major.

We examined the adrenocortical function in 14 italian thalassemic patients (8 f., 6 m.) aged 12 to 28. The following hormones were determined in each subject: plasma cortisol and aldosterone levels in both basal conditions and after maximal and submaximal stimulus (250 and 5 micrograms respectively) with synthetic corticotrophin beta 1-24 (Synacthen Ciba); corticotrophin and cortisol response to insulin-induced hypoglycaemia (0.15 U/kg iv.). Tests were repeated in all patients four years later. Normal controls were a group of 10 normal subjects matched for age, sex and body mass. Normal basal values of cortisol, aldosterone and ACTH were observed. Impaired cortisol response after stimulation with 5 micrograms of ACTH (6 patients) and after hypoglycaemia (4 patients) was identified. At the second test, four years later, one patient showed impaired cortisol response to both ACTH (5, micrograms) and hypoglycaemia, unlike the normal response to the first test. In all the others the cortisol response to stimulation did not differ from previous ones. In conclusion reduced ACTH and cortisol reserves detected in some thalassemic patients may be related to iron infiltration in the pituitary and adrenal glands. However, the present study did not indicate any significant correlation between either total blood load or serum ferritin and adrenal function parameters. Alteration in circulating hormones catabolism and impaired synthesis of transport proteins caused by chronic liver disease made adrenocortical hypofunction an even more complex picture to understand.

Pituitary - adrenocortical function in patients during treatment with the angiotensin-converting enzyme inhibitor captopril.

To study effects on pituitary-adrenocortical activity of a sustained block of angiotensin II formation, six 'drug-resistant' patients with essential hypertension were studied before and during treatment with an inhibitor of the angiotensin-converting enzyme (Captopril, SQ 14,225). The drug was given in increasing doses (100-400 mg/day) for 2 weeks whilst patients received a moderately restricted sodium intake (60-80 mmol/day). Immunoreactive ACTH, cortisol, aldosterone, plasma renin activity (PRA) and the activity of the angiotensin-converting enzyme (ACE) were measured in blood samples drawn at 0800-0900 h. Urinary excretion of cortisol and aldosterone were measured in 24-h urine collections. Further information on pituitary-adreno-cortical function was obtained by measuring serial plasma corticosteroid levels after submaximal stimulation with a synthetic ACTH preparation. ACTH and cortisol did not change an observation which does not support the hypothesis that glucocorticoid activity is influenced by a decrease in plasma angiotensin II concentrations.

The risk of pronounced hyperkalaemia after arginine infusion in the diabetic subject.

Following previous work showing that i.v. arginine induces a fall in blood phosphorus and an increase in blood potassium in normal subjects, investigation of the mechanism underlying these metabolic changes was extended to a group of 14 insulin-dependent diabetics and a further 6 normal volunteers. In the diabetics, arginine (0.5 g/kg body weight) in 30 min caused a slight, but significant fall in blood phosphorus (delta = -0.40 +/- 0.04 mg/ml p less than 0.01). This was well below the fall noted in the normal subjects, which, as demonstrated in the earlier study, is to a great extent mediated by insulin. The increase in blood potassium was much more marked than in the normal subjects (delta = + 1.42 +/- 0.15 mEq /l; p less than 0.001) and rose to pathological levels (5.6 to 6.5. mEg/l) in 9 out of 14 patients. There were no significant changes in blood pH, plasma osmolality, or plasma aldosterone. Inhibition of the glucagon response to arginine by means of a priming dose of 250 micrograms somatostatin, followed by infusion of 1,500 micrograms/hr, did not abolish the rise in blood potassium. These findings indicate that insulin protect against arginine-induced hyperkalaemia and that this metabolic alteration does not depend on glucagon, acidosis, enhance plasma osmolality, nor the suppression of aldosterone secretion. Persons with low insulin secretion due, for example, to stress or diabetes, run the risk of pathological hyperkalaemia if subjected to i.v. infusion of arginine.

Animal and human arteries' "in vitro" response to serum of migraineurs.

"In vitro" experiments carried out by us and partially published have resulted in significant data concerning the contracting activity of migraineurs sera on extracranial animal arteries. In the present study, human and animal arteries (superficial temporal) were tested by means of blood samples taken under identical conditions. No contracting activity from sera taken both in the headache-free period and during the migraine crisis was observed in animal arteries. By contrast, sera obtained in the pre-attack and post-onset stages showed a synergistic effect not only on the action of serotonin and histamine but also on that of norepinephrine. This synergism increases with the worsening of the migraine attack while it decreases as soon as the attack wears off. Other experiments on human specimens provided data which cannot be evaluated yet. There is evidence that, on the occasion of the migraine attack, vasoactive substances which enable isolated organs to contract "in vitro" are released or activated. Moreover, an activity raises in sera which interferes with the other mediators on extracranial arteries.