Pedro Iglesias

Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function

objective  Adipose tissue is a hormonally active system that produces and releases different bioactive substances. Leptin, adiponectin and resistin are some of the recently discovered adipocytokines that participate in the regulation of intermediate metabolism. The aim of this study was to evaluate the circulating levels of leptin, adiponectin and resistin in patients with thyroid dysfunction before and after normalization of thyroid function with appropriate therapy.

Eating behavior disorders in uremia: a question of balance in appetite regulation.

Eating and appetite disorders are frequent complications of the uremic syndrome which contribute to malnutrition in dialysis patients. The data suggest that uremic anorexia may occur with or without abdominal and visceral fat accumulation despite a lower food intake. This form of obesity (i.e., with low food intake and malnutrition) is more common in dialysis patients than obesity with high food intake. This article reviews the current knowledge regarding mechanisms responsible for appetite regulation in normal conditions and in uremic patients. Anorexia in dialysis patients has been historically considered as a sign of uremic toxicity due to ‘‘inadequate’’ dialysis as judged by uncertain means (‘‘middle molecule’’ accumulation, Kt/V, ‘‘peak‐concentration hypothesis,’’ and others). We propose the tryptophan‐serotonin hypothesis, based on a uremia‐induced disorder in patients’ amino acid profile—low concentrations of large neutral and branched‐chain amino acids with high tryptophan levels. A high rate of tryptophan transport across the blood‐brain barrier increases the synthesis of serotonin, a major appetite inhibitor. Inflammation may also play a role in the genesis of anorexia and malnutrition. For example, silent infection with Helicobacter pylori may be a source of cytokines with cachectic action; its eradication improves appetite and nutrition. The evaluation of appetite should take into account cultural and social aspects. Uremic patients showed a universal trend to carbohydrate preference and red meat refusal compared to healthy people. In contrast, white meat was less problematic. Uremic patients also have a remarkable attraction for citrics and strong flavors in general. Eating preferences or refusals have been related to the predominance of some appetite peptide modulators. High levels of cholecystokinin (CCK) (a powerful anorexigen) are associated with early satiety for carbohydrates and neuropeptide Y (NPY) (an orexigen) with repeated food intake. Obesity and elevated body mass index often falsely suggest a good nutritional status. In uremic patients (a hyperinsulinemia state), disorders in the regulation of fat distribution (insulin, leptin, insulin‐like growth factor [IGF]‐1, fatty acids, and disorders in receptors for insulin, lipoprotein lipase, mitochondrial uncoupling protein‐2, and β3‐adrenoreceptors) may cause abdominal fat accumulation without an increase in appetite. Finally, appetite regulation in uremia is highly complex. Disorders in adipose tissue, gastrointestinal and neuropeptides, retained or hyperproduced inflammatory end products, and central nervous system changes may all play a role. Uremic anorexia may be explained by a hypothalamic hyperserotoninergic state derived from a high concentration of tryptophan and low branched‐chain amino acids.

Serum concentrations of tumour necrosis factor‐alpha (TNF‐α) and soluble TNF‐α receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function

backgbound Tumour necrosis factor‐α (TNF‐α) is a cytokine with numerous immunological and metabolic activities. Receptors for TNF‐α have been demonstrated in thyroid follicular cells and TNF‐α and its receptors have been implicated in the cytotoxic mechanisms that characterize the thyroid destruction in autoimmune thyroid disease. In patients with Graves’ disease, serum levels of TNF‐α have been reported to be elevated and administration of TNF‐α to humans has been shown to induce hormonal alterations resembling those seen in the nonthyroidal illness syndrome.

New drugs for the treatment of hypercholesterolaemia.

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome P450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.

Are low concentrations of serum triiodothyronine a good marker for long-term mortality in hemodialysis patients?

INTRODUCTION Low serum free triiodothyronine (FT3) concentrations have been reported in a high percentage of chronic renal failure patients and have been considered as an independent predictor of mortality in dialysis patients. OBJECTIVE Our aim has been to evaluate the prognostic value of FT3 levels for long-term mortality in stable hemodialysis patients surviving at least 12 months. PATIENTS AND MEASUREMENTS We retrospectively analyzed 89 stable hemodialysis patients (50 males; mean age 67.9 +/- 11.8 years). All patients had a baseline clinical and analytical evaluation. We analyzed the relationship between baseline FT3 and mortality by means of survival analysis (Kaplan-Meier) and Cox regression analysis. RESULTS Mean values of thyroid function test were: thyrotropin (TSH) 2.02 +/- 1.5 microU/ml, free thyroxine (FT4) 1.26 +/- 0.23 ng/dl, and FT3 2.7 +/- 0.4 pg/ml. During a median follow-up time of 33.6 +/- 14.9 (12 - 62) months, 41 patients died. FT3 was similar in patients who died or survived (2.6 +/- 0.5 vs. 2.7 +/- 0.4 pg/ml ns). Kaplan-Meier analysis did not show significant differences in mean survival according to tertiles of FT3. In multivariate Cox regression analysis, FT3 was not a predictor of mortality (RR 0,001; 95% CI; 0.000 to 1.73). CONCLUSIONS These data suggest that low FT3 levels are not predictive for mortality in a subgroup of stable HD patients who could survive more than 12 months.

Current management of acromegaly

Acromegaly, a chronic disease of growth hormone (GH) hypersecretion, is most typically caused by a pituitary adenoma. Early diagnosis is critical for prompt intervention to prevent deleterious effects of prolonged exposure to elevated GH and insulin-like growth factor Type I (IGF-I) levels. Current therapy for acromegaly includes several options: surgery, radiotherapy and pharmacotherapy. Transsphenoidal adenomectomy remains a mainstay of therapy for acromegaly. Cure rates are high in microadenomas, but << 50% in macroadenomas. Conventional and stereotactic procedures for radiation therapy are also effective in decreasing GH levels in acromegalic patients, but they need years to normalise GH hypersecretion and carry with them the risk of hypopituitarism. The major classes of drugs currently used to treat acromegaly are dopamine agonists and analogues of somatostatin. Dopamine agonists bind to the D2 receptor and suppress GH hypersecretion in some patients with acromegaly. Their clinical effectiveness is modest, although promising results have been obtained with two novel compounds, quinagolide and cabergoline, that possess long duration of action. Somatostatin analogues have been shown to improve clinical symptoms of acromegaly, decrease hypersecretion of GH and IGF-I and reduce tumour volume in a clinically significant number of patients. Octreotide is administered by sc. route several times a day, but the recently developed sustained release formulations (octreotide LAR and SR lanreotide) are administered only every 7 - 28 days by im. injections. The complications associated with somatostatin analogues are small, relative to the benefits. Lastly, compounds with a novel mechanism of action, the GH receptor antagonists, are presently under investigation.

Growth Hormone Responses to Growth Hormone-Releasing Hormone and Clonidine before and after Erythropoietin Therapy in CAPD Patients

Correction of anemia with recombinant human erythropoietin (rhEPO) in patients with end-stage renal disease has been associated with improvement of several abnormalities in hypothalamo-hypophyseal functions. The aim of the present work was to evaluate the growth hormone (GH) responses to GH-releasing hormone (GHRH) and clonidine stimulation, as well as the baseline concentrations of insulin-like growth factor I(IGF-I), before and after the correction of anemia with rhEPO in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Nine clinically stable patients (1 male, 8 female; mean age 55.4 years; mean duration of CAPD 14.1 months) were studied. Twelve normal volunteers were studied as controls. GHRH and clonidine stimulation tests were performed prior to starting rhEPO and again after partial correction of anemia with rhEPO therapy (60-130 U/kg/week, s.c., for 12 weeks). Blood samples for GH were collected during 2 h after GHRH (100 micrograms i.v. in bolus) or clonidine (0.15 mg/m2, p.o.) administration. In basal plasma samples IGF-I concentrations were also measured. Mean (+/- SEM) blood hemoglobin concentration rose from 5.32 +/- 0.25 to 7.22 +/- 0.25 mmol/l (p < 0.001) after rhEPO treatment. GH responses to GHRH were characterized by marked differences in single patients when compared with the control group. However, the GH peak and the area under the secretory curves (AUC) of GH responses in CAPD patients (9.89 +/- 4.01 micrograms/l and 15.06 +/- 6.02 micrograms.h/l, respectively) did not differ from those obtained in control subjects (14.58 +/- 3.25 microgram/l and 16.94 +/- 4.31 microgram.h/l, respectively). The study after correction of anemia showed an evident potentiation of GH values that reached statistically significant values at 60 and 90 min. GH AUC after rhEPO therapy rose to 25.61 +/- 9.25 micrograms.h/l (p = 0.01). In control subjects, clonidine administration was followed by a GH release that reached a maximum at 90 min (7.67 +/- 2.24 micrograms/l). However, CAPD patients exhibited a blunted response to clonidine both before (2.00 +/- 0.78 microgram/l) and after (2.78 +/- 0.76 microgram/l, NS) correction of the anemia with rhEPO. On the other hand, IGF-I concentrations after rhEPO therapy (32.05 +/- 5.52 nmol/l) were not significantly different from those found prior to starting therapy (38.13 +/- 8.44 nmol/l). In conclusion, these results suggest that correction of the anemia with rhEPO therapy potentiates GH responses to direct pituitary stimulation with GHRH although it is unable to restore the blunted response of GH to clonidine that is found in CAPD patients.

Effects of Erythropoietin on Gonadotropin Responses to Gonadotropin-Releasing Hormone in Uremic Patients

Long-term therapy with recombinant human erythropoietin (rhEPO) in uremic male patients undergoing hemodialysis has been followed by an increase in plasma levels of testosterone and a decrease in baseline levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The aim of the present study was to assess the effect of acutely administered rhEPO on FSH and LH responses to gonadotropin-releasing hormone (GnRH) in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Sixteen clinically stable male patients (age, mean+/-SEM, 45.3+/-3.9 years) with chronic renal insufficiency and 12 healthy volunteers with a normal renal function, matched for age and body mass index, were studied. All patients were on CAPD therapy for at least 3 months, and none of them received rhEPO therapy. Patients were moderately anemic (hemoglobin 11.0+/-0.3 g/dl) and showed testosterone levels significantly lower than those found in control subjects (3.47+/-0.37 vs. 6.91+/-0.49 ng/ml, p < 0.001). Each subject was tested with GnRH (100 microg i.v. as bolus) and with GnRH plus rhEPO (40 U/kg at a constant infusion rate for 30 min, starting 15 min before GnRH injection) on different days. Blood samples for FSH and LH were obtained between -30 and 120 min. In uremic patients the baseline FSH levels were higher than those found in control subjects (18.88+/-5.41 vs. 6.41+/-1.10 mU/ml, p < 0.05). After GnRH administration FSH values reached a maximum of 25.50+/-6.19 mU/ml in patients and of 12.50+/-2.02 mU/ml in controls (p < 0.05). rhEPO infusion produced a significant (p < 0.01) decrease in the area above the baseline value of FSH in uremic patients, with no other change in FSH responses to GnRH both in patients and controls. Baseline LH concentrations were significantly higher in patients than in controls (15.56+/-3.41 vs. 2.58+/-0.36 mU/ml, p < 0.001). LH peak and area under the curve of LH secretion after GnRH were significantly higher in patients than in controls (45.25+/-6.28 vs. 26.83+/-4.62 mU/ml, p < 0.05, and 77.02+/-11.30 vs. 34.40+/-5.22 mU x h/ml, p < 0.005, respectively). When GnRH was injected during the rhEPO infusion, a significant (p < 0.02) reduction in LH concentrations at 60, 90, and 120 min was found in uremic patients. Accordingly, the LH area under the curve was significantly reduced in patients (65.99+/-11.44 mU x h/ml, p < 0.05). rhEPO had no effect on GnRH-induced LH release in control subjects. These results suggest that acute rhEPO administration might reduce the exaggerated LH response to GnRH stimulation found in uremic male patients on CAPD.

Inhaled insulin – a new therapeutic option in the treatment of diabetes mellitus

The beneficial effects of maintaining an optimal glucose control on chronic complications of diabetes have been firmly established in patients with both Type 1 and 2 diabetes mellitus. Effective glucose control usually requires multiple daily injections of subcutaneous insulin. Limitations of these intensive regimens include inconvenience and poor patient adherence and acceptability. As a consequence, several alternative methods for insulin delivery have been developed with the aim of eliminating the pain, inconvenience and disruption of lifestyle associated with the need for insulin injections. Recent evidence suggests that intrapulmonary insulin delivery may be an effective, non-invasive alternative to subcutaneous regular insulin. In fact, clinical trials in the last few years have shown that intrapulmonary insulin was as good as subcutaneous insulin in controlling glucose levels in patients with both Type 1 and 2 diabetes mellitus. It was well-tolerated and, so far, there is no evidence of an increased risk of hypoglycaemia or adverse bronchopulmonary effects. Although the bio-availability of inhaled insulin is lower than that of subcutaneous insulin, the former has a more physiological pharmacokinetic profile than the latter. Inhaled insulin currently represents the most viable alternative insulin delivery method to preprandial subcutaneous injection.

Long-term effects of recombinant human erythropoietin therapy on growth hormone secretion in uremic patients undergoing peritoneal dialysis

Recombinant human erythropoietin (rhEPO) is being successfully used for the treatment of uremic anemia. Short-term studies have proved that correction of anemia with rhEPO therapy is accompanied by several changes in growth hormone (GH) secretion in uremic patients. The present study aimed to assess the influence of long-term rhEPO therapy on baseline and stimulated GH concentrations in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Seven well-nourished and clinically stable CAPD patients were studied. Ten normal subjects were studied as controls. GH responses to direct pituitary stimulation with GH-releasing hormone (GHRH) (100 microg intravenously [i.v.]) and indirect hypothalamic stimulation with insulin-induced hypoglycemia (0.1 U/kg body weight i.v.) and clonidine (0.15 mg/m2 orally), were assessed before and after 3, 6, and 12 months of subcutaneously administered rhEPO therapy. After rhEPO administration, an increase of the hemoglobin concentration was observed in all patients and maintained at about 12 g/dL throughout the study period. rhEPO therapy did not induce any significant change in baseline concentrations of GH and insulin-like growth factor I. Correction of the anemia was accompanied by a clear increase in the area under the curve (AUC) and the area above the baseline (AAB) of GH secretion in response to GHRH stimulation. These changes were statistically significant after 3 and 6 months of therapy, although at 12 months no significant differences in relation to pretreatment values could be observed. rhEPO treatment was associated with a progressive decrement in the GH AUC and AAB in response to hypoglycemic challenge, reaching statistically significant values at months 6 and 12. On the other hand, compared with the control group, GH responses to clonidine were blunted at the start of the study in CAPD patients, and rhEPO therapy was not accompanied by any modification. In conclusion, long-term treatment with rhEPO in CAPD patients is associated with complex and profound effects on somatotrope cell function, characterized by diverse effects on GH responses to stimuli that release GH through different mechanisms. Some of these rhEPO-induced alterations in somatotrope function are dependent on the duration of treatment.