Antonio Martocchia

Recent advances in the role of cortisol and metabolic syndrome in age-related degenerative diseases

AbstractThe metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic–pituitary–adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11β-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity).

Sex-related variations in serum nerve growth factor concentration in humans

A role of nerve growth factor (NGF) in the neuro-endocrine-immune interactions has been recently suggested by the presence of NGF and its receptors in cells of the immune and endocrine systems. The improvement in the comprehension of the role played by NGF in humans is linked to the availability of a sensitive and reliable method to quantify NGF concentrations in body fluids and tissues. As a consequence of different methods used, normal levels of human serum NGF reported in the literature show wide differences. The present results indicate that ELISA appears very sensitive (detection limit 1.4pg/ml) and allows the discrimination of subtle variations of serum NGF concentrations. ELISA performed in serum obtained from men indicated that NGF concentration was 40.8+/-10.8pg/ml, whereas women showed significantly lower levels that were influenced by the menstrual cycle. In particular, the mean value of this neurotrophin during the follicular phase was 8.2+/-1.4pg/ml; the luteal phase, in turn, showed levels up to 14.4+/-2.9pg/ml. The difference of serum NGF concentrations between the follicular and luteal phase in each woman was statistically significant. Differences in NGF concentrations between men and women (in both phases of the menstrual cycles) were also statistically significant. In conclusion, a possible role of sex steroids as modulators of NGF secretion in humans is strongly supported by the present paper. However, mechanisms underlying this phenomenon are still unknown. The evidence indicating physiological sex hormone-related variations in NGF levels would be of interest in view of the possible use of circulating NGF modifications as a laboratory biomarker in different diseases.

Subacute thyroiditis during interferon-alpha therapy for chronic hepatitis C

A 34-year-old woman with chronic hepatitis C received interferon-alpha (IFN-alpha) therapy. Her thyroid function was normal and thyroid autoantibodies were negative before treatment. Four months after the beginning of the therapy she presented a clinical course of thyroiditis with a transient thyrotoxicosis. The diagnosis of subacute thyroiditis was confirmed by laboratory, ultrasonography, radioiodine scanning and fine needle aspiration findings. Thyroid autoantibodies were persisting negative. She suspended IFN-alpha therapy and she started non steroidal anti-inflammatory agents and beta-blockers. Latent hypothyroidism subsequently developed, but L-thyroxine therapy resulted in a rapid normalization of thyroid function tests.

Targets of Anti-glucocorticoid Therapy for Stress-related Diseases

The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the hypothalamus-pituitary-adrenal (HPA) axis. Dysregulation in HPA activity (central and peripheral) has been reported in chronic diseases, like metabolic syndrome, type-2 diabetes mellitus, atherosclerosis-related disease, essential hypertension, dementia, depression, particularly during comorbid conditions. Different targets of anti-glucocorticoid treatment have been proposed, acting at supra-hypothalamic, HPA axis, glucocorticoid receptor and post-receptor levels. The recent promising patents on the therapy against glucocorticoid-mediated damage will be presented and discussed.

Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus

Hepatic glycogenosis (HG) in type 1 diabetes is a underrecognized complication. Mauriac firstly described the syndrome characterized by hepatomegaly with altered liver enzymes, growth impairment, delay puberty and Cushingoid features, during childhood. HG in adulthood is characterized by the liver disorder (with circulating aminotransferase increase) in the presence of poor glycemic control (elevation of glycated hemoglobin, HbA1c levels). The advances in the comprehension of the metabolic pathways driving to the hepatic glycogen deposition point out the role of glucose transporters and insulin mediated activations of glucokinase and glycogen synthase, with inhibition of glucose-6-phosphatase. The differential diagnosis of HG consists in the exclusion of causes of liver damage (infectious, metabolic, obstructive and autoimmune disease). The imaging study (ultrasonography and/or radiological examinations) gives information about the liver alterations (hepatomegaly), but the diagnosis needs to be confirmed by the liver biopsy. The main treatment of HG is the amelioration of glycemic control that is usually accompanied by the reversal of the liver disorder. In selected cases, more aggressive treatment options (transplantation) have been successfully reported.

Association of Severity of Osteoarthritis and Carotid Atherosclerosis in Patients with Metabolic Syndrome

Study Background: Increasing evidence in the literature suggests a link between osteoarthritis and atherosclerosis represented by the pro-inflammatory state, independently by concurrent factors such as the joint overload caused by obesity. In this study we examined the role of metabolic syndrome, a cluster of cardiovascular risk factors with a significant pro-inflammatory background, on the severity of both carotid atherosclerosis and osteoarthritis. Methods: We evaluated 68 patients (14 males, 54 females) with (mean±standard error) age and body mass index of 76.99±1.01 years and 27.63±0.62, respectively. The subjects were divided in two groups by the presence of metabolic syndrome (according to Adult Treatment Panel III criteria). Each patient received a score of severity for carotid atherosclerosis (by echo-doppler examination of supra-aortic arteries) and for osteoarthritis (by standard X-ray). The s ites of osteoarthritis was divided in related or not related to weight overload. Results: The body mass index of patients with (n.42) or without metabolic syndrome (n.26) were 28.94±0.84 and 25.87±0.77, respectively (p<0.025). The severity of carotid atherosclerosis were 1.59±0.17 and 0.82±0.18 in the patients with or without metabolic syndrome (p<0.01). The severity of osteoarthritis were 2.59±0.15 and 2.04±0.27 in the patients with or without metabolic syndrome (p=0.06). Metabolic syndrome was significantly related to severity score of carotid atherosclerosis and osteoarthritis (r=0.932 p<0.01 and r=0.936 p<0.01, respectively). Severity score of carotid atherosclerosis and osteoarthritis were significantly related (r=0.895 p<0.05). Conclusion: In this preliminary study, we showed a link between severity of osteoarthritis and atherosclerosis in metabolic syndrome, pointing out the possibility of a common background belonging to the degenerative and inflammatory reactions involving both the cardiovascular and articular system.

Association of diffuse liver glycogenosis and mild focal macrovesicular steatosis in a patient with poorly controlled type 1 diabetes

We report a case of a 17-year-old female with type 1 diabetes, presenting hepatomegaly and elevated aminotransferases. She received frequent hospitalization for hyperglycaemia and poor glycaemic control (HbA1c = 13%, weight = 52 kg, height = 156 cm, BMI = 21.4). In particular, her compliance to the prescribed diet was poor, with frequent meals and subsequently self-prescribed extra-dose of insulin, in order to control her blood glucose concentrations. During the clinical course she presented hepatomegaly and raised aminotransferase levels (up to AST = 1,620 U/l and ALT = 629 U/l). An extensive evaluation for infectious, autoimmune, toxic, obstructive and metabolic liver disorders (including HAV, HBV, HCV, cytomegalovirus, EBV, ANA, SMA, LKM, AMA, ENA, Wilson’s disease, a1-antitrypsin deficiency, haemochromatosis, ornithine transcarbamylase deficiency, celiac disease) resulted completely negative. An ultrasound (US) scan confirmed an enlargement of the liver with an increased echo level, the absence of the echo attenuation in the deep liver regions and the normal diameters of hepatic and portal veins. A liver biopsy was carried out after 6 months of repeated persisting high aminotransferase levels. Normal lobular structure, absence of portal and lobular inflammation, presence of a mild macrovesicular steatosis with a focal distribution and a large aumont of cytoplasmic glycogen storage with nuclear inclusions in the hepatocytes (Fig. 1), were observed. In order to obtain an improvement of the glycaemic control and a reduction of both hepatomegaly and aminotransferases levels adherence to a hypoglycidic diet, proper psychological support and progressive reduction of insulin requirement were started. In fact, reductions of both HbA1c and GOT/GPT levels (10.7% and 54/61 U/l, respectively), were progressively obtained after over a year of follow-up, even though without reaching a normalization yet, due to a persisting poor diet compliance. Hepatomegaly was reduced but still present.

Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment.

The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential cross-reaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.

Screening of frailty in elderly patients with disability by the means of Marigliano–Cacciafesta polypathology scale (MCPS) and Canadian Study of Health and Aging (CSHA) scales

Frailty is an age-related condition, characterized by a decreased homeostatic reserve and increased vulnerability to stressful events, with high risk of adverse outcomes. The aim of this study was to compare the evaluation of the frailty by the means of the MCPS and the Rockwood criteria. We enrolled 98 patients (mean age ± standard deviation, m ± SD, 80.7 ± 7.0 years) and 20 controls (82.7 ± 3.4 ys), who attended our outpatient clinic for the evaluation of disability and the renewal of driving license, respectively. The multidisciplinary geriatric assessment (MGA) was performed including the administration of the following scales for frailty: MCPS scale (range 0-245), CSHA-Rules-Based Definition of Frailty (CSHA-RBDF) (range 0-3) and CSHA-Clinical Frailty Scale (CSHA-CFS) (range 0-7). The patients and controls showed MCPS=52.39 ± 11.36 and 4.6 ± 3.28, CSHA-RBDF=2.27 ± 0.62 and 0.10 ± 0.44, CSHA-CFS=6.22 ± 0.75 and 2.95 ± 0.51, respectively (p<0.000001). Frailty scores were higher in female than in male (p=0.065 for CSHA-RDBF and p<0.05 for CSHA-CFS). The MCPS scores were significantly related to both CSHA-RDBF (r=0.753, p<0.001) and CSHA-CFS scores (r=0.793, p<0.001). The frailty scales were significantly related to disability, cognitive impairment and polypathology. In conclusion, the frail patient may be a carrier of multiple chronic pathologies and/or of physical/cognitive decline. The frail patient has to be considered the elective geriatric patient, characterized by a continuous multidimensional care requirement. MCPS is an useful tool for the frailty screening and to set up a tailored program of geriatric rehabilitation, in order to prevent or reduce the development of frailty-related complications.

Increased serum concentration of nerve growth factor in patients with microprolactinoma

Nerve growth factor (NGF) is known to play a role as a circulating neurokine, integrating signals from the neuro-immuno-endocrine system. The ability of NGF to activate the pituitary-adrenocortical axis, together with the increase of its serum concentration in pregnancy and lactation, supports the hypothesis that NGF is secreted by the pituitary gland and plays a role as modulator of endocrine functions. Evidence obtained both in vitro and in vivo in experimental animal models suggests that lactotroph cells secrete both prolactin (PRL) and NGF. Furthermore, in previous studies we demonstrate that cell lines derived from dopamine (DA)-sensitive human prolactinomas express high levels of NGF messenger RNA and protein. On these basis, we studied serum NGF concentrations in female patients with microprolactinoma (n = 4) and in control women (n = 5). PRL and NGF were measured at the diagnosis, during the thyrotropin releasing hormone (TRH) test and after the therapy with DA D2 receptor agonist cabergoline (0.25 mg, twice a week). Results obtained suggested that hyperprolactinemia (70.3+/-8.4 ng/ml) paralleled markedly higher NGF levels (58.4+/-18.7 pg/ml) compared to controls (PRL 8.7+/-3.2 ng/ml, NGF 8.4+/-1.3 pg/ml). Serum concentrations of NGF and PRL during the TRH test were closely associated (r = 0.943, p < 0.01). Cabergoline therapy normalized PRL (7.9+/-3.6 ng/ml) and induced a significant decrease of NGF levels (12.5+/-4.9 pg/ml). In conclusions, data reported here indicated that, in human microprolactinomas, NGF is released in the bloodstream paralleling PRL-secretion and it is modulated by a neurotransmitter-regulated mechanism, since the normalization of PRL elicited by the DA D2 receptor agonist cabergoline induced a significant decrease of serum NGF as well.