Luciano Colangelo

Vitamin D and its relationship with obesity and muscle

The skin synthesis of vitamin D represents the first step of a metabolic pathway whose features have been extensively studied and clarified in the last decades. In particular, the production of active and inactive forms of the hormone and the actions of the corresponding enzymes have offered new insights into the knowledge of vitamin D metabolism. Additionally, the description of the different organs and tissues expressing the vitamin D receptor and its possible functions, as well as its genetic determinants, have allowed focusing on the interrelationship between vitamin D and many physiological and pathological functions. In this context, many studies reported the association between vitamin D and adipose tissue metabolism, as well as the possible role of the hormone in obesity, weight, and fat mass distribution. Finally, many reports focused on the vitamin D-related effects on skeletal muscle, particularly on the mechanisms by which vitamin D could directly affect muscle mass and strength. This paper is mainly aimed to review vitamin D metabolism and its relationship with obesity and skeletal muscle function.

Parathyroidectomy eliminates arrhythmic risk in primary hyperparathyroidism, as evaluated by exercise test

OBJECTIVE To investigate whether parathyroidectomy (PTx) reverses risk factors for arrhythmias related to the QT dynamic changes evaluated during bicycle ergometry exercise test (ET). METHODS Twenty-four postmenopausal women with primary hyperparathyroidism (PHPT) (mean age 60.08.4 years) and 30 sex- and age-matched controls underwent ET, echocardiography, and biochemical evaluation. The following stages were considered during ET: rest, peak exercise, and recovery. The patients were randomized to two groups: 12 underwent PTx (group A) and 12 were followed-up conservatively (group B). After 6 months, the patients were studied again. RESULTS Groups A and B showed no differences in mean baseline biochemical values, echocardiographic parameters, and QTC interval. PHPT patients showed an increased occurrence of ventricular premature beats (VPBS) during ET compared with controls (37.0 vs 6.6%, P=0.03). Serum calcium level was a predictor of VPBS (P=0.05). Mean value of QTC was in the normal range at baseline (Group A: 401±16.9; group B: 402.25±13.5 ms) but significantly lower than controls (417.8±25.1 ms, P<0.01). A negative correlation was found between QTc and calcium values (P=0.03). Physiological reduction of QTc interval from rest to peak exercise was not observed in PHPT patients before surgery. After PTx, group A had a significant reduction in VPBs compared with baseline (at baseline, 5 of 12 vs none of 12 patients after PTx, P=0.03) and a restored normal QT adaptation during ET. Group B showed no significant changes after a 6-month period. CONCLUSIONS PTx reduces the occurrence of VPBs and restored the QTc adaptation during ET.

Intermittent High Doses of Vitamin D: A Need for Further Studies?

It was with interest that we read the paper by Sanders et al. [1] enlightening the harmful effects of the administration of huge doses of vitamin D. However, we believe that some points need clarification. There are two studies demonstrating a negative effect of so-called intermittent bolus doses of vitamin D on the incidence of fractures [2, 3]. However, we must recognize that these trials, even though randomized, double-blind, and placebo-controlled, lack important information concerning, for example, the distribution of risk factors for falls in the two arms (cognitive impairment, drug use, units of alcohol consumed, and so on). Such information is essential because, as admitted by the authors, the link between high vitamin D serum levels and fractures remains obscure and mainly speculative. We believe that, at least from a theoretical point of view, the concept that the administration of vitamin D follows simple pharmacokinetic rules should be reinforced; these are based on straightforward parameters such as the actual level in the patient, the desired level (however defined), and the time needed to fill the body stores [4]. This approach is unpractical on a population basis, therefore explaining in part the utilization of intermittent large doses to overcome the problem of compliance. We agree that if the issue is not the absolute peak value reached but the fluctuations of serum 25(OH)D levels [1, 5], then there is at least one possibility of overcoming this problem. Indeed, we previously demonstrated [6] that following intramuscular injection of vitamin D, there is a slow increase of total 25(OH)D, contrary to what is observed after oral administration. We have now extended and confirmed these initial results over a longer period of time (C. Cipriani et al., in preparation). The intramuscular route was also used by Smith et al. [3], but paradoxically they were not able to show any significant increase in 25(OH)D in the subgroup of patients in which this metabolite was measured. Finally, we agree that there is an urgent need of randomized controlled trials with physical outcomes as primary end points, using a number of different regimens to definitively solve this hot issue. In this context, the control of all parameters that are considered risk factors for falls and fractures is critical. The results could have a profound impact on public health systems, considering the low cost of such supplementation.

Effect of a single oral dose of 600,000 IU of cholecalciferol on muscle strength: A study in young women

Background: The effect of a single large oral dose of vitamin D on muscle function in young people with vitamin D deficiency has not been investigated so far. Aim: We evaluated the effect of a single oral dose of 600, 000 IU of cholecalciferol on muscle strength. Subjects and methods: Eighteen young women with vitamin D deficiency received a single oral dose of 600, 000 IU of cholecalciferol. We evaluated changes in maximal voluntary contraction (MVC) and speed of contraction (S) in response to cholecalciferol by using an hand held dynamometer at 3, 15, 30, 60 and 90 days, compared to baseline. Results: We observed no significant change in MVC and S values, a significant increase of 25-hydroxyvitamin D [25(OH)D] and 1, 25-dihydroxyvitamin D [1, 25(OH)2D] and a significant decrease in serum parathyroid hormone (PTH) (p<0.001 for all). A significant correlation was found between MVC and S and serum phosphorus (P) after supplementation (p<0.02 and p<0.05, respectively). Conversely, we observed no association between the parameters of muscle strength and 25(OH)D, ionized calcium (Ca2+), PTH and 1, 25(OH)2D. Conclusions: A single dose of 600, 000 IU of cholecalciferol does not directly enhance handgrip strength in young women with vitamin D deficiency. More studies are needed on the indirect effect of the hormone on muscle.

Adipokines and bone metabolism: an interplay to untangle

is probably mediated by the leptin receptor found on osteoblasts and chondrocytes. The indirect effect is mediated by different pathways. Leptin also impacts and regulates osteocalcin, an osteoblast-derived hormone considered a marker of bone formation, which in turn regulates both bone metabolism and insulin sensitivity [4]. Serum leptin levels have been shown to have a strong positive correlation with bone mineral density (BMD) in women, and high levels of leptin were reported to be predictive of low risk of fractures in some but not all studies [4]. Leptin increases osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) alpha superfamily secreted by osteoblasts which acts as a soluble decoy receptor for the activator of nuclear factor kappa B (RANK), a transmembrane protein expressed by osteoclasts. By preventing the soluble receptor activator of nuclear factor kappa B ligand (RANKL) from binding to RANK, OPG protects bone from excessive resorption. Adiponectin levels have been shown to be inversely related to visceral fat and body mass index [5]; serum values vary largely depending also on age, sex, menopausal status and comorbidities [6]. Secretion of adiponectin may be inhibited by cytokines, such as TNF alpha, interleukin 6 and hormones (cortisol and testosterone), which are also involved in bone metabolism. Adiponectin receptors have been demonstrated on osteoblasts, but also on muscle and liver, which are organs that interplay with adipose tissue and bone metabolism [7]. Osteoblasts and marrow adipocytes originate from a common mesenchymal progenitor, and adiponectin has been postulated as a potential factor that may induce osteoblast proliferation and differentiation. Interestingly, osteocalcin may upregulate the expression of the adiponectin gene in adipocytes, thus improving insulin sensitivity. Adiponectin has been studied also in different clinical conditions such as non-alcoholic Recent evidence of increased fracture risk in obese patients has focused the attention on the relationship between adipose and skeletal tissue [1]. Adipocytes secrete a number of bioactive molecules, such as adipokines, which recently have been shown to have a role in bone metabolism. Adipokines are pleiotropic molecules, investigated in many physiological or pathological processes, including inflammation, endothelial damage, atherosclerosis, impaired insulin signaling and hypertension. Adipokine dysregulation has been shown to be a strong determinant of the low-grade inflammatory state of obesity, which promotes a cascade of metabolic alterations leading to cardiovascular complications, insulin resistance or diabetes mellitus [2, 3]. So far, only a few adipokines (adiponectin, leptin, resistin, visfatin and the newly discovered omentin-1) have been studied in the context of bone metabolism. Leptin was the first adipokine discovered. Circulating levels seem to reflect the amount of energy stored in the adipose tissue; however, a wide variability in leptin levels has been reported in individuals with the same body mass index [4]. A number of factors regulate circulating leptin levels in healthy individuals. In addition, leptin also influences several hypothalamic pituitary peripheral neuroendocrine axes, including the thyroid, gonadal, cortisol and growth hormone axes. Leptin exerts its effect on bone metabolism by means of both direct and indirect mechanisms. The direct mechanism

High prevalence of abdominal aortic calcification in patients with primary hyperparathyroidism as evaluated by Kauppila score

OBJECTIVE The prevalence of abdominal aortic calcification (AAC) in primary hyperparathyroidism (PHPT) is unknown. We assessed both prevalence and severity of AAC in PHPT postmenopausal women. METHODS In this study 70 PHPT postmenopausal women and 70 age- and sex-matched controls were enrolled. Each participant underwent biochemical evaluation, lateral spine radiograph, bone mineral density (BMD) measurement (lumbar, femoral, radial sites), and kidney ultrasound. Lateral lumbar films were analyzed in the region of L1-L4 vertebrae and the Kauppila score (a semi-quantitative grading system) was used to assess the severity of AAC. RESULTS There were no differences regarding demographic and cardiovascular risk factors in the two groups. PHPT patients had higher prevalence of kidney stones (30% vs 7%, P=0.0008) and lower radial BMD values (0.558±0.071 vs 0.588±0.082 g/cm(2), P<0.05) compared with controls. PHPT patients showed higher prevalence of AAC (31 vs 18, P=0.03), with more severe calcifications (Kauppila score 7.35±6.1 vs 5.05±3.5, P=0.007). PHPT patients with AAC were older and had been suffering from the disease for a longer period compared with those without ACC. Moreover, PHPT patients with severe AAC had mean higher serum parathyroid hormone levels compared with patients with moderate or mild calcifications. In PHPT patients with AAC, multiple regression analysis, adjusted for age and years since diagnosis, showed that only parathyroid hormone significantly correlated with Kauppila score. CONCLUSION We found a higher prevalence and severity of AAC in PHPT related to parathyroid hormone effect.

Primary aldosteronism in a patient who exhibited heart failure.

Primary aldosteronism (PA) is a common cause of secondary hypertension due to unilateral adrenocortical adenoma (APA) or idiopathic hyperplasia. There is increased awareness of the possible cardiac sequelae of aldosterone excess, including cardiac hypertrophy, fibrosis, and vascular endothelium injury. A 54-year-old woman was referred for rest and nighttime worsening dyspnea and palpitations. One year earlier she was admitted to another hospital with the same symptoms and discharged with a diagnosis of idiopathic dilated cardiomiopathy. At admission, physical examination revealed a body mass index of 21 kg ⁄m and blood pressure (BP) of 210 ⁄105 mm Hg. Chest auscultation revealed mild expiratory wheezes and rales in both lower lobes. Electrocardiography showed signs of left ventricular (LV) overloading and hypertrophy. Laboratory analysis showed severe hypokalemia (1.8 mEq ⁄L; normal range 3.5–5 mEq ⁄L) and metabolic alkalosis (pH 7.51; partial pressure of carbon dioxide 41 mm Hg; partial pressure of oxygen 86 mm Hg; HCO 3 32.6 mmol ⁄L; excess bases 10 mmol ⁄L) (Table I). Chest radiography revealed an enlarged cardiac silhouette, congested pulmonary hilum, and bilateral pleural effusion (Figure 1A). Echocardiography showed an increase in LV end-diastolic diameter (58 mm) and left atrial volume (46 mm) and a signficant decrease in global LV performance (ejection fraction [EF] 30%) (Table II). The 24hour ambulatory BP monitoring (ABPM) revealed severe systo-diastolic hypertension without physiological nocturnal fall (nondipper pattern). Subsequent investigation showed suppressed plasma renin activity (PRA) (0.08 ng ⁄mL ⁄h; normal range 0.2–2.7 ng ⁄mL ⁄h), high plasma aldosterone (PAC 16.17 ng ⁄dL; normal range 7.5–15 ng ⁄dL), and PAC ⁄ PRA ratio (202.17 ng ⁄dL: ng ⁄ml ⁄h; normal value<30 ng ⁄dL: ng ⁄mL ⁄h). Because of suspicion of PA, we performed a captopril test. After 60 minutes of captopril 50 mg, the PAC ⁄PRA ratio was still elevated (529.93 ng ⁄dL: ng ⁄mL ⁄h). Magnetic resonance imaging of the superior abdomen demonstrated a 20-mm nodule in the left adrenal gland (Figure 2). The patient underwent laparoscopy adrenalectomy, and histopathology revealed an APA. Subsequently, her BP was normalized at 140 ⁄90 mm Hg with amlodipine, ramipril, and serum potassium. After 6 months of follow-up, BP was 110 ⁄80 mm Hg, with normal serum potassium. Chest radiography showed resolution of congestive heart pulmonary imaging with a decreased cardiac silhouette (Figure 1B). Repeat echocardiography demonstrated a significant improvement in LV hypertrophy and EF (50%). Recently, the Primary Aldosteronism Prevalence in Italy Study (PAPY) reported a PA prevalence of 11.2% in patients with new-onset hypertension. The potential comorbidity and prevention of excessive cardiovascular events and organ damage led to development of accurate strategies for diagnosis of PA. PA patients display an unfavorable cardiovascular profile, suggesting a role of aldosterone beyond its well-known hypertensive effects. TABLE I. Laboratory Data and Blood Gas Analysis

Mineral metabolism abnormalities in patients with prostate cancer: a systematic case controlled study

PurposeProstate cancer is the most common tumor in men. To the best of our knowledge a systematic assessment of bone and mineral abnormalities has not been performed in prostatic cancer patients consecutively enrolled.MethodsThis study was therefore carried out to investigate changes of skeletal and mineral metabolism in patients with prostate cancer (n  = 69). A population of patients with cancer of various origin was also investigated as a control group (n  = 53), since a comparison with non-prostate cancer patients has not been previously reported.ResultsIn the prostatic cancer group, one patient had extremely high values of C-terminal Fibroblast Growth Factor 23, low values of tubular reabsorption of phosphate and very high values of bone alkaline phosphatase, suggesting the diagnosis of oncogenic osteomalacia. We found nine patients with primary hyperparathyroidism in the group of prostate cancer vs. only one in cancer patients group (p  <  0.026). We stratified the population on the basis of Gleason score, prostate specific antigen and hormonal therapy. Using a generalized linear model with a logit link to predict the probability of developing primary hyperparathyroidism, only Gleason score, C-terminal fibroblast growth factor 23 and hormonal therapy had a significant effect (p  < 0.05). Controlling for other covariates, a rise in fibroblast growth factor 23 increases the odds of developing primary hyperparathyroidism by 2% (p  = 0.017), while patients with higher values of Gleason score have a much greater probability of developing primary hyperparathyroidism (log-odds  =  3.6, p  <  0.01). The probability decreases with higher values of Gleason score while on hormonal therapy; a further decrease was observed in patients on hormonal treatment and lower values of GS. Finally, lower grade of Gleason score without hormonal therapy have a significant protective factor (p  <  0.01) decreasing the odds of developing primary hyperparathyroidism by 8%.ConclusionWe showed a remarkable prevalence of primary hyperparathyroidism in men with prostate cancer; the multivariate analysis demonstrates that higher aggressiveness of prostate cancer, as determined by Gleason score, is a significant predictor of increased risk of developing primary hyperparathyroidism.

Vitamin D and Secondary Hyperparathyroid States

The interplay between vitamin D and parathyroid hormone (PTH) represents one of the most important metabolic mechanisms of regulation of the calcium/phosphorus homeostasis. Secondary hyperparathyroidism is therefore a major complication that arises as a result of reduced vitamin D levels, both as primary 25-hydroxy-vitamin D (25[OH]D) and/or 1,25-dihydroxyvitamin D (1,25[OH]2D) reduction. Different metabolic pathways are involved, as well as target organs and tissues, with several clinical complications. The skeleton is primarily involved, but many other extra-skeletal organs expressing the vitamin D and/or PTH receptors may theoretically be affected by vitamin D inadequacy and secondary hyperparathyroidism. Mechanisms associated with low vitamin D (mostly, but not exclusively 1,25[OH]2D deficiency) and high serum PTH also intensify chronic kidney disease (CKD), with further consequences on the mineral metabolism system and development of skeletal and cardiovascular disease. Therapeutic intervention is primarily aimed at enhancing serum 25(OH)D levels and reducing secondary hyperparathyroidism, by employing different strategies and endpoints according to the clinical contest. This chapter reviews the current knowledge on the metabolic pathways involved in the vitamin D/PTH axis regulation in different clinical settings and gives an update on the recommended treatment strategies.

Concomitant resolution through fecal microbiota transplantation of Clostridium difficile and OXA-48-producing Klebsiella pneumoniae

We read with great interest the review ‘fecal microbiota transplantation (FMT) for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens’ published in this journal by Manges et al. [1]. In this context, we would like to give our contribution and submit our experience concerning the resolution of a double infection (Clostridium difficile and OXA-48-producing Klebsiella pneumoniae colonization) via fecal microbiota transplantation. In July 2017, a 78-year-old female affected by chronic obstructive pulmonary disease, diabetes, hypertension and osteoporosis was admitted to our department for recurrence of C. difficile infection, previously treated with metronidazole and vancomycin. Rectal swab culture showed OXA-48-producing K. pneumoniae. Despite the use of fidaxomicin, diarrhea persisted (an average of seven bowel movements per day, type 7 sec. Bristol stool scale). In the meantime, the patient experienced septic shock due to Staphylococcus epidermidis, with a rapid response obtained through ‘golden hours strategies’ [2]. Fourteen days of intensive care and appropriate antibiotics improved her clinical performance and blood cultures were negative, but positivity of C. difficile infection and rectal swab for OXA-48-producing K. pneumoniae persisted. An attempt to eradicate C. difficile by use of FMT was performed. The sample (50 g of feces) was collected by a healthy volunteer donor (<30 years of age) screened for infectious, gastrointestinal, neurological and metabolic diseases. The fecal material was mixed and diluted with 250ml of sterile saline solution. The patient carried out an abbreviated regimen of vancomycin (500mg orally four times per day) for three days and bowel lavage using polyethylene glycol on the day prior to FMT. FMT was performed using a nasoduodenal tube. Prior to the infusion, loperamide (4mg) was administered. The time of procedure was 30minutes. The resolution of diarrhea due to C. difficile infection occurred within 36 hours with an average of two bowel movement per day, type 3–4 sec. Bristol stool scale in the days after treatment. After five days, C. difficile toxin test and rectal swab for K. pneumoniae were repeated and resulted negative. Furthermore, 60 days after FMT, bowel movement alterations were not reported and a new rectal swab for K. pneumoniae was performed, which again resulted negative. It is widely recognized that nosocomial infections are associated to a high burden, in terms of costs, broad antibiotic use and high-mortality rate, due to the emergence of multidrug resistant germs and infection spread [3]. FMT efficacy to treat C. difficile infection via nasoduodenal tube is widely proved [4] and this report underlines that FMT might also be useful in order to treat and prevent colonization by carbapenemase-producing Enterobacteriae, which is recognized as a critical condition from both a medical and a social point of view.