Sclerostin, vascular risk factors, and brain atrophy in excessive drinkers.

Objective: Heavy alcohol consumption causes several organic complications, including vessel wall calcification. Vascular damage may be involved in the development of brain atrophy and cognitive impairment. Recently, sclerostin (whose levels may be altered in alcoholics) has emerged as a major vascular risk factor. The objective of the present study is to analyze the prevalence of vascular calcifications in alcoholics, and the relationships of these lesions with brain atrophy, as well as the role of sclerostin on these alterations. Patients and methods: A total of 299 heavy drinkers and 32 controls were included. Patients underwent cranial computed tomography, and several indices related to brain atrophy were calculated. In addition, patients and controls underwent plain radiography and were evaluated for the presence or absence of vascular calcium deposits, cardiovascular risk factors, liver function, alcohol intake, serum sclerostin, and routine laboratory variables. Results: A total of 145 (48.47%) patients showed vascular calcium deposits, a proportion significantly higher than that observed in controls (χ2 = 16.31; p < 0.001). Vascular calcium deposits were associated with age (t = 6.57; p < 0.001), hypertension (t = 5.49; p < 0.001), daily ethanol ingestion (Z = 2.18; p = 0.029), duration of alcohol consumption (Z = 3.03; p = 0.002), obesity (χ2 = 4.65; p = 0.031), total cholesterol (Z = 2.04; p = 0.041), triglycerides (Z = 2.05; p = 0.04), and sclerostin levels (Z = 2.64; p = 0.008). Calcium deposits were significantly related to Bifrontal index (Z = 2.20; p = 0.028) and Evans index (Z = 2.25; p = 0.025). Serum sclerostin levels were related to subcortical brain atrophy, assessed by cella media index (Z = 2.43; p = 0.015) and Huckmann index (ρ = 0.204; p = 0.024). Logistic regression analyses disclosed that sclerostin was the only variable independently related to brain atrophy assessed by altered cella media index. Sclerostin was also related to the presence of vascular calcifications, although this relationship was displaced by age if this variable was also included. Conclusion: Prevalence of vascular calcification in alcoholics is very high. Vascular calcium deposits are related to brain atrophy. Serum sclerostin is strongly related to brain shrinkage and also shows a significant relationship with vascular calcifications, only displaced by advanced age.

Serum Myostatin among Excessive Drinkers.

Myostatin acts as a negative regulator of muscle growth. Its effect on fat mass is subject to debate. Among alcoholics, there is a high prevalence of muscle atrophy, and increased fat deposition has been also described in these patients. Myostatin could be involved in these alterations, but its relationships with body composition have been scarcely studied in alcoholic patients. To analyze the behavior of myostatin among alcoholics and its relationship with alcohol intake, liver function, and body composition. We investigated serum myostatin in 59 male patients and 18 controls. Patients were all heavy drinkers admitted with organic complications related to excessive ethanol ingestion. Densitometry analysis was used to assess body composition in 46 patients. Handgrip was assessed in 51 patients. Patients showed lower myostatin values than controls (Z = 3.80; p < 0.001). There was a significant relationship between myostatin and fat at the right leg (ρ = 0.32; p = 0.028), left leg (ρ = 0.32; p = 0.028), trunk (ρ = 0.31, p = 0.038), total fat proport ion (ρ = 0.33, p = 0.026), and gynecoid fat distribution (ρ = 0.40, p = 0.006) but not with lean mass (total lean ρ = 0.07; p = 0.63; trunk lean ρ = 0.03; p = 0.85; lower limbs ρ = 0.08; p = 0.58; upper limbs ρ = 0.04 p = 0.82; android ρ = 0.02; p = 0.88, or gynoid lean mass ρ = 0.20; p = 0.19). In total, 80.43% of patients showed at least one criterion of osteosarcopenic adiposity (OSA). Myostatin was related to OSA obesity. We also observed higher myostatin values among patients with body mass index > 30 kg/m2. Serum myostatin was lower among excessive drinkers, and it was related to increased fat deposition among these patients but not to lean mass, handgrip, or bone mineral density.

Sclerostin in Excessive Drinkers: Relationships with Liver Function and Body Composition.

BACKGROUND: Sclerostin was initially described as an inhibitor of the Wnt-ß catenin bone-forming pathway, but it also exerts important effects on intermediate metabolism and body composition. Osteosarcopenia and altered body fat distribution are common findings in excessive drinkers. The role of sclerostin in these patients is uncertain. We aim to analyze the behavior of sclerostin in excessive drinkers and its relationships with body composition (fat mass, lean mass, bone mass), handgrip strength, body mass index (BMI), liver function and ethanol intake. METHODS: 107 male active heavy drinkers and 26 age-matched controls were included. Serum sclerostin was determined by ELISA. Body composition analysis was performed by double X-ray absorptiometry. Handgrip strength was recorded using a dynamometer. Liver function was assessed according to Child's classification. RESULTS: Sclerostin was higher among Child's C patients, keeping a relationship with deranged liver function. Obesity, defined according to BMI, and body fat were strongly related to sclerostin, being independent of serum creatinine and of liver function. The relationship of sclerostin with total hip bone mineral density was displaced by BMI. CONCLUSION: Deranged liver function is associated with higher sclerostin levels in alcoholics. Raised sclerostin levels are related to fat deposition and increased BMI.

Metabolic syndrome and cardiovascular risk in diabetic population of El Hierro, Canary Islands / Síndrome metabólico y riesgo cardiovascular en la población diabética de El Hierro, Islas Canarias

Introduction: In the Canary Islands there is a high prevalence of vascular risk factors. Objective: To analyze the clinical characteristics of 300 patients with type 2 diabetes in El Hierro, in the Canary Islands. Methods: Patients were assessed at the Internal Medicine Unit of the hospital from 1982 to 2010, and followed up until December 2014 or until death. The sample is composed of 154 women and 156 men (52%). Results: mean age was 66.40 ± 11.60 years, with an average follow-up time of 11.04 ± 4.93 years, and 80.3% were diagnosed of metabolic syndrome, signifi cantly more frequent among women (86.43% vs74.67%, χ2 = 5.62, p = 0.018). During the follow-up period, 51 patients died and a signifi cant proportion developed new cardiovascular complications, such as heart failure (6.7%), ischemic heart disease (17.3%), atrial fi brillation (14.3%), stroke 7%), or peripheral arterial disease (6.9%). Cox regression analysis showed that, although advanced age was the major factor involved in the development of all these complications and in mortality, low cholesterol levels were related to the development of ischemic heart disease and mortality, results that were not dependent on the consumption of statins (as in other examples of inverse epidemiology). Ethanol consumption was related to the incidence of peripheral arterial disease. Conclusions: Old age was the main factor involved in the development of complications and mortality. In addition, low cholesterol levels were related to the development of ischemic heart disease and mortality.

Introducción: en Canarias existe una elevada prevalencia de factores de riesgo vascular, superior a la del resto de España.Objetivo: analizar las características clínicas de 300 adultos diabéticos tipo II de El Hierro, en el Archipiélago Canario. Métodos: los pacientes fueron valorados en la Unidad de Medicina Interna del hospital entre 1982 a 2010, y seguidos hasta diciembre de 2014 o hasta su fallecimiento. La muestra se compone de 154 mujeres y 156 hombres (52%). Resultados: la edad media fue de 66.40 ± 11,60 años, con un tiempo medio de seguimiento de 11,04 ± 4,93 años, y el 80,3% fue diagnosticados de síndrome metabólico, significativamente más frecuente entre las mujeres (86,43% vs.74,67%; χ2 = 5,62, p = 0,018). Durante el periodo de seguimiento 51 pacientes murieron, y una proporción significativa desarrolló nuevas complicaciones cardiovasculares, como insuficiencia cardiaca (6,7%), cardiopatía isquémica (17,3%), fibrilación auricular (14,3%), ictus (4,7%), o enfermedad arterial periférica (6,9%). Mediante análisis de regresión de Cox observamos que, aunque la edad avanzada fue el factor principal implicado en el desarrollo de todas estas complicaciones y en la mortalidad, los niveles bajos de colesterol se relacionaron con el desarrollo de cardiopatía isquémica y de mortalidad, resultados que no eran dependientes del consumo de estatinas (como en otros ejemplos de epidemiología inversa). El consumo de etanol se relacionó con la incidencia de la enfermedad arterial periférica. Conclusiones: la edad avanzada fue el factor principal implicado en el desarrollo de complicaciones y mortalidad. Además, los niveles bajos de colesterol se relacionaron con el desarrollo de cardiopatía isquémica y mortalidad.

Síndrome metabólico y riesgo cardiovascular en la población diabética de El Hierro, Islas Canarias / Metabolic syndrome and cardiovascular risk in diabetic population of El Hierro, Canary Islands

Introducción: en Canarias existe una elevada prevalencia de factores de riesgo vascular, superior a la del resto de España. Objetivo: analizar las características clínicas de 300 adultos diabéticos tipo II de El Hierro, en el Archipiélago Canario. Métodos: los pacientes fueron valorados en la Unidad de Medicina Interna del hospital entre 1982 a 2010, y seguidos hasta diciembre de 2014 o hasta su fallecimiento. La muestra se compone de 154 mujeres y 156 hombres (52%). Resultados: la edad media fue de 66.40 ± 11,60 años, con un tiempo medio de seguimiento de 11,04 ± 4,93 años, y el 80,3% fue diagnosticados de síndrome metabólico, significativamente más frecuente entre las mujeres (86,43% vs. 74,67%; χ2 = 5,62, p = 0,018). Durante el periodo de seguimiento 51 pacientes murieron, y una proporción significativa desarrolló nuevas complicaciones cardiovasculares, como insuficiencia cardiaca (6,7%), cardiopatía isquémica (17,3%), fibrilación auricular (14,3%), ictus (4,7%), o enfermedad arterial periférica (6,9%). Mediante análisis de regresión de Cox observamos que, aunque la edad avanzada fue el factor principal implicado en el desarrollo de todas estas complicaciones y en la mortalidad, los niveles bajos de colesterol se relacionaron con el desarrollo de cardiopatía isquémica y de mortalidad, resultados que no eran dependientes del consumo de estatinas (como en otros ejemplos de epidemiología inversa). El consumo de etanol se relacionó con la incidencia de la enfermedad arterial periférica. Conclusiones: la edad avanzada fue el factor principal implicado en el desarrollo de complicaciones y mortalidad. Además, los niveles bajos de colesterol se relacionaron con el desarrollo de cardiopatía isquémica y mortalidad (AU)

Introduction: In the Canary Islands there is a high prevalence of vascular risk factors. Objective: To analyze the clinical characteristics of 300 patients with type 2 diabetes in El Hierro, in the Canary Islands. Methods: Patients were assessed at the Internal Medicine Unit of the hospital from 1982 to 2010, and followed up until December 2014 or until death. The sample is composed of 154 women and 156 men (52%). Results: mean age was 66.40 ± 11.60 years, with an average follow-up time of 11.04 ± 4.93 years, and 80.3% were diagnosed of metabolic syndrome, significantly more frequent among women (86.43% vs 74.67%, χ2 = 5.62, p = 0.018). During the follow-up period, 51 patients died and a significant proportion developed new cardiovascular complications, such as heart failure (6.7%), ischemic heart disease (17.3%), atrial fibrillation (14.3%), stroke 7%), or peripheral arterial disease (6.9%). Cox regression analysis showed that, although advanced age was the major factor involved in the development of all these complications and in mortality, low cholesterol levels were related to the development of ischemic heart disease and mortality, results that were not dependent on the consumption of statins (as in other examples of inverse epidemiology). Ethanol consumption was related to the incidence of peripheral arterial disease. Conclusions: Old age was the main factor involved in the development of complications and mortality. In addition, low cholesterol levels were related to the development of ischemic heart disease and mortality (AU)

Bone changes in alcoholic liver disease.

Alcoholism has been associated with growth impairment, osteomalacia, delayed fracture healing, and aseptic necrosis (primarily necrosis of the femoral head), but the main alterations observed in the bones of alcoholic patients are osteoporosis and an increased risk of fractures. Decreased bone mass is a hallmark of osteoporosis, and it may be due either to decreased bone synthesis and/or to increased bone breakdown. Ethanol may affect both mechanisms. It is generally accepted that ethanol decreases bone synthesis, and most authors have reported decreased osteocalcin levels (a "marker" of bone synthesis), but some controversy exists regarding the effect of alcohol on bone breakdown, and, indeed, disparate results have been reported for telopeptide and other biochemical markers of bone resorption. In addition to the direct effect of ethanol, systemic alterations such as malnutrition, malabsorption, liver disease, increased levels of proinflammatory cytokines, alcoholic myopathy and neuropathy, low testosterone levels, and an increased risk of trauma, play contributory roles. The treatment of alcoholic bone disease should be aimed towards increasing bone formation and decreasing bone degradation. In this sense, vitamin D and calcium supplementation, together with biphosphonates are essential, but alcohol abstinence and nutritional improvement are equally important. In this review we study the pathogenesis of bone changes in alcoholic liver disease and discuss potential therapies.

Relative and combined effects of ethanol and protein deficiency on bone manganese and copper.

Both manganese and copper may affect bone synthesis. Bone content of both metals can be altered in alcoholics, although controversy exists regarding this matter. To analyse the relative and combined effects of ethanol and a low protein diet on bone copper and manganese, and their relationships with bone structure and metabolism, including trabecular bone mass (TBM), osteoid area (OA), osteocalcin (OCN), insulin-like growth factor-1 (IGF-1), parathyroid hormone (PTH), urinary hydroxyproline (uHP) and vitamin D. Adult male Sprague-Dawley rats were divided into four groups. The control rats received a 18% protein-containing diet; a second group, an isocaloric, 2% protein-containing diet; a third one, an isocaloric, 36% ethanol-containing diet and a fourth, an isocaloric diet containing 2% protein and 36% ethanol. After sacrifice, TBM and OA were histomorphometrically assessed; bone and serum manganese and copper were determined by atomic absorption spectrophotometry, and serum OCN, IGF-1, PTH, uHP and vitamin D by radioimmunoassay. Ethanol-fed rats showed decreased TBM and bone manganese. Significant relationships existed between bone manganese and TBM, serum IGF-1 and OCN. Ethanol leads to a decrease in bone manganese, related to decreased bone mass and bone synthesis. No alterations were found in bone copper.

Vitamin D and nutritional status are related to bone fractures in alcoholics.

BACKGROUND: Bone fractures are common in alcoholics. AIMS: To analyse which factors (ethanol consumption; liver function impairment; bone densitometry; hormone changes; nutritional status, and disrupted social links and altered eating habits) are related to bone fractures in 90 alcoholic men admitted to our hospitalization unit because of organic problems. METHODS: Bone homoeostasis-related hormones were measured in patients and age- and sex-matched controls. Whole-body densitometry was performed by a Hologic QDR-2000 (Waltham, MA, USA) densitometer, recording bone mineral density (BMD) and fat and lean mass; nutritional status and liver function were assessed. The presence of prevalent fractures was assessed by anamnesis and chest X-ray film. RESULTS: Forty-nine patients presented at least one fracture. We failed to find differences between patients with and without fractures regarding BMD parameters. Differences regarding fat mass were absent, but lean mass was lower among patients with bone fracture. The presence of fracture was significantly associated with impaired subjective nutritional evaluation (χ² = 5.79, P = 0.016), lower vitamin D levels (Z = 2.98, P = 0.003) and irregular eating habits (χ² = 5.32, P = 0.02). Reduced lean mass and fat mass, and altered eating habits were more prevalent among patients with only rib fractures (n = 36) than in patients with multiple fractures and/or fractures affecting other bones (n = 13). These last were more closely related to decompensated liver disease. Serum vitamin D levels showed a significant relationship with handgrip strength (ρ = 0.26, P = 0.023) and lean mass at different parts of the body, but not with fat mass. By logistic regression analysis, only vitamin D and subjective nutritional evaluation were significantly, independently related with fractures. CONCLUSION: Prevalent fractures are common among heavy alcoholics. Their presence is related more closely to nutritional status, lean mass and vitamin D levels than to BMD. Lean mass is more reduced, nutritional status is more impaired and there is a trend to more altered eating habits among patients with rib fractures, whereas multiple fractures depend more heavily on advanced liver disease.

Prognosis of osteopenia in chronic alcoholics.

Osteoporosis is frequent among alcoholics all by a direct effect of ethanol, malnutrition, and liver failure. Therefore, it may be related to survival. The aim of this study was to assess bone mineral density (BMD), bone mineral content, hormonal status, and to determine prognostic value of these parameters in a total of 124 alcoholics followed up for a median period of 57 months. Several bone homeostasis-related hormones were measured in patients and age- and sex-matched controls. Whole-body densitometry was performed by a Hologic QDR-2000 (Waltham, MA) densitometer; nutritional status and liver function were assessed. Sixty patients underwent a second evaluation 6 months later. Patients showed lower serum insulin-like growth factor-1 (median=58, interquartile range [IQR]=33-135 vs. 135ng/mL, IQR=116-243ng/mL, P<.001), vitamin D (25.5, IQR=18.3-36.8 vs. 79.9pg/mL, IQR=59.2-107.8pg/mL, P<.001), and osteocalcin (2.1, IQR=1.1-4.5 vs. 6.5ng/mL, IQR=4.7-8.7ng/mL, P<.001) than controls, and lower BMD values, and lower Z- and T-scores at right and left legs and arms, thoracic and lumbar spine, pelvis, and right and left ribs. By multiple regression analysis, BMD mainly depends on nutritional parameters and liver function. Kaplan-Meier curves show that subtotal BMD and BMD at both arms and pelvis were significantly related with survival. Patients who had lost total hip BMD after 6 months showed a shorter survival than those who had not, but using Cox's regression, encephalopathy, ascites, and nutritional parameters displaced BMD as prognostic factor. Therefore, osteopenia ensues in chronic alcoholic patients. It mainly depends on poor nutrition and is related to survival, although surpassed in this sense by encephalopathy, ascites, and nutritional parameters.

Osteopenia in alcoholics: effect of alcohol abstinence.

AIMS: The aims of this study were to assess bone mineral density (BMD) and content (BMC), osteocalcin, serum telopeptide, PTH and vitamin D in alcoholics, and to determine if a 6-month period of abstinence leads to changes in these parameters. METHODS: Serum osteocalcin, insulin-like growth factor 1 (IGF-1), telopeptide (40 patients) and 1,25 dihydroxyvitamin D, were measured in 28 controls and 77 alcoholic patients, 48 of whom were evaluated again 6 months later. All patients underwent whole-body assessment of BMD by a Hologic QDR-2000 (Waltham, MA, USA) bone densitometer, at the beginning of the study and 6 months later. RESULTS: Patients showed higher serum telopeptide levels (0.59 +/- 0.40 versus 0.19 +/- 0.10 nmol/100 ml, P < 0.001), lower IGF-1 [median = 49, interquartile range (IQR) = 31-121 ng/ml versus 135, IQR = 116-237 ng/ml, P < 0.001], vitamin D [26.5, IQR = 17.0-37.8 pg/ml versus 82.4 (IQR = 60.9-107.4 pg/ml, P < 0.001] and osteocalcin (2.1, IQR = 1.1-3.6 ng/ml versus 6.65, IQR = 4.9-8.8 ng/ml, P < 0.001) than those in controls. Patients also showed lower BMD values, Z- and T-scores at many levels of the skeleton and reduced total BMC. After 6 months, those who continued drinking showed a loss of bone mass, whereas those who abstained showed either no change or increase, differences being especially marked at pelvis, right arm and total BMD and BMC. Simultaneously, abstainers showed a significant increase in osteocalcin (versus a decrease among those who continued drinking). Serum telopeptide increased in both groups. CONCLUSION: Ethanol consumption leads to osteopenia, and decreased serum osteocalcin, which improve with abstinence, whereas those who continue drinking show a worsening of both parameters.

Prognostic value of serum selenium levels in alcoholics.

In alcoholics, exposure of Kupffer cells to intestinal-borne Gram-negative bacteria increases free radical release, which may, in turn, enhance cytokine secretion, creating a positive feedback loop, which contributes to liver inflammation. Impaired antioxidant mechanisms further aggravates this scenario. Some trace elements, such as selenium, are main cofactors of antioxidant enzymes. Some authors have found low Se levels in alcoholics in relation either with undernutrition, liver dysfunction, or intensity of alcoholism, but in general, Se supplementation has no effect on survival. In this study we measured serum Se in 16 controls and 76 alcoholics, 34 of them cirrhotics, 68 of whom were followed up for a median period of 38 months; 17 died during this period. Se levels were lower in patients than in controls and were related to prothrombin activity and nutritional status, more closely to this last parameter (stepwise logistic regression analysis). Patients who died showed lower Se values than those who survived. Se values over the median were associated with better survival, assessed by Kaplan-Meier curves and log-rank test. However, in multivariate analysis (Cox regression model), prothrombin activity displaced serum Se as a prognostic factor. We conclude that serum Se levels are low in alcoholics; these low values depend more heavily on impaired nutrition but also on liver dysfunction; although low Se levels were associated with a higher mortality, prothrombin activity displaced serum Se when survival was assessed using Cox's regression model.