Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus.

INTRODUCTION: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. METHODS: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. RESULTS: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. CONCLUSION: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Homocysteine, Liver Function Derangement and Brain Atrophy in Alcoholics.

AIMS: Hyperhomocysteinemia may be involved in the development of brain atrophy in alcoholics. Its pathogenesis is multifactorial. In the present study, we analyse the relationship between homocysteine levels and brain atrophy, and the relative weight of co-existing factors such as liver function impairment, the amount of ethanol consumed, serum vitamin B12, B6, and folic acid levels on homocysteine levels and brain alterations in alcoholic patients. METHODS: We included 59 patients admitted to this hospital for major withdrawal symptoms and 24 controls. The mini-mental state examination test and a brain computed tomography (CT) scan were performed and several indices were calculated. Serum levels of homocysteine, folic acid, vitamin B6 and vitamin B12 were determined. Liver function was assessed by Child-Pugh score. The daily consumption of ethanol in grams per day and years of addiction were recorded. RESULTS: A total of 83.6% and 80% of the patients showed cerebellar or frontal atrophy, respectively. Patients showed altered values of brain indices, higher levels of homocysteine and vitamin B12, but lower levels of folic acid, compared with controls. Homocysteine, B12 and liver function variables showed significant correlations with brain CT indices. Multivariate analyses disclosed that Pugh's score, albumin and bilirubin were independently related to cerebellar atrophy, frontal atrophy, cella index or ventricular index. Serum vitamin B12 was the only factor independently related to Evans index. It was also related to cella index, but after bilirubin. Homocysteine levels were independently related to ventricular index, but after bilirubin. CONCLUSION: Vitamin B12 and homocysteine levels are higher among alcoholics. Liver function derangement, vitamin B12 and homocysteine are all independently related to brain atrophy, although not to cognitive alterations. SHORT SUMMARY: Hyperhomocysteinemia has been described in alcoholics and may be related to brain atrophy, a reversible condition with an obscure pathogenesis. We studied 59 patients and found that liver function derangement, vitamin B12 and homocysteine levels are all independently related to brain atrophy assessed by computed tomography, although we found no association between these parameters and cognitive alterations.

[Prognostic value of serum homocysteine levels in elderly hospitalized patients]. / VALOR PRONÓSTICO DE LA HOMOCISTEÍNA SÉRICA EN ENFERMOS ANCIANOS HOSPITALIZADOS EN UN SERVICIO DE MEDICINA INTERNA.

BACKGROUND AND OBJECTIVES: Increased serum homocysteine levels are related to vascular disease and increased mortality. The decrease of homocysteine is also associated with a worse prognosis in patients on hemodialysis; however, this relationship has not been well studied in other patients. Our goal is to study the prognosis of increased and decreased serum homocysteine levels in elderly patients admitted to a general internal medicine unit. PATIENTS AND METHODS: We included 239 patients (121 women and 118 men; mean age, 78 years) in which we determined serum homocysteine levels and study its relationship with vascular risk factors, vascular disease: ischemic heart disease, ischemic stroke and peripheral arterial disease, nutritional status, creatinine, albumin, folate and B12 vitamin. RESULTS: Mortality during hospitalization of patients with homocysteine levels below 9 µmol/l was 33%, 9% for those with levels between 9 and 20 µmol/l and 17% for those with levels above 20 µmol/l. Low homocysteine values were related to increased comorbidity, higher degree of weight loss and decreased serum albumin levels. In a survival analysis using Kaplan-Meier curves, increased homocysteine was associated with increased mortality especially in patients with vascular disease. CONCLUSION: In elderly patients with multiple comorbidities, both decreased and increased serum homocysteine levels are associated with increased mortality.

Antecedentes y objetivos: el aumento de la homocisteína se relaciona con la enfermedad vascular y un incremento de la mortalidad. La disminución de la homocisteína se asocia también con un peor pronóstico en enfermos en hemodiálisis; sin embargo, esta relación no ha sido bien estudiada en otro tipo de pacientes. El objetivo del estudio fue analizar el valor pronóstico de los niveles de homocisteína en enfermos ancianos pluripatológicos ingresados en un servicio general de medicina interna Pacientes y métodos: estudiamos a 239 pacientes (121 mujeres y 118 varones; edad media: 78 años) en los que determinamos la homocisteína sérica y la relacionamos con los factores de riesgo vascular, enfermedad vascular: cardiopatía isquémica, ACV isquémico y arteriopatía periférica, estado de nutrición, creatinina, albúmina, ácido fólico y vitamina B12. Resultados: la mortalidad durante el ingreso de los enfermos con homocisteína menor de 9 mol/l fue del 33%, del 9% cuando estaba entre 9 y 20 mol/l y del 17% si era superior a 20 mol/l. La disminución de la homocisteína se relacionó con mayor comorbilidad, pérdida de peso y disminución de la albúmina. A largo plazo, el aumento de la homocisteína se relacionó con mayor mortalidad, especialmente en los pacientes con enfermedad vascular. Conclusión: en los pacientes ancianos pluripatológicos tanto la disminución como el aumento de la homocisteína se asocian con una mayor mortalidad.

Iron and proinflammatory cytokines in chronic hepatitis C virus infection.

Steatohepatitis is a common finding in chronic hepatitis C virus (HCV) infection. As in other forms of steatohepatitis, oxidative damage may play an outstanding role. However, there are conflicting results relative to the role of iron on hepatic lipogenesis. Proinflammatory cytokines up-regulate ferritin expression, probably reflecting a defensive mechanism against increased oxidative stress, capable to open haem ring and release reactive iron. On the contrary, some adipokines, such as adiponectin, are associated with low ferritin levels. The aim of this study is to analyse the relationships of the amount of liver steatosis with serum iron, transferrin and ferritin as well as with proinflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, and adiponectin levels. We included 82 HCV infected patients and assessed the amount of liver fat by histomorphometry and its relationships with serum iron, ferritin and transferrin, adiponectin and TNF-α and IL-6. Liver steatosis was observed in 67 patients out of 82; in the remaining 15 patients, no steatosis at all was found. Patients with steatosis showed significantly higher serum ferritin levels than patients without steatosis (Z = 2.14; p = 0.032). When patients were classified in quartiles according to the intensity of steatosis, we observed that both TNF-α (KW = 10.6; p = 0.014) and IL-6 (KW = 15.2; p = 0.002) were significantly different among the four groups. Patients with more intense steatosis (highest quartile) showed the highest TNF-α and IL-6 values. Patients with severe hepatitis had higher levels of serum iron than patients with mild to moderate hepatitis. Serum iron also showed a correlation with the proportion of fibrosis (ρ = 0.30; p = 0.007). Serum iron levels are related with biochemical and histological parameters derived from liver inflammation in HCV-associated liver disease. Serum ferritin is higher among those with intense steatosis and also shows a (non-significant) trend to be associated with the more severe forms of hepatitis.

Bone alterations in hepatitis C virus infected patients.

BACKGROUND AND AIMS: Most studies have shown that patients with chronic hepatitis C virus (HCV) infection are affected by osteoporosis. However, liver function impairment and deranged nutrition may both play a role in the bone alterations observed. In some works no osteoporosis was found, and some cases of osteosclerosis have been reported. The aim of the study is to assess bone alterations in treatment-naïve, well-nourished HCV patients, in order to discern whether or not HCV infection causes osteoporosis. METHODS: Whole-body bone densitometry and assessment of T-score at lumbar spine and hip were performed to 40 patients and 40 age- and sex-matched controls, with a Lunar Prodigy Advance (General Electric, Piscataway, NJ, USA). All the patients underwent liver biopsy. Nutritional evaluation was performed by subjective nutritional assessment, body mass index (BMI), and densitometric assessment of total lean mass and total fat mass. Serum osteocalcin, osteoprotegerin, RANKL, PTH, crosslaps, vitamin D3, testosterone, IGF-1, and estradiol were determined. RESULTS: Patients did not show differences in total bone mineral density (BMD) or T-score with controls. On the contrary, about a third of them showed positive T scores. Patients showed lower IGF-1, vitamin D3 and testosterone, but higher telopeptide levels, and a trend to higher osteoprotegerin levels. Multivariate analyses disclosed that age, sex, and total lean mass were the only parameters independently related with BMD. CONCLUSIONS: Therefore, chronic HCV infection in well nourished patients with preserved liver function does not cause osteoporosis.

Interleukin-15 and other myokines in chronic alcoholics.

AIMS: Interleukin (IL)-15 is highly expressed in skeletal muscle, where it exerts anabolic effects, increasing protein content in muscle fibres and promoting muscle growth. Alcoholics frequently suffer myopathy. Therefore, we analyse the behaviour of IL-15 (and other myokines, such as IL-6, IL-8 and tumour necrosis factor α (TNF-α)) in alcoholics. METHODS: These myokines and also malondialdehyde (MDA)--a lipid peroxidation product--were determined by radioimmunoanalytic techniques in blood samples of 35 chronic alcoholics and 13 age- and sex-matched controls, and compared with body composition, nutritional status, liver function, amount of ethanol and routine biochemical variables. RESULTS: IL-15, IL-6, TNF-α, IL-8 and MDA were all higher in alcoholics than in controls; MDA and IL-6 were clearly related with liver function impairment and short-term prognosis, whereas IL-15 was higher among those who died and was related to serum bilirubin. No relation was found between IL-15 and lean mass. CONCLUSION: IL-15 levels were higher in alcoholics than in controls, especially among those who died within 18 months after admission. They are not related with muscle mass, intensity of alcoholism or nutritional status, but only with serum bilirubin. IL-6 showed inverse correlations with liver function, intensity of alcoholism, nutritional status, left arm muscle mass and short-term mortality.

Relative and combined effects of selenium, protein deficiency and ethanol on bone.

UNLABELLED: Some observations suggest that oxidative damage may affect both osteoblastic function and osteoclastic activity in alcohol-mediated bone alterations. Selenium, a potent antioxidant, is decreased in alcoholics. OBJECTIVE: To analyse if the supplementation with selenium may alter bone changes observed in a murine model fed ethanol and/or a 2% protein-containing diet, following the Lieber-deCarli design. MATERIAL AND METHOD: Adult male Sprague-Dawley rats were divided into 8 groups, which received the Lieber-DeCarli control diet, an isocaloric, 36% ethanol-containing diet, an isocaloric, 2% protein-containing diet; and an isocaloric diet containing 2% protein and 36% ethanol diet, and another similar four groups to which selenomethionine (1mg/kg body weight). After sacrifice (5 weeks later), trabecular bone mass was histomorphometrically assessed, bone and serum selenium were determined by flame atomic absorption spectrophotometry, and serum osteocalcin, insulin growth factor 1 (IGF-1), PTH and telopeptide, by radioimmunoanalysis. Liver glutathione peroxidase (GPX) activity was also determined. RESULTS: Ethanol-fed rats showed decreased TBM, IGF-1 and osteocalcin, especially when ethanol was added to a 2%-protein diet. Selenium did not modify at all bone parameters, despite a marked increase in serum selenium and a less pronounced one in bone selenium, and an increase in liver GPX. CONCLUSION: Our results do not support the existence of a beneficial effect of selenium addition on bone changes observed in this murine model treated following the Lieber-deCarli experimental design.

Relative and combined effects of chronic alcohol consumption and HCV infection on serum zinc, copper, and selenium.

In alcoholic hepatitis, Kupffer cells are activated by intestinal gram-bacteria, leading to cytokine production and free radicals release, which, enhancing cytokine secretion, create a positive feedback loop which contributes to liver inflammation. Free radicals also damage the liver in chronic hepatitis C virus (HCV) infection, a condition frequently associated to alcohol consumption. In both situations, activity of antioxidant enzymes and of its cofactors zinc (Zn), selenium (Se), and copper (Cu) is important. This study was performed to assess the relative and combined effects of chronic alcoholism and HCV infection on serum Se, Zn, and Cu, and its relation with serum malondialdehyde (MDA) and tumor necrosis factor-α, interferon-γ, and interleukins (IL) 4, 6, and 8, in 19 HCV- alcoholic patients, 12 HCV+ alcoholic patients, nine HCV+ non-alcoholic patients, and 20 controls. Serum Zn and Se were lower in both HCV+ and HCV- alcoholic patients, whereas serum Cu was lower in HCV+ individuals. Serum Zn and Se were related to liver function derangement. MDA levels were higher in alcoholics, but no relation was observed between trace elements and MDA or cytokines, so that our results do not support a relevant role of the analyzed trace elements in the pathogenesis of chronic liver disease.

Cytokines and lipid peroxidation in alcoholics with chronic hepatitis C virus infection.

A major cause of liver cirrhosis and hepatocarcinoma is chronic infection by hepatitis C virus. Ethanol consumption is the most significant environmental factor that exacerbates the progression of chronic hepatitis C to liver cirrhosis and hepatocarcinoma, perhaps due to increased cytokine secretion together with increased lipid peroxidation. In this study, we compare the intensity of lipid peroxidation (estimated as malondialdehyde (MDA) serum levels), the antioxidant status, (measured as glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities in red blood cells), and levels of cytokines derived from Th1 cells (such as interferon gamma (IFNG)), Th2 cells (such as interleukin (IL)-4), Th3 cells (such as transforming growth factor beta (TGF-beta)), and IL-6, IL-8, and tumor necrosis factor (TNF)-alpha in patients affected by chronic hepatitis C virus infection, 26 drinkers of alcohol and 40 nondrinkers of alcohol. Patients showed significantly higher TNF-alpha (Z = 4.92, P < 0.001), IL-8 (Z = 4.95, P < 0.001), IFNG (Z = 2.81, P = 0.005), TGF-beta (t = 2.12, P = 0.037), MDA (Z = 5, P < 0.001), but lower IL-6 (Z = 3.61, P < 0.001) and GPX (F = 4.30, P < 0.05) than controls, whereas no differences were observed regarding IL-4 (Z = 0.35, P = 0.72), GPX and SOD activities. Alcoholics showed significantly higher TNF-alpha, but lower IL-4, MDA, and GPX, than nonalcoholics. TNF-alpha was significantly related to albumin and prothrombin activity, whereas TGF-beta was significantly related to MDA levels. Thus, cytokine secretion is altered in HCV infection. This alteration mainly consists of a stimulation of Th1 cytokines and an inhibition--or at least, no stimulation--of Th2 cytokines; these changes are especially marked among alcoholics with HCV infection, and are accompanied by raised TGF-beta.

Brain atrophy in alcoholics: relationship with alcohol intake; liver disease; nutritional status, and inflammation.

OBJECTIVES: Brain atrophy is a common finding in alcoholics. Several mechanisms may be involved, including ethanol itself, malnutrition, liver failure, and, possibly, ethanol-induced hormone and cytokine changes. The aim of this study was to analyse the relation of brain atrophy-assessed by computerized tomography (CT) scan-and the aforementioned alterations. METHODS: Serum insulin-like growth factor 1 (IGF-1), interleukin (IL)-6, IL-8, IL-10, TNF alpha, PTH, estradiol, free testosterone, and corticosterone were measured in 36 alcoholics, ten of them cirrhotics, who also underwent brain CT, which recorded the presence of cortical atrophy or cerebellar atrophy, Evan's, Huckmann's, cella media, bicaudate, cortical atrophy, bifrontal, and ventricular indices, and diameter of the third ventricle; subjective nutritional assessment, midarm anthropometry, and evaluation of liver function. RESULTS: Patients showed marked alterations of all the CT indices compared with 12 controls, but poor relations between these indices and the other parameters analysed (IGF-1, handgrip strength and years of addiction with bifrontal index (P < 0.025 in all cases); PTH and Evan's index (r = 0.36, P = 0.032); mean corpuscular volume with cella index and cortical atrophy (P < 0.05). Cerebellar atrophy was associated with a greater daily ethanol consumption (t = 2.19, P = 0.034). CONCLUSION: Brain atrophy is frequently observed in alcoholics, but relationships with liver function, cytokines, nutritional status, and hormone levels are poor.

Pro-inflammatory cytokines in stable chronic alcoholics: relationship with fat and lean mass.

Cytokines are mediators of the inflammatory response, secreted by many tissues, including adipocytes. Chronic alcoholic liver disease and alcoholic hepatitis are associated with elevated serum cytokine levels which yield prognostic value in this situation. Most studies have been performed in patients with acute alcoholic hepatitis. However, cytokine alterations in stable alcoholics have been less studied, as is also the case for the relationship between cytokines and fat and lean mass in these patients. The aim of the present study was to analyse the relationships between some proinflammatory serum cytokine levels and lean mass, fat mass, nutritional status, and liver function parameters in stable alcoholic patients. We determined serum TNF-alpha, interleukin (IL)-6, IL-8 and TNF receptor 2 (TNFr2) in 77 male alcoholic patients in a stable phase (before hospital discharge). In all patients we performed a total-body composition analysis (Hologic DEXA), nutritional assessment including body mass index, triceps skinfold, brachial perimeter, and assessment of liver function. Forty-two healthy volunteer health workers served as controls. IL-8, TNF-alpha and TNFr2 were significantly higher in patients than in controls. No differences were observed between patients and controls regarding fat mass, but alcoholics showed significantly decreased lean mass than controls. Only IL-6 was significantly related with body fat in patients with elevated IL-6 levels. Poor relationships were observed between lean mass and cytokines; some nutritional parameters showed inverse relationships with serum TNF, whereas TNF and IL-8 were inversely related with albumin and prothrombin activity. Thus, cytokine levels were elevated in stable alcoholic patients, and IL-6 levels showed significant correlation with body fat mass, raising the possibility that adipose tissue contributes to the persistence of high levels of cytokines in stable alcoholics.

Lipid peroxidation and serum cytokines in acute alcoholic hepatitis.

AIMS: Increased exposure of Kupffer cells to intestinal-borne Gram-negative bacteria enhances the metabolism and leads to cytokine production by these cells. Activation of Kupffer cells increases free radical release, which may, in turn, enhance cytokine secretion, creating a positive feedback loop, which contributes to liver inflammation. Cytokines act on T cells, inducing their proliferation and secretion of additional interleukins. Lipid peroxidation products (malondialdehyde; MDA) form adducts with proteins and acetaldehyde, triggering a T cell immune response. Controversy exists about the predominance of either Th-1 or Th-2 cellular responses. We performed the present study in order to analyse the cytokine pattern in patients with acute alcoholic hepatitis, its relation to MDA and the relation between all these parameters and liver function and prognosis. SUBJECTS AND METHODS: The study included 53 male alcoholics, 47 followed up for a median time of 32 months, during which 17 of them died. We measured serum MDA, tumour necrosis factor-alpha, interferon gamma (IFNG) and interleukins (IL) 4, 6, 8, and 10. RESULTS: MDA levels were raised in cirrhotics and non-cirrhotics with alcoholic hepatitis, maintaining a relationship with bilirubin and Maddrey index, and with mortality in the univariate analysis. Both IFNG and IL-4 were raised in our patients compared with controls, as well as IL-8, and IL-6, but IL-10 were below the detection limit in the majority of cases, especially in cirrhotics. Using a Cox regression model, Maddrey index displaced MDA in the survival analysis. CONCLUSIONS: Our data lend support to the hypothesis that activation of both Th-1 and Th-2 cell subsets take place. MDA levels are raised in alcoholics with alcoholic hepatitis and are closely related to liver function derangement and to survival, although this is displaced by Maddrey index using Cox regression model.

Clinical significance of homocysteine in elderly hospitalized patients.

Serum homocysteine levels, which increase with age, are now recognized as a vascular risk factor and are related to the development of heart failure and dementia in the elderly. However, relatively low serum homocysteine levels have also been reported to be an adverse prognostic factor in dialysis patients. The objective of the study was to analyze the prevalence, clinical significance, and prognostic value of serum homocysteine levels in patients older than 65 years, admitted to a general internal medicine hospitalization unit. We studied 337 hospitalized patients, 184 males and 153 females, aged 77.2+/-0.4 years, whose admission was not determined by an acute vascular event. We recorded past vascular events and vascular risk factors. We determined the body mass index (weight in kilograms divided by the square of height in meters), and cholesterol, triglyceride, folate, vitamin B12, and homocysteine levels. We also studied 36 control subjects (18 males and 18 females) of similar age. After discharge, we assessed the survival status of 301 patients by telephone recall. Survival curves were plotted by the method of Kaplan and Meier. Median survival was 1186 days. The 15th (9.6 micromol/L) and 50th (14.4 micromol/L) percentiles, as the lowest and highest cut-off points, were empirically defined as those related to a shorter survival. Serum homocysteine concentration was significantly positively correlated with age and serum creatinine and albumin concentrations, and negatively correlated with serum cobalamin and folate concentrations. The average serum homocysteine concentration for the patients group, as a whole, was 16.5+/-0.5 micromol/L, not significantly different from the control group, but with a much greater dispersion, as patients with congestive heart failure or cognitive impairment had higher serum homocysteine concentrations, and patients with sepsis, leukocytosis, and hypoalbuminemia had lower concentrations. Malnutrition was associated both with abnormally high and low homocysteine concentrations, and abnormally low and abnormally high homocysteine concentrations were both associated with higher mortality. In conclusion, low homocysteine levels in elderly non-vitamin-supplemented hospitalized patients should not be interpreted as a protective factor in some individuals. Instead, it may be considered as an effect of an inflammatory-malnutrition process associated with a poor prognosis.

Serum osteoprotegerin and RANKL levels in chronic alcoholic liver disease.

OBJECTIVES: Osteoprotegerin (OPG) is a decoy receptor that binds RANK-ligand (RANKL) and prevents osteoclast activation. Oestrogens, androgens, corticosteroids, parathyroid hormone (PTH), vitamin D, and several cytokines exert their effects on bone modulating the OPG/RANKL system. Since these substances become altered in chronic alcoholic liver disease, we investigated the OPG/RANKL system in alcoholic liver disease, its relation with bone mineral density (BMD) and with several hormones and cytokines. METHODS: Serum OPG, RANKL, C-terminal cross-linking telopeptide of type 1 collagen, osteocalcin, insulin-like growth factor 1 (IGF-1), 1,25 dihydroxyvitamin D, IL-6, tumour necrosis factor (TNF)-alpha, PTH, estradiol, free testosterone and corticosterone were measured in 77 male alcoholic patients, 25 of them cirrhotics. All these patients underwent assessment of BMD at lumbar spine and left hip by a Hologic QDR-2000 (Waltham, MA) bone densitometer. Nineteen non-drinkers male sanitary workers of similar age served as controls. RESULTS: Serum OPG levels were higher in patients (12.66 +/- 6.44 pmol/l) than in controls (6.59 +/- 1.58 pml/l, P < 0.005), especially in cirrhotics (15.97 +/- 7.03 pmol/l) vs non-cirrhotics (10.96 +/- 5.45 pmol/l, P < 0.001). Patients also showed higher telopeptide levels (0.60 +/- 0.36 vs 0.20 +/- 0.10 nmol/100 ml, P < 0.001), less IGF-1 [median = 192, interquartile range (IQR) = 46.7-175.99 ng/ml vs 150, IQR = 118.8-239.4 ng/ml, P < 0.001], vitamin D (25.5, IQR = 18.25-35 pg/ml vs 77.89, IQR = 57.48-98.53 pg/ml, P < 0.001) and osteocalcin (1.8, IQR = 1-3.6 ng/ml vs 6.04, IQR = 4.63-8.20 ng/ml, P < 0.001) than controls, but no differences in PTH and RANKL. Patients also showed lower Z-scores than controls at trochanter (-0.36 +/- 1.10 vs 0.26 +/- 0.87 in controls, P = 0.026), intertrochantereal area (-0.56 +/- 1.16 vs 0.46 +/- 1.01, P = 0.001), and total hip (-0.44 +/- 1.12 vs 0.42 +/- 1, P = 0.003). TNF-alpha levels were higher in patients (7.40, IQR = 4.30-17.80 pg/ml) than in controls (5.10, IQR = 4.40-8 pg/ml, P = 0.009), especially in cirrhotics (median = 13.90, IR = 6.10-21.10 pg/ml). OPG levels showed strong correlations with TNF-alpha (rho = 0.57, P < 0.001) and IL-6 (r = 0.62, P < 0.001), but not with BMD. Estradiol levels (31.83 +/- 13.11 pg/ml) were higher and free testosterone lower (13.62 +/- 11.96 pg/ml) in patients than in controls (20.36 +/- 3.08 and 18.19 +/- 4.68 pg/ml, respectively, P < 0.001 in both cases). CONCLUSION: OPG is raised in alcoholics, especially in cirrhotics, showing no relationship with decreased BMD. Also, raised TNF and IL-6 were observed, and were strongly, directly related with OPG levels. Since TNF and IL-6 enhance bone resorption, their relation with OPG suggests a protective effect of raised OPG on bone loss.