Soluble α-Klotho in Liver Cirrhosis and Alcoholism.

AIMS AND BACKGROUND: Alpha Klotho is a transmembrane protein that serves as co-receptor for FGF23. Ectodomain of membrane bound α Klotho may be shed by membrane bound proteases (activated, among other factors, by tumor necrosis factor (TNF)-α) generating the soluble form of the protein (sKl) that functions as a hormone by itself. It modulates calcium influx into cells, blunts IGF-1/Insulin signaling, promotes synthesis of antioxidants, generally slows down tumor progression, delays cell senescence, is neuroprotective and promotes oligodendrocyte maturation and myelin synthesis, and muscle rejuvenation. It may be involved in inflammation and exerts antifibrogenic effects. Some of these pathways may become altered in alcoholism or liver cirrhosis, but data are scattered and scarce and an update is required. METHOD: Literature survey. RESULTS AND CONCLUSIONS: Alcohol consumption in non-alcoholics is inversely related to sKl, but alcoholic cirrhotics showed higher-than-normal sKl values in association with liver function derangement. In hepatoma cells, the intensity of Klotho staining was related to faster tumor progression and a shortened life span. Among severe alcoholic cirrhotics sKl is directly related to serum TNF-α levels, and, inversely, to brain atrophy. Given the antioxidant, anti-inflammatory, and antifibrogenic effects of Klotho, perhaps the increase in cirrhosis (and in other inflammatory conditions, such as sepsis or cancer) reflects an attempt to regulate increased inflammation, but clinical and experimental research is urgently needed in this field.

Serum sclerostin in hepatitis C virus infected patients.

BACKGROUND: Sclerostin inhibits osteoblast functions, differentiations, and survival rates. As an endogenous inhibitor of the Wnt/ß-catenin pathway, the sclerostin should be related to decreased bone masses, although several studies indicate opposite results. In addition, it may be related to insulin resistances and carbohydrate metabolisms, a relation shared with other markers of bone metabolisms, such as osteocalcin. Hepatitis C virus (HCV) infected patients may present osteoporosis, and frequently show liver steatosis, which is a consequence of insulin resistance. The behaviour of sclerostin in these patients is yet unknown. The aim of this work is to analyse the relationships between serum sclerostin and osteocalcin levels and bone mineral density (BMD), liver functions, the intensity of liver steatosis and biochemical markers of bone homeostasis and insulin resistance in HCV-infected patients. METHODS: Forty HCV patients with 20 years of age and gender-matching controls were included in this study and underwent bone densitometry. Serum sclerostin, osteocalcin, collagen telopeptide, adiponectin, leptin, insulin, resistin, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were determined. Liver fat was histomorphometrically assessed. RESULTS: Sclerostin levels were slightly higher in patients than in controls, and were directly related to BMD at different parts of the skeleton, also to the serum telopeptide, and to the liver steatosis and TNF-α. On the contrary, osteocalcin showed a significant direct relationship with serum adiponectin, and an inverse one with IL-6. CONCLUSIONS: Serum sclerostin levels were within the normal range in HCV patients, and correlated directly with BMD and serum telopeptide. In addition, the relationships of sclerostin and osteocalcin with variables associated with insulin resistance suggested the role of bones for intermediary metabolisms.

Vein thrombosis in a patient with agenesis of inferior vena cava

We report a 29-year-old woman with bilateral deep vein thrombosis. CT-scan was performed and an agenesia of inferior vena cava was found. With regard to the case report, we provide a brief review of the embryogenesis of the inferior vena cava, and of anomalies in the genesis of this vessel. In young patients with idiopathic deep venous thrombosis the existence of an abnormality in the inferior vena cava should be considered

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Relative and combined effects of selenium, protein deficiency and ethanol on hepatocyte ballooning and liver steatosis.

Oxidative damage plays a key role in alcohol-mediated liver alterations. Selenium, a potent antioxidant, is decreased in alcoholics. This study was conducted to analyse if the supplementation with selenium may alter liver changes in a murine model fed ethanol and/or a 2 % protein-containing diet, following the Lieber-DeCarli design. Adult male Sprague Dawley rats were divided into eight 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 other similar four groups to which selenomethionine (1 mg/kg body weight) was added. After sacrifice (5 weeks later), liver fat amount and hepatocyte areas of pericentral and periportal cells were measured, and liver and serum selenium, activity of liver glutathione peroxidase (GPX), and liver malondialdehyde were determined. Ethanol-fed rats showed increased hepatocyte areas and fat accumulation especially when ethanol was added to a 2 % protein diet. Selenium caused a decrease in hepatocyte ballooning and liver fat amount, but an increase in GPX activity, and a marked increase in serum and liver selenium. The present study demonstrates that selenium, added to the diet of rats in the form of seleniomethionine, prevents the appearance of early signs of ethanol-mediated liver injury under the conditions of the Lieber-DeCarli experimental design.

Serum sclerostin in alcoholics: a pilot study.

AIMS: Sclerostin is an endogenous inhibitor of the Wnt/ß-catenin pathway secreted by osteocytes, which inhibits osteoblast function, differentiation and survival. As a consequence, sclerostin tends to decrease bone mass. Alcoholics frequently present osteoporosis, mainly due to decreased bone synthesis. The behaviour of sclerostin in these patients is unknown. The aim of this work was to analyse the relationship between serum sclerostin levels and bone mineral density (BMD), ethanol consumption, nutritional status, liver function derangement and biomarkers of bone homeostasis in alcoholic patients. METHODS: We included 31 alcoholic patients, of whom 11 were infected with Hepatitis C virus (HCV) and 7 age and sex-matched controls. All underwent densitometry, and serum sclerostin, osteocalcin, collagen telopeptide, parathyroid hormone (PTH), vitamin D, cortisol and testosterone were determined. RESULTS: Sclerostin levels were significantly higher in patients (30.95 ± 18.91 pmol/l) than controls (t = 4.4; P < 0.001), especially in non-HCV patients; they showed an inverse correlation with osteocalcin, prothrombin activity and serum albumin, and a direct correlation with bilirubin and telopeptide, but not with BMD, nutritional status or ethanol intake. CONCLUSIONS: Serum sclerostin was raised in alcoholic patients, and it correlated with decreased markers of bone synthesis and increased markers of bone breakdown. The elevation in sclerostin levels was clearly related with liver function, but not with ethanol intake, nutritional status or concomitant HCV infection.

TH-1 and TH-2 cytokines in stable chronic alcoholics.

UNLABELLED: In alcoholics, the activation of Kupffer cells by gram negative bacteriae leads to an inflammatory response and cytokine secretion, which in turn activate T-lymphocytes. Possibly, Th-1 lymphocytes are activated first, followed by a Th-2 response. Th-2 cytokines, especially interleukin (IL)-13 (scarcely studied in alcoholics), may be involved in the progression to chronic stages. AIMS: The aim of the study was to analyze the relationship of Th-1 and Th-2 cytokines with liver function, alcohol consumption, nutritional status and survival. METHODS: Serum Th-1 [interferon-γ (IFN-γ)] and Th-2 cytokines (IL-4, IL-13), IL-10, IL-6 and tumor necrosis factor (TNF-α), were determined for 18 controls and 47 stable alcoholics with variable liver function impairment, who were followed-up during a median time of 90 months, a period during which 14 patients died. RESULTS: IL-4 was lower among patients; no differences were observed regarding IL-6, but the remaining ILs were higher among alcoholics. IL-10 and IL-13 were even higher in cirrhotics (Z = 2.88, P = 0.004, and Z = 2.09, P = 0.037, respectively). A significant, direct, correlation was observed between IL-13 and IL-10 (ρ = 0.49, P = 0.001), and non-significant, inverse ones were observed between IFN-γ and IL-13 (ρ = -0.23), IL-4 (ρ = -0.14) and IL-10 (ρ = -0.09). IL-13 and IL-10 were inversely related with liver function and, directly with immunoglobulin A levels, but not with survival. CONCLUSION: Serum IFN-γ values were increased in alcoholics, who also showed raised IL-13 and IL-10, but lower IL-4 levels. Given the immunomodulatory roles of IL-10 and IL-13, this increase may be interpreted as a compensatory rise of anti-inflammatory cytokines. We failed to find any relation with mortality.

Changes in cytokine levels during admission and mortality in acute alcoholic hepatitis.

Cytokine levels are raised in acute alcoholic hepatitis. However, there are disparate results regarding the duration of altered plasma levels, and there are also discrepancies about the relation of changes during the first 15 days after admission with short-term (in-hospital) or long-term mortality. In 56 patients with acute alcoholic hepatitis we found that IL-8, IL-4, Interferon-γ (IFN-γ), malondialdehyde and C-reactive protein remained higher in patients than in 18 age- and sex-matched controls at admission, at the 7th day and at the 15th day after admission. Moreover, IL-4 levels (and to a lesser extent, IL-10 and IFN-γ ones) increased along the three determinations. However, comparing patients who died during the admission with those who did not, there were no statistically significant differences, but there was a nearly significant trend for MDA (Z=1.89; p=0.059), with higher levels among those who died. When changes between the first and the second determinations were compared with long-term survival, only IL-8 and IFN-γ showed a relation with mortality. IFN-γ values increased among those who survived and decreased among those who died (p=0.048). IFN-γ values at the first determination also showed a relation with long-term mortality, especially when patients with IFN-γ values in the first quartile were compared with those of the 4th one (log rank=5.64; p=0.018; Breslow=4.64; p=0.031). Besides Interferon-γ, only C-reactive protein showed differences between the first and the 4th quartile regarding mortality (Log rank=4.50; p=0.034; Breslow 4.33; p=0.038). In contrast with other studies, no relation was found between TNF-α or IL-6 and mortality.

Prognostic value of changes in lean and fat mass in alcoholics.

BACKGROUND & AIMS: The prognostic value of nutritional status and/or lean and fat mass assessed by dual-energy X-ray absorptiometry (DEXA) has been widely analyzed, in both alcoholics and non-alcoholics. However, the prognostic value of changes in fat and lean mass over time in alcoholics has scarcely been studied, nor has the effect of alcohol abstinence on these changes. METHODS: From an initial cohort of 113 alcoholic patients, 70 prospectively underwent two DEXA assessments six months apart. One hundred and five patients (including 66 of those who underwent two DEXA assessments) were followed up for 34.9 ± 36.4 months (median = 18 months, interquartile range = 7.25-53.75 months). During this follow-up period, 33 died (including 20 of those who had undergone a second DEXA assessment). RESULTS: Forty-two of the 70 patients undergoing a second DEXA assessment had abstained from alcohol. Of these, 69.04% (29) gained left arm lean mass, compared with only 35.71% (10 of 28) of those who had continued drinking (χ² = 7.46; p = 0.006). Similar results were observed regarding right arm lean mass (χ² = 4.68; p = 0.03) and right leg lean mass (χ² = 7.88; p = 0.005). However, no associations were found between alcohol abstinence and changes in fat parameters. Analysis by means of Kaplan-Meier curves showed that loss of total lean mass, right leg lean mass, left leg lean mass and total fat mass were all significantly associated with reduced survival. However, within 30 months of the second evaluation, significant associations were observed between changes of all parameters related to lean mass, and mortality, but no association between changes in fat parameters and mortality. CONCLUSIONS: Loss of lean mass over a period of six months after a first assessment is associated with worse prognosis in alcoholics, irrespective of whether they stop drinking during this period or not. Continued drinking is associated with greater loss of lean mass, but not with changes in fat mass.

Alcoholic myopathy: vitamin D deficiency is related to muscle fibre atrophy in a murine model.

AIMS: Chronic myopathy has been described in alcoholics, characterized by atrophy of type II fibres, and vitamin D deficiency. Low serum vitamin D levels are frequent in alcoholics. The possibility exists that serum vitamin D levels are related to muscle changes in a murine experimental model. METHODS: Histological analysis of the right gastrocnemius muscle was performed in four groups of adult Sprague-Dawley rats, sacrificed after 5 weeks of treatment following the Lieber-DeCarli model. We studied the association between muscle histological changes and the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and lipid peroxidation products (malondialdehyde); parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), free testosterone, 1,25 dihydroxyvitamin D3 (vitamin D) and corticosterone; and serum calcium and magnesium. RESULTS: Alcoholic animals showed type IIa and IIb fibre atrophy, especially the low-protein-fed ones, an effect dependent on protein deficiency. A significant relationship was observed between serum vitamin D levels and IIa fibre area (rho = 0.56, P = 0.002), and also, as a trend, between vitamin D and type IIb fibre area (rho = 0.39, p = 0.053); between vitamin D and muscle GPX (rho = 0.40, P = 0.025) and SOD activities (rho = 0.43, P = 0.012). Muscle GPX activity was significantly related with type I fibre area (rho = 0.49, P = 0.01) and muscle SOD, with type IIa fibre area (rho = 0.38, P = 0.045). Serum testosterone was also related with type IIa fibre area (rho = 0.61, P < 0.001). No relation was observed between serum PTH, corticosterone, or IGF-1 and fibre area PTH and antioxidant systems. Multiple regression analysis disclosed that the only parameter independently related with type IIa fibre area was serum vitamin D. CONCLUSION: Low vitamin D levels are related to muscle fibre atrophy, and altered levels of muscle antioxidant enzymes could play a role in alcoholic myopathy.

Relation between body fat and liver fat accumulation and cytokine pattern in non-alcoholic patients with chronic HCV infection.

BACKGROUND: Liver steatosis in chronic hepatitis C virus (HCV) infection is multifactorial. Therefore, there is not necessarily a relation between obesity and liver fat.On the other hand, body fat secretes cytokines, and cytokines and oxidative damage play important roles on progression of liver disease. METHODS: We analyzed the relationships between liver fat (assessed by histomorphometry) and trunk and subcutaneous fat (waist perimeter, triceps skinfold, BMI); the relationships between liver and body fat and cytokines (IL-6, TNF-alpha, IL-8, IFN-gamma, IL-4), adipokines (adiponectin and TIMP-1), and serum malondiladehyde and antioxidants (glutathione peroxidase and superoxide dismutase (SOD) activities); and the relationships of these data with histological changes in 40 HCV-infected non-alcoholic patients. RESULTS: Significant correlations were found between liver fat and waist perimeter and BMI, and between serum TIMP-1 and liver fat. Serum TIMP-1 was significantly related to body fat stores; serum IL-6 and IFN-gamma were related to histological inflammation. Patients with waist perimeter >102 cm (men) or 88 cm (women) showed increased liver fat. In 38.8% of non-obese patients, liver fat accumulation was intense. CONCLUSIONS: There is a relationship between visceral fat, serum TIMP-1 and liver steatosis. However, at least in some patients, factors different from mere adiposity play a role in liver steatosis.

Osteopatía en el paciente afecto de infección por virus C / Bone disease in the virus-C affected patient

Introducción. Si bien se conoce que la hepatopatía alcohólica se asocia a osteopatía, la presencia de esta y su intensidad han sido menos estudiadas en la hepatopatía por virus C. Material y métodos. Se incluyen 28 pacientes con infección por el virus de la hepatitis C (VHC) ingresados en el Servicio de Medicina Interna del Hospital Universitario de Canarias, determinándose marcadores bioquímicos de recambio óseo (cortisol, parathormona [PTH], 1,25 dihidroxivitamina D, factor de crecimiento insulínico [IGF]-1, osteocalcina), estado nutricional (por antropometría), masa grasa, masa magra y densidad mineral ósea (DMO) (por DEXA) y se compararon con un grupo control de similar edad. Resultados. Nuestros pacientes presentaban un descenso de la DMO en relación con los controles, especialmente manifiesto en los coinfectados por el virus de la inmunodeficiencia humana (VIH). Encontramos diferencias significativas de la DMO entre infectados y no infectados por VIH en lo que respecta a costilla derecha (T = 2,26, p = 0,037), columna lumbar (T = 2,45, p = 0,025) y pelvis (T = 2,23, p = 0,04). Se halló una relación significativa entre DMO en el brazo derecho y el perímetro braquial (p = 0,019), ocurriendo lo mismo entre masa magra determinada mediante DEXA en distintos niveles y DMO (masa magra total con DMO a nivel de brazo izquierdo [r = 0,69], a nivel del brazo derecho [r = 0,71], columna torácica [r = 0,79], lumbar [r = 0,53]. En lo que respecta a la actividad histológica, encontramos una relación significativa inversa entre masa ósea e índice de Knodell (relación entre DMO costilla derecha-Knodell p = 0,041; DMO columna lumbar-Knodell p = 0,033). Igualmente encontramos una relación inversa entre carga viral y masa ósea con valores del coeficiente de correlación oscilantes entre -0,52 y -0,48 (p < 0,05)....(AU)

Introduction. Although it is known that alcoholic liver disease is associated with bone disease, there are few studies that analyze bone alterations in chronic hepatitis C virus (HCV) infection. Material and methods. Twenty-eight consecutive patients affected by HCV infection admitted to the Internal Medicine Service of the Hospital Universitario de Canarias were included. Biochemical markers of bone turnover (cortisol, PTH, 1.25 dihydroxyvitamin D, IGF1, osteocalcin) were measured. Nutritional status was assessed by anthropometry, and fat mass, bone mineral density, and lean mass were all determined by densitometry (DEXA). These data were compared with those of a control group of similar age. Results. Our patients had decreased body mass (BMD) values compared to the controls, especially intense among HIV co-infected individuals. We found significant differences between HIV infected and not infected patients in relation to right rib (T = 2.26, p = 0.037), lumbar spine (T = 2.45, p = 0.025) and pelvis (T = 2.23, p = 0.04). There was a significant relation between BMD in the right arm and brachial perimeter (p = 0.019) and between lean mass at different levels and BMD (total lean mass at left arm r = 0.69, at right arm r = 0.71, thoracic spine r = 0.79, lumbar spine r = 0.53). We found a significant inverse relation between BMD and Knodell index (relation between BMD at right rib and Knodell, p = 0.041, and BMD at lumbar spine and Knodell index, p = 0.033). Conclusions. In patients with chronic HCV infection, there is a reduction of bone mass, particularly in HIV co-infected patients. This reduction is related to a reduction of the lean mass but not to fat mass, and maintains a relationship with viral load and histological activity(AU)

Tetraparesia fláccida y desconexión del medio tras neumonía bilateral en un paciente alcohólico / Flaccid tetraparesia and disconnection in an alcoholic patient affected by pneumonia

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Prognostic value of nutritional status in alcoholics, assessed by double-energy X-ray absorptiometry.

OBJECTIVES: This study was performed in order to assess nutritional status of 77 alcoholic patients. METHODS: Patients underwent a total body double-energy X-ray absorptiometry (DEXA) analysis, with estimation of lean and fat mass at different parts of the body. RESULTS: Lean mass, but not fat mass, was significantly reduced among alcoholics, compared to 31 age-matched controls, especially at right arm, legs, and total body. Lean mass at both arms was significantly related to liver function parameters (albumin, prothrombin activity, bilirubin) and, inversely, with ethanol consumption. The 24 patients who died during a follow-up period of 88 months showed less lean mass at both arms, trunk, and left leg, and also less fat at the left arm, than survivors. When right and left arm lean mass were classified in quartiles, Kaplan-Meier curves showed significant differences between dead and survivors. Left arm lean mass was the parameter which was independently related to mortality when encephalopathy was not included in a stepwise Cox regression analysis, but was displaced by this last parameter when it was also introduced in the analysis. CONCLUSION: Lean mass is reduced in alcoholics, is related to liver function derangement and ethanol consumption, and is related to mortality.

Molecular and cellular events in alcohol-induced muscle disease.

Alcohol consumption induces a dose-dependent noxious effect on skeletal muscle, leading to progressive functional and structural damage of myocytes, with concomitant reductions in lean body mass. Nearly half of high-dose chronic alcohol consumers develop alcoholic skeletal myopathy. The pathogenic mechanisms that lie between alcohol intake and loss of muscle tissue involve multiple pathways, making the elucidation of the disease somewhat difficult. This review discusses the recent advances in basic and clinical research on the molecular and cellular events involved in the development of alcohol-induced muscle disease. The main areas of recent research interest on this field are as follows: (i) molecular mechanisms in alcohol exposed muscle in the rat model; (ii) gene expression changes in alcohol exposed muscle; (iii) the role of trace elements and oxidative stress in alcoholic myopathy; and (iv) the role of apoptosis and preapoptotic pathways in alcoholic myopathy. These aforementioned areas are crucial in understanding the pathogenesis of this disease. For example, there is overwhelming evidence that both chronic alcohol ingestion and acute alcohol intoxication impair the rate of protein synthesis of myofibrillar proteins, in particular, under both postabsorptive and postprandial conditions. Perturbations in gene expression are contributory factors to the development of alcoholic myopathy, as ethanol-induced alterations are detected in over 400 genes and the protein profile (i.e., the proteome) of muscle is also affected. There is supportive evidence that oxidative damage is involved in the pathogenesis of alcoholic myopathy. Increased lipid peroxidation is related to muscle fibre atrophy, and reduced serum levels of some antioxidants may be related to loss of muscle mass and muscle strength. Finally, ethanol induces skeletal muscle apoptosis and increases both pro- and antiapoptotic regulatory mechanisms.

Dolor abdominal recurrente-déficit adquirido de C1-inhibidor / Recurrent abdominal pain-acquired deficit of C1-inhibitor

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Relación entre homocisteína y masa ósea en pacientes alcohólicos / Relationship between homocysteine and bone mass in alcoholic patients

Introducción. En el paciente alcohólico se observa la presencia de osteopatía. La homocisteína puede interferir con la formación del colágeno, la mineralización ósea y aumentar el riesgo de fracturas osteoporóticas. Algunos autores han encontrado relación entre la homocisteína y las fracturas óseas pero no se ha estudiado en pacientes alcohólicos. Pacientes y métodos. Estudiar en 43 pacientes alcohólicos la relación entre la densidad mineral ósea, hormonas, osteocalcina, N-Telopéptido terminal y la homocisteína. Grupo control de 63 individuos. Resultados. Los niveles séricos de homocisteína estaban ligeramente más elevados en los pacientes respecto a los controles (más en cirróticos que en no cirróticos) pero no de forma significativa. Un 38,5% de los pacientes presentaba osteoporosis. Aunque en los pacientes con osteoporosis los niveles de homocisteína estaban más aumentados no hallamos relación entre la homocisteína y la densidad mineral ósea en ninguna de las localizaciones analizadas ni en los valores hormonales ni en los marcadores óseos. Conclusiones. No hemos encontrado relación entre el aumento de la homocisteína y la osteoporosis de los pacientes alcohólicos

Introduction. Alcoholism leads to osteoporosis. Homocysteine (tHcys) may weaken bone by interfering with collagen cross-linking. Some authors hve found a relation between tHcys and bone fracture in clinical settings differents from alcoholism. Methods. We studied the relationship between bone mineral density, hormones, bone metabolism markers and homocysteine in 43 alcoholics patients. Data were compared with those obtained on 63 controls. Results. Serum homocysteine were slightly non-significantly higher among patients than controls and among cirrhotic than non-cirrhotic patients. A total of 38.5% patients had osteoporosis. Although homocysteine levels were slightly highly in patients with osteoporosis, no relationships were observed between homocysteine and bone mineral density at any of the bone sites analyzed or in hormones or serum markers of bone metabolism. Conclusion. We found no relationship between the number of homocysteine and osteoporosis of alcoholic patients

Factor V Leiden y trombosis de arteria central de retina / Factor V Leiden and retinal central artery thrombosis

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