Geraldine Quintero-Platt

Alcoholism: a systemic proinflammatory condition.

Excessive ethanol consumption affects virtually any organ, both by indirect and direct mechanisms. Considerable research in the last two decades has widened the knowledge about the paramount importance of proinflammatory cytokines and oxidative damage in the pathogenesis of many of the systemic manifestations of alcoholism. These cytokines derive primarily from activated Kupffer cells exposed to Gram-negative intestinal bacteria, which reach the liver in supra-physiological amounts due to ethanol-mediated increased gut permeability. Reactive oxygen species (ROS) that enhance the inflammatory response are generated both by activation of Kupffer cells and by the direct metabolic effects of ethanol. The effects of this increased cytokine secretion and ROS generation lie far beyond liver damage. In addition to the classic consequences of endotoxemia associated with liver cirrhosis that were described several decades ago, important research in the last ten years has shown that cytokines may also induce damage in remote organs such as brain, bone, muscle, heart, lung, gonads, peripheral nerve, and pancreas. These effects are even seen in alcoholics without significant liver disease. Therefore, alcoholism can be viewed as an inflammatory condition, a concept which opens the possibility of using new therapeutic weapons to treat some of the complications of this devastating and frequent disease. In this review we examine some of the most outstanding consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver.

Thrombin activation and liver inflammation in advanced hepatitis C virus infection

Hepatitis C virus (HCV) infection is associated with increased thrombotic risk. Several mechanisms are involved including direct endothelial damage by the HCV virus, with activation of tissue factor, altered fibrinolysis and increased platelet aggregation and activation. In advanced stages, chronic HCV infection may evolve to liver cirrhosis, a condition in which alterations in the portal microcirculation may also ultimately lead to thrombin activation, platelet aggregation, and clot formation. Therefore in advanced HCV liver disease there is an increased prevalence of thrombotic phenomena in portal vein radicles. Increased thrombin formation may activate hepatic stellate cells and promote liver fibrosis. In addition, ischemic changes derived from vascular occlusion by microthrombi favor the so called parenchymal extinction, a process that promotes collapse of hepatocytes and the formation of gross fibrous tracts. These reasons may explain why advanced HCV infection may evolve more rapidly to end-stage liver disease than other forms of cirrhosis.

Alpha Klotho and Fibroblast Growth Factor-23 Among Alcoholics

Aims Alcoholism may be a cardiovascular risk factor. Osteocyte derived molecules such as fibroblast growth factor 23 (FGF-23) and soluble α Klotho have recently been associated with cardiovascular disease, but their role in alcoholics is unknown. We here analyze the behavior of FGF23 and α Klotho in alcoholics. Methods Ninety-seven alcoholic patients were assessed for liver function, presence of hypertension, diabetes, atrial fibrillation, left ventricular hypertrophy (LVH), vascular calcifications (assessed by chest X-ray) and nutritional status (lean and fat mass measured by densitometry). We measured plasma levels of FGF-23 and serum soluble α Klotho, using ELISA in 97 patients and 20 age- and sex-matched controls. Results FGF-23 levels were higher in patients than in controls (Z = 3.50; P < 0.001). FGF-23 (Z = 5.03; P < 0.001) and soluble α Klotho (Z = 5.61; P < 0.001) were higher in cirrhotics, and both were related to liver function, independently of serum creatinine FGF-23 levels were higher among alcoholics with diabetes (Z = 2.55; P = 0.011) or hypertension (Z = 2.56; P = 0.01), and increased body fat (ρ = 0.28; P = 0.022 for trunk fat), whereas α Klotho levels were higher in patients with LVH (Z = 2.17; P = 0.03) or atrial fibrillation (Z = 2.34; P = 0.019). Conclusions FGF-23 was higher in alcoholics than in controls, especially among cirrhotics, and soluble α Klotho levels were also higher among cirrhotics. Both were related to liver function impairment, independently of serum creatinine levels, and also showed significant associations with vascular risk factors, such as hypertension, diabetes or trunk fat amount in the case of FGF-23, or LVH or atrial fibrillation in the case of α Klotho. Short summary We report increased values of fibroblast growth factor 23 (FGF-23) and soluble α Klotho in cirrhotic alcoholics. Both molecules are associated with liver function impairment, and with some cardiovascular risk factors such as diabetes, hypertension, increased body fat, left ventricular hypertrophy and atrial fibrillation independently of serum creatinine.

Prognostic value of physical function tests and muscle mass in elderly hospitalized patients. A prospective observational study

To determine the prognostic value for mortality of physical function tests, muscle mass loss, disability and frailty in elderly hospitalized patients.

Lipid Profile And Bone Mineral Density In Heavy Alcoholics

BACKGROUND & AIMS Some studies have illustrated the association between serum lipid profile and bone mineral density (BMD) or fractures. None of these studies was performed among alcoholics, despite the fact that alcoholism may affect both bone mass and lipid metabolism. We here analyse the relationship of serum lipid profile with bone mass among a population of 280 heavy alcoholics (29 women). METHODS patients underwent a densitometric assessment of BMD and determination of a serum lipid panel. Castelli index (Total cholesterol/HDL cholesterol) and the LDL/HDL cholesterol index were calculated. RESULTS There was a direct correlation between both total cholesterol and LDL-cholesterol and femoral neck (r = 0.17 and r = 0.20, respectively) and lumbar spine (r = 0.16 and r = 0.20) T score, total BMD (r = 0.14 and r = 0.18) or pelvis BMD (r = 0.16 and r = 0.23; p < 0.025 in all cases). HDL-cholesterol showed no relationship with BMD. Serum triglycerides were also directly related to T score at the lumbar spine (ρ = 0.13; p = 0.032) and pelvis BMD (ρ = 0.13; p = 0.037). Pelvis BMD was significantly related to Castelli index (ρ = 0.15) and LDL/HDL index (ρ = 0.18; p < 0.015 in both cases). Multivariate analysis showed that the association between the serum lipid panel and BMD was independent of liver function and body mass index. CONCLUSIONS Therefore, BMD was directly related to total cholesterol and LDL cholesterol in heavy alcoholism. This counter intuitive observation adds to others derived from several similar studies conducted in different population groups but not in alcoholics as of yet. The mechanisms that explain the association between serum lipids and bone metabolism need further investigation.

Adipokines, cytokines and body fat stores in hepatitis C virus liver steatosis.

AIM To identify patients with or without liver steatosis and its severity in treatment-naïve patients affected by hepatitis C virus (HCV) infection. METHODS We included 56 HCV infected patients, and assessed the amount of liver fat by histomorphometry, and its relationships with fat and lean mass at different parts of the body (by densitometry), hormones [insulin, homeostatic model assessment (HOMA)], adipokines (resistin, adiponectin, leptin), and cytokines (tumor necrosis factor α, interleukin-6). RESULTS Although the intensity of liver steatosis is related to trunk fat mass and HOMA, 33% of patients showed no liver steatosis, and this finding was not related to body mass index or genotype. Besides trunk fat mass, no other factor was related to the presence or not of liver steatosis, or to the intensity of it, by multivariate analysis. Lean mass was not related to liver steatosis. Adiponectin levels were lower among patients. No differences were observed in leptin and resistin. CONCLUSION Steatosis in HCV infection is common (67.2%), and closely related to trunk fat, and insulin resistance, but not with leg fat mass or adipokines.

Interactions Vitamin D – Bone Changes in Alcoholics

Vitamin D deficiency is observed frequently in alcoholics, and the main metabolic bone disease seen in these patients is osteoporosis. Low vitamin D levels may have direct effects on bone metabolism, or indirect effects on: muscle – affecting muscle strength and mechanical load on bone; central nervous system – making the patient more prone to falls; and gonads – lowering testosterone levels, all of which lead to muscle atrophy and subsequent bone loss. We review the mechanisms underlying the bone alterations observed in alcoholics, and emphasize the interactions between vitamin D and bone metabolism. We also stress the importance of alcohol abstinence and vitamin D supplementation in the management of alcoholic bone disease.

Vitamin D, Vascular Calcification and Mortality among Alcoholics

AIMS To analyze the relationship between low vitamin D levels and mortality among alcoholics. METHODS One hundred twenty-eight alcoholic patients admitted to our hospital were followed up as outpatients. Nutritional status was evaluated measuring percentages of fat and lean mass in different body compartments. RESULTS Lower vitamin D levels were observed in patients with worse liver function. Vitamin D was lower in patients with lower total lean mass (Z = 2.8, P = 0.005), but it was not related to fat mass. There was a significant trend to higher long-term mortality among non-cirrhotics with vitamin D levels below 30 ng/ml, although Coxs regression model revealed that only Child score and age were independently related to mortality. CONCLUSION Vitamin D deficiency is common among alcoholic patients and is associated with low lean mass and liver dysfunction. Among non-cirrhotics, serum vitamin D levels below 30 ng/ml are associated with a greater long-term mortality.

Hemophagocytic Lymphohistiocytosis Complicating Myelodysplasia

We describe a 62-year-old patient with a 4-year history of myelodysplasia who later developed striking features that included massive splenomegaly, rapidly evolving visual loss and a sensorimotor polyneuropathy. This led us to consider the diagnosis of haemophagocytic lymphohistiocytosis (HLH). Upon further investigation, we found that he fulfilled the necessary diagnostic criteria for HLH, including the presence of haemophagocytosis of erythroid precursors on bone marrow smear.