Clinical Predictors of Different Grades of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the comorbidities related to obesity. Liver biopsy has been used as the "gold standard" for the diagnosis, grading, and prognosis of obese patients. The objective of the present study was to evaluate clinical predictors of more advanced stages of NAFLD. In this retrospective study we assessed several physical and laboratorial factors, including some cytokines, in morbidly obese patients submitted to Roux-en-Y gastric bypass that could be related to the diagnosis and staging of NAFLD. Fragments of the livers were obtained from wedge biopsies during operation. The medical records of 259 patients were studied. The patients were divided into four groups: normal hepatic biopsy, steatosis, mild nonalcoholic steatohepatitis (NASH), and moderate and severe NASH. There were no differences in cytokine levels among groups. The triglyceride levels were the only variable that could stratify the grades of NAFLD and also differentiate from normal livers in the female patients. Also in this group, the aminotransferases and GGT levels and fasting glucose were predictors of the more advanced stages of NASH, while BMI and weight were predictors of the more advanced stages of NASH in male patients. There are no available markers in clinical practice to detect the initial stages of NAFLD. It is very important to perform a liver biopsy in all patients submitted to bariatric surgery and in obese patients with no indication to be operated in the presence of elevated blood levels of aminotransferases, GGT, and fasting glucose.

Strength training improves plasma parameters, body composition and liver morphology in ovariectomized rats

Objective. - The aim of this study was to identify the effects of strength training on plasma parameters, body composition and the liver of ovariectomized rats. Methods. - Wistar sedentary (SHAM), ovariectomized (OVX), and ovariectomized trained rats (strength training [OVX-EXE]) of 85% of one maximal repetition (1 RM), three times per week, for 10 weeks, were used on this study. We monitored the body weight and visceral (uterine, mesenteric and retroperitoneal) and subcutaneous adiposity, total cholesterol, triglycerides, HDL, blood glucose and liver morphology to identify the presence of macrovesicular steotosis (haematoxylin and eosin staining). Results. - We observed that strength training changed body weight (SHAM 293.0 +/- 14.5 g; OVX 342.6 +/- 10.8 g; OVX-EXE 317.7 +/- 11.9 g, P < 0.05), visceral and subcutaneous adiposity, glucose (SHAM 111.2 +/- 10.0 mg/dL; OVX 147.4 +/- 18.8 mg/dL; OVX-EXE 118.5 +/- 2.2 mg/dL, P < 0.05), increased HDL (SHAM 82.7 +/- 1.4 mg/dL; OVX 64.6 +/- 2.8 mg/dL; OVX-EXE 91.4 +/- 2.6 mg/dL, P < 0.05) and reduced macrovesicular steatosis in liver tissue. Conclusions. - Considering the data obtained in this research, we emphasise the use of strength exercise training as a therapeutic means to combat or control the metabolic disturbances associated with menopause, including adiposity, and adverse changes in blood glucose, blood HDL and macrovesicular steatosis. (C) 2011 Elsevier Masson SAS. All rights reserved.

Ultrasonographic and laboratory markers of metabolic and cardiovascular disease risk in obese women with polycystic ovary syndrome

Objective To evaluate whether the presence of polycystic ovary syndrome (PCOS) alters multiple ultrasonographic and laboratory markers of metabolic and cardiovascular disease risk in obese women without any other health condition that could interfere with combined oral contraceptive (COC) eligibility criteria. Methods This was a case- control study evaluating 90 obese women ( body mass index ( BMI) = 30.0 kg/m2 and < 40 kg/m2) aged between 18 and 40 years without any other health condition that could interfere with COC eligibility criteria, of whom 45 had PCOS and 45 were age- matched controls. BMI, waist and hip circumference, arterial blood pressure, fasting insulin and glucose, quantitative insulin sensitivity check index ( QUICKI), highdensity lipoprotein cholesterol, low- density lipoprotein cholesterol, total cholesterol, triglycerides, testosterone, sex hormone- binding globulin, free androgen index ( FAI), carotid stiffness index, intima media thickness, flowmediated dilatation ( FMD) of the brachial artery and non- alcoholic fatty liver disease ( NAFLD) were assessed. Results In women with PCOS, we observed a higher frequency of NAFLD ( 73.3 vs. 46.7%, P < 0.01) and higher FAI ( 10.4 vs. 6.8%, P < 0.01). We also observed a trend towards increased insulin levels ( 10.06 +/- 6.66 vs. 7.45 +/- 5.88 mu IU/mL, P = 0.05), decreased QUICKI ( 0.36 +/- 0.06 vs. 0.39 +/- 0.07, P = 0.05) and decreased FMD ( 7.00 +/- 3.87 vs. 8.41 +/- 3.79%, P = 0.08). No other significant difference was observed. Conclusions NAFLD is frequent in obese women without any other health condition that could interfere with COC eligibility criteria, especially in those with PCOS. This should be considered when choosing the best contraceptive option. Copyright (C) 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Vitamin C and Vitamin E in Prevention of Nonalcoholic Fatty Liver Disease (NAFLD) in Choline Deficient Diet Fed Rats

Abstract Aim Oxidative stress has been implicated in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD). Vitamin C and vitamin E are known to react with reactive oxygen species (ROS) blocking the propagation of radical reactions in a wide range of oxidative stress situations. The potential therapeutic efficacy of antioxidants in NAFLD is unknown. The aim of this study was to evaluate the role of antioxidant drugs (vitamin C or vitamin E) in its prevention. Methods Fatty liver disease was induced in Wistar rats by choline-deficient diet for four weeks. The rats were randomly assigned to receive vitamin E (n = 6) – (200 mg/day), vitamin C (n = 6) (30 mg/Kg/day) or vehicle orally. Results In the vehicle and vitamin E-treated rats, there were moderate macro and microvesicular fatty changes in periportal area without inflammatory infiltrate or fibrosis. Scharlach stain that used for a more precise identification of fatty change was strong positive. With vitamin C, there was marked decrease in histological alterations. Essentially, there was no liver steatosis, only hepatocellular ballooning. Scharlach stain was negative. The lucigenin-enhanced luminescence was reduced with vitamin C (1080 ± 330 cpm/mg/minx103) as compared to those Vitamin E and control (2247 ± 790; 2020 ± 407 cpm/mg/minx103, respectively) (p < 0.05). Serum levels of aminotransferases were unaltered by vitamin C or vitamin E. Conclusions 1) Vitamin C reduced oxidative stress and markedly inhibited the development of experimental liver steatosis induced by choline-deficient diet ; 2)Vitamin E neither prevented the development of fatty liver nor reduced the oxidative stress in this model.

A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease

Copper has a role in antioxidant defense, lipid peroxidation, and mitochondrial function, and copper deficiency has been linked to atherogenic dyslipidemia. We aimed to investigate the potential role of copper availability in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).

Age dependency of intrarenal resistance index (RI) in healthy adults and patients with fatty liver disease

BACKGROUND: Our aim was to investigate the influence of age and gender on intrarenal resistance index (RI) measurements in 78 healthy subjects (46 males, 32 females; group 1) and 35 subjects (group 2) with fatty liver disease (28 males and 7 females). SUBJECTS AND METHODS: First, each subject underwent a conventional abdominal ultrasound examination. Then, intrarenal RI values were determined from three distinct interlobar and cortical arteries respectively on both kidneys. The correlation of intrarenal RI with age and gender as a variable was statistically evaluated by linear regression. RESULTS: In group 1, the variables gender, kidney region and comparison of right versus left kidney had no significant effect on intrarenal RI (p>0.05). The variable age, on the other hand, showed a significant positive correlation on all four defined measuring points (p<0.01) with linear correlation coefficients of r = 0.26 (left kidney, central) to r = 0.37 (right kidney, cortical). Therefore normal RI values at ages 25, 45, 65 years could be defined as 0.59, 0.61 and 0.63, respectively. Age dependency can thus be expressed as a function with the formula y = 0.565 + 0.001.x. Patients with fatty liver disease showed age dependency on renal RI (p<0.01) as well. CONCLUSION: In accordance with other studies, the influence of age on intrarenal RI measurement is significant in healthy subjects. Intrarenal RI values from subjects with a fatty liver disease showed age dependency as well. Therefore it is necessary to consider the age of the examined person to interpret RI values correctly.

Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease in children, is associated with obesity and insulin resistance. However, the relationship between NAFLD and cardiovascular risk factors in children is not fully understood. The objective of this study was to determine the association between NAFLD and the presence of metabolic syndrome in overweight and obese children. METHODS AND RESULTS: This case-control study of 150 overweight children with biopsy-proven NAFLD and 150 overweight children without NAFLD compared rates of metabolic syndrome using Adult Treatment Panel III criteria. Cases and controls were well matched in age, sex, and severity of obesity. Children with NAFLD had significantly higher fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure than overweight and obese children without NAFLD. Subjects with NAFLD also had significantly lower high-density lipoprotein cholesterol than controls. After adjustment for age, sex, race, ethnicity, body mass index, and hyperinsulinemia, children with metabolic syndrome had 5.0 (95% confidence interval, 2.6 to 9.7) times the odds of having NAFLD as overweight and obese children without metabolic syndrome. CONCLUSIONS: NAFLD in overweight and obese children is strongly associated with multiple cardiovascular risk factors. The identification of NAFLD in a child should prompt global counseling to address nutrition, physical activity, and avoidance of smoking to prevent the development of cardiovascular disease and type 2 diabetes.

Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease

BACKGROUND ; AIMS: Iron perturbations are frequently observed in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate a potential association of copper status with disturbances of iron homeostasis in NAFLD. METHODS: We retrospectively studied 140 NAFLD patients and 25 control subjects. Biochemical and hepatic iron and copper parameters were analyzed. Hepatic expression of iron regulatory molecules was investigated in liver biopsy specimens by reverse-transcription polymerase chain reaction and Western blot analysis. RESULTS: NAFLD patients had lower hepatic copper concentrations than control subjects (21.9 +/- 9.8 vs 29.6 +/- 5.1 microg/g; P = .002). NAFLD patients with low serum and liver copper concentrations presented with higher serum ferritin levels (606.7 +/- 265.8 vs 224.2 +/- 176.0 mg/L; P < .001), increased prevalence of siderosis in liver biopsy specimens (36/46 vs 10/47 patients; P < .001), and with elevated hepatic iron concentrations (1184.4 +/- 842.7 vs 319.9 +/- 451.3 microg/g; P = .020). Lower serum concentrations of the copper-dependent ferroxidase ceruloplasmin (21.7 +/- 4.1 vs 30.4 +/- 6.4 mg/dL; P < .001) and decreased liver ferroportin (FP-1; P = .009) messenger RNA expression were found in these patients compared with NAFLD patients with high liver or serum copper concentrations. Accordingly, in rats, a reduced dietary copper intake was paralleled by a decreased hepatic FP-1 protein expression. CONCLUSIONS: A significant proportion of NAFLD patients should be considered copper deficient. Our results indicate that copper status is linked to iron homeostasis in NAFLD, suggesting that low copper bioavailability causes increased hepatic iron stores via decreased FP-1 expression and ceruloplasmin ferroxidase activity thus blocking liver iron export in copper-deficient subjects.

The Interactions of Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases

A complex interaction among metabolic factors, adipose tissue lipolysis, oxidative stress, and insulin resistance results in a deleterious process that may link nonalcoholic fatty liver disease (NAFLD) with severe cardiovascular (CV) outcomes. Patients with NAFLD are at higher risk of atherosclerosis, new onset of CV events, and overall mortality. The strong association between NAFLD and CV disease should affect clinical practice, with screening and surveillance of patients with NAFLD. This review discusses the data linking these major diseases.

The metabolomic window into hepatobiliary disease

The emergent discipline of metabolomics has attracted considerable research effort in hepatology. Here we review the metabolomic data for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), alcoholic liver disease (ALD), hepatitis B and C, cholecystitis, cholestasis, liver transplantation, and acute hepatotoxicity in animal models. A metabolomic window has permitted a view into the changing biochemistry occurring in the transitional phases between a healthy liver and hepatocellular carcinoma or cholangiocarcinoma. Whether provoked by obesity and diabetes, alcohol use or oncogenic viruses, the liver develops a core metabolomic phenotype (CMP) that involves dysregulation of bile acid and phospholipid homeostasis. The CMP commences at the transition between the healthy liver (Phase 0) and NAFLD/NASH, ALD or viral hepatitis (Phase 1). This CMP is maintained in the presence or absence of cirrhosis (Phase 2) and whether or not either HCC or CCA (Phase 3) develops. Inflammatory signalling in the liver triggers the appearance of the CMP. Many other metabolomic markers distinguish between Phases 0, 1, 2 and 3. A metabolic remodelling in HCC has been described but metabolomic data from all four Phases demonstrate that the Warburg shift from mitochondrial respiration to cytosolic glycolysis foreshadows HCC and may occur as early as Phase 1. The metabolic remodelling also involves an upregulation of fatty acid β-oxidation, also beginning in Phase 1. The storage of triglycerides in fatty liver provides high energy-yielding substrates for Phases 2 and 3 of liver pathology. The metabolomic window into hepatobiliary disease sheds new light on the systems pathology of the liver.

Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis.

BACKGROUND & AIMS Unhealthy lifestyles predispose to non-alcoholic steatohepatitis (NASH), which may further result in the development of hepatocellular carcinoma (HCC). Although NASH patients benefit from physical activity, it is unknown whether regular exercise reduces the risk of developing HCC. Therefore, we studied the effect of regular exercise on the development of HCC in male hepatocyte-specific PTEN-deficient mice (AlbCrePten(flox/flox)), which develop steatohepatitis and HCC spontaneously. METHODS Mice were fed a standardized 10% fat diet and were randomly divided into exercise or sedentary groups. The exercise group ran on a motorized treadmill for 60 minutes/day, 5 days/week during 32 weeks. RESULTS After 32 weeks of regular exercise, 71% of exercised mice developed nodules larger than 15 mm(3) vs 100% of mice in the sedentary group. The mean number of tumors per liver was reduced by exercise, as well as the total tumoral volume per liver. Exercise did not affect steatosis and had no effect on the Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). Exercise decreased tumor cell proliferation. Mechanistically, exercise stimulated the phosphorylation of AMPK and its substrate raptor, which decreased the kinase activity of mTOR. CONCLUSIONS These data show a benefit of regular exercise on the development of HCC in an experimental model of NASH and offer a rationale for encouraging predisposed patients to increase their physical activity for the prevention of HCC.

Physical activity and liver diseases

Regular physical activity beneficially impacts the risk of onset and progression of several chronic diseases. However, research regarding the effects of exercising on chronic liver diseases is relatively recent. Most authors focused on non-alcoholic fatty liver disease (NAFLD), in which increasing clinical and experimental data indicate that skeletal muscle cross-talking to the adipose tissue and the liver regulates intrahepatic fat storage. In this setting physical activity is considered required in combination with calories restriction to allow an effective decrease of intrahepatic lipid component, and despite that evidence is not conclusive, some studies suggest that vigorous activity might be more beneficial than moderate activity to improve NAFLD/NASH. Evidence regarding the effects of exercise on the risk of hepatocellular carcinoma is scarce; some epidemiological studies indicate a lower risk in patients regularly and vigorously exercising. In compensated cirrhosis exercise acutely increases portal pressure, but in longer term it has been proved safe and probably beneficial. Decreased aerobic capacity (VO2) correlates with mortality in patients with decompensated cirrhosis, who are almost invariably sarcopenic. In these patients VO2 is improved by physical activity, which might also reduce the risk of hepatic encephalopathy through an increase in skeletal muscle mass. In solid organ transplantation recipients exercise is able to improve lean mass, muscle strength and as a consequence, aerobic capacity. Few data exist in liver transplant recipients, in whom exercise should be object of future studies given its high potential of providing long-term beneficial effects. Despite evidence is far from complete, physical activity should be seen as an important part of the management of patients with liver disease in order to improve their clinical outcome. This article is protected by copyright. All rights reserved.

Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: A Problem of Growing Magnitude.

Hepatocellular carcinoma (HCC) is a cancer with globally rising incidence. Growing evidence supports associations between metabolic syndrome and diabetes as well as obesity and HCC arising in patients with nonalcoholic fatty liver disease (NAFLD). This constitutes a problem of alarming magnitude given the rising epidemic of these conditions. The role of diabetes seems to be particularly important when associated with obesity or cirrhosis. Excess hepatic iron may be another potential risk factor for the development of NAFLD-associated HCC. In the context of NAFLD, HCC frequently develops in a not-yet cirrhotic liver. As there are no surveillance programs for these patients, diagnosis often occurs at a tumor stage beyond curative options. Clinical, tumor, and patient characteristics in NAFLD-associated HCC differ from other etiologies. Older age and cardiovascular comorbidities may limit treatment options further. The outcome in patients with NAFLD-associated early HCC is excellent and therefore aggressive treatment should be pursued in appropriate patients. Population-based prevention to reduce the culprit-NAFLD-early recognition through targeted surveillance programs in risk-stratified patients and effective treatment of HCC associated with NAFLD are urgently needed. In this review, the authors summarize the epidemiology, risk factors, features, and prevention of NAFLD-associated HCC.

Ferroportin Disease (Haemochromatosis-type IV): a case report

Introdution: Haemochromatosis-type IV, the ferroportin disease, is characterized by an autosomal-dominant transmission and early iron accumulation in macrophages. It is caused by mutations in the transmembrane iron exporter protein ferroportin1 (SLC40A1 gene). In form A (classic), ferroportin loss of function mutants are unable to export iron from cells leading to cellular iron accumulation with decreased availability of iron for serum transferrin (TS). We present a Portuguese rare clinical case of HH-IV. Materials and Methods: A 41-year-old woman with hyperferritinemia and normal TS. Causes of hyperferritinemia (inflammation, chronic alcohol consumption, metabolic syndrome, cell necrosis, non-alcoholic fatty liver disease and aceruloplasminemia) were assessed. Liver iron, evaluated by magnetic resonance imaging (MRI) was carried out. Screening for mutation in HFE and SCL40A1 genes were performed by Sanger sequencing. Baseline: Ferritin:708ng/ml; TS: 27%; MRI:85µmol/g; Hb:13,6g/dl. Therapy: weekly 450ml Therapeutic Phlebotomies (TP) until ferritin≤50ng/ml. Results: Hyperferritinemia comorbidities and common genetic mutations for haemochromatosis were negative. However, sequencing of the patient SLC40A1 gene has revealed the presence in heterozygosity of the variant c.238G>A; p.Gly80Ser. Due to low tolerance to TP, we adopted smaller phlebotomies every three weeks. Conclusion: This patient has a rare autosomal-dominant Ferroportin disease due to a mutated ferroportin which is predicted to be defective in iron cellular export. In agreement, she presents hyperferritinemia, with normal TS and liver iron overload. The genotype/phenotype association allowed to diagnosis this rare FD case. Although a mild form A, we decided to start TP. Her father also has been treated for iron overload.