Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study.

UNLABELLED: Physical activity (PA) is commonly recommended for nonalchoholic fatty liver disease (NAFLD) patients. However, there is limited evidence on the independent role of PA in NAFLD. The aim of this study was to examine the association between PA and NAFLD. We conducted a cross-sectional study of a subsample (n = 375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for liver disease. Participants underwent an abdominal ultrasound examination; biochemical tests, including leptin, adiponectin, and resistin; and the noninvasive biomarker SteatoTest and anthropometric evaluations. A semiquantitative food frequency questionnaire and a detailed PA questionnaire were administered. Three hundred forty-nine patients (52.7% men, 30.9% primary NAFLD) were included. The NAFLD group engaged in less aerobic, resistance, or other kinds of PA (P

Pulmonary manifestations of liver diseases.

Respiratory problems are common in patients with chronic liver diseases. The most common causes are disorders that are not related to liver diseases such as asthma and COPD. In addition certain liver diseases that are associated with specific pulmonary abnormalities, and conditions associated with end stage liver disease like tense ascites and intercostal muscular wasting are considered. Finally two unique disorders characterizing by vascular abnormalities independent of cardiorespiratory disorder-the hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are observed. These disorders have different pathogenesis, different clinical pictures, treatment and prognosis. This article reviews the epidemiology, pathophysiology, clinical features, evaluation and current therapy of these two disorders.

The natural history and management of hepatorenal disorders: from pre-ascites to hepatorenal syndrome.

In cirrhosis, the natural history of hepatorenal disorders starts with a pre-ascitic stage and is followed by the development of ascites; hepatorenal syndrome (HRS) begins with compensated renal sodium retention, or pre-ascites. In pre-ascites, the renal sodium retaining tendency leads to 'overfilling' of total blood volume, with increased glomerular filtration rates (GFR), overcoming the renal sodium retaining tendency possibly due to renal accumulation of angiotensin II. As peripheral vasodilatation increases, the vascular capacity (in effect the arterial blood volume) becomes inadequately filled, GFR falls, compensatory vasoconstrictors rise, and the resulting renal sodium retention results in diuretic-responsive ascites formation. Increasing proximal reabsorption of sodium results in ascites refractory to diuretic therapy. Repeated abdominal paracentesis will not prevent insidious progression to HRS type II, nor to the precipitation of HRS type I. In contrast, liver transplantation, or transjugular intrahepatic hepatoportal stent shunt (TIPS) in refractory ascites, may prevent the onset of, or reverse, HRS. However, recent non-controlled studies indicate exciting possibilities of medical therapy reversing HRS.

Comparison of fatty liver index with noninvasive methods for steatosis detection and quantification.

AIM: To compare noninvasive methods presently used for steatosis detection and quantification in nonalcoholic fatty liver disease (NAFLD). METHODS: Cross-sectional study of subjects from the general population, a subgroup from the First Israeli National Health Survey, without excessive alcohol consumption or viral hepatitis. All subjects underwent anthropometric measurements and fasting blood tests. Evaluation of liver fat was performed using four noninvasive methods: the SteatoTest; the fatty liver index (FLI); regular abdominal ultrasound (AUS); and the hepatorenal ultrasound index (HRI). Two of the noninvasive methods have been validated vs liver biopsy and were considered as the reference methods: the HRI, the ratio between the median brightness level of the liver and right kidney cortex; and the SteatoTest, a biochemical surrogate marker of liver steatosis. The FLI is calculated by an algorithm based on triglycerides, body mass index, γ-glutamyl-transpeptidase and waist circumference, that has been validated only vs AUS. FLI < 30 rules out and FLI ≥ 60 rules in fatty liver. RESULTS: Three hundred and thirty-eight volunteers met the inclusion and exclusion criteria and had valid tests. The prevalence rate of NAFLD was 31.1% according to AUS. The FLI was very strongly correlated with SteatoTest (r = 0.91, P < 0.001) and to a lesser but significant degree with HRI (r = 0.55, P < 0.001). HRI and SteatoTest were significantly correlated (r = 0.52, P < 0.001). The κ between diagnosis of fatty liver by SteatoTest (≥ S2) and by FLI (≥ 60) was 0.74, which represented good agreement. The sensitivity of FLI vs SteatoTest was 85.5%, specificity 92.6%, positive predictive value (PPV) 74.7%, and negative predictive value (NPV) 96.1%. Most subjects (84.2%) with FLI < 60 had S0 and none had S3-S4. The κ between diagnosis of fatty liver by HRI (≥ 1.5) and by FLI (≥ 60) was 0.43, which represented only moderate agreement. The sensitivity of FLI vs HRI was 56.3%, specificity 86.5%, PPV 57.0%, and NPV 86.1%. The diagnostic accuracy of FLI for steatosis > 5%, as predicted by SteatoTest, yielded an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI: 0.95-0.98). The diagnostic accuracy of FLI for steatosis > 5%, as predicted by HRI, yielded an AUROC of 0.82 (95% CI: 0.77-0.87). The κ between diagnosis of fatty liver by AUS and by FLI (≥ 60) was 0.48 for the entire sample. However, after exclusion of all subjects with an intermediate FLI score of 30-60, the κ between diagnosis of fatty liver by AUS and by FLI either ≥ 60 or < 30 was 0.65, representing good agreement. Excluding all the subjects with an intermediate FLI score, the sensitivity of FLI was 80.3% and the specificity 87.3%. Only 8.5% of those with FLI < 30 had fatty liver on AUS, but 27.8% of those with FLI ≥ 60 had normal liver on AUS. CONCLUSION: FLI has striking agreement with SteatoTest and moderate agreements with AUS or HRI. However, if intermediate values are excluded FLI has high diagnostic value vs AUS.

The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease-induced liver injury: a study in the general population.

BACKGROUND AND AIM: Leptin and adiponectin have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). However, the usefulness of adipocytokines as a screening tool for nonalcoholic steatohepatitis (NASH) and fibrosis could not be evaluated in the general population due to the invasive nature of liver biopsy. The aim was to evaluate the association between adipocytokines and presumed liver injury in the general population using noninvasive biomarkers. METHODS: A cross-sectional study of 375 individuals, sampled from the National Health Survey was conducted. The exclusion criterion was any known secondary etiology for liver disease. Anthropometrics, serum leptin, adiponectin, insulin, lipids, and FibroMax were measured. RESULTS: Three hundred and thirty-eight individuals met the inclusion criteria and had valid FibroMax. Fibrosis diagnosed by the FibroTest was found in 25.7% of the patients, of whom 12.8% had significant fibrosis. Steatohepatitis was diagnosed by the NASH test in 0.9% and borderline NASH in 31.4% of the patients. Adiponectin was an independent negative correlate of borderline NASH [odds ratio (OR): 0.92; 95% confidence interval (CI): 0.86-0.98/1 µg/ml] together with high-density lipoprotein, and leptin was a positive correlate (OR: 1.03; CI: 1.01-1.06/1 ng/ml), together with abdominal obesity, serum triglycerides, and HbA1C. The OR for borderline NASH was 20.7 (CI: 7.5-57.5) when both high leptin (upper quartile) and suboptimal adiponectin were present, adjusting for age and sex. The FibroTest was not associated with leptin and adiponectin. The strongest predictors for fibrosis were age, sex, abdominal obesity, and insulin. CONCLUSION: Low adiponectin and high leptin and the combination of both have a strong independent association with presumed early-stage NASH. However, early-stage fibrosis cannot be predicted by these adipocytokines.

Sampling variability of transient elastography according to probe location.

BACKGROUND AND AIMS: Heterogeneity of fibrosis throughout the liver has been reported. However, the need for several measurements when using transient elastography was not thoroughly investigated. The aim was to find out whether measurement of liver stiffness varies according to the probe location. METHODS: Six hundred and twenty-five consecutive patients with chronic liver diseases referred for transient elastography were enrolled. All patients underwent successive liver stiffness measurements at three different sites. Representative measurements were acquisitions with a success rate greater than 60% and an interquartile range lower than 30% of the median. RESULTS: The sample included 371 eligible patients with three representative measurements. Comparing the three successive measurements categorized to fibrosis stages F0-F4, 68.2% of patients had agreement between all three sites. Discordance of one stage was noted in 28.3% of the patients, in 7% for two stages, and in 1.4% for three stages.The κ for comparing the maximal versus the minimal results was 0.43. There was no significant difference in the characteristics of patients with discordance and patients without discordance including age, sex, waist circumference, BMI, and etiology of liver disease. The stage of fibrosis was associated with discordance between measurements (P<0.001), demonstrating low discordance rate in patients with stages F0-F1 or F4 and high discordance rate in patients with stages F2 and F3. CONCLUSION: Sampling variability according to probe location is seen in transient elastography in approximately 30% of patients. Therefore, it may be suggested to perform transient elastography from various sites to minimize the sample error.

Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study.

BACKGROUND/AIMS: Weight loss is considered therapeutic for patients with NAFLD. However, there is no epidemiological evidence that dietary habits are associated with NAFLD. Dietary patterns associated with primary NAFLD were investigated. METHODS: A cross-sectional study of a sub-sample (n=375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for secondary NAFLD. Participants underwent an abdominal ultrasound, biochemical tests, dietary and anthropometric evaluations. A semi-quantitative food-frequency questionnaire was administered. RESULTS: After exclusion, 349 volunteers (52.7% male, mean age 50.7+/-10.4, 30.9% primary NAFLD) were included. The NAFLD group consumed almost twice the amount of soft drinks (P=0.03) and 27% more meat (P<0.001). In contrast, the NAFLD group consumed somewhat less fish rich in omega-3 (P=0.056). Adjusting for age, gender, BMI and total calories, intake of soft drinks and meat was significantly associated with an increased risk for NAFLD (OR=1.45, 1.13-1.85 95% CI and OR=1.37, 1.04-1.83 95% CI, respectively). CONCLUSIONS: NAFLD patients have a higher intake of soft drinks and meat and a tendency towards a lower intake of fish rich in omega-3. Moreover, a higher intake of soft drinks and meat is associated with an increased risk of NAFLD, independently of age, gender, BMI and total calories.

Role of CYP2D6 polymorphism in predicting liver fibrosis progression rate in Caucasian patients with chronic hepatitis C.

OBJECTIVE: Previous studies have demonstrated that CYP2D6 polymorphism is associated with liver cirrhosis. The aim of the present study was to find out whether CYP2D6*4, the poor metabolizer allele can predict fibrosis progression rate. METHODS: Seventy-five Caucasian patients with chronic hepatitis C infection were recruited. They were divided into two groups, 'fast fibrosers' and 'slow fibrosers', according to Poynard's fibrosis progression curves. Sixty-two patients underwent liver biopsy. Twenty healthy neonates were included as control population. DNA was extracted from peripheral blood and CYP2D6*4 was tested by polymer chain reaction using fluorescent hybridization probes in a lightCycler instrument. RESULTS: Forty-two patients were classified as 'fast fibrosers' and 33 patients as 'slow fibrosers'. The frequency of CYP2D6*4 allele in the 'fast fibrosers' (34.5%) was significantly higher compared with the 'slow fibrosers' (15%) (P-value=0.007). There was no significant difference between the frequency of CYP2D6*4 in the 'slow fibrosers' (15%) compared with the controls (12.5%). Carrier state of CYP2D6*4 was the only covariate that was significantly positively correlated with fast progression to cirrhosis (odds ratio=6.5, P=0.01). CONCLUSION: This study indicates for the first time that CYP2D6 genotype might be a significant predictor of liver fibrosis progression rate in chronic hepatitis C patients.

Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study.

BACKGROUND: The upper normal limit (ULN) of serum alanine-aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have 'normal' or near-'normal' ALT levels, and because possible modulators are often ignored in determining normal range. AIM: To estimate the ULN for serum ALT and to identify factors modulating it. SUBJECTS AND METHODS: We reviewed medical records of subjects aged 15-90, who underwent standard panels of laboratory tests, including serum ALT, over 6 months at a central laboratory. Three groups were defined: Group 1, comprised total study population (N=272 273). Group 2 (N=87 020) comprised total study population, excluding those receiving potentially hepatotoxic drugs, or diagnosed with liver disease, or had any abnormal laboratory test results other than for triglycerides, cholesterol, glucose, or HbA1c. Group 3 (N=17 496) the 'healthy' population, from whose ALT values we established the new ULN, comprised Group 2 subjects with normal triglycerides, cholesterol, glucose, and HbA1c levels. RESULTS: The 95th percentile ALT values, corresponding to the ULN, in groups 1, 2, and 3 were 50.1, 40, and 37.5 U/l, respectively. 6.2% (16 943/273 273) of subjects whose ALT was below ULN listed by the test manufacturer (52 U/l), had ALT level above our new ULN. Linear and logistic-regression analyses showed that ALT levels were significantly modified by gender, age, glucose, cholesterol, triglycerides, and overweight/obesity diagnosis. Significant interaction was found between gender, glucose and cholesterol levels. CONCLUSIONS: In this first large-scale study of 'healthy' population, serum ALT ULN was far lower than currently accepted value. Age and gender may be considered when determining the ULN for ALT.