The association between liver fibrosis score and incident dementia: A nationwide retrospective cohort study.

BACKGROUND: We assessed the relationship of liver fibrosis score with incident dementia in a large, national sample. METHODS: For this retrospective cohort study, data of dementia-free individuals aged 40-69 years were derived from electronic records of the largest healthcare provider in Israel. The association between liver fibrosis score (FIB-4), assessed from routine laboratory measurements, and incident dementia was explored through multivariate cox regression models. RESULTS: Of the total sample (N = 826,578, mean age 55 ± 8 years at baseline), 636,967 (77%) had no fibrosis, 180,114 (21.8%) had inconclusive fibrosis status and 9497 (1.2%) had high risk for advanced fibrosis. Over a median follow-up of 17 years, 41,089 dementia cases were recorded. Inconclusive liver fibrosis and advanced fibrosis were associated with increased dementia risk (HR = 1.09, 95%CI: 1.07-1.11 and HR = 1.18, 95%CI: 1.10-1.27, respectively). This association remained robust through seven sensitivity analyses. CONCLUSIONS: Liver fibrosis assessed through a serum-based algorithm may serve as a risk factor for dementia in the general population. HIGHLIGHTS: Liver fibrosis may predict dementia diagnosis in the general population. Inconclusive liver fibrosis was associated with 9% increased dementia risk. Advanced liver fibrosis was associated with 18% increased dementia risk. Findings remained robust in sensitivity analyses and after adjustments.

Liver fibrosis marker is an independent predictor of cardiovascular morbidity and mortality in the general population.

BACKGROUND: A growing body of evidence suggests that Non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are associated with cardiovascular disease (CVD). However, the independent role of liver fibrosis markers in the prediction of CVD in the general population is seldom tested. AIMS: To assess whether a marker of liver fibrosis predicts the first occurrence of a CVD event in a large sample of community-based general population. METHODS: Historical cohort using data from a large health provider that operates a centralized computerized medical record. The level of liver fibrosis was measured by the fibrosis-4 (FIB-4) score, and the association with CVD was adjusted for the European Systematic Coronary Risk Evaluation calculator (SCORE). RESULTS: The study included 8,511 individuals, 3,292 with inconclusive fibrosis and 195 with advanced fibrosis (FIB-4 ≥ 2.67). People with advanced fibrosis had higher risk for CVD, after adjustment for sociodemographic characteristics, the SCORE, use of statins and aspirin (HR [95%CI], 1.63 [1.29-2.06]). The association persisted in both women and men. Using age-specific cut-offs, there was a dose-response association between inconclusive and advanced fibrosis and CVD (HR [95%CI], 1.15 [1.01-1.31]) and HR [95%CI], 1.60 [1.27-2.01], respectively, P for trend<0.001). CONCLUSIONS: A simple fibrosis score is independently associated with CVD, suggesting that fibrosis markers should be considered in primary-care risk assessment.

Comparison of antidepressant use between adult populations living in urban and rural communities in Israel.

Background: Depression and anxiety are among the most prevalent disorders in primary care. City dwelling is commonly cited as a risk factor for mental disorders, but epidemiological evidence for this relationship is inconclusive. Objective: To compare the prevalence of antidepressant use, as a proxy for the level of depressive disorders, between patients in Israeli urban and rural communities. Methods: A cross-sectional study, based on data drawn from the registry of the largest health maintenance organization in Israel. The prevalence of antidepressant purchase during 2014 was evaluated for 581291 patients living in urban and rural communities. Data were also collected for potential confounding variables: age, gender, comorbidity, socioeconomic status and being a holocaust survivor. Results: Results showed higher rates of antidepressant use among patients living in urban (11.8%) compared with rural communities (8.1%; <0.001). A particularly high rate of antidepressant use was found on kibbutz (15.9%), a collective rural community in Israel, compared with both urban and other rural communities. Kibbutz compared with other rural communities: odds ratio (OR) = 1.73, P < 0.001; urban communities compared with non-kibbutz rural communities: OR = 1.21, P < 0.001. A significantly lower rate of antidepressant use was found in urban and rural Arab-majority communities (3.9% and 3.8%, respectively). Conclusions: Antidepressant use varies significantly between different communities in Israel. The highest rate of antidepressant use in our study was found on kibbutz, followed by that in urban communities, with the lowest rates in non-kibbutz rural communities. This difference may derive from different depression rates, stigma of mental illness and awareness of mental disorders.

Validation of the 2016 USPSTF recommendations for primary cardiovascular prevention in a large contemporary cohort.

Aims The aim of this study was to evaluate the performance of the US Preventive Services Task Force (USPSTF) cholesterol recommendations in a contemporary non-US cohort. Methods and results This is a historical cohort analysis of electronic records from Israel's largest health provider. All patients in the Tel Aviv district eligible for primary cardiovascular prevention were followed between January 2005 and December 2015. Risk was estimated by the pooled cohort equations. Statin eligibility was determined by USPSTF and American College of Cardiology and American Heart Association (ACC/AHA) recommendations. Atherosclerotic cardiovascular disease events were retrieved from electronic registration. The mean ± standard deviation age of the 10,889 (98,258 person-years) participants was 60.3 ± 9.4 years, and 69.1% were women. Outcome events were recorded for 1351 patients (12.4%). Treatment recommendations were discordant in 901 patients (8.3%) whose treatment was indicated only by the ACC/AHA guidelines, implying a 26% reduction in newly eligible patients for statin treatment had the USPSTF recommendations been implemented. Among the statin-naive patients, the pooled cohort equations underestimated the risk, with a predicted-to-observed event ratio of 0.88. The recommended treatment thresholds provided excellent calibration, with ratios of 1.0 for USPSTF and 0.98 for ACC/AHA-eligible patients. Both models showed similar discrimination (Harrel's C = 0.63 (0.62-0.65) for USPSTF vs. 0.64 (0.63-0.66) for ACC/AHA, P = 0.26). The USPSTF recommendations were less sensitive and more specific for the detection of outcome events than the ACC/AHA recommendations (61% vs. 75% and 68% vs. 55%, respectively). The net reclassification index was -0.01. Conclusions Calibration, discrimination and net reclassifications were very similar for USPSTF and ACC/AHA recommendations. Applying the USPSTF recommendations could reduce over-treatment.

Role of illness perception and self-efficacy in lifestyle modification among non-alcoholic fatty liver disease patients.

AIM: To describe the relationships between non-alcoholic fatty-liver disease (NAFLD) patient's disease consequences and treatment perceptions, self-efficacy, and healthy lifestyle maintenance. METHODS: A cross-sectional study among 146 ultrasound diagnosed NAFLD patients who visited the fatty liver clinic at the Tel-Aviv Medical Center. Eighty-seven of these individuals, participated in a clinical trial of physical activity and underwent fasting blood tests, analyzed at the same lab. Exclusion criteria included positivity for serum HBsAg or anti-HCV antibodies; fatty liver suspected to be secondary to hepatotoxic drugs; excessive alcohol consumption (≥ 30 g/d in men or ≥ 20 g/d in women) and positive markers of genetic or immune-mediated liver diseases. Patients were asked to complete a self-report structured questionnaire, assembled by the Israeli Center for Disease Control. Nutrition habits were measured using six yes/no questions (0 = no, 1 = yes) adopted from the national survey questionnaire. Participants in the clinical trial completed a detailed semi-quantitative food frequency questionnaire (FFQ) reporting their habitual nutritional intake during the past year. Self-efficacy was assessed by the Self-Efficacy Scale questionnaire, emotional representation, degree of illness understanding, timeline perception, treatment perception and symptoms were measured by the Brief Illness Perception questionnaire. Illness consequences were measured by the Personal Models of Diabetes Interview questionnaire. A path analysis was performed to describe the interrelationships between the patients' illness perceptions, and assess the extent to which the data fit a prediction of nutritional habits. RESULTS: The study sample included 54.1% men, with a mean age of 47.76 ± 11.68 years (range: 20-60) and mean body mass index of 31.56 ± 4.6. The average perceived nutrition habits score was 4.73 ± 1.45 on a scale between 0-6, where 6 represents the healthiest eating habits. Most of the study participants (57.2%) did not feel they fully understood what NAFLD is. Better nutritional habits were positively predicted by the degree of illness understanding (ß = 0.26; P = 0.002) and self-efficacy (ß = 0.25; P = 0.003). Perceptions of more severe illness consequences were related with higher emotional representation (ß = 0.55; P < 0.001), which was related with lower self-efficacy (ß = -0.17; P = 0.034). The perception of treatment effectiveness was positively related with self-efficacy (ß = 0.32; P < 0.001). In accordance with the correlation between self-efficacy and the perceived nutrition habits score, self-efficacy was also correlated with nutrient intake evaluated by the FFQ; negatively with saturated fat (percent of saturated fat calories from total calories) (r = -0.28, P = 0.010) and positively with fiber (r = 0.22, P = 0.047) and vitamin C intake (r = 0.34, P = 0.002). In a sub analysis of the clinical trial participants, objectively measured compliance to physical activity regimen was positively correlated with the self-efficacy level (r = 0.34, P = 0.046). CONCLUSION: Self-efficacy and illness understanding are major determinants of lifestyle-modification among NAFLD patients. This information can assist clinicians in improving compliance with lifestyle changes among these patients.

Protective role of soluble receptor for advanced glycation end-products in patients with non-alcoholic fatty liver disease.

BACKGROUND: Soluble receptor for advanced glycation end-products (sRAGE) exerts protective metabolic effects. AIMS: To identify if sRAGE plays a protective role in NAFLD. METHODS: sRAGE (n=55) and Nε-(Carboxymethyl) lysine (CML) (n=36) serum levels were measured in NAFLD patients. Liver steatosis and fibrosis were non-invasively quantified by the hepatorenal index and the NAFLD fibrosis score (NFS). RESULTS: sRAGE levels were lower in NAFLD patients compared to controls (1207±439 vs. 1596±562ng/l, P<0.001) and were lower among subjects with moderate-severe steatosis compared with mild (1043±287 vs. 1378±506, P=0.005). Higher sRAGE was associated with lower steatosis with adjustment for age, gender, BMI and fasting insulin (OR=0.998, 0.996-0.999 95%CI, P=0.018). CML was not correlated with liver steatosis (r=0.07, P=0.683), but was positively correlated with AST (r=0.34, P=0.04), GGT (r=0.38, P=0.023) and HbA1C (r=0.37, P=0.027). sRAGE tended to be higher in subjects with NFS<-1.455 compared with NFS>-1.455 (1287±450 n=36 vs. 1051±364 n=13, P=0.08). While sRAGE was positively correlated with vegetables consumption (r=0.268, P=0.05), CML levels were not associated with sRAGE or dietary intake. sRAGE increased following a 3 month-lifestyle intervention (1194±446 vs. 1367±440 n=31, P<0.001) and change in sRAGE levels was negatively correlated with change in ALT levels (r=-0.37, P=0.041). CONCLUSION: sRAGE plays a protective role in NAFLD and it is influenced by lifestyle.

Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.

Retrospective studies suggest that coffee consumption may exert beneficial effects in patients with nonalcoholic fatty liver; however, prospective data supporting a protective role on liver steatosis development are lacking. In this study, we aimed to evaluate the association between coffee consumption and fatty liver onset in the general population. The analysis was performed both in a cross-sectional cohort (n = 347) and, prospectively, in a subcohort of patients without fatty liver at baseline and followed-up for 7 years (n = 147). Fatty liver was diagnosed with abdominal ultrasound and liver steatosis was quantified noninvasively by hepatorenal index (HRI) and SteatoTest, whereas FibroTest was used to assess fibrosis degree. A structured questionnaire on coffee consumption was administrated during a face-to-face interview. Neither the incidence nor the prevalence of fatty liver according to ultrasonography, SteatoTest, and the HRI was associated with coffee consumption. In the cross-sectional study, high coffee consumption was associated with a lower proportion of clinically significant fibrosis ≥ F2 (8.8% vs 16.3%; P = 0.038); consistently, in multivariate logistic regression analysis, high coffee consumption was associated with lower odds for significant fibrosis (odds ratio = 0.49, 95% confidence interval, 0.25-0.97; P = 0.041) and was the strongest predictor for significant fibrosis. No association was demonstrated between coffee consumption and the new onset of nonalcoholic fatty liver, but coffee intake may exert beneficial effects on fibrosis progression.

Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial.

AIM: To evaluate the effect of resistance training (RT) on non alcoholic liver disease (NAFLD) patients. METHODS: A randomized clinical trial enrolling NAFLD patients without secondary liver disease (e.g., without hepatitis B virus, hepatitis C virus or excessive alcohol consumption). Patients were randomly allocated either to RT, three times weekly, for 3 mo or a control arm consisting of home stretching. The RT included leg press, chest press, seated rowing, latissimus pull down etc. with 8-12 repetitions, 3 sets for each exercise, for a total duration of 40 min. Hepatic ultrasound, fasting blood tests, anthropometrics and body composition by dual energy X-ray absorptiometry were assessed. At baseline and follow-up, patients filled out a detailed semi-quantitative food frequency questionnaire reporting their habitual nutritional intake. Steatosis was quantified by the hepatorenal-ultrasound index (HRI) representing the ratio between the brightness level of the liver and the right kidney. The HRI has been previously demonstrated to be highly reproducible and was validated against liver biopsy and proton magnetic resonance spectroscopy. RESULTS: Eighty two patients with primary NAFLD were randomized to receive 3 mo of either RT or stretching. After dropout or exclusion from analysis because of protocol violation (weight change > 3 kg), thirty three patients in the RT arm and 31 in the stretching arm completed the study per protocol. All baseline characteristics were similar for the two treatment groups with respect to demographics, anthropometrics and body composition, blood tests and liver steatosis on imaging. HRI score was reduced significantly in the RT arm as compared to the stretching arm (-0.25 ± 0.37 vs -0.05 ± 0.28, P = 0.017). The RT arm had a significantly higher reduction in total, trunk and android fat with increase in lean body mass. There was no correlation between the reduction in HRI in the RT arm and weight change during the study, but it was positively correlated with the change in trunk fat (r = 0.37, P = 0.048). The RT arm had a significant reduction in serum ferritin and total cholesterol. There was no significant difference between arms in dietary changes and these did not correlate with HRI change. CONCLUSION: Three months RT improves hepatic fat content accompanied by favorable changes in body composition and ferritin. RT may serve as a complement to treatment of NAFLD.

Non-high-density lipoprotein cholesterol independently predicts new onset of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular disease (CVD) risk. Non-high-density lipoprotein cholesterol (non-HDL-C), i.e. total cholesterol minus HDL, is a well-established risk factor for CVD; however, its association with NAFLD development has not been established. Our aim was to test whether non-HDL-C is an independent predictor of new onset of NAFLD. METHODS: A prospective cohort study of 213 subjects from the general population, without liver disease, was studied. Evaluation of medical history, dietary and physical activity habits, fasting blood tests and ultrasonographic evidence of NAFLD was performed at baseline and after a 7-year follow-up by identical protocols. RESULTS: From 147 patients that did not have NAFLD at baseline, 28 (19%) developed NAFLD at the 7-year follow-up. The baseline levels of non-HDL-C were higher among subjects who developed NAFLD (179.5 ± 37.1 vs. 157.3 ± 35.1 mg/dl, P = 0.003). Non-HDL-C independently predicted new onset of NAFLD adjusting for age, gender, BMI or waist circumference, lifestyle and serum insulin (OR = 1.02 for every mg/dl increment, 1.01-1.04 95% CI, P = 0.008). Non-HDL-C was a stronger predictor for NAFLD than total cholesterol, low-density lipoprotein cholesterol, triglycerides and HDL. No patients with non-HDL-C < 130 mg/dl developed NAFLD, whereas 20.8% of those with values between 130 to 160 and 24.6% of those with values >160 mg/dl developed NAFLD (P for trend = 0.015). CONCLUSIONS: Non-HDL-C is an independent predictor for NAFLD and a stronger predictor than other lipoproteins. This association may stem from the combined hepato-toxic effect of non-HDL-C and may explain the association between NAFLD and CVD.

Retinal blood flow velocity in metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is characterized by obesity, insulin resistance, dyslipidemia, and hypertension. The Retinal Function Imager (RFI) is a new technique for measuring retinal blood-flow velocity. This study aims to compare retinal blood flow velocity between MetS and healthy subjects. METHODS: Twenty eyes of 20 MetS males and 21 eyes of 21 aged-matched healthy males underwent RFI and carotid-femoral pulse wave velocity (PWV) measurement as well as assessment of MetS parameters. The results in MetS and healthy subjects were compared. RESULTS: The average venular velocity in the MetS patients was significantly higher than in the healthy subjects (2.7 ± 0.0 mm/sec versus 2.5 ± 0.0 mm/sec respectively, P=0.013), following adjustment for age, heart rate and systolic blood pressure. Carotid-femoral PWV was higher in the MetS population than the healthy controls (10.3 ± 1.2 mm/sec versus 9.3 ± 1.5 mm/sec respectively, P=0.005). The diastolic blood pressure and MAP were correlated strongly with the arterial blood flow velocities in healthy subjects (r=0.503, P=0.020 and r=0.474, P=0.030 respectively) but not in MetS subjects. CONCLUSIONS: The RFI was able to distinguish between the retinal blood flow of normal and MetS subjects. Higher venular blood flow velocity and the poor correlation between velocity and blood pressure of MetS subjects suggest that MetS causes microvascular damage.

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.

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.

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.

Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver steatosis.

OBJECTIVE: Quantification of liver steatosis is clinically relevant in various liver diseases but cannot be done by conventional sonography, which only provides a qualitative assessment with significant observer variability. The aim of this study was to assess sonography as an objective tool for the quantification of liver steatosis. MATERIALS AND METHODS: Files of 111 patients with chronic liver disease who were referred for sonographically guided liver biopsy were collected. A hepatorenal sonographic index was calculated on the basis of the ratio between the echogenicity of the liver and that of the right kidney cortex using histogram echo intensity. Liver steatosis was graded by histology. RESULTS: A significant correlation was found between histologic steatosis and the hepatorenal sonographic index (r = 0.82, p < 0.001). The validity of the hepatorenal sonographic index for the diagnosis of fatty liver was compared with liver biopsies with a steatosis level > 5%. The area under the receiver operating characteristic curve was 99.2% (95% CI, 98-100%). The optimal hepatorenal sonographic index cutoff point for the prediction of steatosis > 5% was 1.49, with sensitivity of 100% and specificity of 91%. The optimal hepatorenal sonographic index cutoff point for the prediction of steatosis >/= 25% was 1.86, with sensitivity of 90% and specificity of 90%. The optimal hepatorenal sonographic index cutoff point for the prediction of steatosis >/= 60% was 2.23, with sensitivity of 90% and specificity of 93%. CONCLUSION: The hepatorenal sonographic index is a sensitive noninvasive method for steatosis quantification. It can diagnose small amounts of liver fat that would be missed by conventional sonography. It is reproducible and operator independent and can serve as an efficient tool to follow patients with steatosis and evaluate the efficacy of new treatment techniques.