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Nonalcoholic fatty liver disease (NAFLD), depression, and anxiety disorders are frequent diseases, and data on mutual influence are inconsistent. The aim of this study was to explore the incidence of depression and anxiety in a large primary care cohort in Germany and to study the impact of NAFLD over a 10‐year time frame. Patients with NAFLD diagnosed between 2010 and 2015 were matched to a cohort without NAFLD controlling for age, sex, physician, index year, and Charlson comorbidity index. The primary outcome of the study was the incidence of depression, anxiety, and first prescription of antidepressant drugs. We compared 19,871 patients with NAFLD to 19,871 matched controls. Within 10 years of the index date, 21.2% of patients with NAFLD and 18.2% of controls were diagnosed with depression (P < 0.001). On regression analysis, the hazard ratio (HR) for incidence of depression was 1.21 (P < 0.001). This association was similar for the endpoint of the first prescription of antidepressant drugs (HR, 1.21; P < 0.001). Anxiety disorders were diagnosed in 7.9% of patients with NAFLD and 6.5% of controls during the observation time (P = 0.003). The HR for incidence of anxiety was 1.23 (P < 0.001). This association remained significant in women (P < 0.001), while there was only a trend in men (HR, 1.15; 95% confidence interval, 0.99‐1.34; P < 0.067). The risk of developing anxiety disorders was higher in younger patients. Conclusion: NAFLD constitutes an independent risk factor for emerging depression and anxiety even after controlling for confounding comorbidities.

Reproducible animal models to recapitulate the pathophysiology of non-alcoholic fatty liver disease (NAFLD) are urgently required to improve the understanding of the mechanisms of liver injury and to explore novel therapeutic options. Current guidelines recommend life-style interventions as first-line therapy for NAFLD and these types of intervention are considered standard-of-care. The current study establishes a reproducible mouse model of a life-style intervention in NAFLD using voluntary wheel running (VWR). Male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) to induce NAFLD or a corresponding control diet for 12 weeks. Starting at week 9 of the obesogenic NAFLD diet, mice were randomized to either free access to a running wheel or being single caged resembling a sedentary (SED) life-style. VWR induced a transient weight reduction in HFD-fed mice up until week 10. In contrast to the SED mice, VWR mice exhibited normal ALT at the end of the intervention, while the metabolic alterations including elevated fasting glucose, insulin, triglyceride, and total cholesterol levels remained almost unchanged. Additionally, VWR prevented HFD-induced hepatic steatosis by alterations in key liver metabolic processes including the induction of fatty acid β-oxidation and lipogenesis inhibition following increased AMP-activated protein kinase (AMPK)-α activity. Phosphorylation of the serine kinase Akt in hepatic tissue was enhanced following VWR. Furthermore, VWR mice were protected from HFD-induced expression of pro-inflammatory cytokines, chemokines and liver macrophage infiltration. The SED/HFD group exhibited increasing activity of hepatic nuclear factor (NF)-κB p65, which was absent following exercise in the VWR/HFD group. In summary, in an obesogenic mouse model of NAFLD physical exercise improves fatty acid and glucose homeostasis and protects from macrophage-associated hepatic inflammation.

The prevalence of liver disease, and especially of advanced liver fibrosis, in the German population is poorly defined. The aim of the study was to explore liver enzymes and surrogate scores of hepatic steatosis and advanced hepatic fibrosis in a population‐based cohort study in Germany. In the cross‐sectional population‐based Gutenberg Health study, data of 14,950 participants enrolled between 2007 and 2012 were captured and analyzed. The distribution of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‐glutamyltransferase (GGT), fatty liver index (FLI), and Fibrosis‐4 (FIB‐4) score, as well as the underlying risk factors, were assessed by regression models. Elevated liver enzymes in this population‐based sample were seen in 19.9% for ALT, 12.8% for AST, and 14% for GGT. Risk factors for liver disease included alcohol use and the presence of the metabolic syndrome, which were both risk factors associated with increased liver enzymes. The FLI suggested that 37.5% of the population exhibited hepatic steatosis and 1.1% of patients exhibited a FIB‐4 above the upper cutoff, while 19.2% were in the intermediate range. Interestingly, advanced fibrosis was significantly more frequent in men compared with women (FIB‐4: 1.5% vs. 0.6% [P < 0.0001]; NFS: 3.6% vs. 1.9% [P < 0.0001]). In addition, age was a relevant risk factor for exhibiting a noninvasive surrogate score suggestive of advanced fibrosis in the current study population. Conclusion: Elevated liver enzymes were seen in almost a fifth of the German population. At the population‐based level, the prevalence of advanced fibrosis was estimated at 1% in Germany.

Background In hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed. Methods IGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS). Results Liver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC ( p  < 0.01). A lower serum level of IGF-1 was associated with more advanced stages of liver cirrhosis ( p  < 0.05) and cancer stages ( p  < 0.001). Median OS in the cohort was 11.4 months (range 0.5–118.2 months). OS was significantly higher (10.9 vs. 7.9 months; p < 0.05) in patients with a serum IGF-1 level above the median of 43.4 ng/mL. Patient reassignment using IGF-CTP scoring reclassified 35.6% of patients. Through reassignment, stratification regarding OS was comparable to CTP. Conclusions This study is the first to investigate IGF-1 and the IGF-CTP classification in a European cohort of HCC patients. Serum IGF-1 correlates with OS in patients with HCC. However, the IGF-CTP classification was not superior compared to CTP score regarding OS.

Hepatic steatosis (HS) related to nonalcoholic fatty liver disease (NAFLD) is increasing globally. In people living with human immunodeficiency virus (PLWH) risk factors of HS are increased. The impact of HS on outcomes and in particular health‐related quality of life (HRQL) in PLWH remains unknown. The aim of this cross‐sectional cohort study (FLASH, Prevalence of Advanced Fibrosis in Patients Living With HIV) was to determine the contribution of HS on HRQL in PLWH and to identify confounders on HRQL. A total of 245 PLWH were prospectively enrolled. HS was assessed using vibration‐controlled transient elastography and defined as a controlled attenuation parameter (CAP) of ≥ 275 dB/m. The analysis was performed between CAP < 275 and ≥ 275 dB/m. The generic European Quality‐of‐Life 5‐Dimension 5‐Level questionnaire was used to determine differences in the HRQL. Univariable and multivariable linear regression models were applied to identify predictors with impaired HRQL in both groups. In this cohort, 65% (n = 160) presented without and 35% (n = 85) with HS, of whom most had NAFLD (n = 65, 76.5%). The HRQL (UI‐value) was significantly lower in PLWH and steatosis (0.86 ± 0.18) in comparison with no steatosis (0.92 ± 0.13). Unemployment (p = 0.025) and waist circumference (p = 0.017) remained independent predictors of a poor HRQL in the steatosis subgroup. In turn, age (p = 0.045), female sex (p = 0.030), body mass index (p = 0.010), and arterial hypertension (p = 0.025) were independent predictors of a low HRQL in the subgroup without steatosis. Conclusion: HS and metabolic comorbidities negatively affect the HRQL. Addressing these factors may improve patient‐reported and liver‐related outcomes in PLWH. Despite a high prevalence of hepatic steatosis and NAFLD in people living with HIV (PLWH), the impact on health‐related quality of life (HRQL) remains unknown to date. We analyzed the HRQL in PLWH and hepatic steatosis using the generic EQ‐5D‐5L questionnaire and observed a lower HRQL compared to PLWH without steatosis. Addressing hepatic steatosis and its metabolic comorbidities may improve patient reported and liver‐related outcomes in PLWH.

Despite the negative impact of covert hepatic encephalopathy on the outcome of patients with liver cirrhosis, data regarding the ability of different testing strategies to predict overt hepatic encephalopathy (OHE) development and mortality are limited. This study aimed to compare the ability of Psychometric Hepatic Encephalopathy Score (PHES), critical flicker frequency (CFF), simplified animal naming test (S-ANT1), and clinical covert hepatic encephalopathy (CCHE) score to predict OHE development and mortality. A total of 224 patients with liver cirrhosis were tested with different testing strategies and prospectively followed up regarding clinically relevant outcomes (OHE or death/liver transplantation). Prevalence of pathological results varied among the testing strategies: PHES 33.9%, CFF 17.9%, S-ANT1 41.5%, and CCHE score 33.9%. All testing strategies were independent predictors of OHE development after adjusting for model of end-stage liver disease (MELD) score and history of OHE. The predictive performances of PHES (area under the receiver operating characteristic curve, 0.742) and CCHE (area under the receiver operating characteristic curve, 0.785) regarding OHE development during the next 180 days were significantly better than those of CFF and S-ANT1. In multivariable analysis, pathological results in PHES, S-ANT1, and CCHE score were independently associated with higher mortality. CFF did not correlate with mortality in the whole cohort. In the subgroup of patients with a MELD score <15, pathological results in PHES, CFF, or CCHE score were independent predictors of higher mortality. PHES and CCHE score predict OHE development and mortality in patients with liver cirrhosis. In particular, in patients with low MELD score, both testing strategies could help to identify patients who might benefit from liver transplantation.

Cardiovascular disease (CVD) is the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The current analysis expands the knowledge on atherogenic lipid profiles in NAFLD by modeling changes in low‐density lipoprotein cholesterol (LDL‐C) and total cholesterol (TC) in a prospectively enrolling real‐life study cohort to inform physicians on the cardiovascular (CV) event risk based on these changes. A total of 304 patients with histologically confirmed NAFLD were included (mean age, 52 years; equal sex distribution). Of these, 129 (42.4%) patients exhibited a NAFLD activity score ≥4 and 186 (61.2%) had at least intermediate fibrosis ≥F2. The median TC levels were 209 mg/dL (interquartile range [IQR], 183, 239), LDL‐C 131 mg/dL (IQR, 103, 152), and high‐density lipoprotein cholesterol (HDL‐C) 45 mg/dL (IQR, 38, 52). Only 16.9% of patients received lipid‐lowering therapy. According to the LDL/HDL ratio, 69 (23.7%) patients exhibited a high CV risk. The 10‐year CV event risk according to the Framingham risk score (FRS) was low in 91 (41.2%), intermediate in 59 (26.7%), and high in 71 (32.1%) patients and higher in the ≥F2 NAFLD population. A moderate increase in LDL‐C levels by 20 mg/dL led to a transition of 20% of patients into the high‐risk group when assessing the LDL/HDL ratio. According to the FRS, 6 (2.7%) patients moved from low to intermediate and 11 (4.9%) from intermediate to high CV risk. Conclusion: Patients with NAFLD exhibit a substantial CV event risk and are frequently undertreated with lipid‐lowering medication. Moderate increases in LDL‐C would result in worsening of the CV event risk in approximately 7.8% of all patients without a history of CVD. NAFLD patients exhibit an increased cardiovascular mortality. Assessment of the cardiovascular event risk will help clinicians to manage these patients. The current analysis provides real‐world evidence in a cohort of biopsy‐proven NAFLD patients and segregates high and low risk categories for incident CVD disease. This data will support in the decision on pharmacotherapy and in particular NASH‐directed therapies in the future.

Physical activity confers a broad spectrum of health benefits. Beyond the obvious role in metabolically driven diseases, the role of physical activity in acute liver injury is poorly explored. To study the role of physical activity in acute liver injury, a novel model of voluntary distance running in mice was developed and mice were subjected to acute liver injury induced by N -galactosamine (GalN) and lipopolysaccharide (LPS). Analyses included histological stains, immunoblotting, qRT-PCR and FACS analysis. Voluntary distance running increased to an average of 10.3 km/day after a learning curve. Running lead to a decrease in the absolute numbers of intrahepatic CD4+ T and B lymphocytes and macrophages after 7 weeks. In parallel, hepatic mRNA expression of inflammatory cytokines including IL-6 and IL-1beta, TGF-beta and monocyte chemoattractant protein-1 (MCP-1/CCL2) were suppressed, while TNF-α was not affected by exercise. Likewise, expression of the macrophage-specific antigen F4/80 was downregulated 1.6-fold from exercise. Notably, acute liver injury from GaIN/LPS was significantly blunted following 7 weeks of voluntary exercise as determined by liver histology, a 84.6% reduction of alanine aminotransferase ( P <0.01) and a 54.6% reduction of aspartate aminotransferase ( P <0.05) compared with sedentary mice. Additionally, proinflammatory cytokines, activation of caspase 3 and JNK were significantly lower, while antiapoptotic protein A20 increased. Voluntary distance running alters the intrahepatic immune phenotype producing an environment that is less susceptible to acute liver injury.

BackgroundPatients with NAFLD are considered at a high risk of cardiovascular events due to underlying metabolic risk factors. Currently, data related to the impact of NAFLD on cardiovascular risk in the general population are lacking.AimsThe aim of this study was to investigate the role of NAFLD on risk of myocardial infarction (MI), coronary heart disease (CHD), atrial fibrillation (AF), and stroke in primary care in Germany.MethodsThe study included patients diagnosed with NAFLD in primary care between 2010 and 2015. NAFLD cases (n = 22,048) were matched to a cohort without NAFLD (n = 22,048) based on age, sex, treating physician, type 2 diabetes, arterial hypertension, and hyperlipidemia. The primary outcome of the study was the incidence of MI, CHD, AF, and stroke.ResultsWithin 10 years of the index date, 12.8% of patients with NAFLD and 10.0% of controls were diagnosed with CHD (p < 0.001). Additionally, frequency of MI was significantly higher in NAFLD (2.9% vs. 2.3%, p < 0.001). On regression analysis, HR for incidence of MI was 1.34 (p = 0.003) in all NAFLD patients and 1.35 (p = 0.013) for men. Incidence of AF was significantly higher in patients with NAFLD. On regression analysis, HR for incidence of AF was 1.15 (p = 0.005). NAFLD was not associated with a higher incidence of stroke (HR 1.09, p = 0.243).ConclusionsNAFLD constitutes an independent risk factor for CHD, MI, and AF in primary care in Germany. Identification of patients with NAFLD in primary care will allow specifically managing and modifying underlying risk factors to improve the overall prognosis.

Physical inactivity is a major risk factor for nonalcoholic fatty liver disease (NAFLD). Exercise-based prevention interventions for improving cardiorespiratory fitness are a recommended complementary treatment for NAFLD. Achievement of minimally effective physical activity to improve cardiorespiratory fitness among patients typically involves high personal and financial expenses in face-to-face settings. We designed an eHealth approach for patients with NAFLD to improve the cardiorespiratory fitness and report the first results of the HELP (Hepatic Inflammation and Physical Performance in Patients With NASH [nonalcoholic steatohepatitis]) study. We aimed to assess the effectiveness of an 8-week, tailored, Web-based exercise intervention for cardiorespiratory fitness improvement, expressed as peak oxygen uptake (peak volume of oxygen [VO ]), in patients with histologically confirmed NAFLD. In a 24-month period, 44 patients were enrolled into an 8-week, prospective, single-arm study with 12 weeks of follow-up. After a medical examination and performance diagnostics, a sports therapist introduced the patients to a Web-based platform for individualized training support. Regular individual patient feedback was provided to systematically adapt the weekly exercise schedule, which allowed us to monitor and ensure patient adherence to strength and endurance training and optimize the step-wise progressive exercise load. Exercise progression was based on an a priori algorithm that considered the subjective rate for both perceived exhaustion and general physical discomfort. The VO was assessed at baseline and at the end of the study by spiroergometry. A total of 43 patients completed the intervention with no adverse events. The VO increased significantly by 2.4 mL/kg/min (8.8%; 95% confidence interval [CI]: 1.48-3.27; P<.001) accompanied by a reduction of 1.0 kg in a body weight (95% CI: 0.33-1.58; P=.004) and 1.3 kg in body fat mass (95% CI: 0.27-2.27; P=.01). In an exploratory analysis, step-wise logistic regression analysis revealed low body fat and VO at baseline and the total minutes of endurance training during the intervention as main contributors to a positive change in VO . Our predictive model indicated that the average patient with NAFLD needed 223 min for stabilization of VO and 628 min for average improvement in VO . However, in patients with a VO approximately 20% higher than the average VO , 628 min were only sufficient to stabilize the VO and >40% reduction in the average fat mass would be required to achieve an average outcome. This is the first study to show that patients with NAFLD can be effectively supported by a Web-based approach, which can increase the VO to a similar extent as face-to-face interventions. Patients with low body fat and low VO benefited the most from our intervention. In terms of future treatment strategies, NAFLD patients with high body fat may particularly benefit from body-fat reduction through a strict nutritional intervention, subsequently enabling a more effective exercise intervention. ClinicalTrials.gov NCT02526732; https://clinicaltrials.gov/ct2/show/NCT02526732 (Archived by WebCite at http://www.webcitation.org/74pXhXXfq). RR2-10.2196/resprot.8607.