Pre-existing Non-alcoholic Fatty Liver Disease Research Articles

Baseline and change in serum uric acid level over time and resolution of nonalcoholic fatty liver disease in young adults: The Kangbuk Samsung Health Study.

To determine the association between: (i) baseline serum uric acid (SUA) level and (ii) SUA changes over time, and nonalcoholic fatty liver disease (NAFLD) resolution. A retrospective cohort study, comprising 38 483 subjects aged <40 years with pre-existing NAFLD, was undertaken. The effects of SUA changes over time were studied in 25 266 subjects. Participants underwent a health examination between 2011 and 2019, and at least one follow-up liver ultrasonography scan up to December 2020. Exposures included baseline SUA level and SUA changes between baseline and subsequent visits, categorized into quintiles. The reference group was the third quintile (Q3) containing zero change. The primary endpoint was resolution of NAFLD. During a median follow-up of 4 years, low baseline SUA level and decreases in SUA levels over time were independently associated with NAFLD resolution (p for trend <0.001). Using SUA as a continuous variable, the likelihood of NAFLD resolution was increased by 10% and 13% in men and women, respectively, per 1-mg/dL decrease in SUA. In a time-dependent model with changes in SUA treated as a time-varying covariate, adjusted hazard ratios (95% confidence intervals) for NAFLD resolution comparing Q1 (highest decrease) and Q2 (slight decrease) to Q3 (reference) were 1.63 (1.49-1.78) and 1.23 (1.11-1.35) in men and 1.78 (1.49-2.12) and 1.18 (0.95-1.46) in women, respectively. Low baseline SUA levels and a decrease in SUA levels over time were both associated with NAFLD resolution in young adults.

Weight loss induced alleviation of sleep-disordered breathing is associated with improvement of non-alcoholic fatty liver disease

IntroductionSleep-disordered breathing (SDB) and non-alcoholic fatty liver disease (NAFLD) are both common comorbidities in obese patients. Structured weight loss programs are effective and can reduce the incidence and severity of obesity-related comorbidities. The objective of the present analysis is to test whether weight loss induced alleviation of SDB is a predictor for improvement of NAFLD. MethodsObese participants underwent a standardized non-surgical 3 months weight reduction program (800 kilocalories per day with low carbohydrate and fat content). Abdominal sonography for NAFLD (grade 0 to 3) and monitoring for SDB (defined as apnea-hypopnea index [AHI] ≥ 15/h) were performed at baseline and after 3 months. Alleviation of SDB was defined as a shift from AHI≥ 15/h to <15/h. Results48 patients (48% female, age 42 ± 12 years, body-mass index 40.3 ± 8.1 kg/m2, AHI 14 ± 17/h, 85% NAFLD grade ≥1) participated in the weight loss program. In contrast to the no SDB group, in patients with SDB weight loss of 27.1 ±0 .9 kg (8.4 ± 2.8 kg/m2) after three months was paralleled by a reduction in AHI (-22 ± 17/h), prevalence of SDB (from 31% to 13%), and oxidized low-density lipoprotein (-13 ± 11 U/l). In individuals with preexisting SDB NAFLD grade improved more (2 versus 1, p<0.001) and was at a lower degree at 3 months than in those without SDB (0 versus 1, p = 0.015). In multivariable analysis models, SDB at baseline was associated with improvement of NAFLD grade (B 0.908; 95% CI 0.125, 1.691; p = 0.024), independently of age, sex, and BMI (each p>0.05, respectively). Decreasing BMI (B 0.16 [95%-CI 0.08; 0.23], p<0.001) and alleviation of SDB (B 0.90 [95%-CI 0.21; 1.58], p = 0.012) were independently associated with improvement of NAFLD grade. ConclusionPreexisting SDB and weight loss induced alleviation of SDB are predictors for improvement in NAFLD grade, independent of the extent of weight loss. SDB may contribute to the pathogenesis of NAFLD via SDB-induced oxidative stress and inflammation, but the causal mechanism remains unclear.

Impact of nonalcoholic fatty liver disease on clinical outcomes in patients with COVID-19 among persons living with HIV: A multicenter research network study

BackgroundPeople living with human immunodeficiency virus (PLWH) are at an increased risk of nonalcoholic fatty liver disease (NAFLD) but how these patients react to COVID-19 infection is unclear. We examined the clinical characteristics and outcomes of patients with and without nonalcoholic fatty liver disease (NAFLD) among people living with human immunodeficiency virus (PLWH) diagnosed with COVID-19. MethodsA multicenter, retrospective cohort study was conducted using TriNetX. Participants diagnosed with COVID-19 between January 20, 2020, and October 31, 2021, in PLWH were identified and divided into cohorts based on preexisting NAFLD. The primary outcome was all-cause mortality, and secondary outcomes were hospitalization, severe disease, critical care, need for mechanical ventilation, and acute kidney injury(AKI). Propensity score matching (PSM) mitigated the imbalance among group covariates. Risk ratios (RR) with 95 % confidence intervals (CI) were calculated. ResultsOf the 5012 PLWH identified with confirmed COVID-19 during the study period, 563 had a diagnosis of NAFLD. After PSM, both groups were well-matched with 561 patients. The primary outcome did not differ between the cohorts at 30-days, even after a fully adjusted analysis, and the risk of all-cause mortality did not differ at 60 and 90 days. NAFLD had a significantly higher risk for hospitalization rates (RR 1.32; 95 % CI, 1.06–1.63) and AKI (RR 2.55; 95 % CI 1.42–4.57) than the non-NAFLD group at 30 days. No other differences were detected in other secondary outcome measures. ConclusionsPreexisting NAFLD is associated with an increased risk for hospitalization and AKI among PLWH infected with COVID-19. The potential role of NAFLD in developing severe COVID-19 among PLWH remains to be elucidated in future studies. Still, this study indicates the need for careful monitoring of this at-risk population.

ODP008 Nonalcoholic Fatty Liver Disease (NAFLD) Impacts Weight Loss after Bariatric Surgery

Abstract Background Gastric bypass (GB) and sleeve gastrectomy (SG) remain the most effective intervention for weight loss in obesity. Our previous data showed a significant effect of preexisting diabetes on weight loss over 5 years. Since nonalcoholic fatty liver disease (NAFLD) is implicated as a precursor to clinical diabetes in obesity, we sought to determine if preexisting NAFLD modified weight loss outcomes. Methods 714 patients [79. 0% females, median age: 45 (37-53)] undergoing bariatric surgery were followed for 5 years. Clinically significant NAFLD at baseline was defined with a composite definition, combining the presence diagnosis on the medical record, definitive evidence for fat on imaging studies, presence of biopsy proving NAFLD, and/or elevation of liver function tests without another explanation. To screen for the presence of NAFLD, a natural language-processing tool EMERSE was utilized, and results were verified manually. Presence of diabetes, hypertension, and dyslipidemia were also defined using a combination of diagnostic codes, natural language processing and manual verification. Weight loss was tracked during annual visits and calculated using baseline weight and BMI. Total percent weight loss from baseline (%TWL) was also calculated. Results Of the 714 patients, 380 underwent GB [80.3% females, age 45 (35-53), median BMI 46.4 (41.6-51.9)] and 334 underwent SG [77.5% females, age 46 (39-54), BMI 49.7 (43.7-54.1)]. Overall, 31. 0% patients had clinically significant NAFLD at baseline, while the prevalence of diabetes, hypertension and dyslipidemia were 36. 0%, 54.9%, and 29.4% respectively. %TWL was impacted significantly by NAFLD in the GB group, as individuals without NAFLD lost medians of32.30 (26. 07-37.35), 32.33 (25. 04-39.21),31.12 (21.89-37.64), 26.40 (19.96-36.20), and 25.86 (18.16-34.79)%TWL versus29.63 (24.14-35.28),27.88 (21.44-35.11),24.15 (18.80-34.42),22. 09 (17. 03-30. 07), and21. 06 (14.92-30.25)%TWL compared to those with NAFLD by years1, 2, 3, 4, and 5 (p=0. 014,0. 002,0. 001,0. 002, and 0. 008). Among the SG group, differences in %TWL in NAFLD and non-NAFLD groupswere also significant, but only during year 1 and 2; non-NAFLD group had medians of25.73 (21.36-31.97) and24.55 (18.35-31.24) %TWL vs,22.48 (17.10-27.63) and22.28 (14.75-28.31)%TWL in NAFLD-group (p=&amp;lt;0. 001 and 0. 02). In a multivariable model for %TWL, preexisting NAFLD remained a highly significant covariate when adjusted for baseline BMI, age, gender, surgery type, time (year of follow up), time by surgery type, preexisting diabetes, baseline cholesterol and triglyceride levels (Beta; 95% CI: - 2.288; -3.938, -0.639 p=0. 0067). Of note, the only other significant covariate with regards to comorbidities was presence of baseline diabetes (Beta; 95% CI: -2.811; -4.602, -1. 021, p=0. 0022). Conclusions Preexisting NAFLD impacts weight loss outcomes in patients undergoing bariatric surgery, more so in GB than SG. Mechanisms for the role of clinically significant NAFLD or diabetes in reducing weight loss potential after bariatric surgery require further studies. Presentation: No date and time listed

Resolution of, and Risk of Incident Non-alcoholic Fatty Liver Disease With Changes in Serum 25-hydroxy Vitamin D Status.

A protective or causative role of vitamin D status on the risk of nonalcoholic fatty liver disease (NAFLD) remains inconclusive. To evaluate the association between changes in serum 25-hydroxyvitamin D [25(OH)D] status during follow-up and the risk of incident NAFLD and resolution of preexisting NAFLD. A retrospective cohort study. Kangbuk Samsung Health Study based on routine health screening examinations. Korean adults (mean age, 36.8 years; range, 18-96 years) who underwent comprehensive health examinations including assessment of serum 25(OH)D levels. The main outcomes were (1) incidence and (2) resolution of NAFLD assessed by liver ultrasound. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs for outcomes according to serum 25(OH)D levels. Among 139 599 participants without NAFLD at baseline, 27 531 developed NAFLD during follow-up. Serum 25(OH)D levels were significantly and inversely associated with NAFLD development. Among 48 702 participants with NAFLD at baseline, 13 449 showed NAFLD resolution. Multivariable-adjusted HR (95% CI) for NAFLD resolution comparing 25(OH)D 10 to <20, 20 to <30, and ≥30 ng/mL to <10 ng/mL were 1.09 (1.03-1.15), 1.13 (1.06-1.21), and 1.21 (1.09-1.35), respectively. Additionally, an increase in 25(OH)D levels between baseline and the subsequent visit (median, 1.8 years) was associated with decreased NAFLD incidence, while persistently adequate 25(OH)D levels over time was associated with decreased incidence and increased resolution of NAFLD. Maintaining adequate serum 25(OH)D concentrations may be beneficial for both prevention as well as resolution of NAFLD.

Pharmaconutrition strategy to resolve SARS-CoV-2-induced inflammatory cytokine storm in non-alcoholic fatty liver disease: Omega-3 long-chain polyunsaturated fatty acids.

Inflammation is one of the primary factors associated with the causation and/or progression of several lifestyle disorders, including obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of disorders, and starts with simple steatosis, progresses to non-alcoholic steatohepatitis, and then advances to fibrosis, cirrhosis and finally, hepatocellular carcinoma, due to perpetual cycles of insults caused by inflammation and other cellular stress. Emerging evidence has documented that patients with NAFLD have severe coronavirus disease 2019 (COVID-19), and patients with COVID-19 have a higher liver injury and mortality. Although the exact cause or mechanism is not known, inflammatory cytokine storm is a characteristic feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is known to be associated with higher mortality among COVID-19 patients. Therefore, the COVID-19 pandemic seems to be a major concern in NAFLD patients, who have contracted SARS-CoV-2 infection and develop COVID-19. This is evident in patients at any stage of the NAFLD spectrum, as the inflammatory cytokine storm may cause and/or aggravate the progression or severity of NAFLD. Thus, there is a need for resolution of the inflammatory cytokine storm in these patients. A large body of evidence has demonstrated the efficacy of omega-3 long-chain polyunsaturated fatty acids (ω-3 LCPUFA) in NAFLD conditions, due to their anti-inflammatory, immunomodulatory and anti-viral properties. Therefore, intervention with ω-3 LCPUFA, an effective pharmaconutrient along with the standard treatment for COVID-19 may be useful in the management of the NAFLD spectrum in COVID-19 patients with pre-existing NAFLD conditions by resolving the inflammatory cytokine storm and thereby attenuating its progression. Although there are challenges in implementation, optimistically they can be circumvented and the pharmaconutrition strategy may be potentially helpful in tackling both the pandemics; NAFLD and COVID-19 at least in this subset of patients.

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study

Background & AimsThe development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD.MethodsThis multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination.ResultsA total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0–48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m2 (IQR 23.8–28.1 kg/m2). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained.ConclusionsThe inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD.Lay summaryThe development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.

Implications of COVID-19 for patients with pre-existing digestive diseases: an update

Implications of COVID-19 for patients with pre-existing digestive diseases: an update

Citrulline supplementation attenuates the development of non-alcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase

Non-alcoholic fatty liver disease (NAFLD) is by now the most prevalent liver disease worldwide. The non-proteogenic amino acid l-citrulline (L-Cit) has been shown to protect mice from the development of NAFLD. Here, we aimed to further assess if L-Cit also attenuates the progression of a pre-existing diet-induced NAFLD and to determine molecular mechanisms involved. Female C57BL/6J mice were either fed a liquid fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C) for 8 weeks to induce early stages of NASH followed by 5 more weeks with either FFC-feeding +/- 2.5 g L-Cit/kg bw or C-feeding. In addition, female C57BL/6J mice were either pair-fed a FFC +/- 2.5 g L-Cit/kg bw +/- 0.01 g/kg bw i.p. N(ω)-hydroxy-nor-l-arginine (NOHA) or C diet for 8 weeks.The protective effects of supplementing L-Cit on the progression of a pre-existing NAFLD were associated with an attenuation of 1) the increased translocation of bacterial endotoxin and 2) the loss of tight junction proteins as well as 3) arginase activity in small intestinal tissue, while no marked changes in intestinal microbiota composition were prevalent in small intestine. Treatment of mice with the arginase inhibitor NOHA abolished the protective effects of L-Cit on diet-induced NAFLD. Our results suggest that the protective effects of L-Cit on the development and progression of NAFLD are related to alterations of intestinal arginase activity and intestinal permeability.

Non-alcoholic Fatty Liver Disease and COVID-19 Susceptibility and Outcomes: a Korean Nationwide Cohort.

BackgroundEvidence for the association between underlying non-alcoholic fatty liver disease (NAFLD), the risk of testing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive, and the clinical consequences of coronavirus disease 2019 (COVID-19) is controversial and scarce. We aimed to investigate the association between the presence of NAFLD and the risk of SARS-CoV-2 infectivity and COVID-19-related outcomes.MethodsWe used the population-based, nationwide cohort in South Korea linked with the general health examination records between January 1, 2018 and July 30, 2020. Data for 212,768 adults older than 20 years who underwent SARS-CoV-2 testing from January 1 to May 30, 2020, were obtained. The presence of NAFLDs was defined using three definitions, namely hepatic steatosis index (HSI), fatty liver index (FLI), and claims-based definition. The outcomes were SARS-CoV-2 test positive, COVID-19 severe illness, and related death.ResultsAmong 74,244 adults who completed the general health examination, there were 2,251 (3.0%) who were SARS-CoV-2 positive, 438 (0.6%) with severe COVID-19 illness, and 45 (0.06%) COVID-19-related deaths. After exposure-driven propensity score matching, patients with pre-existing HSI-NAFLD, FLI-NAFLD, or claims-based NAFLD had an 11–23% increased risk of SARS-CoV-2 infection (HSI-NAFLD 95% confidence interval [CI], 1–28%; FLI-NAFLD 95% CI, 2–27%; and claims-based NAFLD 95% CI, 2–31%) and a 35–41% increased risk of severe COVID-19 illness (HSI-NAFLD 95% CI, 8–83%; FLI-NAFLD 95% CI, 5–71%; and claims-based NAFLD 95% CI, 1–92%). These associations are more evident as liver fibrosis advanced (based on the BARD scoring system). Similar patterns were observed in several sensitivity analyses including the full-unmatched cohort.ConclusionPatients with pre-existing NAFLDs have a higher likelihood of testing SARS-CoV-2 positive and severe COVID-19 illness; this association was more evident in patients with NAFLD with advanced fibrosis. Our results suggest that extra attention should be given to the management of patients with NAFLD during the COVID-19 pandemic.

Harnessing Muscle-Liver Crosstalk to Treat Nonalcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, affecting an estimated one-quarter of the world’s adult population. Multiple organ systems have been implicated in the pathophysiology of NAFLD; however, the role of skeletal muscle has until recently been largely overlooked. A growing body of evidence places skeletal muscle—via its impact on insulin resistance and systemic inflammation—and the muscle-liver axis at the center of the NAFLD pathogenic cascade. Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum in that it is tightly linked to an increased risk of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis, all independent of obesity and insulin resistance. Longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Adverse muscle composition, comprising both low muscle volume and high muscle fat infiltration (myosteatosis), is highly prevalent in patients with NAFLD. The risk of functional disability conferred by low muscle volume in NAFLD is further exacerbated by the presence of myosteatosis, which is twice as common in NAFLD as in other chronic liver diseases. Crosstalk between muscle and liver is influenced by several factors, including obesity, physical inactivity, ectopic fat deposition, oxidative stress, and proinflammatory mediators. In this perspective review, we discuss key pathophysiological processes driving sarcopenia in NAFLD: anabolic resistance, insulin resistance, metabolic inflexibility and systemic inflammation. Interventions that modify muscle quantity (mass), muscle quality (fat), and physical function by simultaneously engaging multiple targets and pathways implicated in muscle-liver crosstalk may be required to address the multifactorial pathogenesis of NAFLD/NASH and provide effective and durable therapies.

Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity

Microcystin-leucine arginine (MC-LR) is a potent liver toxin produced by freshwater cyanobacteria, also known as blue-green algae. While harmful algal blooms are increasing in frequency and severity worldwide, there is still no established method for the diagnosis and assessment of MC-LR induced liver damage. The guidelines for MC-LR safe exposure limits have been previously established based on healthy animal studies, however we have previously demonstrated that pre-existing non-alcoholic fatty liver disease (NAFLD) increases susceptiblity to the hepatotoxic effects of MC-LR. In this study, we sought to investigate the suitability of clinically used biomarkers of liver injury, specifically alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as potential diagnostic tools for liver damage induced by chronic low dose administration of MC-LR in the setting of pre-existing NAFLD. In our Leprdb/J mouse model of NAFLD, we found that while MC-LR induced significant histopathologic damage in the setting of NAFLD, gene expression of ALT and ALP failed to increase with MC-LR exposure. Serum ALT and ALP also failed to increase with MC-LR exposure, except for a moderate increase in ALP with the highest dose of MC-LR used (100 μg/kg). In HepG2 human liver epithelial cells, we observed that increasing MC-LR exposure levels do not lead to an increase in ALT or ALP gene expression, intracellular enzyme activity, or extracellular activity, despite a significant increase in MC-LR induced cytotoxicity. These findings demonstrate that ALT and ALP may be unsuitable as diagnostic biomarkers for MC-LR induced liver damage.

Circulating total bilirubin and risk of non-alcoholic fatty liver disease in the PREVEND study: observational findings and a Mendelian randomization study

The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28–75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73–0.92; p = 0.001) per 1 standard deviation (SD) change in loge total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78–0.97; p = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69–1.38; p = 0.900) for FLI and 1.14 (0.81–1.59; p = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.

Omega-3 fatty acids and nonalcoholic fatty liver disease in adults and children: where do we stand?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic fatty liver disease worldwide. The incidence of NAFLD parallels the prevalence of obesity. Moreover, NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). As such, NAFLD has become a major public health concern. We discuss recent clinical trials and meta-analyses evaluating the efficacy of C20-22 ω3 polyunsaturated fatty acids (PUFA) to attenuate preexisting NAFLD in adults and children. Humans with NAFLD and NASH; and preclinical mouse models of NASH, have a high abundance of hepatic saturated (SFA) and monounsaturated (MUFA) fat, but a low abundance of hepatic C20-22 ω3 PUFA. This change in hepatic fat type and abundance is associated with hepatic lipotoxicity, inflammation, oxidative stress and fibrosis. Recent meta-analyses and clinical trials evaluated the capacity of C20-22 ω3 PUFA dietary supplementation to improve health outcomes in adults and children with preexisting NAFLD. Diets supplemented with docosahexaenoic acid (DHA, 22 : 6,ω3) alone or with eicosapentaenoic acid (EPA, 20 : 5,ω3) are tolerated and effective at lowering liver fat in NAFLD patients. However, outcomes are mixed with respect to C20-22 ω3 PUFA attenuation of more severe NAFLD markers, such as hepatic injury, inflammation and fibrosis. These studies suggest that dietary supplementation with C20-22 ω3 PUFA should be considered as a viable and effective option to lower liver fat in obese adults and children with NAFLD.

The effects of perfluorooctanoate on high fat diet induced non-alcoholic fatty liver disease in mice

Non-alcoholic fatty liver disease (NAFLD) is affecting up to one-third of the general population in western countries. While the major cause of NAFLD is related to an unhealthy lifestyle, recent evidence has shown a role of chemical exposure in the induction and progression of NAFLD. Perfluorooctanoate (PFOA) is a ubiquitous environmental contaminant that exerts its hepatotoxicity mainly through the activation of peroxisome proliferator-activated receptor α (PPARα). We examined how PFOA might affect the progression of NAFLD and whether a preexisting fatty liver intensified or alleviated the effects of PFOA in the livers. As such, male C57BL/6 mice were fed with a low-fat control diet (CD) or a high fat diet (HFD) for 16 weeks to model normal or steatotic livers, respectively. Mice were then administered with PFOA (1mg/kg/d) by oral gavage for an additional 2, 8, and 16 weeks. Dietary treatment was continued throughout the whole study. We found HFD induced hepatic steatosis, lobular inflammation, and progressive fibrosis in mice. As expected, PFOA activated PPARα, constitutive androstane receptor (CAR) and pregnane X receptor (PXR), regardless of the diet. Gene expression analysis showed the interactions between HFD and PFOA on hepatic nuclear receptors were time-dependent. Hepatocytes growth as measured by DNA synthesis and cell growth genes induced by PFOA were exacerbated in the HFD group after 2 weeks, along with the enhanced activation of PPARα. In contrast, PFOA decreased the severity of hepatic steatosis. In HFD-fed mice, the hepatic triglyceride levels were reduced to 75%, 47%, and 40%, after 2, 8, and 16 weeks of PFOA treatment, respectively, compared to vehicle controls. Transcriptomic analysis showed the preexisting NAFLD enhanced PFOA related lipid oxidation pathways in mice. HFD induced hepatic fibrosis as measured by collagen staining and fibrosis gene markers were also attenuated by PFOA. Taken together, this study demonstrated that the preexisting NAFLD might impact on many biological effects induced by PFOA and thus need to be carefully considered as a factor in risk assessment.

Non-alcoholic fatty liver disease and colorectal cancer survival.

Liver diseases including non-alcoholic fatty liver disease (NAFLD) and ensuing alterations to the micro-environment may affect development of liver metastasis. Mirroring the rise in obesity rates, prevalence of NAFLD is increasing globally. Our objective was to examine the association between NAFLD and mortality in colorectal cancer patients. Colorectal Cancer-Sarcopenia and Near-term Survival (C-SCANS) is a retrospective cohort study which included 3,262 stage I-III patients, aged 18-80years, and diagnosed between 2006 and 2011at Kaiser Permanente Northern California. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI). After up to 10years of follow-up, 879 deaths, including 451 from CRC were identified. Cases diagnosed with NAFLD before and within 1 month after CRC diagnosis (pre-existing NAFLD; n = 83) had a HR of 1.64 (95% CI 1.06-2.54) for overall and a HR of 1.85 (95% CI 1.03-3.30) for CRC-specific mortality compared to those without NAFLD. Findings did not differ significantly by sex, stage, tumor location, and smoking status, and were also similar when restricted to obese patients only. Independent of body mass index and prognostic indicators, CRC patients with pre-existing NAFLD had a worse prognosis than those without NAFLD.

Liver Disease in Men Undergoing Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy is associated with the development of diabetes and metabolic syndrome. To our knowledge its effect on the development of nonalcoholic fatty liver disease, a condition which frequently co-occurs with metabolic syndrome and other subsequent liver conditions such as liver cirrhosis, hepatic necrosis or any liver disease, has not been investigated. We identified 82,938 men 66 years old or older who were diagnosed with localized prostate cancer in the SEER (Surveillance, Epidemiology and End Results)-Medicare database from 1992 to 2009. Men with preexisting nonalcoholic fatty liver disease, liver disease, diabetes or metabolic syndrome were excluded from study. Propensity score adjusted, competing risk regression models were created to compare the risk of nonalcoholic fatty liver disease in men who were vs were not treated with androgen deprivation. We also explored the influence of cumulative exposure to androgen deprivation therapy, calculated as monthly equivalent doses of gonadotropin-releasing hormone agonists/antagonists (fewer than 7, 7 to 11 or more than 11 doses). Overall 37.5% of men underwent androgen deprivation therapy. They were more likely to be diagnosed with nonalcoholic fatty liver disease (HR 1.54, 95% CI 1.40-1.68), liver cirrhosis (HR 1.35, 95% CI 1.12-1.60), liver necrosis (HR 1.41, 95% CI 1.15-1.72) and any liver disease (HR 1.47, 95% CI 1.35-1.60). A dose-response relationship was observed between the number of androgen deprivation therapy doses, and nonalcoholic fatty liver disease and any liver disease. Androgen deprivation therapy in men with prostate cancer is associated with the diagnosis of nonalcoholic fatty liver disease. The usual limitations of an observational study design apply, including possible inaccuracy in defining outcomes in a population based registry.

MP21-04 NON-ALCOHOLIC FATTY LIVER DISEASE IN MEN UNDERGOING ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I1 Apr 2018MP21-04 NON-ALCOHOLIC FATTY LIVER DISEASE IN MEN UNDERGOING ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER Philipp Gild, Alexander P. Cole, Nicolas von Landenberg, Anna Krasnova, Maxine Sun, Lorelei A. Mucci, Stuart R. Lipsitz, Felix K.H. Chun, Paul L. Nguyen, Shehzad Basaria, Adam S. Kibel, and Quoc-Dien Trinh Philipp GildPhilipp Gild More articles by this author , Alexander P. ColeAlexander P. Cole More articles by this author , Nicolas von LandenbergNicolas von Landenberg More articles by this author , Anna KrasnovaAnna Krasnova More articles by this author , Maxine SunMaxine Sun More articles by this author , Lorelei A. MucciLorelei A. Mucci More articles by this author , Stuart R. LipsitzStuart R. Lipsitz More articles by this author , Felix K.H. ChunFelix K.H. Chun More articles by this author , Paul L. NguyenPaul L. Nguyen More articles by this author , Shehzad BasariaShehzad Basaria More articles by this author , Adam S. KibelAdam S. Kibel More articles by this author , and Quoc-Dien TrinhQuoc-Dien Trinh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.695AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy (ADT) is associated with development of diabetes and metabolic syndrome. However, its effect on the development of non-alcoholic fatty liver disease (NAFLD), a condition frequently co-occuring with metabolic syndrome, and other liver conditions, has not been investigated. We studied the dose-dependent effect of ADT for localized prostate cancer on the risk of NAFLD, liver cirrhosis, hepatic necrosis, and any liver disease. METHODS We identified 82,938 men aged 66 and older diagnosed with localized prostate cancer (PCa) within the Surveillance, Epidemiology and End Results-Medicare (SEER) database between 1992 and 2009. Men with pre-existing NAFLD, liver disease, diabetes, and metabolic syndrome were excluded. Using competing-risk regression models, we compared the risk of NAFLD between men who received ADT within 6 months of diagnosis versus those who did not. We also explored the influence of cumulative exposure to ADT, calculated as monthly equivalent doses of gonadotropin-releasing hormone (GnRH) agonists or antagonists (<7, 7-11, >11 doses). RESULTS Overall, 37.5% of men received ADT within six months of diagnosis. Men treated with ADT were more likely to be diagnosed with NAFLD (hazard ratio [HR] 1.54, 95 % confidence interval [CI] 1.40-1.68), liver cirrhosis (HR 1.35, 95 % CI 1.12 -1.60), liver necrosis (HR 1.41, 95% CI 1.15-1.72) and any liver disease (HR 1.47, 95% CI 1.35-1.60). A dose-response relationship was observed between the number of doses of ADT, NAFLD and any liver disease. CONCLUSIONS Use of ADT in men with PCa is associated with an elevated risk of NAFLD, which is dose-dependent. Further investigation is needed to elucidate the mechanisms that lead to development of NAFLD. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e263 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Philipp Gild More articles by this author Alexander P. Cole More articles by this author Nicolas von Landenberg More articles by this author Anna Krasnova More articles by this author Maxine Sun More articles by this author Lorelei A. Mucci More articles by this author Stuart R. Lipsitz More articles by this author Felix K.H. Chun More articles by this author Paul L. Nguyen More articles by this author Shehzad Basaria More articles by this author Adam S. Kibel More articles by this author Quoc-Dien Trinh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Traffic-related air pollution associations with cytokeratin-18, a marker of hepatocellular apoptosis, in an overweight and obese paediatric population.

Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic-related air pollution was characterized as vehicle traffic volume on major roads within a 1km residential buffer, and as residential nitrogen dioxide (NO2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150U/L to almost 200U/L as residential traffic volume increased from 220000 vehicle-km to 330000 vehicle-km, after adjustment for baseline CK-18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140U/L to 200U/L (a 1.5 standard deviation increase in CK-18) as NO2 increased from 8 to 10ppb. Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry.

Nonalcoholic steatohepatitis and the intestinal microbiota

Nonalcoholic steatohepatitis and the intestinal microbiota