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Previous studies have suggested consumption of red meat may be associated with an increased risk of developing nonalcoholic fatty liver disease (NAFLD). However, large-scale, prospective data regarding red meat consumption in relation to the incidence of NAFLD are lacking, nor is it known whether any association is mediated by obesity. We aimed to evaluate the relationship between red meat consumption and the subsequent risk of developing NAFLD. This prospective cohort study included 77,795 women in the Nurses' Health Study II cohort without NAFLD at baseline (in 1995), who provided detailed, validated information regarding diet, including consumption of red meat, every 4 years, followed through 2015. Lifestyle factors, clinical comorbidities and body mass index (BMI), were updated biennially. Cox proportional hazard models were used to estimate multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1,444,637 person years of follow-up, we documented 3130 cases of incident NAFLD. Compared to women who consumed ≤1 serving/week of red meat, the multivariable-adjusted HRs of incident NAFLD were 1.20 (95% CI: 0.97, 1.50) for 2–4 servings/week; 1.31 (95% CI: 1.06, 1.61) for 5–6 servings/week; 1.41 (95% CI: 1.13, 1.75) for 1 serving/day; and 1.52 (95% CI: 1.23, 1.89) for ≥2 servings/day. However, after further adjustment for BMI, all associations for red meat, including unprocessed and processed red meat, were attenuated and not statistically significant (all P -trend>0.05). BMI was estimated to mediate 66.1% (95% CI: 41.8%, 84.2%; P < 0.0001) of the association between red meat consumption and NAFLD risk. Red meat consumption, including both unprocessed and processed red meat, was associated with significantly increased risk of developing NAFLD. This association was mediated largely by obesity. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) affects 25% of adults in the general population and is a disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) to end-stage liver disease. NAFLD is an independent risk factor for cardiovascular disease, diabetes mellitus, and all-cause mortality, and NASH cirrhosis is a frequent indication for liver transplantation. In persons with human immunodeficiency virus (PWH), chronic liver disease is the second leading cause of non–human immunodeficiency virus–related mortality. Between 20% and 63% of PWH have NASH, and 14% to 63% have NASH with fibrosis. However, little is known about the optimal diagnostic strategies, risk factors for, and treatment of NAFLD in PWH. Here, we review current data on and identify knowledge gaps in the epidemiology, pathophysiology, diagnosis, and management of NAFLD in PWH and highlight priorities for research. [Display omitted] [ABSTRACT FROM AUTHOR]

People with HIV (PWH) are at an increased risk of developing nonalcoholic fatty liver disease (NAFLD). Interleukin (IL)-18 is regulated by inflammasomes in response to pathogens and danger signals and has been implicated in both the pathogenesis of NAFLD and HIV disease progression. We hypothesized that increased IL-18 may be associated with NAFLD and liver injury in PWH. This was an observational study of 125 PWH and 59 individuals without HIV in the Boston area. Participants with known hepatitis B, hepatitis C, and excessive alcohol use were excluded. IL-18 was measured in serum by enzyme-linked immunosorbent assay. Liver lipid content was assessed by liver-to-spleen computed tomography (CT) attenuation ratio. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and IL-18 levels were higher in PWH than in controls. In PWH, log10 IL-18 was associated with log10AST (r = 0.34, p = .0001), log10ALT (r = 0.33, p = .0002), log10HIV RNA (r = 0.29, p = .002), and inversely associated with liver-to-spleen ratio (r = −0.24, p = .02). In addition, log10 IL-18 was associated with log10 triglycerides (r = 0.26, p = .003), log10 MCP-1 (monocyte chemoattractant protein-1; r = 0.33, p = .0004), log10caspase-1 (r = 0.35, p < .0001), log10LPS (r = 0.28, p = .004), and inversely associated with high-density lipoprotein (r = −0.28, p = .002), and CD4+/CD8+ T cell ratio (r = −0.24, p = .007). In controls without HIV, log10 IL-18 was also associated with log10ALT (r = 0.44, p = .0005). After adjusting for potential confounders, the relationships between IL-18 and AST (p = .004) and ALT (p = .003) remained significant, and the relationship between IL-18 and liver-to-spleen ratio (p = .02). Increased inflammasome activation and subsequent monocyte recruitment in PWH may contribute to the development and progression of NAFLD. Clinical Trials Registration. NCT00455793. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, with global public health impact affecting more than 25% of the global population. NAFLD is associated with significant morbidity and mortality from cirrhosis, hepatocellular carcinoma, solid organ malignancies, diabetes mellitus, cardiovascular disease, and obstructive sleep apnea, resulting in significant health care resource use and decreased health-related quality of life. NAFLD cirrhosis is a leading indication for liver transplantation in the United States. Lifestyle modification to achieve weight loss remains a first-line intervention in patients with NAFLD. We summarize evidence-based interventions for lifestyle modification in the treatment of NAFLD and provided best practice advice statements to address key issues in clinical management. [ABSTRACT FROM AUTHOR]

Patients with obesity are at increased risk for nonalcoholic fatty liver disease (NAFLD). The effectiveness of noninvasive screening tests for ruling out advanced fibrosis (stage 3–4) is unknown. To determine the prevalence of advanced fibrosis in patients undergoing routine liver biopsy during bariatric surgery and assess the effectiveness of existing noninvasive risk calculators. Academic medical center in the United States. Routine liver biopsies were obtained during first-time bariatric surgery (January 2001–December 2017). Patient demographic characteristics, co-morbidities, and preoperative laboratory values were compiled. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were compared between 3 noninvasive risk calculators for advanced fibrosis: the fibrosis-4 index, NAFLD fibrosis score, and aminotransferase-to-platelet ratio index (APRI). Among 2465 patients, the prevalence of advanced fibrosis (stage 3–4) was 3.4%. The mean age was 45.5 years, and the mean body mass index was 46.8. The sensitivity of noninvasive risk calculators ranged from 85% (NAFLD fibrosis score) to 24% (APRI). The NAFLD fibrosis score performed best in screening out advanced fibrosis, with an NPV of 99%. The PPV ranged from 9% to 65%. In this study cohort, the use of the NALFD fibrosis score correctly ruled out advanced fibrosis in 893 (36%) patients, with 13 false negatives. The prevalence of advanced fibrosis in individuals undergoing routine first-time bariatric procedures is 3.4%. Use of the NALFD fibrosis score can rule out advanced fibrosis in one-third of this population, and guide surgical decision-making. [ABSTRACT FROM AUTHOR]

Despite evidence for the benefits of palliative care (PC) referrals and early advance care planning (ACP) discussions for patients with chronic diseases, patients with end-stage liver disease (ESLD) often do not receive such care. We sought to examine physicians' perceptions of the barriers to PC and timely ACP discussions for patients with ESLD. We conducted a cross-sectional survey of hepatologists and gastroenterologists who provide care to adult patients with ESLD, recruited from the American Association for the Study of Liver Diseases 2018 membership registry. Using a questionnaire adapted from prior studies, we assessed physicians' perceptions of barriers to PC use and timely ACP discussions; 396 of 1236 eligible physicians (32%) completed the questionnaire. The most commonly cited barriers to PC use were cultural factors that affect perception of PC (by 95% of respondents), unrealistic expectations from patients about their prognosis (by 93% of respondents), and competing demands for clinicians' time (by 91% of respondents). Most respondents (81%) thought that ACP discussions with patients who have ESLD typically occur too late in the course of illness. The most commonly cited barriers to timely ACP discussions were insufficient communication between clinicians and families about goals of care (by 84% of respondents) and insufficient cultural competency training about end-of-life care (81%). There are substantial barriers to use of PC and timely discussions about ACP—most hepatologists and gastroenterologists believe that ACP occurs too late for patients with ESLD. Strategies are needed to overcome barriers and increase delivery of high-quality palliative and end-of-life care to patients with ESLD. [ABSTRACT FROM AUTHOR]

Obesity is a known risk factor for nonalcoholic fatty liver disease (NAFLD). However, among individuals undergoing bariatric surgery, the prevalence and risk factors for NAFLD, as well as distinct phenotypes of steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis remain incompletely understood. To determine the prevalence and risk factors for steatosis, NASH, and fibrosis in individuals undergoing routine bariatric surgery. Academic medical center in the United States. Liver wedge biopsies were performed at the time of surgery between 2001 and 2017. Pathology reports were reviewed, and individuals were grouped by NAFLD phenotype. Covariates including demographic characteristics, co-morbidities, and preoperative laboratory values were compared between groups using Student's t test, Pearson's χ2, and logistic regression. Liver biopsies were obtained in 97.7% of first-time bariatric procedures, representing 2557 patients. Mean age was 45.6 years, mean body mass index was 46.7, and most were non-Hispanic white (76.1%) and female (71.6%). On histologic review 61.2% had steatosis and 30.9% NASH. Fibrosis was identified in 29.3% of individuals, and 7.8% had stage ≥2 fibrosis. On logistic regression, elevated aspartate aminotransferase (odds ratio [OR] 1.87; P <.001) and elevated alanine aminotransferase (OR 1.62; P <.001) were independently associated with fibrosis. Elevated hemoglobin A1C of 5.7% to 6.5% (OR 1.29; P <.01) and >6.5% (OR 3.23; P <.001) were also associated with fibrosis. A similar trend was seen for NASH. NASH and/or fibrosis is present in nearly one third of patients undergoing routine bariatric surgery. Risk factors include diabetes, elevated liver enzymes, and diabetes. Risk assessment and aggressive screening should be considered in patients undergoing bariatric surgery. • In 2,557 routine hepatic wedge biopsies performed during bariatric surgery, steatosis was present in 61.2%, NASH in 30.9%, and fibrosis in 29.3%. • Risk factors for NASH and fibrosis include diabetes, elevated transaminases, and low HDL. • Given the high prevalence of significant liver disease in this population may benefit from more aggressive screening. [ABSTRACT FROM AUTHOR]

Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR -reductive stress-ChREBP axis influences multiple human metabolic traits. [Display omitted] • Increases in hepatic cytosolic NADH/NAD+ (reductive stress) change the hepatic transcriptome • These transcriptional changes are mediated by ChREBP, which is activated by reductive stress • GCKR ' s metabolic pleiotropy is explained in part by ChREBP's activation via reductive stress • Multiple human metabolic traits may be influenced by a GCKR -NADH/NAD+-ChREBP-FGF21 axis Singh et al. find that increased hepatic cytosolic NADH/NAD+ activates the transcription factor ChREBP. This pathway underlies some metabolic traits associated with common GCKR genetic variants, such as circulating FGF21 and triglyceride levels, and likely more generally influences certain deleterious metabolic traits in humans. [ABSTRACT FROM AUTHOR]

Background Patients who undergo bariatric surgery often have inadequate weight loss or weight regain. Objectives We sought to discern the utility of weight loss pharmacotherapy as an adjunct to bariatric surgery in patients with inadequate weight loss or weight regain. Setting Two academic medical centers. Methods We completed a retrospective study to identify patients who had undergone bariatric surgery in the form of a Roux-en-Y gastric bypass (RYGB) or a sleeve gastrectomy from 2000–2014. From this cohort, we identified patients who were placed on weight loss pharmacotherapy postoperatively for inadequate weight loss or weight regain. We extracted key demographic data, medical history, and examined weight loss in response to surgery and after the initiation of weight loss pharmacotherapy. Results A total of 319 patients (RYGB = 258; sleeve gastrectomy = 61) met inclusion criteria for analysis. More than half (54%; n = 172) of all study patients lost≥5% (7.2 to 195.2 lbs) of their total weight with medications after surgery. There were several high responders with 30.3% of patients (n = 96) and 15% (n = 49) losing≥10% (16.7 to 195.2 lbs) and≥15% (25 to 195.2 lbs) of their total weight, respectively, Topiramate was the only medication that demonstrated a statistically significant response for weight loss with patients being twice as likely to lose at least 10% of their weight when placed on this medication (odds ratio = 1.9 ; P = .018). Regardless of the postoperative body mass index, patients who underwent RYGB were significantly more likely to lose≥5% of their total weight with the aid of weight loss medications. Conclusions Weight loss pharmacotherapy serves as a useful adjunct to bariatric surgery in patients with inadequate weight loss or weight regain. [ABSTRACT FROM AUTHOR]

Summary Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the United States and is associated with an increased risk of cardiovascular disease (CVD) and cardiovascular (CV) mortality, independent of traditional cardiovascular risk factors. CVD is one of the most common causes of death among individuals with NAFLD and management of NAFLD must extend beyond liver disease to include CVD risk modification. Clinicians should assess CVD risk with the Framingham Risk Score and screen for CVD risk factors including dyslipidemia, diabetes mellitus, hypertension, tobacco use, and the metabolic syndrome. CVD risk factors, particularly dyslipidemia, require aggressive medical management to reduce the high risk of CVD events and death in individuals with NAFLD. [Copyright &y& Elsevier]

The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). GEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1–4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1–3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. IGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. IGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH. • GH and IGF-1 have been implicated in the pathogenesis of NAFLD. • Lower IGF-1 expression is associated with more severe NAFLD. • Expression of IGF-1 and GH receptors is unchanged with increasing severity of NAFLD. • The GH/IGF-1 axis is a potential therapeutic target in NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: There are no clinically available biomarkers for nonalcoholic steatohepatitis (NASH); differentiating between steatosis and NASH requires histologic evaluation. Noninvasive methods are needed to replace liver biopsy and its associated risks. Production of very low density lipoprotein (VLDL) contributes to the development of NASH and might be used to distinguish steatosis from NASH. However, it is not possible to measure levels of VLDL directly in the clinic. Non–high-density lipoprotein-cholesterol (non–HDL-C) encompasses all apolipoprotein-B–containing lipoproteins, including VLDL, and can be calculated from standard lipid panels without additional cost. Methods: We evaluated the ability of non–HDL-C to differentiate steatosis from NASH in a prospective study of 218 patients with suspected NASH (steatosis, n = 100 and NASH, n = 118). Results: Patients with NASH had a trend toward increased levels of non–HDL-C, compared with those with steatosis (P = .08). However, among subjects not on lipid-lowering medications, those with NASH had significantly higher levels of non–HDL-C (144.6 mg/dL) than those with steatosis (129.3 mg/dL; P = .025). This difference remained significant when adjusted for levels of cholesterol and triglycerides, indicating that the difference results from increased levels of apolipoprotein B including VLDL. These findings were validated in a cohort of 40 patients with steatosis or NASH who were not taking lipid-lowering agents. The NASH group had significantly higher levels of non–HDL-C than the steatosis group (162.8 vs 145.9 mg/dL; P = .04). Conclusions: NASH is associated with significantly higher levels of non–HDL-C than steatosis in patients who do not take lipid-lowering agents. This low-cost biomarker could be used in noninvasive differentiation between steatosis and NASH. [ABSTRACT FROM AUTHOR]

Background & Aims: Acute hepatitis C infection progresses to chronic infection in up to 80% of infected persons. Reports from Europe indicate that early treatment of acute hepatitis C infection produces sustained virologic response rates as high as 80%–98%. However, the outcome of acute hepatitis C infection in United States cohorts is not well-characterized. Methods: We describe the clinical course of 28 episodes of acute hepatitis C infection in 24 persons at our institution. Results: Of the 28 infections, 7 episodes resolved spontaneously. Of the remaining 21 episodes, 16 were treated, and 5 did not receive treatment. Of the 16 treated episodes, 4 received interferon and ribavirin, 11 received pegylated interferon and ribavirin, and 1 was treated initially with interferon monotherapy followed by pegylated interferon monotherapy. Among those episodes treated with interferon, 3 of 4 experienced sustained virologic response. Among those episodes treated with pegylated interferon, all 12 achieved SVR. In total, 15 of 16 treated patients (94%) experienced SVR. In all, 18 of the 24 patients (75%) experienced spontaneous or treatment-induced sustained virologic clearance. Conclusions: Our experience with treated and untreated acute HCV infection is comparable to that observed in Europe. Patients treated with antiviral therapy had an excellent response. Randomized trials to investigate immediate versus delayed treatment of acute hepatitis C infection are warranted. In view of these strongly positive outcomes, increased vigilance for acute hepatitis C becomes essential. [Copyright &y& Elsevier]

Hepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA). We conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months. Among the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16–2.48; P =.006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16–2.54; P =.007) or obesity (adjusted HR, 1.75; 95% CI, 1.19–2.59; P =.005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis. Hepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550 [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk. We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI). Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86–0.97, I2 = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83–0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87–1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02–1.14, I2 = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02–1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89–1.60, I2 = 72%). Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease. • Thiazolidinedione use appeared to reduce hepatocellular carcinoma risk in Asians. • Alpha-glucosidase inhibitor use appeared to increase hepatocellular carcinoma risk. • Sulfonylurea use was associated with increased hepatocellular carcinoma risk. • Meglitinide use was not associated with hepatocellular carcinoma incidence. [ABSTRACT FROM AUTHOR]

In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition. We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case–control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank. Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10–8) and the replication studies (P <.05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score—defined as the top quintile of the distribution—was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P <.001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P <.001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P interaction <.001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P interaction <.001). Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), affecting up to around 30% of the world's adult population, causes considerable liver-related and extrahepatic morbidity and mortality. Strong evidence indicates that NAFLD (especially its more severe forms) is associated with a greater risk of all-cause mortality, and the predominant cause of mortality in this patient population is cardiovascular disease (CVD). This narrative review aims to discuss the strong association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications. Also discussed are the putative mechanisms linking NAFLD to CVD and other cardiac/arrhythmic complications, with a brief summary of CVD risk prediction/stratification and management of the increased CVD risk observed in patients with NAFLD. NAFLD is associated with an increased risk of CVD events and other cardiac complications (left ventricular hypertrophy, valvular calcification, certain arrhythmias) independently of traditional CVD risk factors. The magnitude of risk of CVD and other cardiac/arrhythmic complications parallels the severity of NAFLD (especially liver fibrosis severity). There are most likely multiple underlying mechanisms through which NAFLD may increase risk of CVD and cardiac/arrhythmic complications. Indeed, NAFLD exacerbates hepatic and systemic insulin resistance, promotes atherogenic dyslipidaemia, induces hypertension, and triggers synthesis of proatherogenic, procoagulant and proinflammatory mediators that may contribute to the development of CVD and other cardiac/arrhythmic complications. Careful assessment of CVD risk is mandatory in patients with NAFLD for primary prevention of CVD, together with pharmacological treatment for coexisting CVD risk factors. [ABSTRACT FROM AUTHOR]