Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

C, the latter had a higher proportion of patients with genotype 3 HCV infection. Because 4 of the 6 HCC patients had ultrasound as pretreatment imaging, it may be argued that HCC may have been missed on the initial screening examination. With only 1 HCC lesion being <1 cm at diagnosis, the accuracy of ultrasound examination of >90% for lesions >1 cm, and tumor doubling time of about 6 months, we feel that this is unlikely. 3 Our study may be limited by its retrospective design and selection bias given that 57 of the initial 123 patients wee excluded from the analysis. However, baseline characteristics on important variables predictive of HCC occurrence were similar between excluded and analyzed patients. Prospective multicenter studies are suggested to confirm these findings. The mechanisms of these study findings remain unclear. It may be speculated that a rapid reduction in the HCV viral load may impact the tumor immunity, because the development of HCC in HCV cirrhosis depends on the balance between pro-tumor and anti-tumor immune function. 8 In conclusion, DAA therapy seems to increase the de novo occurrence of HCC among patients with HCV-related cirrhosis. Patients with HCV cirrhosis receiving DAA therapy may need more rigorous and closer follow-up for surveillance of HCC.

Coronary artery disease (CAD) is the principal cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate whether NAFLD is causally involved in the pathogenesis of CAD. For this, previously reported NAFLD susceptibility genes were clustered and tested for an association with CAD in the Coronary Artery Disease Genome‐Wide Replication and Meta‐Analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium data set. The role of plasma lipids as a potential mediator was explored by using data from the Global Lipids Genetics Consortium. Statistical analyses revealed that the combination of 12 NAFLD genes was not associated with CAD in 60,801 CAD cases and 123,504 controls (odds ratio [OR] per NAFLD risk allele , 1.0; 95% confidence interval [CI], 0.99‐1.00). In a subsequent sensitivity analysis, a positive relationship was observed after exclusion of gene variants that are implicated in NAFLD through impaired very low‐density lipoprotein secretion (i.e., microsomal triglyceride transfer protein [ MTTP ] , patatin‐like phospholipase domain containing 3 [ PNPLA3 ] , phosphatidylethanolamine N‐methyltransferase [ PEMT ] , and transmembrane 6 superfamily member 2 [ TM6SF2 ]) (OR, 1.01; 95% CI, 1.00‐1.02). Clustering of the excluded genes showed a significant negative relationship with CAD (OR, 0.97; 95% CI, 0.96‐0.99). A substantial proportion of the observed heterogeneity between the individual NAFLD genes in relation to CAD could be explained by plasma lipids, as reflected by a strong relationship between plasma lipids and CAD risk conferred by the NAFLD susceptibility genes ( r = 0.76; P = 0.004 for low‐density lipoprotein cholesterol). Conclusion: NAFLD susceptibility genes do not cause CAD per se . The relationship between these genes and CAD appears to depend to a large extent on plasma lipids. These observations strongly suggest taking plasma lipids into account when designing a new drug to target NAFLD.

Background There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. Objectives The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Methods Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (&lt;7.5 g/meal and &lt;10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. Results Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: −57.0 g/d; 95% CI: −77.9, −39.5 g/d; and −38.8 μmol/d; 95% CI: −91.2, −10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P &lt; 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: −0.7% point, 95% CI: −2.0, −0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. Conclusions Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group. This trial was registered at clinicaltrials.gov as NCT03067428.