Statins and non-alcoholic fatty liver disease

Dear Editor, In April 9 issue, van den Berg et al1 report interesting results on the indication for lipid‐lowering treatment in a large cohort with suspected non‐alcoholic fatty liver disease (NAFLD) within the population‐based Lifelines Cohort Study. Fatty liver index (FLI) ≥60 was used as a proxy of NAFLD and the NAFLD fibrosis score (NFS) to identify the NAFLD patients with suspected advanced fibrosis. Cardiovascular disease (CVD) risk was established by the 2016 European society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines for the Management of Dyslipidemias.2 Subjects with FLI ≥ 60 (suspected NAFLD) had an increased 10‐ year predicted cardiovascular risk compared to those with FLI < 60 with an approximately 2 times higher need for statin therapy based on CVD risk prediction and their LDL cholesterol level. Subjects with a FLI ≥ 60 were more likely to be classified with type 2 diabetes, Metabolic Syndrome (MetS), history of CVD and impaired renal function. Interestingly, estimated 10‐year very high cardiovascular risk was approximately 4 times higher in subjects with a NFS > 0.676 compared to those with the absence of advanced fibrosis. Finally, indication for statin treatment was positively associated with a FLI ≥ 60 after controlling for age, sex, current smoking, impaired renal function, and the presence of MetS and its individual components. The above results have an even greater relevance if we consider that all the subjects who were already on statin therapy were subtracted from the analysis. These findings may have an important clinical relevance and emphasize the need for effective treatment with statins in patients with NAFLD. Indeed, accumulating evidence suggests that CVD, rather than liver disease, dictates the outcomes in NAFLD.3 Besides, in most subjects NAFLD constitutes the hepatic component of MetS and numerous patients have atherogenic dyslipidemia. This study further supports the results of a previous study by our group where under prescription of statins in patients with NAFLD was observed.4 In fact, mild liver enzyme elevation remains a concern and despite its proven efficacy and safety,5 statin administration is sometimes limited by the worry about related side effects. Indeed, there is a tendency of general physicians to discourage statin use in patients with baseline elevation of serum liver enzymes and/ or to discontinue medication when minor alterations were appreciated. Of note, in our study, statin under‐use was high also in patients at very high CV risk such as those with a previous CV event. This study by van den Berg et al further stresses the issue of under prescription of statins in people with NAFLD and indication for treatment, based on CV risk class and low‐density lipoprotein cholesterol target according to ESC/EAS guidelines

The Ljapunov-Schmidt reduction for some critical problems

This is a survey about the application of the Ljapunov-Schmidt reduction for some critical problems

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting

Long-term prediction of adherence to continuous positive air pressure therapy for the treatment of moderate/severe obstructive sleep apnea syndrome

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is a highly effective treatment for obstructive sleep apnea syndrome (OSAS). However, poor adherence is a limiting factor, and a significant proportion of patients are unable to tolerate CPAP. The aim of this study was to determine predictors of long-term non-compliance with CPAP. METHODS: CPAP treatment was prescribed to all consecutive patients with moderate or severe OSAS (AHI ≥15 events/h) (n = 295) who underwent a full-night CPAP titration study at home between February 1, 2002 and December 1, 2016. Adherence was defined as CPAP use for at least 4 h per night and five days per week. Subjects had periodical follow-up visits including clinical and biochemical evaluation and assessment of adherence to CPAP. RESULTS: Median follow-up observation was 74.8 (24.2/110.9) months. The percentage of OSAS patients adhering to CPAP was 41.4% (42.3% in males and 37.0% in females), and prevalence was significantly higher in severe OSAS than in moderate (51.8% vs. 22.1%; p < 0.001; respectively). At multivariate analysis, lower severity of OSAS (HR = 0.66; CI 95 0.46-0.94) p < 0.023), cigarette smoking (HR = 1.72; CI 95 1.13-2.61); p = 0.011), and previous cardiovascular events (HR = 1.95; CI 95 1.03-3.70; p = 0.04) were the only independent predictors of long-term non-adherence to CPAP after controlling for age, gender, and metabolic syndrome. CONCLUSIONS: In our cohort of patients with moderate/severe OSAS who were prescribed CPAP therapy, long-term compliance to treatment was present in less than half of the patients. Adherence was positively associated with OSAS severity and negatively associated with cigarette smoking and previous cardiovascular events at baseline

Recent advances in the integrated geophysical exploration of buried archaeological targets

We propose the integration of magnetic, electromagnetic (groundpenetrating radar, GPR) and seismic methods to study the inner structure of prehistoric funerary mounds. The combination of techniques allows high-resolution imaging and detection of buried targets and characterization of subsurface materials based on magnetic susceptibility, dielectric permittivity, conductivity and seismic velocity/attenuation. The 2012 archaeo-geophysical expedition to Scythian necropoleis in Kazakhstan allowed advancement of the integrated procedure through optimization of the individual techniques. We improve the results of seismic tomography inversion through an ART algorithm with a relaxation parameter which is progressively reduced during the iterative reconstruction process. We use instantaneous attributes and spectral decomposition to improve the interpretation of GPR reflection data. The results obtained from the 2012 dataset allow detailed reconstruction of the inner structure of three kurgans (i.e. funerary mounds) with maximum 7m central elevation. In particular, localized anomalies related to metallic targets smaller than the GPR and seismic resolution limits are identified from magnetic data after high pass filtering; GPR data allow imaging of inner stratigraphy up to a maximum depth of about 250 cm; seismic tomography maps large traveltime anomalies probably related to funerary chambers at the base of the mound

Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network)

Dietary fat intake as a risk factor for the development of diabetes. Multinational, multicenter study of the Mediterranean Group for the Study of Diabetes (MGDS)

In the context of the Multinational MGSD Nutrition Study, three groups of subjects were studied: 204 subjects with recently diagnosed diabetes(RDM),42subjectswithundiagnoseddiabetes(UDM)(AmericanDiabetesAssociation criteria—fasting plasma glucose [FPG] 126 mg/dl), and 55 subjects with impaired fasting glucose(IFG)(FPG 110and126mg/dl).Eachgroupwascomparedwithacontrolgroupof nondiabetic subjects, matched one by one for center, sex, age, and BMI. Nutritional habits were evaluated by a dietary history method, validated against the 3-day diet diary. In RDM, the questionnaire referred to the nutritional habits before the diagnosis of diabetes. Demographic data were collected, and anthropometrical and biochemical measurements were taken. RESULTS— Compared with control subjects, RDM more frequently had a family history of diabetes(49.0vs.14.2%;P0.001),exercisedless(exerciseindex53.5vs.64.4;P0.01),and more frequently had sedentary professions (47.5 vs. 27.4%; P 0.001). Carbohydrates contributed less to their energy intake (53.5 vs. 55.1%; P 0.05), whereas total fat (30.2 0.5 vs. 27.8 0.5%; P 0.001) and animal fat (12.2 0.3 vs. 10.8 0.3%; P 0.01) contributed moreandtheplant-to-animalfatratiowaslower(1.50.1vs.1.80.1;P0.01).UDMmore frequentlyhadafamilyhistoryofdiabetes(38.1vs.19.0%;P0.05)andsedentaryprofessions (58.5vs.34.1%;P0.05),carbohydratescontributedlesstotheirenergyintake(47.61.7vs. 52.81.4%;P0.05),totalfat(34.71.5vs.30.41.2%;P0.05)andanimalfat(14.2 0.9 vs. 10.6 0.7%; P 0.05) contributed more, and the plant-to-animal fat ratio was lower (1.6 0.2 vs. 2.3 0.4; P 0.05). IFG differed only in the prevalence of family history of diabetes (32.7 vs. 16.4%; P 0.05). CONCLUSIONS— Our data support the view that increased animal fat intake is associated with the presence of diabetes

Evaluation of polygenic determinants of non-alcoholic fatty liver disease (NAFLD) by a candidate genes resequencing strategy

NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P 0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity

Off-the-Wall Higgs in the Universal Randall-Sundrum Model

We outline a consistent Randall-Sundrum (RS) framework in which a fundamental 5-dimensional Higgs doublet induces electroweak symmetry breaking (EWSB). In this framework of a warped Universal Extra Dimension, the lightest Kaluza-Klein (KK) mode of the bulk Higgs is tachyonic leading to a vacuum expectation value (vev) at the TeV scale. The consistency of this picture imposes a set of constraints on the parameters in the Higgs sector. A novel feature of our scenario is the emergence of an adjustable bulk profile for the Higgs vev. We also find a tower of non-tachyonic Higgs KK modes at the weak scale. We consider an interesting implementation of this ``Off-the-Wall Higgs'' mechanism where the 5-dimensional curvature-scalar coupling alone generates the tachyonic mode responsible for EWSB. In this case, additional relations among the parameters of the Higgs and gravitational sectors are established. We discuss the experimental signatures of the bulk Higgs in general, and those of the ``Gravity-Induced'' EWSB in particular.Comment: 27 pages, 4 figure

New insights into the pathogenesis of non-alcoholic fatty liver disease: gut-derived lipopolysaccharides and oxidative stress

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The intricate NAFLD pathogenesis is summarized by the multiple-hits hypothesis, which combines all the environmental and genetic factors that promote the development of NAFLD into a single scenario. Among these, bacterial lipopolysaccharides (LPS) are derived from the overgrowth of Gram-negative bacteria and translocated mainly as a consequence of enhanced intestinal permeability. Furthermore, oxidative stress is increased in NAFLD as a consequence of reactive oxygen species (ROS) overproduction and a shortage of endogenous antioxidant molecules, and it is promoted by the interaction between LPS and the Toll-like receptor 4 system. Interestingly, oxidative stress, which has previously been described as being overexpressed in cardiovascular disease, could represent the link between LPS and the increased cardiovascular risk in NAFLD subjects. To date, the only effective strategy for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH) is the loss of at least 5% body weight in overweight and/or obese subjects. However, the dose-dependent effects of multispecies probiotic supplementation on the serum LPS level and cardiometabolic profile in obese postmenopausal women were demonstrated. In addition, many antibiotics have regulatory effects on intestinal microbiota and were able to reduce serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor alpha (TNF-α) in NASH animal models. Regarding the oxidant status, a Mediterranean diet has been reported to reduce oxidant stress, while vitamin E at high daily dosages induced the resolution of NASH in 36% of treated patients. Silymarin had the positive effect of reducing transaminase levels in NAFLD patients and long-term treatment may also decrease fibrosis and slow liver disease progression in NASH. Finally, the influence of nutraceuticals on gut microbiota and oxidant stress in NAFLD patients has not yet been well elucidated and there are insufficient data either to support or refuse their use in these subjects