Current Vascular Pharmacology - Volume 16, Issue 3, 2018

First described in 1980, nonalcoholic fatty liver disease (NAFLD) has become more common although the exact incidence and prevalence is unknown. While the exact prevalence varies from region to region, the overall trend shows an increased number of patients with NAFLD. Risk factors for the development of NAFLD includes advanced age, male gender, obesity, and having elements of the metabolic syndrome. There is also an association between the presence of NAFLD and coronary atherosclerosis. Persons of Hispanic descent tend to have higher rates of NAFLD when compared with other populations. Genetics, specifically polymorphisms in the gene PNPLA3, may explain the difference among these different groups. As the rates of obesity increases throughout the world, it is anticipated that the rate of NAFLD will continue to increase. This has large scale implications on the rates of cirrhosis, hepatocellular carcinoma, liver transplantation and cardiovascular events that could impact hundreds of millions of people.

The implications and prognosis of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are substantially different. The aim of the present review is to describe and compare the pathological and clinical implications of these two conditions. Patients with NASH have a higher risk of progressing to cirrhosis than patients with NAFL but without steatohepatitis, who tend to have a non-progressive disease and only a minority progresses to NASH. Patients with NASH also are at greater risk to develop hepatocellular cancer (HCC) and NASH is the third commonest cause of HCC. In contrast, only few cases of HCC have been reported in patients with isolated NAFL. Given that nonalcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, it is also strongly related to cardiovascular disease (CVD). Again, it appears that patients with NASH have higher cardiovascular risk than patients with NAFL. Finally, all-cause mortality is also higher in patients with NASH than in patients with NAFL; mortality rates in the latter patients do not differ from the general population. In conclusion, NAFL and NASH have different prognosis and therefore it is imperative to develop accurate, noninvasive methods that will identify the presence of steatohepatitis in this population.

Metabolic syndrome (MetS) is a cluster of central obesity, dyslipidaemia, insulin resistance and hypertension. MetS frequently co-exists with non-alcoholic fatty liver disease (NAFLD), which is characterized by fat accumulation in the liver in the absence of alcohol abuse, viral hepatitis and other causes of chronic liver diseases. Both MetS and NAFLD are associated with an increased risk for cardiovascular disease and type 2 diabetes mellitus. There are also other associations between MetS and NAFLD. In the present narrative review, we discuss the links between MetS and NAFLD in terms of prevalence, risk factors and treatment (both lifestyle interventions and drug therapy). Such associations highlight the common pathophysiological pathways of these metabolic disorders, although data for an independent association are not robust. Nevertheless, NAFLD may be regarded as a hepatic manifestation of MetS.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as progressive form of the disease are associated with cardiovascular risk factors including obesity, dyslipidaemia, hyperglycaemia and hypertension. When NAFLD is associated with cardiovascular disease, mortality of NAFLD patients is increased due to cardiovascular disease. Prevalence of NAFLD and NASH is high, but it seems that epidemic of the disease is under-recognized and under-appreciated. Linking pathophysiological mechanisms are complex and still not well understood. The main related pathophysiological mechanisms are lipid factors, insulin resistance, inflammation, proinflammatory cytokines, oxidative stress, pro-coagulant status, hyperglycaemia and adipokines. First-line management focuses on lifestyle modifications in both diseases. Several therapeutic interventions, insulin sensitizer agents, lipid lowering drugs, antioxidants, such as vitamin E, have been proposed. Statins appear to be safe, but their use in the treatment of NAFLD and NASH is under-appreciated. Many different agents are being investigated as future drugs for the treatment of this clinical entity. The aim of the review is to examine the extent of the epidemic and the mediating mechanisms, to critically evaluate current guideline recommendations, and to consider current and future medications for this disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide, affecting more than 30% of general population. High-fat diets, physical inactivity and obesity, all prevalent in the western societies, are strongly associated with the development and progression of NAFLD. Current drug therapies have not consistently shown substantial beneficial effects. Thus, lifestyle modification appears to be the optimal intervention in combating the disease. Accordingly, several studies have concluded that weight loss, via increase in physical activity, and dietary interventions could potential ameliorate biochemical, histological, and structural abnormalities of non-alcoholic fatty liver disease. The aim of this review is to summarize the findings of these lifestyle intervention studies and discuss the implementation of each intervention, and its effectiveness in the management of the disease in everyday clinical practice.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease (30% of the general population) and up to 40% of cases advance to the more severe form of the disease: nonalcoholic steatohepatitis (NASH), which is causally related to cirrhosis and cardiovascular disease (CVD). There is no generally accepted effective treatment for NAFLD/NASH. The joint guidelines of the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity (EASO) suggest the “off label” use of pioglitazone in patients without type 2 diabetes mellitus (T2DM) and pioglitazone in subjects with T2DM or vitamin E or their combination for the treatment of NASH; however pioglitazone has considerable limitations: weight gain, bone fractures in women, and heart failure.

The aim of this narrative review is to assess the existing evidence supporting statin use for the treatment of NASH and the reduction of the high CVD risk of these patients. Animal data suggest that there is some benefit from statin use in liver histology in models of NASH. In humans, 3 post hoc analyses of randomised controlled trials (n=1,600, n=1,123, n=8,864) suggest that the use of atorvastatin (even in 80 mg/day) has a beneficial effect on NAFLD/NASH, in terms of liver enzyme reduction and ultrasonographic amelioration. Moreover, and most importantly, statin treatment halved CVD morbidity and mortality in statin-treated NAFLD/NASH patients compared with statin-treated participants with normal liver structure and function and reduced by 2/3rds CVD events in comparison with NAFLD/NASH patients that were not on a statin (90% of this population is not on statins because of the unjustified fear for liver damage). Three biopsy studies (n=20, n=107 and n=356) showed that statin treatment had a protective effect on steatosis, steatohepatitis and fibrosis.

Data suggest that statin treatment in humans substantially improve or cure NAFLD/NASH, but above all substantially reduce CVD morbidity and mortality. Administration of potent statins appears safe and effective in saving lives in NAFLD/NASH patients.

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease. NAFLD may evolve to non-alcoholic steatohepatitis (NASH), which is causally related to cirrhosis and cardiovascular disease (CVD) mortality. There is no generally accepted effective treatment for NAFLD/NASH. Chronic kidney disease (CKD) is relatively common and might co-exist with NAFLD/NASH, aggravate one another, and increase CVD risk. Common therapies could improve outcome. Potent statins at high doses, such as atorvastatin and rosuvastatin, ameliorate NAFLD/NASH and reduce the mortality rates by half as compared with those on the same statins but without liver disease and CVD-related events are reduced by atorvastatin for patients with all stages of CKD. The new anti-diabetic medication classes, the sodium-glucose co-transporter-2 inhibitors (SGLT2i) and the glucagon like peptide receptor agonists (GLP1 RA) for patients with NAFLD/NASH, CKD and T2DM are useful because they ameliorate NAFLD/NASH, delay the evolution of CKD, and substantially reduce CVD and all-cause mortality. Thus, the common use of high potency statins, renin-angiotensin-aldosterone system inhibitors, and the newer anti-diabetic agents increase compliance and can substantially reduce CVD risk and the rate of liver and kidney adverse events, improving quality of life and survival.

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries with potential progression to nonalcoholic steatohepatitis (NASH) and cirrhosis, is associated with cardiovascular disease (CVD) mortality. Several studies have reported a relationship between uric acid and NAFLD/NASH and it seems that serum uric acid (SUA) is a significant independent factor for the development of NAFLD. Potential mediating mechanisms include insulin resistance, endothelial dysfunction, and activation of inflammasome, especially NLRP3. Moreover, emerging evidence indicates a strong association between elevated SUA, metabolic syndrome (MetS), NAFLD, and CVD. The emphasis of the present review is whether common therapy of elevated SUA levels and NAFLD can improve compliance. There are several drugs with “off target” properties that show some separate benefit on SUA reduction (e.g. losartan) or NAFLD/NASH (pioglitazone); however, there is no randomized controlled trial (RCT) of a single drug with beneficial outcome for both diseases. Allopurinol reduces SUA levels and ameliorates NAFLD/NASH; however, no RCTs have been performed up to now to explore potential survival benefits. Atorvastatin, which has proven safe in NAFLD/NASH, reduces SUA levels, ameliorates NAFLD/NASH, prevents liver fibrosis, and above all substantially reduces CVD morbidity and mortality in comparison with those on statins but without NAFLD/NASH. This drug could be a solution to improve compliance in both diseases, which are prevalent and becoming even more common with the obesity, MetS, and type 2 diabetes mellitus epidemic.

Background: Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the general population. The disease ranges from simple steatosis, to non-alcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. Several drugs are used in daily clinical practice to manage the disease. However, data on their efficacy in liver histology are not consistent. Aim: We discuss current treatment options for NAFLD and NASH and preliminary results from novel drugs under investigation. Results: Among various drugs assessed for the management of NAFLD and NASH, only pioglitazone and vitamin E have provided consistent benefits on liver histology, and are recommended by the European and American guidelines. Statins were shown to produce clinically meaningful results in patients with NAFLD or NASH. Other drugs such as metformin and polyunsaturated fatty acids that are being used in clinical practice off-label have provided benefits on terms of hepatic biochemical and diabetesrelated markers; data on liver histology with these drugs are scarce and from small studies. Several new approaches to reduce inflammation, steatosis or fibrosis have shown promising results in experimental models of NAFLD or NASH lesions and are being evaluated in humans. Conclusion: Pioglitazone and vitamin E are the only drugs providing consistent benefits and are currently recommended for NASH. Various pathogenetic pathways are being targeted to reduce steatosis, inflammation and fibrosis and early data on several novel drugs are very promising. On-going human trials will unveil their true impact.

Background: Vitamin D (Vit D) insufficiency has been implicated in the pathophysiology of numerous diseases. Obstructive sleep apnoea syndrome (OSAS), a disorder associated with increased cardiovascular and cerebrovascular morbidity, has been associated with decreased Vit D levels, but reports are inconclusive. Aim: To evaluate the association between serum 25-hydroxyvitamin D [25(OH)D], a marker of Vit D status, with anthropometric and sleep characteristics of OSAS patients and to compare those levels between OSAS patients and non-apnoeic controls. Method: Consecutive subjects who had undergone polysomnography and pulmonary function testing were divided into controls (apnoea-hypopnea index, AHI <5/h) and OSAS group (AHI ≥5/h). Results: A total of 169 subjects (135 men) were included. OSAS patients (n=139) significantly differed from non-apnoeic controls in terms of age (53.9±12.8 vs. 44.9±12.8 years, p=0.002) and body mass index (BMI) (35.9±6.9 vs. 29.9±6.8 kg/m2, p<0.001). Serum 25(OH)D levels were lower in OSAS patients (17.8±7.8 vs. 23.9±12.4 ng/ml, p=0.019). In OSAS patients, levels of serum 25(OH)D were negatively correlated with sleep stage transitions (r=-0.205, p=0.028), AHI (r=-0.187, p=0.045), oxygen desaturation index (r=-0.234, p=0.011) and percentage of time with oxyhaemoglobin saturation <90% (r=-0.172, p=0.041). In contrast, they were positively correlated with average oxyhaemoglobin saturation during sleep (r=0.179, p=0.033), forced expiratory volume in 1 sec (r=0.207, p=0.037) and oxygen partial pressure (r=0.197, p=0.029). Conclusion: Vit D levels were lower in OSAS patients compared with non-apnoeic controls. Several indices of OSAS severity also correlated with Vit D levels.

Background: Patients with end-stage renal disease (ESRD) exhibit high morbidity as well as mortality for atherosclerotic cardiovascular diseases (CVD). Therefore, we investigated differences in individual lipoprotein classes and subclasses in ESRD patients under chronic high volume hemodiafiltration (HV-HDF) in comparison with a control group. We also assessed the prognosis of these patients and analyzed these parameters after 5 years follow-up. Methods: 57 patients and 50 controls were enrolled. We analysed high density (HDL) and low density (LDL) lipoprotein subfractions using the Quantimetrix Lipoprint(R) system. Subfractions were correlated with selected clinical-biochemical parameters including risk factors for atherosclerotic CVD at the beginning of and after 5 years follow-up. Results: Fourteen patients survived the 5-year follow-up. Follow-up results revealed a shift toward smaller HDL subfractions. In lipoproteins carrying apolipoprotein B, there was a shift of cholesterol from very low density (VLDL) to intermediate density (IDL) lipoproteins and LDLs. Hypolipidaemic therapy did not influence lipoprotein profiles in HV-HDF patients. Conclusion: 1. HV-HDF patients exhibit specific lipid profiles with elevated triacylglycerol, low HDL and LDL and higher content of cholesterol in remnant particles (VLDL and IDL) at the expense of large LDL. HDL subfractions were linked to the number of risk factors for CVD in the control group only. 2. Baseline lipoprotein profiles did not differ between survivors and non-survivors. Non-survivors had higher CRP and lower HDL-C. 3. During the 5 year follow-up period, cholesterol in HDL particles and lipoproteins carrying apolipoprotein B redistributed in survivors towards smaller particles, thus resembling the profile of control patients.