Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

Statins and nonalcoholic fatty liver disease: a bright future?

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease affecting up to 30% of adults in Western countries. NAFLD and mainly nonalcoholic steatohepatitis (NASH) are independent cardiovascular disease (CVD) risk factors; more of these patients are expected to die from CVD rather than from liver disease. The effect of statins on newer risk factors that may influence the pathobiology of liver damage in NASH is considered. These include microparticles, inflammasomes, gut–liver axis abnormalities and dietary lipids. Evidence suggests that statins induce NAFLD/NASH resolution and substantially improve symptom-free survival from CVD to a greater extent than in patients without NAFLD. However, large randomized clinical trials are needed to verify these findings.     

Which treatment for nonalcoholic fatty liver disease?

Subjects with nonalcoholic fatty liver disease are at risk of progressive liver failure. Lifestyle changes including weight-loss strategies and increased physical activity remain the first-line approach, but a few pharmacological treatments have also been successfully tested. Several drugs improve biochemistry, only a few improve histology; in all cases, the results were not sustained after treatment stop. Pharmacological treatment is not so far indicated outside controlled clinical trials with histological outcomes.     

Drug-induced liver injury: Is chronic liver disease a risk factor and a clinical issue?

Introduction: Clinicians and practitioners caring for patients with chronic liver disease are often unsure whether drug therapy is a hazard that increases their patient’s risk for drug-induced liver injury (DILI).

Areas covered: We searched for reports of drug induced liver injury, both idiosyncratic and intrinsic, in patients with chronic liver disease including non-alcoholic and alcoholic liver disease, and cirrhosis. Reports we analyzed include statin treatment in patients with fatty liver, acetaminophen use in alcoholic fatty liver, antituberculous drugs in patients with tuberculosis and viral hepatitis, antiviral medications in hepatitis and antiretroviral medications in HIV/AIDS. The most challenging cases we found are drug therapy in patients with decompensated liver cirrhosis.

Expert opinion: We identified many case reports and case series discussing a potential increased risk of DILI in patients with pre-existing liver disease. However, most of these reports were retrospective and ambiguous. With few exceptions, we conclude that drugs seem to be well tolerated by the majority of patients with pre-existing, non-cirrhotic chronic liver diseases. Special care is needed for some therapies, however, including antiviral therapy in chronic hepatitis B and C and in decompensated liver cirrhosis with impaired drug metabolism. Prospective studies are warranted to valid our conclusions.     

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis,classification, and effect on drug metabolizing enzymes and transporters

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a “three-hit” process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters.

Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.     

Drugs with anticholinergic properties: a potential risk factor for psychosis onset in Alzheimer's disease?

Psychosis in Alzheimer's disease is common and troublesome. The impact on the quality of life of both patients and caregivers is high and drug treatments raise concern in terms of both efficacy and safety. Therefore, identifying the risk factors that play an important role in the onset of psychosis is mandatory for the prevention of this clinical condition. From a biological point of view, drugs with anticholinergic properties are a reasonable cause of psychosis. Demented patients have been found to use a disproportionate amount of drugs with anticholinergic properties. On the other hand, new evidence suggests that the cholinergic system may be implicated not only with the onset of cognitive impairment, but even in the genesis of psychosis symptoms. This review focuses on biological and clinical data which suggest that anti-cholinergic drugs should be regarded as a potential risk factor for psychosis in Alzheimer's disease.     

Atherogenesis in renal patients: a model of vascular disease?

Chronic kidney disease (CKD), and particularly kidney failure, is associated with accelerated atherosclerosis and approximately a 20-fold increased risk of cardiovascular death. The majority of these patients die from complications directly attributed to atherosclerosis and their life expectancy is decreased. Established risk factors are involved in the pathogenesis of this phenomenon. Age, gender, smoking, hypertension, dyslipidaemia and diabetes mellitus are among the established risk factors. Inflammation, qualitative lipid disorders (e.g. small dense low density lipoprotein), vascular calcification and oxidative stress represent emerging risk factors. The precise mechanism of atherosclerosis in patients with kidney failure is not yet known. CKD might represent a clinical model of atherogenesis. Thus, the evidence obtained from investigating "renal" atherogenesis could be of interest in improving our understanding of this disease process in the non-renal population. We review the relationship between "renal" and non-renal atherosclerosis focusing on pathogenesis, risk factors and clinical events and how they interact with treatment options. Overall, the "later" stages of CKD may eventually be considered as a coronary heart disease equivalent condition.     

Serum and mucosal cytokine profiles in patients with active Helicobacter pylori and ischemic heart disease: is there a relationship?

This study is designed to investigate, for the first time, circulating and gastric mucosal levels of IL1-alpha, IL-6, IL-8 and TNF-alpha in patients with ischemic heart disease (IHD) and matched controls, according to the presence or absence of active Helicobacter pylori infection. Furthermore, in order to evaluate whether modified lipid profile was associated to an increased cardiovascular risk, this was determined in the same groups. Cytokine levels were measured using ELISA in 58 patients with IHD and 52 controls. Active H. pylori infection was assessed if either culture of H. pylori or rapid urease test gave a positive result. Our findings indicate increasing cytokine mucosal levels in H. pylori-positive patients compared to H. pylori-negative subjects. However, the increase was statistically significant only for IL-6 and TNF-alpha in the gastric mucosa of IHD patients. In H. pylori-positive controls, IL-8 mucosal levels positively correlated with both IL1-alpha (r = 0.98; P = 0.0003) and IL-6 (r = 0.83; P = 0.03) levels. Circulating cytokine levels were comparable in IHD and healthy subjects, regardless of H. pylori status. There were no correlations between mucosal and circulating cytokine levels. Active H. pylori infection was not associated with a modified lipid profile in either controls or IHD patients, although ApoAI levels were significantly higher in H. pylori-positive controls compared to those H. pylori-negative. Taken together, the results of the present study provide evidence that active H. pylori infection may play a role as a trigger factor in the pathophysiology of IHD by inducing an inflammatory cascade concentrated on gastric mucosa.