Reviews on Recent Clinical Trials - Volume 9, Issue 3, 2014

Non Alcoholic Fatty Liver Disease (NAFLD), defined as the presence of a significant amount of lipid accumulation in the liver (at least in 5% of hepatocytes), represents a challenging issue for the Hepatologists. NAFLD is not represented by a single entity, but rather by two different entities that have different natural history and evolution that range from simple fat accumulation in the liver (without any consequence), to necroinflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The reason of these differences has to be found in the host characteristics and associated risk factors. Globally, its prevalence among liver diseases, and in the general population, is rising in the recent years along with its associated conditions: obesity, insulin resistance, metabolic syndrome and diabetes. This increment, together with the reported clinical conditions, may be accounted for changes in dietary habits and the increase of sedentary lifestyle. Its diffusion seems to be pandemic, given that it is beginning to affect the populations in the developing world due to the spread of Western lifestyle. This is particularly worrying in young adults and children in what seems to have become the main cause of liver disease. Even if the real rate of global incidence of NAFLD are not known, its worldwide prevalence in general population is estimated to be 20-30% in Western Countries and 5-18% in Asia and it is increasing over time. In this review we will report on the global and regional prevalence of NAFLD, the principal risk factors and the natural history of its different presentations.

One of the most common hepatic manifestations of the metabolic syndrome is non-alcoholic fatty liver disease (NAFLD). This disease varies from simple steatosis to cirrhosis and hepatocellular carcinoma. Different molecules secreted from adipose tissue such as adiponectin, leptin, resistin and visfatin and pro-inflammatory cytokines such as tumour necrosis factor-α, and interleukins, can be involved in the pathogenesis of NAFLD. In this review we describe the role of these adipokines and cytokines in the pathogenesis of NAFLD. We comment on their potential use as non-invasive biomarkers of steatosis and fibrosis, and their potential therapeutic role.

The gut-liver axis model has helped to explain the liver steatosis (NAFLD) and steatohepatitis (NASH) etiopathogenesis. The discovery of a key role for an altered intestinal permeability (IP) in this pathophysioligcal framework has closed the link between gut lumen antigenic/toxic substances and systemic and liver inflammation in NAFLD and obesity, metabolic syndrome. Recent evidence from the literature show how IP can be modulated by several non-pharmacological and pharmacological agents and be the target for future preventive and curative treatment of NAFLD and NASH. In this review we describe the concept of IP, its ultrastructural basis, its role in the NALFD pathophysiology and emerging evidence on non-pharmacological and pharmacological agents able to favourably modulate it.

Nonalcoholic fatty liver disease (NAFLD) is an important cause of chronic liver disease; including simple steatosis, steatohepatitis, fibrosis, or cirrhosis. The metabolic syndrome (MS) is the existence of metabolic alterations that confer an increased risk for developing cardiovascular disease and diabetes. NAFLD and MS frequently coexist and 90% of NAFLD patients have more than one manifestation of the MS. In addition, both entities are related to other comorbid conditions. Scientific advances in the understanding of the association between NAFLD and the MS have identified insulin resistance as a key aspect in the pathophysiology of both diseases. Knowledge gained from these advances can be applied clinically in the management and prevention of NAFLD, the MS, and associated metabolic alterations. Cardiovascular disease is the leading cause of death in patients with NAFLD and the MS, therefore adequate diagnosis and effective treatment are critical. This review analyzes current evidence of the association between NAFLD and the MS. The growing prevalence of both entities is highlighted. Next, the common mechanisms leading to insulin resistance are discussed. Manifestations and diagnosis of the MS and NAFLD are reviewed, pointing out the associated comorbid conditions shared by both diseases. Finally, a brief overview regarding NAFLD treatment is presented.

Liver biopsy, since 1883, when were first performed, became the gold standard to confirm the earlier stages of fibrosis and grading of non-alcoholic fatty liver disease (NAFLD) and for distinguishing simple steatosis from non- alcoholic steatohepatitis (NASH). General limitations of liver biopsy are sampling error and inter- and intraobserver variability. Also procedure is invasive and that’s why associated with some potential adverse effects and complications which may be minor (pain or vagal reactions, transient hypotension) or major such as visceral perforation, bile peritonitis or significant bleeding. Presence of steatosis, hepatocellular injury in the form of ballooning, lobular inflammation and perisinusoidal fibrosis, usually with a zone 3 distribution are considered to be most important histological features of adult NAFLD which may differ from bariatric surgery or pediatric patients. In addition, grading and staging and current semiquantitative systems for NAFLD assessment are discussed.

Non-alcoholic fatty liver disease (NAFLD) is extremely prevalent in the Western world. Non-invasive diagnostic methods should be able to reflect the presence and severity of liver fatty changes and the presence and severity of hepatic inflammation and fibrosis (features of non-alcoholic steato-hepatitis), since these are related to the risk of progression and clinical complications. This article will: a) review the rational basis for the use of ultrasound and transient elastography in patients with NAFLD; b) summarize available data regarding the diagnostic performance of these two widely used non-invasive imaging methods in patients with NAFLD; and c) give an overview of newer sonographic applications that might be used in clinical practice in the near future in this field.

As the prevalence of obesity and insulin-resistance continues to increase in the general population, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions, thus becoming one of the leading causes of chronic liver disease worldwide. It may present as simple steatosis (NAFL) or steatohepatitis (NASH), which in turn may develop fibrosis and ultimately cirrhosis. Conventional biochemical liver test and radiological investigations are not able to provide reliable information on liver functional reserve, and liver biopsy remains the gold standard to stage NAFLD, differentiate simple steatosis from NASH, and grade fibrosis. However, liver biopsy has some limitations, and is not preferred by patients due to its invasiveness. Thus, non-invasive assessment of disease stage by using liver breath tests – which are based on hepatic clearance of non-radioactive stable 13C-labelled drugs – may be of interest to stage disease and assess patients prognosis due to good accuracy and repeatability. These substrates are orally administered and are cleaved by enzymes specifically located in the liver thus reflecting either the microsomal, cytosolic, or mitochondrial functions. 13C-Breath Tests have been initially oriented to differentiate broad categories of patients and more recently to refine stage differentiation in patients with early stages of liver disease. In NAFLD patients, 13C-BTs were able to distinguish simple steatosis from NASH and had good correlation with both histological fibrosis stage and biochemical markers of fibrogenesis. Although promising results have been achieved in this field, their use in clinical practice is still restricted to a specialized niche. However, concordant data from literature conferred to 13C-Breath Tests a potential role in providing punctual and longitudinal evaluation of patients, identifying those patients where liver biopsy may selectively be performed to stage disease, monitoring and predicting therapeutic response.

Hepatic steatosis, a hallmark of non-alcoholic fatty liver diseases (NAFLD), is an early marker as well as a cause of the cardiometabolic syndrome, prediabetes and NIDDM. Its high prevalence in the general population and its many causes and complex mechanisms make it a pathology which must be treated and requires careful diagnosis also in terms of underlying causes, which may strongly vary among subjects. The recent awareness of the commonness of NAFLD has prompted intensive research which unraveled many different mechanisms causing hepatic steatosis, from diet to intestinal diseases and liver receptors. Epigenetic factors must be added to this list. A variety of causes and mechanisms open many different potential therapeutic approaches. This review aims at summarizing the effects of a selected series of old and new treatments for which there exist at least a reasonable amount of data. Many show efficacy in animals but human data are less convincing largely because of poor amount of data and generally they lack histological confirmation. Many drugs either induce undesirable side-effects or have tight therapeutic dose windows. The recent recognition of a key role of intestinal microbiota in NAFLD and metabolic syndrome may represent a major therapeutic breakthrough by the modulation of bacteria in the gut. Performing randomized long-term clinical studies including liver biopsies appears as prerequisite to determine which treatment is the most valuable, however not ignoring that the therapeutic choice may require individualization among subjects as a function of the origins of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a global problem and one of the most common liver diseases in the world. Various pharmacological and non-pharmacological therapies seem to be non-effective and the patients are often advised not to expect a positive outcome. Hence, even in the modern Western society many patients reach for traditional herbal products. Silymarin, a lipophilic extract derived from milk thistle (Silybum marianum) has been used in liver and bile disorders for centuries. Strong antifibrotic, antioxidant, antiviral and anti-inflammatory activities of silymarin joined with its metabolic effect proven in vitro make it ideal as a drug candidate in the therapy of NAFLD. Several recent randomized clinical studies have demonstrated that silymarin versus placebo significantly contributes to amelioration of the liver condition affected by NAFLD since it reduces steatosis severity, liver ballooning and fibrosis, followed by lowered aminotransferase levels in both short and long lasting therapies. Silymarin is also as efficient as an insulin sensitizer in the NAFLD therapy, but with less adverse effects. Phase III clinical trials have confirmed silymarin to be currently the best medication for the NAFLD patients, but the problems associated with its standardization, formulation and dosage are yet to be solved. However, green tea (Camellia sinensis) and licorice (Glycyrrhiza glabra) root extracts have also been studied in the clinical trials in the therapy of NAFLD patients. Some other herbal products, which have been tested on animals and have the potential to be used in clinical trials, are briefly summarized in this paper.

Due to their high prevalence, non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR) and hepatitis C virus (HCV) infection are bound to cohabit. However, the relationship between these 3 entities is complex and multilayered. HCV, particularly genotype 3, may induce a “viral” steatosis, morphologically indistinguishable from the steatosis of NAFLD but with different implications and prognosis. On the other hand, epidemiological and experimental data show that patients with HCV have a higher risk of developing IR and, in susceptible individuals, type 2 diabetes (T2D). In patients with HCV, T2D increases fibrosis progression rate, increases the incidence of HCC, worsens liver-related outcomes and worsens response to interferon-α based therapy. We conclude by discussing a possible increased incidence of cardiovascular events in HCV patients.

Non-alcoholic fatty liver disease (NAFLD) is a frequent etiology of liver disease in Western Countries and non-alcoholic steato-hepatitis (NASH) is becoming a leading indication for liver transplantation in US, with constant increase overtime. Specific co-morbidities correlated to the presence of obesity and associated with metabolic syndrome should always be ruled out in patients affected by NASH-related end-stage liver disease, who are potential candidates for liver transplantation. Patients transplanted for NAFLD present similar outcomes compared with patients transplanted for other indications. With regards to post-transplant outcomes in obese patients, available data are contradictory, with reported increased mortality only in patients with BMI >40. A new multidisciplinary protocol of liver transplantation and sleeve gastrectomy seems to be effective and safe in obese patients who were not able to lose weight before liver transplantation. However prospective studies are needed. The NASH recurrence rate after liver transplantation ranges between 20-40%, but its variability largely depends on the methodology used for the diagnosis (i.e. liver tests, liver histology or imaging technique).

In the last 10 years, more and more clinical trials have come to China because of potential market/easy access of patient and cost-effectiveness, but if we look back, there had been minimum changes on the regulatory requirements, and there is a possibility that China government could further strengthen the regulatory requirements for the global pharma/foreign pharma. In 2013, there was a breaking news that China government would start to investigate the corruption of GSK. So now, should the global pharma/foreign pharma go to China to conduct clinical trial? If the sponsor wants to access China market and provide unmet medical needs to China market, there are still many opportunities and there are ways to get all of these barriers resolved.