Dawn M. Torres

Features, diagnosis, and treatment of nonalcoholic fatty liver disease.

As the global incidence of obesity has increased, nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern. NAFLD occurs in children and adults of all ethnicities and includes isolated fatty liver and nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma and have increased all-cause mortality. NAFLD is associated with a variety of clinical conditions and is an independent risk factor for hepatocellular carcinoma. The pathogenesis of NAFLD and the specific steps that lead to NASH and advanced fibrosis are not fully understood, although researchers have found that a combination of environmental, genetic, and metabolic factors lead to advanced disease. There have been improvements in noninvasive radiographic methods to diagnose NAFLD, especially for advanced disease. However, liver biopsy is still the standard method of diagnosis for NASH. There are many challenges to treating patients with NASH, and no therapies have been approved by the U.S. Food and Drug Administration; multimodal approaches are being developed and becoming the standard of care. We review pathogenesis and treatment approaches for the Wests largest liver-related public health concern.

Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma: fertile soil.

Nonalcoholic fatty liver disease (NAFLD) is easily the most common cause of chronic liver disease in the United States (U.S.) as the hepatic manifestation of the metabolic syndrome. Although only 5 to 20% of patients with NAFLD are generally considered to meet criteria for nonalcoholic steatohepatitis (NASH), with its inherent risk for progression to cirrhosis, this still represents an alarmingly large number of individuals. The exponentially growing rates of hepatocellular carcinoma (HCC) in the U.S. may be partially attributable to increased numbers of NASH cirrhotics, although recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis. This review focuses on HCC in noncirrhotic NASH with an emphasis on clinical presentation, pathogenesis, and implications for screening.

Nonalcoholic Fatty Liver Disease

As the hepatic manifestation of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of asymptomatic liver enzyme elevations in Western nations. Although it is easy to diagnose NAFLD, a liver biopsy is currently required to diagnose nonalcoholic steatohepatitis (NASH). Patients with NASH are those at greatest risk of progression to cirrhosis and, thus, treatment efforts are targeted to these individuals. Although currently there are no FDA-approved treatments for NASH, a multidisciplinary approach that addresses comorbid conditions and promotes modest weight loss comprises the backbone of therapy.

Review of Treatment Options for Nonalcoholic Fatty Liver Disease

Although the future of NAFLD and NASH treatment has many promising agents, clinicians are currently faced with limited options with an emphasis on lifestyle modification. Figs. 1 and 2 summarize current practices for the diagnosis and treatment of NAFLD with the understanding that each patients treatment must be customized to their comorbidities, exercise tolerance, and willingness to comply with therapy.

Nutrition in Cirrhosis and Chronic Liver Disease

Nutrition has not been a primary focus of many medical conditions despite its importance in the development and the severity of these diseases. This is certainly the case with nutrition and end-stage liver disease despite the well-established association of nutritional deficiencies and increased rates of complications and mortality in cirrhosis. This review provides an overview of nutrition in chronic liver disease with an emphasis on its pathogenesis as well as ways to assess nutritional status and intervene in an effort to improve nutrition.

Hepatic progenitor cells: Another piece in the nonalcoholic fatty liver disease puzzle

B oth pediatric and adult liver disease specialists are acutely aware of the growing problem of nonalcoholic fatty liver disease (NAFLD). The rise in the prevalence of NAFLD parallels the increase in global obesity rates, and the vital role of obesity and insulin resistance (IR) in NAFLD is undisputed. Not all obese individuals develop fatty NAFLD, however, and only a relative minority (5%-30%) meet strict histopathologic criteria for nonalcoholic steatohepatitis (NASH). Essential questions remain as to why some patients with NAFLD develop NASH and others do not. As those with NASH are at the greatest risk of progression to cirrhosis and liver cancer, it is important to understand the mechanisms that lead to necroinflammation and fibrosis from a substrate of hepatic steatosis. The mediators of hepatic fibrosis have recently become a focal point for investigation as researchers attempt to gain a better understanding of the processes that trigger the cascade of activity that leads to collagen formation and deposition within the hepatic parenchyma. Zone 3 perisinusoidal fibrosis is commonly found in early adult disease with subsequent progression to portal fibrosis, whereas in pediatric NASH portal fibrosis is typically found early. Hepatocyte regeneration in a normal liver occurs in the lobules by way of replication of hepatocytes. In the setting of liver injury, hepatic progenitor cells (HPCs), which are normally quiescent and are located in the canals of Hering, appear to play an essential role in the development of portal fibrosis. HPCs come into play as a secondary source of hepatocytes by way of hedgehog ligand-mediated epithelial to mesenchymal transformation (EMT). EMT also occurs during normal development as well as in tumor metastasis resulting in increased cellular proliferation. In the liver, EMTderived hepatocytes are less vulnerable to apoptosis, although activation of HPCs also leads to the so-called ductular reaction (DR) with small biliary ductules composed of stromal and inflammatory cells producing proteins that activate hepatic stellate cells leading to fibrosis. This was elegantly shown by Richardson et al. in a study of 107 adult NAFLD patients and 11 controls where HPC expansion and DR was strongly associated with NASH and stage of fibrosis. Further study in obese murine models has supported the role of EMT in hepatic fibrosis where exposure to the hepatotoxin ethionine leads to liver injury and subsequent expansion of hedgehog-responsive epithelial progenitor cells. Similarly, cirrhotic murine livers have been shown to demonstrate features of EMT compared to normal liver-derived hepatocytes after treatment with the apoptosis-inducing cytokine transforming-growth factor beta (TGF-b). In pediatric NAFLD, while the role of portal fibrosis has been established, the role of HPCs has not previously been investigated. In this issue of HEPATOLOGY, Nobili et al. assessed the role of HPCs in pediatric NAFLD comparing histologic specimens from normal controls, isolated fatty livers, and those meeting histopathologic criteria for NASH. This study confirmed an expanded HPC compartment in the setting of pediatric NASH that was correlated to the degree of fibrosis. This intuitively makes sense given the degree of portal-based fibrosis seen in pediatric populations and this study points to the role of DR in fibrosis in pediatric as well as adult NASH. The importance and prominence of an intermediate hepatocyte (IH) pool was an additional novel finding of this study. IHs were defined as cells of intermediate size that showed faint cytokeratin-7 (CK7) immunoreactivity as found in cells of biliary epithelial lineage. In other chronic liver diseases such as hepatitis C, IHs Abbreviations: CK7, cytokeratin-7; DR, ductular reaction; EMT, epithelial to mesenchymal transformation; HCC, hepatocellular carcinoma; HPC, hepatic progenitor cell; IH, intermediate hepatocyte; IR, insulin resistance; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis. Address reprint requests to: Stephen A. Harrison, M.D., Division of Gastroenterology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX 78234. E-mail: Stephen.harrison@amedd.army. mil; fax: 210-916-2601. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25903 Potential conflict of interest: S.A.H.: Research support: Rottapharm, Mochida. Ad hoc advisory board: Amylin Pharmaceuticals. Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense or the U.S. Government.

Noninvasive Methods of Assessing Nonalcoholic Fatty Liver Disease: What the Clinician Needs to Know

onalcoholic fatty liver disease (NAFLD) has become Nrecognized as a worldwide problem, approaching epidemic status in parts of the Western world. Current preva lence estimates for NAFLD range from 30% to 75%, depending on ethnicity, body mass index (BMI), and the presence of dia betes mellitus. Significant necroinflammation with or without fibrosis on liver biopsy is required to diagnose nonalcoholic steatohepatitis (NASH). Data suggest that 10% to 30% of NAFLD patients meet the criteria for NASH, with an overall prevalence ranging from 3% up to 25%, depending on the population studied. Natural history data suggest that although overall NAFLD pa tients are at an increased risk for developing type 2 diabetes and cardiovascular disease, patients with biopsy proven isolated fatty liver have very little risk of progressing to cirrhosis and hepatic decompensation. Alternatively, patients with NASH and fibrosis are at significant risk of disease progression. All NAFLD patients are at risk for hepatocellular carcinoma, although this risk appears greatest in those with advanced fibrosis and cirrhosis. The high prevalence of NAFLD coupled with the need for liver biopsy to differentiate NASH from not NASH presents the clinician with several potential dilemmas. Despite the fact that patients with isolated fatty liver have a very low probability of progressing to cirrhosis or hepatic decompensation, they still should be identified given the association of NAFLD with other conditions resulting in decreased survival. Typically, patients will be identified by the incidental finding of hepatic steatosis on abdominal imaging or a mild asymptomatic increase of serum aminotransferase levels on routine testing in the absence of other chronic liver disease, particularly alcohol related. Once a patient has been identified as having NAFLD, the next clinical decision is whether to perform a liver biopsy to establish a diagnosis of NASH. It is unreasonable to perform a biopsy on every patient with NAFLD because liver biopsies are invasive, expensive, subject to sampling error, and, rarely, associated with severe complications such as hemorrhage or even death. How ever, liver biopsy is currently the best available way to identify the histopathologic features of NASH that have been shown to correlate with disease progression. NASH with advanced fibrosis on liver biopsy has greater clinical implications than NASH with no or minimal fibrosis. Noninvasive testing is needed to identify NAFLD patients as a whole, but even more importantly to identify patients with NASH, and specifically those with advanced fibrosis. Noninva sive methods that have been used to date include radiographic studies, laboratory tests, and scoring systems that combine clinical and laboratory data to predict the presence of NAFLD, NASH, or fibrosis. An ideal test would be easy to obtain, of low cost, and have appropriately high sensitivity and specificity to answer the desired question: NAFLD vs no NAFLD, NASH vs not NASH, and mild fibrosis vs advanced fibrosis. A test that could be repeated over time to monitor disease progression or response to therapeutic intervention would be even more desirable. Table 1 summarizes the tests investigated to date to answer each of these clinical questions.

Nonalcoholic Fatty Liver Disease: Clinical Features, Disease Modifiers, and Natural History

Nonalcoholic fatty liver disease (NAFLD) typically presents as an asymptomatic elevation of liver-associated enzymes and has been associated with a number of clinical conditions that are included in the definition of the metabolic syndrome such as obesity, hyperlipidemia, and insulin resistance. NAFLD also has been shown to be related to a variety of conditions such as cardiovascular disease and obstructive sleep apnea. This review will address the clinical presentation and natural history of NAFLD as the hepatic manifestation of the metabolic syndrome.

Nonalcoholic Fatty Liver Disease and Extra-hepatic Malignancy

Nonalcoholic fatty liver disease (NAFLD) has risen to become the most common cause of chronic liver disease in Western nations in concert with rising rates of obesity. The majority of patients with NAFLD meet criteria for the metabolic syndrome and are often found to have insulin resistance (IR) or frank diabetes along with increased rates of cardiovascular disease, overall mortality, and primary hepatocellular carcinoma (HCC). The association of NAFLD with cancer specifically is an area of more recent investigation with the majority of data coming indirectly from population based studies linking obesity and a variety of extra-hepatic malignancies. Research specifically linking NAFLD with cancer has been limited to colorectal adenomas and colorectal cancer (CRC), with the majority of data showing an increased prevalence of both in NAFLD populations.