In-Depth Review: Excess Adiposity and DiseaseReview ArticleObesity and the liver: nonalcoholic fatty liver disease
Introduction
The exploding rate of obesity in the United States over the past several decades has led to an increased prevalence of diabetes and cardiovascular disease as well as nonalcoholic fatty liver disease (NAFLD). NAFLD is present in ∼20%–30% of adults in the United States and ∼10% of children.1, 2, 3 NAFLD represents a spectrum of disease with most patients having only steatosis; however, a sizable number of patients can also develop inflammation, cellular injury, and fibrosis, termed nonalcoholic steatohepatitis (NASH). The cellular injury in NASH is characterized by ballooned hepatocytes, which frequently contain Mallory-Denk bodies.4 Patients with NAFLD found to have only steatosis are unlikely to progress to cirrhosis; however, steatosis can accelerate other forms of liver disease.5, 6, 7 Patients found to have NASH represent a subset of those with NAFLD at the greatest risk of progressing to cirrhosis, and it is estimated that ∼3%–5% of the general population has NASH.8 NASH now represents the third most common indication for liver transplantation, although at its current trend it is expected to soon eclipse alcohol as an indication for liver transplantation (Fig 1). In addition to increasing rates of transplantation for NASH, increased prevalence of obesity and diabetes in potential cadaveric donors has led to increased organ discard rate exacerbating the mismatch between supply and demand for liver transplants.9
The rising rate of childhood obesity has also led to the development of NAFLD in the pediatric population. Estimates based on elevated Alanine Aminotransferase and an autopsy series suggest a prevalence of pediatric NAFLD of ∼8%–10%.10 Risk factors for pediatric NAFLD mirror those for adult NAFLD and children with NASH can even progress to cirrhosis and require liver transplantation.11 Similar histologic changes are often noted in pediatric NASH compared with adult NASH; however, some cases of pediatric NASH present with less hepatocyte ballooning and more portal-based inflammation and fibrosis.4, 10
Although NAFLD leads to increased morbidity and mortality from liver disease, the most frequent cause of morbidity and mortality in the NAFLD population remains cardiovascular. Efforts continue to better understand the pathophysiology of NAFLD and develop treatments addressing those patients who develop NASH and have progressive liver disease. However, NAFLD should continue to be viewed as the hepatic manifestation of the metabolic syndrome and treatment of associated diabetes, hyperlipidemia, and hypertension are equally as important as the treatment of the actual liver disease. This review will discuss current understanding of the pathophysiology of NAFLD and its management.
Section snippets
Pathogenesis of NAFLD
Fat accumulation in the liver is the culmination of dysregulation of fatty acid influx to the liver, fatty acid efflux, and hepatic de novo lipogenesis. Circulating adipokines and cytokines mediate and result from this process. Insulin resistance is near universally present in NAFLD and diabetes is a very frequent finding in those patients who develop NASH. Lipotoxicity, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum (ER) stress are involved in hepatic injury. Adipose
Management of NAFLD
According to the joint practice guideline from the American Association for the Study of Liver Disease, the American College of Gastroenterology, and the American Gastroenterological Association, the diagnosis of NAFLD requires the presence of steatosis by imaging or histology, the lack of any significant alcohol consumption, and the exclusion of other forms of chronic liver disease as well as no plausible alternative explanation for the development of hepatic steatosis.8 Simple steatosis is
Conclusions
The obesity epidemic has led to an increased burden of liver disease with increasing numbers of patients requiring liver transplants for NASH cirrhosis and its complications. The pathogenesis of NAFLD involves insulin resistance, adipose tissue distribution, and dietary and genetic factors that place an individual at risk of NASH. Like many obesity-related complications, addressing NAFLD is best accomplished with preventive approaches to promote calorie restriction and favorable dietary
Acknowledgments
Conflict of interests: None.
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