Ghassan M. Hammoud, MD, MPH
Associate Professor of Clinical Medicine
Director of liver and Pancreatobiliary Program
Division of Gastroenterology and Hepatology
University of Missouri School of Medicine, Columbia, MO
1.
Discuss epidemiology and conditions associated with NAFLD
2.
Discuss clinical features of NAFLD
3.
Discuss evaluation and diagnosis of NAFLD
4.
Discuss genesis of hepatic steatosis
5.
Review pharmacologic and non-pharmacologic management of NAFLD

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of persistent abnormalities in liver enzyme test results in North America. The rising prevalence of NAFLD is related to the epidemic of obesity. By definition, the diagnosis of NAFLD requires the exclusion of significant intake of alcohol. The histologic hallmark of the disease is predominantly macrovesicular steatosis. NAFLD is currently one of the leading causes of end stage liver disease, hepatocellular carcinoma, liver transplantation, and death.
Key Points:
Diagnosis
Clinically most patients have vague complaints of fatigue or malaise. Abdominal obesity and hepatomegaly are the most common physical findings. Mild to moderate elevation in serum ALT and/or AST is the most common and often the only laboratory abnormalities found in patients with NAFLD. ALT lacks sensitivity for detecting nonalcoholic steatohepatitis (NASH) and it cannot distinguish early disease with simple steatosis without much necroinflammation from
NASH. AST/ALT ratio is usually less than 1. Liver enzymes are rarely above 300 U/L. Synthetic function of the liver is usually preserved unless advanced disease. The diagnosis requires exclusion of other alternative causes of chronic liver disease such as hepatitis C.
Imaging
MR spectroscopy is the most sensitive but most expensive. Ultrasound is the easiest and least expensive, but misses steatosis when it is < 30%. Imaging cannot distinguish NASH from non-
NASH NAFLD.
Pathology
Liver biopsy is the gold standard for the diagnosis of NAFLD although it is subject to significant sampling variability. The diagnostic criteria for NASH are a combination of history (minimal alcohol) and histology. A widely used scoring system for NASH that graded the necroinflammatory changes and staged the fibrosis was proposed by Brunt in 1999 and became widely used. The NASH Clinical Research Network developed and validated the NAFLD Activity
Score, or “NAS”, for use in clinical trials. The NAS uses numerical scores for steatosis (0 to 3), inflammation (0 to 3) and ballooning (0 to 2); these scores are added in an unweighted fashion to achieve a NAS of 0 to 8. Although a biopsy with a low NAS (eg, 2 or 3) is less likely to have
NASH and a biopsy with a high NAS (5 or 6) is more likely to have NASH, the diagnosis of
NASH is a pathological interpretation of the biopsy that is independent of the NAS.
Pathogenesis
NAFLD is characterized by lipid accumulation in the liver, mainly in the form of triglycerides.
Peripheral insulin resistance plays an important role in exposing the liver to high free fatty acid and insulin levels. The two main source of FFA is diet and peripheral lipolysis. The liver cannot regulate uptake of free fatty acids from peripheral stores, so inappropriate peripheral lipolysis exposes the liver to fatty acids that it must dispose of by mitochondrial β-oxidation or secretion as triglyceride in VLDL. Excess carbohydrate consumption (diet) contributes to de novo lipogenesis in the liver, further contributing to the burden of fat that must be processed. If fat cannot be metabolized or secreted, it accumulates as triglyceride. Steatohepatitis is characterized by the presence of inflammation, increased cell injury, apoptosis, and the development of fibrosis. Oxidative stress is a key mechanism in the genesis of steatohepatitis which once developed can lead to fibrosis and cirrhosis. Gut flora, dietary lipids, genetic makeup and leptin are all contribute to the proinflammatory state seen in NASH.

Treatment
Weight loss is a standard recommendation for overweight patients with NASH. The goal of weight management is to bring the weight as close to ideal body weight as possible. Losing
10% of body weight can significantly improve NASH. Exercise improves insulin sensitivity, even in the absence of weight loss and should be recommended to all patients with NASH.
Metformin, despite being an insulin sensitizing agent, has not been found to be helpful for
NASH. Thiazolidinediones (TZDs, “glitziness”) acts via PPAR-γ improves insulin sensitivity.
Rosiglitazone has been associated with an increased risk of cardiovascular disease and all
TZDs can exacerbate CHF and are contraindicated in NY class III-IV CHF. TZDs may also accelerate bone loss in older women. Lipid lowering agents had no beneficial effect on liver function. Antioxidants such as vitamin E and C had been shown to improve steatosis but did not affect inflammation. UDCA in one study produced improvement in liver enzymes. Similarly,
Betaine showed some improvement in steatosis but did not affect other parameters of NAS.
Pentoxifylline showed some improvement in ALT although histologic data are lacking. Bariatric surgery (roux-en-Y, gastric banding) improves NASH.
References
1. Chalasani et al. The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease:
Practice Guideline by the American Association for the Study of Liver Diseases,
American College of Gastroenterology, and the American Gastroenterological
Association. Gastroenterology. 2012 Jun;142(7):1592-609.
2. Ruhl CE, Everhart JE. Epidemiology of nonalcoholic fatty liver. Clin Liver Dis
2004;8:501-519.
3. Neuschwander-Tetri BA, Clark JM, Bass NM, et al. NASH Clinical Research
Network.Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010 Sep;52(3):913-24.
4. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745-
750.
5. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al.
Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
Hepatology 2005;41:1313-1321.
6. Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut 2007;56:1760-
1769.
7. Pillai AA, Rinella ME. Non-alcoholic fatty liver disease: is bariatric surgery the answer?
Clin Liver Dis. 2009 Nov;13(4):689-710.