Non-alcoholic Fatty Liver Disease (NAFLD) is an alcohol-like liver disease that occurs in individuals who do not consume excessive alcohol. Similar to alcohol-induced liver disease, NAFLD encompasses a spectrum of liver damage, ranging from non-alcoholic fatty liver (NAFL) on the most clinically benign end of the spectrum to cirrhosis on the opposite extreme where most liver-related morbidity and mortality occur. In NAFL, the liver is steatotic but generally healthy. Nonalcoholic steatohepatitis (NASH) is a more severe form of liver damage than NAFL because there is increased hepatocyte death in addition to steatosis. The liver injury in NASH triggers a repair response that sometimes leads to cirrhosis.1-3 The architecture of cirrhotic livers is distorted by regenerating nodules and fibrous tissue. Cirrhosis results when fibrosis disrupts the normal liver architecture, carving the parenchyma into nodules of hepatocytes that are separated from each other by bands of connective tissue. Some individuals with NAFLD develop cirrhosis. As in other types of liver disease, progression to this advanced stage of liver damage from NAFLD is generally thought to require many years, perhaps decades. Because most liver-related morbidity and mortality occur in cirrhotic individuals, researchers are trying to understand the basis for inter-individual differences in the tendency to develop cirrhosis. Exiting blood tests and imaging modalities have limited sensitivity for detecting liver steatosis, steatohepatitis and cirrhosis. In addition, there is no test that can distinguish NAFLD from other causes of fatty liver disease. Thus, at the present time, NAFLD is a diagnosis of exclusion.

Results from two large population-based studies are extremely useful in defining the prevalence of NAFLD in the general US adult population.4,5 The Dallas Heart Study used liver imaging to assess the prevalence of fatty liver in over 2200 adults. The overall prevalence of fatty liver in that study was 31% with a range of 24-45% of the population demonstrating hepatic steatosis. Of note, most individuals with elevated liver fat content did not demonstrate aminotransferase elevations. The latter finding helps to explain why NHANES III, another large population-based study, suggested a much lower prevalence of NAFLD in the general US adult population. In NHANES III, serum aminotransferases were used to assess NAFLD prevalence in over 15,000 adults and that approach suggested that 5.5% of the population has NAFLD. Based on the results of the Dallas Heart Study it is likely that the approach used in NHANES III underestimated the true prevalence of NAFLD in US adults. In any case, the net results from these two studies suggest that between 5.5 to 31% of the adult US population has NAFLD. To appreciate the significance of this finding, it is useful to compare the prevalence of NAFLD to that of hepatitis C, which is thought to exist in 1.8% of the US population.6 NAFLD is three to ten times more common than hepatitis C-related liver disease in the US.

Population-based studies and case series demonstrate strong associations between NAFLD and several conditions, including obesity, type 2 diabetes, and dyslipidemia, that comprise the metabolic syndrome.4,5,7-13 This suggests that the prevalence of NAFLD is likely to be much greater in these high risk populations. Studies of morbidly obese patients undergoing gastric bypass surgery support this concept. In most of these individuals, liver disease was unsuspected pre-operatively. However, intraoperative liver biopsies consistently demonstrate NAFLD. In four recent series that included over 600 subjects, the prevalence of NAFL (steatosis) ranged from 30-90% and NASH (steatohepatitis) was documented in 33-42%. Thus, over two-thirds of morbidly obese patients undergoing gastric bypass surgery have NAFL/NASH. Although overt manifestations of portal hypertension likely excluded patients as candidates for elective abdominal surgery, these four surgical series consistently identified individuals with hepatic fibrosis. Well-established cirrhosis was relatively unusual, occurring in 1-2% of the group. However, advanced fibrosis was noted in 12% and a third had unexplained periportal fibrosis. There is also a high prevalence of NAFLD is high in populations of patients with type 2 diabetes mellitus. A recent survey of 100 non-alcoholic patients with type 2 diabetes used ultrasonography to screen for NAFLD and demonstrated fatty liver in half of the group. Subsequent liver biopsy revealed NAFL in 12% and NASH in 87% of those with ultrasonographic evidence of fatty liver. Fibrosis or cirrhosis were noted in 20%.14 In patients with metabolic syndrome and hyperlipidemia, fatty liver was detected in 50% of 95 adults using ultrasonography to screen for unsuspected hepatic steatosis.15

Similar to other types of chronic liver disease, liver-related morbidity and mortality are dictated by the severity of liver damage. This concept explains observations that NAFL has a relatively benign prognosis, whereas NAFLD-related cirrhosis may be complicated by portal hypertension and hepatocellular carcinoma, eventuating in death from liver disease.2 Studies disease.2 Studies in the US and France independently demonstrated 3 easily-assessed clinical parameters that identify individuals with cryptogenic hepatitis who are likely to have advanced fibrosis on liver biopsy. These parameters are older age (greater than 45-50 years), overweight or obese body mass index, and type 2 diabetes. The probability of having bridging fibrosis or cirrhosis on liver biopsy is approximately 66% in individuals with cryptogenic hepatitis who are older and either overweight/obese or diabetic.16,17 Identification of individuals who have NASH with fibrosis has important prognostic implications. Follow-up of patients with NASH and fibrosis demonstrates that almost 30% of these individuals become cirrhotic within 5-10 years. In contrast, only about 3% of individuals with milder forms of non-alcoholic fatty liver disease develop cirrhosis after more than a decade of follow-up. Therefore, NASH with fibrosis progresses to cirrhosis both more consistently and more rapidly than simple NAFL.2,13

In order to provide optimal therapy for individuals with NAFLD, their liver disease must be diagnosed. The diagnostic evaluation of an individual who is suspected of having NAFLD has 3 goals. The first goal is to establish fatty liver disease as the etiology of the liver disease. Unfortunately, no specific serologic marker for NAFLD has been identified yet. Moreover, all of the current diagnostic tests for NAFLD have some limitation. Standard imaging tests such as ultrasonography and CT scan, may under- or over-estimate hepatic fat content.1,18 Moreover, detecting liver fat by abdominal imaging can neither distinguish alcoholic- from non-alcoholic-fatty liver disease, nor exclude other types of liver disease that might co-exist with hepatic steatosis. The second goal is to confirm the specific type of fatty liver disease, alcoholic fatty liver disease (AFLD) or non-alcoholic fatty liver disease (NAFLD). These two entities cannot be distinguished by histologic parameters but only by assessment of drinking habits of the patient. The third and arguably most important, goal of the diagnostic work-up is to establish the clinical severity and prognosis of the liver disease. Because NAFLD is common and often generates few manifestations of liver disease, it is necessary to have a high index of suspicion to identify individuals who might have NAFLD. This includes individuals with the metabolic syndrome (at least 2 of the following disorders: obesity, type 2 diabetes, hypertension and dyslipidemia) or detection of fatty liver on an imaging study of the abdomen. Imaging studies or laboratory tests may point to advanced liver disease but early cirrhosis and NAFLD without fibrosis cannot be reliably diagnosed without liver biopsy.

At this time, liver biopsy remains the "gold standard" for staging the severity of liver damage in NAFLD and all other types of chronic liver disease.2 This biopsy is traditionally performed percutaneously with or without ultrasound guidance. Needle entry for biopsy is typically into the right lobe below the diaphragm between the ribs in the right mid-axillary line. Alternatively, this may be done by an anterior approach into the left lobe. However, there are potential limitations with percutaneous biopsy including sampling error19,20 (which may not be representative of the hepatic architecture) and complications (pain, bleeding and puncture of another organ, not obtaining liver tissue). Due to anatomical considerations, some patients are not even candidates for liver biopsy by the percutaneous approach. In this case, biopsy may be performed by the transjugular method. This technique involves use of conscious sedation followed by needle access of the jugular vein. A wire is then passed through the heart and into a branch of a hepatic vein to guide a needle biopsy of the liver. Similar to percutaneous biopsy, this procedure is safe when performed by experienced operators. However, complications including neck hematoma, hepatic arteriovenous fistula, liver capsular puncture, intraperitoneal hemorrhage and death have been reported by this technique.21,22 Regardless of the approach, liver biopsy incurs monetary cost, including fees for the facility, equipment, hepatologist and pathologist, as well as for processing the tissue sample itself. On the other hand, the expense of a liver biopsy is roughly equivalent to that of magnetic resonance imaging (MRI), which is the most sensitive radiologic test for quantifying liver fat,fat; an MRI is inferior to biopsy for detecting liver inflammation and fibrosis.23

Alternative methods for acquisition of a core biopsy of the liver may be helpful in patients in whom percutaneous and transjugular liver biopsies would be difficult, risky or contraindicated. Endoscopic ultrasound (EUS)-guided fine needle aspiration (EUS-FNA) has been used for over 15 years at Indiana University Medical Center and other hospitals to sample lymph nodes and masses in the posterior mediastinum, upper abdomen and pelvis.24-29 In 2003, we published our experience of EUS-FNA of the liver using a 22-gauge needle in 77 patients without complications and to date this remains the largest series reported in the literature.30 Since that report, we have performed this procedure in over 100 patients also without a known complication (not published). In 2003, the FDA approved development of a 19-gauge Trucut biopsy (TCB) device (Wilson-Cook Medical, Inc.; Winston-Salem, North Carolina) that provides a histologic tissue sample for use with EUS. The initial reported use of this device demonstrated its safety and utility for biopsy of major upper abdominal organs (including the liver) in a swine model.31 Its subsequent use for sampling of gastrointestinal stromal tumors (GISTs), pancreatic masses and mediastinal lymph nodes in humans has also been reported.312-35 We have also studied its use in the diagnosis of nonfocal chronic pancreatitis.36 At Indiana University, we our EUS group have used this device in over 30 patients off protocol for various accepted indications without known complications (not published). The use of this EUS-TCBdevice for liver biopsy has been reported in abstract form in only two patients with suspected metastatic malignancy.37 No complications were reported in these two patients. Its use for suspected benign disease of the liver has not been reported to date.