Endoscopic Ultrasound(EUS)-Guided TRUCUT Biopsy (EUS-TCB) of Suspected Nonalcoholic Fatty Liver Disease(NAFLD.)
Endoscopic Ultrasound(EUS)-Guided TRUCUT Biopsy (EUS-TCB) of Suspected Nonalcoholic Fatty Liver Disease(NAFLD.)
Endoscopic Ultrasound involves the placement of a small flexible camera through the mouth and
 into the stomach to image various parts of the body. A small piece of tissue called a biopsy,
 of your liver nay be obtained by this method. the tissue (biopsy) would be obtained by
 inserting a small needle through the lining of the stomach into the liver. Consideration for
 this biopsy is because there may be extra fat stored within the liver. In some people who
 drink too much alcohol, extra fat may be stored in the liver, however, in some people who
 don't drink too much alcohol, this may also occur and is called :non-alcoholic fatty liver
 disease or NAFLD. Over time, this extra fat may lead to liver irritation and scar tissue
 called cirrhosis. If NAFLD is detected early enough, then treatment with medications, losing
 weight, or dietary changes may help avoid cirrhosis. the purpose of this study is to learn
 about whether doctors can obtain the biopsy from the liver by a new method. The biopsy of the
 liver allows the doctors to look for any signs of scar tissue or inflammation from any cause.
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.
Inclusion Criteria:

 1. Patients between the ages of 18 and 70 years old referred to Indiana University
 Hospital for outpatient upper EUS for clinical purposes (e.g., pancreatic disease).

 2. Increased hepatic enzymes (AST or ALT) above the upper limit of normal within the past
 3 months. These values at University Hospital are ALT>45 U/L and AST> 41 U/L but may
 vary among laboratories at different institutions.

 3. Evidence of fatty liver (as detected by an increase in echogenicity or brightness of
 the liver) by EUS exam.

 4. Liver biopsy for suspected NAFLD is clinically indicated as determined by Dr Naga
 Chalasani, one of our staff hepatologists who is an expert in NAFLD.

 Exclusion Criteria:

 1. Inpatient status.

 2. Normal liver enzyme tests (AST, ALT).

 3. Previous or current alcohol abuse (≥3 drinks/day for men; ≥2 drinks/day for women)

 4. Planned liver biopsy within 30 days for known or suspected liver disease.

 5. Suspected metastatic lesion in the liver by any previous imaging study or discovered
 during EUS exam.

 6. EUS-FNA of the liver is required for another reason (i.e. suspected metastatic lesion)

 7. Newly diagnosed, currently treated or suspected malignancy. (In this case, the
 diagnosis of NAFLD would not likely impact patient care or survival). Patients with a
 previously diagnosed malignancy that is in remission will be considered eligible.

 8. Previously diagnosed NAFLD including steatosis or NASH (in this situation, another
 biopsy is not beneficial to the patient).

 9. Chronic liver disease including Hepatitis B, Hepatitis C, Wilson's disease,
 alpha-1-antitrypsin disease, autoimmune hepatitis.

 10. Known or suspected cirrhosis.

 11. Esophageal or gastric varices by previous imaging or discovered during EUS.

 12. Previous liver surgery including resection or transplant.

 13. Thrombocytopenia (platelets <150,000)

 14. Anemia (hemoglobin <10 gm/dL).

 15. Coagulopathy (INR>1.2 or aPTT > 35 secs).

 16. Use of coumadin or other anticoagulants.

 17. Use of aspirin or nonsteroidal antinflammatory product within 7 days of EUS.

 18. Total bilirubin >2.0 mg/dL and dilated bile duct on previous imaging study.

 19. Inability to provide informed consent.

 20. Pregnancy or suspected pregnancy.