Bariatric Embolization of Arteries for the Treatment of Nonalcoholic Steatohepatitis

Obesity:In adults, obesity is defined as a BMI of greater than 30 kg/m2. It is estimated
that, by the year 2030, 38% of the world's adult population will be overweight and another
20% obese.An expert panel convened by the NIH stated that for the first time in history, the
steadily improving worldwide life expectancy could level off or even decline, as the result
of increasing obesity.

NAFLD and NASH:

The Problem: Obesity is a chronic disease that is strongly associated with a number of
diseases with an increase in mortality and morbidity. Metabolic syndrome (obesity, diabetes
mellitus, hyperlipidemia) has been established as risk factor for primary nonalcoholic fatty
liver disease (NAFLD) .In the US, recent estimates suggest that NAFLD affects 30% of the
general population, 90% of the morbidly obese . NAFLD can progress to nonalcoholic
steatohepatitis (NASH) in up to 25% . Of patients with NASH progression of fibrosis is seen
in 26-37% and progressing to cirrhosis in 9-25 % . NASH cirrhosis can result in liver
failure, portal hypertension, and hepatocellular carcinoma(HCC) .

Current options in management of NASH: The goal of managing NASH is to eliminate risk factors
and preventing fibrosis by treating metabolic syndrome, primarily obesity [10]. Although
dietary modification and exercise can achieve weight loss, this is difficult to sustain .
Very few effective medical therapies are available, and are associated with adverse effects.
Although weight loss after bariatric surgery has demonstrated histological improvement in
NASH, a recent Cochrane review concluded that there is insufficient data to determine if
bariatric surgery is an effective treatment. Also high mortality rates are seen
post-bariatric surgery.

Thus a safe and effective minimally invasive option is needed. Based on currently available
data, Left gastric artery embolization (LGAE) appears effective in inducing weight loss of
about 10.5% in 3-6 months, with a high safety profile. In patients with NAFLD, a 3-5% weight
loss is thought to improve steatosis, 7- 10% may be needed to improve necroinflammation.
Thus, LGAE has the potential to reverse the histology of NASH to prevent progression to
cirrhosis, HCC and its sequale.

Inclusion Criteria:

- Male or Female, aged 22 years or older.

- Willing, able and mentally competent to provide written informed consent and willing
to comply with all study procedures and be available for the duration of the study

- BMI >35 kg/m2

- Adequate hematological, hepatic and renal function as follows:

- Hematological: Platelets > 50 x 109/L, INR <1.5

- Hepatic : Total bilirubin <3 mg/dL

- Renal: Estimated GFR > 60ml/min.1.73m2

- Elevated alanine or aspartate aminotransferase values (ALT >41 or AST>34 U/L).

- Liver biopsy showing evidence of NASH in the past 12 months.

- No evidence of another form of liver disease.

- Patients diagnosed with NASH and have evidence of failing other methods of weight loss
through diet, exercise and behavior modification.

Exclusion Criteria:

Pregnancy Active substance abuse Significant psychiatric problems, severe enough to cause
suffering or a poor ability to function in life. Center for Epidemiological Studies
Depression (CESD) score < 16.

Significant alcohol consumption ( >20 g/day in women, >30 g/day in men) Weight > 400 lbs,
BMI > 50 kg/m2. Contraindications to obtaining a liver biopsy Subjects with pre-existing
abdominal pain will be excluded (because of the potential confusion with pain related to
the procedure).

Subjects who are intolerant to PPIs Subjects requiring any anticoagulant medications should
be excluded. Subjects who are taking aspirin/ NSAIDs and in whom these medications are
unable to be withdrawn from aspirin and NSAIDs for at least 3 days prior to the LGAE
procedure and for 30 days following the LGAE procedure (because of the potential risks of
gastric bleeding following the procedure).

Presence of systemic illness or other medical conditions relevant to survival .(Note that
in the HCC pre liver transplant cohort, the presence of HCC will not be considered an
exclusion criteria) Metastatic cancer Evidence of decompensated liver disease (uncontrolled
ascites, or uncontrolled spontaneous encephalopathy) Prior surgical weight loss procedures
including gastroplasty, jejunoileal, or jejunocolic bypass, total parenteral nutrition
within the past 6 months; Prior history of gastric pancreatic, hepatic, and/or splenic
surgery Prior embolization to the stomach, spleen or liver. If review of available prior
imaging studies (i.e CT, MRI, or US)shows potential anatomical variations, presence of
severe atheromatous disease, large arteriovenous shunting of blood.

Abnormal Endoscopy - large sliding hiatal hernia or paraesophageal hernia, active peptic
ulcer disease, active H. pylori infection History of abnormal Nuclear Gastric Motility
examination-defined as delayed emptying of gastric contents > 90%, 60% and 10% at 1 hour, 2
hours, and 4 hours respectively.

ASA Class 4 or 5 Child Pugh classification C Known aortic disease, such as dissection or
aneurysm; peripheral arterial disease or other cardiovascular disease.

Type 2 diabetes on anti-diabetic medications that are known to cause hypoglycemia. e.g.
sulphonylureas, meglitinidine Patients with a known other cause for their increased liver
enzyme levels such as viral hepatitis (B or C), autoimmune/chronic immune hepatitis,
primary biliary cholangitis, metabolic and genetic hemochromatosis, Wilson's disease, or
alpha-1 antitrypsin deficiency Patient taking hepatotoxic drugs. List of drugs causing
steatohepatitis include but are not limited to: amiodarone, chemotherapy (5-fluorouracil,
tamoxifen, irinotecan, cisplatin, and asparaginase), glucocorticoids, methotrexate,
sulfonamides, antithyroid drugs, phenytoin, tetracyclines, isoniazid, salicylates, and
valproic acid.

Contraindications to obtaining a liver biopsy (NASH cohort) Patients taking other trial
medications for NASH.