Gastric Sleeve Pilot Study in Morbidly Obese Undergoing Liver Transplantation

PROCEDURAL DETAILS

A sleeve gastrectomy is performed with the patient in reverse Trendelenburg position. The
liver is retracted cephalad and to the right, and the short gastric vessels of the greater
curvature and retrogastric attachments are divided from the angle of His to approximately
6-8cm from the pylorus. A 30-40 French bougie is placed in the stomach and directed along
the lesser curve. The antrum is preserved and a vertical subtotal, sleeve gastrectomy is
then fashioned along the lesser curvature 1 cm away from the bougie toward the
esophagogastric junction using linear staplers, beginning 6 cm from the pylorus on the
greater curve side and continuing up to the angle of His. The staple line may be oversewn
with a running absorbable suture or an absorbable staple buttress material may also be used
to help prevent bleeding. Air is infused via an endoscope into the newly created "sleeve" to
rule out a leak ([33]).

CLINICAL DATA TO DATE

Weight Loss Weight loss surgery has been shown to be a safe, effective and durable option
for the treatment of morbid obesity.[34, 35] The primary weight loss effectiveness
parameters measured are percent excess weight loss (%EWL), defined as the difference in the
baseline and post-surgery weight divided by the difference in baseline weight and ideal body
weight (based on the 1983 Metropolitan Tables for Life Insurance) multiplied by 100, and
reduction in BMI. Studies on the early outcomes of sleeve gastrectomy report a mean EWL of
51-85% at 3 years and 43-58% after 6 years. [36, 37] Additionally, patients have been shown
to reduce their (average) BMI more than 15 points in the first year. [38-40]

Improvements in Obesity-related conditions after bariatric surgery Patients undergoing
sleeve gastrectomy experience a statistically significant (p<0.001) reduction in
glycosylated hemoglobin (HbA1c). Over two-thirds of patients return to a HbA1c of 6.5% or
less within a year. [41, 42] In addition, more than half of patients experience complete
resolution of diabetes within one year. Blood pressure normalization is seen in 50-75% of
patients who undergo gastric sleeve, and these rates are comparable with those of Roux en Y
gastric bypass and adjustable gastric banding (AGB).[42] Hyperlipidemia, present in nearly
half of patients undergoing sleeve gastrectomy, has also shown a resolution rate of nearly
100%.[43]

Improvements in Quality of Life Fezzi et all conducted a one year follow-up of 78 patients
after sleeve gastrectomy. The SF-36 Questionnaire and Impact of Weight on Quality of
Life-Lite questionnaire (IWQOL-Lite) were used to measure quality of life. In general, there
was an improvement in all eight SF-36 component and domain scores compared to baseline for
all post-surgery visits.[44] Quality of Life (BQL) assessment has shown that compared with
patients who undergo AGB, sleeve gastrectomy patients demonstrated a significantly greater
BQL composite score (66.5 versus 57.9), indicating greater quality of life. Sleeve
gastrectomy patients also report significantly less vomiting than AGB patients (2% versus
43%).[45]

Mortality Benefit for bariatric surgery Morbid obesity is associated with increased
mortality and morbidity due to its association with many disease states and reduces life
expectancy by five to 20 years.[46] Two recent landmark studies confirmed the benefits of
bariatric surgery in not only achieving substantial weight loss and improving the
co-morbidities of obesity, but in reducing mortality. In the Swedish Obesity Study[10]
researchers enrolled 4,047 obese subjects who underwent vertical banded gastroplasty,
gastric bypass or adjustable gastric band surgery at 25 surgical departments and 480 primary
health care centers. After ten years, weight loss was 25±11% for gastric bypass, 16±11% for
vertical-banded gastroplasty, and 14±14% for banding, as compared with the baseline weight.
Most importantly, they demonstrated in a prospective, case-controlled surgical intervention
trial that bariatric surgery in obese subjects is associated with a reduction in overall
mortality, as compared with conventional treatment in matched obese controls (hazard ratio
0.76).

Adams et al[11] also demonstrated similar results in a large U.S. retrospective cohort trial
comparing 7,925 bariatric surgery patients to matched severely obese controls, followed for
a mean of 7.1 years. The study concluded that adjusted long-term mortality from any cause in
the surgery group decreased by 40%, as compared to controls. Specifically, compared to
controls, the surgically treated group had a 56% decrease in mortality for coronary artery
disease, a 92% decrease in diabetes and a 60% decrease in mortality from cancer. In
addition, in a large systematic review and meta-analysis of 136 studies, bariatric surgery
achieves significant results in attaining long-term weight loss and resolution of
comorbidities such as diabetes, hyperlipidemia, hypertension and obstructive sleep
apnea.[35]

Overall Safety Profile The American College of Surgeons - Bariatric Surgery Center Network
(ACS-BSCN) Accreditation Program recently published its first report on the safety and
effectiveness of sleeve gastrectomy as compared to the Adjustable Gastric Band(AGB),
Laparoscopic Roux-en-Y Gastric Bypass(LRYGB) and the Open Roux-en-Y Gastric Bypass(ORYGB)
for the treatment of obesity and obesity-related diseases[38]. Univariate and multivariate
analyses compare 30-day, 6-month, and one-year outcomes including morbidity and mortality,
readmissions and reoperations as well as reduction in body mass index (BMI) and
weight-related comorbidities. 109 hospitals submitted data for 28,616 patients, from 7/2007
to 9/2010. Sleeve gastrectomy was found to have higher risk-adjusted morbidity, readmission
and reoperation/intervention rates compared to the AGB, but lower reoperation/intervention
rates compared to the LRYGB and ORYGB. There were no differences in mortality. Reduction in
BMI and most of the weight-related comorbidities following the LSG also lies between those
of the LAGB and the LRYGB/ORYGB.

The ACS-BSCN accredits facilities in the United States that have undergone an independent,
voluntary and rigorous peer evaluation in accordance with nationally recognized bariatric
surgical standards[47]. Hospitals are accredited as Level I, Level II, Level II New or
Outpatient facilities, depending on hospital surgical volume and resources. Level I
hospitals must perform over 125 cases per year, and demonstrate sufficient resources to care
for the most challenging and complex patients. They are accredited to care for patients with
all levels of obesity, ages, comorbidities and are accredited to perform elective revisional
surgery. Level II hospitals have lower volume requirements - 25 cases per year—and are
accredited for the care of less complex obese patients. Level II centers may not perform
elective revisional operations, or any elective primary procedure on high-risk patients.
High-risk patients are defined as follows: non-ambulatory patients, patients over 60 years
old, adolescents under the age of 18, high Body Mass Index (BMI) patients (male patients may
not have a BMI ≥55 and female patients may not have a BMI ≥60), patients who have organ
failure, an organ transplant, or are a candidate for a transplant, and patients with
significant cardiac or pulmonary comorbid conditions. Northwestern Memorial Hospital's
Bariatric Surgery Program is a Level I accredited center and thus adheres to the highest
safety and excellence standards as put forth by the ACS-BSCN.

Hutter et al. observed a 30-day mortality of 0.1% and a 1-year mortality of 0.2% in their
prospective study of over 28,000 patients. These rates were higher than those observed for
AGB (0.05% and 0.08%) but lower than for RYGB (0.14% and 0.34%). Thirty-day morbidity was
5.6% and reoperation rate 3%.[38] The 30-day morbidity rate for LSG (5.61%) is statistically
higher than the LAGB rate (1.44%), however this is comparable to the LRYGB rate (5.91%).
Similarly, 30-day readmission rate for the LSG (5.4%) is statistically higher than for the
LAGB (1.71%), but comparable to the LRYGB (6.47%). Reoperation/intervention rates for the
LSG (2.97%) are positioned between the LAGB (0.92%) and the LRYGB (5.02%), which is
significant on both univariate and multivariate analyses. Overall, complication rates
following the LSG seem to be positioned between those for the LAGB (which has lower 30 day
morbidity, readmission and reoperation/intervention rates) and the LRYGB (which has higher
reoperation rates)[38].

Unlike other bariatric procedures, patients undergoing sleeve gastrectomy have not been
found to suffer from nutritional deficits following surgery, but close monitoring of B12,
folic acid, zinc, calcium and iron are recommended.[48] The most common long-term
complication of sleeve gastrectomy is gastroesophageal reflux disease (GERD), which is
reported in 22% of patients at 1 year, but declines to less than 5% after 3 years. A
recurrence has been observed in a small population after 6 years, and has been attributed to
asymmetric stapling of the gastric sleeve leading to a conical shape and relative
mid-stomach stenosis.[37] In addition, compared to the AGB, the sleeve gastrectomy has
statistically higher rates for peripheral nerve injury, pulmonary embolism, pneumonia,
unplanned intubation, renal insufficiency, urinary tract infection, organ space infection,
and sepsis. When compared to the LRYGB, sleeve gastrectomy has higher rates of organ space
infection, renal insufficiency, and sepsis but lower rates of ventilator dependence.
Bariatric surgery-specific postoperative occurrences requiring readmission, reoperation or
an intervention within 30-days show that compared to the AGB, LSG has a higher rate of
anastomotic/staple line leaks, fluid/electrolyte/nutrition problems, strictures,
infection/fevers, pulmonary embolism, bleeding and events not otherwise specified. Compared
to LRYGB, sleeve gastrectomy has a comparable rate of nearly all postoperative bariatric
specific occurrences requiring readmission, reoperation or an intervention, except for a
lower rate of stricture, intestinal obstruction, and anastomotic ulcer.

Safety in a liver transplant population Campsen and colleagues recently published a case
report of a young morbidly obese woman (BMI 42) with diabetes, hypertension and obstructive
sleep apnea who underwent adjustable gastric banding (AGB) during liver transplantation.[24]
Six months after surgery, the patient experienced a 45% excess weight loss with resolution
of her hypertension, diabetes and sleep apnea. In another publication, two morbidly obese
patients who were transplanted for nonalcoholic steatohepatitis (NASH) cirrhosis, and
subsequently developed graft dysfunction secondary to disease recurrence, next underwent
Roux-en-Y gastric bypass (RYGB) surgery and at two years post-op showed significant
improvement in liver histology.[49] A recently published case series in obese patients
undergoing sleeve gastrectomy post liver transplant demonstrated efficacy and no adverse
effects on graft function.[27] Finally, researchers at Mayo have recently reported a small
case series of 7 patients with end-stage liver disease who were unsuccessful with
pre-transplant weight loss and underwent combined liver transplant plus gastric sleeve
resection. They report minimal additional time added to the transplant procedure, and to
date, there has been no morbidity in 6 to 24 months of follow-up for 6 of the 7
patients[28]. One patient experienced a gastric leak with a complicating intra-abdominal
infection that has since resolved, and he was well with normal liver function and a BMI of
24 kg/m2 6 months after transplantation[29]. However, no prospective studies have been
conducted to examine the impact of sleeve gastrectomy on the reduction of metabolic risk
factors in obese patients undergoing liver transplantation.

Inclusion Criteria:

- Subjects must be willing to give written informed consent.

- Adult subjects 18-75 years of age of any race or gender who are listed for liver
transplantation.

- For consideration of sleeve gastrectomy placement patients must meet the following
criteria:

1. Class III Obesity (BMI ≥ 40 kg/m2); or 2. Class II Obesity (BMI 35-39.9 kg/m2 in
conjunction with any of the following severe obesity related co-morbidities): i.
Obstructive sleep apnea defined as a formal sleep study consistent with this
diagnosis with a) an Epworth sleepiness scale ≥ 6 and b) polysomnography with
respiratory disturbance index ≥ 10 and/or apneic episodes per hour of sleep; or ii.
Cardiovascular disease defined as prior history of stroke, myocardial infarction,
stable or unstable angina pectoris, or prior coronary artery bypass); or iii.
Medically refractory hypertension defined as blood pressure greater than 140 mmHg
systolic and/or 90 mmHg diastolic despite concurrent use of 3 anti-hypertensive
agents of different classes iv. Type 2 diabetes mellitus, defined as individuals
taking insulin or oral hypoglycemic agents or who have a fasting glucose > 126 mg/dL
2. Have attempted (and failed) previous weight loss efforts over at least a three
month period with diet, exercise, lifestyle changes or medications.

3. Show understanding of the risks and benefits of surgery and side effects of the
procedure.

4. Be committed to lifestyle changes. All patients will be evaluated by the
transplant psychologist as well as the bariatric surgery psychologist prior to
consideration for study enrollment to ensure appropriate psychological motivation.

5. Do not have any medical, psychiatric or emotional condition that would prohibit
surgery (e.g. severe irreversible coronary artery disease, untreated schizophrenia,
active substance abuse, and/or noncompliance with previous medical care)

Exclusion Criteria:

- Status 1 listing (fulminant hepatic failure) for liver transplant

- Active drug abuse or alcohol use within six months

- Positive urine pregnancy test (females)

- Diagnosis of active malignancy

- History of prior bariatric surgery

- Failure to attend the initial patient information sessions or history of
noncompliance

- Failure to give consent for the study or to understand the proposed consent

- Failure of patient's insurance company to approve surgical intervention so as to
avoid extensive cost burden on the patient