Gastric Sleeve Pilot Study in Morbidly Obese Undergoing Liver Transplantation
Condition: Obesity; Cardiovascular Disease; Type 2 Diabetes; Hypertension; Complication of Transplant
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      The rapid rise in obesity (body mass index (BMI) ≥ 30 kg/m2) in the US over the past decade
      is responsible for more disease and death than any other single factor. Severe obesity is
      associated with numerous co-morbidities contributing to increased mortality risk, including
      end stage liver disease. Liver transplantation is a life-saving procedure for patients with
      end stage liver disease and obesity is becoming increasingly prevalent in this population. In
      one study, 54% of patients undergoing orthotopic liver transplant (OLT) were either
      overweight or obese [body mass index (BMI) >25 kg/m2], and 7% were severely or morbidly obese
      (BMI > 35 kg/m2). In addition, weight gain after solid organ transplantation is common
      because of steroid-containing immunosuppression and physical inactivity from decreased
      exercise tolerance.

      Obesity has been shown to increase the surgical morbidity, including wound infections, wound
      dehiscence, and hernias after transplantation. More significantly, excess pretransplant body
      weight hinders the rate of improvement in health-related quality of life after liver
      transplantation[7].

      One possible approach for treating obesity after a liver transplant is to use bariatric
      surgery. Currently, bariatric surgery is established as the most effective means for both
      weight loss and resolution of metabolic disease in the morbidly obese. Recent publications
      emphasize the usefulness of bariatric surgery in the reduction of long-term cardiometabolic
      risk, cardiovascular disease incidence and mortality, and the management of uncontrolled type
      2 diabetes (T2DM). In addition, it decreases mortality and improves both social functioning
      and quality of life.

      Bariatric surgery may improve eligibility for transplant in patients previously excluded due
      to excessive weight. Bariatric procedures, such as sleeve gastrectomy, allow for significant
      weight loss over time that greatly reduces or eliminates obesity related illnesses such as
      diabetes, high blood pressure and liver disease.

      According to the National Institutes of Health, bariatric surgery is reserved for patients
      with a BMI of > 40 or > 35 kg/m2 in the presence of major co-morbidities (e.g. type 2
      diabetes, hypertension, sleep apnea, heart disease, etc).

      A significant number of liver transplant candidates have obesity-related illnesses, thus
      putting them at risk for cardiovascular and metabolic complications post-transplant. In
      addition, patients awaiting OLT are typically no longer medically stable to undergo intensive
      diet and exercise regimens as treatment for their diseases. Finally, decreased activity and
      medications used to prevent liver graft rejection all contribute to increased weight gain
      following transplant. In fact, in a series of 320 non-obese liver transplant recipients,
      21.6% of patients became obese within two years of transplant. These comorbidities also
      contribute to poorer post-transplant outcomes and development of what is known as the
      post-transplant metabolic syndrome. Morbidly obese patients (BMI > 40 kg/m2) may also have
      higher frequencies of morbidities such as prolonged hospitalization and readmission as well
      as infectious, wound, and cardiovascular complications after transplantation. Finally,
      intra-abdominal adiposity creates a technically more challenging operative dissection, but no
      data exist on whether it increases perioperative morbidity or mortality in liver transplant
      patients.

      Sleeve gastrectomy is the most attractive restrictive procedure in a liver transplant
      population for several key reasons. One, sleeve gastrectomy does not require the implantation
      of a foreign body, such as placement of an adjustable gastric band, which in an
      immunocompromised post-transplant patient raises concern for severe infectious complications.
      Secondly, as stated previously, sleeve gastrectomy is a purely restrictive procedure, and
      therefore is least likely to cause significant macronutrient and micronutrient deficiencies.
      Finally, when compared to other restrictive procedures, such as adjustable gastric band
      placement, it has a lower likelihood of treatment failure (i.e. <50% excess weight loss). In
      fact, recent reports describe not only high failure rates with adjustable gastric band
      placement, but also high reintervention rates for both band-related complications (e.g. band
      erosion, leakage, slippage, port infection and esophageal dilatation) and failure to lose
      weight such that as few as 54% of patients may have their band in place after 10 years.
    

Detailed description: 
      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.
    

Intervention name(s): Sleeve Gastrectomy
Intervention type(s): Procedure
Intervention description(s): To assess the safety, tolerability and feasibility of sleeve gastrectomy in the perioperative period following liver transplantation in obese (BMI of > 40 or > 35 kg/m2 in the presence of at least one major obesity related co-morbidities (e.g. type 2 diabetes, hypertension, sleep apnea, heart disease, etc) adult subjects aged 18-75 years of age.
Other intervention name(s): Gastric Sleeve
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Obesity; Transplant; Sleeve Gastrectomy; Liver Transplantation; Weight Loss