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## **Meet the editor**

Dr Chih-Kun Huang is the director of the B.M.I. Surgery center and International Minimally Invasive Surgery Training Center of E-Da hospital in Kaohsiung, Taiwan, as well as the president of Taiwan Obesity Support Association (T.O.S.A). Dr Huang has been devoted to minimally invasive surgery and bariatric surgery since 2004. He performed the first single incision trans-umbilical

laparoscopic Roux-en-Y gastric bypass in 2008, and the first laparoscopic adjustable gastric banded application in the world in 2009. His center was also designated as the first International Center of Excellence for Bariatric Surgery (I.C.E) in Asia-Pacific area in 2009. Due to his contribution and devotion, he was awarded the Endos Award in Medical Science & Technology in 2010, and the International Award by American Society for Metabolic and Bariatric Surgery (ASMBS) in 2011. Dr Huang is also included in the Marquis Who's Who in Medicine and Healthcare 2011-2012.

Contents

**Preface IX**

John N. Fain

Chapter 1 **Surgical Procedures to Achieve Weight Loss 1**

**and Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients 19**

Chapter 2 **Effect of Obesity on Circulating Adipokines**

Chapter 3 **The Economic Impact of Bariatric Surgery 61**

Wen Bun Leong and Shahrad Taheri

Susan F. Franks and Kathryn A. Kaiser

Chapter 8 **BPD and BPD-DS Concerns and Results 175**

Corrado Parodi and Francesca Pagliardi

Chapter 6 **Bariatric Surgery – Anesthesiologic Concerns 143**

Henry Alder and Diana Brixner

Chapter 4 **Medical Assessment and Preparation**

Chapter 5 **Rethinking the Preoperative**

Johan Raeder

Chapter 7 **Gastric Banding and Bypass**

Roman Grinberg, John N. Afthinos and Karen E. Gibbs

Anke-Peggy Holtorf, Harald Rinde, Frederic Rupprecht,

**of Patients Undergoing Bariatric Surgery 87**

**Psychological Evaluation – A New Paradigm**

**for Morbid Obesity – Preoperative Assessment,**

Brane Breznikar, Dejan Dinevski and Milan Zorman

**Operative Techniques and Postoperative Monitoring 157**

Francesco Saverio Papadia, Hosam Elghadban, Andrea Weiss,

**for Improved Outcomes and Predictive Power 117**

### Contents

#### **Preface XI**

X Contents

#### Chapter 16 **Scarless Bariatric Surgery 317**  Chih-Kun Huang, Rajat Goel and Satish Pattanshetti

### Preface

Obesity was formally recognized as a disease by the World Health Organization (WHO) in 1997, and its prevalence is increasing at epidemic proportions worldwide. The enormous changes in human life regarding labor, exercise and diet habits have largely provoked the development of this multi-factorial disease. It has been confirmed that obesity causes many diseases, including cardiovascular disorders, type 2 diabetes mellitus, obstructive sleep apnea and degenerative joint disease. Even though many kinds of medical treatment are recommended, most therapies have not been successful in keeping sustained weight loss and controlling obesity-related comorbidity, especially in morbid obesity. Until now, only bariatric surgery has proven to be an effective procedure, and in the last 40 years, the number of bariatric procedures has been increasing exponentially in the world. This book provides an overview and updated knowledge of bariatric surgery and patient care. In it, we discussed various procedures, preoperative preparation, perioperative care and postoperative nutrition support, and the brand new, "transformed" bariatric surgery in type 2 diabetes–metabolic surgery and scarless bariatric surgery has also been included. We hope that this book will contribute to the future development of weight loss management.

#### **Chih-Kun Huang**

Bariatric & Metabolic International (B.M.I) Surgery Center, E-Da hospital, Taiwan International Minimally Invasive Surgery Training Center of E-Da hospital, Taiwan Republic of China

**1**

*F.A.C.S., USA*

**Surgical Procedures to Achieve Weight Loss**

Obesity is one of the leading medical problems facing our society today. At least two thirds of the U.S. adult population is considered overweight and approximately one-third of American adults are obese, creating an epidemic of obesity. Clearly, there has been an increase in the number of individuals struggling to lose weight. Additionally, obesity has become increasingly prevalent in the pediatric population and 30% of U.S. children have a BMI greater than the 85th percentile for their age.1 The relationship of childhood and adolescent obesity to adult obesity is a strong one with 20% of children who are obese at 4 years of age and 80% of adolescents who are obese will be obese as adults.2 The annual cost of managing obesity in the United States alone amounts to approximately \$100 billion, of which \$52 billion are direct healthcare costs. Hypertension, sleep apnea, diabetes, stroke, myocardial infarction and malignancy is a short but representative list of problems associated with obesity. Approximately 300,000 U.S. deaths per year are related to obesity. While medical options such as weight loss programs, diets and drug therapies are ever-present and increasing, only 3-7% of patients with a diagnosis of obesity are able to achieve effective and consistent weight loss. 3 This statistic demonstrates the continued failure of the medical management of obesity. On the other hand, patients undergoing bariatric surgery demonstrate 23% weight loss at 2 years after operative intervention and 16% by 10 years.4 These patients had dramatic improvement in quality of life scores and validated measures of psychiatric dysfunction compared with only minor and inconsistent improvement in patients undergoing medical treatment for their obesity. After 10 years of follow up the improvement in the surgical group diminished somewhat due to weight regain. Regardless, outcomes of groups of patients undergoing surgical treatment were superior to those treated medically.5,6 Surgical options for weight loss have been consistently more successful at helping individuals to lose

Weight loss surgery has been evolving since its inception and the final chapter is yet to be written. Since the 1950's astute minds and dedicated surgeons have tried to find the one operation that would yield the definitive answer to the problem of obesity. As time has progressed, no silver bullet has been identified. It is clear that there is no procedure that is

Each operation that will be discussed here has its own story to tell in terms of patient selection, operative technique, outcomes and complications. Each has an important role to play in the world of weight loss surgery and it behooves those involved in the trenches of

**1. Introduction**

weight and maintain that achievement permanently.7-9

superior to another for every patient.

Roman Grinberg, John N. Afthinos and Karen E. Gibbs

### **Surgical Procedures to Achieve Weight Loss**

Roman Grinberg, John N. Afthinos and Karen E. Gibbs *F.A.C.S., USA*

#### **1. Introduction**

Obesity is one of the leading medical problems facing our society today. At least two thirds of the U.S. adult population is considered overweight and approximately one-third of American adults are obese, creating an epidemic of obesity. Clearly, there has been an increase in the number of individuals struggling to lose weight. Additionally, obesity has become increasingly prevalent in the pediatric population and 30% of U.S. children have a BMI greater than the 85th percentile for their age.1 The relationship of childhood and adolescent obesity to adult obesity is a strong one with 20% of children who are obese at 4 years of age and 80% of adolescents who are obese will be obese as adults.2 The annual cost of managing obesity in the United States alone amounts to approximately \$100 billion, of which \$52 billion are direct healthcare costs. Hypertension, sleep apnea, diabetes, stroke, myocardial infarction and malignancy is a short but representative list of problems associated with obesity. Approximately 300,000 U.S. deaths per year are related to obesity.

While medical options such as weight loss programs, diets and drug therapies are ever-present and increasing, only 3-7% of patients with a diagnosis of obesity are able to achieve effective and consistent weight loss. 3 This statistic demonstrates the continued failure of the medical management of obesity. On the other hand, patients undergoing bariatric surgery demonstrate 23% weight loss at 2 years after operative intervention and 16% by 10 years.4 These patients had dramatic improvement in quality of life scores and validated measures of psychiatric dysfunction compared with only minor and inconsistent improvement in patients undergoing medical treatment for their obesity. After 10 years of follow up the improvement in the surgical group diminished somewhat due to weight regain. Regardless, outcomes of groups of patients undergoing surgical treatment were superior to those treated medically.5,6 Surgical options for weight loss have been consistently more successful at helping individuals to lose weight and maintain that achievement permanently.7-9

Weight loss surgery has been evolving since its inception and the final chapter is yet to be written. Since the 1950's astute minds and dedicated surgeons have tried to find the one operation that would yield the definitive answer to the problem of obesity. As time has progressed, no silver bullet has been identified. It is clear that there is no procedure that is superior to another for every patient.

Each operation that will be discussed here has its own story to tell in terms of patient selection, operative technique, outcomes and complications. Each has an important role to play in the world of weight loss surgery and it behooves those involved in the trenches of

Surgical Procedures to Achieve Weight Loss 3

All bariatric operations have been performed using the open approach. With increases in knowledge, technology, skill and ingenuity, all of these procedures are now possible via a laparoscopic approach. Over time, laparoscopic surgery has gained wide acceptance and is now more common in primary procedures in bariatric surgery than the open approach.14-16 Regardless of the method used to perform any particular weight loss procedure the surgical endpoints are the same. All primary bariatric procedures can generally be performed laparoscopically with clinical results comparable to those of an open counterpart. The major reported benefits of the laparoscopic approach include: superior exposure, reduced soft tissue trauma, better postoperative pulmonary function, less postoperative pain, decreased rates of wound infection, decreased rates of abdominal wall hernias, earlier return to physical activities, decreased length of stay, earlier return to work and better cosmetic results. The laparoscopic approach can also serve as a useful diagnostic tool in bariatric patients when imaging studies may be impossible to perform, or when signs and symptoms of an ongoing surgical problem may be vague due to the patient's body habitus. Disadvantages of the laparoscopic approach primarily include higher operative costs, longer

In general, the bariatric surgical procedures are classified by their mechanism of action.

1. Restrictive operations are based on decreasing the size of the stomach, limiting portion

2. Malabsorptive operations rely on the surgical rearrangement of the gastrointestinal system to decrease the absorption by limiting the exposure of the small bowel to the

3. Mixed operations are a combination of the restrictive and malabsorptive procedures.17,18

The Vertical Banded Gastroplasty (VGB) is like many other bariatric operations which experienced changes from its initial inception until the accepted version that was performed. The procedure, which was first performed in 1971 by Mason, underwent an evolution. The initial operation included a transverse gastroplasty which served to partition the stomach. The final variation involved the creation of a vertical gastroplasty along the lesser curvature. Operatively, a window is made through the anterior and posterior gastric wall using a

Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass (LSG-DB)

operative times, need for specialized training and steep learning curves.

**2. Laparoscopic vs. Open Approach**

**3. Types of Surgery**

ingested meal. 17,18

They are subdivided in three types:

Sleeve Gastrectomy (SG)

Jejuno-ileal bypass (JIB)

**4. Vertical Banded Gastroplasty**

size, and increasing early satiety. 17,18 Vertical Banded Gastroplasty (VBG)

Adjustable Gastric Banding (AGB)

Roux-en-Y Gastric Bypass (RYGB)

Biliopancreatic Bypass with Duodenal Switch (BPD-DS)

Ileal Interposition with Sleeve Gastrectomy (IL-SG)

bariatric surgery and the subsequent care of these patients to be familiar with the individual nuances of the operations. In this chapter, we will discuss the various common, and not so common, surgical options currently being employed to assist the morbidly obese patient.

#### **1.1 Patient selection**

The patient selection criteria consist of a group of objective and variable components. The objective component was set by the National Institutes of Health (NIH) in 1991. In order to be eligible for bariatric surgery the patient must have a body mass index (BMI) of 40kg/m2 or a BMI of 35 kg/m2 with associated co-morbidities. These co-morbidities can include medical conditions such as:

Other subjective criteria include:

#### **1.2 Weight loss**

Weight loss patterns in bariatric surgery are one of the major differences between the various surgical tools available. While most patients are concerned about the absolute weight loss in terms of pounds or kilograms, in order for there to be an objective method of comparing the differences in weight loss between the different procedures other means of measurement have evolved with time. Weight loss is generally measured according to the patient's BMI or a change in the percentage of excess weight lost (%EWL).12,13

#### **1.3 Complications**

Intimate knowledge of the exact operation is necessary for any clinician to be able to assess and manage post bariatric surgical patients. Some postoperative complications such as infection, pneumonia, urinary tract infections, deep venous thrombosis and pulmonary embolism may be standard concerns after intra-abdominal surgery but other issues such as erosions or slippage of a gastric band, internal hernias, bleeding and anastomotic leakage require a physician to be knowledgeable about the intricacies and variations of weight loss operations, as many complications may be overlooked or missed by the unsuspecting observer. Complications specific to each operation will be discussed with the review of each operation.

bariatric surgery and the subsequent care of these patients to be familiar with the individual nuances of the operations. In this chapter, we will discuss the various common, and not so common, surgical options currently being employed to assist the morbidly obese patient.

The patient selection criteria consist of a group of objective and variable components. The objective component was set by the National Institutes of Health (NIH) in 1991. In order to be eligible for bariatric surgery the patient must have a body mass index (BMI) of 40kg/m2 or a BMI of 35 kg/m2 with associated co-morbidities. These co-morbidities can include

3. Demonstration of a reasonable understanding of the surgical tools available for weight

4. Ability to understand and conform to the postoperative diet and lifestyle changes

Weight loss patterns in bariatric surgery are one of the major differences between the various surgical tools available. While most patients are concerned about the absolute weight loss in terms of pounds or kilograms, in order for there to be an objective method of comparing the differences in weight loss between the different procedures other means of measurement have evolved with time. Weight loss is generally measured according to the

Intimate knowledge of the exact operation is necessary for any clinician to be able to assess and manage post bariatric surgical patients. Some postoperative complications such as infection, pneumonia, urinary tract infections, deep venous thrombosis and pulmonary embolism may be standard concerns after intra-abdominal surgery but other issues such as erosions or slippage of a gastric band, internal hernias, bleeding and anastomotic leakage require a physician to be knowledgeable about the intricacies and variations of weight loss operations, as many complications may be overlooked or missed by the unsuspecting observer. Complications specific to each operation will be discussed with the review of each

1. Sustained attempts at weight loss over a period of at least five years 2. Recognition of the effect of morbid obesity on the patient's health

patient's BMI or a change in the percentage of excess weight lost (%EWL).12,13

loss with the associated risks and benefits

5. Realistic expectations of the desired surgical procedure.10,11

**1.1 Patient selection**

medical conditions such as:

3. Obstructive sleep apnea

6. Degenerative joint disease4 Other subjective criteria include:

necessary for success

**1.2 Weight loss**

**1.3 Complications**

operation.

1. Hypertension 2. Diabetes

4. Hyperlipidemia

5. GERD

#### **2. Laparoscopic vs. Open Approach**

All bariatric operations have been performed using the open approach. With increases in knowledge, technology, skill and ingenuity, all of these procedures are now possible via a laparoscopic approach. Over time, laparoscopic surgery has gained wide acceptance and is now more common in primary procedures in bariatric surgery than the open approach.14-16 Regardless of the method used to perform any particular weight loss procedure the surgical endpoints are the same. All primary bariatric procedures can generally be performed laparoscopically with clinical results comparable to those of an open counterpart. The major reported benefits of the laparoscopic approach include: superior exposure, reduced soft tissue trauma, better postoperative pulmonary function, less postoperative pain, decreased rates of wound infection, decreased rates of abdominal wall hernias, earlier return to physical activities, decreased length of stay, earlier return to work and better cosmetic results. The laparoscopic approach can also serve as a useful diagnostic tool in bariatric patients when imaging studies may be impossible to perform, or when signs and symptoms of an ongoing surgical problem may be vague due to the patient's body habitus. Disadvantages of the laparoscopic approach primarily include higher operative costs, longer operative times, need for specialized training and steep learning curves.

#### **3. Types of Surgery**

In general, the bariatric surgical procedures are classified by their mechanism of action. They are subdivided in three types:

	- Vertical Banded Gastroplasty (VBG)
	- Sleeve Gastrectomy (SG)
	- Adjustable Gastric Banding (AGB)
	- Jejuno-ileal bypass (JIB)
	- Roux-en-Y Gastric Bypass (RYGB)
	- Biliopancreatic Bypass with Duodenal Switch (BPD-DS)
	- Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass (LSG-DB)
	- Ileal Interposition with Sleeve Gastrectomy (IL-SG)

#### **4. Vertical Banded Gastroplasty**

The Vertical Banded Gastroplasty (VGB) is like many other bariatric operations which experienced changes from its initial inception until the accepted version that was performed. The procedure, which was first performed in 1971 by Mason, underwent an evolution. The initial operation included a transverse gastroplasty which served to partition the stomach. The final variation involved the creation of a vertical gastroplasty along the lesser curvature. Operatively, a window is made through the anterior and posterior gastric wall using a

Surgical Procedures to Achieve Weight Loss 5

possible to restaple a dehisced staple line; however, reapplying staples to a thickened, scarred stomach wall may be associated with not only another dehiscence, but tearing of the tissue. The success rate in resuming and maintaining weight loss with reapplication of staples is also generally less satisfactory when compared to the degree of weight loss after

Pouch enlargement was another well recognized complication of this procedure leading to gastric stasis and reflux. It primarily occurs due to repetitive vomiting, inclusion of an excessive amount of fundus during the initial procedure or continued overeating. One should be aware of the fact that one of the innate functions of the fundus is to dilate to accommodate ingestion of the food bolus. Thus, inclusion of a significant amount of fundus may promote pouch dilation. To help to avoid this, the initial vertical staple line should be placed precisely at the angle of His. The VBG was quite popular in the 1970's but is much

The Sleeve Gastrectomy (SG) was initially used as the first part of a two-stage procedure for the super-obese patients who were considered poor surgical candidates and who would not tolerate a prolonged or more involved procedure. The operation was designed to allow the patients an opportunity to achieve some weight loss before being converted to the more complex gastric bypass or biliopancreatic diversion with duodenal switch (BPD-DS).27 Keen observation noted that the weight loss with the gastric sleeve alone was significant and, in fact, many patients refused further operative intervention to promote continued weight loss. Currently, this procedure is used as a definitive weight loss procedure. Despite the perceived simplicity and efficacy of gastric sleeve, enthusiasm for this procedure is often tempered by the lack of data on long-term outcomes beyond 5 years. It was discovered that SG also produces a decrease in ghrelin levels for up to a year, which may reduce the desire

The operation involves a vertical gastrectomy performed parallel to the lesser curvature. The more receptive greater curvature is resected and the patient is left with a long tube-like

the initial operation.

less commonly performed today. 25,26

**5. Sleeve Gastrectomy**

for food.28,29

Fig. 2. Sleeve Gastrectomy

circular stapler positioned close to the lesser curvature. A linear non-cutting stapler is then applied through the gastric window, created by the circular stapler, in a vertical fashion directed towards the angle of His. A ring of polypropylene mesh is then placed through the gastric window around the lesser curvature (see Figure 1). This procedure has since been adapted to the laparoscopic approach in which the stomach is generally transected vertically.17,18,19,20 This anatomic change results in early satiety with reduced meal portions.

Fig. 1. Vertical Banded Gastroplasty

#### **4.1 Weight loss**

This procedure generally was able to effect a 50-60% EWL within two years. The VBG appears to be more dependent on the patient's ability to maintain lifelong alterations of his or her eating habits. These changes include avoiding high-calorie liquids and such calorierich foods as cake, cookies, and other junk foods that undergo substantial liquefaction in the mouth and thus arrive in the VBG pouch as a liquid slurry that is not restricted by the outlet. This dependence on patient behavior led to a higher failure rate due to weight regain which in turn has led many to abandon the VBG in preference to other simpler restrictive procedures.20-22

#### **4.2 Complications**

The majority of problems with the VBG generally surrounded stomal issues. The stoma could be too loose which would lead to little restriction and ultimately poor weight loss. Conversely, the stoma could develop a stricture which could then lead to difficulty with oral intake.

Staple-line dehiscence was also a well known problem. Small dehiscences do not substantially impede the restrictive effects of the operation. A dehiscence larger than 1 cm would generally lead to both weight regain and gastroesophageal reflux disease. This would render the operation ineffective as the restriction would be lost, yield inadequate long-term weight loss and require revision of the initial operation. Sporadic staple–line dehiscence was also seen in postpartum patients—the reason for this association is unknown.23,24 It is

circular stapler positioned close to the lesser curvature. A linear non-cutting stapler is then applied through the gastric window, created by the circular stapler, in a vertical fashion directed towards the angle of His. A ring of polypropylene mesh is then placed through the gastric window around the lesser curvature (see Figure 1). This procedure has since been adapted to the laparoscopic approach in which the stomach is generally transected vertically.17,18,19,20 This anatomic change results in early satiety with reduced meal portions.

This procedure generally was able to effect a 50-60% EWL within two years. The VBG appears to be more dependent on the patient's ability to maintain lifelong alterations of his or her eating habits. These changes include avoiding high-calorie liquids and such calorierich foods as cake, cookies, and other junk foods that undergo substantial liquefaction in the mouth and thus arrive in the VBG pouch as a liquid slurry that is not restricted by the outlet. This dependence on patient behavior led to a higher failure rate due to weight regain which in turn has led many to abandon the VBG in preference to other simpler restrictive

The majority of problems with the VBG generally surrounded stomal issues. The stoma could be too loose which would lead to little restriction and ultimately poor weight loss. Conversely,

Staple-line dehiscence was also a well known problem. Small dehiscences do not substantially impede the restrictive effects of the operation. A dehiscence larger than 1 cm would generally lead to both weight regain and gastroesophageal reflux disease. This would render the operation ineffective as the restriction would be lost, yield inadequate long-term weight loss and require revision of the initial operation. Sporadic staple–line dehiscence was also seen in postpartum patients—the reason for this association is unknown.23,24 It is

the stoma could develop a stricture which could then lead to difficulty with oral intake.

Fig. 1. Vertical Banded Gastroplasty

**4.1 Weight loss**

procedures.20-22

**4.2 Complications**

possible to restaple a dehisced staple line; however, reapplying staples to a thickened, scarred stomach wall may be associated with not only another dehiscence, but tearing of the tissue. The success rate in resuming and maintaining weight loss with reapplication of staples is also generally less satisfactory when compared to the degree of weight loss after the initial operation.

Pouch enlargement was another well recognized complication of this procedure leading to gastric stasis and reflux. It primarily occurs due to repetitive vomiting, inclusion of an excessive amount of fundus during the initial procedure or continued overeating. One should be aware of the fact that one of the innate functions of the fundus is to dilate to accommodate ingestion of the food bolus. Thus, inclusion of a significant amount of fundus may promote pouch dilation. To help to avoid this, the initial vertical staple line should be placed precisely at the angle of His. The VBG was quite popular in the 1970's but is much less commonly performed today. 25,26

#### **5. Sleeve Gastrectomy**

The Sleeve Gastrectomy (SG) was initially used as the first part of a two-stage procedure for the super-obese patients who were considered poor surgical candidates and who would not tolerate a prolonged or more involved procedure. The operation was designed to allow the patients an opportunity to achieve some weight loss before being converted to the more complex gastric bypass or biliopancreatic diversion with duodenal switch (BPD-DS).27 Keen observation noted that the weight loss with the gastric sleeve alone was significant and, in fact, many patients refused further operative intervention to promote continued weight loss. Currently, this procedure is used as a definitive weight loss procedure. Despite the perceived simplicity and efficacy of gastric sleeve, enthusiasm for this procedure is often tempered by the lack of data on long-term outcomes beyond 5 years. It was discovered that SG also produces a decrease in ghrelin levels for up to a year, which may reduce the desire for food.28,29

Fig. 2. Sleeve Gastrectomy

The operation involves a vertical gastrectomy performed parallel to the lesser curvature. The more receptive greater curvature is resected and the patient is left with a long tube-like

Surgical Procedures to Achieve Weight Loss 7

Banding System was introduced in 1985 by Dr. Dag Hallberg of Sweden. Laparoscopic adjustable gastric banding (LAGB) was advocated in 1992 by Favretti and Cadiere and made a revolutionary change in the history of bariatric surgery. Over time and with technological improvements, the first laparoscopic adjustable gastric band device was approved by the

Adjustable Gastric Banding (AGB) procedures have now virtually replaced the VBG throughout the world. A number of bands are available on the market, but only two devices

Gastric banding procedures rely on the restriction of enteral intake to achieve weight loss and its maintenance. There is no alteration of the native anatomy and as such the

Over a period of time many modifications to the gastric band were created by different

The AGB is commonly placed laparoscopically, generally with a short operative time and limited morbidity. Hospital stay is often one day and, recently, is more commonly being performed as an outpatient procedure. Operatively, the goal is to place the band in a position at the gastric cardia near the gastroesophageal junction that will yield a small gastric pouch with a 20-30 mL capacity. The small pouch provides the restriction needed to assist in weight loss. The optimal technique has changed with time and is now agreed upon to be the pars flaccida technique. The band encircles the upper stomach, and its ultimate position is determined by using a calibration tube as a guide intraoperatively. It is then sutured in place with the use of anterior gastro-gastric sutures for stability, while posteriorly the band is held in place by natural attachments between the posterior stomach and the

1. The band which is placed at the gastric cardia near the gastroesophageal junction and effectively divides the stomach into two segments; an upper smaller pouch and the

neurohormonal mechanisms involved in weight control are largely left intact.34,35

are currently FDA approved and available in the United States.

The band system consists of three components (see Figure 3):

FDA for use in the United States in 2001.

Fig. 3. Adjustable Gastric Banding

manufacturers.

right diaphragmatic crus.34,35

larger intact stomach.

stomach (see Figure 2). The operation consists of releasing the vascular supply of the greater curvature as well as the posterior gastric attachments. A bougie is advanced into the distal stomach or duodenum and the greater curvature of the stomach is resected. The transection of the stomach is begun approximately 4-5cm proximal to the pylorus. With the bougie in place to size the stomach along the lesser curvature, a vertical gastrectomy is created using a linear cutting stapler.27 Different sized bougies have been used to date, somewhat limiting the comparison of available results. Standardization is still awaited for this procedure that is certainly a valuable addition to the surgical armamentarium.

#### **5.1 Weight loss**

While no long term weight loss statistics are available, medium-term results are indeed encouraging with an expected 62% EWL at 12 months and 68% EWL at 24 months.27,30 Review of current literature also demonstrates that at 6 years, the %EWL is approximately 57.3-72.3%.24,31

#### **5.2 Complications**

Along with the standard postoperative concerns, the most common complications with the SG have surrounded staple line disruption, leakage from the long staple line and bleeding. The majority of leaks occur in the area of gastroesophageal junction.32,33 It most likely occurs because this area has diminished blood supply compared to the rest of the stomach. Also the stomach wall in this area is thinner and hence less resistant to ischemia and thermal injuries by energy devices. 32,33 Another common site for a leak is along the antral staple line. Disruption of the staple line in this location is believed to occur due to the relative obstruction caused by the nearby pylorus.

Stenosis and dilatation of this narrow tubular stomach has also been reported.

The gastroesophageal junction and the angularis incisura are the two most common areas where stenosis occurs, and this can be diagnosed by an upper gastrointestinal series. The most common reasons for the development of narrowing or stenosis are over-sewing the staple line, using a bougie that is too small, creating non-parallel staple lines or using nonabsorbable suture material.

Even though we mentioned that variable bougie sizes are being used by different surgeons, a 32 to 40 French bougie is most often utilized when SG is performed as a definitive operation. Larger bougie sizes, up to 60 French, can be used when SG is being performed as a part of a staged procedure such as BPD-DS.32 Management of stenosis primarily consists of endoscopic dilation vs. stent placement. If the area of stenosis is too long, surgical intervention may be necessary with conversion to a gastric stricturoplasty, RYGB or resection with gastrogastrostomy. Management of gastric sleeve stretching is currently controversial. There are multiple reports of successful repeat sleeve gastrectomy as well as conversion of SG to RYGB or BPD-DS.

#### **6. Adjustable Gastric Banding**

In 1983, while looking for a safe surgical method to fight obesity, Dr. Lubomyr Kuzmak introduced a Dacron-reinforced silicon band. This original system had no ability to adjust the gastric restriction and was considered a permanent implant. The Adjustable Gastric

stomach (see Figure 2). The operation consists of releasing the vascular supply of the greater curvature as well as the posterior gastric attachments. A bougie is advanced into the distal stomach or duodenum and the greater curvature of the stomach is resected. The transection of the stomach is begun approximately 4-5cm proximal to the pylorus. With the bougie in place to size the stomach along the lesser curvature, a vertical gastrectomy is created using a linear cutting stapler.27 Different sized bougies have been used to date, somewhat limiting the comparison of available results. Standardization is still awaited for this procedure that is

While no long term weight loss statistics are available, medium-term results are indeed encouraging with an expected 62% EWL at 12 months and 68% EWL at 24 months.27,30 Review of current literature also demonstrates that at 6 years, the %EWL is approximately

Along with the standard postoperative concerns, the most common complications with the SG have surrounded staple line disruption, leakage from the long staple line and bleeding. The majority of leaks occur in the area of gastroesophageal junction.32,33 It most likely occurs because this area has diminished blood supply compared to the rest of the stomach. Also the stomach wall in this area is thinner and hence less resistant to ischemia and thermal injuries by energy devices. 32,33 Another common site for a leak is along the antral staple line. Disruption of the staple line in this location is believed to occur due to the relative

The gastroesophageal junction and the angularis incisura are the two most common areas where stenosis occurs, and this can be diagnosed by an upper gastrointestinal series. The most common reasons for the development of narrowing or stenosis are over-sewing the staple line, using a bougie that is too small, creating non-parallel staple lines or using non-

Even though we mentioned that variable bougie sizes are being used by different surgeons, a 32 to 40 French bougie is most often utilized when SG is performed as a definitive operation. Larger bougie sizes, up to 60 French, can be used when SG is being performed as a part of a staged procedure such as BPD-DS.32 Management of stenosis primarily consists of endoscopic dilation vs. stent placement. If the area of stenosis is too long, surgical intervention may be necessary with conversion to a gastric stricturoplasty, RYGB or resection with gastrogastrostomy. Management of gastric sleeve stretching is currently controversial. There are multiple reports of successful repeat sleeve gastrectomy as well as

In 1983, while looking for a safe surgical method to fight obesity, Dr. Lubomyr Kuzmak introduced a Dacron-reinforced silicon band. This original system had no ability to adjust the gastric restriction and was considered a permanent implant. The Adjustable Gastric

Stenosis and dilatation of this narrow tubular stomach has also been reported.

certainly a valuable addition to the surgical armamentarium.

**5.1 Weight loss**

57.3-72.3%.24,31

**5.2 Complications**

obstruction caused by the nearby pylorus.

absorbable suture material.

conversion of SG to RYGB or BPD-DS.

**6. Adjustable Gastric Banding**

Banding System was introduced in 1985 by Dr. Dag Hallberg of Sweden. Laparoscopic adjustable gastric banding (LAGB) was advocated in 1992 by Favretti and Cadiere and made a revolutionary change in the history of bariatric surgery. Over time and with technological improvements, the first laparoscopic adjustable gastric band device was approved by the FDA for use in the United States in 2001.

Fig. 3. Adjustable Gastric Banding

Adjustable Gastric Banding (AGB) procedures have now virtually replaced the VBG throughout the world. A number of bands are available on the market, but only two devices are currently FDA approved and available in the United States.

Gastric banding procedures rely on the restriction of enteral intake to achieve weight loss and its maintenance. There is no alteration of the native anatomy and as such the neurohormonal mechanisms involved in weight control are largely left intact.34,35

Over a period of time many modifications to the gastric band were created by different manufacturers.

The AGB is commonly placed laparoscopically, generally with a short operative time and limited morbidity. Hospital stay is often one day and, recently, is more commonly being performed as an outpatient procedure. Operatively, the goal is to place the band in a position at the gastric cardia near the gastroesophageal junction that will yield a small gastric pouch with a 20-30 mL capacity. The small pouch provides the restriction needed to assist in weight loss. The optimal technique has changed with time and is now agreed upon to be the pars flaccida technique. The band encircles the upper stomach, and its ultimate position is determined by using a calibration tube as a guide intraoperatively. It is then sutured in place with the use of anterior gastro-gastric sutures for stability, while posteriorly the band is held in place by natural attachments between the posterior stomach and the right diaphragmatic crus.34,35

The band system consists of three components (see Figure 3):

1. The band which is placed at the gastric cardia near the gastroesophageal junction and effectively divides the stomach into two segments; an upper smaller pouch and the larger intact stomach.

Surgical Procedures to Achieve Weight Loss 9

operation consisted of creating a jejunoileostomy and shortening the effective length of the small intestine. Observing patients suffering from short gut syndrome spawned the idea of using jejunoileal bypass in order to lose weight. A short length of proximal jejunum (8 to 14 inches from the ligament of Treitz) was connected to the distal ileum (4 to 12 inches proximal to the ileocecal valve) as an end-to-end or end-to-side anastomosis (see Figure 4). Patients with the end-to-end anastomosis, which could achieve a higher degree of weight loss, also required decompression of the bypassed small intestine into the colon via an ileocecostomy. The diminished length of the functional small bowel exposed to food boluses as well as the diminished surface area for absorption was the key to the JIB. It was indeed successful in its objective of weight loss but it later became apparent that the dramatic

Approximately 25,000 patients underwent JIB in the United States when it was realized that complications of this procedure were, ultimately, common and would present with significant morbidity and mortality. Complications such as severe diarrhea, electrolyte imbalance, kidney stones, kidney failure, gastro-intestinal tract bacterial overgrowth and liver failure were unexpected problems which ultimately led to the abandonment of this procedure and the reversal of JIB in many patients. Variations of this small bowel bypass were used in the 1960's, but over time these were abandoned as well given inadequate weight loss or unacceptable complication rates. As a result, the JIB is only discussed today for its historical significance. Armed with the knowledge that surgical manipulation of the gastrointestinal (GI) tract could lead to significant and reproducible weight loss, many surgeons embarked on this journey in pursuit of the perfect operation which could

The Gastric Bypass (GB) has emerged as the most common operation performed for weight loss in the United States. In fact, it is often referred to as the "gold standard" of bariatric

produced the desired weight loss with an acceptable complication profile.17,18,38

weight loss was not the only outcome.

Fig. 4. Jejunoileal Bypass

**8. Gastric Bypass**

The major advantages of the gastric band include the minimally invasive nature of the operation, its reversibility, the adjustability of the band and the maintenance of gastrointestinal anatomy.

#### **6.1 Weight loss**

The weight loss patterns for the two available AGBs are comparable. The expectations for weight loss are for the patient to obtain a 30-35% EWL in the first year, 50% EWL at the second year and 60% EWL in the third year. Ultimately the goal is to achieve a gradual, effective and durable means to lose weight. These results have been quite variable in the literature and ultimately are still being debated.34-37

#### **6.2 Complications**

Perioperative complications occur in 1-2% of cases and this safety profile associated with the AGBs make them an attractive choice for many patients and surgeons when compared to the other surgical options available for weight loss. One band-related complication includes stoma obstruction. This occurs most commonly due to inclusion of excess perigastric fat, use of a band of insufficient diameter for the thickness of the tissue, significant tissue edema, band infection, delayed gastric emptying or gastric perforation. The majority of these require surgical management, including band removal or repositioning.

Late band related complications include erosions, slippage or gastric prolapse, port or tubing malfunction, port migration, leakage at the port site, tubing or band, pouch or esophageal dilatation and esophagitis.35 Slippage is diagnosed when a portion of the stomach below the band has traversed the band and now lies above it. This movement initially creates a large upper gastric pouch which diminishes the restrictive function of the adjustable band. As more of the inferior stomach passes cephalad, it ultimately leads to obstruction of the stoma which will present with persistent nausea and vomiting and inability to tolerate even saliva. This is a scenario which must be diagnosed early as it can lead to gastric necrosis if not identified and treated in a timely fashion. Erosion is an infrequent but serious complication of gastric banding. It often presents with evidence of a port site infection, but there have been reports of gastric outlet obstruction from an intraluminal band. A high index of suspicion is crucial to avoid a delay in diagnosis. The diagnosis of an erosion mandates the removal of the gastric band. This can be done operatively or endoscopically in select cases.

#### **7. Jejunoileal Bypass (JIB)**

The jejunoileal bypass (JIB) was first introduced in the 1950s at the University of Minnesota. It was the first most commonly used procedure for the treatment of severe obesity. The

2. The port which is the access point for adjustments. The port is placed on the abdominal wall, directly attached to the rectus abdominis fascia. An adjustment consists of using a Huber needle to access the subcutaneous port at which point normal saline can be injected or aspirated from the band. The injection or aspiration of fluid changes the tightness of the band around the stomach and can therefore assist with the management

The major advantages of the gastric band include the minimally invasive nature of the operation, its reversibility, the adjustability of the band and the maintenance of

The weight loss patterns for the two available AGBs are comparable. The expectations for weight loss are for the patient to obtain a 30-35% EWL in the first year, 50% EWL at the second year and 60% EWL in the third year. Ultimately the goal is to achieve a gradual, effective and durable means to lose weight. These results have been quite variable in the

Perioperative complications occur in 1-2% of cases and this safety profile associated with the AGBs make them an attractive choice for many patients and surgeons when compared to the other surgical options available for weight loss. One band-related complication includes stoma obstruction. This occurs most commonly due to inclusion of excess perigastric fat, use of a band of insufficient diameter for the thickness of the tissue, significant tissue edema, band infection, delayed gastric emptying or gastric perforation. The majority of these

Late band related complications include erosions, slippage or gastric prolapse, port or tubing malfunction, port migration, leakage at the port site, tubing or band, pouch or esophageal dilatation and esophagitis.35 Slippage is diagnosed when a portion of the stomach below the band has traversed the band and now lies above it. This movement initially creates a large upper gastric pouch which diminishes the restrictive function of the adjustable band. As more of the inferior stomach passes cephalad, it ultimately leads to obstruction of the stoma which will present with persistent nausea and vomiting and inability to tolerate even saliva. This is a scenario which must be diagnosed early as it can lead to gastric necrosis if not identified and treated in a timely fashion. Erosion is an infrequent but serious complication of gastric banding. It often presents with evidence of a port site infection, but there have been reports of gastric outlet obstruction from an intraluminal band. A high index of suspicion is crucial to avoid a delay in diagnosis. The diagnosis of an erosion mandates the removal of the gastric band. This can be done

The jejunoileal bypass (JIB) was first introduced in the 1950s at the University of Minnesota. It was the first most commonly used procedure for the treatment of severe obesity. The

require surgical management, including band removal or repositioning.

of food consumption, appropriate early satiety and subsequent weight loss.

3. The silastic tubing which connects the band to the port.

literature and ultimately are still being debated.34-37

operatively or endoscopically in select cases.

**7. Jejunoileal Bypass (JIB)**

gastrointestinal anatomy.

**6.1 Weight loss**

**6.2 Complications**

operation consisted of creating a jejunoileostomy and shortening the effective length of the small intestine. Observing patients suffering from short gut syndrome spawned the idea of using jejunoileal bypass in order to lose weight. A short length of proximal jejunum (8 to 14 inches from the ligament of Treitz) was connected to the distal ileum (4 to 12 inches proximal to the ileocecal valve) as an end-to-end or end-to-side anastomosis (see Figure 4). Patients with the end-to-end anastomosis, which could achieve a higher degree of weight loss, also required decompression of the bypassed small intestine into the colon via an ileocecostomy. The diminished length of the functional small bowel exposed to food boluses as well as the diminished surface area for absorption was the key to the JIB. It was indeed successful in its objective of weight loss but it later became apparent that the dramatic weight loss was not the only outcome.

Fig. 4. Jejunoileal Bypass

Approximately 25,000 patients underwent JIB in the United States when it was realized that complications of this procedure were, ultimately, common and would present with significant morbidity and mortality. Complications such as severe diarrhea, electrolyte imbalance, kidney stones, kidney failure, gastro-intestinal tract bacterial overgrowth and liver failure were unexpected problems which ultimately led to the abandonment of this procedure and the reversal of JIB in many patients. Variations of this small bowel bypass were used in the 1960's, but over time these were abandoned as well given inadequate weight loss or unacceptable complication rates. As a result, the JIB is only discussed today for its historical significance. Armed with the knowledge that surgical manipulation of the gastrointestinal (GI) tract could lead to significant and reproducible weight loss, many surgeons embarked on this journey in pursuit of the perfect operation which could produced the desired weight loss with an acceptable complication profile.17,18,38

#### **8. Gastric Bypass**

The Gastric Bypass (GB) has emerged as the most common operation performed for weight loss in the United States. In fact, it is often referred to as the "gold standard" of bariatric

Surgical Procedures to Achieve Weight Loss 11

The overall expectation of the operation is a 60-70% EWL over the course of 12-18 months. During this period of time, close follow-up is essential in order to identify any potential problems which the patient may experience and prevent micronutrient and protein

Complications associated with LRYGB are often divided into early and late complications. The most notable early complications after the gastric bypass operation are: bleeding, pulmonary embolism, and anastomotic dehiscence. Pulmonary embolism and anastomotic dehiscence are the two most common reasons for mortality associated with the gastric bypass. The mortality rate varies between reports but generally ranges between 0.5 to 1%.

The bleeding can be either intra-luminal or extra-luminal. Intraluminal bleeding may present with signs and symptoms of upper or lower GI bleeding such as hematemesis, bright red blood per rectum or melena. Extra-luminal bleeding may only be suspected by clinical findings such as hypotension and tachycardia with a falling hematocrit and decreased urine output. Abdominal distention and abdominal pain are often not reliable

Persistent tachycardia is the hallmark sign for a leak and requires immediate investigation, with a low threshold to return to the operating room. Late complications of the gastric bypass include anastomotic stricture (2-16%). The etiology is unclear, however tissue ischemia or increased tension on the gastrojejunostomy are the most likely reasons. The rate of stenosis is higher when a circular stapler is used for creation of the gastrojejunostomy or when the Roux limb is in an ante-colic position. Marginal ulceration (1-5%), another late complication of RYGB, can develop due to different reasons including re-exposure of the gastrojejunostomy to gastric acid via a gastro-gastric fistula, ischemic changes to the anastomosis most often due to nicotine use, the presence of foreign material (sutures and

Iron deficiency (6-52%), vitamin B12 deficiency (3-37%), calcium, thiamine and folate deficiency are the most common micronutrient deficiencies observed in post-bariatric surgery patients. If dietary changes are not maintained, protein malnutrition can result which presents

as hair loss. This is reversible if adjustments are made to increase protein intake.

**8.1 Weight loss**

deficiencies.40

**8.2 Complications**

1. Incision/port sites

4. Divided mesentery

1. Gastrojejunostomy 2. Gastric pouch staple line 3. Gastric remnant staple line

4. Jejunojejunostomy

Bleeding can occur from a number of sites including:

3. Gastric pouch or remnant staple line

physical findings in the morbidly obese patient. Leakage, likewise, can occur at a number of sites:

staples), chronic NSAID use and H. pylori infection.

2. Anastomotic sites (gastrojejunostomy is more common)

surgery. Its long history of good weight loss with low complication rates have led to this status. The original GB was performed by Mason and Ito in 1967, after they recognized that patients undergoing partial gastrectomy for indications other than weight loss, like peptic ulcer disease, had difficulty gaining weight in the postoperative period.39 The original version of gastric bypass consisted of a 150-mL gastric pouch and a loop gastrojejunostomy. It has subsequently undergone a number of modifications until it was recognized that a smaller gastric pouch of 20 – 30 mL in conjunction with a Roux-en-Y reconstruction is the most effective combination to achieve maximum weight loss with the lowest rates of amount of complications. The laparoscopic Roux-en-Y gastric bypass (LRYGB) was introduced in 1994 by Wittgrove and Clark.

Fig. 5. Gastric Bypass

The operation uses two methods to achieve weight loss. First, the restrictive component of the procedure is created by dividing the stomach to create a smaller gastric pouch. The larger remnant is left in situ. Second, the malabsorptive component is created when the remnant stomach, duodenum, and a short segment of the proximal jejunum is bypassed. Initially the jejunum is divided 30-50 cm distal to the ligament of Treitz. The length of the Roux limb, which consists of the distal transected jejunum, is selected based on the patient's BMI. A 75-100 cm long Roux limb is chosen for a BMI < 50 kg/m2 and a 150 cm long Roux limb is used for a BMI ≥ 50 kg/m2. A jejunojejunostomy between the Roux limb and biliopancreatic limb is created in a side-to-side fashion. The Roux limb is brought up to the transected stomach and a gastrojejunostomy is created (see Figure 5).

Several techniques for the creation of the gastrojejunostomy exist. It can be hand sewn or stapled with either a linear stapler or circular stapler. The gastrojejunostomy can be created in a retrogastric or antegastric fashion, while the Roux limb can be passed in an antecolic or retrocolic fashion. The decision for which approach is used ultimately depends on a few factors, but is largely surgeon preference.17,40,41 There are advantages and disadvantages to each approach and the surgeon should be familiar with these so as to be able to address post-operative complications.

#### **8.1 Weight loss**

10 Advanced Bariatric and Metabolic Surgery

surgery. Its long history of good weight loss with low complication rates have led to this status. The original GB was performed by Mason and Ito in 1967, after they recognized that patients undergoing partial gastrectomy for indications other than weight loss, like peptic ulcer disease, had difficulty gaining weight in the postoperative period.39 The original version of gastric bypass consisted of a 150-mL gastric pouch and a loop gastrojejunostomy. It has subsequently undergone a number of modifications until it was recognized that a smaller gastric pouch of 20 – 30 mL in conjunction with a Roux-en-Y reconstruction is the most effective combination to achieve maximum weight loss with the lowest rates of amount of complications. The laparoscopic Roux-en-Y gastric bypass (LRYGB) was

The operation uses two methods to achieve weight loss. First, the restrictive component of the procedure is created by dividing the stomach to create a smaller gastric pouch. The larger remnant is left in situ. Second, the malabsorptive component is created when the remnant stomach, duodenum, and a short segment of the proximal jejunum is bypassed. Initially the jejunum is divided 30-50 cm distal to the ligament of Treitz. The length of the Roux limb, which consists of the distal transected jejunum, is selected based on the patient's BMI. A 75-100 cm long Roux limb is chosen for a BMI < 50 kg/m2 and a 150 cm long Roux limb is used for a BMI ≥ 50 kg/m2. A jejunojejunostomy between the Roux limb and biliopancreatic limb is created in a side-to-side fashion. The Roux limb is brought up to the

Several techniques for the creation of the gastrojejunostomy exist. It can be hand sewn or stapled with either a linear stapler or circular stapler. The gastrojejunostomy can be created in a retrogastric or antegastric fashion, while the Roux limb can be passed in an antecolic or retrocolic fashion. The decision for which approach is used ultimately depends on a few factors, but is largely surgeon preference.17,40,41 There are advantages and disadvantages to each approach and the surgeon should be familiar with these so as to be able to address

transected stomach and a gastrojejunostomy is created (see Figure 5).

introduced in 1994 by Wittgrove and Clark.

Fig. 5. Gastric Bypass

post-operative complications.

The overall expectation of the operation is a 60-70% EWL over the course of 12-18 months. During this period of time, close follow-up is essential in order to identify any potential problems which the patient may experience and prevent micronutrient and protein deficiencies.40

#### **8.2 Complications**

Complications associated with LRYGB are often divided into early and late complications. The most notable early complications after the gastric bypass operation are: bleeding, pulmonary embolism, and anastomotic dehiscence. Pulmonary embolism and anastomotic dehiscence are the two most common reasons for mortality associated with the gastric bypass. The mortality rate varies between reports but generally ranges between 0.5 to 1%.

Bleeding can occur from a number of sites including:

The bleeding can be either intra-luminal or extra-luminal. Intraluminal bleeding may present with signs and symptoms of upper or lower GI bleeding such as hematemesis, bright red blood per rectum or melena. Extra-luminal bleeding may only be suspected by clinical findings such as hypotension and tachycardia with a falling hematocrit and decreased urine output. Abdominal distention and abdominal pain are often not reliable physical findings in the morbidly obese patient.

Leakage, likewise, can occur at a number of sites:

Persistent tachycardia is the hallmark sign for a leak and requires immediate investigation, with a low threshold to return to the operating room. Late complications of the gastric bypass include anastomotic stricture (2-16%). The etiology is unclear, however tissue ischemia or increased tension on the gastrojejunostomy are the most likely reasons. The rate of stenosis is higher when a circular stapler is used for creation of the gastrojejunostomy or when the Roux limb is in an ante-colic position. Marginal ulceration (1-5%), another late complication of RYGB, can develop due to different reasons including re-exposure of the gastrojejunostomy to gastric acid via a gastro-gastric fistula, ischemic changes to the anastomosis most often due to nicotine use, the presence of foreign material (sutures and staples), chronic NSAID use and H. pylori infection.

Iron deficiency (6-52%), vitamin B12 deficiency (3-37%), calcium, thiamine and folate deficiency are the most common micronutrient deficiencies observed in post-bariatric surgery patients. If dietary changes are not maintained, protein malnutrition can result which presents as hair loss. This is reversible if adjustments are made to increase protein intake.

Surgical Procedures to Achieve Weight Loss 13

to this Roux limb at 50 cm from the ileocecal valve to create the common channel (see Figure 6). This results in malabsorptive anatomy with modest restriction and without many of the side effects of the JIB. In 1993 Marceau described modifications to the BPD which have come to be known as the biliopancreatic diversion with duodenal switch (BPD-DS).10,44-46 In this modification the horizontal gastrectomy was substituted by SG, which allowed for

Even with the combined restrictive and malabsorptive properties of the gastric bypass, many super-obese patients fail to obtain the desired weight loss. The BPD-DS takes the surgical intensity to another level. It combines a moderate food restriction in the form of a vertical sleeve gastrectomy with the malabsorption of a long intestinal bypass. The sleeve gastrectomy capacity is approximately 100-150 mL. After completion of the sleeve gastrectomy, the pylorus is preserved and the duodenum is transected. The small bowel is then measured and marked 100 cm proximal from the ileocecal valve. This ultimately serves as the site for the anastomosis of a 100 cm common channel. An additional 150 cm of small bowel is measured from the future common channel towards the stomach. The small bowel is then transected at this site. The proximal site of transection is brought up and a duodenoilieal anastomosis is created. The distal small bowel transection site is brought to the 100 cm site and an ileoileal anastomosis performed. Ultimately the alimentary channel is 150 cm and the common channel is 100cm. The remaining small bowel is bypassed.10,17 Modifications to these measurements are common in clinical practice. The first laparoscopic

At 24 months postoperatively the patients can achieve up to 80% EWL with the BPD-DS, and an average of 76% at 10 years. Weight loss certainly exceeds that of the other bariatric

procedures but it comes with a greater risk of nutritional complications.

preservation of the pylorus and a decreased incidence of dumping syndrome.

Fig. 6. Biliopancreatic Diversion with Duodenal Switch

duodenal switch was performed by Gagner in 2000.

**9.1 Weight loss**

Along with vitamin deficiencies gastric bypass, due to the lack of a pylorus, can result in dumping syndrome. Dumping syndrome occurs in early and late forms. Early dumping syndrome (10 to 30 minutes after ingestion of a meal) is the more common form and occurs in about 25% of patients after gastric surgery. It is characterized by the rapid gastric emptying of hyperosmolar contents into the small bowel. Patients can suffer from abdominal cramps, nausea, explosive diarrhea, tachycardia, lightheadedness and syncope. This is often a self-limited phenomenon and can be treated by dietary modification or manipulation. Late dumping syndrome is usually associated with meals that have high carbohydrate contents. The symptom onset begins from 1 to 4 hours after ingestion of such meals and invariably includes reactive hypoglycemia in addition to some of the vasomotor symptoms seen with early dumping syndrome.

Endoscopic access to the gastric remnant and proximal small bowel becomes challenging and poses potential difficulties in the future, specifically when evaluating for remnant gastric lesions or attempting endoscopic retrograde cholangiopancreatography.4

Small bowel obstructions are a standard postoperative risk after any abdominal surgery. They can occur in 1-10% of patients and can be specifically related to trocar sites in laparoscopic surgery. Internal hernias are a special cause of bowel obstructions and have occurred most frequently in the setting of marked weight loss and the creation of intermesenteric defects or by failure to close mesenteric defects at the primary operation.

Three potential areas of internal herniation are:

Internal hernias can be intermittent and, therefore, difficult to detect radiographically. Several studies have shown that the "mesenteric swirl" sign on computed tomography (CT) scan is the best indicator of an internal hernia following gastric bypass.42 Although often debated, closure of all potential sites for internal hernias is highly recommended at the original operation. Long-term follow-up is essential with these patients as complications, such as internal hernias and nutritional deficiencies, can occur at any time. Intimate knowledge of the new anatomy is essential in order to optimally diagnose and treat these potential complications.43

#### **9. Biliopancreatic Diversion with Duodenal Switch**

The Biliopancreatic Diversion (BPD) was described and championed by Dr. Nicola Scopinaro of Italy in 1979. To date it still remains the most effective surgical intervention for morbid obesity. It is particularly suited for patients who fall in the super-obese category with a BMI greater than 50kg/m2. The main limitation has been that which is common to intense malabsorptive procedures: potential significant long-term nutritional deficiencies.

The BPD involves a horizontal gastrectomy that leaves a gastric pouch of about 250 mL that is anastomosed to a 200- to 250-cm Roux limb. The long biliopancreatic limb is anastomosed

Along with vitamin deficiencies gastric bypass, due to the lack of a pylorus, can result in dumping syndrome. Dumping syndrome occurs in early and late forms. Early dumping syndrome (10 to 30 minutes after ingestion of a meal) is the more common form and occurs in about 25% of patients after gastric surgery. It is characterized by the rapid gastric emptying of hyperosmolar contents into the small bowel. Patients can suffer from abdominal cramps, nausea, explosive diarrhea, tachycardia, lightheadedness and syncope. This is often a self-limited phenomenon and can be treated by dietary modification or manipulation. Late dumping syndrome is usually associated with meals that have high carbohydrate contents. The symptom onset begins from 1 to 4 hours after ingestion of such meals and invariably includes reactive hypoglycemia in addition to some of the vasomotor

Endoscopic access to the gastric remnant and proximal small bowel becomes challenging and poses potential difficulties in the future, specifically when evaluating for remnant

Small bowel obstructions are a standard postoperative risk after any abdominal surgery. They can occur in 1-10% of patients and can be specifically related to trocar sites in laparoscopic surgery. Internal hernias are a special cause of bowel obstructions and have occurred most frequently in the setting of marked weight loss and the creation of inter-

The space between the transverse mesocolon and Roux-limb mesentery (Peterson's

 The defect in the transverse mesocolon if the Roux-limb is passed in a retrocolic fashion Internal hernias can be intermittent and, therefore, difficult to detect radiographically. Several studies have shown that the "mesenteric swirl" sign on computed tomography (CT) scan is the best indicator of an internal hernia following gastric bypass.42 Although often debated, closure of all potential sites for internal hernias is highly recommended at the original operation. Long-term follow-up is essential with these patients as complications, such as internal hernias and nutritional deficiencies, can occur at any time. Intimate knowledge of the new anatomy is essential in order to optimally diagnose and treat these

The Biliopancreatic Diversion (BPD) was described and championed by Dr. Nicola Scopinaro of Italy in 1979. To date it still remains the most effective surgical intervention for morbid obesity. It is particularly suited for patients who fall in the super-obese category with a BMI greater than 50kg/m2. The main limitation has been that which is common to intense malabsorptive procedures: potential significant long-term nutritional

The BPD involves a horizontal gastrectomy that leaves a gastric pouch of about 250 mL that is anastomosed to a 200- to 250-cm Roux limb. The long biliopancreatic limb is anastomosed

gastric lesions or attempting endoscopic retrograde cholangiopancreatography.4

mesenteric defects or by failure to close mesenteric defects at the primary operation.

symptoms seen with early dumping syndrome.

Three potential areas of internal herniation are:

space)

potential complications.43

deficiencies.

The mesenteric defect at the jejunojejunostomy

**9. Biliopancreatic Diversion with Duodenal Switch**

to this Roux limb at 50 cm from the ileocecal valve to create the common channel (see Figure 6). This results in malabsorptive anatomy with modest restriction and without many of the side effects of the JIB. In 1993 Marceau described modifications to the BPD which have come to be known as the biliopancreatic diversion with duodenal switch (BPD-DS).10,44-46 In this modification the horizontal gastrectomy was substituted by SG, which allowed for preservation of the pylorus and a decreased incidence of dumping syndrome.

Fig. 6. Biliopancreatic Diversion with Duodenal Switch

Even with the combined restrictive and malabsorptive properties of the gastric bypass, many super-obese patients fail to obtain the desired weight loss. The BPD-DS takes the surgical intensity to another level. It combines a moderate food restriction in the form of a vertical sleeve gastrectomy with the malabsorption of a long intestinal bypass. The sleeve gastrectomy capacity is approximately 100-150 mL. After completion of the sleeve gastrectomy, the pylorus is preserved and the duodenum is transected. The small bowel is then measured and marked 100 cm proximal from the ileocecal valve. This ultimately serves as the site for the anastomosis of a 100 cm common channel. An additional 150 cm of small bowel is measured from the future common channel towards the stomach. The small bowel is then transected at this site. The proximal site of transection is brought up and a duodenoilieal anastomosis is created. The distal small bowel transection site is brought to the 100 cm site and an ileoileal anastomosis performed. Ultimately the alimentary channel is 150 cm and the common channel is 100cm. The remaining small bowel is bypassed.10,17 Modifications to these measurements are common in clinical practice. The first laparoscopic duodenal switch was performed by Gagner in 2000.

#### **9.1 Weight loss**

At 24 months postoperatively the patients can achieve up to 80% EWL with the BPD-DS, and an average of 76% at 10 years. Weight loss certainly exceeds that of the other bariatric procedures but it comes with a greater risk of nutritional complications.

Surgical Procedures to Achieve Weight Loss 15

Short term EWL after LSG-DJB is comparable to EWL after LRYGB.49 However, long-term data is lacking as this procedure is relatively new. Complications specific for LSG-DJB include bleeding, leak, stenosis at any of the anastomotic sites, marginal ulceration,

Ileal Interposition with Sleeve Gastrectomy (II-SG) is another operation that has been performed outside of the United States. It was one of many bariatric operations to treat morbid obesity, but also is used in non-obese patients with BMI 21-29 kg/m2 to treat poorly controlled diabetes. In this case, II-SG is also called the neuroendocrine brake.50 The sleeve gastrectomy is performed and then the jejunum is divided with a linear stapler 50 cm distal to the ligament of Treitz. The distal ileum is divided 30 cm proximal to the ileocecal valve. Subsequently, the ileum is divided a further 170-200 cm proximally. This segment of ileum is interposed with the proximal jejunum and anastomosed in an isoperistaltic fashion. Then three enteroanastomoses are performed to complete the operation: ileoileostomy,

After 5-year follow up, the EWL associated with II-SG is 60%. It is still unclear what percentage of the total weight loss that each part of the operation is responsible for and this requires further investigation. The rate of diabetes remission is reported at 84%.51 The potential complications of II-SG combine complications of small bowel bypass and SG. The incidence of complications after II-SG is approximately 0.8-2.0% and they include gastric and anastomotic leak, intestinal obstruction, internal hernia, gastric sleeve stricture, GI bleed

**10.1 Weight loss & complications**

duodenal stump blowout and dumping syndrome.48

**11. Ileal Interposition with Sleeve Gastrectomy**

jejunoileostomy, ileojejunostomy (see Figure 8).

Fig. 8. Ileal Interposition with Sleeve Gastrectomy

**11.1 Weight loss & complications**

and nutritional deficiencies.52

#### **9.2 Complications**

Dedicated, long term follow up with nutritional counseling is essential. Patients are educated on the importance of a protein rich, low-carbohydrate diet and the necessity of life-time daily vitamin supplementation which includes iron, calcium, vitamin B12, folate, and a multivitamin. Separate fat soluble vitamin supplementation is also necessary.44-46

As with the gastric bypass, other significant complications include bleeding and leaks. Leaks can occur at a number of locations including the gastrectomy site, the anastomosis of the ileum to the duodenum or at the distal Roux-en-Y. These complications require the attention of the knowledgeable and astute physician for diagnosis and management. Internal hernias can also occur if mesenteric defects are not closed or if they reopen after significant weight loss.47

#### **10. Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass**

Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass (LSG-DJB) was introduced as a valuable bariatric procedure. The advantage of not having an excluded stomach after SG eliminates the need for technically complicated double-balloon enteroscopy used for surveillance of the excluded stomach after a RYGB. This advantage and the potential significant durable weight loss has made LSG-DJB a very popular surgical intervention in Asia, where the incidence of gastric cancer has been high and obesity is now on the rise.48 The sleeve gastrectomy is performed, then the first portion of the duodenum is mobilized and subsequently divided with a linear cutting stapler. The biliopancreatic limb is measured to a distance of 150-200 cm and, at this location the small intestine is divided with a linear cutting stapler. A jejunojejunostomy is created, after which the mesenteric defect is closed. A gastrojejunostomy is created in an end-to-side fashion with the distal limb to restore intestinal continuity (see Figure 7). This procedure combines both restrictive and malabsorptive components to achieve weight loss.

Fig. 7. Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass

#### **10.1 Weight loss & complications**

14 Advanced Bariatric and Metabolic Surgery

Dedicated, long term follow up with nutritional counseling is essential. Patients are educated on the importance of a protein rich, low-carbohydrate diet and the necessity of life-time daily vitamin supplementation which includes iron, calcium, vitamin B12, folate, and a multivitamin. Separate fat soluble vitamin supplementation is also necessary.44-46

As with the gastric bypass, other significant complications include bleeding and leaks. Leaks can occur at a number of locations including the gastrectomy site, the anastomosis of the ileum to the duodenum or at the distal Roux-en-Y. These complications require the attention of the knowledgeable and astute physician for diagnosis and management. Internal hernias can also occur if mesenteric defects are not closed or if they reopen after

Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass (LSG-DJB) was introduced as a valuable bariatric procedure. The advantage of not having an excluded stomach after SG eliminates the need for technically complicated double-balloon enteroscopy used for surveillance of the excluded stomach after a RYGB. This advantage and the potential significant durable weight loss has made LSG-DJB a very popular surgical intervention in Asia, where the incidence of gastric cancer has been high and obesity is now on the rise.48 The sleeve gastrectomy is performed, then the first portion of the duodenum is mobilized and subsequently divided with a linear cutting stapler. The biliopancreatic limb is measured to a distance of 150-200 cm and, at this location the small intestine is divided with a linear cutting stapler. A jejunojejunostomy is created, after which the mesenteric defect is closed. A gastrojejunostomy is created in an end-to-side fashion with the distal limb to restore intestinal continuity (see Figure 7). This procedure combines both restrictive and

**10. Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass**

**9.2 Complications**

significant weight loss.47

malabsorptive components to achieve weight loss.

Fig. 7. Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass

Short term EWL after LSG-DJB is comparable to EWL after LRYGB.49 However, long-term data is lacking as this procedure is relatively new. Complications specific for LSG-DJB include bleeding, leak, stenosis at any of the anastomotic sites, marginal ulceration, duodenal stump blowout and dumping syndrome.48

#### **11. Ileal Interposition with Sleeve Gastrectomy**

Ileal Interposition with Sleeve Gastrectomy (II-SG) is another operation that has been performed outside of the United States. It was one of many bariatric operations to treat morbid obesity, but also is used in non-obese patients with BMI 21-29 kg/m2 to treat poorly controlled diabetes. In this case, II-SG is also called the neuroendocrine brake.50 The sleeve gastrectomy is performed and then the jejunum is divided with a linear stapler 50 cm distal to the ligament of Treitz. The distal ileum is divided 30 cm proximal to the ileocecal valve. Subsequently, the ileum is divided a further 170-200 cm proximally. This segment of ileum is interposed with the proximal jejunum and anastomosed in an isoperistaltic fashion. Then three enteroanastomoses are performed to complete the operation: ileoileostomy, jejunoileostomy, ileojejunostomy (see Figure 8).

Fig. 8. Ileal Interposition with Sleeve Gastrectomy

#### **11.1 Weight loss & complications**

After 5-year follow up, the EWL associated with II-SG is 60%. It is still unclear what percentage of the total weight loss that each part of the operation is responsible for and this requires further investigation. The rate of diabetes remission is reported at 84%.51 The potential complications of II-SG combine complications of small bowel bypass and SG. The incidence of complications after II-SG is approximately 0.8-2.0% and they include gastric and anastomotic leak, intestinal obstruction, internal hernia, gastric sleeve stricture, GI bleed and nutritional deficiencies.52

Surgical Procedures to Achieve Weight Loss 17

[13] Oria HE. Reporting Results in Obesity Surgery: Evaluation of a Limited Survey. Obes

[14] Nguyen NT, Ho HS, Palmer LS, Wolfe BM: A comparison study of laparoscopic verses

[15] Nguyen NT, Goldman C, Rosenquist CJ, et al: Laparoscopic versus open gastric bypass:

[16] Gentileschi P, Kini S, Catarci M, Gagner M: Evidence-based medicine: open and

[17] Buchwald H, Buchwald JN. Evolution of operative procedures for the management of

[19] Mason EE. Vertical banded gastroplasty for morbid obesity. Arch Surg 1982; 117:701-706 [20] Sugarman HJ, Starkey JV, Birkenhauer R. A randomized prospective trial of gastric

[21] Van Hout GC, Jakimowicz JJ, Fortuin FA, et al. Weight loss and eating behavior following vertical banded gastroplasty. Obes Surg. 2007 Sep; 17(9):1226-34 [22] Kalfarentzos F, Kechagias I, Soulikia K, et al. Weight loss following vertical banded

[23] Blackburn GL, Hu FB, Harvey AM, Evidence-based recommendations for best practices

[24] Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and

[25] Balsiger BM, Poggio, JL, Mai J, et al. Ten and more years after vertical banded

[26] Del Amo DA, Diez MM, Guedea ME, et al. Vertical banded gastroplasty: is it a durable

[27] Regan JP, Inabnet WB, Gagner M, et al. Early experience with two-stage laparoscopic

[28] Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and

[29] Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Langer FB,

[30] Arias E, Martinez PR, Ka Ming Li V, Szomstein S, Rosenthal RJ. Mid-term Follow-up

[31] Laparoscopic sleeve gastrectomy as a single-stage procedure for the treatment of

operation for morbid obesity? Obes Surg. 2004 Apr; 14(4):536-8

Luger A, Ludvik B, Prager G. Obes Surg. 2005;15(7):1024).

(2011) 25:2498-2504, DOI 10.1007/s00464-011-1572-x

laparoscopic bariatric surgery. Surg Endosc 2002; 16(5):736-744

[18] Buchwald H. Overview of bariatric surgery. J Am Coll Surg 2002; 194:367-375

morbid obesity 1950-2000. Obes Surg 2002; 12:705-717

sweet versus non-sweet eaters. Ann Surg 1987;205:613-624

in weight loss surgery. 2005;13:203.Obes Res

Alexandrides TK Ann Surg. 2008;247(3):401.

meta-analysis. 2004;292(14):1724.JAMA

open gastric bypass for morbid obesity. J Am Coll Surg 2000; 191:149-155;

a randomized study of outcomes, quality of life and costs. Ann Surg 2001; 234:279-

bypass versus vertical banded gastroplasty for morbid obesity and their effects on

gastroplasty: intermediate results of a prospective study. Obes Surg. 2001 Jun;

gastroplasty as primary operation for morbid obesity. J Gastrointest Surg. 2000

Roux-en-Y gastric bypass as an alternative in the super-super obese patient. Obes

peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Karamanakos SN, Vagenas K, Kalfarentzos F,

Reza Hoda MA, Bohdjalian A, Felberbauer FX, Zacherl J, Wenzl E, Schindler K,

after Sleeve Gastrectomy as a Final Approach for Morbid Obesity. Obes Surg. 2009

morbid obesity and the resulting quality of life, resolution of comorbidities, food tolerance, and 6-year weight loss. Mathieu D`Hondt et al, Surgical Endoscopy

Surg. 1996 Aug; 6 (4):361-368

discussion 155-157

11(3):265-70

Nov-Dec; 4(6):598-605

Surg 2003 Dec; 13(6)861-4

May; 19(5):544-8

289; discussion 289-291

#### **11.2 Conclusion**

Weight loss surgery has been in evolution since the very beginning with the introduction of the JIB. The GB was introduced in the 1960's. Various gastroplasties were in common practice in the 1970s. We returned to the GB in the 1980's given the failure of the gastroplasties. The Scopinaro procedure (BPD) was introduced in the 1979. Modifications of the BPD were introduced in the 1980's. The 1990's brought us the AGBs. The SG became a distinct entity unto itself in the early 21st century and is the newest contender on the field. Finally, we have briefly described two other operations that are not widely used in the U.S. but may become much more common in the future. Not one operation has met all the needs of every patient and as such the search continues for the ultimate operation which will be performed using minimally invasive techniques and produce outstanding and sustainable weight loss with a limited complication profile.

#### **12. References**

Weight loss surgery has been in evolution since the very beginning with the introduction of the JIB. The GB was introduced in the 1960's. Various gastroplasties were in common practice in the 1970s. We returned to the GB in the 1980's given the failure of the gastroplasties. The Scopinaro procedure (BPD) was introduced in the 1979. Modifications of the BPD were introduced in the 1980's. The 1990's brought us the AGBs. The SG became a distinct entity unto itself in the early 21st century and is the newest contender on the field. Finally, we have briefly described two other operations that are not widely used in the U.S. but may become much more common in the future. Not one operation has met all the needs of every patient and as such the search continues for the ultimate operation which will be performed using minimally invasive techniques and produce outstanding and sustainable

[1] Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and trends in overweight among US

[2] Guss SS, Chumlea WC. Tracking of body mass index in children in relation to overweight in adulthood. Am J Clin Nutr. 1999;70(suppl):145S-145S. [3] National Heart, Lung, and Blood Institute (NHLBI) and National Institute for Diabetes

[4] Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery.

Obese Subjects Study Scientific Group, N Engl J Med. 2004;351(26):2683. [5] Ten-year trends in health-related quality of life after surgical and conventional treatment

[6] Swedish obese subjects (SOS)--an intervention study of obesity. Two-year follow-up of

[7] Wang Y, Beydoun MA. The obesity epidemic in the United States—gender, age,

[8] Baskin ML, Ard J, Franklin F, Allison DB. Prevalence of obesity in the United States.

[10] NIH Conference: Gastrointestinal surgery for severe obesity: Consensus Development

[11] Bult MJ, van Dalen T, Muller AF. Surgical treatment of obesity. Eur J Endocrinol.

[12] Dixon JB, McPhail T, O'Brien PE. Minimal reporting requirements for weight loss:

and Digestive and Kidney Diseases (NIDDKD). Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. The

Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjöström CD, Sullivan M, Wedel H, Swedish

for severe obesity: the SOS intervention study. Karlsson J, Taft C, Rydén A,

health-related quality of life (HRQL) and eating behavior after gastric surgery for severe obesity. Karlsson J, Sjöström L, Sullivan M, Int J Obes Relat Metab Disord.

socioecomomic, racial/ethinic and geographic characteristics: a systematic review

children and adolescents, 1999–2000. JAMA 2002; 288:1728–1732).

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Sjöström L, Sullivan M, Int J Obes (Lond). 2007;31(8):1248.

and meta-regression analysis. Epidemiol Rev. 2007; 29:6-28

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[9] Korenkov M. Bariatric surgery. Contrib Nephrol. 2006; 151:243-53

Conference Statement 1991: March 25-27; 9(1)

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**11.2 Conclusion**

**12. References**

1998;22(2):113.

Obes Rev.2005 Feb; 6(1):5-6

2008Feb; 158(2):135-45

weight loss with a limited complication profile.

**2**

**Effect of Obesity**

*Department of Molecular Sciences,*

John N. Fain

*USA*

**on Circulating Adipokines and Their**

**of Female Bariatric Surgery Patients**

 *University of Tennessee Health Science Center, Memphis,*

**Expression in Omental Adipose Tissue**

This chapter is a review of the effects of excessive, formerly known as morbid, obesity on circulating levels and gene expression of adipokines and related factors in the visceral omental adipose tissue of women undergoing bariatric surgery. The current paradigm is that most of the deleterious metabolic effects of excessive obesity are due to Type 2 diabetes and/or hypertension secondary to the mild inflammatory process resulting from visceral adiposity. The visceral adipose tissue, which is primarily omental fat, acts as an endocrine tumor secreting adipokines that result in hypertension and diabetes. These deleterious effects are

The circulating levels and gene expression in fat of many adipokines are affected by excessive obesity. However, a major problem is determining which adipokine alterations are causally related and which are secondary effects of the inflammatory state seen in obesity. Many reports have focused on only one adipokine and suggested that it has a causal relationship but at least 40 adipokines have been linked to excessive obesity by one or more investigators. The relative role of each of these adipokines in human obesity is discussed in this review. It should be noted that the term adipokine refers to any factor, including cytokines, whose circulating levels are affected by release from either the fat or nonfat cells

reversible after bariatric surgery due to a massive reduction in adipose tissue mass.

**2. The deleterious effects of human obesity are secondary to enhanced**

i. it plays a key role in the pathogenesis of the deleterious metabolic consequences of

iii. most intra-abdominal fat is omental fat. The omentum also has a central role in an inflammatory response that involves macrophages in defending against peritonitis

**1. Introduction**

of human adipose tissue.

obesity and

**accumulation of visceral adipose tissue**

The visceral omental fat of women is important because

ii. women comprise 80 to 90% of bariatric surgery patients and

### **Effect of Obesity on Circulating Adipokines and Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients**

John N. Fain *Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, USA*

#### **1. Introduction**

18 Advanced Bariatric and Metabolic Surgery

[32] Laparoscopic sleeve gastrectomy: surgical technique, indications and clinical results.

[33] Laparoscopic sleeve gastrectomy: a multi-purpose bariatric operation. Baltasar A, Serra C, Pérez N, Bou R, Bengochea M, Ferri L, Obes Surg. 2005;15(8):1124 [34] Dixon JB, O'Brien PE. Selecting the optimal patient for the Lap-Band placement. Am J

[35] O'Brien PE, Dixon JB. Weight loss and early and late complications-the international

[36] Kuzmak LI. A review of seven years' experience with silicon gastric banding. Obes Surg

[37] Belachew M, Legrand MJ, Defechereux TH, et al. Laparoscopic adjustable silicone

[38] Buchwald H, Rucker RD. The rise and fall of jejunoileal bypass. In: Nelson RL, Nyhus

[40] Brolin RE, Kenler HA, Gorman JH, et al. Long-limb gastric bypass in the superobese;

[41] Wittgrove AC, Clark GW, Tremblay LJ. Laparoscopic gastric bypass, Roux-en-Y:

[42] Sensitivity and specificity of eight CT signs in the preoperative diagnosis of internal

[44] Scopinaro N, Gianetta E, Civalleri D, et al. Bilio-pancreatic bypass for obesity: II. Initial

[45] Hess DW, Hess DS. Biliopancreatic diversion with a duodenal switch. Obes Surg, 1998;

[46] Marceau P, Hould FS, Simard S, et al: (1998) Biliopancreatic diversion with duodenal

[47] Gagner M. Laparoscopic Bilipancreatic Diversion with Duodenal Switch. In: Inabnet

[48] Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass: Technique and Preliminary Results. Kazunori Kasama et al, Obes. Surg. 2009. 19:1341-1345 [49] Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass: Technique and Preliminary Results. Kazunori Kasama et al, Obes. Surg. 2009. 19:1341-1345. [50] DePaula AL, Macedo ALV, Rassi N, Machado CA, Schraibman, V, Silva LQ, Halpern H

[51] Systematic review of sleeve gastrectomy as staging and primary bariatric procedure. Brethhauer SA, Hammel JP, Schauer PR, Surg Obes Relat Diseas. 2009;5:469-75 [52] Surgical Treatment of Morbid Obesity: Mid term outcomes of the Laparoscopic Ileal

Philadelphia, PA: Lippincott Williams & Wilkins; 2005; 133-142

WB, Demaria EJ, Ikrammuddin S, eds. Laparoscopic Bariatric Surgery.

(2008) Laparoscopic treatment of type 2 diabetes mellitus for patients with a body

Interposition Associated to a Sleeve Gastrectomy in 120 Patients. Aureo L DePaula

gastric banding in the treatment of morbid obesity: a preliminary report. Surg

LM, eds. Surgery of the small intestine. Norwalk, CT: Appleton Century Crofts;

mesenteric hernia following Roux-en-Y gastric bypass surgery. Iannuccilli JD, Grand D, Murphy BL, Evangelista P, Roye GD, Mayo-Smith W. Clin Radiol. 2009;64(4):373) [43] Rogula T, Yenumula PR, Schauer PR. A complication of Roux-en-Y bypass: intestinal

Rodríguez A, Burgos AM, Brunet L, Obes Surg.,2007;17(11):1442

Surg 2002; 184:17S-20S

Endosc 1994; 8:1354-1356

1991; 1:403-408

1987; 529-541

8:267-282

experience. Am J Surg 2002; 184:42S-45S

[39] Gastric bypass. Mason EE, Ito C, Ann Surg. 1969;170(3):329

obstruction. Surg Endosc 2007 Nov; 21(11):1914-8

experience in man. Br J Surg 1979; 66:618-620

mass index less than 35. Surg Endosc 22:706–16

et al, Obesity surgery (2011), 21:668-675

switch. Word J Surg 1998; 947-954

apropective randomized study. Ann Surg 1992; 215:387-395

preliminary report of five cases. Obes Surg 1994; 4:353-357

Braghetto I, Korn O, Valladares H, Gutiérrez L, Csendes A, Debandi A, Castillo J,

This chapter is a review of the effects of excessive, formerly known as morbid, obesity on circulating levels and gene expression of adipokines and related factors in the visceral omental adipose tissue of women undergoing bariatric surgery. The current paradigm is that most of the deleterious metabolic effects of excessive obesity are due to Type 2 diabetes and/or hypertension secondary to the mild inflammatory process resulting from visceral adiposity. The visceral adipose tissue, which is primarily omental fat, acts as an endocrine tumor secreting adipokines that result in hypertension and diabetes. These deleterious effects are reversible after bariatric surgery due to a massive reduction in adipose tissue mass.

The circulating levels and gene expression in fat of many adipokines are affected by excessive obesity. However, a major problem is determining which adipokine alterations are causally related and which are secondary effects of the inflammatory state seen in obesity. Many reports have focused on only one adipokine and suggested that it has a causal relationship but at least 40 adipokines have been linked to excessive obesity by one or more investigators. The relative role of each of these adipokines in human obesity is discussed in this review. It should be noted that the term adipokine refers to any factor, including cytokines, whose circulating levels are affected by release from either the fat or nonfat cells of human adipose tissue.

#### **2. The deleterious effects of human obesity are secondary to enhanced accumulation of visceral adipose tissue**

The visceral omental fat of women is important because

Effect of Obesity on Circulating Adipokines and

and secretory phospholipase A2 [PLA2] (Table 1).

protein expression is not equivalent to gene expression.

circulating hormones.

**Circulating levels are elevated in obesity**

Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients 21

for their assay and this is a special problem with regard to TNF and IL-1. These adipokines may be very important in the inflammatory response seen in obesity but they primarily act as local autocrine or paracrine mediators of inflammation rather than as

The effects of obesity and coronary artery disease on circulating levels of 16 adipokines are summarized in Table 1. The coronary artery disease patients were 16 individuals undergoing coronary artery bypass surgery. They had an average BMI of 30.1 and were compared with 12 controls undergoing open heart surgery for other reasons. The controls had a BMI of 27.3 and were younger than the coronary artery disease patients. The data were adjusted for age which eliminated effect of CAD on circulating levels of IL-8 and osteoprotegerin leaving only CD14 and adipsin as adipokines affected by coronary artery disease (Sacks et al., 2011). In contrast, obesity over the BMI range of 38 to 66 [mean was 50], in women undergoing bariatric surgery increased the circulating levels of adipsin, FABP4,

Adipsin Adipsin CD-163 IL-8 NGF FABP4 CD14 sFLT1 Lipocalin-2 RANTES IL-1Ra GPX-3 MCP-1 IL-10

sPLA2 ZAG Osteoprotegerin Table 1. Comparison of effects of obesity versus CAD on circulating levels of 17 adipokines. The effects of severe coronary artery disease (CAD) are taken from the report by (Sacks et al., 2011) while the data for obese women is for the same circulating adipokines with significant positive correlation coefficients [Pearson r of 0.51] between waist circumference and circulating levels in 12-23 bariatric surgery patients not taking drugs for hypertension with BMI values ranging from 38 to 66 and waist circumference from 107 to 168 cm (Fain, 2011).

Only with IL-1Ra was a significant positive correlation seen between waist circumference and circulating levels as well as mRNA expression in omental fat of severely obese female bariatric patients (Fain, 2011). There was no significant correlation between waist circumference and mRNA level for FABP4, adipsin, & PLA2 in omental fat (Fain, 2011). Circulating levels of adipsin, FABP4 & PLA2 correlated with waist circumference but not with mRNA levels in omental fat. These data suggest that if mRNA levels in omental fat are equivalent to protein expression, then the circulating levels are not regulated solely by omental fat mRNA expression. It may well be that the source of these adipokines is other fat depots. Alternatively the data could be interpreted as compatible with the hypothesis that

I have examined the effects of obesity in women on gene expression of almost all the putative adipokines discussed in the next section, except for CRP, which is not released by human fat (Fain, 2006). I found significant positive correlations between waist circumference and mRNA levels in human omental fat for 4 of the 40 proteins: amyloid A [r = 0.57], PAI-1 [r = 0.53], IL-1Ra [r = 0.45] and leptin [r = 0.48] (Fain, 2011).

**Circulating levels are not elevated by excessive obesity or CAD**

**Circulating levels are elevated in CAD**

(Platell et al., 2000). In obesity per se, this macrophage infiltration into the omentum may result in an enhanced inflammatory response that promotes insulin resistance and ultimately diabetes/hypertension and it has been reported that omentectomy in connection with open bariatric surgery resulted in an enhanced insulin sensitivity as compared to patients undergoing open bariatric surgery without omentectomy (Thorne et al., 2002).

Extreme obesity results in increased risk for hypertension and/or diabetes (Cottam et al., 2004, Pories, 2008, Sugerman et al., 2003). The type 2 diabetes is reversible since, after weight loss of approximately 40 kg or more due to bariatric surgery, the diabetes disappears in over 80% of humans (Pories, 2008; Sugerman et al., 2003). Not all extremely obese individuals develop diabetes or hypertension and for these individuals there is no increased risk of morbidity (Livingston & Ko, 2005). However, there is increasing evidence that the accumulation of visceral omental fat is associated with the development of diabetes/hypertension (Despres & Lemieux, 2006). It is recognized that waist circumference is an effective and inexpensive measure of visceral fat accumulation (Scherzer et al., 2008; Shen et al., 2006) and is a better predictor of coronary heart disease than is BMI (Canoy et al., 2007; Despres et al., 2008; Pischon et al, 2008).

#### **3. Most release of adipokines is by the nonfat cells in human adipose tissue except for leptin**

Originally it was postulated that most of the adipokine release by adipose tissue was due to the fat cells but it is now clear that leptin is the only adipokine released exclusively by the fat cells. In fact, over a 48h incubation, the release of leptin was 1800% of that by the nonfat cells derived from the same amount of human adipose tissue, while that of adiponectin, amyloid proteins 1&2, haptoglobin and NGF was only 64, 144, 75 and 72% respectively of that by nonfat cells (Fain, 2006). Release of MIF and PAI-1 by fat cells was 37 and 23% of that by nonfat cells while that of cathepsin S, HGF, IL-1, IL-1Ra, IL-6, IL-8, IL-10 MCP-1, TGF- 1, VCAM-1 and VEGF was 12% or less of that by nonfat cells (Fain, 2006). Clearly, the majority of the inflammatory adipokines are released by the nonfat cells of human adipose tissue, which is hardly surprising since per g of fat in obese women two-thirds of the cells are nonfat cells (Fain, et al., 2006) and it is established that obesity is accompanied by macrophage infiltration into human adipose tissue (Weisberg et al., 2003; Xu et al., 2003).

#### **4. Relationship between circulating levels of adipokines and obesity**

There is evidence that the circulating levels of many adipokines are elevated in obesity (Fain, 2010). Since the deleterious effects of obesity on diabetes is reversed in over 80% of the patients after bariatric surgery which reduced the BMI from above 45 to 35 or less (Pories, 2008), it is clear that the appropriate criteria for correlating decreases or increases in circulating adipokines is what happens over the range of BMI values from 30 to 70. Another way of assessing effects of obesity is to examine which adipokines show decreases in their circulating levels after bariatric surgery. An additional problem with regard to circulating adipokines is that the circulating levels of some are either at or below the limits of sensitivity

Extreme obesity results in increased risk for hypertension and/or diabetes (Cottam et al., 2004, Pories, 2008, Sugerman et al., 2003). The type 2 diabetes is reversible since, after weight loss of approximately 40 kg or more due to bariatric surgery, the diabetes disappears in over 80% of humans (Pories, 2008; Sugerman et al., 2003). Not all extremely obese individuals develop diabetes or hypertension and for these individuals there is no increased risk of morbidity (Livingston & Ko, 2005). However, there is increasing evidence that the accumulation of visceral omental fat is associated with the development of diabetes/hypertension (Despres & Lemieux, 2006). It is recognized that waist circumference is an effective and inexpensive measure of visceral fat accumulation (Scherzer et al., 2008; Shen et al., 2006) and is a better predictor of coronary heart disease than is BMI (Canoy et al., 2007; Despres et al., 2008; Pischon et al, 2008).  Most release of adipokines is by the nonfat cells in human adipose tissue**

Originally it was postulated that most of the adipokine release by adipose tissue was due to the fat cells but it is now clear that leptin is the only adipokine released exclusively by the fat cells. In fact, over a 48h incubation, the release of leptin was 1800% of that by the nonfat cells derived from the same amount of human adipose tissue, while that of adiponectin, amyloid proteins 1&2, haptoglobin and NGF was only 64, 144, 75 and 72% respectively of that by nonfat cells (Fain, 2006). Release of MIF and PAI-1 by fat cells was 37 and 23% of that by nonfat cells while that of cathepsin S, HGF, IL-1, IL-1Ra, IL-6, IL-8, IL-10 MCP-1, TGF- 1, VCAM-1 and VEGF was 12% or less of that by nonfat cells (Fain, 2006). Clearly, the majority of the inflammatory adipokines are released by the nonfat cells of human adipose tissue, which is hardly surprising since per g of fat in obese women two-thirds of the cells are nonfat cells (Fain, et al., 2006) and it is established that obesity is accompanied by macrophage infiltration into human adipose tissue (Weisberg et al., 2003; Xu et al., 2003).

**4. Relationship between circulating levels of adipokines and obesity**

There is evidence that the circulating levels of many adipokines are elevated in obesity (Fain, 2010). Since the deleterious effects of obesity on diabetes is reversed in over 80% of the patients after bariatric surgery which reduced the BMI from above 45 to 35 or less (Pories, 2008), it is clear that the appropriate criteria for correlating decreases or increases in circulating adipokines is what happens over the range of BMI values from 30 to 70. Another way of assessing effects of obesity is to examine which adipokines show decreases in their circulating levels after bariatric surgery. An additional problem with regard to circulating adipokines is that the circulating levels of some are either at or below the limits of sensitivity

mass as measured by bioelectrical impedance (Madan et al., 2006).

et al., 2002).

**except for leptin**

(Platell et al., 2000). In obesity per se, this macrophage infiltration into the omentum may result in an enhanced inflammatory response that promotes insulin resistance and ultimately diabetes/hypertension and it has been reported that omentectomy in connection with open bariatric surgery resulted in an enhanced insulin sensitivity as compared to patients undergoing open bariatric surgery without omentectomy (Thorne for their assay and this is a special problem with regard to TNF and IL-1. These adipokines may be very important in the inflammatory response seen in obesity but they primarily act as local autocrine or paracrine mediators of inflammation rather than as circulating hormones.

The effects of obesity and coronary artery disease on circulating levels of 16 adipokines are summarized in Table 1. The coronary artery disease patients were 16 individuals undergoing coronary artery bypass surgery. They had an average BMI of 30.1 and were compared with 12 controls undergoing open heart surgery for other reasons. The controls had a BMI of 27.3 and were younger than the coronary artery disease patients. The data were adjusted for age which eliminated effect of CAD on circulating levels of IL-8 and osteoprotegerin leaving only CD14 and adipsin as adipokines affected by coronary artery disease (Sacks et al., 2011). In contrast, obesity over the BMI range of 38 to 66 [mean was 50], in women undergoing bariatric surgery increased the circulating levels of adipsin, FABP4, and secretory phospholipase A2 [PLA2] (Table 1).

Table 1. Comparison of effects of obesity versus CAD on circulating levels of 17 adipokines. The effects of severe coronary artery disease (CAD) are taken from the report by (Sacks et al., 2011) while the data for obese women is for the same circulating adipokines with significant positive correlation coefficients [Pearson r of 0.51] between waist circumference and circulating levels in 12-23 bariatric surgery patients not taking drugs for hypertension with BMI values ranging from 38 to 66 and waist circumference from 107 to 168 cm (Fain, 2011).

Only with IL-1Ra was a significant positive correlation seen between waist circumference and circulating levels as well as mRNA expression in omental fat of severely obese female bariatric patients (Fain, 2011). There was no significant correlation between waist circumference and mRNA level for FABP4, adipsin, & PLA2 in omental fat (Fain, 2011). Circulating levels of adipsin, FABP4 & PLA2 correlated with waist circumference but not with mRNA levels in omental fat. These data suggest that if mRNA levels in omental fat are equivalent to protein expression, then the circulating levels are not regulated solely by omental fat mRNA expression. It may well be that the source of these adipokines is other fat depots. Alternatively the data could be interpreted as compatible with the hypothesis that protein expression is not equivalent to gene expression.

I have examined the effects of obesity in women on gene expression of almost all the putative adipokines discussed in the next section, except for CRP, which is not released by human fat (Fain, 2006). I found significant positive correlations between waist circumference and mRNA levels in human omental fat for 4 of the 40 proteins: amyloid A [r = 0.57], PAI-1 [r = 0.53], IL-1Ra [r = 0.45] and leptin [r = 0.48] (Fain, 2011).

Effect of Obesity on Circulating Adipokines and

demonstrated but these are intriguing possibilities.

is no evidence that circulating levels of ACE are altered in obesity.

**5.4 Angiotensin converting enzyme (ACE)**

**5.3 Amyloid A**

**5.5 Angiotensinogen**

Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients 23

found in murine adipocytes and circulating levels were lower in several animal models of obesity (Rosen et al., 1989). However, Napolitano et al., (1994) found that in humans just the opposite was seen in that circulating levels of adipsin positively correlated with the extent of obesity. I found a similar correlation between circulating adipsin and BMI but there was no effect of obesity on the gene expression of adipsin in omental adipose tissue of obese women (Fain, 2011). The complement system is an essential element in our innate defense system and it is possible that the increase in adipsin/complement D seen in human obesity is a reflection of an enhanced inflammatory response to obesity. What accounts for the elevations in

The serum amyloid A proteins are major acute-phase reactants released by the liver whose circulating levels increase dramatically in inflammation and obesity (Poitou et al., 2005; 2006; Yang et al., 2006a). Circulating levels of amyloid A (Yang et al., 2006a) as well as gene expression in adipose tissue (Yang et al., 2006a; Fain, 2011) correlated with BMI. In fact of over 100 genes whose expression was correlated in omental adipose tissue with BMI, the highest positive correlation was seen for amyloid A (Fain 2011). A major expression site of Amyloid A is adipose tissue, which is postulated to contribute to circulating levels (Poitou et al., 2005; Sjoholm et al., 2005) and Yang et al (2006a) have suggested that amyloid A is both a proinflammatory and lipolytic adipokine in humans. Whether this is the case remains to be

ACE is a zinc metallopeptidase that cleaves the C-terminal dipeptide from angiotensin I to form Angiotensin II. The presence of the major components of the renin-angiotensin system in human adipose tissue has led to the suggestion that its regulation and function are involved in the hypertension linked to visceral adiposity (Giacchetti et al., 2002). The circulating levels of ACE are unchanged in obesity as is its gene expression in adipose tissue of humans but there is a positive correlation with blood pressure (Gorzelniak et al, 2002). It has been difficult to get evidence for a key role of ACE but recently it was reported that ACE inhibition using captopril treatment of mice on a high fat diet reduced the extent of obesity and the expression of markers of inflammation in murine adipose tissue (Premaratna et al. 2011). Lee at al (2008a) reported that in obese rats, angiotensin receptor blockade reduced insulin resistance by modification of adipose tissue metabolism. Abuissa et al (2005) demonstrated that anti-hypertensive agents such as ACE inhibitors or angiotensin receptor blockers can reduce the onset of diabetes in humans by approximately 25%. However, there

This protein is made in large quantities by the liver and secreted into the circulation where it can be cleaved by renin and/or cathepsin D to form angiotensin I. Karlsson et al (1998) demonstrated that angiotensinogen is also made in adipose tissue and is enriched in adipocytes, which was confirmed by Fain et al., (2008a). The reason for this is still not well understood but it could be a link between obesity and hypertension. Gorzelniak et al (2002) reported that angiotensinogen gene expression in human subcutaneous adipocytes was

circulating adipsin/complement D in obesity is unclear, but it is an obesity marker.

#### **5. Individual adipokines**

The following sections discuss 40 putative adipokines listed in alphabetical order that have been linked to obesity and inflammation. It should be noted that correlations between waist circumference or BMI and circulating levels of any protein indicate only that the protein is a marker molecule rather than the maker of obesity. In view of the many known circulating marker molecules for obesity, caution should be exercised and direct proof demanded before any causal relationship is established. Furthermore, most reports are linked to a particular molecule and the professional careers of the authors are directly linked to their ability to persuade others that the particular marker of interest to them is causally linked to obesity.

#### **5.1 Adiponectin**

Adiponectin is a protein that circulates at relatively high levels in humans and is related to the C1q complement factor.  Within 10 years of its discovery adiponectin was accepted as an anti-diabetic, anti-atherosclerotic and anti-inflammatory agent secreted by adipocytes whose low levels in obesity were related to the insulin-resistance in obesity (Trujillo & Scherer, 2005). While the circulating levels of most adipokines are elevated in obesity, this is not the case for adiponectin whose circulating levels negatively correlate with BMI values between 18 and 30, but in males there was no further drop in circulating adiponectin at BMI values above 32 (Arita et al., 1999). Negative effects of obesity on circulating adiponectin have been reported comparing individuals with mean BMI values of 27 versus 35 by Engeli et al., (2003) and by Hoffstedt et al., (2004) comparing humans with BMI values of 24 versus 37. One complexity with regard to circulating levels of adiponectin (Hung et al., 2008) and leptin (Thomas et al., 2000) is that they are both higher in women than in men but the significance of this is not yet understood.

Elevated concentrations of circulating adiponectin have been associated with a lower incidence of type 2 diabetes (Li et al., 2009; Zhu et al., 2010). However, circulating adiponectin is actually positively correlated with all cause mortality as well as cardiovascular mortality in type 2 diabetics (Forsblom et al., 2011). In another study Luc et al., (2010) found no correlation between total circulating adiponectin and cardiovascular disease in men enrolled in the PRIME study. Elevated levels of adiponectin have also been associated with stroke mortality (Nagasawa et al, 2011). Clearly low adiponectin levels in plasma of obese individuals may not necessarily be linked to increased mortality or development of type 2 diabetes and are not consistently seen. I conclude that adiponectin is not produced solely by fat cells and the function of adiponectin remains to be elucidated as well as whether it is causally linked to the development of type 2 diabetes in obesity. It may just be a unique marker of obesity whose levels are sometimes, but not always, lower in obesity.

#### **5.2 Adipsin/complement D**

Adipsin is another name for complement factor D that is a novel serine protease whose only known substrate is another complement serine protease known as factor B (Volanakis and Narayan, 1996). Complement factor D was re-discovered and named adipsin since it was found in murine adipocytes and circulating levels were lower in several animal models of obesity (Rosen et al., 1989). However, Napolitano et al., (1994) found that in humans just the opposite was seen in that circulating levels of adipsin positively correlated with the extent of obesity. I found a similar correlation between circulating adipsin and BMI but there was no effect of obesity on the gene expression of adipsin in omental adipose tissue of obese women (Fain, 2011). The complement system is an essential element in our innate defense system and it is possible that the increase in adipsin/complement D seen in human obesity is a reflection of an enhanced inflammatory response to obesity. What accounts for the elevations in circulating adipsin/complement D in obesity is unclear, but it is an obesity marker.

#### **5.3 Amyloid A**

22 Advanced Bariatric and Metabolic Surgery

The following sections discuss 40 putative adipokines listed in alphabetical order that have been linked to obesity and inflammation. It should be noted that correlations between waist circumference or BMI and circulating levels of any protein indicate only that the protein is a marker molecule rather than the maker of obesity. In view of the many known circulating marker molecules for obesity, caution should be exercised and direct proof demanded before any causal relationship is established. Furthermore, most reports are linked to a particular molecule and the professional careers of the authors are directly linked to their ability to persuade others that the particular marker of interest to them is causally linked to

Adiponectin is a protein that circulates at relatively high levels in humans and is related to the C1q complement factor.  Within 10 years of its discovery adiponectin was accepted as an anti-diabetic, anti-atherosclerotic and anti-inflammatory agent secreted by adipocytes whose low levels in obesity were related to the insulin-resistance in obesity (Trujillo & Scherer, 2005). While the circulating levels of most adipokines are elevated in obesity, this is not the case for adiponectin whose circulating levels negatively correlate with BMI values between 18 and 30, but in males there was no further drop in circulating adiponectin at BMI values above 32 (Arita et al., 1999). Negative effects of obesity on circulating adiponectin have been reported comparing individuals with mean BMI values of 27 versus 35 by Engeli et al., (2003) and by Hoffstedt et al., (2004) comparing humans with BMI values of 24 versus 37. One complexity with regard to circulating levels of adiponectin (Hung et al., 2008) and leptin (Thomas et al., 2000) is that they are both higher in women than in men but the

Elevated concentrations of circulating adiponectin have been associated with a lower incidence of type 2 diabetes (Li et al., 2009; Zhu et al., 2010). However, circulating adiponectin is actually positively correlated with all cause mortality as well as cardiovascular mortality in type 2 diabetics (Forsblom et al., 2011). In another study Luc et al., (2010) found no correlation between total circulating adiponectin and cardiovascular disease in men enrolled in the PRIME study. Elevated levels of adiponectin have also been associated with stroke mortality (Nagasawa et al, 2011). Clearly low adiponectin levels in plasma of obese individuals may not necessarily be linked to increased mortality or development of type 2 diabetes and are not consistently seen. I conclude that adiponectin is not produced solely by fat cells and the function of adiponectin remains to be elucidated as well as whether it is causally linked to the development of type 2 diabetes in obesity. It may just be a unique marker of obesity whose levels are sometimes, but not always, lower in

Adipsin is another name for complement factor D that is a novel serine protease whose only known substrate is another complement serine protease known as factor B (Volanakis and Narayan, 1996). Complement factor D was re-discovered and named adipsin since it was

**5. Individual adipokines**

obesity.

obesity.

**5.2 Adipsin/complement D**

**5.1 Adiponectin**

significance of this is not yet understood.

The serum amyloid A proteins are major acute-phase reactants released by the liver whose circulating levels increase dramatically in inflammation and obesity (Poitou et al., 2005; 2006; Yang et al., 2006a). Circulating levels of amyloid A (Yang et al., 2006a) as well as gene expression in adipose tissue (Yang et al., 2006a; Fain, 2011) correlated with BMI. In fact of over 100 genes whose expression was correlated in omental adipose tissue with BMI, the highest positive correlation was seen for amyloid A (Fain 2011). A major expression site of Amyloid A is adipose tissue, which is postulated to contribute to circulating levels (Poitou et al., 2005; Sjoholm et al., 2005) and Yang et al (2006a) have suggested that amyloid A is both a proinflammatory and lipolytic adipokine in humans. Whether this is the case remains to be demonstrated but these are intriguing possibilities.

#### **5.4 Angiotensin converting enzyme (ACE)**

ACE is a zinc metallopeptidase that cleaves the C-terminal dipeptide from angiotensin I to form Angiotensin II. The presence of the major components of the renin-angiotensin system in human adipose tissue has led to the suggestion that its regulation and function are involved in the hypertension linked to visceral adiposity (Giacchetti et al., 2002). The circulating levels of ACE are unchanged in obesity as is its gene expression in adipose tissue of humans but there is a positive correlation with blood pressure (Gorzelniak et al, 2002). It has been difficult to get evidence for a key role of ACE but recently it was reported that ACE inhibition using captopril treatment of mice on a high fat diet reduced the extent of obesity and the expression of markers of inflammation in murine adipose tissue (Premaratna et al. 2011). Lee at al (2008a) reported that in obese rats, angiotensin receptor blockade reduced insulin resistance by modification of adipose tissue metabolism. Abuissa et al (2005) demonstrated that anti-hypertensive agents such as ACE inhibitors or angiotensin receptor blockers can reduce the onset of diabetes in humans by approximately 25%. However, there is no evidence that circulating levels of ACE are altered in obesity.

#### **5.5 Angiotensinogen**

This protein is made in large quantities by the liver and secreted into the circulation where it can be cleaved by renin and/or cathepsin D to form angiotensin I. Karlsson et al (1998) demonstrated that angiotensinogen is also made in adipose tissue and is enriched in adipocytes, which was confirmed by Fain et al., (2008a). The reason for this is still not well understood but it could be a link between obesity and hypertension. Gorzelniak et al (2002) reported that angiotensinogen gene expression in human subcutaneous adipocytes was

Effect of Obesity on Circulating Adipokines and

**5.9 C reactive protein [CRP]**

**5.10 Endothelin-1**

endothelial cells.

**5.11 Fatty acid binding protein 4 [FABP-4]**

Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients 25

circulating levels of CD 14 (Fain, 2011; Manco et al., 2007) despite the fact that release of CD14 by explants of human omental adipose tissue was enhanced in fat from obese individuals (Fain

CRP is a prototypical acute phase protein released by the liver and its circulating levels can increase by 10,000-fold within hours of infection or injury. Recently CRP has been proposed as a predictive biomarker for cardiovascular disease risk although it has poor predictive value in humans (Levinson et al., 2004). Yudkin et al., (1999) originally reported that obesity is associated with elevated release of IL-6 by human adipose tissue and enhanced circulating levels of IL-6 and CRP. These results have been confirmed by Festa et al., (2001), Hanusch-Enserer et al., (2003) and Maachi et al., (2004). There is virtually no synthesis of CRP by adipose tissue and the small amount of release seen in vitro could be due to release of CRP taken up from the circulation (Fain, 2006). CRP levels in humans correlate with those of serum amyloid (Larsson and Hansson, 2003) suggesting that both are inflammatory markers released by the liver in response to the low-grade inflammation induced by obesity. At least for CRP in mice there is direct evidence that it is not involved in the development of atherosclerosis,

clearly indicating that it is a marker not a maker of atherosclerosis (Nilsson, 2005).

Endothelin is a potent vasoconstrictor peptide that is released by endothelial cells. Yudkin (2007) pointed out that obese humans show endothelial dysfunction that may be due to vascular insulin resistance. Takahashi et al., (1990) had earlier reported that circulating levels of endothelin-1 are 3-fold higher in diabetics than in non-diabetic humans. Van Harmelen et al., (2008) reported that the release of endothelin-1 by subcutaneous adipose tissue in vivo was greater in obese individuals and that endothelin blocked the anti-lipolytic action of insulin in omental but not subcutaneous adipocytes. Gogg et al., (2009) subsequently reported that in microvascular endothelial cells isolated from subcutaneous adipose tissue of type 2 diabetics, insulin action was impaired at the level of IRS-1 and the PI 3-kinase pathways. They suggested that enhanced endothelin-1 was responsible for this impairment. These results suggest that studies should be designed to test the hypothesis that impaired insulin action in obesity is secondary to enhanced endothelin-1 release by

FABP4 is a member of a family of lipid chaperone proteins that bind with high affinity hydrophobic ligands such as long chain fatty acids (Furuhashi et al., 2008). FABP4 is also known as aP2 and appears to be involved in the movement of fatty acid out of the fat cell during lipolysis (Coe et al., 1999). In the absence of FABP4 there is enhanced accumulation of fatty acids in fat cells (Coe et al., 1999) and reduced expression of inflammatory cytokines in macrophages (Furahashi et al, 2008). Hotamisligil et al., (1996) reported that in FABP4 knockout mice, obesity still developed on a high-fat diet but insulin resistance or diabetes was not seen. These data support the hypothesis that the link between obesity and inflammation in adipose tissue is enhanced lipolysis and free fatty acid release seen in the enlarged fat cells that accumulate in obese animals. In the absence of FABP4 the release of

et al., 2010). I conclude that circulating CD 14 is not an obesity marker.

negatively correlated with the BMI of the adipocyte donors and this may be an adaptive response to reduce angiotensin II formation in obesity. Angiotensinogen gene expression has consistently been reported to be lower in subcutaneous than in omental adipose tissue of humans (Giacchetti et al., 2002, van Harmelen et al., 2000; Fain, 2010) but the significance of this is also unknown. However, this might be linked to the deleterious effects of visceral obesity on the development of hypertension and diabetes in obese humans but the role of angiotensinogen made in fat is unclear.

#### **5.6 Apelin**

Apelin is a novel bioactive peptide that is the endogenous ligand of the orphan G proteincoupled receptor AJP (Masri et al., 2005; Castan-Laurell et al., 2011). The circulating levels of apelin and leptin are elevated in obesity but unlike leptin, the gene expression of apelin is found to the same extent in both nonfat and fat cells of human adipose tissue (Boucher et al., 2005; Heinonen et al., 2005). The apelin receptor is expressed on the surface of T lymphocytes and endothelial cells (Masri et al., 2005) and the enhanced levels seen in obesity may reflect release by nonfat cells of fat. A null mutation of the apelin receptor in mice had little effect except for an enhanced vasopressor response to apelin (Ishida et al., 2004). Hung et al (2011) found that inhibitors of the renin-angiotensin system enhanced the secretion of apelin by adipocytes. Fain (2011) found that extremely obese women taking anti-hypertensive agents had decreased expression of apelin in their omental adipose tissue that was accompanied by an enhanced expression of the renin receptor and CD150/SLAMF-1. These data suggest a counter regulatory role of apelin signaling to that of the angiotensin with regard to blood pressure regulation in humans.

#### **5.7 Cathepsin S**