Advances in the surgical treatment of morbid obesity

Advances in the surgical treatment of morbid obesity

JMAM 528 No. of Pages 11, Model 3G 26 October 2012 Molecular Aspects of Medicine xxx (2012) xxx–xxx 1 Contents lists available at SciVerse ScienceD...

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JMAM 528

No. of Pages 11, Model 3G

26 October 2012 Molecular Aspects of Medicine xxx (2012) xxx–xxx 1

Contents lists available at SciVerse ScienceDirect

Molecular Aspects of Medicine journal homepage:




Advances in the surgical treatment of morbid obesity



Margaret Stefater a, Rohit Kohli b, Thomas Inge a,⇑ a

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Division of Pediatric and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States

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Article history: Available online xxxx

a b s t r a c t Due to the rapidly expanding prevalence of obesity, bariatric surgery is becoming an increasingly popular treatment option. Bariatric surgeries including Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) produce long-term weight loss and metabolic improvement, reducing mortality. This review discusses the important benefits and risks of RYGB and VSG, highlighting hypothesized mechanisms for these effects. We present data suggesting that VSG, albeit a newer procedure, may be as effective as RYGB with fewer adverse effects including less surgical risk, reduced nutritional deficiency, and less incidence of dumping syndrome. This may position VSG as an increasingly important procedure, particularly for the treatment of pediatric obesity. Ó 2012 Elsevier Ltd. All rights reserved.



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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important clinical benefits of RYGB and VSG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. RYGB and VSG produce early and potent improvements in glucose metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. RYGB and VSG improve cardiovascular risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Other benefits of Bariatric surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . As yet unknown possible long-term side effects of Bariatric surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Surgical morbidity and mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Risk for postoperative nutritional deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Adverse effects of Bariatric surgery on bone mineral density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Gastroesophageal reflux disease following gastric volume reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Dumping syndrome and hypoglycemia following bariatric surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pediatric morbid obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Q3 1. Introduction Lifestyle interventions including diet and exercise have traditionally been used for the treatment of overweight and obesity, but it is becoming increasingly clear that these modalities are falling short in reversing the obesity problem in this nation. More than two-thirds of Americans are overweight or obese (Flegal et al., 2010), and it is estimated that half of the U.S. ⇑ Corresponding author. E-mail address: [email protected] (T. Inge). 0098-2997/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.

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population will meet criteria for obesity by the year 2030 (Wang et al., 2008), leading to a decrease in lifespan in the US (Fontaine et al., 2003). BMI predicts mortality risk (Greenberg, 2001), reflecting an association between obesity and multiple comorbidities including but not limited to type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), kidney failure, pulmonary disease, and cancer. Treatment of obesity is a major challenge, however. Diet and exercise have limited efficacy, usually resulting in regain of body weight over time (Anderson et al., 2001; Kraschnewski et al., 2010; Leibel et al., 1995; Schwartz et al., 2003; Weiss et al., 2007), due to powerful central mechanisms that seek to defend body weight against voluntary weight loss attempts. Pharmacologic treatment of obesity is plagued by limited efficacy and severely limited drug choices (Bray, 2008). Bariatric surgery, on the other hand, is gaining increasing popularity for its ability to produce potent and long-term changes in body weight. Additionally, bariatric surgery reduces overall mortality despite surgical risks (Adams et al., 2007; Sjostrom et al., 2007). Increasingly, studies have shown that Roux-en-Y gastric bypass (RYGB) is an effective long-term treatment for obesity (Buchwald et al., 2009; Pories et al., 1995) and, until recently, was arguably the most effective procedure to produce weight loss and metabolic improvement in obese patients. In recent years, several newer, minimally invasive procedures have emerged with similar efficacy to RYGB. The most popular among these newer procedures are the adjustable gastric band (AGB) and the vertical sleeve gastrectomy (VSG). While RYGB includes both transection of the stomach to create a small stomach pouch and diversion of the alimentary stream to bypass the duodenum, VSG and AGB do not involve intestinal manipulation. Specifically, in VSG procedures, generous portions of gastric fundus, body, and antrum are removed resulting in an 80–85% reduction of stomach volume (Marceau et al., 1998). AGB is a silicon band with an inner circular balloon that is placed around the stomach and filled with saline to produce a desired level of gastric restriction (Miller and Hell, 2003). Of these procedures, RYGB and VSG are the most effective procedures in the short term (1 year) (Benaiges et al., in press; Lakdawala et al., 2010), while some data suggest that weight loss due to application of AGB may be comparable over a 5 year period (O’Brien et al., 2006). Other conflicting data have shown that both RYGB and VSG achieve a superior level of weight loss as compared to AGB, a difference which is maintained over long periods of time (Franco et al., 2011). Furthermore, resolution of T2DM is superior following RYGB as compared with AGB (Buchwald et al., 2009), whereas similar improvements in glucose tolerance have been observed following VSG and RYGB in morbidly obese people (de Gordejuela et al., 2011; Woelnerhanssen et al., in press). For these reasons, RYGB and VSG are increasing in popularity. Although VSG is a newer procedure for which less longitudinal data are available, it is becoming increasingly accepted as an alternative to RYGB for the treatment of obesity and metabolic syndrome. Indeed, this acceptance is based on emerging data suggesting that VSG is as effective as RYGB for improvement in body weight and metabolic health, and speculation that this operation will produce fewer adverse effects due to less anatomic manipulation and no intestinal diversion. Here, we review clinical findings as well as basic science studies describing the effects of RYGB and VSG. The objective of this review is to compare and contrast the effects of the two procedures and to highlight important mechanisms that underlie these outcomes.


2. Important clinical benefits of RYGB and VSG


2.1. RYGB and VSG produce early and potent improvements in glucose metabolism


An important consequence of long-standing obesity is insulin resistance and progressively worsening glucose tolerance, predisposing to T2DM. Insulin resistance can be reduced or even reversed in response to weight loss, but this reversal takes time and recurs if weight loss is not durable (Weinstock et al., 1998). As a powerful weight loss tool, bariatric surgery effectively improves insulin resistance as well as T2DM. In fact, these improvements are greater than those expected for the observed level of weight loss. Interestingly, resolution of diabetes is more dramatic following procedures involving intestinal diversion than following AGB (Buchwald et al., 2009), strongly suggesting a complex interplay between gastric, intestinal, adipose, and pancreatic function to mediate the dramatic effects on carbohydrate metabolism. RYGB improves glucose tolerance both in patients with diabetes and with impaired glucose tolerance (Pories et al., 1995). Glycemic improvement following RYGB is superior to dieting alone (Laferrere et al., 2008). Remarkably, improvement can be seen within days of operation, prior to any significant weight loss (Rubino et al., 2004). These findings provide evidence that RYGB acts to improve glucose homeostasis via specific enteroendocrine mechanisms. Postulated mechanisms include reduced levels of gastric inhibitory protein (GIP) and enhanced production of the antidiabetic hormone glucagon-like peptide (GLP)-1 (Korner et al., 2007). GLP-1 is a 30 amino acid product of the preproglucagon (PPG) gene and is produced by L-cells of the intestine, mainly the ileum. As an incretin, this molecule participates in crosstalk between the gut and pancreas, with the main action of GLP-1 to stimulate insulin secretion from pancreatic beta cells (Fehmann et al., 1995). However, GLP-1 is also known to act in the CNS to inhibit appetite (Donahey et al., 1998). GLP-1 release depends on nutrient delivery to the hindgut (Herrmann et al., 1995; Layer et al., 1995). Consistent with a greater improvement in diabetes following intestinal procedures than AGB (Korner et al., 2007, 2009), it might be predicted that procedures altering the flow of nutrients to the ileum would have the most profound impact on GLP-1 secretion. This principle is referred to as the ‘‘hindgut hypothesis,’’ which states that more rapid delivery of nutrients to the distal small intestine following RYGB may be a mechanism for enhanced enteroendocrine hormone release and, therefore, to aspects of metabolic improvement such as improved glucose homeostasis. Consistent

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with this hypothesis, fasting GLP-1 levels were unaltered after RYGB as compared with control subjects (Korner et al., 2007, 2009). On the other hand, postprandial GLP-1 levels were markedly increased in RYGB patients. Thirty minutes following a mixed meal challenge 6 and 12 months after surgery, GLP-1 levels were3-fold higher after RYGB than after AGB (Korner et al., 2009). This trend has also been observed in weight-stable RYGB and AGB patients of variable but matched postoperative duration (Korner et al., 2007). GIP is another key component of the enteroendocrine system that may affect glucose tolerance by modulating insulin secretion. GIP is secreted from duodenal K cells and is secreted in response to intestinal glucose. As for GLP-1, the main effect of RYGB on GIP is nutrient-driven. Minimal changes to fasting GIP secretion have been observed after RYGB, but RYGB blunts postprandial GIP secretion (Korner et al., 2007). Improved glycemic control following RYGB could represent either enhanced insulin secretion, one effect of the incretins, or improved insulin action. One recent study suggests that improved insulin resistance following RYGB is due to increased skeletal muscle and liver insulin receptor expression, enhanced GLUT4 expression in skeletal muscle and adipose tissue, increased levels of phosphorylated insulin receptor in liver, and increased levels of phosphorylated IRS-1 and IRS-2 in skeletal muscle and liver (Bonhomme et al., 2011). Consistent with this report, improved insulin-mediated glucose disposal has been demonstrated via euglyemic clamp 4 and 14 months after RYGB (Pereira et al., 2003). However, another recent study demonstrated improved fasting insulin and glucose levels only one week following RYGB surgery, despite persistent insulin resistance (Reed et al., 2011). This latter study suggests that very early changes in carbohydrate metabolism following RYGB may more likely be due to changes in postprandial insulin secretion secondary to increased incretin release. The effects of RYGB on glucose homeostasis are thought to be due to changes in intestinal anatomy which alter nutrientdriven enteroendocrine function. VSG does not involve any intestinal manipulation but, surprisingly, produces dramatic improvements in glycemic control which are remarkably comparable to those observed after RYGB. Specifically, changes to fasting blood glucose and HOMA index are comparable as early as 1 week and persisting for at least 52 weeks after VSG and RYGB (Woelnerhanssen et al., in press). (Peterli et al., 2009) demonstrated greater post operative augmentation of insulin release one week after RYGB versus VSG. However, comparable insulin secretion was observed 3 months after surgery. It is unclear what differences between the two procedures might be responsible for this difference in kinetics of insulin secretory changes, but emerging mammalian data suggest that effects on the enteroendocrine axis might underlie the ability for both RYGB and VSG to improve glucose tolerance and glycemic control. Similar to what is observed following RYGB, postprandial GLP-1 secretion is enhanced following VSG in humans (Peterli et al., 2009) and in rats (Chambers et al., 2011). This response is, in fact, similar in magnitude and kinetics to what has been observed for RYGB. In a study directly comparing the two procedures, enhanced GLP-1 secretion was observed as early as 10 days following both VSG and RYGB (Peterli et al., 2009). This effect has also been shown in rats and is greater than what is expected for the level of weight loss at this time (Chambers et al., 2011). Interestingly, meal-stimulated secretion of the intestinal peptide YY (PYY) is also increased 1 week and 3 months following both VSG and RYGB (Peterli et al., 2009), but it is yet unclear how PYY might act to improve glucose homeostasis. What is increasingly apparent, however, is that VSG and RYGB elicit metabolic improvement through similar changes at the level of the intestinal enteroendocrine system and suggest a common denominator between these procedures that may be related to neuroendocrine interactions between the foregut and hindgut L cell function.


2.2. RYGB and VSG improve cardiovascular risk


Given the importance of cardiovascular (CV) disease as a leading cause of morbidity and mortality in obese patients, an ideal treatment plan should target not only body weight and glucose metabolism but also should reduce CV risk. CV events are collectively the leading cause of death in the U.S.(Heron et al., 2009), likely reflecting the prevalence of obesity in this country. Obesity increases the risk of CV disease (Rimm et al., 1995), perhaps as a result of obesity-related dyslipidemia and atherosclerosis. Specifically, obesity is associated with high total cholesterol, LDL, and triglycerides and with low levels of HDL (Howard et al., 2003). One important benefit of bariatric surgery is to reduce CV risk. Framingham risk scores indicate reduced 10-year risk for CV disease in patients who have had RYGB (Arterburn et al., 2009; Torquati et al., 2007). A similar effect might be predicted for VSG, as both RYGB (Zlabek et al., 2005) and VSG (Karamanakos et al., 2008) can correct plasma lipid derangements associated with obesity. Both procedures are also associated with reduced systolic as well as diastolic blood pressure (Iannelli et al., 2011; Sjostrom et al., 2004; Vidal et al., 2008). These and other changes may translate into improved CV function after surgery, as one study has documented improved left ventricular ejection fraction and reduced New York Heart Association classification in a group of patients who underwent various bariatric procedures including VSG and RYGB (McCloskey et al., 2007). RYGB in adolescents reduces left ventricular hypertrophy while improving diastolic function (Ippisch et al., 2008). However, these parameters have not yet been investigated in VSG patients, thus precluding a valid comparison between the two procedures. Weight loss itself clearly contributes to metabolic and CV improvement following bariatric surgery, but findings suggest that some procedures may produce weight-independent CV benefits. For example, RYGB and VSG elicit comparable weight loss, but appear to have disparate effects on plasma lipid profiles. Although both procedures comparably reduce plasma triglycerides (Benaiges et al., in press; Woelnerhanssen et al., in press), variable data suggest that RYGB may produce more dramatic improvement to total cholesterol and LDL levels (Benaiges et al., in press). However, HDL appears to be improved to a

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similar degree following these two procedures (Benaiges et al., in press; Woelnerhanssen et al., in press), perhaps contributing to an improved total cholesterol-to-HDL cholesterol ratio in each case (Woelnerhanssen et al., in press). Supporting the hypothesis that disparate effects of RYGB and VSG result from specific physiologic outcomes of each surgery, it was recently demonstrated that VSG elicits potent postprandial and weight-independent reductions in plasma triglyceride levels in rats (Stefater et al., 2011). The effect is thought to be due to attenuation of intestinal triglyceride secretion following VSG. It is yet unclear whether RYGB may have similar, weight-independent effects on lipid homeostasis. Fat malabsorption can occur following bariatric surgery (Kumar et al., 2011) and, when present, could certainly contribute to postoperative correction of dyslipidemia. Although increased fecal fat has been documented following RYGB, it is unclear what role malabsorption may play, if any, to reduce plasma lipid levels since steatorrhea is not a commonly reported effect of RYGB. Postprandial plasma triglyceride reduction following VSG occurs in the absence of malabsorption and is thought to be due to an independent effect of the surgery to affect intestinal triglyceride secretion(Stefater et al., 2011), suggesting the possibility that RYGB may also have malabsorption-independent effects on lipid homeostasis. Obesity is characterized by chronic, systemic inflammation. Increasing evidence indicates that this type of inflammatory state might increase risk for CV disease. CRP is an acute-phase reactant which is, for poorly understood reasons, increased in obese individuals (Nakamura et al., 2008; Visser et al., 1999). Elevated CRP however is highly predictive of CV disease risk and may contribute to the production of atherosclerotic lesions (Ridker et al., 2000). One hypothesis is that bariatric surgery reduces CV risk by reducing systemic and or vascular inflammation, based on reduced CRP levels after both RYGB (Woodard et al., 2010) and VSG (Hakeam et al., 2009). In a study comparing VSG and RYGB patients with comparable postoperative weight loss, reduction in CRP was similar in magnitude at 6 and 12 months postoperatively (Iannelli et al., 2011). Other proinflammatory markers shown to be reduced after RYGB are Plasminogen Activator Inhibitor (PAI)-1, leptin, and fibrinogen (Brethauer et al., 2011). In contrast, the anti-inflammatory mediator adiponectin was shown to be increased following RYGB (Brethauer et al., 2011). Fibrinogen and PAI-1 levels have not been measured after VSG, but it is known that leptin levels decline (Stefater et al., 2010) and that adiponectin levels rise (Woelnerhanssen et al., in press) following the procedure. Although it is unknown whether RYGB and/or VSG have weight-independent actions to dampen systemic inflammation, reduced CRP levels appear to correlate with the degree of postoperative BMI reduction (Wong et al., 2011). On the other hand, plasma leptin reduction following both RYGB (Korner et al., 2006) and VSG (Stefater et al., 2010) exceeds what would be expected given the level of achieved weight loss, a finding which may be mediated in part by improved insulin sensitivity. Leptin is an adipokine which is known to elicit activation of the sympathetic nervous system through both neural and hormonal activation (Haynes et al., 1997; Satoh et al., 1998). Hyperleptinemia has been hypothesized to contribute to obesityrelated hypertension and resulting CV disease (Rahmouni and Haynes, 2004). No studies have yet examined whether RYGB and/or VSG elicit weight-independent improvements to CV function including blood pressure by interaction with the reninangiotensin system. Clearly, mechanisms by which VSG and RYGB improve CV health should be an important focus for future studies.


2.3. Other benefits of Bariatric surgery



In addition to the potent weight loss and metabolic benefits, bariatric procedures including RYGB and VSG dramatically improve quality of life, in part by reversing several other obesity-related comorbidities. For example, obstructive sleep apnea is improved following both RYGB and VSG (Chouillard et al., 2011). It is unclear what role the procedures play to produce weight-independent improvements versus which of these co-morbidities resolve due to the level of weight lost following surgery. In addition, obesity is strongly linked to the development of polycystic ovary syndrome (PCOS) due to insulin resistance (Gambineri et al., 2002). VSG may be useful for reducing body weight in women with PCOS, as demonstrated by one recent study using the DHT-induced rodent model of PCOS (Wilson-Perez and Seeley, in press). Although VSG did not reverse PCOS-related glucose intolerance in this model, the study raises important questions about whether VSG in humans might improve circulating androgen levels, ovarian cyclicity, and ultimately insulin sensitivity. Obesity, with or without T2DM, is associated with renal hyperfiltration which can lead to kidney failure (Chagnac et al., 2000). RYGB has been shown to improve glomerular but not tubular function (Saliba et al., 2010). The improved glomerular function was slower in diabetic patients, suggesting that glycemic control might play a role to mediate the improvement. RYGB in humans has been shown not only to improve all aspects of NAFLD including steatoheptatitis but to halt progression of fibrosis as well (Furuya et al., 2007). VSG in both humans (Karcz et al., 2011) and rats(Wang and Liu, 2009) has been shown to improve steatohepatitis, but no studies have looked specifically at whether VSG prevents the progression of hepatic fibrosis. We speculate that due to the growing popularity of RYGB and VSG, a rapidly expanding body of clinical data will allow for these missing analyses.


3. As yet unknown possible long-term side effects of Bariatric surgery


3.1. Surgical morbidity and mortality


An important aspect of the decision faced by a patient seeking surgical treatment for obesity is the risk inherent to each surgical procedure. VSG requires fewer suture lines than RYGB and no anastomoses, suggesting that postoperative

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complications may be reduced following VSG as compared with RYGB. However, although relatively uncommon, staple line dehiscence can occur following both RYGB (Arteaga et al., 2002) and VSG (Burgos et al., 2009) and can lead to significant morbidity and mortality. Mortality in general is rare following both RYGB and VSG. Major postoperative complications including hemorrhage, fistula, and obstruction can be seen with both procedures, although obstruction should be less common after VSG. Indeed, data suggest that morbidity may be less following VSG as compared with RYGB (Chouillard et al., 2011). According to a meta-analysis, rates of intraoperative conversion from laparoscopy to laparotomy may be increased during RYGB as compared with VSG. Complications including minor bleeding, infection, atelectasis, and superficial venous thrombosis were reported at a rate of 20.5% of RYGB patients versus 6.5% of VSG patients. These findings most likely underlie an increased duration of hospital stay following RYGB (Chouillard et al., 2011). Furthermore, although uncommon, reoperation was more common following RYGB than VSG. Another study found no significant differences in either complication rate or readmission rate following RYGB versus VSG (Benaiges et al., in press), perhaps reflecting differences in the criteria used to define ‘‘complication.’’ Clearly, more prospectively collected data are needed to fully understand the long-term and short-term safety of VSG versus RYGB. Efforts including the Longitudinal Assessment of Bariatric Surgery (LABS), a large prospective NIH-sponsored study of bariatric outcomes will inevitably contribute new knowledge to better inform medical decision-making in the future.


3.2. Risk for postoperative nutritional deficiencies


Intestinal bypass modestly reduces absorptive surface area following RYGB, but importantly removes the duodenal mucosa from the alimentary stream, providing a clear risk for development of specific postoperative micronutrient deficiencies. Nutritional deficiencies have indeed been observed following bariatric surgery and, in particular, after RYGB (Gehrer et al., 2010) and other diversionary operations such as duodenal switch. The fact that calcium, vitamin D, and iron deficiencies are common in obese patients prior to surgery (Bloomberg et al., 2005) further compounds the risks after surgery. Following bariatric surgery, patients experience dramatic dietary changes which certainly also influence nutritional status. While mild fat malabsorption can occur following RYGB (Kumar et al., 2011), deficiencies in the fat-soluble vitamins A, E, and K are very rare following this procedure (Gehrer et al., 2010). Vitamin D deficiency has been documented following RYGB (Gehrer et al., 2010) and malabsorption may play a role in this observation. In fact, cholecalciferol absorption may be reduced by 25% after RYGB (Aarts et al., 2011). Vitamin D absorption can lead to secondary hyperparathyroidism and contribute to greater bone turnover postoperatively, even in the presence of normal calcium levels. Therefore, indefinite vitamin D supplementation is a universal recommendation for all RYGB patients (Poitou Bernert et al., 2007). VSG does not produce fat malabsorption in rodents fed a high-fat diet (Stefater et al., 2010) and is not expected to occur in humans. Nevertheless the surgery is associated with low vitamin D levels (Gehrer et al., 2010). The prevalence of vitamin D deficiency is comparable following RYGB and VSG, but it is unclear whether a common mechanism(s) impairs vitamin D intake and/or absorption. Bioavailability of vitamin B12 is dependent on ileal absorption, gastric acid, and intrinsic factor (Schjonsby and Andersen, 1974). Due presumably to gastric exclusion or resection, vitamin B12 deficiency has been documented following both RYGB and VSG (Gehrer et al., 2010). Vitamin B12 deficiency may be more common following RYGB than VSG (Gehrer et al., 2010), perhaps reflecting a greater detrimental effect of gastroduodenal bypass (reduced action of proteases to release B12) with RYGB compared to partial gastric resection with VSG. Folic acid deficiency can occur following VSG and is slightly more common following VSG than RYGB (Gehrer et al., 2010). Because folic acid absorption depends on gastric acid secretion (Zhao et al., 2009), reduced folic acid absorption could perhaps be due to a more specific removal of acid-producing fundal tissue by VSG, versus the fundus-sparing RYGB procedure. Iron deficiency is an important cause of microcytic anemia and may lead to symptoms of fatigue, dyspnea, and exercise intolerance. Anemia is particularly important in young menstruating women, who may have low iron stores preoperatively. Iron deficiency has been observed following both VSG and RYGB (Gehrer et al., 2010). Reduced dietary intake, specifically reduced intake of red meats, might contribute to iron deficiency anemia after either VSG or RYGB. Additionally, because iron is primarily absorbed in the duodenum (Shayeghi et al., 2005), iron deficiency following RYGB clearly occurs at least in part secondary to the diversionary component. Duodenal absorption should remain intact following VSG, but reduced hydrochloric acid production secondary to partial gastrectomy might impair conversion of ferric (Fe3+) iron to the absorbable ferrous (Fe2+) form. Further studies are needed, however, to conclude how changes in hepatic inflammation, absorption, and iron intake differentially affect iron homeostasis in RYGB as compared to VSG. Other nutritional deficiencies are known to occur following both VSG and RYGB, such as zinc deficiency (Gehrer et al., 2010) and, rarely, vitamin B1 deficiency (Aarts et al., 2011; Tageja, 2010). These conditions can have wide-ranging yet devastating clinical effects, ranging from hair loss due to zinc deficiency to Wernicke’s encephalopathy or dry beriberi as we and others have shown in the case of low vitamin B1 (Towbin et al., 2004). While severe outcomes are rare, it is important to understand the nutritional consequences of these procedures. Few studies have attempted to quantify micronutrient absorption following each procedure. Little existing data describes the nutritional outcomes of VSG, and only one study (Gehrer et al., 2010) has compared the nutritional outcomes of VSG and RYGB. In order to more completely compare the safety of these two operations, an important goal for future clinical and basic research will be to explore mechanistic aspects of micronutrient processing, absorption, and bioavailability following each procedure.

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3.3. Adverse effects of Bariatric surgery on bone mineral density



A complex relationship links body weight to bone mineral density (BMD) (Soleymani et al., 2011), but in general higher BMI is correlated with greater BMD due to mechanical load-induced bone mineralization. Bariatric surgery not only reduces BMI but also affects the levels and action of several hormones known to affect bone metabolism. Bone loss has been documented following RYGB (Coates et al., 2004; Kaulfers et al., 2011; Mahdy et al., 2008; von Mach et al., 2004), an effect which is probably multifactorial. A recent report suggests that bone loss might be less pronounced after VSG than after RYGB, although this difference did not reach statistical significance (Nogues et al., 2010). Although the weight loss which occurs after bariatric surgery is a likely contributor to the physiologic loss of BMD postoperatively, subtle differences in BMD loss following VSG and RYGB suggest that other mechanisms are also responsible for the loss, given similar weight loss following the two procedures (Chouillard et al., 2011). Factors affecting BMD after bariatric surgery may include impaired calcium and/ or vitamin D absorption, differential effects on plasma ghrelin, and reduced circulating leptin levels. Bone metabolism is highly dependent upon adequate nutrition, especially the absorption and action of vitamin D. Despite recommended vitamin D supplementation, low vitamin D levels occur following both RYGB and VSG (Gehrer et al., 2010; Sinha et al., 2011). Calcium levels will be defended by the action of parathyroid hormone, at the expense of bone demineralization and, eventually, osteopenia (Talmage and Elliott, 1958). Vitamin D supplementation after RYGB has been shown to retard loss of BMD but may not completely abolish postoperative bone loss (Carlin et al., 2009), suggesting that other mechanisms may account for altered bone mineral turnover following surgery. Ghrelin is another hormone known to influence bone metabolism. Serum ghrelin levels predict bone density in obese children (Pacifico et al., 2009). This correlation is probably based on several mechanisms, including a direct effect of ghrelin to stimulate osteoblasts (Maccarinelli et al., 2005) and an important role of ghrelin to stimulate growth hormone release from the pituitary gland (Sun et al., 2004). Ghrelin is predominantly secreted by gastric mucosa (Kojima et al., 1999) and the role of this hormone in appetite, satiety, and regulation of lean mass (including bone mass) is a subject of intense investigation. Given that VSG largely removes the primary cellular source of ghrelin, the effects of VSG on ghrelin levels and ghrelin-mediated physiology are of significant research and clinical interest. Leptin is another hormone which is thought to affect BMD. Leptin is secreted from white adipose tissue as well as stomach tissue and acts in the CNS to reduce food intake. Leptin levels are very high in obese individuals (Maffei et al., 1995), as is associated with leptin resistance (El-Haschimi et al., 2000; Scarpace et al., 2001). Although a role for leptin in regulation of bone density is controversial (Ruhl and Everhart, 2002; Thomas et al., 2001), leptin is also known to inhibit growth hormone secretion (Carro et al., 1997) and therefore may promote bone density. Circulating leptin is reduced in a comparable manner following both VSG and RYGB (Woelnerhanssen et al., in press) and therefore by indirect mechanisms, reduced leptin levels following bariatric surgery may actually counteract the detrimental effects of bariatric surgery on BMD. In fact, reduction in leptin after RYGB in humans (Korner et al., 2006) and VSG in rats (Stefater et al., 2010) has been observed. Intriguingly, this reduction in leptin is more dramatic than expected for the observed level of weight loss, suggesting a potential advantage of certain bariatric procedures over weight loss alone. Although not studied with respect to RYGB, leptin action does not appear to mediate weight loss after VSG (Stefater et al., 2010). However, irrespective of any role in weight regulation postoperatively, changes to plasma leptin levels following bariatric procedures may influence BMD. It is important to determine and compare the long-term effects of currently-used bariatric surgical procedures on BMD. Many of these questions remain unanswered, and a future understanding of the mechanisms responsible for BMD changes following each procedure are likely to reveal important principles regarding the differing mechanisms of action of each operation.


3.4. Gastroesophageal reflux disease following gastric volume reduction


Obesity is an independent risk factor for gastroesophageal reflux disease (GERD) (El-Serag et al., 2005; Friedenberg et al., 2008; Hampel et al., 2005), a disease with serious consequences including esophageal adenocarcinoma. GERD has been reported in up to 70% of patients evaluated for bariatric surgery(Braghetto et al., 2010; Soricelli et al., 2010). Weight loss alone may or may not improve GERD (Kjellin et al., 1996). However, GERD often improves following RYGB (Merrouche et al., 2007). VSG, on the other hand, is associated with both persistent GERD and may increase the risk of new-onset GERD (Carter et al., in press). It has been speculated that increased intragastric pressure following VSG may predispose to increased GERD symptoms. Currently, objective data documenting GERD severity before and after VSG in humans are elusive. Although GERD is a common problem, affecting two-thirds of patients one month after surgery, it is resolved in most patients within 2 years (Weiner et al., 2007). GERD symptoms may be biphasic, with early symptoms and a second peak between 3 and 6 years postoperatively due to development of a ‘‘neofundus’’ and to enhanced acid production (Himpens et al., 2010). Reduced pressure at the lower esophageal sphincter has also been reported and is thought to contribute to GERD symptoms following VSG (Braghetto et al., 2010), perhaps due to surgical manipulation of the gastroesophageal junction, the angle of His, or the phrenoesophageal ligament. Additionally, altered gastric emptying may affect esophageal sphincter function and therefore the incidence of GERD postoperatively, but studies investigating neither gastric emptying nor manometry following VSG have reached consensus. On the other hand, some patients with preoperative GERD may experience resolution postoperatively (Himpens et al., 2006; Nocca et al., 2008), implying either that mechanisms which produce GERD after VSG are not universal or that heterogeneity of surgical technique is responsible for difference observed. We anticipate that a greater future under-

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standing of gastric function following VSG and RYGB will lead to greater treatment options for GERD post-VSG and, perhaps, to the refinement of surgical techniques so as to avoid postoperative GERD.


3.5. Dumping syndrome and hypoglycemia following bariatric surgery


Dumping syndrome is cluster of gastrointestinal and vasomotor symptoms which occurs following meal ingestion and which is a consequence of pyloroplasty procedures as well as gastrojejunostomy, as performed during RYGB (Abell and Minocha, 2006; Mallory et al., 1996). In one study, 44% of RYGB patients reported symptoms of dumping syndrome following an oral glucose load. Dumping syndrome is highly correlated with the ingestion of sweet foods, leading to the speculation that RYGB might be particularly effective at reducing caloric intake in those who crave sweet foods. Two phases of dumping, ‘‘early’’ and ‘‘late,’’ may occur and refer to two separate syndromes. Early dumping is due to accelerated gastric emptying and may include GI symptoms such as abdominal pain, bloating, diarrhea, and nausea as well as vasomotor symptoms such as facial flushing, palpitations, tachycardia, perspiration, hypotension, and even syncope (Tack et al., 2009). Until recently, it was unknown whether VSG might be associated with symptoms of dumping syndrome. Reports documenting gastric emptying following VSG are inconsistent, some demonstrating accelerated gastric emptying (Braghetto et al., 2009; Melissas et al., 2007), but other data conflict with these reports. Recently, however, Tzovaras et al. (2011) reported symptoms of early dumping syndrome in nearly half of a cohort of VSG patients tested 6 weeks postoperatively. This is the only study to date examining symptoms of dumping in VSG patients, but it suggests that VSG might have mechanisms of action which are more similar to RYGB than previously thought. Late dumping syndrome occurs 1 to 3 h following meal ingestion and is due to reactive hypoglycemia (Tack et al., 2009). Symptoms of late dumping syndrome include tremors, palpitation, confusion, and syncope. Severe postprandial hypoglycemia and hyperinsulinemia, or nesidioblastosis, is a rare complication of RYGB and is related to pancreatic islet hyperplasia and hypertrophy (Cummings, 2005; Service et al., 2005). Because hypoglycemia is a late complication of RYGB, occurring 1 to 5 years after surgery, it has been suggested that a slow, progressive process is responsible (Cummings, 2005; Service et al., 2005). Histologically, beta cell volume and nuclear diameter are increased, reflecting both hyperplasia and hypertrophy (Meier et al., 2006). Furthermore, ectopic location of beta cells in the pancreatic parenchyma, outside of the islet of Langerhans, has been reported in one patient (Rabiee et al., 2011). Enhanced GLP-1 secretion has been proposed to underlie these changes (Cummings, 2005), as GLP-1 is known to have proliferative and antiapoptotic properties at the level of the beta cell (Farilla et al., 2002; Xu et al., 1999). Consistent with this hypothesis, a case report demonstrates in a RYGB patient increased


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Table 1 Physiologic changes after RYGB and VSG. "/;: increased/decreased levels or incidence. +: observed phenomenon. ?: not yet studied.

Glucose metabolism Insulin sensitivity Postprandial GLP-1 Postprandial GIP Plasma lipids HDL Total cholesterol (TC) TC: HDL LDL Systemic inflammation CRP PAI-1 Fibrinogen Leptin Adiponectin Obstructive sleep apnea Renal glomerular function Steatohepatitis Hepatic fibrosis Nutrition Vitamin A deficiency Vitamin E deficiency Vitamin K deficiency Vitamin D deficiency Vitamin B12 deficiency Vitamin B1 deficiency Folic acid deficiency Iron deficiency Zinc deficiency Bone mineral density GERD



" " Blunted "

" " ?

" ; ; ;

" ; ; ;

; ; ; ; " ; improved ; ;

; ? ? ; " ; improved ; ;

rare rare rare + + + + + + ; ;

rare rare rare + + + + + + ; "

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pancreatic expression of PDX-1 (Rabiee et al., 2011), whose expression is important for beta cell growth and is enhanced by GLP-1. Gastrostomy tube feeding into the bypassed stomach remnant was used in one patient to successfully eliminate postprandial hypoglycemia and was found to be associated with accentuated postprandial insulin excursions, insulin-to-glucose ratios, GLP-1, and GIP, as compared with oral feeding (McLaughlin et al., 2010). Together, these data suggest that GLP-1 may have both immediate and long-term effects to promote postprandial insulin secretion. However, a causal link has not yet been established. In contrast, although postprandial GLP-1 secretion is also enhanced following VSG (Chambers et al., 2011; Peterli et al., 2009), very little data exist to document the existence of dumping syndrome following VSG, and no studies have compared the severity and kinetics of dumping symptom following VSG versus RYGB. In a study of 31 patients receiving VSG, only one patient was found to have reactive hypoglycemia following a glucose load (Tzovaras et al., 2011). Given similar changes to postprandial GLP-1 secretion (Chambers et al., 2011) the relative rarity of late dumping syndrome after VSG as compared with RYGB, suggests that postprandial hypoglycemia in RYGB may involve GLP-1 independent mechanisms as well. As the popularity of VSG is increasing, clinical studies should focus on better delineating possible adverse effects of the procedure. Although reactive hypoglycemia may be viewed as an undesirable adverse effect of RYGB surgery, both early and late dumping syndrome could contribute to voluntary changes in dietary composition and pattern following surgery, perhaps through aversion to sugar-sweetened foods. Thus, increased understanding of the relative effects of each procedure to produce dumping syndrome may not only allow for a comparison of the safety of each procedure, but might promote further understanding of the mechanisms for weight loss following RYGB and VSG.


4. Pediatric morbid obesity



Children have not been spared from the adverse effects of the obesity pandemic. In fact, 16.9% of children aged 2–19 years are obese, and as many as 3% of Caucasian and 5% of Latino and Black children have BMI values > 99th percentile (Ogden et al., 2010). These data highlight an urgent need for effective and safe treatments for obese children who are at risk of developing adult-like comorbidities of obesity at very young ages. Life expectancies for these children will be reduced in the absence of effective treatment. As early adult outcome data have been reported, VSG has been considered by increasing numbers of pediatric providers (Bondada et al., 2011; Inge and Xanthakos, 2010). Prospective clinical research studies such as the NIH-funded Teen-LABS ( may shed light on advantages and potential adverse effects of VSG and RYGB in children and will lay the groundwork for further mechanistic studies of these procedures in young populations.


5. Conclusions



For decades, RYGB has stood as an effective and durable operation for those suffering with clinically severe obesity. Considering the long-term risks of progressive, poorly-treated obesity, RYGB long been considered to have a favorable risk:benefit ratio. However, more recently VSG has gained popularity as an alternative to RYGB. Early data suggest weight loss efficacy comparable to RYGB and comorbidity improvement is also increasingly documented. VSG may accomplish these beneficial outcomes with less early surgical risk, reduced long-term postoperative nutritional risk, and possibly reduced late metabolic risks such as postprandial hypoglycemia when compared to RYGB (Table 1). VSG is a newer procedure and although less data are currently available to explain these effects, the anatomic advantages of less surgical manipulation with VSG are attractive for surgeons and patients alike. It is also becoming increasingly clear that VSG and RYGB may share at least some mechanisms of action to elicit metabolic and weight loss benefit. This argument diverges from the conventional line of thought which holds that non-diversionary procedures must exert effects by gastric restriction alone. Instead, like RYGB, VSG favorably affects production of gastrointestinal hormones believed to play a fundamental role in energy balance and metabolism in mammals. However, the data are as yet insufficient to fully understand the dynamic physiologic changes which occur following these procedures. We expect that the increasing popularity of bariatric surgery, the growth in NIHsupported studies of bariatric mechanisms, and the recent development of animal models of the most commonly used procedures will lead to an improved understanding of these myriad effects of these operations.



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