| Abstract |
Introduction
Obesity, nowadays, is considered to be a major health problem that has up-taken epidemic dimensions. It's been officially recognised as a disease since 1948, when the World Health Organisation, newly founded at the time, included it in the International Classification of Diseases. It is a constantly increasing problem, if one takes under consideration the increased morbidity and mortality of obese individuals, because of secondary diseases such as Diabetes Mellitus (44% obesity induced), Hypertension (23% obesity induced), Sleep Apnoea (15-50% obesity induced), as well as some forms of malignancy (a variant 7-41% is considered obesity induced or obesity related).
However, the very nature of obesity, as a disease, is completely different from any other. It depends on socio-economic and cultural factors to such an extend, as to consist a complex phenomenon of a social epidemic that evolves parallel to the development of every day life, especially involving the medial and lower social classes of the developed and developing Western civilisations.
So, it's exactly that unique profile that makes obesity the ideal target for a holistic approach to its therapeutic strategy in terms of conservative treatment. Unfortunately, because of the great heterogeneity of the population, something like that seems impossible, bringing society and the scientific world against a therapeutic challenge. And it all happened at the very moment when the surgical world was actually looking for new fields to expand and evolve into.
The combination of all of the above was the stimulation in the creation of Bariatric and Metabolic Surgery. It really seems that surgical treatment is the most effective way of treatment for morbid obesity in our disposition at the moment. The main reason for it is that, not only it ensures the best rate of excess weight loss, but it's also responsible for the improvement or even resolution of the obesity-associated morbidity.
Definition
Obesity is the increase of body weight above the standard ideal weight for a given height. It's measured and classified by several ways. However, the most popular one is the Body Mass Index (BMI), calculated through the relation of the body weight divided by the square of the height in kg/m2.
One of the observations in many of the body analysis studies done so far, is the fact that BMI correlates to the amount of body-fat (correlation coefficient >0.9) as well as to most of the laboratory methods to define body weight, therefore it is considered a very reliable index for obesity.
Background
Having weight-loss as a target, the initial thought was to invent operations that would result in food-and-calorie-intake restriction as the main means for weight loss. These interventions constituted the group of "Restrictive operations" with the pioneering Vertical Banded Gastroplasty (Mason's) leading the way, followed by the Intragastric Ballon and the Adjustable Gastric Banding. Initially, Sleeve Gastrectomy was also categorised as a restrictive operation, but that was not the case as proved later.
At a later stage the target was redefined to the final total calorie intake, so the interest was now turning towards the absorption mechanisms of the digestive pathway. Malabsorption was suddenly the main goal of a new group of surgical interventions, the "Malabsorptive Operations", including the Roux-en-Y Gastric Bypass (in several variations) and the Biliopancreatic Diversion (later evolved into Biliopancreatic Diversion with a Duodenal Switch as a variant). This group's operations are of grater gravity, fatally accompanied by increased intra-operative and post-operative morbidity and mortality.
Of course, in time, the fact that weight alone would not provide the necessary information concerning the gravity of obesity could not go unnoticed. So, attention was drawn to the body distribution of adipose tissue. It is now assumed that body fat distribution mirrors the balance between lipogenic and lipolytic actions, or even more so, the balance among the factors that influence those actions.
The discovery of leptin in 1994, a hormone produced and released by the adipose cells, was the main stimulus for the re-investigation of the adipose tissue, but as an endocrine organ this time. The most recent discoveries of resistin, of Acrp 30 (Adipocyte-complement-related-protein 30) and of the systemic activity of the insulin-regulated GLUT 4 (GLUcose Transporter type 4: transporter found primarily in the adipose tissue as well as in striated muscle), brought up the importance of adipose tissue in the pathophysiology of obesity related metabolic diseases. All these discoveries led to the gradual change of focus and interest from Bariatric Surgery, with main goal the achievement of weight loss, to Metabolic Surgery with a newly defined target to solve the hormonal disturbances that lead to fat accumulation by interfering with the neuroendocrine pathways of digestion.
Sleeve Gastrectomy may have been, in a way, the switch between the two types of Surgery. It started out as an innovative way to downside the intraoperative - postoperative risk for super-obese patients and in order to prepare them for a more complicated malabsorptive procedure at a later stage, having achieved first a significant amount of weight loss. The postoperative results, however, in that first stage were in fact so satisfactory, that patients were hesitating to enter the second stage process. That hit success was the reason for the investigation that led to the discovery of Ghrelin, the first orexigenic hormone ever discovered. The removal of the gastric fundus (the main Ghrelin production site) was the key that made Sleeve Gastrectomy the first procedure to be listed in the third group, the "Mixed Operations" with both a restrictive and a malabsorptive element. As the effort to clarify the exact mechanisms behind the various operations was going forward, the gastric bypass and the evolving variants (Sleeve Gastrectomy with Duodenal Switch, Mini Gastric Bypass etc) gradually became part of the group as well. These "Mixed Operations" are now considered to be the most effective, as they have a recognised component of regulation ability on the gastro¬intestinal neuroendocrine setting.
The constantly increasing number of patients that undergo this kind of operations globally, has provided the scientific community with the satisfying sample for further investigation and research on the unknown mechanisms and hormonal pathways that control the neuroendocrine environment of digestion and metabolism.
Incretins
The pioneering step after Ghrelin was the discovery and description of the "Incretin Effect" phenomenon, according to which oral glucose administration leads to faster insulin response in comparison to intravenous administration. The definition of incretin includes all of those hormones that are considered to contribute to the control of the simultaneous metabolism of insulin and glucose, after oral glucose administration, thus leading to the pre-mentioned phenomenon. The first ones that fell into the category were: the GIP proteins
(gastric inhibitory polypeptide/ glucose-dependent insulinotropic polypeptide) and the GLP-1 (glucagon-like peptide 1). These proteins are already the objective of exploitation by grand pharmaceutical companies against Diabetes Mellitus type 2.
GLP-1, in particular, seems that in addition to its incretin characteristics, also possesses other qualities, still under investigation, that include fruition of pancreatic function, by promoting the proliferation and development of β-cells and increase of the peripheral adipose cells sensitivity to insulin. Both activities mentioned actually lead to faster and more substantial weight loss. The final ileum, as the main production site of GLP-1, is now the main target of any effective metabolically surgical approach and all the technical innovations aim to the premature stimulation of it.
Both on an experimental and clinical trial basis, DePaula, Rubino, Santoro and Marescaux have independently described procedures with either physical or functional transposition of the final ileum, in combination with Sleeve Gastrectomy, or not, coming to conclusions and results that justify all the previously reported theories. And it's not just the incretins, but possibly additional unknown hormonal factors, yet to be discovered and investigated, that reveal one more piece of the complicated intestinal puzzle as an independent and united organ with the ability of autonomous neuroendocrine feedback, with the participation of both the foregut and the hindgut.
Patients & Methods
The current trend led us to design, apply and study a technically innovative procedure constituted of Sleeve Gastrectomy in combination with a side-to-side jejunoileal anastomosis. The additional anastomosis is a fully reversible and technically easy procedure that aims to functionally decrease the total length of the small intestine, thus leading to faster stimulation of the final ileum.
The operation was performed on 32 individuals and laboratory studies were done on 16 of them, in a period of 3 years, after obtaining approval from the Ethics Committee and the Scientific Board of both the University Hospital of Heraklion and the University of Crete. All the patients signed informed consents after extensive pre-operative evaluation.
In the proposed combination, Sleeve Gastrectomy provides the endocrine asset of the fundus excision/ removal of Ghrelin production, as well as the prompt gastric evacuation (mechanism unknown so far), which probably contributes to the final ileum's faster irritation as an independent factor. On the other had, the side-to-side jejunoileal anastomosis, although creating two parallel food paths, also leads to faster qualitative stimulation of the final ileum, succeeding in earlier GLP-1 release, which ultimately has as a result earlier satiety via neuroendocrine feedback pathways, accelerated gastric evacuation and pancreatic function fruition as previously discussed.
In order to prove and further understand the significance of the added anastomosis, we compared this group of patients to a group of patients that underwent Sleeve Gastrectomy alone.
In terms of surgical characteristics, technical difficulties and complications in Sleeve Plus were relatively comparable to Sleeve Gastrectomy alone, except the frequency of postoperative bowel obstruction. In order to prevent the latter we added stabilizing continuous bowel-to-bowel suturing on both sides of the anastomosis.
The development of hypoalbuminaemia in one patient made us take under consideration the adjustment of the anastomosis length in comparison to the total intestinal length, and the ideal position for the anastomosis.
The first encouraging results were in our clinical observations conserning the supremacy of Sleeve Plus in weight loss, BMI decrease and comorbidity improvement in comparison to the Sleeve Gastrectomy alone group.
The laboratory studies included pre- and post- operative evaluation of the fasting and post-pradial levels of intestinal hormones: Ghrelin, Insulin, Amylin, PP, PYY, Leptin and GLP-1 in 0, 6 months and 12 months postoperatively. They were compared to those of patients who underwent Sleeve Gastrectomy alone.
It seems that, basically, change in hormone levels follows the exact same pattern in both cases, but in Sleeve Plus they reach their peak-D(value) in half the time (6 months postoperatively that is), while in simple Sleeve Gastrectomy that happens at least one year postoperatively. It's possible that this phenomenon is what it takes to explain the faster
excess-weight loss, the faster improvement/resolution of the associated co-morbidities, as well as the fact that overall clinical improvement starts before even a substantial weight loss has taken place. That could also be suggestive of the important role of hormones and their function in the control of metabolic diseases, rather than just weight loss itself.
Going through the analysis of the findings after a Sleeve Plus operation, we will see how and when these changes take place and we will compare them to those happening after a simple Sleeve Gastrectomy.
Possible interaction patterns among the involved metabolic mechanisms will be suggested and commented on in an effort to reveal probable new aspects of the intestinal feedback network that may worth further investigation.
Ultimately, the goal would be to highlight the dynamics of the proposed operation and its future potential as an easy and effective procedure in the standard classification of metabolic interventions.
Finally, what's absolutely certain, after all this research, is that although Obesity is a complex and multifactorial disease, it's only the tip of the iceberg in the disturbances of the human
organism's metabolic laboratory. Therefore, we should not aim solely to achieving weight loss, but to effectively and correctly regulate the neuroendocrine mechanisms of the intestine in the long term, as this seems to be the absolute controller in total energy homeostasis.
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