**3. Advantages of reconstructive procedures with preservation duodenal passage after total gastrectomy**

The survival rate after TG in GC has been improved thanks to early diagnostics and advanced operating techniques. Many reconstructive techniques after TG have been developed in efforts to prevent postgastrectomy syndrome and preserve the physiological nutritional status of patients and rapid return to normal daily preoperative activities [47]. At the same time, the procedure for gastric reconstruction should be technically easily performed with minimal postoperative complications. RP that meet these requirements are those with the preservation of DP RY configuration of DT, Longmire procedure for the esophagus interposition of the jejunal segment, as well as the procedure of interposition with the jejunal pouch (e.g., Hunt-Lawrence pouch) [31].

Following a RP, the RY configuration of DT, food on the intestinal digestive pathway passes the duodenum and makes the intestinal wall distension by stimulating the ganglion cells of the myenteric and submucosal plexus, thereby leading to an adequate regulation of intestinal motility. This physical contact with the intestinal mucosa stimulates a large number of cells to produce peptides with hormonal, paracrine, and neurocrine effects. Chymus entering the duodenum primarily stimulates secretion: secretin, cholecystokinin, cholecystokininpancreozymin, enteroglucagon, vasoesthetic peptide, motilin, somatostatin, gastric inhibitory peptide, intestinal gastrin, serotonin, insulin, insulin glucagon, P substance, neurotensin, and enkephalin. These numerous polypeptides have a complex initial and stimulating regulatory role in the food digestion phase: bile release, gallbladder contact stimulation, Oddi sphincter relaxation, pancreatic juice secretion, vasodilation of the blood vessels of the mesentery of the intestinum and portal vein, intestinal secretion and peristalsis, absorption of food, secretion of insulin, and inhibitory effects in the interdigestive phase [48]. Kelly and authors suggest an explanation of the cause of the secondary deficiency of pancreatic secretion, inadequate stimulation, insufficient microvasculus of the heme and pancreatic enzymes, and weakened dietary fat assimilation in the new conditions of the absence of DP after TG [49]. Some non-randomized, retrospective studies have demonstrated the superiority of the performance of the jejunal interposition on the RY configuration of esophagojejunostomy when it comes to nutrition and the ability of postoperative rehabilitation [50–52]. However, due to a terminal vascular stem, the interposition of the jejunal segment as a free intestinal transplant between the esophagus and the duodenum is considered a high-risk procedure compared to other RP [53].

stimulation of pancreatic and bile secretions, inappropriate or inadequate mixing of food with bile and pancreatic juice, increased bowel motility, and excessive bacterial colonization of the small intestine. Carbohydrate absorption can be reduced by excessive bacterial colonization

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Postgastrectomy sideropenia anemia is caused by iron-induced malabsorption that occurs after reconstruction with the circumvention of the duodenal segment in which its resorption normally occurs. The iron resorption disorder in patients following TG is due to gastric acid deficiencies that allow the passage of nonabsorptive Fe2+ into the absorbent Fe3+ form and the removal of the

In a study by Bae and authors, there were very serious deficiencies of vitamin B12 in patients after TG. This indicates that parenteral substitution of vitamin B12 in gastrectomized patients is necessary due to inadequate absorption in the intestines. The serum level of vitamin B12 was significantly reduced after TG and is believed to be due to its deficiency in absorption. Bae also pointed out that anemia due to deficiency of vitamin B12 is a process that develops within a few years [54]. The term postgastrectomy bone disease describes bone disease after TG. It can occur as an osteomalacia or osteoporosis that is more pronounced than in normal physiological aging. Postgastrectomy bone disease is probably due to RP after TG in which the duodenum and proximal jejunum from food passage are excluded, since they are the major sites for the absorption of calcium in physiological conditions [59]. Calcium absorption is primarily performed in the duodenum and jejunum and depends on the level of vitamin D [60]. Accelerated transit of food through the intestinum also reduces calcium absorption time, while the presence of steatorrhea leads to the formation of insoluble calcium soaps that can contribute to calcium

Liedman reported in his study that a significant increase in alkaline phosphatase levels in patients after 3–10 years after TG, in a group of patients with a RY RP [61]. Heiskanen and authors have reported that the serum level of alkaline phosphatase has been used to detect postgastrectomic osteomalacia. In other prospective studies after partial gastrectomy and TG, normal and elevated serum levels of alkaline phosphatase were observed [62]. In a group of patients with reconstructed RY configurations in the study of Iivonen and authors, serum alkaline phosphatase activity increased significantly over the course of 3 postoperative years

Bassotti and authors were probably the first to examine the intestinal motility of the Roux loop after a complete gastrectomy by manometric route and concluded that patients with reconstruction of the Roux-en-Y configuration had significant motor abnormality in the Roux loop [64]. Sun and authors in their study claimed that the continuity of the gastrointestinal tract plays a key role in the coordination of intestinal motility [65]. Studies have shown that surgical manipulation of the gastrointestinal tract, in the form of resection followed by reanastomosis, results in intestinal motility disturbance [47, 64]. In support of this assertion, several studies suggest that the interruption of motility due to gastrointestinal resection is actually due to damage to the pacemaker for the gastrointestinal tract, i.e., interstitial cell of Cajal (ICC). The ICC is responsible for the creation and propagation of slow electrical waves that coordinate the stages of contraction of the intestine [65]. The entire problem of postgastrectomy symptoms

with a tendency to be higher than the group of patients with DP preservation [63].

duodenum as the main site of absorption of iron from the passage of the chymus [55].

and the use of nonmalignant carbohydrates [57].

malabsorption [59].

The nutritional status of patients after TG is changed. In many patients, calorie intake is inadequate, thus making it impossible to regain preoperative body weight. The causes of nutritional status disorders are the lack of appetite or problems caused by abnormal food passage. In order to maintain an ideal nutritional status, i.e., to preserve the integrity of the tissue and the function of the cells of the organism, nutrition requires essential nutrients and energy materials, regularity of food intake, regularity of passage and digestion, adequate resorption, and utilization of nutrients. Loss of body weight after TG is temporary and represents a significant postoperative problem in asthenic patients with GC. The mechanism of body weight loss includes malabsorption, malnutrition, and the consumption of material elements due to tissue restitution. It is known that the state of nutrition of the patient correlates with morbidity and mortality. Malnutrition usually manifests itself as a weight loss (15–24% of preoperative weight), which many authors cite in their studies in patients after TG [54]. If ingested food does not pass through the duodenum, an adequate mixture of the chymus with gallbladder and pancreatic enzymes is not formed. Therefore, the mixing of chymus and gallbladder and pancreatic contents is delayed beyond the time required for proper digestion in the distal parts of the jejunal Roux loop beneath the anastomosis with a jejunum in reconstruction without DP. Relative pancreatic insufficiency may also lead to malabsorption of patients in whom reconstruction excludes the passage of food through the duodenum [54]. Studies have shown that patients with TG who have undergone DP prevention have less loss of body weight and body mass index and have fewer symptoms as consequences of RP [55–58]. Fat and protein malabsorption occurs in over 50% of patients after total gastrectomy. In most patients, malabsorption of fat after TG is of doubtful clinical significance. The cause of steatorrhea after gastrectomy is most likely multifactorial: loss of digestive enzymes of the stomach, reduced stimulation of pancreatic and bile secretions, inappropriate or inadequate mixing of food with bile and pancreatic juice, increased bowel motility, and excessive bacterial colonization of the small intestine. Carbohydrate absorption can be reduced by excessive bacterial colonization and the use of nonmalignant carbohydrates [57].

Following a RP, the RY configuration of DT, food on the intestinal digestive pathway passes the duodenum and makes the intestinal wall distension by stimulating the ganglion cells of the myenteric and submucosal plexus, thereby leading to an adequate regulation of intestinal motility. This physical contact with the intestinal mucosa stimulates a large number of cells to produce peptides with hormonal, paracrine, and neurocrine effects. Chymus entering the duodenum primarily stimulates secretion: secretin, cholecystokinin, cholecystokininpancreozymin, enteroglucagon, vasoesthetic peptide, motilin, somatostatin, gastric inhibitory peptide, intestinal gastrin, serotonin, insulin, insulin glucagon, P substance, neurotensin, and enkephalin. These numerous polypeptides have a complex initial and stimulating regulatory role in the food digestion phase: bile release, gallbladder contact stimulation, Oddi sphincter relaxation, pancreatic juice secretion, vasodilation of the blood vessels of the mesentery of the intestinum and portal vein, intestinal secretion and peristalsis, absorption of food, secretion of insulin, and inhibitory effects in the interdigestive phase [48]. Kelly and authors suggest an explanation of the cause of the secondary deficiency of pancreatic secretion, inadequate stimulation, insufficient microvasculus of the heme and pancreatic enzymes, and weakened dietary fat assimilation in the new conditions of the absence of DP after TG [49]. Some non-randomized, retrospective studies have demonstrated the superiority of the performance of the jejunal interposition on the RY configuration of esophagojejunostomy when it comes to nutrition and the ability of postoperative rehabilitation [50–52]. However, due to a terminal vascular stem, the interposition of the jejunal segment as a free intestinal transplant between the esophagus

14 Gastric Cancer - An Update

and the duodenum is considered a high-risk procedure compared to other RP [53].

The nutritional status of patients after TG is changed. In many patients, calorie intake is inadequate, thus making it impossible to regain preoperative body weight. The causes of nutritional status disorders are the lack of appetite or problems caused by abnormal food passage. In order to maintain an ideal nutritional status, i.e., to preserve the integrity of the tissue and the function of the cells of the organism, nutrition requires essential nutrients and energy materials, regularity of food intake, regularity of passage and digestion, adequate resorption, and utilization of nutrients. Loss of body weight after TG is temporary and represents a significant postoperative problem in asthenic patients with GC. The mechanism of body weight loss includes malabsorption, malnutrition, and the consumption of material elements due to tissue restitution. It is known that the state of nutrition of the patient correlates with morbidity and mortality. Malnutrition usually manifests itself as a weight loss (15–24% of preoperative weight), which many authors cite in their studies in patients after TG [54]. If ingested food does not pass through the duodenum, an adequate mixture of the chymus with gallbladder and pancreatic enzymes is not formed. Therefore, the mixing of chymus and gallbladder and pancreatic contents is delayed beyond the time required for proper digestion in the distal parts of the jejunal Roux loop beneath the anastomosis with a jejunum in reconstruction without DP. Relative pancreatic insufficiency may also lead to malabsorption of patients in whom reconstruction excludes the passage of food through the duodenum [54]. Studies have shown that patients with TG who have undergone DP prevention have less loss of body weight and body mass index and have fewer symptoms as consequences of RP [55–58]. Fat and protein malabsorption occurs in over 50% of patients after total gastrectomy. In most patients, malabsorption of fat after TG is of doubtful clinical significance. The cause of steatorrhea after gastrectomy is most likely multifactorial: loss of digestive enzymes of the stomach, reduced Postgastrectomy sideropenia anemia is caused by iron-induced malabsorption that occurs after reconstruction with the circumvention of the duodenal segment in which its resorption normally occurs. The iron resorption disorder in patients following TG is due to gastric acid deficiencies that allow the passage of nonabsorptive Fe2+ into the absorbent Fe3+ form and the removal of the duodenum as the main site of absorption of iron from the passage of the chymus [55].

In a study by Bae and authors, there were very serious deficiencies of vitamin B12 in patients after TG. This indicates that parenteral substitution of vitamin B12 in gastrectomized patients is necessary due to inadequate absorption in the intestines. The serum level of vitamin B12 was significantly reduced after TG and is believed to be due to its deficiency in absorption. Bae also pointed out that anemia due to deficiency of vitamin B12 is a process that develops within a few years [54].

The term postgastrectomy bone disease describes bone disease after TG. It can occur as an osteomalacia or osteoporosis that is more pronounced than in normal physiological aging. Postgastrectomy bone disease is probably due to RP after TG in which the duodenum and proximal jejunum from food passage are excluded, since they are the major sites for the absorption of calcium in physiological conditions [59]. Calcium absorption is primarily performed in the duodenum and jejunum and depends on the level of vitamin D [60]. Accelerated transit of food through the intestinum also reduces calcium absorption time, while the presence of steatorrhea leads to the formation of insoluble calcium soaps that can contribute to calcium malabsorption [59].

Liedman reported in his study that a significant increase in alkaline phosphatase levels in patients after 3–10 years after TG, in a group of patients with a RY RP [61]. Heiskanen and authors have reported that the serum level of alkaline phosphatase has been used to detect postgastrectomic osteomalacia. In other prospective studies after partial gastrectomy and TG, normal and elevated serum levels of alkaline phosphatase were observed [62]. In a group of patients with reconstructed RY configurations in the study of Iivonen and authors, serum alkaline phosphatase activity increased significantly over the course of 3 postoperative years with a tendency to be higher than the group of patients with DP preservation [63].

Bassotti and authors were probably the first to examine the intestinal motility of the Roux loop after a complete gastrectomy by manometric route and concluded that patients with reconstruction of the Roux-en-Y configuration had significant motor abnormality in the Roux loop [64]. Sun and authors in their study claimed that the continuity of the gastrointestinal tract plays a key role in the coordination of intestinal motility [65]. Studies have shown that surgical manipulation of the gastrointestinal tract, in the form of resection followed by reanastomosis, results in intestinal motility disturbance [47, 64]. In support of this assertion, several studies suggest that the interruption of motility due to gastrointestinal resection is actually due to damage to the pacemaker for the gastrointestinal tract, i.e., interstitial cell of Cajal (ICC). The ICC is responsible for the creation and propagation of slow electrical waves that coordinate the stages of contraction of the intestine [65]. The entire problem of postgastrectomy symptoms may be attributed to accelerated intestinal transit. Fast transit results in accelerated glucose uptake, which causes increased insulin secretion. Accelerated transport of peptides and lipids gives an unusually large incentive to the secretion of cholecystokinin and stimulation of feedback regulation. In the end, there are abnormally high levels of gastrointestinal hormones and increased production of somatostatin. Excreted somatostatin has an inhibitory effect on GUT hormones, but this further reduces bowel motility and digestive juice production. This entire phenomenon becomes less significant in time due to the adaptation of the intestine [66].

physical, and social aspects, as well as from subjective disease symptoms and adverse effects of therapy. Controlling gastrointestinal symptoms seems important in an attempt to reduce damage to quality of life [70]. In their study, Hoksch and authors confirmed that reconstruction with the preservation of DP is the most optimal procedure in improving the quality of

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TG is widely used as a major surgical treatment for GC. TG results in risk of postgastrectomy syndrome, such as weight loss, dumping syndrome, biliary reflux esophagitis, and a reduction in the quality of life [3, 4]. The ideal RP after TG should replace all lost functions of the stomach, provide an optimal enough reservoir that can accommodate to the size of the meal, prevent reflux, ensure strong propulsion of equal-sized boluses of chyme entering the duodenum, and respond properly to the changing levels of gastrointestinal hormones and neural information [7]. The choice of RP should ensure good digestive function to prevent persistent postgastrectomy syndrome. Preservation of duodenal transit with replacement of the jejunal segment, the so-called physiological route, is now believed to be preferential for postoperative nutritional condition. RP which allow DP should be regarded as a key to physiological reconstruction.

The author would like to thank Professor Dr. Dobrila Stanković Djordjević, Dean of the Faculty of the Medicine and Professor Dr. Nebojsa Djordjević, Chairman of Department of Surgery, Faculty of the Medicine, University of Nis, Nis, Serbia for constructive support; his

, Miroslav P. Stojanovic<sup>1</sup>

,

teacher of surgery Professor Dr. Miroslav Jeremic for helping generously.

\*, Tomislav D. Randjelovic<sup>2</sup>

1 Department of Surgery, School of Medicine, University of Nis, Nis, Serbia

2 Department of Surgery, School of Medicine, University of Belgrade, Belgrade, Serbia

and Miodrag N. Djordjevic<sup>1</sup>

\*Address all correspondence to: n.ignjat@gmail.com

life of patients after TG [58].

**Acknowledgements**

**Conflict of interest**

**Author details**

Nebojsa S. Ignjatovic<sup>1</sup>

Goran Z. Stanojevic<sup>1</sup>

The authors declare no conflict of interest.

**4. Conclusion**

Several studies have shown that the presence of postprandial hyperglycemia following TG reconstruction can indicate an abnormal glucose metabolism, possibly representing intolerance to glucose or diabetes at an early stage [43]. In relation to the type of RP, Schwarz and authors have found significantly higher levels of glucose in a patient with RY reconstruction, when there was no DP preservation in patients with pouch, as opposed to patients undergoing a RP in which DP was preserved. There was no development of pathological glucose tolerance in patients with established DP prevention [43]. Kalmár and authors have published significantly higher levels of postprandial glucose in patients with exclusion of DP RY reconstruction than the control group, thus supporting the hypothesis that the exclusion of DP disrupts homeostasis of glucose more than reconstruction with the preservation of DP [66]. Observing duodenal preservation, the glucose homeostasis disorder was significantly higher in patients with RY procedure [65].

With the standardization of TG performance due to GC, the survival period of operative patients has significantly increased and hence the possibility of postgastrectomy syndrome. The causes of the postgastrectomy syndrome can be hypocaloric food intake, exclusion of duodenal passage, loss of absorption surface, lack of peptic digestion, excessive bacterial colonization, and the occurrence of exocrine and endocrine pancreatic insufficiency [57]. Symptoms related to food intake due to abnormal transit reported in several studies relate to the onset of early and late dumping syndrome, alkaline reflux, pyrosis, loss of appetite, feeling of satiety and fullness, epigastric pain, meteorism, dysphagia, and diarrhea [67]. Schwarz and authors, as well as Zherlov and authors, have shown in their studies that reconstruction in which DP is preserved has a lower incidence of postgastrectomy symptoms [43, 68]. Persistent postprandial discomfort and fullness may be to some extent due to poor receptive adaptation of the proximal part of the small intestine. In addition to poor receptive adaptation of the proximal part of the small intestine, the distal end of the Roux loop can also act as a functional obstruction, which leads to Roux-stasis syndrome, which is characterized by epigastric pain, nausea, and vomiting, and is most likely due to the lack of motor function in the distal region Roux loop [57, 69].

The lack of gastric acid after TG and altered intestinal motility in reconstruction with RY configuration with or without pouch seems to lead to bacterial colonization, which may be one of the main causes of malnutrition after TG. Excessive bacterial growth leads to the formation of damage to the mycelium and decongestion of bile salts. Several mechanisms blame for malabsorption of fat: loss of gastric emulsification of triglycerides, rapid food passage, and pancreatic stimulation disorder [63].

The overall impact of many symptoms after a RP can be summarized in the health quality of life. The quality of life is a multidimensional approach that consists of functional, emotional, physical, and social aspects, as well as from subjective disease symptoms and adverse effects of therapy. Controlling gastrointestinal symptoms seems important in an attempt to reduce damage to quality of life [70]. In their study, Hoksch and authors confirmed that reconstruction with the preservation of DP is the most optimal procedure in improving the quality of life of patients after TG [58].
