Interconnection of severe obesity, gastric intestinal metaplasia, gastric cancer, bariatric surgery and the necessity of preoperative endoscopy

– Obesity is a growing challenge around the globe accounting for approximately 1.7 billion adults with reduced life expectancy of 5 – 20 years and these patients are at greater risk for various cancers. Bariatric surgery is one ef ﬁ cient an approved treatment of severe obesity for losing weight and to decrease associated health complications. Besides correct indications and contraindications as well as the various risks of individual bariatric surgical procedures, many more variables in ﬂ uence decision-makings, such as patient ’ s family history of diseases, as well as individual patient-speci ﬁ c factors, patient and family socioeconomic and nutrition status, and professionalism of a bariatric surgical unit and the presence of intestinal metaplasia that is the replacement of columnar epithelial cells by intestinal architecture and morphology. Patients with severe obesity undergoing esophagogastroduodenoscopy (EGD) and biopsy prior to bariatric surgery may present with gastric IM because regular follow-up to early diagnosis of any subsequent pathological changes is necessary and reveals the importance of addressing interconnections between pre-existing conditions and outcomes. However, there is currently no uni ﬁ ed recommendation about preoperative EGD before bariatric surgery. With this short review, we point out the necessary knowledge that undermines why the responsibility for a patient with severe obesity cannot be divided across various disciplines, and why we recommend that EGD always be performed preoperatively.


Introduction
Obesity is a chronic disease that is accompanied by increasing medical and socioeconomic problems.Its prevalence is growing across the world [1].Moreover, it accounts for approximately 1.7 billion adults leading to lower life expectancies of 5-20 years [2] Obesity is related to several different diseases, consisting of gallstones, high blood pressure with insulin resistance and visceral fat hyperglycemia (metabolic syndrome), gastroesophageal reflux disease, type II diabetes mellitus, degenerative joint diseases, obstructive sleep apnea syndrome, fatty liver, and mental health issues [3].Furthermore, the patients with severe obesity are at risk for various cancers, such as esophageal, gastric, pancreatic and colorectal cancer [4].
The available non-surgical treatments of severe obesity are effective only when they are actively used.On the other hand, weight regain usually occurs after cessation of this option [5].Bariatric surgery is the mainstay treatment with respect to weight loss and remission of obesity associated medical problems [6].Beyond the knowledge of the correct indications and contraindications as well as the various risks of individual bariatric surgery procedures, many more variables influence decision makings, such as the patient and family history of diseases, as well as individual patient and family socioeconomic and nutrition status, and professionalism of a bariatric unit [7].One important variable is intestinal metaplasia.

Intestinal metaplasia
Replacement of columnar epithelial cells by intestinal architecture and morphology defines intestinal metaplasia (IM) as a conversion of the cells in the coating of the upper digestive tract, mostly the stomach or the esophagus as a precancerous gastric lesion with a 6-fold increased cancer risk [8,9].Although the risk of gastric cancer is increase in IM patients, the total risk is modest [10] and the reason is unknown.
Higher body mass index (BMI) in patients with severe obesity is shown to correlate with the presence of IM [11][12][13][14].However, the literature refers to a gender and epidemiology differences as in Korea and that obesity and gastric cancer are more likely associated in men while women show gastric dysplasia regardless of Helicobacter pylori (H.pylori) infection [15].
Patients with obesity undergoing esophagogastroduodenoscopy (EGD) and biopsy prior to bariatric surgery, may have gastric IM [16,17] and regular follow-up to early diagnosis of any subsequent pathological changes is recommended [4,18].
IM is associated with age [19], smoking, alcohol consumption, and chronic biliary reflux [20,21].A cohort study with large sample size showed that obesity was independently related to an increased risk of new-onset IM [22].
A prospective, longitudinal and multicenter study from Singapore revealed that IM has an adjusted-HR 5.36-fold risk variable for early gastric neoplasia [23] which is in line with earlier reports of gastric carcinogenesis [10] and involves the influence of the microbiome [24] without the need to invoke somatic mutations [25][26][27][28].
The challenge of IM is that it is asymptomatic and it is assumed that it takes 4-7 years to develop gastric cancer [29].Furthermore, IM is assumed to not be reversible ( [8,30,31] reviewed in [29]) meaning that the precancerous niche (PCN) during the multistep carcinogenesis sequence [28] would have irreversibly passed.
Although the annual risk for IM transforming to gastric cancer is less than 1.8% [16],the presence of IM requires surveillance by EGD in high-risk populations, such as the patient with familial gastric cancer or Southeast Asian ethnicity [9].In high-risk patients, surveillance EGD with mapping is necessary to have enough histologic specimens for a full evaluation [32].
Having a familial history is a risk factor for IM and gastric cancer according to recently updated European guidelines [33].Based on the previous studies, patients whose first-degree relatives have gastric cancer are more prone to neoplastic progression after IM when compared to patients with no first-degree relatives with gastric cancer [34][35][36].
Some autoimmune disorders, such as autoimmune gastritis [37] and rheumatologic disorders [38] have been associated with risk for IM.Although the prevalence of IM is largely unknown, it is assumed to be related to regional gastric cancer incidence [39].

Types of gastric intestinal metaplasia
Gastric IM is divided into two complete (type-I) and incomplete (type-II) types.Type-I is described as small intestinal-type mucosa with goblet cells with a brush border and full absorptive cells.Type-II discharges sialo-mucins and is akin to colonic epithelium with intermediate cells in different phases of differentiation.
Mucin droplets are irregular and the brush border is absent [40].The risk of developing gastric cancer in regard to IM is dependent on whether IM occurs completely or incompletely as "the risk significantly increases with IM over 20% of the gastric mucosa" and even H. pylori eradication seems to not influence regression of IM [8].A recent analysis evaluated 10 studies in Asia, Europe, and Latin America with a follow up period of 10 months to 19 years and showed that incomplete IM led to the highest risk of gastric cancer [41].

Helicobacter pylori (H. pylori)
Helicobacter pylori is a known risk factor for IM [19,42] and its eradication by Celecoxib for 8-12 weeks may lead to the regression of IM to normal mucosa [9,43].It is estimated that approximately 75% of IM cases are due to inflammation caused by H. pylori [44].H. pylori migrates to the epithelial cells of the stomach and stimulate proteins that cause IM and eventually cancer.Although all subjects infected with H. pylori do not develop IM, chronic H. pylori infection is a known factor in the etiology of IM [45].Also, it has long been known that H. pylori-related and non-related gastric cancers do not differ in regard to chromosomal aberrations [46].H. pylori infected patients reveal a higher IM prevalence of 33.9% and at younger ages compared to 15.2% without H. pylori infection [47].Phosphoglycerate kinase 1 (PGK1) was shown in 2010 to be crucial for peritoneal dissemination in gastric cancer [48] and for IM [49].In addition, H. pylori infection is related to iron deficiency anemia [50][51][52] and iron deficiency anemia is associated with both IM [53] and gastric cancer [54].

Preoperative EGD recommendations
Today it is unquestioned that the appropriate bariatric surgical procedure needs to be chosen in an interdisciplinary and multifactorial manner.
Preoperative EGD as a routine diagnostic test prior to bariatric surgery was stated to be a conditional recommendation within the Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery and its update in 2020 which was endorsed by the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO-EC), the European Association for the Study of Obesity (EASO) and the European Society for the Peri-operative Care of the Obese Patient (ESPCOP) [59].Otherwise, the American Gastrointestinal Endoscopy Association (AGEA) recommends endoscopy only for symptomatic patients scheduled for bariatric surgery [60,61].

Personal opinion
It has been pointed out that "Guidelines are and will continue to be an important scientific instrument to help physicians taking the best decisions according to the current state of science in many fields of medicine" but in the same context it was also pointed out that "there are not meant, however, to be absolute rules with legal implications because they may be the result of a complex drafting process involving schools of thought, conflicts of interest, industrial lobbying and dealing with areas of uncertainty and rapidly evolving concepts from research" [62].
Bariatric surgery is not just performing surgery at the highest technical quality.As discussed here a bariatric surgeon needs to minimize risk for the individual patient.In this regard, the patient's safety and needs are the most important ones.This includes from our perspective any kind of condition, which could result into an overlooked precancerous or cancerous lesion before bariatric surgery [4,63,64].
Due to this consideration, it seems to us to be logical to screen bariatric patients for H. pylori and other risk factors such as IM, preoperatively and attempt to eliminate them or even change the plan of surgery [65,66] and to ensure that bariatric centers have full access for EGD after surgery in patients at the risk of gastric cancer [67].However, independent from the bariatric surgical approach, there can be limitations for routine EGD after bariatric gastric bypass procedures.We are also aware; that there were associative findings between IM and H. pylori infection [68,69] while in some studies, no association between H. pylori and IM was reported [70].
As the responsibility for a surgery patient cannot be divided across various disciplines, we recommend performing EGD before bariatric surgery in each patient.