If fluid drainage in  cirrhotic  ascites is more than 5 litres, patients may receive  intravenous   serum albumin  (25% albumin, 8 g/L) to prevent  hypotension  (low blood pressure). [ 7 ]  There has been debate as to whether albumin administration confers benefit, but a recent 2016  meta-analysis  concluded that it can reduce mortality after large-volume paracentesis significantly. [ 8 ]  However, for every end-point investigated, while albumin was favorable as compared to other agents (e.g., plasma expanders, vasoconstrictors), these were not statistically significant and the meta-analysis was limited by the quality of the studies—two of which that were in fact unsuitable—included in it. [ 8 ]


The procedure generally is not painful and does not require  sedation . The patient is usually discharged within several hours following post-procedure observation provided that blood pressure is otherwise normal and the patient experiences no dizziness. [ 1 ] [ 9 ] [ 10 ]


Paracentesis is known to be a safe procedure when ascitic fluid is readily visible, so complications are typically rare. Possible complications following or during the procedure involve infection, bleeding, the leakage ascitic of fluid, or  bowel perforation . [ 7 ] [ 5 ]  Of these, the most concerning in the immediate setting is bleeding within the peritoneal cavity. [ 11 ]


The z-tracking technique has held particular importance in performing paracentesis. A z-track is a technique that allows for decreased ascitic fluid leak following the paracentesis by displacing the needle tracks with respect to the  epidermis  and the  peritoneum . [ 6 ]


The  serum-ascites albumin gradient  can help determine the cause of the ascites. [ 7 ]


The color of the ascitic fluid can also be useful in analysis. Blood fluid can indicate trauma or  malignancy . A milky appearance of the fluid can indicate  lymphoma  or malignant peritoneal ascites. Cloudy or turbid fluid can indicate possible infection or inflammation within the peritoneal cavity. Straw or light yellow colored fluid indicates more plasma-like and benign causes of peritoneal ascites. [ 3 ]


The ascitic white blood cell count can help determine if the ascites is infected. A count of 250 neutrophils per ml or higher is considered diagnostic for spontaneous bacterial peritonitis. Cultures of the fluid can be taken, but the yield is approximately 40% (72–90% if  blood culture  bottles are used). Empiric antibiotics are typically started when  spontaneous bacterial peritonitis  is highly suspected. A third-generation cephalosporin is typically started in these cases to cover the most common organisms,  E. coli  and  Klebsiella , in SBP. [ 7 ]


Mild hematologic abnormalities do not increase the risk of bleeding. [ 12 ] [ 7 ]  The risk of bleeding may be increased if: [ 13 ]


Absolute contraindication is the acute abdomen that requires surgery.


Relative contraindications are: [ 6 ]


Pediatric end-stage liver disease  ( PELD ) is a disease severity scoring system for children under 12 years of age. [ 1 ]  It is calculated from the patient's  albumin ,  bilirubin , and  international normalized ratio  (INR) together with the patient's age and degree of  growth failure . This score is also used by the  United Network for Organ Sharing  (UNOS) for prioritizing allocation of  liver transplants .


PELD uses the patient's values for serum  bilirubin , serum  albumin , the  international normalized ratio for prothrombin time (INR) , whether the patient is less than 1 year old, and whether the patient has growth failure (<-2 standard deviation) to predict survival. It is calculated according to the following formula: [ 2 ]


The PELD score calculated for any given patient is correlated to their prognosis and how likely they are to die within a certain time period. [ 3 ]  A higher score correlates with a more critical condition. Thus, liver donations are usually allocated by UNOS according to the PELD score to maximize the life-saving capability of each donated liver. [ 4 ]


Peritoneal dialysis  ( PD ) is a type of  dialysis  that uses the  peritoneum  in a person's  abdomen  as the membrane through which fluid and dissolved substances are exchanged with the  blood . [ 1 ] [ 2 ]  It is used to remove excess fluid, correct  electrolyte problems , and remove toxins in those with  kidney failure . [ 3 ]  Peritoneal dialysis has better outcomes than  hemodialysis  during the first two years. [ 4 ]  Other benefits include greater flexibility and better tolerability in those with significant  heart disease . [ 4 ]


Complications may include  infections within the abdomen ,  hernias ,  high blood sugar , bleeding in the abdomen, and blockage of the catheter. [ 3 ]  Peritoneal dialysis is not possible in those with significant prior  abdominal surgery  or  inflammatory bowel disease . [ 3 ]  It requires some degree of technical skill to be done properly. [ 4 ]


In peritoneal dialysis, a specific solution is introduced through a permanent tube in the lower abdomen and then removed. [ 3 ]  This may either occur at regular intervals throughout the day, known as continuous ambulatory peritoneal dialysis (CAPD), or at night with the assistance of a machine, known as automated peritoneal dialysis (APD) [ 3 ]  or continuous cycling peritoneal dialysis (CCPD). [ 5 ]  The solution is typically made of  sodium chloride ,  bicarbonate , and an  osmotic agent  such as  glucose . [ 3 ]


The solution used for peritoneal dialysis is on the  World Health Organization's List of Essential Medicines . [ 6 ] [ 7 ]  As of 2009, peritoneal dialysis was available in 12 of 53 African countries. [ 8 ]


Peritoneal dialysis is a method of  renal replacement therapy  for those needing maintenance therapy for late stage  chronic kidney disease  and is an alternative to the most common method  hemodialysis .


A common cause of  peritonitis  is touch contamination, e.g. insertion of catheter by un-sanitized hands, which potentially introduces bacteria to the abdomen; other causes include catheter complication, transplantation of bowel bacteria, and systemic infections. [ 9 ]  Most common type of PD-peritonitis infection (80%) are from bacterial sources. [ 9 ]  Infection rates are highly variable by region and within centers with estimated rates between 0.06 - 1.66 episodes per patient year. [ 10 ]  With recent technical advances peritonitis incidence has decreased over time. [ 11 ]


Antibiotics are needed if the source of infection is bacterial; there is no clear advantage for other frequently used treatments such as routine peritoneal lavage or use of  urokinase . [ 12 ]  The use of preventative nasal  mupirocin  is of unclear effect with respect to peritonitis. [ 13 ]  Of the three types of connection and fluid exchange systems (standard, twin-bag and y-set; the latter two involving two bags and only one connection to the catheter, the y-set uses a single y-shaped connection between the bags involving emptying, flushing out then filling the peritoneum through the same connection) the twin-bag and y-set systems were found superior to conventional systems at preventing peritonitis. [ 14 ]


The fluid used for dialysis uses  glucose  as a primary osmotic agent. According to a 2020 review published in the  American Journal of Nephrology , some studies suggest that the use of glucose increases the risk of  peritonitis , possibly as a result of impaired host defenses, vascular disease, or damage to the peritoneal membrane. [ 15 ]  The  acidity , high concentration and presence of  lactate  and products of the degradation of glucose in the solution (particularly the latter) may contribute to these health issues [ ambiguous ] .  Solutions that are  neutral , use  bicarbonate  instead of lactate and have few glucose degradation products may offer more health benefits though this has not yet been studied. [ 16 ]


The mortality rate of peritoneal dialysis related peritonitis is estimated to be 3-10%, with approximately 50% of cases resulting in hospitalization. [ 17 ]  Peritoneal fluid studies with a white blood cell count greater than 100 per μL and greater than 50% neutrophils strongly suggest peritonitis, with a definitive diagnosis based on culture of microorganisms from the peritoneal fluid. [ 17 ]  In order to avoid delaying treatment, a cloudy fluid in the dialysate fluid can be assumed to be due to peritonitis unless an alternative cause is identified. [ 17 ]  Peritonitis in those undergoing PD is usually due to  gram positive bacteria . [ 17 ]  Intraperitoneal antibiotics are preferred to  intravenous  as they have a greater effect at the area of infection, unless  sepsis  is present, in which case intravenous antibiotics are indicated. [ 17 ]  The peritoneal dialysis catheter may have to be removed if the infection does not resolve with antibiotics, and it is recommended that the PD catheter be removed in all cases of fungal peritonitis. [ 17 ]


The volume of dialysate removed as well as patient's weight are monitored. If more than 500ml of fluid are retained or a liter of fluid is lost across three consecutive treatments, the patient's physician is generally notified. [ citation needed ]   Excessive loss of fluid can result in  hypovolemic shock  or  hypotension  while excessive fluid retention can result in  hypertension  and  edema .  Also monitored is the color of the fluid removed:  normally it is pink-tinged for the initial four cycles and clear or pale yellow afterward.  The presence of pink or bloody effluent suggests bleeding inside the abdomen while feces indicates a  perforated bowel  and cloudy fluid suggests infection.  The patient may also experience pain or discomfort if the dialysate is too acidic, too cold or introduced too quickly, while diffuse pain with cloudy discharge may indicate an infection.  Severe pain in the  rectum  or  perineum  can be the result of an improperly placed catheter.  The dwell can also increase pressure on the  diaphragm  causing impaired breathing, and  constipation  can interfere with the ability of fluid to flow through the catheter. [ 18 ]


Long term use of PD is rarely associated with fibrosis of the peritoneum. [ 11 ]  A potentially fatal complication estimated to occur in roughly 2.5% of patients is  encapsulating peritoneal sclerosis , in which the bowels become obstructed due to the growth of a thick layer of  fibrin  within the peritoneum. [ 19 ]


Other complications include  low back pain  and  hernia  or leaking fluid due to high pressure within the abdomen. [ 20 ]   Hypertriglyceridemia  and  obesity  are also concerns due to the large volume of glucose in the fluid, which can add 500-1200  calories  to the diet per day. [ 21 ]


Best practices for peritoneal dialysis state that before peritoneal dialysis should be implemented, the person's understanding of the process and support systems should be assessed, with education on how to care for the catheter and to address any gaps in understanding that may exist.  The person should receive ongoing monitoring to ensure adequate dialysis, and be regularly assessed for complications. Finally, they should be educated on the importance of infection control and an appropriate medical regimen established with their cooperation. [ 22 ]


The abdomen is cleaned in preparation for surgery and a  catheter  is surgically inserted with one end in the abdomen and the other protruding from the skin. [ 23 ]  Catheters can also be inserted without a general anaesthetic by a physician using a needle, known as a medical insertion. Both methods have similar safety profiles. [ 24 ] [ 25 ]  Before each infusion the catheter must be cleaned, and flow into and out of the abdomen tested.  2-3 liters of dialysis fluid is introduced into the abdomen over the next ten to fifteen minutes. [ 18 ]   The total volume is referred to as a  dwell [ 26 ]  while the fluid itself is referred to as dialysate.  The dwell can be as much as 3 liters, and medication can also be added to the fluid immediately before infusion. [ 18 ]  The dwell remains in the abdomen and waste products diffuse across the peritoneum from the underlying blood vessels.  After a variable period of time depending on the treatment (usually 4–6 hours [ 18 ]  ), the fluid is removed and replaced with fresh fluid.  This can occur automatically while the patient is sleeping (automated peritoneal dialysis, APD), or during the day by keeping two litres of fluid in the abdomen at all times, exchanging the fluids four to six times per day (continuous ambulatory peritoneal dialysis, CAPD). [ 26 ] [ 27 ]


The fluid used typically contains  sodium chloride ,  lactate  or  bicarbonate  and a high percentage of  glucose  to ensure  hyperosmolarity .  The amount of dialysis that occurs depends on the volume of the dwell, the regularity of the exchange and the concentration of the fluid. APD cycles between 3 and 10 dwells per night, while CAPD involves four dwells per day of 2-3 liters per dwell, with each remaining in the abdomen for 4–8 hours.  The viscera accounts for roughly four-fifths of the total surface area of the membrane, but the parietal peritoneum is the most important of the two portions for PD.  Two complementary models explain dialysis across the membrane - the three-pore model (in which molecules are exchanged across membranes which sieve molecules, either  proteins , electrolytes or water, based on the size of the pores) and the distributed model (which emphasizes the role of  capillaries  and the solution's ability to increase the number of active capillaries involved in PD).  The high concentration of glucose drives the filtration of fluid by osmosis (osmotic UF) from the peritoneal capillaries to the peritoneal cavity. Glucose diffuses rather rapidly from the dialysate to the blood (capillaries). After 4-6 h of the dwell, the glucose osmotic gradient usually becomes too low to allow for further osmotic UF. Therefore, the dialysate will now be reabsorbed from the peritoneal cavity to the capillaries by means of the plasma colloid osmotic pressure, which exceeds the colloid osmotic pressure in the peritoneum by approximately 18-20 mmHg (cf. the Starling mechanism). [ 28 ]  Lymphatic absorption will also to some extent contribute to the reabsorption of fluid from the peritoneal cavity to the plasma. Patients with a high water permeability (UF-coefficient) of the peritoneal membrane can have an increased reabsorption rate of fluid from the peritoneum by the end of the dwell. The ability to exchange small solutes and fluid in-between the peritoneum and the plasma can be classified as high (fast), low (slow) or intermediate.  High transporters tend to diffuse substances well (easily exchanging small molecules between blood and the dialysis fluid, with somewhat improved results with frequent, short-duration dwells such as with APD), while low transporters have a higher UF (due to the slower reabsorption of glucose from the peritoneal cavity, which results in somewhat better results with long-term, high-volume dwells), though in practice either type of transporter can generally be managed through the appropriate use of either APD or CAPD. [ 29 ]


Though there are several different shapes and sizes of catheters that can be used, different insertion sites, number of cuffs in the catheter and immobilization, there is no evidence to show any advantages in terms of morbidity, mortality or number of infections, though the quality of information is not yet sufficient to allow for firm conclusions. [ 30 ]


A  peritoneal equilibration test  may be done to assess a person for peritoneal dialysis by determining the characteristics of the peritoneal membrane mass transport characteristics.


Peritoneal dialysis can be improvised in conditions such as combat surgery or disaster relief using surgical catheters and dialysate made from routinely available medical solutions to provide temporary renal replacement for people with no other options. [ 31 ]


As of 2017, hemodialysis is the most widely available renal replacement modality found in 96% of countries whereas peritoneal dialysis (PD) is only available in 75% of countries. [ 11 ]  In 2016, the proportion of people receiving peritoneal dialysis (PD) was estimated at 11% with wide differences between different countries and regions. [ 32 ]  In Hong Kong and  Mexico , PD is more common than the world average, with Mexico conducting most of its dialysis through PD, while  Japan  and  Germany  have rates lower than the world average. [ 33 ]  Peritoneal dialysis first models, patients requiring renal replacement therapy are placed on PD first, and financial incentives for using PD are associated with increase uptake of PD in multiple countries. [ 32 ]


Hong Kong has the highest rate of PD use worldwide at 71.9% in 2014, while in Mainland China had 20% in 2014, 23% in Thailand during 2012, and 10-20% in Vietnam during 2011. [ 32 ]  Hong Kong had a PD-first model since 1985, Thailand began a PD-first model since 2008 which increased their levels of PD from <10%. [ 32 ]


Prevalence in of PD use was 9.7% in USA during 2013 and 16.3% in Canada during 2013. [ 32 ]  The lower PD rates in the USA are due to higher availability of large corporate owned hemodialysis centers. There have been recent increase in PD uptake in the USA due to changes to medicare reimbursement such as  bundled payment  for dialysis this incentivizes use of PD which is a less costly modality for dialysis. [ 32 ]


Overall, prevalence of PD use is 24.6% in Latin America during 2011. [ 32 ]  Within Latin America, hemodialysis has a higher growth rate in use compared to PD between 1994 - 2010. In 2010, the most prevalent use of PD were in Mexico 55.9% and El Salvador 67.6%. Between 2000 - 2010, Colombia's PD rate dropped from 54% to 31.3%. [ 34 ]


Peritoneal dialysis was first carried out in the 1920s; however, long-term use did not come into medical practice until the 1960s. [ 35 ]  The timeline was


Compared to hemodialysis, PD allows greater patient mobility, produces fewer swings in symptoms due to its continuous nature, and  phosphate  compounds are better removed, but large amounts of  albumin  are removed which requires constant monitoring of nutritional status. [ 11 ]   The costs of PD are generally lower than those of HD in most parts of the world, this cost advantage is most apparent in developed economies. [ 42 ]  There is insufficient research to adequately compare the risks and benefits between CAPD and APD; a  Cochrane Review  of three small  clinical trials  found no difference in clinically important outcomes (i.e.  morbidity  or  mortality ) for patients with  end stage renal disease , nor was there any advantage in preserving the functionality of the kidneys.  The results suggested APD may have psychosocial advantages for younger patients and those who are employed or pursuing an education. [ 43 ] [ needs update ]


PD may also be used for patients with  cardiac instability  as it does not result in rapid and significant alterations to body fluids, and for patients with  insulin -dependent  diabetes mellitus  due to the inability to control  blood sugar  levels through the catheter.


The cost of dialysis treatment is related to how wealthy the country is. [ 8 ]  In the United States peritoneal dialysis costs the government about $53,400 per person per year. [ 4 ]


Rapid urease test , also known as the  CLO test  (Campylobacter-like organism test), is a  rapid diagnostic test  for diagnosis of  Helicobacter pylori . [ 1 ]  The basis of the test is the ability of  H. pylori  to secrete the  urease  enzyme, which catalyzes the conversion of  urea  to  ammonia  and  carbon dioxide .


The test is performed at the time of  gastroscopy . A  biopsy  of mucosa is taken from the  antrum  of the  stomach , and is placed into a medium containing urea and an indicator such as  phenol red . The urease produced by  H. pylori  hydrolyzes urea to ammonia, which raises the  pH  of the medium, and changes the color of the specimen from yellow (NEGATIVE) to red (POSITIVE).


Among different kinds of rapid urease tests (liquid-based, gel-based, dry cool) there is a design type with single-layer sensitive element — a layer impregnated simultaneously with urea and an indicator composition. Such a design bears the risk of false-positive result due to the pH value of the gastric biopsy when it is placed on the sensitive element. Excessive salivation and alkaline bile reflux into the stomach can shift the pH value of the biopsy of the stomach towards alkaline. Drugs that reduce the acidity of the stomach, also contribute to false positive results resulting from the alkalization. In each of these cases, the pH of the biopsy will be shifted to the alkaline side. All of these factors may trigger a non-targeted coloration of the sensitive element in a single-layer rapid urease test. The indicator would change color not in the course of the enzymatic reaction, which then causes alkalization of the medium as a result of ammonia formation, but under the effect of the pH of the gastric biopsy. [ 2 ]


Selective urease tests differ from the single-layer rapid urease tests by their design and higher sensitivity and specificity. [ 3 ]  In contrast to single-layer rapid urease tests, selective urease tests have several layers, enabling separate enzymatic and indicator reactions. The sample is placed on the first layer impregnated with urea. Ammonia formed during the hydrolysis of urea by urease penetrates through a special selective membrane to the layer impregnated with the indicator composition. [ 4 ]  Accordingly, the color change occurs directly during the enzymatic reaction. This avoids the influence of the pH value of the sample (gastric biopsy) on the result of a selective urease test, which virtually eliminates the occurrence of false-positive results. If the pH value of the sample is shifted to the acidic side, for example, in the case of increased acidity of gastric juice, this also does not distort the result of the selective urease test. [ 5 ]


There is evidence to suggest that  H. pylori  moves proximal in the stomach in patients on therapy with  proton pump inhibitors [ citation needed ] , and, as such, samples from the  fundus  and  body  should be taken in these patients.


Active gastrointestinal bleeding reduces accuracy of the test. [ 6 ]


The specificity and sensitivity of this test is high compared with  urea breath test [ citation needed ] . The test is often done as part of point-of-care diagnostics, to eliminate the time and expense required to detect  H. pylori  on  pathology  testing.


Sialoendoscopy  is a  minimally invasive technique  that allows for  salivary gland   surgery  for the safe and effective treatment of  obstructive salivary gland disorders  and other conditions of the salivary glands.  During sialoendoscopy a small  endoscope  is placed into the salivary glands through the  salivary ducts  that empty into the  mouth . The procedure is not exclusively diagnostic, but is interventional; thus, it can be used for the extraction of salivary stones, salivary duct lavage, dilatation of stenotic segments, or instillation of various medications such as corticosteroids or antibiotics. [ 1 ]  Thus, sialoendoscopy is an efficient yet simple mode of treatment for major salivary gland obstructions, strictures and  sialoliths  (salivary stones).  Depending on the obstruction, sialoendoscopy can be conducted under  local anesthesia  in an  outpatient  office or in the  operating room  under  general anesthesia .


Salivary gland  stones  are one of the major causes of salivary gland infections (sialadenitis). These types of stones can be found in 1.2 percent of the general population. [ 2 ]


The second leading cause of salivary obstruction is from strictures and adhesions, which can happen from prior salivary gland infections, including childhood  infections  like  mumps . Most strictures could be seen in the  parotid duct  and mostly in the disease process of chronic recurrent sialadenitis. [ citation needed ]


Generally, the salivary duct opening needs to be either  dilated  or incised prior to introduction of the  endoscope .  Once the sialoendoscope is in place,  saline  is utilized to dilate the salivary duct and its branching.  [ citation needed ]


Once the endoscopes are introduced into  gland , the internal anatomy is explored either for  diagnosis  or for treatment of a specific disease entity.  The endoscope is introduced into the gland through its natural  orifice  in the mouth or by making a small incision in the duct opening.  These techniques for introduction are completely intraoral techniques.


In the case of  strictures  or  adhesions , the following technique can be used as a treatment  modality . First the surgeon will make their diagnosis and find the exact location of the obstruction using a  sialogram .  Following this, the surgeon can use the endoscopic method. The first step in this is anesthetizing and laving the duct with 2 percent  lidocaine  and saline. If there is no improvement, the surgeon then can insert a  dilation balloon , which can be inflated up to 3 mm. The pressure created by the inflation can be sufficient to dilate most strictures. Another technique for dilating strictures is to expand the stricture region with grasping  forceps  used as a dilator. [ citation needed ]


The ability to perform this technique is the result of the development of miniaturized endoscopic imaging tools.  The majority of sialoendoscopes that are currently in use are of the semirigid type. The semirigid endoscope allows for visualization of the diseased process, but the stiffness allows manipulation and navigation of the internal salivary anatomy.


Multiple types of micro instrumentation are available, including grasping forceps, biopsy forceps,  drills ,  needles ,  laser  fibers, and  lithotripters  (although the last is currently unavailable in the US pending  U.S. Food and Drug Administration  approval).  Multiple companies make various types of sialoendoscopes and instrumentation.  There are advantages and disadvantages to all of the systems and none are recommended over the other [ citation needed ] .  Different practitioners utilize different systems due to the experience and clinical training of the surgeon.


Sleeve gastrectomy  or  vertical sleeve gastrectomy , is a  surgical weight-loss procedure , typically performed  laparoscopically , in which approximately 75 - 85% of the stomach is removed, [ 1 ] [ 2 ]  along the  greater curvature , [ 3 ]  which leaves a cylindrical, or "sleeve"-shaped stomach the size of a banana. [ 1 ] [ 2 ]  Weight loss is affected not only through the reduction of the organ's size, but by the removal of the portion of it that produces  ghrelin , the hormone that stimulates appetite. Patients can lose 50-70 percent of excess weight over the course of the two years that follow the surgery. [ 2 ]  The procedure is irreversible, [ 4 ]  though in some uncommon cases, patients can regain the lost weight, via resumption of poor dietary habits, or dilation of the stomach over time, which can require gastric sleeve revision surgery to either repair the sleeve or convert it to another type of weight loss method that may produce better results, such as a  gastric bypass  or  duodenal switch . [ 5 ]


A meta-analysis of 174,772 participants published in  The Lancet  in 2021 found that  bariatric surgery  was associated with 59% and 30% reduction in all-cause mortality among  obese  adults with and without  type 2 diabetes , respectively. This meta-analysis also found that median life-expectancy was 9.3 years longer for obese adults with diabetes who received bariatric surgery as compared to routine (non-surgical) care, whereas the life expectancy gain was 5.1 years longer for obese adults without diabetes. [ 6 ]


Sleeve gastrectomy was originally performed as a modification to another  bariatric  procedure, the  duodenal switch , and then later as the first part of a two-stage  gastric bypass  operation on extremely  obese  patients for whom the risk of performing gastric bypass surgery was deemed too large. The initial weight loss in these patients was so successful it began to be investigated as a stand-alone procedure. [ 7 ]


Sleeve gastrectomy is the most commonly performed bariatric surgery worldwide. [ 8 ] [ 9 ]  In many cases, sleeve gastrectomy is as effective as gastric bypass surgery, including improvements in glucose homeostasis before substantial weight loss has occurred. This weight-loss independent benefit is related to the decrease in gastric volume, changes in gut peptides, and expression of  genes involved in glucose absorption . [ 10 ] [ 11 ]


The procedure involves a longitudinal resection of the stomach starting from the antrum at the point 5–6 cm from the pylorus and finishing at the fundus close to the cardia. [ 12 ]  The remaining gastric sleeve is calibrated with a  bougie . Most surgeons prefer to use a bougie between 36 and 40  Fr  with the procedure and the ideal approximate remaining size of the stomach after the procedure is about 150 mL. [ 13 ]


Endorsed by the International Federation for the Surgery of Obesity and Metabolic Disorders [ 14 ]  and the  American Society for Metabolic and Bariatric Surgery , [ 15 ]  sleeve gastrectomy is gaining popularity in children and adolescents. Studies by Alqahtani and colleagues have found that sleeve gastrectomy causes large weight loss in children and adolescents aged 5 to 21 years. [ 16 ]  Moreover, they compared weight loss with adults and found comparable weight loss. [ 17 ]  A study published in 2016 showed that growth progresses were unaffected after sleeve gastrectomy in children younger than 14 years of age. [ 18 ]   Depression  following the procedure has been noted in some individuals. Another side effect is  insomnia . After this surgery many people can only sleep when they take  melatonin  or sleeping medications. [ 19 ]


Sleeve gastrectomy may cause complications; some of them are listed below:


Micsorare stomac/ gastric sleeve  - info related


Stretta  is a minimally invasive  endoscopic  procedure for the treatment of  gastroesophageal reflux disease  (GERD) that delivers  radiofrequency energy  in the form of  electromagnetic waves  through electrodes at the end of a  catheter  to the  lower esophageal sphincter  (LES) and the  gastric cardia  – the region of the stomach just below the LES. The energy heats the tissue, ultimately causing it to swell and stiffen; the way this works was not understood as of 2015, but it was thought that perhaps the heat causes local inflammation, collagen deposition and muscular thickening of the LES and that it may  disrupt the nerves  there. [ 1 ]


Its relative efficacy is controversial, with the  American College of Gastroenterology  recommending against its use in 2013, and in the same year the  Society of American Gastrointestinal and Endoscopic Surgeons  (SAGES) giving it a strong recommendation for people who refuse laparoscopic  Nissen fundoplication , which involves making incisions in the torso and wrapping part of the stomach around the base of the esophagus, and which is considered the gold standard for efficacy. [ 2 ] [ 3 ] [ 4 ]  In 2015 an  American Society for Gastrointestinal Endoscopy  guideline noted that the quality of evidence was low for Stretta and the other available endoscopic treatment for GERD ( transoral incisionless fundoplication ) and called for better research to be conducted; it suggested that endoscopic treatments for GERD be considered. [ 5 ]


The device for carrying out the procedure was originally developed by a company called Curon which obtained FDA approval for the device in 2000 but then went bankrupt in 2006; the device was brought back to market by Mederi Therapeutics in 2010. [ 2 ] [ 6 ]  The procedure costs between $3,000 and $4,000 as of 2004. [ 7 ]


An American Society of Gastrointestinal Endoscopy (ASGE) statement in June 2015 state that endoscopic antireflux therapy is a potential treatment based on the 2012 review. [ 8 ]


In 2015 three reviews were published discussing the relative safety and effectiveness of the procedure compared with other endoscopic procedures delivered through the mouth, drug treatment (generally  proton-pump inhibitors ), and fundoplication. [ 1 ] [ 2 ] [ 6 ]


One was a systematic review and meta-analysis of clinical trials conducted with Stretta, done in response to the 2013 SAGES review (which did not include meta-analysis). [ 2 ]  This review found that quality of studies that had been conducted was generally poor, and that compared with sham therapy (used a placebo for medical device clinical trials), the procedure did not change time spent at a pH less than 4, did not increase lower esophageal sphincter pressure (LESP), did not allow people to stop treatment with proton-pump inhibitors, and did not improve health-related quality of life. [ 2 ]


Another of the 2015 reviews was a narrative  literature review , noted its long history of use, and found the procedure safe and effective, and noted that the procedure complemented drug treatment and fundoplication, providing a useful option. [ 6 ]


The other 2015 review was a narrative literature review was more tentative, noting the long safety record but only willing to state that the procedure "may be effective in reducing symptom burden and quality of life scores up to 8 years post-intervention. However, there does not appear to be any sustained improvement in objective outcomes and there is no evidence that Stretta results in improved outcomes as compared to surgical intervention. [ 1 ]


A more recent study published in 2020 [ 9 ]  evaluated 25 patients post Stretta Procedure  and the results concluded significant improvement in reflux symptoms and quality of life, lowering Heartburn Score (DeMeester score) [ 10 ]  from 3.7 in women and 4.0 in men to 1.6±1 (p = 0.05) in women and 1.68±1.19 (p = 0.05) in men.


A 2012 systematic review and meta-analysis upon which the 2013 SAGES review had relied, had found that it improves GERD symptoms. [ 11 ]


Therapeutic endoscopy  is the medical term for an endoscopic procedure during which treatment is carried out via the endoscope. This contrasts with  diagnostic endoscopy , where the aim of the procedure is purely to visualize a part of the  gastrointestinal ,  respiratory  or  urinary tract  in order to aid  diagnosis . In practice, a procedure which starts as a diagnostic endoscopy may become a therapeutic endoscopy depending on the findings, such as in cases of upper  gastrointestinal bleeding , or the finding of  polyps  during  colonoscopy .


A number of different techniques have been developed to allow treatment to be carried out endoscopically, to treat disorders such as  bleeding ,  strictures  and polyps.


Endoscopic injection of bleeding peptic ulcers with  adrenaline  has been practised since the 1970s, [ 1 ]  endoscopic heater probes have been used since the 1980s, [ 2 ]  and  Argon plasma coagulation  has been used since the 1990s. More recently, adrenaline injection tends to be combined with either heater probe coagulation or argon plasma coagulation to minimize the chance of an ulcer rebleeding. The disadvantage of this treatment is a low risk of  perforation  of the gastric wall and a low risk of peritonitis. [ 3 ]  Combined therapy may work better than epinephrine alone. However, there is no evidence that one kind of treatment is more effective than the other. [ 3 ]


Injection  sclerotherapy  has been used to treat  oesophageal varices  since the 1960s. [ 4 ]  A sheathed needle is passed through a channel in the endoscope, unsheathed and pushed into a varix. A sclerosing agent, such as  ethanolamine  or  absolute alcohol , is then injected into the varix to cause scarring and constriction of the varix with the aim of obliterating the varix (or varices). This technique has now largely been superseded by variceal band ligation. [ citation needed ]


Sclerotherapy has also been used in the treatment of gastric varices since the late 1980s. [ 5 ]  In this case Histoacryl glue ( cyanoacrylate ) is commonly used as the sclerosant. [ 6 ]  This technique is favoured over band ligation because the position of the varices in the stomach, most often in the gastric  fundus , makes the placing of bands very difficult.


Argon plasma coagulation (APC) has been used to provide tissue coagulation and haemostasis since the early part of the 1990s. [ 7 ]  A stream of argon gas is passed through an endoscopic catheter; this is then ionized at the tip of the catheter by an electric current. The tip of the catheter is held close to the tissue to be treated, and the current arcs across to the tissue causing a superficial (2–3 mm) burn. The lack of contact between the catheter and the tissue stops the tendency of the catheter to stick to the tissue, reducing unwanted tissue damage. [ 8 ]


Its principal use is in providing haemostasis in gastrointestinal bleeding;  angiodysplasia ,  GAVE , [ 9 ]  bleeding  malignant tumours  and bleeding  peptic ulcers  can all be treated. Trials have also been carried out to assess its use in eradicating Barrett’s oesophagus, but have found that relapse is common. [ 10 ]


Dilatation of  benign oesophageal strictures  using semi-rigid bougies existed long before the advent of flexible endoscopes. [ 11 ]  Since that time oesophageal dilatation has been carried out using either bougies or endoscopic balloons, and can be used to treat benign oesophageal strictures and  achalasia . [ citation needed ]


Initially, bougies were used to dilate benign strictures of the oesophagus. These could be passed alongside the endoscope, allowing visualisation of the bougie passing through the stricture, [ 12 ]  but the technique of passing a guidewire through the stricture endoscopically, then removing the endoscope and passing the bougie over the guidewire was more commonly used. [ 13 ]


More recently, balloon dilatation of the oesophageal strictures has become more common. It is thought that this technique carries a lower complication rate than the use of bougies, and since endoscopy balloons are single use items there are no concerns about equipment sterilization. [ 11 ]  In addition to oesophageal dilatation, endoscopic balloons can also be used to dilate pyloric strictures. [ 14 ]


Endoscopic polypectomy has been carried out since the early 1970s by both endoscopic snare removal and fulguration of polyps with hot biopsy forceps. [ 15 ] [ 16 ]


Oesophageal varices have been treated by band ligation since the late 1980s. [ 17 ]


Expandable mesh stents can be deployed in the oesophagus at endoscopy, primarily in patients with inoperable oesophageal cancer which is causing  dysphagia . [ 18 ]


Plastic stents can also be used to relieve obstruction of the  common bile duct  at  ERCP . [ 19 ]


A method for inserting a feeding gastrostomy tube without the need for surgery was first described in 1980. [ 20 ]   This endoscopic technique is of particular use as many patients who require feeding tubes (such as after patients with swallowing difficulties after a  stroke ) are at high risk for complications from  anaesthesia  and  surgery ; the endoscopic technique usually requires mild sedation only. [ citation needed ]


Foreign bodies commonly impact in the lower oesophagus, and removal of these by pushing them into the stomach has been practised since the Middle Ages. [ 11 ]  Foreign body retrieval, using forceps and magnets, has been practised since the time of rigid oesophagoscopy and  bronchoscopy . [ citation needed ]


A number of techniques are being developed for the endoscopic treatment of  gastro-oesophageal reflux disease  as an alternative to laparoscopic  Nissen fundoplication . [ 21 ]


Endoscopic circumferential radiofrequency ablation is being developed in an effort to obviate long-term endoscopic surveillance in patients with Barrett's oesophagus, and to reduce the risk of development of oesophageal carcinoma. Previous techniques, such as Argon plasma coagulation, have been unsuccessful because of incomplete removal of the Barrett's mucosa and therefore relapse of part of the treated area. [ 10 ]  Newer techniques using circumferential radiofrequency ablation, which allows larger areas of the oesophagus to be treated at one time giving a more uniform area of treatment, are showing more promising short-term results. [ 22 ]


Early trials are under way to evaluate an endoscopic technique for gastric stapling, a type of  bariatric surgery , which aims to induce long-term weight loss in  morbidly obese  patients. [ 23 ]


Transoral incisionless fundoplication  ( TIF ) is an endoscope treatment designed to relieve symptoms of  gastroesophageal reflux disease  (GERD). The TIF procedure, similar to  Nissen fundoplication , alleviates GERD symptoms by wrapping a portion of the stomach around the esophagus. [ 1 ]


The TIF procedure, unlike laparoscopic fundoplication, does not require surgical incisions. Instead a surgical device (called the EsophyX) is inserted into the mouth, passed through the throat, and into the stomach. An  endoscope  is utilized to perform the procedure. [ 2 ]


A minority of individuals who undergo the TIF procedure also require a  hiatal hernia  repair operation. [ 3 ]  The procedure is performed while the person is under general anesthesia [ 4 ]  and is typically an outpatient procedure. [ 1 ]


Transoral incisionless fundoplication may improve symptoms in  gastroesophageal reflux disease , at least in the short term. [ 5 ]   Benefits from the TIF procedure may last for up to 6 years. [ 6 ]


The risk of severe complications is 2.4%. [ 7 ]  About 1 in 30 people have major complications from the procedure. [ 5 ]


The device utilized to perform the procedure, called EsophyX, was developed by EndoGastric Solutions. The first TIF procedure utilizing the device was performed in 2005. [ 8 ]   The device received European Union CE mark in 2006 and United States Food and Drug Administration issued initial 510(k) clearance in 2007. [ 2 ] [ 9 ]


In February 2015, the  American Medical Association 's CPT Editorial Panel reviewed whether to create a new category 1  current procedural terminology  (CPT) code for the TIF procedure. In January 2016, a unique code for the transoral incisionless fundoplication procedure was created and implemented. [ 10 ]


As of 2016, more than 17,000 TIF procedures had been performed. [ 8 ]


In July 2016,  Health Care Service Corporation  (HCSC) became the first United States health insurance company to add the TIF procedure to their medical coverage policy. HSCS added the TIF procedure to their health insurance policy at the recommendation of both the  American Gastroenterological Association  (AGA) and  The Society of American Gastrointestinal and Endoscopic Surgeons  (SAGES). [ 11 ]


The TIF procedure is not the ideal GERD solution for all people. Other medical and endoscopic treatments to alleviate GERD symptoms include:  Stretta procedure [ 12 ]  and  proton-pump inhibitors (PPIs) . [ 13 ]


The  United Kingdom Model for End-Stage Liver Disease  or  UKELD  is a  medical  scoring system used to predict the prognosis of patients with  chronic liver disease . It is used in the  United Kingdom  to help determine the need for  liver transplantation . [ 1 ]  It was developed from the  MELD  score, incorporating the  serum sodium  level. [ 2 ]


The UKELD score is calculated from the patient's  INR , serum  creatinine , serum  bilirubin  and serum sodium, according to the formula: [ 3 ]


(
 5.395
 ×
 ln

 I
 N
 R
 )
 +
 (
 1.485
 ×
 ln

 c
 r
 e
 a
 t
 i
 n
 i
 n
 e
 )
 +
 (
 3.13
 ×
 ln

 b
 i
 l
 i
 r
 u
 b
 i
 n
 )
 −
 (
 81.565
 ×
 ln

 N
 a
 )
 +
 435

 {\displaystyle (5.395\times \ln INR)+(1.485\times \ln creatinine)+(3.13\times \ln bilirubin)-(81.565\times \ln Na)+435}


Higher UKELD scores equate to higher one-year mortality risk. A UKELD score of 49 indicates a 9% one-year risk of mortality, and is the minimum score required to be added to the liver transplant waiting list in the U.K. [ 1 ]  A UKELD score of 60 indicates a 50% chance of one-year survival. [ 2 ]


The UKELD score was developed in 2008 to aid in the selection of patients for liver transplantation in the U.K. [ 4 ]


The  urea breath test  is a rapid  diagnostic  procedure used to identify  infections  by  Helicobacter pylori , a spiral  bacterium  implicated in  gastritis ,  gastric ulcer , and  peptic ulcer  disease. It is based upon the ability of  H. pylori  to convert  urea  to ammonia and carbon dioxide. Urea breath tests are recommended in leading society guidelines as a preferred non-invasive choice for detecting  H. pylori   before and after treatment. [ 1 ] [ 2 ]


Patients swallow  urea  labelled with an uncommon  isotope , either  radioactive   carbon-14  (nowadays preferred in many countries) or non-radioactive  carbon-13 . In the subsequent 10–30 minutes, the detection of isotope-labelled  carbon dioxide  in exhaled breath indicates that the urea was split; this indicates that  urease  (the  enzyme  that   H. pylori  uses to  metabolize  urea to produce  ammonia ) is present in the  stomach , and hence that   H. pylori  bacteria are present.


For the two different forms of urea, different instrumentation is required. Carbon-14 is normally measured by  scintillation , whereas carbon-13 can be detected by  isotope ratio mass spectrometry  or simpler by  nondispersive infrared (NDIR) spectrometry . For each of these methods, a baseline breath sample is required before taking the isotope-labeled urea, for comparison with the post-urea sample, with a 15- to 30-minute duration between them. Samples may be sent to a reference laboratory for analysis. Alternatively, NDIR spectrometry can be performed by a table-top instrument as an office-based test, and results are provided immediately within minutes. [ 3 ] [ 4 ] [ 5 ]


The difference between the pre- and post urea measurements is used to determine infection. This value is compared to a cut-off value. Results below the value are assumed to be negative, those above positive. The cut-off value itself is determined by comparing the results of patients with two or more different detection methods. The value is chosen that gives the best combination of  sensitivity  and  specificity . Both carbon-14 and carbon-13 urea breath tests have high sensitivity and specificity, though the carbon-13 test is preferred in certain populations due to its non-radioactive nature. [ 6 ]


The test measures active  H. pylori  infection. If antibiotics are depressing the amount of  H. pylori  present, or the stomach conditions are less acidic than normal, the amount of urease present will be lessened.


Accordingly, the test should only be performed 14 days after stopping acid reducing medication ( proton pump inhibitors , PPI) or 28 days after stopping antibiotic treatment. Some clinicians believe that a reservoir of  H. pylori  in dental plaque can affect the result. [ 7 ]


The test is especially done accompanying an eradication therapy by antibiotics (to avoid overdosing) or to check the success of an ulcer operation. In both cases, immunological tests can give false positive results. [ 1 ] [ 2 ]


Helicobacter pylori , previously known as  Campylobacter pylori , is a  gram-negative ,  flagellated ,  helical bacterium . Mutants can have a rod or curved rod shape that exhibits less  virulence . [ 1 ] [ 2 ]  Its  helical  body (from which the  genus  name  Helicobacter  derives) is thought to have evolved to penetrate the  mucous lining  of the  stomach , helped by its  flagella , and thereby establish infection. [ 3 ] [ 2 ]  The bacterium was first identified as the causal agent of  gastric ulcers  in 1983 by Australian  physician-scientists   Barry Marshall  and  Robin Warren . [ 4 ] [ 5 ]  In 2005, they were awarded the  Nobel Prize in Physiology or Medicine  for their discovery. [ 6 ]


Infection of the stomach with  H. pylori  is not the cause of illness itself: over half of the global population is infected, but most individuals are asymptomatic. [ 7 ] [ 8 ]  Persistent  colonization  with more virulent strains can induce a number of gastric and non-gastric disorders. [ 9 ]  Gastric disorders due to infection begin with  gastritis , or inflammation of the stomach lining. [ 10 ]  When infection is persistent, the prolonged inflammation will become  chronic gastritis . Initially, this will be non-atrophic gastritis, but the damage caused to the stomach lining can bring about the development of  atrophic gastritis  and ulcers within the stomach itself or the  duodenum  (the nearest part of the intestine). [ 10 ]  At this stage, the risk of developing  gastric cancer  is high. [ 11 ]  However, the development of a  duodenal ulcer  confers a comparatively lower risk of cancer. [ 12 ]   Helicobacter pylori  are  class 1 carcinogenic bacteria , and potential cancers include gastric  MALT lymphoma  and  gastric cancer . [ 10 ] [ 11 ]  Infection with  H. pylori  is responsible for an estimated 89% of all gastric cancers and is linked to the development of 5.5% of all cases cancers worldwide. [ 13 ] [ 14 ]   H. pylori  is the only bacterium known to cause cancer. [ 15 ]


Extragastric complications that have been linked to  H. pylori  include  anemia  due either to iron deficiency or  vitamin B12 deficiency ,  diabetes mellitus , cardiovascular illness, and certain neurological disorders. [ 16 ]  An inverse association has also been claimed with  H. pylori  having a positive protective effect against  asthma ,  esophageal cancer ,  inflammatory bowel disease  (including  gastroesophageal reflux disease  and  Crohn's disease ), and others. [ 16 ]


Some studies suggest that  H. pylori  plays an important role in the natural stomach ecology by influencing the type of bacteria that colonize the gastrointestinal tract. [ 17 ] [ 18 ]  Other studies suggest that non-pathogenic strains of  H. pylori  may beneficially normalize stomach acid secretion, and regulate appetite. [ 19 ]


In 2023, it was estimated that about two-thirds of the world's population was infected with  H. pylori , being more common in  developing countries . [ 20 ]  The prevalence has declined in many countries due to  eradication treatments  with antibiotics and  proton-pump inhibitors , and with increased  standards of living . [ 21 ] [ 22 ]


Helicobacter pylori  is a species of  gram-negative bacteria  in the  Helicobacter  genus. [ 23 ]
About half the world's population is infected with  H. pylori  but only a few strains are  pathogenic .  H pylori  is a  helical bacterium  having a predominantly  helical shape , also often described as having a spiral or  S  shape. [ 24 ] [ 25 ]  Its helical shape is better suited for progressing through the viscous  mucosa lining of the stomach , and is maintained by a number of  enzymes  in the  cell wall's   peptidoglycan . [ 1 ]  The bacteria reach the less acidic mucosa by use of their  flagella . [ 26 ]  Three strains studied showed a variation in length from 2.8–3.3 μm but a fairly constant diameter of 0.55–0.58 μm. [ 24 ]   H. pylori  can convert from a helical to an inactive  coccoid  form that can evade the immune system, and that may possibly become viable, known as  viable but nonculturable  (VBNC). [ 27 ] [ 28 ]


Helicobacter pylori  is  microaerophilic  – that is, it requires  oxygen , but at lower concentration than in the  atmosphere . It contains a  hydrogenase  that can produce energy by oxidizing molecular  hydrogen  (H 2 ) made by  intestinal bacteria . [ 29 ]


H. pylori  can be demonstrated in tissue by  Gram stain ,  Giemsa stain ,  H&E stain ,  Warthin-Starry silver stain ,  acridine orange stain , and  phase-contrast microscopy . It is capable of forming  biofilms . Biofilms help to hinder the action of antibiotics and can contribute to treatment failure. [ 30 ] [ 31 ]


To successfully colonize its host,  H. pylori  uses many different  virulence factors  including  oxidase ,  catalase , and  urease . [ 32 ]  Urease is the most abundant protein, its expression representing about 10% of the total protein weight. [ 33 ]


H. pylori  possesses five major  outer membrane protein  families. [ 32 ]  The largest family includes known and putative  adhesins . The other four families are  porins , iron transporters,  flagellum -associated proteins, and proteins of unknown function. Like other typical gram-negative bacteria, the outer membrane of  H. pylori  consists of  phospholipids  and  lipopolysaccharide  (LPS). The  O-antigen  of LPS may be  fucosylated  and mimic  Lewis blood group antigens  found on the gastric epithelium. [ 32 ]


Helicobacter pylori  consists of a large diversity of strains, and hundreds of  genomes  have been completely  sequenced . [ 34 ] [ 35 ] [ 36 ]  The genome of the strain  26695  consists of about 1.7 million  base pairs , with some 1,576 genes. [ 37 ] [ 38 ]  The  pan-genome , that is the combined set of 30 sequenced strains, encodes 2,239 protein families ( orthologous groups  OGs). [ 39 ]  Among them, 1,248 OGs are conserved in all the 30 strains, and represent the  universal core . The remaining 991 OGs correspond to the  accessory genome  in which 277 OGs are unique to one strain. [ 40 ]


There are eleven  restriction modification systems  in the genome of  H. pylori . [ 38 ]  This is an unusually high number providing a  defence against bacteriophages . [ 38 ]


Single-cell transcriptomics  using  single-cell RNA-Seq  gave the complete  transcriptome  of  H. pylori  which was published in 2010. This analysis of its  transcription  confirmed the known acid induction of major  virulence  loci, including the urease (ure) operon and the Cag  pathogenicity island  (PAI). [ 41 ]  A total of 1,907  transcription start sites  337 primary  operons , and 126 additional suboperons, and 66 mono cistrons  were identified. Until 2010, only about 55 transcription start sites (TSSs) were known in this species. 27% of the primary TSSs are also antisense TSSs, indicating that – similar to  E. coli  –  antisense transcription  occurs across the entire  H. pylori  genome. At least one antisense TSS is associated with about 46% of all  open reading frames , including many  housekeeping genes . [ 41 ]  About 50% of the  5 ′  UTRs  (leader sequences) are 20–40 nucleotides (nt) in length and support the AAGGag motif located about 6 nt (median distance) upstream of start codons as the consensus  Shine–Dalgarno sequence  in  H. pylori . [ 41 ]


The  proteome  of  H. pylori  has been systematically analyzed and more than 70% of its  proteins  have been detected by  mass spectrometry , and other methods. About 50% of the proteome has been quantified, informing of the number of protein copies in a typical cell. [ 42 ]


Studies of the  interactome  have identified more than 3000  protein-protein interactions . This has provided information of how proteins interact with each other, either in stable  protein complexes  or in more dynamic, transient interactions, which can help to identify the functions of the protein. This in turn helps researchers to find out what the function of uncharacterized proteins is, e.g. when an uncharacterized protein interacts with several proteins of the  ribosome  (that is, it is likely also involved in ribosome function). About a third of all ~1,500 proteins in  H. pylori  remain uncharacterized and their function is largely unknown. [ 43 ]


An infection with  Helicobacter pylori  can either have no symptoms even when lasting a lifetime, or can harm the stomach and duodenal  linings  by  inflammatory responses  induced by several mechanisms associated with a number of  virulence factors .  Colonization  can initially cause  H. pylori induced gastritis , an  inflammation of the stomach lining  that became a listed disease in  ICD11 . [ 44 ] [ 45 ] [ 46 ]  This will progress to  chronic gastritis  if left untreated. Chronic gastritis may lead to  atrophy  of the stomach lining, and the development of  peptic ulcers  (gastric or duodenal). These changes may be seen as stages in the development of  gastric cancer , known as  Correa's cascade . [ 47 ] [ 48 ]  Extragastric complications that have been linked to  H. pylori  include  anemia  due either to iron-deficiency or vitamin B12 deficiency, diabetes mellitus, cardiovascular, and certain neurological disorders. [ 16 ]


Peptic ulcers are a consequence of inflammation that allows stomach acid and the digestive enzyme  pepsin  to overwhelm the protective mechanisms of the  mucous membranes . The location of colonization of  H. pylori , which affects the location of the ulcer, depends on the acidity of the stomach. [ 49 ]  In people producing large amounts of acid,  H. pylori  colonizes near the  pyloric antrum  (exit to the duodenum) to avoid the acid-secreting  parietal cells  at the  fundus  (near the entrance to the stomach). [ 32 ]   G cells  express relatively high levels of  PD-L1  that protects these cells from  H. pylori -induced immune destruction. [ 50 ]  In people producing normal or reduced amounts of acid,  H. pylori  can also colonize the rest of the stomach.


The inflammatory response caused by bacteria colonizing near the pyloric antrum induces G cells in the antrum to secrete the hormone  gastrin , which travels through the bloodstream to parietal cells in the fundus. [ 51 ]  Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well. [ 52 ]  The increased acid load damages the duodenum, which may eventually lead to the formation of ulcers.


Helicobacter pylori  is a class I  carcinogen , and potential cancers include gastric  mucosa-associated lymphoid tissue  (MALT)  lymphomas  and  gastric cancer . [ 10 ] [ 11 ] [ 53 ]  Less commonly,  diffuse large B-cell lymphoma  of the stomach is a risk. [ 54 ]  Infection with  H. pylori  is responsible for around 89 per cent of all gastric cancers, and is linked to the development of 5.5 per cent of all cases of cancer worldwide. [ 13 ] [ 14 ]  Although the data varies between different countries, overall about 1% to 3% of people infected with  Helicobacter pylori  develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no  H. pylori  infection. [ 55 ] [ 32 ]   H. pylori -induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018. [ 56 ]  Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed. [ 57 ]


Chronic inflammation that is a feature of cancer development is characterized by infiltration of  neutrophils  and  macrophages  to the gastric epithelium, which favors the accumulation of  pro-inflammatory cytokines ,  reactive oxygen species  (ROS) and  reactive nitrogen species  (RNS) that cause  DNA damage . [ 58 ]  The  oxidative DNA damage  and levels of  oxidative stress  can be indicated by a biomarker,  8-oxo-dG . [ 58 ] [ 59 ]  Other damage to DNA includes  double-strand breaks . [ 60 ]


Small  gastric  and  colorectal polyps  are  adenomas  that are more commonly found in association with the mucosal damage induced by  H. pylori  gastritis. [ 61 ] [ 62 ]  Larger polyps can in time become cancerous. [ 63 ] [ 61 ]  A modest association of  H. pylori  has been made with the development of  colorectal cancers , but as of 2020 causality had yet to be proved. [ 64 ] [ 63 ]


Most people infected with  H. pylori  never experience any symptoms or complications, but will have a 10% to 20% risk of developing  peptic ulcers  or a 0.5% to 2% risk of stomach cancer. [ 8 ] [ 65 ]   H. pylori induced gastritis  may present as acute gastritis with  stomach ache ,  nausea , and ongoing  dyspepsia  (indigestion) that is sometimes accompanied by depression and anxiety. [ 8 ] [ 66 ]  Where the gastritis develops into chronic gastritis, or an ulcer, the symptoms are the same and can include  indigestion , stomach or abdominal pains, nausea,  bloating ,  belching , feeling hunger in the morning, feeling full too soon, and sometimes  vomiting , heartburn, bad breath, and weight loss. [ 67 ] [ 68 ]


Complications of an ulcer can cause severe signs and symptoms such as black or tarry stool indicative of  bleeding  into the stomach or duodenum; blood - either red or coffee-ground colored in vomit; persistent sharp or severe abdominal pain; dizziness, and a fast heartbeat. [ 67 ] [ 68 ]  Bleeding is the most common complication. In cases caused by  H. pylori  there was a greater need for  hemostasis  often requiring gastric resection. [ 69 ]  Prolonged bleeding may cause anemia leading to weakness and fatigue. Inflammation of the pyloric antrum, which connects the stomach to the duodenum, is more likely to lead to duodenal ulcers, while inflammation of the  corpus  may lead to a gastric ulcer.


Stomach cancer  can cause nausea, vomiting, diarrhoea, constipation, and unexplained weight loss. [ 70 ]   Gastric polyps  are  adenomas  that are usually asymptomatic and benign, but may be the cause of dyspepsia, heartburn, bleeding from the stomach, and, rarely, gastric outlet obstruction. [ 61 ] [ 71 ]  Larger polyps may have  become cancerous . [ 61 ]
 Colorectal polyps  may be the cause of rectal bleeding, anemia, constipation, diarrhea, weight loss, and abdominal pain. [ 72 ]


Virulence factors  help a pathogen to evade the immune response of the host, and to successfully  colonize . The many virulence factors of  H. pylori  include its flagella, the production of urease, adhesins,  serine protease   HtrA  (high temperature requirement A), and the major  exotoxins   CagA  and  VacA . [ 30 ] [ 73 ]  The presence of VacA and CagA are associated with more  advanced outcomes . [ 74 ]  CagA is an oncoprotein associated with the development of gastric cancer. [ 7 ]


H. pylori  infection is associated with  epigenetically  reduced efficiency of the  DNA repair  machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. [ 75 ]  It has been shown that expression of two DNA repair proteins,  ERCC1  and  PMS2 , was severely reduced once  H. pylori  infection had progressed to cause  dyspepsia . [ 76 ]  Dyspepsia occurs in about 20% of infected individuals. [ 77 ]  Epigenetically reduced protein expression of DNA repair proteins  MLH1 ,  MGMT  and  MRE11  are also evident. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of gastric carcinogenesis. [ 59 ] [ 78 ] [ 79 ]  These  epigenetic alterations  are due to  H. pylori -induced  methylation of CpG sites in promoters of genes [ 78 ]  and  H. pylori -induced altered expression of multiple  microRNAs . [ 79 ]


Two related mechanisms by which  H. pylori  could promote cancer have been proposed. One mechanism involves the enhanced production of  free radicals  near  H. pylori  and an increased rate of host cell  mutation . The other proposed mechanism has been called a "perigenetic pathway", [ 80 ]  and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as  adhesion  proteins.  H. pylori  has been proposed to induce inflammation and locally high levels of  tumor necrosis factor  (TNF), also known as tumor necrosis factor alpha (TNFα)), and/or  interleukin 6  (IL-6). [ 81 ]  According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in  tumor suppressor genes , such as genes that code for cell adhesion proteins. [ 82 ]


The first virulence factor of  Helicobacter pylori  that enables colonization is its  flagellum . [ 83 ]   H. pylori  has from two to seven flagella at  the same polar location  which gives it a high motility. The flagellar filaments are about 3 μm long, and composed of two copolymerized  flagellins , FlaA and FlaB, coded by the genes  flaA , and  flaB . [ 26 ] [ 73 ]  The minor flagellin FlaB is located in the proximal region and the major flagellin FlaA makes up the rest of the flagellum. [ 84 ]  The flagella are sheathed in a continuation of the bacterial outer membrane which gives protection against the gastric acidity. The sheath is also the location of the origin of the outer membrane vesicles that gives protection to the bacterium from bacteriophages. [ 84 ]


Flagella motility is provided by the  proton motive force  provided by urease-driven hydrolysis allowing  chemotactic movements  towards the less acidic  pH  gradient in the mucosa. [ 30 ]  The mucus layer is about 300  μm  thick, and the helical shape of  H. pylori  aided by its flagella helps it to burrow through  this layer where it colonises a narrow region of about 25 μm closest to the epithelial cell layer, where the pH is near to neutral. They further colonise the  gastric pits  and live in the  gastric glands . [ 1 ] [ 84 ] [ 85 ]  Occasionally the bacteria are found inside the epithelial cells themselves. [ 86 ]  The use of  quorum sensing  by the bacteria enables the formation of a biofilm which furthers persistent colonisation. In the layers of the biofilm,  H. pylori  can escape from the actions of antibiotics, and also be protected from host-immune responses. [ 87 ] [ 88 ]  In the biofilm,  H. pylori  can change the flagella to become adhesive structures. [ 89 ]


In addition to using  chemotaxis  to avoid areas of high acidity (low pH),  H. pylori  also produces large amounts of  urease , an  enzyme  which breaks down the  urea  present in the stomach to produce  ammonia  and  bicarbonate , which are released into the bacterial cytosol and the surrounding environment, creating a neutral area. [ 90 ]  The decreased acidity (higher pH) changes the mucus layer from a gel-like state to a more viscous state that makes it easier for the flagella to move the bacteria through the mucosa and attach to the gastric epithelial cells. [ 90 ]   Helicobacter pylori  is one of the few known types of bacterium that has a  urea cycle  which is uniquely configured in the bacterium. [ 91 ]  10% of the cell is of  nitrogen , a balance that needs to be maintained. Any excess is stored in urea excreted in the urea cycle. [ 91 ]


A final stage enzyme in the urea cycle is  arginase , an enzyme that is crucial to the pathogenesis of  H. pylori . Arginase produces  ornithine  and urea, which the enzyme urease breaks down into carbonic acid and ammonia. Urease is the bacterium’s most abundant protein, accounting for 10–15% of the bacterium's total protein content. Its expression is not only required for establishing initial colonization in the breakdown of urea to carbonic acid and ammonia, but is also essential for maintaining chronic infection. [ 92 ] [ 65 ]  Ammonia reduces stomach acidity, allowing the bacteria to become locally established. Arginase promotes the persistence of infection by consuming arginine; arginine is used by macrophages to produce nitric oxide, which has a strong antimicrobial effect. [ 91 ] [ 93 ]  The ammonia produced to regulate  pH  is toxic to epithelial cells. [ 94 ]


H. pylori  must make attachment with the epithelial cells to prevent its being swept away with the constant movement and renewal of the mucus. To give them this adhesion,  bacterial outer membrane proteins  as virulence factors called  adhesins  are produced. [ 95 ]  BabA (blood group antigen binding adhesin) is most important during initial colonization, and SabA (sialic acid binding adhesin) is important in persistence. BabA attaches to glycans and mucins in the epithelium. [ 95 ]  BabA (coded for by the  babA2  gene) also binds to the  Lewis b antigen  displayed on the surface of the epithelial cells. [ 96 ]  Adherence via BabA is acid sensitive and can be fully reversed by a decreased pH. It has been proposed that BabA's acid responsiveness enables adherence while also allowing an effective escape from an unfavorable environment such as a low pH that is harmful to the organism. [ 97 ]  SabA (coded for by the  sabA  gene) binds to increased levels of  sialyl-Lewis  X  antigen expressed on gastric mucosa. [ 98 ]


The outer membrane contains  cholesterol glucoside , a sterol glucoside that  H. pylori   glycosylates  from the  cholesterol  in the gastric gland cells, and inserts it into its outer membrane. [ 99 ]  This cholesterol glucoside is important for membrane stability, morphology and immune evasion, and is rarely found in other bacteria. [ 100 ] [ 101 ]


The enzyme responsible for this is  cholesteryl α-glucosyltransferase  (αCgT or Cgt), encoded by the  HP0421  gene. [ 102 ]  A major effect of the depletion of host cholesterol by Cgt is to disrupt cholesterol-rich  lipid rafts  in the epithelial cells. Lipid rafts are involved in cell signalling and their disruption causes a reduction in the immune inflammatory response, particularly by reducing  interferon gamma . [ 103 ]  Cgt is also secreted by the type IV secretion system, and is secreted in a selective way so that gastric niches where the pathogen can thrive are created. [ 102 ]  Its lack has been shown to give vulnerability from environmental stress to bacteria, and also to disrupt CagA-mediated interactions. [ 99 ]


Colonization induces an intense anti-inflammatory response as a first-line immune system defence. Phagocytic leukocytes and monocytes infiltrate the site of infection, and antibodies are produced. [ 104 ]   H. pylori  is able to adhere to the surface of the phagocytes and impede their action. This is responded to by the phagocyte in the generation and release of oxygen metabolites into the surrounding space.  H. pylori  can survive this response by the activity of  catalase  at its attachment to the phagocytic cell surface. Catalase decomposes hydrogen peroxide into water and oxygen, protecting the bacteria from toxicity. Catalase has been shown to almost completely inhibit the phagocytic oxidative response. [ 104 ]  It is coded for by the gene  katA . [ 105 ]


TNF-inducing protein alpha (Tipα) is a carcinogenic protein encoded by  HP0596  unique to  H. pylori  that induces the expression of  tumor necrosis factor . [ 82 ] [ 106 ]  Tipα enters gastric cancer cells where it binds to cell surface  nucleolin , and induces the expression of  vimentin . Vimentin is important in the  epithelial–mesenchymal transition  associated with the progression of tumors. [ 107 ]


CagA  (cytotoxin-associated antigen A) is a major  virulence factor  for  H. pylori , an  oncoprotein  that is encoded by the  cagA  gene. Bacterial strains with the  cagA  gene are associated with the ability to cause ulcers, MALT lymphomas, and gastric cancer. [ 108 ] [ 109 ]  The  cagA  gene codes for a relatively long (1186- amino acid ) protein. The  cag   pathogenicity island  (PAI) has about 30 genes, part of which code for a complex  type IV secretion system  (T4SS or TFSS). The low  GC-content  of the  cag  PAI relative to the rest of the  Helicobacter  genome suggests the island was acquired by  horizontal transfer  from another bacterial species. [ 38 ]  The  serine protease   HtrA  also plays a major role in the pathogenesis of  H. pylori . The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA. [ 110 ]


The virulence of  H. pylori  may be increased by genes of the  cag  pathogenicity island; about 50–70% of  H. pylori  strains in Western countries carry it. [ 111 ]  Western people infected with strains carrying the  cag  PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island. [ 32 ]  Following attachment of  H. pylori  to stomach epithelial cells, the type IV secretion system expressed by the  cag  PAI "injects" the  inflammation -inducing agent, peptidoglycan, from their own  cell walls  into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic  pattern recognition receptor  (immune sensor) Nod1, which then stimulates expression of  cytokines  that promote inflammation. [ 112 ]


The type-IV  secretion  apparatus also injects the  cag  PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the  cytoskeleton , adherence to adjacent cells, intracellular signaling,  cell polarity , and other cellular activities. [ 113 ]  Once inside the cell, the CagA protein is  phosphorylated  on  tyrosine residues  by a host cell membrane-associated  tyrosine kinase  (TK). CagA then allosterically activates  protein tyrosine phosphatase / protooncogene   Shp2 . [ 114 ]
These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault. [ 115 ]  Pathogenic strains of  H. pylori  have been shown to activate the  epidermal growth factor receptor  (EGFR), a  membrane protein  with a TK  domain . Activation of the EGFR by  H. pylori  is associated with altered  signal transduction  and  gene expression  in host epithelial cells that may contribute to pathogenesis. A  C-terminal  region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell  gene transcription , independent of protein tyrosine phosphorylation. [ 109 ]  A great deal of diversity exists between strains of  H. pylori , and the strain that infects a person can predict the outcome.


VacA  (vacuolating cytotoxin autotransporter) is another major virulence factor encoded by the  vacA  gene. [ 116 ]  All strains of  H. pylori  carry this gene but there is much diversity, and only 50% produce the encoded cytotoxin. [ 92 ] [ 33 ]  The four main subtypes of  vacA  are  s1/m1, s1/m2, s2/m1,  and  s2/m2 .  s1/m1  and  s1/m2  are known to cause an increased risk of gastric cancer. [ 117 ]  VacA is an oligomeric protein complex that causes a progressive vacuolation in the epithelial cells leading to their death. [ 118 ]  The vacuolation has also been associated with promoting intracellular reservoirs of  H. pylori  by disrupting the calcium channel cell membrane  TRPML1 . [ 119 ]  VacA has been shown to increase the levels of  COX2 , an up-regulation that increases the production of a  prostaglandin  indicating a strong host cell inflammatory response. [ 118 ] [ 120 ]


About 4% of the genome encodes for  outer membrane proteins  that can be grouped into five families. [ 121 ]  The largest family includes  bacterial adhesins . The other four families are  porins , iron transporters,  flagellum -associated proteins, and proteins of unknown function. Like other typical gram-negative bacteria, the outer membrane of  H. pylori  consists of  phospholipids  and  lipopolysaccharide  (LPS). The  O-antigen  of LPS may be  fucosylated  and mimic  Lewis blood group antigens  found on the gastric epithelium. [ 32 ]


H. pylori  forms blebs from the outer membrane that pinch off as  outer membrane vesicles  to provide an alternative delivery system for virulence factors including CagA. [ 99 ]


A  Helicobacter   cysteine-rich protein  HcpA is known to trigger an immune response, causing inflammation. [ 122 ]
A  Helicobacter pylori  virulence factor  DupA  is associated with the development of duodenal ulcers. [ 123 ]


The need for survival has led to the development of different mechanisms of tolerance that enable the persistence of  H. pylori . [ 124 ]  These mechanisms can also help to overcome the effects of antibiotics. [ 124 ]   H. pylori  has to not only survive the harsh gastric acidity but also the sweeping of mucus by continuous  peristalsis , and  phagocytic  attack accompanied by the release of  reactive oxygen species . [ 125 ]   All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage. [ 126 ]  Stress conditions activate bacterial response mechanisms that are regulated by proteins expressed by  regulator genes . [ 124 ]  The  oxidative stress  can induce potentially lethal mutagenic  DNA adducts  in its genome. Surviving this  DNA damage  is supported by  transformation -mediated  recombinational repair , that contributes to successful colonization. [ 127 ] [ 128 ]   H. pylori  is naturally competent for transformation. While many organisms are competent only under certain environmental conditions, such as starvation,  H. pylori  is competent throughout logarithmic growth. [ 126 ]


Transformation  (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation for  DNA repair . [ 126 ]   Homologous recombination  is required for repairing  double-strand breaks  (DSBs). The AddAB helicase-nuclease complex resects DSBs and loads  RecA  onto single-strand DNA (ssDNA), which then mediates strand exchange, leading to homologous recombination and repair. The requirement of RecA plus AddAB for efficient gastric colonization suggests that  H. pylori  is either exposed to double-strand DNA damage that must be repaired or requires some other recombination-mediated event. In particular, natural transformation is increased by DNA damage in  H. pylori , and a connection exists between the DNA damage response and DNA uptake in  H. pylori . [ 126 ]   This natural competence contributes to the persistence of  H. pylori .  H. pylori  has much greater rates of recombination and mutation than other bacteria. [ 3 ]   Genetically different strains can be found in the same host, and also in different regions of the stomach. [ 129 ]  An overall response to multiple stressors can result from an interaction of the mechanisms. [ 124 ]


RuvABC  proteins are essential to the process of recombinational repair, since they resolve intermediates in this process termed  Holliday junctions .  H. pylori  mutants that are defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reduced survival within macrophages, and are unable to establish successful infection in a mouse model. [ 130 ]  Similarly, RecN protein plays an important role in DSB repair. [ 131 ]  An  H. pylori  recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival of  H. pylori  within its host. [ 131 ]


An effective sustained colonization response is the formation of a  biofilm .
Having first adhered to cellular surfaces, the bacteria produce and secrete  extracellular polymeric substance  (EPS). EPS consists largely of  biopolymers  and provides the framework for the biofilm structure. [ 90 ]   H. pylori  helps the biofilm formation by altering its flagella into adhesive structures that provide adhesion between the cells. [ 89 ]  Layers of aggregated bacteria as microcolonies accumulate to thicken the biofilm.


The matrix of EPS prevents the entry of antibiotics and immune cells, and provides protection from heat and competition from other microorganisms. [ 90 ]  Channels form between the cells in the biofilm matrix allowing the transport of nutrients, enzymes, metabolites, and waste. [ 90 ]  Cells in the deep layers may be nutritionally deprived and enter into the coccoid dormant-like state. [ 132 ] [ 133 ]  By changing the shape of the bacterium to a coccoid form, the exposure of  LPS  (targeted by antibiotics) becomes limited, and so evades detection by the immune system. [ 134 ]  It has also been shown that the  cag  pathogenicity island remains intact in the coccoid form. [ 134 ]  Some of these antibiotic resistant cells may remain in the host as  persister cells . Following eradication, the persister cells can cause a recurrence of the infection. [ 132 ] [ 133 ]  Bacteria can detach from the biofilm to relocate and colonize elsewhere in the stomach to form other biofilms. [ 90 ]


Colonization with  H. pylori  does not always lead to disease, but is associated with a number of  stomach diseases . [ 32 ]  Testing is recommended in cases of  peptic ulcer disease  or low-grade gastric  MALT lymphoma ; after  endoscopic  resection of early  gastric cancer ; for first-degree relatives with gastric cancer, and in certain cases of indigestion. Other indications that prompt testing for  H. pylori  include long term  aspirin  or other  non-steroidal anti-inflammatory  use, unexplained  iron deficiency anemia , or in cases of  immune thrombocytopenic purpura . [ 135 ]  Several methods of testing exist, both invasive and non-invasive.


Non-invasive tests for  H. pylori  infection include  serological tests  for  antibodies ,  stool tests , and  urea breath tests . Carbon urea breath tests include the use of  carbon-13 , or a radioactive  carbon-14  producing a labelled carbon dioxide that can be detected in the breath. [ 136 ]  Carbon urea breath tests have a high  sensitivity and specificity  for the diagnosis of  H. pylori . [ 136 ]


Proton-pump inhibitors and antibiotics should be discontinued for at least 30 days prior to testing for  H. pylori  infection or eradication, as both agents inhibit  H. pylori  growth and may lead to false negative results. [ 135 ]  Testing to confirm eradication is recommended 30 days or more after completion of treatment for  H. pylori  infection.  H. pylori  breath testing or stool antigen testing are both reasonable tests to confirm eradication. [ 135 ]   H. pylori  serologic testing, including  IgG antibodies , are not recommended as a test of eradication as they may remain elevated for years after successful treatment of infection. [ 135 ]


An endoscopic biopsy is an invasive means to test for  H. pylori  infection. Low-level infections can be missed by biopsy, so multiple samples are recommended. The most accurate method for detecting  H. pylori  infection is with a  histological  examination from two sites after endoscopic  biopsy , combined with either a  rapid urease test  or microbial culture. [ 137 ]  Generally, repeating endoscopy is not recommended to confirm  H. pylori  eradication, unless there are specific indications to repeat the procedure. [ 135 ]


Helicobacter pylori  is contagious, and is  transmitted  through direct contact either with  saliva  (oral-oral) or  feces  ( fecal–oral route ), but mainly through the oral–oral route. [ 8 ]  Consistent with these transmission routes, the bacteria have been isolated from  feces ,  saliva , and  dental plaque . [ 138 ]   H. pylori  may also be transmitted by consuming contaminated food or water. [ 139 ]  Transmission occurs mainly within families in developed nations, but also from the broader community in developing countries. [ 140 ]


To prevent the development of  H. pylori -related diseases when infection is suspected, antibiotic-based therapy regimens are recommended to  eradicate the bacteria . [ 46 ]  When successful the disease progression is halted. First line therapy is recommended if low-grade gastric MALT lymphoma is diagnosed, regardless of evidence of  H. pylori . However, if a severe condition of atrophic gastritis with gastric lesions is reached antibiotic-based treatment regimens are not advised since such lesions are often not reversible and will progress to gastric cancer. [ 46 ]  If the cancer is managed to be treated it is advised that an eradication program be followed to prevent a recurrence of infection, or reduce a recurrence of the cancer, known as metachronous. [ 46 ] [ 141 ] [ 142 ]


Due to  H. pylori 's  role as a major cause of certain diseases (particularly cancers) and its consistently increasing  resistance to antibiotic therapy , there is an obvious need for alternative treatments. [ 143 ]  A vaccine targeted towards the development of gastric cancer, including MALT lymphoma, would also prevent the development of gastric ulcers. [ 5 ]  A vaccine that would be prophylactic for use in children, and one that would be therapeutic later are the main goals. Challenges to this are the extreme genomic diversity shown by  H. pylori  and complex host-immune responses. [ 143 ] [ 144 ]


Previous studies in the Netherlands and in the US have shown that such a prophylactic vaccine programme would be ultimately cost-effective. [ 145 ] [ 146 ]  However, as of late 2019 there have been no advanced vaccine candidates and only one vaccine in a Phase I clinical trial.  Furthermore, development of a vaccine against  H. pylori  has not been a priority of major pharmaceutical companies. [ 147 ]  A key target for potential therapy is the  proton-gated urea channel , since the secretion of urease enables the survival of the bacterium. [ 148 ]


The 2022 Maastricht Consensus Report recognised  H. pylori  gastritis as  Helicobacter pylori induced gastritis , and has been included in  ICD11 . [ 44 ] [ 45 ] [ 46 ]  Initially the infection tends to be superficial, localised to the upper mucosal layers of the stomach. [ 149 ]  The intensity of chronic inflammation is related to the cytotoxicity of the  H. pylori  strain. A greater cytotoxicity will result in the change from a non-atrophic gastritis to an atrophic gastritis, with the loss of  mucous glands . This condition is a prequel to the development of peptic ulcers and gastric adenocarcinoma. [ 149 ]


Eradication of  H. pylori  is recommended to treat the infection, including when advanced to  peptic ulcer disease .  The recommendations for first-line treatment is a quadruple therapy consisting of a  proton-pump inhibitor ,  amoxicillin ,  clarithromycin , and  metronidazole . Prior to treatment, testing is recommended to identify any pre-existing antibiotic resistances. A high rate of resistance to metronidazole has been observed. In areas of known clarithromycin resistance, the first-line therapy is changed to a  bismuth  based regimen including  tetracycline  and metronidazole for 14 days. If one of these courses of treatment fails, it is suggested to use the alternative. [ 44 ]


Treatment failure may typically be attributed to antibiotic resistance, or inadequate acid suppression from proton-pump inhibitors. [ 150 ]  Following clinical trials, the use of the  potassium-competitive acid blocker   vonoprazan , which has a greater acid suppressive action, was approved for use in the US in 2022. [ 151 ] [ 150 ]  Its recommended use is in combination with amoxicillin, with or without clarithromycin. It has been shown to have a faster action and can be used with or without food. [ 150 ]  Successful eradication regimens have revolutionised the treatment of peptic ulcers. [ 152 ] [ 153 ]  Eradication of  H. pylori  is also associated with a subsequent decreased risk of duodenal or gastric ulcer recurrence. [ 135 ]


Plant extracts  and  probiotic  foods are being increasingly used as  add-ons  to usual treatments. Probiotic yogurts containing  lactic acid bacteria   Bifidobacteria  and  Lactobacillus  exert a suppressive effect on  H. pylori  infection, and their use has been shown to improve the rates of eradication. [ 14 ]  Some commensal intestinal bacteria as part of the  gut microbiota  produce  butyrate  that acts as a  prebiotic  and enhances the mucosal immune barrier. Their use as probiotics may help balance the gut dysbiosis that accompanies antibiotic use. [ 154 ]  Some probiotic strains have been shown to have bactericidal and bacteriostatic activity against  H. pylori , and also help to balance the gut dysbiosis. [ 155 ] [ 134 ]  Antibiotics have a negative impact on gastrointestinal microbiota and cause nausea, diarrhea, and  sickness  for which probiotics can alleviate. [ 134 ]


Increasing  antibiotic resistance  is the main cause of initial treatment failure. Factors linked to resistance include mutations,  efflux pumps , and the formation of  biofilms . [ 156 ] [ 157 ]  One of the main  antibiotics  used in eradication therapies is  clarithromycin , but clarithromycin-resistant strains have become well-established and the use of alternative antibiotics needs to be considered. Fortunately, non-invasive stool tests for clarithromycin have become available that allow selection of patients that are likely to respond to the therapy. [ 158 ]  Multidrug resistance has also increased. [ 157 ]  Additional rounds of antibiotics or other therapies may be used. [ 159 ] [ 160 ] [ 161 ]   Next generation sequencing  is looked to for identifying initial specific antibiotic resistances that will help in targeting more effective treatment. [ 162 ]


In 2018, the  WHO  listed  H. pylori  as a high priority pathogen for the research and  discovery of new drugs  and treatments. [ 163 ]  The increasing antibiotic resistance encountered has spurred interest in developing alternative therapies using a number of plant compounds. [ 164 ] [ 165 ]  Plant compounds have fewer side effects than synthetic drugs. Most plant extracts contain a complex mix of components that may not act on their own as antimicrobials but can work together with antibiotics to enhance treatment and work towards overcoming resistance. [ 164 ]  Plant compounds have a different mechanism of action that has proved useful in fighting antimicrobial resistance. For example, various compounds can act by inhibiting enzymes such as urease, and weakening adhesions to the mucous membrane. [ 166 ]  Sulfur-containing compounds from plants with high concentrations of polysulfides,  coumarins , and  terpenes  have all been shown to be effective against  H. pylori . [ 164 ]


H. pylori  is found in saliva and  dental plaque . Its transmission is known to include oral-oral, suggesting that the dental plaque biofilm may act as a reservoir for the bacteria. Periodontal therapy or  scaling and root planing  has therefore been suggested as an additional treatment to enhance eradication rates, but more research is needed. [ 139 ] [ 167 ]


Helicobacter pylori  is a risk factor for  gastric adenocarcinomas . [ 168 ]  Treatment is highly aggressive, with even localized disease being treated sequentially with chemotherapy and radiotherapy before surgical resection. [ 169 ]  Since this cancer, once developed, is independent of  H. pylori  infection, eradication regimens are not used. [ 170 ]


MALT lymphomas  are  malignancies  of  mucosa-associated lymphoid tissue . Early gastric MALTomas due to  H. pylori  may be successfully treated (70–95% of cases) with one or more  eradication programs . [ 14 ]  Some 50–80% of patients who experience eradication of the pathogen develop a remission and long-term clinical control of their lymphoma within 3–28 months.  Radiation therapy  to the stomach and surrounding (i.e. peri-gastric) lymph nodes has also been used to successfully treat these localized cases. Patients with non-localized (i.e. systemic Ann Arbor stage III and IV) disease who are free of symptoms have been treated with  watchful waiting  or, if symptomatic, with the  immunotherapy  drug  rituximab  (given for 4 weeks) combined with the  chemotherapy  drug  chlorambucil  for 6–12 months; 58% of these patients attain a 58% progression-free survival rate at 5 years. Frail stage III/IV patients have been successfully treated with rituximab or the chemotherapy drug  cyclophosphamide  alone. [ 171 ]  Antibiotic-proton pump inhibitor eradication therapy and localized radiation therapy have been used successfully to treat H. pylori-positive MALT lymphomas of the rectum; however radiation therapy has given slightly better results and therefore been suggested to be the disease's preferred treatment. [ 172 ]  However, the generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy drugs often combined with rituximab.


A MALT lymphoma may rarely transform into a more aggressive  diffuse large B-cell lymphoma  (DLBCL). [ 173 ]  Where this is associated with  H. pylori  infection, the DLBCL is less aggressive and more amenable to treatment. [ 174 ] [ 175 ] [ 176 ]  When limited to the stomach, they have sometimes been successfully treated with  H. pylori  eradication programs. [ 54 ] [ 175 ] [ 177 ] [ 176 ]  If unresponsive or showing a deterioration, a more conventional chemotherapy ( CHOP ), immunotherapy, or local radiotherapy can be considered, and any of these or a combination have successfully treated these more advanced types. [ 175 ] [ 176 ]


Helicobacter pylori  colonizes the stomach for decades in most people, and induces chronic gastritis, a long-lasting inflammation of the stomach. In most
cases symptoms are never experienced but about 10–20% of those infected will ultimately develop gastric and duodenal ulcers, and have a possible 1–2% lifetime risk of gastric cancer. [ 65 ]


H. pylori  thrives in a high salt diet, which is seen as an environmental risk factor for its association with gastric cancer. A diet high in salt enhances colonization, increases inflammation, increases the expression of  H. pylori  virulence factors, and intensifies chronic gastritis. [ 178 ] [ 179 ]  Paradoxically, extracts of  kimchi , a salted probiotic food, has been found to have a preventive effect on  H. pylori –associated gastric  carcinogenesis . [ 180 ]


In the absence of treatment,  H. pylori  infection usually persists for life. [ 181 ]  Infection may disappear in the elderly as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. Some studies in young children up to two years of age have shown that infection can be transient in this age group. [ 182 ] [ 183 ]


It is possible for  H. pylori  to re-establish in a person after eradication. This recurrence can be caused by the original strain ( recrudescence ), or be caused by a different strain ( reinfection ). A 2017 meta-analysis showed that the global per-person annual rates of recurrence, reinfection, and recrudescence is 4.3%, 3.1%, and 2.2% respectively. It is unclear what the main risk factors are. [ 184 ]


Mounting evidence suggests  H. pylori  has an important role in protection from some diseases. [ 16 ]  The incidence of  acid reflux disease ,  Barrett's esophagus , and  esophageal cancer  have been rising dramatically at the same time as  H. pylori ' s presence decreases. [ 185 ]  In 1996,  Martin J. Blaser  advanced the hypothesis that  H. pylori  has a beneficial effect by regulating the acidity of the stomach contents. [ 51 ] [ 185 ]  The hypothesis is not universally accepted, as several  randomized controlled trials  failed to demonstrate worsening of acid reflux disease symptoms following eradication of  H. pylori . [ 186 ] [ 187 ]  Nevertheless, Blaser has reasserted his view that  H. pylori  is a member of the normal  gastric microbiota . [ 17 ]  He postulates that the changes in gastric physiology caused by the loss of  H. pylori  account for the recent increase in incidence of several diseases, including  type 2 diabetes ,  obesity , and asthma. [ 17 ] [ 188 ]  His group has recently shown that  H. pylori  colonization is associated with a lower  incidence  of childhood asthma. [ 189 ]


In 2023, it was estimated that about two-thirds of the world's population were infected with  H. pylori  infection, being more common in  developing countries . [ 20 ]   H. pylori  infection is more prevalent in South America, Sub-Saharan Africa, and the Middle East. [ 153 ]  The global prevalence declined markedly in the decade following 2010, with a particular reduction in Africa. [ 21 ]


The age when someone acquires this bacterium seems to influence the pathologic outcome of the infection. People infected at an early age are likely to develop more intense inflammation that may be followed by atrophic gastritis with a higher subsequent risk of gastric ulcer, gastric cancer, or both. Acquisition at an older age brings different gastric changes more likely to lead to duodenal ulcer. [ 181 ]  Infections are usually acquired in early childhood in all countries. [ 32 ]  However, the infection rate of children in developing nations is higher than in  industrialized nations , probably due to poor sanitary conditions, perhaps combined with lower antibiotics usage for unrelated pathologies. In developed nations, it is currently uncommon to find infected children, but the percentage of infected people increases with age. The higher prevalence among the elderly reflects higher infection rates incurred in childhood. [ 32 ]  In the United States, prevalence appears higher in  African-American  and  Hispanic  populations, most likely due to socioeconomic factors. [ 190 ] [ 191 ]  The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of  H. pylori  infection is declining. [ 192 ]  However, antibiotic resistance is appearing in  H. pylori ; many metronidazole- and clarithromycin-resistant strains are found in most parts of the world. [ 193 ]


Helicobacter pylori   migrated out of Africa  along with its human host around 60,000 years ago. [ 194 ]  Research has shown that  genetic diversity  in  H. pylori , like that of its host, decreases with geographic distance from  East Africa . Using the genetic diversity data, researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by  H. pylori  before their migrations out of Africa, and it has remained associated with human hosts since that time. [ 195 ]


H. pylori  was first discovered in the stomachs of patients with gastritis and  ulcers  in 1982 by  Barry Marshall  and  Robin Warren  of  Perth, Western Australia . At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005  Nobel Prize in Physiology or Medicine . [ 196 ]


Before the research of Marshall and Warren, German scientists found spiral-shaped  bacteria  in the lining of the human stomach in 1875, but they were unable to  culture  them, and the results were eventually forgotten. [ 185 ]  The Italian researcher  Giulio Bizzozero  described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893. [ 197 ]  Professor  Walery Jaworski  of the  Jagiellonian University  in  Kraków  investigated sediments of gastric washings obtained by  lavage  from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called  Vibrio rugula . He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in the  Handbook of Gastric Diseases , but it had little impact, as it was published only in Polish. [ 198 ]  Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomachs of many people with peptic ulcers and stomach cancers. [ 199 ]  Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies. [ 200 ]