Proton-pump inhibitor

Last updated

Proton-pump inhibitor
Drug class
Proton pump inhibitors structure.svg
General structure of a proton-pump inhibitor
Class identifiers
UseReduction of gastric acid production
ATC code A02BC
Mechanism of action Enzyme inhibitor
Biological target H+/K+ ATPase
Clinical data
Drugs.com Drug Classes
WebMD MedicineNet  
External links
MeSH D054328
Legal status
In Wikidata

Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. [1] The body eventually synthesizes new proton pumps to replace the irreversibly inhibited ones, a process driven by normal cellular turnover, which gradually restores acid production. [2]

Contents

Proton-pump inhibitors have largely superseded the H2-receptor antagonists, a group of medications with similar effects but a different mode of action, and heavy use of antacids. [3] A potassium-competitive acid blocker (PCAB) revaprazan was marketed in Korea as an alternative to a PPI. A newer PCAB vonoprazan with a faster and longer lasting action than revaprazan, and PPIs has been marketed in Japan (2013), Russia (2021), and the US (2023). [4] [5] [6]

PPIs are among the most widely sold medications in the world. The class of proton-pump inhibitor medications is on the World Health Organization's List of Essential Medicines. [7] [8] Omeprazole is the specific listed example. [7] [8]

Medical uses

These medications are used in the treatment of many conditions, such as:

Specialty professional organizations recommend that people take the lowest effective PPI dose to achieve the desired therapeutic result when used to treat gastroesophageal reflux disease long-term. [20] [21] [22] In the United States, the Food and Drug Administration (FDA) has advised that over-the-counter PPIs, such as Prilosec OTC, should be used no more than three 14-day treatment courses over one year. [23] [24]

Despite their extensive use, the quality of the evidence supporting their use in some of these conditions is variable. The effectiveness of PPIs has not been demonstrated for every case. For example, although they reduce the incidence of esophageal adenocarcinoma in Barrett's oesophagus, [16] they do not change the length affected. [25] In addition, research in the UK has suggested that PPIs are not effective at treating persistent throat symptoms. [26] [27]

Indications for stopping PPIs

PPIs are often used longer than necessary. In about half of people who are hospitalized or seen at a primary care clinic there is no documented reason for their long-term use of PPIs. [28] Some researchers believe that, given the little evidence of long-term effectiveness, the cost of the medication and the potential for harm means that clinicians should consider stopping PPIs in many people. [29]

Adverse effects

In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. The range and occurrence of adverse effects are similar for all of the PPIs, though they have been reported more frequently with omeprazole. This may be due to its longer availability and, hence, clinical experience.[ citation needed ]

Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness. [30] Infrequent adverse effects include rash, itch, flatulence, constipation, anxiety, and depression. Also infrequently, PPI use may be associated with occurrence of myopathies, including the serious reaction rhabdomyolysis. [31]

Long-term use of PPIs requires assessment of the balance of the benefits and risks of the therapy. [32] [33] [34] [35] As of March 2017, various adverse outcomes have been associated with long-term PPI use in several primary reports, but reviews assess the overall quality of evidence in these studies as "low" or "very low". [34] They describe inadequate evidence to establish causal relationships between PPI therapy and many of the proposed associations, due to study design and small estimates of effect size. [35]

As of March 2017, benefits outweighed risks when PPIs are used appropriately, but when used inappropriately, modest risks become important. [34] [36] They recommend that PPIs should be used at the lowest effective dose in people with a proven indication, but discourage dose escalation and continued chronic therapy in people unresponsive to initial empiric therapy. [35]

With regard to iron and vitamin B12, the data is weak and several confounding factors have been identified. [33] Low levels of magnesium can be found in people on PPI therapy and these can be reversed when they are switched to H2-receptor antagonist medications. [33] [37] [24]

Bone

High dose or long-term use of PPIs carries an increased risk of bone fractures which was not found with short-term, low dose use; the FDA included a warning regarding this on PPI drug labels in 2010. [23]

In infants, acid suppression therapy is frequently prescribed to treat symptomatic gastroesophageal reflux in otherwise healthy infants (that is: without gastroesophageal reflux disease). A study from 2019 showed that PPI use alone and together with histamine H2-receptor antagonists was associated with an increased bone fracture hazard, which was amplified by days of use and earlier initiation of therapy. [38] The reason is not clear; increased bone break down by osteoclasts has been suggested. [39]

A recent 2024 study published in the Journal of Clinical Endocrinology & Metabolism found that chronic use of PPIs in men is linked to lower trabecular bone quality. [40] Specifically, PPI use was associated with reduced lumbar spine trabecular bone score (TBS), as well as lower bone mineral density (BMD) T-scores in the lumbar spine, total hip, and femoral neck. [41] These findings suggest that long-term PPI use may negatively affect bone health in men.

Gastrointestinal

Some studies have shown a correlation between use of PPIs and Clostridioides difficile infection. While the data are contradictory and controversial, the FDA had sufficient concern to include a warning about this adverse effect on the label of PPI medications. [33] Concerns have also been raised about spontaneous bacterial peritonitis (SBP) in older people taking PPIs and in people with irritable bowel syndrome taking PPIs; both types of infections arise in these populations due to underlying conditions and it is not clear if this is a class effect of PPIs. [33] PPIs may predispose an individual to developing small intestinal bacterial overgrowth or fungal overgrowth. [42] [43]

In cirrhotic patients, large volume of ascites and reduced esophageal motility by varices can provoke GERD. [44] [45] [46] Acidic irritation, in return, may induce the rupture of varices. [47] Therefore, PPIs are often routinely prescribed for cirrhotic patients to treat GERD and prevent variceal bleeding. However, it has been recently shown that long term use of PPIs in patients with cirrhosis increases the risk of SBP and is associated with the development of clinical decompensation and liver-related death during long-term follow-up. [48]

There is evidence that PPI use alters the composition of the bacterial populations inhabiting the gut, the gut microbiota. [49] Although the mechanisms by which PPIs cause these changes are yet to be determined, they may have a role in the increased risk of bacterial infections with PPI use. [50] These infections can include Helicobacter pylori due to this species not favouring an acid environment, leading to an increased risk of ulcers and gastric cancer risk in genetically susceptible patients. [50]

PPI use in people who have received attempted H. pylori eradication may also be associated with an increased risk of gastric cancer. [51] The validity and robustness of this finding, with the lack of causality, have led to this association being questioned. [52] It is recommended that long-term PPIs should be used judiciously after considering individual's risk–benefit profile, particularly among those with history of H. pylori infection, and that further, well-designed, prospective studies are needed. [53]

Long-term use of PPIs is associated with the development of benign polyps from fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. [33] There is concern that use of PPIs may mask gastric cancers or other serious gastric problems. [33]

PPI use has also been associated with the development of microscopic colitis. [54]

Cardiovascular

Associations of PPI use and cardiovascular events have also been widely studied but clear conclusions have not been made as these relative risks are confounded by other factors. [55] [56] PPIs are commonly used in people with cardiovascular disease for gastric protection when aspirin is given for its antiplatelet actions. [55] [57] An interaction between PPIs and the metabolism of the platelet inhibitor clopidogrel is known and this drug is also often used in people with cardiac disease. [58] [59] [22] There are associations with an increased risk of stroke, but this appears to be more likely to occur in people who already have an elevated risk. [60]

One suggested mechanism for cardiovascular effects is because PPIs bind and inhibit dimethylargininase, the enzyme that degrades asymmetric dimethylarginine (ADMA), resulting in higher ADMA levels and a decrease in bioavailable nitric oxide. [61]

Cancer

A 2022 umbrella review of 21 meta-analyses shows an association between proton-pump inhibitor use and an increased risk of four types of cancer. [62]

Other

Associations have been shown between PPI use and an increased risk of pneumonia, particularly in the 30 days after starting therapy, where it was found to be 50% higher in community use. [63] [64] Other very weak associations of PPI use have been found, such as with chronic kidney disease, [65] [66] [67] [22] [68] [69] dementia [70] [34] [71] and Hepatocellular carcinoma (HCC). [72]

As of 2016, results were derived from observational studies, it remained uncertain whether such associations were causal relationships. [34] [35] [73]

Mechanism of action

The activation of PPIs Proton pump inhibitors mechanism.svg
The activation of PPIs

Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells. [74] The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.[ citation needed ] Because the H,K-ATPase is the final step of acid secretion, an inhibitor of this enzyme is more effective than receptor antagonists in suppressing gastric acid secretion. [75] All of these drugs inhibit the gastric H,K-ATPase by covalent binding, so the duration of their effect is longer than expected from their levels in the blood. [76]

Targeting the terminal step in acid production, as well as the irreversible nature of the inhibition, results in a class of medications that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. [77]

Decreasing the acid in the stomach can aid the healing of duodenal ulcers and reduce the pain from indigestion and heartburn. However, stomach acids are needed to digest proteins, vitamin B12, calcium, and other nutrients, and too little stomach acid causes the condition hypochlorhydria.[ citation needed ]

The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.

In H. pylori eradication, PPIs help by increasing the stomach pH, causing the bacterium to shift out of its coccoid form which is resistant to both acids and antibiotics. PPIs also show some weaker additional effects in eradication. [78]

Pharmacokinetics

The rate of omeprazole absorption is decreased by concomitant food intake. [79] In addition, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. It has been reported, however, that these pharmacokinetic effects have no significant impact on efficacy. [80] [81]

In healthy humans, the half-life of PPIs is about 1 hour (9 hours for tenatoprazole), but the duration of acid inhibition is 48 hours because of irreversible binding to the H,K-ATPase. [82] All the PPIs except tenatoprazole are rapidly metabolized in the liver by CYP enzymes (mostly by CYP2C19 and 3A4). [82] Dissociation of the inhibitory complex is probably due to the effect of the endogenous antioxidant glutathione which leads to the release of omeprazole sulfide and reactivation of the enzyme. [83] [84]

Examples

Medically used proton pump inhibitors:[ citation needed ]

There is no clear evidence that one proton pump inhibitor works better than another. [1] [89]

History

PPIs were developed in the 1980s, with omeprazole being launched in 1988. Most of these medications are benzimidazole derivatives, related to omeprazole, but imidazopyridine derivatives such as tenatoprazole have also been developed. [77] Potassium-competitive inhibitors such as revaprazan reversibly block the potassium-binding site of the proton pump, acting more quickly, but are not available in most countries. [90]

Society and culture

Economics

In British Columbia, Canada the cost of the PPIs varies significantly from CA$0.13 to CA$2.38 per dose [91] while all agents in the class appear more or less equally effective. [1] [89]

Regulatory approval

A comparative table of FDA-approved indications for PPIs is shown below.

Comparative indications [92]
Indication Omeprazole Esomeprazole Lansoprazole Dexlansoprazole Pantoprazole Rabeprazole
Gastroesophageal reflux disease
Erosive esophagitis-healingYesYesYesYesYesYes
Erosive esophagitis-maintenanceYesYesYesYesYesYes
Nonerosive reflux diseaseYesYesYesYesNoYes
Peptic ulcer disease
Duodenal ulcer-healingYesNoYesNoNoYes
Duodenal ulcer-maintenanceNoNoYesNoNoNo
Gastric ulcer-healingYesNoYesNoNoNo
NSAID induced ulcer-healingNoNoYesNoNoNo
NSAID induced ulcer-prophylaxisNoYesYesNoNoNo
Zollinger–Ellison syndrome YesYesYesNoYesYes
Treatment of Helicobacter pylori
Dual therapyYesNoYesNoNoNo
Triple therapyYesYesYesNoNoYes

Related Research Articles

<span class="mw-page-title-main">Peptic ulcer disease</span> Ulcer of an area of the gastrointestinal tract

Peptic ulcer disease is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines is a duodenal ulcer. The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain, and upper abdominal pain that improves with eating. With a gastric ulcer, the pain may worsen with eating. The pain is often described as a burning or dull ache. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people with peptic ulcers have no symptoms. Complications may include bleeding, perforation, and blockage of the stomach. Bleeding occurs in as many as 15% of cases.

Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid into the esophagus. It is the major symptom of gastroesophageal reflux disease (GERD).

<span class="mw-page-title-main">Gastroesophageal reflux disease</span> Flow of stomach contents into the esophagus

Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or complications. Symptoms include dental corrosion, dysphagia, heartburn, odynophagia, regurgitation, non-cardiac chest pain, extraesophageal symptoms such as chronic cough, hoarseness, reflux-induced laryngitis, or asthma. In the long term, and when not treated, complications such as esophagitis, esophageal stricture, and Barrett's esophagus may arise.

H<sub>2</sub> receptor antagonist Class of medications

H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomach acid. H2 antagonists can be used in the treatment of dyspepsia, peptic ulcers and gastroesophageal reflux disease. They have been surpassed by proton pump inhibitors (PPIs). The PPI omeprazole was found to be more effective at both healing and alleviating symptoms of ulcers and reflux oesophagitis than the H2 blockers ranitidine and cimetidine.

<span class="mw-page-title-main">Omeprazole</span> Medication to treat gastroesophageal reflux disease and other conditions

Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper gastrointestinal bleeding in people who are at high risk. Omeprazole is a proton-pump inhibitor (PPI) and its effectiveness is similar to that of other PPIs. It can be taken by mouth or by injection into a vein. It is also available in the fixed-dose combination medication omeprazole/sodium bicarbonate as Zegerid and as Konvomep.

<span class="mw-page-title-main">Pantoprazole</span> Stomach acid suppressing medication

Pantoprazole, sold under the brand name Protonix, among others, is a medication used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger–Ellison syndrome. It may also be used along with other medications to eliminate Helicobacter pylori. Pantoprazole is a proton-pump inhibitor (PPI) and its effectiveness is similar to that of other PPIs. It is available by mouth and by injection into a vein.

<span class="mw-page-title-main">Nissen fundoplication</span> Surgical procedure to treat gastric reflux and hiatal hernia

A Nissen fundoplication, or laparoscopic Nissen fundoplication when performed via laparoscopic surgery, is a surgical procedure to treat gastroesophageal reflux disease (GERD) and hiatal hernia. In GERD, it is usually performed when medical therapy has failed; but, with a Type II (paraesophageal) hiatus hernia, it is the first-line procedure. The Nissen fundoplication is total (360°), but partial fundoplications known as Thal, Belsey, Dor, Lind, and Toupet fundoplications are alternative procedures with somewhat different indications and outcomes.

<span class="mw-page-title-main">Famotidine</span> Medication that reduces stomach acid

Famotidine, sold under the brand name Pepcid among others, is a histamine H2 receptor antagonist medication that decreases stomach acid production. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. It is taken by mouth or by injection into a vein. It begins working within an hour.

<span class="mw-page-title-main">Esomeprazole</span> Medication which reduces stomach acid

Esomeprazole, sold under the brand name Nexium [or Neksium] among others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Its effectiveness is similar to that of other proton pump inhibitors (PPIs). It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">Rabeprazole</span> Stomach acid suppressing medication

Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Ellison syndrome. It may also be used in combination with other medications to treat Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.

<span class="mw-page-title-main">Achlorhydria</span> Lack of hydrochloric acid production in the digestive organs

Achlorhydria and hypochlorhydria refer to states where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low, respectively. It is associated with various other medical problems.

Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier than expected when eating. Indigestion is relatively common, affecting 20% of people at some point during their life, and is frequently caused by gastroesophageal reflux disease (GERD) or gastritis.

Gastric hydrogen potassium ATPase, also known as H+/K+ ATPase, is an enzyme which functions to acidify the stomach. It is a member of the P-type ATPases, also known as E1-E2 ATPases due to its two states.

Helicobacter pylori eradication protocols is a standard name for all treatment protocols for peptic ulcers and gastritis in the presence of Helicobacter pylori infection. The primary goal of the treatment is not only temporary relief of symptoms but also total elimination of H. pylori infection. Patients with active duodenal or gastric ulcers and those with a prior ulcer history should be tested for H. pylori. Appropriate therapy should be given for eradication. Patients with MALT lymphoma should also be tested and treated for H. pylori since eradication of this infection can induce remission in many patients when the tumor is limited to the stomach. Several consensus conferences, including the Maastricht Consensus Report, recommend testing and treating several other groups of patients but there is limited evidence of benefit. This includes patients diagnosed with gastric adenocarcinoma, patients found to have atrophic gastritis or intestinal metaplasia, as well as first-degree relatives of patients with gastric adenocarcinoma since the relatives themselves are at increased risk of gastric cancer partly due to the intrafamilial transmission of H. pylori. To date, it remains controversial whether to test and treat all patients with functional dyspepsia, gastroesophageal reflux disease, or other non-GI disorders as well as asymptomatic individuals.

<span class="mw-page-title-main">Laryngopharyngeal reflux</span> Flow of stomach contents into the throat (larynx and pharynx)

Laryngopharyngeal reflux (LPR) or laryngopharyngeal reflux disease (LPRD) is the retrograde flow of gastric contents into the larynx, oropharynx and/or the nasopharynx. LPR causes respiratory symptoms such as cough and wheezing and is often associated with head and neck complaints such as dysphonia, globus pharyngis, and dysphagia. LPR may play a role in other diseases, such as sinusitis, otitis media, and rhinitis, and can be a comorbidity of asthma. While LPR is commonly used interchangeably with gastroesophageal reflux disease (GERD), it presents with a different pathophysiology.

Proton pump inhibitors (PPIs) block the gastric hydrogen potassium ATPase (H+/K+ ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs also can bind to other types of proton pumps such as those that occur in cancer cells and are finding applications in the reduction of cancer cell acid efflux and reduction of chemotherapy drug resistance.

<span class="mw-page-title-main">Ilaprazole</span> Stomach acid suppressing medication

Ilaprazole is a proton pump inhibitor (PPI) used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD) and duodenal ulcer.

There are several classes of drugs for acid-related disorders, such as dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), or laryngopharyngeal reflux.

<span class="mw-page-title-main">Acid peptic diseases</span> Overview of the acid peptic diseases of the stomach and gastrointestinal tract

Acid peptic diseases, such as peptic ulcers, Zollinger-Ellison syndrome, and gastroesophageal reflux disease, are caused by distinct but overlapping pathogenic mechanisms involving acid effects on mucosal defense. Acid reflux damages the esophageal mucosa and may also cause laryngeal tissue injury, leading to the development of pulmonary symptoms.

Anti-ulcer agents are medications or supplements used to cure the damage of mucosal layer on organs to prevent the damage from further extending to deeper regions to cause complications.

References

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  35. 1 2 3 4 Vaezi MF, Yang YX, Howden CW (July 2017). "Complications of Proton Pump Inhibitor Therapy". Gastroenterology. 153 (1): 35–48. doi: 10.1053/j.gastro.2017.04.047 . PMID   28528705. In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered, along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.
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    Nutritional

    Gastric acid is important for breakdown of food and release of micronutrients, and some studies have shown possibilities for interference with absorption of iron, calcium, magnesium, and vitamin B12.<ref name="pmid20882439">Ito T, Jensen RT (December 2010). "Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium". Current Gastroenterology Reports. 12 (6): 448–57. doi:10.1007/s11894-010-0141-0. PMC   2974811 . PMID   20882439.
  42. ↑ Fujimori S (June 2015). "What are the effects of proton pump inhibitors on the small intestine?". World Journal of Gastroenterology. 21 (22): 6817–9. doi: 10.3748/wjg.v21.i22.6817 . PMC   4462721 . PMID   26078557. Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridioides difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO.
  43. ↑ Erdogan A, Rao SS (April 2015). "Small intestinal fungal overgrowth". Current Gastroenterology Reports. 17 (4): 16. doi:10.1007/s11894-015-0436-2. PMID   25786900. S2CID   3098136. Small intestinal fungal overgrowth (SIFO) is characterized by the presence of excessive number of fungal organisms in the small intestine associated with gastrointestinal (GI) symptoms. Candidiasis is known to cause GI symptoms particularly in immunocompromised patients or those receiving steroids or antibiotics. However, only recently, there is emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained GI symptoms. Two recent studies showed that 26% (24/94) and 25.3% (38/150) of a series of patients with unexplained GI symptoms had SIFO. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear but small intestinal dysmotility and use of proton pump inhibitors has been implicated. However, further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth, both in healthy subjects and in patients with otherwise unexplained GI symptoms.
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