Gastroesophageal reflux disease (GERD) resistant to proton pump inhibitors: Causes of ineffective treatment (Part 2)

Posted by Master, Doctor Mai Vien Phuong - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital

There are many potential causes of refractory gastroesophageal reflux disease (GERD), which vary in incidence, clinical importance, and symptom severity and frequency. Compliance and poor compliance should first be assessed before continuing with the assessment.

1.1 Psychosomatic illness Data on the contribution of psychological comorbidities to refractory gastroesophageal reflux disease (GERD) are combined with multiple factors and are inconsistent. Several studies have shown that GERD patients, especially those with NERD non-erosive reflux, have high rates of psychiatric morbidity and psychosocial stressors.
In a recent analysis of PPI therapy in patients with psychological stress, high baseline anxiety and depression levels, and decreased overall well-being, predicted lower treatment response. Another study also found that comorbid psychological distress was independently associated with more severe initial GERD symptoms, more residual symptoms, and poor disease-specific quality of life. worse both before and after PPI treatment. Sleep disturbances and a history of psychotherapy or psychiatric medication use were also significantly associated with poor response to PPI treatment.
However, contrary to these findings, a recent prospective study of GERD patients treated with PPIs once or twice daily showed poor treatment response unrelated to anxiety or depression. A study of GERD patients in a primary care setting also found that the relative risk of anxiety or depression when PPI failure was minimal, with an odds ratio of 1.15.
Reported relationship between PPI failure and psychological problems is inconsistent, there are conclusive studies involved, there are studies that do not. Mental illness can compromise motor function of the esophagus by affecting the enteric nervous system. Some research suggests that reflux symptoms can be influenced by the use of psychiatric medications and substances, such as benzodiazepines, which can reduce lower esophageal sphincter (LES) pressure, and tricyclic antidepressants (TCAs), which block cholinergic receptors and may affect acid clearance. Sleep disturbances have also been associated with greater severity of reflux symptoms and poorer response to treatment.
Psychological comorbidities can also affect perceptions of treatment success. In the acute stress setting, patients reported increased severity and frequency of GERD symptoms regardless of changes in esophageal acid exposure. In a study of endoscopic antireflux surgery for the treatment of GERD, patients with existing major depressive disorder were more likely to report residual symptoms despite improved objective scoring. . A prospective controlled trial of patients undergoing endoscopic antireflux Nissen angioplasty also found that patients with refractory GERD symptoms had significantly higher levels of infection.
1.2 Irritable Bowel Syndrome The overlap between GERD and irritable bowel syndrome (IBS) has been recognized for more than 20 years, with up to 71% of GERD patients reporting IBS symptoms. The association between IBS and GERD is thought to be due to common underlying mechanisms or symptoms.
Data are limited, but studies have shown that patients with concomitant IBS have a poorer response to treatment than in patients with GERD. In a prospective study, patients with IBS-like symptoms and GERD showed decreased response rates to pantoprazole compared with patients without IBS-like symptoms. Another study also found that IBS with comorbidities was associated with increased GERD symptoms and lower quality of life both before and after PPI treatment, although this may reflect symptoms of GERD. More severe underlying symptoms are less responsive to treatment.

Weakly acidic reflux is defined as a reflux phenomenon in which esophageal pH decreases by at least one unit but not less than four. The exact mechanism by which weak acid reflux produces symptoms is still unclear, but several theories have been proposed based on the volume or concentration of the reflux substance.
Large amounts of weakly acidic reflux material can cause mechanical dilation of the esophagus and cause reflux symptoms, as demonstrated by studies in which direct mechanical dilation of the bulb of the esophagus causes a feeling of heartburn. GERD symptoms can also be caused by bile acids, which can be contained in weak acid reflux. The proteolytic effects of pepsin, which can be introduced into the esophagus in cases of weakly acidic reflux, may also contribute to unpleasant symptoms.
While pepsin is maximally active at pH 1.9–3.6, it maintains some activity up to pH 6. In addition, pepsin maintains its structure at a pH of at least 7, 5 and can be reactivated by subsequent acid reflux events or acidic meals. Esophageal healing may also be compromised because mucosal repair and regeneration is inhibited at pH < 6.5. Finally, previous exposure of the esophagus to acid can lead to subsequent hyperemia to mechanical and chemical stimuli.
In addition, patients with PPI-resistant GERD have been found to have slower esophageal clearance, possibly exacerbating all of the above mechanisms.
The clinical significance of weak acid reflux in refractory GERD remains unclear. Although numerous studies have shown that only a small number of cases of weak acid reflux co-occur with refractory symptoms, a wide range (16.7–40%) has been reported.

DGER refers to the reflux of substances in the duodenum, including bile, through the stomach and into the esophagus. Esophageal bilirubin exposure can occur with or without weak acid reflux and leads to reduced esophageal mucosal integrity through epithelial cell apoptosis, interstitial spaces, and increased mucosal permeability. In a study of treatment-resistant GERD, DGER was found in 88% of PPI nonresponders and only 27% of responders. Another study also found that 64% of patients with GERD who did not respond to standard dose PPI therapy were pathologically DGER.
Delayed gastric emptying In refractory GERD, the role of delayed gastric emptying, theoretically leading to greater or more frequent reflux events, remains unclear. A study of 66 patients with refractory GERD who underwent gastric emptying studies found no statistical difference between patients with gastroparesis and controls in total or duration of acid reflux and nonacid.
However, a smaller study found that after 8 weeks of PPI therapy, patients with persistent symptoms and EE presented more abnormal gastric emptying than patients with persistent EE but no have symptoms. A possible association between gastric emptying and resistant GERD was also demonstrated in a small study in which 88% of patients who improved in their gastroparesis symptoms also reported a reduction in GERD symptoms.

4.1 Role of acid sacs After eating, there may exist a region of highly acidic gastric juice at the esophageal junction, called the acid sac, which contains newly secreted acid that does not mix with the food and therefore remains undigested. pinched. This pouch can move into the esophagus and cause reflux symptoms after eating. Although the use of PPIs can alter the location or decrease the size of the vesicles, one of the only studies investigating this mechanism found no difference in the position or pH of the acid vesicle between responders. PPI responders and partial responders.
4.2 Nocturnal Acidity (NAB) NAB was defined as gastric pH <4 for at least 1 hour during the night in PPI-treated patients. Although NAB is very common, occurring in 75% of patients on twice-daily PPIs, it likely does not play a role in the pathogenesis of drug-resistant GERD. In a study of resistant GERD, 37 of 52 patients were found to have NAB, but only 17 had concomitant GERD symptoms. In addition, there are some similar symptoms in patients with and without NAB. Another study found that adding ranitidine to omeprazole twice daily did not improve nocturnal heartburn symptoms or sleep quality despite a reduction in NAB.

5.1 Rapid PPI metabolism PPIs are metabolised in the liver by cytochrome P450 2C19 (CYP2C19) and to a much lesser extent by cytochrome P450 3A4. Because of genetic polymorphisms, CYP2C19 exists as 3 genotype groups that may have different metabolic activity: homozygous broad metabolites (carrying 2 mutant alleles), heterozygous widespread metabolites (carrying one mutant and one wild-type allele) and poor metabolisers (carrying two wild-type alleles). There is a significant ethnic difference in the distribution of these alleles, as up to 70% of Caucasians, compared with 30–40% of Asians, are highly transgenic.
Widespread metabolites are expected to decrease acid suppression in response to PPI therapy because faster elimination leads to reduced mean length of stay and AUC. The area under the curve is reported to be 5–12 times higher in poor metabolizers than in high metabolizers. A recent meta-analysis showed that PPI response rates in GERD in rapid, intermediate, and poor metabolizers were 52.2%, 56.7%, and 61.3%, respectively.
The impact of CYP2C19 activity on resistant GERD symptoms is unclear, as nearly all studies used standard rather than double dose PPI therapy. Only one study examined the difference in response rates between high and poor metabolizers on both standard and twice daily pantoprazole. After 8 weeks of treatment, sustained symptomatic response (SSR) was not different between poor metabolizers receiving either dose of pantoprazole.
Heterozygous extensively metabolisers showed an SSR of 94.9% when administered twice daily but only 73.7% at the standard dose. Similarly, homozygous extensive metabolisers showed an SSR of 82.1% when administered twice daily compared with 68.4% at the standard dose. The difference between response rates of double-dose and standard-dose PPIs among extensive metabolizers suggests that PPI metabolism may play an important role in refractory GERD.
5.2 PPI resistance A summary from 1995 suggested that mutations in the cysteine ​​residue of the alpha subunit of the proton pump could inhibit omeprazole binding and lead to PPI resistance, although two patients were treated with PPI resistance. The review found no such mutation. No studies have identified mutations leading to PPI resistance, suggesting that it has no role in resistant GERD.
Most people with GERD will not notice serious complications, especially if treated. However, potentially serious complications can sometimes occur in people with severe GERD. Vinmec International General Hospital is a prestigious address trusted by many patients in performing diagnostic and treatment techniques for reflux esophagitis, refractory reflux esophagitis, gastritis .. Along with that, at Vinmec Hospital, the diagnosis through colonoscopy with the Olympus CV 190 endoscope, with the function (Narrow Banding Imaging - endoscopy with narrow light frequency band) gives imaging results. The analysis of mucosal pathology is clearer than that of conventional endoscopy, detecting ulcerative lesions, reflux in the esophagus, stomach, Barrett's modified lesions, and early cancerous lesions. .... Vinmec Hospital with modern facilities and equipment and a team of experienced experts who are always dedicated in medical examination and treatment, customers can rest assured with the online endoscopy service. colon at Vinmec International General Hospital.

References
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