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Reflux: Advanced Information

Condition

Symptoms:

Reflux is the most common recorded gastrointestinal diagnosis in outpatient clinics. It is physiological to have some reflux, but is considered problematic when it causes symptoms, considered to be “at least two heartburn episodes per week and/or complications.”1

 

Reported symptoms vary greatly. Classically, reflux is described as a burning sensation with pain or discomfort that starts from the epigastrium and radiates retrosternally, most frequently post meals. There may be associated regurgitation, with the sensation of stomach contents flowing into the mouth or pharynx.

 

Other descriptions include chest pain, chest discomfort, globus sensation (the feeling that there is pressure or something stuck, most commonly in the upper throat not related to swallowing), throat or mouth burning, belching, bloating or nausea. Some patients or their dentist may note enamel erosion on their teeth. Nearly half of patients with reflux describe nocturnal symptoms which impacts quality of life and may indicate more severe disease.2

 

Red flags

 

Dysphagia, or difficulty swallowing is a sign of possibly more advanced pathology in the setting of chronic reflux. Odynophagia, or pain on swallowing is not common with straightforward reflux, and may indicate significant oesophageal ulceration.

 

Additional red flag alarm symptoms in conjunction with reflux include:

 

  • New onset symptoms in a patient older than 60
  • Evidence of bleeding (usually melaena or dark bowel motions)
  • Iron deficiency anaemia
  • Weight loss
  • Persistent vomiting
  • Anorexia
  • Family history of upper gastrointestinal cancer

 

Symptoms may vary depending on ethnicity, particularly in Asian patients. Perhaps due to a lack of precise translation for ‘heartburn’ in most Asian languages and the higher relative prevalence of ‘dyspepsia’ and the confounding effect of higher Helicobacter pylori prevalence, reflux can be more difficult to diagnose and manage successfully.  

 

Symptoms have been shown to have significant impact on quality of life and productivity. This includes sleep interference, physical activity, social functioning and work absenteeism.3 Despite this, in a study from Wellington, only 17% of those with reflux symptoms had consulted a doctor.4

 

Respiratory symptoms:

Chronic cough, laryngitis with hoarse voice, throat clearing and asthma have good evidence of causality with reflux.

 

Asthma:

Reflux can exacerbate asthma symptoms. Nearly 60% of patients with asthma report reflux symptoms.5 Studies also suggest a bidirectional relationship, with asthma worsening reflux.

 

Specific elements reported by these patients may include development of asthma symptoms or use of an inhaler during reflux episodes, or following consumption of reflux trigger foods such as chocolate, caffeine, alcohol or fatty foods.

 

The mechanisms through which this this thought to occur includes possible microaspiration, vagal reflex activation through acid stimulation and heightened bronchial reactivity and sensitivity.

 

Treating reflux has been shown to potentially improve asthma control, especially in patients whose asthma is difficult to manage.6 However, many studies also note no benefit of proton pump inhibitor (PPI) therapy in patients with asthma but without reflux symptoms.

 

Epidemiology:

 

Reflux was only initially recognised as a clinical entity in the 1930’s. The prevalence of reflux is now estimated to be at least 20% in Western countries, with increasing rates including among younger patients.7,8  A community survey of 1000 adults from Wellington reported rates of reflux of 34%.4

 

In contrast, most Asian studies using similar methodologies report prevalence rates that are 2 to 4 times lower.9 This discrepancy is thought to be multifactorial, stemming from lower rates of obesity and hiatus hernias, as well as reduced awareness and consultation rates, possibly due to the limited terminology used to describe the condition and consequently less detection.

 

The prevalence of reflux is influenced by age. Nearly 50% of newborns experience daily regurgitation or vomiting, but this resolves spontaneously in 90% of children by the age of 1. Thereafter, reflux progressively increases with older age.

 

Pathophysiology / aetiology:

It is normal to have some reflux. Over 24 hours, up to 30 acidic reflux events is considered as normal, with between 50-100 non-acidic events also seen in healthy individuals. These events are often not noticeable, and tend to occur post-meals, are short lived, and rarely occur at night.

 

As opposed to other sphincters in the body, which are a defined set of muscle groups (such as the anal sphincter), the lower oesophageal sphincter (LOS) is a complex anatomic zone which creates an anti-reflux barrier that includes muscle fibres of the lower oesophagus, muscles of the upper stomach (cardia) and the diaphragm, as well as intra-abdominal pressure.

 

This zone of increased pressure relaxes in response to oesophageal peristalsis to reflexively allow food into the stomach. Reflux occurs most commonly when this zone inappropriately transiently relaxes.

 

Additional key components include:

 

Hiatus hernia:

It is estimated that between 30-60% of patients with symptomatic reflux have a hiatus hernia. Reflux is induced as the stomach and the sphincter complex is displaced to above the diaphragm, often sliding between the peritoneum and the intrathoracic posterior mediastinum (‘sliding hernia’). This pressure shift allows gastric contents to pass back and forth leading to often larger volume reflux.

 

Motility disorders:

Poor oesophageal motility leads to sluggish clearance of ingested food, in addition to poor clearance of acidic refluxed gastric contents. Smoking leads to a nearly 30% greater likelihood of reflux compared to non-smokers also prolongs oesophageal acid clearance times.10

 

Slowed motility of the stomach, such as gastroparesis, leads to stasis of acid and food which is then more likely to be regurgitated and also lead to nausea and early satiety. It is noteworthy that marijuana can frequently cause slowed gastric emptying.

 

Increased intra-abdominal pressure:

Higher pressures from obesity, pregnancy (30-50% of pregnant woman suffer from reflux), straining with constipation, chronic cough or sneezing, tight clothing or activities such as heavy lifting or bending over promote reflux.

 

Patients with obesity were found to have a prevalence of reflux of 22%, a rate 70% higher than those not-obese.10 Obesity is also associated with disruption of the gastro-oesophageal junction (GOJ)  leading to development of hiatus hernia.

 

Medications and diet:

Medications that may relax the LOS include anticholinergics, nitrates, calcium channel blockers, erectile dysfunction medicines, tricyclic antidepressants, opioids and benzodiazepines. Oestrogen replacement therapy in post-menopausal woman reduces LOS tone. Fatty foods, chocolate, peppermint, caffeine, alcohol and smoking have a similar effect at the LOS.

 

Stress:

Psychosocial factors and sleep deprivation affect reflux and also perception and awareness of symptoms and reported severity.11

 

Genetics:

Twin studies suggest that heritability accounts over 30% of the susceptibility to developing reflux. Some research has identified genetic risk factors linked to reflux, although no specific genome anomaly has been identified.12

 

Helicobacter pylori: not to blame

 

Whilst H. pylori can be attributed to many upper gastrointestinal symptoms and pathology, it infrequently causes reflux. In fact, this bacterium often causes gastric atrophy with resultant achlorydria (low levels of acid) which explains why treatment may worsen reflux for a period as acid levels return to normal following eradication.13 This is often confounded by the use of omeprazole in the H. pylori treatment regimen, which may initially improve reflux symptoms.

 

There have even been concerns with widespread eradication regimens utilised to prevent gastric cancer that this may increase the risk of reflux related oesophageal adenocarcinoma, although this is now thought to be less likely.14

 

Differential diagnosis:

 

Symptoms of reflux are common but other conditions which may mimic reflux should still be considered, which can be differentiated on history and standard investigations (see investigations below). These include:

 

Non-reflux oesophagitis:

This includes inflammation of the oesophagus due to infection, such as candida, irritants such as pills (medication stuck inside causing ulceration of mucosal lining – most commonly doxycycline, tetracycline, potassium tablets), reflux induced by medication such as bisphosphonates like alendronate (fosamax).

 

Oesophageal disorders: structural and motility:

Oesophageal strictures or narrowing’s can be caused by reflux, but also form in other cases, such as an oesophageal ring or web (benign tissue that can quite randomly develop which narrows the lumen) or eosinophilic oesophagitis. Zenkers and oesophageal diverticulum (outpouchings in the lining of the oesophageal muscle) may lead to regurgitation and discomfort and difficulty swallowing.

 

Disorders of oesophageal motility and muscle function, including conditions such as achalasia, rumination syndrome or aperistalsis associated with conditions such as scleroderma may mimic reflux.

 

Functional gastrointestinal symptoms (disorders of the gut-brain axis)

Dyspeptic symptoms including bloating, abdominal pain (functional dyspepsia) and irritable bowel syndrome with fullness and variable bowel motions may overlap with reflux that can be difficult to differentiate clinically.

 

Cardiac causes:

Angina and acute coronary syndrome may mimic reflux. They also share many risk factors such as obesity, smoking, alcohol consumption, male gender and older age. Differentiating factors on history that favour reflux include:

 

  1. Timing: reflux may be worse after eating and positional with symptoms worse when flat. Reflux is more likely to improve with antacids, however interestingly, antacids such as Gaviscon or Acidex may also relieve cardiac symptoms and this feature should not be used in isolation.
  2. Pain description: reflux is often burning and epigastric in location, as opposed to pressure or tightness with radiation in cardiac causes
  3. Associated symptoms: reflux may occur with a cough and regurgitation, whereas cardiac causes more often have shortness of breath, sweating, dizziness or palpitations.

 

Biliary tract disease:

There may be some overlap with gallbladder pathology including atypical biliary colic or milder forms of pancreatitis which can be assessed with liver enzymes, lipase and an ultrasound scan if clinically suspicious.

 

Other subsets of reflux:

 

 

 

Non-erosive reflux disease:

 

Termed NERD, this subset of reflux includes the typical reflux symptoms, but without evidence of overt oesophageal mucosal injury seen on a gastroscopy. Up to 70% of patients with symptoms will have a normal gastroscopy. Of these, 50% of the patients will have evidence of increased oesophageal acid exposure on 24-hour pH monitoring (see investigations below).

 

The exact mechanisms underlying NERD are not fully understood, but it is thought that there is a combination of reflux and hypersensitivity to this. PPI treatment is often still trailed, as two-thirds of these patients have microscopic evidence of oesophageal injury on biopsy that responds to acid suppression.16 Carefully selected patients may benefit from endoscopic or surgical treatments of reflux if medical therapies fail.

 

Reflux hypersensitivity:

Patients will have reflux symptoms, a normal appearing gastroscopy and biopsies, normal manometry testing (no abnormal oesophageal motility) and no evidence of increased or pathologic acid exposure on 24-hour pH monitoring. During the pH monitoring test, patients will record push a button and record in a time-stamped diary when the notice symptoms. When analysed, there is evidence of a correlation between patients’ heartburn and physiological or non-acidic (pH >4) reflux. This is thought to account for 14% of all patients presenting with reflux. There is a considerable degree of overlap with functional and psychological diagnoses, and may be reponsive to neuromodulators to alter pain perception.

 

Functional heartburn:

Similar to hypersensitivity, these patients have reflux symptoms and investigations, except the 24-hour pH monitoring demonstrates no evidence of abnormal acid exposure or reflux with no evidence of a correlation between symptoms and physiological reflux events.

 

These are classified as a disorder of the gut-brain axis.  Symptom severity may vary over time, and often are associated with anxiety or depression. Nearly 60% of patients with PPI-refractory reflux symptoms are thought to have this diagnosis, which is the point at which it should generally be considered.17 This phenomenon is thought to arise as a result of a generalized increased in perception of visceral stimuli, and tricyclic antidepressants such as nortriptyline or amitriptyline may be beneficial.

 

This is an important entity to recognise as many patients will remain on PPI treatment or have anti-reflux surgery where there will be limited benefit and possible harm.

 

Silent Reflux

These patients do not have symptoms of reflux, but have endoscopic evidence of inflammation. One study from Taiwan estimated the prevalence to be nearly 60% of patients diagnosed with erosive oesophagitis at gastroscopy (i.e.16% of the whole study population of 2568 subjects).18  This is clearly a difficult population to diagnose or identify. Chronic unrecognised reflux may lead to severe complication, where in one series, more than 40% of patients with oesophageal adenocarcinoma did not recall having reflux symptoms. However, most studies of asymptomatic patients have found only low grade oesophagitis, with only a minority progressing to severe diseases.19

 

Consequences and sequelae of reflux:

 

Oesophagitis:

Visible erosion and ulceration occurs in 25% of patients with reflux symptoms. Endoscopists most commonly grade these on the Los Angeles Classification: A to D, indicating progressive severity and increasing oesophageal surface area affected. Over time, particularly if in combination with anticoagulation or anti-platelet medication, iron deficiency anaemia can develop from slow bleeding.

 

Stricture:

In patients with long term reflux damage, chronic inflammation leads to scarring and fibrosis which leads to thickening and narrowing of the wall. This may eventually occur in more than 20% of patients with untreated erosive oesophagitis.20 This development may be the first impetus to seek medical attention, often with symptoms of intermittent dysphagia, regurgitation or odynophagia.

 

Treatment of strictures depends on symptoms and severity. Long term PPI may reduce inflammation and oedema enough to be symptom free, however others may require balloon dilatation to disrupt the scarring. A balloon is inserted through the gastroscope and inflated across the narrowed component to widen the lumen. This often requires two to three separate sessions, 2-3 weeks apart to achieve full effect.

 

Barrett’s oesophagus

This metaplastic condition occurs as chronically irritated and inflamed oesophageal squamous cells are replaced by thicker intestinal columnar cells, which are better able to withstand acidic conditions. However, if these cells are exposed to further ongoing reflux inflammation, dysplasia may occur leading to possible oesophageal cancer. Whilst reflux is a strong risk factor and driver (in particular duration of >5 years), obesity and cigarette smoking are important co-factors. Non-modifiable risk factors include male gender, older age, Caucasian ethnicity, family history of Barrett’s oesophagus or oesophageal adenocarcinoma.

 

The prevalence of Barrett’s oesophagus is thought to be 1-2% of the general population in New Zealand (over 5% in the United States).21 The prevalence in patients with symptomatic reflux that have a gastroscopy is as high as 15%.22 Therefore the majority of patients are undiagnosed. Despite these extraordinary rates, only a minority of these individuals will progress to oesophageal adenocarcinoma.

 

Progression to cancer occurs stepwise and slowly on a scale from low grade to high grade dysplasia to frank adenocarcinoma. The annual progression rate to cancer is estimated to be around 0.5-1% per year, depending on a number of factors. For individuals with already high grade dysplasia, this may be as high as 5-8% per year, which justifies intervention with either endoscopic excision of the dysplastic area or radiofrequency ablation (burning) of the Barrett’s lining to prevent further progression.

 

Once diagnosed, surveillance is recommended, with interval timing largely based on the length of the Barrett’s segment. Less than 3cm of involvement is considered short segment, with surveillance recommendations varying between 3 to 5 yearly. If low grade dysplasia is present, surveillance and biopsies are recommended 6 monthly.

 

Given the poor outcomes of patients with oesophageal cancer (overall less than 20% survive more than 5 years once diagnosed), targeted screening for Barrett’s oesophagus in patients with risk factors has been proposed. However, due to the high prevalence of reflux, even applying a screening criteria of individuals with >/= 3 risk factors: male sex, Caucasian ethnicity, age >50, history of smoking, chronic reflux, obesity or a family history of Barrett’s or oesophageal adenocarcinoma would make over 120 million people eligible in the United States alone (equivalent to over 50% of their >18 year old population), which clearly represents an overwhelming resource burden.23 In addition, screening has never been shown to reduce mortality. Use of non-invasive screening modalities, such as the non-endoscopic sponge capsule has been proposed. This is a capsule swallowed on a string which dissolves, with a sponge emerging, which then is pulled out through the mouth, taking a sample of oesophageal cells with it, which can then be analysed.24

 

Further elucidation and refinement of screening criteria, better understanding of risks and benefits of screening and surveillance, and high-performing, scalable, non-invasive modalities such as the endosponge will be needed if screening is ever to become a reality. 

 

Oesophageal adenocarcinoma:

Very low numbers of patients with reflux will develop this cancer, yet, there has been a substantial increase of a factor of 2 to 6 times in the last 20 years, particular in Western countries.25  In New Zealand, the age standardised registration rate for oesophageal cancer in 1950 was 2.2/100,000 with 46 total cases diagnosed. This increased to 4.3/100,000 with 364 cases diagnosed in 2000.26  More recently there are reports of an annual increase of 4.2% per year in Australia.27

 

Early detection is crucial, but requires careful endoscopic examination and review, which can be challenging. Early dysplasia and cancer detection can be difficult due to patchy distribution and subtle appearance changes only. Recommended biopsy protocols of sampling the oesophagus during gastroscopy every 1-2cm in 4 quadrants are imprecise and prone to sampling error, with less than 1% of the Barrett’s change evaluated with this method. Over 25% of high grade dysplasia or early cancer can be missed at the initial surveillance gastroscopy.28

 

Most concerningly is the aggressive nature and poor prognosis of the disease. When detected early, 5-year survival is over 50% for in-situ disease, as opposed to 10% for cancer with regional spread.  Treatment may still offered at this stage, usually with neo-adjuvant chemoradiotherapy, prior to oesophagectomy (removal of the oesophagus).

 

Despite advances in awareness and diagnosis and Barrett’s surveillance programs, over 50% of patients have either unresectable lesions or metastasis at diagnosis.29 In addition, there is a disproportionate incidence in ethnic minorities with poorer global outcomes. Averaged over time, excess mortality is 68% greater for Māori oesophageal cancer patients, and patients in the lowest income quintile experience 10% greater excess mortality compared to patients in the highest income quintile.30 Once the disease is very advanced with difficulty swallowing necessitating oesophageal stent placement, our study from Auckland showed patients passed away on average after 3 months.31

 

Investigations and diagnostics:

 

The diagnosis or reflux can be based on classical symptoms alone. Further, more invasive investigation should be primarily reserved for patients whose diagnosis is less clear with atypical symptoms, those with alarm features, to identify possible complications of long-term reflux such as Barrett’s oesophagus, and to evaluate treatment failures.

 

Trial of PPI:

 

The vast majority of patients with reflux will have some response to PPI therapy. In patients with typical symptoms and response to PPI, no further diagnostic tests are required. However, symptom response alone is unreliable, and is therefore not part of the diagnostic criterion for reflux, as it is not correlated well with more objective markers of reflux such as 24 hour pH testing (sensitivity and specificity of PPI response as a test for reflux is less than 80%).32

 

Gastroscopy:

 

A gastroscopy is a 10-minute procedure, usually performed in New Zealand under light conscious sedation. This is usually a mixture of fentanyl for analgesia and midazolam as an anxiolytic, along with topical local anaesthetic spray in the mouth to reduce gag sensation. The risks of complications for a diagnostic gastroscopy such as bleeding or perforation is very low, estimated at less that 1 per 5000 cases.

 

Passing the 1 metre long, 9mm diameter soft flexible tube through the mouth allows direct visualisation of oesophageal mucosa and also provides information on anatomy, including the presence of a hernia. Gastroscopy also allows diagnosis, evaluation, assessment and biopsy of Barrett’s oesophagus. Alternative causes of symptoms are also able to be assessed with gastroscopy, in particular eosinophilic oesophagitis which is only confirmed on biopsy.    

 

However, even in untreated reflux patients, less than 50% may have visible inflammation or ulceration. There is a poor correlation between the severity and duration of symptoms and the extent of oesophagitis observed during gastroscopy.

 

24-Hour pH Monitoring: the gold standard for assessing oesophageal acid exposure

 

This procedure involves the insertion of a thin catheter with a pH sensor through the nose, typically positioned about 5 cm above the lower oesophageal sphincter. It measures pH levels in the distal oesophagus, specifically focusing on pH values below 4, which indicates acid exposure.

 

Key components measured includes frequency and duration of reflux episodes and accumulated exposure time. These are integrated into a composite score (DeMeester score) that is reproducible and independent of gender and race. This score has been demonstrated to be the most reliable measure for assessing the efficacy of therapeutic acid suppression regimens or evaluating the success of anti-reflux surgery.

 

In practice, this investigation is used infrequently. It is primarily used for patients with atypical symptoms and incongruous gastroscopy findings, ongoing symptoms despite maximal dose of medical therapy and patients with possible NERD or functional reflux.

 

In patients who do not exhibit typical reflux symptoms, it can be beneficial to test off PPI therapy. This helps determine if reflux is indeed contributing to their symptoms, as the absence of PPIs can reveal the true nature of acid exposure.

 

For patients who have a poor or partial response to PPIs, conducting tests while they are still on therapy is useful. This approach helps to identify whether there is ongoing pathological acid reflux or non-acid exposure that could be contributing to their symptoms, guiding further management.

 

Oesophageal manometry: assessing motility

 

This evaluates the pressures and patterns of muscle contractions in the oesophagus. It is often performed alongside 24-hour pH monitoring.

 

During the 30 minute test, following local anaesthetic spray to the nose and throat, a thin catheter is inserted through the nostril and into the oesophagus. Small sips of water and jelly are consumed with measurements of contraction and relaxation performed. 

 

This test is indicated in patients with suspected reflux with also chest pain or dysphagia and a normal appearing gastroscopy, specifically to exclude a motility disorder that may be causative of the symptoms such as oesophageal spasm, achalasia or rumination.

 

It is also useful in in patients with reflux who may be considering intervention to tighten the GOJ to assess strength of peristaltic function before anti-reflux surgery. Some patients may have very weak oesophageal function, which may increase the possibility of dysphagia post any intervention that aims to tighten this.

 

Medical Treatment: multimodal.   

 

Lifestyle:

 

All patients should be counselled regarding these interventions including:

 

  1. Identification and reduction of trigger foods: most commonly carbonated beverages, alcohol, spicy foods, fatty or fried foods, excess caffeine (including black tea which although contains less than an espresso shot of caffeine, may add up over the day if many cups are consumed). Smoking cessation should be encouraged.

 

  1. Avoid late meals: consume last meal 3 hours before lying flat

 

  1. Sleeping position: left lateral is the most beneficial to prevent reflux. Elevation of the head of the bed may be helpful in some. This is best trialled with a foam wedge under the mattress or blocks under the legs of the head of the bed, prior to purchase of often expensive, purpose-built electric beds. These should only be recommended to patients with nocturnal symptoms.

 

  1. Weight loss: This has been consistently shown in randomised control trials to be effective at reducing reflux.33

 

  1. Chewing gum or sucking on lozenges increases the rate of oesophageal acid clearance and saliva may neutralise refluxed acid.

 

Ant-acids:

 

In the community study of patients with reflux from Wellington, the majority reported using over the counter medications.4 Acidex and Gaviscon are desirable as they provide immediate relief, however with effect reduction after at most 60 minutes. They do not prevent reflux, but neutralize the acid effect, which we describe to patients like a soothing cream for the oesophagus, but without addressing the underlying cause.

 

Proton pump inhibitors (PPIs): overused?

 

PPIs are still the most effective medical treatment of reflux symptoms and inflammation. They bind irreversibly to the hydrogen-potassium ATPase in the parietal cells of the stomach to prevent acid secretion.

 

PPI usage has radically increased since their introduction in the late 1980s. They are now estimated to account for over 50% of prescriptions for all digestive diseases, and are the second most common medication class prescribed with over 113 million prescriptions dispensed every year.34

 

Overutilisation and inappropriate ongoing prescribing is also of concern, estimated to be even up to 70% of prescriptions in the United States. In New Zealand, PPI used increased by 27% from 2005 to 2013 in patients over 65.35

 

An approach to start PPIs:

 

Empiric therapy based on reported frequency and severity with a step-up approach is reasonable at initial assessment. A trial of once daily treatment for 4-8 weeks could be started, with an increase in dose (omeprazole 20mg to 40mg), timing (30 minutes prior to a meal is optimal) or frequency (once daily to twice daily) considered. Use of twice daily PPI has a low evidence base but is frequently used in clinical practice and has been shown to be effective at reducing acid levels.

 

If there is an adequate response along with lifestyle intervention, you can attempt to stop or lower the dose. Stopping should be done with a wean to prevent rebound acid hypersecretion, by tapering to every second day for a week then every third day for a week prior to complete cessation. Acid secretion returns to normal within 12-24 hours after stopping.

 

If there are recurrent symptoms or atypical features or concern of Barrett’s oesophagus, investigation and a prolonged or indefinite course of PPI should be considered.

 

In patients with proven oesophagitis, reduction of acid as a result of the PPI allows healing, with usually complete response after 2 months. The rate of healing with PPI was 83% compared to 52% with histamine receptor antagonists and 8% placebo.36

 

As PPI is usually so highly effective, treatment failures should be assessed with firstly checking on patient adherence, prior to consideration of further investigation.

 

Changing PPI type

There are no major differences in efficacy noted among various PPIs available in New Zealand: omeprazole, pantoprazole and lansoprazole when used in standard doses. Pantoprazole is the smallest tablet in size and so may be preferred in those with swallowing difficulty. However it is the ‘weakest,’ with 20mg equivalent to 4.5mg of omeprazole, as opposed to lansoprazole 15mg equivalent to 13.5mg of omeprazole.37

 

In clinical practice, clinicians often trial switching between PPI types, with some patients perhaps noticing a difference and expressing a preference. 

 

Differences in PPI metabolism:

PPIs are primarily metabolized through the CYP liver enzyme system. 5% of Asian patients and 10% of Caucasian patients are homozygous for a CYP2C19 mutation, classifying them as slow metabolisers, leading to greater acid suppression, with a smaller proportion of patients wild type homozygotes, leading to rapid metabolism and possible PPI failure.

 

PPIs and drug interactions:

There are some relatively minor possible interactions to bear in mind.

 

  1. PPI-mediated CYP inhibition: Increase in serum concentrations of drugs metabolized by CYP2C19 (eg, phenytoin, diazepam) and CYP3A4 (eg, carbamazepine, tacrolimus, and cyclosporine)
  2. Inhibition of CYP2C19 may hinder metabolism of clopidogrel rendering it less effective. Clinical relevance is disputed, but omeprazole could be switched to pantoprazole which does not inhibit this enzyme.

 

Competitive inhibition can be minimized by separating the administration of interacting drugs by several hours.

 

There may also be reduction of B12, magnesium and iron levels via reduced absorption.

 

Acute PPI side-effects:

Headache, diarrhea, constipation, and abdominal pain are frequently reported, although in trials are not seen significantly more than placebo.

 

PPI long term safety

Given their widespread use, there have been many concerns raised about long-term safety including multiple observational studies with noted associations with increased risk of pneumonia, fracture, enteric infection, clostridium difficle diarrhoea, stroke, renal failure, dementia, diabetes, gastric cancer and all-cause mortality. To address these studies and confounding factors, starting in 2013 nearly 18,000 patients were randomised to either pantoprazole 40mg daily or placebo. Patients were followed for over 3 years for a total of 53,000 patient years of follow-up.38 Participants were interviewed every 6 months to assess for outcomes including cognitive assessments to assess for dementia development.

 

Overall, there was no statistically significant difference between the pantoprazole and placebo groups in all safety events except for enteric infections (1.4% vs 1.0% in the placebo group). This calculates as a number needed to harm (NNH) of >300 over 3 years.38

Full paper available:

https://www.gastrojournal.org/article/S0016-5085(19)40974-8/fulltext?referrer=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F

Despite this reassuring work demonstrating no evidence of harm, and confirming suspicion of the associations from other studies likely relating to residual confounding or unaccounted biases, we advocate that patients should be on the lowest dose that keeps symptoms at bay. PPI should be stopped if not needed, but encouraged with confidence where it is required where evidence demonstrates that benefits outweigh very low risk of infrequently enteric infections.

 

Pregnancy

It may be preferrable to use pantoprazole or lansoprazole, graded by FDA as category risk B (no evidence for risk in humans), as compared to omeprazole, classed as Category C (“risk cannot be ruled out”). In practice, many studies have demonstrated safety of all PPIs in pregnant women with no difference in case control studies with regards to birth defects.39

 

Histamine receptor antagonists 

Ranitidine (now withdrawn in New Zealand, United States and Europe due to a possible carcinogenic focus) and famotidine (which does not have this) block histamine receptors in the parietal cells of the stomach, thereby reducing the production of acid. It may be used in those who cannot tolerate PPI due to adverse effects or in those with persistent acid reflux despite PPI therapy. We suggest to start by using famotidine, 20mg in the evening. Unlike PPI, tolerance frequently develops, even after one week of treatment. If this occurs, it can be stopped for a period, prior to recommencement or used on an as-needed basis.

 

Potassium-competitive acid blocker (PCAB):

Vonoprazan is recently FDA approved medicine, used in Japan since 2015 as an alternative to PPI that we anticipate will be available in New Zealand at some point in the future. It has a very rapid onset of action with potent acid neutralization effect even after a single dose. It has a longer half-life than PPIs, with a single dose working over 24 hours that therefore can taken with meals.

 

Prokinetics:

Domperidone or metoclopramide may be trialled but at best may only result in modest improvement, often at the expense of adverse effects and undesirable pill burden.40  

 

Baclofen

This is a muscle relaxant that is primarily used to treat conditions involving muscle spasticity. There is evidence it may be an effective adjunct for reflux treatment by helping to reduce LOS relaxation episodes. In practice it is very rarely used, with even low doses (5-10mg twice daily) often leading to drowsiness.

 

Acupuncture:

One small study has demonstrated improvement of symptoms in patients with refractory heartburn. We don’t dissuade patients who wish to try this avenue, which may improve visceral pain and certainly may also assist those whose symptoms may be influenced by the gut-brain axis as well.41

 

Endoscopic anti-reflux surgery:

Endoscopic anti-reflux therapies are intended to offer an alternative for patients unwilling to undergo surgery with PPI refractory reflux, or those in which medication compliance, side-effects and patient preference may limit efficacy.

 

Over the last 30 years, more therapies have been developed as an alternative to surgery or as a bridge between medical treatment and surgery.

 

Patient selection is vital, as techniques do not currently allow repair of the hiatus and therefore generally exclude patients with hernias larger than 2cm. Options available in New Zealand include Stretta (endoscopic-guided application of non-ablative radiofrequency energy to the muscle fibres of the lower oesophagus and upper stomach to promote muscular hypertrophy) and ARMA (anti-reflux mucosal ablation), which ablates mucosa with argon plasma coagulation at the GOJ to create ulceration, fibrosis and subsequent constriction with the scar development. Other techniques, including TIF (transoral incisionless fundoplication) are not available.

 

Few studies exist comparing endoscopic to surgical techniques. A retrospective review comparing ARMA to laparoscopic Nissen fundoplication (see laparoscopic surgery below) suggested better perioperative outcomes with regard to operation time, blood loss, hospital stay and pain, with comparable reflux quality of life outcomes to 2 years.42 However there are a considerable number of confounders. We are currently enrolling for a world first prospective randomised trial comparing these two interventions.43

 

Laparoscopic surgery

Anti-reflux surgery, particularly laparoscopic fundoplication, is another option for patients with persistent or complicated reflux who meet specific criteria.

Surgery may be suitable for patients who:

  • Experience ongoing symptoms despite optimal medical management, including medications and lifestyle adjustments.
  • Prefer a long-term surgical solution due to an inability to tolerate medication or a desire to avoid continuous medication.
  • Develop serious reflux complications that do not respond to medication, such as oesophageal strictures, recurrent aspiration, or severe ulcerations.
  • Have large hiatus hernias causing significant symptoms such as dysphagia, regurgitation, shortness of breath, or anaemia.
    • Additionally, guidelines recommend surgical repair for symptomatic para-oesophageal hernias and for cases where more than 75% of the stomach herniates into the chest, to reduce risks of complications such as bleeding or gastric volvulus.44

 

Laparoscopic Fundoplication

Laparoscopic fundoplication is a minimally invasive "keyhole" surgery that involves wrapping the top portion of the stomach (fundus) around the lower oesophagus. This creates a valve-like effect to reinforce the lower oesophageal sphincter and prevent acid from refluxing back into the oesophagus. The procedure takes between 40-80 minutes under general anaesthesia and, when performed by experienced surgeons, has a low major complication rate of less than 1%. Compared to traditional open surgery, the laparoscopic approach offers reduced pain and faster recovery, allowing patients to typically mobilise and begin drinking on the same day without the need for catheters or drains. Most patients are discharged home the day after surgery. The post-operative diet is then gradually progressed from liquids to puréed to soft foods over 3–4 weeks as postoperative swelling resolves. Patients need to avoid any heavy lifting until six weeks after their operation.

 

Long-Term Outcomes

Long-term studies have demonstrated that anti-reflux surgery is both effective and durable. In one study that followed 215 patients for 20 years after undergoing fundoplication, 87% reported they would choose to have the surgery again, indicating high satisfaction.45 Up to 90% of patients experience lasting symptom relief. Many also report improved sleep quality, reduced dependence on medication, and the ability to tolerate a wider variety of foods.

However, mild complications such as gas bloat or occasional dysphagia can arise. While these issues are usually manageable, they may persist for some patients and affect daily comfort. In such cases, revisional surgery due to recurrent symptoms is required in approximately 4–7% of patients.46

 

Factors Influencing Surgical Success

Certain factors may impact the long-term success of surgery, including:

  • Elevated BMI: Increased intra-abdominal pressure from a higher BMI can strain the repair, so weight management is advised.
  • Heavy Lifting Post-Op: Strenuous activity should be avoided early in recovery to prevent disruption of the repair.
  • Pre-existing Motility Disorders: Weak oesophageal motility may increase dysphagia risk, making careful surgical calibration essential.
  • Lifestyle Factors: Smoking and poor dietary habits can interfere with healing and increase the risk of complications.

 

Patient Selection and Preoperative Assessment

A thorough preoperative assessment, including oesophageal manometry and 24-hour pH monitoring, is essential for confirming the diagnosis and tailoring the surgical approach for anti-reflux surgery. Manometry helps determine the strength and coordination of oesophageal muscles during swallowing. This allows for appropriate calibration of the wrap and associated tightening of the GOJ to balance effective reflux prevention with minimal risk of swallowing difficulties.

For patients with severe motility disorders, anti-reflux surgery may not be recommended due to potential for significant postoperative swallowing issues.

 

Anti-Reflux surgery in Obese Patients

For obese patients, a laparoscopic Roux-en-Y gastric bypass (LRYGB) may be a more effective option than fundoplication. Fundoplication tends to have a higher failure rate in patients with obesity due to increased intra-abdominal pressure. LRYGB not only provides effective reflux control but also promotes significant weight loss and improvement in obesity-related conditions, such as type 2 diabetes and sleep apnoea. However, LRYGB requires lifelong vitamin supplementation and is a more complex surgery, necessitating an experienced bariatric surgeon.47

 

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