Mathematical Setup

There is a potential genetic component to the development of GORD and perhaps Barrett’s esophagus.⁵⁷ The likelihood of reflux disease accounted for by genetics is 31% - 43%.¹⁹ In the US, although the frequency of GORD symptoms does not differ between Caucasians and African Americans, the latter group have a persistently lower risk of oesophagitis.⁴ In a study from Johannesburg, of the 216 consecutive Barrett’s oesophagus patients only 5% were black despite the ratio of Blacks to Whites in the city being 5:1.¹⁷

There is evidence for an association between having GORD symptoms and having a genetically related family member with gastrointestinal symptoms.⁶⁷ El-Serag et al in a systematic review reported good evidence for familial clustering of GORD: association with a parental family history of reflux disease [odds ratio (OR) 1.46 (95% Confidence Interval, CI: 1.22 – 1.74)]; higher concordance in prevalence in monozygotic over dizygotic twins (p <

0.0001).⁵⁷ Nasseri-Moghaddamet al however reported no association between having GORD and having an immediate family history of the disease.⁶¹ There was no association between having GORD and having a spouse with a history of gastrointestinal symptoms.⁵⁷

2.3. 11 Exacerbating factors

Potential GORD triggers or exacerbating factors include dietary and lifestyle factors such as specific foods, eating habits, obesity, alcohol consumption, smoking, physical activity, sleeping position, pregnancy, hormones, hiatal hernia, and certain medications.^19,72

While some of these factors are thought to play a significant and documented role in GORD pathogenesis or pathophysiology, others, primarily dietary and lifestyle factors, lack convincing or consistent documentation of a role in triggering or worsening GORD

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symptoms.45,56,77 This is because of the nature of the studies conducted, which have been generally small and inconclusive and have yielded conflicting results in different patient groups. The treatment of GORD, however, is oriented toward the individual patient’s symptoms, and in practice this includes providing specific advice regarding individual dietary intolerances and lifestyle factors.⁴⁵

A careful history can help to identify specific factors in individual patients, to avoid unnecessarily restricting patients who might not benefit from such measures. Therefore, while little consistent data support the role of lifestyle modifications alone as an effective treatment, avoidance of exacerbating factors can be helpful for individual patients.^19,78,79 Lifestyle measures are considered to be of some potential benefit and no proven harm.^7,32 2.3.11.1 Obesity

Obesity is an independent risk factor for development of GORD as demonstrated by multiple investigators from North America, Europe, and Asia.^56,80 A meta-analysis documented that individuals with BMI greater than 30 kg/m² have a 1.5- to 2-fold increased risk of GORD and erosive oesophagitis compared with individuals with normal BMI.⁸¹ Kulig et al in the multinational ProGERD study reported normal weight (BMI < 25kg/m²) in one third (33%), overweight (BMI 25 – 29.9kg/m²) in 47%, and obesity (BMI > 30kg/m²) in 20% of participants 18 years and above wherein 80% had heartburn and 74% had regurgitation.³¹ The exact pathophysiological mechanisms that demonstrate the association/relationship between being overweight/obese and GORD have not been fully identified, but some hypotheses have been suggested viz; that visceral adiposity, expressed by an increased abdominal waist circumference, could be associated with increased intra-abdominal pressure which would, in turn, promote GORD by increasing intragastric pressure (IGP); a separation between LOS and the extrinsic crural diaphragm, an anatomic disruption which could predispose obese subjects to hiatal hernia; slower oesophageal acid clearance and other

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oesophageal motor abnormalities such as hypotensive LOS pressure, nutcracker oesophagus and non-specific motility disorders.^19,46,72 More so, visceral fat is metabolically active and it has been associated with low serum levels of protective cytokines, such as adiponectin, and high levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β and IL-6. An increase in these inflammatory cytokines in patients with erosive oesophagitis and Barrett’s oesophagus has also been observed.¹⁹ Sensitization of oesophageal chemoreceptors, either directly by intermittent exposure to refluxed acid or indirectly through oesophagitis-associated inflammatory mediators, is thought to be one of the most important mechanisms responsible for symptom generation in GORD.¹⁹

2.3.11.2 The role of diet

Since GORD symptoms are most commonly reported postprandially, the role of diet components in inducing or worsening symptoms has been suggested. However, different and conflicting results exist in the literature for identifying the most “refluxogenic” foods.¹⁹ Meals are the major aggravating factor of GORD symptoms, since they stimulate the production of gastric acid available for reflux into the oesophagus. Food in general and large meals in particular induces TLOSRs.⁴⁶

Many substances directly irritate the lining of the oesophagus and can contribute to heartburn.

These potential oesophageal irritants should be restricted.⁵⁶ Specific foods that have been identified as potentially aggravating factors in certain patients include spicy foods, citrus fruits and juices, tomatoes products and tomato sauces, raw onions, mint, alcohol, cigarette smoke and coffee.^46,56 Some of these foods can also increase the production of stomach acid and decrease the LOS pressure, leading to heartburn.⁴⁶

46 2.3.11.3 Spicy foods/meals

There are no demonstrable sphincter pressure and pH effect reported with spicy foods.⁴⁶ Spicy products due to the presence of irritant alkaloids such as capsaicin, stimulate mechanoreceptors in the oesophagus, which may cause unpleasant symptoms, especially in inflammatory lesions of the mucous membrane.⁸² Capsaicin can modulate gastrointestinal sensation via capsaicin or transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors.⁸³ These receptors have been found at different levels through-out the gastrointestinal tract. Capsaicin, acid, and heat can stimulate the TRPV1 receptors and mediate a sensation of burning and pain.⁸³ Several studies suggested that TRPV1 receptors can mediate sensations of warmth, pressure, cramping, and pain in the human gut.⁸⁴

2.3.11.4 Timing of meals

Meals eaten within 2 to 3 hours of bedtime, which increase acid availability at nighttime, or with alcohol, can predispose patients to nocturnal reflux.⁵⁶ It is recommended to eat at least 3 moderate meals a day (preferably 4 – 5 meals) and to eat dinner (less than often portion) at appropriate times 2 to 3 hours before reclining to bed instead of one big meal in the evening.^82,85

2.3.11.5 The role of factors contributing to increased intra-abdominal pressure

The role of factors contributing to increased intra-abdominal pressure cannot be overlooked.

These include overeating, obesity, bending over after eating, lying down after eating, and consuming fatty foods. Eating a big meal causes excess gastric distension, which leads to intense stimulation of both stretch and tension mechanoreceptors in the proximal stomach with excess acid production.^19,46 Smaller meal portion exerts less stomach workload and therefore less gastric acid secretion.¹⁹

47 2.3.11.6 Sleep position

A change in sleep position is reported as being beneficial to the health of people who suffer a range of medical conditions such as heartburn, chronic indigestion, asthma or other respiratory illness and sleep apnoea.⁸⁶ The pattern of oesophageal acid exposure, in fact, has been linked to increasing GORD severity. The reported risk of severe GORD increased progressively with the different reflux patterns, from postprandial to upright to supine to bipositional.⁵⁶ Patients with known GORD or symptoms suggesting GORD, may benefit from sleeping on the left side if possible as the oesophagogastric junction is beyond the level of gastric juice in this position.⁴⁵ Total reflux time, average acid clearance, and lower oesophageal sphincter relaxations have been reported to be significantly prolonged in patients laying on their right sides compared to the left lateral decubitus position.⁴⁶ Laying on the left side has been shown to increase sphincter pressure and oesophageal pH.⁴⁶

2.3.11.7 Dietary fat

Dietary fat in the duodenum also appears to be a strong reflux trigger, in part by impairing gastric emptying.⁵⁶ High fat foods remain in the stomach longer, thus causing the need for more stomach acid in order to digest them. Fat also reduces the lower oesophageal sphincter pressure.⁴⁵

2.3.11.8 Sweets and chocolate

Sweets such as candy bars have high osmolality and fat content and have been shown to provoke reflux by decreasing the lower oesophageal sphincter pressure and delaying stomach emptying similar to chocolate effect which contains methylxanthine.^45,19

2.3.11.9 Peppermint and Spearmint

Peppermint and spearmint are plant extracts that are commonly used in foods and flavourings of toothpaste, mouthwash, and candy. Peppermint and Spermint are thought to lower LOS tone, facilitating reflux.⁸² Thus it is commonly recommended that patients with GORD avoid

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ingesting mint.⁷⁷ A randomized double-blind placebo-controlled trial in which the LOS tone of healthy volunteers was measured in response to spearmint found no difference in symptoms, sphincter pressure, or reflux episodes with ingestion of spearmint.⁷⁷ This was in healthy volunteers and not GORD patients. More so, there were no studies published on the effect of cessation of mint intake on GORD symptoms.

2.3.11.10 Carbonated beverages

Carbonated beverages have the unique properties that may potentially exacerbate GORD, such as high acidity and carbonation.⁸⁷ Cola drinks, coffee, tea and soft drinks can have an acidic pH, lowering lower oesophageal sphincter pressure to precipitate symptoms.^87,88 A recent systematic review reported that carbonated beverages results in a very short decline in intra-oesophageal pH and may lead to TLOSRs.⁸⁷ There was no evidence that carbonated beverages directly cause oesophageal damage and they have not been shown to consistently cause GORD-related symptoms.

2.3.11.12 Alcohol

While some authors have suggested that alcohol is an independent risk factor for GORD-related symptoms, others have not found such a relationship.¹⁹ Patients with GORD often report heartburn after ingesting alcoholic beverages.⁴⁵ Alcohol consumption may precipitate GORD by its direct toxic effect on oesophageal mucosa and/or increasing acid secretion through gastrin stimulation, reducing lower oesophageal sphincter pressure, increasing spontaneous LOS relaxations, and impairing oesophageal motility and gastric emptying.^45,89 2.3.11.12 Cigarette smoking

A number of potentially contributory factors have been identified. Studies show that smoking decreases LOSP, thereby promoting reflux, and predisposes to strain-induced reflux.^19,45,77 The abrupt decline in LOSP at the start of smoking returns to normal within minutes of completion of the cigarette. Higher rates of reflux symptoms in tobacco smokers compared

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with non-smokers have been reported and is also increased with increased duration of smoking.^45,77

Abrupt increases in intra-abdominal pressure, as occur during coughing or deep inspiration, have been associated with reflux symptoms in smokers.^45,19 Smoking also decreases salivary bicarbonate secretion, thus reducing the physiological neutralizing effect of saliva on intra-oesophageal acid and prolonging acid clearance with potential tissue damage.19,45,56,77

Smoking is nevertheless not considered a major risk factor for GORD.⁵⁶ 2.3.11.13 Exercise

The relationship between exercise and GORD is also controversial and may be a consequence of differences in the populations studied (age, race), evaluation of exercise (short-term, long-term), assessment of physical activity (different questionnaires) and diagnosis of the disease (symptom scale or pH-metry). A positive association between exercise and GORD is present in vigorous, but not in moderate exercise and may alter oesophageal motility and worsen symptoms of the upper gastrointestinal tract.¹⁹ Normal physical activity has been demonstrated to have a protective effect against GORD.¹⁹ Specific types of exercise are more likely to induce reflux symptoms, with running and resistance exercises being more refluxogenic than cycling.¹⁹

2.3.11.14 Medications

A wide variety of medications can promote GORD symptoms as a result of their effects on gastric emptying of acid, LOSP reduction to promote reflux, oesophageal motility, wakefulness or salivation.⁵⁶ Medications that can decrease LOSP, leading to reflux, include anticholinergics, sedatives or tranquilizers (particularly benzodiazepines), tricyclic antidepressants, theophylline, prostaglandins, dihydropyridine calcium channel blockers, alpha-adrenergic blockers, beta blockers, and progesterones. Potassium tablets, nonsteroidal anti-inflammatory drugs (NSAIDs), and alendronate can also cause oesophagitis.^48(270)

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NSAIDs disrupt tissue resistance, and more severe cases of oesophagitis might be more common among chronic NSAID users as in osteoarthritis, back pain, and tension headache.⁵⁶ Damage to the oesophagus might occur as a result of toxicity from the medication itself as well as from nonspecific irritation caused by contact between the pill and the oesophageal mucosa (pill oesophagitis).⁵⁶

2.3.11.15 Hiatal hernia

A hiatal hernia is frequently found among patients with GORD.^56,72 The proximal stomach is dislocated through the hiatus of the diaphragm into the chest, and the crural diaphragm becomes separated from the LOS.⁵⁶ Hiatal hernia disrupts the integrity of the gastro-oesophageal sphincter resulting in decreased LOSP, reduced gastro-oesophageal acid clearance and increased oesophageal acid exposure. ^56,72 It may be a factor in GORD pathogenesis, especially if the patient has severe symptoms. Hiatal hernias are present in more than 90% of patients with severe erosive oesophagitis, especially if complications are present (such as oesophageal stricture or Barrett’s oesophagus) and they likely contribute to the complication development.⁵⁶ Whether or not the hernia is an initiating factor in GORD, it clearly plays a role in sustaining GORD, accounting for the chronicity of the disease.⁵⁶

Depending on their size, hiatal hernias can displace and disable the diaphragmatic sphincter (the crural diaphragm) to increase susceptibility to reflux during sudden increases in intra-abdominal pressure. Large hiatal hernias also serve as a reservoir for refluxates and impair oesophageal emptying during swallowing, thus prolonging acid clearance time.⁵⁶ Oesophageal acid clearance might also be impaired by diaphragmatic contractions.⁵⁶

2.3.11.16 Pregnancy

Pregnancy is the most common condition predisposing to GORD and is generally associated with symptomatic GORD, typically heartburn, rather than oesophagitis.⁵⁶ Heartburn affects approximately two thirds of all pregnancies and it is thus considered by many to be a normal

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occurrence during pregnancy. In most cases, symptoms occur for the first time during the pregnancy, subside soon after delivery and with a possibility for recurrence in subsequent pregnancies.⁵⁶

While the pathogenesis is thought to be multifactorial, the primary pathophysiology of GORD during pregnancy is probably that of decreased LOSP resulting from the effects of progesterone and oestrogen on LOS function.⁵⁶ The two hormones appear to act together, with progesterone acting as a mediator of LOS smooth-muscle relaxation and oestrogen as a

“primer” of LOS relaxation.⁵⁶ Mechanical factors, such as increased abdominal pressure due to enlargement of the uterus, are believed to play a smaller role.

2.4 CLINICAL FEATURES OF GORD