Ms. Liu is a middle-aged professional woman who has been visiting the hospital for the past 2 years because of a recurring “heartburn” in her chest. She often feels a burning pain in her chest, sometimes involving her neck, and when it is severe, it occurs more than 3 times a day, occasionally waking up at night with heartburn. Three months ago, she started taking an acid control drug called “proton pump inhibitor” and felt relief from the symptoms for 2 weeks at first, but the symptoms returned after 2 weeks. She took many medications under the guidance of her physician, but still did not see any improvement. Why did the medication for “reflux disease” not work? ”Reflux disease”, or “gastroesophageal reflux disease”, refers to damage or discomfort to the esophageal mucosa caused by the reflux of stomach or duodenal contents into the esophagus. As the esophagus enters the stomach, there is a cartilage-like valve called the lower esophageal sphincter. If the lower esophageal sphincter does not function properly, stomach acid or duodenal fluid can reflux into the esophagus. When this valve opens during normal swallowing, it closes again after food enters the stomach from the esophagus, but when it does not close properly, food and stomach acid or even duodenal fluid from the stomach will flow back into the esophagus. The esophagus is often “corroded” by gastric acid, and over time there will be esophageal damage and various discomforts, including heartburn, acidity, reflux, and sore throat. At present, the treatment of “reflux disease” can only reduce or alleviate the symptoms by inhibiting stomach acid to reduce the continued damage to the esophagus, but there is no solution for the dysfunction of the “living door” between the esophagus and the stomach for the time being. The most common and effective drugs used to suppress gastric acid are proton pump inhibitors (PPIs). With the use of proton pump inhibitors, about 80% of patients with reflux disease can show significant symptom relief and healing of esophageal mucosal damage. However, in recent years, it has been clinically found that about 40-80% of patients will experience ineffectiveness or failure to respond to drug therapy. Reasons for ineffective drug therapy 1. Non-erosive reflux disease (NERD): Reflux disease in which no signs of esophageal damage are seen on gastroscopy but the patient still has symptoms such as heartburn. Although the esophagus is normal under gastroscopy, if we use the instrument to determine the pH of the lower esophagus (esophageal pH test), we can find that some patients have evidence of acid reflux into the esophagus, but some other patients do not have severe acid reflux, the latter we also call “functional heartburn”, either NERD or functional heartburn Both NERD and functional heartburn show a poor response to drug therapy. 2. “Reflux disease” with mild acid reflux: This refers to a mild degree of acid reflux into the esophagus, where the pH of the lower esophagus is between 4 and 7 as measured by pH. A recent study using an impedance meter with pH measurement found that the pH of the lower esophagus in these patients was not less than 4. Other forms of reflux, such as gas, liquid, or a mixture of gas and liquid, could also be found. The heartburn associated with mild acid reflux in these patients is often less severe than in typical reflux disease, but other symptoms such as reflux, a bitter taste in the mouth, and a sour taste are more common. About 1/3 of the reflux patients who are not treated with medication have mild reflux. Half of the symptoms in these patients are not related to acid reflux, and only 11% of the symptoms are caused by acid reflux. Visceral hypersensitivity: These patients are often more sensitive to pain than patients with other types of reflux disease if a balloon is placed in the esophagus or if electrical stimulation is given, a phenomenon we call “visceral hypersensitivity. Because of this increased sensitivity to the esophagus, the slightest “breeze” in the lower esophagus can cause an attack of heartburn, not necessarily acid reflux. 4. Gastroduodenal reflux: Reflux of duodenal contents into the esophagus through the stomach. Recently, it was reported that 64% of patients who had heartburn despite using standard doses or double doses of proton pump inhibitors had duodenal reflux, while only 37% still had acid reflux. Duodenal fluid contains bile acid, which is an alkaline fluid, and as usual, it can cause various discomforts due to destruction of the esophageal mucosa. 5, gastric motility disorders: such as reflux disease patients combined with diabetes, often combined with gastric motility disorders, gastric emptying disorders can increase the pressure in the stomach, aggravate the reflux of acid, resulting in drug treatment failure. 6. nocturnal acid breakthrough: refers to the time when the pH in the stomach is <4 at night for at least 1 h. Nocturnal acid breakthrough may be another potential cause of ineffectiveness to drugs. 71% of patients with poor efficacy to PPI twice daily have nocturnal acid reflux. All of these factors are newly recognized as causes of heartburn other than gastric acid. Therefore, simple acid suppression may not be able to help "heartburn" caused by these factors. If a patient fails to take once-daily PPI, the first thing to check is whether the time of taking the medication is correct. The best time to take it is before breakfast and half an hour before dinner. Next, you can switch to another PPI or to a newer formulation twice a day. The usual course of treatment is at least 2 months, and after 2 months if the symptoms are relieved, you can continue to take it or reduce it to once a day. If the symptoms still do not improve, you may choose to have an esophageal pH test or impedance test. Based on the results of the test, the doctor will determine the type of reflux and choose the appropriate treatment, such as adding a gastrointestinal motility drug, or an H2 receptor blocker. It is important to emphasize that lifestyle has a significant impact on the outcome of "reflux disease", such as reducing excessive weight, quitting smoking, reducing alcohol consumption, and avoiding overeating. It is believed that after careful examination and active cooperation of the patient, a solution to Ms. Liu's troubles will be found.