Non-Acid Dyspepsia – Causes, Symptoms, Treatment

Non-Acid Dyspepsia – Causes, Symptoms, Treatment

Non-Acid Dyspepsia is characterized by discomfort and pain involving the upper gastrointestinal tract. It is a common condition that is present in 15–20 percent of the population. Symptoms are often mistaken for acid reflux disease, but functional dyspepsia is a separate entity, though there can be overlap.

Typical dyspeptic symptoms in functional dyspepsia include epigastric pain, sensations of pressure and fullness, nausea, and early subjective satiety. The etiology of the disorder is heterogeneous and multifactorial. Contributory causes include motility disturbances, visceral hypersensitivity, elevated mucosal permeability, and disturbances of the autonomic and enteric nervous system. There is as yet no causally directed treatment for functional dyspepsia. Its treatment should begin with intensive patient education regarding the benign nature of the disorder and with the establishment of a therapeutic pact for long-term care

Functional dyspepsia is one of the most common functional gastrointestinal disorders and affects more than 20% of the population.  There are three different subtypes:

  • epigastric pain syndrome (EPS),
  • postprandial distress syndrome (PDS), and
  • overlapping PDS and EPS.


Although the exact mechanism is not well understood, the pathophysiology of functional dyspepsia is complex. Several different mechanisms are thought to contribute to each subtype. Traditionally, functional dyspepsia has been attributed to disturbances in gastric physiologic factors divided into macroscopic and microscopic mechanisms. Macroscopic mechanisms include gastroesophageal reflux (GERD), delayed gastric emptying, and visceral hypersensitivity alterations in the nervous system. Microscopic mechanisms include impaired barrier function, altered sensitivity to duodenal acid or lipids, and gastroduodenal inflammation. Additional mechanisms include environmental insults like food inducing gastroduodenal physiologic changes, infections causing inflammation, and allergen exposure can lead to eosinophil recruitment in genetically predisposed patients. Psychological factors like anxiety and depression can cause a negative stimulus to the brain-gut axis, suggesting that there is central processing of visceral stimuli from sensations in the gastrointestinal tract.

Causes of Non-Acid Dyspepsia

The etiology of functional dyspepsia is likely multifactorial; however, the exact cause is not clearly understood.  Several risk factors have been seen to be associated with the condition.

  • Enteric infections: H. pylori, Escherichia coli O157, Campylobacter jejuni, and Salmonella.
  • Recent antibiotic use
  • Use of non-steroidal anti-inflammatory drugs
  • Being overweight
  • Smoking
  • Psychosocial dysfunction

 Symptoms Of Non-Acid Dyspepsia

Diagnosis of Non-Acid Dyspepsia

Functional dyspepsia is diagnosed based on the Rome IV criteria.  It is defined by the presence of one or more of the following symptoms: epigastric pain or burning, early satiety, and postprandial fullness in the absence of structural disease using imaging or endoscopy. First, patients should be tested and treated for Helicobacter pylori (H. pylori) if they are less than 60 years of age. Then, further treatment consists of symptom management with proton pump inhibitors (PPI), H2 receptor antagonists (H2RA), prokinetic agents, and even antidepressants. Alarms symptoms such as weight loss, dysphagia, or vomiting, or if greater than age 60, warrant an endoscopic evaluation.

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History and Physical
  • Typical symptoms can be divided into the subtypes PDS and EPS, and there exists an overlap between the two syndromes. These symptoms can be acute or chronic. PDS patients report loss of appetite, early satiation, nausea, retching, vomiting, and bloating.
  • In EPS, patients have stomach cramping and other upper abdominal pain. Some symptoms are non-gastrointestinal. Patients often report associated diaphoresis, headache, sleep disorders, and irritable bladder.
  • Functional dyspepsia symptoms usually do not progress and lack red flag signs of unintentional weight loss, dysphagia, night sweats, and persistent vomiting. Patients usually have an unremarkable physical exam, and this can assist in excluding other diagnoses.

The American College of Gastroenterology (ACG) recommends the routine use of upper endoscopy in patients older than 60 years to rule out malignancy, especially in the setting of red flag signs. If patients do not respond to treatment, it is reasonable to pursue more specialized testing specific to the symptoms.

In addition to a physical exam and questions about your symptoms, a doctor may perform the following tests. To exclude organic causes, evaluation can start with laboratory tests, including blood count, complete metabolic panel, thyroid function, and inflammatory markers.

Treatment of Non-Acid Dyspepsia

Treatment can be challenging, where the main aim is symptom control. Initial management begins with an explanation of the diagnosis and discussing the patient’s expectations for treatment. If it is suspected, H. pylori eradication is recommended as the first treatment for all patients with functional dyspepsia, as this improves symptoms and decreases the risk of peptic ulcers and gastric cancer. After this, treatment is a two-step process.

  • The first-line treatment is with a proton pump inhibitor or H2 receptor antagonist for at least four weeks.
  • AntacidsThese counter the effects of stomach acid. Examples include Alka-Seltzer, Maalox, Rolaids, Riopan, and Mylanta. These are over-the-counter (OTC) medicines that do not need a prescription. A doctor will usually recommend an antacid medication as one of the first treatments for dyspepsia.
  • H-2-receptor antagonistsThese reduce stomach acid levels and last longer than antacids. However, antacids act more quickly. Some of these are OTC, while others are only available on prescription. Some people may experience nauseavomiting, constipation, and headaches after taking these. Other side effects may include bruising or bleeding.
  • Proton pump inhibitors (PPIs) – Examples include Aciphex, Nexium, Prevacid, Prilosec, Protonix, and Zegerid. PPIs are highly effective for people who also have gastroesophageal reflux disease (GERD). They reduce stomach acid and are stronger than H-2-receptor antagonists.
  • Prokinetics – This medication is helpful for stomachs that empty slowly. One example of a prokinetic drug is Reglan. Side effects may include tiredness, depression, sleepinessanxiety, and muscle spasms.
  • Antibiotics –  If H. pylori are causing peptic ulcers that result in indigestion, an antibiotic will be prescribed. Side effects may include an upset stomach, diarrhea, and fungal infections.
  • Antidepressants – If the doctor finds no causes for indigestion after a thorough evaluation, and the person with dyspepsia has not responded to treatments, the doctor may prescribe low-dose antidepressants.
  • Antidepressants sometimes ease discomfort by reducing the sensation of pain. Side effects may include nauseaheadaches, agitationconstipation, and night sweats.
  • Psychological therapy – For people with functional dyspepsia, psychological therapy can help manage the cognitive aspects of indigestion. Cognitive-behavioral therapy, biofeedback, hypnotherapy, and relaxation therapy may be recommended.
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Then, if symptoms persist, subsequent treatment with tricyclic antidepressants, or prokinetic agents like metoclopramide and acotiamide are pursued. Adjunctive or alternative non-pharmacologic therapies include psychotherapy, herbal supplementation, lifestyle modification, dietary interventions, acupuncture, and electrical stimulation.

Treatment algorithm for dyspepsia, modified from ()

  • Proton pump inhibitors
  • Helicobacter pylori eradication treatment
  • Phytotherapy
  • Antidepressants
  • Psychotherapy.

Acid-suppressing medications

Numerous multinational randomized controlled trials of proton pump inhibitors (PPI) have demonstrated a significant favorable effect against functional dyspepsia compared with placebo [. One meta-analysis showed a 10 to 20% higher treatment effect for PPI than for placebo with a number needed to treat of patients [. In subgroup analysis, the PPI effects are limited to epigastric pain syndrome or dyspeptic symptoms with accompanying [, , .

Further general measures

  • Conflict resolution in the psychosocial domain
  • Encouraging the patient to take responsibility
  • Relaxation exercises
  • Treatment alliance for long-term care
  • Psychotherapeutic options

Despite the positive study data, the PPIs have not been approved for the treatment of functional dyspepsia in Germany. In the context of the recent public discussion of the potential side effects of PPIs, it can be stated that when used according to the indications these drugs are very safe, particularly since they are not employed for long-term management of functional dyspepsia [.

Eradication of Helicobacter pylori in functional dyspepsia

The effect of H. pylori eradication treatment in functional dyspepsia has been the subject of a large number of placebo-controlled trials. Meta-analyses of all of these studies show a significant difference with an NNT of 15 [, . After H. pylori eradication in H. pylori-positive functional dyspepsia, around 10% of patients stay symptom-free in the long term, while in the remaining patients the symptoms persist or return despite extirpation. It remains a topic of controversy in the literature on whether H. pylori-associated dyspepsia is a subgroup of functional dyspepsia or represents an independent entity [, .

However, this discussion is irrelevant in clinical practice. In view of the absence of causal treatments for functional dyspepsia, H. pylori eradication is an important treatment option because of its curative potential. For this reason, it is recommended in German and international guidelines [.

Treatment options

  • Proton pump inhibitors
  • Helicobacter pylori eradication treatment
  • Phytotherapy
  • Antidepressants
  • Psychotherapy

In the current guideline of the German Society for Gastroenterology, Digestive and Metabolic Diseases (Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, DGVS) [ H. pylori eradication is a “can” indication. The potential side effects of antibiotic treatment must always be taken into consideration in the course of decision making.

Phytotherapy and complementary treatment options

Eradication of Helicobacter pylori

In view of the absence of causal treatments for functional dyspepsia, H. pylori eradication is an important treatment option because of its curative potential. For this reason, it is recommended in German and international guidelines.

Phytotherapeutics have long been used in medicine. Numerous placebo-controlled trials have shown a significant positive effect of phytotherapy compared with placebo in the treatment of functional dyspepsia [, . Combined preparations are often used to treat functional dyspepsia. Mostly these are fixed combinations of peppermint and caraway oil or mixtures of bitter candytuft, wormwood, gentian, and angelica root, usually in combination with spasmolytic and sedative extracts such as chamomile, peppermint, caraway, and lemon balm. Phytotherapeutics exert a spasmolytic tonus-stimulating and/or sedative effect on the gastrointestinal tract and this may relieve the symptoms of functional dyspepsia [[. In a meta-analysis of three placebo-controlled trials, treatment with STW 5 for 4 weeks was significantly superior to placebo [. A subsequent larger multicenter placebo-controlled trial over a period of 8 weeks confirmed the treatment effect [. In the wake of numerous positive placebo-controlled studies, phytotherapy is now recommended in German and international guidelines for use against functional gastrointestinal disorders, in particular functional dyspepsia and IBS [, . Treatment of functional dyspepsia with digestive enzymes has also been studied, whereby the clinical action of the fixed combinations of gastric mucosal extract and amino acid hydrochlorides that are used is exerted not via substitution but by supporting the proteolytic release of amino acids.

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Antidepressants and psychotherapy


Phytotherapeutic preparations are mostly fixed combinations of peppermint and caraway oil or mixtures of bitter candytuft, wormwood, gentian, and angelica root, usually in combination with spasmolytic and sedative extracts such as chamomile, peppermint, caraway, and lemon balm.

Antidepressants are used after the failure of the above-mentioned treatments. Efficacy has been confirmed for tricyclic antidepressants but not for serotonin reuptake inhibitors [. The largest study to date investigated the effect of amitryptiline (25 mg for 2 weeks, then 50 mg for 10 weeks), escitalopram (10 mg for 12 weeks). While escitalopram showed no effect, amitryptiline reduced the burden of the predominant symptom, abdominal pain, significantly compared with placebo [. Other studies have also shown that antidepressants are particularly effective against dyspepsia symptoms when the predominant complaints are abdominal and/or mental comorbidity. There are also data supporting the use of psychotherapy, which should be considered particularly in the case of treatment resistance [,


Because motility disorders are a possible underlying cause of functional dyspepsia, prokinetics can be considered for treatment.[, . Cisapride and domperidone were the substances mostly studied. Cisapride was withdrawn from the market some time ago owing to cardiotoxicity, while the adverse effects of domperidone and metoclopramide mean that their use is restricted, particularly in long-term treatment. Thus, there are currently no prokinetics that can be used in daily clinical practice. The selective 5-HT4 agonist prucalopride is effective against functional dyspepsia when the indication for treatment is refractory obstipation, but no controlled trials have been performed so prucalopride has not been licensed. Acetamide (a muscarinic autoreceptor inhibitor and cholinesterase inhibitor), itopride, and levosulpiride (both selective dopamine-D2 antagonists) are further prokinetically active pharmaceuticals that have proven effective in controlled studies but have not yet been approved for use in Germany [.


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