Patients with esophageal diseases may only report that they are nauseated and deny more typical symptoms of heartburn, dysphagia, or regurgitation. Table 3.1 lists esophageal diseases associated with nausea and vomiting. Even minimal substernal burning should raise suspicions that gastroesophageal reflux disease (GERD) is a possible mechanism for nausea symptoms. In the author’s experience, nausea due to GERD is frequently present when the patient awakens in the morning and reflects nocturnal GERD. The nausea may improve temporarily after meals in patients with GERD-related nausea. Patients may report the nausea rises into the substernal chest (with or without burning symptoms) as shown in Fig. 3.1. This history and nausea location should also suggest GERD as a potential mechanism for nausea.

Esophageal acid reflux events detected with 24-h pH tests correlated with nausea episodes in patients with chronic unexplained nausea, normal gastric emptying, and GMA and confirmed GERD-related mechanism of nausea [1]. These patients had minimal or no heartburn symptoms. Nausea decreased with aggressive acid suppression and one patient with drug refractory nausea improved after fundoplication. Nausea symptoms poorly correlate with gastroparesis and in some gastroparesis patients, esophageal acid reflux may be the actual mechanism for nausea. Almost 30 % of patients with gastroparesis and gastric dysrhythmias reported nausea episodes that correlated with esophageal acid or non-acid reflux events during 24-h pH monitoring [3].

These esophageal pH studies in patients with or without gastroparesis indicate that the symptom of nausea in some patients is elicited by acid (or non-acid) reflux. In a majority of patients with acid-induced nausea, overall esophageal acid reflux was within the normal range, indicating esophageal mucosal hypersensitivity to the refluxate was the likely underlying mechanism driving symptoms of nausea. Esophageal manometry revealed hypotensive lower esophageal sphincter pressure in a minority of these patients. On the other hand, some patients with predominant nausea and vomiting have severe esophagitis that may be unexpected until documented at endoscopy. In most patients with GERD-related nausea, however, endoscopy is completely normal and GERD may not be suspected as the cause of nausea.

Dysphagia also suggests esophageal motility disorders are present in patients with unexplained nausea. GERD-associated defects in esophageal peristalsis and achalasia may result in increased acid contact time of the esophageal mucosa and elicit nausea [4]. Patients with dysphagia due to esophageal spasm may also experience nausea during severe chest discomfort [5].

Regurgitation is oftentimes confused with vomiting by the patient with esophageal motility disorders. If the patient reports vomiting, then the physician should clarify what the patient is actually experiencing. Failure to do so may lead to diagnostic testing of the stomach and small bowel function and esophageal disorders may be overlooked. Regurgitation is the unpleasant reflux of stomach contents, both liquids and solids, into the esophagus. Hypotensive LES pressure is associated with regurgitation, but LES pressure is usually normal in patients with regurgitation. The regurgitated materials may reflux through the esophagus and into the oropharynx, but the patients report they “vomited” the material. However, patients may be spitting out the refluxed material and not actually vomiting. Moreover, after some regurgitation episodes, patients can take swallows that elicit esophageal peristalsis that returns the refluxed material to the stomach. In contrast, during vomiting the gastric contents are forcefully ejected from the stomach through the relaxed LES, esophagus, oropharynx, and mouth with considerable velocity as the abdominal wall muscles contract vigorously [6]. The subject has no control over the vomiting sequence. The physiology of vomiting is described in detail in Chap. 2.

In contrast to regurgitation and vomiting, rumination is the effortless return of gastric contents into the esophagus and mouth [7]. Rumination is not unpleasant for the patient and is not associated with heartburn, pain, nausea, or other symptoms. Gastric content that rises into the oropharynx is usually re-swallowed without difficulty or distress. Rumination occurs in otherwise healthy individuals and should not be confused with vomiting or regurgitation.

The general physical examination may be entirely normal in patients with nausea from GERD or esophageal motility disorders. Physical findings may include loss of dental enamel in patients with severe GERD. Sclerodermatous changes in the face and digits may be found. Abdominal tenderness, particularly along the rectus muscles or lower rib margins, may be present due to frequent retching and vomiting.

If the history suggests GERD and nausea is located in the substernal area of the chest, then an empiric trial of proton pump inhibitor therapy for 4 weeks is reasonable. This therapeutic trial with a proton pump inhibitor (PPI) twice a day will be diagnostic in that the degree to which nausea is decreased reflects the degree to which acid is the mechanism of the nausea. If PPI therapy markedly reduces the frequency and severity of nausea, then this response is clinical evidence that acid is a key mechanism driving the nausea symptoms.

The diagnostic evaluation should include upper endoscopy for patients with persistent nausea who are already on PPI therapy or who failed an empiric PPI trial. Upper endoscopy will detect macroscopic evidence of esophagitis as well as other causes of nausea, such as gastritis, pyloric stenosis, or duodenitis. In most patients with unexplained nausea and vomiting, the endoscopy findings are normal. The normal endoscopy only indicates no obvious mucosal diseases are present. Eosinophilic esophagitis may present with nausea and vomiting and if suspected on the basis of endoscopy findings, then esophageal biopsies should be obtained [8].

If endoscopy is normal, then more subtle esophageal disorders such as GERD or esophageal motility disorders should be considered. An esophageal manometry and a 24-h pH study are needed to link unexplained nausea and GERD. Acid reflux can be markedly increased or normal in these patients who may or may not have gastroparesis and who have little or no heartburn symptoms [1, 3]. PPI therapies should be stopped seven days before the 24-h pH study in order to increase the chances of esophageal acid reflux to determine if nausea episodes occur during reflux events.

An evaluation of the gastric component of GERD should be considered. Severe difficult-to-control GERD should also raise the possibility of gastroparesis. Gastroparesis occurs in 30–40 % of patients with GERD and is a risk factor for GERD [9]. Obstructive gastroparesis, a subtype of gastroparesis, should also be considered in patients with refractory GERD. Obstructive gastroparesis is due to pyloric dysfunction, either fixed stenosis or neuromuscular dysfunction of the pyloric sphincter termed dyschalasia [10] that results in delayed gastric emptying. The severe delay in gastric emptying secondary to obstructive GP contributes to frequent reflux episodes that are difficult to control with medications and result in severe esophagitis. In these patients the underlying pathophysiological mechanism for GERD includes gastric outlet obstruction. Patients with the obstruction phenotype of gastroparesis have normal or increased amplitude 3 cycles per minute (cpm) GMA as described below.

If a relationship between nausea and acid reflux is suspected, then an empiric trial with proton pump inhibitor therapy is warranted. If endoscopy reveals obvious esophagitis, then aggressive PPI therapy is usually successful in reducing nausea as the mucosa heals. Candida or eosinophilic esophagitis are treated if those diseases are documented. In cases of severe and refractory esophagitis, gastroparesis from an obstructive abnormality at the pylorus or post bulbar region should be considered. Treatment of gastroparesis is discussed below.

If the endoscopy is normal and the pH study shows a positive relationship between acid reflux events and nausea episodes (e.g., >50 % of reflux events correlated with nausea episodes), then treatment with maximum doses of PPIs is needed. Sucralfate in liquid form (1 g four times per day) may be added for esophageal mucosal barrier therapy. Sucralfate helps decrease nausea in the patient with hypersensitivity to reflux esophageal acid in the author’s experience, but placebo-controlled trials of PPI therapy plus sucralfate for nausea symptoms have not been performed. A histamine₂ antagonist drug at bedtime may be used to further suppress acid during the night. These various treatments to control GERD often help the morning nausea frequently reported by patients. Antacids can be used as needed to reduce discrete nausea episodes related to acid reflux. Reduction of nausea by ingestion of antacids also helps convince the patient (and physician) that acid reflux is a mechanism driving their recurrent nausea.

Treatment of documented gastroparesis with diet and drugs may also help reduce esophageal reflux and contribute to decreased nausea. For patients with severe esophagitis and obstructive gastroparesis, pyloric treatments range from endoscopic dilation of the pylorus to botulinum toxin A injection of the pylorus to pyloroplasty [11–13]. Patients with GERD and dyspepsia symptoms reported decreased symptoms and had restoration of normal 3 cpm GMA and improved gastric emptying after radiofrequency ablation procedures for GERD [14]. In a minority of patients with GERD-induced nausea, fundoplication may be considered. A subset of GERD patients also has gastroparesis which limits the fundoplication approach.

On the other hand, if ingestion of small quantities of food increases nausea and produces early satiety, excess fullness, or upper abdominal distention, then disorders of gastric accommodation, gastric dysrhythmias, gastroparesis, or pylorospasm-underlying gastric neuromuscular abnormalitie-should be considered. The symptoms typically associated with gastroparesis are early satiety, abdominal discomfort or pain, prolonged fullness, and nausea and vomiting [16]. These symptoms are non-specific, however, and the rate of gastric emptying itself does not correlate with symptoms of nausea and vomiting [16].

These postprandial symptoms plus epigastric or right upper quadrant discomfort or pain may also reflect gallbladder or pancreatic diseases. IBS may also be confused with gastric disorders or gallbladder diseases or even gastroparesis – all of which are associated with nausea. Most patients learn to adjust their dietary choices during the day to avoid foods that they know will worsen nausea or provoke vomiting. The physician should be aware how the patient has altered their diet to decrease postprandial symptoms and whether or not weight loss has occurred.

Patients learn to snack on small volumes of food throughout the day and thereby limit their postprandial nausea and especially vomiting episodes by their dietary choices. Oftentimes patients do not eat lunch if they are at work and are afraid to evoke symptoms by eating. By dinnertime, patients may only ingest small amounts of starches or light meals to limit symptoms. The foods selected by patients with gastroparesis can help to control symptoms and maintain nutrition. Dietary/nutritional recommendations for patients with nausea and vomiting are discussed in Chap. 11. A differential diagnosis can be formulated as the chronology of the patient’s nausea, early satiety, and discomfort/pain are understood.

As described above, the location of nausea may also help the physician develop a differential diagnosis and diagnostic test approach. Some patients locate their nausea in the epigastrium and in the chest area, suggesting gastric-related and esophagus-related mechanisms of nausea are present (Fig. 3.3). Only 20–30 % of patients with symptoms associated with gastroparesis actually have delayed gastric emptying tests [17, 18]. The majority of symptomatic patients have normal endoscopy and normal gastric emptying and have disorders named with several terms: functional dyspepsia, postprandial distress syndrome, “gastroparesis-like” syndrome, chronic idiopathic nausea, or chronic unexplained nausea and vomiting [17, 19].

The nature of the vomitus also helps in differential diagnosis. Vomitus containing undigested, chewed food suggests gastroparesis. Vomitus containing small amounts of yellow fluid reflects gastric juice. Vomitus containing finely milled particles reflects gastric outlet obstruction. Hematemesis indicates erosion or ulcers reflecting mucosal disease. Recurrent vomiting and retching can lead to Mallory-Weiss tears and hematemesis. Vomiting bilious liquids suggests small bowel obstruction. Uncontrolled, severe vomiting episodes lasting for days but followed by complete recovery may indicate cyclic vomiting syndrome. Projectile vomiting is classically associated with central nervous system (CNS) diseases.

In addition to considering a differential diagnosis of gastric disorders, CNS and autonomic nervous system (ANS) diseases should always be reviewed while obtaining the chronology of the unexplained nausea. Patients who describe nausea upon standing up or getting up from a supine position (in contrast to postprandial exacerbation of nausea) may have orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS). Nausea and vomiting dominates the clinical presentation in some patients with POTS [15], while lightheadedness and syncope are less obvious components of the presentation. Patients with POTS have gastric dysrhythmias and a minority have gastroparesis [15]. POTS needs to be differentiated from orthostatic hypotension due to dehydration. ANS disorders and nausea are reviewed in Chap. 7.

CNS disorders also need to be considered in the evaluation of patients with nausea and vomiting, even those who have an established esophageal or gastric diagnosis. Less than 1% of patients seen in our clinic indicated the location of their nausea was in their head (Fig. 3.4) [2]. These patients had migraine. Patients with migraine headaches can usually differentiate the nausea associated with their headaches and the nausea they perceive in their abdomen. Movement-induced nausea may indicate vestibular diseases, but vertigo should be described by the patient. Nausea and vomiting related to CNS disorders are reviewed in Chap. 8.

To understand symptoms of postprandial nausea, early satiety, and excess gastric fullness and discomfort, it is important to appreciate normal postprandial gastric neuromuscular function. Therefore, the normal gastric neuromuscular activities in the postprandial period are reviewed below.

After ingestion of foods, healthy individuals experience a comfortable fullness in the epigastrium, a pleasurable reward for ingesting foods that will nourish the body. During this pleasant postprandial period, the stomach produces considerable neuromuscular work (Fig. 3.5). Gastric neuromuscular work begins with fundic relaxation which occurs to accommodate the volume of food ingested [6]. Vagal-mediated release of nitric oxide relaxes the fundic smooth muscle.

Solid foods within the fundus are slowly emptied into the corpus and antrum which together are considered the mixing chamber of the stomach. Ingested solid foods are mixed or triturated until the foods are reduced to a nutrient suspension termed chyme which contains one to two millimeter food particles in suspension of gastric juices. As chyme is formed, the work of gastric emptying begins. Gastric emptying is highly regulated such that each peristaltic wave empties 2–4 ml of chyme through the pylorus and into the duodenum.

Three gastric peristaltic contractions normally occur each minute because they are paced by the normal 3 cycles per minute (cpm) gastric slow waves (Fig. 3.6). Gastric slow waves originate from interstitial cells of Cajal (ICC) and propagate from the pacemaker area on the greater curvature of the proximal corpus and migrate aborally toward the pylorus at a rate of 3 cpm. Plateau and action potentials linked to the slow waves form the migrating circular muscle contractions that are the gastric peristaltic waves that triturate and empty gastric contents. The pylorus regulates outflow by contracting or relaxing in coordination with the 3 cpm antral peristaltic waves [6]. This process of emptying a solid meal is slow and gentle. In healthy subjects, a 257 calorie Eggbeaters™ test meal elicits the gastric neuromuscular work of fundic relaxation and antro-pyloric peristalsis to accomplish trituration and emptying of the test meal over a 4-h process to completely empty the meal from the stomach into the duodenum.

The physical examination in patients with nausea and vomiting and gastric neuromuscular disorders may be normal. Patients often appear healthy. Surprisingly, over 40 % of patients with gastroparesis are overweight or obese [25]. These patients’ physical appearance is unfortunately off-putting to many physicians given that patients are presenting with nausea and vomiting symptoms. The weight gain in these patients is not understood but has been attributed, in part, to the high starch diets that are easier for the stomach to empty compared with healthier foods like fresh fruits and vegetables that often elicit noxious early satiety and nausea symptoms. Decrease in physical activity often accompanies chronic nausea, a symptom which also elicits depression and fatigue, all of which leads to weight gain.

However, a subset of patients with nausea and vomiting and gastroparesis cannot maintain their weight. These patients appear emaciated. Cheilosis and hair loss may be noted. Heart and lung exams are usually normal. The abdomen may be scaphoid or distended and tympanitic. A distended abdomen suggests intestinal pseudo-obstruction, bacterial overgrowth, or constipation, or all of the above. An abdominal bruit may be present and may indicate chronic mesenteric ischemia, a rare but reversible cause of gastroparesis.

Abdominal scars from previous surgical incisions should be palpated for local tenderness. Oftentimes these scars are exquisitely tender and may actually represent the source of the patient’s abdominal pain and nausea. Carnett’s sign should be elicited [26, 27]. If Carnett’s sign is positive, then the abdominal pain is actually due, at least in part, to an abdominal wall syndrome. This abdominal pain may have been attributed to “the stomach” by the patient and physician. For this reason, Carnett’s sign is extremely important in the physical examination of patients with unexplained nausea and abdominal pain and is described below in detail.

To test for Carnett’s sign, the patient lies in supine position on the examination table and indicates with their hand where the abdominal pain is located. Abdominal wall pain is localized by a single finger to a highly focused point, often at or near an abdominal scar produced at a trocar site from previous laparoscopic cholecystectomy or other abdominal operations. The examining physician gently presses on the tender point until modest discomfort is elicited (e.g., two or three over ten). The patient is then asked to flex their head until the physician feels the rectus muscles contract. At the same time the patient is asked to rate their abdominal pain. Carnett’s sign is positive if the abdominal pain immediately increases to a higher level (perhaps even to a seven or nine over ten) and reproduces the patient’s typical abdominal pain, the same pain often attributed to the stomach disorder or gastroparesis. This is a positive Carnett’s sign and indicates the source of pain is in the abdominal wall. (Another and more provocative way to increase rectus muscle contraction is to ask the patient to do a straight leg lift.) In many cases, the patient’s typical nausea is also elicited as the pain increases during a positive Carnett’s test.

If pain does not increase during head flexion, then the scar is not relevant to the pain syndrome. If pain decreases during head flexion, then the pain may be due to an intra-abdominal disease or disorder. The splinting of the abdominal wall during head flexion reduces the pressure on the diseased intra-abdominal organ and thus pain is reduced. Treatment of an abdominal wall syndrome should be addressed by pain clinic specialists. Abdominal hernias and other anatomical defects should also be excluded as a cause of pain. See Chap. 5 for a full review of abdominal wall pain and nausea and vomiting.

Routine laboratory tests should be ordered. A CBC is obtained to determine if anemia is present. Liver function tests and a lipase exclude hepatitis and pancreatitis. Vitamin D and B₁₂ levels are determined. In the appropriate patients, HbA1c, rheumatoid factor, ANA, and CRP are measured. Tests for TSH and fasting cortisol are important to rule out hypo- or hyperthyroidism and adrenal diseases. A low-fasting cortisol should be followed up with a cosyntropin stimulation test. Referral to endocrinology should be considered. Nausea and vomiting due to endocrine disorders are discussed in Chap. 6.

Endoscopy is performed to diagnose esophageal, gastric, or duodenal mucosa abnormalities which may underlie the patient’s nausea and vomiting. Chronic cholecystitis or gallbladder emptying abnormalities may also cause the same postprandial symptoms associated with gastroparesis. Gallbladder diseases must be excluded as chronic gallbladder symptoms are similar to nausea, abdominal discomfort/pain and vomiting that are caused by gastric, small bowel (small bowel bacterial overgrowth), and colonic neuromuscular disorders (irritable bowel syndrome). Gallbladder ultrasound and emptying tests are needed to exclude gallbladder disease. A breath test for small bowel bacterial overgrowth should be ordered. Celiac disease and malabsorption should be considered. Symptoms consistent with irritable bowel syndrome should be treated.

In many patients with unexplained nausea and vomiting, the standard diagnostic tests are normal and empiric treatment with acid suppression therapy or prokinetic drugs are not helpful. Gastric neuromuscular disorders should be considered and tests to diagnose these disorders are reviewed below.