2.

The following should also be included during the case discussion:

A. Definition of Condition(s)
I. Gastroesophageal Reflux Disease (GERD)
II. Diabetic Gastroparesis and,
III. Nausea and Vomiting caused by chemotherapy

B. Etiology And Epidemiology

I. Gastroesophageal Reflux Disease (GERD)

ETIOLOGY

Gastroesophageal Reflux Disease (GERD) is caused by frequent acid reflux or reflux of nonacidic
content from the stomach. When you swallow, a circular band of muscle around the bottom of your
esophagus (lower esophageal sphincter) relaxes to allow food and liquid to flow into your stomach.
Then the sphincter closes again. If the sphincter does not relax as it should or it weakens, stomach
acid can flow back into your esophagus. This constant backwash of acid irritates the lining of your
esophagus, often causing it to become inflamed.

EPIDEMIOLOGY

Gastroesophageal Reflux Disease (GERD) is one of the most common gastrointestinal disorders, with a
prevalence of approximately 20% of adults in western culture. A systematic review by El-Serag et al.
estimated the prevalence of GERD in the US between 18.1% to 27.8%. However, the true prevalence
of this disorder could be higher because more individuals have access to over-the-counter acid,
reducing medications. The prevalence of GERD is slightly higher in men compared to women. A large
meta-analysis study estimated the pooled prevalence of GERD symptoms to be marginally higher in
women compared with men (16.7% (95% CI 14.9% to 18.6%) vs. 15.4% (95% CI 13.5% to 17.4%).
Women presenting with GERD symptoms are more likely to have NERD than men who are more likely
to have erosive esophagitis. However, men with longstanding symptoms of GERD have a higher
incidence of Barrett's esophagus (23%) compared to women (14%).

C. Signs And Symptoms

Common signs and symptoms of Gastroesophageal Reflux Disease (GERD) include:

 A burning sensation in your chest (heartburn), usually after eating, which might be worse at
night or while lying down
 Backwash (regurgitation) of food or sour liquid
 Upper abdominal or chest pain
 Trouble swallowing (dysphagia)
 Sensation of a lump in your throat

If you have nighttime acid reflux, you might also experience:

 An ongoing cough
 Inflammation of the vocal cords (laryngitis)
 New or worsening asthma
D. Normal Physiology And Pathophysiology

The pathophysiology of GERD is multifactorial and is best explained by various mechanisms involved,
including the influence of the tone of the lower esophageal sphincter, the presence of a hiatal
hernia, esophageal mucosal defense against the refluxate and esophageal motility.

Impaired Lower Esophageal Sphincter (LES) Function and Transient Lower Esophageal Sphincter
Relaxations (TLESRs)

The LES is a 3-4 cm tonically contracted smooth muscle segment located at the esophagogastric
junction (EGJ) and, along with the crural diaphragm forms the physiological EGJ barrier, which
prevents the retrograde migration of acidic gastric contents into the esophagus. In otherwise healthy
individuals, LES maintains a high-pressure zone above intragastric pressures with transient relaxation
of the LES that occurs physiologically in response to a meal facilitating the passage of food into the
stomach. Patients with symptoms of GERD may have frequent transient LES relaxations (TLESRs) not
triggered by swallowing, resulting in exceeding the intragastric pressure more than LES pressures
permitting reflux of gastric contents into the esophagus. The exact mechanism of increased transient
relaxation is unknown, but TLESRs account for 48-73% of GERD symptoms. The LES tone and TLESRs
are influenced by factors such as alcohol use, smoking, caffeine, pregnancy, certain medications like
nitrates, and calcium channel blockers .

Hiatal hernia

Hiatal hernia is frequently associated with GERD and can exist independently without causing any
symptoms. Nonetheless, the presence of hiatal hernia plays a vital role in the pathogenesis of GERD
as it hinders the LES function. Patients with proven GERD with or without a small hiatal hernia had
similar LES function abnormalities and acid clearance. However, patients with large hiatal hernias
were noted to have shorter and weaker LES resulting in increased reflux episodes. It was also pointed
out that the degree of esophagitis was worse in patients with large hiatal hernias. A study evaluating
the relationship between hiatal hernia and reflux esophagitis by Ott et al. demonstrated the presence
of hiatal hernia in 94% of patients with reflux esophagitis.

Impaired esophageal mucosal defense against the gastric refluxate

The esophageal mucosa comprises various structural and functional constituents that function as a
protective defense barrier against the luminal substances encountered with GERD. This defensive
barrier can be breached by prolonged exposure to the refluxate, which consists of both acidic gastric
contents (hydrochloric acid and pepsin) and alkaline duodenal contents (bile salts and pancreatic
enzymes) leading to mucosal damage. The influence of gastroparesis on GERD is unknown. It is
believed that delayed gastric emptying contributes to GERD symptoms due to gastric distention and
increased exposure to the gastric refluxate.

Defective esophageal peristalsis

Normally, the acidic gastric contents that reach the esophagus are cleared by frequent esophageal
peristalsis and neutralized by salivary bicarbonate. In a prospective study, patients with GERD were
noted to have impaired esophageal peristalsis leading to decreased clearance of gastric reflux
resulting in severe reflux symptoms and mucosal damage.
B. Etiology And Epidemiology

II. Diabetic Gastroparesis

ETIOLOGY

Hyperglycemia (blood glucose greater than 200 mg/dL), commonly seen in poorly controlled diabetes,
has been associated with diabetic gastroparesis resulting from neuropathy in the setting of chronic
hyperglycemia and does not resolve with improved glycemic control. Acute hyperglycemia, on the
other hand, though it can also result in delayed gastric emptying, is often reversible with improved
glycemic control.

Gastric emptying requires coordination of fundal tone and antral phasic contraction with
simultaneous inhibition of pyloric and duodenal contractions. This coordination also requires
interactions between the enteric and autonomic nervous systems, smooth muscle cells, and the
stomach's specialized pacemaker cells (myenteric interstitial cells of Cajal; ICCs). The gastric motor
dysfunction that is encountered in the setting of diabetes may occur as a result of autonomic
neuropathy (both sympathetic and parasympathetic), enteric neuropathy (both excitatory and
inhibitory neurons), ICC abnormalities (intrinsic neuropathy), acute blood glucose fluctuations, use of
incretin-based medications, or psychosomatic factors. As a result, most patients with diabetes tend to
have dysfunction at multiple points in the process of gastric emptying. This includes abnormal
postprandial proximal gastric accommodation and contraction, as well as abnormalities in antral
motor function.

EPIDEMIOLOGY

Although idiopathic gastroparesis is the most common form of gastroparesis, diabetes is the most
common disease associated with the condition. Upper gastrointestinal symptoms are reported in 11%
to 18% of patients with diabetes, most of which are associated with delayed gastric emptying.
Gastroparesis is seen in approximately 4.8% of individuals with type 1 diabetes, 1% of those with type
2 diabetes, and 0.1% of those without diabetes. Although there is a stronger association between
type 1 diabetes and gastroparesis, the incidence of type 2 diabetes is much greater, and therefore,
gastroparesis associated with type 2 diabetes is seen more frequently. Additionally, incretin mimetics
are used to treat patients with type 2 diabetes, and these medications pose an additional risk factor
for developing gastroparesis.

Signs and symptoms of delayed gastric emptying are seen more frequently in individuals with type 1
versus type 2 diabetes and typically in those who have had the disorder for at least five years. It has
been observed that gastroparesis typically occurs in patients with a diagnosis of diabetes of at least
ten years and is therefore seen more commonly in older individuals with type 2 diabetes.

C. Signs And Symptoms

Signs and symptoms of gastroparesis include:

 Vomiting
 Nausea
 Abdominal bloating
 Abdominal pain
 A feeling of fullness after eating just a few bites
 Vomiting undigested food eaten a few hours earlier
 Acid reflux
 Changes in blood sugar levels
 Lack of appetite
 Weight loss and malnutrition
D. Normal Physiology And Pathophysiology

Diabetic gastroparesis occurs as a result of dysfunction in the autonomic and enteric nervous systems.
Chronically high levels of blood glucose (or inefficient glucose uptake) lead to neuronal damage
resulting in abnormal myenteric neurotransmission (e.g., vagus nerve), impaired inhibitory (nitric
oxide) neuronal function, and dysfunctional smooth muscle and pacemaker (interstitial cells of Cajal)
cells. Altogether, this dysfunction results in a combination of fewer contractions of the antrum,
uncoordinated antro-duodenal contractions, and pyloric spasms, ultimately resulting in delayed
gastric emptying (gastroparesis).

Delayed gastric emptying in patients with diabetes, particularly of solids, may also occur in the setting
of abnormal small bowel motility, which is thought to occur by a similar mechanism as that which is
described in the stomach. Some patients with diabetes may additionally experience changes in gastric
compliance, both increased or decreased, which may also contribute to delayed gastric emptying.

In addition to this, serum (postprandial) glucose levels have a direct relationship with gastric
emptying. In the setting of diabetic autonomic neuropathy, acute hyperglycemia stimulates gastric
electrical activity. In patients with diabetes (without neuropathy) and healthy controls, acute
hyperglycemia will instead relax the proximal stomach and suppress gastric electrical activity (e.g.,
reduced the frequency, propagation, and contraction of the antrum) in both fasting and post-prandial
conditions, thereby slowing gastric emptying.

Acute hyperglycemia has also been associated with increased sensitivity in the gastrointestinal tract.
This may be responsible for the postprandial dyspepsia (e.g., early satiety, nausea, vomiting,
heartburn, bloating, and pain) frequently experienced by patients with diabetic gastroparesis.

Carbohydrate absorption is highly dependent on the speed of gastric emptying through the release of
peptides such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, in which
slower gastric emptying results in a higher level of carbohydrate absorption. Therefore, a higher
serum glucose level due to delayed gastric emptying can itself lead to the worsening of gastroparesis.
C. Etiology And Epidemiology

III. Nausea and Vomiting caused by chemotherapy

ETIOLOGY AND EPIDEMIOLOGY

Researchers estimate that up to 80 percent of cancer patients treated with chemotherapy experience
chemotherapy-induced nausea and vomiting (CINV). Nausea is characterized by an unpleasant feeling
in the back of the throat or a queasy feeling in the stomach, which may or may not be associated with
vomiting. Certain other triggers, such as sights, smells, taste, motion, anxiety or pain, may also
stimulate nausea and/or vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of cancer treatment,
affecting up to 40% of patients. Nausea and vomiting are the most feared, as well as the most
common adverse effects among patients undergoing chemotherapy. Despite the development of new
antiemetic agents, CINV remains an issue for many patients. Additionally, there are numerous unmet
needs, such as optimizing control of non-acute forms of CINV, identifying and managing patients
prone to CINV, and increasing adherence to guidelines.

E. Signs And Symptoms

Nausea can be described as having a sick or uncomfortable feeling in the back of your throat and
stomach. There are many other words describing the feeling of nausea, including "sick to one's
stomach", "queasy", or "upset stomach". Other symptoms can happen at the same time as nausea,
such as increased saliva (spit), dizziness, light-headedness, trouble swallowing, skin temperature
changes, and a fast heart rate.

F. Normal Physiology And Pathophysiology

Nausea is the subjective experience of an unpleasant, wavelike sensation in the back of the throat
and/or the epigastrium that may culminate in vomiting (emesis). Vomiting (emesis) is the forceful
expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching
involves the gastric and esophageal movements of vomiting without expulsion of vomitus; it is also
referred to as dry heaves.

Progress has been made in understanding the neurophysiological mechanisms that control nausea
and vomiting (N&V). Both are controlled or mediated by the central nervous system but by different
mechanisms. Nausea is mediated through the autonomic nervous system. Vomiting results from
stimulation of a complex reflex that includes a convergence of afferent stimulation from the
following:

 A chemoreceptor trigger zone (CTZ, area postrema).

 The cerebral cortex and the limbic system in response to sensory stimulation (particularly
smell and taste), psychological distress, and pain.
 The vestibular-labyrinthine apparatus of the inner ear in response to body motion.
 Peripheral stimuli from visceral organs and vasculature (via vagal and spinal sympathetic
nerves) as a result of exogenous chemicals and endogenous substances that accumulate
during inflammation, ischemia, and irritation.

Neurotransmitters (including serotonin, substance P, and dopamine) found in the CTZ, the vomiting
center (thought to be located in the nucleus tractus solitarius), and enterochromaffin cells in the
gastrointestinal tract release efferent impulses. These impulses are transmitted to the abdominal
musculature, salivation center, and respiratory center. The relative contribution from these multiple
pathways, culminating in N&V symptoms, is complex. It is postulated to account for agents' variable
emetogenicity (intrinsic emetogenicity and mitigating factors [i.e., dosage, administration route, and
exposure duration]) and emetogenic profile (i.e., time to onset, symptom severity, and duration).
Carbohydrate absorption is highly dependent on the speed of gastric emptying through the release of
peptides such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, in which
slower gastric emptying results in a higher level of carbohydrate absorption. Therefore, a higher
serum glucose level due to delayed gastric emptying can itself lead to the worsening of gastroparesis.