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Dyspepsia (from the Greek - dys-, "bad" or "difficult", and pepsis"digestion"), also

known as indigestion or heartburn, is a condition of impaired digestion.[1] It is a medical

condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal
fullness and feeling fullearlier than expected when eating.[2] It can be accompanied
by bloating,belching, nausea, or heartburn. Dyspepsia is a common problem and is frequently
caused by gastroesophageal reflux disease (GERD) or gastritis.[3] In a small minority it may be
the first symptom of peptic ulcer disease (an ulcer of the stomach or duodenum) and
occasionally cancer. Hence, unexplained newly onset dyspepsia in people over 55 or the
presence of other alarming symptoms may require further investigations.[4]

Functional dyspepsia (previously called nonulcer dyspepsia[5]) is dyspepsia "without evidence of

an organic disease that is likely to explain the symptoms".[6] Functional dyspepsia is estimated to
affect about 15% of the general population in western countries.[5]

Signs and symptoms[edit]

In most cases, the clinical history is of limited use in distinguishing between organic causes from
functional dyspepsia. A large systematic review of the literature was recently performed to
evaluate the effectiveness of diagnosing organic dyspepsia by clinical opinion versus computer
models in patients referred for upper endoscopy. The computer models were based on patient
demographics, risk factors, historical items,and symptoms. The study showed that neither clinical
impression nor computer models were able to adequately distinguish organic from functional
disease.[citation needed]

In a recent study, patients with peptic ulcer disease were compared with patients with functional
dyspepsia in an age and sex-matched study. Although the functional dyspepsia group reported
more upper abdominal fullness, nausea, and overall greater distress and anxiety, almost all the
same symptoms were seen in both groups. Therefore, it is the clinicians challenging task to
separate patients who may have an organic disorder, and thus warrant further diagnostic testing,
from patients who have functional dyspepsia, who are given empiric symptomatic treatment.The
workup should be targeted to identify or rule out specific causes. Traditionally, people at high-risk
have been identified by alarm features. However, the utility of these features in identifying the
presence of upper cancer of the esophagus or stomach has been debated. A meta analysis
looking at the sensitivity and specificity of alarm features found a range of 080% and 4098%,
respectively. However, there was high heterogeneity between studies.[citation needed]

The physical examination may elicit abdominal tenderness, but this finding is nonspecific. A
positive Carnett sign, or focal tenderness that increases with abdominal wall contraction and
palpation, suggests an etiology involving the abdominal wall musculature. Cutaneous
dermatomal distribution of pain may suggest a thoracic polyradiculopathy. Thump tenderness
over the right upper quadrant may suggest chronic cholecystitis.[7]

Non-ulcer dyspepsia[edit]
In about 50-70% of patients with dyspepsia, no definite organic cause can be determined. In this
case, dyspepsia is referred to as non-ulcer dyspepsia and its diagnosis is established by the
presence of epigastralgia for at least 6 months, in the absence of any other cause explaining the

Post-infectious dyspepsia[edit]
Gastroenteritis increases the risk of developing chronic dyspepsia. Post infectious dyspepsia is
the term given when dyspepsia occurs after an acute gastroenteritis infection. It is believed that
the underlying causes of post-infectious IBS and post-infectious dyspepsia may be similar and
represent different aspects of the same pathophysiology.[8]

Functional Dyspepsia[edit]
This is the most common cause of chronic dyspepsia. Up to three-fourths of patients have no
obvious organic cause for their symptoms after evaluation. Symptoms may arise from a complex
interaction of increased visceral afferent sensitivity, gastric delayed emptying or impaired
accommodation to food, or psychosocial stressors. Although benign, these symptoms may be
chronic and difficult to treat.

Diseases of the gastrointestinal tract[edit]

When dyspepsia can be attributed to a specific cause, the majority of cases
concern gastroesophageal reflux disease(GERD) and peptic ulcer disease. Less common
causes include gastritis, gastric cancer, esophageal cancer, coeliac disease, food
allergy, inflammatory bowel disease, chronic intestinal ischemia and gastroparesis.

Liver and pancreas diseases[edit]

These include cholelithiasis, chronic pancreatitis and pancreatic cancer.

Food or drug Intolerance[edit]

Acute, self-limited dyspepsia may be caused by overeating, eating too quickly, eating high-fat
foods, eating during stressful situations, or drinking too much alcohol or coffee. Many
medications cause dyspepsia, including aspirin, nonsteroidal anti-inflammatory
drugs (NSAIDs), antibiotics (metronidazole, macrolides), diabetes drugs (metformin, Alpha-
glucosidase inhibitor, amylin analogs, GLP-1 receptor antagonists), antihypertensive medications
(angiotensin converting enzyme [ACE] inhibitors, Angiotensin II receptor antagonist), cholesterol-
lowering agents (niacin, fibrates), neuropsychiatric medications (cholinesterase inhibitors
[donepezil, rivastigmine]), SSRIs (fluoxetine, sertraline), serotonin-norepinephrine-reuptake
inhibitors (venlafaxine, duloxetine), Parkinson drugs (Dopamine agonist, monoamine
oxidase [MAO]-B inhibitors),corticosteroids, estrogens, digoxin, iron, and opioids.[9]

Helicobacter pylori Infection[edit]

The role of H. pylori in functional dyspepsia is controversial, and no clear causal relationship has
been established. This is true for both the symptom profile and pathophysiology of functional
dyspepsia. Although some epidemiologic studies have suggested an association between H.
pylori infection and functional dyspepsia, others have not. The discrepancy may stem in part from
differences in methodology and lack of adequate consideration of confounding factors such as
past history ofpeptic ulcer disease and socioeconomic status.[10] Controlled trials disagree about
whether or not H. pylori eradication is beneficial in functional dyspepsia, with roughly half of the
trials showing improvement and the other half no improvement.In a recent multicenter U.S.trial
that randomized 240 patients to treatment or placebo, and followed patients for 12 months, 28%
of treated patients versus 23% of those receiving placebo reported relief of symptoms at the 12-
month follow-up. Similarly, recent European trials have not shown significant differences in
symptoms after H pylori eradication as compared with controls. Systematic reviews of eradication
have been conducted, with varying results.A systematic review in the Annals of Internal Medicine
suggested no statistically significant effect, with an odds ratio (OR) for treatment success versus
control of 1.29 (95% CI, 0.891.89;P= 0.18).Still,no effect was seen after adjusting for
heterogeneity and for cure of H. pylori. In contrast, the most recent update of a Cochrane
Database review showed a small but statistically significant effect in curing symptoms (H pylori
cure vs placebo, 36% vs 30%, respectively; relative risk reduction [RRR],8% [95% CI,3
18%],number needed to treat [NNT] = 18]).[11][12]

Systemic diseases[edit]
There is a number of systemic diseases that may involve dyspepsia and include coronary
disease, congestive heart failure,diabetes mellitus, hyperparathyroidism, thyroid disease, chronic
renal disease and adrenal fatigue.[13]

Psychosomatic and cognitive factors are important in the evaluation of patients with chronic
dyspepsia. The psychiatric hypothesis holds that the symptoms of dyspepsia maybe due to
depression,increased anxiety,or a somatization disorder. Epidemiologic studies suggest there is
an association between functional dyspepsia and psychological disorders. Symptoms of
neurosis, anxiety, hypochondriasis, and depression are more common in patients being
evaluated for unexplained gastrointestinal complaints than in healthy controls.Comparisons of
functional and organic dyspepsia have demonstrated that patients with functional dyspepsia are
less likely to have decreased stress or anxiety at 1-year follow-up after being reassured of having
no serious disease. This suggests that functional dyspepsia symptoms are long-lasting,
compared with those of organic dyspepsia,and that the emotional ties are strong.[14]

People under 55 years without alarm symptoms can be treated without investigation. People over
55 years with recent onset dyspepsia or those with alarm symptoms should be urgently
investigated by upper gastrointestinal endoscopy. This will rule out peptic ulcer disease,
medication-related ulceration, malignancy and other rarer causes.[4]
People under the age of 55 years with no alarm features do not need endoscopy but are
considered for investigation for peptic ulcer disease caused by Helicobacter pylori infection.
Investigation for H. pylori infection is usually performed when there is a moderate to high
prevalence of this infection in the local community or the person with dyspepsia has other risk
factors for H. pylori infection, related for example to ethnicity or immigration from a high-
prevalence area. If infection is confirmed, it can usually be eradicated by medication.

Medication-related dyspepsia is usually related to NSAIDs and can be complicated by bleeding

or ulceration with perforation of stomach wall.

Functional and undifferentiated dyspepsia have similar treatments. Decisions around the use of
drug therapy are difficult because trials included heartburn in the definition of dyspepsia. This led
to the results favoring proton pump inhibitors(PPIs), which are effective for the treatment of

Traditional therapies used for this diagnosis include lifestyle modification, antacids, H2-receptor
antagonists (H2-RAs),prokinetic agents, and antiflatulents. It has been noted that one of the most
frustrating aspects of treating functional dyspepsia is that these traditional agents have been
shown to have little or no efficacy.[15]

Pharmacological acid suppression[edit]

Antacids and sucralfate were found to be no better than placebo in a literature review.[16] H2-RAs
have been shown to have marked benefit in poor quality trials (30% relative risk reduction[16]), but
only a marginal benefit in good quality trials.[15]Prokinetic agents would empirically seem to work
well since delayed gastric emptying is considered a major pathophysiological mechanism in
functional dyspepsia.[15] They have been shown in a meta-analysis to produce a relative risk
reduction of up to 50%, but the studies evaluated to come to this conclusion used the
drug cisapride which has since been removed from the market (now only available as an
investigational agent)[17] due to serious adverse events such astorsades, and publication bias has
been cited as a potential partial explanation for such a high benefit.[16] Modern prokinetic agents
such as metoclopramide, erythromycin and tegaserod have little or no established efficacy and
often result in substantial side effects.[16] Simethicone has been found to be of some value, as
one trial suggests potential benefit over placebo and another shows equivalence with
cisapride.[16] So, with the somewhat recent advent of the proton pump inhibitor (PPI) class of
medications, the question of whether these new agents are superior to traditional therapy has

A 2002 systemic review of herbal products found that several herbs,

including peppermint and caraway, have anti-dyspeptic effects for non-ulcer dyspepsia with
"encouraging safety profiles".[18] A 2004 meta-analysis, pooling data from three double-
blind placebo-controlled studies, found the multiple herbal extract Iberogast to be significantly
more effective than placebo (p value = .001) at treating patients with functional dyspepsia
through the targeting of multiple dyspeptic pathologies.[19]This German-made
phytopharmaceutical was found to be equivalent to cisapride and significantly superior to
metoclopramide at reducing the symptoms of functional dyspepsia over a four-week
period.[20][21] Retrospective surveillance of 40,961 children (12 years and under) found no serious
side-effects.[22] Red pepper powder has also found to be promising.[23] Ginger and related
products made therefrom have been shown to have some positive alleviation of symptoms, in
particular for motion sickness and pregnancy-related nausea [24]

Currently, PPIs are, depending on the specific drug, FDA indicated for erosive esophagitis,
gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, eradication of H. pylori,
duodenal and gastric ulcers, and NSAID-induced ulcer healing and prevention, but not functional
dyspepsia. There are, however, evidence-based guidelines and literature that evaluate the use of
PPIs for this indication. A helpful chart summarizing the major trials is available from the
functional dyspepsia guidelines published in the World Journal of Gastroenterology in 2006.[15]

The CADET study was the first to compare a PPI (omeprazole 20 mg daily) to both an H2-RA
(ranitidine 150 mg BID) as well as a prokinetic agent (cisapride 20 mg BID) alongside
placebo.[25] The study evaluated these agents in patients at 4 weeks and 6 months and noted that
omeprazole had a significantly better response at 6 months (31%) than cisapride (13%) or
placebo (14%) (p = .001) while it was just above the cutoff for being statistically significantly
better than ranitidine (21%) (p = .053). Omeprazole also showed a significant increase in quality
of life scores over the other agents and placebo in all but one category measured (p = .01 to .05).

The ENCORE study, which was a follow-up of patients from the OPERA study, showed
responders to omeprazole therapy had fewer clinic visits than non-responders (1.5 vs 2.0) over a
three-month period (p < .001).[26][27]

Acotiamide is a new drug approved in Japan in March 2013 for the treatment of meal related
symptoms of functional dyspepsia. It is an acetylcholinesterase inhibitor