Peptic Ulcer

Peptic ulcerFrom Wikipedia, the free encyclopedia

Peptic ulcer

Classification and external resources

Deep gastric ulcer

ICD-10 K 25. -K 27.

ICD-9 531-534

DiseasesDB 9819

eMedicine med/1776 ped/2341

MeSH [1]

A benign gastric ulcer (from the antrum) of a gastrectomy specimen.

Three duodenal ulcers.

A peptic ulcer, also known as ulcus pepticum, PUD or peptic ulcer disease,[1] is an ulcer

(defined as mucosal erosions equal to or greater than 0.5 cm) of an area of

the gastrointestinal tract that is usually acidic and thus extremely painful. As many as 80%

of ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the

acidic environment of the stomach, however only 20% of those cases go to a doctor. Ulcers

can also be caused or worsened by drugs such as aspirin and other NSAIDs.

Contrary to general belief, more peptic ulcers arise in the duodenum (first part of the small

intestine, just after the stomach) than in thestomach. About 4% of stomach ulcers are

caused by a malignant tumor, so multiple biopsies are needed to exclude cancer. Duodenal

ulcers are generally benign.

Contents

 [hide]

1 Classification

2 Signs and symptoms

3 Complications

4 Pathophysiology

o 4.1 Stress

5 Differential diagnosis of epigastric pain

6 Diagnosis

o 6.1 Macroscopic appearance

o 6.2 Microscopic appearance

7 Treatment

o 7.1 Natural Remedies

8 Epidemiology

9 History

10 References

11 External links

[edit]Classification

Stomach  (called gastric ulcer)

Duodenum  (called duodenal ulcer)

Oesophagus  (called Oesophageal ulcer)

Meckel's Diverticulum  (called Meckel's Diverticulum ulcer)

Types of peptic ulcers:

Type I: Ulcer along the lesser curve of stomach

Type II: Two ulcers present - one gastric, one duodenal

Type III: Prepyloric ulcer

Type IV: Proximal gastroesophageal ulcer

Type V: Anywhere along gastric body, NSAID induced

[edit]Signs and symptoms

Symptoms of a peptic ulcer can be

abdominal pain , classically epigastric with severity relating to mealtimes, after around 3

hours of taking a meal (duodenal ulcers are classically relieved by food, while gastric

ulcers are exacerbated by it);

bloating and abdominal fullness;

waterbrash (rush of saliva after an episode of regurgitation to dilute the acid in

esophagus);

nausea, and copious vomiting;

loss of appetite and weight loss;

hematemesis  (vomiting of blood); this can occur due to bleeding directly from a gastric

ulcer, or from damage to the esophagus from severe/continuing vomiting.

melena  (tarry, foul-smelling feces due to oxidized iron from hemoglobin);

rarely, an ulcer can lead to a gastric or duodenal perforation. This is extremely painful

and requires immediate surgery.

A history of heartburn, gastroesophageal reflux disease (GERD) and use of certain forms of

medication can raise the suspicion for peptic ulcer. Medicines associated with peptic ulcer

include NSAID (non-steroid anti-inflammatory drugs) that inhibit cyclooxygenase, and

most glucocorticoids (e.g. dexamethasone and prednisolone).

In patients over 45 with more than two weeks of the above symptoms, the odds for peptic

ulceration are high enough to warrant rapid investigation by EGD (see below).

The timing of the symptoms in relation to the meal may differentiate

between gastric and duodenal ulcers: A gastric ulcer would give epigastric pain during the

meal, as gastric acid is secreted, or after the meal, as the alkaline duodenal contents reflux

into the stomach. Symptoms of duodenal ulcers would manifest mostly before the meal—

when acid (production stimulated by hunger) is passed into the duodenum. However, this is

not a reliable sign in clinical practice.

[edit]Complications

Gastrointestinal bleeding  is the most common complication. Sudden large bleeding

can be life-threatening.[2] It occurs when the ulcer erodes one of the blood vessels.

Perforation (a hole in the wall) often leads to catastrophic consequences. Erosion of the

gastro-intestinal wall by the ulcer leads to spillage of stomach or intestinal content into

the abdominal cavity. Perforation at the anterior surface of the stomach leads to

acute peritonitis, initially chemical and later bacterial peritonitis. The first sign is often

sudden intense abdominal pain. Posterior wall perforation leads to pancreatitis; pain in

this situation often radiates to the back.

Penetration  is when the ulcer continues into adjacent organs such as the liver

and pancreas.[3]

Scarring and swelling due to ulcers causes narrowing in the duodenum and gastric

outlet obstruction. Patient often presents with severe vomiting.

Pyloric stenosis

[edit]Pathophysiology

Tobacco smoking, not eating properly, blood group, spices and other factors that were

suspected to cause ulcers until late in the 20th century, are actually of relatively minor

importance in the development of peptic ulcers.[4]

A major causative factor (60% of gastric and up to 90% of duodenal ulcers) is

chronic inflammation due to Helicobacter pylori that colonizes the antral mucosa. The

immune system is unable to clear the infection, despite the appearance of antibodies. Thus,

the bacterium can cause a chronic active gastritis (type B gastritis), resulting in a defect in

the regulation of gastrinproduction by that part of the stomach, and gastrin secretion can

either be decreased (most cases) resulting in hypo- or achlorhydria or

increased. Gastrin stimulates the production ofgastric acid by parietal cells and, in H. pylori

colonization responses that increase gastrin, the increase in acid can contribute to the

erosion of the mucosa and therefore ulcer formation. Studies [5] have shown eating cabbage

or cabbage juice can increase the mucosa lining in the stomach.

Another major cause is the use of NSAIDs (see above). The gastric mucosa protects itself

from gastric acid with a layer of mucus, the secretion of which is stimulated by certain

prostaglandins. NSAIDs block the function of cyclooxygenase 1 (cox-1), which is essential for

the production of these prostaglandins. Newer NSAIDs (celecoxib, rofecoxib) only inhibit cox-

2, which is less essential in the gastric mucosa, and roughly halve the risk of NSAID-related

gastric ulceration. As the prevalence of H. pylori-caused ulceration declines in the Western

world due to increased medical treatment, a greater proportion of ulcers will be due to

increasing NSAID use among individuals with pain syndromes as well as the growth of aging

populations that develop arthritis.

The incidence of duodenal ulcers has dropped significantly during the last 30 years, while

the incidence of gastric ulcers has shown a small increase, mainly caused by the widespread

use of NSAIDs. The drop in incidence is considered to be a cohort-phenomena independent

of the progress in treatment of the disease. The cohort-phenomena is probably explained by

improved standards of living which has lowered the incidence of H. pylori infections.[6]

Glucocorticoids lead to atrophy of all epithelial tissues. Their role in ulcerogenesis is

relatively small.

Smoking leads to atherosclerosis and vascular spasms, causing vascular insufficiency and

promoting the development of ulcers through ischemia. Nicotine contained in cigarettes can

increase parasympathetic nerve activity to the gastrointestinal tract by acting on the

nicotinic receptors at synapses - increased stimulation to the enterochromaffin-like

cells and G cellsincreases the amount of histamine and gastrin secreted and therefore

increases the acidity of the gastric juice.

A family history is often present in duodenal ulcers, especially when blood group O is also

present. Inheritance appears to be unimportant in gastric ulcers.

Gastrinomas (Zollinger Ellison syndrome), rare gastrin-secreting tumors, cause multiple and

difficult to heal ulcers.

[edit]Stress

Despite the finding that a bacterial infection is the cause of ulcers in 80% of cases, bacterial

infection does not appear to explain all ulcers and researchers continue to look at stress as a

possible cause, or at least a complication in the development of ulcers.

There is debate as to whether psychological stress can influence the development of peptic

ulcers. Burns and head trauma, however, can lead to physiologic stress ulcers, which are

reported in many patients who are on mechanical ventilation.

An expert panel convened by the Academy of Behavioral Medicine Research concluded that

ulcers are not purely an infectious disease and that psychological factors do play a

significant role.[1] Researchers are examining how stress might promote H. pylori infection.

For example, Helicobacter pylori thrives in an acidic environment, and stress has been

demonstrated to cause the production of excess stomach acid.

A study of peptic ulcer patients in a Thai hospital showed that chronic stress was strongly

associated with an increased risk of peptic ulcer, and a combination of chronic stress and

irregular mealtimes was a significant risk factor.[7]

A study on mice showed that both long-term water-immersion-restraint stress and H.

pylori infection were independently associated with the development of peptic ulcers.[8]

[edit]Differential diagnosis of epigastric pain

Peptic ulcer

Gastritis

Stomach cancer

Gastroesophageal reflux disease

Pancreatitis

Hepatic  congestion

Cholecystitis

Biliary colic

Inferior myocardial infarction

Referred pain  (pleurisy, pericarditis)

Superior mesenteric artery syndrome

[edit]Diagnosis

An esophagogastroduodenoscopy (EGD), a form of endoscopy, also known as a gastroscopy,

is carried out on patients in whom a peptic ulcer is suspected. By direct visual identification,

the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD

can often provide an alternative diagnosis.

The diagnosis of Helicobacter pylori can be made by:

Urea breath test  (noninvasive and does not require EGD);

Direct culture from an EGD biopsy specimen; this is difficult to do, and can be expensive.

Most labs are not set up to perform H. pylori cultures;

Direct detection of urease activity in a biopsy specimen by rapid urease test;

Measurement of antibody levels in blood (does not require EGD). It is still somewhat

controversial whether a positive antibody without EGD is enough to warrant eradication

therapy;

Stool antigen test;

Histological examination and staining of an EGD biopsy.

The possibility of other causes of ulcers, notably malignancy (gastric cancer) needs to be

kept in mind. This is especially true in ulcers of the greater (large) curvature of the stomach;

most are also a consequence of chronic H. pylori infection.

If a peptic ulcer perforates, air will leak from the inside of the gastrointestinal tract (which

always contains some air) to the peritoneal cavity (which normally never contains air). This

leads to "free gas" within the peritoneal cavity. If the patient stands erect, as when having a

chest X-ray, the gas will float to a position underneath the diaphragm. Therefore, gas in the

peritoneal cavity, shown on an erect chest X-ray or supine lateral abdominal X-ray, is an

omen of perforated peptic ulcer disease.

[edit]Macroscopic appearance

Gastric ulcers are most often localized on the lesser curvature of the stomach. The ulcer is a

round to oval parietal defect ("hole"), 2 to 4 cm diameter, with a smooth base and

perpendicular borders. These borders are not elevated or irregular in the acute form of

peptic ulcer, regular but with elevated borders and inflammatory surrounding in the chronic

form. In the ulcerative form of gastric cancer the borders are irregular. Surrounding mucosa

may present radial folds, as a consequence of the parietal scarring.

[edit]Microscopic appearance

A gastric peptic ulcer is a mucosal defect which penetrates the muscularis mucosae and

muscularis propria, produced by acid-pepsin aggression. Ulcer margins are perpendicular

and present chronic gastritis. During the active phase, the base of the ulcer shows 4 zones:

inflammatory exudate, fibrinoid necrosis, granulation tissue and fibrous tissue. The fibrous

base of the ulcer may contain vessels with thickened wall or with thrombosis.[9]

[edit]Treatment

Younger patients with ulcer-like symptoms are often treated with antacids or H2

antagonists before EGD is undertaken. Bismuth compounds may actually reduce or even

clear organisms, though it should be noted that the warning labels of some bismuth

subsalicylate products indicate that the product should not be used by someone with an

ulcer.

Patients who are taking nonsteroidal anti-inflammatories (NSAIDs) may also be prescribed

a prostaglandin analogue (Misoprostol) in order to help prevent peptic ulcers, which may be

aside-effect of the NSAIDs.

When H. pylori infection is present, the most effective treatments are combinations of 2

antibiotics (e.g. Clarithromycin, Amoxicillin, Tetracycline, Metronidazole) and 1 proton pump

inhibitor(PPI), sometimes together with a bismuth compound. In complicated, treatment-

resistant cases, 3 antibiotics (e.g. amoxicillin + clarithromycin + metronidazole) may be

used together with a PPI and sometimes with bismuth compound. An effective first-line

therapy for uncomplicated cases would be Amoxicillin + Metronidazole + Pantoprazole (a

PPI). In the absence of H. pylori, long-term higher dose PPIs are often used.

Treatment of H. pylori usually leads to clearing of infection, relief of symptoms and eventual

healing of ulcers. Recurrence of infection can occur and retreatment may be required, if

necessary with other antibiotics. Since the widespread use of PPI's in the 1990s, surgical

procedures (like "highly selective vagotomy") for uncomplicated peptic ulcers became

obsolete.

Perforated peptic ulcer is a surgical emergency and requires surgical repair of the

perforation. Most bleeding ulcers require endoscopy urgently to stop bleeding with cautery,

injection, orclipping.

[edit]Natural Remedies

There have been studies which found raw cabbage juice to be useful in treating ulcers. The

high glutamine and S-methylmethionine content of cabbage may be responsible. The studies

most often mentioned were conducted between 1949 and 1952 at Stanford University by Dr.

Garrett Cheney.

Garnett Cheney, M.D. had 100 peptic ulcer patients drink four glasses of raw cabbage juice

daily. The patients reported dramatically less pain, and X-ray examination confirmed faster

healing time. There was no other change in their diet, and they did not have drug therapy.

81% of the patients were symptom-free within one week; over two-thirds were better in just

four days. The average healing time for patients given standard hospital treatment was over

a month. Cabbage juice worked well for other types of ulcers, also.[5]

[edit]Epidemiology

The lifetime risk for developing a peptic ulcer is approximately 10%.[10]

In Western countries the prevalence of Helicobacter pylori infections roughly matches age

(i.e., 20% at age 20, 30% at age 30, 80% at age 80 etc). Prevalence is higher in third world

countries. Transmission is by food, contaminated groundwater, and through human saliva

(such as from kissing or sharing food utensils.)[citation needed]

According to Mayo Clinic, however, there is evidence that the infection can be transmitted

by kissing.[citation needed]

A minority of cases of Helicobacter infection will eventually lead to an ulcer and a larger

proportion of people will get non-specific discomfort, abdominal pain or gastritis.

[edit]History

See also: Timeline of peptic ulcer disease and Helicobacter pylori

John Lykoudis, a general practitioner in Greece, treated patients for peptic ulcer

disease with antibiotics, beginning in 1958, long before it was commonly recognized

that bacteria were a dominant cause for the disease.[11]

Helicobacter pylori was rediscovered in 1982 by two Australian scientists, Robin

Warren and Barry J. Marshall as a causative factor for ulcers.[12] In their original paper,

Warren and Marshall contended that most stomach ulcers and gastritis were caused by

colonization with this bacterium, not by stress or spicy food as had been assumed before.[13]

The H. pylori hypothesis was poorly received, so in an act of self-experimentation Marshall

drank a Petri dish containing a culture of organisms extracted from a patient and soon

developed gastritis. His symptoms disappeared after two weeks, but he took antibiotics to

kill the remaining bacteria at the urging of his wife, since halitosis is one of the symptoms of

infection.[14]This experiment was published in 1984 in the Australian Medical Journal and is

among the most cited articles from the journal.

In 1997, the Centers for Disease Control and Prevention, with other government agencies,

academic institutions, and industry, launched a national education campaign to inform

health care providers and consumers about the link between H. pylori and ulcers. This

campaign reinforced the news that ulcers are a curable infection, and that health can be

greatly improved and money saved by disseminating information about H. pylori.[15]

In 2005, the Karolinska Institute in Stockholm awarded the Nobel Prize in Physiology or

Medicine to Dr. Marshall and his long-time collaborator Dr. Warren "for their discovery of the

bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease". Professor

Marshall continues research related to H. pylori and runs a molecular biology lab at UWA in

Perth, Western Australia.

It was a previously widely accepted misunderstanding that the use of chewing gum resulted

in gastric ulcers. The medical profession believed that this was because the action of

masticating on gum caused the over-stimulation of the production of hydrochloric acid in the

stomach. The low (acidic) pH (pH 2), or hyperchlorhydria was then believed to cause erosion

of the stomach lining in the absence of food, thus causing the development of the gastric

ulcers.[16]

On the other hand, in the recent past, some believed that natural tree resin extract, mastic

gum, actively eliminates the H. pylori bacteria.[17] However, multiple subsequent studies

have found no effect of using mastic gum on reducing H. pylori levels.[18][19]

[edit]References

1. ^ a b "GI Consult: Perforated Peptic Ulcer". Retrieved 2007-08-26.

2. ̂  Cullen DJ, Hawkey GM, Greenwood DC, et al. (1997). "Peptic ulcer bleeding in the elderly: relative

roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs". Gut 41 (4): 459–62. PMID

9391242. PMC:1891536.

3. ̂  "Peptic Ulcer: Peptic Disorders: Merck Manual Home Edition". Retrieved 2007-10-10.

4. ̂  For nearly 100 years, scientists and doctors thought that ulcers were caused by stress, spicy food,

and alcohol. Treatment involved bed rest and a bland diet. Later, researchers added stomach acid

to the list of causes and began treating ulcers with antacids. National Digestive Diseases

Information Clearinghouse

5. ^ a b Cheney G. Rapid (1949). "Healing of peptic ulcers in patients receiving fresh cabbage

juice". Calif Med 70 (10): 10–5. PMID 18104715.

6. ̂  Johannessen T. "Peptic ulcer disease". Pasienthandboka.

7. ̂  Wachirawat W, Hanucharurnkul S, Suriyawongpaisal P, et al. (2003). "Stress, but not Helicobacter

pylori, is associated with peptic ulcer disease in a Thai population". J Med Assoc Thai 86 (7): 672–

85. PMID 12948263.

8. ̂  Kim YH, Lee JH, Lee SS, et al. (2002). "Long-term stress and Helicobacter pylori infection

independently induce gastric mucosal lesions in C57BL/6 mice". Scand. J. Gastroenterol. 37 (11):

1259–64.doi:10.1080/003655202761020515. PMID 12465722.

9. ̂  "ATLAS OF PATHOLOGY". Retrieved 2007-08-26.

10. ̂  Snowden FM (October 2008). "Emerging and reemerging diseases: a historical

perspective". Immunol. Rev. 225: 9–26. doi:10.1111/j.1600-065X.2008.00677.x. PMID 18837773.

11. ̂  Marshall B.J., ed. (2002), "Helicobacter Pioneers: Firsthand accounts from the scientists who

discovered helicobacters, 1892–1982", ISBN 0-86793-035-7. Basil Rigas, Efstathios D.

Papavasassiliou. John Lykoudis. The general practitioner in Greece who in 1958 discovered the

etiology of, and a treatment for, peptic ulcer disease.

12. ̂  Marshall B.J. (1983). "Unidentified curved bacillus on gastric epithelium in active chronic

gastritis". Lancet 1 (8336): 1273–5. PMID 6134060.

13. ̂  Marshall B.J., Warren J.R. (1984). "Unidentified curved bacilli in the stomach patients with gastritis

and peptic ulceration". Lancet 1 (8390): 1311–5. doi:10.1016/S0140-6736(84)91816-6. PMID

6145023.

14. ̂  Van Der Weyden MB, Armstrong RM, Gregory AT (2005). "The 2005 Nobel Prize in physiology or

medicine". Med. J. Aust. 183 (11–12): 612–4. PMID 16336147.

15. ̂  Ulcer, Diagnosis and Treatment - CDC Bacterial, Mycotic Diseases

16. ̂  Medicine for Nurses (Toohey, 1974)

17. ̂  Huwez FU, Thirlwell D, Cockayne A, Ala'Aldeen DA (December 1998). "Mastic gum kills

Helicobacter pylori [Letter to the editor, not a peer-reviewed scientific article]". N. Engl. J.

Med. 339 (26): 1946. PMID 9874617. Retrieved 2008-09-06. See also their corrections in the next

volume.

18. ̂  Loughlin MF, Ala'Aldeen DA, Jenks PJ (February 2003). "Monotherapy with mastic does not

eradicate Helicobacter pylori infection from mice". J. Antimicrob. Chemother. 51 (2): 367–

71. doi:10.1093/jac/dkg057.PMID 12562704.

19. ̂  Bebb JR, Bailey-Flitter N, Ala'Aldeen D, Atherton JC (September 2003). "Mastic gum has no effect

on Helicobacter pylori load in vivo". J. Antimicrob. Chemother. 52 (3): 522–

3. doi:10.1093/jac/dkg366. PMID 12888582.

DUODENAL

Introduction

Background

When we speak of duodenal ulcers, we often imply that these are part of what is known as peptic ulcer disease; duodenal ulceration may be only rarely due to other conditions. Most duodenal ulcers are associated with a Helicobacter pylori   infection , or the use of gastric irritating medications such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), or bisphosphonates.

Duodenal ulcers are a common condition characterized by the presence of a well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum (see Images 1-3 or below). More than 95% of duodenal ulcers are found in the first part of the duodenum; most are less than 1 cm in diameter.1 

Duodenal ulcer in an elderly patient who presented with melena and hypotension.

Duodenal ulcer in a 35-year-old woman who presented with tarry stools and a hemoglobin

level of 75 g/L.

Pathophysiology

The duodenal mucosa resists damage from the effect of aggressive factors, such as gastric acid and the proteolytic enzyme pepsin, with the help of several protective factors, such as a mucous layer, bicarbonate secretion, and protective prostaglandins.

The epithelial cells of the stomach and duodenum secrete mucus in response to irritation of the epithelial lining and as a result of cholinergic stimulation. A portion of the gastric and duodenal mucus exists in the form of a gel layer, which is impermeable to acid and pepsin. Other gastric and duodenal cells secrete bicarbonate, which aids in buffering acid that lies near the mucosa. Prostaglandins of the E type (PGE) have an important protective role, because PGE increases the production of both bicarbonate and the mucous layer.

In the event of acid and pepsin entering the epithelial cells, additional mechanisms are in place to reduce injury. Within the epithelial cells, ion pumps in the basolateral cell membrane help to regulate intracellular pH by removing excess hydrogen ions. Through the process of restitution, healthy cells migrate to the site of injury. Mucosal blood flow removes acid that diffuses through the injured mucosa and provides bicarbonate to the surface epithelial cells.

A duodenal ulcer occurs when an alteration occurs in the aggressive and/or protective factors such that the balance is in favor of gastric acid and pepsin. Any process that increases gastric acidity (eg, individuals with increased maximal and basal acid output), decreases prostaglandin production (eg, NSAIDs), or interferes with the mucous layer (eg, H pylori infection) can cause such an imbalance and lead to peptic ulcer disease.

Full understanding of the pathophysiology and pathogenesis of duodenal ulcers requires a brief discussion of the 2 major etiologies: NSAID use and H pylori infection. NSAIDs are pathogenic through their inhibition of the cyclooxygenase-1 (COX-1) pathway, which normally produces protective prostaglandins. These prostaglandins are protective because they augment both bicarbonate and mucous production, as mentioned above. However, perhaps more important, prostaglandins augment mucosal blood flow, and their inhibition leads to impairment of blood flow, leaving the mucosa vulnerable to damage.

Infection with H pylori is likely pathogenic by means of a variety of indirect mechanisms as the organism does not generally colonize the duodenum. The mechanisms are described as follows2 :

H pylori infection that follows an antral predominant pattern leads to an inflammatory state in which high levels of tumor necrosis factor-alpha (TNF-alpha) and other cytokines are produced. These stimulate gastric acid production directly by increasing gastrin release from G cells and inhibit somatostatin production by antral D cells. This leads to a net increase in gastric acid secretion, which leads to an increased acid load in the duodenum, overwhelming the mucosal defense.3,4

Duodenal acid exposure can lead to gastric metaplasia, whereby the duodenal mucosa can take on characteristics of gastric mucosa. H pylori can then colonize the duodenal mucosa and adhere to cells. This adherence leads to a variety of second-messenger signals, which invoke an immunologic response against those cells causing mucosal damage by host neutrophils and other inflammatory cells.

H pylori also affects the gastric and duodenal mucous layer, because this organism produces proteases that degrade the protective mucous layer. Moreover, H pylori infection decreases the production of epidermal growth factor, which normally promotes healing of gastric and duodenal mucosa.

H pylori organisms produce urease. Urease hydrolyzes urea to ammonia and carbon dioxide. Hydroxide ions produced by equilibration of ammonia with water may damage the gastric and duodenal mucosa. H pylori produces proteins that may serve as chemotactic factors for neutrophils and monocytes, which act as proinflammatory cells. H pylori also affects the gastric and duodenal mucous layer, because these organisms produce proteases that degrade the protective mucous layer. H pylori does not lead to the development of gastric and duodenal ulcers through alteration of the bacterial flora.

H pylori gene cagA and s1 or m1 forms of VacA (especially the intermediate region) are more common in disease-associated strains,5 especially cagPA1 and vacA s1 genotypes.6  CagA may be a risk factor for intestinal metaplasia.7

The cellular immune response in the H pylori– infected gastric mucosa is predominantly the T helper cell type 1 (Th1) type. Interleukin (IL)-18 levels are increased in this setting.8  The acidic environment of the gastric lumen induces the gastric mucosal production of IL-8, which is involved in the proinflammatory pathways.9

The receptors for bacterial adhesins include the Lewis b structures of the secretory M4C 5AC mucin, and inH pylori –positive duodenal ulcer patients, the initial low level of MUC1 mucin in gastric juice increases with eradication of this organism.10

The secretion of soluble triggering receptor is increased in H pylori –positive persons with gastric but not duodenal ulcers,11 suggesting that the host response may determine the site of ulceration. The age of the host may also influence the type of immune mechanism(s) involved in the pathogenesis of the H pylori –associated gastroduodenal disease.12

The 3 putative regions of H pylori include strain-specific genes, phase-variable genes, and genes with variable structures/genotype.13  Some strain-specific genes are in the plasticity regions, away from the cag pathogenicity island.14

Enhanced expression and release of endothelins (ET-1), an increase in the expression of the immediate early gene EGR-1, and the upregulation of angiogenic growth factors necessarily initiated by hydrochloric acid and proteolytic enzymes are also mechanisms in duodenal ulceration.15

There are new controversies emerging in the H pylori story, including investigators that question whether H pylori does cause duodenal ulcers and whether H pylori infection persists until it is pharmacologically eradicated.16

Frequency

United States

The prevalence of duodenal ulcers is estimated to be 6-15% in the general population. Most individuals do not have clinically significant ulcer disease, peptic ulcer disease is decreasing,17 and ulcers have become a rare cause for hospital admission.18 The prevalence is linked to the presence of H pylori. Approximately only 10% of young persons have H pylori infection, and the proportion of people with the infection increases steadily with age.

Approximately 10% of the US population has evidence of a duodenal ulcer at some time. Of those infected with H pylori, the lifetime prevalence is approximately 20%. Overall, the incidence of duodenal ulcers has been decreasing over the past 3-4 decades.

International

As in the US, duodenal ulcer disease prevalence is linked to H pylori infection. The prevalence of H pylori infection varies widely among countries and even in regions within countries.

Mortality/Morbidity

Duodenal ulcers cause significant morbidity, which is mainly related to pain, and hospitalization for complications, such as ulcer hemorrhage, perforation, penetration, and obstruction.

Rates of duodenal ulcer complications and mortality are generally increased in elderly patients, perhaps because of the high incidence of comorbid diseases in this group and their increased use of NSAIDs.

With NSAID-related ulcers, the incidence of perforation is approximately 0.3% per patient year and of obstruction, approximately 0.1% per patient year. Combining both duodenal ulcers and gastric ulcers, the rate of any complication in all age groups combined is approximately 1-2% per ulcer per year.

Over the last 20 years, the mortality rate in the setting of ulcer hemorrhage has not changed appreciably despite the advent of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). However, evidence from meta-analyses and other studies has shown a decreased mortality rate from bleeding peptic ulcers when intravenous PPIs are used after successful endoscopic therapy.19,20,21,22 In general, if one considers all patients with duodenal ulcers, the mortality rate due to ulcer hemorrhage is approximately 5%.

The mortality rate of patients requiring surgical intervention for complications of duodenal ulcers, such as perforation and obstruction, is significantly higher than the general rate and related to the age of the patient. Most deaths in this setting result from postoperative complications.

Giant duodenal ulcers have high rates of morbidity and mortality.23

Race

No specific relationship between race and the occurrence of duodenal ulcers exists. In general, areas with a high prevalence of H pylori infection have a high prevalence of duodenal ulcers.

Sex

Over the last several years, a trend toward an increasing incidence of duodenal ulcers in females and decreasing incidence in males has been observed, especially in younger males, in whom the prevalence ofH pylori infection is decreasing.

Historically, duodenal ulcers were believed to be more common in men than in women. Today, the prevalence is probably equal in men and women.

Age

The prevalence of duodenal ulcers increases with age. This is probably related to the increased prevalence of H pylori infection in older age groups, coupled with increased use of NSAIDs.

Clinical

History

Patients with duodenal ulcers have a variety of clinical presentations, ranging from individuals who are completely asymptomatic to those who develop severe complications, such as gastrointestinal (GI) hemorrhage. Some generalizations can be made with respect to common clinical presentations of duodenal ulcers.

Some common symptoms in patients with duodenal ulcers follow:o Epigastric pain can be sharp, dull, burning, or penetrating.o Many patients experience a feeling of hunger.o The pain may radiate into the back.o About 20-40% of patients describe bloating, belching, or symptoms suggestive

of gastroesophageal reflux.o Ulcer-related pain generally occurs 2-3 hours after meals and often awakens the patient

at night. This pattern is believed to be the result of increased gastric acid secretion, which occurs after meals and during the late night and early morning hours when circadian stimulation of gastric acid secretion is the highest.

o About 50-80% of patients with duodenal ulcers experience nightly pain, as opposed to

only 30-40% of patients with gastric ulcers and 20-40% of patients with nonulcer dyspepsia (NUD).

o Pain is often relieved by food, a finding often cited as being specific for a duodenal ulcer.

However, this symptom is present in only 20-60% of patients and is probably not specific for duodenal ulcers.

The pain of duodenal ulcers is generally episodic; however, the pain can evolve into a chronic, daily occurrence in some patients.

o A change in the patient's usual pattern of ulcer pain should be considered serious,

because it may herald an imminent complication. When food or antacids fail to relieve the pain or when the pain begins to radiate to new anatomic locations, a high index of suspicion of a complication is warranted.

Concern is especially warranted in the setting of new-onset nausea and vomiting, decreased appetite, and weight loss.

GI bleeding is a common complication of duodenal ulcers and can have serious consequences.o Patients may present with melena, coffee-ground emesis, or hematemesis.o The passage of frank blood in the stool or maroon-colored stool in the presence of a

bleeding duodenal ulcer suggests precipitous GI bleeding.

Patients who develop gastric outlet obstruction as a result of a chronic, untreated duodenal ulcer usually report a history of fullness and bloating associated with nausea and emesis that occurs several hours after food intake. A common misconception is that adults with gastric outlet obstruction present with nausea and emesis immediately after a meal.

A few individuals with duodenal ulcers are completely asymptomatic.o According to one study, typical epigastric pain was rare in patients older than 65 years

with peptic ulcer disease (ie, gastric ulcer and duodenal ulcer).o Elderly patients are more likely than younger patients to present in an asymptomatic

fashion, which is especially common in the setting of NSAID use.

Physical

No characteristic physical findings are associated with duodenal ulcers. In general, most patients have tenderness over the epigastrium, but this finding has a low sensitivity and specificity. Less often, tenderness is present over the right upper quadrant (RUQ), left upper quadrant (LUQ), or supraumbilical region. Most patients with an uncomplicated duodenal ulcer do not have any other physical findings.

In the presence of a complication, such as gastric outlet obstruction, the physician may note upper abdominal distention and hear a succussion splash on auscultation.

Perforation of peptic ulcers  is common in older persons using aspirin (ASA)/NSAIDs.24

Perforation usually results in classic findings of diffuse peritonitis with abdominal rigidity, guarding, and rebound tenderness. Bowel sounds may initially be hyperactive but, with time, become absent.

Risk factors for mortality from peptic ulceration include preoperative metabolic acidosis, renal insufficiency at the time of admission, reduced serum albumin concentrations on admissions or poor postoperative nutrition.25

Causes

The understanding of the etiology of duodenal ulcers changed dramatically in the latter part of the 20th century. Historically, duodenal ulcers were thought to be a disease related to diet and environmental stress alone. Subsequent studies revealed the importance of pepsin and acid secretion in the pathogenesis of duodenal ulcers. The most revolutionary change in the knowledge of duodenal ulcers was the discovery in 1982 that the bacterium H pylori was present in most affected patients.

NSAIDso Long before the discovery of H pylori, NSAIDs were known to be associated with GI

toxicity, including the formation of gastric ulcers and duodenal ulcers.26  H pylori enhances the damaging effect of NSAIDs on the gastroduodenal mucosa,27  and NSAID GI-complications also occur in children.28

o As many as 4-10% of patients on daily therapeutic-dose NSAIDs develop a duodenal

ulcer within 3 months of initiation of therapy, and up to 1% of these duodenal ulcers are clinically significant.

o A clear dose-response relationship exists, with high NSAID doses associated with

increased risk of duodenal mucosal damage. Clinically, NSAID-induced duodenal ulcers are most likely to bleed. In one study, NSAID use was associated with a relative risk for bleeding of 8.4, as opposed to 1.5 for H pylori –associated duodenal ulcers. Patients

taking NSAIDs, especially elderly patients, are most likely to present with an asymptomatic bleeding duodenal ulcer.

o Factors associated with an increased risk of duodenal ulcers in the setting of NSAID use

are a history of previous peptic ulcer disease, advanced age, female sex, high doses or combinations of NSAIDs, long-term NSAID use, concomitant use of anticoagulants, and severe comorbid illnesses. Corticosteroids do not increase the risk of duodenal ulcers by themselves, but the risk of duodenal ulcers is increased when corticosteroids are used in combination with NSAIDs, as compared to NSAID use alone.

o Aspirin is a significant risk factor for damage to the gastroduodenal mucosa.29,30 ; however,

its damaging effect does not depend on an H pylori infection.31

o Giving a PPI with the episodic use of the naproxen (500 mg bid) reduces gastroduodenal

ulcers from 46.9% to 11.8%,32 as well as reduces the risk of ulcers in persons with continuous low dose aspirin.33

o H pylori eradication in persons on long-term therapy with an NSAID has no beneficial

effect on the development of ulcers, erosions, or dyspepsia.34

o Using the antiplatelet drug clopidrogel rather than aspirin plus a PPI causes fewer GI

complications in persons with no pervious history of duodenal or gastric ulcers, but the difference is very small and the number-needed-to-treat (NNT) to prevent 1 episode of bleeding per year is approximately 200.35

o Acetaminophen given with a PPI is associated with the same increased risk of

hospitalization as with a traditional NSAID plus a PPI.36

o Although initially controversial, most evidence now supports the assertion that H

pylori and NSAIDs are synergistic with respect to the development of peptic ulcer disease. Eradication of H pylori in the setting of chronic NSAID use is associated with a decreased risk of ulcer bleeding.37  A meta-analysis found that H pylori eradication in NSAID-naive users before the initiation of NSAIDs was associated with a decrease in peptic ulcers.38

o The potential for decreased GI mucosal injury with newer COX-2–selective inhibitors,

celecoxib and rofecoxib, has been emphasized. On September 30, 2004, Merck & Co, Inc, announced a voluntary withdrawal of rofecoxib (Vioxx) from the US and worldwide markets because of its association with an increased rate of cardiovascular events (including heart attacks and strokes) compared with placebo. The newer NSAIDs do not inhibit COX-1 and, therefore, do not have the disadvantage of reducing the synthesis of protective prostaglandins. Overall, selective COX-2 inhibitors are associated with, at best, a modest decrease in the risk of ulcer bleeding. One study showed that the combination of a traditional NSAID with a daily PPI had the same risk of bleeding as that of a COX-2 inhibitor alone.39

H pylori bacteriao H pylori bacteria are small, microaerophilic, spiral-shaped, gram-negative rods. The

presence of H pylori in the stomach and duodenum is probably the most common bacterial infection in the world. Areas with a high prevalence of H pylori infection have a high incidence of duodenal ulcer.

o H pylori infection is generally regarded as the most important etiologic factor in the

development of duodenal ulcer.40 Most authors regard H pylori as the cause of 85-95% of duodenal ulcers. Even in chronic scarred duodenal ulcers, H pylori may be found in 63% of subjects.41

o The bacterium can induce duodenal mucosal damage by means of several mechanisms

(seePathophysiology).

o All evidence supports the assertion that H pylori is the major cause of duodenal ulcers.

However, the risk of developing a duodenal ulcer in an individual infected with H pylori is only about 1% per year, and only 10-15% of individuals with H pylori infection develop a duodenal ulcer at any point in life. Therefore, other pathogenic factors must function either independently or in concert with H pylori to produce duodenal ulcers.

o Factors other than H pylori are likely involved in the pathogenesis of peptic ulcer disease

in persons with hepatic cirrhosis42 and chronic renal failure on dialysis.43 The eradication of H pylori does not prevent ulcer formation or complications in persons with cirrhosis.44  Endoscopic lesions of the upper GI tract are less common in those persons as compared with individuals without end-stage renal disease (ESRD).45 Chronic obstructive pulmonary disease (COPD) increases the 30-day mortality in patients with bleeding or perforated peptic ulcers.46

o Duodenal ulcers that are not associated with H pylori or NSAIDs may include Crohn

disease,47lymphoma or adenocarcinoma, selective internal radiation therapy,48  or localized ischemia fromsickle cell disease.49

H pylori –negative duodenal ulcero In one study, among 608 patients with duodenal ulcers, 42 (6.9%) were classified as

idiopathic, but 3% had isolated duodenal colonization.50  Some studies have shown that the proportion of H pylori –related duodenal ulcers is significantly less than the commonly reported 85-95%. One group examined nearly 2400 cases of endoscopically proven, non–NSAID-related duodenal ulcers and found that only 73% patients were positive for H pylori.51 However, other studies have produced conflicting results, and another study showed that antibiotic use within 1 month of diagnosis may have resulted in false-negative results.

o Epstein-Barr virus  either alone or in combination with H pylori infection may be

associated with peptic ulcer disease.52

o In up to one third of patients with duodenal ulcers, basal acid output (BAO) and maximal

acid output (MAO) are increased. In one study, increased BAO was associated with an odds ratios [OR] of up to 3.5, and increased MAO was associated with an OR of up to 7, for the development of duodenal ulcers. People at especially high risk are those with a BAO greater than 15 mEq/h. The increased BAO may reflect the fact that, in a significant proportion of patients with duodenal ulcers, the parietal cell mass is increased to nearly twice that of the reference range.53

o In addition to the increased gastric and duodenal acidity observed in some patients with

duodenal ulcers, accelerated gastric emptying is often present. This acceleration leads to a high acid load delivered to the first part of the duodenum, where 95% of all duodenal ulcers are located. Acidification of the duodenum leads to gastric metaplasia, which indicates replacement of duodenal villous cells with cells that share morphologic and secretory characteristics of gastric epithelium. Gastric metaplasia may create an environment that is well suited to colonization by H pylori.

o Tramadol also increases a person’s risk of perforation and mortality from peptic ulcers.54

o Duodenal ulcers occur in 3.6% of dyspeptic persons infected with the human

immunodeficiency virus (HIV) and treated with highly active antiretroviral therapy (HAART); gastric ulcers occur in 2.7%.55  H pylori becomes more prevalent as the CD4 cell count rises, and endoscopy becomes more useful for persons with CD4 cell counts less than or equal to 200, when opportunistic infections and malignancies are more common.

Lifestyle factors

o Smoking: Evidence that tobacco use is a risk factor for duodenal ulcers is not conclusive.

Evidence supporting a pathogenic role for smoking comes from the finding that smoking may accelerate gastric emptying and decrease pancreatic bicarbonate production. However, studies have produced contradictory findings. In one prospective study of more than 47,000 men with duodenal ulcers, smoking did not emerge as a risk factor.56 However, smoking in the setting of H pylori infection may increase the risk of relapse of PUD.57

o Smoking is harmful to the gastroduodenal mucosa, and H pylori infiltration is denser in

the gastric antrum of smokers.58

o Alcohol use: Ethanol is known to cause gastric mucosal irritation and nonspecific

gastritis. Evidence that consumption of alcohol is a risk factor for duodenal ulcer is inconclusive. A prospective study of more than 47,000 men with duodenal ulcer did not find an association between alcohol intake and duodenal ulcer.56

o Caffeine intake: Little evidence suggests that caffeine intake is associated with an

increased risk of duodenal ulcers.o Diet: Historically, diet was considered one of the primary causes of peptic ulcer disease.

However, current knowledge indicates that diet probably has little influence on the pathogenesis of duodenal ulcers. Deficiency of certain essential fatty acids necessary for prostaglandin production has been examined as a possible risk factor. Moreover, some physicians hypothesize that regional variability of duodenal ulcer prevalence not directly related to H pylori prevalence may be related to diet. In general, evidence linking diet and duodenal ulcer is weak.

Geneticso More than 20% of patents have a family history of duodenal ulcers, compared with only

5-10% of control groups. In addition, weak associations have been observed between duodenal ulcers and blood type O. Furthermore, patients who do not secrete ABO antigens in their saliva and gastric juices are known to be at higher risk. The reason for these apparent genetic associations is unclear.

o A rare genetic association exists between familial hyperpepsinogenemia type I (a genetic

phenotype leading to enhanced secretion of pepsin) and duodenal ulcers. However, H pylori can increase pepsin secretion, and a retrospective analysis of the sera of one family studied before the discovery of H pylori revealed that their high pepsin levels were more likely related to H pylori infection.

Other causeso Acid hypersecretory syndromes

Gastrinoma (Zollinger-Ellison syndrome): First described in 1955, Zollinger-Ellison syndrome is caused by a tumor of pancreatic islet cells that produces gastrin. It is associated with gastric acid hypersecretion and development of peptic ulcer disease. From 0.1% to 1% of duodenal ulcers are thought to be secondary to an underlying gastrin-secreting tumor.59  With the shortage of secretion for diagnostic testing in persons suspected of Zollinger-Ellison syndrome, the glucagon provocative test may prove to be a suitable alternative.60

Systemic mastocytosis: Systemic mastocytosis is a disease associated with diffuse infiltration of the skin, GI tract, bone marrow, spleen, and liver with mastocytes. Gastric acid hypersecretion occurs in response to histamine production by mastocytes.

Basophilia: In the setting of a myeloproliferative disorder, basophilia can be associated with duodenal ulcer secondary to histamine production, as is systemic

mastocytosis. This tends to occur more frequently after chemotherapy-induced cell lysis that causes increased release of histamine from cells.

o Other factors

Infection: Some evidence suggests that herpes simplex virus-1 (HSV-1) and cytomegalovirus (CMV) may be associated with duodenal ulcers and gastric ulcers in a minority of patients.

Chemotherapy: Chemotherapeutic agents, such as 5-fluorouracil (5-FU), methotrexate (MTX), and cyclophosphamide, have been associated with development of duodenal ulcers.

Radiation: Local radiation can result in mucosal damage, which may lead to the development of duodenal ulcers.

Crack cocaine: Use of crack cocaine causes localized vasoconstriction, and the reduced blood flow may lead to mucosal damage.

The risk of upper GI tract bleeding may be increased in users of the diuretic spirolactone,61  or moderate and high affinity serotonin reuptake inhibitors.62