ACID PEPTIC DISORDERS AND THERAPY
PROF. DR. OMAR HEIKAL
Prof. of Internal Medicine & GIT, Military Medical Academy
Gastric infection with the bacterium H.Pylori accounts for the majority of PUD.
This organism also plays a role in the development of gastric mucosal associated lymphoid tissue ( MALT )
lymphoma and gastric adenocarcinoma. Although, the entire genome of H.Pylori has been sequenced. It is
still not clear how this organism, which is in the stomach, causes ulceration in the duodenum.
THE BACTERIUM :
The bacterium, initially named campylobacter pyloridis, is a gramnegative microaerophilic rod found most
commonly in the deeper portions of the mucous gel coating of gastric mucosa or between the mucous layer
and the gastric epithelium.
It May attach to gastric epithelium but under normal circumstances does not appear to invade cells.
It is strategically designed to live within the aggressive environment of the stomach. It is S - shaped and
contains multiple sheathed flagella. Initially, H. Pylori resides in the antrum but, over time, migrates towards
the more proximal segments of the stomach.
The organism is capable of transforming into a coccoid form, which represents a dormant state that may
facilitate survival in adverse condition. The bacterium expresses a host of factors that contribute to its ability
to colonize the gastric mucosa and produce mucosal injury.
Several of the key bacterial factors include urease (converting urea to NH3 and water, thus alkalinization
the surrounding acidic environment), catalase, lipase, adhesions, platelet activating factor, cytotoxin
associated gene protein(Cag A), pic B (induces cytokines) and vacuolating cytotoxin (Vac A)
Multiple strains of H. Pylori exist and are characterized by their ability to express several of these
factors(Cag A , Vac A, etc. ). It is possible that the different diseases related to H. Pylori infection can be
attributed to different strains of the organism with distinct pathogenic features.
The prevalence of H. Pylori varies throughout the world and depends to a great extent on the overall
standard of living in the region. In developing parts of the world 80% of the population may be infected by
the age of twenty. In contract in the developed countries, this organism is rare in childhood.
This rate of colonization increases with age, with about 50% of individual aged 50% being infected. Factors
that predispose to higher colonization rate include poor socioeconomic status and less education.
These factors not race, are responsible for the rate of H.Pylori infection in blacks and Hispanic Americans
being double the rate seen in whites of comparable age. Summary of risk factors for H.Pylori infection is
shown in the table.
Transmission of H.Pylori from person to person following an oral - oral or fecal - oral route. The risk
H.Pylori is declining in developing countries. The rate of infection in the United states has fallen by >50%
when compared to 30years ago.
RISK FACTORS FOR H.PYLORI INFECTION
Birth or residence in a developing country.
Low socioeconomic status.
Unsanitary living conditions.
Unclean food or water.
Exposure to gastric contents of infected individual.
H.Pylori infection is a virtually always associated with a chronic active gastritis, but only 10 to 15%of
infected individuals develop Frank peptic ulseration. The basis for these differences is unknown. Initial
studies suggested that >90% of all DId where associated with H.Pylori, but H.Pylori is present in only 30 -
60% Of individuals with DU and 70% of patients with GU . The pathophysiology of ulcers not associated
with H.Pylori or NASID ingestion or the rare zollinger Ellison syndrome (DES) is unclear. The particular
end result of H.Pylori infection (gastritis, PUD, gastric MALT lymphoma, gastric cancer ) is determined by a
complex interplay between bacterial and host factors.
1- Bacterial factors:
H.Pylori is able to facilitate gastric residence, induce mucosal injury, and avoid host defenst defense.
Different strains of H.Pylori produce different virulence factors. A specific region of the bacterial genome, the
pathogenicity island, encodes the virulence factors Cag A and pic B. Vac A also contributes to pathogenicity,
though it is not encoded within the pathogenicity island.
These virulence factors, in conjunction with additional bacterial constituents, can cause mucosal damage.
Urease, which allows the bacteria to reside in the acidic stomach, generates NH3, which can damage
epithelial cells. The bacteria produce surface factors that are chemotactic for neutrophils and monocytes,
which in turn contribute to epithelial cell injury.
H.Pylori makes proteases and phospholipases that break down the glycoprotein lipid complex of the
mucous gel, thus reducing the efficacy of this first line of mucosal defensive.
H.Pylori expresses adhesins, which facilitate attachment of the bacteria to gastric epithelial cells.
Although lipopolysacchaaride (LPS) of gram - negative bacteria often plays an important role in the
H.Pylori LPS has low immunologic activity compared to that of other organisms . It May promote a
smoldering chronic inflammation.
2- Host factors:
The host responds to H.Pylori infection by mounting an inflammatory response, which contributes to
gastric epithelial cell damage without providing immunity against infection.
The neutrophil response is strong both in acute and chronic infection.
In addition, T lymphocytes and plasma cells are components of the chronic inflammatory infiltrate,
supporting the involvement of antigen - specific cellular and humoral responses.
A number of cytokines are released from both epithelial and immune modulatory cells in response to
H.Pylori infection including the proinflammatory cytokines tumor necrosis factor (TNF)a, interleukin (IL)
Ia /b, IL-6, interferon (IFN). The reason for H.Pylori - mediated duodenal ulceration remains unclear.
One potential explanation is that gastric metaplasia in the duodenum of DU patients permits H.Pylori to
bind to it and produce local injury secondary to the host response. Another hypothesis is that H.Pylori antral
infection could could lead to increased acid production, increased duodenal acid. and mucosal injury.
H.Pylori infection might induce increased acid secretion through both direct actions of H.Pylori and
proinflammatory cytokines(IL-8, TNF,and IL-1). H.Pylori infection has also been associated with decreased
duodenal mucosal bicarbonate production.
THERAPY OF H.PYLORI :
Extensive effort has been placed into determining who of the many individuals with H.Pylori infection
should be treated.
The common conclusion arrived at by multiple consensus conferences(National Institutes of Health
consensus Development, American Digestive Health Foundation International Updated Conference,
European Maastricht Consensus, and Asia Pacific Consensus Conference) is that H.Pylori should be
eradicated in patients with documented PUD.
This holds true independent of time of presention(fits episode or not), severity of symptoms, presence of
confounding factors such as ingestion of NSAIDs, or whether the ulcer is in remission.
Some have advocated treating patients with a history of documented PUD who are found to be H.Pylori -
positive by serology or breath testing.
Over half of patients with gastric MALT lymphoma experience comission of the tumor in response to
Treating patients with NUD or to prevent gastric cancer remains controversial.
Multiple drugs have been evaluated in the therapy of H.Pylori. on single agent is effective in eradicating the
Combination therapy for 14days provides the greatest efficacy.
A short time course administration (7 to 10 days), although attractive, has not proven as successful as the
14 day regimens.
The agents used with the greatest frequency include amoxicillin metronidazole.
Tetracycline, clarithromycin, and bismuth compounds.
The physician›s goal in treating PUD is to provide relief of symptoms(pain or dyspepsia), promote ulcer
healing, and ultimately prevent ulcer recurrence and complications.
The greatest impact of understanding the role of H.Pylori in peptic disease has been the ability to prevent
recurrence of what was often recurring disease.
Documented eradication of H.Pylori in patients with PUD is associated with a dramatic decrease in ulcer
recurrence to 4% (as compared to 59% )in HI patients and 6% (compared to 67%) in DU patients.
Eradication of the organism may lead to diminished recurrent ulcer bleeding.
The impact of its eradication on ulcer perforation is unclear.
Suggested treatment regimens for H.Pylori are outlined in below.
Choice of a particular regimen will be influenced by several factors including efficacy, patient tolerance,
existing antibiotic resistance and cost of the drugs.
The aim for initial eradication rates should be 85 to 90% Dual therapy (PPL plus amoxicillin, PPL plus
clarithromycin, ranitidine bismuth citrate (Tritec) plus clarithromycin) are not recommended in view of
studies demonstrating eradication rates of < 80 to 85 % .
The combination of bismuth, metronidazole, and tetracycline was the first triple regimen found effective
against H.Pylori .
Addition of acid suppression assists in providing early symptom relief and may enhance bacterial
Triple therapy, although effective, has several drawbacks, including the potential for poor patient
compliance and drug induced side effects.
Compliance is being addressed somewhat by simplifying the regimens so that patients can take the
medications twice a day.
Simpler( dual therapy )and shorter regimens ( 7 and 10 days ) are not as effective as triple therapy for 14 days.
Two anti-H.Pylori regimens are available in prepack aged formulation : prevpac ( lansoprazole,
clarithromycin, and amoxicillin ) and Helidac ( bismuth subsalicylate, tetracycline, and metronidazole ) .
The contents of the prevpac are to be taken twice per day for 14 days, whereas Helidac constituents are
taken four times per day with an antisecretory agent( PPI or H2 blocker), also taken for at least 14days.
Side effects have been reported in up to 30% of patients on triple therapy.
Bismuth may cause black stools, constipation, or darkening of the tongue.
The most feared complication with amoxicillin is pseudomembranous colitis, but this occurs in < 1 to 2%
Amoxicillin can also lead to antibiotic associated diarrhea nausea, vomiting, skin rash, and allergic
Tetracycline has been reported to cause rashes and very rarely hepatotoxicity and anaphylaxis.
One important concern with treating patients who may not need treatment is the potential for
development of antibiotic resistant strains.
The incidence and type of antibiotic resistant H.Pylori strains very worldwide.
Strains resistant to metronidazole, clarithromycin, amoxicillin. And tetracycline have been described, with
the latter two being uncommon.