Patient Presentation
D.S. is a 36 yo female who presented with lower and upper gastrointestinal complaints of several years duration. Specifically, she complained of constipation with history of anal fissures. She had also had intermittent rectal bleeding. Previous flexible sigmoidoscopy and colonoscopy showed internal hemorrhoids and 10-15 cm of moderate colonic inflammation. Biopsy showed no abscesses. She was treated with azulfidine, proctofoam, and steroid enemas.
Her rectal bleeding improved but she continued to experience epigastric pain and burning. She had been taking ranitidine for these symptoms. She presented to NCBH in 1993.
PMH: colitis, hemorrhoids
Meds: Zantac and intermittent OTC NSAID.
PE: benign, including rectal
She underwent upper gastrointestinal series with small bowel follow-through which showed a small antral ulcer versus a mucosal fold. She subsequently underwent upper endoscopy which showed a small antral ulcer. A CLO test was positive. Her dose of ranitidine was increased and she was counseled to avoid NSAIDs. She improved.
Two years later her symptoms of epigastric burning returned, despite therapy with ranitidine. Her exam was unchanged. A repeat upper endoscopy was performed which showed new gastric ulcers. A CLO test was positive. She was treated with omeprazole, clarithromycin, and metronidazole. Ranitidine was continued. Patient’s symptoms improved.
Helicobacter pylori, the discovery
The discovery of Helicobacter pylori was made by Barry Marshall at the Royal Perth Hospital in Western Australia in collaboration with Robin Warren. Warren, a histopathologist, was investigating a bacterium which he had observed on gastric biopsies in 1979. He thought this bacterium was associated with gastric inflammation. Marshall, working as a fellow in gastroenterology, cultured a spiral shaped organism in 1982. This organism did not resemble any known species, either in morphology or biochemistry. It was cultured using isolation techniques for Campylobacter. Thus, initially it was named Campylobacter pyloridis. The name was grammatically corrected to Campylobacter pylori.
In 1983, Marshall and Warren published letters in Lancet titled "Unidentified Curved Bacilli On Gastric Epithelium In Chronic Gastritis." In the first letter, Warren revealed his observation of the presence of small curved and S-shaped bacilli in 135 gastric biopsy specimens.
The bacilli were:
-closely associated with the surface epithelium.
-usually seen in the antrum.
-varied in distribution-patchy, focal, or continuous.
-difficult to see with traditional H & E staining but easily visible on Warthin-Starry silver method.
-associated with inflammation
Warren defined histologic findings of "chronic gastritis" and "active chronic gastritis." It is important to realize that the gastritis which H. pylori uniformly causes is a reference to histologic findings not symptomatology or endoscopic findings.
Marshall’s letter described historical reference to "spirochetes" in association with ulcers. A 1954 study of 1140 gastric suction biopsy specimens showed no "spirochetes." Silver staining was not used in this study. The organism is difficult to see on routine H & E staining unless one is looking for it. This study seemed to halt further investigation into gastric microbiology. From 1954 to 1983 only rare mention of gastric bacteria was made in the literature. Though Marshall cultured the bacteria using Campylobacter isolation techniques, he questioned to what genus this bacteria would eventually be classified. He closed his letter with a prediction:
"The pathogenicity of these bacteria remains unproved, but their association with polymorphonuclear infiltration in the human antrum is highly suspicious. If these bacteria are truly associated with antral gastritis as described by Warren, they may have a part to play in other poorly understood gastritis associated diseases (ie, peptic ulcer and gastric cancer)."
Intensive research on this organism followed leading to our present incomplete understanding of the role H. pylori plays in these diseases.
Helicobacter pylori, the organism
Helicobacter pylori is a gram negative, microaerophillic, curved bacillus found in gastric biopsy specimens from patients with histologic gastritis. It was originally named Campylobacter pylori but in 1989 after further study of the organism it was reclassified as Helicobacter pylori.
Some of its properties include:
-Potent urease activity which is probably important in its pathogenicity. Free urea is broken down to carbon dioxide and ammonia, which is thought to provide an "acid-neutralizing cloud" that protects the organism until it reaches a safer environment. Once in a safe area the urease production continues, perhaps it has a metabolic role in nitrogen assimilation. Urease also likely plays a role in the pathogenicity of H. pylori. The urease activity is also important in diagnosis and may be important in determining efficacy of treatment.
-It is a motile organism with multiple flagella which allow it to move effectively in the viscous environment of gastric mucus.
-It produces adhesins which are specific to gastric mucosa.
-It lives only in areas overlying gastric epithelium.
-Its preferred niche is the gastric antrum where it usually produces inflammation, not ulceration. When it is found outside the gastric antrum it is often seen in association with ulceration.
-There are multiple strains of H. pylori. No standard typing scheme has been developed.
-It has plasmids, all of which are cryptic, to date.
-It is the first organism to have its entire genomic sequence determined.
Helicobacter Pylori, epidemiology
Helicobacter pylori has been isolated from persons worldwide. H. pylori has not been found in other species, though there are now nine known species of Helicobacter all of which seem to be species specific. H. pylori is not found in food, soil, or water. It seems that humans are the major, if not sole, reservoir of H. pylori.
The mode(s) of transmission is still unclear. Transmission must be from person to person and is most likely oral to oral. Transmission has been documented via infected endoscopes and also by ingestion in volunteers. Fecal-oral spread may occur. The role of fecal-oral transmission has been investigated in underdeveloped countries. In Gambia H. pylori has been cultured from the stool. In Peru epidemiological studies suggest fecal-oral transmission plays a significant role in transmission where prevalence rates reach 80% at an early age. The organism has also been cultured in dental plaque. Clustering occurs in families. Studies show evidence that H. pylori is not sexually transmitted.
Prevalence is variable, though generally high. It is chiefly related to age and geographic location (living density). In non-Hispanic Caucasians prevalence increases with age to » 50% by the age of 60. Higher prevalence rates are found in African-Americans and Hispanics. H. pylori is more common in developing countries where prevalence reaches 80%. Prevalence is very high among institutionalized patients. Some data suggest the prevalence may be declining in more developed countries.
Helicobacter pylori, pathogenesis
Initial H. pylori infection produces a seven to ten day period of acute neutrophilic gastritis. Symptoms, if present, are mild. Some of the organisms then penetrate the viscous mucus layer and multiply in close proximity to the apical membranes of the surface epithelial cells. Some organisms become adherent and attach to the plasma membrane. Others penetrate between epithelial cells and may access the lamina propria. A few organisms may invade cells, but no proof of endocytosis in humans exists. The majority of organisms live free in the lumen of the stomach.
Tissue invasion produces a marked inflammatory response leading to degenerative changes. A small number of people who are infected may spontaneously eradicate the organism with complete resolution of the inflammatory response. Most will not eradicate the organism and will continue with chronic active gastritis. In most people infected with H. pylori, the organism is a colonizer. It does not cause symptoms but it uniformly produces histologic gastritis of varying severity.
The inflammation is a result of bacterial products, the nature of these products is uncertain. Some strains of H. pylori produce a cytotoxin, its significance is debated. Ammonia, or its degradation products, produced by the urease activity may be cellular toxins. H. Pylori also produces phospholipases which may disrupt cell membranes. Other substances are being investigated. The inflammatory response produces many native cytokines including interleukins, interferon, and tumor necrosis factor and results in killing of both H. pylori and gastric epithelium.
H. pylori only overlays gastric epithelium. For it to cause injury, gastric epithelium must be present. Normally, injury, with inflammation, does occur, but is limited to the antrum and is asymptomatic. The duodenum normally has absorptive, intestinal type epithelium. The duodenum can develop areas of gastric metaplasia, probably in the setting of decreased pH. The most current theory is that H. pylori alone can not cause ulceration. Other abnormalities have been described in duodenal ulcer patients, including increased parietal cell mass, exaggerated postprandial gastrin release, rapid gastric emptying with increased duodenal acid load, and impaired duodenal mucosal bicarbonate secretion. Some of these abnormalities may be a result of H. pylori infection, in particular increased gastrin secretion. Increased acid leads to gastric metaplasia in the duodenum. If H. pylori infects the area of gastric metaplasia active chronic inflammation in the duodenum results. The inflamed duodenum is more susceptible to acid attack and ulceration can ensue.
The schematic below summarizes the possible outcomes of H. pylori infection.
H. pylori infection
ò
Chronic Superficial Gastritis
years-decades
ò ò ò ò
Chronic Atrophic Chronic Superficial Lymphoproliferative Peptic ulcer
Gastritis Gastritis disease disease
ò
Gastric Adenocarcinoma
Blaser MJ, Parsonet J. Parasitism by the slow bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J Clin Invest 1994; 94:4-8.
Helicobacter pylori, the diagnosis
There are several very good methods for obtaining evidence of H. pylori infection. These methods are microscopic examination of biopsy, culture, serology, biopsy urease test (CLO test), and urea breath test (ubt).
Culture-Can be performed on gastric tissue samples using isolation techniques for campylobacter. The culture is considered a "gold standard" but success rates vary with experience. H. pylori culture is laborious to perform, thus expensive. False negatives are a result of sampling error or failure of technique. The test is invasive, requiring endoscopy. No cultures have been performed at NCBH for several years.
Sensitivity-70-90%, Specificity-100%.
Biopsy-Specimens of gastric tissue are viewed microscopically using standard H & E staining. Warthin-Starry silver or Giemsa may also be used. Studies have demonstrated that this test is highly operator dependent, i.e. an experienced pathologist is better than an inexperienced pathologist. An advantage to this test is that it is permanent allowing for retrospective review. Disadvantages are that it is invasive, requiring endoscopy. False negatives can occur from sampling error or misinterpretation.
Sensitivity-98%, Specificity-98%.
Biopsy Urease Test (CLO test)-This test is currently in use at NCBH. It involves taking a biopsy of grossly normal appearing antral mucosa and placing it in an agar well which contains urea and a pH indicator. Metabolism of the urea by bacterial urease changes the pH of the agar and produces a color change within 24 hours. False negatives occur as a result of sampling era. The rate of false negatives can be reduced by taking multiple biopsies.
Sensitivity-92%, Specificity-98%.
Serology-Serum samples can be measured for IgG specific to H. pylori. Serology allows for the simplest and least expensive method to detect H. pylori infection. Bacterial colonization elicits a systemic immune response. IgA and IgG antibodies directed at H. pylori antigens can be detected in the serum of infected individuals. Sensitive, specific, and quantitative ELISA assays are available. Rapid qualitative office-based tests are available. These detect antibodies in undiluted serum specimens. Office-based whole blood tests are awaiting approval. Once infected a person retains positive serology, probably for life. With successful treatment there will be a drop in the titer which is predictive of cure. Though the test is minimally invasive, positive results are difficult to interpret without knowing the pathology which lies within the stomach. Since H. pylori infection is highly prevalent, a large portion of patients in any internal medicine practice will probably be seropositive with or without symptoms of ulcer disease.
Sensitivity-95%, Specificity-95%.
Urea Breath Test-This test is currently awaiting FDA approval. It involves patients ingesting a meal containing labeled urea. The labeling involves use of 13C or 14C urea which is administered as liquid or capsule. With active H. pylori infection, the urea is metabolized and free 13C or 14C is released, absorbed, then exhaled. By measuring breath samples for the isotope, presence of H. pylori infection is documented. The test is non-invasive and reportedly less expensive than all other tests used to diagnose H. pylori except serology. Unlike serology, a positive test indicates active infection. False negatives occur if the test is administered to soon after antibiotic treatment or use of a proton-pump inhibitor or bismuth. False positives result from the fact that 13 C is naturally occurring. Some individuals may produce significant levels. NCBH is awaiting FDA approval and funding for a machine to be put in use. Use of 13C requires mass spectrometry. Use of 14C requires compliance with the many regulations governing handling of radioactive materials. It exposes the patient to small amounts of radiation, equivalent to one-tenth of the radiation of a chest x-ray.
Sensitivity-96%, Specificity-98%.
Polymerase chain reaction-Available but expensive with false positives limiting its utility.
Table of Diagnostic Methods
| Method | Cautions | S/S1 | Comment | Cost2 |
Serology-office |
false + after recent antibiotic | 93/90 | undiluted sera, takes 4-15 min. | 30-40 |
| ELISA |
as above and 1-5% of pts do not produce detectable levels of antibody. | 93/95 | measures titer, fall in titer may be meaningful. Detectable levels remain after treatment. | 60-120 |
| Urea breath test (ubt) |
bismuth, antibiotics, & omeprazole may cause false neg. Do 4 wks post Rx. | 96/98 | positive test indicates active infection. | 100-200? |
| RUA3
|
requires biopsy, false + as for ubt | 92/98 | known as CLO4 test, false neg from sampling error. | 20 |
| Histology |
operator dependent, subject to sampling error | 98/98 | special stains may be needed | 250 |
| Culture |
lab dependent, "gold standard?" | 90/100 | useful if antibiotic sensitivity is needed to guide Rx. | 150
|
1
Sensitivity and specificity, number indicate averages from literature.2
Cost in dollars, does not include costs of endoscopy.3
Rapid urease assay.4
Campylobacter like organism.
Adapted from: Smoot DT, Cutler AF, Helicobacter pylori: Diagnostic Tests, Gastroenterology & Endoscopy News, Vol. 45 No. 10, October 1994.
Helicobacter pylori, the treatment
The goals of treatment of H. pylori are eradication of the organism, ulcer healing, and symptom relief.
The treatment options for H. pylori are several. All include antibiotic therapy. Some include treatment with omeprazole or ranitidine. Specific choice of therapy is guided by several factors including efficacy, compliance, cost, and side effect profiles. Problems with treatment include development of drug resistance, allergy to drug, and drug side effects including pseudomembranous colitis. There are presently no single drug regimens. The table below list several different regimens and their efficacies. With the regimens listed the use of an anti-secretory drug is recommended for 6 weeks to ensure ulcer healing. There is an invasive one hour treatment being studied which is outlined below. Physicians should be very familiar with 1-2 regimens with the added awareness that other options are available. In regimens using omeprazole the efficacy is reduced if treatment with omeprazole begins before antibiotic therapy.
Therapeutic options for treatment of H. pylori infection
| Drug 1 | Drug 2 | Drug 3 | Notes | Cost | Success |
| tetracycline 500 mg qid | metronidazole 250 mg tid | bismuth 2 tabs qid |
with meals for 14 days + an antisecretory drug | $40 | >90% |
| tetracycline 500 mg qid | clarithromycin 500 mg tid | bismuth 2 tabs qid |
with meals for 14 days + an antisecretory drug | $155 | >90% |
| amoxicillin 500 mg qid |
clarithromycin 500 mg tid | bismuth 2 tabs qid |
with meals for 14 days + an antisecretory drug | $168 | >90% |
| amoxicillin 500 mg qid |
metronidazole 250 mg tid | bismuth 2 tabs qid |
for 7 to 14 days | $45 | >90% |
| clarithromycin 500 mg bid |
metronidazole 500 mg bid |
omeprazole 20 mg bid |
with meals for 14 days + an antisecretory drug | $202 | >90% |
| amoxicillin 750mg tid |
clarithromycin 500 mg tid | with meals for 14 days + an antisecretory drug | $155 | >90% | |
| clarithromycin 500 mg tid | omeprazole 20 mg bid |
with meals for 14 days | $227 | 70-80% | |
| amoxicillin 750mg tid |
omeprazole 40 mg bid |
with meals for 14 days | $208 | >90% | |
| amoxicillin 1 gm tid |
omeprazole 20 mg bid |
with meals for 14 days | 35-60% |
Adapted from: Graham DY, Peptic Ulcer. In: Current Practice of Medicine, Current Medicine, Philadelphia, (in press).
| One Hour Cure for Helicobacter pylori Infection |
| Pretreatment-Lansoprazole-30 mg qd and pronase-18,000 units bid for two days. |
| Treatment 1. Place and inflate balloon in distal duodenum 2. Instill in stomach 100 cc 7% sodium bicarbonate, 2 gm amoxicillin, 1 gm bismuth subnitrate, and 36,000 units pronase. 3. Wait one hour and drain stomach. |
The question a clinician will confront is which regimen is best? Choice of regimen will be guided by several factors. First is efficacy. The regimen chosen should be efficacious. Efficacy rates of 80-95 % are now the expectation. With efficacy being nearly equal cost, compliance, and side effect profile become very important. A consideration regarding cost is that in some "antibiotic-only" regimens the addition of an anti-secretory agent, (proton pump inhibitor or H-2 blocker), is recommended. This addition is to speed symptom relief, not improve efficacy. The addition of this drug drives up the cost considerably. It is important to realize that successful treatment of H. pylori induced peptic ulcer disease the expectation is for cure. By successfully treating H. pylori one can expect to prevent the need for additional treatment, thus prevent continued costs.
Successful treatment is dependent on many factors, including compliance. Choosing a regimen with which the patient will be compliant is another important factor in regimen selection. Some patients may be able to take 15 pills a day for two weeks. Other patients may find it difficult to take 6 pills a day for one week. This decision must be tailored individually.
Drug allergies obviously will effect selection.
Side effects of the drugs available are many, most are not severe. The table below lists the side effects of the various agents used in treatment of H. pylori.
Major Side Effects of Agents Used to Treat Helicobacter pylori Infection
| Bismuth-dark stool. |
| Omeprazole-dizziness, possible risk to fetuses and nursing infants. |
| Tetracycline-diarrhea, photosensitivity, gi intolerance,
pseudomembranous colitis, exacerbation of renal insufficiency. |
| Metronidazole-metallic taste, vomiting, anorexia, headache, fever,
rash, neuropathy, disulfiram-like reaction with alcohol ingestion. |
| Amoxicillin-diarrhea, candidiasis, rash, pseudomembranous colitis. |
| Clarithromycin-diarrhea, nausea, dyspepsia, headache, pseudomembranous colitis. |
Drug resistance, particularly to metronidazole is not uncommon and may influence regimen selection.
None of the drugs listed has FDA approval for treating H. pylori.
Mucolytic therapy is being investigated and may be used in future regimens.
Vaccine development is currently being pursued.
Helicobacter pylori, the significance
Marshall’s speculation regarding H. pylori’s role in the pathogenesis was tested and debated over the following years. Since then studies have shown that H. pylori fulfills Koch’s postulates establishing it as the causative agent for chronic gastritis.
Data has accumulated which strongly implicates if not proves H. pylori’s role in duodenal ulcer disease. Data has also accumulated implicating H. pylori as one causative agent of gastric ulcer disease. Studies have also suggested a role in gastric malignancies, including adenocarcinoma and lymphoma, non-hodgkin’s and mucosal associated lymphatic tumors (malt). H. pylori’s role in non-ulcer dyspepsia is a controversial topic at present.
The data regarding H. pylori’s role in duodenal ulcer disease is convincing. Many studies have documented 90-95% prevalence rates of H. pylori in patients with duodenal ulceration. Furthermore, recurrence of duodenal ulcer is dramatically less in patients treated with regimens which eradicate H. pylori versus standard treatment for peptic ulcer disease. Though H. pylori has not been proven to be a causative agent in peptic ulceration, the reduction in recurrence of disease makes the argument for treating H. pylori infection in duodenal ulcer disease compelling. Until recently there was suggestion that H. pylori was merely a commensal organism, not in any way responsible for ulceration. The reduction in recurrence of duodenal ulcer in patients with H. pylori who were treated versus those with H. pylori who were not treated is dramatic, 59-90% recurrence if not treated, 2-27% if treated. Furthermore, the relapses in patients treated to eradicate H. pylori often occur where eradication was unsuccessful. In most of the studies follow-up intervals were generally one year with one study following patients for four years. Patients in these studies had repeat endoscopies with repeat testing to determine if treatment was successful. The current NIH recommendation is to treat all patients with duodenal ulcer disease and evidence of H. pylori infection with a regimen to eradicate H. pylori.
In gastric ulcer the association with H. pylori is still significant. Incidence of H. pylori infection in patients with gastric ulcer is as high as 75%, somewhat higher than the prevalence of H. pylori in the general population. Treatment of H. pylori significantly reduces recurrence rates. NIH recommendations are to treat all patients with gastric ulcer disease and evidence of H. pylori infection with a regimen to eradicate H. pylori. This recommendation includes patients in whom NSAID use was present.
In non-ulcer dyspepsia the evidence is not clear. There is a high incidence of H. pylori in patients with non-ulcer dyspepsia. Treatment of H. pylori has had mixed results in producing and maintaining symptom relief.
H. pylori has been strongly implicated in oncogenesis of gastric adenocarcinoma and the mucosal associated lymphatic tumors. Further research is ongoing. Currently there are many unanswered questions regarding if infection with H. pylori should be treated in an effort to prevent gastric cancers.
Helicobacter pylori, discovery’s impact on treatment
The time of H. pylori’s discovery was also the time H-2 blockers became available for use in the treatment of acid related gastric disorders. This class of drugs became dominant in treatment of most upper gastrointestinal tract disease. They were a new treatment option where previously only antacids and surgery were available. H. pylori’s discovery has altered the approach to treatment of these disorders though not as dramatically as the advent of H-2 blockers did. Physicians and some patients are now aware of an infectious etiology to peptic ulcer disease. Consensus guidelines for the treatment of H. pylori have been established and will continue to evolve as more information becomes available. Those guidelines make clear the need to treat H. pylori infection in all patients with peptic ulcer disease with a documented H. pylori infection. Patients with previously documented ulcer disease never treated for H. pylori, now with recurrent symptoms and non-invasive evidence of H. pylori infection should also be treated.
NIH guidelines also recommend not treating patients with H. pylori infection without symptoms or with non-ulcer dyspepsia. Treatment is not recommended to prevent ulcer disease in the future or to prevent gastric cancers.
The presentation of a patient with peptic ulcer disease is difficult if not impossible to distinguish from the patient with non-ulcer dyspepsia. The incidence of dyspepsia is not known. 50% of patients with dyspepsia will have no structural or functional abnormality identified. 20-40% may have peptic ulcer disease. 15-25% may have reflux esophagitis. The prevalence of H. pylori infection is high, increasing with age. Thus when a patient presents with dyspepsia, the physician is faced with a dilemma. The dilemma results from the availability of multiple diagnostic modalities, (some invasive, some not), the availability of effective therapies for dyspepsia, and the high prevalence of an infectious disease. A disease which causes "treatable disease" in only a segment of patients infected. The effectiveness of therapy chosen will depend on the "specific" disease present. Empiric therapy of dyspepsia is antacid, or H-2 blockade, now available without a prescription, or proton-pump inhibition. If peptic ulcer disease is present choosing the latter may influence the effectiveness of future treatment. If H-2 blockade is chosen, the likelihood of recurrence is high. Non-invasive tests do not distinguish the patient with peptic ulcer disease from the patient with H. pylori colonization. The dilemma gives rise to these questions:
Who should be treated empirically and for what?
What empiric treatment should be chosen?
Who should be endoscoped (or x-rayed) and when?
If treatment of H. pylori is given should the patient be tested to ensure eradication?
The answers to the above questions are a matter of active debate. "Cost-effectiveness" is invoked in trying to answer the questions above. Indeed economic analyses have been published with conflicting results. Knowledge that H. pylori exists will be only one element in each physician’s decision on how best to treat the patient.
As far as changing treatment H. pylori is beginning to have an impact. The current generation of physicians in training will leave formal training with an understanding of peptic ulcer disease different from their predecessors 10 years before. Informal surveys at gastroenterology meetings demonstrate an increased number of physician’s treating H. pylori in peptic ulcer disease. H. pylori’s discovery may have affected the surgical approach to peptic ulcer disease as well. As research on H. pylori was in progress, laparoscopic surgery was booming. Surgical literature discussed the role laparoscopic surgery would have in treating peptic ulcer disease. The impetus for undertaking procedures such as highly selective vagotomy was the fact that peptic ulcer disease so often recurred. Reducing recurrence reduces this impetus to move toward surgical therapy.
Clearly, H. pylori’s discovery has affected treatment to date. Further research may broaden or narrow the role treatment of H. pylori will play in the future.
I wish to thank Dr. Kevin High, Dr. Richard Weinberg, and Dr. Jim Geissinger for help in the preparation of this paper. I also wish to thank Dr. Matt Wood, Dr. Brent Geissinger, and Dr. Barbara Vanderwerken for their help and support. Lastly, thanks to Dr. David Humphrey for computer assistance.
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