1
Q
What is the most common cause of gastric and duodenal ulcers?
A
Helicobacter pylori (Hp) is the most common cause
2
Q
List some causes of peptic ulcer disease
A
- Helicobacter pylori
- NSAIDs
- The rest:
- Cancer especially if of a certain age
- Other drugs
- Zollinger-Ellison syndrome (Gastrinoma)
3
Q
describe the epidemiology of PUD
A
- The incidence and prevalence of PUD varies depending on the presence of H. pylori in the community
- The incidence of PU in infected individuals is 1% per year.
- Endoscopic point prevalence of PU in ASYMPTOMATIC subjects is 1-2%.
- PUs becoming less common over time because of falling rates of Hp infection
- But NSAID-induced ulcers are becoming more common.
4
Q
Describe clincial manifestiations,c omplications and Dx
A
- Symptoms:
- Asymptomatic in ~70%, especially the elderly. Fluctuates. Is acid level dependent. Peaks 15-20m after meals. Can wake at night. Damage related to exposed mucosa to acid
- Epigastric (foregut) pain
- Complications:
- Gastrointestinal bleeding (ulceration into vessel)
- Perforation
- Penetration i.e. going retroperitoneally
- Obstruction due to fibrosis
- [Cancer]
- Diagnosis:
- Test (for Hp) and treat (– whether or not on NSAIDs)
- Upper GI endoscopy and biopsy
5
Q
Describe the prevalene of Hp
A
- Over 50% of people worldwide are colonized by Hp
- Around 70%
- Africa
- South America
- Western Asia
- Around 30-40%
- Northern America
- Western Europe
- Around 20-25%
- Oceania, including Australia
H. PYLORI PREVALENCE
- Hp is present in 50-95% of duodenal ulcers and 65-95% of gastric ulcers
- Hp also found in:
- 20-45% asymptomatic
- 20-60 % dyspepsia
- 70-90% gastric cancer
- Gastric MALT lymphoma (mucosa-associated lymphoid tissue)
- Eradication of Hp is effective treatment in 70–95% of cases
- Gastric MALT lymphoma (mucosa-associated lymphoid tissue)
6
Q
List eh outcomes of Hp colonisation
A
- 10-20% develop ulcers
- <2-5% cancer - considered type I carcinogen by WHO
7
Q
Describe how colonisation occurs(transmission and extra effects)
A
- Mode of Transmission – unknown but probably oral-oral or fecal-oral routes
- Initial colonization likely occurs in childhood in developing countries, adulthood in developed countries
- Rapid bacterial growth and increased acid secretion:
- Acute infection leads to a short period of hypochlorhydria (hydrochloric acid in gastric secretions is low)
- Chronic infection leads to increases in basal and stimulated acid output
- Increased release of gastrin (G cells), subsequent decrease in somatostatin (inhibits acid secretion)
8
Q
WHY DO ONLY 10-20 % OF THOSE INFECTED DEVELOP ULCERS?
A
- cagA (cytotoxin-associated gene A), a 128-140 kDa protein that is co-expressed with;
- VacA (vacuolating cytotoxin) that causes cell injury
- 85-100% of patients with DU have cagA+ strains, compared to 30-60% of infected patients who do not develop ulcers
- Host genetic factors (sensitivity to gastrin, higher parietal cell mass – cells that secrete HCl)
- Environmental factors: smoking (73 vs 27%), NSAID use (61 times more likely if colonized by Hp), alcohol usage
9
Q
Explain how Hp survives in the stomach
A
- Hp use urea present in gastric juice
- Urease enzyme produced by every strain to combat the acidic environment of the stomach by producing ammonia
- Breaks down urea into NH3,which neutralises acid, and CO2
- Cytosolic urease can constitute up to 10% of bacterial protein
- Basis of the urease breath test
- 2-6 sheathed unipolar flagellae for motility through the mucus layer
- Chemotaxis: sensors will be on the lookout for bicarbonate or neutral compounds
- Lipopolysaccharide (LPS) and outer membrane proteins for adherence to host cells
- vacA (exotoxin) and secretory enzymes (mucinase, lipase, protease) cause gastric mucosal injury (Acute and chronic inflammation)
- Type IV secretion system for injecting effectors
- cagA (effector) causes actin remodeling, IL-8 induction, inhibits apoptosis and T-cell activation and proliferation
HP TYPE IV SECRETION SYSTEM AND CAGA
- cagA encoded on a pathogenicity-associated island (PAI)- e.g. antibiotic resistance genes
- More commonly associated with symptomatic disease and cancer
- PAIs, in general:
- Encode genes involved in virulence
- Large segments of DNA encode numerous genes
- Acquired through horizontal gene transfer
- A pathogenic strain may have more than one PAI
10
Q
List the diagnostic tests available and broadly describe how they work
A
- Urease breath test – detection of C14 labelled urea
- Endoscopy and biopsy – histology or CLO test - to check out complications or confirm healing
- Blood test – antibody test
- Stool antigen test
11
Q
List hte disadvantages of the diagnsotic test
A
- Urease breath test:
- False-negative results possible in the presence of PPIs and recent antibiotic or bismuth compound use. Less sensitive than biopsy test. Considerable resources and personnel required to carry out test. Not widely available.
- CLO test (biopsy test):
- Invasive ie needs endoscopy. Expensive.
- Antibody test:
- Cannot confirm whether it is a past or present infection. Not recommended for confirming eradication.
- Stool test:
- False-negative results possible in the presence of PPIs and recent antibiotic or bismuth compound use. Stool collection may be considered distasteful to the patient.
12
Q
List the advantages og the diagnostic tests
A
- Urease breath test:
- Provides rapid results (when available). Excellent specificity and very good sensitivity.
- CLO test (biopsy):
- Allows culture and therefore determination of antibiotic resistance profiles. -
- Blood antibody test:
- Inexpensive, widely available, very good NPV.
- Stool test:
- Identifies active Hp infection. Excellent PPV and NPV regardless of Hp prevalence. Useful before and after therapy.
13
Q
List the conditions for confiratory tests for Hp eradication
A
In patients treated for Hp, eradication of infection should be confirmed four or more weeks after the completion of therapy.
- PPIs should be withheld for one to two weeks prior to repeat testing to reduce false-negative results.
- Serologic testing should not be performed to confirm eradication as patients will continue to have antibodies after eradication.
14
Q
Describe PUD therapy
A
- Triple therapy, most commonly used in Australia, involves:
- Proton pump inhibitor (PPI) with
- Two antibiotics:
- Most commonly used – clarithromycin and amoxicillin
- Also – metronidazole, tinidazole, tetracycline, azithromycin, levofloxacin
- Quadruple therapy may also be used – includes bismuth compound
15
Q
Describe how to choose antibiotics
A
- Choose two antibiotics with different modes of action:
- Amoxicillin - for peptidoglycan;
- Tetracycline
- Clarithromycin
- Azithromycin
- for the ribosomes
16
Q
Describe the disease outcomes
A
- 60% heal spontaneously but with Hp eradication rates are >90%
- 5 -10% of ulcers are refractory to PPI therapy.
- The risk of complications is 2-3% per year.
- Even with continued PPI use, 5 – 30% recur within 12 months based on whether Hp has been successfully eradicated.
- Recurrent ulcers are usually due to Hp infection or NSAID usage.
17
Q
Do PPIs cause death?
A
- associated but not causative
- 60% and 40% of nursing home and hospital patients, respectively, are treated with PPIs for stress ulcer prevention
- 30% of dialysis patients take PPIs for peptic symptoms and the prevention of GI bleeding. Dialysis itself carries a 50%, 3-year mortality rate.
- Patients taking anticoagulants or antiplatelet medications receive PPIs for upper GI protection, as do up to 80% of liver cirrhosis patients.
- Conditions with high lethality are associated with the use of PPIs to prevent upper GI bleeding. This can lead to blaming the treatment instead of the underlying condition for the death — reverse “causality.”
GIT Mol Sci
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