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Interpreting the DRG Helicobacter Plus Profile (HPP)
Report
Bernadette M. Mandes Wildemore, MD
Medical and Laboratory Director
DRG Laboratory
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This test was developed and its performance characteristics determined by DRG Laboratory.
Diagnosis and treatment are the responsibility of the ordering physician.
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Helicobacter Plus Profile (HPP)
Performed on biopsy samples submitted to lab
Evaluates for molecular evidence of
Helicobacter pylori (H. pylori)
H. pylori virulence factor cagA
H. pylori virulence factor iceA
H. pylori virulence factor oipA
H. pylori virulence factor vacA
H. pylori clarithromycin susceptibility
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Interpreting the HPP report
Helicobacter pylori (H. pylori):
Result: Negative or Positive
This is a quantitative value that informs the clinician if the H.pylori bacterium is
(or has been) present
PLEASE NOTE: This value is only evidence that the bacterium has been present at some
point during the past few years. The molecular evidence of the organism may remain even
if the bacterium itself has been eradicated, either by the patient’s own immune system
OR by exogenous therapy (antibiotics or the like). It is NOT evidence of an active or
current infection
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Interpreting the HPP report
If the clinician chooses to use the HPP assay in isolation, the clinician must
work in concert with the laboratory for the best patient outcome
The clinician (gastroenterologist) MUST be vigilant to perform regular follow
up endoscopies to determine for the development of pre-neoplastic changes
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Endoscopic photos of H. pylori
Helicobacter pylori Helicobacter pylori
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Histologic photos of H. pylori
H & E stain (note PMNs) Warthin-Starry stain
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Interpreting the HPP report
H. pylori virulence factor cagA: Negative or positive
H. pylori virulence factor iceA: Negative or positive
H. pylori virulence factor oipA: Negative or positive
H. pylori virulence factor vacA: Negative or positive
If any of the above virulence factors are positive, this indicates that the patient is at increased
risk for the development of significant consequences of HP infection
Furthermore, note that virulence factors may be present, even in the absence of HP infection
Schmidt 2004
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What are the virulence factors?
Several factors have been implicated as virulence determinants of HP, and
associated with advanced GI disease
CagA protein (encoded by cagA gene): Found in 50-60% HP of Western patients
Induces inflammation via IL-8 secretion and NF-kB activation
Member of cag pathogenicity island CagA protein translocated in GI epithelial cells and
tyrosine phosphorylated induces growth factor like phenotypes in host cell
Ogura 2000
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What are the virulence factors, cont.?
Several factors have been implicated as virulence determinants of HP,
and associated with advanced GI disease
Ice protein (encoded by iceA gene)
The function of this gene is not yet fully elucidated
Currently thought to be upregulated when HP contacts GI epithelium
Strongly believed to be a marker for peptic ulcer disease (PUD)
Mousavi 2014
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What are the virulence factors, cont.?
Several factors have been implicated as virulence determinants of HP,
and associated with advanced GI disease
Oip A protein (encoded by oipA gene)
Upregulated when HP contacts GI epithelium
Induces IL-8 secretion
Associated with clinically significant presentation of PUD
Mousavi 2014
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What are the virulence factors, cont.?
Several factors have been implicated as virulence determinants of HP,
and associated with advanced GI disease
VacA protein (encoded by vacA gene)
Results in cytotoxic vacuolation
Vacuolation more frequently associated with severe gastritis and metaplasia
Ogura 2000
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Interpreting the HPP report
Virulence factors give additional information to the treating physician regarding the
potential for the development of gastric cancer (GC)
The development of GC involves the interplay among three important factors
The agent (generally, H. pylori) and its pathogenicity
Host (patient) characteristics
Environment
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Interpreting the HPP report
Regarding H. pylori, some studies show that eliminating the infection may reduce the
incidence of GC in patients without pre-neoplastic lesions
If pre-neoplastic lesions are present, elimination of the H. pylori infection may reduce the
incidence of GC
In patients with a previously resected gastric adenocarcinoma (GA), H. pylori eradication
may decrease the recurrence of metachronous GA
Roesler 2012
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Interpreting the HPP report
Again, if the practice chooses to use the HPP in isolation, alertness is even more
imperative on the part of the physician to perform regular endoscopies to carefully
evaluate for the endoscopic evidence of pre-neoplastic mucosal changes
Pre-neoplastic lesions examples
1. Gastric mucosal atrophy
2. Intestinal metaplasia
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Pre-neoplastic lesions by endoscopy
Gastric atrophy Intestinal metaplasia
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Interpreting the HPP report
Intestinal vs. diffuse adenocarcinoma GC types
Intestinal GC (well-differentiated) believed to be preceded by sequence of precursor lesions
Chronic inflammation of gastric mucosa (usually in older patients)
Atrophic gastritis
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Intestinal metaplasia
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Dysplasia
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Gastric cancer
Takenda 2007
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Interpreting the HPP report
Intestinal vs. diffuse GC types
Intestinal type GC (60-70%)
Older age, > incidence in males
Environmental causes
Discrete, defined tumor
H.pylori important
Roesler 2012
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Interpreting the HPP report
Intestinal vs. diffuse GC types
Diffuse GC (poorly-differentiated) (30-40%)
Associated issues include
Familial distribution, usually younger patients
Chronic inflammation of gastric mucosa (particularly in the cardia)
Mutation of CDH-1 (e-cadherin) gene
Downstream activation leads to further proliferation
Cancer formation
Roesler 2012
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Interpreting the HPP report
Virulence factors (VF)
The high level of genetic diversity may play a critical role in the
adaptation of the host gastric mucosa with VF
VF may also contribute to the ultimate clinical outcome of the patient
(although research is ongoing)
Nevertheless, the virulence factors have been associated with increased
virulence of the infecting organism
Pacheco (2008), Roesler (2011
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Interpreting the HPP report
Results suggest that HP eradication improves neutrophil
(polymorphonuclear cell, or PMN) infiltration and intestinal
metaplasia in the gastric mucosa inhibiting new, early stage gastric
carcinoma
Uemura 1997
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Interpreting the HPP report Research is ongoing; however
The risk of GA is related to severity and extent of atrophy, intestinal metaplasia, and
presence of dysplasia at original detection
Pre-neoplastic lesions regress at a rate equal to the square of time in patients rendered
free of H. pylori infection
Patients should be determined to be free of infection via a reliable method at regular time points –
for example, HPE should be performed at 3, 6, and 9 months following completion of therapy to
confirm eradication (For more information, please see presentation on HPE)
Roesler (2011)
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Interpreting the HPP report
H. pylori Clarithromycin resistance: Susceptible or resistant
This line gives information on the ability clarithromycin to effectively
target the detected HP, if present. Remember that the value is not
organism specific; rather, it is patient specific
Furthermore, a resistant value indicates that this antibiotic will likely
NOT work in THIS patient, and an alternative should be used to avoid the
development of additional resistance
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Summary
HPE* (or equivalent test) should be performed at
3, 6, and 9 months following completion of
therapy to confirm eradication
*HP Eradication assay (DRG’s HP stool antigen assay)
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Next steps
Please review additional DRG presentations to help elucidate the
choice among antibiotics and appropriate methods to determine
eradication
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References
Kabir S. (2009). Effect of Helicobacter pylori eradication on incidence of gastric cancer in human and animal models: underlying biochemical and molecular events. Helicobacter. 2009 Jun;14(3):159-71.
Kamada T. et. al. (2015) Time Trends in Helicobacter pylori Infection and Atrophic Gastritis Over 40 Years in Japan. Helicobacter. 2015 Jun;20(3):192-8. doi: 10.1111/hel.12193. Epub 2015 Jan 7.
Kamada T. (2005) Clinical features of gastric cancer discovered after successful eradication of Helicobacter pylori: results from a 9-year prospective follow-up study in Japan. Aliment Pharmacol Ther. 2005 May 1;21(9):1121-6.
Mousavi S, Dehkordi FS, Rahimi E. (2014) Virulence factors and antibiotic resistance of Helicobacter pylori isolated from raw milk and unpasteurized dairy products in Iran. J Venom Anim Toxins Incl Trop Dis. 2014 Dec 4;20:51. Ogura K, et al. (2000) Virulence Factors of Helicobacter pylori Responsible for Gastric Diseases in Mongolian Gerbil. J. Exp. Med. 2000 Dec;192(11):1601-1609.
Roesler BM, Costa SC, Zeitune JM. Eradication Treatment of Helicobacter pylori Infection: Its Importance and Possible Relationship in Preventing the Development of Gastric Cancer. ISRN Gastroenterol. 2012;2012:935410.
Schmidt H, Hensel M. (2004) Pathogenicity Islands in Bacterial Pathogenesis. Clin Microbiol Rev. 2004 Jan;17(1):14-56. Review. Erratum in: Clin Microbiol Rev. 2006 Jan;19(1):257.
Take S, et. al. (2011) The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori. J Gastroenterol. 2011 Mar;46(3):318-24.
Takenaka R et.al. (2007) Helicobacter pylori eradication reduced the incidence of gastric cancer, especially of the intestinal type. Digestion. 2006;74(3-4):206-7. Epub 2007 Mar 6.
Uemura N, et. al. (1997) Effcet of Helicobacter pylori Eradication on Subsequent Development of Cancer after Endoscopic Resection of Early Gastric Cancer. Cancer Epidemiology, Biomarkers & Prevention. Vol 6. 639-642, August 1997.
http://www.ncbi.nlm.nih.gov/pubmed/19702845
Interpreting the DRG �Helicobacter Plus Profile (HPP) ReportSlide Number 2Slide Number 3Helicobacter Plus Profile (HPP)Interpreting the HPP reportInterpreting the HPP reportEndoscopic photos of H. pyloriHistologic photos of H. pyloriInterpreting the HPP reportWhat are the virulence factors?What are the virulence factors, cont.?What are the virulence factors, cont.?What are the virulence factors, cont.?Interpreting the HPP reportInterpreting the HPP reportInterpreting the HPP reportPre-neoplastic lesions by endoscopyInterpreting the HPP reportInterpreting the HPP reportInterpreting the HPP reportInterpreting the HPP reportInterpreting the HPP reportInterpreting the HPP reportInterpreting the HPP reportSummaryNext stepsReferences