Interpreting the DRG Helicobacter Plus Profile (HPP) Report · Interpreting the HPP report Again,...

Interpreting the DRG Helicobacter Plus Profile (HPP)

Report

Bernadette M. Mandes Wildemore, MD

Medical and Laboratory Director

DRG Laboratory

This test was developed and its performance characteristics determined by DRG Laboratory.

Diagnosis and treatment are the responsibility of the ordering physician.

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

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


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

Endoscopic photos of H. pylori

Helicobacter pylori Helicobacter pylori

Histologic photos of H. pylori

H & E stain (note PMNs) Warthin-Starry stain


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

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

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




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




VacA protein (encoded by vacA gene)

Results in cytotoxic vacuolation

Vacuolation more frequently associated with severe gastritis and metaplasia

Ogura 2000


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


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


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

Pre-neoplastic lesions by endoscopy

Gastric atrophy Intestinal metaplasia


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

↓

Intestinal metaplasia

↓

Dysplasia

↓

Gastric cancer

Takenda 2007


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


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


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


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

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)


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

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)

Next steps

Please review additional DRG presentations to help elucidate the

choice among antibiotics and appropriate methods to determine

eradication

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

Interpreting the DRG Helicobacter Plus Profile (HPP) Report · Interpreting the HPP report Again,...

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