H Pylori, colorectal cancer, and ??general screening

 A recent large-scale analysis found that H Pylori infections may be associated with colorectal cancer (See hpylori and colon cancer gastro2018 in dropbox or doi.org/10.1053/j.gastro.2018.09.054 

Details:

--4063 incident cases of colorectal cancer (CRC) were compared with 4063 matched controls without CRC, from 10 prospective cohort studies of very diverse populations: Southern Community Cohort Study (low-income white and African-Americans), Multiethnic Cohort Study (Hawaiian, Japanese and those of European ancestry in Hawaii, and people of African and Latino ancestry in Los Angeles), Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, New York University Women's Health Study, Women's Health Initiative, Campaign Against Cancer and Stroke (suburban Maryland), Cancer Prevention Study-II of the Am Cancer Society, and the PLCO study

--information was available for antibody responses to 13 H Pylori proteins, including virulence factors VacA and CagA

--confounders assessed in their analysis included: age, sex, race, education level, BMI, family history of CRC, previous colonoscopy/sigmoidoscopy, hormone therapy, daily intake of fruit/veges/red meat, aspirin use and diabetes

Results:

--40% of controls and 41% of cases were H Pylori sero-positive

--though there were different demographics in the different studies, overall CRC cases were more likely to be obese, diabetic, former smokers, have a positive family history of CRC, eat more red meat

--association of H Pylori and CRC overall:

    --white patients: no association, OR: 1.06 (0.95-1.18)

    --Latinos: no association, OR: 0.84 (0.55-1.30)

    --Asian Americans: trend to association, OR: 1.30 (0.94-1.81)

    --African Americans: trend to association, OR: 1.30 (0.97-1.76)

--H Pylori VacA-specific sero-positivity was associated with an 11% increased odds of CRC, OR 1.11 (1.01–1.22)

    --African Americans had a 45% increased odds, OR 1.45 (1.08–1.95)

    --no clear association with Asian Americans, whites, or Latinos

--odds of CRC increased with level of VacA antibody in the overall cohort (P=.008): those in the fourth quartile of antibody response to VacA were at a 25% greater odds of developing CRC, OR: 1.25 (1.07-1.47)

    --African Americans odds of CRC also increased with VacA antibody titers (P=.007): those in the fourth quartile of antibody response to VacA were at a 70% greater odds of developing CRC, OR: 1.70 (1.12-2.58) 

    --Asian Americans in the fourth quartile had an 86% greater odds, OR: 1.86 (1.06-3.25)

Commentary:

--H Pylori is the most common bacterial infection in the world, infecting 50-60% of the population

--current estimates are that 15% of all incident cancers are caused by an infection.  And, H Pylori is the leading infectious carcinogen, associated with 770,000 gastric cancer cases worldwide.

--H Pylori prevalence is mostly in East Asia, Africa, parts of South and Central America; lower rates in US, Oceania, and Western Europe

--H Pylori is also pretty prevalent in the US: the third National Health and Nutritional Examination Survey (1988-91) of 7465 adults found: overall 32.5% seropositivity, with increases by age (16.7% 20-29 yo, up to 56.9% of >70yo), and by ethnicity/race (52.7% of non-Hispanic blacks, 61.6% of Mexican Americans, 26.2% non-Hispanic whites. see https://academic.oup.com/jid/article/181/4/1359/856832 ]

    --it is also pretty striking that 40% of both the cases and controls in the above amalgam of studies for CRC were H Pylori positive

    --and from these 10 cohort studies, H Pylori positivity was 34% in whites, 43% Asian-Americans, 68% in African-Americans, 75% in Latinos

--the epidemiology of H Pylori is unclear. Likely fecal/oral or oral/oral transmission. And reinfection seems to be quite uncommon (?related to immunologic memory, or decreased exposure with aging??). but the finding in the US of increasing H pylori with age may suggest that younger people are less exposed to it than the older generation.

--the presumed mechanism for gastric cancer is chronic inflammation (but notably lots of H Pylori infections are asymptomatic). And studies still suggest both increased risk of gastric cancer and decreased risk after therapy, even in asymptomatic people. See http://gmodestmedblogs.blogspot.com/2019/04/h-pylori-eradication-and-reduced-risk.html  )

--not sure why there is an increase in colorectal cancer, though this has been found in prior studies/meta-analyses, on the order of 30-50% increase; there have also been reports of patients having documented H Pylori on gastric biopsy having more colorectal adenomas and polyps on simultaneous colonoscopy (on the order of 50% increase)

--one issue is that there are different strains of H Pylori, some more virulent than others (eg CagA, an oncogenic effector protein, as well  as Vacuolating cytotoxin A or VacA). Given that only a very small portion of the 50% of the world’s infected population get gastric cancer, it is important to consider bacteria-specific virulence factors to assess their role in order to risk-stratify patients (these tests of potential virulence factors are not generally available)

    --VacA is a known gastric cancer virulence factor; one difference between CagA and VacA is that the former needs to have direct contact with the host cells, whereas VacA may have effects beyond the gastric mucosa (and potentially explaining the higher CRC risk).

    --another possible mechanism is H Pylori-induced gastric microbiome changes, leading to intestinal microbiome changes

--this same research group in the above study has found that in the southeast US, there was a very high prevalence of H Pylori, and a much higher prevalence of both VacA and CagA in African-Americans; those with Vac A had an 84% increased CRC risk, and a strong dose-response association of VacA antibody titers and CRC

--limitations of this study include: no data on antibiotic use (see http://gmodestmedblogs.blogspot.com/2017/04/antibiotics-microbiome-changes-and.html  , for a study finding that antibiotic-induced microbiome changes are associated with adenomas), no data on whether the patients had symptomatic gastritis, or inflammatory bowel disease. Also, the data were from blood serology, which remains positive even after the infection is cured or no longer present. They also only adjusted for the potential confounders of socio-economic status (only by education), BMI and smoking status

so, this study refines our understanding of H Pylori and CRC: it seems that H Pylori infection itself is not so related to CRC, but those with VacA and a few other proteins have a much higher risk, on the order of 60-80%. This brings up a few issues:

--perhaps we should be testing for and treating H Pylori infections regularly:

    --one interesting thought is that African-Americans do seem to get CRC younger than white patients, with some medical societies suggesting that screening should start at a younger age (see new guidelines: http://gmodestmedblogs.blogspot.com/2018/04/2-new-colorectal-cancer-screening.html ). The above finding of higher rates of potentially H Pylori-associated CRC in African-Americans (who seem to have the VacA protein more frequently) may explain some of this. And perhaps screening for, finding and treating H Pylori might lower their risk....

    --my experience in our health center with patients coming from endemic H Pylori countries is that it is not worth checking sero-positivity (it is so high) but i routinely check H Pylori stool antigen, even in asymptomatic patients. And treat them.

    --there are pretty good data that such treatment lowers the risk of gastric cancer (see http://gmodestmedblogs.blogspot.com/2019/04/h-pylori-eradication-and-reduced-risk.html  ). And that the major H Pylori-associated cancer mortality is from gastric cancer (which seems to be associated with CagA), so it is not just the CRCs with VacA

So, seems reasonable to me to look into a strategy of testing and treating all comers for H Pylori, and getting a better handle on the modes of transmission in order to prevent new infections….

geoff

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