Tack­ling the germ be­hind stom­ach ul­cers and can­cer

Re­searchers in Ire­land are striv­ing to find a vac­cine for H.py­lori as re­sis­tance to an­tibi­otics in­creases

The Irish Times - Tuesday - Health - - Health Gastric Conditions - Ge­orge Win­ter

The his­to­rian Thomas Car­lyle (1795-1881) de­scribed his stom­ach as “that di­a­bol­i­cal ar­range­ment”, and un­doubt­edly harsh con­di­tions pre­vail in the tummy.

In fact, any­thing we swal­low – from a Miche­lin-starred truf­fle to a fish sup­per – gets taken apart by a gang of acids, en­zymes and bile salts, all ea­ger for a piece of the di­ges­tive ac­tion.

Such a hos­tile en­vi­ron­ment makes it im­pos­si­ble for bugs to sur­vive down there. At least, that was the ac­cepted wis­dom among med­i­cal sci­en­tists who con­sid­ered the stom­ach ul­cer as a stress-re­lated con­di­tion best treated with long-term med­i­ca­tion or surgery. But they were wrong. Al­though as­pirin and drugs used for the treat­ment of arthri­tis can cause stom­ach ul­cers and ul­cer com­pli­ca­tions, the bac­terium Heli­cobac­ter py­lori (H. py­lori) not only causes most stom­ach ul­cers but also has a cru­cial role in the de­vel­op­ment of gas­tric can­cer. The story of the or­gan­ism’s dis­cov­ery be­gins in Aus­tralia, but land­mark find­ings in Ire­land con­trib­uted greatly to the rapid progress in our un­der­stand­ing of its role in gas­tric dis­ease.

In 1979, Dr Robin War­ren, a pathol­o­gist at the Royal Perth Hospi­tal, Aus­tralia, was ex­am­in­ing a stom­ach biopsy sam­ple from a pa­tient with dys­pep­sia when he spot­ted spi­ral-shaped bac­te­ria. To in­ves­ti­gate its sig­nif­i­cance, War­ren was joined by Dr Barry Mar­shall, who in 1981 be­gan a six-month gas­troen­terol­ogy as­sign­ment.

War­ren and Mar­shall tried and failed sev­eral times to grow the or­gan­ism. Their fail­ure was partly due to faulty in­cu­ba­tors and to their habit of dis­card­ing agar plates af­ter two days if there was no vis­i­ble growth. So it was a stroke of luck that brought about a four-day Easter week­end in April 1982. This meant that a cul­ture was in­cu­bated for five days – long enough for vis­i­ble colonies to ap­pear.

Acid se­cre­tions

In 1983 War­ren and Mar­shall re­ported their find­ings in the Lancet jour­nal and sug­gested that not only might bac­te­ria cause stom­ach ul­cers, but also that pa­tients with ul­cers could be treated with an­tibi­otics. This of­fended both the med­i­cal es­tab­lish­ment and drug com­pa­nies: af­ter all, went their rea­son­ing, drugs treated ul­cers by re­duc­ing acid se­cre­tions into the stom­ach, and the drugs worked, so ul­cers must be caused by acid­ity. They too were wrong. It is thought that H.py­lori bur­rows into the stom­ach’s mu­cous layer where it is pro­tected from gas­tric acids. In some in­di­vid­u­als, a com­bi­na­tion of in­fec­tion and acid at­tack causes a lo­cal in­flam­ma­tion which can even­tu­ally lead to ul­cer­a­tion and pos­si­ble gas­tric can­cer.

De­ter­mined to prove that H.py­lori in­fec­tion causes gas­tri­tis, in July 1984 Mar­shall – him­self free of gas­tric dis­ease – drank a cul­ture of the bac­te­ria (don’t try this at home). A week later he had breath like a bear, he was vom­it­ing and a biopsy con­firmed he had an award-win­ning bout of gas­tri­tis, com­plete with spi­ral bac­te­ria.

By 2005, War­ren and Mar­shall had won the No­bel Prize in Phys­i­ol­ogy or Medicine for their dis­cov­ery that H.py­lori causes most stom­ach ul­cers.

But a ma­jor ad­vance was made by Ir­ish re­searchers. One of them, Prof Colm O’Mo­rain, pro­fes­sor of medicine at Trin­ity Col­lege, Dublin, is a world ex­pert on H.py­lori and a founder mem­ber of the Euro­pean Board of Gas­troen­terol­ogy. Prof O’Mo­rain told The Ir­ish Times: “My in­ter­est in H.py­lori dates back to its dis­cov­ery in 1982, and it stim­u­lated me to un­der­take a study on pep­tic ul­cer dis­ease as we had so many pa­tients with the con­di­tion.

“We were the first to show that erad­i­ca­tion of H.py­lori led to a cure of ul­cer dis­ease, find­ings that were pub­lished in the Lancet in 1987. One year later, War­ren and Mar­shall, whose No­bel Prize was well de­served, pub­lished a re­port which agreed with our find­ings.”

Gas­tric can­cer

In 1987, Prof O’Mo­rain helped found a H.py­lori study group to pro­mote re­search into the or­gan­ism and the group has drawn up guide­lines on who, how and when to treat. “Our lat­est ini­tia­tives,” ex­plained Prof O’Mo­rain, “are di­rected to its role in gas­tric can­cer. H.py­lori has been de­scribed as a class 2 car­cino­gen by the World Health Or­gan­i­sa­tion.”

Be­tween 1983 and the early 1990s a shift in med­i­cal think­ing on the cause of stom­ach ul­cers oc­curred. This cul­mi­nated in 1994 at a con­fer­ence in Wash­ing­ton DC con­vened by the United States Na­tional In­sti­tutes of Health (NIH). Its pur­pose was to ex­am­ine the claim that pep­tic ul­cers are caused by H.py­lori. Most of the 22 re­searchers, in­clud­ing Prof O’Mo­rain, who made pre­sen­ta­tions to the panel, sup­ported the claim. On Fe­bru­ary 9th, 1994 the NIH panel con­cluded that ul­cer pa­tients with H.py­lori in­fec­tion should be treated with an­timi­cro­bial agents.

How­ever, we are now liv­ing in the age of an­timi­cro­bial re­sis­tance (AMR), and an in­crease in the preva­lence of an­tibi­otic-re­sis­tant bac­te­ria has con­trib­uted to a fall in Ir­ish erad­i­ca­tion rates for H.py­lori. This prompted Prof Deirdre McNa­mara and col­leagues at Tal­laght Hospi­tal and Trin­ity Col­lege Dublin to ques­tion cur­rent man­age­ment strate­gies and to as­sess, re­vise and tai­lor cur­rent avail­able rec­om­men­da­tions for adult pa­tients.

On June 22nd, 2016, ex­perts from Ire­land and Europe con­vened in Dublin,

where the Ir­ish Heli­cobac­ter py­lori Work­ing Group (IHPWG) was es­tab­lished.

This year, the IHPWG pub­lished 15 state­ments and rec­om­men­da­tions in the Euro­pean Jour­nal of Gas­troen­terol­ogy & Hepa­tol­ogy. Its re­port in­cludes the rec­om­men­da­tion that all pa­tients with symp­toms re­lated to the up­per gas­troin­testi­nal tract should be tested for H. py­lori since erad­i­ca­tion of the or­gan­ism “pro­vides a long-term cure for both duo­de­nal and gas­tric ul­cers in the ma­jor­ity of pa­tients whose ul­cers are not associated with non-steroidal anti-in­flam­ma­tory drugs”.

The IHPWG also rec­om­mended that fol­low­ing com­ple­tion of any ther­apy for H. py­lori a con­fir­ma­tory urea breath test (UBT) should be per­formed be­cause “erad­i­ca­tion rates for H. py­lori are de­creas­ing and symp­toms are not a good in­di­ca­tor of treat­ment suc­cess”.

Typ­i­cally, the treat­ment of H.py­lori in­fec­tion has in­volved triple ther­apy with two an­tibi­otics such as clar­ithromycin, metron­ida­zole and/or amox­i­cillin in com­bi­na­tion with a drug called a pro­ton pump in­hibitor (to re­duce the amount of acid in the stom­ach). How­ever, the IHPWG states that the “stan­dard triple ther­apy for a du­ra­tion of seven days can no longer be rec­om­mended”, cit­ing a re­cent Ir­ish study by Prof Sinead Smith re­port­ing an erad­i­ca­tion rate for clar­ithromycin-based triple ther­apy of only 57 per cent. With Euro­pean guide­lines stat­ing that erad­i­ca­tion rates less than 80 per cent are un­ac­cept­able, the IHPWG now rec­om­mends a 14-day clar­ithromycin-based triple ther­apy with a high-dose pro­ton pump in­hibitor.

Fu­ture prospects

As far as fu­ture prospects are con­cerned, the man­age­ment and treat­ment of H.py­lori in the age of AMR means that an­tibi­otic ther­a­pies which are ef­fec­tive to­day may not be ef­fec­tive to­mor­row be­cause of the de­vel­op­ment of an­tibi­otic re­sis­tance.

It re­mains to be seen whether a vac­cine can be suc­cess­fully de­vel­oped – so far it hasn’t – and if it can be, could it be af­forded in de­vel­op­ing coun­tries?

Fi­nally, eth­i­cal is­sues re­main. For ex­am­ple, should there be univer­sal screen­ing for H.py­lori, which, af­ter all, causes stom­ach ul­cers and is im­pli­cated in gas­tric can­cer?

In­ves­ti­ga­tion of H.py­lori con­tin­ues world­wide, with Ir­ish re­searchers mak­ing sub­stan­tial con­tri­bu­tions to the grow­ing ev­i­dence base.

And the IHPWG has launched an app called “H.py­lori Care”, which is de­signed to en­hance ac­cess to clin­i­cal guide­lines and pro­vide in­for­ma­tion to both clin­i­cians and pa­tients.

De­ter­mined to prove that H.py­lori in­fec­tion causes gas­tri­tis, in July 1984 Mar­shall drank a cul­ture of the bac­te­ria

PHO­TO­GRAPH: GETTY

Heli­cobac­ter py­lori: It is thought the bac­te­ria bur­row into stom­achs’ mu­cous layer where they are pro­tected from gas­tric acids.

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