Interview with Paulo Fidalgo

Up until the discovery of the bacteria Helicobacter pylori, in 1982, diseases of the stomach were thought to be due to excess gastric acidity. Today, we know that the vast majority of stomach cancers are caused by a sustained infection by Helicobacter, and that eradicating it is enough to drastically reduce stomach cancer risk. However, it is less known that, even after the bacteria’s eradication, unhealthy diets can promote the development of gastric cancers. And what almost nobody knows is that one of the main risk factors for stomach cancer is… salt. Among your good resolutions for the New Year, you might consider drastically reducing your salt intake.

Portugal is the Western European country with the highest mortality rate from stomach cancer, together with a high prevalence of Helicobacter pylori – the bacteria that gives rise to the overwhelming majority of gastric cancers. But according to Paulo Fidalgo, gastroenterologist at the Digestive Unit of the Champalimaud Clinical Centre (CCC) and head of the Risk Assessment and Early Diagnosis Programme of the CCC, it is already possible to prevent the by far most frequent stomach cancer (representing 90 to 95% of all cases), called, intestinal type adenocarcinoma. This cancer arises from pre-cancerous lesions, called intestinal metaplasia, which in turn are caused by Helicobacter and can evolve into gastric cancer under the effect of prolonged infection by the bacteria.

For this 66-year-old doctor, with extensive experience of oncologic risk assessment from his time at the IPO (Portuguese Institute of Oncology), it would be advisable for every person, when they do their first colonoscopy for colon cancer screening, to also submit to a high resolution endoscopy (still not accessible to the general population). That would allow for the detection, in one go, of infection by Helicobacter and the presence of intestinal metaplasia. From there, those who have neither, would essentially not have to worry about stomach cancer ever again. Those with metaplasia, on the other hand, could, once the bacteria was eradicated from their organism, be periodically monitored by doing additional endoscopies – and surgically treated if ever their metaplasia were to present signs of progression. “That’s my job, I’m always on the hunt for metaplasia,” Paulo Fidalgo explained during this conversation.

You are interested in the relationship between dietary habits and the emergence of so-called intestinal metaplasia in the stomach. What is intestinal metaplasia?

In certain conditions, areas develop on the gastric wall, in which normal stomach cells are replaced by cells that, under the microscope, look rather like intestinal cells. It is that phenomenon that we call intestinal metaplasia of the stomach. “Metaplasia” means “out of place.”

This is not due to the migration of intestinal cells to the stomach, but to the stomach cells themselves transforming, changing into something that under the microscope looks more like an intestinal cell.

Why does this happen?

It is a defence mechanism mounted by the stomach wall to the continued presence of Helicobacter pylori bacteria. Helicobacter is a potent irritant of the gastric mucosa, and the mucosa, to protect itself, turns into intestinal metaplasia. The bacteria, being averse to this environment, flees to other sites of the stomach that are free of intestinal metaplasia.

It was the Australian physician Barry Marshall (together with the Australian pathologist Robin Warren) who discovered the bacteria, isolated it and demonstrated its pathogenicity – for this, they jointly received the Nobel Prize in Medicine. Up to that time, the whole theory of gastric disease was built on hyperacidity. Since the 1920’s, 1930’s, there existed a powerful industry of antacids around this big narrative construction of stomach acidity. When Marshall put it into doubt, there was a certain resistance from experts – we could even call it bullying – towards the new bacteria.

Intestinal metaplasia arises from infection with Helicobacter

But nowadays, no one denies that, in the vast majority of cases, stomach cells transform into intestinal metaplasia due to the presence of Helicobacter pylori.

Although there are also a few other rare syndromes that give rise to intestinal metaplasia, we can say that 99% of metaplasia observed today in stomach diseases result from an infection with Helicobacter – which can still be present or was present at some point and left intestinal metaplasia behind. The intestinal metaplasia cell is very robust. So much so that, although we can eradicate the bacteria, we are unable to make the intestinal metaplasia regress. The cellular transformation is irreversible.

What are the consequences of having metaplasia?

It depends. If we eliminate the bacteria, the process slows down and can even stabilise. So one of the questions that determines cancer risk is whether the bacteria is still present or not. Today, in our clinical practice, when we see intestinal metaplasia in a patient still infected by the bacteria, we proceed to its eradication. The bacteria is detected through a respiratory test that entails blowing into a balloon; this exhaled air test is very reliable for detecting Helicobacter. 

Most patients with intestinal metaplasia will never develop an evolved disease. But we are more and more convinced that the most frequent variant of stomach cancer – intestinal type adenocarcinoma – cannot arise in the stomach without being preceded by intestinal metaplasia. That means there is a clear causal link between having intestinal metaplasia and the risk of developing adenocarcinoma. The real cumulative lifetime risk of intestinal metaplasia becoming cancer is very modest: 2% per year in a lifetime. This means that, out of 40 people with intestinal metaplasia, after 20 years of follow-up, two or three of them will have needed a more evolved treatment of their metaplasia.

The risk is a modest one, and it is very much under the influence of a particular factor: the extension of the metaplasia. Luckily, the great majority of people have very limited and not very extended forms of metaplasia. Only a small number of people have metaplasia at various locations in their stomach, which is a multifocal extended form of the lesion. Those are the ones who have the most significant risk and need to be monitored.

Is metaplasia extension caused by infection levels by Helicobacter pylori or genetic factors?

Both. It is clearly known that there are stomach cancers that run in families. We often attribute this to the fact that all affected family members share the same bacteria, but in truth we have to admit – and this has not been studied – that there is a series of adverse factors in the hosts themselves that influence the type of response the host mounts in the presence of the bacteria, and that can increase cancer risk.

What percentage of the Portuguese population has intestinal metaplasia?

That data does not exist. I don’t know. What I can say is that in order to have a good inventory of the situation we would have to perform high resolution endoscopies, because only state-of-the-art endoscopes are equipped with a device that uses light to detect the areas of the stomach with metaplasia. Before this technique came into use, biopsies were performed at random and you could either “hit” a site with metaplasia or not. With these new techniques, I would say that, out of a week of endoscopies, 10 to 15% of my patients have intestinal metaplasia, but this hasn’t been studied yet.

Does this mean that the percentage is likely to be higher in the general population? 

Yes. But the metaplasia that matter, which are the high-risk metaplasia – whether multifocal or extended – are much less frequent. In a week, out of 25-30 endoscopies, I catch one or two patients with more serious metaplasia. It’s not a very prevalent disease and it can be monitored.

Do metaplasia cause symptoms?

No. Normally, the symptoms that make people consult a doctor are coincidental. Metaplasia is the incidental result of an exam performed because there are symptoms of reflux, of dyspepsia, or because the esophagogastric valve doesn’t close completely. Intestinal metaplasia is never the cause of the digestive complaints attributed to it. It is a silent disease that can only be detected by stomach biopsies.

Metaplasia are precancerous lesions?

They are. Precancerous meaning that they are benign, but that there is a certain risk that they will progress to cancer.

When detected, do metaplasia have to be treated?

Not necessarily. Our practical attitude towards intestinal metaplasia is contemplative. We don’t do anything, we don’t intervene; we watch. We know that the development process of stomach cancer goes through several steps, like a ladder. First, the stomach is normal, then it has gastritis, then atrophy, intestinal metaplasia, dysplasia [the presence of abnormal cells] – and finally cancer.

Given that many times metaplasia doesn’t progress, what we do, in persons at risk, is to just monitor the intestinal metaplasia, searching for signs of progression to dysplasia. Today, as I already mentioned, it is already possible to perform endoscopies that, thanks to new methods of digital coloration, allow us not only to detect metaplasia by highlighting their colour, but also the signs of progression, which make the transformation into cancer more imminent. It is when we detect dysplasia that we offer treatment to the patient, which consists of an endoscopic resection of the area where the mucosa is altered. After this intervention, the gastric wall regrows normally and the tendency to progression is cancelled. 

I want to insist again on the fact that the main driving force to climb the “ladder” to cancer is the continued presence of Helicobacter pylori. Once the bacteria is eradicated, all that impulse decelerates. 

“Stomach cancer is a disease of the poor”

What is the proportion of the Portuguese population infected with the bacteria?

The infection by Helicobacter is a disease of bad sanitary, living and social conditions. To simplify, we can say that stomach cancer is a disease of the poor. In the 1990’s, I was the first to measure the number of Helicobacter carriers among the healthy population in Portugal. In that study, we concluded that 70% of Portuguese people were infected by the bacteria. In Sweden, for instance, or in the countries of Northern Europe, 20 to 30% of the population was infected. Now, the rate of infection in Portugal is no longer 70% [according to published data, the rate was close to 50% in 2016. 

With time, stomach cancer declined in the United States and in Northern Europe because people had refrigerators and access to tap water – and by virtue of these developments, less Helicobacter. [In Portugal, the mortality due to stomach cancer only started to decrease in the early 1970’s.]

When the bacteria is eradicated in a person with intestinal metaplasia, does this cancel the risk of stomach cancer?

No. Helicobacter is not the only determinant of intestinal metaplasia’s progression to cancer. There are also other, “softer” variables, which can still make intestinal metaplasia progress to cancer. Let’s say their impulse is not as strong, but they exist.

Can the formation and progression of intestinal metaplasia be influenced by dietary habits?

Yes.

And what can we do, in terms of diet, to prevent this?

We can decrease the so-called “oncologic stress” of our diet. Oncologic stress is defined as the diet that is correlated with the highest cancer incidence: specifically, a diet of the “western stress diet” type, an expression coined by a mentor of mine, American gastroenterologist Harold Newmark (it’s a diet basically consisting of McDonald’s and the like). There is a lot of experimental evidence in animal studies that show the promoter effect of this type of diet in the formation and growth of tumours.

Less than 5% of Portuguese may have an inadequate diet in terms of cancer prevention

Do some types of diet reduce oncologic stress?

The most likely candidate to become the best option to reduce oncologic stress is the mediterranean diet. Evidence about the benefits of this diet is still fragmented, results are not yet very robust, but nobody is showing any evidence to the contrary.

That is why we systematically recommend a mediterranean-type diet to people who consult us. And we also recommend, specifically concerning stomach cancer, that they avoid ingesting excessive amounts of salt – there is a series of arguments in favour of the idea that a high intake of salt promotes the progression of intestinal metaplasia. People should also not be constantly consuming processed meats, which are rich in nitrates, since these compounds also favour tumour growth and progression in the stomach.

What we do first is to try to find out how distant from or close to the mediterranean model diet a given patient’s diet is at the start. For this, we use Predimed – a scale with 14 points, where a score of over 10 points is good in dietary terms and a score below 10 points means that the person is far from having adequate eating habits in terms of cancer prevention. I must say that the percentage of people with good Predimed scores on the first interview (performed by our early assessment of oncologic risk team) is less than 5%.

What is the most toxic food ingredient in terms of gastric oncology?

From the gastric oncology perspective, I would say salt is the single most toxic dietary ingredient.

But no one is aware of that!

[Laughs] Jozef Joossens, a Belgian physician, made a fundamental discovery in the 1960’s. He observed that two villages in Belgium had high numbers of strokes. He was curious about this and went there to see what was going on. And he realised that the people who lived in those two villages all had high blood pressure, because they all ate a lot of salt.

Those same two villages also had high numbers of stomach cancer. So Joossens hypothesised that the same reason explained the high numbers of stroke and stomach cancer: high intake of salt. And guess where he traveled to prove his theory in the field? To Portugal, because exactly the same phenomenon happens in Portugal. We have lots of cases of stroke and lots of cases of stomach cancer. That was where the theory of excessive exposure to salt, as a factor of formation and progression of pre-malignant stomach lesions, was born.

All this to say that if we want to intervene in the diet in order to prevent stomach cancer, we should have salt reduction campaigns.

Who knows about the gastric microbiome?

You are also interested in the link between stomach cancer and the so-called “gastric microbiome”. We hear a lot about the intestinal microbiome, but there is also a gastric microbiome?

The reason for which the study of the gastric microbiome is just beginning is that, until a few years ago – actually until the discovery of Helicobacter pylori – we didn’t even believe that any bacteria could survive in an environment of chlorhydric acid, which is the acid produced by the stomach. It didn’t make sense in our heads that life could exist in a pool of chlorhydric acid. But not only does such bacterial life exist, there are even bacteria for which acidity is advantageous, such as Helicobacter. The gastric microbiome is different from the gut microbiome, but it is pretty diverse. We know today that there are many bacteria in the stomach.

Recently, our team has started to try to study the gastric microbiome. We think that there is indirect evidence that people with intestinal metaplasia have a profoundly altered gastric microbiome compared to people who do not have intestinal metaplasia.

How do you explain that?

Intestinal metaplasia is associated with a reduction of stomach acidity, which is a determinant factor of the type of microbiome that exists in the stomach. And it could be that, in carriers of intestinal metaplasia, this acidity decrease leads to substantial changes of the microbiome.

An example of the issues that arise from this concerns the fact that we currently use many drugs that inhibit acid secretion in the stomach in order to manage reflux, such as omeprazole. Omeprazole virtually shuts down acid secretion in the stomach. And what we don’t know is whether, after a certain time of treatment with omeprazole, this may or may not entail detrimental modifications of the gastric microbiome.

There is a study from Hong Kong, which was published in the journal Gut three or four years ago, which suggests that people who use omeprazole for many years can see their intestinal metaplasia progress even after the eradication of Helicobacter.

This could indicate that the ecological environment created inside the gastric cavity by the intake of these drugs acts, in a certain way, as a promoter of intestinal metaplasia progression.

So on the one hand, we want to really understand whether there is an interaction between the gastric microbiome and intestinal metaplasia progression, in order to determine if certain actions we are taking to treat stomach diseases could reveal themselves as detrimental, in the long run, because they alter that microbiome. Our other aim is to use the microbiome as a marker of what is going on in the stomach.

I know that all this is scarcely proven and not robust enough. But when I see a person with extended intestinal metaplasia, and that person needs drugs like omeprazole because he or she complains of reflux, I try to dissuade that person from systematically taking omeprazole. I encourage him or her to periodically pause the medication or to try to live with drugs that do not so drastically inhibit acidity (namely, the drugs that were used before the invention of omeprazole, some which are still on the market).

Do you think that we should all submit to state-of-the-art endoscopies?

I’m one of those people in favour of the idea that all Portuguese people – all people – should be screened for colon cancer, preferably through colonoscopy. And that they should seize the opportunity, when they have their first colonoscopy, to profit from the sedation needed for the colonoscopy to also do a high resolution endoscopy at the same time. This would allow doctors to distinguish those who have Helicobacter from those who don’t. And more: to determine who has signs of oncologic risk on their gastric mucosa and who doesn’t – that risk sign being intestinal metaplasia. 

If a 50 years-old person has the bacteria, even with a super-healthy stomach, the bacteria must be eradicated. If the person has neither Helicobacter nor intestinal metaplasia, he or she doesn’t need to ever again do another stomach examination (adults who don’t have the bacteria will never catch it, because it doesn’t infect adults). We are calling out for this preventive practice. National and European health authorities have not yet assumed that orientation, but neither have they said it’s wrong.

Are there people who come to the Digestive Unit with stomach cancer? What is their prognosis? 

In general, patients with stomach cancer already have symptoms when they arrive, and their disease is already in a very advanced state. Stomach cancer survival is terrible. That’s why it is important to make an early assessment of the risk and to modify the risk factors.

Medicine for sick people is a kind of medicine that deals with a relatively small universe. I think that medicine has to take an interest in apparently healthy people.

By Ana Gerschenfeld, Health & Science Writer of the Champalimaud Foundation.