Proton Pump Inhibitors – the NET Effect


Proton pump inhibitors (PPIs) reduce the production of acid by blocking the enzyme in the wall of the stomach that produces acid. Acid is necessary for the formation of most ulcers in the oesophagus, stomach, and duodenum, and the reduction of acid with PPIs prevents ulcers and allows any ulcers that exist in the oesophagus, stomach, and duodenum to heal. PPIs are prescribed to treat acid related conditions such as:

  • Esophageal duodenal and stomach ulcers
  • NSAID-associated ulcer
  • Ulcers
  • Gastroesophageal reflux disease (GERD)
  • Zollinger-Ellison Syndrome – ZES (note this is a syndrome associated with a functioning duodenal or pancreatic NET known as a Gastrinoma)
  • They also are used in combination with antibiotics for eradicating Helicobacter pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum for eradicating H. pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum.

Although this should not be considered a full list applicable to all countries, the drugs tend to be prescribed or purchased under the following names:

  • Aspirin and Omeprazole (Yosprala)
  • Dexlansoprazole (Dexilent, Dexilent Solutab)
  • Esomeprazole (Nexium, Nexium IV, Nexium 24 HR)
  • Esomeprazole magnesium/naproxen (Vimovo)
  • Lansoprazole (Prevacid, Prevacid IV, Prevacid 24-Hour, Zoton FasTab)
  • Omeprazole (Prilosec, Prilosec OTC, Losec, Mepradec)
  • Omeprazole and sodium bicarbonate (Zegerid, Zegerid OTC)
  • Pantoprazole (Protonix, Pantoloc Control)
  • Rabeprazole (Aciphex, Aciphex Sprinkle, Pariet)

PPIs have revolutionized the management of acid-related diseases and there is evidence supporting their superior efficacy and overall safety profile. Unfortunately, it would appear this has possibly led to their overuse and inappropriate use. When used appropriately, the overall benefits significantly outweigh the potential risks in most patients.

One US pharmacist magazine has stated that almost half of all patients taking a PPI do not have a clear indication. It follows that PPIs may not be the appropriate treatment for many people. The American Gastro Journal nicely covers this issue – click here.

What is the connection with NETs?

Millions of people will have been prescribed these drugs for the various reasons listed above and as I said above quoting from a reputable US Pharmacist magazine, perhaps many do not have a clear indication for their use. So this issue is much wider than NETs.

Above, you can see a direct link to duodenal/pancreatic NET syndrome – ZES. However, there is also a known link between the use of PPIs and the effect on the Chromogranin A blood test, the most common tumour marker used in the diagnosis and surveillance of many types of NET. Several studies have concluded that PPIs falsely elevate Chromogranin A – read more here.

Any other risks of using PPIs?

There are several well-known risks of using PPIs in the long-term. However, many drugs have side effects, often the risks of not taking a particular drug can be outweighed by taking it. I will not comment further but leave you with some references to read yourself:

1. From the UK National Health Service (NHS). They took a balanced view adding the risk element I described above. Importantly they stated that PPIs are not usually intended to be taken long-term. Read more here. The British Medical Journal (BMJ) published the study referred to by the NHS here.

2. The NHS also published an article based on the results of a US study. Again, they indicated the study had similar limitations to the one above. Read more here (links to the study contained within).

3. There are literally dozens of similar articles but most seem to point to these two studies. However, it should also be noted that the US FDA has issued safety warnings about long-term use of PPIs. This is covered in the aforementioned US Pharmacist magazine article here.

Are there alternatives to PPIs?

Firstly, you should NEVER stop taking PPIs without speaking to the doctor who prescribed them.

There’s a class of drugs known as Histamine H2 Receptor Antagonists (H2RA) that reduce the amount of acid produced by the cells in the lining of the stomach. They are also commonly called H2 blockers. They include Cimetidine (Tagamet, Tagamet HB), Famotidine (Pepcid, Pepcid AC), Nizatidine (Axid) and Ranitidine (Zantac). Brand names may differ from country to country. From what I read, they are not as powerful as PPIs but for some people they may prove adequate. Read more about H2 blockers here.

So I can just stop taking PPIs and start taking H2 blockers?

NO. As I said above, you should never discontinue a prescription for PPI without talking to your doctor. However …. it’s not common knowledge that suddenly stopping PPIs is not a good idea – you must gradually reduce (i.e. taper off).

Why taper? PPIs block the production of acid in your stomach which can help with the symptoms but that also turns on the release of gastrin. This is not ideal for two reasons according to NOLANETS:

  1. When you try to get off of PPI, the gastrin stimulates acid production and stays elevated, potentially for several months (depending on how long you were on the PPIs). This makes your reflux worse than before and makes getting off of this medication very difficult. Gastrin also stimulates Chromogranin A thus why this can be elevated in patients who have been taking PPIs.
  2. Gastrin also acts like a growth factor and stimulates the growth of ECL cells (enterochromaffin like cells). Clearly this does not happen to everyone on PPIs. However, and as per the NHS advice above, PPIs should not be considered a long-term solution except for conditions for which they are clinically indicated (e.g. Barrett’s oesophagus, Gastrinoma (Zollinger Ellison Syndrome).

What are NET Specialists saying about this?

The best source of information on this seems to be in two main areas:

1. One is NOLANETS (Dr Eugene Woltering et al) who appear to be leading the way on identifying those who may have a clinical indication for use of H2 blockers rather than PPI and this NET Specialist organisation has produced a sheet showing how to taper people off the drug and onto the less risky H2 blockers. Read the NOLANETS “Get off PPIs” Sheet by clicking here. They state that PPI use increases circulating gastrin which in turn increases the amount of acid in the stomach. The increase in gastrin also stimulates the enterochromaffin like cells (ECL) of the stomach to produce Chromogranin A and this explains why it can be elevated in PPI users. The US Pharmacy magazine quoted above, appears to confirm this thinking.

2. The European NET Society (ENETS) discusses the issue in their guidelines but only in relation to Zollinger-Ellison Syndrome (ZES). This is a direct quote from ENETS 2016 Guidance – “The widespread use of PPIs is a major problem for the diagnosis of ZES because these drugs have an extended duration of action (up to one week), they cause hypergastrinemia in 80-100% of all normal subjects, and can confound the diagnosis. Furthermore, if PPIs are abruptly stopped in a true ZES patient, anti-peptic complications can rapidly develop, and therefore some expert groups have recently recommended that the diagnosis of ZES should be established without stopping the PPIs or by attempting to taper the dose. Unfortunately, as suggested in a number of recent papers, in most patients, the diagnosis cannot be easily established without an interruption of the PPIs. Furthermore, a secretin test cannot be used while a patient is taking PPIs because it can result in a false positive test. Other tumour markers such as serum chromogranin A were found to be not reliable for the diagnosis of ZES patients, as up to 30% have normal plasma chromogranin A levels. PPIs also lead to increased chromogranin A levels on their own. It is therefore recommended that if the diagnosis is unclear, the patient should be referred to a centre of excellence and if this is not possible, PPI withdrawal should be cautiously performed (in an asymptomatic patients with no active acid-peptic disease or damage) and with adequate cover by H2 blockers and careful patient monitoring”.

PPIs and PERT

I have anecdotal evidence that people are being prescribed PPIs alongside Pancreatic Enzymes Replacement Therapy (e.g. Creon, Nutrizym etc). While most types of PERT are gastro-resistant, a high acid environment may impair their efficacy. The rationale behind using PPI (or H2 blocker) is to decrease the acid level and allow the PERT to work better. Given the research behind this article, I would certainly challenge the use of PPI alongside long-term use of PERT.

Summary

The aim of this article is not to scare anyone, I’ve been careful with the sources, quotes and facts. Like anything in life (including the medical world), there are risks and knowing about them allows us to manage these risks in conjunction with our doctors and healthcare specialists. If you are concerned about anything you find inside this article, I suggest you speak directly to your doctor/specialist for advice.

Personally speaking, I would like to see more from the NET Specialist community on this issue.

Thanks for reading

Ronny

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Neuroendocrine Cancer and Pancreatic Enzyme Replacement Therapy (PERT) – the Digested Version (Nutrition Series Article 5)


pancreatic enzyme replacement therapy nutrition article 5

After 7 years of avoiding pancreatic enzyme replacement therapy (PERT), I finally asked for some on a trial basis at the end of 2017.  To be honest, for some time, I thought they were really only needed in the NET world for those with pancreatic issues (pNETs).  I’ve always known I’ve had some digestive issues related to malabsorption. However, I’m not losing weight – this has been stable for some years (but see below).  Plus my key vitamin levels (B12 and D) are in range.  However, I had been struggling with a lot of bloating issues, thus the trial.  You know me, I like to research and analyse such things! I’ve actually written about a lot of these issues in my Nutrition series ….. so this is now ‘Article Number 5’.

Crash Course. We eat food, but our digestive system doesn’t absorb food, it absorbs nutrients. Food has to be broken down from things like steak and broccoli into its nutrient pieces: amino acids (from proteins), fatty acids and cholesterol (from fats), and simple sugars (from carbohydrates), as well as vitamins, minerals, and a variety of other plant and animal compounds. Digestive enzymes, primarily produced in the pancreas and small intestine, break down our food into nutrients so that our bodies can absorb them.

Background

Some of the common symptoms of NETs are gas, bloating, cramping and abdominal pain and the root cause of these issues can sometimes be as a result of insufficient ‘digestive’ enzymes.  They are primarily produced in the pancreas (an exocrine function) and the small intestine but also in the saliva glands and the stomach.  This post will focus on pancreas and to a certain extent, the small intestine.  There are actually some key tell-tale signs of a pancreatic enzyme deficiency, such as steatorrhoea which is described as an excess of fat in faeces, the stool may float due to trapped air, the stool can be pale in colour, may be foul-smelling, and you may also notice droplets of oil or a ‘slick’ in the toilet pan.  Steatorrhoea is mainly (but not always) due to malabsorption of fat from the diet and this can actually be caused or made worse by somatostatin analogues which are known to inhibit the supply of pancreatic enzymes. Of course if fat is not being absorbed, then the key nutrients your body needs to function properly might not be either.  The signs from that might not be so noticeable but can be even more problematic over time. Please see Article 1.

Those who have had surgery, in particular, in GI tract/digestive system, are at risk of malabsorption; as are those prescribed somatostatin analogues (Lanreotide/Octreotide) as these drugs can inhibit digestive enzymes, causing or adding to the malabsorption effect.  For those who need to read more, see Article 2.

One way to combat these issues when they are caused by pancreatic insufficiency is with Pancreatic Enzyme Replacement Therapy (PERT) which can mimic the normal digestive process. However, this is not the whole story as there could be numerous reasons for these issues, perhaps even some which are unrelated to NETs. If you are in doubt about whether you suffer from malabsorption and/or any form of digestive enzyme insufficiency, you should consult your doctors.

Pancreatic Enzyme Replacement Therapy

Many NET patients succumb to malabsorption due to pancreatic insufficiency and are prescribed Pancreatic Enzyme Replacement Therapy, or PERT for short.  There are various brands available (e.g. Creon®, Nutrizym®, Pancrease HL® or Pancrex®). Most are in capsule form in various doses.

How does PERT work? Most people experiencing the issues above are going to benefit from a multiple-enzyme replacement which tend to include the key ones such as:

  • protease which breakdown proteins (e.g meat, fish, seafood, dairy, nuts, etc)
  • lipase which break down fats (e.g from many different foods)
  • amylase which breaks down starchy carbohydrates (e.g. potatoes, bread, rice, pasta, cereals, fruits, fibre, etc).

The dose sizes tend to be based on the amount of lipase, i.e. a 25,000 strength would mean 25,000 units of lipase and (normally) a lesser amount of amylase and protease.  The entire mix of enzymes may be given a name, e.g. ‘Pancreatin’ or ‘Pancrealipase’.  You will be given a number of capsules to be used from your prescribing doctor.

The pancreatic enzyme capsule is swallowed along with food and digests food as they pass through the gut. If your capsules contain an enteric coat or enteric coated granules (delayed release), they should not be affected by stomach acid. The replacement enzymes will help to break down food allowing the nutrients to be absorbed beyond the stomach (i.e. in the small intestine). Do not be alarmed at the dose sizes, a healthy pancreas will release about 720,000 lipase units during every meal!

Frequently Asked Questions (FAQ)

When I first started taking the supplements, I thought of numerous questions, many of which I could not find definitive answers to! Different sites say different (and contradictory) things.  Clearly, you should always consult your prescribing doctor and the medicine patient information leaflet. That said, I found the patient information leaflet which came with the capsules is just not detailed enough for an inquisitive patient such as myself!

I always like to refer to best practice which is why I’ve consulted one of the top NET Dietitians, Tara Whyand of Royal Free London. She agreed to an online Q&A session on 28 Feb 2018.  This took place on my private Facebook group click here or search Facebook for this group “Neuroendocrine Cancer – Ronny Allan’s Group“.  Join, answer some simple questions and then your application will be processed.

The output from the online with with Tara Whyand is below:

Thanks for attending the online event. Here is a tidy summary of the many comments. I hope this is also useful for those who were unable to attend.

  1. Why would I need PERT and are there any tests that can be done to validate this?

“Somatostatin analogues, pancreatic surgery, pancreatitis and cystic fibrosis can cause exocrine pancreatic insufficiency (EPI). This means that the pancreas does not produce enough enzymes to break down food. It results in fatty loose stools called steatorrhoea.

Patients who have exocrine pancreatic insufficiency (EPI) require PERT (pancreatic enzyme replacement therapy) to break down food (fat, protein and carbohydrate). There are many brands of pancreatic enzymes, the most commonly used are Creon and Nutrizyme. Both have different dose levels to choose from.

The fecal elastase test was traditionally used to test the function of the pancreas, although it may not be that useful in NETs. This is because a NET team in Wales found that some NET patients who reported steatorrhoea had a false negative result.

Steatorrhoea may also be a result of bile acid malabsorption and small intestinal bacterial overgrowth which can co-exist and are common especially after surgery. They can both be tested for at a hospital.”

Supplementary Questions:

1a. Would the treatment be different for both EPI and bile acid malabsorption? If not how different?

“Yes BAM requires bile acid sequestrants rather than PERT”.

1b. would this be something you would take in general to help overall digestion and absorption of nutrients?

“No only if you have reasons for EPI to occur”.

  1. PERT dosage. Is there a set dosage for all patients or does it depend on type of NET or surgery? And can I overdose on PERT?

“It depends on what you eat. PERT dose is normally tailored on fat content (the more fat you have, the more enzymes you need), but patients who have had a total pancreatectomy will have to have PERT for all food and drink (apart from water) as carbohydrate and protein needs to be broken down too.”

Supplementary Questions

2a. “What about when taking medication such as Cholesteramine or pills in the morning and evening. Do I need to take it to absorb these?”

“see question 5”.

2b. I had a total pancreatectomy and was told I do not need PERT for fruit and veg?

“there’s carbs in all fruit and veg and often fat and protein too, so no different really.”

  1. Some sources say to take the capsules at the beginning of a meal, some say it’s also at the end of a meal is also OK. How critical is this?

“You must always take the capsules at the beginning of the meal and if the meal goes on longer than ~30 minutes, or there are several courses, you will need to have another capsule/tablet/scoop of enzymes. If you don’t, food will pass by the pancreas undigested and ‘malabsorption occurs. This leads to fatty stools (steatorrhoea), fat soluble vitamin deficiency and weight loss. Unbroken down food can also feed bacteria and you can develop small intestinal bacterial overgrowth as a result.”

Supplementary Questions

3a. so if my oncologist says to take four capsules per meal, then I should take all four at the same time?

“see question 11”

3b. if you have had a total gastrectomy (total removal of the stomach), is there a different procedure for taking PERT? I am on Creon and have heard that perhaps I need to open up the capsules as I can not break down the gelatin casing. Not sure if this is true or not.

“See question 11”

  1. What is a meal? Is it multiple courses, or is there a strategy for each individual course? What about snacks? (i.e. a single biscuit with a cup of tea)

“The standard starting dose for snacks: 22-25,000 units lipase, titrating up when symptoms have not resolved. Most people end up taking 44,000-50,000 for snacks.

For main meals start on 44,000/50,000 and most people will need 66,000-100,000 units lipase/meal for the long term.”

Supplementary Questions:

4a. I have to eat multiple small meals a day (like every 3 hours, so 7 to 8 small meals). Is there a limit on the amount of Creon I can take in a day?

“see question 11”

4b. What is a snack?

“No official definition. Something with a little fat and maybe 50-200kcals.

  1. Are there any problems taking PERT at the same time as other drugs? e.g. I like to take my vitamin supplements with food. And it’s recommended that some drugs be taken with food.

“PERT only breaks down food, but it is important to take your PERT to ensure food and drugs are absorbed. If you do not take you PERT with the meal, it is likely that food and drugs will rush through your bowel without being absorbed. There is no problem taking vitamins and minerals with food and PERT.

Supplementary Questions:

5a. I take a probiotic also, when is best time to take this, before, during or after food?

“Timing doesn’t matter”

  1. I heard PERT is a porcine produce but I’m a vegan? Is there anything else for me?

There are no other recommended products, and you should only have prescription PERT’s. This is for safety and reliability. Other off the shelf enzymes are unlikely to work.

Pigs are not slaughtered for PERT, they are slaughtered for meat and enzymes are a by-product if that makes anyone feel more comfortable with the idea.”

  1. I heard PERT is a porcine produce but my religion does not allow me to eat such produces. Is there anything else for me?

“PERT are only sourced from a pigs pancreas but Jewish and Muslim patients have been granted approval to take the enzymes on medical grounds from their religious leaders because there is no alternative.”

  1. Some doctors are prescribing PPIs along with PERT claiming that they help the PERT do the job. Do you have a view on this and are there any general diet tips to support the job of PERT without resorting to other drugs?

“Yes if you have had a whipples operation or you have acid reflux you must take an anti-acid (proton-pump inhibitor-PPI) drug to reduce the acid level. If left untreated it can cause ulcers, and when they bleed it can sometimes lead to a life threatening situation. PERT are gastro-resistant-they do not work in too high an acid environment. Sometimes a PPI / H2 blocker can decrease the acid level and allow the PERT to work better. There is no other reliable way of reducing stomach acid.

Note: Ronny Allan input that there is information published about the over-subscribing of PPI for long term use. Additionally that some NET specialists are suggesting a preference for H2 Blockers rather than PPI for NET Patients. H2 Receptor Blockers include Nizatidine (Axid), Famotidine (Pepcid, Pepcid AC), Cimetidine (Tagamet, Tagamet HB), Ranitidine (Zantac). The exceptions would be for PPI therapy necessary for Barrett’s Esophagus and Zollinger Ellison Syndrome (Gastrinoma). Read my article on PPIs by clicking here

Supplementary Questions:

8a. I had a whipples two and a half years ago and have recently stopped taking omperazole as I didn’t seem to need them. Do you think I should still be taking something to reduce acid level anyway?

“yep think you should be on Ranitadine or a PPI long term.”

8b. Is it possible to suffer from excess acid without even knowing it? I also take probiotics, is it possible they could be minimising any excess acid? Also, I seem to be able to eat whatever I want without consequence but am worried now in case I am doing wrong and storing up trouble for myself.

yes you can have silent reflux but after a total pancreatectomy you needs lots of adjustments and insulin dosing advice.”

9. How will I know the PERT is working for me? And are there any tests to validate this?

“You will know if your PERT is working well if your symptoms improve – i.e. you get normal (mid brown and formed) stools.

Patients taking enough PERT will not become fat soluble vitamin deficient or lose weight in the long term.

You could do a fecal elastase test (if stools are not liquid), but this is not a very reliable test especially for patients with NETs.

If symptoms do not resolve entirely, there may be a co-existing cause of malabsorption e.g. bile acid malabsorption or small intestinal bacterial overgrowth.”

Supplementary Questions:

9a. With regards to Question 9, how would you know if you have bile acid malabsorption or SIBO? Can you be tested for those?

“If PERT doesn’t resolve things, SIBO testing is another thing to look at using a lactulose drink and hydrogen breath test. If the NET is in the terminal ileum, bile acid malabsorption (BAM) is likely. The test is a SeHCAT scan and treatment usually Questran or Colesevelam.

  1. If I need to stop taking PERT, do I just stop or do I need to taper off consumption over time?

“No, just stop. But only do so if it has caused a side effect and report the reaction to the doctor and pharmaceutical company. If you don’t think they are working, speak with a specialist Dietitian and you may need a PPI or H2 blocker or change brand/dose.”

  1. If someone has had a total gastrectomy, can they take Creon? If so, do they need to open up the pill to remove the gelatin to help the enzymes to work?

“They are to be taken as normally directed. You can open capsules but only into an acidic fruit juice (a pH of 4.5 or below) and swallow immediately. It could be argued that PERT will work most easily in patients having a gastrectomy as you cannot get too high a stomach acid level without stomach P-cells. By the way, shouldn’t be any gelatin in the prescribed PERT”

Supplementary Questions:

11a. Are there any problems with taking too much in a day? I have to have 7 to 8 meals (minimum). I am losing weight. Take with every snack and meal?

“You can overdose – for Creon this is 6000 units lipase per kg of body weight. If you are still losing weight, PERT is not working or something else is the cause of malabsorption”

  1. SUPPLEMENTARY QUESTIONS AT THE END

12A. My steatorrhoea only occurs once/twice a month. Is PERT indicated if steatorrhoea is not chronic?

“Yes, probably need to take all month as steatorrhoea is only a sign of extreme malabsorption, small amounts of malabsorption aren’t noticeable visibly but will reflect in weight and blood vitamin levels.”

12B. I do not need Creon as I am a Lung NET; although I have had my gall bladder removed.

“May need PERT if on somatostatin analogues. Some people take a bile acid sequestrants after gall bladder removal. PERT won’t work for that.”

Summary

I’ve always known about issues such as steatorrhoea and vitamin/mineral deficiency. My weight is fine but very happy to trial PERT to see the differences. I made a mistake of starting the capsules on Dec 23rd just before Christmas – it made for an interesting week!  Early days so far but I’m getting used to taking them (and remembering to take them ….). Still seeing signs of steatorrhoea but am tracking this against diet.  Not seeing any change to stool frequency. I would appear to be belching more though!  I will keep this post live as I learn more.

You may wish to see the output from an online chat I carried out, the link is above.

UPDATE 1st Feb 2019.  After 1 year, I’m not sure if there has been any difference to signs of malabsorption with Creon, although the supplement did help with weight gain in the period Oct – Dec 2018 after a dose increase. I had lost weight earlier in 2018 due to a bad chest infection and was having trouble regaining it.  Despite the success with the weight gain, that is no long an issue, so I commenced a 3 month trial of Nutrizym to see any change in intermittent but frequent steatorrhea, which potentially indicates a continuing malabsorption issue.

You may also enjoy these articles:

“Nutrition Article 1 – Vitamin/Mineral Risks”click here.

“Nutrition Article 2 – GI Malabsorption”click here.

“Nutrition Article 3 – SIBO/Probiotics”click here

“Nutrition Article 4 – Food for Thought – amines etc”click here

Post publishing edit:  “I feel like I now take food with my medicine” 🙂

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!



patients included

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Neuroendocrine Cancer – tumour markers and hormone levels


blood

I think most people have had a form of medical testing at some point in their life, i.e. the sampling and testing of blood, urine, saliva, stool or body tissue. In a nutshell, the medical staff are just measuring the content of a ‘substance’ and then taking a view whether this is normal or not based on pre-determined ranges. These tests are normally done as a physician’s reaction to symptom presentation or maintenance/surveillance of an existing diagnosed condition. Sometimes, abnormal results will lead to more specialist tests.

In cancer, these tests are frequently called ‘markers’. Most tumour markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumour tissue, or other tissues or bodily fluids of some patients with cancer. Most tumour markers are proteins. However, more recently, patterns of gene expression and changes to DNA have also begun to be used as tumour markers.  Many different tumour markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. No “universal” tumour marker that can detect any type of cancer has been found.

markers

There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumour marker associated with that cancer. Moreover, tumour markers have not been identified for every type of cancer. Tumour markers are not foolproof and other tests and checks are usually needed to learn more about a possible cancer or recurrence.

I’d also like to talk about a group of associated tests, in particular, hormone levels as these tests are really important to help determine the type of Neuroendocrine Tumour.  NETs will sometimes oversecrete hormones and this can give clues to the type.  The constraints mentioned above apply to hormone levels and other tests to a certain extent.

What this article will not cover

Routine Testing – the post will not cover routine blood tests (i.e. complete blood count etc).  Although they may point to a problem, these tests do not necessarily indicate a particular type of NET without other supporting evidence.

Biopsy Testing – Technically, the Immunohistochemical ‘stains’ used in biopsy testing are tumour markers but I’ll not be discussing that today. I did cover the output of biopsies in my blog on NETs – Stages and Grades.

Genetic Testing.  This is very specialised but you may find my Genetics and NETs article is of interest.

Sequencing of marker testing – diagnosis

The sequencing of marker testing may have been different for many patients.  In my own experience, I had a biopsy and then the biochemical checks were carried out. So regardless of the results of my marker tests, I was to be diagnosed with NETs. Those with lengthy and difficult diagnostic phases will perhaps have had a different sequence with the biochemical markers providing evidence for further tests to formally diagnose.  Markers alone will normally not be enough for a diagnosis but they do, however, feed into the treatment plan and provide a baseline at diagnosis and for tracking going forward.

Interpreting test results – International/National/Regional differences

The use of markers tends to be different on an international basis, e.g. specific marker tests can be developed in-country by independent labs. Testing can also vary in the same country as in-country labs use different commercially available ‘testing kits’. Not all tests are available in all countries.

Reference ranges can be dependent on many factors, including patient age, gender, sample population, and test method, and numeric test results can have different meanings in different laboratories. The lab report containing your test results should include the relevant reference range for your test(s). Please consult your doctor or the laboratory that performed the tests to obtain the reference range if you do not have the lab report. Moreover, the ‘normal’ test range can vary from hospital to hospital, even within the same tests. I suspect clinical staff have their own versions of risk thresholds when dealing with test results. Even when results are just above or below, individual physicians can take their own view in a subjective manner. Testing is best done at the same lab each time if possible.

There’s a great website called LabTestsOnline which can describe each test. It’s peer-reviewed, non-commercial and patient-focused but just please note you should always refer to your own lab ‘normal ranges’ which will be printed on your test results.  For these reasons, you will not find reference ranges for the majority of tests described on this web site.  The link above will take you to the list of ‘country’ affiliated versions with specific information on a country basis.

Here’s some tips I always give people:

1 – Always try to get your own copy of results (preferably on paper) and track them yourself (I use a spreadsheet).

2 – When comparing results inside patient forums, always add the range and if possible, the unit of measurement (i.e. g/L, mmol/L, umol/L etc etc).  Failure to do this can at best confuse, and at worst frighten patients.  Compare apples with apples not with pears! (this is why it’s important to know the unit of measure and the reference range in addition to the figure).

3 – Don’t get too excited about rises if the test is still inside the normal range – normal is normal!

4 – Don’t get too excited about rises taking you just outside of normal range – your doctors are looking for bigger spikes.

5. Don’t get too excited about a single test result, your doctors are looking for trends, a single test result is not much to go on.

NET Markers

Although some routine blood markers (complete blood count etc) are useful in NETs, it’s pretty much impossible to cover these in any general detail.  I’m going to focus on tumor and hormone associated markers

There are many markers involved with NETs. Some do different jobs and some are just variants measuring the same thing (more or less efficiently). You may also see something called ‘gold standard’ in reference to NET Tumour markers. Although thinking is changing (more on this below) and can vary from country to country, it is generally accepted that Chromogranin A and 5HIAA are the gold standard markers for tumour bulk and tumour functionality respectively.  These gold standard tests may not be applicable to every type of NET, particularly 5HIAA. I’m also aware that US doctors are reducing the dependency on CgA and using Pancreastatin instead (although many are measuring both).

NETs are known to be heterogeneous in nature (i.e. consisting of or composed of dissimilar elements; not having a uniform quality throughout).  Whilst some markers can be used widely, it follows that there are many very specialist marker tests for individual types of NET.  I think this applies to 3 broad categories of NETs: Tumours known to potentially oversecrete Serotonin and and perhaps others (mainly midgut), Pancreatic NETs (or pNETs) secreting various hormones by type; and other less common types and/or syndromes which might be considered by some to be even more complex than the former two and in some cases there are big overlaps.

Another interesting thing about NET markers is that an undiagnosed patient may undergo several specialist tests to eliminate the many possibilities that are being presented as vague and common symptoms.  Sometimes this is necessary to eliminate or ‘home in’ on a tumour type or syndrome/hormone involved (it’s that jigsaw thing again!).

Markers too can be divided into broad categories, those measuring how much tumour is in your body and its growth potential and those measuring how functional (or not) those tumours are.  The latter can probably be expanded to measure/assess excess hormone secretion and syndromes.

The Anatomy

Certain tests can be anatomy related so to add context and to prevent big repetitive lists when using the terms ‘foregut’, ‘midgut’ and ‘hindgut’, you may find this graphic useful.

foregut midgut hindgut

Markers for measuring Tumour bulk or load/growth prediction

Chromogranin (plasma/blood test)

cgaChromogranin is an acidic protein released along with catecholamines from chromaffin cells and nerve terminals. This statement alone might explain why it is a good marker to use with NETs.  Depending on the test kit being used, you may see test results for Chromogranin A (CgA) and Chromogranin B (CgB) – the inclusion of CgB tends to be confined to Europe. There is also mention of Chromogranin C (CgC) in places but I’ve never heard of this being used in conjunction with NETs.

One of the disadvantages of CgA is that the results can be skewed by those taking Proton Pump Inhibitors (PPIs).  Many NET patients are taking PPIs to treat GERD (….and Zollinger-Ellison Syndrome). In the long-term, this has the result of increasing gastrin levels which can lead to an increase of CgA in the blood including for some months after discontinuing.  Opinions differ but many texts I found did suggest stopping PPIs for 2 weeks before the CgA blood test.  CgB is said not be as influenced by the use of PPI as CgA. In addition to the issue with PPIs, CgA levels may also be elevated in other illnesses including severe hypertension and renal insufficiency. CgB is also said to be more sensitive to Pheochromocytoma.

Elevated CgA is a constant and somewhat excitable discussion point on patient forums and not just because of the lack of unit of measurement use I discussed above. Some people get quite excited about a single test result.  I refer to Dr Woltering et al (ISI Book) where it clearly states that changes in CgA levels of more than 25% over baseline are considered significant and a trend in serial CgA levels over time has been proven to be a useful predictor of tumour growth (i.e. a single test result with an insignificant rise may not be important on its own).  Dr Woltering also gives good advice on marker tests when he says “normal is normal” (i.e. an increased result which is still in range is normal).

Here is a nice graphic explaining what else could be the cause of elevated CgA:

causes-of-cga-elevated

CgA appears to be a widely used tumour marker and is effective in most NETs (foregut, midgut and hindgut). It is also sensitive to Pheochromocytoma, particularly when correlated with a 131I-MIBG scan. Interestingly Chromogranin can also be used in the immunohistochemical staining of NET biopsy samples (along with other methods).

As for my own experience, my CgA was only elevated at diagnosis, remained elevated after intestinal surgery but returned to normal after liver surgery (indicating the effect of liver tumour bulk on results).  It also spiked out of range when some growth in a distant left axillary node was reported in Jan 2012.  Following a lymphadenectomy, it returned to normal again and has remained in range to this day.  It has been a good predictor of tumour bulk for me and I’m currently tested every 6 months.

Pancreastatin

In effect, this marker does the same job as CgA.  Interestingly, Pancreastatin is actually a fragment of the CgA molecule. There have been many studies (mainly in the US) indicating this is a more efficient marker than CgA, and not only because it is not influenced by the use of PPI.  It has also been suggested that it’s more sensitive than CgA and therefore capable of detecting early increases in tumour burden. It has also been suggested it can be an indication of tumour ‘activity’ (whatever that means). It is widely used in the US and some physicians will use it in preference to CgA (…..although from what I read, CgA also seems to be tested alongside).  I’m starting to see this mentioned in the UK.

Neurokinin A (NKA)

This is not a well publicised test. However, it is something used in USA but I’d like to hear from others to validate its use elsewhere.  In a nutshell, this test, which only applies to well differentiated midgut NETs, appears to have some prognostic indication.  I discovered this test in the ISI NET Guidance and it’s backed up by a study authored by names such as Woltering, O’Dorisio, Vinik, et al.  This is not a one-off test but one designed to be taken serially, i.e. a number of consecutive tests.  These authors believe that NKA can also aid in the early identification of patients with more aggressive tumors, allowing for better clinical management of these patients.  NKA is sometimes called Substance K.

Neuron-Specific Enolase (NSE)

In patients with suspected NET who have no clear elevations in the primary tumor markers used to diagnose these conditions, an elevated serum NSE level supports the clinical suspicion.

Markers for measuring Tumour functionality/hormone/peptide levels

So far, I’ve covered basic tumor markers which have a tumor bulk and/or prognostic indication.  This section is a slightly more complex area and many more tests are involved. There’s often a correlation between CgA/Pancreastatin and these type of markers in many patients i.e. a serial high level of CgA might indicate a high level of tumour bulk and therefore increased production of a hormone in patients with a syndrome or oversecreting tumor. However, it frequently does not work out like that, particularly when dealing with non-functioning tumours.

The type of marker for this element of NET diagnosis and surveillance will vary depending on the type of NET and its location (to a certain extent).  Like tumour bulk/growth, there might be different options or test variants on an international basis. There are too many to list here, so I’ll only cover the most common.

Serotonin Secreting Tumors

There are a few markers in use for measuring the functionality of this grouping of tumours. This tumour group has a tendency to secrete excess amounts of the hormone Serotonin although it differs depending on the area of the primary. For example, hindgut tumours tend to secret lower levels than foregut and midgut and therefore this test may present within range.  Please also note there may be other hormones of note involved. The antiquated and misleading term ‘Carcinoid’ is sometimes used as a descriptor for these tumours and more and more NET scientific organisations and specialists are now avoiding use of this term.

lug-the-jug
Lug the Jug

5HIAA.  5HIAA is a metabolite of Serotonin thus why it’s a useful thing to measure to assess functionality in this grouping of tumours. 5HIAA is actually the ‘gold standard’ test for functioning serotonin secreting tumours. It’s a key measure of the effects of carcinoid syndrome and the risk of succumbing to carcinoid heart disease.  However, there are two methods of testing:  Urine and Plasma. The latter is mainly used in USA but other countries are now looking at implementing the plasma version (in fact I’m now tested in both at my local hospital in UK).  The rather obvious key difference between the two is practicality. With the 24 hour urine, there are two key issues: 1.  The logistics (i.e. lug the jug).  2.  Fasting for up to 3 days prior to the test (4 if you count the day of the test). There are numerous variations on the fasting theme but most labs tend to say not to eat at least the following foods that contain high levels of serotonin producing amines: avocados, bananas, chocolate, kiwi fruit, pineapple, plums, tomatoes, and walnuts.  Some lists contain additional items. With the plasma version, the fasting period is reduced to 8 hours. There are also medicinal limitations including drugs that can also alter 5-HIAA urine values, such as acetanilide, phenacetin, glyceryl guaiacolate (found in many cough syrups), methocarbamol, and reserpine. Drugs that can decrease urinary 5-HIAA levels include heparin, isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, and tricyclic antidepressants. Patients should talk to their doctor before decreasing or discontinuing any medications.

As for my own experience, my 5HIAA (urine) was elevated at diagnosis only returning to normal after removal of my primary and commencement of Lanreotide. It has been a good measure of tumour functionality for me and I’m currently tested every 6 months.

Other tests for the tumour subgroup include but not limited to:

Serum Serotonin (5-HydroxyTryptamine; 5-HT).  Firstly let’s deconflict between 5HIAA above and the serotonin (5-HT) blood test.  5HIAA is a metabolite of serotonin but the serotonin test is a measure of pure serotonin in the blood.  Morning specimens are preferred and this is a fasting test (10-12 hours).  There is always debate on forums about Serum Serotonin results.  I have Dr Liu on record as saying “a high serotonin level measured in the blood in isolation really isn’t that dangerous. It’s the 5HIAA (a breakdown product of serotonin, which is easily measured in the blood and urine) that is considered to be more indicative of persistent elevated hormone. It’s this test that is most closely related to the carcinoid heart disease”.

Substance P.   A substance associated with foregut and midgut tumours.  It is a vasoactive protein that can cause wheezing, diarrhea, tachycardia, flushing

Histamines – Usually associated with foregut tumors. Appears to be involved in patchy rashes and flushing.  The advice in the ISI NET book is no anti-histamine medication to be taken for 48 hours prior to blood draw.

Gastric NETs (Stomach)

Testing will be different depending on the Type:

  • Type 1 – Typical Low Grade, tends to be caused by atrophic gastritis.
  • Type 2 – Atypical Intermediate Grade and tends to be caused by gastrin secreting tumours.  Type 2 normally needs a check for MEN1/Zollinger-Ellison Syndrome.
  • Type 3 – Tend to be larger and more aggressive tumours.

The key makers are CgA and Gastrin although Gastrin may not be elevated in Type 3. Gastrin ph is useful to differentiate between Type 1 and Type 2.  5HIAA can be considered but Carcinoid Syndrome is rare in Gastric NETs.

NETs of the Pancreas (pNETs)

pancreatic-cells
There are many different types of cells in the pancreas

pNETs can be very difficult to diagnose and not only because they share some presentational similarities to their exocrine counterparts.  Some pNETs actually comprise tumours arising in the upper part of the duodenum (small intestine) close to the Pancreas. Moreover, more than half of pNETs are non-functional which increases the difficulty in suspecting and then finding the tumours.  However, where there is clinical presentation or suspicion, these symptoms can lead to the appropriate testing to support the output of scans. The fasting gut profile mentioned above can be useful in identifying the offending hormones when the type of NET is not yet known.

Gut Hormones (Glucagon, Gastrin, VIP, Somatostatin, Pancreatic Polypeptide)

A gut hormone screen is used for the diagnosis of a variety of endocrine tumours of the pancreas area. Analysis includes gastrin, VIP, somatostatin, pancreatic polypeptide, and glucagon, but there may be others depending on processes used by your ordering specialist or hospital.

Notes:

1. You may see this referred to as a ‘Fasting Gut Profile’ or a ‘Fasting Gut Hormone Profile’.

2.  The individual hormones measured seem to differ between hospital labs.

3.  The fasting conditions also vary between hospitals and labs but all agree the conditions are critical to the most accurate results. Always ask for instructions if you’re offered this test.

The gastrin test is usually requested to help detect high levels of gastrin and stomach acid. It is used to help diagnose gastrin-producing tumours called gastrinomas, Zollinger-Ellison (ZE) syndrome, and hyperplasia of G-cells, specialised cells in the stomach that produce gastrin. It may be measured to screen for the presence of multiple endocrine neoplasia type I (MEN) It may be used if a person has abdominal pain, diarrhoea, and recurrent peptic ulcers. A gastrin test may also be requested to look for recurrence of disease following surgical removal of a gastrinoma.

Vasoactive intestinal peptide (VIP) measurement is required for diagnosis of pancreatic tumour or a ganglioneuroma which secretes VIP. Administration of VIP to animals causes hyperglycaemia, inhibition of gastric acid, secretion of pancreatic bicarbonate and of small intestinal juice, and a lowering of systemic blood pressure with skin flush. These features are seen in patients with a tumour of this type which is secreting VIP.

Glucagon is measured for preoperative diagnosis of a glucagon-producing tumour of the pancreas in patients with diabetes and a characteristic skin rash (necrolytic migratory erythema).

Pancreatic polypeptide (PP) production is most commonly associated with tumours producing vasoactive intestinal polypeptide and with carcinoid syndrome and, less commonly, with insulinomas and gastrinomas.

When secreted by endocrine tumours, somatostatin appears to produce symptoms similar to those seen on pharmacological administration, i.e. steatorrhoea, diabetes mellitus and gall stones.

There are several types of pNETs, each with their own syndrome or hormone issue.  When they are suspected due to the presentational symptoms, the markers that could be used are listed below.  These types of tumours are complex and can be related to one or more syndromes.  A patient may be tested using multiple markers to include or exclude these.  Depending on other factors, some physicians may recommend additional marker testing in addition to the most common types below.

Insulinoma – Insulin, Proinsulin, C-peptide

Gastrinoma– Gastrin, Gastrin pH

Glucagonoma – Glucagon, Insulin, Pancreatic Polypeptide (PP), Adrenocorticotropic hormone (ACTH)

VIPoma – Vasoactive Intestinal Polypeptide (VIP), Electrolytes (due to profuse diarrhea)

Somatostatinoma – Somatostatin (plasma somatostatin like immunoreactivity)

PPoma – Pancreatic Polypeptide (PP)

Other NETs/Syndromes

Pheochromocytoma/Paraganglioma – Adrenaline-producing tumours. Plasma and urine catecholamines, plasma free total metanephrines, urine total metanephrines, vanillylmandelic acid (VMA)

Medullary Thyroid Cancer. Medullary thyroid cancer (MTC) starts as a growth of abnormal cancer cells within the thyroid – the parafollicular C cells. In the hereditary form of medullary thyroid cancer (~20% of cases, often called Familial MTC or FMTC), the growth of these cells is due to a mutation in the RET gene which was inherited. This mutated gene may first produce a premalignant condition called C cell hyperplasia. The parafollicular C cells of the thyroid begin to have unregulated growth. In the inherited forms of medullary thyroid cancer, the growing C cells may form a bump or nodule in any portion of the thyroid gland.  Unlike papillary and follicular thyroid cancers, which arise from thyroid hormone-producing cells, medullary thyroid cancer originates in the parafollicular cells (also called C cells) of the thyroid. These cancer cells make a different hormone called calcitonin, which has nothing to do with the control of metabolism in the way  thyroid hormone does.  The other test often seen in MTC is Carcinoembryonic Antigen (CEA). CEA is a protein that is usually found in the blood at a very low level but might rise in certain cancers, such as medullary thyroid cancer. There is no direct relationship between serum calcitonin levels and extent of medullary thyroid cancer.  However, trending serum calcitonin and CEA levels can be a useful tool for doctors to consider in determining the pace of change of a patient’s medullary cancer.

[please note there are extremely rare occurrences of elevated calcitonin from places outside the thyroid – read more here.

Parathyroid– Parathyroid hormone (PTH), Serum Calcium.  Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low.  A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1 – see MEN below.

Pituitary/Cushings – Adrenocorticotropic hormone (ACTH), Cortisol.

HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands.

Adrenocorticotropic hormone (ACTH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ACTH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ACTH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ACTH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ACTH may be due to:

Cushing’s disease – this is the most common cause of increased ACTH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ACTH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.

Cortisol

This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome.  Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.

Other hormones related to ACC include:

Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.

Estrogen – early signs of puberty in children, enlarged breast tissue in males.

Aldosterone – weight gain, high blood pressure.

Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.

A tumour outside the pituitary gland, producing ACTH (also called ectopic ACTH). With NETs, this is normally a pNET, Lung/Bronchial NET or Pheochromocytoma.

Multiple Endocrine Neoplasia (MEN).  Please note MEN is a group of distinct syndrome not a tumor.  Complex area and tends to be multiple instances of some of the tumours above.  For a breakdown of MEN types and locations, check out my MEN blog ‘Running in the Family’

Carcinoid Heart Disease(CHD) (Hedinger syndrome)  I’m not really talking directly about a tumour here but thought it would be useful to include a blood test called NT-proBNP.  I’ve left a link to my CHD article in the paragraph heading for those who wish to learn more about CHD in general.  For those not offered an annual Echocardiogram or are ‘non-syndromic’ there is a screening test that can give an indication of any heart issue which might then need further checks.

The Future – Molecular Markers?

This is testing using DNA and genes.  Exciting but complex – check out this article which involved some NETs.

Tumour Markers and Hormone levels – complex subject!

tt

Neuroendocrine Cancer Nutrition Series – Article 3 – Gut Health

OPINION.  Nutritional issues are one of the biggest challenges affecting most Neuroendocrine Cancer patients.  It is also a key factor in maintaining a decent quality of life and for most countries without adequate NET Specialist Dietitian support, it remains an unmet need. In this article, I’m discussing the use of probiotics to combat the potential issue of small intestine bacterial overgrowth (SIBO) in Neuroendocrine Tumours.  

When I first indicated this nutrition series was under construction, a few people got quite excited anticipating me to produce advice on what to eat.  However, that was never my intention. What people should or should not eat is such a varied problem (or solution?) that anything I said would only really be of help to those for whom it worked – this area is not an exact science. I’ve seen several ‘what to or not to eat’ publications/articles out there aimed at NET patients; some more up to date than others – all I would say is to interpret them carefully.

What my nutrition series actually covers is what causes the nutritional related issues and to a certain extent, try to work out how to tell if these issues are caused by either treatment or an associated syndrome, leaving fellow patients to make up their own minds about what to eat; or arm themselves with the necessary knowledge whether this applies to them or not.

The first two articles in the series were Article 1 – Vitamin and Mineral Challenges and Article 2 – Malabsorption. These remain popular and have a constants stream of views – no surprises as these are well known side effects of many types of NETs…… or at least they should be well known.

This particular article “Gut Health” is not as ‘clear cut’ or simple as the first two and I suggest you read Articles 1 and 2 first if you are not familiar with the issues.  Again I’m grateful to Tara Whyand (NET Specialist Dietician and researcher from Royal Free London) for some of the input below. Although I marked this with ‘Opinion’, some of it has references but I still decided to use ‘Opinion’ as the science is not yet 100%.

What is the “Gut” ?

When I first met my surgeon, I found one of his favourite words was ‘Gut‘.  Like me before diagnosis, many of you will have heard or used the word but in an intentionally non-medical context, e.g.  guts (bravery), ‘gut feeling’ or ‘gut instinct’ (intuition). I’ll return to that theme later but when you look at these contextual uses of the word, it’s no surprise why some scientists refer to our gut as a ‘second brain’.

I always thought the gut referred to just the ‘belly’ area but in medical parlance, the gut has a much bigger geography.  It is sometimes used interchangeably with the term Gastrointestinal (GI) Tract and stretches from the throat to the anus and is responsible (in the most general terms) for food intake, digestion/absorption,  waste processing and finally waste ejection.  NET patients should be familiar with the terms ‘foregut’, ‘midgut’ and ‘hindgut’ which are sometimes used to define the embryological origin and grouping of Neuroendocrine primary tumours, although the boundaries and constituent parts can vary from site to site.  The inclusion of certain anatomical locations as a sub-section of the gut is clearly for convenience rather than anatomical accuracy (e.g. Lung).

This is a massive subject but I wanted to ‘cut to the chase’ in this article and focus on the use of probiotics to combat the potential issue of small intestine bacterial overgrowth (SIBO) in Neuroendocrine Tumours.  The symptoms and signs of SIBO can be similar to they symptoms and side effects of treatment that many patients report anecdotally on patient forums.  I also found the science is complex and not really 100% tied down.

Probiotics

One of the first pieces of advice I was given after my initial surgery was to take probiotics – to keep up my stocks of ‘good’ bacteria.  I didn’t really understand why, I just complied. I started with the liquid drinks you can buy in most supermarkets and supplemented this by eating bioactive yoghurt.  I didn’t really notice any difference from either but the yoghurt was nice to eat!

Tara Whyand then confirmed this advice when I first met her in 2012 at a NET Patient conference.  In 2013 when I started looking for a new normal, I realised that the supermarket drinks and yoghurts were simply not enough good bacteria for my ‘new plumbing’, and decided to take a high-grade daily capsule containing 5 billion friendly bacteria multiple strains (Tara does recommend at least 2 billion and multiple strain).  Within weeks I was noticing a difference in bowel motility although I confess to changing other elements of my lifestyle at the same time given that I was embarking on finding my new normal.  Nonetheless, I sense probiotics are helping and I won’t be reducing or stopping them any time soon.  If you look at several NET specific dietician/nutrition presentations, most appear to promote the use of probiotics for NET patients.

Bacteria

One of the terms you find in this complex area is the ‘human gut microbiota‘, sometimes known as ‘gut flora‘. Our ‘gut’ harbours a complex community of over 100 trillion microbial cells, approx 3% of our body mass! The human gut microbiota is known to have an influence on every part of our body (including the brain…..) and disruption of this ‘community’ has been linked with several gastrointestinal conditions such as Inflammatory Bowel Disease (IBD) and obesity.

Probiotics are said to help keep the balance and mix of bacteria stable within the gut which can be affected by many different factors, including the use of antibiotics, aging, illnesses (such as IBD), following infective gastroenteritis and (of interest to NET patients) after cancer treatment or gastrointestinal surgery. {1}  Incidentally, the reference here is authored by Tara Whyand and Professor Martyn Caplin (a Neuroendocrine Tumour expert who also happens to be a Gastroenterologist). Useful reading if you have any of the conditions in the report or have had gut surgery (or like me you are a total geek!).  They are also frequently used in Irritable Bowel Syndrome (IBS).

Small Intestine Bacterial Overgrowth (SIBO)

Another interesting area of research into something called Small Intestinal Bacterial Overgrowth (SIBO), a condition where the small intestine is populated by an abnormal amount and/or types of bad bacteria. It follows that probiotics (good bacteria) may be useful in combatting this by helping to maintain balance.

So how does SIBO potentially and specifically affect NET patients?

  • It can be caused or exacerbated by abdominal surgery to stomach, duodenum, pancreas or via whipples, small & large intestine,
  • poorly controlled diabetes,
  • the long-term use of Proton Pump Inhibitors (PPI) (e.g. omeprazole and lansoprazole, etc). Several studies link to these drugs including this one,
  • possibly long term use of antibiotics which can kill good bacteria.Some evidence of surgical involvement can be found here – this link – particularly the bit about the prevalence of patients who have had an “abdominal surgery” or an “Ileocaecal valve resection”.  I guess that would include many NET patients?  (this is a big article so just focus on table 1 near the beginning).

Symptoms vary for everyone from watery diarrhoea suddenly starting 20 times a day to just bloating and wind in both directions, to nothing at all.  These symptoms are regularly reported by patients so working out the root cause might need some professional help.

Is there any testing for SIBO?

There is a test to check for SIBO is called the Hydrogen breath test. This test uses lactulose ingestion to measure the hydrogen in the breath. If SIBO is diagnosed, treatment is normally via antibiotics. However, advice is to leave a 2 hour gap between taking probiotics and antibiotics and a high dose multi-strain probiotic should be applied.  Our friend Tara has done some work on this alongside Professor Martyn Caplin which was featured at ENETS 2017.

ENETS Research – Assessment of Small Intestinal Bacterial Overgrowth (SIBO) in NET Patients Abstract #1698

Introduction: SIBO is not uncommon in NETs. Hydrogen Breath testing (HBT) using glucose may be more sensitive to proximal SIBO as glucose rarely reaches the colon. Many NET patients are likely to have distal SIBO however, as factors such as ileocecal valve removal apparently increase distal SIBO risk. Thus glucose BT alone may limit sensitivity for detecting SIBO in some NET diagnoses.

Aim(s): Assess likely risk factors for SIBO. Assess sensitivity of additional lactulose HBT and CH4 BT.

Materials and methods: Retrospective data (n=55) of NET patients undergoing HBT was examined. Twelve patients (12/55) who tested negative for glucose HBT but continued to have diarrhoea +/- wind had repeat BT using lactulose. These patients had both H2 & CH4 BT.

Results:
Midgut NET diagnoses were most frequently referred for BT (n=43, 78%). Twenty four (24/55, 44 %) had prior right hemicolectomy. Ten (10/24 ,42%) of those were SIBO positive. Ten patients were positive for HBT prior to being given the glucose substrate, they all had abdominal surgery in the past. Twelve patients who tested negative for glucose HBT had repeat testing using lactulose and measured both H2 and CH4 production. This led to an additional 3 (25%) positive results.

Conclusion:
Abdominal surgery, especially right hemicolectomy increases the likelihood of a positive glucose HBT. Glucose may still be sensitive in those with risk factors for distal SIBO. Additional lactulose use with H2 and CH4 measurement increases the sensitivity in diagnosing SIBO.

Conference:
14th Annual ENETS conference (2017)
Presenting Author: Tara Whyand

Keywords: nets, sibo, dysbiosis

My own Experience

I personally take a 5 billion dosage and am happy to recommend the source offline. However, in addition to obtaining from a reputable provider (i.e. in UK, MHRA approved supplier), there is evidence to suggest as long as it has some or all of the following strains that are widely available, they should provide benefit: Lactobaccilus plantarum, Lactobaccilus acidophilus, Lactobaccilus brevis, Bifidobacterium lactis and Bifidobacterium longum.

This article could have been 10 x longer!  I didn’t even get to the bit about the relationship between the gut and the brain – perhaps another day?

None of this should be considered medical advice.

Article 1 – Vitamin and Mineral Challenges.   This was co-authored by Tara Whyand, UK’s most experienced NET Specialist Dietician.  This blog provides a list of vitamins and minerals which NET Cancer patients are at risk for deficiencies, together with some of the symptoms which might be displayed in a deficiency scenario.

Article 2 – Malabsorption.  Overlapping slightly into Part 1, this covers the main side effects of certain NET surgical procedures and other mainstream treatments. Input from Tara Whyand.

Article 3 – ‘Gut Health’.  This followed on from the first two blogs looking specifically at the issues caused by small intestine bacterial overgrowth (SIBO) as a consequence of cancer treatment. Also discusses probiotics.  Input from Tara Whyand.

Article 4 – Food for Thought.  This is a blog about why certain types of foods or particular foodstuffs can cause issues.

Article 5 – ‘Pancreatic Enzyme Replacement Therapy’. The role of PERT (Creon etc) in helping NET Patients. Input from Tara Whyand.

You may also appreciate these articles where there is overlap:

The Diarrhea Jigsaw – different things can cause diarrhea, it’s not all about syndromes.

The Constipated NET Patient – yes they exist!

Very grateful to Tara for the input.

Other useful links which have an association to this blog:

{a} Read a Nutrition Booklet co-authored by Tara – CLICK HERE

{b} Follow Tara on Twitter – CLICK HERE

{c} Watch a video of Tara presenting to a group of NET Patients – CLICK HERE

{d} Now Watch Tara answering the Q&A from patients – I enjoyed this – NET patients are very inquisitive! CLICK HERE

Thanks for listening