Serotonin – the NET effect

A team of researchers from Case Western Reserve University School of Medicine have used high-powered microscopes for the first time to view serotonin activating its receptor

Background

I’d never heard of Serotonin until I was diagnosed with Neuroendocrine Cancer in 2010.  It is frequently discussed, often with contrasting views from the respondents. One common assumption/question is that it is responsible for many things that can go wrong with Neuroendocrine Cancer patients who have serotonin-producing tumours. “It’s the hormones” is an easy assumption to make or an easy answer to give in response to a complex set of circumstances.  It’s difficult to get a definitive answer and the science behind the behaviour of our hormones isn’t really 100% tied down.

You may see serotonin referred to as a ‘neurotransmitter’, a ‘chemical’ and a ‘hormone’ – this is complex but it is my understanding that it can add context in respect the role/location of the serotonin, e.g. chemical and hormone are essentially synonymous and are endocrine related whereas neurotransmitter is concerned with the nervous system (the neuro in neuroendocrine) and the brain (more on this below). Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).

Serotonin and NETs

One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, in particular, those resulting in carcinoid syndrome which can manifest as a number of symptoms including but not limited to flushing and diarrhea.  Although serotonin is one of the main ‘hormones’ released in excess by certain NETs (mainly midgut), it is not thought to be the main culprit behind some of the symptoms produced by Carcinoid Syndrome.  For example, flushing, the most common symptom (and a cardinal one) is thought to be caused by a number of hormones/peptides – too many to list but the main ones are histamine (particularly foregut), tachykinins (Substance P), bradykinins, prostaglandins …….. and I’m sure serotonin’s in there too!  It does, however, appear to be massively guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.

Where does Serotonin come from?

Serotonin’s technical name is 5-hydroxyltryptamine (5-HT).  It is converted from 5-Hydrotryptophan (5-HTP) which is also known as oxitriptan. 5-HTP is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of serotonin (…..and melatonin) from tryptophan. Tryptophan is interesting as that brings in one of the missing pieces of the jigsaw – food!  Tryptophan cannot be manufactured in the body, it must be brought in via diet. There is no serotonin in food, it is only manufactured in the body.

Tryptophan in food enters the body and serotonin is created by a biochemical conversion process which combines tryptophan (essentially a protein) with tryptophan hydroxylase (TPH), a chemical reactor. I suspect other substances might be involved in that process.  There are two forms of tryptophan hydroxylase – TPH1 and TPH2, which are encoded on two independent genes. TPH1 is linked to peripheral serotonin while TPH2 is related to brain serotonin.

While serotonin cannot cross the blood-brain barrier, tryptophan can, and once there, almost all of it is converted to serotonin. Unlike, peripheral setotonin where only a small percentage is used to generate serotonin. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below and nutrition Blog 4). When you look at the role in brain serotonin, this might have an adverse effect. 

Are you happy with your serotonin?

Serotonin Inhibitors

The introduction of Somatostatin analogues (SSAs) such as Octreotide and Lanreotide, help reduce the secretion of “tumour-derived serotonin”  by binding to its receptors on the outside of the cell.  If you ever wondered why receptors are important, please check out my blog on this subject (click here).

I mentioned tryptophan hydroxylase (TPH) above and that is actually very interesting as this is how Telotristat Ethyl (XERMELO) is able to help with the symptoms of Carcinoid Syndrome diarrhea (not adequately controlled by SSAs) or where patients are unable to be treated by somatostatin analogues for whatever reason. It’s a potent inhibitor of TPH which will disrupt the manufacturing of tumour-derived serotonin. There is also evidence that it can help reduce the effects or halt the growth of the fibrosis leading to carcinoid heart disease.  Slight digression but useful to aid/enhance understanding at this point.  Read about Telotristat Ethyl here.

Serotonin and the Brain

There is constant discussion and assumption that serotonin-producing tumours are somehow causing depression, anxiety and rage.  Not as simple as that, it’s way more complicated.  Certain NETs can overproduce serotonin in the gut but the issues concerning depression and anxiety are normally associated with low levels of serotonin in the brain.

“>Cancer anger” is a normal response to fear, despair and grief – a range of feelings which cancer brings into our lives. It can show as frustration, irritability, emotional withdrawal or aggression. You can feel it whether you have been diagnosed or you are a relative or friend. Cancer anger can happen at any stage of the illness, even years after treatment. I know that many people with cancer suffer from depression, anxiety and anger but they do not all have serotonin-producing tumours.  What they do have is a life threatening and/or life changing condition which is bound to have an effect on mind as well as body.  Hormones including Serotonin are natural substances found in the body and not just there to service NETs.

Serotonin is separately manufactured in the brain (~10%) and in the gastrointestinal tract (~90%).  The serotonin in the brain must be manufactured in the brain, it cannot be directly increased or reduced external to the brain, i.e. it cannot be directly reinforced by gut serotonin (peripheral serotonin). It follows that ‘brain serotonin’ and ‘gut serotonin’ are held in separate stores, they are manufactured in those stores and remain in those stores – there is no cross-pollination. This is managed by something called the blood-brain-barrier (BBB). Therefore, excess serotonin from NETs does not infiltrate the brain. As low-level of ‘brain serotonin’ is often linked to depression, it also follows that it’s possible to have high levels of serotonin in the gut but low levels in the brain.

My simple way of thinking about such things as outlined above, is that low levels of tryptophan in the brain might be contributing to low levels of serotonin in the brain.  To clarify that, I researched the reasons why there could be low serotonin in the brain.

First, let’s dismiss any connection that the type of anti-depressant is called Selective serotonin reuptake inhibitors (SSRIs) is involved. It’s thought that SSRIs work by increasing serotonin levels in the brain. Serotonin is a neurotransmitter (a messenger chemical that carries signals between nerve cells in the brain). We already discussed that it’s thought to have a good influence on mood, emotion and sleep. After carrying a message, serotonin is usually reabsorbed by the nerve cells (known as “reuptake”). SSRIs work by blocking (“inhibiting”) reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells. So tryptophan or peripheral serotonin are not really involved.

It would be too simplistic to say that depression and related mental health conditions are caused by low serotonin levels (in the brain), but a rise in serotonin levels (in the brain) can improve symptoms and make people more responsive to other types of treatment, such as Cognitive Behaviour Therapy (CBT).  It’s also too simple to suggest that NET patients get depression and anxiety due to all the “hormones” these tumours produce.  Of course hormones can be involved in depression and anxiety but hormones aren’t their just for NET patients.  Cancer patients without hormone secreting tumours also get anxiety and depression so it’s possible that NET patients can get depression and anxiety in the same way.

It should also be noted that the precursor to serotonin, tryptophan, does pass through the BBB and it is therefore possible that tryptophan depletion can lead to less availability in the brain for the manufacture of brain serotonin.  Tryptophan depletion can be caused by dietary restrictions (i.e. lack of tryptophan foods) and also by the effects of certain types of tumours as excess serotonin is made leading to less availability of tryptophan.  Both could lead to low serotonin in the brain as less tryptophan gets there. It follows that foods containing tryptophan remain important in order to help maintain normal brain serotonin levels.

Measuring Serotonin levels

Measuring levels of serotonin is important in both diagnosis and management of certain NETs – although it’s probably sensible to test all potential NET patients during diagnosis when the type of tumour is not yet known.  Testing for tumour markers will differ between countries and within countries but the most common standard for testing Serotonin appears to be 5-HIAA (5-hydroxyindoleacetic acid) either via a 24-hour urine test or via a plasma version (mainly used in USA but now creeping into UK).  5-HIAA is the output (metabolite) of 5-HT (Serotonin). Not to be confused with the less reliable ‘serum serotonin’ which is a different test.

Another frequently asked question about serotonin tests is whether they are testing the amount in the brain or the gut. The answer is …… they are testing the levels in the blood. Furthermore, if you are measuring serotonin as an indicator for Carcinoid Syndrome, it has to be remembered that the majority of serotonin is in the gut, so even if serotonin levels in the brain were being measured alongside the gut levels, I don’t believe it would  influence the result in any significant way (but I have no science to back that up). It also has to be remembered that serum serotonin and 5HIAA are not absolute tests, they are not 100% sensitive, they are simply indicators of a potential problem. There are methods of measuring brain serotonin but it is very complex and beyond the purposes of this article.  However, I would just add that it is the reuptake of Serotonin in the brain (plus some other stuff) that can cause depression, not the actual level or amount in the brain.

I intentionally did not mention the other common test (Chromogranin A) or other markers as they are measuring different things but you can read about in my Testing for Markers blog.

Serotonin Video with myself and Dr Mike Morse

I made a video in 2019 with Dr Mike Morse sponsored by Lexicon Pharmaceuticals, Inc.  It’s all about Carcinoid Syndrome with a slant towards hormones, in particular Serotonin. Entitled “Likely Suspects: How Hormones May Lead to Carcinoid Syndrome – What People Living With Carcinoid Syndrome Need to Know”

You need to register to watch although some of you will already be registered and just need an email to login to see the this webcast. The one I’m featured in is the latest in a series on the subject and I’d like to break the record for views please! Please help me achieve this 💙 I would also love to get your feedback and sincerely hope you will find the time to listen in.  Please also find the time to complete the survey at the end.  Thanks

Click on the link here: www.CarcinoidWebcast.com

Don’t forget to press the play button and ensure your sound is turned up, particularly on mobile devices.

webcast morse allan

Summary

I did say it was a difficult jigsaw!

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

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Neuroendocrine Cancer Nutrition Series Part 4 – Food for Thought?

Food for thought

Nutrition is an important subject for many cancers but it is particularly important for Neuroendocrine Cancer.  In the previous parts of this series I focussed on the following:

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

I said in Article 1 that my intention is not to tell you what to eat, even though that might be a challenge for many and this theme continues. The issue with Nutrition and Diet in general, is that it’s very individual and what works for one may not work for another. Rather I’d like to focus in on why such things might have an effect – patients can then experiment and see what works for them. NET patients may have multiple problems and issues (including the effects of eating) which people may be relating to their cancer or the effects of a particular syndrome or treatment (working that out can be difficult!).  Even if I link you to an authoritative site, it will most likely only show GENERAL GUIDELINES, since patients with NET Cancer should really be assessed on a case-by-case basis.  However, I can say that from personal experience, these guidelines are a good base to start in understanding the issue.  You should always seek professional advice from a reliable ‘NETs aware’ nutritionist that can help you determine what your nutritional needs are and also can guide you in the right direction regarding food and supplement intakes.  Be wary of the internet on diet and nutrition, there is much ‘quackery’ out there and normally they want to sell something regardless of whether it’s good for you or not.  Fake healthcare news is big business unfortunately.  You may also enjoy article 2 and article 3 of this series in internet dangers.

In this article, I want to cover the ‘knotty’ problem of what is in food that might be provoking a reaction and why.  The other thing I would emphasise is that the cause of ‘provocation’ might not just be from what you have eaten, but how much. Moreover, whether the cause is syndromic, due to treatment; or from a comorbidity. For example, if you’ve had classic small intestinal NET surgery, you’re likely to be missing a few feet of small intestine and at least your ascending colon and all that goes with that (i.e. you’ve had a right hemicolectomy).  It follows that your food might transit quicker than normal on its journey from mouth to toilet.  There are no doubt other issues which might cause you to ‘move quickly’ and most of these issues will have been covered in Series Articles 1, 2 and 3.  For those with Carcinoid Syndrome, you may also find my blog on the 5 E’s useful.

A high level of serotonin is something people might be looking to avoid due to its relationship with midgut NETs and in particular those with Carcinoid Syndrome. One thing I noticed is that experienced dietitians are not saying you must totally avoid foods associated with serotonin.  I say “associated” because serotonin is not found in foods (another NET myth), it is manufactured from the amines in food.  The only time dieticians would recommend staying totally away from these foods is before and during a 5HIAA urine test (5HIAA is a by-product of serotonin) as this could skew the results. Experienced NET dieticians will also tell you that amines in foods containing the precursor to Serotonin will not affect tumour growth.  

It’s not just a serotonin problem – it is actually a much wider issue with something ‘vasoactive amines’ (or pressor amines).  They are precursors for catecholamines such as adrenaline, which trigger some NETs to secrete vasoactive substances, which cause symptoms or in extreme cases, carcinoid crisis.  Tyramine is the most active of these amines. Other strongly active vasoactive amines found in food include histamine that can cause strong dilation of capillaries, and also cause hypertensive crisis.  Reported reactions from these vasoactive amines are acute hypertension, headache, palpitations, tachycardia, flushing and unconsciousness. As a general rule, Tyramine and other pressor amines are usually only present in aged, fermented, spoiled protein products, but quite often, it’s food containing a precursor amine that is what you are looking for (for example Tryptophan is a precursor to Serotonin).

Personally I cannot think of a single food which causes me to have a ‘reaction’ other than if I eat too much or eat something with a high fat content.  Basically for someone who has had abdominal surgery, the system cannot cope for one reason or more – see Series Article 2.   It’s important to distinguish this type of reaction which is actually something caused by the consequences of cancer treatment rather than one of the ‘syndrome’ effects .  The answer might simply be to reduce or adjust food intake rather than cut foods out, particularly foods that you may need for nutrition and energy.  And of course, foods you enjoy which don’t cause issues, are related to quality of life.

What I do know from masses of experimentation and running a diary, is that large meals can give me issues. However, as hinted above, I put that down to surgery – NOT syndrome.  I also reduced consumption of fatty foods but that was mainly to combat malabsorption caused by my surgery and exacerbated by Somatostatin Analogues. Again NOT syndrome. I reduced alcohol but mainly because I was concerned about my compromised liver after surgery.

So what are the most provocative foods?  This diagram here is extremely handy BUT I must emphasise that the cause of the provocation may not have been caused by the food itself, just what people think and reported (clearly scientific intervention might prove it was caused by something else).  Everyone is different, so some people might not have any reaction to these foods.  As you can see, a large meal is top and I can almost guarantee much of this was caused by people having a shorter bowel due to surgery.

foods provoking
Graphic courtesy of The Carcinoid Cancer Foundation (CCF)

What are the foods containing high levels of these vasoactive amines?  It is here that I refer you to a site which was one of the very first things I read after my diagnosis, and I re-read it after my initial treatment when I discovered that my debulking and cytoreductive surgery came with some consequences.   This is an amazing piece of research put together by the late Monica Warner (wife of Dr Richard Warner) who herself said “It has not been an easy task to put these guidelines together“.  I don’t believe there is another source of such detailed research and guidelines on the Nutritional Concerns for the NET Patient (note the term Carcinoid is used throughout, therefore it tends to be focused on carcinoid syndrome.  Many other NET Syndromes have associated diet and nutrition constraints and problems too.

This is not an exact science and as the author said “I must emphasize at this point that these are only GENERAL GUIDELINES since patients with carcinoid (sic) may have multiple problems and must be assessed on a case-by-case basis.”. So for example eating a big meal comes out top of the survey and does not necessarily mean that is caused by carcinoid syndrome – as I said above, it’s very frequently caused by having a shorter gut, or no gallbladder, and other issues. You can eat a large meal containing very low levels of the offending amines and still run to the bathroom because your waste disposal system can’t cope with the amount – that is not a syndrome problem.  One person’s perceived ‘syndrome’ problem is another person’s cancer treatment ‘side effect’.  Working out which one is not easy but it’s worth the effort to try to understand which one might be causing the problem.

READ THE RESEARCH AND GUIDELINES BY CLICKING HERE

I hope you found my ‘food for thought’ tasty 🙂

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

[e] There is an excellent video from the NET Research Foundation (what to eat and why) – CLICK HERE

 

You can hear me talk about my diagnosis by clicking here

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

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