I quite like the Facebook memory thing. This morning I got a reminder of a post I made from 7 years ago whilst I was in hospital recovering from my 9 Nov surgery. It had taken 12 days for me to feel strong enough to venture onto social media with a simple message “I’m feeling perkier”. For those not familiar with English localisms, it just means lively, spirited, bright, sunny, cheerful, animated, upbeat, buoyant, bubbly, cheery, bouncy, genial, jaunty, chirpy, sprightly, vivacious, in fine fettle, full of beans, bright-eyed and bushy-tailed. I guess I met some of these descriptors most of the time! I had gotten through the worst and the light at the end of the tunnel was now a faint glimmer.
I’ve recently had a ton of ‘7 years ago cancerversaries’ and there’s still a few to go! I’m currently being reminded of an issue that started just after my initial treatment and by coincidence (perhaps?) the commencement of my Lanreotide (Somatuline Autogel). Itching! However, for me, it’s mainly the right leg below the knee (go figure!). Much less frequently on my arms and sides. I know many people have the same issue but no-one ever seems to find out why – I guess it’s that Neuroendocrine jigsaw thing again?
Initially, I put the issue down to Lanreotide, as this is mentioned in the side effect list on the drug instructions. The initial connection was made because it seemed to be happening immediately after my monthly ‘dart’. A really annoying itch mostly around my ankles and which had to be scratched! An application of a general emollient cream for a few days seemed to do the trick and after a week it was gone (until the next injection …..). However, after a few years, I sensed the issue was drifting away from the injection cycle and adopting a different and more random pattern. I’m also suspicious of a nutritional connection and checking my article Nutrition for NETs -Vitamins and Mineral Challenges, I can see Vit B3 (Niacin) and Vit E are mentioned in regards skin issues. I’d be confused if this was an issue today as I now take plenty supplements to offset GI malabsorption. However, I probably wasn’t taking sufficient between surgery and 2013 as I lacked the knowledge to do so at the time. So nutritional deficiency remains a possibility or at least an added complication. The most recent outbreak has unusually gone on for the last 4 weeks.
I also seem to have had an eczema type issue in my right ear and mild rosacea for more than 7 years (pre diagnosis). As you can imagine my ‘inner detective’ is working overtime! One thing is clear – this itchy leg issue has plagued me for 7 years.
I know that many people have real issues with rashes and skin itching, I’ve seen this so many times with some people describing it as severe. Clearly when this is the case, a doctor’s intervention is generally required. I’ve seen the following connections to NETs and skin issues:
Glucagonoma – a type of functioning pNET can often come with dermatological issues.
Of course there is a Neuroendocrine Carcinoma of the skin known as Merkel Cell Carcinoma – more of a skin lesion effect than regular dermatological issues.
Edit: 2019. Winter in UK has made my itching seem worse, perhaps the cold weather plays a factor. Maybe I just currently have what many people have – dry flaky skin and the onset of winter probably isn’t helping?
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 andnutrition Blog 4). When you look at the role in brain serotonin, this might have an adverse effect.
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 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
Neuroendocrine Cancers can sometimes present with one or more vague symptoms which occasionally results in a lengthy diagnostic phase for some. Sure, there can be issues with doctor experience and knowledge that can add to the problem. However, some people do present with multiple vague and confusing symptoms and some people have comorbidities which have similar symptoms. Textbook diagnostics just don’t make sense, sometimes even when the doctor suspects Neuroendocrine Cancer i.e. classic symptoms of ‘something’ but with negative markers for NETs. Clearly those are extreme cases and just like other complex diseases, many diagnoses of Neuroendocrine Cancer can be extremely challenging. Even for an experienced doctor, it can be a difficult jigsaw!
Most types of Neuroendocrine Cancer can be accompanied by a ‘syndrome’ i.e. the tumours are ‘functional’ and this is normally (but not always) associated with metastatic disease. At this point it’s also worthwhile saying that some Neuroendocrine Cancers can be ‘silent’ (non-functional) for years before any symptoms show and it’s normally only when they metastasize, that these clinical syndromes come to life. Ironically, the manifestation of the disease with a syndrome can occasionally turn out to be a life saver albeit the cancer is normally incurable at this stage – but still treatable.
The most common type of Neuroendocrine Cancer can often present as a collection of symptoms known as Carcinoid Syndrome and the most common of these is flushing with approximately 84% frequency. Others symptoms include (but are not limited to) diarrhoea, heart palpitations, stomach cramps and general abdominal pain/discomfort, shortness of breath, wheezing. You can see the scope for confusion and misdiagnosis. You may find my blog on the ‘5 E’s of Carcinoid Syndrome’ useful.
When you look at these general Carcinoid Syndrome symptoms, flushing seems to be the one that stands out as a ‘cardinal sign’ whereas many others are vague and easily confused with common/regular illnesses. However, the flushing is reported to be different from most people’s perceptions of a ‘flush’. The Carcinoid flush is almost always ‘dry’. To quote my ‘amazing yellow book‘ (co-authored by Woltering, Vinik, O’Dorisio et al), “…. a good rule of thumb is if the flushing is wet (accompanied by sweating), it is due to a cause other than Carcinoid”. Dr James Yao, another well known NETs guru also raises this distinction by stating…. “The facial flushing of carcinoid syndrome is usually a dry flushing, and not associated with sweating like other kinds of flushing. The flushing is often a symptom that others notice before patients do. They may not feel it themselves.”
Additionally, from the same source, there appears to be at least two varieties of flushing in Carcinoid Syndrome related to two different anatomical regions of the primary tumour (again a useful guide from my amazing yellow book):
What to Look For in Flushing – Distinguishing Signs and Symptoms
There are two varieties of flushing in carcinoid syndrome:
1. Midgut: The flush usually is faint pink to red in color and involves the face and upper trunk as far as the nipple line. The flush is initially provoked by alcohol and food containing tyramine (e.g., blue cheese, chocolate, aged or cured sausage, red wine). With time, the flush may occur spontaneously and without provocation. It usually lasts only a few minutes and may occur many times per day. It generally does not leave permanent discoloration.
2. Foregut tumors: The flush often is more intense, of longer duration, and purplish in hue. It is frequently followed by telangiectasia and involves not only the upper trunk but may also affect the limbs. The limbs may become acrocyanotic, and the appearance of the nose resembles that of rhinophyma. The skin of the face often thickens, and assumes leonine facies resembling that seen in leprosy and acromegaly.
Another source for flush descriptions comes from a paid article written by well known NET Endocrinologist – Kjell Öberg.
Four different types of flushing have been described in the literature.
Endocrinology: Adult and Pediatric – 7th Edition 2016.
The first type is the diffuse, erythematous flush, usually affecting the face, neck, and upper chest (i.e., normal flushing area). This flush is commonly of short duration, lasting from 1 to 5 minutes, and is related to early stages of malignant midgut NETs.
The second type is violaceous flush, which affects the same areas of the body and has roughly the same time course or sometimes lasts a little longer. These patients also may have facial telangiectasia. This flush is related to the later stages of malignant midgut NETs and is normally not felt by the patients because they have become accustomed to the flushing reaction.
The third type is prolonged flushing, lasting for hours up to several days. It sometimes involves the whole body and is associated with profuse lacrimation, swelling of the salivary glands, hypotension, and facial edema. These symptoms are usually associated with malignant bronchial carcinoids.
Finally, the fourth type of flushing reaction is bright red, patchy flushing, which is seen in patients with chronic atrophic gastritis and ECLomas (derived from enterochromaffin-like cells) of the gastric mucosa with evidence of increased histamine production.
Differential diagnoses for flushing?
The facial flushing associated with NETs should be distinguished from other causes of flushes. The carcinoid syndrome flush is provoked by spicy food, alcohol, and physical and psychological stress, and it is often worse in the morning. Patients with idiopathic flushes usually have a long history of flushing, starting rather early in life and sometimes with a family history without occurrence of a tumor. Menopausal flushes usually involve the whole body and might be related to release of calcitonin gene–related peptide (CGRP) with transient vasodilation, a so-called dry flush. Another type of menopausal symptom is the wet flush, which includes epinephrine-induced sweating. Proposed mediators of flushing in menopause are CGRP, histamine, prostaglandins, serotonin, lysyl-bradykinin, and substance P. Estrogen is known to have an impact on the production and release of different signaling substances such as noradrenaline and β-endorphin. Low estrogen levels cause lower β-endorphin activity, which in turn enhances the release of gonadotropin-releasing hormone (GnRH), which gives rise to high luteinizing hormone (LH)levels. Postmenopausal women in whom a true carcinoid syndrome is developing can tell the difference between the two types of flushes. Sometimes patients with medullary thyroid carcinoma have brief flushes provoked by alcohol. In patients with watery diarrhea, hypokalemia, achlorhydria syndrome (WDHA; vasoactive intestinal peptide [VIP]omas), a purple-red constant flushing of the whole body may develop. This flushing reaction is related to the vasodilator effects of VIP. Flushes seen in mastocytosis are related to release of histamine from mast cell granules. Mastocytosis is a rare disease of mast cell proliferation that occurs both cutaneously and systemically.
So it’s clear from our experts that the flushing symptom has many potential triggers and can be attributed to the secretion of excess hormones associated with Neuroendocrine Tumours. It’s also clear that the symptom is not just associated with carcinoid syndrome. Although many people focus on serotonin as the main culprit, there appears to be significant evidence to suggest that other hormones may be playing a bigger part with this symptom, e.g. histamine (particularly foregut), tachykinins (Substance P), bradykinins, and prostaglandins.
If you study the online forums, there are frequent questions about flushing, particularly from those looking for a diagnosis and are suspecting Carcinoid Syndrome due to a flushing symptom. However…… even flushing cannot always be attributed to a NET, particularly if it’s the only symptom being presented.
This is a very useful table taken from my amazing yellow book which gives the tests required to determine the potential source of a flushing (differential diagnosis). I strongly suspect this is not an exact science (…..is anything in medicine?) but it’s extremely useful. Personally I would have included Rosacea :-). The referenced article “>Endocrinology: Adult and Pediatric – 7th Edition 2016 by Öberg, Grosssman et al, generally agrees with this list but adds WHDA Syndrome (a pNET called VIPoma), food, drugs, ethanol and idiopathic. It also generalises Neurologic disorders (see more below).
Öberg, Grosssman, et al list the following drugs that can cause flushes:
Calcium channel blockers
Öberg, Grosssman, et al list the following foods that can cause flushes:
Öberg, Grosssman, et al also list the following neurologic disorders that can cause flushes:
Spinal cord lesions
Clearly these lists are those that can cause a flush but not everyone will experience this. For example, when I was syndromic with flushing, I never had any issues with hot beverages.
My own experience with flushing brings back some memories and it emphasises something I say a lot – the patient has a big part to play in their own diagnosis. Please check out this 90 second video about how I did not play my part! I was experiencing a mild and innocuous flushing sensation for some months before I was diagnosed with metastatic Neuroendocrine Cancer. Even though I knew it was weird and something I hadn’t experienced before, I totally ignored it. I failed to mention it at any of my routine GP appointments or my annual asthma clinic. I failed to mention it to my specialist who was investigating a GP/PCP diagnosis of Iron Deficiency Anemia/weight loss. After a CT scan, the specialist appeared to be scratching his head ….. at that point he knew I had cancer but he also knew it was unusual. I suddenly mentioned the flushing and ‘bingo’. It was the face of a man who had just found a missing piece of a jigsaw and he correctly predicted the output from my subsequent liver biopsy.
For the next few months, I was keeping my condition private at work but it was sometimes difficult to disguise the flushing. At least one person thought my blood pressure was going up! Fortunately, my flushing disappeared after treatment.
I’ll complete this post with an interesting summary from an online forum post in which I was participating. There was a general discussion about the severity of ‘syndrome symptoms’ including triggers and I was staggered to read that people were experiencing flushing whilst carrying out routine day-to-day tasks. I’m so happy I don’t flush when I eat one square of chocolate (that would be a complete disaster!). The one which caught my attention was the simple act of washing hair. Whilst I initially raised my eyebrows and laughed, it did make me think back to the last flush I experienced (and touch wood it was the last …..). Following my diagnosis, I commenced daily injections of Octreotide. These injections reduced the flushing but it didn’t eliminate it. However, after my ‘debulking’ surgery in Nov 2010, my flushing disappeared. However, I do remember this small flush coming out of nowhere whilst I was recovering in hospital after that surgery. I was cleaning my teeth and I do vividly remember this minor task taking some effort!
I haven’t had a flush since and if this symptom comes back, I’ll know I have a new problem to contend with.