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Ronny Allan
Background. It’s important to note that not every type of Neuroendocrine Neoplasm will get the same tests due to the heterogenous nature of this cancer type. Some are more specific than others. A wide range of tests may be necessary at diagnosis if the type of NET is not clear.
This post will cover one of the main tests to check for a common type of Neuroendocrine Tumour (NET) that is known to secrete excess amounts of the hormone Serotonin leading to symptoms indicative of Carcinoid Syndrome.
These tumours are often labelled using the antiquated and misnomer term ‘Carcinoid Tumour’ but more and more healthcare organisations and specialists are avoiding use of this term for several reasons. Mainly because the word has been 99% removed from the widely accepted World Health Organisation (WHO) tumour classification system but more importantly because it masks the hidden dangers within Neuroendocrine Neoplasms given its misnomer meaning. I also note many sites have started using the term “serotonin secreting NETs”. That said, the term “Carcinoid Syndrome” still lingers along with other misnomers.
Functional/Non-functional
NETs can be ‘functional’ meaning they oversecrete particular hormones leading to a hormonal syndrome associated with their primary tumour. These are known as functional tumours. Most NETs are actually non-functional, but the likelihood of being or becoming functional is higher in certain types of serotonin secreting NETs, particularly in the midgut small intestine area.
What is 5-HIAA?
5-Hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin thus why it is used to help diagnose or at least suspect (so called) carcinoid syndrome. However, a positive test result in the absence of a biopsy is suggestive but not diagnostic of a serotonin secreting NET. It’s also useful to check the risk of succumbing to (or monitoring) Hedinger Syndrome (carcinoid heart disease). The sensitivity and specificity are both fairly high.
5-HIAA can also be used for surveillance, i.e. to monitor previously diagnosed serotonin secreting NET patients where they are still actively functional or where this patient may be at risk for refractory symptoms. I will also cover the Serotonin test as it is often used alongside/instead of 5-HIAA (…. rightly or wrongly).
Things to know about test results and restrictions
It’s really important to understand these points when discussing test results and restrictions:
1. Test Name. When discussing your test, it’s important to avoid general terms such as “24-hour urine” as there is actually a kidney function test known by that name. Plus, there is more than one 24-hour urine test used in NETs (keep reading). Moreover, they all have different results information and restrictions. Different labs may have different names too.
2. Results. These can differ between laboratories in terms of the unit of measure and the reference range. This can cause havoc and misunderstandings in patient groups as people try to compare apples with pears. Always know your lab data so you can filter out responses in patient groups.
3. Restrictions. Ditto. Different test kits not only produce different testing score outputs (unit of measure and reference ranges) but also the testing constraints. 5-HIAA has many restrictions including fasting (including certain supplements) and drugs for co-existing conditions. The fasting periods can also be different. You must adhere to the restrictions list from your own lab.
There are two methods of testing: Urine and Plasma. The latter is a much newer addition to the testing capability and may not yet be available where you live. The rather obvious difference between the two is practicality.
Note: Healthcare organisations buy their test kits from commercial companies, there are many different test kits in use, each with potentially different instructions. Labs may also have different processes for handling and storing. Thus, why it is advisable where possible to use the same lab.
5-HIAA (urine)
Synonyms include “24-hour urinary 5-HIAA”, “u5-HIAA” and many sites will exclude the hyphen, e.g. 5HIAA. A 24-hour urine sample is preferred for the 5-HIAA test because the amount of 5-HIAA in the urine can vary throughout the day. Snapshots are therefore unreliable.
With the 24-hour urine, there are two key challenges:
1. The logistics (i.e. collecting, storing and transporting the container). Containers normally need to be collected which adds to the logistical problems but if you are also doing blood tests, you can make one of the trips to collect/deliver for those. I personally found it easier to collect the container and then return with the container completed as per the instructions, dropping it off at the lab and then get the bloods done. The container in my lab has a small amount of preservative in them as 5HIAA can degrade. You will also find that some countries specify fridge storage during the test which adds another level of logistic need. Most countries are told to keep it in a cool damp place and that isnt necessarily a fridge. I guess there may be certain factors taken into account when labs issue this detail, e.g. local temperatures and also whether container preservative is used or not.
2. Fasting. I find many instructions confusing. Some are worded to suggest 3 days before the test starts (i.e. 4 days if you include fasting during the test), e.g. “Restricted foods should be avoided for 3 days prior to and during urine collection“, another stated “You will be told not to eat certain foods for 3 days before the test“. I think both are badly worded. In fact, there are numerous variations on the fasting theme, but most labs tend to restrict at least the following foods that contain high levels of serotonin producing amines: bananas, plantain, plums, pineapples, kiwi fruit, figs, dates, cantaloupe melon, honeydew melon, grapefruit, walnuts, pecan, macadamia, brazil nuts, aubergine, olives, broccoli, spinach, cauliflower. Your lab may also list health food supplements containing 5-hydroxytrytophen (5-HTP). 5-HTP is a chemical that the body makes from tryptophan, an essential amino acid that you get from food. After tryptophan is converted into 5-HTP, the chemical is changed into serotonin. Always follow your own lab instructions.
Drug contraindications. There are also medicinal limitations including drugs that can also alter 5-HIAA urine values, such as acetanilide (paracetamol/acetaminophen), glyceryl guaiacolate (found in many cough syrups), cisplatin, fluorouracil, melphalan. Drugs that can decrease urinary 5-HIAA levels include isocarboxazid, moclobemide, isoniazid, levodopa, ethanol, methyldopa, chlorpromazine, and imipramine (tricyclic antidepressants). Patients should talk to their doctor before decreasing or discontinuing any medications. Always follow your own lab instructions.
If you’re not given instructions from your testing site prior to the test (i.e. 3 days before picking up your container to start the test), someone is not doing their job. I can’t put that any other way.
Please note the test results from 5HIAA urine. There will be 3 figures normally. One is the volume of urine sample provided. There is the 5-HIAA figure over 24 hours (this is the one you are most interested in as a measure) and there is normally a urine creatinine level given too.
5-HIAA Plasma
Clearly a more practical method of testing compared with urinary 5-HIAA above and has been clinically validated and provides equivalent clinical information.
My own Centre of Excellence hospital has produced a sheet “Preparing for the Blood Serum 5HIAA Test”. In addition to the usual list of foods to avoid as per urine 5HIAA, it says to avoid those foods for 24 hours before the test, a 10 hour fast before the test and only drink water 8 hours before the test
Looking at other sites, I can see there doesn’t appear to be a consensus. For example, I did find some links to sites who say 2 and 3 days before the test – that looks like a cut and paste from the urine test without fact checking.
Again, always follow your own lab instructions.
5HIAA vs Serotonin testing
I know from my private group that many people (particularly in US) get a Serotonin test in addition to 5HIAA with some just doing the Serotonin test. The issue with just measuring serotonin alone is the possibility of a timing issue, a snapshot may be taken at a time when serotonin is not oversecreting – it’s known to fluctuate throughout the day. This is precisely why the 24-hour Urine 5-HIAA was introduced. It smooths out these fluctuations (but only if the test is carried out properly).
The Serotonin blood test is also known as 5-HydroxyTryptamine or 5-HT. 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”.
Many sites have different test preparations with some only suggesting a contraindication with drugs missing out constraints on food. There are a variety of drugs that can affect the serotonin test result, including morphine, monoamine oxidase (MAO) inhibitors, methyldopa, and lithium. Some sites do not specify any food restrictions for the serotonin. Once again, always go by your own lab instructions.
My own experience as a Small Intestine NET
My 5-HIAA (urine) was elevated at diagnosis (133 umol/24hr (reference range <42). It returned to normal after removal of my primary and commencement of Lanreotide. It was a good measure of tumour functionality while I was functional.
2. I was moved to the plasma version in 2019. Pleased to be doing this test, it is so much easier than the urine version.
3. As I’m non-functional, I’m currently tested every 12 months. Clearly if I report any hormonal over secretion symptoms, ad hoc tests would be conducted.
Opinion: Test Instructions and Restrictions
Given the wide discrepancies that exist on the fasting and contraindications that can be found on the internet, I’ve always been sceptical of the instruction sheets handed out from various labs. I think there are a number of issues:
1. I also think that many sites produce the same information sheet for all types of 24-hour urine test for NET, e.g. for 5-HIAA and catecholamines and this explains why caffiene sometimes appears on 5-HIAA when it only appears to be necessary for catecholamines due to the specific requirement this test has (caffeine is a stimulant, which means it increases the circulation of chemicals such as cortisol and adrenaline in the body, so that makes sense for the catecholamine secreting NETs called Pheochromoctyoma/Paragaglioma).
2. Hospital instructions may often be compiled by people who are not comparing with the test assay in use but instead finding out of date info on the internet and copy and pasting.
3. Others may be just a ‘versioning’ issues as instructions are not updated following the commissioning in the laboratory of a new or updated test assay exacerbated by the fact that many tests or sent to off-site labs, but the offsite lab has not provided test instructions i.e. the hospital ordering the test is responsible for updating and issuing the instructions to patients but is unaware of changes in assay instructions from the lab.
4. Judging by the amount of people asking for advice in my patient group, some testing sites are not providing test instructions. This can only provide skewed results and/or confusing outputs not fully understood.
I recently found a study which was published in an Endocrine magazine. The objective of the study was to: To re-evaluate the recommendations for urinary sampling (preservatives, diet, drugs, etc.) as many of the reported analytical interferences supporting these recommendations are related to obsolete assays. The link to the whole document is given below. The article also covers the 24-hour urine catecholamines and/or their methoxylated metabolites (metanephrines) test for Pheochromocytoma/ Paraganglioma
I very much suspect that many hospitals continue to send out of date instructions to patients and that view is cemented after reading the attached. For example, one quote from the reference below states:
Modern assays for the determination of the excretion of urinary 5HIAA and metanephrines are electrochemical or mass spectrometry assays. Molecules are detected after HPLC to sort the molecules in both techniques. Electrochemical quantification is very sensitive but interferences may occur (e.g. paracetamol). Mass spectrometry now achieves high sensitivity along with its high specificity (although for a higher cost). Subsequently, some ancient recommendations for urine collection are thus obsolete.
Urinary sampling for 5HIAA and metanephrines determination: revisiting the recommendations
in Endocrine ConnectionsAlways follow your own lab instructions, regardless of this blog post
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Dear Mr. Allen, I’m so very confused. I was diagnosed with Carcinoid Syndrome 8 months ago. My CgA numbers went up to 20,000, my oncologist started monthly shots of Sandostatin LAR. This helped to bring my CgA numbers down to 12,000. They increased my shots to every 3 weeks now and it has brought my numbers down to 200. I’ve had scopes and scans, everything they’ve found so far has been negative. My confusion is if they continue to not find any growth, dose that mean I won’t develop NETS. I really don’t like not knowing. Thank you.
this is not really the best way to have a conversation. It is better to ask in the group or message me on facebook. But the questions I would be asking you are:
1. Carcinoid Syndrome is caused by over secretion of serotonin from a neuroendocrine tumour and an elevated 5HIAA is the test for carcinoid syndrome. Has that been tested?
2. Chromogranin A is a test for NET (not carcinoid syndrome but there can be loose correlation). Those numbers are big and could be falsely raised due to (amongst other things) the use of acid reflux medications, do you take this type of medication?
3. It’s impossible to answer the question about growth as no-one knows, not even your doctor.
4. They need to identify the tumours, which means CT, MRI, Ga68 PET/CT scans, endoscopy, colonoscopy, etc etc etc. Have all those things been done?