Research Forum
Testing for Poison/"Vitamin A" is practically DESIGNED to avoid looking in the right places!
Quote from Dr. Garrett Smith on January 15, 2019, 9:16 pmMy video covering the different tests for Poison/"Vitamin A":
https://youtu.be/A37MeQknnio
Let's go over the big types of Poison/"Vitamin A" first, and how they show up in the body:
- Retinyl esters - This is retinol bound to a fatty acid...an example is retinol + palmitic acid = retinyl palmitate. These are the main "storage" forms in the liver and tissues.
- Retinoic acid (and all its variations) - This is the most "biologically active" (read: damaging) form of Poison/"Vitamin A". Retinoic acid is used as a "chemical peel" on the skin to cause "controlled wounds". Yeah, it's NASTY stuff.
- Retinol - This is called "animal Vitamin A", as opposed to carotenoids being "plant Vitamin A".
- Retinol Binding Protein - This carts retinol around the body, protecting us from free retinol, and that free retinol turning into retinoic acid (see above).
People wonder, if there is this supposed "epidemic" of Poison/"Vitamin A" toxicity around, why isn't it showing up in the research and on blood tests? I'm going to tell you why. It's hard to find something toxic when: 1) it is thought to be a nutrient we need, when it isn't, 2) no one knows how to look for it, and even if they did, 3) the tests aren't easily available.
You need to know that the only real mainstream test commonly used by physicians to look for Poison/"Vitamin A" in the body is called serum retinol. It is widely available, through both LabCorp and Quest Diagnostics. I do use this test in my Nutritional Restoration clients, because it is really the best we have for now. You'll see below.
From what I said above, wouldn't retinoic acid be the best one to test? From the scientists themselves:
Retinol (vitamin A) circulates at 1–4 μM concentration and is easily measured in serum. However, retinol is biologically inactive. Its metabolite, retinoic acid (RA), is believed to be responsible for biological effects of vitamin A, and hence the measurement of retinol concentrations is of limited value. A UHPLC-MS/MS method using isotope-labeled internal standards was developed and validated for quantitative analysis of endogenous RA isomers and metabolites. The method was used to measure retinoids in serum samples from 20 healthy men. In the fed state, the measured concentrations were 3.1 ± 0.2 nM for atRA, 0.1 ± 0.02 nM for 9-cisRA, 5.3 ± 1.3 nM for 13-cisRA, 0.4 ± 0.4 nM for 9,13-dicisRA, and 17.2 ± 6.8 nM for 4oxo-13-cisRA. The concentrations of the retinoids were not significantly different when measured after an overnight fast (3.0 ± 0.1 nM for atRA, 0.09 ± 0.01nM for 9-cisRA, 3.9 ± 0.2 nM for 13-cisRA, 0.3 ± 0.1 nM for 9,13-dicisRA, and 11.9 ± 1.6 nM for 4oxo-13-cisRA). 11-cisRA and 4OH-RA were not detected in human serum. The high sensitivity of the MS/MS method combined with the UHPLC separation power allowed detection of endogenous 9-cisRA and 4oxo-atRA for the first time in human serum.
In case you missed the above:
- Retinol - (supposedly) biologically INactive form, easy to test, limited value
- Retinoic acid - biologically active (in a BAD way), harder to test, assumed to be of greater value (I agree)
- It required TWO methods to be combined, and they actually tested for SEVEN different forms of retinoic acid (only finding 5 of those 7)!
- Side note - Levels of retinoic acid didn't significantly change when the subjects were fed vs. fasted. Detoxing Poison/"Vitamin A" out of the system is not an overnight process.
Retinoic acid(s) testing is more difficult (two methods), with more tests (five forms), leading to much more research and interpretation necessary. Most doctors don't know anything about Poison/"Vitamin A" to begin with. Which route do you think they would pick?
The bigger problem is, that while scientists in studies have measured these retinoic acids, I can't find any major laboratories that offer this service to physicians (if you do, please share with me!). A great test doesn't matter if it can't be applied to the general public.
Next, testing retinyl esters. By assessing the ratio of retinyl esters (storage form) to the total amount of retinol + retinyl esters in the blood, the liver's saturation/toxicity level of Poison/"Vitamin A" can be indirectly assessed. This is a great test, but also relatively unavailable. The only one I can find is from ARUP Labs, a specialty reference laboratory. They measure serum retinol and serum retinyl palmitate...BUT, retinyl palmitate isn't the only retinyl ester, it's just the main one...in essence, it isn't the same test! Here is the full list of retinyl esters present in a study on ferrets: retinyl palmitate, retinyl stearate, retinyl oleate, retinyl linoleate, retinyl myristate, retinyl heptadecanoate, retinyl arachidonate, and retinyl laurate. Another type of retinyl ester is used in supplements and food fortification, and that is retinyl acetate.
To assess the liver toxicity via this test, a percentage is calculated: [serum retinyl palmitate / (serum retinol + serum retinyl palmitate)] * 100% = percentage of total VA as retinyl palmitate. Note that retinyl palmitate isn't all of the retinyl esters though! At best, it probably accounts for around half of them.
Yet again, we have a test that will be more expensive, more challenging to get (trust me, I'm still figuring out how to make it happen for my US clients across the country, I have no idea where to even begin for my international clients), and incomplete in the information it provides compared to the research. Are you seeing a pattern yet?
Finally, we have serum retinol and retinol binding protein (RBP). I'm going to talk about them together.
First, because Poison/"Vitamin A" is so misunderstood in the research, I believe RBP to be EVEN more misunderstood (I'm still working on figuring it all out myself...the good news is I don't think complete understanding of it is necessary).
Next, looking at serum retinol is only useful when people understand that Poison/"Vitamin A" is NOT a nutrient and that the desired range is MUCH lower than the "normal" range. "Normal" is SICK these days, folks. You don't want to be "normal".
Serum retinol combined with RBP testing together could potentially be useful. Why is this? Because free retinol is toxic too:
Vitamin A Metabolism in the Fetus and Neonate
Hypervitaminosis A occurs when the amount of plasma retinol exceeds the availability of RBP to bind it, leading to unbound and elevated levels of free retinol in plasma, and formation of excess retinoid metabolites.
Excessive quantities of free retinol will damage plasma membranes of the liver and other tissues, as well as hepatic lysosomal membranes.
I have not had the time to search for the science on what the ratio of free retinol is that indicates toxicity. Again, this would require two separate tests, increasing the cost, difficulty (2 tests is harder than 1, more chance for error), and interpretation requirement.
To sum up, testing for Poison/"Vitamin A" is going to be difficult, regardless of the direction taken. Let's use the above information to show how all of the information points towards the innate toxicity of Poison/"Vitamin A":
- Retinoic acid - Seriously, it's used as a chemical peel!
- Retinyl esters - The storage form of Poison/"Vitamin A", and research shows that if more than 7.5% of your circulating Poison/"Vitamin A" is made up of retinyl esters, your liver is toxic with it for sure (see more at the reference link above).
- Retinol - Free retinol is toxic. It's only safe when it is bound to RBP, which implies that the body has to make proteins to protect you from it!
Which part of this PATTERN OF TOXICITY holds true for ANY OTHER "VITAMIN'???
The answer is NONE. That's because it is toxic to the core. It is not a "vitamin" now, nor ever was one. Don't confuse "having a biological effect" with "required to be obtained from food to live".
In my practice currently, I do like to use the serum retinol test to establish a baseline level. Not perfect by any means, yet it gives the most information possible at the lowest cost and least inconvenience to the client/patient.
My video covering the different tests for Poison/"Vitamin A":
Let's go over the big types of Poison/"Vitamin A" first, and how they show up in the body:
- Retinyl esters - This is retinol bound to a fatty acid...an example is retinol + palmitic acid = retinyl palmitate. These are the main "storage" forms in the liver and tissues.
- Retinoic acid (and all its variations) - This is the most "biologically active" (read: damaging) form of Poison/"Vitamin A". Retinoic acid is used as a "chemical peel" on the skin to cause "controlled wounds". Yeah, it's NASTY stuff.
- Retinol - This is called "animal Vitamin A", as opposed to carotenoids being "plant Vitamin A".
- Retinol Binding Protein - This carts retinol around the body, protecting us from free retinol, and that free retinol turning into retinoic acid (see above).
People wonder, if there is this supposed "epidemic" of Poison/"Vitamin A" toxicity around, why isn't it showing up in the research and on blood tests? I'm going to tell you why. It's hard to find something toxic when: 1) it is thought to be a nutrient we need, when it isn't, 2) no one knows how to look for it, and even if they did, 3) the tests aren't easily available.
You need to know that the only real mainstream test commonly used by physicians to look for Poison/"Vitamin A" in the body is called serum retinol. It is widely available, through both LabCorp and Quest Diagnostics. I do use this test in my Nutritional Restoration clients, because it is really the best we have for now. You'll see below.
From what I said above, wouldn't retinoic acid be the best one to test? From the scientists themselves:
Retinol (vitamin A) circulates at 1–4 μM concentration and is easily measured in serum. However, retinol is biologically inactive. Its metabolite, retinoic acid (RA), is believed to be responsible for biological effects of vitamin A, and hence the measurement of retinol concentrations is of limited value. A UHPLC-MS/MS method using isotope-labeled internal standards was developed and validated for quantitative analysis of endogenous RA isomers and metabolites. The method was used to measure retinoids in serum samples from 20 healthy men. In the fed state, the measured concentrations were 3.1 ± 0.2 nM for atRA, 0.1 ± 0.02 nM for 9-cisRA, 5.3 ± 1.3 nM for 13-cisRA, 0.4 ± 0.4 nM for 9,13-dicisRA, and 17.2 ± 6.8 nM for 4oxo-13-cisRA. The concentrations of the retinoids were not significantly different when measured after an overnight fast (3.0 ± 0.1 nM for atRA, 0.09 ± 0.01nM for 9-cisRA, 3.9 ± 0.2 nM for 13-cisRA, 0.3 ± 0.1 nM for 9,13-dicisRA, and 11.9 ± 1.6 nM for 4oxo-13-cisRA). 11-cisRA and 4OH-RA were not detected in human serum. The high sensitivity of the MS/MS method combined with the UHPLC separation power allowed detection of endogenous 9-cisRA and 4oxo-atRA for the first time in human serum.
In case you missed the above:
- Retinol - (supposedly) biologically INactive form, easy to test, limited value
- Retinoic acid - biologically active (in a BAD way), harder to test, assumed to be of greater value (I agree)
- It required TWO methods to be combined, and they actually tested for SEVEN different forms of retinoic acid (only finding 5 of those 7)!
- Side note - Levels of retinoic acid didn't significantly change when the subjects were fed vs. fasted. Detoxing Poison/"Vitamin A" out of the system is not an overnight process.
Retinoic acid(s) testing is more difficult (two methods), with more tests (five forms), leading to much more research and interpretation necessary. Most doctors don't know anything about Poison/"Vitamin A" to begin with. Which route do you think they would pick?
The bigger problem is, that while scientists in studies have measured these retinoic acids, I can't find any major laboratories that offer this service to physicians (if you do, please share with me!). A great test doesn't matter if it can't be applied to the general public.
Next, testing retinyl esters. By assessing the ratio of retinyl esters (storage form) to the total amount of retinol + retinyl esters in the blood, the liver's saturation/toxicity level of Poison/"Vitamin A" can be indirectly assessed. This is a great test, but also relatively unavailable. The only one I can find is from ARUP Labs, a specialty reference laboratory. They measure serum retinol and serum retinyl palmitate...BUT, retinyl palmitate isn't the only retinyl ester, it's just the main one...in essence, it isn't the same test! Here is the full list of retinyl esters present in a study on ferrets: retinyl palmitate, retinyl stearate, retinyl oleate, retinyl linoleate, retinyl myristate, retinyl heptadecanoate, retinyl arachidonate, and retinyl laurate. Another type of retinyl ester is used in supplements and food fortification, and that is retinyl acetate.
To assess the liver toxicity via this test, a percentage is calculated: [serum retinyl palmitate / (serum retinol + serum retinyl palmitate)] * 100% = percentage of total VA as retinyl palmitate. Note that retinyl palmitate isn't all of the retinyl esters though! At best, it probably accounts for around half of them.
Yet again, we have a test that will be more expensive, more challenging to get (trust me, I'm still figuring out how to make it happen for my US clients across the country, I have no idea where to even begin for my international clients), and incomplete in the information it provides compared to the research. Are you seeing a pattern yet?
Finally, we have serum retinol and retinol binding protein (RBP). I'm going to talk about them together.
First, because Poison/"Vitamin A" is so misunderstood in the research, I believe RBP to be EVEN more misunderstood (I'm still working on figuring it all out myself...the good news is I don't think complete understanding of it is necessary).
Next, looking at serum retinol is only useful when people understand that Poison/"Vitamin A" is NOT a nutrient and that the desired range is MUCH lower than the "normal" range. "Normal" is SICK these days, folks. You don't want to be "normal".
Serum retinol combined with RBP testing together could potentially be useful. Why is this? Because free retinol is toxic too:
Vitamin A Metabolism in the Fetus and Neonate
Hypervitaminosis A occurs when the amount of plasma retinol exceeds the availability of RBP to bind it, leading to unbound and elevated levels of free retinol in plasma, and formation of excess retinoid metabolites.
Excessive quantities of free retinol will damage plasma membranes of the liver and other tissues, as well as hepatic lysosomal membranes.
I have not had the time to search for the science on what the ratio of free retinol is that indicates toxicity. Again, this would require two separate tests, increasing the cost, difficulty (2 tests is harder than 1, more chance for error), and interpretation requirement.
To sum up, testing for Poison/"Vitamin A" is going to be difficult, regardless of the direction taken. Let's use the above information to show how all of the information points towards the innate toxicity of Poison/"Vitamin A":
- Retinoic acid - Seriously, it's used as a chemical peel!
- Retinyl esters - The storage form of Poison/"Vitamin A", and research shows that if more than 7.5% of your circulating Poison/"Vitamin A" is made up of retinyl esters, your liver is toxic with it for sure (see more at the reference link above).
- Retinol - Free retinol is toxic. It's only safe when it is bound to RBP, which implies that the body has to make proteins to protect you from it!
Which part of this PATTERN OF TOXICITY holds true for ANY OTHER "VITAMIN'???
The answer is NONE. That's because it is toxic to the core. It is not a "vitamin" now, nor ever was one. Don't confuse "having a biological effect" with "required to be obtained from food to live".
In my practice currently, I do like to use the serum retinol test to establish a baseline level. Not perfect by any means, yet it gives the most information possible at the lowest cost and least inconvenience to the client/patient.
Licensed Naturopathic Physician (NMD) in Arizona
NutritionDetective.com, home of the Love Your Liver program
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