The Pyroluria & Omega-3 Paradox
In a recent post we wrote about pyroluria, a genetic condition that is highly implicated in many mental health disorders including depression, anxiety and schizophrenia, as well as addiction and alcoholism. Pyroluria is best known for its tendency to deplete zinc and vitamin B6, which can lead to mood disturbances and inner tension. Although not as widely known, pyroluria also depletes other nutrients.
In this post we will continue the discussion by focusing on the role of omega-3 and omega-6 fatty acids in pyroluria. The omega-3 fatty acids EPA and DHA, mostly commonly found in cold-water fatty fish like salmon, sardines and anchovies are highly touted for their ability to reduce inflammation and positively impact mental health conditions. Omega-3s are now well supported in the research for the treatment of depression and anxiety (1) (2).
But as always, it’s critical to understand the mechanism behind each individual’s symptoms. Many different biochemical causes can lead to symptoms of depression and anxiety, and it’s important to view patients on a case-by-case basis. Pyroluria is a great example of this, because although many depressed and anxious people stand to benefit from increasing their omega-3 consumption if it’s deficient, doing so can actually make some people with pyroluria worse.
Terminology: mauve factor / HPL
As discussed in our previous pyroluria post, the term pyrrole refers to a whole family of chemical compounds. The specific pyrrole implicated in pyroluria is hydroxyhemopyrrolin-2-one (HPL), and researchers are now suggesting that pyroluria be renamed to “mauve factor” or HPL, which is the terminology we’ll use in this post.
Omega-3 and omega-6 balance
Omega-3 and omega-6 fats are both polyunsaturated fatty acids that must remain in balance with each other. It is now well known that the Standard American Diet is often too high in omega-6 fats, which in general tend to be pro-inflammatory, and too low in the anti-inflammatory omega-3 fats EPA and DHA. Mauve factor (pyroluria) adds an extra layer to the story, however, as it can interfere with the synthesis of omega-6 fats.
Without understanding this important caveat, many people who suffer from depression or anxiety supplement with omega-3 fish oil. In some cases, doing so may be counterproductive for people with high mauve / pyroluria. If high mauve is an individual’s underlying root cause, they may unwittingly push the omega-3 and omega-6 ratio too far in favor of omega-3 with high dose supplementation. We’ll see why this is a problem in the next section.
Omega-3s can worsen anxiety
There are reports of omega-3 fish oil actually contributing to symptoms of anxiety in some people. One interesting case study from 2015 relates an instance of a 55-year old man who reports mild panic attacks, general anxiety, shortness of breath and insomnia that result from taking fish oil.
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He reports experiencing anxiety and insomnia for several months while taking fish oil supplements, symptoms which he says “largely disappeared” after stopping the fish oil. Several weeks later, he resumed fish oil again and experienced a recurrence of symptoms. After two days, he stopped the fish oil once again and saw his symptoms nearly vanish again. The case study report does not mention mauve factor or pyroluria, so we don’t know whether he was tested or not (3).
This is an area that needs further study. Sadly, there is not a lot of research on high mauve in general, probably because there is no pharmaceutical treatment for the condition. In addition to the case study above, several health websites and online forums report anecdotal cases of fish oil supplements worsening anxiety, such as a comment on this pyroluria blog post by Trudy Scott (4). Of course, these type of anecdotal reports must be taken with a grain of salt if not disregarded entirely, but in the absence of better quality research they are worth mentioning.
To understand why HPL / high mauve can cause low omega-6 fats, let’s look next at the biochemistry of the omega-6 pathway in the body.
Omega-6 fat synthesis
Low levels of omega-6 fats with pyroluria appear to result from a problem with the production of arachidonic acid (AA). This is different from the mechanism behind low vitamin B6 and zinc in high mauve. HPL depletes zinc and B6 by binding to these nutrients, which causes them to be excreted in urine. So it’s not that the omega-6 arachidonic acid is depleted in pyroluria, it’s that its synthesis is inhibited.
This block in AA synthesis appears to result from a problem with delta-6-desaturase, the enzyme which converts the omega-6 precursor linoleic acid into gamma-linoleic acid (GLA), which is then converted into AA. This same enzyme is also required for the synthesis of omega-3 fatty acids, so both omega-3 and -6 PUFA synthesis may be inhibited, but it appears that with high mauve, it’s more common for just the omega-6 eicosanoids to be affected. You can see where the delta-6-desaturase enzyme factors into PUFA synthesis.
One study from 1986 on schizophrenia proposes a subtype of schizophrenia that is characterized by high linoleic acid, high fasting insulin and elevated urinary pyrroles / HPL. The authors explain this subtype as resulting from blocked delta-6-desaturase, which would yield elevated linoleic acid that is unable to be converted into GLA (5). To understand why the delta-6-desaturase enzyme underperforms, we need to look back at the two nutrients most associated with HPL – zinc and vitamin B6.
Zinc and Vitamin B6
As mentioned previously, zinc and vitamin B6 are the primary nutrients depleted in HPL. The depletion of these nutrients may explain the reduced activity of delta-6-desaturase and resulting deficiency of GLA, arachidonic acid and other downstream omega-6 fatty acids. Both zinc and B6 are cofactors required for the proper function of delta-6-desaturase (6)(7). Reduced omega-6 fatty acid levels may therefore be a secondary deficiency resulting from low zinc and B6.
EPA inhibits omega-6 eicosanoids
It’s interesting to note that EPA itself, a primary constituent of fish oil, inhibits the conversion of arachidonic acid into later stage omega-6 eicosanoids. In addition to zinc and B6 and the role these nutrients play in delta-6-desaturase, EPA itself may be implicated (8). This issue may present different sequelae than issues with D6D, as it comes into play in series 2 prostaglandins, which are synthesized from AA later in the omega-6 pathway than the previous issues. Many of the problems hypothesized to account for schizophrenia related to the omega-6 pathway have to do with prostaglandin E1 (PGE1), a series 1 prostaglandin.
As you can see from the flow chart above, PGE1 is synthesized from DGLA earlier in the pathway from DGLA before the synthesis of arachidonic acid, whereas several other prostaglandins and leukotrienes are synthesized from AA itself. It’s possible that by inhibiting conversion of AA into later stage eicosanoids, EPA may increase levels of other prostaglandins and leukotrienes by increasing levels of AA.
Other omega-6 pathway inhibitors
Alcohol is well known to exacerbate mood issues. Drinking alcohol has also been shown to inhibit both delta-6-desaturase as well as delta-5-desaturase, which catalyzes the conversion of DGLA into AA (9). Consequently, individuals with high mauve and low omega-6 levels would be advised to minimize consumption.
Trans fatty acids inhibit liver D6D activity in animal models and leads to decreased GLA and prostaglandin levels (10).
Fructose has also been shown to depress D6D gene expression in spontaneously hypertensive rats. The rats also had decreased levels ofomega-6 linoleic acid as well as its derivatives. Interestingly, D6D omega-3 gene expression decreased, yet activity of omega-3 D6D increased (11). By decreasing omega-6 D6D activity while increasing omega-3 D6D would lead to omega-3 dominance.
Chronic viral infections may also decrease D6D activity in both the omega-3 and omega-6 pathways. AA and EPA both have antiviral activity, even at low concentrations (12).
Diabetes also inhibits D6D and D5D activity, which is reversed by insulin in rat models (13).
Magnesium deficient rats exhibit decreased D6D activity and a slower conversion of linoleic acid to AA (14).
Now that we know some of the issues that can inhibit the omega-6 pathway and its prostaglandins, let’s move on to more detail about the prostaglandins themselves. Many of the effects of low omega-6 levels are manifested though low levels of its prostaglandins. As mentioned earlier, PGE1 in particular is implicated in schizophrenia.
Prostaglandins and pyroluria
Prostaglandins are classified as eicosanoid hormones and are found in virtually all cells in the body except erythrocytes (red blood cells). They are also involved in platelet activation, vasodilation and constriction and respiration. Other roles include altering glandular secretions, reproductive processes, platelet function and immune response. They also mediate inflammation, fever and pain. NSAIDs work by inhibiting cyclooxygenase (COX), a key enzyme in prostaglandin synthesis (15).
As mentioned earlier, Prostaglandin E1 plays a central role in schizophrenia. It is also relevant to mood disorders and is elevated in mania, the “high” side of bipolar disorder, and low in the depressive state. Another effect of alcohol, which we discussed in the last section, is that consumption stimulates PGE1 while drinking but leads to depressed levels afterwards, contributing to depression (16).
PGE1 also factors into gut health and has been shown to improve intestinal permeability (17). The gut-brain connection and role of intestinal permeability in mood disorders are well established at this point. Because high mauve can interfere with the synthesis of DGLA, which in turn can decrease PGE1, it may contribute to intestinal permeability and secondary symptoms of depression and anxiety.
The many effects of high mauve
As we’ve seen in this post, pyroluria or high mauve is not as simple as a zinc and Vitamin B6 deficiency. There are many other potential sequelae, including inhibited production of omega-6 fatty acids. As a result, PGE1 may be low as well, which has its own consequences for mood. Patients who know about the benefits of omega-3s for depression and anxiety may be supplementing high dose fish oil in an attempt to improve their symptoms. If they have high mauve and don’t know it, they may be unwittingly contributing to their symptoms.
Now that we know how high mauve can affect omega fatty acid balance and some effects of that imbalance, let’s move on to treatment recommendations, supplement recommendations and lab testing.
It’s important to question patients thoroughly about their omega-3 intake from fish oil and cod liver oil as well as food sources like cold-water fish, grass-fed beef, flax seed and walnuts. Weighing benefits against potential issues is key. It can also be useful to question them about when symptoms of anxiety in particular started, how long they’ve been taking fish oil, and whether there is any correlation between the two. Patients may be unaware of the connection.
In addition to the supplement recommendations in our last post on pyroluria which focus primarily on B6 and zinc, it can be useful to supplement GLA in the form of evening primrose oil (EPO) or borage oil. Another option is to swap out their omega-3 fish oil for a combination product that includes GLA fatty acids as well. If a patient is not already taking adequate zinc and B6 that is the most important area to begin, and getting those levels up may help omega-6 eicosanoids as well because both B6 and zinc are required for proper D6D activity.
The most important test when pyroluria, or high mauve is suspected is the urinary pyrrole test which evaluates the presence of HPL in the urine. This is the only way to conclusively diagnose high mauve. This urine test is the best starting point. We like the one from Health Diagnostics Research Institute. A questionnaire like this one by Trudy Scott can also be helpful if you are unsure whether testing is warranted. The questionnaire can also help with buy-in from the patient, as they can see how high their score is.
Another test that’s worth considering is an essential fatty acid test like the Essential & Metabolic Fatty Acid Analysis by Genova. This test reveals levels of omega-3 and omega-6 fatty acids in the blood and can help to identify whether they are out of balance. Another good option is a micronutrient test that looks at levels of zinc and B6 like the Vibrant Wellness Micronutrient Test. It’s also wise to compare zinc and copper levels as the two need to remain in a certain ratio with each other.
In this post we’ve explored how pyroluria, or high mauve can affect fatty acid balance and potentially lead to low levels of omega-6 fats. We also examined how low levels of these eicosanoids can also affect prostaglandins like PGE1, and how that may contribute to symptoms of depression, anxiety and even schizophrenia. If you have patients with pyroluria who have made incomplete recovery even after supplementing with zinc and B6, it may be worthwhile to look at omega-6 eicosanoids and PGE1. That may be the missing piece!
Ideas for those who have tested for or strongly suspect high mauve / HPL:
- Cover the bases with zinc and vitamin B6 (see previous post for more details)
- Limit supplementation with fish oil and moderate cold-water fatty fish intake*
- Add GLA from evening primrose oil
- Limit or eliminate alcohol intake
- Add magnesium glycinate, taurate, and/or l-threonate (total of 400-1000mg daily)
- Limit fructose consumption (aside from a moderate amount of whole phytonutrient-rich fruits)
- Test for chronic viral infections and work with a functional medicine practitioner to resolve them
*Fish oil must be weighed with an understanding of benefits and possible issues. There was great cardiovascular promise from early short-term fish oil studies. Later long-term studies did not show significant benefit. There is some concern with high dose fish oil for long-term use for anyone, not just those with high mauve / HPL. That being said, there is of course some anti-inflammatory benefit from a healthy omega 3 : 6 ratio. This must also be considered. In the case of high mauve / HPL, extra attention and care should be taken to observe if a level of omega 3 may be a cause of worsened anxiety and/or depression.
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- Martins, Julian G. “EPA but Not DHA Appears To Be Responsible for the Efficacy of Omega-3 Long Chain Polyunsaturated Fatty Acid Supplementation in Depression: Evidence from a Meta-Analysis of Randomized Controlled Trials.” Journal of the American College of Nutrition, vol. 28, no. 5, 2009, pp. 525–542., doi:10.1080/07315724.2009.10719785.
- Bozzatello P, Brignolo E, De Grandi E, Bellino S. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. Brown L, Rauch B, Poudyal H, eds. Journal of Clinical Medicine. 2016;5(8):67. doi:10.3390/jcm5080067.
- Blanchard LB, McCarter GC. Insomnia and exacerbation of anxiety associated with high-EPA fish oil supplements after successful treatment of depression. Oxford Medical Case Reports. 2015;2015(3):244-245. doi:10.1093/omcr/omv024.
- Scott, Trudy. “The Anxiety Summit: How Zinc and Vitamin B6 Prevent Pyroluria and Social Anxiety.” everywomanover29, Trudy Scott, 31 May 2016, www.everywomanover29.com/blog/anxiety-summit-how-zinc-vitamin-b6-prevent-pyroluria-social-anxiety/.
- Heleniak, E.p., and S.w. Lamola. “A New Prostaglandin Disturbance Syndrome in Schizophrenia: Delta-6-Pyroluria.” Medical Hypotheses, vol. 19, no. 4, 1986, pp. 333–338., doi:10.1016/0306-9877(86)90106-4.
- Yary, T., et al. “Omega-6 Polyunsaturated Fatty Acids, Serum Zinc, Delta-5- and Delta-6-Desaturase Activities and Incident Metabolic Syndrome.” Journal of Human Nutrition and Dietetics, vol. 30, no. 4, July 2016, pp. 506–514., doi:10.1111/jhn.12437.
- Bordoni, A, et al. “Dual Influence of Aging and Vitamin B6 Deficiency on Delta-6-Desaturation of Essential Fatty Acids in Rat Liver Microsomes.” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 58, no. 6, 1998, pp. 417–420., doi:10.1016/s0952-3278(98)90163-6.
- Culp, Brenda R., et al. “Inhibition of Prostaglandin Biosynthesis by Eicosapentaenoic Acid.”Prostaglandins and Medicine, vol. 3, no. 5, 1979, pp. 269–278., doi:10.1016/0161-4630(79)90068-5.
- Nervi, Anibal Mario, et al. “Effect of Ethanol Administration on Fatty Acid Desaturation.” Lipids, vol. 15, no. 4, 1980, pp. 263–268., doi:10.1007/bf02535837.
- Kinsella, J E, et al. “Metabolism of Trans Fatty Acids with Emphasis on the Effects of Trans, Trans-Octadecadienoate on Lipid Composition, Essential Fatty Acid, and Prostaglandins: an Overview.” American Journal of Clinical Nutrition, vol. 34, ser. 10, 1981, pp. 2307–18.10.
- Comte, C., et al. “Effects of Streptozotocin and Dietary Fructose on Delta-6 Desaturation in Spontaneously Hypertensive Rat Liver.” Biochimie, vol. 86, no. 11, 2004, pp. 799–806., doi:10.1016/j.biochi.2004.10.002.
- Puri, B K. “Long-Chain Polyunsaturated Fatty Acids and the Pathophysiology of Myalgic Encephalomyelitis (Chronic Fatigue Syndrome).” Journal of Clinical Pathology, vol. 60, no. 2, Feb. 2006, pp. 122–124., doi:10.1136/jcp.2006.042424.
- Rimoldi, Omar J., et al. “Effects of Diabetes and Insulin on Hepatic Î6 Desaturase Gene Expression.” Biochemical and Biophysical Research Communications, vol. 283, no. 2, 2001, pp. 323–326., doi:10.1006/bbrc.2001.4785.
- Mahfouz, M. M., and F. A. Kummerow. “Effect of Magnesium Deficiency on Î6 Desaturase Activity and Fatty Acid Composition of Rat Liver Microsomes.” Lipids, vol. 24, no. 8, 1989, pp. 727–732., doi:10.1007/bf02535212.
- Tortora, Gerard J., and Bryan Derrickson. Principles of Anatomy & Physiology. John Wiley & Sons, 2012.
- Horrobin DF, Manku MS. Possible role of prostaglandin E1 in the affective disorders and in alcoholism. British Medical Journal. 1980;280(6228):1363-1366.
- Empey, L.r., and R.n. Fedorak. “Effect of Misoprostol in Preventing Stress-Induced Intestinal Fluid Secretion in Rats.” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 38, no. 1, 1989, pp. 43–48., doi:10.1016/0952-3278(89)90146-4.
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Great article, really explains a lot of my own issues with fish oils. Interestingly in the Essential fatty acids section of my Nutreval I have:
– High ALA (I eat a lot of butter/canola oil spreads)
– High EPA (I don’t take any fish oil and don’t eat much fish)
– DHA is in the green but it’s just above the threshold and much lower then EPA
– LA is high
– GLA is in the middle of the range
– AA is low
I had these markers tested 12 months ago when I wasn’t consuming the butter/canola oil spread and my ALA level was much lower and EPA was a little lower then previous. The AA levels were slightly higher, LA was lower and GLA lower. My tests seem to indicate supplementing with DHA only would be beneficial and to cut out the ALA sources.
I do have pyroluria, methylation, gut issues etc