by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc
The last several weeks I’ve written a lot about cardiovascular disease, with posts on pomegranate, Dan Shen and hawthorn. This week I’m going to shift gears and cover pyroluria, which is a genetic condition that is characterized by elevated excretion of pyrroles in the urine. If you got your hopes up (as I did) the first time I saw the term “pyroluria” thinking it had something to do with fire, you may be disappointed to learn that the “pyro” part of the name comes from the pyrroles which are excreted in high levels in the urine, not the “pyro” prefix of pyromaniac.
All the same, pyroluria is an interesting condition that is seldom discussed in mainstream medicine or psychiatry, despite the fact that it is associated with many psychiatric conditions and autism. As we’ll see in the coming sections, pyroluria depletes the body of several nutrients required for neurotransmitter production and stable mood, namely Vitamin B6 and zinc. Before I get into the details of how these nutrients become depleted, let me first give a brief history of pyroluria.
History of pyroluria
Pyrroles were first discovered in the urine of schizophrenic patients in 1958 by Dr. Abram Hoffer, who was then a Director of Psychiatric Research in Saskatchewan. He originally called pyrroles “mauve factor” because of the color they stained the paper chromatogram, and termed their presence “malvaria.” Dr. Carl Pfeiffer, a pioneer in the field of orthomolecular psychiatry, later renamed this phenomenon “pyroluria.” As we’ll see shortly, even this name is something of a misnomer. The term “pyrrole” is actually somewhat broad and refers to a family of chemical compounds, including but not limited to mauve factor, the specific substance that is implicated in pyroluria.
In the 1960s, some researchers misidentified mauve factor as a similar but distinct substance, kryptopyrrole. This error was published in a high profile scientific journal in 1969 (1), and was repeated in another article in 1970 (2). Subsequent research with improved technology went on to demonstrate that kryptopyrroles are not found in urine at all (3), and mauve factor is a distinct substance from kryptopyrrole. Furthermore, some researchers have argued that the term “pyrrole” lacks specificity as it refers to a whole family of substances that appear in urine, and pyroluria should be renamed.
What is mauve factor?
If kryptopyrrole is not the substance responsible for pyroluria, what is? Improved technology revealed that mauve factor is actually a substance known as hydroxyhemopyrrolin-s-one (HPL), which is the hydroxylactam of hemopyrrole. The two terms “mauve factor” and “hydroxyhemopyrrolin-2-one” (HPL) refer to the same substance and I will use them interchangeably in this article. Newer research uses these terms to replace “kryptopyrrole,” which was used erroneously in older research, and refers to subjects with elevated HPL as “high-mauve.”
Now that we have our terminology straight, I’ll next review symptoms of high mauve, and then explore possible causes, how to test for high mauve, the consequences of this condition, and finally I’ll conclude with treatment options.
Symptoms of pyroluria / high mauve
Many of the signs and symptoms of pyroluria are symptoms of deficiencies of Vitamin B6 and zinc, as those are primary nutrients depleted by the condition. There are many, and they are admittedly not well studied. Here is a list from a review study on pyroluria (4):
- Poor dream recall (Vitamin B6)
- Nail spots (zinc)
- Stretch marks
- Pale skin/poor tanning
- Coarse eyebrows
- Knee and joint pain
- Cold hands or feet
- Abdominal tenderness
- Stitch in side
- Morning nausea
- Light/sound/odor intolerance
- Hypoglycemia/glucose intolerance
- Delayed puberty
- Amenorrhea/irregular periods
- B6-responsive anemia
- Attention deficit/hyperactivity
- Crime and delinquency
- Substance abuse/alcoholism
- Stress intolerance
- Explosive anger
- Social withdrawal
- Disordered perception
- Bipolar disorder
Causes of pyroluria / high mauve
Now that we know some of the possible signs and symptoms of pyroluria, let’s examine possible causes. Today, the causes of elevated HPL remain elusive and largely unknown, although several theories have been presented over the years. High mauve may result from dietary sources, altered heme production, porphobilinogen (PBG), porphyrins, genetic causes and altered gut bacteria.
- Dietary sources: Some foods contain pyrrole subunits, and ingestion of large amounts has been proposed to increase HPL. Examples include coffee, tea, cola drinks, chlorophyll, tobacco, tryptophan and Vitamin B12. However, a study evaluating high intake of these foods in psychiatric patients did NOT find an increase in HPL excretion (5).
- Heme: Dr. Carl Pfeiffer suggested that HPL results from breakdown of heme (6), but research that attempted to produce HPL from heme, bilirubin or bile pigments under laboratory conditions was unsuccessful. Furthermore, large doses of hemoglobin from blood sausage produced no effect on HPL excretion (7).
- Porphobilinogen (PBG): PBG is a pyrrole involved in porphyrin metabolism and is generated by aminolevulinate (ALA). HPL may be a metabolite of PBG or porphyrins from the heme biosynthetic pathway. One study found that a large dose of ALA did double urinary HPL in one subject (8), but in an in vitro experiment researchers were unable to produce HPL from porphyrins (7).
- Isocoproporphyrin is a porphyrin that is the most homologous to HPL. It is produced from altered heme biosynthesis (9). Isocoproporphyrins are increased by CPOX polymorphism and toxins like mercury (10) and hexachlorobenzene (11).
- High-mauve schizophrenics exhibited greater coproporphryin concentrations than other schizophrenics (12). and rats injected with HPL increased urinary coproporphyrins (13).
- Altered gut bacteria: Production of isocoproporphyrin from altered heme biosynthesis involves activity from gut flora. Oral dosing with antibiotics reversibly abolished or sharply reduced urinary HPL in a small cohort study (14).
Consequences of high mauve
As I mentioned in the introduction, HPL binds certain nutrients and causes them to be excreted in urine, leading to deficiencies. The two main nutrients implicated are zinc and Vitamin B6, which are heavily involved in the production of neurotransmitters. Interestingly, although zinc and Vitamin B6 deficiencies appear to result from high mauve, supplementation with these nutrients also reduce levels of HPL in urine in a “chicken and egg” scenario. Clinicians have reported proportionality between symptom severity and mauve excretion (15).
Prevalence of HPL in mental illness
HPL is highly correlated with many forms of mental illness, including down syndrome, depression, anxiety, schizophrenia, bipolar disorder, substance abuse and autism. Because Vitamin B6 and zinc are both required for the synthesis of neurotransmitters like serotonin and dopamine it’s easy to see how deficiencies of these nutrients can lead to mood issues. Disturbances in these neurotransmitters are implicated in many, if not all of the mental health issues I listed above.
High mauve may account for some of these disturbances by reducing levels of Vitamin B6 and zinc, which in turn leads to disturbances in neurotransmitters. Research has illuminated the prevalence of high mauve in the following mental health disorders:
Diagnosis % High Mauve
Down syndrome 71
Schizophrenia, acute 59-80
Schizophrenia, chronic 40-50
Bipolar disorder 47-50
Depression, non schizophrenic 12-46
The numbers are somewhat staggering. It certainly seems from these figures that HPL may play a significant role in many forms of mental illness and addressing it may be a way to provide significant relief to these populations of people.
Vitamin B6 and zinc
Ongoing supplementation with Vitamin B6 and zinc is generally believed to be necessary to suppress HPL and manage symptoms. Dosage requirements are usually proportional to the levels of mauve excreted in urine, and needs may be elevated during certain phases of treatment. Initial levels are often higher than ongoing supplementation requirements, which can be reduced in maintenance doses. In addition, zinc requirements sometimes increase during growth spurts.
In addition to zinc and Vitamin B6, low biotin may also be implicated. In a small, mixed cohort study conducted by the Vitamin Diagnostics Laboratory, 24-hour urinary concentrations of HPL were strongly correlated with biotin deficiency in a group of 24 subjects. Elevated HPL predicted low plasma biotin in 16 out of 16 subjects (discerning mauve pt 1). Biotin deficiency results in neurological disease in animals (16) and humans (17) and is more common than is often believed (18).
Neurotoxicity of HPL
In addition to its role in certain nutrient deficiencies, as discussed in the previous section, HPL itself appears to be neurotoxic. Pyrroles as a class are known to be “nerve poisons” (19) and monopyrroles, of which HPL is an example are well known for biotoxicity (20). Another neurotoxic monopyrrole is batrachotoxin from the poison dart frog (21), which exerts potent effects on the nervous system.
HPL and stress
HPL excretion is not static; it varies over the course of the day and also increases in response to stress. Based on his clinical experience, Dr. Pfeiffer declared that mauve is “a stress-induced factor” (22) and this observation is borne out in research as well (23), which has concluded that symptoms and HPL excretion both increase in response to stress. Furthermore, an unpublished 1992 study on men in the Navy found that urinary HPL increased after volunteers were subjected to cold-water immersion stress. In addition, stress contributes to intestinal inflammation and permeability (24), which I will discuss in the next section.
HPL and the gut
It’s well established at this point that gut health issues are also strongly correlated with mental illness, so it probably should come as no surprise that HPL is associated with gut health issues as well. In addition to neurobehavioral symptoms, high mauve is also associated with abdominal signs and symptoms. A large percentage of high mauve subjects report abdominal tenderness (25). One reason for this phenomenon may have to do with intestinal permeability.
Zinc deficiency results in damage to the small intestinal epithelium and increases permeability due to increased intestinal nitric oxide (15). Because HPL is associated with zinc deficiency, it is probably also associated with increased intestinal permeability. Zinc reduces intestinal permeability in humans (26).
HPL and oxidative stress
Deficiencies of zinc and Vitamin B6 result in increased oxidative stress. Even slightly depressed Vitamin B6 is associated with lower glutathione peroxidase (GSHPx), glutathione (GSH) reductase, reduced/oxidized glutathione ratios and higher lipid peroxide levels and mitochondiral decay (27) (28) (29). In addition, B6 itself is highly vulnerable to damage by reactive oxygen species (30) and P5P, the activated form of B6, protects neurons from oxidative stress (31). Furthermore, zinc supplementation has been shown to decrease oxidized biomolecules (32). Because HPL is a marker for B6 and zinc status, HPL is also a potential biomarker for oxidative stress.
Consequences of pyroluria
As I mentioned earlier, the main consequence of high mauve is the depletion of nutrients. The two most commonly depleted nutrients are zinc and Vitamin B6. Biotin is also depleted in some people. Another nutrient that is impacted is arachidonic acid (AA), an omega-6 fatty acid. This is an interesting deficiency because the Standard American Diet tends to be very high in omega-6 fats and low in omega-3s, which must remain in balance with each other. Omega-3s are commonly supplemented in many cases of mental illness. Individuals with pyroluria may benefit from adding some omega-6 (but not from industrial seed oils like canola oil, sunflower oil, safflower oil, corn oil, soy oil or peanut oil which can be pro-inflammatory — instead from whole seeds, nuts, avocados, olive oil, etc.) in addition to the omega-3s.
Other consequences are downstream from those deficiencies. As I already mentioned, Vitamin B6 and zinc are both needed to synthesize serotonin and other neurotransmitters, so low levels of neurotransmitters may result. In addition, increased intestinal permeability is another possibility because of the role zinc plays in maintaining the integrity of the intestinal lining. High mauve can also contribute to elevated oxidative stress and a reduced ability to respond appropriately to stress. In the next section I’ll review how to test for high mauve, and then conclude with treatment options.
Testing for pyroluria / HPL
HPL is unstable outside the body and is rapidly broken down by heat and light. Urine collection and assay for pyroluria testing, which we now know should be more accurately referred to as HPL, is ideally performed under very dim light. If this method of testing is not available, the problem can be abated somewhat by adding Vitamin C (ascorbic acid) to the urine sample, which helps protect HPL from degradation. Most, if not all laboratories that perform this testing require samples to be frozen and shipped overnight for assay.
We prefer to use the Health Diagnostics Research Institute (HDRI) urine test for pyroluria because they are very careful about avoiding light exposure. Because pyrroles are easily degraded, samples that are exposed to light can result in a false negative test result. We also occasionally use LabCorp as another option for patients, though we are unsure about how careful and promptly the test is being completed and have some concern about validity of results. HDRI provides the following reference range for urinary pyrroles:
Urine level Diagnosis Recommendation
< 15 µg/dL negative no evidence of pyroluria
15-25 µg/dL elevated may benefit from treatment
> 25 µg/dL positive treatment recommended
> 50 µg/dL strongly positive treatment strongly recommended
Another method of evaluating pyroluria involves using a symptom questionnaire. Several practitioners have made questionnaires. I like the one by Trudy Scott, a nutritionist who (like myself) specializes in nutrition for mental health and works primarily with women dealing with depression and anxiety. Her questionnaire is from her book The Antianxiety Food Solution and an online version is available on her blog. This questionnaire can be useful if a patient either can’t afford the cost of the urine test, or if you’re trying to decide whether the test would be worthwhile. You can use the questionnaire to narrow down where pyroluria is likely based on symptoms.
Treating pyroluria / HPL
The primary treatment approach for high mauve involves supplementing zinc and Vitamin B6. Biotin and omega-6 fatty acids may be necessary also. Research notes that the initial starting doses of Vitamin B6 and zinc are often considerably higher than maintenance doses required long-term. Long-term supplementation is usually necessary. Dosage increases can also be necessary during growth spurts. Progress can be gauged by symptom improvement and completing the questionnaire again. Urine can also be retested. When the zinc and Vitamin B6 dosage is adequate, urine levels of HPL will decrease into normal range.
Pyroluria, which is more accurately referred to as high mauve or HPL is a condition with causes that are still unknown. It is associated with many forms of mental illness and mood disorders, primarily due to its effects on zinc and Vitamin B6 levels. Treatment options primarily involve long-term supplementation with those nutrients, and potentially also biotin and omega-6 fatty acids. Hopefully in the future science will reveal more about the causes of pyroluria and what can be done to prevent or treat it without the need for long-term supplementation. We suspect other nutrients may also be depleted but need more research to know which nutrients and how significant those depletions are.
But in the meantime, zinc and B6 supplementation, plus the possible addition of biotin, is a relatively simple, safe and inexpensive way to treat symptoms and make significant improvements to people dealing with a whole host of mental illness, including depression, anxiety, bipolar disorder and schizophrenia. Pyroluria, or high mauve goes a long way to explain a biochemical mechanism for mental illness.
Our recommended forms of zinc and vitamin B6:
- Zinc Carnosine: great for if there are also digestive/stomach issues, H. Pylori, and/or leaky gut. Dose is smaller and more expensive than other zinc supplements, though, so we only recommend this versus other zinc if gut issues are present. A small amount of this can be combined with other forms of zinc for cost-effectiveness.
- Zinc Sulfate: avoid supplementing with this form. It is not very bioavailable and can cause symptoms.
- Zinc Acetate, Citrate, Methionine, Picolinate, Glycinate: these are all fine forms to supplement with.
- Zinc dosage: avoid dosing more than 40mg per day for long-term dosing (from all supplement sources). Consider getting increased zinc from foods like oysters (highest), and red meat like beef and lamb. Short-term dosing (up to 100mg / day) is probably safe for most people for short-term dosing (i.e. for a couple of days when getting sick). Larger short-term dosing in some cases of HPL elevation (>40mg) for a fixed period of time may be therapeutic (please only do this under the supervision of an experienced functional medicine practitioner who knows what they are doing). Also, we suggest adding some copper when supplementing with zinc, especially if in higher doses or for a long period of time. We suggest about a 1:10 ratio of copper:zinc. So take 1/10th the amount of copper as you are zinc. If you are supplementing with higher doses (20mg+ of zinc daily), a low dose of trace minerals (be sure to choose a high-quality brand as some have been contaminated with lead) is recommended to keep a balance of multiple minerals.
- Vitamin B6: Peroxidal-5-Phosphate (P5P) is the preferred form. 100mg per day for adults is the upper limit recommended for long-term use. If supplementing with more than this, do so temporarily and under the guidance of a skilled functional medicine practitioner. We suggest generally starting with 50mg unless there is a test indicating significant elevation of HPL.
- Irvine DG, Bayne W, Miyashita H, Majer JR. Identifi cation of kryptopyrrole in human urine and its relation to psychosis. Nature. 1969;224(5221):811-813.
- Sohler A, Beck R, Noval JJ. Mauve factor re-identified as 2,4-dimethyl-3-ethyl pyrrole and its sedative effect on the CNS. Nature. 1970;228(5278):1318-1320.
- Gendler PL, Duhan HA, Rapoport H. Hemopyrrole and kryptopyrrole are absent from the urine of schizophrenics and normal persons. Clin Chem. 1978;24(2):230-233.
- McGinnis, W R, et al. “Discerning the Mauve Factor, Part 1.” Alternative Therapies in Health and Medicine, vol. 14, no. 2, 2008, pp. 40–50.
- Irvine DG. Kryptopyrrole in molecular psychiatry. In: Hawkins D, Pauling L, eds. Orthomolecular Psychiatry: Treatment of Schizophrenia. San Francisco: WH Freeman and Company; 1973:146-178.
- Pfeiffer CC, Bacchi D. Copper, zinc, manganese, niacin and pyridoxine in the schizophrenias. J Appl Nutr. 1975;27:9-39.
- Irvine DG. Clinical, EEG and biochemical correlates of hydroxyhemopyrrolenone excretion. Proceedings of the 22nd Annual Psychiatric Research Meeting, Saskatoon Psychiatric Research Division. Saskatoon, Saskatchewan; May 1977: 59-60.
- Hoffer A. The presence of malvaria in some mentally retarded children. Am J Ment Def. 1963;67:730-732.
- Irvine DG, Wilson DL. Oxidized monopyrroles in porphyric disorders and related conditions. In: Doss M, ed. Porphyrins in Human Diseases: Proceedings of the International Porphyrin Meeting, 1st, Freiburg, Germany, May, 1975. Basel, Switzerland: Karger Publishers; 1976. pp 217-224.
- Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS. A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathways and porphyrin production. Toxicol Lett. 2006;161(2):159-166.
- Cooper CL, Stob CM, Jones MA, Lash TD. Metabolism of pentacarboxylate porphyrinogens by highly purified human coproporphyrinogen oxidase: further evidence for the existence of an abnormal pathway for heme biosynthesis. Bioorg Med Chem. 2005;13(22):6244-6251.
- Pfeiffer CC, Sohler A, Jenney EH, et al. Treatment of pyroluric schizophrenia (malvaria) with large doses of pyridoxine and a dietary supplement of zinc. J Appl Nutr. 1974;26:21-28.
- Graham DJM, Thompson GG, Moore MR, Goldberg AA. The effects of selected monopyrroles on various aspects of heme biosynthesis and degradation in the rat. Arch Biochem Biophys. 1979;65(1):132-138.
- Irvine DG. Mauve factor and 6-sulfatoxy skatole: two biochemical abnormalities associated with specifi c measures of psychiatric disease. Clin Chem. 1963;9:444-445.
- Cui L, Takagi Y, Wasa M, Sando K, Khan J, Okada A. Nitric oxide synthase inhibitor attenuates intestinal damage induced by zinc deficiency in rats. J Nutr. 1999;129(4):792-798.
- Bregola G, Muzzolini A, Mazzari S, et al. Biotin deficiency facilitates kindling hyperexciability in rats. Neuroreport. 1996;7(11):1745-1748.
- Grünewald S, Champion MP, Leonard JV, Schaper J, Morris AA. Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics. 2004;35(4):211-216.
- Mock DM, Henrich CL, Carnell N, Mock NI. Indicators of marginal biotin deficiency and repletion in humans: validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. Am J Clin Nutr. 2002;76(5):1061-1068.
- Corwin AM, et al. Encyclopaedia Britannica. 1960;18:801.
- Irvine DG. Kryptopyrrole and other monopyrroles in molecular neurobiology. Int Rev Neurobiol. 1974;16(0):145-182.
- Dumbacher JP, Wako A, Derrickson SR, Samuelson A, Spande TF, Daly JW. Melryrid beetles (Choresine): putative source for batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds. Proc Natl Acad Sci U S A. 2004;101(45):15857-15860.
- Pfeiffer CC. The schizophrenias ‘76. Biol Psychiatry. 1976;11(6):773-775.
- Ward JL. Relationship of kryptopyrrole, zinc and pyridoxine in schizophrenics. J Orthomolec Psychiatr. 1975;4:27-31.
- Hart A, Kamm MA. Review article: mechanisms of initiation and perpetuation of gut inflammation by stress. Ailment Pharmacol Ther. 2002;16(12):2017-2028.
- McCabe DL. Kryptopyrroles. J Orthomolec Psychiatr. 1983:12:2-18.
- Bates CJ, Evans PH, Dardenne M, et al. A trial of zinc supplementation in young rural Gambian children. Br J Nutr. 1993;69(1):243-255.
- Cabrini L, Bergami R, Fiorentini D, Marchetti M, Landi L, Tolomelli B. Vitamin B6 deficiency affects antioxidant defences in rat liver and heart. Biochem Mol Biol Int. 1998;46(4):689-697
- Park LC, Zhang H, Sheu KF, et al. Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates key mitochondrial enzyme in microglia. J Neurochem. 1999;72(5):1948-1958.
- Atamna H, Walter PB, Ames BN. The role of heme and iron-sulfur clusters in mitochondrial biogenesis, maintenance, and decay with age. Archiv Biochem Biophys. 2002;397(2):345-353.
- Bilski P, Li MY, Ehrenshaft M, Daub ME, Chignell CF. Vitamin B6 (pyridoxine) and its derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants. Photochem Photobiol. 2000;71(2):129-134.
- Yamashima T, Zhao L, Wang XD, Tsukada T, Tonchev AB. Neuroprotective effects of pyridoxal phosphate and pyridoxal against ischemia in monkeys. Nutr Neurosci. 2001;4(5):389-397.
- Maret W. Metallothionein/disulfide interactions, oxidatives stress, and the mobilization of cellular zinc. Neurochem Int. 1995;27(1):111-117.