Pyroluria and Adrenal Fatigue Syndrome – Part 1

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM; Dorine Lam, RDN, MS, MPH

Pyroluria and adrenal fatigue/Pyroluria is a genetically inherited but correctable biochemical imbalance involving an abnormality in hemoglobin synthesis. It can be purely genetic or acquired through environmental and emotional stress and especially from leaky gut syndrome and the overuse of antibiotics. Charles Darwin is thought to be afflicted by this condition.

Pyroluria is known by many different names including Pyrrole Disorder, Kryptopyrrole, Kryptopyrroluria, Pyrroluria, Pyrolle Disorder, Mauve Factor and Hemepyrrole.

What is Pyroluria?

Pyroluria is a blood disorder first and foremost. Hemoglobin is a particular protein whose job it is to keep and maintain iron in red blood cells. Because of an abnormality in the synthesis of hemoglobin, a by product is created called kryptopyrrole, known scientifically as hydroxyhemoppyrrolin-2-one (HPL). This is the chemical that is involved in the production of heme, the substance that causes blood to be red in color. In most humans, HPL causes no problems and is simply excreted from the body via the urine.

With pyroluria, the level of pyrroles/HPL in the blood is abnormally high, and as a result, the receptor sites for Vitamin B6 and zinc are bound up and blocked. Kryptopyrroles target aldehydes in order to bind to them, and specifically targets pyridoxine (Vitamin B6). Together they attach to zinc, which creates a complex that is ultimately eliminated through the urine. If there is excessive binding and excretion out of the body, Vitamin B6 and zinc may be deficient.

Zinc and B6 are essential for production of neurotransmitters such as serotonin (our happy hormone), melatonin (our sleep hormone), GABA (our calming hormone), and acetylcholine (our housekeeping hormone). They are also involved in production of our steroid hormones such as cortisol (our anti-stress hormone) and the conversion of oils in the body (fat metabolism, liver, gall bladder issues, and weight control).

Triggers of Pyroluria

The condition usually presents itself in the late teens and persists throughout the balance of the person’s life. Any stressful experience can trigger the condition to be symptomatic because stress increases the production of pyrroles. They include:

  • Poor dietary choices and poor digestive health as a poor diet and digestion robs your body of essential nutrients.
  • Those with leaky gut syndrome are particularly vulnerable.
  • Prolonged laxative use, especially those containing magnesium sulphate and bisacodyl (a laxative drug), increases leaky gut syndrome. Frequent use of enemas (especially soap suds and tap water) result in loss of the intestinal lining, leading to leaky gut. Excessive stress also adds to this burden.
  • Unhealthy lifestyle habits, including excessive intake of alcohol, smoking, and drugs, can dramatically increase blood pyrrole levels as well. This is why sufferers of pyroluria tend to get a worsening of their symptoms twenty-four to forty-eight hours after a big alcohol party or recreational drug use.

Neurobehavioral Disorders Linked to High Levels of HPL

Pyroluria and Neurobehavioral DisordersPyroluria, elevated pyrroles, or a high kryptopyrrole in laboratory test results are frequently associated and identified in behavior disorders, autism, ADHD, Asperger’s, anxiety, ADD, depression, bipolar disorders, aggressive behavior, schizophrenia and other mental and emotional conditions.

It can also create poor tolerance of physical and emotional stress, poor anger control, emotional mood swings, anxiety, frequent infection, inability to tan, poor dream recall, poor short-term memory, abnormal fat distribution, sensitivity to light and sound, as well as tactile sensitivities.

About 10 percent of the population at large has the disorder. Only a small percentage of those afflicted has clinical symptoms. There is as many as 20 percent of those under psychiatric care suffering from pyroluria. It is estimated that 40 percent of patients diagnosed with schizophrenia have the condition. It affects women more than men.

Physical characteristics associated with Pyroluria:

  • Acne, eczema, or herpes
  • Coarse eyebrows and lack of hair on head, eyebrows and eyelashes
  • Cold hands and feet
  • White spots on fingernails (zinc deficiency)
  • Paper thin skin
  • Creaking knees
  • Fat concentrated in mid-section
  • Increased number of stretch marks
  • Poor tooth enamel
  • Sweet fruity smelling breath

Symptoms of Pyroluria

Pyrroles are classed as nerve poisons and as such can cause damage to nerves, nerve cells and tissue, and the brain, affecting transmission of information by nerves. Symptoms of pyroluria therefore spread across a broad spectrum. Because they are rather subtle, most are easily missed unless one is on the lookout. They include acne, allergies to food and the environment, anemia, anxiety and nervousness, delayed onset of puberty, delusions and hallucinations, unexplained chills and fever, poor sense of smell or taste, depression, digestive disturbances (constipation, abnormal tenderness), outbursts of temper, fatigue, glucose intolerance/hypoglycemia, gluten intolerance, and hyperactivity. The list continues with insomnia, irregular menstruation in females, increases in sensitivity or intolerance to light, sunlight and sound, crowded front teeth, irritable bowel syndrome, joint pain in knees and legs, loss of appetite, brain fog, low tolerance to stress, memory loss, poor dream recall, restless leg syndrome, sensitivity to medications, social withdrawal, and many more.

Do not be overwhelmed. No single person has all the signs and symptoms. The key to recognizing pyroluria is to detect a pattern of nonspecific symptoms pointing to an underlying general discontent of the body accompanied by a relevant history.

Diagnosing Pyroluria

Though having been around since the beginning of civilization, Adrenal Fatigue Syndrome (AFS), pyroluria, mitochondrial disease, and methylenetetrahydrofolate reductase (MTHFR) are some conditions coming to the forefront of scientific investigations because laboratory tools are now available to validate its scientific merit.

A qualified medical practitioner, after reviewing the complete medical and psychiatric history, will start the workup with a urine test for excess kryptopyrroles. Most have less than 10 mcg/dL of KPU. Persons with 10-20 mcg/dl are considered to have borderline pyroluria and may still benefit from treatment. Persons with levels above 20 mcg/dl are considered to have pyroluria. Some have levels in the hundreds.

Your diagnosing doctor will likely run urine tests to establish pyroluriaIf a person has been taking B6 and zinc, then the urine test can show a negative reading or a lower reading than if they were not taking the supplements. This is because the pyrroles will be bound and in a non-detectable form.

In order to treat the pyroluria nutritionally, further tests may be needed, including zinc and copper.

Bear in mind that blood measurements of B6 or zinc is not an accurate way of making this diagnosis as that is highly variable on vitamin intake or diet. Just having a deficiency in these nutrients doesn’t in itself cause an increase in pyrroles. It is rather a faulty enzyme pathway in the liver that causes them to increase.

The differential diagnosis should include Adrenal Fatigue Syndrome, histapenia (low histamine), histadelia (high histamine), and hypercupremia (high copper). There is also a rare genetic condition called acute intermittent porphyria (AIP), which is very severe and quite similar that is often linked with pyroluria. The fact is that of AIP patients tested, 100 percent of them showed positive results for having pyroluria.

Clinical presentation of pyroluria ranges from mild to severe. It depends on the genotype and the level of toxins exposed to in their environment and stress level. Concurrent presence of genetic defects like histapenia, histadelia and hypercupremia mentioned above further complicates the clinical presentation. As a result, symptoms do vary greatly among individuals across a wide spectrum.

Remember that just because one has clinical signs of pyroluria as well as positive laboratory tests does not mean that treatment is necessary. The vast majority of people with pyroluria are in fact asymptomatic and live normal lives.

Treatments for Pyroluria

Because the treatment is metabolic rather than pharmacologic, treatment needs to be titrated to individual requirements. The first thing to do nutritionally is to take more supplements of zinc and Vitamin B6 than is stated as the daily average requirement. This will compensate for the deficits resulting from this condition. These are essential nutrients, which will reduce the amount of HPL excreted, therefore improving all neurobehavioral symptoms linked with having these deficits.

The recommended forms for these nutritional supplements are specifically zinc picolinate and pyridoxal-5-phosphate (P5P).

Vitamin B6 is naturally found in our food in three different forms: pyridoxamine, pyridoxine, and pyridoxal. The last one, pyridoxal is the one that joins with a phosphate forming the metabolically active coenzyme, which is used in our bodies. This is called P5P. The most commonly used supplement of Vitamin B6 is pyridoxine hydrochloride and most people find this very useful. But with this supplement the body still needs to convert the pyridoxine in the small intestine into P5P so that it can be utilized.

The body cannot directly use pyridoxine. The metabolic processes that must take place first are called phosphorylation and oxidation. For these processes to take place, they need riboflavin (Vitamin B2), zinc and magnesium. They should be considered.

Recommended Supplements for Healthy People with Pyroluria

Supplements can help your pyroluriaThe higher the pyrrole level, the higher the need for B6 and zinc to bind and clear it safely from the body as well as replete the deficiency state that can cause many symptoms.

  • Vitamin B6: 50-300 mg of P5P and 200-400 mg of pyridoxine hydrochloride. Vitamin B6 is converted (metabolized) into P5P although taking the P5P metabolite can have a stronger effect than B6 and avoid the risk of a B6 overdose. P5P has been found to be most effective if taken every three to four hours during the day in doses of 10 to 20 mg each. Because P5P is water-soluble it is easily depleted and cannot be stored in the body. This is especially true for people who drink coffee or tea or anything else having a diuretic effect.
  • Zinc Picolinate: 25-75 mg of zinc picolinate daily is recommended for adults with severe cases of pyroluria. It should be taken after breakfast in the morning. Dosages of zinc need to be increased slowly, building up in the system according to lab results measuring levels of zinc, copper and ceruloplasmin, as well as the level of HPL in the urine. Another consideration is the vitality of the patient and their ability to adapt and in general cope with chelation therapy.
  • Copper: Excessive imbalance is common in those with pyroluria and needs to be detoxified. It is advisable to have mineral and metal levels checked in complicated cases as well.
  • Manganese: This vital nutrient is depleted when zinc is taken at the high levels that are necessary for overcoming pyroluria. Manganese is necessary for the metabolism of certain proteins; it is also important to joint development and neurotransmitter production.
  • Magnesium: Taking B6 in large amounts can deplete magnesium levels. Adding magnesium can reduce irritability and hypersensitivity to light and sound, reducing chances of peripheral nerve sensitivity, helping the body to calm down, promoting better sleep, and reducing constipation. The liposomal form is preferred.
  • Niacinamide (Vitamin B3): This nutrient is necessary for the production of tryptophan, which in turn is necessary for the production of serotonin. Taking niacinamide helps to speed the pyroluria recovery process. Compared to niacin, niacinamide does not cause skin flushes.
  • Vitamin C and Pantothenic Acid: These nutrients help to rebuild adrenal glands that become exhausted from coping with the ongoing tension caused by pyroluria; adding them to pyroluria supplementation allows patients to overcome the weakness and fatigue they often feel.

All nutritional supplements should be titrated professionally to each person’s body weight, age, lab results, symptom severity and their ability to absorb the supplements. Other considerations would be if the patient were suffering from any underlying digestive disorders affecting their ability to absorb nutrients. Disorders such as: Coeliac disease, Crohn’s disease, food allergies or intolerances, gastritis, GI Tract infections such as clostridia, H. pylori, parasites, or yeast, inflammatory bowel disease, intestinal dysbiosis, which is an imbalance of the flora in the bowel, irritable bowel syndrome, leaky gut syndrome, and/or peptic ulcer.

Crohn's disease can be another obstacle to overcome with PyroluriaIf there is a pre-existing deficiency of zinc and Vitamin B6 then secondary deficiencies should be addressed, since these nutrients are vital for the production of certain other nutrients, hormones, neurotransmitters and over one hundred different enzymatic reactions in the body.

Those with a history of liver pathology or congestion need to be specially careful using the right dosage of Vitamin B6 and zinc due to possible faulty liver cytochrome P450 metabolic detoxification pathways within that leads to a higher internal pyrrole load.


Normal healthy people without food allergies, methylation issues, underlying chronic illness, internal chemical imbalances, or digestive disorders can see improvement within a short time, sometimes within days, by only supplementing with the right dose of Vitamin B6 and zinc. The result can be quite dramatic. In fact, experienced clinicians will often proceed with a clinical trial of B6 and zinc if there is suspected polyuria and the right clinical conditions are met. There is often no need for laboratory testing prior to the clinical trial.

Healthy people with severe pyroluria usually require several weeks before progress is seen and improvement may be gradual over three to twelve months. Features of pyroluria usually recur within two to four weeks if the nutritional program is stopped. Thus, the need for treatment is indefinite.

People who are constitutionally weak or have underlying chronic illness fare differently. They usually do not respond with the normal expected outcome and may in fact get worse. Those that have underlying Adrenal Fatigue Syndrome can find this often challenging.

Read Part 2 Now!

© Copyright 2016 Michael Lam, M.D. All Rights Reserved.

Dr. Lam’s Key Questions

There should be no correlation.

No. If you are bleeding heavily due to menstruation, there may be a connection through OAT axis imbalance.

The Blood Disorder Pyroluria can interact negatively with Adrenal Fatigue
5 -
This is the simplest yet most comprehensive review of CFS, AFS, mitochondrial dysfunction and pyroluria linked together. I am experiencing them all and my heart goes out to all those whose lives are so much more severely limited than I am.
This is the only report that enables me to understand why all the natural help my very alternative doctor has suggested for sleep has just left me more wide awake, even though still quite relaxed. I was aware that taking pyrole supplements was doing some rather risky detox of copper but we got that under control. Now i have a bigger picture which I can share with my doctor who is learning as we go along. i wont be consulting Dr Lam from Australia but I feel I am helped and will continue to do my best to manage my supplements
Linda Whitefeather