Biochemical Diagnosis

What is Pyrrole Disorder?

Pyrrole Disorder is an abnormality in biochemistry resulting in the overproduction of a urinary pyrrole called OHHPL (hydroxyhemoppyrrolin-2-one). It was first discovered in the late 1950′s by a team of Canadian researchers lead by Abram Hoffer, MD when they identified a novel compound in the urine of patients with schizophrenia. OHHPL produced a lilac-colored (mauve) spot on chromatographic urine testing and has also been referred to as Mauve Factor. It is both heat- and light-sensitive; therefore, proper collection, transport and testing precautions are required to ensure proper testing.

In the 1960s Dr. Hoffer and colleagues published clinical outcomes of schizophrenic and other mentally ill patients with high urinary pyrrole levels showing that treatment with high dose niacinamide (the amide form of Vitamin B-3) both normalized the urinary pyrrole level and treated the clinical symptoms characteristic of pyrrole disorder (see below). In the 1970s Carl Pfeiffer, MD showed similar results with high doses of vitamin B6 and zinc as the current treatment of choice.

Vitamin B6, P5P (pyridoxal-5-phosphate), niacinamide and zinc all have important antioxidant roles. Clinical experience at the Pfeiffer Treatment Center in Warrenville, Illinois suggests that an elevated urinary pyrrole may a good biomarker for oxidative stress.

What are the symptoms of Pyrrole Disorder?

The common clinical symptoms in patients with pyrrole disorder are anxiety (fear); poor stress tolerance; sensory hypersensitivity to light, sound, smell and/or touch; mood and emotional lability; social anxiety and/or withdrawal; poor dream recall; and commonly, explosive temper and aggression. Clinical signs are pale skin (china doll appearance), stretch marks, and white spots on the nails due to the commonly concomitant zinc deficiency. An adverse reaction to omega-3 fish oil can be an important piece of the past medical history raising clinical suspicion for the presence of pyrrole disorder.

How is Pyrrole Disorder diagnosed?

Pyrrole disorder is primary a clinical diagnosis requiring a patient with characteristic clinical symptoms and often a concomitantly elevated urinary pyrrole test result who responds to appropriate nutrient therapy with improvement in their clinical symptoms. Patients with urinary pyrrole levels of 20 mg/dl or higher often exhibit several of the characteristic clinical symptoms. An intermediate level of 10-20 mcg/dl does not rule out pyrrole disorder because it is response to treatment that confirms the diagnosis.

How is Pyrrole Disorder Treated?

The core treatment of pyrrole disorder is vitamin B6 and/or pyridoxal-5-phosphate (the active form of vitamin B6) along with magnesium and zinc. Vitamin C, vitamin E, and niacinamide are often part of treatment due to their strong antioxidant properties, synergistic metabolic roles, and in the case of niacinamide was originally shown by Dr. Hoffer to be effective as monotherapy in treatment of clinical symptoms and elevated urinary pyrrole levels.

Unlike zinc where proper dosing of zinc is based on zinc levels, adequate dosing of vitamin B6 and P5P are based on resolution of the presenting clinical symptoms. Stress, illness, and injury all exacerbate zinc deficiency and pyrrole disorder; therefore, lifestyle changes, counseling and exercise are all necessary adjuncts to nutrient therapy. In times of severe stress or illness, additional doses of core nutrients (stress dosing) can be helpful in mitigating emergence of clinical symptoms.

Evening primrose oil is also utilized in treatment. Based on work by Bibeus et al. patients with elevated urinary pyrroles had a higher prevalence of low arachadonic acid levels on fatty acid analysis.

Clinical symptoms often return if nutritional treatment is discontinued, suggesting that once pyrrole disorder becomes clinically evident, the need for some treatment will be lifelong.


McGinnis, WJ. Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and Anxiety Symptoms.

McGinnis, WJ et al. Discerning the Mauve Factor, Part 1. Altern Ther Health Med. 2008 Mar-Apr; Vol 14(2): 40-50.

McGinnis, WJ et al. Discerning the Mauve Factor, Part 2. Altern Ther Health Med. 2008 may-Jun; Vol 14(3): 56-62.

Pfeiffer, CC. Nutrition and Mental Illness.

What is Zinc? 

Zinc is an essential trace metal required for cell growth & repair, immune function, gastrointestinal function, neurologic function, and many other important biochemical functions in the body. Zinc deficiency results in impaired antioxidant defenses and negative effects on many important proteins and enzymes.

There are more than 100 zinc-dependent enzymes in the body and are found in every organ system. As part of the biochemical machinery of the brain, zinc is involved in production of neurotransmitters, especially GABA. This is the catalytic role of zinc in biological systems. Zinc also serves to provide structure to proteins and cell membranes thereby protecting them from oxidative stress and impaired function.

In addition to the catalytic and structural roles of zinc, in the form of zinc finger proteins, it is involved in gene expression by acting as transcription factors which turn on or off expression of our DNA. This influence can alter cell signaling and thereby influence release of hormones or in other cases transmission of a nerve signal along the cell.

The role of zinc in protection from oxidative stress should not be underestimated. Zinc ingestion is a potent inducer of metallothionein, a family of proteins involved in copper metabolism, zinc transport, recycling of reduced and functional form glutathione (the currency of antioxidant action in the body), protection from heavy metal toxicity, and pruning during development and learning.

What are the symptoms of Zinc Deficiency?

Because of the many effects of zinc, deficiency signs and symptoms can be quite diverse. White spots on the nails, psoriasis, acne, eczema, poor wound healing and hypogeusia (impaired sensitivity to taste) are related to the adverse effects on the dermal and immune systems. Decreased appetite, diarrhea, stunted growth, and delayed maturation are adverse effects on the endocrine and gastrointestinal system. Poor memory, irritability, and other behavioral disturbance are negative effects of zinc deficiency on brain function. Recurrent infections or increased susceptibility to unusual infections are negative effects on immune function

A high incidence of zinc deficiency is found in patients with ADHD, autism spectrum disorders, depression, schizophrenia, and bipolar disorder.

How is Zinc Deficiency Diagnosed?

Zinc deficiency is diagnosed by a finding a plasma zinc level below 100 mcg/dl. Plasma zinc is the most reliable measure of zinc adequacy and is preferred to serum zinc or intracellular zinc levels, which are less accurate.

The clinical sign of zinc deficiency is white spots on the nails.

How is Zinc Deficiency treated?

Zinc deficiency is corrected with supplementation of zinc intake. The severity of the deficiency, based on laboratory findings and clinical symptoms, determines the starting dose of zinc. The final dose is based upon ongoing measurement of plasma zinc to achieve a plasma level of 100-120 mcg/dl.

Zinc citrate is the most common form of zinc found in breast milk and is one of the preferred zinc salts to use for supplementation. Zinc picolinate is also well absorbed and is also used. Zinc arginate is potentially more absorbable in certain bowel diseases because it is absorbed at the base and not the end of the intestinal villus (often shortened in bowel disease).  Zinc sulfate is useful dosing of zinc for dermal (skin) absorption; however, due to nausea is not well tolerated orally.  Because vitamin B6, vitamin C, vitamin E, and magnesium are often co-factors with zinc, they are also included as part of zinc deficiency treatment.

Zinc supplementation can lower copper levels; therefore, serum copper levels are also followed to ensure that supplementation of zinc has not adversely affected copper metabolism. Supplemental copper is rarely needed; however, is the solution when higher zinc doses are needed clinically, yet lead to low copper levels. In the case of concomitant abnormally high copper levels, supplementation with zinc needs to proceed gradually because zinc will induce copper elimination which can induce irritability.


Micronutrient Information Center at the Linus Pauling Institute.

Pfeiffer, CC.  Nutrition and Mental Illness.

What is Low Histamine Chemistry?

Histamine is the chemical commonly associated with the allergy symptoms of runny nose, itchy eyes, hives and sedation. Histamine is also a neurotransmitter and can influence mood and behavior. Low histamine chemistry, as known as histapenia and originally described by Dr. Carl Pfeiffer, MD, PhD, is the constellation of clinical symptoms commonly found in persons with a low whole blood histamine level.

What are the symptoms of Low Histamine chemistry?

Persons with Low Histamine chemistry are often creative, artistic, and nurturing individuals. They also tend to be compassionate caregivers and non-competitive, accepting individuals so when manifested normally, these traits can contribute to a successful life developing authentic friendships and often choosing the greater good over self. Low Histamine chemistry is prevalent among musicians, artists, actors, composers, architects, nurses and other direct patient care positions in health care.

However, individuals with Low Histamine chemistry can have high internal tension and anxiety, may overreact to life experiences and have a tendency to dwell on the negative. Rather than inhalant allergies, they may have food and chemical sensitivities though seasonal allergies may occur. They may also struggle with underachievement regardless of intelligence and may have trouble with achieving restful sleep.

Children with low histamine tend to be overstimulated and hyperactive. They may may struggle with anxiety, fear and low motivation. In the teenage years, depression is common. Because they tend to be nurturing individuals and peacekeepers they are often very sensitive to unkindness and disapproval.

It is common for persons with Low Histamine chemistry to experience poor response to or negative consequences with medications or supplements with antihistaminic effects, such as anti-histamines, H2 blockers, and the sedating atypical anti-psychotics. Furthermore, medications that are activating or serotonergic (SSRIs and St. Johns Wort) are often poorly tolerated. In fact, a history of adverse or ineffective response to psychiatric medications is common.

How is Low Histamine Chemistry diagnosed?

Low Histamine is diagnosed by an depressed whole blood histamine. Antihistamines or medications with antihistaminic properties can cause this test to be falsely low, so the clinical picture is an important factor in making the diagnosis.

Blood histamine represents a biological marker for response to low histamine treatment and the level is not affected by targeted nutrient therapy even when the person notices improvement in their clinical symptoms. Therefore, once the diagnosis is established further testing is not needed.

How is Low Histamine chemistry treated?

Low Histamine chemistry is treated with folic acid, niacin/niacinamide, vitamin B12 and vitamin C. Response to targeted nutrient therapy tends to be apparent in 4-6 weeks and is more obvious in 4-6 months, though many persons report steady, gradual improvements for years.

The greatest challenge for treatment of persons with low histamine chemistry may be an initial 3-6 week period of exacerbations in symptoms when targeted nutrient therapy is started. However, once past this initial period most persons will comment that they have never felt as well as they do with targeted nutrient therapy and compliance thereafter is rarely a problem.


Pfeiffer, CC. Nutrition and Mental Illness.

What is High Histamine Chemistry?

Histamine is the chemical commonly associated with the allergy symptoms of runny nose, itchy eyes, hives and sedation. Histamine is also a neurotransmitter and can influence mood and behavior. High histamine chemistry, as known as histadelia and originally described by Dr. Carl Pfeiffer, MD, PhD, is the constellation of clinical symptoms commonly found in persons with an elevated whole blood histamine level.

What are the symptoms of High Histamine Chemistry?

Persons with High Histamine chemistry are often motivated, attentive to detail and have good organizational abilities. When manifest normally these traits can be nurtured and thereby lead to a lifetime of success and achievement. In this case being self-motivated, achievement or goal directed and an authentic leader may be ways to describe such a person.

However, these similar traits can manifest to the extreme as perfectionism, obsessive and compulsive behaviors, competitiveness, a very high-energy/strong will and a desire for control. Depression, addictiveness, and social withdrawal are not uncommon from being at the extreme over time.

Children with more extreme symptoms can be controlling, strong-willed, and have great difficulty with authority. They can have trouble socializing with peers preferring the company of younger children or adults. Traditional parenting is difficult and physical discipline often makes behavior worse. Parents will often describe these children as a “difficult child.”

Teens and adults with extreme symptoms can become obsessive and compulsive about a variety of things– substances (caffeine, tobacco, alcohol, drugs), food (carbs, eating disorders), electronics (especially video and online gaming), gambling, and satisfying their high libido.

Common traditional diagnoses associated with high histamine chemistry are ADHD, ODD, depression, alcoholism, drug abuse, and a type A personality. Concomitant physical symptoms are headaches, stomach aches, muscle cramps, itching (and the tendency to pick scabs), and allergies.

Based on the clinical history of persons with high histamine chemistry, they seem to be deficient in methyl groups, the one carbon building block needed for many of the neurotransmitters in the brain. One of the most important of these neurotransmitters is serotonin. Persons with high histamine often do well with the SSRI (selective serotonin re-uptake inhibitors) class of medications. Medications with an antihistaminic effect is often well tolerated. Unfortunately, drugs with antihistaminic effects, especially cocaine, are particularly addicting for persons with high histamine.

How is High Histamine Chemistry diagnosed?

High Histamine is diagnosed by an elevated whole blood histamine. Anti-histamines or medications with antihistaminic properties can cause the test to be falsely low so the clinical picture is an important factor in making the diagnosis.

Blood histamine represents a biological marker for response to high histamine treatment and its level doesn’t change with nutrient therapy even when the person sees improvement in their clinical symptoms. Therefore, once the diagnosis is established further testing of histamine is not needed.

How is High Histamine Chemistry treated?

High histamine chemistry is treated with calcium, vitamin A, and methionine (sometimes as SAMe). Inositol, Vitamin B6, and magnesium are adjunctive nutrients that are often also needed due to the associated symptoms.

As described above, High Histamine chemistry seems to be a low serotonin state; therefore, treatments supportive of serotonin can also be helpful – 5-HTP, L-Trytophan and St. John’s Wort.

The greatest challenges to treatment of persons with high histamine are poor compliance, a tendency to stop treatment early on and a 6-12 month response time to treatment. Compliance is difficult both because of the number of supplements needs and the temperament of persons with high histamine. The latter often is a struggle to maintain compliance once improvements are seen and to hang in there because of the delay until the full effect of treatment.


Pfeiffer, CC. Nutrition and Mental Illness.


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