VI.c. Low thyroxine, histadelia and B12

BH4 (biopterin) is required in converting tyrosine into thyroid hormone, dopamine and norepinephrine; and for forming serotonin from tryptophan.   If, in the homocysteine-to-methionine step  of the methylation cycle,  methyl folate cannot give up its methyl to B12, you get what is called a folate trap. Methyl folate accumulates (actually, 5-methyl-hydrofolate), and cannot break down into usable folate (5HTF), needed in creating biopterin. (Scroll up to the diagram at the top of this link). 

Again, if BH4 is limited, then so are thyroid hormones, and key antidepressant neurotransmitters.
So you get undermethylation and low thyroid, along with low dopamine, norepinephrine and serotonin.

In other words, we have here a subset of histadelics with difficulty transferring methyl from folate to B12, prone to low levels of thyroxine (T4).

Odd, isn't it, when histadelics generally have high metabolism. Perhaps, in some cases, T3 compensates.

For more on the folate trap, look here.

For a wider view of thyroid, histadelia, and bipolar disorder, you may want to see my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.
 

VI.b. Autoimmune thyroid, histadelia and glutathione

Histadelics (undermethylated, high folate individuals) can be either high, low or normal thyroid. What follows is a possible association between undermethylation and autoimmune thyroid.

1 Undermethylation is commonly associated with low glutathione
Almost all histadelics  are low in glutathione, a critical antioxidant, because:
—  An efficiently functioning methylation cycle is needed to supply precursors of glutathione as well as other important sulfur antioxidants. 
— Also, in some, due to specific problems in feedback mechanisms between the methylation cycle and transsulfuration pathway.

2 Low glutathione may foster thyroid autoimmunity
The thyroid uses hydrogen peroxide to create thyroid hormones. Glutathione peroxidase then detoxes the hydrogen peroxide. If glutathione is lacking, however, the hydrogen peroxide, a potent free radical, will react with thyroid proteins. The immune system may then fail to recognize these altered proteins as normal constituents of the thyroid, and launch an autoimmune attack.   C Duthoit (2001)
suggests this scenario as a possible etiology of autoimmune thyroid.

In this vein, Dr. Rich van Konynenburg reports that thyroid function improved markedly in a number of his chronic fatigue, autoimmune hypothyroid patients, upon methylation and glutathione support. They find glutathione stimulating, perhaps due to enhancement of thyroid function

-- suggesting caution with glutathione during episodes of thyroid hyperactivity (and perhaps mania) that can occur with early thyroid autoimmunity.

For a wider view of thyroid, histadelia, and bipolar disorder, you may want to see my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.

VI.d. Thyroid / Histamine Interactions

Chronic elevated histamine is one of the chief means of diagnosing histadelia, the most common biotype in bipolar disorder. Histamine interactions with the thyroid are complex, and not well-explored. Here is some food for thought:

The thyroid can either increase or decrease histamine:

— The thyroid may suppress the brain's histamine release and decrease its histamine-containing mast cells.
— Or increase body sensitivity to histamine and block its degradation.
 Sabria 1987, Uhpadhyaya, 1993,  Mariano 2009

Histamine may alter thyroid function

Histamine is known to strongly influence hypothalamus regulation of cellular metabolism, energy production and food intake. The thyroid is a major target gland in hypothalamic governance of  metabolism and energy production.
 Elmhar 2006,  Sakata 1997, Masaki 2001

Allergies and associated histamine release may be hard on the thyroid

Allergic reactions, which cause the profuse mast cells of the thyroid to dump histamine, and perhaps iodine, may thereby interfere with thyroid function. (Elmhar, Do low thyroids suffer more with allergies?)

Histamine may contribute to thyroid autoimmunity

Histamine-releasing antibodies are often found during increased thyroid autoimmunity, suggesting histamine may contribute to the immune attack on the thyroid (Mariano, 2009) -- perhaps via inflammation and increased permeability. (Melander 1975)


For a more comprehensive view of thyroid, histamine, and bipolar disorder, you may want to see my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Each person's biochemical requirements tend to be unique. So if you need treatment for bipolar, thyroid disorder or any other medical condition, please consult a knowledgeable physician.

VI.a. Thyroid, histamine and methylation in bipolars

Thyroid disorders, like histamine imbalances, pervade the bipolar population. Metabolism is low in histapenia and hypothyroid, high in histadelia and hyperthyroid. Some histamine/thyroid symptoms match up, others do not. The relationship of thyroid to histamine and methylation is complex, and not well explored.

The following posts will look at this relationship, particularly as regards bipolars.


For more on thyroid and bipolar disorder, you may want to see my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.

V. Hyperthyroid and Bipolar Mania

High thyroid can interact with, trigger, or intensify mania, (Nath 2001, Escamilla 2001)  and can also increase switching on antidepressants. (Bottlender, 2000). Even levels in the high-normal range can contribute to the development of mania. (Lee 2000, Roca 1990)

Joyce (1991), for instance, reported more than one-third of manics with elevated thyroid, and in the other two-thirds, various individuals with higher thyroid in mania than depression. Moreover, a number of researchers have suggested lithium’s anti-thyroid effects may underly its benefit to mania.
In some manics, however, thyroid can test low.

Mental symptoms that can be common to both hyperthyroid and mania

High irritability, tension, emotional instability, explosiveness, anxiety; exhilaration, increased motor activation, restlessness, tremors, hyperactivity, insomnia and other sleep problems; and, in some cases, erratic bizarre behavior, mood swings, impulsive destructive tendencies, psychosis, paranoia.

Eventually, perhaps, exhaustion or depression

Over time, hyperthyroids may succumb to depression and social withdrawal, perhaps due to an exhaustion caused by extended thyroid overstimulation. Similarly (although usually sooner), manic overstimulation eventually gives way to depression.


To get a comprehensive view of the interaction with bipolar disorder, you may want to look through my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.


Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Each person's biochemical requirements tend to be unique. So if you need treatment for bipolar, thyroid disorder or any other medical condition, please consult a knowledgeable physician.

IV.a. Autoimmune thyroid and bipolar disorder

Autoimmune Thyroid (Hashimoto's disease)

An estimated 50 to 90% of cases of hypothyroidism result from anti-thyroid antibodies. Hashmimoto's antibodies seem to be more common in people with bipolar depression, mixed state, and rapid cycling (and to a lesser degree, in other affective disorders) than in the general population.

Symptoms

Symptoms usually start with neck tenderness, and may be otherwise unnoticeable. Depression, memory and concentration problems may be the next to emerge.
Thyroid activity may cycle initially, so you can get periods of insomnia, anxiety, inner tension, panic attacks, hypomania, rapid heart beat, etc. due to thyroid hyperactivity. In some cases, overactivity is severe, creating hashitoxicosis.
Over years, the ongoing attack on thyroid tissue suppresses function causing hypothyroidism, with typical symptoms such as weight gain, chronic depression and fatigue, constipation, kidney and heart complications, etc.  (See previous post)

Potential Causes 

Psychosocial stressors.
Overstimulation with iodine or certain drugs.
Chronic exposure to fluoride, chlorine.
Toxic exposure.
Immune challenge (e.g., Candida, Epstein Barr).
Undermethylation and lack of glutathione
More on this later.


To get a more comprehensive view of the implications of thyroid function, and other endocrine status on bipolar disorder, you may want to look through my book, Natural Healing for Bipolar Disorder,
                available here.

To contact me, click here.


Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Each person's biochemical requirements tend to be unique. So if you need treatment for bipolar, thyroid disorder or any other medical condition, please consult a knowledgeable physician.

III. Low Thyroid and Depression

Thyroid: Mood and Cognitive Symptoms

Thyroid imbalances, particularly hypothyroid (low thyroid), pervade the depressed population.
Conversely, depression (and low energy) is a major symptom for almost all hypothyroid patients, even if only mildly low thyroid. (Fardella 2000, Pies 1998, Placidi 1998, Prange 1996, Musselman 1996)

Typical mental symptoms also include: apathy, loss of interest or pleasure, cognitive slowing, difficulty concentrating, suicidal ideas, memory problems, weakness, pervasive fatigue (may literally sleep one's life away), emotional instability, anxiety, perhaps panic, delusions and fears, suspiciousness and resentment.

Greater Severity and Myxedematous Madness 

Progressive hypothyroidism (myxedemia) steadily slows mental and physical functioning, compromising memory, concentration, comprehension, energy, and reflexes.
Before hormone treatment developed, up to 50% developed a psychosis, termed, myxedematous madness.
Symptoms could include melancholia, mania, and psychosis. Also,  slowed thinking, dementia, morbid dreams, obsessions, frightening hallucinations, persecutory delusions, paranoia, suicidal ruminations, along with physical symptoms of low metabolism.   (Gull 1873,  Clinical Society of London 1888,  Asher 1949)

Missed Thyroid Diagnoses

Psychiatric hypothyroid symptoms frequently precede physical, often leading to misdiagnosis as depression, and incorrect treatment. (Asher 1949, Reed 1977, Boillet 1998)
Low thyroid decreases cerebral glucose metabolism and blood flow (Marangell 1997), suppresses catecholamine activity and receptor sensitivity (Mano 1998), and is associated with more lengthy, frequent and severe depressions. Subclinical or clinical hypothyroidism is especially common in antidepressant-resistant affectives. (Frye 1999)

Note: Physical Symptoms

Weight gain, increased fat, difficult to reverse unless thyroid activity improves. Appetite changes.
Dry, puffy, rough skin; flaky acne. Pallor, yellow tinge (due to difficulty metabolizing carotene).
Water-logged tissue, e.g., ankles, face, especially under the eyes. 
Missing outer third of eyebrows. Eyebrows may be permanently raised to keep lids open.
Brittle, easily broken nails. Thinning, dry, brittle, hair. 
Vision problems, night blindness. Hearing problems.
Hoarseness, slurred speech, tongue thick and swollen, difficulty swallowing.
Anemia, poor circulation, cold sensitivity; perhaps also intolerant to heat.
Joint pain or stiffness, arthritis. Fatigue after minor exertion. Muscle weakness, aches, cramps.
Headaches, migraines.
Indigestion, gas, chronic constipation. Sensitive to drugs and toxins.
Prone to allergies, Candida, hypoglycemia, diabetes.
Low libido, PMS, fertility problems. Menses tend to be irregular, profuse, painful.
Shortness of breath, chest pain, slow pulse. Low blood pressure; but eventually too high, elevated cholesterol, atherosclerosis, heart disease. Prone to lung disorders.

To get a comprehensive view, you may want to look through my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.


Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Each person's biochemical requirements tend to be unique. So if you need treatment for bipolar, thyroid disorder or any other medical condition, please consult a knowledgeable physician.

II. Thyroid and bipolars: Some Iodine Issues

I. Thyroid and Bipolar Disorder

The thyroid gland is crucial to metabolism, growth and immunity, as well as supporting heart and kidney function, bone development, and maturation of the nervous system. Thyroid is also critical to cognition and mood.

In fact, thyroid hormones have been used to augment antidepressants and convert nonresponders, and to treat certain rapid cycling and hypomanic patients unresponsive to other treatments (though careful medical evaluation is essential, as thyroid hormone may promote mania).

Thyroid status in bipolars

Bipolars frequently exhibit thyroid underactivity or sometimes other thyroid conditions.* (Lasser 1997, Pies 1998)  Moreover, two of the major mood stabilizers (lithium and carbamazepine) may suppress the thyroid further. (Lazarus 1998)

In some bipolars, thyroid activity cycles with affective state.  Bipolars may be particularly sensitive to such fluctuations, even when within the normal range. (Cole 2002)  Cognitive function, for instance seems to be significantly linked to thyroid status, rather than lithium levels. (Tremont 1997)

Barnes (1976) warned that many patients medicated for depression, anxiety, and so forth, have undetected thyroid dysfunction, causing mood symptoms. Unfortunately, effective thyroid  status is often obscured by distorted interactions of the hypothalamus/pituitary/thyroid axis, and by difficulty determining peripheral sensitivity to thyroid.**(Pies 1998)

* Even as compared to the general psychiatric populations, in which thyroid problems are common. (Gloger, 1997, Fardella 2000, Placidi 1998)
** For example, you can get high thyroxine, with an elevated pituitary TSH nonresponsive to regulatory feedback, so continuing to stimulate the thyroid further. Along with high thyroid symptoms of, for example, weight loss, rapid heart beat, etc., the patient may manifest selective insensitivity to T4 in mood-modulating neural pathways, fostering the low thyroid symptom of depression. Labs also will be contradictory: with high T4, suggesting hyperthyroid; high TSH, hypothyroid. Thus neither effective thyroid status nor appropriate treatment will be readily apparent.

Affective symptoms in thyroid disorder patients

Thyroid dysfunction alters mood (as well as cognition and behavior), (Lasser 1997, Loosen 1987, Prange, Whybrow 1987, Tremont 1997)  typically creates affective symptoms, (Gibson 1962, Graves 1843) and is associated with increased incidence of depression, dysthymia, bipolar disorder, cyclothymia, panic disorder, phobia, and obsessive compulsive disorder. (Placidi 1998)

Hypothyroidism characteristically creates a depressive syndrome; even subclinical hypothyroidism may be associated with mood cycling, depression, and poor or slow response to affective treatment. Autoimmune thyroiditis is often associated with depression (especially postpartum), and with rapid cycling. Hyperthyroidism creates symptoms of, and contributes to, mania. (Pies 1998)

Nonetheless, the precise impact of thyroid activity can vary from one individual to another. (Loosen 1987)

I have excerpted the above post from the first page of a 32-page section on thyroid in my book, Natural Healing for Bipolar Disorder (copyright 2009).

To get a comprehensive view, you may want to look through my book, on bipolar disorder
                available here.

To contact me, click here.


Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Each person's biochemical requirements tend to be unique. So if you need treatment for bipolar, thyroid disorder or any other medical condition, please consult a knowledgeable physician.

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Help people find out about natural approaches for bipolar and schizophrenia by providing a link on your website to http://boragebooks.com
and/or to http://naturalhealingforbipolardisorder.blogspot.com
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Eva Edelman

Histadelia and Other Approaches for Bipolar Disorder

Readers interested in reviewing entries for histadelia (brain undermethylation and folate accumulation) can start at the 12/3/10 post on histadelia and bipolar depression and go on from there.
Most of the posts which follow are on histadelia, although from July 21 to Aug 20, 2011,  I talk about histapenia, in many ways the opposite biotype.
The early histadelia posts are more basic. Recently, I have turned the focus to histadelia biochemistry.
Remember, though histadelia is the largest biotype in bipolars, any combo of pyroluria, histapenia, allergies/immune dysfunction, oxidative stress, metal metabolism issues, Candida, blood sugar problems, hormone imbalances, toxicity, neurological disorders, etc., may be the relevant factor(s) for a specific individual.
 
To get a comprehensive view, you may want to look through my book,  Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.


Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Each person's biochemical requirements tend to be unique. So if you need treatment for bipolar, or any other medical condition, please consult a knowledgeable physician.

Notes: Histadelia, Sulfur, and Autism

Notes on histadelia, sulfur metabolism, and autism spectrum chemistry

1 Undermethylation. Dr. William J. Walsh (1999) originally found,* in reviewing 20,000 labs taken on hundreds of autistic individuals, that 90% showed brain undermethylation (histadelia). Drs. S Jill James and Richard Deth have since confirmed this. Dr. Amy Yasko's nutrigenomic research, which targets specific enzymes causing methyl metabolism problems, further confirms this chemisty. (Also see Nutrigenomics discussion, here.)

2 Sulfur Metabolism. The research of Dr. Rosemary Waring (2000) first drew attention to sulfur pathway problems in most autism spectum patients, specifically inadequate sulfation and PST activity, probably due to insufficient sulfate, and overzealous excretion. Follow up work suggests high sulfite, CBS overactivity, and other sulfur issues are also prevalent.

3 Metal metabolism. But unlike most other histadelics, autistics also tend to metal metabolism dysfunction, with elevated copper and toxic metals, and zinc and B6 inadequate. This aggravates oxidative stress further, even beyond what you find in other psych patients. (Walsh)

4 Severe oxidative stress. Profound oxidative stress** and metallothionein depletion*** at fetal and infant levels, slows and distorts brain development. Oxidative stress and sulfur pathway issues also impair brain and gut barriers and protein digestion. (Walsh)

5 Triggers. Later insult -- e.g., injection of toxic metals into the blood stream (as in mercury-containing vaccines),  chronic reactivity to gluten and dairy, or ongoing excitotoxic exposures -- can attack the already beleaguered brain all too readily, compounding toxicity and inflammation, and further fueling oxidative stress, thus triggering onset of identifiable symptoms, and a progression of developmental problems.

* Data presented at a DAN think tank in Cherry Hill, NJ, 1999, also showing low zinc and B6, high copper and toxics.
** Walsh reports extreme oxidative stress, with low glutathione,  low cysteine (its precursor), low selenium (its cofactor), and low SOD (a key endogenous antioxidant).
*** Metallothioneins (MTs) are the enzymes critical to transport and removal of  divalent heavy metals (e.g., mercury, cadmium, arsenic), and the regulation of zinc, copper and selenium. Undermethylation may compromise MT production.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for autism, bipolar, or any other medical condition, please consult a knowledgeable physician.
 
For info on the role of undermethylation in bipolar disorder, see my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.

Bipolar Histadelia and Sulfur: V-e. A Summary.

Histadelia (brain undermethylation) is the primary imbalance in an estimated 35% of bipolars. Most histadelics have problems in the trans-sulfuration pathway, because it is so closely connected to the methylation cycle.  On the one hand, methylation cycle distortions change precursor availability and enzyme activation in the trans-sulfuration pathway. On the other, insufficient sulfur antioxidants and high oxidative stress, will interfere with formation of methyl-B12 and divert too much homocysteine into forming sulfur compounds, compromising the methylation cycle. (Walsh)
To resolve sulfur issues, increasing glutathione and other antioxidants turns out to be sufficient for some histadelics. However, in a significant number of cases, attention to some of the other trans-sulfuration issues we have been discussing becomes necessary.
See part 4 and 5 of this diagram.

How trans-sulfuration problems can impact histadelia and bipolar symptoms:

1 Skyrocketing oxidative stress can compromise brain methylation. Causes may include:
— overactive SUOX, creating a buildup of ammonia and toxic sulfurs, and fostering excitotoxicity
— a buildup of toxic sulfur compounds due to poor sulfite to sulfate conversion.
— drastically reduced formation of glutathione and sulfur antioxidants

Glutathione then becomes much less available to connect to B12 and enable formation of methyl-B12. Blocking this step, formation of methionine and SAM, and methylation of DNA and proteins are impeded.*
For a review of undermethylation symptoms, see here and here. 

2  Poor sulfation compromises normal metabolism of mood-altering molecules and toxins.

— If sulfate is low (whether due to excess urinary loss, or reduced sulfate formation), then sulfation tends to be compromised. This leads to phenol accumulation and increased sensitivity reactions, inflammation,  and oxidative stress.
—  Poor sulfation can also compromise amine metabolism. This can lead to an accumulation of stimulatory neurotransmitters and altered regulation of estrogen and cortisol, contributing to anxiety, tension, irritability, insomnia, mania, etc.

3 Formation of taurine may be compromised.
—   Taurine is a critical inhibitory neurotransmitter, lack of which would tend to destabilize mood, and foster overstimulation, neurological instability, tension, irritability, etc.

4  Increasing toxicity compromises brain function.
Toxicity can be due variously to lack of sulfur antioxidants and glutathione, poor metabolism of sulfurs, phenol and amine accumulation, overproduction of ammonia (which creates brain fog) and sulfur compounds, excitotoxicity and profound oxidative stress. Toxicity can attack receptor accuracy, second messaging, axonal transmission, neurotransmitter systems, astrocyte activity, as well as specific brain structures. Functional deterioration may manifest as learning or behavior disorders, depression, mood instability, OCD, dementia, etc.,  and in severe cases in the very young, especially if metal metabolism is suppressed, autistic symptoms. (See Notes, next post.)

*The betaine pathway may take up some of the slack in some individuals. Nevertheless, problems with the transsulfuration pathway generally foster undermethylation.


Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician.
 
For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder
                available here.

To contact me, click here.

Histadelia and Sulfur: Part V-d: Phenol sensitivity

What are Phenols?
Phenol is C6H5OH. It alone is toxic, as are certain phenol compounds. However, phenols are also found in many healthful fruits, vegetables, herbs, seeds and nuts. And certain phenols are, variously, important in normal metabolism, including metabolism of adrenal stress hormones; in countering oxidative stress, inflammation and toxicity;  and, possibly, as a protective agent in diabetes, cancer, and aging.
Phenols include flavonoids (the coloring matter in plant foods, known for antioxidant and anti-inflammatory properties),  resveratrol (in grape skin), tocopherols (vitamin E), carotenoids (which have vitamin A-like activity), and salicylates (this guide lists salicylate-rich foods), as well as the flavoring compound in raspberries, the agent which makes cayenne hot, the source of the smoky/ pungent scent in many perfumes, and a breakdown product of hemoglobin.

Sulfation of Phenols
Phenol accumulation, however, presents toxicity issues. Normally, a process called sulfation* attaches sulfate to the phenols in food and chemicals, making them less toxic, and facilitating elimination. Specifically, the enzyme, PST (phenol sulfur-transferase), sulfo-conjugates phenols, creating phenol-sulfates.
The basic chemistry is:    phenols --via PST-- yield phenol-sulfates
* Sulfation is also one of the major processes in liver detox activity, targeting various compounds, not just phenols.

Phenol Sensitivity
Too few sulfates, too many phenols, or downregulation of PST allows phenols to accumulate instead of being detoxed and eliminated via sulfation. Thus, phenol sensitivity is a good indicator of sulfation problems.

The development of phenol sensitivity is accelerated by a leaky gut, which would allow poorly digested phenol foods into the bloodstream. As mentioned in the previous post, insufficient sulfates also means poor mucin creation, compromising gut integrity.

Amine Sensitivity. Accumulation of stimulating neurotransmitters and hormones.

People who have problems with phenols also often show sensitivity to amines, which also need sulfates and sulfo-transferase enzymes to inactivate them. Amines include the antidepressant neurotransmitters: serotonin, epinephrine, norepinephrine and dopamine; the amino acids, one of the metabolites of thyroid hormone, and tyramine. 
Sulfation also seems to be needed to metabolize or regulate estrogen and adrenal stress hormones. 


 In summary, a lack of sulfates, subfunctional sulfo-transferases, and too many phenols and amines taxing the system, leads to phenol and amine accumulation, often producing sensitivity. (See Rosemary Waring, PhD,  on amine sensitivity), This biochemistry also increases overall toxicity, excitotoxicity, and oxidative stress, with profound effects on brain function. Moreover, inadequate sulfation prevents the body from adequately removing stimulating neurotransmitters and hormones, thereby increasing the tendency to anxiety, insomnia and mania.

CONSIDERATIONS (John Pietryka, ND, presents a good summary of specific effects, from which the following is derived)

Sensitivity reactions to salicylates and other phenols can include affective symptoms, such as:

Mood swings, depression.

Hyperactivity, irritability, sudden anger, overstimulation, hypomania.
Other mental and physical symptoms:
Delusions, phobias, dysperceptions, feelings of unreality, perhaps hallucinations.
Sensitivity to light and sound, ringing in the ears. Dark circles under the eyes.
Sleep problems, night sweats.
Memory and concentration problems, episodes of blank mind, disorientation, vertigo.
Socialization problems (associated with low CCK activity).
The following physical symptoms:
Rash, eczema, red face, hives, feeling of something crawling on the skin, other skin conditions.
Frequent urination or urinary retention, dehydration.
Nausea, gastrointestinal symptoms, gall bladder problems.
Hyperventilation, tachycardia, racing pulse, breathing issues, excess or suppressed perspiration.
Muscle or joint aches. Migraines.

Family history of:
Migraines, allergies, chemical sensitivity.
Perhaps, Alzheimers, Parkinsons, motor neurone disease, or cirrhosis.
(Similar to whats found in histadelia.)

Look for:

Hyperactivity or lethargy when taking Tylenol, and/or reactivity to aspirin.
Urinary loss of potassium and sodium bicarbonate.
Toxic metal buildup. Problems eliminating toxins.
Low plasma sulfate, often high urinary levels.

TREATMENT APPROACHES  (Petryka,   Roberts,    and here)

Potentially helpful nutrients:

Molybdenum (especially if sulfite conversion is a factor). 
B6 can inhibit PST, but generally supports sulfoxidation. Adverse symptoms reduced if 1:1 with magnesium. (See: Rosemary Waring, PhD)
Other B vitamins are often useful.
Epsom salt bath or cream, as relevant. (See Kurt Woeller, DO)
Additional sulfate sources such as taurine and glucosamine sulfate may or may not help. Similarly, for sulfur foods. Avoid sulfites.   
Pancreatic digestive enzymes (suppressed by low sulfate), which break down fats, proteins, nucleic acids and carbs, as relevant.
Enzymes which digest veggies, fruits, nuts and grain (e.g., breaking down xylose, cellulose, glucans, phytins, galactose, and carbs), as relevant.  
Possibly, baking soda.  (Interesting anecdote on suggestions by Rich Van Konynenburg, PhD)
Possibly, cranberry juice (anecdotal). (John Petryka, ND)

Supporting sulfation after long impaired can cause intolerable detox reactions and discourage use of nutrients needed for healing.  Which is why certain nutrients (even glutathione) may have to be introduced gradually. 

Issues with otherwise healthy foods  (John Petryka)

Salicylates and other phenol-rich foods (apple, citrus, chocolate...) use up, sulfate. Many also inhibit sulfation itself.* Similarly, amine-rich foods (tyramine, etc.), use up sulfate.
Boron (found in apples pears, legumes, nuts, leafy greens, grapes) interferes with phenol breakdown.
* Oranges, spinach, radish, grapefruit, beet, pepper, squash, vanillan, tomato, food color as well as flavonoids, inhibit sulfating enzymes. 

Nevertheless, such foods and nutrients clearly convey important health benefits, so are restricted mainly at the beginning of treatment (until reasonable sulfation can be established), and mainly to the extent to which they are causing significant adverse symptoms. 

Restrictions vary with the individual. People commonly react to certain foods, but not others. Reactive foods may need to temporarily be avoided or, at least, eaten less frequently, and in smaller amounts. Eventually though, with enough sulfation support, reactivity should diminish enough so that most such foods can be eaten in reasonable quantities.

Avoid:

Eliminate unnecessary sources of phenols such as food additives (dyes, flavors, preservatives), perfumes and room scents, coal-tar-derived (not high-quality) vitamins, perfumes and certain drugs (notably, the salicylate of aspirin).

See also, previous post.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician.  

Next post:  Applicability of sulfur pathway issues to histadelic bipolars.

For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

   available at  boragebooks.com/orderBooks.html

Histadelia and Sulfurs: Part V-c: Sulfites to Sulfates

Another subset of high-oxidative-stress, undermethylated bipolars have problems converting sulfites to sulfates. Overloaded sulfites transform into toxic sulfur compounds which increase the burden on antioxidants and detox agents, using up glutathione. Moreover the sulfates which should have been formed are important antioxidant and detox agents, which help spare glutathione. So, again, we can have difficulty joining methyl to B12, impeding formation of methionine and SAM, thereby fostering undermethylation.

Difficulty metabolizing sulfites to sulfates can be due to

A simple lack of molybdenum.

Chronic overload of sulfur compounds.

Underactivity of the enzyme, SUOX (sulfite oxidase) which catalyzes the oxidation of sulfite to sulfate.  

The basic chemistry is 
Sulfite + molybdenum + B6 (P5P) + SUOX  yields  Sulfate
See Methionine cycle, step 4, lower half of diagram. 

or lower right of this diagram

CONSIDERATIONS.
Check for elevated urinary sulfites.
Doing okay with sulfates and taurine (which converts to a sulfate without using SUOX), but reacting to sulfur supplements and foods, especially eggs, suggests sulfite to sulfate conversion problems.

Sulfates are needed in nerve, bone and cartilege formation, mucin creation, liver detox, and catecholamine inactivation. Thus, the following conditions may be associated with low sulfate formation (or with low sulfation):

—Overstimulation: Sulfation inactivates thyroid hormone and catecholamines (e.g., dopamine).  (Interesting overview at http://what-when-how.com/molecular-biology/sulfation-molecular-biology/)
— Inflammation.
—Migraines.
—Arthritis and other joint/cartilege maintenance and repair problems (think MSM and glucosamine).
—Digestive symptoms: leaky gut, irritable bowel, low stomach acid, gall bladder hypofunction (problems with fats), low digestive enzymes, constipation.

TREATMENT APPROACHES  (Petryka,  Roberts)

Molybdenum (in legumes) helps form sulfate (as well as BH4 -- see previous post). Low uric acid or intolerance to alcohol can also suggest low molybdenum.
P5P (a form of B6) may also be needed.
However, too much of either can be counterproductive.
Hydroxy B12, boron, and vitamin E (along with the molybdenum 2x/day) may help increase SUOX activity. (Roberts)
Restict/avoid sulfites. (An upbeat non-medical discussion of sulfites here).
 

Sulfates, if depleted, will be helpful: 
—Epsom salt (magnesium sulfate).  Can be added to baths, but this is contraindicated if there is any danger of falling asleep in the bath, or if taking antipsychotics, anxiety or sleep meds, or consuming alcohol or other suppressants. An epsom salt foot soak, epsom sprays, or creams may be used instead.  Or a combo of sources.  E.g., see enzyme stuff, about half-way down the page. 

—Taurine.
—MSM, glutathione sulfate, or NAC may or may not help.

Phenol and salicylate restriction is often indicated as sulfates are used up in their metabolism. More on phenols and salicylates next post.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 

For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

   available at  boragebooks.com/orderBooks.html

Histadelia and Sulfur: Part V-b: Oxidative stress

Transsulfuration pathway malfunctions occur in some histadelic bipolars (and most autistics). And if such problems involve underproduction of glutathione or other sulfur antioxidants, they can be an important cause of the undermethylation.

Overactivity of CBS causes low glutathione,  high ammonia and overproduction of sulfur compounds. This is very common, especially in autistics. CBS*  is the critical enzyme in converting  homocysteine to cystathionine (see Methionine cycle, step 4, lower half of diagram). 
 * Cystathionine beta synthase.

Thus, with upregulation of CBS: 
Homocysteine  + B6  (as P5P) + Mg   + CBS  yields overabundant Cystine (instead of cysteine) + excess Ammonia + AKG

Accumulating sulfur metabolites promote formation of cystine rather than cysteine (and then, hydrogen sulfide and thiosulfates.) Lacking cysteine, glutathione cannot be formed. Oxidative stress becomes profound. Methyl cannot attach to B12, impeding the transformation of homocysteine to methionine. Formation of homocysteine from SAH is also suppressed.

The ammonia creates brain fog. In part, because ammonia inhibits axonal electrical potentials, decreases brain ATP, causes astrocyte inflammation. And also because it depletes BH4, which is used in forming tyrosine, dopamine, norepinephrine and serotonin.
 
In summary, CBS upregulation leads to:  Severe oxidative stress. Failure to form methionine and glutathione. Low SAM. SAH  and perhaps some HCY accumulation. Toxic sulfur compounds. Ammonia overload. Brain fog.

Considerations (Roberts)

Brain fog.

Reacts to intake of sulfur foods, meds, or supplements.

High-normal to elevated urinary ammonia
Elevated urinary sulfurs.  (Check ammonia and sulfur periodically. The individual can do this themselves with urinary test strips.)
Homocysteine on the low side.

Treatment Approaches (Walsh, Pietryka, Roberts)

Sulfur issues.

Excess B6 can worsen symptoms. P5P may be a better choice (Roberts). Rosemary Waring suggests  increasing magnesium (to at least 1:1, magnesium:B6; or 2:1 magnesium:P5P).
Diets high in sulfur foods worsen the accumulation of detrimental sulfurs. Animal proteins, and sulfur in foods, nutrients and meds often need to be restricted (perhaps even NAC and glutathione), at least until sulfurs start to normalize. 
GABA may be indicated, if anxiety or overstimulation is developing. (Roberts)
Toxic metal accumulation and metal metabolism dysfunction may have some association with CBS overactivity. (Roberts, See section on CBS.)

Ammonia issues (Yasko, Roberts)

Yucca to help detox ammonia.
RNA support to help neutralize ammonia.
Activated charcoal to neutralize ammonia (at night, with magnesium citrate to insure removal).
Carnitine / CoQ10/ and or NADH if needed to support energy levels.

Countering oxidative stress.
NAC and selenium foster creation of glutathione. Reduced glutathione can be taken. Relatively absorbable forms include sublinguals, creams, sprays (as liposomal preparations), IVs, or suppositories.
Reduce factors worsening oxidative stress, such as, toxicity, illness, poor diet, stress, overexertion and metal metabolism dysfunction. Also, avoid excitotoxins.
Mercury levels may need attention, as mercury will readily bind to the abundant sulfhydryl (thiol) groups and, via the bloodstream, gain greater access to body tissues (Cutler).
 
Methylation cycle issues.
The sulfur pathway may need to be dealt with first to prevent draining out of precursors, as well to encourage enough glutathione to methylate B12. (Roberts)
To support methylation, glutathione and methyl-B12 may need to be provided directly. (Walsh)
Betaine may help create some methionine, if the betaine pathway is working effectively. But usually, methionine and/or SAM is needed. (Walsh)

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 


Next posts: Sulfites, sulfates. Salicylates and phenols.

For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

Buy the Natural Healing for Bipolar Disorder book by Eva Edelman and get to question the author

For a limited time only,  if you purchase a new Natural Healing for Bipolar Disorder from Borage Books, you will be able to set up a free 20 minute phone session (at your convenience).
Get your questions answered!  I look forward to talking with you.
                                                                                     Eva Edelman

Histadelia and Methylation. Part V-a: TransSulfuration Pathway

Homocysteine

Despite the notorious dangers of excess homocysteine,* normal levels are necessary to body chemistry, particularly the methylation cycle and the transsulfuration pathway. Homocysteine lies at the intersection of the two, serving as a precursor to methionine (which forms SAM), and also as the antecedent to cysteine, taurine, glutathione and sulfate.
* Chronically elevated homocysteine is infamous for its association with heart disease and may also play a role in memory impairment. It degrades collagen and elastin and damages the lining of blood and lymphatic vessels, via oxidative stress, inflammation, fibrin deposits, etc.  Similarly, it compromises the blood brain barrier.

The Transsulfuration Pathway (under the Methionine cycle (4) on the bottom right of this diagram)

During the methylation cycle, insufficient glutathione at the homocysteine-to-methionine step prevents methyl from linking to B12, and thereby impedes methionine formation.
Homocysteine  is instead diverted down the transsulfuration pathway to form glutathione.
This pathway transforms homocysteine into sulfur antioxidants and detox agents. And typically removes half the homocysteine from the methylation cycle.  But when it goes wrong, it produces toxic sulfur compounds. 
Here is an introduction to the chemistry:

Essentially:

 Homocysteine with the help of:
        vitamin B6 (as P5P), vitamin B3 (as NAD),

         magnesium, serine, selenium, molybdenum and oxygen

                       produces cysteine, glutathione, taurine and sulfate.
 Or, lacking required nutrients or energy, or with sulfur accumulation or dietary sulfur overload:
      Homocysteine forms cystine (instead of cysteine), excessive ammonia,  hydrogen sulfide and other toxic sulfur compounds.

Specifically (enzymes are in parenthesis):
1 Homocysteine  + B6  (as P5P*) + Mg   (via CBS)  yields Cysteine (+ AKG** + Ammonia).
2 Cysteine + serine + selenium + glutamate   yields  Glutathione.
3 Cysteine  + vitamin B3  (as NAD)   yields  Taurine.
4a Sulfite (from cysteine or food)  + molybdenum + B6 (P5P) + oxygen  (via SUOX***)   yields  Sulfate.
4b Without these nutrients, Sulfite produces toxic sulfur compounds.

* B6 metabolism to P5P is supported by AKG, B6, and magnesium. If there is difficulty forming P5P, it is often supplemented directly. 
** AKG (alpha-ketoglutaric acid) is a Kreb's energy cycle component. AKG also helps remove ammonia, and form P5P.

*** SUOX also influences the creation of glutathione.

Importance of Glutathione, Cysteine and Taurine

Glutathione is the body's premiere counter to oxidative stress, and is critical in encouraging homocysteine metabolism to methionine and SAM.
Cysteine is the precursor of glutathione, taurine and sulfate.

Taurine is a major inhibitory neurotransmitter, which often seems to stabilize both mood and neural activity (and also is critical in heart, eye, liver, and gall bladder function).

Next post: Sulfates, sulfites, and sulfur and phenol sensitivity.
For information on effects of histadelia on bipolar symptoms, see my book, Natural Healing for Bipolar Disorder.

Histadelia and Methylation. Part IVB: SAM to HCY

1. In giving up its methyl to proteins and DNA, SAM becomes SAH.

2. SAH then releases adenosine and re-forms homocysteine. 
See diagram here.

SAH accumulation when adenosine is over-elevated
This latter reaction (2), however, is suppressed if adenosine and homocysteine are already excessive. Moreover, the reaction itself is reversible.

When SAH accumulates, it suppresses methylation (by inactivating methyltransferases).

This situation is usually due to severe oxidative stress, interfering with both methylation and glutathione availability.*

* Note: And is common in autistics. A study by Dr. S. Jill James, for instance, finds methionine, SAM and glutathione low, but excessive SAH, adenosine, homocysteine and oxidized glutathione. Sulfur antioxidants, including glutathione are excessively low, but excreted in the urine. Severe oxidative stress (compounded by metal metabolism dysfunction) interferes with methionine formation via methyl B12, thus compromising methylation. Further discussion of autism chemistry here.

Histadelic bipolar treatment (Walsh) 

(In presence of severe oxidative stress, creating SAH and perhaps some HCY accumulation.)

1 Supply glutathione to create homocysteine from SAH, and to attach methyl to B12 so it will convert HCY to methionine. Or, methyl-B12 may need to be provided directly.

2 Address any factors worsening oxidative stress, such as metal metabolism dysfunction.


On the other hand, if the cycle proceeds normally, we get:
SAM methylation reactions  --via methyl transferase--   yield SAH
SAH  --via  SAH hydrolase--- yields adenosine + homocysteine

At homocysteine we come to diverging paths

1 Homocysteine may continue within the methylation cycle.
2 However, when more glutathione is needed to support the methyl B12/ methionine synthase step, which turns homocysteine into methionine,
homocysteine is diverted down the transsulfuration pathyway to create more glutathione.

See Dr. Deth's discussion of this choice point here:
 

Our next post, will explain more about the Trans-Sulfuration Pathway, which, when functioning well, creates critical sulfur antioxidants, and ultimately transforms or eliminates problematic sulfur compounds and other toxins.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 


For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder
 

Histadelia and Methylation. Part IV. What SAM does.

S-Adenosyl methionine (SAM) and Genetic Expression

1 By methylating DNA, regulates, usually suppressing, genetic expression, the process by which our genes cause RNA or specific proteins to be formed.
On the other hand, acetylation --by acetyl CoA, bolstered by folic acid-- typically promotes genetic expression.
So from moment to moment, the balance of SAM to folic acid at the chromatin strands, determines whether the chemical blue print encoded in the DNA will be used to form a new biomolecule, or will be suppressed.

2 Protects, repairs and stabilizes DNA.

Influence of SAM on dopamine, norepinephrine and serotonin activity

1 Functions as a natural reuptake inhibitor* for dopamine, norepinephrine and serotonin, increasing availability/activity of these neurotransmitters in the synapse.
Walsh explains that SAM inhibits reuptake epigenetically, by methylating (turning off) the neural membrane DNA which creates transporter proteins. If undermethylated, these transporters would remove neurotransmitters from the synapse, returning them to previous (pre-synaptic) neurons. Methylation by SAM, on the other hand, suppresses transporter creation, leading to an accumulation of dopamine, norepinephrine and serotonin in the synapse, thereby increasing neurotransmitter activity. (For more, see Nutrient Power by Dr. Walsh)

2 Influences tetrahydrobiopterin (BH4) synthesis of serotonin and dopamine: via methyl folate, which regulates BH4 production (click to enlarge).


3 Is used to recycle/inactivate norepinephrine, dopamine, epinephrine and serotonin.
  — With magnesium, forms COMT, which removes epinephrines and dopamine from the synapse. 
  — Regulates stress by metabolizing norepinephrine and epinephrine (adrenalin):  Methylates norepinephrine into epinephrine which, via COMT, is broken down into metanephrine.
  — With B5, metabolizes serotonin into melatonin (the hormone which triggers sleep).


SAM provides methyl to form proteins and lipids critical to mental function
1 Including melatonin, phosphatidyl choline, myelin, epinephrine, carnitine, Co-Q10, and creatine. 
2 Also helps form  cholesterol, steroids, calmodulin (which modulates calcium use) and polyamines (from histamine). Inactivates estrogen by (forming a methyl estrogen).

SAM is important in immune function (which repercusses on mental function)

1  In turning off DNA replication, helps defend against viruses which use our DNA to replicate. 
2 Important to cell-mediated (non-antibody) immune function.
3 Helps flag and remove toxins.
4  Helps regulate the formation of sulphur molecules, such as cysteine, glutathione, sulphate, and taurine. These are major antioxidant and detox agents.

See next post, The Transsulfuration Cycle.

Review the methylation diagram here

These diagrams provide a wider picture of cycle interactions (scroll down)

For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

Histadelia and methylation. Part IIC: A Note on the Betaine Pathway

Betaine is trimethyl glycine. It is particular rich in beets and quinoa, and also found in spinach, broccoli and grains. The betaine-to-methionine pathway looks like this:

choline --via NAD (from B3) + choline-dehydrogenase + aldehyde-dehydrogenase-- yields betaine* 
* That is: trimethylethanolamine  --via NAD... -- goes to trimethylglycine

homocysteine + betaine   --via zinc + betaine-homocysteine-S-methyltransferase--  yields methionine + dimethyl glycine


Methionine proceeds, as in my previous post, to form SAM:
methionine   --via magnesium (or cobalt) + potassium + methionine adenosyl transferase--  yields SAM

See: diagram of the betaine pathway (enlarge)

Use of the folate vs. the betaine pathway

The betaine pathway is often not very efficient, especially when the folate/B12 to methionine pathway (previous posts) is being reasonably well-utilized

However, in people who drink alcohol regularly and in some others, the methyl-folate pathway may be too compromised to be effective, even with nutrient support. 
So you would then get homocysteine elevation, even when methyl is added to the system (e.g., with supplements of methyl B12, methionine and/or SAM).  The added methyl cannot help convert enough homocysteine back to SAM.
This situation is not common in histadelia, but can occur.

Therapeutic approaches (Walsh)

To restore methylation and better protect the heart:
1 Recycle HCY through the betaine pathway, above (and keep folate low to encourage this path).
2 Vitamin B6 and serine to convert homocysteine to sulfur antioxidants (coming up, post after next).
3 Address oxidative stress.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 


For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder

In the next post we will talk about what SAM does.

Histadelia and Methylation. Part III: Forming SAM.

In the next step, methionine is transformed into SAM, the most important methylator in the human body:

  Methionine  --via ATP + magnesium + MAT*--  yields SAM

Problems forming SAM in the brain** (assuming methionine is sufficient):
1 A genetic enzyme disorder. 
2 Scarcity of magnesium.
3 Conceivably, insufficient brain ATP.*** 

Therapeutic Considerations (Walsh)
Give SAMe, perhaps magnesium.
 Methionine and TMG are of little benefit.

Caution: Some psychiatrists warn against giving SAMe to bipolars, even for bipolar depression.

Walsh, on the other hand, states that when you are dealing with histadelics with subnormal production  of SAMe, supplementation is helpful, rather than a problem, as long as introduced gradually, to the level appropriate for the individual. Then, once improvement is established (within a month or so), most patients are tapered off while introducing methionine (which is cheaper).

* The enzyme, methionine adenosyltransferase
** These occur in a small number of histadelics.
***ATP provides energy to our cells. It is formed via glycolysis (carbohydrate to pyruvate metabolism), acetyl-CoA creation, and the mitochondrial Krebbs cycle and electron transport chain. Some of the nutrients involved in this process: vitamins B3 (NADH), B2 (R5P), B5, B6 (P5P), B12, B1, C; biotin, CoQ10, carnitine, alpha lipoic acid, malic acid, magnesium, chromium, sufficient oxygen and antioxidants, and thyroid-support nutrients, as relevant.

To review where we are in the methylation cycle click here.

Reminder: This information is presented for educational purposes only, and is not intended as diagnosis or treatment recommendations for the individual. Even within the histadelic subgroup, each person's biochemical requirements tend to be unique. So if you need treatment for depression, mania, bipolar, or any other medical condition, please consult a knowledgeable physician. 


For info on the role of histadelia in bipolar disorder, see my book, Natural Healing for Bipolar Disorder
In the next post we will talk about what SAM does.