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Volume 36, No. 3

Fatigue

INTRODUCTION
Fatigue, as employed in medical terms, describes a reduction in performance due to an experienced deterioration in capacity. Fatigue can be local or general, acute or chronic, and depending upon circumstances, a sense of exhaustion may follow attempts at either motor or intellectual effort.

Short term fatigue can be often traced to acute systemic illness, severe emotional disturbances, or intense physical or emotional efforts.

As many as one fifth of patients presenting to primary physicians complain of weakness or fatigue as a prominent symptom. Weakness is arbitrarily defined as reduced muscle power compared with a person's normal muscle power. Physiologic weakness can be focal in which case the individual is referring to a specific loss of strength during particular actions such as walking, lifting, playing a musical instrument, or this can be generalized accompanying several acute or subacute systemic disorders as well as early stages of a number of neurologic conditions.

Recurrent rapidly developing fatigue can be a sign of myasthenia gravis (disorder of neuromuscular function) and less often, the metabolic myopathies (muscle diseases). Multiple sclerosis and Parkinson's disease are characteristically accompanied by chronic feelings of fatigue usually at the end and the beginning of the day. Sometimes difficult to diagnose diseases such as tuberculosis, systemic cancer, subacute endocarditis, vascular disease, and certain metabolic or endocrine disorders will present as fatigue. Fatigue can also accompany HIV involvement of the brain. Ordinarily, that would also cause recognizable abnormalities in cognitive functioning. Fatigue can occur from any infection, including Lyme disease.

Fatigue can occur in adreno-cortical insufficiency, ankylosing spondylitis (inflammation of the vertebrae), and cardiovascular disease, diabetes, lipid storage diseases such as Gaucher's disease, lung disease, such as interstitial lung disease, and iron deficiency anemia as well as intestinal malabsorption, multiple myeloma (malignant neoplasm usually arising in bone marrow), and rheumatoid arthritis. Fatigue can also be the result of certain medications.

Disturbed sleep patterns, including sleep apnea and other sleep disorders, can also be responsible for fatigue. Other causes for fatigue are anti-cancer chemotherapy, acute and chronic hepatitis, chronic granulomatous diseases, such as sarcoidosis, and sustained drug use. So it would seem that there is an unending multitude of conditions that can cause fatigue, including acute, subacute, and chronic viral and bacterial infections which would include unsuspected chronic sinusitis, prostatitis, and unsuspected infections in the teeth or roots of teeth. Collagen vascular and connective tissue disorders, including lupus, can also cause fatigue. Chronic liver and kidney disease can be associated with fatigue.

Depression can be accompanied by fatigue, but even with depression there may sometimes be an organic cause, or contribution.

The condition defined as "chronic fatigue syndrome," usually presents with a duration by definition of greater than six months and accompanied by low grade fever, painful lymph nodes, and a non-exudative pharyngitis. This Doctors Corner does not

address the so-called "chronic fatigue syndrome" since there are multiple papers dealing with the diagnosis and the attempted treatments of this condition. So far no universally satisfactorily evaluated treatment program has been forthcoming for persons with "chronic fatigue syndrome."

This Doctor's Corner deals with a number of medically identifiable, diagnosable, and treatable conditions, which are often missed in clinical practice and can clearly be responsible for fatigue. This Doctor's Corner is going to discuss allergy, hypothyroidism, vitamin B12 deficiency, iron deficiency, and yeast imbalance as identifiable, diagnosable, and treatable causes of fatigue.

ALLERGY
Allergy has long been known to cause fatigue. In fact, many years ago, Dr. Frederic Speer, a prominent allergist in Kansas City, Missouri and Kansas, wrote a book called "The Allergic Tension Fatigue Syndrome." He coined that term and practicing allergists in general are very aware that fatigue is often associated with allergic states. The allergy may not necessarily be to foods, but also may occur with severe inhalant sensitivity. Patients with seasonal hay fever due to pollens often experience fatigue and certainly the same is even more true of mold. This is also true of perennial inhalants such as house dust and house dust mites as well as animal danders.

As an allergist, much emphasis in our training and subsequent retraining after our formal education, is on what we call allergy mimicries. We therefore need to know all the things that look like allergy but aren't, since the treatment obviously can be so different. Sometimes patients are very allergic without realizing it since they don't have the usual symptoms that are popularly associated with allergy, such as runny nose, itchy skin, hives, eczema, or shortness of breath, or asthma, or itchy eyes. Sometimes the only symptom of allergy is fatigue but again this would represent a minority of patients who present to an allergist's office or for that matter, who present to a primary care physician, with fatigue. As an allergist, I have seen it often enough that it is significant and certainly merits consideration.

Food allergy particularly can cause this fatigue and is often unsuspected and undiagnosed, especially because one or two or three days could pass after the ingestion of the food before the symptoms occur so they would not necessarily be suspected as due to the ingestion of the food. Some patients report overwhelming fatigue and sleepiness, occasionally within hours of eating a certain meal, and they can only resort to lying down and taking a twenty or thirty minute nap since nothing else seems to help. Some patients have actually used antihistamines with moderate success. When fatigue follows eating, and is relieved by a short nap, one needs to be suspicious of allergy. This is not due necessarily to pooling of blood in the so-called splanchnic areas, i.e. in the gut, but can be truly an allergic reaction which in part is central in origin, i.e. the nervous system is affected.

YEAST IMBALANCE
Yeast imbalance is another condition that we have had extensive experience with over the last twenty-seven years, evaluating approximately 3,400 patients, and treating probably over 95% of them. Generally, patients have been reading and educating themselves by the time they come to the office. We were made aware of this important condition by the various astute observations of Dr. Orian Truss, an internist/allergist from Birmingham, Alabama. Dr. Truss's work was popularized and publicized by the many books and speeches written by and presented by the late Dr. William Crook from Jackson, Tennessee. Dr. Truss, besides publishing articles, also wrote a book designed mostly for medical professionals, and this book is called The Missing Diagnosis.

Although yeast imbalance patients can present with a variety of symptoms, fatigue and depression are two of the most frequent symptoms. Many of these patients also present with increased sensitivity to odors and tobacco smoke.

Two thirds of the patients with yeast imbalance are women. The risk factors include multiple pregnancies, hormone replacement therapy, i.e. estrogens and progesterone, birth control pills, antibiotics, and corticosteroids (cortisone or prednisone). We have seen a few patients with what would appear to be well established yeast imbalance, at least in regard to blood test results and response to therapy, who had none of the identifiable risk factors. If the symptoms are there and the doctor has a high degree of suspicion, the patient should be, in our opinion, tested, and even at times, trial treated regardless of the test results. Treatment fortunately is not harmful, even if it turns out that the patient does not have this condition.

Treatment for yeast imbalance basically is a diet free of artificial and natural sweeteners (some would eliminate carbohydrates on a much broader basis). Also the diet is free of yeasty foods, both Baker's and Brewer's yeast, and generally excludes aged cheese and mushrooms.

Many of us who treat yeast imbalance use Nystatin in powdered form with a swish, gargle, and swallow routine. Not all patients respond to this, and some don't tolerate it. Caprylic acid, oil of oregano, and probiotics are useful in many patients. Some have recommended garlic and tahebo tea. While these may be useful, sometimes teas are mold laden, and there can be allergies to both garlic and tahebo tea.

We have had to use azole antifungals, such as Diflucan, Sporonox, Lamisil, or even Nizoral, in approximately 10% of the patients, or roughly 340 patients. The problem with the azole antifungals is their potential toxicity, which creates an essential need for careful and frequent laboratory monitoring. We have found that we must chart the lab values in order to pick up trends since several values in succession may be within normal limits, but may be becoming abnormal. We try to pick this up early, and so far we have avoided any serious problems in the 340 patients. We have only had to stop the medication in five patients. Some patients actually do better with Nystatin than they do with the azole antifungals, possibly because the concentration at the mucosal surface may be higher than antifungal medication given systemically. This is an individual matter and in almost all patients that we have treated with systemic azole antifungals, we have continued Nystatin unless the Nystatin had not been tolerated. We have had some very limited experience with Amphotericin B orally. There will probably be more medications and more insights into this puzzling condition in the future and I am sure that we do not at this time have all of the answers. It seems to be a fact that the vast majority of physicians are still very reluctant to accept even the concept of yeast imbalance in spite of what must be hundreds if not thousands of patients reporting to their doctors benefit from specific therapy.

Although the treatment for yeast imbalance, using Nystatin and diet, is safe, even those of us who believe in it and treat it do need to keep an open mind and to look forward to studies in the future that might help to clarify both the existence and diagnosis, as well as the treatment of this controversial condition.

HYPOTHYROIDISM
Another unsuspected cause of fatigue can be undiagnosed and often unsuspected hypothyroidism. Hypothyroidism is probably more prevalent than it would appear on the surface. The tests that most doctors run may not necessarily be the most precise ones for identifying hypothyroidism. Dr. John Dommisse from Tucson, Arizona, has spoken at a number of meetings that I have attended and he feels that, if the thyroid stimulating hormone (TSH) is over 3, a Free T3 should be done. Actually, I think he now feels that under any circumstances a Free T3 should be done and I agree that this seems to be more reflective of the actual status of the thyroid than the Total T3. We also recommend obtaining a Free T4 as well as the Free T3 and a TSH. Some have recommended a Reverse T3, a form which may show up as T3, but may be metabolically inactive. We have not had that much experience with Reverse T3. Autoantibodies to thyroid have been available for many years to help diagnose autoimmune thyroiditis, which is one cause for hypothyroidism.

There is a form of hypothyroidism called secondary hypothyroidism where the TSH does not increase as one would expect in hypothyroidism. This is a form of pituitary failure. Ordinarily, as the thyroid hormone level falls, the TSH, which comes from the pituitary, increases and this then causes an increase in the manufacture and secretion of thyroid hormone. It is a simple feedback mechanism that is common in nature.

There has been some controversy about Armour's thyroid, as well as with Synthroid and other forms of T4. Armour's thyroid is a combination of T4 and T3. T4 is converted to T3 in some of the body tissues and sometimes there is a defect in the conversion. T3 is responsible for many of the effects of thyroid, although T4 also has a metabolic effect. For those patients who have low or low normal T3, administering very small doses of pure T3 (Cytomel) several times a day may be helpful, although the patients need to be monitored for side effects. I am hopeful that some of the newer forms of long acting T3 used in Europe will find their way into the United States and this may make the treatment more popular with endocrinologists. Presently, very few endocrinologists seem willing or anxious to use T3 which is probably the more active of the two hormones, perhaps because of the frequency of side effects. When I was an intern and resident, we only used 25 mg. of Cytomel but it is available in doses as low as 5 mg. Again, it should ordinarily be given several times a day and even half tablets can be given, although the tablets are small and difficult to cut in half. Dr. Dommisse has made the comment that zinc is one of the elements that is required by the liver to convert T4 to T3, so in patients who have a disparity, it could be wise to check their zinc levels. We have had extensive experience with zinc and copper levels, particularly in children with ADD and ADHD, as well as other patients, but we have not yet looked into this association that he suggests.

Because Armour's thyroid is a mixture of T3 and T4, but not a precisely or consistently defined mixture, it is sometimes associated with undesirable side effects and some patients do better with Synthroid or other forms of T4 but this is an individual situation. Synthroid and other forms, such as Levoxyl, are pure T4 and of course the amount is precisely defined.

I think, and certainly hope, that in the next ten or fifteen years, we will see some very interesting new insights in regard to hypothyroidism and its treatment.

VITAMIN B12
The vitamin B12 issue is an equally fascinating problem. I took off a year between internship and residency to work for the Chicago Board of Health and also worked for a general practitioner on the West Side of Chicago in a busy practice in order to repay debts that I had incurred going through medical training. This doctor used vitamin B12 injections liberally and I was impressed that it seemed to be much more than just a placebo in contradistinction to what was suggested to us as students and interns.

In practice, I have seen patients with peripheral neuropathy who had normal B12 levels, but since it was so safe, sometimes we tried giving them B12 injections and frequently they were helped. About fifteen or twenty years ago, I saw an article in a major medical journal which referred to patients with neurologic problems who had responded to vitamin B12 injections. These patients had normal Serum Vitamin B12 levels, as had our patients. The article pointed out that these patients frequently had high Methyl Malonic Acid. This metabolite could be measured either in urine or blood and this information has now been in standard medical text books for the past ten years. So it would appear that there are a number of patients who have what many consider normal B12 levels, but who have neurologic symptoms, and many of these patients respond to B12 injections. Most doctors would be reluctant to give them injections when their level was normal to begin with.

Again, some years ago, Dr. Dommisse shed some additional light, or at least some criteria, which seem to parallel our experience. He felt that if patients had a Vitamin B12 below 500 picograms/ml, they should be given a trial of B12 injections. More recently, he has even suggested that if it is below 600, that should be done. He does point out that when blood levels of B12 go below 500, there is a tendency to have lower levels in the cerebrospinal fluid, and this can cause neuro-psychiatric disturbances, not necessarily fatigue. Most laboratories often indicate that anything above 200, or even above 188 in some instances, is normal. This is in picograms/ml. Dr. Dommisse speculates that those low levels are the levels that patients probably would have if they in fact had pernicious anemia. He feels that patients, who are often having psychiatric or neurologic, or perhaps subtle other physiologic effects, have values above 200 but below 500 or 600 and he is a psychiatrist with a fair amount of experience in this area.

We have seen fewer patients than he has but our experience has been similar. If a patient does have a level below 500, or even in some instances below 600, we will recommend a trial of vitamin B12 injections. We prefer that the regular physician administer this. Ordinarily, 1 cc of 1,000 mcg. of vitamin B12 is given intramuscularly twice weekly for five weeks and then the patient is put on oral (sublingual) vitamin B12 in high concentrations, usually 2,000 mcg. per day. Since vitamin B12 is water soluble, excesses are secreted and it is considered safe. Generally, Folic Acid or Folate is administered along with B12.

Dr. Dommisse has made the point that vitamin B12 is absorbed in the last twelve inches of the ileum, so that patients with Crohn's disease may still need to have B12 by injection. It is necessary to have intrinsic factor in order to absorb vitamin B12 when it is taken orally. It may also be necessary to have sufficient Hydrochloric Acid in the stomach. The sublingual route or nasal gel route may circumvent those potential problems. Dr. Dommisse suggests that vitamin B12 in the form of Hydroxy Cobalamin may have some advantages although Methyl Cobalamin and Hydroxy Cobalamin are difficult to obtain and ordinarily Cyano Cobalamin is administered, including by Dr. Dommisse. He also makes the point that Methyl Cobalamin crosses the blood brain barrier best and gets into the cerebrospinal fluid. Ultimately the patients who do need to have injections may get by with as little as once a month but patients who remain at the lower levels may need it as often as twice a week.

Dr. Dommisse also points out that patients who have copper excess, zinc deficiency, or liver damage can't form the Methyl Cobalamin in the liver. Alcoholics should have this kind of B12 preferably. Liver Function tests and Copper and Zinc are important as part of the work-up.

He has treated even paranoid psychosis as well as some violent criminals and even bipolar disease as well as regular depression and neuropathy. We are of course interested in fatigue that B12 deficiency causes, perhaps partly because of it*s effect on the brain and partly because anemia may accompany severe deficiency.
The reason that it is often necessary to give vitamin B12 by injection intramuscularly is that absorption through the intestinal tract is sometimes so impaired that the patient needs to be jump started in a sense. In other words, it is really a vicious cycle that needs to be broken by this aggressive direct intervention.

Recently, we have a patient in the office who has true pernicious anemia, actually picked up by doing B12 levels and referring her back to her internist who then referred her to a hematologist for her anemia. When her levels are normal according to the usual criteria, she doesn't feel well, and she only feels well when she has quite high B12 levels that can be produced by giving her injections. Again, I think looking at each patient's biochemical individuality is important.

We ask patients ideally to obtain their B12 injections from their regular doctor's office and I hope that this Doctors Corner article stimulates some additional interest among physicians in this regard.

IRON DEFICIENCY
We often see patients who have multiple complaints, some of which are typically allergic and sometimes their complaints are not. Fatigue is frequently a complaint that we see and we have been interested in patients who have frequent infections since that can also be due to allergy. We are also interested in patients who have difficulty in learning, or even behavioral problems, because sometimes these are also affected by allergy. We have found, as have others who have published, that iron deficiency is sometimes manifested by fatigue, low resistance to infection, and difficulty in learning or behavior.

Sometimes iron deficiency is preceded by low Ferritin, although this is not always the case, and I am certainly not an expert in iron metabolism. This, however, has been in the literature for some time and if the patient has a really low Ferritin and a low normal or low Serum Iron, we will suggest that their primary care physician prescribe iron, and most often patients improve. We think that it is very important to measure the Serum Iron and to follow this every two to three months because an excess of iron can be deposited in the vital organs and can cause serious irreversible damage. We have not seen any problems in patients that were closely followed and that means all of the patients with whom we have been involved.

If a patient had a high Serum Iron, obviously they would not be given additional iron. Interestingly, there are a number of conditions where Serum Iron is too high, which can also be accompanied by fatigue, and those conditions are treated by physicians other than allergists.

CONCLUSION
In summary, and in conclusion, although we have pointed out that allergy, yeast imbalance, hypothyroidism, B12 deficiency, and subtle iron deficiency, are diagnosable and treatable causes of fatigue, I again want to emphasize that there are a multitude of other important and often treatable causes, which can only be ascertained by a competent medical evaluation. This article did not address chronic fatigue syndrome, a diagnosable but poorly understood and inadequately treatable cause of chronic fatigue as of this date.

Further, this article reflects my experience and opinion (influenced by others who have, of course, taught me as referred to in the article) and does not necessarily reflect the position of any of the professional or lay organizations, including NOHA, to which I belong and from which I benefit by learning and expanding my knowledge base.
 


by Robert W. Boxer, MD, Fellow of the American Academy of Environmental Medicine, the American Academy of Allergy, Asthma, and Immunology, and the American College of Allergy, Asthma, and Immunology, and Member of the NOHA Professional Advisory Board.
 

Article from NOHA* NEWS, Summer 2003

*The American Nutrition Association was formerly known as the Nutrition for Optimal Health Association [NOHA].

For informational purposes only - not intended as medical advice, diagnosis or treatment, nor an endorsement by the American Nutrition Association®. Use permitted for non-profit and non-commercial uses or by healthcare professionals in their practice, with attribution to www.AmericanNutritionAssociation.org. Other use only with written ANA℠ permission. Views expressed are those of the author and not necessarily those of the ANA℠. Works by a listed author subject to copyrights as marked. © 2010 ANA℠


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