From The Great Smokies Diagnostic Laboratory

Chronic Fatigue Syndrome (CFS) is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of any other definable diagnosis. Symptoms of CFS may include depression, hypotension, weight loss, and inability to endure stress.

Over time, CFS can make life miserable, wearing down the body, depressing the spirit, and making a person much more vulnerable to a wide range of related illnesses. Living with CFS can be even more difficult when the individual--and those others around him or her--do not fully understand the factors behind this debilitating condition.

CFS is often part of a complex, multifactorial health condition. There are myriad possible internal and external mechanisms whereby the body's metabolic system can get thrown "out of whack" and induce feelings of exhaustion--and many of these mechanisms are interrelated.

The following are possible underlying causes and contributing factors of both fatigue and Chronic Fatigue Syndrome (CFS). It is important to distinguish between the two conditions, because each one can be triggered by different mechanisms in the body, and thus may have very different diagnostic indicators.

Fatigue and Thyroid Function: Fatigue is a hallmark symptom of thyroid hormone imbalances.

Fatigue and Adrenal Hormones: Chronically high or low levels of powerful adrenal hormones can wear the body down and produce feelings of exhaustion.

Fatigue and Cellular Energy: About 90% of the body's energy is generated by a cellular energy cycle that depends on a healthy balance of organic acids.

Fatigue and Detoxification: Fatigue can develop from toxic stress when the liver is no longer able to detoxify the body's harmful waste by-products and heavy metals begin accumulating from external exposure.

Fatigue and Oxidative Stress: Oxidative stress caused by unstable free radical molecules can damage the energy-producing mechanisms inside the body's cells.

Fatigue and Gastrointestinal Parasites: The incidence of infection from gastrointestinal parasites is increasing in the U.S., and once these microscopic creatures establish themselves inside the GI tract, they can dramatically sap the body's energy.

Fatigue and Digestive Function: Fatigue is often triggered by malabsorption of important nutrients, along with the overgrowth of intestinal yeasts such as Candida albicans.

Fatigue and Glucose and Insulin: Insulin and glucose are two key hormones highly involved in the body's regulatory action of fuel metabolism.

Fatigue and Allergies: Fatigue and allergic sensitivity often go hand-in hand, with a multitude of possible allergenic substances hidden in the food we eat.

Fatigue and Toxins and Nutrients: Exposure to toxins from the environment, especially in combination with key nutrient shortages, can be an insidious source of chronic fatigue.

Fatigue and Fatty Acids: Identifying and treating fatty acid deficiencies has been shown to increase energy levels in many patients with chronic fatigue.

Fatigue and Amino Acids: As the primary source of important proteins, amino acids play a key role in the body's production of energy.

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Journal of Chronic Fatigue Syndrome 2006; 13(1)

Lipid Replacement and Antioxidant Nutritional Therapy for Restoring Mitochondrial Function and Reducing Fatigue in Chronic Fatigue Syndrome and other Fatiguing Illnesses*

Garth L. Nicolson, Ph.D. and Rita Ellithorpe, M.D. The Institute for Molecular Medicine, Huntington Beach, California, USA

ABSTRACT. Evidence in the literature indicates that diminished mitochondrial function through loss of efficiency in the electron transport chain caused by oxidation occurs during aging and in fatiguing illnesses. Lipid Replacement Therapy (LRT) administered as a nutritional supplement with antioxidants can prevent oxidative membrane damage, and LRT can be used to restore mitochondrial and other cellular membrane functions via delivery of undamaged replacement lipids to cellular organelles. Recent clinical trials using patients with chronic fatigue have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. These studies indicate the benefits of LRT plus antioxidants in reducing fatigue and preventing loss of mitochondrial function, most likely by protecting mitochondrial and other cellular membranes from oxidative and other damage and removing damaged lipids by lipid replacement. In one clinical study we determined if mitochondrial function is reduced in subjects with mild to severe chronic fatigue, and if this can be reversed with NTFactor®, a nutritional supplement that replaces damaged cellular lipids. Using the Piper Fatigue Scale there was a significant time-dependent reduction in overall fatigue in moderately or severely fatigued subjects while on the dietary supplement for 4-8 weeks. Analysis of mitochrondrial function indicated that four and eight weeks of the dietary supplement in moderately or severely fatigued subjects significantly increased mitochondrial function. Similarly, chronic fatigue syndrome patients administered antioxidants plus LRT also show reductions in fatigue. The results indicate that LRT plus antioxidants can significantly reduce moderate to severe chronic fatigue and restore mitochondrial function. Dietary use of unoxidized membrane lipids plus antioxidants is recommended for patients with moderate to severe chronic fatigue.

KEYWORDS. lipids, antioxidants, therapy, dietary supplement, fatigue, mitochondria, chronic fatigue syndrome

Address correspondence to: Prof. Garth L. Nicolson, Department of Molecular Pathology, The Institute for Molecular Medicine, 16371 Gothard St. H, Huntington Beach, California 92647, Tel: +1-714-596-6636, Email: gnicolson@immed.org, Website: www.immed.org ; Fax: +1-714-596-3791.

*The authors have no financial interest in the products discussed in this contribution.

INTRODUCTION

One of the most important changes in tissues and cells that occurs during aging and chronic degenerative disease is accumulated oxidative damage due to cellular reactive oxygen species (ROS). ROS are oxidative and free radical oxygen- and nitrogen-containing molecules, such as nitric oxide, oxygen and hydroxide radicals and other molecules [1]. Critical targets of ROS are the genetic apparatus and cellular membranes [1,2], and in the latter case oxidation can affect lipid fluidity, permeability and membrane function [3,4]. Similar changes occur in fatiguing illnesses, such as chronic fatigue syndrome (CFS), where patients show increased susceptibility to oxidative stress and peroxidation [5,6]. One of the most important changes caused by accumulated ROS damage during aging and in fatigue is loss of electron transport function, and this appears to be directly related to mitochondrial membrane lipid peroxidation [1], which can induce permeability changes in mitochondria and loss of transmembrane potential and oxidative phosphorylation [1,2].

We will concentrate this brief review on recent clinical trials that have shown the effectiveness of lipid replacement therapy (LRT) plus antioxidants in the treatment of certain clinical disorders and conditions, such as chronic fatigue [7]. LRT is not just the dietary substitution of certain lipids with proposed health benefits; it is the actual replacement of damaged cellular lipids with undamaged lipids to ensure proper structure and function of cellular structures, mainly cellular and organelle membranes [7]. Damage to membrane lipids can impair fluidity, electrical properties, enzymatic activities and transport functions of cellular and organelle membranes [1-6]. During LRT lipids must be protected from oxidative and other damage, and this is also necessary during storage as well as during ingestion, digestion, and absorption in vivo. LRT must result in delivery of high concentrations of unoxidized, undamaged membrane lipids in order to reverse the damage and restore function to oxidized cellular membranes. Combined with antioxidant supplements, LTR has proven to be an effective method to prevent ROS-associated changes in certain cellular activities and functions and for use in the treatment of certain clinical conditions [7].

HEALTH BENEFITS OF LIPID SUPPLEMENTS

Mixtures of lipids introduced as dietary supplements have been used to improve general health [8,9], and they have also been used as an adjunct therapy in the treatment of various clinical conditions, for example, the use of n-3 fatty acids in cardiovascular diseases and inflammatory disorders [9-12]. Although not every clinical study has found health benefits from lipid dietary supplementation [13], most studies have documented the value of dietary supplements that favor certain types of lipids over others, such as when n-3 polyunsaturated fatty acids (mainly fish- or flaxseed-derived) are favored relative to n-6 lipids [8-12]. Cellular lipids are in dynamic equilibrium in the body, and this is why LRT is possible [7]. Orally ingested lipids diffuse to the gut epithelium and are bound and eventually transported into the blood and lymph using specific carrier alipoproteins and also by nonspecific partitioning and diffusion mechanisms [14,15]. Within minutes, lipid molecules are transported from gut epithelial cells to endothelial cells, then excreted into and transported in the circulation bound to lipoproteins and blood cells where they are generally protected from oxidation [16,17]. Once in the circulation, specific lipoprotein carriers and red blood cells protect lipids throughout their passage and eventual deposition onto specific cell membrane receptors where they can be taken into cells via endosomes and by diffusion [17]. After binding to specific cell surface receptors that bring the lipids into cells, lipid transporters in the cytoplasm deliver specific lipids to cell organelles where they are taken in by specific transport proteins, partitioning, and diffusion [18]. The concentration gradients that exist from the gut during the digestion of lipids to their absorption by gut epithelial cells and their transfer to blood and then tissues are important in driving lipids into cells. Similarly, damaged lipids can be removed by a similar reverse process that may be driven by lipid transfer proteins and by enzymes that recognize and degrade damaged lipids and remove them [18].

CHRONIC FATIGUE AND OXIDATIVE DAMAGE TO MITOCHONDRIA

Intractable or chronic fatigue lasting more than 6 months that is not reversed by sleep is the most common complaint of patients seeking medical care [19,20]. It is also an important secondary condition in many clinical diagnoses and occurs naturally during aging [19,20]. The phenomenon of fatigue has only recently been defined as a multidimensional sensation, and attempts have been made to determine the extent of fatigue and its possible causes [21-23]. Most patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion. Many medical conditions are associated with fatigue, including respiratory, coronary, musculoskeletal, and bowel conditions as well as infections and cancer [7,20-23]. Fatigue is related to cellular energy systems found primarily in the cells' mitochondria. Damage to mitochondrial components, mainly by ROS oxidation, can impair their ability to produce high-energy molecules such as ATP and NADH. This occurs naturally with aging and during chronic illnesses, where the production of ROS can cause oxidative stress and cellular damage, resulting in oxidation of lipids, proteins and DNA [24,25]. When oxidized, these molecules are structurally and sometimes functionally changed. Important targets of ROS damage are mitochondria, mainly their phospholipid-containing membranes, and cellular and mitochondrial DNA [1,24,25].

Excess ROS production throughout our lifetimes can result in accumulation of mitochondrial and nuclear damage [1,24-26]. Opposed to this, cellular free-radical scavenging enzymes neutralize excess ROS and repair the enzymes that reverse ROS-mediated damage [25,26]. Although some ROS production is important in triggering cell proliferation, gene expression and destruction of invading microbes [27,28], with aging ROS damage accumulates [1,24-26]. When this occurs, antioxidant enzymes and enzyme repair mechanisms along with biosynthesis cannot restore or replace enough ROS-damaged molecules[1,24,28-30]. Disease and infection can result in oxidative damage that exceeds the abilities of cellular systems to repair and replace damaged molecules [6,24,27], and this is also the situation in fatiguing illnesses [5,6].

In CFS patients there is evidence of oxidative damage to DNA and lipids [reviewed in 5,6] as well as the presence of blood markers, such as methemoglobin, that are indicative of excess oxidative stress [31]. Fulle et al. [32] found oxidative damage in the DNA and membrane lipids from muscle biopsy samples obtained from CFS patients. They also found increases in antioxidant enzymes, such as glutathione peroxidase, and suggested that this was an attempt to compensate for excess oxidative stress in CFS. Pall [33] has proposed that CFS patients have sustained elevated levels of the RNS peroxynitrite due to excess nitric oxide and that this results in lipid peroxidation and loss of mitochondrial function as well as changes in cytokine levels that exert a positive feedback on nitric oxide production. In addition to mitochondrial membranes, mitochondrial enzymes, such as succinic dehydrogenase and cis-aconitase, are inactivated by peroxynitrite, and this could also contribute to loss of mitochrondrial function [34,35]. Also, cellular molecules that could counteract the excess oxidative capacity of ROS/RNS, such as glutathione and cysteine, have been found in lower levels in
CFS patients [36].