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CFS and FMS Research
BLOOD LIPIDS
Background biochemistry of lipids
Lipids are a group of organic compounds that make up the fats and other esters. They are relatively insoluble in water and readily soluble in chemicals such as alcohol, chloroform, hexane and ether. Lipids vary greatly in structure and include triacylglycerides, phospholipids, steroids, fatty acids and many other molecules.
Lipids serve as membrane components, storage molecules for carbon and energy, precursors for other cellular reactions and protective barriers against water loss.
Analysis of lipids
The analysis of the complex lipids is difficult due the range in sizes and molecular properties. During the sample preparation procedure, the lipids are broken down to their composite building blocks (by saponification). © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
These saponified products are then measured and identified by techniques such as gas chromatography mass spectrometry.
Overview of major lipid classes
Fatty acids
Most complex lipids contain fatty acids that can be grouped on the basis of their size, and whether or not they contain double bonds in their carbon chain.
Saturated Fatty Acids
Saturated fatty acids (SFA) lack double bonds in their carbon chains.
Unsaturated Fatty Acids
Unsaturated fatty acids have one or more double bonds. Those with just one double bond are called "mono-unsaturated" fatty acids (MUFA) and those with 2 or more double bonds are called "poly-unsaturated" fatty acids (PUFA).
Triacylglycerols
A significant number of fatty acids in animals exist as triacylglycerols. These lipids are the major energy reserve and the principal neutral derivatives of glycerol found in the body.
Phospholilids
These lipids constitute one of the largest classes of natural lipids. They are essential components of the cell membrane. The basic structure is referred to as "phosphatidic acid", and a variety of groups can be esterified to the phosphate group to form the range of phospholipids required for cellular structure and function. The most common phospholipids include:
1. phosphatidylcholine (or lecithin)
2. phosphatidylethanolamine
3. phosphatidylserine
Phosphatidylcholine and phosphatidylethanolamine are 2 of the most common constituents of biological membranes. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Ether glycerophospholipids
Ether glycerphospholipids possess an ether linkage instead of the acyl group at the C-1 position of glycerol. An example is platelet activating factor (PAF), and another is ethanolamine plasmalogen.
Sphingolipids
An 18 carbon amino alcohol, sphingosine, forms the backbone of these lipids rather than glycerol. Typically, a fatty acid is joined via an amide linkage to form a creamed.
Sphingomyelins represent a phosphorous containing subgroup of sphingolipids, which are very important in nervous tissues.
Glycosphingolipids consist of ceramics with one or more sugars attached which are important components of nerve and muscle membranes.
Waxes
Waxes are esters of long chain alcohol's with long chain fatty acids and are extremely insoluble in water. This property is used to confer water repellent characteristics to animal skins. Lanolin, a component of wool wax, is used as a base for pharmaceutical and cosmetic products because it is rapidly assimilated by human skin. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Steroids
Cholesterol is the most common steroid in animals and the precursor for all other animal steroids. Cholesterol is a principal component of animal cell plasma membranes. Cholesterol is also a component of lipoprotein complexes in the blood and it is one of the constituents in the plaques that form on arterial walls in arteriosclerosis. The steroids derived from cholesterol in animals include several families of hormones:
1. Androgens (testosterone, sexual characteristics and function).
2. Oestrogen's (oestradiol, sexual characteristics and function).
3. Progestins (progesterone, control of menstrual cycle and pregnancy).
4. Glucocortioids (cortical, control of carbohydrate, protein and lipid metabolism.
5. Mineralocorticoids (regulate sodium, potassium and chlorine).
6. Bile acids (chalice and deoxycholic acids, detergent molecules secreted in bile from gallbladder that assist in absorption of dietary lipids in the intestine).
Ketone body production and diabetes
Most of the acetyl-CoA produced by oxidation of fatty acids in liver mitochondria undergoes further oxidation via TCA cycle metabolism and oxidative phosphorylation. Some of the acetyl-CoA is converted to acetone, and other chemicals, by a process called "ketogenesis". These products all known as ketone bodies, and are produced primarily in the liver. These represent important energy sources for many peripheral tissues, including the brain during periods of starvation.
In diabetes mellitus, the cells are metabolically starved of glucose and respond by switching on gluconeogenesis and catabolism of fat and protein. The catabolism of fat yields large amounts of acetyl-CoA that normally enters the TCA cycle. However, since oxaloacetate is in short supply (due to consumption of oxaloacetate by gluconeogenesis in type I diabetes), the acetyl-CoA is used to make large amounts of ketone bodies. Acetone can be detected in the breath.
Citric acid production
If TCA cycle metabolism is inhibited, but the cell has an adequate supply of glucose, then acetyl-CoA from the catabolism of fatty acids can react with oxaloacetate to form citric acid. Citric acid has been reported to build up in tissues where TCA cycle is impaired, and may offer an explanation for the high citric acid levels in the urine samples from many CFS patients.
Plasma fatty acid and sterol analyses
What can the analysis of lipids show?
The results can indicate:
1. which essential fatty acids (EFAs) are in excess
2. which essential fatty acids (EFAs) are at low levels
3. when problems in fatty acid and cholesterol biosynthesis have occurred
4. if the patient has a post viral condition or is experiencing viral reactivation
5. possible dietary and supplement regimes
6. possible genetic anomalies
Detailed evaluations
The values for all measured lipid products can be used to assess potential supplementation protocols. The data can be collated into the following groups:
1. polar lipid components
2. saturated fatty acids (SFA)
3. unsaturated non-essential fatty acids (omega 7 and omega 9 families)
4. unsaturated essential fatty acids (omega 3 and omega 6 families)
5. sterols
The statistical analysis of blood lipid data has indicated that several distinct subgroups of CFS could be defined on the basis of their profile patterns. A system of indices has been devised to calculate the likely involvement of subgroup characteristics in any given patient. This is displayed as a simple set of bar charts for easy evaluation (see plasma lipid index report).
A score greater than 5 represents a significant contribution of a particular lipid anomaly to the patient’s CFS symptoms. A patient would normally have one primary type of lipid abnormality, but multiple lipid anomalies can also be observed. Statistical methods have been used to divide patients into distinct subgroups based on their lipid test characteristics.
Note: The word ‘profile’ relates to the way in which statistical data can be used to define various characteristics. It has nothing to do with the actual measurement of blood cell width or size.
The five types of CFS
The primary lipid anomalies characterising the polysymptomatic subgroups are summarised below.
Type 1
These changes indicate possible alterations in membrane phospholipid structures and cholesterol levels. These may alter membrane receptor and pumping functions, leading to symptom expression.
The main characteristic anomalies are:
1. low trans-9-octadecenoate
2. high cholesterol & sitosterol
3. high DDE and HCB © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
This type indicates that HDL/LDL ratios and liver function should be checked.
Type 2
This pattern may represent a catabolic situation where there is an increased energy demand associated with infections, stress, genetic disorders, toxic exposures and trauma.
The main characteristic anomalies are:
1. low levels of C22:0, C23:0, C24:0 and cis-15-C24:1
2. elevated levels of glycerol
3. cholesterol can be low
Type 2 CFS patients should be checked for high triglyceride levels.
Type 3
The accumulation of long chain fatty acids can be associated with pain symptoms. This can indicate a susceptibility to certain viral infections or the reactivation of viruses such as CMV or EBV. Careful evaluation of dietary intake of fatty acids should be made for this type of profile.
The main characteristic anomalies are:
1. elevated levels of C20 poly saturated fatty acids
2. some polar lipid components may also be elevated
Type 4
This profile represents an alteration or dysregulation in medium chain fattyacid metabolism.
The main characteristic anomalies are:
1. reductions in lauric and myristic fatty acids
2. increased stearic acid3. elevated phosphate levels
Type 5
The low relative abundance of cholesterol may be an indication of a disturbance to the CFS patient’s capacity to synthesize cholesterol. This may be due to a genetic anomaly or an infection and may be addressed by dietary supplementation with certain precursor nutrients (currently under investigation).
The main characteristic anomalies are:
1. low relative abundance of cholesterol
2. elevated levels of omega 6 essential fatty acids
Supplementation with coenzyme Q10 (an off-shoot of cholesterol biosynthesis) has been beneficial for certain patients. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Note:
The lipid profiles described above are independent of the type of onset of the subjects and therefore may represent a predisposition to fatigue related illnesses.
A computer program can be used to calculate index values for each CFS patient. These values would then indicate the most likely lipid profile type characterising the patient.
The importance of lipid ratios
Trans-9-C18:1:C18:0 ratio
This ratio is very different in CFS patients compared to control subjects. This may indicate an alteration in the R1 position saturated fatty acid contents of phospholipids. A low level may indicate increased cytochrome P450 activation. (Refer to 1 below.)
Lathosterol:cholesterol ratio
An increase in serum lathosterol and a reduction in cholesterol occur when there is a cytokine (immune system chemical) mediated event.
Therefore an increase in this ratio and the arachidonic acid level possibly indicate that the patient had a cytokine mediated change in metabolism on the day of the test. Investigation of potential infectious agents or auto-immune conditions may be warranted. (Refer to 2 and 3 below.)
Sitosterol:cholesterol ratio
An increase in sitosterol in relationship to cholesterol has been linked to increased absorption of cholesterol. This may also indicate a reduction in removal of sterols (refer to 4 below). Increases in the sitosterol:cholesterol ratio may also be seen in vegans.
Lower serum HDL levels or any reduction in bile excretion would result in an increase in this ratio. Patients with increases in this ratio may need to be assessed for liver disease. If the HDL levels are low they should be assessed for organophosphate and organochlorine accumulation. HDLs contain paroxonase (refer to 5 below) and similar degradation enzymes and, if low, may predispose the patient to increased lipid soluble pesticide toxicity.
If HDL levels are normal and there are increased lipid soluble pesticides concentrations, then the levels of paroxonase and similar enzymes may be low. Reduced HDL or paroxonase levels are likely to result in increased oxidation of LDL and increase interferon like activity.
Note: Interferon is an immune system chemical that can cause symptoms of illness.
References:
1.Sawamura-A; Kusunose-E; Satouchi-K; Kusunose-M Catalytic properties of rabbit kidney fatty acid omega-hydroxylase cytochrome P-450ka2 (CYP4A7).Biochim-Biophys-Acta. 1993; 1168(1): 30-6 © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
2.Dixon RM, Borden EC, Keim NL, et al. Decreases in serum high-density-lipoprotein cholesterol and total cholesterol resulting from naturally produced and recombinant DNA-derived leukocyte interferons. Metabolism 1984; 33:400-4.
3.Pfeffer LM, Kwok BC, Landsberger FR, Tamm I. Interferon stimulates cholesterol and phosphatidylcholine synthesis but inhibits cholesterol ester synthesis in HeLa-S3 cells. Proc Natl Acad Sci U S A 1985; 82:2417-21
4.Miettinen TA, Tilvis RS, Kesaniemi YA. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol. 1990; 131(1): 20-31.
5.MacKness et al, Protection of low density lipoprotein against oxidative modification by high density lipoprotein associated paronase. 1993 104:129-35.
The omega 3 and omega 6 essential fatty acids (EFAs) are polyunsaturated fatty acids that play an important role in keeping us healthy. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
“Non-essential” fatty acids
The omega 7 and omega 9 series of fatty acids are “non-essential” because they can be produced by the human body. High levels of these fatty acids can indicate:
1. a disturbance in the EFA metabolism
2. essential fatty acid deficiencies.
Cholesterol
Newcastle research has found that many CFS patients have lower than average blood cholesterol levels. The biosynthetic pathway for cholesterol synthesis yields coenzyme Q10, dollichol and vitamin K, and leads to the production of the steroid hormones.
Viruses
Some viruses such as EBV can alter the patient’s fatty acid metabolism and homeostasis (the balance and regulation of functions). Other viruses need certain fatty acids to be able to multiply.
Disturbances in the homeostasis of the omega 3 and omega 6 essential fatty acids (EFAs) can be caused by viral infections. If significant changes in the levels of these EFAs are detected, this could indicate the presence of an undiagnosed viral infection and/or reactived virus.
Essential fatty acid deficiencies
If essential fatty acid levels are low, supplementation with the appropriate types of EFAs is recommended. The use of cofactors to assist with the desatuartion and elongation reactions is also suggested. These cofactors are: zinc, magnesium, vitamins A and B6.
Disrupted EFA Homeostasis
Linoleic acid is usually high in CFS patients, and this is often associated with high levels of long chain saturated fatty acids. This indicates a catabolic response, and provides indirect evidence for a low grade persistent infection and/or viral reactivation. Further investigation of these conditions is recommended.
It has been found that essential fatty acids tend to minimise the catabolic response and act to normalise homeostasis. Therefore, supplementation with EFAs such as flax or fish oil, along with the appropriate cofactors is recommended.
Note: Evening primrose oil should not be used if linoleic acid levels are high.
© Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
For more information, please refer to:
“Interpretation notes for use by the consulting medical or health practitioner”. These notes are normally supplied with each completed blood plasma lipid report.
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