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CFS and FMS Research
URINE ANALYSIS
"The University of Newcastle in Australia has been at the forefront of CFS research for some time. I believe that the research team has developed the most comprehensive CFS tests and treatment protocols currently available".
Urine analysis is an important part of the testing procedure. The research team has found a number of characteristic abnormalities in urine of CFS patients.
The following article aims to introduce this topic.
Chronic fatigue syndrome (CFS) is a condition that is currently diagnosed by symptoms alone. Prominent features include fatigue, impaired short term memory and concentration, sleep disturbance and musculoskeletal symptoms.
No validated diagnostic tests have previously been available. Following an investigation of 20 CFS patients and 45 non-CFS subjects, the Newcastle research group has recently published results that have found that CFS patients have anomalies in the urinary excretion of amino acids and organic acids.
These alterations in urine metabolite profiles can be interpreted to reflect changes in homeostasis involving nitrogen and energy metabolism suggestive of a low grade catabolic disturbance.
Changes in metabolite excretion were strongly correlated with the detection of an unusual metabolite referred to as CFSUM1. More recently, another unusual molecule, designated UM15b, has been strongly associated with CFS symptoms.
These results provide the basis for the development of objective diagnostic tests characterising polysymptomatic patients. The measurement of levels of CFSUM1, UM15b, b-alanine and other relevant components of the urine samples has been developed as the first objective diagnostic test to assist the clinical assessment of patients. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
The urine test can also identify subgroups of patients characterised by subtle differences in symptom presentation and urine profile characteristics. In addition, the test can provide evidence for dysfunctional metabolism and, therefore, also offer some assistance in the management of CFS sufferers.
When should this test be performed?
According to Newcastle, “This test is suggested following the clinical evaluations recommended by the CDC (Fukuda, K. et al., 1994, Ann Intern Med;21,953-959).”
In other words, it is advisable that people have been diagnosed by a competent doctor before the test is performed.
Please note: This test has recently become available to people living outside of Australia.
The analysis of samples
Test samples are analysed to determine the composition of specific compounds in the urine. The detailed relative abundances of urine components can then be used in scientific and clinical evaluation.
The urine index report:
This report is generated from the results of the laboratory analysis of each sample. The first page of this report basically consists of a table of data that has been organised into a number of columns.
The "average values" column gives the mean values for the groups of healthy, normal subjects which we have evaluated.
The "patient data" column gives the patient results for the sample analysis.
The next 3 columns are designed to give an indication of how the patient test values compare with the range of "normal" values seen in the general population.
Further comments:
Chronic fatigue related illness can involve multisystem dysfunction. The data can also indicate the presence of some underlying genetic anomalies such as hyperglycinuria and hyperlysinuria. This can also indicate a number of changes to homeostasis associated with the presence of CFSUM1, UM15b and beta-alanine.
Characterising polysymptomatic patients:
Statistical analysis and case selection allocation techniques allow division of CFS patients into distinct subgroups based on their urinary index results. These results can then be assessed against symptom expression to determine whether specific symptoms were associated with the subgroup excretion profiles.
The research team has expanded its database of urine and symptom data and several subgroups of polysymptomatic patients are now discernible. The urine report has been designed to show which excretion pattern is most relevant to the patient at hand. The urine excretion indices, which have a maximum score of 10 out of 10, are used to indicate which patterns(s) are most relevant to the patient. The higher the score, the greater the contribution of that pattern to the patient's symptoms.
© Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Biochemical Excretion Patterns
Three major excretion patterns have been observed in the polysymptomatic CFS patients. These are:-
1. Hyperglycinuria:
Approximately 8-10% of CFS patients have urinary excretion patterns consistent with hyperglycinuria, where the relative abundance of glycine comprises more than 40% of the total urine organic and amino acid profile. These patients will need to be investigated for two basic conditions:
a) Ketotic hyperglycinaemia
b) Non-ketotic hyperglycinaemia.
Whilst adult patients with these defects are unlikely to have the full blown enzyme anomalies, marginal enzyme anomalies can not be disregarded. Abnormalities in short chain fatty acid metabolism are also likely to be able to precipitate a similar disorder. These types of conditions are likely to be manifested following, or associated with, a catabolic event such as that observed in polysymptomatic patients.
Check for:
* carriage of alpha-haemolytic streptococci (throat, nose)
* reduced lymphocyte count
* increased neutrophil count
2. Hyperlysinuria.
From Newcastle's database, approximately 10-15% CFS subjects have urinary excretion patterns consistent with hyperlysinuria, where the relative abundance of lysine comprises more than 20% of the total urine organic and amino acid profile. These patients should be investigated for cystinuria. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Abnormal glycine levels - more comments
Hyperglycinuria:
Increases in the amino acid glycine are seen in about 10% of pain/fatigue patients. This may be related to either an increase in serum bicarbonate or an increase in citric acid. Large increases in glycine levels may indicate a genetic condition, such as non-ketotic hyperglycinuria, which would need further investigation.
Reductions in glycine are seen in about 80% of pain/fatigue patients and are largely associated with increases in hippuric acid. This indicates an active glycine-conjugation detoxifying reaction in the liver. Reductions may be associated with reductions in inhibitory neurotransmission and increases in problems such as muscle cramps.
Abnormal lysine levels - more comments
Hyperlysinuria:
This can be significantly elevated in some pain/fatigue patients and may indicate:
* possible genetic hyperlysinuria (levels greater than 20%)
* a possible liver disorder (levels usually between 7 and 14%)
* an overgrowth of gut bacteria producing lysine. This group warrants further investigation.
The urine test can identify a number of biochemical responses active in the body at the time of the test, such as fibrillar and non-fibrillar catabolism.
Catabolic Metabolism
Many patients have evidence of catabolic responses suggestive of either infection, trauma or fatigue-associated changes in amino acid metabolism. The actual level of energy required from muscle is associated with increased release of glutamic acid (Ott, et al., Crit Care Med 22:393-398; 1994).
In many CFS patients, the duration of the illness has been associated with increasing levels of glutamic acid. Catabolic events result in 2 basic responses: a non-fibrillar response and a fibrillar response.
1. The Non-fibrillar Response
A non-fibrillar response usually results from an increased energy requirement. The loss of amino acids from muscle has been correlated with the severity of the traumatic or septic event. (Wolfe et al., Diabetes Metab Rev 5:149-164; 1989.)
The increased excretion of tyrosine has been associated with the non-fibrillar response.
The non-fibrillar response is usually associated with increases in stress, trauma, toxic exposures, cachexia and genetic disorders. It can be initiated by the immune system chemical interkeukin-1 (IL-1) and tumour necrosis factor (TNF).
2. The Fibrillar Response
a. A fibrillar response is usually initiated in severe catabolic events, such as in major infections, where the amino acids supplied to the blood from muscles by the non-fibrillar response is inadequate.
b. The increased excretion of 3-methylhistidine is associated with the initiation of a muscle fibrillar protein catabolic event. The muscle is actively degrading muscular proteins to release amino acids into the bloodstream.
The fibrillar response is usually associated with combined increases in the immune chemicals IL-1 and IL-6.
Urinary excretion patterns are associated with 3 main types of fatigue and pain.
Type 1 is related to regional pain and high lysine output.
Type 2 is linked to the presence of irritable bowel symptoms and a gastrointestinal problem at onset. This type correlates with a high citrate output.
Type 3 is associated with generalised body pain and a high output of the urinary marker 15b (UM15b). © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Urinary excretion patterns can reflect disturbances in the urea cycle activity and the glutamate family of amino acids (P5C enzyme).
The actual level of energy required from muscle is associated with increased release of glutamic acid (Ott, et al., Crit Care Med 22:393-398; 1994).
Conclusions
1. The urine excretion test profile is assessed to determine if the pattern is consistent with the 5 major patterns that Newcastle researchers have observed in CFS patients.
2. Unusual patterns may indicate disturbances to homeostasis and metabolism. These disturbances have been associated with characteristic presentations of pain and/or fatigue symptoms observed in chronic fatigue patients.
Possible supplementation strategies based upon urine test results
1. Citric acid levels:
Increased excretion of citric acid is the most common change seen in pain/fatigue patients. The excretion of citric acid has been associated with increased loss of chemicals such as calcium, magnesium and sodium.
Prolonged citric acid excretion is probably the major reason why many CFS patients have reduced whole body potassium and magnesium levels.
Although blood plasma levels are not changed, intracellular levels may be depleted. Therefore, supplementation with some form of potassium and magnesium should be considered. (This may also be the reason behind the neurogenic hypotension in CFS subjects observed by Rowe et al. 1995.)
2. Reduced levels of many amino acids:
Reduced levels of alanine, glycine, valine, threonine, isoleucine, aspartic acid and glutamic acid have been found in some CFS patients. Amino acid supplements such as l-glutamine, aspartic acid or suitable amino acid mixtures can be considered if all the amino acids are reduced.
3. L-glutamine or aspartic acid precautions:
L-glutamine or aspartic acid should not be taken if test results show evidence of elevated hyperglycinura. Symptoms of hyperglycinura may include chest pain, palpitations and breathlessness. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Urine report - some conclusions
Infectious associations:
Newcastle research has associated changes in the urine of many CFS patients with infection related symptoms and gut dysfunction. If evidence for a persistent infection is found, then the sinus, prostrate, pelvic and urogenital regions should be investigated for microbial infections.
Staphylococci bacteria have been associated with symptoms of chronic pain and fatigue.
Evidence for viral reactivation has also been found in a number of cases.
Amino acid malabsorption:
Low levels of amino acid output can indicate poor digestive absorption of amino acids. Amino acid supplementation may therefore be required.
Digestion problems can be treated with specific digestive enzyme supplements.
Gut dysfunction:
Newcastle research has shown that patients with gut dysfunction problems often have an incorrect balance of intestinal bacteria.
CFS symptoms and associated urinary metabolites
The table below shows that many CFS symptoms can be linked to the metabolites found in urine of CFS patients. (Note: This table was written in plain text, and may therefore appear to have columns that are not perfectly straight). © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
CFS SYMPTOMS ASSOCIATED METABOLITE
Infection-related Symptoms:
Cervical lymphodynia.................................CFSUM1
Low grade fever*.......................................CFSUM1*
Axial lymphodynia*............................. hippuric acid*
Sore throats*..............................................CFSUM1*
Neurological Symptoms:
Severe fatigue*............................................CFSUM1
Dizziness...................................................... b-alanine
Tinnitus................................................... hippuric acid
Paraesthesia................................................CFSUM2
Hyperaesthesia ........................................... b-alanine
Photophobia*...............................................b-alanine*
Musculoskeletal Symptoms:
Myalgia*........................................................b-alanine*
Muscle fatigue*............................................CFSUM1*
Muscle weakness*.............................. ........CFSUM1*
Muscle twitches..............................................CFSUM1
Muscle cramps...............................................b-alanine
TMJ clicking................................................... b-alanine
Gastrointestinal Symptoms:
Nausea..................................................................lanine
Abdominal pain...............................................b-alanine
Diarrhoea...................................................aconitic acid
Gastric reflux....................................................b-alanine
Abdominal bloating.............................................alanine
Constipation......................................................... UM13
Irritable bowel syndrome...........................aconitic acid
Genitourinary Symptoms:
Urinary frequency............................................CFSUM1
Recurrent genital infections............................b-alanine
Suprapubic pain.............................................. b-alanine
Groin lymphodynia*..................................hippuric acid*
Dysuria...................................................................UM13
Other Symptoms:
Dysrhythmias...................................................CFSUM2
Allergies...........................................................CFSUM1
Chest pain....................................................... CFSUM2
Breathlessness............................................... CFSUM1
Hair loss................................................................. UM13
* These represent core CFS symptoms (1)
Part 9 of this series had a table showing that CFS symptoms can be associated with specific urinary metabolites.
More details on these important urinary metabolites are given below:
1. CFSUM1
This metabolite has been identified as the chemical: 'amino-hydroxyl-N-methyl-pyridine. It correlates with changes in 3-methylhistidine, citric acid and UM28. It occurred in 85% of Newcastle’s original CFS study group and was also noted at lower levels in 47.6% of the control group. Its association with citric acid links it to an acid-base disturbance.
In addition, its correlation with 3-methylhistidine indicates the presence of a “breaking down” process involving muscular proteins (catabolism). This is similar to that seen with a cytokine response. (Cytokines are immune system chemicals that are produced by the body when an infection occurs.)
Patients with increased levels of CFSUM1 usually have a number of prominent symptoms, such as cognitive changes, musculoskeletal symptoms, infective symptoms and increased degrees of somatization.
2. CFSUM2
This metabolite (now identified as phosphoserine) appears to be produced by the bacteria that are found in the intestines. Reductions in this metabolite have been linked to reductions in gut bacteria such as E. coil.
3. Hippuric acid
This metabolite has been identified as benzylglycine. Increases in hippuric acid indicate an increased liver conjugation reaction. This may indicate increased degradation of tyrosine, phenylalanine or phenylacetic acid.
4. B-Alanine
Increases in b-alanine are associated with significant levels of symptoms in a subgroup of CFS patients. B-alanine highly correlates with increases in musculoskeletal pain and gastrointestinal symptoms. It may be the product of:
a. A viral infection.
b. Muscle catabolism (although this is not supported by current data).
c. Bacterial production in the gut. Elevations in b-alanine are usually seen in the most severe cases of CFS.
5. Alanine
Increases in alanine are seen in about 20% of patients suffering from pain/fatigue and this correlates with increases in ethanolamine and tyrosine. The exact nature of this increase is unknown. © Bioscreen, CPRU, S Ashton and F Bartosy 1999 - 2001
Reductions in alanine are seen in about 80% of pain/fatigue patients. This may indicate a reduction in the ability of muscle to supply alanine following prolonged catabolism.
6. Aconitic acid
This metabolite is highly correlated with succinic acid and with symptoms of gut disturbances and tooth grinding.
7. UM13
Increases in UM13 have no known significance in pain/fatigue patients.
© CPRU and F Bartosy 1999
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