Polio 2000 Conference Melbourne21/1/00Tessa JUPP RNDr John NIBLETT FRCR FRACRPolio Clinic – Western Australia
ABSTRACT.A progressive study of serum carnitine levels (over 250 polio survivors as at 1/12/99) as a treatment criteria for Post Polio Syndrome (PPS).PPS as defined – the symptom cluster of new weakness, fatigue and pain resulting in declining ability and/or new disability, corresponds with symptoms for carnitine deficiency. At the Polio Clinic in Western Australia (WA) serum levels were initially commenced in 1996 in conjunction with a double-blind trial started on 20 patients successfully using carnitine to alleviate the above symptoms. The double-blind trial was not continued after the original 20 as it was found to be detrimental to cease supplementation and new patients wanted results rather than a possible placebo. Since then serum levels on future carnitine users have been obtained to confirm use of carnitine supplementation as a treatment option. Levels have demonstrated that many polio survivors do actually have reduced serum levels and/or abnormal acyl/total percentage levels and that supplementing with an appropriate dose of carnitine returns readings to a more normal level with a corresponding improvement in post polio status. It has also been demonstrated that a number of progeny of polio survivors complaining of fatigue and muscle pain, are also recording abnormal serum levels indicating a worsening secondary carnitine deficiency in successive generations, a hither-to unsuspected complication of PPS.Late onset diabetes may also be a complication of longterm carnitine insufficiency.
A Pilot Study by the Polio Clinic in WA begun in June 1994 used verbal and questionnaire assessment of a trial and error regime (overdose gives diarrhoea, underdose is ineffective) to estimate carnitine dosage as a treatment option for the symptoms of PPS.It became obvious from questionnaire data that many people were reducing red meat intake (a primary source of carnitine in the diet), on doctors’ advice to lower cholesterol, heart disease and cancer risk.
As research into the utilisation of carnitine grows, more known actions within the body are revealed. Primarily it is the essential co-factor in the transfer of long chain fatty acids across the inner mitochondrial membrane in type 1 muscle. Inability for this to occur results in lipid myopathy as is found in muscle biopsies of both genetic carnitine deficiency and post polio.3, 4Acyl-Coenzyme A (Acyl-Co A) synthesis by carnitine is assisted by carnitine palmitoyl-transferase 1 & 2 enzymes and acyl-carnitine translocase(ACT).
Carnitine acts as an acyl sink to maintain adequate cellular levels of free Co-A.Carnitine also has a supportive effect on the immune system and in the maturation of the surficant of the lung lining.
PILOT STUDY RESULTS
The initial pilot study results established:
1.– that appropriate levels of carnitine supplement-ation did in fact benefit people experiencing the late effects of polio. Required dosage may vary from 250mg – 3000mg.
2.– that supplementation was best taken as a single dose on rising, early in the day, before any strenuous activity was undertaken.
- – that extra may be required above usual dose if greater that usual physical activity was attempted.eg physiotherapy session, sporting activities, shopping or other strenuous outings (best taken prior to activity).
- – that cessation of supplementation eventually results in return of symptoms (anywhere from 2 days to several months) and that resumption after a period of previous stability then cessation may result in a permanent increase in dosage requirements.
5.– that it is possible that progeny of polio survivors may present with a secondary carnitine deficiency.
6.– that a minority of polio people did not appear to benefit from supplementation (usually where more muscle wastage from polio and greater disability).
Following the pilot study, serum levels, initially undertaken as part of a double blind trial, were continued as an investigative procedure prior to commencing new patients on supplementation and as a means of confirming appropriate dosage. Serum levels in WA are processed at PMH (Princess Margaret Children’s Hospital)
The double blind trial revealed that after a period of 4 weeks on a placebo, deterioration time on ceasing carnitine varied from 2 days to several months depending on the individual and that even after a month back on supplementation at the same dose, serum levels were still inadequate and deficiency symptoms did not resolve until a higher dose was taken. Several participants experienced problems such as pinched nerve and mobility deterioration that may be attributable to lessened support muscle function thus leading to permanent further disability. The trial was therefore discontinued on people already benefiting from carnitine supplementation.
SERUM LEVEL RESULTS
When determining carnitine levels, 2 readings are given – free and total. Free carnitine is the pool available to draw from. Total carnitine includes free and acyl- (used or in use) carnitine.The difference between the 2 readings is the acyl-carnitine level; ie carnitine in use either as a long or short chain fatty acid combined with carnitine.Acyl-carnitine is eventually excreted via the kidneys. see diagram on previous page. Other carnitine studies also show that there is a significance in determining the acyl/free ratio (N = < 0.4) and acyl/total percentage.
Varying levels are given as normal depending on the carnitine research study.PMH formals are free carnitine 30-60 umol/L, total carnitine 35-65 umol/L.
There are no other research results available for carnitine in Post Polio except Dr Lehmann’s brief Swiss Study on 27 patients 1991-1993.Dr Tesch in Berlin had a polio/carnitine study in progress but the results were inconclusive.So for the purpose of this study the following levels were taken as normal.
|free carnitine30-60umol/Ltotal carnitine35-65 umol/Lfor polio – free carn> 45 female> 50 male
There appears to be a need for differing levels of free carnitine in male and female polio people.(Other carnitine research shows that males require a slightly higher level as carnitine is used in sperm quality and motility.)
The observations of symptomatic improvement by participants would suggest that for female polios a free carnitine level of at least 45 umol/L is necessary.Male polios appear to need to be at least 50 umol/L or even more.
Free and acyl/total percentage were used as the main indicators of status as they appear to encompass availability and usage.Free carnitine is presumed to demonstrate amount available for future use.Adequate reserves appear necessary to enable a tidal volume.Acyl/total percentage is presumed to indicate amount in use at present, either as usable or used portions.Other carnitine research indicates that too great a percentage of acyl to total leaves inadequate free reserves available ie over 50%, which could have potentially serious consequences.(One study shows death of a child with 50% ratio as possible cause of death.)Too low a percentage would indicate too little being used.The aim of this trial is to get a percentage value of around midway
ie 17% – 18% and free levels above 45 – 50.
A sample of 13 male and 14 female participants have been graphed (see next page) to show common initial unsupplemented free carnitine levels with each individual’s reading paired to a second higher reading when on supplementation and at which they have reported subsequent improvement in symptoms; particularly, of fatigue, muscle pain and endurance.Other improvements commonly reported include improved sleep and reduction in brain fog.
It can be seen that nearly all initial readings are in the lower half of normal or below normal and that the graphs showing corresponding percentage reading for the same participants, usually come up or descend to a better mid-range percentage.Where this is not so, a further change in dosage usually achieves this.
Further charts below show pre-carnitine and on-carnitine free levels for male and female participants.Readings are sorted on age basis with youngest first.As levels are undertaken as part of clinical assistance provided, it has been difficult to get people to have further tests, particularly when they feel better, get on with their lives and see no necessity to return to the clinic.
Invariably, most people have taken themselves off carnitine and other supplements at some stage.Most find that, eventual return of symptoms, prompts them to return to supplementation.People are encouraged to include more red meat and/or avocado in their daily diet.Some can notice the effects of stopping carnitine within a day or so.Others may take a number of weeks to get back to previous low level symptoms.
The best way found to determine dose, is to start with 250mg daily and increase by 250mg every 3 days until diarrhoea is reached (overload), then reducing by the last 250mg will give dose point for the individual.This is confirmed if possible with serum levels.
The dose required by each person varies and there doesn’t appear at present to be any other indicator as to how to determine appropriate dose for each individual.Some people get by on 250mg – 500mg
Others may need up to 2,500mg.All have found it better to take the whole dose all together before breakfast for best effect.A few who have delayed until lunch time, have found it reflected in lower serum levels and do not get the boost an early morning dose gives.Taken at night, sleep is usually disturbed due to excess energy.
Participants are encouraged to experiment and feed information back.If after taking normal dose, extra activity is undertaken or anticipated later in the day, an extra 250mg gives another boost to meet increased activity without fatigue and/or pain.
eg playing golf, shopping day, physio session etc.
It has been noted that blood types A1 seem to have higher initial serum levels and don’t seem to require as high a dose to get benefit.Types O and A2 are often lower and may require more supplementation.Other work engaged upon by the Clinic, looking at diet in relation to blood groups, indicate that A1 is suited to a more vegetarian style diet and may have a greater dominance of type 2 muscles.Types O and A2, particularly seem to do better on a red meat and root vegetable diet and may have more Type 1 muscles.In general, eating for blood types, ie O & AB (hot) and A & B (cold) climate foods, appears to improve general health status. 17, 18, 19
A number of WA polios can relate deterioration in polio status to coincide with less red meat consum-ption.In particular, those of O or A2 blood groups, who endeavour to become semi vegetarian, report rapid deterioration over 1-2 years and subsequent improvement again on carnitine supplementation and resumption of a carnivorous diet.
PREGNANCY – CHILDREN of POLIOS
Enquires from participants about the health concerns of offspring from birth to middle age resulted in consideration of levels and supplementation for progeny as well.See 60 “children” with low levels.
One member, having her first child at 37, had been faring poorly through her pregnancy when she attended the Polio Clinic in June 1997.Her carnitine levels at 21 weeks were found to be free 16, total 17 and 6%.(Other carnitine research has observed that carnitine levels halve by 16 weeks gestation. ) On 1.25 G of carnitine her levels were 36 and 50 and 24%.Her vomiting ceased and energy levels returned. We’ve had other similar pregnancy stories.
Others have presented with a history of lethargy in children, often in subsequent siblings, although some families eg 4 under 6 years now, have all but first child with low levels. Improvement is noted with supplementation usually in the 250 – 1000mg range. Other progeny presenting to trial carnitine have been aged 2 – 63, may have a history of poor athletic ability at school, always fatigued and worse in pregnancy where female.One 6 year old grandchild on carnitine has had comment from teachers of improvement in school work and is now joining other schoolmates for playtime activities.
It would appear there is greater risk to progeny where parents were experiencing deterioration at time of conception of children. Levels of increasing numbers of children of polio survivors are showing that often they record lower levels than the polio parent, who is low. Where there are grandchildren these may be lower again.A recent surprise was the daughter of polio who has 7 year-old twins.Mother and one son always tired. Their levels were below normal but other twin was normal.It would appear one twin got more carnitine during develop-ment to the detriment of the mother and other twin.
Carnitine supplementation during pregnancy has made a difference to quite number of daughters of polios over the last few years in WA.Most report extreme fatigue and morning sickness which corresponds with their extremely low carnitine levels.Where polio survivors themselves are still having children there is often some abnormality and delayed milestones.Secondary carnitine deficiency can be triggered later.Trigger factors, similarly to genetic carnitine trigger factors, include, vaccination, severe illness, exhaustion, insufficient dietary carnitine, pregnancy, fractures, surgery, fasting.These same trigger factors have been noticed to precipitate PPS.
It has been noted that quite a number of WA members are reporting late onset diabetes.Some report pre-diabetic symptoms of thirst, hypoglyc-aemia, craving carbohydrate foods, mushrooms (high source of chromium – required for glucagon production).Subsequent diabetes has been observed in one member who appeared to have low chromium levels and a requirement for supplemental carnitine.As she was a disabled pensioner and the cost of supplements not financially viable, she did not continue and 12 months later was diagnosed as diabetic by her GP.Others, supplemented with carnitine (long term) and chromium (short term only) show improvement and apparent resolution of pre-diabetic state where GP has been concerned about glucose tolerance levels.
It would appear that Type 1 muscles, although designed to utilise carnitine and fatty acids as fuel of choice, can substitute glycogen if necessary.However greater quantities of carbohydrates are required for same energy production as protein fuel.eg via Krebs Cycle – 36 ATP using glucose/insulin cycle compared to 129 ATP with fatty acid/carnitine cycle.It is suggested that if carnitine insufficiency occurs over a prolonged period, pancreatic exhaustion may occur leading ultimately to diabetes.Other carnitine research does report that carnitine supplementation stabilises diabetic levels.We will be assessing glucose tolerance, insulin levels, chromium levels etc in at risk polio patients as part of our carnitine research over the next few years.
The carnitine levels of 10 non polio chronic fatigue sufferers have been surveyed in conjunction with this trial and although their levels are usually low with low percentages too, the level of improvement on supplementation is not as successful as with polios.Several carnitine studies have been done already looking at chronic fatigue.6
GENETIC CARNITINE DEFICIENCY
As this is a reasonably rare condition, participants are hard to find.Two families with suspected carnitine deficiency that have had levels done would suggest that in some instances with this condition, before carnitine readings, are initially high ie free carnitine above 60 umol/L and on appropriate supplementation of 2-3 Gm the levels reduce to below 60 with a corresponding improvement of symptoms and no signs of overdose.It is surmised that by increasing the available pool of carnitine, more is able to filter through to the muscle, so lowering serum levels.Thus a totally different serum picture is shown to that of post polio.
QUALITY of CARNITINE
There have been some concerns on the quality of carnitine available.Carnitine can be observed to be pure powder or to have a crystalline (sparkling) consistency.Participants report problems from crystalline carnitine (ie ineffective, need to double dose, rash).This seems to be particularly so where general health is not good as in post polio, CFS.
The manufacturing process for carnitine in the last few years, has now cut out the final stage that reduced crystalline to powder but we have found that a further grinding process tried in desperation by our pharmacist supplier, restores it to powder with beneficial results.Participants, unaware we had been having problems with quality, have rung in to say that their last lot (powder) was working better than the previous bottle.
There seems to be a correlation between B6 availability/levels and carnitine in particular, and also with magnesium.These are the most common extra supplements required by polio survivors.B6 has been found to be effective on nerve pain ie sharp electric shock pain or pins and needles.Magnesium is a natural muscle relaxant.Other items commonly required are glutamine, (neurotransmission in the brain and also required in muscle function when exhaustion levels reached) and choline (which is instrumental in acetylcholine production (the neurotransmitter for muscles).
Where weakness is occurring there seems to be a need, particularly in those with more damage from polio, for nerve support.This is being achieved with appropriate doses of B6, choline and glutamine.B12 may also be required.Low B12 levels allows greater excretion of carnitine as shown by Dr Vogelaar, a clinical biochemist, visiting WA from Holland.
CARNITINE and BETABLOCKERS
An interesting study found on Medline may explain why polio survivors have problems with some hypertensive drugs, beta-blockers in particular.20
It was observed that in a study of dogs with heart failure, beta-blockers decreased carnitine palmitoyl transferase 1 enzyme, essential for facilitating the progress of acyl carnitine through the mitochondrial membrane.If, as the WA study shows, carnitine levels are already low in polio survivors, the addition of beta-blockers would further jeopardise carnitine utilisation in the body, thereby explaining the international alert on beta-blockers in post polio.
The article concludes “Metoprolol (Betaloc) induced a decrease in CPT-1 activity and an increase in triglyceride content.These results suggest that the improved function observed with beta-blockers in heart failure could be due, in part, to a decrease in CPT-1 activity and less fatty acid oxidation by the heart.” 20
Yet another Medline study shows significantly improved exercise tolerance of patients with effort angina, concluding “these results indicate that L-carnitine is a useful therapeutic agent for the treat-ment of congestive heart failure in combination with traditional pharmacological therapy.” Japan Circ 1992 56(1)
It has been noted amongst WA carnitine users that the inexplicable chest pain often encountered in post polio and attributed to muscle spasm as ECG is normal, disappears when on carnitine.
Many post polio difficulties appear to be linked to a metabolic problem caused ultimately by decline in general health and exacerbated by muscle type change due to the recovery process after polio.
Lately attention has been drawn to the effects of improved liver function on supplemental carnitine requirements.A trial on supplementation of the amino acid, taurine, over the last 18 months has shown the benefit of 500mg of taurine daily.
This has slowly been effective on the liver, allowing ultimate dose reduction of carnitine and also B6 and Vitamin A requirements.
A further trial has started in 1999 to look into the effectiveness of a Sunflower Oil (detox and immune stimulation) morning mouth rinse “An Explanation of the Unconventional Healing Process within the Human Body by Sunflower Oil.” published in “Australasian Health and Healing “Vol 15 No 1;
Nov 95-Jan 96 attributed to a Dr Karach.Initial participants have reported a further reduction in carnitine dose requirements and other supplements.
A lot more work needs to be done in this area before firm conclusions can be reached as to the reason for low levels in post polio people.Not withstanding, carnitine supplementation is a safe, easily available, though reasonably expensive, adjunct to present treatment options for PPS.
The WA Polio Clinic is essentially a small preliminary assessment and referral clinic staffed by a registered nurse with a supervising honorary doctor (polio survivor).There is no funding for research and the study outlined here has been developed from clinical attempts to improve the symptomology of patients attending the clinic seeking help.Success must also be attributed to patient feedback.It has been a partnership program.
Some very interesting results and observations on utilising carnitine to best advantage, have been made by participants.The WA Polio Clinic is looking at a number of areas in an effort to assist with individual problems presented by polio survivors.
The symptoms of PPS appear to be tied to a deterioration in general health status that has a cascade effect.Polio survivors seem to have less leeway than other members of our community before running into problems.As certain vitamins and minerals seem to be also tied into protein metabolism as is carnitine, a lot of other minor problems indirectly associated with post polio, can be resolved by correcting vitamin and mineral imbalances.For example tight muscle problems like cramps, spasm, backache, headache, respond well to an appropriate dose of a magnesium supplement, a safer alternative to valium in post polios.
The Polio Clinic has four further studies under way.
1Emu Oil as an alternative to cholesterol reducing drugs – which can increase muscle deterioration in post polios.
2Supplemental boron to assist with arthritic type problems, common with overuse in post polios.
3 Gelatine supplementation for joint problems is showing success.Gelatine is the precursor for cartilage formation (Type 2 collagen) and has all but disappeared from our normal diet.
4 Creatine as an adjunct to relieving fatigue and increasing stamina.
The object of this paper is to stimulate further research that is beyond the capacity of this small clinic, by other Polio Clinics and researchers.It is hoped that in the near future supportive evidence by other similar studies to the WA study will emerge from other parts of the world.
- Borum P. ‘Carnitine’ Dept Biochemistry VanderbiltSchool of Medicine Tennesseepp 233-257
- Carter A et al’Biosynthesis and Metabolism of Carnitine’J Child Neurology 1995; 10 (Suppl) 2S3-2S7
- Gilbert E.’Carnitine Deficiency’Dept Pathology /Lab Med Wisconsin Uni.Pathology 1985 17pp161-169
- Halstead LS Grimby G (eds) Post Polio Syndrome.Philadelphia: Hanley & Belfus Inc 1995
- Shils et al‘Modern Nutrition in Health & Disease’Baltimore: Williams & Wilkins1999
- Kuratsune H, et al.Acylcarnitine Deficiency in Chronic Fatigue SyndromeClinical Infectious Diseases 1994:18 (Suppl 1) S62-67
- Lehmann T C.’L-Carnitine and Post Polio Syndrome‘1994Dept Ventilators & Post Polio Bern Switzerland
- Martini F.Fundamentals of Anatomy and PhysiologyNew Jersey.Prentice Hall Inc 1989.
9.Moffett D, Moffett S, Schauf C.Human Physiology St Louis Missouri. Mosby1993 2nd Edition
- Murray MT.’ Carnitine’.In:Encylopaedia of Nutritional Supplements – The Essential Guide for Improving Health Naturally.California: Prima Printing 1996: 283-295
- Pons R , de Vivo D’Primary and Secondary Carnitine Deficiency Syndromes’J Child Neurology 1995; 10 (Suppl) 2S8-2S24
- Rebouche CJ, Engel AG, ‘ Carnitine Metabolism and Deficiency Syndromes’Mayo Clinic Proc 1983: 58: 533-540
- Schater M, Medoff G, Schlessinger D (eds) Mechanisms of Microbial Disease.Baltimore: Williams & Wilkins1989
14 .Finnin B, Finnin K, ‘Essential guide to l-Carnitine’ Victoria Aust Harrisons 1999
- Trojan DA, Cashman NR.Current Trends in Post Polio Syndrome.Montreal: Milestone Medical Communications 1996
- Williams S R,‘Nutrition and Diet Therapy‘St Louis, Missouri: Times Mirror/Mosby College Publishing1989.
17.D’Adamo P, ‘Eat Right 4 Your Type’ New YorkUSA Putmans 1996
- Jupp T, Foster B, ‘Is Your Blood Group Written on Your Face?’ PPNWA booklet 1995
- Jupp T, ‘Balance by Blood Groups’ PPNWA booklet 1998
- Panchal A et al ‘Beta-receptor blockade decreases carnitine palmitoyl-transferase 1 activity in dogs with heart failure’
J Card Fail 1998 June; 4 (2):121-6
Asociación Post Polio Litaff A.C, No sé hace responsable