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http://www.umdf.org/atf/cf/{28038c4c-02ee-4ad0-9db5-d23e9d9f4d45}/supplements and nutrition - tarnopolsky.pdf
Supplements
• Mitochondrial dysfunction leads to increased free radical production, a reduction
in aerobic energy provision, and increased flux through anaerobic pathways that
can increase serum lactate (lower pH) and deplete tissue phosphocreatine 1
. Many
of the suggested supplements for mitochondrial disease have been based upon
the predicted ability to mitigate against these effects and are often given in
combination (“mitochondrial cocktail”) 2
.
• No long-term (> several months), randomized studies have been completed to
date and all recommendations are somewhat empiric and must be individualized.
In theory, combinations of supplements that target more than one of the
consequences of mitochondrial dysfunction should be superior to single agents,
and some evidence suggests that combination therapies can improve surrogate
markers of efficacy, including oxidative stress markers and lactate, and improved
mitochondrial function 3-5. Most studies have evaluated coenzyme Q10, creatine
monohydrate, riboflavin, vitamin E, vitamin C, α-lipoic acid, and thiamine (Table 1).
Until evidence of safety and efficacy is established, patients should avoid the
hundreds of other supplements on the market.
• Coenzyme Q10 is a co-factor involved in electron transfer from complex I and II to
complex III of the electron transport chain and can function as an anti-oxidant.
There are many studies that have evaluated the potential efficacy of CoQ10 in
mitochondrial disease, but the literature is not conclusive due to different
formulations (some of which are poorly absorbed), small sample size, and
variability in clinical features and outcome variables. The balance of data
suggests that CoQ10 is likely to be of benefit in primary, and some secondary,
mitochondrial disorders (review see 1, 2, 6).
• Alpha-lipoic acid is an anti-oxidant located in the mitochondria with high
theoretical potential for use in mitochondrial disease 1
, although to date it has
been studied only as part of a combination 3
.
• Creatine monohydrate is a quanidino compound that is consumed in meat/fish
and produced endogenously. It is involved in temporal and spatial energy
buffering in the cell and has anti-oxidant and neuroprotective effects 7-9. Animal
models of complex I and II deficiency, cerebral ischemia, seizures, and oxidative
stress, all show beneficial effects from creatine supplementation 7-10. Human
studies using creatine monohydrate in isolation have been equivocal: some have
reported benefit11-14, others have not 15, 16.
• L-carnitine is required for the entry of long-chain fatty acids into the mitochondria
for β-oxidation. Supplementation is recommended if plasma levels are low, or if
patients are taking valproic acid or statins (both relatively contraindicated in
mitochondrial disease).
• A randomized double-blind, cross-over study using a combination of α-lipoic acid
+ creatine monohydrate + CoQ10 in proven mitochondrial disease showed
decreased levels of lactate and of a marker of oxidative stress 3
, and another similar
combination also found evidence for efficacy 5
.
• Vitamins E and C are lipid- and water-soluble anti-oxidant vitamins, respectively.
Free radicals are produced in excess from complex I and III of the electron
transport chain in response to mitochondrial dysfunction and results in oxidative
stress. It is important that anti-oxidants be given as redox-couples because each
anti-oxidant can become a pro-oxidant. Examples of redox-couples include
vitamin E and C, vitamin C and CoQ10. The use of a mitochondrial cocktail avoids
the use of single anti-oxidants and reduces the risk that they become pro-oxidants.
• A wide variety of other supplements have been advocated for use in mitochondrial
cytopathies including: riboflavin (co-factor for complex II), thiamine (co-factor for
pyruvate dehydrogenase), vitamin K3 (electron donor), succinate (co-factor for
complex II), yet none have been independently evaluated in a randomized clinical
trial. Most physicians do not prescribe vitamin K3 anymore as there may be the
potential for blood clotting issues.
• Supplements should be introduced in a step-wise fashion and increased slowly to
identify and minimize potential intolerances.
• All supplements can lead to drug interactions with prescription medications. In
those people taking concomitant medications, it is important to evaluate drug
levels (when possible) after starting a mitochondrial cocktail, especially if there is a
change in clinical condition or if a new sign/symptom emerges.
• With the exception of coenzyme Q10, where there is some evidence that
liquid/hydrosoluble formulations are better absorbed and lead to higher blood
levels than powder preparations 3
, for the other components of mitochondrial
cocktails there is no credible data to suggest that one formulation is better than
any other (Table 1).
• Targeted formulations have been designed to be more specific for the
mitochondria (e.g. MitoQ) 17, and future clinical trials will be important to evaluate
their clinical utility.
Nutrition.
• Before starting any diet or dietary supplement, ensure that energy, protein, and
micronutrient intake are sufficient. Some patients have increased energy
expenditure (e.g. because of fever, rigidity, dystonia) and/or reduced energy intake
(e.g. because of low intake due to oro-facial weakness or dyskinesia), or poor
absorption (e.g. due to intestinal pseudo-obstruction) that can lead to relative
under-nutrition. Identification of deficiencies that may require specific
supplementation can be done with blood tests and are most commonly seen for
protein (albumin or pre-albumin), folate (RBC folate), vitamin B12 (B12 level), and
carnitine (total and free carnitine levels). Other deficiencies reported include; zinc,
selenium, vitamin A, vitamin D, and vitamin E.
• A multivitamin supplement is safe and may alleviate micronutrient deficiencies.
Patients with LHON, NARP, or other mitochondrial disorders with eye involvement
should take a multivitamin with lutein.
• Some patients require a G- or J-tube to safely provide adequate nutrition +/-
medications.
• There is no scientific data to support specific macronutrient profiles (protein,
carbohydrate and fat) in mitochondrial disease, but protein needs should at least
meet the guidelines set out in the Dietary Reference Intake Tables prepared by the
US Department of Agriculture,
http://fnic.nal.usda.gov/nal_display/index.php?info_center=4&tax_level=3&tax_su
bject=256&topic_id=1342&level3_id=5140
A ketogenic diet is used in the treatment of refractory seizures and is not
contraindicated in mitochondrial disease. Although there may be potential
benefits from a ketogenic diet in complex I deficiency 18, the long-term health risks
would preclude its use except in the case of severe refractory seizures.
• Fasting should be avoided and frequent small meals are preferable. If fasting is
unavoidable (e.g. for religious reasons), a meal with fat and protein (slow digestion)
and complex carbohydrates (slow absorption) should be taken prior to a planned
fast.
• Fluid intake is essential during times of increased heat and metabolic stress to
avoid heat stroke. Fluid intake should match the environmental demands (more
fluid intake in hot/humid conditions). A general rule is to consume or administer
adequate fluids to keep the urine color light yellow or clear. Absence of sweating
in a warm environment is a serious sign of heat stress and must be dealt with
promptly. Guidelines on the recognition of heat stress and heat stroke and
prevention can be best obtained through documents designed for sporting events:
http://www.acsm-msse.org/pt/pt-core/template-journal/msse/media/0207.pdf
Table 1. Nutraceutical compounds often used with mitochondrial cytopathies
Compound Dose (mg/kg/d) Rationale
Coenzyme Q10 3.5 – 15.01
By-pass complex I defect/anti-oxidant
Creatine monohydrate 100.02
(max, 7g/d) Alternative energy
source/neuroprotection
Riboflavin 2.5 – 5.0 By-pass complex I defect
Αlpha-lipoic acid 3.5 – 10.0 Anti-oxidant
Vitamin E 5.0 – 10.03
Anti-oxidant
Vitamin C 5.0 – 10.0 Anti-oxidant
L-carnitine 15.0 – 50.04
Free fatty acid transport/neuroprotection
Thiamine 2.5 – 5.0 Enhance pyruvate entry into mitochondria
Although most of the above compounds are Generally Regarded As Safe (GRAS), none
of the above have been proven to be safe during pregnancy. Since pregnancy is a
metabolic stress and the developing fetus may be affected with mitochondrial disease,
the risk/benefit ratio is unclear and must be individualized. The doses given are the
best estimate from studies and empirical experience and the total daily doses should
be divided twice daily. The supplements are best given with food to enhance
tolerance. Gastrointestinal upset is the most common side effect (seen in about 5 % of
patients with creatine for example). 1 – Higher doses are required for coenzyme Q10
deficiency; 2 – Uptake into the brain may require higher doses or a loading with up to
300 mg/kg/d for 4 weeks to increase levels by ~ 9 % 19 (consequently, using creatine in
an acute stroke or seizure situation is totally useless), uptake into muscle can occur
after 30 days with the above dose and 5 days with loading (300 mg/kg/d) 20; 3 –
maximum daily dose should not exceed 800 mg = IU; 4 – I tend to adjust the dose to
get plasma levels into the mid-normal range for the reference laboratory used
Supplements
• Mitochondrial dysfunction leads to increased free radical production, a reduction
in aerobic energy provision, and increased flux through anaerobic pathways that
can increase serum lactate (lower pH) and deplete tissue phosphocreatine 1
. Many
of the suggested supplements for mitochondrial disease have been based upon
the predicted ability to mitigate against these effects and are often given in
combination (“mitochondrial cocktail”) 2
.
• No long-term (> several months), randomized studies have been completed to
date and all recommendations are somewhat empiric and must be individualized.
In theory, combinations of supplements that target more than one of the
consequences of mitochondrial dysfunction should be superior to single agents,
and some evidence suggests that combination therapies can improve surrogate
markers of efficacy, including oxidative stress markers and lactate, and improved
mitochondrial function 3-5. Most studies have evaluated coenzyme Q10, creatine
monohydrate, riboflavin, vitamin E, vitamin C, α-lipoic acid, and thiamine (Table 1).
Until evidence of safety and efficacy is established, patients should avoid the
hundreds of other supplements on the market.
• Coenzyme Q10 is a co-factor involved in electron transfer from complex I and II to
complex III of the electron transport chain and can function as an anti-oxidant.
There are many studies that have evaluated the potential efficacy of CoQ10 in
mitochondrial disease, but the literature is not conclusive due to different
formulations (some of which are poorly absorbed), small sample size, and
variability in clinical features and outcome variables. The balance of data
suggests that CoQ10 is likely to be of benefit in primary, and some secondary,
mitochondrial disorders (review see 1, 2, 6).
• Alpha-lipoic acid is an anti-oxidant located in the mitochondria with high
theoretical potential for use in mitochondrial disease 1
, although to date it has
been studied only as part of a combination 3
.
• Creatine monohydrate is a quanidino compound that is consumed in meat/fish
and produced endogenously. It is involved in temporal and spatial energy
buffering in the cell and has anti-oxidant and neuroprotective effects 7-9. Animal
models of complex I and II deficiency, cerebral ischemia, seizures, and oxidative
stress, all show beneficial effects from creatine supplementation 7-10. Human
studies using creatine monohydrate in isolation have been equivocal: some have
reported benefit11-14, others have not 15, 16.
• L-carnitine is required for the entry of long-chain fatty acids into the mitochondria
for β-oxidation. Supplementation is recommended if plasma levels are low, or if
patients are taking valproic acid or statins (both relatively contraindicated in
mitochondrial disease).
• A randomized double-blind, cross-over study using a combination of α-lipoic acid
+ creatine monohydrate + CoQ10 in proven mitochondrial disease showed
decreased levels of lactate and of a marker of oxidative stress 3
, and another similar
combination also found evidence for efficacy 5
.
• Vitamins E and C are lipid- and water-soluble anti-oxidant vitamins, respectively.
Free radicals are produced in excess from complex I and III of the electron
transport chain in response to mitochondrial dysfunction and results in oxidative
stress. It is important that anti-oxidants be given as redox-couples because each
anti-oxidant can become a pro-oxidant. Examples of redox-couples include
vitamin E and C, vitamin C and CoQ10. The use of a mitochondrial cocktail avoids
the use of single anti-oxidants and reduces the risk that they become pro-oxidants.
• A wide variety of other supplements have been advocated for use in mitochondrial
cytopathies including: riboflavin (co-factor for complex II), thiamine (co-factor for
pyruvate dehydrogenase), vitamin K3 (electron donor), succinate (co-factor for
complex II), yet none have been independently evaluated in a randomized clinical
trial. Most physicians do not prescribe vitamin K3 anymore as there may be the
potential for blood clotting issues.
• Supplements should be introduced in a step-wise fashion and increased slowly to
identify and minimize potential intolerances.
• All supplements can lead to drug interactions with prescription medications. In
those people taking concomitant medications, it is important to evaluate drug
levels (when possible) after starting a mitochondrial cocktail, especially if there is a
change in clinical condition or if a new sign/symptom emerges.
• With the exception of coenzyme Q10, where there is some evidence that
liquid/hydrosoluble formulations are better absorbed and lead to higher blood
levels than powder preparations 3
, for the other components of mitochondrial
cocktails there is no credible data to suggest that one formulation is better than
any other (Table 1).
• Targeted formulations have been designed to be more specific for the
mitochondria (e.g. MitoQ) 17, and future clinical trials will be important to evaluate
their clinical utility.
Nutrition.
• Before starting any diet or dietary supplement, ensure that energy, protein, and
micronutrient intake are sufficient. Some patients have increased energy
expenditure (e.g. because of fever, rigidity, dystonia) and/or reduced energy intake
(e.g. because of low intake due to oro-facial weakness or dyskinesia), or poor
absorption (e.g. due to intestinal pseudo-obstruction) that can lead to relative
under-nutrition. Identification of deficiencies that may require specific
supplementation can be done with blood tests and are most commonly seen for
protein (albumin or pre-albumin), folate (RBC folate), vitamin B12 (B12 level), and
carnitine (total and free carnitine levels). Other deficiencies reported include; zinc,
selenium, vitamin A, vitamin D, and vitamin E.
• A multivitamin supplement is safe and may alleviate micronutrient deficiencies.
Patients with LHON, NARP, or other mitochondrial disorders with eye involvement
should take a multivitamin with lutein.
• Some patients require a G- or J-tube to safely provide adequate nutrition +/-
medications.
• There is no scientific data to support specific macronutrient profiles (protein,
carbohydrate and fat) in mitochondrial disease, but protein needs should at least
meet the guidelines set out in the Dietary Reference Intake Tables prepared by the
US Department of Agriculture,
http://fnic.nal.usda.gov/nal_display/index.php?info_center=4&tax_level=3&tax_su
bject=256&topic_id=1342&level3_id=5140
A ketogenic diet is used in the treatment of refractory seizures and is not
contraindicated in mitochondrial disease. Although there may be potential
benefits from a ketogenic diet in complex I deficiency 18, the long-term health risks
would preclude its use except in the case of severe refractory seizures.
• Fasting should be avoided and frequent small meals are preferable. If fasting is
unavoidable (e.g. for religious reasons), a meal with fat and protein (slow digestion)
and complex carbohydrates (slow absorption) should be taken prior to a planned
fast.
• Fluid intake is essential during times of increased heat and metabolic stress to
avoid heat stroke. Fluid intake should match the environmental demands (more
fluid intake in hot/humid conditions). A general rule is to consume or administer
adequate fluids to keep the urine color light yellow or clear. Absence of sweating
in a warm environment is a serious sign of heat stress and must be dealt with
promptly. Guidelines on the recognition of heat stress and heat stroke and
prevention can be best obtained through documents designed for sporting events:
http://www.acsm-msse.org/pt/pt-core/template-journal/msse/media/0207.pdf
Table 1. Nutraceutical compounds often used with mitochondrial cytopathies
Compound Dose (mg/kg/d) Rationale
Coenzyme Q10 3.5 – 15.01
By-pass complex I defect/anti-oxidant
Creatine monohydrate 100.02
(max, 7g/d) Alternative energy
source/neuroprotection
Riboflavin 2.5 – 5.0 By-pass complex I defect
Αlpha-lipoic acid 3.5 – 10.0 Anti-oxidant
Vitamin E 5.0 – 10.03
Anti-oxidant
Vitamin C 5.0 – 10.0 Anti-oxidant
L-carnitine 15.0 – 50.04
Free fatty acid transport/neuroprotection
Thiamine 2.5 – 5.0 Enhance pyruvate entry into mitochondria
Although most of the above compounds are Generally Regarded As Safe (GRAS), none
of the above have been proven to be safe during pregnancy. Since pregnancy is a
metabolic stress and the developing fetus may be affected with mitochondrial disease,
the risk/benefit ratio is unclear and must be individualized. The doses given are the
best estimate from studies and empirical experience and the total daily doses should
be divided twice daily. The supplements are best given with food to enhance
tolerance. Gastrointestinal upset is the most common side effect (seen in about 5 % of
patients with creatine for example). 1 – Higher doses are required for coenzyme Q10
deficiency; 2 – Uptake into the brain may require higher doses or a loading with up to
300 mg/kg/d for 4 weeks to increase levels by ~ 9 % 19 (consequently, using creatine in
an acute stroke or seizure situation is totally useless), uptake into muscle can occur
after 30 days with the above dose and 5 days with loading (300 mg/kg/d) 20; 3 –
maximum daily dose should not exceed 800 mg = IU; 4 – I tend to adjust the dose to
get plasma levels into the mid-normal range for the reference laboratory used
