Methylation Diet and Lifestyle
Dr. Fitzgerald received her doctorate of naturopathic medicine from National College of Natural
Medicine in Portland, Oregon. She completed the first CNME-accredited post-doctorate
position in nutritional biochemistry and laboratory science at Metametrix (now Genova) Clinical
Laboratory under the direction of Richard Lord, Ph.D. Her residency was completed at
Progressive Medical Center, a large, integrative medical practice in Atlanta, Georgia. Dr.
Fitzgerald is lead author and editor of Case Studies in Integrative and Functional Medicine, a
contributing author to Laboratory Evaluations for Integrative and Functional Medicine and the
Institute for Functional Medicine’s updated Textbook for Functional Medicine. She has been published in numerous peerreviewed journals. Dr. Fitzgerald is on faculty at the Institute for Functional Medicine, and is an Institute for Functional
Medicine Certified Practitioner. She is a clinician researcher for The Institute for Therapeutic Discovery. Dr. Fitzgerald
regularly lectures internationally for several organizations and is in private practice in Sandy Hook, Connecticut.
Romilly Hodges completed her Master’s degree in Human Nutrition at the University of Bridgeport,
CT. She is a Certified Nutrition Specialist through the Board for the Certification of Nutrition
Specialists, and completed her practice hours under the supervision of Dr. Deanna Minich, PhD
and Dr. Kara Fitzgerald, ND. She has published in the Journal of Nutrition and Metabolism on
food-based modulators of detoxification enzymes, and has been a contributing author to Sinatra &
Houston, Nutritional and Integrative Strategies for Cardiovascular Medicine. She has been
teaching assistant to Dr. Minich for the Certified Food and Spirit Practitioner Program and the Food and Spirit Advanced
Detoxification Module. She is the staff nutritionist at the office of Dr. Kara Fitzgerald where she advises and supports
patients in the implementation of complex, multi-layered dietary and nutritional protocols that are uniquely personalized to
each individual’s needs.
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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Methylation Diet and Lifestyle
All contents copyright © 2016 by Kara Fitzgerald, ND. All rights reserved. No part of this document or the related documents may be reproduced or
transmitted in any form, by any means (electronic, photocopying, recording, or otherwise) without the prior written permission of the publisher.
Disclaimer: No publication can be assumed to encompass the full scope of information that an individual practitioner brings to his or her practice and,
therefore, this book is not intended to be used as a clinical manual recommending specific treatments or tests for individual patients. It is intended for
use as an educational tool, to broaden the knowledge and perspective of the practitioner. It is the responsibility of the healthcare practitioner to make
his or her own determination of the usefulness and applicability of any information contained therein. If medical advice is required, the services of a
competent professional should be sought. The final decision to engage in any medical treatment should be made jointly by the patient and his or her
healthcare practitioner. Neither authors assume any liability for any errors or omissions or for any injury and/or damage to persons or property arising
from the use of information to be found in this publication.
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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TABLE OF CONTENTS
1 Abbreviations ..........................................................................................................................................................6
2 Preface: The Need For Conservative Yet Effective Methylation Support .......................................................8
3 Introduction ...........................................................................................................................................................11
4 An Introduction to Methylation ..........................................................................................................................14
4.1
The Biochemistry of Methylation ..........................................................................................................14
4.2
Endogenous Methylation Uses ..............................................................................................................15
4.3
DNA Methylation Plasticity ..................................................................................................................17
5 The Clinical Problem ............................................................................................................................................19
5.1
Methylation Deficits................................................................................................................................19
5.2
Folic Acid Concerns ................................................................................................................................22
5.3
Methyl Donor Intolerance ......................................................................................................................23
5.4
Methylation Gone Awry ........................................................................................................................25
5.5
Reason to Tread Carefully......................................................................................................................32
6 Assessment of Methylation Status ......................................................................................................................33
6.1
Genetic Profiling ......................................................................................................................................33
6.2
Nutrient status .........................................................................................................................................37
6.3
Methylation Metabolites ........................................................................................................................41
6.4
Nutrient Assimilation Capability..........................................................................................................43
6.5
Inflammation ...........................................................................................................................................43
6.6
Oxidative Stress .......................................................................................................................................44
7 The Methylation Diet and Lifestyle ....................................................................................................................46
7.1
Food-Based Nutrients .............................................................................................................................47
7.2
Support for Nutrient Assimilation ........................................................................................................51
7.3
Microbiome ..............................................................................................................................................52
7.4
Inflammation ...........................................................................................................................................53
7.5
Oxidative Stress .......................................................................................................................................54
7.6
Detoxification ...........................................................................................................................................55
7.7
Stress Management .................................................................................................................................57
7.8
Exercise .....................................................................................................................................................58
7.9
Nutraceutical Interactions ......................................................................................................................60
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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7.10
Medication Interactions ..........................................................................................................................61
8 The Methylation Diet Food Plan .........................................................................................................................63
9 Menu Plans.............................................................................................................................................................71
10
9.1
Sample Menu 1: Gluten-Free, Dairy-Free ............................................................................................71
9.2
Sample Menu 2: Paleo.............................................................................................................................72
9.4
Menu Nutrient Analyses ........................................................................................................................73
RECIPES ............................................................................................................................................................74
Breakfast ................................................................................................................................................................75
Lunch .....................................................................................................................................................................85
Dinner ....................................................................................................................................................................96
Side Dishes ..........................................................................................................................................................106
Snacks...................................................................................................................................................................114
Smoothies & Juices .............................................................................................................................................121
11
Appendix A: Checklist for Methylation Assessment ................................................................................128
12
Appendix B: Checklist for Methylation Interventions ..............................................................................129
13
References .......................................................................................................................................................130
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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1 ABBREVIATIONS
AHYC
AGE
AIP
ALU
ATP
ADD
ADHD
Bcl-2
BHMT
BH2
BH4
BMI
BMPRII
CBS
CDC
CIDP
COMT
CoQ10
CpG
CRP
DFE
DHA
DHF
DHFR
DNA
DNMT
EGCG
Fli-1
FODMAPs
FR
GI
HPA axis
HVA
IgE
IL
Adenosyl homocysteinase
Advanced glycation end-product
Autoimmune pancreatitis
Arthrobacter luteus
Adenoise triphosphate
Attention deficit disorder
Attention deficit hyperactivity disorder
B-cell lympoma 2
Betaine homocysteine methyltransferase
Dihydrobiopterin
Tetrahydrobiopterin
Body mass index
Bone morphogenetic protein receptor 2
Cystathionine beta-synthase
Centers for Disease Control and Prevention
Chronic inflammatory demyelinating polyneuropathy
Catechol-O-methyltransferase
Ubiquinone or coenzyme Q10
C: Cytosine triphosphate deoxynucleotide p: phosphodeister, G:
guanine triphosphate deoxynucleotide
C-reactive protein
Dietary folate equivalents
Docosahexaenoic acid
Dihydrofolate
Dihydrofolate reductase
Deoxyribonucleic acid
Deoxyribonucleic methyltransferase
Epigallocatechin 3-gallate
Friend leukemia integration 1 transcription
Fermentable Oligo –Di- Monosaccharides and Polyols
Folate receptor
Gastrointestinal
Hypothalamic-pituitary-adrenal axis
Homovanillate
Immunoglobulin E
Interleukin
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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KLF5
L-Dopa
MBP
5-mC
5-hmC
MAO
MAT
MDL
MS
MST1
MTFHR
MTHF
MTRR
MTR
MTases
NK
NRF2
NFkB
NHANES
NLRP3
8-OHdG
PABA
POP
RBC
REST
RNA
SNP
SAH
SAHH
SAMe
SIBO
SAHH
TET
TNF
UMFA
VMA
Kruppel-like factor 5
Levodopa or L-3,4-dihydroxyphenylalanine
Mega base pair
5-methylcystosine
5-hydroxymethylcystosine
Monoamine oxidase
Methionine adenosyltransferase
Methylation Diet and Lifestyle
Methionine synthase
Macrophage stimulating 1
Methylene tetrahydrofolate reductase
Methyltetrahydrofolate
Methyl tetrahydrofolate-homocysteine methyltransferase
reductase
Methyl tetrahydrofolate-homocysteine methyltransferase
SAMe dependent methyltransferases
Natural killer
Nuclear factor erythroid 2 [NF-E2]-related factor 2
Nuclear factor kappa-B
National health and nutritional examination survey
Nod-like receptor protein 3
8-hydroxy-2’-deoxyguanosine
Para-aminobenzoic acid
Persistent organic pollutants
Red blood cell
RE1-silencing transcription factor
Ribonucleic acid
Single nucleotide polymorphism
S-adenosyl homocysteine
S- adenosyl homocysteine hydrolase
S-adenosyl methionine
Small intestine bacterial overgrowth
S-adenosyl-L-homocysteine hydrolase
Ten-eleven translocation
Tumor necrosis factor
Unmetabolized folic acid, sometimes referred to as folic acid,
synthetic folate or oxidized folate
Vanilmandelic acid
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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2 PREFACE: THE NEED FOR CONSERVATIVE YET EFFECTIVE
METHYLATION SUPPORT
From the desk of Dr. Kara Fitzgerald, ND
With the mapping of the human genome in 2001, the era of Systems Medicine has burst forth.
At about 24,000 genes, the code for our lives was smaller than expected (you’ve no doubt heard
the humorous comparison: “less than a grape, but more than a chicken”). Significant attention is
now being paid to the regulatory aspects of the genome, and research on the heritable
epigenome in particular is galloping ahead. At this writing, a PubMed search on
“methylation”—a cornerstone epigenetic and metabolic process—yields more than 85,000 hits.
Many genetic methylation research abstracts are summarized with the preface statement, “For
the first time ever, we’ve shown that…”
With rapidly emerging understandings, and ready access to genetic testing, it is indeed a wildly
exciting time to be practicing Functional Medicine, the clinical application of Systems Medicine.
Many of our patients now arrive at our offices with some knowledge of their genetics, and most
often with regard to their single nucleotide polymorphisms (SNPs) relating to methylation.
Many assumptions are made around the phenotypic expression of these single nucleotide
variations. Last week, a new patient sat before me, stating with grim determinism that her
heterozygous mutation in MTHFR A1298C SNP made it impossible for her body to detoxify
efficiently.
To those of us looking for biochemical “lesions” in methylation enzymes using a combination of
genetic testing and the currently available metabolic biomarkers they appear to be common...
Sometimes correcting identified imbalances can be highly clinically significant, other times
(arguably more often than not) shifting biochemical methylation activity with high-dose methyl
donors such as folate and B12 doesn’t appear to have a huge, immediate clinical outcome. But
we know that methylation is incredibly fundamental and operates in many “behind the
scenes” activities not limited to detoxification, neurotransmitter production and of course the
all-important black box of epigenetic regulation. We’ve seen the powerful impacts of folic acid
fortification in the reduction of neural tube defects, where augmenting methylation activity is a
piece of the folic acid success story.
The spark of inspiration behind creating the Methylation Diet and Lifestyle (MDL) program
was wanting to “do right by my patients” by embracing both the importance of healthy
methylation balance while recognizing the limitations of our current understanding. What
we don’t know in the biological sciences always far outweighs what we do know, and this is
especially true in our understanding of methylation. Imbalanced methylation of the epigenome
(comprising both hyper- and hypomethylation primarily of gene promoter regions) is an
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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emerging area of investigation implicated in many disease processes, ranging from aging and
allergies to neurodegenerative processes and cancer. Regulation of the epigenome is a highly
complex process; we cannot state with certainty what the impact is of high-dose, long term
methylation interventions.
Thus, for the vast majority of our patients we need to consider whether high-dose, long-term
supplementation really is the right approach. There is a dearth of research in this area, with
the exception of folic acid, where, as we discuss below, reasonable concerns exist. There are also
those patients who do not tolerate methyl donor supplementation, suspected to be chiefly due
to either poor clearance of epinephrine and other biogenic amines, or “ramped up”
detoxification activity.
While homage to Dr. Bruce Ames and his remarkable work around increasing enzyme kinetics
using high dose cofactor supplementation is due, and understanding that this approach may
indeed be appropriate for methylation in the short-term, our emerging understanding on the
epigenome suggests that more “up-stream” and nuanced interventions are in order when
possible. Food-based folates, for instance, have only been shown to be protective. Numerous
additional phytochemicals, not directly tied to methylation, appear to favorably modulate
global epigenetic and biochemical methylation activity. And reducing methyl donor depletion
by minimizing toxic exposures, nourishing the microbiome, augmenting the stress response and
far more, is safe and impactful. By removing the obstacles and drains on methylation while
providing broad spectrum nutrient ingredients for balanced activity, we are allowing
physiological wisdom to manage the process.
The Methylation Diet and Lifestyle would not have been brought into being in my clinical
practice or in this eBook without the years of frank discussions I’ve had with leading expert
Michael Stone, MD on current research and patient care approaches1. Likewise with my Journal
Club comrades, where each month for over the last three years we meet and “tussle with” new,
often complex concepts in the biological sciences. A heart-felt “shout out” goes to my
nutritionist extraordinaire, Romilly Hodges, who has worked tirelessly with me to capture the
bulk of our thoughts in the below text.
This eBook serves as a guide to understand the current methylation issues and challenges facing
practitioners, the potential concerns with supplementation alone, how to assess methylation
Drs. Leslie and Michael Stone, along with their daughter, nutritionist Emily Rydbom, are doing
remarkable work in the field of methylation assessment and support during preconception, pregnancy
and the postnatal period at their clinic in Ashland, Oregon. Find them at www.ashlandmd.com and
www.growbabyhealth.com.
1
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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status, and how to incorporate an MDL program into your protocols. Not only are there easyto-apply menus, recipes and nutrient guidelines but important lifestyle factors are reviewed
as well.
How should we determine when to use the MDL? Well, it may be the optimal way to offer
methylation support right off the bat, especially for those who cannot tolerate
supplementation. It is also a sensible and safe long-term strategy for most patients who have
achieved balance through a short-term course of higher-dose methyl donors. Importantly, the
full MDL program also supports detoxification, stress reduction, microbiome and hormone
balance, and can be readily modified to incorporate other programs that we routinely prescribe
such as elimination diets, grain and lectin-free plans, low FODMAP diets and general gut
restoration programs. Highly restricted plans, such as the calorie restricted ketogenic diet,
sometimes used in cancer and epilepsy, can incorporate aspects of the methylation diet with
additional nutraceutical support. Virtually any dietary program can work with the MDL as a
foundation.
Acknowledgements
We would like to acknowledge P. Michael Stone, MD, MS,
Institute for Functional Medicine, for his groundbreaking work in
the area of methylation.
We would also like to thank Lara Zakaria MS for her
contributions to the menus, recipes and figures, and Brigid Krane
(www.brigidkrane.com) for the cover and logo design.
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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3 INTRODUCTION
It has become increasingly common for functional medicine practitioners to recommend highdose supplementation with methyl donors, such as 5-methyltetrahydrofolate (5-MTHF) and
methylcobalamin, in certain patients. For example in those with genetic polymorphisms that
may impair the functionality of relevant enzymes, most commonly methylenetetrahydrofolate
reductase (MTHFR), or in those with out-of-range methylation-related biomarkers such as in
hyperhomocysteinemia. Deficiency in methyl donors is a fairly frequent finding in laboratory
analyses, depending on your population, and can relate directly to clinical symptoms; for
example B12 deficiency-associated neuropathy, which is relatively common. Some practitioners
may even look to supporting methylation as a means to improve inherited or environmentally
acquired epigenetic programming.
Of course, improving global methylation status and averting the pathways of disease and
dysfunction associated with a potential deficit in methylation activity is a commendable goal.
However, as with other biochemical processes, methylation activity exists ideally in a state of
active balance, or homeodynamics. Imbalance in these mechanisms can lead to dysfunction and
disease. So while we can be confident that ensuring the adequacy of available methyl donors for
use in the body is important, we have to question whether “pushing” reaction rates using
supraphysiological doses is always safe. Rather than bluntly forcing reactions forward, perhaps
our ultimate goal should instead be enabling the body to do the right thing at the right time.
There are a number of potential issues with long-term high-dose methyl-donor
supplementation:
The impact of genetic alterations is unclear. Aside from the altered activity of MTHFR C677T
and A1298C single nucleotide polymorphisms (SNPs) which has indeed been studied to some
degree, the discovery of other SNPs remains a qualitative rather than quantitative indicator of
enzyme functionality. The overall effect of these SNPs on methylation depends on the activity
of many enzymes working together in the context of one’s internal and external environment.
This fact underlies the many variable results found in genome-wide association studies. As a
result, it isn’t readily possible at this time to determine exactly how much of an impact any one
of those alterations, even MTHFR C677T, has on overall methylation status [1].
The correct supplementation dose is as yet unknown, and may vary between individuals. No
studies have clarified yet what the right dosage or duration of methyl donor supplementation is
needed to rebalance biochemical or epigenetic methylation status Some side effects of high-dose
5-methyltetrahydrofolate supplementation have been reported in clinical practice, including
worsening of symptoms and anxiety. Consequently it may be safer in the long term to stay
within physiologic levels [2].
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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Hypermethylation states may occur and may also be detrimental: The scientific literature
contains many examples of region-specific DNA hypermethylation associated with adverse
outcomes, including cancer, immune dysfunction and Downs Syndrome. Interestingly, both
DNA hyper- and hypomethylation states can be identified in states of methyl donor deficiency
and repletion. Certainly folic acid, in either deficiency or excess, has been associated with
increased rates of cancer and immune hypersensitivity, but since the mechanism is not fully
understood, should we not also be cautious with high levels of methylated folate? The
mechanisms controlling DNA methylation and demethylation are incredibly complex, yet we
know that pushing reaction rates through supraphysiological dosing of nutrient cofactors is
possible [3]. The bottom line is that we don’t know what effect long-term, high-dose methylfactor supplementation has on DNA methylation.
Methylation status depends on many dietary and lifestyle inputs: A complex interaction of
dietary and lifestyle factors (including medications, stress, sleep, exercise and toxin exposure)
plays a role in the methylation end-result. Singular interventions with high dose nutrient
supplementation miss this intricate web of inputs and may lack long-term effectiveness, or may
not achieve desired results.
Dietary and lifestyle interventions may be the best, and safest, long term option for most
individuals with suspected methylation imbalances. This may be particularly true for certain
vulnerable populations such as individuals with active cancers. Aging is known to be associated
with diminished methylation activity, so there is a good rationale for using the MDL as an antiaging tool. Careful methylation evaluation and treatment is essential during preconception,
pregnancy and the postnatal period2. A good evaluation coupled with the MDL program and
appropriate nutraceutical support is a useful starting place.
A dietary and lifestyle approach can also be used as a long term follow-up plan to those
requiring early high-dose nutraceutical support. Food sources of methylation nutrients can be
abundant, and with proper planning, dietary modifications have been found to favorably
influence methylation activity [4], [5].
In this eBook, you’ll find a comprehensive dietary and lifestyle approach to support
methylation, aligned with a functional medicine approach and including important methylation
nutrients, specific foods to include, foods to avoid, two 7-day menu plans (with calculated
2
Drs. Leslie and Michael Stone, along with their daughter, nutritionist Emily Rydbom, are doing
remarkable work in the field of methylation assessment and support during preconception, pregnancy
and the postnatal period at their clinic in Ashland, Oregon. Find them at www.ashlandmd.com and
www.growbabyhealth.com.
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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levels of methylation nutrients), recipes and lifestyle factors. You’ll also learn the basic
biochemistry of methylation, the many roles of methylation in the body, how to assess patient
methylation status, the beneficial and potentially detrimental clinical impacts of supplemental
methyl donor interventions, and the potential issues with too little, or too much methylation
activity.
© 2016 Kara Fitzgerald, ND
www.drkarafitzgerald.com
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