Work Up of the Toxic Patient
Root causes and Imbalances
P. Michael Stone, M.D., M.S.
2014 Australia
Disclosure and
Acknowledgements
• P. MICHAEL STONE, M.D., M.S.
CONSULTANT FOR INSTITUTE FOR
FUNCTIONAL MEDICINE, EPIGENEATING.COM,
AND IN PRIVATE PRACTICE
• ACKNOWLEDGMENTS: IFM AND THE IFM
DETOX TEAM: KRISTI HUGHES, ND, RICK
MAYFIELD DC, DEANNA MINICH PHD, CCN,
ROBERT ROUNTREE, M.D., IFM CNI TEAM
AND ELIZABETH BOHAM MD,MS,RD.
FUNCTIONAL MEDICINE
addresses the underlying causes of disease, using a systemsoriented approach and engaging both patient and practitioner
in a therapeutic partnership.
Who is Looking for and dealing with Toxicants?
Naturopaths
J ALT COMPLEMENTARY MED 17(12)1175–1180 2011.
Environmental Exposure
Preventative Medicine/General Cleansing
Gastrointestinal Disorders
82-50% of Patients
Inflammation
With These DX
Fibromyalgia
Were Rx with Detox
Chronic Fatigue Syndrome
Weight Loss
Endocrine Disorders
Multiple Chemical Sensitivity...
Liver disease
CVD
Mercury Amalgam Removal
J ALT COMPLEMENTARY MED 17(12)1175–1180 2011.
Cleansing foods (i.e., Brassica family, beet root, dandelion, etc).
Increased fruit/vegetable intake
Vitamin/mineral/antioxidants
Organic foods
Elimination diet
Probiotics
Reduce environmental exposure
Stool bulking agents/fiber
Cholagogue herbs
91-47% Used
Sauna
these interventions
Chelating agents
Skin brushing
Lymphagogue herbs
Avoidance of animal products
Functional Toxicology
Triggers
Toxicants
Genomic Predisposition
Mediators
Chronic Disease
©2014 The Institute for Functional Medicine
TOTAL TOXICANT LOAD
equals
Total Toxicant Exposure
minus
Ability to Detoxify
and
Eliminate Toxins
©2014 The Institute for Functional Medicine
How Long
How Much
How Often
Individual Variables
Age
BMI
Physical Condition
Smoker
Drug/Alcohol Use
Competitive Load
©2014 The Institute for Functional Medicine
Pattern Recognition
Undernourished
Reduce Exposures
Ensure a Safe Detox
Work up of the Toxic Patient?
Pattern Recognition
Pattern Recognition
In Patients with Toxin
Associated Diagnosis
Start with Condition or Symptom which is not
improving with the conventional treatment
- ADHD, Allergies, Alzheimers, Anemia/immune suppression,
- Autism, Autoimmune Disease, Cancer, Chronic Fatigue,
- Fibromyalgia, Diabetes/IR, Fertility Issues, Inflammation,
- Neurobehavioral Issues, Neurodevelopment issues,
- Osteoporosis, Parkinsons, Peripheral Neuropathy...
Fm. Hx Mediators-Perpetuators-Drivers
Genetics
Triggering Events
Age
Birth
Signs, Symptoms, Diseases
Gather The History of Health and Illness on a Timeline
Two Key Detox Screening Questionnaires
Medical Symptoms
Questionnaire (MSQ)
Toxin Exposure
Questionnaire (TEQ)
Medical
Symptom
Questionnaire
P: Pattern Recognition
MSQ: Quantifies Symptom Severity
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
HEAD
EYES
EARS
NOSE
MOUTH/THROAT
SKIN
HEART
LUNGS
DIGESTIVE TRACT
JOINTS/MUSCLE
WEIGHT
ENERGY/ACTIVITY
MIND
EMOTIONS
OTHER
71 questions
Scored: 0 – 4
Total: 0 – 284
Medical Symptom
Questionnaire
• >50 = Risk of
Increased Toxicity
• Concern: if 10 or
more subsection
points
• >100: more fragile
“Start slow, go low”
Toxin Exposure Questionnaire
Identifies Exposure Sources:
1. Community
2. Home
3. Occupational
4. Hobbies
5. Diet & Lifestyle
6. Medical/Dental
Ability to Control or
Alter Exposures:
Identify
Control
Remove
Mitchel Reference here also
Saunders
COMMUNITY
HOME
HOBBIES
OCCUPATION
PERSONAL
HABITS
DIET
DRUGS
Patterns of Exposure and Disease
Occurrence
Persistent Organic Pollutants
RA (8X), OA, CVD(3.5X)
DM (38X)
Polychlorinated Biphenyls
RA, OA (3X)
Organochlorines-Pesticides
IR ABD Obesity,
Neurodegeneration 2X
Food Triggered Response
Celiac, High Carbohydrate
Heavy Metals
IR, DM, Neurodegeneration
Obesity
92% children in US risk of
Neurodevelop lead tox.,
CVD, MI, Htn, Osteoporosis,
Neuropathy, Dementia. DM
Pizzorno, J, J Katzinger: Clinical pathophysiology a functional perspective 3.1-3.27, 2012
Quality
Context
ABCD of
Nutrition Evaluation
-Anthropometrics
-Biochemical Markers
-Clinical Findings
-Diet Evaluation
Quantity
Company
Toxic Patient Physical Exam
partial list of possible findings
• Hair: change in luster, change in texture, change in color
• Eyes: Arcus, pigmentation (copper, iron), Hippus (adrenal),
Sclera (yellowed), Conjunctiva (anemias)....
• Nose: rhinorrhea, boggy turbinates, altered smell, seborrheic
changes...
• Mouth- Lips:blue tint, cracking (vitamin A), Hypersalivation,
xerostomia, soft palate/ tonsils, congenital disorders, tongue
(coating, fissuring, scalloping, atrophic tastebuds, altered
taste), Gums: heavy metal lines, periodontitis, Buccal
Mucosa: tattoing, mucosal changes (leukoplakia, squamous
cancers), Teeth: enamel dystophia, dissimilar metals...
• Neck: Acanthosis nigricans, thyroid enlargement,
• Lungs: decreased PEFR, Wheezing, distant breath sound,...
• CV: brady cardia, tachycardia, arrhythmia, HTn, Hypotension,
cardiomegaly...
Toxic Patient Physical Exam
partial list of possible findings
• Musculoskeletal: fibromyalgia trigger points,
muscle tenderness...
• Skin: acne, acanthosis nigracans, xerosis,
hyperkeratosis pilari, rashes, palmer changes
(erythema, peeling), seborrheic keratosis, basal
cell or squamous cell cancers,...
• Nails: mees lines, leukonychia, leukostriae, beaus
lines, psoriatic nails...
• Neuro Altered level of consciousness, memory
change, cognitive change, focus change, balance
and sensation change, visual contrast changes,
peripheral exam- small fiber pattern, large fiber
pattern, mixed pattern, balance, rhomberg, tremor,
change in hand writing,...
Pattern
Recognition
Endocrine
Genotoxic
Neurologic
Immune
Metabolic
The Patient’s Story Retold
Physiology and Function: Organizing the Patient’s Clinical Imbalances
Assimilation
Antecedents
Triggering Events
Defense & Repair
Genotoxicity
Structural Integrity
Energy
Immunotoxicity
Endocrine Toxicity
Mediators/Perpetuators
Communication
Spiritual
Biotransformation & Elimination
Mitochondrial
Toxicity
Transport
Metabolic Toxicity
Personalizing Lifestyle Factors
Sleep & Relaxation
Neurodevelopmental
Stress & Resilience
Nutrition & Hydration
Toxicity
Exercise & Movement
Name:____________________________ Date:___________ CC:_____________________________________
Relationships & Networks
© Copyright 2011 Institute for Functional Medicine
Work up of the Toxic Patient?
Pattern Recognition
Toxins from Outside
Toxins from Inside
Toxicants
• Triggers of Imbalance
• Disruptors of Function
Exotoxins
• Heavy Metals
• Persistent Organic Pollutants
• Organochlorine Pesticides
• Polychlorinated Biphenyls
• Mycotoxins
Endotoxins
• Imbalanced Phase 1, 2, or 3
• Products of Metabolism
Journal of Environmental and Public Health
Volume 2012, Article ID 356798
P: Pattern Recognition
Disease and Toxin Associations
ADHD
Allergies
BPA
Lead
Mercury
Phthalates
PCBs
Antimony
BPA
Cadmium
Formaldehyde
Mold
Nickel
Phthalates
Source: IFM Toolkit
Alzheimer’s
Aluminum
Lead
Mercury
Anemia/
Immune
Suppression
Benzene
Cadmium
Lead
PAHs
Autism
AI
Diseases
BP and Kidney
Disease
Mercury
Arsenic
Lead
Mercury
Mold
Arsenic
Lead
Mercury
Cancer
Aluminum
(breast?)
Arsenic
Benzene
BPA
Cadmium
EMFs
Formaldehyde
HAs
Lead
Nickel
Perchloroethylene
Phthalates
Solvents
Vinyl chloride
PVC
Dioxin
Disease and Toxin Associations
CFS,
Diabetes/IR
Fibromyalgia
Arsenic
Benzene
Cd
EMR
FA
Pb
Hg
Mold
Ni
PCE
POPs
PCBs
Solvents
PVC
Dioxin
Arsenic
BPA
EMFs
Pesticides
PCBs
PVC
Dioxin
Vinyl
chloride
Fertility Issues
& Menstrual
Disorders
Arsenic
BPA
Cd
EMF
FA
Pb
Hg
Phthalates
PCBs
PAHs
Solvents
PVC
Dioxin
Multiple
Chemical
Sensitivities
Neurobehavioral
issues
Benzene
FA
Mold
Pesticides
PCBs
Solvents
Vinyl
chloride
PVC
Dioxin
Al
As
EMFs
Pb
Hg
Mold
Phthalate
PCBs
Solvents
FA: Formaldehyde, PVC; Polyvinyl Chloride; Source: IFM Toolkit
Neurodevelopment
issues
Osteoporosis
As
Pb
Hg
PCBs
Solvents
Cd
Pb
Parkinson’s
Peripheral
neuropathy
Mn
Pesticides
As
Pb
Hg
PCBs
mycotoxin
Pesticides
Food
Allergy
and
Reactions
Barbeque: nitrosamines
Gluten
Heavy metal/bacteria
Eggs/Pesticides...
M.Stone,
M.D: .
Food Photos:
Allergens
and Toxins
Images-M Stone, M.D.
Contents/Reactants in Foods
Protein, Carbohydrate, Lectins,
Food-Pollen Homology,
Fruit juice-cellulase…Many,
Preservatives (citric acid), Antibiotics,
Hormones, Enzymes
(lactase, bread-amylase, ), colorings…
Basic
Contents
Additives
Canning, Freezing,
Heating, Salting, Smoking
marinating, microwave
Treatments
Natural Processes
Protectants
Pesticides
Genetic
Engineering
Soy, Coffee, Squash, Tomato
Sugar Beet, Salmon…
Spoilage
Bacterial, Fungal, Toxins, Histamine,
Pathogens, Heavy Metals…
Aging, Insects, Worms,
Fungi (grapes, tomato)
Fermentation (chocolate
tea, malt)
Pesticides, Fungicides,
Antibiotics…
Toxins In...
Sears, M, SJ Genius: J Env Pub Health 2012, ID356798, doi:10.1155/2012/356798
Toxins In...
Sears, M, SJ Genius: J Env Pub Health 2012, ID356798, doi:10.1155/2012/356798
Hg+ Dose Burden
.
Curr Probl Pediatr Adolesc Health Care 2010 September; 40(8):186-215
Copper
+
Decreased liver and plasma Cu, Reduced
plasma ceruloplasmin concentration
Iron
Decreased Hct, Hgb, Binds ferritin and
transferring, Anemia
Zinc
Decreased GI absorption, Disturbed Zn
metabolism, inhibits Zn containing
enzymes, replaces Zn: Metallothionein
Calcium
Osteoporosis, osteomalacia, cadmium
deposition in bones, Hypercalciuria
Cadmium
Mitochondrial injuries, Altered
Antioxidant Defense, Decreased DNA
Repair, Altered Gene expression
Toxic Minerals:
Cd, Pb, Hg, As
Damage antioxidant
defense system
Depletion of thiol Status
ROS
LIPID
PROTEINS
DNA
Lipid Peroxidation
Protein Oxidation
Oxidized Nucleic Acids
Membrane Damage
Protein Dysfunction
Impaired DNA Repair
Cell DEATH
Mechanism of heavy metal induced oxidative stress
Mutagenicity
Carcinogenesis
Dirty Dozen vs. Clean 15
External
Environmental
Exposure
“Outside
Getting In”
Raising Havoc
metabolic, genomic, physiologic,
endocrine, immune (matrix) havoc.
Adverse Reactions>>
Health Effect>>
Disease
Toxicity
Internal
Environmental
Exposure
“Inside
Getting Out”
Work up of the Toxic Patient?
Pattern Recognition
Location of Toxicity altering
Function- looking for imbalance
Enzyme
Inhibition
Toxicant
Exposure
Damaged
Cell
Membranes
Endocrine
disruption
DNA
Damage
Oxidative
Damage
BioMarkers and
Functional Labs
Conventional Laboratory
Functional Laboratory
Conventional Laboratory
Associated markers of Toxicity
• CBC with differential
• Magnesium
– >0.7 mg/L
– <2meq/dL
• Gamma-glutamyltransferase
– (GGT) >40 units/L
• Uric acid
– >8mg/dl
• Homocysteine
– >11 micromol/L
• hsC-reactive protein
– >0.7 mg/L
• Antinuclear antibody titer
– >1:125
• Apo B/Apo A1
– >0.6
• Hemoglobin A1c
– >5.5%
• 25-Hydroxyvitamin D3
– <30 ng/ml
• Urinary microalbumin
– >30 mg in 24 hr
Conventional Lab Tests
To assist in evaluation of the toxic patient
• CBC
– Leukopenia (Benzene, Arsenic, Strotium, hexavalent
chromium, Copper,
– Pancytopenia (Benzene)
– Thrombocytopenia (strontium)
– Anemia
• Chemistry Panel
– Liver Function Tests
•
•
•
•
AST/ALT
ALP/LD
GGT
Bilirubin
– Renal panel, cystatin C
• HbA1C
Liver Enzyme Markers
•
•
•
•
•
ALT: alanine transaminase
AST: aspartate aminotransferase
ALP: alkaline phosphatase
LD: L-lactate dehydrogenase
GGT: γ-glutamyl transpeptidase
Liver Enzyme Markers
Damaged/destroyed hepatocytes leak enzymes into blood.
• ALT aids protein metabolism, almost exclusively found in liver.
• AST metabolizes alanine, found primarily in liver, muscle.
• ALP Nonspecific: Liver bone, intestine, & placenta.
• LD Nonspecific: Liver, RBC, cardiac/skeletal muscle.
• ALT, AST (& LD) rise with liver damage.
• ALP & GGT (& bilirubin) rise when bile flow is slow or blocked.
• ALP Isolated increases are usually from liver damage.
GGT / GGTP
• Readily induced by medications (barbiturates,
phenytoin, NSAIDs), alcohol, obesity, POPs & other
toxic chemicals
• Elevated levels found with liver disease, especially
fatty liver and biliary disease
• May be a marker for increased metabolic,
cardiovascular, CKD risk & all-cause mortality
Prev Cardiol. 2010 Winter;13(1):36-41
• Possible marker for oxidative stress associated with
glutathione metabolism
• Level of concern
– Men: 30-40 IU/L increased suspicion; >50 IU significant
– Women: >37.5 IU/L significant
Is Serum GGT a Biomarker of Xenobiotics, Which Are
Conjugated by Glutathione?
Arterioscler Thromb Vasc Biol, 2008: e26-28
• Lead, cadmium, dioxins, or OC pesticides are positively
and monotonically related to serum GGT in the general
population without any occupational exposure
• Associations between environmental pollutants and
serum ALT (more specific to liver and more commonly
used as a marker of NAFLD) were opposite to those of
serum GGT, suggesting that the associations of serum
GGT may not be related to liver toxicity.
Functional Laboratory
Assessing Toxicity
• Identify triggers
– Toxic metals: hair, blood, urine analysis pre and post DMSA
challenge, occasionally fingernail/toenail clippings, fecal
metals. Byproducts of metabolism- porphyrins
– Organic toxicants (fat biopsy; blood, urine)
– Stool analysis
– Hepatic detoxification and oxidative stress profiles
– Intestinal permeability testing (lactose/mannitol)(Food
Allergy/hypersensitivity)
• Identify mediators- or byproducts
–
–
–
–
Extra and intracellular antioxidant level
Porphyrins
Oxidative stress markers
Essential fatty acid profile
Toxins inducing Porphyrinurias
Environmental Toxin
Urinary Porphyrin Elevation
Arsenic
Uroporphyrins, pentacarboxyporphyrin, coprophyrin1,
High copro I:III ratio
Mercury
Precoproporphyrin, Pentacarboxyporphyrin,
Coproporphyrin (total)
Lead
Aminolevulinic acid (ALA) coproporphyrin III,
Coproporphyrin 1 (sometimes) zinc protoporphyrin
Hexachlorobenzene
Uroporphyrins
Methyl chloride
Coproporphyrins
Dioxin
Uroporphyrins
Polyvinylchloride
Coproporphyrins
Polybrominated biphenyl
Coproporphyrins (uroporphyrins)
Lord Bralley
Glucose Tolerance Test
SI - International Units
75 gm dextrose
Optimal Levels
Fasting insulin 28-35 pmol/L
1/2 hour insulin <215 pmol/L
1 and 2 hour insulin <215
Fasting glucose-4.4-5.0mmol/L
•
•
•
•
•
• 2 hour glucose- 4.4-6.6mmol/L •
•
•
•
•
• HgA1C < 0.055
•
•
•
Diagnostic IR
>85 pmol/L
> 395 insulin
> 350 insulin
> 5.5 = hypergly
>7.0 = DM2
> 11 mmol/L - 2
hour glucose
> 0.06 – HgA1C
JAMA 2007;297:2092-102.
McAuley, K. Diabetes Care. 2001;24:460-464.
Functional Lab Tests
To assist the evaluation of the toxic patient
Nutritional &
Assimilation
Toxic
Damage
Body
Burden
Genetic
Susceptibility
• Dysbiosis/SIBO: overgrowth of
pathogenic microorganisms
• Increased levels of β-glucuronidase
• Markers of GI inflammation
• Intestinal Permeability
Functional Lab Tests
To assist the evaluation of the toxic patient
Nutritional &
Assimilation
Toxic
Damage
Body
Burden
Genetic
Susceptibility
Oxidative stress tests:
•
•
•
•
•
8-Hydroxy-Deoxyguanosine (8-OH-dG)
Thiobarbituric acid reactive substances (TBARS)
Oxygen radical absorbance capacity (ORAC)
Lipid Peroxides
Isoprostanes
Functional Lab Tests
To assist the evaluation of the toxic patient
Nutritional &
Assimilation
Toxic
Damage
Body
Burden
Genetic
Susceptibility
“Biomonitoring” for Body Burdens:
• Measurement of exogenous agents in biological
media (blood, urine, hair, nail, stool, adipose)
• Measurement of markers that indicate presence or
effects of an exogenous agent
Test Evaluation for Environmental Toxins
1 part per million or billion?
• 1 ppm
• 1/1,000,000
• 0.001 mg is
1/1,000,000 of a kg.
• 1 ounce in 31.25 tons
• 1 minute in 1.9 years
• 1 drop vodka in 80
fifths of 7-up
• 1 ppb
• 1/1,000,000,000
• 0.000001 mg is
1/1,000,000,000 of a kg.
• 1 ounce in 31,250 tons
• 1 minute in 19000 years
• 1 drop vodka in 80000
fifths of 7-up
• The power of
small.........................
• The power of really
small.......................
Response to Mold
Immune
Response
?
Endocrinologic
Response
Biotoxin
Response
Mycotoxins
• Aspergillus flavus(aflatoxin)-chronic exposure can
cause liver, and gallbladder cancer, immune
suppression.
• Penicillium citrinin, Aspergillus oryzae, Monascus
ruber (citrinin)-present in wheat, oats, rye, corn,
barley, rice, italian sausages-nephrotoxin.
• Claviceps (ergot alkaloids)
• Fusarium verticillioides(Fumonison B)
esophageal cancer. In corn, grits in the south.
Mycotoxins
• Aspergillus ochraceaus(Ochratoxin) Kidney is the
target. Inhibits mitochondrial ATP production,
stimulates lipid peroxidation. In port, chicken.
• Penicillium patulum(patulin) blue mold on apples,
pears, cherries- found in apple juice. Maximum
intake 0.4mg/kg.
• Fusarium, Stachybotrys (trichothecenes) moldy
straw, hay, wet building material. Leads to
hemorrhages, vomiting, dermititis.
• Fusarium graminearum(zearalenone) increased
estrogen activity. Early menarche, infertility.
Mycotoxemia
Metabolite
Disease
Organisms
Health Concerns
Gliotoxin
Invasive
aspergillosis
Aspergilus,
Trichoderma,
Penicillium,
Candida
Immune toxicity,
suppression,
neurotoxicity
Aspergillic acid,
Carcinogenesis
Aspergillus flavus
Liver cancer,
immune toxicity
Aflatoxins
Carcinogenesis,
reye syndrome,
kwashiorkor,
hepatitis, cirrhosis
Aspergillus,
Penicillium,
Fusarium
Liver pathology
(including cirrhosis)
and cancer,
immune toxicity
Fumigaclavines,
gliotoxin
Aspergillosis
Aspergillus
fumigatus
Lung disease,
neurotoxicity,
tremors, immune
toxicity
Mycotoxemia
Metabolite
Disease
Organisms
Health Concerns
Ochratoxin A
Urinary tract
tumors,
aspergillosis, renal
cell carcinoma
Aspergillus niger,
penicillium,
aspergillus
ochraceus
Nephropathology
including chronic
kidney disease.
Trichothecenes
IgA nephropathy
Trichoderma
Trochothecene
toxicity
Fumonisins
CNS birth defects
Fusarium
merticillioides
(moniliforme
Neural tube defects,
liver pathology,
esophageal cancer.
Satratoxins (FGH),
Stachybotrylactams
Pulmonary Bleeding
Chachybotrys
chartarum
Respiratory
bleeding, Protein
synthesis, inhibition,
neurotoxicity,
cytotoxicity
Elimination
Gut-Lungs-Skin-Kidneys
Deutscher
70
Imbalanced Detoxification
Phase 1
CYP P450
Non-Polar
Xenobiotic
Phase 2
Conjugation
Reactive Intermediate
Inert
Water-Soluble
Metabolite
Damage to DNA, RNA, Proteins
Reactive Oxygen Species
Glucuronidation
Works with Sulfation, acetaminophen, low activity
liver, high activity gut microflora, Gilbert. Increased
colon cancer, modify heterocyclic amines
Sulfation
Alzheimers, Parkinsons, motor neuron disease, RA,
delayed food sensitivity , Multiple Chemical
Sensitivities, Diet responsive Autism
Acetylation
(NAT) Carcinogens from cigarette smoke, barbeque
associated with breast cancers in smokers
Quinone Reductase
Auto exhaust, cigarette smoke, burned organic
materials. Inhibited by benzopyrene, quercetin,
resveratrol. Associated with Parkinsons. Key Benzene
Epoxide Hydrolases
Oxidative defense, Polycyclic aromatic hydrocarbons,
benzopyrene. Low activity decrease lung cancer,
involved in BP regulation, inflammation, CA
N-,O-, S-Methylation
Methylate sulfur>methionine, homocysteine.
Methylation of DNA nucleotides. Inadequate
methylation>Breast CA, Alzheimers, Parkinsons, CAD
Amino Acid Conjugation
Xenobiotic acyl CoA thioester. Heavy alcohol
consumption, intestinal toxicity, toxemia of Pregnancy
have inadequate amino acid conjugation
Glutathione Conjugation
Absence> lung & breast. Kidney, bladder, colorectal
CA. Low levels. Upregulation protects against diesel
exhaust. Low in HIV, ETOH, Cd,MDG. Parkinsons
Functional Lab Tests
To assist the evaluation of the toxic patient
Nutritional &
Assimilation
Toxic
Damage
Body
Burden
Genetic
Susceptibility
1. Nutritional & Assimilation Tests
2. Toxic Damage Assays
3. Body Burden Tests (Biomonitoring)
4. Genetic Susceptibility (SNP Tests)
“Sorry Doc...I drank last night I have a headache- but a
Triple Espresso, 2 Tylenol and an Aspirin...poof! works everytime!”
Caffeine
ASA
Phase 1 Oxidation
Caffeine
Clearance
Demethylated
Products
Acetaminophen
Salicylic acid
P450s
Catechol
23 Dihydroxybenzoate
Toxic Metabolite
Tissue Damage (NAPQI)
Phase II Conjugation
Glutathione
Conjugation
Mercapturate
Sulfation
Acetaminophen
Sulfate
Glucuronidation
Acetaminophen
glucuronide
Glycine
Conjugation
2 hydroxyhippurate
Acetaminophen with Alcohol Phase 1 and 2
Mismatch
Phase I
[cytochrome P450
enzymes]
Lipid-soluble
molecule
Phase II
[conjugation
pathways]
Activated
Intermediates
GSH
excretory
derivatives
riboflavin
(vitamin B2)
polar
CYP2E1
( water-soluble
)
ATP
niacin (vitamin B3)
glutathione
pyridoxine (vitamin B6)
glycine
Serum
folic acid, vitamin B12
taurine
1) Alcohol
CYP2E1
Vitamin C,induces
glutathione,
CoQ10
glutamine
Kidneys
alpha lipoic acid
2) Increased
Acetaminophen breakdown
ornithine and
branched-chain amino acids
arginine
Urine
production of Reactive metabolite
NAPQI
flavonoids
methyl donors
phospholipids
Bile
N-acetylcysteine
(N-acetyl-p-benzoquinoneimine)
pantothenic acid
cysteine
3)This
is
TOXIC
and
requires
Glutathione
(GSH) in
Iron Selenium, Copper, Zn, Mn
methionine
Feces/stools
the Phase 2 pathway to Clear.
4) Alcohol consumers have lower GSH levels
(PHASE III)
Genomic Testing
Methylation SNPS
• Detoxification SNPS
Genetics
Epigenetics (Lifestyle)
Phenotype
Metabolomics
Work up of the Toxic Patient?
Pattern Recognition
Total Toxic Load
(Body Burden)
Over extended periods of time,
small daily doses of multiple
contaminants have cumulative
detrimental effects on physiologic
pathways that can eventually impair
health and cause disease.
Toxicant-Induced Loss of
Tolerance (TILT)
NA Ashford, Chemical Exposures: Low Levels and High Stakes, 1998
• Loss of tolerance following acute or chronic
exposures to pesticides or carpet vapors
• Manifests as triggering of symptoms involving
multiple organ systems by minute quantities of
formerly tolerated chemical substances
P: Pattern Recognition
Gathering and Organizing History
Agent Orange
DM, CRF
Age
Birth
22
45
ap photo/viktor pobedinsky/efrem Lukatsky
March 28, 2002
Dec 6 2004
Dioxin Poisoning
Endocrine Toxicity
Tetrachlorodibeno-p-dioxin
How Long-time
How Much- dose
How Often- frequency
Individual variables:
Birth
age, body mass
physical condition
Smoker, drug/alcohol
Chloracne
21 months
Age
Dioxin 2,3,7,8-tetrachlorodibenop-dioxin (TCDD) on Physical Exam
• Erythema or edema face
• Non infllamatory comedones straw colored cysts in a few days,
occasional pustules, non infectious abscesses
• Face neck, then trunk extremities, genitalia
• Comedones face and neck especially below the outer side of the
eye (malr crescent), postauricular triangles.
• Cysts: neck, shoulders, chest-back, penis, scrotum, axilla. Nose
perioral skin and supraorbital regions usually spared.
• Other skin lesions: xerosis, pigmentation, porphyrinopathy,
hirsutism, skin thickening palmoplantar hydrosis, palmoplantar
hyperkeratosis.
• Symptoms: fatigue, anorexia, neuropathy, impotence, liver
dysfunction, hyperlipemia, anemia, arthritis, thyromegaly onset 2-4
weeks, last 2-3 to 15-30 years.
• Chilren (<8 years) with light hair color more susceptible to
chloracnegens.
SGA, Stress
Maternal Exposures>
Fetal Exposures
DM, CVD
HTn, Obesity
Signs, Symptoms or Diseases Reported
over time until a TILT to Diagnosis
Antecedents
Parenthood
Pregnancy
Job/Economic
Stress
Preconception
>First Month
12-18 months
10-18 yrs
B Vitamin
Tanner Changes
Stores
Androgenation
Triggers
or Triggering Events
decrease
18-30
6-7 years
Social
EFA change
Habits
•Foods
•Stress
Birth
Prenatal
Preconception
Pregnancy
Cognitive changes
Latency diseases
•Microbes
30-50s Glucose
•Toxins
Intolerance
•Allergens
Current
Concerns
Latency Diseases...
Or Seasons of Vulnerability
Signs, Symptoms or Diseases Reported
http://www.panna.org/publication/generation-in-jeopardy
Age
Birth
Further considerations for this physical exam finding…
Significant associations between low intakes of various
nutrients (retinol, calcium, fiber, folate, iron, riboflavin,
thiamin, vitamins A, C, and E) and keratotic skin lesion
incidence in people exposed to environmental arsenic.
Greater intakes of methionine, Cysteine, protein and
vitamins such as thiamin and niacin increased arsenic
secretion.
Mekonian S et al: J Nutr 142:2126-2134,2012
Metabolic Toxicity
Genotoxicity
Stevens Johnsons
.
Photos: M.Stone,M.D
Immunotoxicity
The Patient’s Story Retold
Physiology and Function: Organizing the Patient’s Clinical Imbalances
Assimilation
Antecedents
Triggering Events
Defense & Repair
Genotoxicity
Structural Integrity
Energy
Immunotoxicity
Endocrine Toxicity
Mediators/Perpetuators
Communication
Spiritual
Biotransformation & Elimination
Mitochondrial
Toxicity
Transport
Metabolic Toxicity
Personalizing Lifestyle Factors
Sleep & Relaxation
Neurodevelopmental
Stress & Resilience
Nutrition & Hydration
Toxicity
Exercise & Movement
Name:____________________________ Date:___________ CC:_____________________________________
Relationships & Networks
© Copyright 2011 Institute for Functional Medicine
Work up of the Toxic Patient?
Identification, Evaluation, Treatment
“Cannot Detox The Burden”
Overtly Undernourished
Functionally Undernourished
Quality
Diet, Food, Nutrient
Context
Company
History-Timeline
Network Influences
Symptoms, Other Signs
Current Biochemical Markers
Quantity
Diet, Food, Nutrient
The ABCDs of Functional
Nutrition Evaluation
(Identifying Detox Related Nutrition Concerns)
Functional Nutrition Evaluation
(ABCD)
1) Anthropometrics: weight, change, height, Waist,Hip
circumference, routine vitals, bioelectric impedance
analysis,
2) Biochemical Indicators-Labs; conventional and
functional.
3) Clinical Indicators: Physical exam Hair to toenails.
Functional testing: smell, peak expiratory flow rate,
oxygen saturation, visual contrast testing.
4) Diet, Nutrition, and Lifestyle evaluation: includes
exercise, food, timing of eating, supplement intake,
medication intake, sleep,
Assessing Body Composition
Dx:OverVAT or OverSAT
Dx: Overweight
Abnormal
High BMI?
NO
YES
>25 Overwt
>30 Obese NO
Increased
WC or WHR?
YES
NO
YES
YES
YES
Increased
BIA Fat%?
YES
Increased
BIA Fat%?
NO
NO
YES
Increased
WHR?
NO
Increased
WHR?
Increased
BIA Fat%?
NO
YES
Increased
WC?
Dx: OverFAT
Android Obesity
(OverVAT)
NO
Metabolically Gynoid Possible High
Increased
Obese
Obesity/ Muscle Mass
BIA Fat%?
or Large
(OverVAT)
overSAT
Skeletal Frame
YES
MetSyn?
YES
Ideal Skinny Fat or Possible High Gynoid
Metabolically Muscle Mass Obesity/
Obese
or Athlete overSAT
Gut/Detox/HPATGG
dysfunctions?
TLC
Nx/ Rx
Assessing Body Composition
Dx:OverVAT or OverSAT
Dx: Overweight
YES
Abnormal
High BMI?
YES
Increased
WC?
>25 Overwt
NO
>30 Obese NO
Immunotoxicity
Increased
WC or WHR?
YES
NO
Increased
BIA Fat%?
YES
YES
Endocrine Toxicity
Android Obesity
(OverVAT)
NO
Metabolically Gynoid Possible High
Increased
Obese
Obesity/ Muscle Mass
BIA Fat%?
or Large
(OverVAT)
overSAT
Skeletal Frame
Mitochondrial Toxicity
NO
YES
NO
Genotoxicity
Increased
BIA Fat%?
YES
NO
Increased
WHR?
Increased
BIA Fat%?
YES
Increased
WHR?
Metabolic Toxicity
NO
Dx: OverFAT
YES
MetSyn?
YES
Ideal Skinny Fat or Possible High Gynoid
Metabolically Muscle Mass Obesity/
Obese
or Athlete overSAT
Gut/Detox/HPATGG
dysfunctions?
TLC
Nx/ Rx
Anthropometrics
Biomarkers and Functional Labs
(PFC-MVP)
Clinical Indicators from
Nutrition Physical Exam
Diet and Lifestyle Assessment
P
F
C M V
P
R
A
A
R
I
I
H
Y
O
T
E
I
T
B
O
H
Y
D
R
N
E
R
A
T
A
M
I
T
O
N
U
T
R
I
A
T
E
L
S
N
S
EN
TS
N
&
O
I
L
S
Anthropometrics
Biomarkers and Functional Labs
(PFC-MVP)
Clinical Indicators from
Nutrition Physical Exam
Diet and Lifestyle Assessment
Core Aspects of
the Nutrition Physical Exam
1) Vitals and Body Composition
2) Evaluate Smell and taste
3) Look in the Mouth
4) Look at and feel the Skin
5) Look at the Nails
6) Evaluate Peripheral Sensation
Clinical Indicators
Using a nutrition-focused physical exam
gingivitis
koilonychia
Keratosis pilaris
geographic
Nutritional Assessment by
Nutrient and Location
Tongue
• Geographic tongue: Folate, Vitamin B12, Zinc, Genetic
• Sore, reddened tongue: Niacin, folate, vitamins B12 and B6,
biotin, riboflavin
• Filiform papillary atrophy: Niacin, iron, folate, vitamin B12,
riboflavin
• Glossitis: Riboflavin, folic acid, pyridoxine, niacin, vitamin B12,
iron
• Hypogeusia (diminished taste acuity): Zinc
• Teeth indentations on tongue: Food allergy(ies)
• Tongue fissuring: Niacin
• Halitosis: Niacin
Hands/Fingers/Fingernail
s
• Cracks and splitting of skin on fingertips: Zinc, Essential fatty
acids
• Slightly swollen, painful PIP joints: Glucosamine sulfate and
chondroitin
– Niacinamide, "Nightshade" vegetable allergies
• Painful, swollen MCP joints, as well as wrists and other joints:
(rheumatoid arthritis) Food allergy(ies), Niacinamide,
Eicosatetraenoic acids,
• Tender lumps on finger end joints: Niacinamide, vitamin B6
• Fingernails that are weak, thin, bend easily, frequently crack
and chip: Underfunctioning stomach (low acid, low pepsin),
Essential fatty acids, Calcium, Zinc
• Transverse depigmentation: Protein
Hands/Fingers/Fingernails
• White pitting, Spots (leukonychia): Zinc
• Psoriatic nails: Vitamin D
• Fingernails that are ridging, brittle, easily broken,
flattened, spoon-shaped, thin, lusterless, Beau's
lines, Meuhreke's lines: Iron, copper, zinc,
protein
• Onycholysis: Iron, niacin
• Chronic paronychia: Zinc
• Splinter hemorrhages: Vitamin C
• Pale nail beds: Iron
Zinc
• Look at clinical signs - dermatitis, hair
loss, frequent infection, glossitis and
nail dystrophy.
•
•
•
•
•
•
Lab clues:
Low alk. Phosphatase
Low RBC / WBC Zn
High copper
Low vitamin A / beta carotene ratio.
Plasma zinc responds to
supplementation.
Laboratory Tests and Diag Procedures 5th edition, 2008
Journal of Nutrition. 2000;130:1350S-1354S
Prasad AS, et al. Am J Clin Nutr. 2007 Mar;85(3):837-44
Leukonychia ??
Magnesium
• Neurological: sleep disturbances, over-sensitivity to
light and noise, autism, ADD, ADHD, depression,
anxiety, confusion, disorientation, tingling, numbness,
seizures, migraine
• Cardiovascular: mitral valve prolapse, hypertension,
myocardial infarction, arrhythmias
• Autoimmune: RA, MS, ALS
• Misc. metabolic: Insulin resistance, diabetes,
metabolic syn., PMS, chronic fatigue, renal stones,
asthma, alcoholism
• Musculoskeletal: cramps, fibromyalgia, osteoporosis
• Gastrointestinal: constipation, Crohn’s,
gluten enteropathy, intestinal surgery
Iron Deficiency
•
•
•
•
Reduced physical work capacity
Impaired cognitive function
Pale tongue, cheeks, and conjunctivas
Angular stomatitis, filiform papillary atrophy,
glossitis, temperature control issues
• Fingernails that are ridging, brittle, easily
broken, flattened, spoon-shaped,
shaped, thin,
lusterless, pale nail beds
• Microcytic anemia
• Plummer Vinson syndrome
– esophageal constriction, weakness
Vinik AL: Diabetic Neuropathy in Older Adults. Clin Geriatr Med 24(3)407-v, doi:10.1016/j.cger.2008.03.011, 2008.
Nutrition and Neuropathy
Nutrient
Neurologic Symptoms
Thiamin
Beriberi (dry, wet, infantile, gastrointestinal, bariatric), Wernicke
encephalopathy or Korsakoff syndrome, encephalopathy,
sensorimotor distal axonal peripheral neuropathy, calf cramping,
muscle tenderness, burning feet, irritability.
Niacin
Peripheral neuropathy, encephalopathy
Pyridoxine
Peripheral neuropathy, pure sensory neuropathy in toxicity
Folate
Similar to cobalamin deficiency, peripheral neuropathy
Cobalamin
Myelopathy, peripheral neuropathy, neuropsychiatric, optic
neuropathy, autonomic dysfunction
Vitamin D
Cutaneous hyperalgesia, bone pain of osteomalacia
Vitamin E
Spinocerebellar syndrome, peripheral neuropathy,
opthalmoplegia
Copper
Myelopathy/myeloneuropathy
Protein
Muscle wasting, weakness, hypotonia, hyporeflexia
Kumar, N: Neurologic Presentations of Nutritional Deficiencies. Neurol Clin 28:107-170. 2010.
Nutrition and Neuropathy
Nutrient
Lab
Treatment
Thiamin
Serum Thiamin, RBC transketolase, RBC thiamin
diphosphate, Urinary Thiamin
Thiamin IV, IM, Oral
Niacin
Urinary excretion of methylated niacin
metabolites
Nicotinic acid oral, IM
Pyridoxine
Plasma pyridoxal phosphate, P5P
Pyridoxine oral (P5P over
Pyridoxine HCL if using higher
doses)
Folate
Serum, RBC Folate, Plasma Hcy,…SNP- MTHFR,
Urine Formiminoglutamic Acid
Methyl folate, folate
Cobalamin
Serum Cbl, MMA, plasma Hcy, CBC, MCV…
IM B12, Methyl cobalamin,
Hydroxy cobalamin
Vitamin D
25 OH vitamin D, 1,25 DHCC, PTH, Ionized Ca
Appropriate Vitamin D dosing
Vitamin E
Serum Vitamin E ratio (a-tocopherol to sum
serum cholesterol+TG)
Vitamin E oral or IM
Copper
Serum, RBC, Urinary Copper, serum
ceruloplasmin, CBC (anemia, neutropenia,
vacuolated myeloid precursors)
Oral elemental copper
Glucose
Fasting, 2 hour GTT, Insulin, Hgb A1C,
triglycerides
Low Glycemic Index, Movement,
Multifactorial
Kumar, N: Neurologic Presentations of Nutritional Deficiencies. Neurol Clin 28:107-170. 2010.
Mitochondrial Toxicity
Figure 8.9 Functional Medicine Clinical Nutrition Textbook
Anthropometrics
Biomarkers and Functional Labs
(PFC-MVP)
Clinical Indicators from
Nutrition Physical Exam
Diet and Lifestyle Assessment
Diet, Nutrition, and Lifestyle Journal
1- Diet and Nutrition...
Eat Not too much, mainly plants...
2- Lifestyle...
Does it Stack Vulnerabilities
by Increasing Toxicant Exposure?
3-Is there a Quality to Quantity Mismatch?
Macronutrients
Micronutrients &
Phytonutrients
Immunotoxicity
Genotoxicity
Mitochondrial Toxicity
Endocrine Toxicity
Metabolic Toxicity
Neurodevelopmental
Toxicity
Complete Workup of the Toxic
Patient
• Who: symptoms,
diseases use
questionnaires to help
• What: Exotoxins/
endotoxins-labs as
needed
• Where: What part of the
system is affected.
Physical exam and
Laboratory
• When: Timeline to help
pinpoint exposure or
ongoing issues with
clearance
• Why: ABCD of Nutrition
Evaluation The power
of identifying basic
insufficiencies and
excesses
• Now Proceed to
Treatment
Restoration of Health in the
Toxic Patient depends on• Pattern Recognition
• Undernutrition-Correcting mismatch of
nutrition requirements
• Reduce Exposure
• Ensure safe detoxification
Functional Nutrition
Fundamentals & PFC-MVP
Nutrition Assessments
Gather
Organize
Re-Tell
Order/Prioritize
Initiate
PFC-MVP
Assessments
Thank you for the Opportunity to Participate in this Great Event
Thank you to Institute for Functional Medicine for their contributions.
I want to acknowledge the IFM Detox Team: Kristi Hughes, N.D
Bob Rountree, MD Deanna Minich PhD, Rick Mayfield DC,
Our Clinic Staff at at Stone Medical. mstone@ashlandmd.com