clinical assessments of detoxification - functional medicine · sources and potential health...

Functional Medicine University’s Functional Diagnostic Medicine

Training Program

Module 6 * FMDT 553A

Clinical Assessments of Detoxification

By Wayne L. Sodano, D.C., D.A.B.C.I., & Ron Grisanti, D.C., D.A.B.C.O., M.S. http://www.FunctionalMedicineUniversity.com

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Module 6: FDMT 553A: Clinical Assessments of Detoxification Copyright © 2010 Functional Medicine University, All Rights Reserved

http://www.functionalmedicineuniversity.com/

Functional Medicine University’s

Functional Diagnostic Medicine Training Program

Module 6: FDMT 553A: Clinical Assessments of Detoxification

By Wayne L. Sodano, D.C., D.A.B.C.I., & Ron Grisanti, D.C., D.A.B.C.O., M.S.

http://www.FunctionalMedicineUniversity.com

1

Contents

Toxic Load 2

Patient History 2

Areas of Assessment 3

Sources and Potential Health Effects (PHE) of Major Indoor Air Pollutants 3

Patient Evaluation Forms 5

Assessment of Potential Toxicant from Standard Serum Chemistry 6

Products of Intestinal Bacterial Activity 7

Testing for Hepatic Detoxification Capacity 8

Phase I Testing by Caffeine Clearance 11

Phase II Testing by Acetaminophen Challenge 12

Phase II Testing by Salicylic Acid Challenge 13

Toxic Effects Profiles 14

Summary 20

References 20






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Toxic Load

Toxic load is the summation of body burden in terms of the amount of toxins (exogenous + endogenous) that the body has

to process. Toxins can come from infections, medication, psychological factors, foods, water and air pollutants,

electromagnetic field, ionizing radiation, metabolic by-products and bacterial by-products. Two concepts to keep in mind

during patient evaluation for toxicological impairment are:

Reducing the toxic load

Restoring optimal nutritional status (essential for restoring physiological balance)

The ultimate goal of the detoxification assessment is to:

Identify toxic sources [and removing the source(s)]

Assess nutritional status (The detoxification process is energy dependent and , therefore optimal nutritional status

is paramount to prevent toxic buildup in the body)

Assess the gastrointestinal system (Almost all of the liver Phase I and Phase II reactions occur in the intestinal

mucosa. Intestinal bacteria also participate in biotransformation. The detoxification process has been said to start

in the GI tract.)

Adequate rest (Essential elements of detoxification include proper rest and stress management.)

Daily detoxification habits (Most toxins are unavoidable. Specific supplement and specific foods should be

ingested on a daily basis to prevent specific or broad spectrum toxic buildup.)

Patient History

A detail history is vital when assessing the patient for toxicological impairment. (Use FMU’s Patient History Form)

The classic presentations of toxicity include:

Fatigue

Depression

Chemical sensitivity

Autoimmune disease

Allergy

Asthma

Infertility

Headaches

Diabetes

Obesity

Hormonal imbalances

(Be aware that patients who are unresponsive to treatment may have toxicity as the root cause)






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Areas of Assessment

Air Quality Index – The AQI is provided by U.S. government. It tells you how clean or polluted the outdoor air is,

and what associated health effects are of concern. The AQI evaluates for ground-level ozone, particulate matter,

carbon monoxide, sulfur dioxide, and nitrogen dioxide. Just go to www.airnow.gov and type in the appropriate zip

code.

Pollution report in your patient’s community: go to www.scorecard.org enter zip code – It’s a good idea to

investigate the surrounding areas as well

Occupation – workplace toxicities

Current medications, supplements and herbs

Diet history – organic, non-organic, farm raised food, etc.

Dental history – root canals (source of chronic infection; sinusitis – amalgams, missing teeth)

Lifestyle –exercise, stress level, alcohol intake, smoking

Past History: occupations, hobbies, injuries, etc.

Developmental History – It’s important to obtain a history about the mother’s pregnancy. Toxic exposure to the

mother is likely to enter the developing fetus. Toxics can also be taken in via breastfeeding.

Home Toxicity Assessment

- Pet dander

- Hobbies (ask about patient’s hobbies, as well as the hobbies of other household members)

- Cigarette smoke/secondhand smoke/third-hand smoke

- Mold

- Dust – dust mites on pillows, blankets, carpets, furniture

- Water quality – toxic metals and chemicals

- Volatile organic compounds (VOCs) – paints, resins, and other chemical products

Sources and Potential Health Effects (PHE) of Major Indoor Air Pollutants1

(Indoor air quality is usually more toxic than outdoor air quality)

Asbestos - Building materials in older homes disturbed during renovation. Naturally occurring in some soils.

o PHE -Lung cancer, asbestosis, mesothelioma

Biological Agents (bacteria, fungi, viruses, house dust mites, animal dander, cockroaches, microbial VOCs)

o House & floor dust; bedding; poorly maintained air-conditioners, humidifiers, dehumidifiers; moist

structures; insect infestation; building occupants; pets

o PHE -Allergic reactions; asthma; eye, nose, and throat irritation; humidifier fever, influenza, other

infectious diseases

http://www.airnow.gov/

http://www.scorecard.org/






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Carbon Monoxide - Unvented/malfunctioning gas & propane appliances, woodstoves, fireplaces, tobacco smoke,

vehicles in garages

o PHE - Headache; nausea; angina; impaired vision and mental functioning; fatal at high concentrations

Endocrine Disruptors (PBDEs, some phthalates, some pesticides)

o Flame retardants, plastics, pesticides

o PHE - Mimic or block natural effects of hormones (estrogen and others); developmental abnormalities

Environmental Tobacco Smoke (ETS) Cigarettes, cigars, and pipes

o PHE - Respiratory irritation, bronchitis and pneumonia in children; asthma in preschool children; lung

cancer; heart disease; aggravated asthma; decreased lung function

Formaldehyde, Other Aldehydes - Composite wood products such as plywood and particleboard, furnishings,

wallpaper, durable press fabrics, paints, combustion appliances, tobacco smoke

o PHE - Cancer; eye, nose, and throat irritation; headache; allergic reactions; aggravated asthma, decreased

lung function

Lead - Lead paint chips, contaminated soil

o PHE - Learning impairment

Nitrogen Dioxide - Unvented or malfunctioning gas appliances, other combustion appliances

o PHE - Aggravated asthma; decreased lung function; eye, nose, and throat irritation; increased respiratory

disease in children

Organic Chemicals (benzene, chloroform, paradichlorobenzene, methylene chloride, perchloroethylene, others)

o Solvents, glues, cleaning agents, pesticides, building materials, paints, treated water; moth repellents, dry-

cleaned clothing, air fresheners

o PHE - Cancer; eye, nose, throat irritation; aggravated asthma; decreased lung function; at high levels: loss

of coordination, damage to liver, kidney, brain






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Ozone - Infiltration of outdoor air, some air “purifiers”, office machines

o PHE - Lung inflammation, aggravated asthma, cough, wheeze, chest pain

Particulate Matter - Cigarettes, wood stoves, fireplaces, cooking, candles, aerosol sprays, house dust

o PHE - Increased mortality and hospital admissions; lung cancer; irritation; susceptibility to sinus and

respiratory infections; bronchitis; aggravated asthma; decreased lung function

Pesticides - Insecticides, herbicides, sanitizers, disinfectants used indoors, or tracked in or blown in from outdoors

o PHE - Neurological impairment; nausea, headache, dizziness; skin and eye irritation; hormone disruption

Polycyclic Aromatic Hydrocarbons (PAH) - Cigarette smoke, cooking, wood burning

o PHE - Cancer, gene mutation

Radon - Uranium-bearing soil under buildings, ground-water, construction materials

o PHE - Lung cancer (especially in smokers)

Patient Evaluation Forms

[Two patient questionnaire forms can be downloaded with this lesson.]

Environmental Influences Questionnaire (EIQ) – This form will provide you with a broad view of your patient’s

toxic exposure, and therefore, Total Toxic Load. Toxic exposure(s) must be identified in order to effectively treat

the patient. Just removing the toxic exposure(s) may be the only treatment required for some patients.

Detoxification Questionnaire – This form provides an overview of the Review of Systems (ROS) as it related to

body toxicity. This form can also be used for patient progress. The treatment for toxins can (and usually does)

extend over several months. Most patients will not realize the improvement they have achieved early on in the

treatment. Having the patient complete this form on a regular basis (every 4-6 weeks) will motivate them to stay

with the program as they see their score dropping.

The scoring key for the detoxification questionnaire is as follows:

- A score of less than or equal to 15 Excellent

- A score of 16 – 30 Good

- A score of 31 – 40 Marginal

- A score greater than or equal to 51 Very Poor






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Assessment of Potential Toxicant from Standard Serum Chemistry

Blood Urea Nitrogen – BUN is the normal detoxified form of ammonia. Nitrogen enters the body as dietary free amino

acids, protein, and the ammonia produced by intestinal bacteria. Aminotransaminases [e.g. ALT and AST- you should

recall that the prosthetic group of transaminase is pyridoxal phosphate, a derivative of B6 and that low liver enzymes are

a sign of B6 deficiency] equilibrate amino groups permitting the synthesis of non-essential amino acids. These reactions

help maintain the balance of amino acids as proteins of varied amino acids contents are synthesized. One of the end

products of amino acid catabolism is ammonia. The hepatic enzymes make it possible to control ammonia incorporation

into either urea or glutamine, the latter leads to excretion of ammonia by the kidney. About 80% of the excreted nitrogen

is in the form of urea which is mainly produced in the liver through a series of reactions collectively known as the Urea

Cycle.

Reprinted with permission: Laboratory Evaluations for Integrative and Functional Medicine, 2nd ed., Richard S. Lord, J. Alexander Bralley,

Metametrix Institute, Duluth, GA






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BUN is an indirect and rough measurement of renal function and glomerular filtration rate (if normal liver function

exists). It is also used to measure liver function. BUN reflects the difference between production and clearance of urea.

Increased Bun may be due to increased production or decreased excretion of urea. Increase in BUN is seen in chronic

renal disease, UTI’s, renal hypertension, BPH, dehydration, medication (diuretics, anti-inflammatory, etc), and

obstruction of urinary flow. Decreased BUN is seen in reduced liver function (esp. liver failure, malnutrition,

malabsorption (e.g. Celiac disease), and Nephrotic syndrome (due to loss of protein in the urine)

From a functional medicine perspective, an elevated BUN is a sign of increased ammonia loading and conversion by the

urea cycle. An elevated BUN is expected to be found in patients where urinary orotate is elevated. When there is

insufficient capacity for detoxifying ammonia via the urea cycle orotic acid (orotate) is synthesized. (This reaction is

explained in the lesson on Organic Acid Testing)

Products of Intestinal Bacterial Activity

Many other nitrogenous compounds are found in the intestine, most of which are bacterial products of protein

degradation. Some of these have powerful pharmacological effects.

Substrate Vasopressor Amines Other

Lysine Cadaverine

Arginine Agmatine

Tyrosine Tyramine

Ornithine Putresine

Histadine Histamine

Tryptophan Indole and skatole

All amino acids NH4+

The vasopressor effects can magnify migraines and hypertension. As always, evaluation and treatment of bowel dysbiosis

is paramount in the treatment of all chronic disease of which detoxification treatment toxicity is no exception.

[Ammonia is neurotoxic. Marked brain damage is seen in cases of failure to make urea via the urea cycle or to eliminate

urea through the kidneys. The result of either of these events is a buildup of circulating levels of ammonium ion. Aside

from its effect on blood pH, ammonia readily traverses the brain blood barrier and in the brain is converted to glutamate

via glutamate dehydrogenase, depleting the brain of α-ketoglutarate. As the α-ketoglutatrate is depleted, oxaloacetate

falls correspondingly, and ultimately Krebs cycle activity comes to a halt. In the absence of aerobic oxidative

phosphorylation and Krebs cycle activity, irreparable cell damage and neural cell death ensue

In addition, the increased glutamate leads to glutamine formation. This depletes glutamate stores which are needed in

neural tissue since glutamate is both a neurotransmitter and a precursor for the synthesis of gamma-aminobutyric acid

(GABA). Therefore, reductions in brain glutamate affect energy production as well as neurotransmission.2]






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Bilirubin – Bilirubin is used to evaluate liver function and is part of the evaluation of adults with hemolytic anemia and

newborns with jaundice. Bilirubin can also be elevated due to impaired glucuronidation (Phase II detoxification) as seen

in Gilbert’s syndrome. Patients with Gilbert’s syndrome will have elevated indirect (unconjugated) bilirubin. A patient

with even mildly elevated serum bilirubin is immediately among those where therapeutic drug monitoring is important

because of the likelihood that drug half-lives are significantly extended. Rising bilirubin levels in patients without

Gilbert’s syndrome can signal liver disease.3

Creatinine - Creatinine, measured concurrently in serum and urine can be used to calculate creatinine clearance for

assessment of kidney damage. Increased serum creatinine can indicate kidney damage due to autoimmune diseases,

congestive heart failure, atherosclerosis or complications of diabetes. Any loss of kidney function is a major consideration

for before beginning a detoxification protocol.3

Testing for Hepatic Detoxification Capacity

As outline in a prior lesson, the detoxification process involves two phases that normal functions in a serial fashion. Phase

I involves the cytochrome P450 enzymes and Phase II involves the enzymes of conjugation. Efficient clearance of a given

compound may require only Phase I or Phase II type reactions or both.3

The following tables summarize the compounds that are acted upon (the substrates)by the P450 enzymes and conjugation

enzymes, and the and the nutrient involved in the regulation of Phase I, the intermediate phase, and Phase II.






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PHASE I REGULATION

B2, B3, B6, B12, and folate Glutathione (glycine, glutamine, and cysteine) or NAC. Branch chain amino acids

(leucine, isoleucine, and valine)

Selenium

Zinc

Lipoic Acid

Betacarotene

Magnesium

Vitamins C, E, CoEnzyme Q10

Bioflavinoids (Quercetin, green tea catechin, Silymarin, Ginkgo) (Brassica Family)

Naringenin (glycoside found in grapefruit juice) will slow Phase I down in the gut

INTERMEDIATE

Vitamins A, C & E, CoEnzyme Q10, Zinc, Selenium, Magnesium, Manganese

* Up-regulation of Phase I will cause an increase in free radical production and activity. Antioxidants will help prevent

cellular damage caused by free radicals

PHASE II REGULATION

GLUTATHIONE – N-acetylcysteine (precursor to GSH synthesis and enhances glutathione-5-transferase activity);

Selenium, B6, B12, Folate

Carnosol and camosic acid (Rosemary), Curcumin

Indole-3-Carbinol, glutathione

SULPHATION – Sulphur containing amino acids (cyteine, methionine and taurine), Vitamin A, adequate protein,

garlic, and onions, magnesium, molybdenum

GLUCURONIDATION – Calcium d-glucerate, magnesium, Essential Fatty Acids, DIM, Probiotics

GLYCINATION – Glycine, glutamine, gluceronic acid, ornithine, arginine, magnesium

ACETYLATION – Acetyl-CoA, B5, B2, B3

METHYLATION – SAMe, Mg, Folic Acid, B12

Functional medicine testing for hepatic detoxification capacity can be performed ordering a Detoxification Profile Test.

This test shows the activity of the major enzymes systems and can provide clinical insight regarding how patients Phase I

and Phase II systems respond to toxic load. The goal is to evaluate toxic clearance by administering three non-prescriptive

drugs (caffeine, aspirin, and acetaminophen) and assess their clearance capacity.






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Phase I Testing by Caffeine Clearance

Caffeine is detoxified through Phase I cytochome P450 enzymes. After the challenge dose is administered, the clearance

capacity is evaluated by saliva samples taken at intervals of two and eight hours post-ingestion. This test only evaluates

the isoforms of cytochrome P450 that act on the caffeine molecule, therefore, the clearance capacity of other isoforms is

not evaluated.

A high caffeine clearance signifies that the liver is very actively removing caffeine and similar compounds using

this pathway. There is usually an increase in free radical production. The patient should also be evaluated for gut-

derived toxins and intestinal hyperpermeability. Nutritional considerations include increasing antioxidant and

nutritionally supporting the Phase II pathways to prevent buildup of toxic intermediate metabolites.






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A low caffeine clearance can indicate exposure to P450 inhibitors, hypothyroidism, genetic polymorphism and/or

decreased liver function. General treatment considerations include: eliminating any inhibiting substances, correct

any nutrient deficiency (high quality protein, iron, riboflavin, vitamin C, niacin, and magnesium), and provide

nutritional support for Phase II and antioxidants.

Phase II Testing by Acetaminophen Challenge

Acetaminophen is converted to various conjugation products. The pathways utilizing glutathione, glucuronic acid or

sulfate produce mercapturate, glucuronate, or sulfate conjugates, respectively. Acetaminophen is initially oxidized to the

reactive metabolite, N-acetyl-p-benzoquinone imine, which is highly toxic and must be remove by conjugation with

mercapturic acid via glutathione activation.

A low acetaminophen mecapturate (glutathione conjugation) indicates an insufficient glutathione conjugation.

The patient will have difficultly in removing toxins from the body. The possible causes include; depletion of

reduced glutathione (due to excess exposure to xenobiotics and/or free radicals), genetic polymorphisms,

nutritional deficiency, induced Phase I activity and excess bile production. Treatment considerations include;

eliminating the source of toxins, increase glutathione (reduced glutathione, NAC, glycine, glutamine, vitamin C,

methionine), increase cruciferous vegetables, and increase intake of nutrient cofactors (zinc, copper, B2, B3,

selenium, magnesium, B6, B12, folic acid)

A low acetaminophen sulfate indicates insufficient sulfation. These patients will have difficulty with perfumes,

diesel fumes and exhaust fumes. The possible causes include; depletion of sulfate, induced P450 enzymes,

molybdenum deficiency (low uric acid), and genetic polymorphisms. Treatment considerations include; rule out

excessive xenobiotic exposure, and rule out nutrient deficiency (esp. sulfur containing food and supplements).






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A low acetaminophen glucuronide is indicative of an impaired glucuronidation. Glucuronidation is considered an

important detoxification pathway when sulfation and glycination is diminished or in excessive used. Oxidative

stress and Gilbert’s syndrome are also causes of a decrease in glucuronidation. Supplements of consideration

include: glutamine, niacin, B6, magnesium, iron and aspartic acid.

Phase II Testing by Salicylic Acid Challenge

The Phase II detoxification of aspirin includes conjugation with glycine, and glucuronic acid.

This test will be interpreted for the adequacy of glucuronide and glycine conjugation capacity. Low percentage conversion

to salicyluric acid means poor glycine conjugation due to inadequate hepatic glycine or coenzyme A (B5), availability.

Such individuals will have slow clearance of many drugs and natural toxicants. Oral supplementation with glycine and

pantothenic acid can be effectives for increasing rates of glycination.3

Abnormalities in the ratios of Phase I to Phase II can be an early warning sign of carcinogenic or hepatotoxic compound

accumulation.








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[Note: There has been a decrease in the availability of Detoxification Profile Testing. I was recently told by a reliable

source that the test was ordered infrequently and that it was not cost effective to continue to provide this service. An

adequate replacement test is the Organic Acids Test. Another test that is available for evaluating detoxification capacity is

based on genetic testing for single nucleotide polymorphisms of the detoxification enzymes. These SNPs can be

associated with increased risk of impaired detoxification, however due to the numerous enzymes not tested for; the

clinical application of this test can pose an interesting debate.

Toxic Effects Profile

New toxicity testing profiles have recently been offered by Metametrix Laboratory. These include:

Chlorinated pesticides – identifies exposure to chlorinated pesticides, such as DDT. These toxins can cause or

complicate a broad range of illnesses including allergies, asthma, cardiovascular disease and cancer.

Polychlorinated biphenyls (PCBs) – this test measures six common PCBs. The health problems associated with

these toxins include neurobehavioral, endocrine and immunological.

Volatile solvents – these toxins are associated with many illness such as diabetes, fibromyalgia, brain fog, and

mood disorders.






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Summary

Assessing total body toxics is often overlooked by most practitioners. Due to the ubiquitous environmental toxins, and the

fact that every person has some level of stored toxins in their body, evaluation and treatment of toxins is often the missing

link in the unresponsive patient. A comprehensive patient history along with the environmental questionnaire and

detoxification questionnaire are the keys to guide you in the right direction for toxicant evaluation.

References

1. Indoor Air Quality and Personal Exposure Assessment Program, Fact Sheet: Sources and Potential Health Effects of

Indoor Air Pollutants, March 24, 2003, http://arb.ca.gov/research/indoor/healtheffects1table1.htm

2. The Medical Biochemistry Page, Dr. Michael W. King, PhD, http://themedicalbiochemistrypage.org

3. Laboratory Evaluations for Integrative and Functional Medicine, 2nd

ed., Richard S. Lord, J. Alexander Bralley,


http://arb.ca.gov/research/indoor/healtheffects1table1.htm

http://themedicalbiochemistrypage.org/

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