Functional Medicine "Advancing The Medical Health Model"

You've seen body-weight scales at stores, online, in gyms and at the doctor's office that utilize bioimpedance analysis. These scales can be expensive and wondered what is bioimpedance analysis and is it worth the price?

Bioelectrical impedance analysis may sound complicated, however, BIA devices use today's technology. It measures the rate at which low-level electrical current is run through the body. Based on the rate that it travels, algorithms are used to measure fat-free mass, along with other data, such as height, gender, and weight measurements to determine your body fat percentage.

• There are different types of devices, but each device requires two points of contact.
• Handheld devices use two points, which are the hands (called hand-hand BIA).
• Typical BIA scale uses the feet (called foot-foot BIA).
• You place each foot on a pad and the current travels through your body between the feet.
• There are also hand-to-foot BIA devices.

• There are many brands that make different types of BIA scales (also called bioimpedance scales)
• Newer models link with a smartphone app so you can track your progress.

• Prices of a BIA scale depend on the sophistication of the equipment.
• Some scales use multiple frequencies and more advanced algorithms, as well.
• Some provide segmental fat analysis, which means, you can get body fat measurements for each arm, leg, and belly.

• There are reports that segmental fat analysis (utilizing hand-foot BIA) are more accurate because hand-hand devices focus on measuring the upper body.
• Foot-foot scales primarily measure the lower body.

• These devices are considered safe for most people. Except:
• Bioelectrical impedance analysis should not be used by anyone with an electronic medical implant, (e.g. heart pacemaker).
• Not be used by pregnant women.

• Studies have shown that bioelectrical impedance analysis is an accurate method for measuring body fat.
• But these studies generally do not test the scales from the store.
• Experts agree the accuracy of the measurement depends on the quality of the equipment.

Parameters

(R) Resistance

• Resistance and reactance are terms from physics, which are part of the field of materials and the effects on electricity. In reality, resistance and reactance are easy to understand.
• Resistance is the ratio of electrical potential (voltage) to the current in a material. Put simply, a material with high resistance needs a high potential to generate a given amount of current in the material. A material with low resistance requires a low potential to produce the same amount of current in the material.
• The easiest way to remember is:
• Material with low resistance conducts well.
• Material with high resistance conducts poorly.
• When material conducts, it releases energy in the form of heat.
• The resistance of a material is related to the material’s ability to dissipate energy.
• Units of resistance are called ohms.
• In the human body
• Low resistance is associated with large amounts of fat-free mass.
• High resistance is associated with smaller amounts of fat-free mass.

The Case

• Primary conductor in the human body is ionized water.
• As the percentage of body weight that is water increases, the conductivity of the body increases.
• Body water is contained solely in fat-free mass
• Conductivity of body is proportional to amount of fat-free mass.

Resistance is Measured by

• A small current is applied through the body.
• The potential required to generate the current is measured.
• The ratio of potential and current along with a process called correlation and integration are used to determine the resistance and reactance.
  NOTE: This alternating current resistance is not the same resistance that can be measured by a standard store ohmmeter.

(X) Reactance

• Reactance: the effect on an electrical current caused by a material's ability to store energy.
• A time delay between applied electrical potential and current.
• Material that stores energy easily causes high reactance, and causes a large delay in the current.
• Material that stores energy poorly has low reactance and causes a small delay in the current.
• Example: Water poured onto top of a sponge will flow out of the bottom after a delay.
• Large sponge will cause a large delay in the flow of water out the bottom
• Small sponge would cause a small delay.
• Current flows in material the same way.
• The delay flow of current from storage is the reactance.
• Units of reactance are ohms.
• In the human body:
• High reactance: large amounts of body cell mass (intracellular mass).
• Low reactance: small amounts of body cell mass.

The Case

• Cell membranes consist of a layer of nonconductive lipophilic material interposed between two layers of conductive molecules.
• Behave like tiny capacitors and store energy.
• Reactance in the body reflects the strength of capacitance.
• Intact cellular membranes contained primarily within body cell mass
• Reactance of the body is proportional to the amount of body cell mass

Reactance is Measured by

• Small current is applied through the body.
• The potential required to generate the current is measured.
• Ratio of potential and current along with process correlation and integration used to determine the reactance.

(Z) Impedance

• Total impedance (Z): The vector sum of effects of resistance and reactance on a current in the human body.
• Technically, impedance is the ratio of potential (V) to current (I) and is used in bioimpedance analysis.

How R, X, & Z Relate

Mathematical relationship between Resistance (R), Reactance (X), and Impedance (Z) are:
Z = sqrt (X2+R2)
X = Z * sin (α)
R = Z * cos (α)
phase angle = arcsin (X/Z)
phase angle = arctan (X/R)

(α) Phase Angle

• Phase angle is indicator of cellular health and integrity.
• Research has shown the relationship between phase angle and cellular health is increasing and nearly linear.
• Low phase angle: Consistent with inability of cells to store energy and
• Indication of a breakdown in cellular membranes.
• High phase angle: Consistent with large quantities of intact cell membranes and body cell mass.

• Phase angle reflects the ratio of body cell mass to fat-free mass.
• Phase angle is proportional to the ratio of reactance and resistance (proportional body cell mass to fat-free mass.)

Phase Angle Increase

• Increase in body cell mass relative to fat-free mass.
• Increase in fat-free mass relative to body weight.
• Improved hydration of fat-free mass

Phase Angle: Useful For Comparing

• Reactance along with the patient's weight indicates an absolute amount of body cell mass (BCM).
• Reactance is best applied when comparing test results in a single patient at different times.
• Two patients with exact reactance (X) can have different amounts of BCM, depends on patient's weight.
• Any patient with a higher phase angle will always have a higher proportion of BCM than patient with low phase angle.
• Phase angle indicates number of intact cell membranes.
• Phase angle does not include statistical regression analysis effect.
• Phase angle is direct measurement of relative amounts of intact cellular membranes.

Phase Angle Works How?

• A bioimpedance analyzer applies 50-kilohertz alternating current to the body.
• Phase angle is delay in time between the electric potential and current.
• Oscilloscope connected to the body appears as delay between the voltage waveform and current waveform.
• The period of each wave at 50 kilohertz is 20 microseconds. If, for example, the time delay is ten percent of the
• period, then the time delay is 2 microseconds.
• When expressed in units of time, it is said that the phase delay is 2 microseconds.
• Time delay can be seen as percentage of entire wave period in degrees.
• Complete wave period consists of 360 degrees. If time delay is one-tenth the total period of the wave, it is equivalent to 36 degrees.
• When time delay is expressed this way (in degrees of total wave period),
• This is the phase angle.

• When electrical potential and current are depicted sweeping around a circle
• Instead of moving over time
• The relationship between reactance, resistance, and phase angle is easier to see.
• Shown below:
• Range of phase angle in the human body is 1 to 20 degrees.
• Phase angle is the arctangent of (X/R)

Bioimpedance Analysis (BIA) is defined as the analysis of resistance and reactance in the human body.

• Energy dissipation is called resistance (R).
• Energy storage is called reactance (X).
• Units of resistance and reactance are called ohms.
• Resistance and reactance taken together create impedance (Z).

• Fat-free mass in the human body is proportional to its resistance.
• Body cell mass is proportional to its reactance.

• A bioimpedance analyzer is a device that contains a highly precise frequency meter, a processor, and a printer. The meter is called an impedance meter. It measures resistance and reactance.
• The microprocessor computes the size of the fat-free mass and body cell mass along with all subsequent calculations.
• A bioimpedance analyzer measures resistance and reactance, computes fat-free mass, body cell mass, total body water, and intracellular water.
• To measure resistance and reactance, the bioimpedance analyzer generates a small electrical current to the body.

Measurements

• Bioimpedance analysis is an assessment of change in electrical tissue conductivity, which indicates altered body composition.
• The following electrical characteristics are measured and used to evaluate body composition.
• Impedance (Z)
• Impedance is a measurement of a medium to conduct current. It is a ratio of voltage injected current in a conductive medium and has two components: resistance and reactance.
• Resistance (R)
• Resistance is the component of impedance related to the dissipation of energy.
• Reactance (X)
• Reactance is the component of impedance related to the storage of energy.
• Phase Angle (α)
• Phase angle is a time delay between stimulating current and the voltage generated by an alternating current. The phase angle is expressed in degrees.
• Electrical characteristics and their relation to each other?
• The time relationship of voltage, current, and phase is shown below. 

The Circuit

• Water is the body's conductor and determines the resistance.
• Electrolytic fluid in fat-free mass consists of water and charged ions that conduct electrical current.
• Extracellular fluid (water and ionized sodium Na+) provides a low-resistance pathway.
• Intracellular fluid (water and ionized potassium K+) provides a low-resistance pathway.
• Fat mass is non-conductive because there is no water.
• Cell membranes within intracellular mass determine reactance.
• The cell membranes consist of a layer of nonconductive, lipophilic material interposed between two layers of conductive molecules. They are tiny capacitors that store electrical charge.

• Extracellular pathway (which is sodium ionized water) is represented by single resistance.
• Intracellular pathway (potassium ionized water and cell membranes) is represented by resistance and reactance.
• Total resistance is proportional to the amount of fat-free mass.
• Reactance is proportional to body cell mass (intracellular mass).
• The meter reports total resistance and total reactance to the microprocessor.

Equation for Regression

• Bioimpedance analyzers use algorithms to compute amounts of fat-free mass, body cell mass, body water, and intracellular water.
• What is the regression equation?
• This equation is a mathematical formula that predicts the relationship between two or more variables based on the analysis of data.
• For example, total body water regression equation
• (TBW) = form:
• TBW = a * Ht2 / R + b * Weight + c * Age + d
• The terms are Ht2 / R, Weight, and Age.
• The weighting constants are a, b, c, and d.
• Resistance, height, weight, gender, and age are supplied for each subject. A computer then generates an algorithm which best describes the relationship between TBW, resistance, height, weight, gender, and age.
• This is called Regression Analysis.

How do you use regression equations?

• Once the bioimpedance analyzer measures the resistance and reactance, the results are sent to the microprocessor to perform the calculations. All the equations, (FFM, BCM, TBW, and ICW) are encoded into the analyzer's software.

Diagram

• Fat-Free Mass
• Fat-free mass is derived by applying a small alternating current to the body.
• The resistance of the body is measured using the measured resistance (R), the analyzer estimates the fat-free mass.
• Body Cell Mass
• Body cell mass is derived by measuring both the resistance (R) and reactance (X) of the body. With this measurement, the analyzer estimates body cell mass.
• Total Body Water
• Using the measured resistance, the analyzer estimates total body water.
• Intracellular Water
• Using the measured resistance and reactance, the analyzer estimates intracellular water.

Hoy comenzaremos a analizar cómo el espectro que la medicina actualmente considera “normal” puede no ser realmente óptimo para su salud y bienestar general. Estos rangos de referencia pueden cambiar según la edad, el sexo, la actividad física y más. De hecho, si evaluáramos el peso de una persona en los Estados Unidos, se consideraría “normal” tener sobrepeso, simplemente porque el 70 por ciento de la población tiene sobrepeso. Los rangos de referencia para las pruebas de laboratorio de hoy se basan en una población enferma cuando debemos aspirar a un bienestar óptimo.

Luego, les demostraré cómo este conocimiento puede aplicarse a las medidas médicas más básicas: sus signos vitales. Todo el mundo sabe que cuando se visita a un médico por primera vez, toman sus signos vitales, incluyendo su peso, su presión arterial, su frecuencia cardíaca y su temperatura. Sin embargo, ¿su médico le dice lo que significan sus resultados? ¿Cómo puede saber si está sano?

Body composition analysis is becoming a standard tool that is being used by fitness experts, coaches, and healthcare professionals.

In 2019 we can discard reliance on body mass index (BMI) as a means to measure health.

Other than our appearance, there is a list of diseases associated with obesity. This is what's at the top of our minds. The list is long and includes heart disease, hypertension, cancer, joint problems, dementia, and diabetes.

Body composition analysis is defined as the clinical assessment of tissue and fluid in the human body.

• Fat Mass
• Fat-Free Mass
• Body Cell Mass
• Extracellular Mass
• Total Body H2O
• Intracellular H2O
• Extracellular H2O

Normal distribution of tissue and fluid is associated with immunity, high function, and longevity.

However, not being able to have detailed insight into your personal body composition can lead to critical errors in understanding what's going on, along with recommendations. This can hinder the ability to reach a specific fitness goal.

Body composition analysis is utilized in preventative, therapeutic, and research applications.

• Nutrition
• Anti-Aging
• Physical Performance Assessment
• Weight Management
• Geriatrics
• Lifestyles Assessment
• Athletic Performance

To perform body composition analysis, mass and fluid are modeled, measurements taken, and results analyzed.

Bioimpedance (BIA) body composition analyzers measure body composition electronically. However, they do not, diagnose disease, or calculate treatment options. Only qualified health care professionals can diagnose and recommend treatment options.

There are concerns that affect everyone, which is why knowledge of body composition is important for your health in 2019 onward.

Model Body

Look at the images below of six males, all of whom are 5' 9" and 170 pounds. There could be some envy from their 25.4 BMI, as the results are come up on the computer screen. However, looking at the actual patient or their scans using today's technology, the results are pretty revealing.

Notice the difference in the midsection, where there is an abnormal accumulation of visceral fat.

This occurs in metabolic syndrome and what is known as Adiposity disease.

• Fat Mass (FM): Total amount of stored lipids in the body and consists of the following types:
• Subcutaneous Fat is located right under the skin. Subcutaneous fat functions as an energy reserve and as insulation from the cold.
• Visceral Fat is located deeper in the body. This fat serves as an energy reserve and as a cushion between the organs.
• Fat-Free Mass (FFM), aka Lean Body Mass (LBM): Total amount of nonfat (lean) parts of the body.
• Consists of approximately 73% water, 20% protein, 6% mineral, and 1% ash.
• Fat-free mass divides further into body cell mass and extracellular mass:
• Body Cell Mass (BCM): All the metabolically active tissues (cells) of the body, which include muscle, organ, blood, and immune cells.
• BCM includes the "living" portion of fat cells, but not fat lipids.
• BCM also includes H2O inside living cells. This water is called Intracellular Water (ICW). The main electrolyte is potassium.
• Extracellular Mass (ECM): All the metabolically inactive (non-living) parts of the body, such as bone minerals and blood plasma. ECM includes water contained outside living cells. This water is called Extracellular Water (ECW). The main electrolyte is sodium.

Composition & Body Health 

• Body composition correlates directly to maintained proper health, that range from mortality/morbidity to immunity, longevity, high function, and athletic performance.
• Body composition analysis' purpose is to monitor and improve function.
• Healthy patients analysis of fat-free mass and body cell mass helped maintain function, productivity, immunity, physical performance, and longevity.

Every case is different but through body composition analysis, people can have a better understanding of their body, what options are available to them, and most importantly do not have to be on medication/s for the rest of their lives.

References:

• Kyle UG, et al. Physical activity and fat-free and fat mass by bioelectrical impedance in 3853 adults. Medicine and Science in Sports and Exercise, 2001;33:576-584.
• Mattar JA, et al. Application of total body bioimpedance to the critically ill patient. New Horizons, 1995, Vol 4., No. 4; 493-503.
• Ott M, et al. Bioelectrical impedance analysis as a predictor of survival in patients with human immunodeficiency virus infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 1995; 9:20-25.

The InBody770 represents the apex of BIA technology. The InBody770 reports on body composition, and also reports a complete breakdown of body water. There are 6 frequencies, which create a total of 30 impedance values. There is no other machine on the planet that can match the accuracy and dependability of the InBody770.

The InBody 770

Quick Tests

Measure fat mass, muscle mass, and body water levels in under a minute. No dunking, pinching or discomfort. Stand on the device and hold the hand electrodes.

No Predicting

Just impedance is used to determine your body composition; No estimations like age and gender are needed or required to predict your composition.

Cloud Software

Automatically save all of the information from InBody to Lookin'Body Web, InBody's cloud database management system. Easily view and manage customer's results and see progress anytime.

Check Out The InBody 770 Result Sheet

To find out how to use this data in practice? Download free guide here.

Today we will discuss the fundamentals of functional medicine and how you can build a healthy doctor-patient relationship.

If you visit the doctor because you’ve been experiencing migraines, eczema, irritable bowel syndrome and depression, you’re most likely going to be referred to four different specialists and you may even be prescribed four different drugs and/or medications, at minimum. A functional medicine approach understands that there may be common underlying health issues which can be causing a patient’s symptoms. Once you get to the source of the problem, you can fix the health issues that create the symptoms.

Functional medicine asks, “Why do you have those symptoms and how can we treat the source of the problem and improve your overall health and wellness?” rather than, “What disease do you have and what drug do you use to treat it?

Pain Anxiety Depression Everyone has experienced pain, however, there are those with depression, anxiety, or both. Combine this with pain and it can become pretty intense and difficult to treat. People that are suffering from depression, anxiety or both tend to experience severe and long term pain more so than other people.

The way anxiety, depression, and pain overlap each other is seen in chronic and in some disabling pain syndromes, i.e. low back pain, headaches, nerve pain and fibromyalgia. Psychiatric disorders contribute to the pain intensity and also increase the risk of disability.

Depression: A (major depressive disorder or clinical depression) is a common but serious mood disorder. It causes severe symptoms that affect how an individual feels, thinks, and how the handle daily activities, i.e. sleeping, eating and working. To be diagnosed with depression, the symptoms must be present for at least two weeks.

• Persistent sad, anxious, or “empty” mood.
• Feelings of hopelessness, pessimistic.
• Irritability.
• Feelings of guilt, worthlessness, or helplessness.
• Loss of interest or pleasure in activities.
• Decreased energy or fatigue.
• Moving or talking slowly.
• Feeling restless & having trouble sitting still.
• Difficulty concentrating, remembering, or making decisions.
• Difficulty sleeping, early-morning awakening & oversleeping.
• Appetite & weight changes.
• Thoughts of death or suicide & or suicide attempts.
• Aches or pains, headaches, cramps, or digestive problems without a clear physical cause and/or that do not ease with treatment.

Not everyone who is depressed experiences every symptom. Some experience only a few symptoms while others may experience several. Several persistent symptoms in addition to low mood are required for a diagnosis of major depression. The severity and frequency of symptoms along with the duration will vary depending on the individual and their particular illness. Symptoms can also vary depending on the stage of the illness.

PAIN ANXIETY DEPRESSION

Objectives:

• What is the relationship?
• What is the neurophysiology behind it?
• What are the central consequences?

Brain Changes In Pain

Conclusion:

• Pain, especially chronic is associated with depression and anxiety
• The physiological mechanisms leading to anxiety and depression can be multifactorial in nature
• Pain causes changes in brain structure and function
• This change in structure and function can alter the ability for the brain to modulate pain as well as control mood.

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The western diet is associated with inflammation, and inflammation is central to autoimmunity and autoimmune diseases. Keeping the inflammation down can help in lengthening time between attacks. What to eat and what not to eat are the common questions. In order to quiet  inflammation triggers, educate ourselves and live a normal life is the focus.

My 2006 Seminar Series

“Understanding the Origins of Autoimmune Disease”

Autoimmunity:

The Central Question I Asked In This series,

Are We Allergic to Ourselves?

– Autoantibodies

– Are they really “autoantibodies”?

– Self or Non‐self?

I would like to re‐explore this question using what we have learned in 2018.

www.aarda.org

Endocrine

Endocrine Thyroid

Endocrine‐Thyroid

Musculoskeletal

Musculoskeletal & Kidney

Neurological

Autoimmunity

Our Immune system in battle with our self?

Presence of Anti‐Chromatin, DNA and RNA Antibodies

What Biological Processes May Make Self Into Non‐Self?

• Post‐translationalmodificationofProtein
  – Glycation of protein
  – Protein Oxidation
  – Amino Acid Conjugation of Protein (Citrullinated Protein/AntiCCP and RA)
• ProteinSynthesisErrors
• DNA and RNA Changes
  – Radiation Induced Crosslinking of DNA
  – Oxidation of DNA
  – Copy Errors not corrected by DNA repair process – Epigenetic Changes (the methylome)

Where Do Anti‐Cyclic Citrullinated Peptides (AntiCCPs) Come From?

• Activation of the immune system resulting in increased iNOS production of nitric oxide
• Arginine residues in proteins can be converted in situ into citrulline with the release of nitric oxide by iNOS
• The citrulline produced in the protein is now “foreign” and can be recognized by the immune system as such
• Antibodies can then be produced against this “foreign protein”

Disease Modifying Anti‐Rheumatic Drugs (DMARDs)

The Facts on Methotrexate For Rheumatoid Arthritis Treatment

Methotrexate is the most commonly prescribed drug to treat rheumatoid arthritis, yet it only helps about half of those who try it. Find out how it works and how to lessen its side effects.

Folate Inhibition To Block Immune Cell Proliferation

TNF Alpha Blocking Biologicals 

• Humira

• Enbrel

UNASSISTED COST APPROXIMATELY $6000 PER MONTH

• Xeljanz

Targeting The Autoimmune Inflammatory Signaling Process With Phytochemicals

Autoantibodies Are Increasing At Least Five Years Before Diagnosis Of SLE

NEJM 2003; 349: 1526‐33.

The Argument For Preventing Self From Becoming Non‐Self

A Systems Biology Approach To Prevention

NEJM. 2018; 378: 1761‐64.

NEJM. 2017; 377: 465‐74.

J Autoimmun. 2012; 39(3): 154‐60.

Mechanisms By Which Hypomethylated Immune Cells Can Induce Antibodies Associated With SLE

NEJM. 2018; 378: 1323‐34.

Transmitting SNPs Through Behavioral Epigenomics

Science. 2018; 359: 424‐28.

The Atlantic March 3, 2017

Frage MF et al. PNAS 2005; July 26: 10604‐09.

Environ Health Perspect. 2008; 116(11): 1547‐1552.

High Correlation Of POPs With DNA Hypomethylation

Environ Health Perspect. 2008; 116(11): 1547‐1552.

Jeffrey Bland, PhD

Chairman Emeritus & Member, Board of Directors The Institute for Functional Medicine

Autoimmunity is the reaction of cells (lymphocytes) or antibodies of the immune system along with the body’s own tissues leading to certain pathology. Autoimmunity can produce various conditions, which depend upon the target of the attack. While intrinsic factors, which include age, sex, and genetics contribute to autoimmunity, it is believed that extrinsic factors such as drugs, chemicals, microbes, and/or the environment can trigger the initiation of autoimmune responses.

Autoimmune Disease & Environmental Toxicants

Educational Objectives

1. Review air pollution, cigarette smoking, and citrullination as models for the genesis of autoimmune disease
2. Explore the role of general cell stressors in autoimmune disease
3. Discuss the impact of lung and gut barrier disruption by environmental toxins and food additives in autoimmune disease
4. Utilize the Functional Medicine ATM model to illustrate the various mechanisms by which toxicants could contribute to the pathophysiology of autoimmune disease.

“Mild forms of the autoimmune response probably occur naturally in most people. But, for people with a predisposition to autoimmunity, environmental factors, such as toxic chemicals, drugs, bacteria or viruses, may trigger a full‐fledged response.”

“NOVEL CRYSTAL BALL: One day Y‐shaped molecules called autoantibodies in a patient’s blood may tell doctors whether a patient is “brewing” certain diseases and may even indicate roughly how soon the individual will begin to feel symptoms.”

Autoimmune Disease: “Delayed Gratification”

Scientific American, March, 2007

• Many autoimmune diseases do not develop spontaneously, but instead evolve through an extended germination period before they become clinically evident...
• Well over 10 million people test positive for ANA, years before they have any symptoms.
• This implies the presence of additional environmental factors that dampen or amplify the process over time.

Arbuckle MR, et al, N Engl J Med. 2003 Oct 16;349(16):1526‐33.

Elevated Levels Of Antibodies Against Xenobiotics In A Subgroup Of Healthy Subjects

Vojdani, A, Kharrazian, D, Mukherjee, PS

• Some environmental chemicals, acting as haptens, can bind to a high‐ molecular‐weight carrier protein such as human serum albumin (HSA), causing the immune system to misidentify self‐tissue as an invader and launch an immune response against it, leading to autoimmunity
• The levels of specific antibodies against 12 different chemicals bound to HSA were measured by ELISA in serum from 400 blood donors.
• 10% (IgG) and 17% (IgM) of tested individuals showed significant antibody elevation against aflatoxin‐HSA adduct.
• The percentage of elevation against the other 11 chemicals ranged from 8% to 22% (IgG) and 13% to 18% (IgM).
• Detection of antibodies against various protein adducts may indicate chronic exposure to these chemical haptens in about 20% of the tested individuals

J Appl Toxicol. 2015 Apr; 35(4): 383–397.

Could Environmental Toxins Be A Key Missing Link That Pushes The Immune System Over The Brink To Permanently Lose Control Of Its Tolerance To Self‐Antigens?

(A Corollary Question: Does The Persistent Presence Of Autoantibodies Or Autoreactive T Cells Imply An Inevitable Progression To Full‐Blown Autoimmune Disease?)

Rheumatoid Arthritis: Swan neck deformity from chronic synovitis

Anti‐Cyclic Citrullinated Peptide Antibody

• Current method is 96% specific for RA
• Elevated titers detected >10 years before onset of clinical disease
• Sensitivity (likelihood of positive test) increases from 50% at Dx to >75% over course of disease
• Likely involved in pathogenesis
• Citrullinated Ags are highly expressed in inflamed joints
• Positive test predicts joint erosion
• Antigen‐antibody complexes activate complement = inflammatory
• Autoantibodies to citrullinated peptides
• Citrulline is formed by posttranslational modification of arginine residues by peptidyl arginine deiminases (PADs)
• PADs are upregulated by inflammation, injury, and toxicants
• Inflammation and injury thus increases citrullination of multiple synovial proteins
• Multiple HLA‐DR variants (shared epitope) associated with RA preferentially display citrullinated Ags on MHCII — activating citrulline‐specific autoreactive T cells
• Smoking increases risk of +anti‐CCP when coupled with HLR‐DR shared epitope

Floris van Gaalen et al. J Immunol 2005;175:5575-5580

Autoimmunity To Specific Citrullinated Proteins Gives The First Clues To The Etiology Of Rheumatoid Arthritis

Four citrullinated whole protein antigens, fibrinogen, vimentin, collagen type II, and alpha‐enolase, are now well established, with others awaiting further characterization
All four proteins are expressed in the joint, and there is evidence that antibodies to citrullinated fibrinogen and collagen type II mediate inflammation by the formation of immune complexes
Antibodies to citrullinated proteins are associated with HLA 'shared epitope' alleles
Porphyromonas gingivalis, pathogenic bacteria that is a major cause of periodontal disease, expresses endogenous citrullinated proteins
Thus, both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunity triad of RA.

Wegner N, Lundberg K, Kinloch A, et al, Immunol Rev. 2010 Jan;233(1):34‐54

“More than 20,000 physicians, after Luckies had been furnished them for tests, basing their opinions on their smoking experience, stated that Luckies are less irritating than other cigarettes.”
Mad Men?

Holy Smokes!!

Cigarette Smoking Has Been Strongly Linked To Numerous Autoimmune Diseases

Cigarette Smoking & Autoimmune Disease: What Can We Learn From Epidemiology?

• Rheumatoid arthritis and cigarette smoking:
• Risk is highest in men: OR up to 4.4 X
• Smoking increases risk of seropositive RA 2.4X in women
• Smoking intensity and duration both greatly increase risk
• Smoking increases severity of symptoms
• Increased risk remains for 20 yrs after cessation
• “Cigarette smoking is the most conclusively established environmental risk factor for RA”

Costenbader, KH, Lupus, Vol. 15, No. 11, 737‐745 (2006)

Smoking & Air Pollution As Pro‐Inflammatory Triggers For The Development Of Rheumatoid Arthritis.

• Smoking initiates chronic inflammatory events in the lungs.
• These, in turn, promote the release of the enzymes, peptidylarginine deiminases 2 and 4 from smoke‐activated, resident and infiltrating pulmonary phagocytes.
• Peptidylarginine deiminases mediate conversion of various endogenous proteins to putative citrullinated autoantigens.
• In genetically susceptible individuals, these autoantigens trigger the production of autoantibodies to anti‐citrullinated peptide, an event which precedes the development of RA.

Anderson R, Meyer PW, Ally MM, Tikly M, Nicotine Tob Res. 2016 Jul;18(7):1556‐65

Floris van Gaalen et al. J Immunol 2005;175:5575-5580

Cigarette Smoking & Autoimmune Disease: What Can We Learn From Epidemiology?

• Systemic lupus erythematosis
• Highest risk in current smokers
• Current smokers have higher levels of anti‐dsDNA Ab
• Multiple sclerosis
• Increased risk of MS in both current & past smokers
• Risk increases with intensity of smoking (more cigarettes per day)
• Increased severity of MS in current smokers
• Cirtrullination of myelin‐basic protein ‐‐ antigenic
• Graves’ hyperthyroidism
• Smoking is esp. strong risk factor for opthalmopathy
• Primary biliary cirrhosis
• Smoking increases risk by 1.5 to 3x

Costenbader, KH, Lupus, Vol. 15, No. 11, 737‐745 (2006)

Industrial Air Emissions & Proximity To Major Industrial Emitters, Are Associated With Anti‐Citrullinated Protein Antibodies.

• Randomly sampled 1586 subjects out of 20,000 population from Quebec, Canada
• After adjusting for age, sex, smoking, and ethnicity, found
• Positive association between anti‐CCPA and annual industrial PM 2.5 and sulfur dioxide emissions (i.e. living closer to emitters increases anti‐CCPA)
• Negative association between anti‐CCPA and to a major industrial emitter of both PM 2.5 and SO2 (living further away from emitters decreases anti‐CCPA)
• “These analyses suggest that exposure to industrial emissions of air pollutants is related to ACCPA positivity.”

Bernatsky S, Smargiassi A, Joseph L, et al, Environ Res. 2017 Aug;157:60‐63

Air Pollution As A Determinant of Rheumatoid Arthritis

• The induction by air pollution of an inflammatory environment with high citrullination levels in the lung may induce iBALT formation, thereby causing a transition toward a more specific immune response via the production of anti‐citrullinated peptide antibodies.
• Air pollution not only triggers innate immune responses at the molecular level, increasing the levels of proinflammatory cytokines and reactive oxygen species, but is also involved in adaptive immune responses.
  Thus, via the aryl hydrocarbon receptor (AHR), diesel exhaust particles can trigger a T‐cell switch to the Th17 profile.

Sigaux J, et al Joint Bone Spine. 2018 Mar 7. pii: S1297‐319X(18)30043‐5

The Aryl Hydrocarbon Receptor Links TH17‐Cell‐ Mediated Autoimmunity To Environmental Toxins

• The aryl hydrocarbon receptor (AhR) is a ligand‐dependent transcription factor that mediates a range of critical cellular events in response to halogenated aromatic hydrocarbons and non‐halogenated polycyclic aromatic hydrocarbons such as dioxin (TCDD)
• In a murine model of multiple sclerosis, which is mediated by Th17 cells, activation of cells using the AhR exacerbated disease, whereas mice deficient in the AhR had attenuated autoimmune disease.
• This paper thus links activation of Th17 cells with environmental toxins, suggesting a plausible hypothesis for the increase in such diseases with industrialization.

Veldhoen, M., Hirota, K., Westendorf, A.M, et al Nature. 2008 May 1;453(7191):106‐9

J Inflamm (Lond). 2015; 12: 48.

Does Rheumatoid Arthritis (& Other Autoimmune Diseases) Start In The Gut, Or In The Lungs?

Gomez‐Mejiba SE, Zhai Z, Akram H, et al. Inhalation of Environmental Stressors & Chronic Inflammation: Autoimmunity and Neurodegeneration.

Mutation research. 2009;674(1‐2):62‐72.

Citrullination & Autoimmunity

• Environmental exposure to cigarette smoke and nanomaterials of air pollution may be able to induce citrullination in lung cells prior to any detectable onset of inflammatory responses, suggesting that protein citrullination could be considered as a sign of early cellular damage
• Citrullination has been reported to be a process present in a wide range of inflammatory tissues. Indeed, citrullinated proteins have been detected also in other inflammatory arthritides and in inflammatory conditions other than arthritides (multiple sclerosis, polymyositis, inflammatory bowel disease and chronic tonsillitis)
• Histone hypercitrullination can activate neutrophil extracellular traps (NETS)— high inflammatory
• These data support the hypothesis that rather than being a disease‐dependent process, citrullination is an inflammatory‐dependent condition that plays a central role in autoimmune diseases.

Valesini G, Shoenfeld Y, et al Autoimmun Rev. 2015 Jun;14(6):490‐7 Wang S,

Wang Y.Biochim Biophys Acta. 2013 Oct;1829(10):1126‐35

Air Pollution In Autoimmune Rheumatic Diseases: A Review

• Environmental factors contribute to the onset of autoimmune diseases, especially smoking and occupational exposure to silica dust in rheumatoid arthritis and systemic lupus erythematosus
• Scleroderma may be triggered by the inhalation of chemical solvents, herbicides and silica dust.
• Primary vasculitis associated with anti‐neutrophil cytoplasmic antibody (ANCA) may be triggered by silica exposure
• Air pollution is one of the environmental factors involved in systemic inflammation and autoimmunity

Farhat SC, et al, Autoimmun Rev. 2011 Nov;11(1):14‐21

Silica, Silicosis & Autoimmunity

• Exposure to respirable crystalline silica (<10 μm in size) occurs most often in occupational settings – the “dusty” trades
• Epidemiological studies link occupational exposure to crystalline silica dust with systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis
• Findings from human and animal model studies are consistent with an autoimmune pathogenesis that begins with activation of the innate immune system leading to proinflammatory cytokine production (NLRP3 inflammasome), pulmonary inflammation leading to activation of adaptive immunity, breaking of tolerance, and autoantibodies and tissue damage

Pollard KM, Front Immunol. 2016; 7: 97.

Asbestos = Magnesium Silicate

Assessment Of Autoimmune Responses Associated With Asbestos Exposure In Libby, Montana, USA

• The population in Libby, Montana, provides a unique opportunity for study because of both occupational and environmental exposures that have occurred as a result of the mining of asbestos‐contaminated vermiculite near the community
• Libby serum samples showed significantly higher frequency of positive ANA and ENA tests, increased mean fluorescence intensity and titers of the ANAs, and higher serum IgA, compared with Missoula serum samples
• The results support the hypothesis that asbestos exposure is associated with autoimmune responses and suggests that a relationship exists between those responses and asbestos‐related disease processes.

Pfau JC, et al Environ Health Perspect, 2005, Vol 113: 25-30

Air Pollution, Oxidative Stress & Exacerbation Of Autoimmune Diseases

• Particulate matter present in air pollution can induce oxidative stress and cell death, both by apoptosis and necrosis of human cells leading to aggravation of chronic inflammation, i.e. the tissue damaging reaction observed in autoimmune diseases.
• Therefore, identification of strong inducers of oxidative stress among components of PM seems to be crucial for their neutralization and elimination from the ambient environment.
• It seems likely that PM 2.5 may exacerbate the onset of the SLE because they were attributed to a significant increase of the level of anti‐dsDNA antibodies, and the presence of the renal casts in SLE patients
• Exposure to ozone, sulphates, and other pollutants present in the air has been associated with type 1 diabetes in children
• MS occurrence and hospitalization was associated with exposure to air pollutants such as PM10, SO2, NO2, and NOx
• In addition to tobacco smoke and silica, pollution emissions from road traffic may be an environmental factor responsible for exacerbation of RA

Gawda, A, et al, Central European Journal of Immunology 2017; 42(3)

What Do Environmental Pollutants, Toxins, Infections & Unhealthy Diets Have In Common?

Environmental Toxicants, Oxidized PUFAs, Excessive Calories, Refined Sugars & AGEs...

• Increase inflammation and additional free radical production,
• Which damages tissues (bystander effect), disrupts barriers, and/or modifies DNA...
• Creating “foreign‐like” tissues that break immune tolerance (eg anti‐nuclear antibodies)

Cell Stressors

Macario, A. J.L. et al. N Engl J Med 2005;353:1489-1501

Damage Associated Molecular Patterns

• Molecular structures that activate immunologic receptors
• Released with cellular injury and/or necrosis after exposure to cellular stressors
• DNA fragments
• Mitochondria
• Misfolded proteins
• Advanced glycation end products have similar biological effects
• Initiate and perpetuate inflammatory response (esp NLRP3 inflammasome)

Ojcius D, Saïd‐Sadier N. Alarmins, inflammasomes and immunity. Biomedical Journal. 2012;35(6):437.

Vakrakou AG, Boiu S, Ziakas PD, et al, Systemic activation of NLRP3 inflammasome in patients with severe primary Sjögren's syndrome fueled by inflammagenic DNA accumulations.

J Autoimmun. 2018 Mar 15. pii: S0896‐8411(17)30789‐8.

Environmental Xenobiotic Exposure & Autoimmunity

• We argue that localized tissue damage and chronic inflammation elicited by xenobiotic exposure leads to the release of self‐antigens and damage‐associated molecular patterns ...
• As well as the appearance of ectopic lymphoid structures and secondary lymphoid hypertrophy,
• Which provide a milieu for the production of auto-reactive B and T cells that contribute to the development and persistence of autoimmunity in predisposed individuals.

Pollard KM, Christy JM, Cauvi DM, Kono DH, Current Opinion in Toxicology, Volume 10, August 2018, Pages 15‐22

The Functional Medicine Paradigm (Slightly Modified)

The Inflammatory Process: A Physiologic Algorithm

Toxicants & Autoimmunity: General Mechanisms

• Effect on antecedents:

• Genetic/epigenetic alterations: eg altered methylation, acetylation
• Damaged membrane barriers (leaky gut, skin, brain) allowing increased exposure to triggers
• Immune disruption = increased susceptibility to triggers
• Overload in hepatic detoxification pathways

• Effect on triggers:

• Synergistic action (immunotoxicant)
• Adjuvant: chemical modification of self‐antigen to make it appear foreign or immunogenic (neoantigens)
• Enhanced apoptosis: danger/damage signals (DAMPs)

• Effect on mediators:

• Amplified inflammatory pathways
• Increased oxidative stress
• Disruption of pro‐resolution counter‐regulatory mechanisms

Functional Toxicology

Changes In Intestinal Tight Junction Permeability Associated With Industrial Food Additives Explain The Rising Incidence Of Autoimmune Disease

• The incidence of autoimmune diseases and food additive consumption are both increasing in parallel
• Dysfunction of intestinal tight junctions is common in multiple autoimmune diseases
• Commonly used industrial food additives including glucose, salt, solvents, emulsifiers, gluten, microbial transglutaminase, and nanoparticles increase intestinal tight junction leakage.
• Intestinal entry of foreign antigen activates the autoimmune cascade

Lerner A, Matthias T. Autoimmunity Reviews 14 (2015) 479–489

Autoimmunity Reviews 14 (2015) 479–489

Autoimmune Disease: “Two‐Hit” Signal Theory

1. Barrier disruption allows immune system to be repeatedly exposed to a combination of an autoantigen & an “adjuvant” [Adjuvants can be toxicants, microbes, foods]
2. This triggers a genetically predisposed immune system to react to the autoantigen as a non‐self “stranger”
3. “Danger” signals released at the site of clearance of dead cells amplify the process; shaping the features & severity of the resulting autoimmune disease
4. Persistent “Stranger + Danger” = loss of tolerance
5. Based on this model, strategies aimed at preventing the accumulation of dying cells lowering the adjuvant (toxic) load may be beneficial for the prevention & treatment of autoimmune disease

Anaya JM, Ramirez‐Santana C, Alzate MA, Molano‐Gonzalez N, Rojas‐Villarraga A, The Autoimmune Ecology., Front Immunol. 2016 Apr 26;7:139

Bannerjee, B.D., Toxicology Letters, 1999, Vol 107: 21-31

Oxidatively Modified Autoantigens In Autoimmune Diseases

• Oxidative modification of proteins has been shown to elicit antibodies in a variety of diseases, including SLE, diabetes mellitus & RA.
• Oxidatively modified DNA & LDL occur in SLE, a disease in which premature atherosclerosis is a serious problem. AGE pentosidine & AGE‐modified IgG have been shown to correlate with RA disease activity.
• In the face of overwhelming evidence for the involvement of oxidative damage in autoimmunity, the administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease...”

Kurien BT, Hensley K, Bachmann M, Scofield RH., Free Rad Biol & Med, 2006, Vol 41: 549-556

Oxidative Stress In The Pathology & Treatment Of Systemic Lupus Erythematosus.

• Oxidative stress is increased in SLE, and it contributes to immune system dysregulation, abnormal activation and processing of cell‐ death signals, autoantibody production and fatal comorbidities.
• Oxidative modification of self antigens triggers autoimmunity, and the degree of such modification of serum proteins shows striking correlation with disease activity and organ damage in SLE.
• Reactive oxygen intermediates (ROI) mostly originate from mitochondria, and T cells from patients with SLE exhibit mitochondrial dysfunction
• In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and serine/threonine‐protein kinase mTOR undergoes redox‐dependent activation.
• In turn, reversal of glutathione depletion by application of its amino acid precursor, N‐acetylcysteine, improves disease activity in lupus‐ prone mice; pilot studies in patients with SLE have yielded positive results that warrant further research.
• Antioxidant therapy might also be useful in ameliorating damage caused by other treatments.

Perl, A, Nat Rev Rheumatol. 2013 Nov;9(11):674‐86

Environmental Agents, Oxidative Stress & Autoimmunity

• Oxidative stress (OS) plays an important role in the pathogenesis of a variety of autoimmune diseases (ADs) and many environmental agents participate in this process.
• Environmental agents, including trichloroethylene (TCE), silica, pristane (TMPD in mineral oil), mercury, and smoke, are known to induce an autoimmune response, potentially through OS‐mediated mechanisms.
• Antioxidants can attenuate SLE disease activity by down regulating NLRP3 inflammasome activation and activating Nrf2 signaling.

Khan MF, Wang G. Curr Opin Toxicol. 2018 Feb;7:22‐27.

Xenobiotics Associated With Autoimmune Diseases

• Organochlorines (dioxin, PCBs) & polyvinyl chloride
• Polybrominated biphenyls
• Organic solvents: benzene, toluene, trichloroethylene
• Polycyclic aromatic hydrocarbons (cigarette smoke, automotive exhaust, charbroiled meat)
• Hydrazines: rocket fuels
• Airborne particulates
• Pharmaceuticals & inhalant anesthetics
• Preservatives (formaldehyde)
• Permanent hair dyes
• Food dyes (tartrazine)
• L‐canavanine (in alfalfa sprouts), an arginine analog
• Adulterated rapeseed oil (aniline‐denatured):“Spanish toxic oil syndrome”
• L‐tryptophan (contaminated): eosinophilic myositis

Metals & Minerals Associated With Autoimmune Diseases

• Heavy metals

• Mercury
• Cadmium
• Lead
• Gold

• Minerals & Metalloids

• Silica (crystalline silicon dioxide)
• Asbestos (chrysotile = magnesium silicate)
• Arsenic
• Lithium
• Iodine

Bigazzi PE., Metals and kidney autoimmunity. Environ Health Perspect. 1999 Oct;107 Suppl 5:753‐65

Biologic Markers in Immunotoxicology National Research Council (US) Subcommittee on Immunotoxicology. Washington (DC): National Academies Press (US); 1992.

Garza, A, Drug‐Induced Autoimmune Diseases. Pharmacy Times 1‐20‐16
http://www.pharmacytimes.com/publications/issue/2016/january2016/drug‐induced‐autoimmune‐diseases

“Lupus Erythematosus & Other Autoimmune Diseases Related To Statin Therapy: A Systematic Review”

• 28 published cases of statin‐induced autoimmune disease:
• 10 cases SLE (2 with autoimmune hepatitis)
• 3 cases subacute cutaneous SLE
• 14 cases dermatomyositis & polymyositis
• Most cases needed systemic immunosuppression
• In many patients, antinuclear antibodies were still positive many months after clinical recovery

Noel, B; J Eur Acad Dermatol Venereol 2007; 21(1):17‐24

Putting It All Together...

Anaya JM, et al, The Autoimmune Ecology., Front Immunol. 2016 Apr 26;7:139

Messages To Take Home

• Autoimmune and autoinflammatory diseases are steadily increasing in our society
• The rise in exposure to environmental pollutants and other toxins is increasing the total body burden of xenobiotics
• A central theme in the development of autoimmune diseases is the loss of immune tolerance
• Immune tolerance can be broken by disruption of barriers (skin, lung, gut, brain) and/or immune dysregulation
• Numerous xenobiotics have been shown to disrupt healthy barriers and dysregulate immune responses
• Xenobiotics may play a central role in the initiation and perpetuation of autoimmune disease

Explosion Of Autoimmune Diseases: The Mosaic Of Old & Novel Factors

• Modern life and exposures to novel chemical and xenobiotic compounds may lead to the development of new complexes of symptoms that do not necessarily belong to one of the well‐known autoimmune diseases
• As physicians and scientists, we must continue to study novel pathogenic mechanisms and susceptible alleles to help us identify new therapeutic venues.

Agmon‐Levin N, Lian Z, Shoenfeld Y. Cell Mol Immunol. 2011 May; 8(3): 189–192.

IFM Annual International Conference Hollywood, Florida May, 2018

Robert Rountree, MD

Robert Rountree, MD is a speaker, consultant, and advisory board member for Thorne and Balchem. He is also a clinical trial board member for Thorne Research.

Prostate Cancer: Abstract

Prostate cancer (PCa) remains a leading cause of mortality in US men and the prevalence continues to rise world-wide especially in countries where men consume a ‘Western-style’ diet. Epidemiologic, preclinical and clinical studies suggest a potential role for dietary intake on the incidence and progression of PCa. 'This minireview provides an overview of recent published literature with regard to nutrients, dietary factors, dietary patterns and PCa incidence and progression. Low carbohydrates intake, soy protein, omega-3 (w-3) fat, green teas, tomatoes and tomato products and zyflamend showed promise in reducing PCa risk or progression. A higher saturated fat intake and a higher β-carotene status may increase risk. A ‘U’ shape relationship may exist between folate, vitamin C, vitamin D and calcium with PCa risk. Despite the inconsistent and inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa is promising. The combination of all the beneficial factors for PCa risk reduction in a healthy dietary pattern may be the best dietary advice. This pattern includes rich fruits and vegetables, reduced refined carbohydrates, total and saturated fats, and reduced cooked meats. Further carefully designed prospective trials are warranted.

Keywords: Diet, Prostate cancer, Nutrients, Dietary pattern, Lifestyle, Prevention, Treatment, Nutrition, Dietary intervention, Review

Introduction: Prostate Cancer

Prostate cancer (PCa) is the second most common cancer in men, with nearly a million new cases diagnosed worldwide per year [1], with approximately a six-fold higher incidence in Western than in non-Western countries. Diet, lifestyle, environmental and genetic factors are hypothesized to play a role in these differences. This review focuses on the latest evidence of the potential role of dietary factors on PCa and includes epidemiologic and clinical trial evidence for the impact of protein, fat, carbohydrate, fiber, phytochemicals, other food components, whole foods and dietary patterns on PCa incidence, development and/or progression. Data from meta-analyses or well-designed randomized trials and prospective studies are emphasized in this review. It should be noted that studies of dietary intake or nutrition and cancer are often subject to various limitations and thus complicate interpretation of results. For example, when a study is designed to examine the effect of the amount of fat intake, alteration in fat intake inevitably will change intake of protein and/or carbohydrate, and may change the intake of other nutrients as well. As a result, it is difficult to attribute the effect to change in fat intake alone. In addition, the impact of macronutrients potentially involves aspects of both absolute quantity and the type of macronutrients consumed. Both aspects may potentially affect cancer initiation and/or development independently, but they are not always distinguishable in research designs. Though this topic was recently reviewed [2], given the extensive new literature on the topic, an updated review is presented herein and a summary table is provided for a quick reference (Table 1).

Nutrients Carbohydrates Given the hypothesis that insulin is a growth factor for PCa, it has been hypothesized that reducing carbohydrates and thus lowering serum insulin may slow PCa growth [3]. Indeed, in animal models, either a no-carbohydrate ketogenic diet (NCKD) [4,5] or a low-carbohydrate diet (20% kcal as carbohydrate) has favorable effects on slowing prostate tumor growth [6,7]. In human studies, one study found that high intake of refined carbohydrates was associated with increased risk of PCa [7]. In addition to the amount of carbohydrates, type of carbohydrates may impact on PCa but research has been inconclusive. The potential to reduce PCa risk and progression via impacting carbohydrate metabolism is actively being investigated with Metformin. Metformin reduced PCa cell proliferation and delayed progression in vitro and in vivo, respectively [8-10] and reduced incident risk and mortality in humans [11-13]. Two single arm clinical trials also showed a positive effect of metformin in affecting markers of PCa proliferation and progression [14,15]. However, other retrospective cohort studies have not supported an effect of metformin on recurrence or incident risk of PCa [16-22]. Despite the potential for reducing either total or simple carbohydrates in benefiting PCa control, evidence is lacking from randomized controlled trials (RCT). Two randomized trials are on-going examining the impact of a low-carbohydrate diet (approximately 5% kcal) on the PSA doubling time among PCa patients post radical prostatectomy (NCT01763944) and on glycemic response among patients initiating androgen deprivation therapy (ADT) (NCT00932672 ). Findings from these trials will shed light on the effect of carbohydrate intake on markers of PCa progression and the role of reduced carbohydrate intake on offsetting the side effects of ADT.

Protein

The ideal level of protein intake for optimal overall health or prostate health is unclear. Despite the popularity of low carbohydrate diets that are high in protein, recent human studies reported that low protein intake was associated with lower risk for cancer and overall mortality among men 65 and younger. Among men older than 65, low protein intake was associated with a higher risk for cancer and overall mortality [23]. In animal models the ratio between protein and carbohydrate impacted on cardiometabolic health, aging and longevity [24]. The role of dietary protein and the protein to carbohydrate ratio on PCa development and progression requires further study.

Animal-Based Proteins

Studying protein intake, like all aspects of nutritional science, can be challenging. For example, animal meat, which is a source of protein in Western diets, is composed not only of protein, but also of fat, cholesterol, minerals and other nutrients. The amount of these nutrients including fatty acids may vary from one animal meat to the other. Previous studies in human have shown that consumption of skinless poultry, which is lower in cholesterol and saturated fat than many red meats, was not associated with the recurrence or progression of PCa [25]. However, consumption of baked poultry was inversely associated with advanced PCa [26,27], while cooked red meat was associated with increased advanced PCa risk [26,27]. Thus, how the food is prepared may modify its impact on PCa risk and progression. Overall, fish consumption may be associated with reduced PCa mortality, but high temperature cooked fish may contribute to PCa carcinogenesis [28]. Thus, it may be advisable to consume fish regularly but cooking temperature should be kept moderate.

Dairy-Based Protein

Another common protein source is dairy products, such as milk, cheese and yogurt. Previous studies have shown that dairy increased overall PCa risk but not with aggressive or lethal PCa [29,30]. In addition, both whole milk and low-fat milk consumption were reported to either promote or delay PCa progression [29,31]. In the Physicians Health follow up cohort with 21,660 men, total dairy consumption was found to be associated with increased PCa incidence [32]. In particular, low fat or skim milk increased low grade PCa, whereas whole milk increased fatal PCa risk. Though the exact component(s) of dairy products driving these associations is unknown, the high concentrations of saturated fat and calcium may be involved. A cross-sectional study of 1798 men showed that dairy protein was positively associated with serum IGF-1 [33] levels which may stimulate initiation or progression of PCa. Thus, further research is needed to clarify the relationship between dairy intake and PCa. There is insufficient data to provide recommendations specifically related to dairy or dairy protein and PCa risk or progression.

Plant-Based Proteins

Soy and soy-based products are rich in protein and phytoestrogens that may facilitate PCa prevention, but its role on PCa is unclear. In a study in mice, intake of soy products was associated with decreased hepatic aromatase, 5α-reductase, expression of androgen receptor and its regulated genes, FOXA1, urogenital tract weight and PCa tumor progression [34]. A recent randomized trial of 177 men with high-risk disease after radical prostatectomy found that soy protein supplementation for two years had no effect on risk of PCa recurrence [35]. Although epidemiological and pre-clinical studies [36,37] support a potential role for soy/soy isoflavones in PCa risk reduction or progression, a meta-analysis did not find significant impact of soy intake in PSA levels, sex hormone-binding globulin, testosterone, free testosterone, estradiol or dihydrotestosterone [38]. Another RCT in patients before prostatectomy also did not find any effect of soy isoflavone supplement up to six weeks on PSA, serum total testosterone, free testosterone, total estrogen, estradiol or total cholesterol [39]. Since most RCTs conducted have been small and of short duration, further examination is needed.

Many studies have continued to examine the primary isoflavone in soy, genistein, and its effect on PCa. The potential for genistein to inihibit PCa cell detachment, invasion and metastasis is reported [40]. Genistein may modify glucose update and glucose transporter (GLUT) expression in PCa cells [41], or exert its anti-tumor effect by down regulating several microRNAs [42]. Studies using tumor cells and animal models suggest genistein may compete with and block endogenous estrogens from binding to the estrogen receptor, thereby inhibiting cellular proliferation, growth, and inducing differentiation and, specifically, genistein may inhibit cell detachment, protease production, cell invasion and thus prevent metastasis [36,40,43]. However, neither plasma nor urinary genistein levels were associated with PCa risk in case control studies [44,45]. In a phase 2 placebo-controlled RCT with 47 men, supplementation of 30 mg genistein for three to six weeks significantly reduced androgen-related markers of PCa progression [46]. In addition, genistein may be beneficial in improving cabazitaxel chemotherapy in metastatic castration-resistant PCa [37]. Clinical studies are warranted to further examine the role of soy and soy isoflavones for PCa prevention or treatment. A definitive recommendation regarding protein intake for PCa prevention or treatment is not available yet.

Fat

Research findings examining fat consumption with PCa risk or progression are conflicting. Both the total absolute intake [47] of dietary fat and the relative fatty acid composition may independently relate to PCa initiation and/or progression. While animal studies repeatedly show that reducing dietary fat intake slows tumor growth [48-50] and high fat diets, especially animal fat and corn oil increase PCa progression [51], human data are less consistent. Case–control studies and cohort studies have shown either no association between total fat consumption and PCa risk [52-55] or an inverse association between fat intake and PCa survival, particularly among men with localized PCa [47]. In addition, a cross-sectional study showed that fat intake expressed as percent of total calorie intake was positively associated with PSA levels in 13,594 men without PCa [56]. Given these conflicting data, it is possible that the type of fatty acid [56] rather than total amount may play an important role in PCa development and progression. A study found plasma saturated fatty acids to be positively associated with PCa risk in a prospective cohort of 14,514 men of the Melbourne Collaborative Cohort Study [57]. In addition, another study found that eating more plant-based fat was associated with reduced PCa risk [58]. These studies support the current dietary guideline of eating less animal-based fat and more plant-based fat.

The data regarding omega-6 (w-6) and omega-3 (w-3) polyunsaturated fatty acid (PUFA) consumption and PCa risk are also conflicting. While there are data to support a link between increased w-6 PUFA intake (mainly derived from corn oil) and risk of overall and high-grade PCa [57,59], not all data support such a link [60]. In fact, a greater polyunsaturated fat intake was associated with a lower all cause mortality among men with nonmetastatic PCa in the Health Professionals Follow-up study [58]. The postulated mechanism linking w-6 PUFAs and PCa risk is the conversion of arachidonic acid (w-6 PUFA) to eicosanoids (prostaglandin E-2, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids) leading to inflammation and cellular growth [61]. Conversely, w-3 PUFAs, which are found primarily in cold water oily fish, may slow growth of PCa through a number of mechanisms [61-63]. In a study of 48 men with low risk PCa under active surveillance, repeat biopsy in six months showed that prostate tissue w-3 fatty acids, especially eicosapentaenoic acid (EPA), may protect against PCa progression [64]. In vitro and animal studies suggest that w-3 PUFAs induce anti-inflammatory, pro-apoptotic, antiproliferative and anti-angiogenic pathways [65,66]. Moreover, a mouse study comparing various types of fat found that only the fish oil diet (that is, omega-3 based diet) slowed PCa growth relative to other dietary fats [67]. In regards to human data, a phase II randomized trial showed that a low-fat diet with w-3 supplementation four to six weeks prior to radical prostatectomy decreased PCa proliferation and cell cycle progression (CCP) score [62,68]. A low-fat fish oil diet resulted in decreased 15(S)- hydroxyeicosatetraenoic acid levels and lowered CCP score relative to a Western diet [69]. The potential benefits of omega-3 fatty acids from fish are supported by epidemiological literature showing that w-3 fatty acid intake was inversely associated with fatal PCa risk [70,71]. Despite the promise of omega-3 fatty acids, not all studies agree. Supplementing 2 g alpha-linolenic acid (ALA) per day for 40 months in 1,622 men with PSA <4 ng/ml did not change their PSA [72]. However, another study found that a high blood serum n-3 PUFA and docosapentaenoic acid (DPA) was associated with reduced total PCa risk while high serum EPA and docosahexaenoic acid (DHA) was possibly associated with increased high-grade PCa risk [73]. Further research is required to understand better the role of omega-3 PUFAs in PCa prevention or treatment.

Cholesterol

Many pre-clinical studies have shown that the accumulation of cholesterol contributes to the progression of PCa [74-76]. It was suggested that a high cholesterol in Lin et al. BMC Medicine (2015) 13:3 Page 5 of 15 circulation may be a risk factor for solid tumors, primarily through the upregulation of cholesterol synthesis, inflammatory pathways [77] and intratumoral steroidogenesis [78]. According to a recent study with 2,408 men scheduled for biopsy, serum cholesterol was independently associated with prediction of PCa risk [79]. Consistent with the cholesterol findings, usage of the cholesterol lowering drug statin post radical prostatectomy (RP) was significantly associated with reduced risk of biochemical recurrence in 1,146 radical prostatectomy patients [80]. Another study also showed that statins may reduce PCa risk by lowering progression [81]. Although the mechanism has not been established, more recent studies also showed that a low high-density lipoprotein (HDL) cholesterol level was associated with a higher risk for PCa and, thus, a higher HDL was protective [81-84]. These findings support the notion that a heart-healthy dietary intervention that lowers cholesterol may benefit prostate health also.

Vitamins & Minerals

Herein we will review the recent data on vitamins A, B complex, C, D, E, and K and selenium. In the two large clinical trials: the Carotene and Retinol Efficacy Trial (CARET; PCa was a secondary outcome) and the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health prospective cohort study, excessive multivitamin supplementation was associated with a higher risk of developing aggressive PCa, particularly among those taking individual β-carotene supplements [85,86]. Similarly, high serum β-carotene levels were associated with a higher risk for PCa among 997 Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor cohort [87]. However, β-carotene supplement was not found to affect risk for lethal PCa during therapy [88], or in the Danish prospective cohort study of 26,856 men [89]. Circulating retinol also was not associated with PCa risk in a large case–control study [90]. Thus, the association between vitamin A and PCa is still unclear.

Preclinical evidence suggests folate depletion may slow tumor growth, while supplementation has no effect on growth or progression, but may directly lead to epigenetic changes via increases in DNA methylation [91]. Two meta-analyses also showed that circulating folate levels were positively associated with an increased risk of PCa [92,93], while dietary or supplemental folate had no effect on PCa risk [94] in a cohort study with 58,279 men in the Netherlands [95] and a case–control study in Italy and Switzerland [96]. In fact, one study of a cohort of men undergoing radical prostatectomy at several Veterans Administration facilities across the US even showed that higher serum folate levels were associated with lower PSA and, thus, lower risk for biochemical failure [97]. Another study using data from the 2007 to 2010 National Health and Nutrition Examination Survey showed that a higher folate status may be protective against elevated PSA levels among 3,293 men, 40-years old and older, without diagnosed PCa [98]. It was suggested that folate may play a dual role in prostate carcinogenesis and, thus, the complex relationship between folate and PCa awaits further investigation [99].

Despite the potential role of vitamin C (ascorbic acid) as an antioxidant in anticancer therapy, trials examining dietary intake or supplementation of vitamin C are few. A RCT showed no effect of vitamin C intake on PCa risk [89]. Furthermore, vitamin C at high doses may act more as a pro-oxidant than antioxidant, complicating the research design and interpretation.

The primary active form of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol) aids in proper bone formation, induces differentiation of some immune cells, and inhibits pro-tumor pathways, such as proliferation and angiogenesis, and has been suggested to benefit PCa risk [100]; however, findings continue to be inconclusive. More recent studies found that increased serum vitamin D levels were associated with decreased PCa risk [101,102]. Further, supplementing vitamin D may slow PCa progression or induce apoptosis in PCa cells [103-105]. Other studies, however, reported either no impact of vitamin D supplement on PSA [106] or no effect of vitamin D status on PCa risk [107,108]. Some studies contrarily reported that a lower vitamin D status was associated with a lower PCa risk in older men [109], or a higher serum vitamin D was associated with a higher PCa risk [110,111]. A study even suggested that a ‘U’ shaped relationship may exist between vitamin D status and PCa and the optimal range of circulating vitamin D for PCa prevention may be narrow [112]. This is consistent with the findings for other nutrients that a greater intake of a favorable nutrient may not always be better.

A recent study showed that the association between vitamin D and PCa was modulated by vitamin D-binding protein [113] which may have partially explained the previous inconsistent findings. Further, a meta-analysis investigating the association between Vitamin D receptor (VDR) polymorphisms (BsmI and FokI) and PCa risk reported no relationship with PCa risk [114]. Thus, the role of vitamin D in PCa remains unclear.

In a large randomized trial with a total of 14,641 US male physicians ≥50-years old, participants randomly received 400 IU of vitamin E every other day for an overall mean of 10.3 (13.8) years. Vitamin E supplementation had no immediate or long-term effects on the risk of total cancers or PCa [115]. However, a moderate dose of vitamin E supplement (50 mg or about 75 IU) resulted in lower PCa risk among 29,133 Finnish male smokers [116]. Multiple preclinical studies suggest vitamin E slows tumor growth, partly due to inhibiting DNA synthesis and inducing apoptotic pathways [117]. Unfortunately, human studies have been less than supportive. Two observational studies (the Cancer Prevention Study II Nutrition Cohort and the NIH-AARP Diet and Health Study) both showed no association between vitamin E supplementation and PCa risk [118,119]. However, a higher serum α-tocopherol but not the γ-tocopherol level was associated with decreased risk of PCa [120,121] and the association may be modified by genetic variations in vitamin E related genes [122]. On the contrary, a prospective randomized trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), showed vitamin E supplementation significantly increased PCa risk [123] and that a higher plasma α-tocopherol level may interact with selenium supplements to increase high grade PCa risk [124]. This finding is consistent with a case-cohort study of 1,739 cases and 3,117 controls that showed vitamin E increased PCa risk among those with low selenium status but not those with high selenium status [125]. Thus, more research is needed to examine the association between vitamin E and PCa and the dose effect and interaction with other nutrients should be considered.

Vitamin K has been hypothesized to help prevent PCa by reducing bioavailable calcium. Preclinical studies show the combination of vitamins C and K have potent antitumor activity in vitro and act as chemo- and radiosensitizers in vivo [126]. To date, few studies have investigated this, although one study using the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort found an inverse relationship between vitamin K (as menaquinones) intake and PCa incidence [127]. Little to no preclinical studies have been conducted to examine the role of calcium with PCa. Retrospective and meta-analyses suggest increased or reduced PCa risk with increased calcium intake, while others suggest no association [128,129]. Another study suggests a ‘U’-shaped association, where very low calcium levels or supplementation are both associated with PCa [130].

Selenium, on the other hand, has been hypothesized to prevent PCa. While in vitro studies suggested that selenium inhibited angiogenesis and proliferation while inducing apoptosis [131], results from SELECT showed no benefit of selenium alone or in combination with vitamin E for PCa chemoprevention [123]. Further, selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status in a randomly selected cohort of 1,739 cases with high-grade (Gleason 7–10) PCa and 3,117 controls [125]. A prospective Netherlands Cohort Study, which included 58,279 men, 55- to 69-years old, also showed that toenail selenium was associated with a reduced risk of advanced PCa [132]. Further research is needed to clarify the role of selenium with PCa.

Phytochemicals

Along with vitamins and minerals [2], plants contain phytochemicals with potential anti-cancer effects. Typically not considered essential compounds, phytochemicals have antioxidant and anti-inflammatory properties.

Silibinin is a polyphenolic flavonoid found in the seeds of milk thistle. It has been shown in vitro and in vivo to inhihit PCa growth by targeting epidermal growth factor receptor (EGFR), IGF-1 receptor (IGF-1R), and nuclear factor-kappa B (NF-kB) pathways [133,134]. A recent study showed that silibinin may be useful in PCa prevention by inhibiting TGFβ2 expression and cancerassociated fibroblast (CAF)-like biomarkers in the human prostate stromal cells [135]. Thus, silibinin is a promising candidate as a PCa chemopreventive agent that awaits further research.

Curcumin is used as food additive in Asia and as an herbal medicine for inflammation [136]. In vitro, curcumin inhibits the pro-inflammatory protein NF-κB while inducing apoptosis through increased expression of proapoptotic genes [137]. In vivo, curcumin slows PCa growth in mice while sensitizing tumors to chemo- and radiotherapies [136]; however, no human trial has examined its impact on PCa.

Pomegranate

The peel and fruit of pomegranates and walnuts are rich in ellagitannins (punicalagins). These phytochemicals are readily metabolized to the active form ellagic acid by gut flora [138]. Preclinical experiments show ellagitannins inhibit PCa proliferation and angiogenesis under hypoxic conditions and induce apoptosis [137,138]. In prospective trials in men with a rising PSA after primary treatment, pomegranate juice or POMx, a commercially available pomegranate extract, increased the PSA doubling time relative to baseline [139,140], although no trials included a placebo group. Results are pending from a prospective placebo RCT using pomegranate extract in men with a rising PSA. However, in a placebo controlled trial, two pills of POMx daily for up to four weeks prior to radical prostatectomy had no impact on tumor pathology or oxidative stress or any other tumor measures [141].

Green Tea

Green tea contains a number of antioxidant polyphenols including catechins, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG) and (−)-epicatechin. Preclinical studies suggest EGCG inhibits PCa growth, induces intrinsic and extrinsic apoptotic pathways and decreases inflammation by inhibiting NFkB [137]. Furthermore, the antioxidant properties of EGCG are 25 to 100 times more potent than vitamins C and E [131]. In a prospective randomized preprostatectomy trial, men consuming brewed green tea Lin et al. BMC Medicine (2015) 13:3 Page 7 of 15 prior to surgery had increased levels of green tea polyphenols in their prostate tissue [142]. In a small proof-ofprinciple trial with 60 men, daily supplementation of 600 mg green tea catechin extract reduced PCa incidence by 90% (3% versus 30% in the placebo group) [143]. Another small trial also showed that EGCG supplement resulted in a significant reduction in PSA, hepatocyte growth factor and vascular endothelial growth factor in men with PCa [144]. These studies suggest green tea polyphenols may lower PCa incidence and reduce PCa progression but more research is needed to confirm and clarify its mechanism [137,143,145].

Resveratrol

While most in vitro studies suggest resveratrol inhibits PCa growth [146-148], resveratrol suppresses tumor growth in some [137] but not all animal models [149], possibly due to limited bioavailability [150,151]. To date, there are no clinical trials investigating the preventive or therapeutic effects of resveratrol on PCa.

Zyflamend

Zyflamend is an anti-inflammatory mixture of herbs that has been shown to reduce PCa progression by lowering the expression of markers including pAKT, PSA, histone deacetylases and androgen receptor in animal models and PCa cell line [152-154]. Despite its anti-cancer potential [155], very few studies have been conducted in humans [156,157]. In an open-label Phase I trial of 23 patients with high-grade prostatic intraepithelial neoplasia, Zyflamend alone or in conjunction with other dietary supplements for 18 months reduced the risk for developing PCa [156]. More RCTs in humans are needed to confirm the efficacy and clinical application of this herbal supplement.

Other Whole Foods Fruits & Vegetables

Fruits and vegetables are rich sources of vitamins, minerals and phytochemicals. Several epidemiologic studies found inverse relationships between total fruit and vegetable intake [158], and cruciferous vegetable intake and PCa risk [159,160]. Allium vegetables, such as garlic, leeks, chives, and shallots, contain multiple sulfurous phytochemicals that were suggested to enhance the immune system, inhibit cell growth, modulate expression of androgen-responsive genes and induce apoptosis [161]. Although the number of published studies is limited, both preclinical and epidemiologic data suggest allium vegetable intake may be protective against PCa, particularly localized disease [162]. A randomized trial with 199 men also found that a blend supplement of pomegranate, green tea, broccoli and turmeric significantly reduced the rate of rise in PSA in men with PCa [163].

Tomatoes & Tomato Products

A number of studies have examined the association between tomatoes and tomato products with PCa but the findings are inconclusive. The antioxidant lycopene, which is rich in tomatoes, has also been studied specifically for its impact on PCa. In vitro, lycopene halts the cell cycle in several PCa cell lines and decreases IGF-1 signaling by inducing IGF-1 binding proteins [131]. While some animal studies found lycopene specifically slows PCa growth [164] or reduces PCa epithelial cells at stages of initiation, promotion and progression [165], two studies found conflicting findings between tomato paste and lycopene [166,167]. Prospective human studies found higher lycopene consumption [168,169] or higher serum levels were associated with lower PCa risk [170], but others have not [171,172]. Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PCa at six-month follow-up biopsy (P = 0.003) [173]. Two short-term preprostatectomy trials using tomato sauce or lycopene supplementation demonstrated lycopene uptake in prostate tissue and antioxidant and potential anticancer effects [174,175]. While several clinical trials suggested an inverse relationship between lycopene supplementation, PSA levels and decreases in cancerrelated symptoms [171,176], no large-scale randomized trials have tested the role of lycopene or tomato products on PCa prevention or treatment.

Coffee

Coffee contains caffeine and several unidentified phenolic compounds that may serve as antioxidants. Epidemiological studies suggest an inverse relationship between coffee consumption and PCa risk, mainly for advanced or lethal stage disease, and the findings were independent of caffeine content [177,178]. Although several epidemiological studies [179-182] found no association between coffee consumption and PCa risk, a recent meta-analysis of prospective studies concluded that coffee consumption may reduce PCa risk [183]. The potential mechanism(s) and pathway(s) involved are unknown but may include antioxidant, anti-inflammatory effects, glucose and insulin metabolism, and potential impact on IGF-I and circulating sex hormones.

Dietary Patterns

Even though many single nutrients or food factors have been examined for their impact or association with PCa risk or progression, the results have largely been inconclusive. A potential reason for the inconsistency is the fact that the impact of single nutrient or food factor may be too small to be detected. In addition, nutrients naturally existing in foods often are highly correlated and may interact with each other and, thus, affect the impact on PCa. Thus, dietary pattern analysis has received an increasing Lin et al. BMC Medicine (2015) 13:3 Page 8 of 15 interest but research has been limited and the existing results have been inconclusive. In a cohort of 293,464 men, a high dietary quality, as indicated by the Healthy Eating Index (HEI) score, was associated with a lower risk of total PCa risk [70]. The Mediterranean diet, which is high in vegetables, olive oil, complex carbohydrates, lean meats and antioxidants, is consistently recommended to patients for prevention of cardiovascular disease and obesity [184], and may show promise in PCa prevention [185]. Fish and omega-3 fatty acid consumption in the Mediterranean pattern were significantly and inversely associated with fatal PCa risk. In addition, adherence to the Mediterranean diet after diagnosis of non-metastatic PCa was associated with lower overall mortality [186]. Whereas, a Western pattern with high intakes of red meats, processed meats, fried fish, chips, high-fat milk and white bread, was associated with a higher risk for PCa [187].

Furthermore, Asian countries with high consumption of omega-3 PUFAs, soy and green tea-based phytochemicals, have lower PCa incidences versus countries consuming a ‘Western-style’ diet [188]. However, not all studies [189-191] supported an association between certain dietary pattern and risk of PCa. It is possible that the methodology used in identifying dietary patterns may not have captured all the dietary factors associated with PCa risk. Alternatively, each dietary pattern may contain both beneficial and harmful components resulting in an overall null association. More research is needed to continue searching for dietary patterns that combine most of the beneficial nutrients/food factors for PCa and limit most of the negative nutrients/ food factors.

Future Direction For Clinical Trials

Based on the multitude of epidemiologic, preclinical and clinical trials described in this review, dietary interventions for the prevention and treatment of PCa hold great promise. In addition, several dietary factors and vitamins/supplements may be associated with PCa risk and/ or progression of disease. Prospective randomized trials are clearly indicated to identify specific nutrients or combination therapies for the prevention and treatment of PCa.

Recently, active surveillance (AS) has emerged as a viable option for men with lower risk PCa. Men on AS are motivated to adhere to diet and lifestyle modifications [192], making this subset a good target for dietary intervention and quality of life trials [193]. PCa survivors who are more active and report ‘healthy’ eating habits (that is, consuming low-fat, low-refined carbohydrate diets rich in fruits and vegetables) have better overall quality of life versus their inactive, unhealthy counterparts [194]. Thus, more randomized trials are warranted to determine the overall long-term effects of dietary intervention in this population. Specifically, key questions to address in future trials are: 1) Can dietary interventions delay the need for treatment in men on AS; 2) Can dietary interventions prevent recurrence for men after treatment; 3) Can dietary interventions delay progression among men with recurrent disease and, thus, delay the need for hormonal therapy; 4) Can dietary interventions reduce the side effects of PCa treatments including hormonal therapy and newer targeted therapies; and 5) Is there any role for dietary interventions alone or combined with targeted therapies in men on hormonal therapy to prevent castrate-resistance or after the emergence of castrate resistance disease? Because increasing evidence shows that metabolic abnormalities increase risk for PCa, lifestyle intervention that improves metabolic profile is a win-win option for PCa prevention and treatment [195,196].

Conclusions: Prostate Cancer

Future research is required to determine the ideal diet for PCa prevention or treatment. However, several dietary factors and some dietary patterns hold promise in reducing PCa risk or progression and are consistent with current dietary guidelines for Americans [197]. For counseling patients on diet for primary and secondary PCa prevention, many believe ‘heart healthy equals prostate healthy.’ Thus, given the current inconclusive results, the best dietary advice for PCa prevention or management seems to include: increasing fruits and vegetables, replacing refined carbohydrates with whole grains, reducing total and saturated fat, reducing overcooked meats and consuming a moderate amount of calories or reducing carbohydrates with a primary goal of obtaining and maintaining a healthy body weight.

Competing interests The authors declare that they have no competing interests.

Authors’ contributions P-HL and SF conducted the review, P-HL drafted the manuscript and SF and WA edited and provided critical input. All authors read and approved the final manuscript.

Acknowledgements Funding was provided by grants 1K24CA160653 (Freedland), NIH P50CA92131 (W. Aronson). This manuscript is the result of work supported with resources and the use of facilities at the Veterans Administration Medical Center, West Los Angeles (W. Aronson).

Author details 1 Department of Medicine, Division of Nephrology, Duke University Medical Center, Box 3487, Durham, NC 27710, USA. 2 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. 3 Department of Urology, UCLA School of Medicine, Los Angeles, CA, USA. 4 Urology Section, Department of Surgery, Durham Veterans Affairs Medical Center, Division of Urology, Durham, NC, USA. 5 Duke Prostate Center, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC, USA.

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1997&ndas

Dietary fat has several essential functions in the human body. First, it functions as a supply of energy and structural components for the cells and second, it functions as a regulator of gene expression, which influences lipid, carbohydrate, and protein metabolism, along with cell growth and differentiation. The effects of fatty acids on gene expression are cell-specific and influenced by structure and metabolism. Fatty acids interact with the genome. They regulate PPAR, and the activity or nuclear abundance like SREBP. Fatty acids bind directly with one another to regulate gene expression.

What’s the role of fatty acids towards disease pathogenesis?

Alternately, fatty acids behave on gene expression through their effects on specific enzyme-mediated pathways, such as cyclooxygenase, lipoxygenase, protein kinase C, or sphingomyelinase signal transduction pathways, or through pathways that require changes in tissue lipid to lipid raft composition which affect G-protein receptor or tyrosine kinase-linked receptor signaling. Additional definition of these fatty acid-regulated pathways can offer insight into the role dietary fat plays in human health as well as the beginning and growth of many chronic diseases, such as coronary artery disease and atherosclerosis, dyslipidemia and inflammation, obesity and diabetes, cancer, major depressive disorders, and schizophrenia. The effects of fatty acids on gene expression, however, have been widely described on inflammatory bowel disease, or IBD.

Psoriasis Abstract

Psoriasis is a common T-cell-mediated immune disorder characterized by circumscribed, red, thickened plaques with an overlying silver-white scale. It occurs worldwide, although the incidence is lower in warmer, sunnier climates. The primary cause of psoriasis is unknown. During an active disease state, an underlying inflammatory mechanism is frequently involved. Many conventional treatments focus on suppressing symptoms associated with psoriasis and have significant side effects. This article reviews several of the researched natural approaches to psoriasis treatment, while addressing its underlying cause. (Altern Med Rev 2007;12(4):319-330)

Introduction

Recent genetic and immunological advances have greatly increased understanding of the pathogenesis of psoriasis as a chronic, immune-mediated inflammatory disorder. The primary immune defect in psoriasis appears to be an increase in cell signaling via chemokines and cytokines that act on upregulated gene expression and cause hyper-proliferation of keratinocytes. A new understanding of this complex disease has catalyzed the development of targeted biological treatments. These revolutionary therapies are not without potential risk, however. A review of alternative natural therapies provides some options for increasing safety and efficacy in the management of psoriasis. Psoriasis – Pathophysiology, Conventional, and Alternative Approaches to Treatment Michael Traub, ND, and Keri Marshall MS, ND

Epidemiology

The prevalence of psoriasis varies widely depending on ethnicity. Psoriasis occurs most commonly in Caucasians, with an estimated occurrence of 60 cases per 100,000/year in this population. Its prevalence in the United States is 2-4 percent, although it is rare or absent in Native American and certain African-American populations. While common in Japan, it is much less common in China, with an estimated incidence of 0.3 percent. The prevalence in the general population of Northern Europe and Scandinavia is 1.5-3 percent. Women and men are equally affected by this condition. The observation that latitude affects prevalence is most likely related to the beneficial effect of sunlight on the disease.1 Although psoriasis can occur at any age, the mean age of onset for chronic plaque psoriasis is estimated at 33 years, with 75 percent of cases initiated before age 46.2 The age of onset appears to be slightly earlier in women than men. Longitudinal studies suggest spontaneous remission may occur in about one-third of patients with psoriasis.3

Pathophysiology

Until recently psoriasis was considered a disorder of epidermal keratinocytes; however, it is now recognized primarily as an immune-mediated disorder. In order to properly understand the immune dysfunction present in psoriasis, it is imperative to understand the normal immune response of skin. Skin is a primary lymphoid organ with an effective immunological surveillance system equipped with antigen presenting cells, cytokine synthesizing keratinocytes, epidermotropic T cells, dermal capillary endothelial cells, draining nodes, mast cells, tissue macrophages, granulocytes, fibroblasts, and non-Langerhans cells. Skin also has lymph nodes and circulating T lymphocytes. Together these cells communicate by means of cytokine secretion and respond accordingly via stimulation by bacteria, chemical, ultraviolet (UV) light, and other irritating factors. The primary cytokine released in response to antigen presentation is tumor necrosis factor-alpha (TNF-α). Generally, this is a controlled process unless the insult to the skin is prolonged, in which case imbalanced cytokine production leads to a pathological state such as psoriasis.

Debate continues whether psoriasis is an autoimmune disorder or a T-helper 1 (Th1) immune dysfunction. T-cell activation, TNF-α, and dendritic cells are pathogenic factors stimulated in response to a triggering factor, such as a physical injury, inflammation, bacteria, virus, or withdrawal of corticosteroid medication. Initially, immature dendritic cells in the epidermis stimulate T-cells from lymph nodes in response to as yet unidentified antigen stimulation. The lymphocytic infiltrate in psoriasis is predominately CD4 and CD8 T cells. Adhesion molecules that promote leukocyte adherence are highly expressed in psoriatic lesions.4 After T cells receive primary stimulation and activation, a resulting synthesis of mRNA for interleukin-2 (IL-2) occurs, resulting in a subsequent increase in IL-2 receptors. Psoriasis is considered a Th1-dominant disease due to the increase in cytokines of the Th1 pathway – interferon gamma (IFN-γ), IL-2, and interleukin 12 (IL-12) – found in psoriatic plaques.

The increased IL-2 from activated T cells and IL-12 from Langerhans cells ultimately regulate genes that code for the transcription of cytokines such as IFN-γ, TNF-α, and IL-2, responsible for differentiation, maturation, and proliferation of T cells into memory effector cells. Ultimately, T cells migrate to the skin, where they accumulate around dermal blood vessels. These are the first in a series of immunologic changes that result in the formation of acute psoriatic lesions. Because the above-described immune response is a somewhat normal response to antigen stimulation, it remains unclear why the T-cell activation that occurs, followed by subsequent migration of leukocytes into the epidermis and dermis, creates accelerated cellular proliferation. Upregulated gene regulation may be a causative factor. Vascular endothelial growth factor (VEGF) and interleukin-8 released from keratinocytes may contribute to the vascularization seen in psoriasis.5

Dendritic cells appear to be involved in the pathogenesis of psoriasis. One type of dendritic cell involved is the Langerhans cells, the outermost sentinel of the immune system that recognizes and captures antigens, migrates to local lymph nodes, and presents them to T cells. The activation of T lymphocytes releases pro-inflammatory cytokines such as TNF-α that lead to keratinocyte proliferation. This hyperproliferative response decreases epidermal transit time (the approximate time it takes for normal maturation of skin cells) from 28 days to 2-4 days and produces the typical erythematous scaly plaques of psoriasis. This understanding of pathogenic mechanisms has led to the development and therapeutic use of TNF-α blocking agents.

About 30 percent of individuals with psoriasis have a family history of the disease in a first- or seconddegree relative. At least nine chromosomal susceptibility loci have been elucidated (PSORS1-9). HLA-Cw6 is a major determinant of phenotypic expression. An association with the PSORS has been found with functional polymorphisms in modifier genes that mediate inflammation (e.g., TNF-α) and vascular growth (e.g., VEGF).6

It is known that psoriasis develops in bone marrow transplant recipients from donors with psoriasis, clears in recipients from donors without psoriasis, and that immunosuppressive drugs are effective in reducing psoriasis.7,8 Given the genetic predisposition to this disease, what can be done to reduce the genetic expression besides resorting to immunosuppressive therapies? A naturopathic approach consists of dietary modification, therapeutic fasting, omega-3 supplementation, topical natural medicines, herbal medicine, and stress management.

Pizzorno and Murray propose the above-mentioned “unidentified antigens” result from incomplete protein digestion, increased intestinal permeability, and food allergies; bowel toxemia (endotoxins); impaired liver detoxification; bile acid deficiencies; alcohol consumption; excessive consumption of animal fats; nutrient deficiencies (vitamins A and E, zinc, and selenium); and stress.9 These hypotheses, although plausible, have not been adequately tested.

Co-Morbidities

Psoriasis is associated with several co-morbidities, including decreased quality of life, depression, increased cardiovascular risk, type 2 diabetes mellitus, metabolic syndrome, cancer, Crohn’s disease, and psoriatic arthritis. It remains unclear whether cancers, in particular skin cancer and lymphoma, are related to psoriasis or to its treatment. Phototherapy and immunosuppressive therapy can increase the risk of non-melanoma skin cancer, for example.10

Of particular concern is the observed link between psoriasis and cardiovascular disease. Evidence indicates psoriasis is an independent risk factor for cardiovascular disease.11 Dyslipidemia, coronary calcification, increased highly sensitive C-reactive protein (CRP), decreased folate, and hyperhomocysteinemia are found with significantly higher frequency in psoriasis patients.12 Inflammation is the common theme underlying both conditions, characterized by the presence of pro-inflammatory cytokines and endothelial activation.

The inflammatory processes underlying psoriasis also suggest the possibility of omega-3 fatty acid, folate, and vitamin B12 deficiencies, which are also often found in cardiovascular disease.13 High homocysteine and decreased folate levels correlate with Psoriasis Area and Severity Index (PASI). A rapid skin cell turnover rate in psoriasis may result in increased folate utilization and subsequent deficiency.14 The author of one study concludes: “Dietary supplementation of folic acid, B6, and B12 appears reasonable in psoriasis patients, particularly those with elevated homocysteine, low folate and additional cardiovascular risk factors.”15

Psoriatic arthritis is a clinical condition occurring in 25 percent of individuals afflicted with psoriasis.16 In approximately 10 percent of this population, the arthritic symptoms precede the skin lesions. Psoriatic arthritis often presents as seronegative inflammatory arthritis, with a classic presentation consisting of oligoarthritis, distal interphalangeal joint involvement, dactylitis (inflammation of the digits), and calcaneal inflammation.

Opinions conflict whether the skin condition and arthritis represent a differing manifestation of the same disease. Genetic evidence, immunological studies, and treatment response variability suggest they may be two different conditions, perhaps with similar underlying inflammation and immune irregularity.17,18

Although palmoplantar pustulosis (PP) is often described as a subtype of psoriasis, different demographics and genetic analysis suggests a different etiology than psoriasis. On appearance, PP has yellowbrown sterile pustules that appear on palms and soles. Only 25 percent of those affected report chronic plaque psoriasis. PP occurs more frequently in women (9:1/ female:male) and 95 percent of affected people have a current or previous history of smoking. As a result, PP may be considered a co-morbid condition rather than a distinct form of psoriasis.19

Diagnostic Criteria

Psoriasis is classified into several subtypes, with the chronic plaque (psoriasis vulgaris) form comprising approximately 90 percent of cases. Sharply demarcated erythematous silvery scaling plaques occur most commonly on the extensor surface of the elbows, knees, scalp, sacral, and groin regions. Other involved areas include the ears, glans penis, perianal region, and sites of repeated trauma. An active inflammatory case of psoriasis can demonstrate the Koebner phenomenon in which new lesions form at a site of trauma or pressure.

In the future, chronic plaque psoriasis might be found to consist of several related conditions with distinct phenotypical and genotypical characteristics, providing an explanation for its variable response to therapy, especially with biologic agents.

Inverse psoriasis occurs in intertriginous sites and skin folds and is red, shiny, and usually without scaling. Sebopsoriasis, which is often confused with seborrheic dermatitis, is characterized by greasy scales in the eyebrows, nasolabial folds, and postauricular and presternal areas.

Acute guttate psoriasis occurs in children, adolescents, and young adults approximately two weeks after an acute beta-hemolytic streptococcal infection, such as tonsillitis or pharyngitis, or a viral infection. It manifests as an erythematous, papular eruption with lesions less than 1 cm in diameter on the trunk and extremities. Acute guttate psoriasis is usually self-limited, resolving within 3-4 months. One study indicated only one-third of individuals with guttate psoriasis develop classic plaque psoriasis.20

Pustular psoriasis (von Zumbusch) is also an acute psoriatic eruption. The patient presents with fever and small, monomorphic, painful, sterile pustules, often precipitated by an intercurrent infection or the abrupt withdrawal of systemic or superpotent topical steroids. It can be localized to the palms and soles (palmar-plantar psoriasis) or it can be generalized and potentially life-threatening.

Erythrodermic psoriasis, also life threatening, involves the entire body surface and can result in hypothermia, hypoalbuminemia, anemia, infection, and high-output cardiac failure.

Psoriatic nail disease occurs in approximately 50 percent of psoriasis patients and most commonly manifests as pitting. Other nail changes can include onycholysis, discoloration, thickening, and dystrophy.

Risk Factors

Development of psoriasis involves interaction of multiple genetic risk factors with environmental factors, such as beta-hemolytic streptococcal infection, HIV, stress, and medications (e.g., beta-blockers and lithium). As previously mentioned, folate and vitamin B12 deficiency can also predispose. In addition, there is evidence that alcoholism, cigarette smoking, obesity, type 2 diabetes mellitus, and metabolic syndrome increase risk for developing psoriasis.

With the exception of VEGF, no biomarkers have been found as reliable predictors of psoriasis activity. CRP, soluble adhesion molecules, and soluble cytokine receptors have been investigated but do not correlate with severity.21

Conventional Treatment

Conventional treatment of psoriasis is based on the degree of severity. Mild and limited psoriasis treatment includes topical corticosteroids, tars, anthralin, calcipotriene (a vitamin D3 analog), tazarotene (a retinoid), and phototherapy. Physicians can set realistic expectations for therapy, giving the patient control over the disease without expectation of complete cure. Scalp psoriasis usually responds to salicylic acid shampoos.

Narrow-band UVB is less effective but safer than psoralen plus ultraviolet A (PUVA), which carries with it an increased risk of skin cancer. Sun exposure is another form of phototherapy. UV exposure reduces antigen presenting and affects cell signaling, favoring development of T-helper 2 (Th2) immune responses. Antigen-presenting Langerhans cells are decreased in both number and function.22

A topical combination of calcipotriene and betamethasone (Taclonex®) has shown greater efficacy in severe psoriasis than monotherapy with either alone.23

Patient compliance must be considered when developing a treatment plan. The use of less messy topical solution and foam preparations of topical corticosteroids and calcipotriene (compared to ointments and creams) can improve compliance.

Systemic treatment of severe psoriasis usually involves the use of oral retinoids, methotrexate, cyclosporine, and biological agents that can significantly impact other bodily systems.

The oral retinoid acitretin is teratogenic and is converted to etretinate with concomitant alcohol ingestion. Etretinate has a longer half-life and is more teratogenic than acitretin. Female patients must use two forms of birth control and must not become pregnant for at least three years after treatment. Because of possible interaction with oral contraceptives, St. John’s wort (Hypericum perfoliatum) should be avoided. Other adverse effects include mucocutaneous effects, elevated triglycerides, alopecia, and hepatitis. Treatment with acitretin requires frequent monitoring of blood counts, comprehensive metabolic profiles, and urinalysis. Strategies to reduce acitretin toxicity include intermittent use, reduction of maintenance dose to every other day or every third day, combination treatment with PUVA or topical calcipotriene, low-fat diet, aerobic exercise, fish oil supplementation, and as stated above, alcohol avoidance.

Methotrexate (MTX) is the most commonly used systemic agent for psoriasis and, because it has been available for 35 years, most dermatologists are comfortable with its use. Methotrexate inhibits dihydrofolate reductase (resulting in a deficiency of active folic acid) and induces adenosine A1, a potent anti-inflammatory agonist. Its mechanism of action may be even more complex, evidenced by the fact that caffeine inhibits MTX’s anti-inflammatory effects in rheumatoid arthritis but not in psoriasis or psoriatic arthritis.24 The most common serious adverse effects of MTX are myelosuppression and liver fibrosis. While myelosuppression does not frequently occur, patients using MTX often report symptoms of headache, fatigue, and nausea. Folate supplementation reduces the incidence of megaloblastic anemia, hepatotoxicity, and gastrointestinal intolerance. Although folic acid and folinic acid appear to be equally effective, folic acid is more cost effective.25 However, a recent double-blind study of 22 psoriasis patients stable on long-term MTX therapy revealed folic acid reduced MTX’s efficacy in controlling psoriasis. Patients were randomly assigned to receive 5 mg/day folic acid or placebo for 12 weeks. The mean PASI increased (worsened) in the folic acid group, from 6.4 at baseline to 10.8 at 12 weeks. In the placebo group, the mean PASI fell from 9.8 at baseline to 9.2 at 12 weeks (p<0.05 for the difference in the change between groups).26

Cyclosporine, a potent and toxic drug, is sometimes considered for cases not controlled with acitretin, PUVA, or MTX, but is contraindicated in patients with abnormal renal function, poorly controlled hypertension, hepatic dysfunction, or immunosuppression. Prolonged use inevitably results in renal damage. Blood pressure and creatinine monitoring is essential.

Biological agents block T-cell activation and TNF-α. Alefacept (Amevive®) interferes with T-cell activation and reduces circulating CD 45 RO+ T cells. This drug is a fusion protein of the Fc receptor of human IgG1 and LFA3, a co-stimulatory ligand, which interacts with CD2 on the surface of T-cells. CD4 cells must be monitored weekly during treatment with this agent.

Efalizumab (Raptiva®) is a humanized antibody to CD11 that interferes with T-cell trafficking into inflamed tissues and prevents T-cell activation. Although it is rapidly effective, rebound may occur.

TNF-α blockers downregulate proinflammatory gene expression and reverse the psoriatic phenotype. Etanercept (Enbrel®) is a fusion protein directed against soluble TNF-α. Infliximab (Remicade®) is a mouse/human chimeric monoclonal antibody against soluble and cell-bound TNF-α, while adalimumab (Humira®) is a human monoclonal antibody against TNF-α. These TNF-α inhibitors are administered by injection and have been associated with the induction of various autoimmune phenomena. Like TNF-α itself, TNF-α inhibitors can have both proinflammatory and anti-inflammatory activities. Just because a particular agent blocks TNF-α, it does not necessarily benefit psoriasis. If a patient is genetically predisposed to overproducing TNF-α, blocking it may not be sufficient to produce benefit.27 Possible risks of TNF-α blockers include reactivation of latent tuberculosis, hepatotoxicity, lymphoma, and congestive heart failure.

Challenges that remain with biologics for psoriasis include: (1) understanding the predominant mechanism in psoriasis and psoriatic arthritis; (2) understanding different patient responses to therapy; (3) predicting clinical response before or early in therapy; (4) developing oral, inhaled, and topical formulations; and (5) determining whether treatment alters longterm outcome.

Fumaric acid is the primary psoriasis therapy in Germany. It decreases T-cell dependent cytokines, but is not as effective as other conventional treatments, and carries a high risk of toxicity and gastrointestinal intolerance.

Providing rotational and combination therapies increases efficacy and decreases toxicity of treatment. The future may bring stem-cell therapy and gene-based therapies, including “antisense” treatments that directly inhibit psoriasis-specific genes. However, the adverse effects and toxicity of conventional psoriasis treatments necessitate safer and effective natural treatments that can be used as alternatives or in an integrative fashion.

Natural Treatments For Psoriasis

Diet

An evidence-based approach suggests psoriasis, essentially an inflammatory disorder, should benefit from an anti-inflammatory diet, identification, elimination and/or rotation of allergenic foods, and therapeutic fasting.28-30 Although there is no published data on food allergy avoidance, many psoriasis patients show increased sensitivity to gluten and their psoriasis symptoms improve on a gluten-free diet.31 Measurement of antibodies to tissue transglutaminase and gliadin can help identify this subgroup. Evidence also suggests maintaining a healthy weight benefits psoriasis patients, since psoriasis positively correlates with increased body mass index.32

The balance between proinflammatory and anti-inflammatory eicosanoids is influenced in large part by the type of dietary fatty acids consumed. An antiinflammatory diet consists basically of an emphasis on “good fats” (cold water fish, nuts, seeds, olive oil, other high quality oils), whole grains, legumes, vegetables, and fruits and the avoidance of “bad fats” (saturated animal fats, trans fats, fried and processed foods, poor quality oils) and refined carbohydrates. In addition, an excessive amount of omega-6 fatty acids in the diet can contribute to an inflammatory response.33 The primary sources of dietary omega-6 oils are vegetable oils such as corn, soy, safflower, and sunflower, while the primary sources of arachidonic acid are meat, eggs, and dairy.

Prostaglandin E2 (PGE2) is a prominent eicosanoid derived from the omega-6 fatty acid arachidonic acid. A dominant action of PGE2 as a messenger molecule is to enhance sensitivity in pain neurons, increase swelling, and constrict blood vessels. Over-consumption of omega-6 oils provides excess substrate for the synthesis of PGE2, which drives an aggressive and sustained inflammatory response. Prostaglandin E3 (PGE3) is derived from the omega-3 fatty acid, eicosapentaenoic acid (EPA). Higher levels of PGE3 reduce sensitivity to pain, relax blood vessels, increase blood flow, and support the body’s natural anti-inflammatory response (Figure 1).

While both PGE2 and PGE3 are necessary for proper homeostasis, the relative amounts of these competing messenger molecules either contribute to or mitigate chronic inflammatory syndromes. EPA is thought to act by competing with arachidonic acid for binding sites on cyclooxygenase-2 (COX-2), producing a less potent inflammatory mediator, therefore reducing inflammation.34

Prior to the Industrial Revolution, there were no significant sources of omega-6 vegetable oils in the diet. Most cultures consumed diets low in these oils and high in fish or range-fed beef or bison higher in omega-3s, creating a ratio of omega-6:omega-3 that was approximately 3:1. The Industrial Revolution brought with it the knowledge and tools to refine vegetable oils, resulting in a rapid shift in dietary habits for most Western cultures. The ratio of omega-6:omega-3 was quickly pushed toward the current estimate of as high as 11:1 omega-6:omega-3.35 The human body has not been able to genetically adapt to this dramatic shift in fatty acid consumption.

Many modern cultures consume copious amounts of vegetable oils, mostly in processed foods. For example, soy oil production for food consumption increased 1,000-fold between 1909 and 1999.36 In addition, livestock, poultry, and farmed fish are being fed cornmeal and soy-based feed, which raises the omega-6 content of the meat and fish. When farm animals are raised on grass, worms, or other natural diets, the tissues are naturally higher in omega-3 fatty acids.37

The beef industry touts “marbling” in finished beef products, which is due to the corn and soy feed. Corn- and soy-fed cattle have a higher omega-6 fatty acid content compared to grass-fed cattle. While grassfed cattle can contain up to 4-percent omega-3 fatty acids, corn-fed cattle typically contains 0.5-percent omega-3s.37

The standard American diet supplies an average omega-6:omega-3 ratio of approximately 11:1. A vegetarian-based diet may put an individual at risk for eating high amounts of vegetable oils and soy products, and low amounts of fish, which can tip the balance toward a pro-inflammatory state. Reducing dietary vegetable oils and increasing the omega-3 fats EPA and docosahexaenoic acid (DHA) by consuming fatty fish such as cod, salmon, mackerel, and sardines can benefit individuals experiencing chronic inflammatory conditions.33

Several herbs used as seasonings, including turmeric, red pepper, cloves, ginger, cumin, anise, fennel, basil, rosemary, garlic, and pomegranate, can block nuclear factor-kappaB (NFκB) activation of inflammatory cytokines.38

Dietary approaches that modify fatty acid intake can influence the eicosanoid profile in such a way that inflammatory processes such as arachidonic acid production and T-cell activation are dampened, while cytokines such as interleukin-4 (the primary cytokine responsible for stimulating a Th2 immune response) are upregulated.34

Nutritional Supplementation

Essential Fatty Acids

Essential fatty acids (EFAs) influence the pathophysiology of psoriasis in three ways: first, EFAs impact the kinetics of cell membranes; second, EFAs impact dermal and epidermal blood flow via improved endothelial function; and third, EFAs act as an immunomodulating agent through their impact on eicosanoids. EFAs are used as basic substrates in the development of the phospholipid bi-layer in virtually every cell in the human body, including the dermis and epidermis. They create structural integrity that regulates fluidity, which impacts cell transport, messenger binding, and cell communication. Omega-3 fatty acids can act both directly and indirectly on endothelial function by reducing mononuclear cell cytokines such as IL-1 and TNFα, 39 decreasing formation of chemo-attractant protein platelet-derived growth factor (PDGF), increasing bioavailability of nitric oxide, and reducing expression of adhesion molecules. The cumulative effect modulating these bioactive mediators is to prevent vascularization, or new blood vessel growth within the psoriatic plaque, while simultaneously allowing improved perfusion of dermal tissue.

Components of both natural and acquired immunity, including the production of key immune modulators, can be affected by omega-3 and -6 fatty acid intake, as discussed above. Immunomodulatory effects of omega-3 fatty acids include suppression of lymphoproliferation, CD4+ cells, antigen presentation, adhesion molecule presentation, Th1 and Th2 responses, and pro-inflammatory cytokine production.34

Several studies have demonstrated the benefit of intravenous or oral supplementation of fish oil for psoriasis.40-42 In a study by Mayser et al, intravenous infusions of omega-3 fatty acids led to an increase in the anti-inflammatory leukotriene B5 (LTB5) within 4-7 days of starting treatment, when compared to control patients.43 In this trial, patients received either an omega-3 or omega-6 preparation twice daily for 10 days. No side effects were noted.

EPA competes with arachidonic acid (AA) for 5-lipoxygenase and produces LTB5, which is only one-tenth as potent as the inflammatory mediator leukotriene B4 (LTB4). Levels of LTB4 have been shown to be elevated in psoriatic plaques and demonstrate chemotactic properties necessary for infiltration of leukocyte and keratinocyte proliferation.43

Ziboh’s review article on omega-3s and psoriasis references six studies conducted using oral fish oil supplementation with mixed results. Unfortunately, original references cannot be found. Two studies were double-blind and placebo-controlled, using 1.8 g EPA and DHA over courses of eight weeks and 12 weeks. The eight-week study demonstrated benefit in itching, scaling, and erythema, while the 12-week study showed no benefit.44

Three open studies were conducted, providing 10-18 g EPA and DHA daily for eight weeks. All studies showed improvement, with two studies demonstrating mild-to-moderate and one study demonstrating moderate-to-excellent improvement in scaling, itching, and lesion thickness. One open study combined with a low-fat diet showed a significant reduction in psoriatic symptoms.44,45

Several studies have explored the use of topical fish oil at varying EPA concentrations. Some studies reported benefits, including a reduction in plaque thickness and scaling.46,47 In one study by Puglia et al, fish oil extracts and ketoprofen were applied topically to psoriatic lesions, with an observed reduction in erythema.48 The most significant drawback to topical fish oil application is compliance due to the odor.

Fish oil has also proven to be beneficial in autoimmune joint conditions such as rheumatoid arthritis (RA).49 While fish oil supplementation has not been used in clinical trials for the treatment of psoriatic arthritis, it may be beneficial in treating this condition, which has many similarities to RA, including a common underlying inflammatory mechanism and immune dysfunction.

Folate

Methotrexate therapy results in a folate deficiency. As mentioned above, in patients receiving MTX for psoriasis, folate supplementation reduced the incidence of hepatotoxicity and gastrointestinal intolerance but might impair the efficacy of MTX.24 When supplementing with folic acid or the active forms, folinic acid or 5-methyltetrahydrofolate, the recommended dose is 1-5 mg/day.

Bioactive Whey Protein Isolate

XP-828L is a novel dietary supplement made of a protein extract derived from bovine whey that has recently been shown to be beneficial in psoriasis.50,51 The bioactive profile of XP-828L is likely due to the presence of growth factors, immunoglobulins, and active peptides found in this specific whey extract. An in vitro study demonstrated XP-828L has immune-regulating effects, including inhibiting the production of Th1 cytokines such as IFN-g and IL-2, which may make it effective in treating T-helper 1-related disorders, such as psoriasis.52

An open-label study was conducted on 11 adult patients with chronic, stable plaque psoriasis on two percent or more of total body surface area. Study participants received 5 g twice daily of XP-828L for 56 days. Evaluations using PASI and Physician’s Global Assessment (PGA) scores were made on the initial screening day and again on days 1, 28, and 56. At the conclusion of the study, seven of the 11 subjects had a reduced PASI score that ranged from 9.5 percent to 81.3 percent.50 The results of a larger double-blind, placebo-controlled study of 84 individuals with mildto-moderate psoriasis showed XP-828L (5 g/day for 56 days) significantly reduced the PGA score compared to placebo (p<0.05). No adverse affects were noted from any study participants in either study.50,51

Vitamin D

It has been established that patients with disseminated psoriasis have significantly decreased serum levels of the biologically active form of vitamin D, 1-alpha,25-dihydroxyvitamin D3 (1-α,25(OH)2D3; calcitriol) compared to age- and sex-matched controls and also compared to patients with moderate psoriasis.53 Whether this is a contributing factor to psoriasis or a result of the disorder has not been elucidated.

Keratinocytes in the epidermis convert 7-dehydrocholesterol to vitamin D3 in the presence of UVB. Sunlight, UVB phototherapy, oral calcitriol, and topical vitamin D analogs are effective therapy for psoriasis due to vitamin D’s anti-proliferative and pro-differentiating actions on keratinocytes.54-56

Calcitriol-binding to vitamin D receptors (VDR) in the skin modulates the expression of a large number of genes including cell cycle regulators, growth factors, and their receptors. Polymorphisms of the VDR gene are associated with psoriasis and may predispose to the development of psoriasis and resistance to calcipotriol therapy, as well as contribute to liver dysfunction in patients with psoriasis.57

Given vitamin D’s importance in psoriasis, cancer, inflammatory diseases, and other conditions, it has been suggested by some investigators that recommendations for sun protection and skin cancer prevention may need to be re-evaluated to allow for sufficient vitamin D status. A recent study showed abundant sun exposure in a sample of adults in Hawaii did not necessarily ensure vitamin D adequacy, which points to the need for vitamin D supplementation to achieve optimal blood levels.58

Studies have demonstrated that oral vitamin D can be safely taken in daily doses of up to 5,000 IU, with some experts recommending up to 10,000 IU daily to correct a deficiency.59-61 Oral and topical vitamin D, sunlight, and UVB phototherapy have shown considerable efficacy in the treatment of psoriasis.56

Topical Treatments Of Psoriasis

Several topical treatments for psoriasis may provide benefit, including calcipotriene (Dovonex®; a synthetic vitamin D3 analogue), Berberis aquifolium cream (10%)62 (Psoriaflora®; Relieva®), curcumin gel (1%), Aloe vera, and a flavonoid-rich salve (Flavsalve®).

Curcumin gel yielded 90-percent resolution of plaques in 50 percent of patients within 2-6 weeks; the remainder of the study subjects showed 50- to 85-percent improvement. Curcumin was found to be twice as effective as calcipotriol cream (which generally takes three months to exert its full effect). The mechanism of curcumin is as a selective phosphorylase kinase inhibitor, thereby reducing inflammation through inhibition of NFκB.63

A controlled trial of Aloe vera extract cream (0.5%) in 60 patients for 4-12 months demonstrated a significant clearing of psoriatic plaques (82.8%) compared to placebo (7.7%) (p<0.001). In addition, the PASI decreased to a mean of 2.2.64

The scaliness of psoriasis benefits from the use of emollients. Intercellular lipids such as ceramides (lipid molecules composed of fatty acids and sphingosine) play an important role in the regulation of skin-water barrier homeostasis and water-holding capacity. It has been shown that ceramides are decreased in the psoriatic epidermis. Newer ceramide-containing emollients (e.g., CeraVe®, Mimyx®, Aveeno Eczema Care) have shown benefit in psoriasis and may improve skin barrier function and decrease water loss.65

Botanical Influences

A Chinese herbal formula (Herose® Psoria Capsule) has demonstrated safety and efficacy in the treatment of severe plaque psoriasis.66 Herose consists of rhizoma Zingiberis, radix Salviae miltiorrhizae, radix Astragali, ramulus Cinnamomi, radix Paeoniae alba, radix Codonopsis pilosula, and semen Coicis. In an openlabel trial, 15 subjects took four Herose capsules (450 mg each) three times daily for 10 months. The investigator evaluated the PASI and therapeutic response to Herose for each patient. The formula is intended for warming the yang and promoting blood circulation.

Lifestyle Interventions

Lifestyle factors such as cigarette smoking and alcohol consumption are associated with severity of psoriasis.67 Physical activity and outdoor activities (taking precautions not to sunburn) are beneficial.68 Bathing and sunbathing at the Dead Sea for four weeks resulted in a decrease of PASI of 81.5 percent, a 78-percent decrease in keratinocyte hyperplasia, and almost total elimination of T lymphocytes from the epidermis, with a low number remaining in the dermis.69

Stress management can benefit individuals with psoriasis. Subjects who listened to a guided meditation tape while undergoing phototherapy cleared four times faster than those who received phototherapy only, as judged by two independent dermatologists. Psoriasis status was assessed in three ways: direct inspection by clinic nurses; direct inspection by physicians blinded to the patient’s study condition (tape or no-tape); and blinded physician evaluation of photographs of psoriasis lesions. Four sequential indicators of skin status were monitored during the study: a First Response Point, a Turning Point, a Halfway Point, and a Clearing Point. Subjects in the tape groups reached the Halfway Point (p= 0.013) and the Clearing Point (p=0.033) significantly more rapidly than those in the no-tape condition, for both UVB and PUVA treatments.70 Finally, psychotherapy can be an essential adjunct for individuals with persistent unresolved psychological issues such as anxiety, depression, and the psychosocial stress of this chronic skin disease.

Discussion

Psoriasis is characterized by T-cell activation that releases pro-inflammatory cytokines such as TNF-α, leading to keratinocyte proliferation and the typical skin lesions of psoriasis.

The conventional approach to psoriasis consists of utilizing topical and/or oral corticosteroids, other immunosuppressant drugs, oral retinoids, UV light, and several (not necessarily novel, having been used previously for Crohn’s and RA) biological agents. Although these treatments can be highly effective at controlling the disease, none are universally safe and effective, and each carries a considerable risk profile.

There is some evidence for the use of dietary modification and fish oil to decrease inflammation in psoriasis. More research is warranted to clarify the use of these and various topical botanical therapies and lifestyle interventions for improving clinical symptoms, decreasing the phenotypic expression of psoriasis, and providing safe and effective treatments.

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The most important function of the intestinal barrier is to balance the absorption of nutrients, electrolytes and water from the lumen into the blood flow and to prevent the entry of pathogenic microorganisms and toxic luminal substances. Additional regulation of this exchange of molecules between the environment and the host over the intestinal barrier affects the balance between immunity and tolerance to both self and non-self-antigens.

What's the significance of intestinal barrier function?

From a structural standpoint, intestinal barrier function is maintained by many components like a mucous coating and a single layer of epithelial cells connected with tight junctions. The mucus layer is made up of secretory immunoglobulin (Ig) A and antimicrobial peptides which cover the epithelial cell lining to ease gastrointestinal transport, or GI transport, and provide a protective coating against bacterial invasion. The colonic mucous coating consists of two layers, an outer and inner layer consisting of gel forming highly glycosylated proteins known as mucins. These are generated and preserved by goblet cells which repair the internal mucus layer roughly every hour. These dynamic procedures are subject to extensive and constant interactions between the gut microbiota, where the disruption of such may have consequences for the sustenance of crucial intestinal barrier function.

Hello there, it’s Dr. Alex Jimenez again and welcome to part four of “Taking Control of your Healthcare”. Today, we’re going to discuss hormones. Hormones regulate most of the human body’s systems as they are recognized as the messenger molecules of the endocrine system. Hormone imbalances can cause subtle changes, however, their effects can tremendously impact an individual’s overall health and wellness. And what’s worse, most healthcare professionals don’t treat hormonal imbalances unless they’ve already been considered extreme.

The sex hormones, the thyroid hormones, and the adrenal hormones are the most important hormones we have to keep in balance. There’s a variety of other hormones, of course, but health issues associated with those are often more rare. Many doctors generally won’t test a person for hormone imbalances unless they’ve been trying to conceive a baby or they have sexual dysfunction or any other health issue of this type. And frequently, many doctors miss other problems by performing a screening test rather than a complete test.

Cada reacción química que ocurre en el cuerpo humano requiere de enzimas y cada uno de estos procesos necesita una coenzima. Pero ¿qué son las coenzimas? Son vitaminas y minerales. Aproximadamente 37 billones, billones de reacciones químicas ocurren en el cuerpo humano cada segundo.

Es por eso que una nutrición adecuada y una dieta balanceada rica en alimentos integrales con vitaminas y minerales es fundamental para la salud y el bienestar general. La mayoría de las personas en los Estados Unidos son deficientes en vitaminas y / o minerales. Pero, ¿cómo sabes si eres parte del 90 por ciento de las personas con suficientes deficiencias para desarrollar una enfermedad? Discutiremos las pruebas que puede realizar para averiguar si tiene deficiencia de vitaminas y / o minerales y qué puede hacer al respecto.

Hoy analizaremos los fundamentos de la medicina funcional y cómo puede construir una relación saludable entre médico y paciente.

Si visita al médico porque ha experimentado migrañas, eczema, síndrome del intestino irritable y depresión, lo más probable es que lo refieran a cuatro especialistas diferentes e incluso se le receten un mínimo de cuatro medicamentos diferentes. Un enfoque de la medicina funcional comprende que puede haber problemas comunes de salud que pueden estar causando los síntomas de un paciente. Una vez que llegue al origen del problema, se puede solucionar los problemas de salud que crean los síntomas.

La medicina funcional pregunta: “¿Por qué tiene esos síntomas y cómo podemos tratar la fuente del problema y mejorar su salud y bienestar general?”, en lugar de “¿Qué enfermedad tiene y qué medicamento usa para tratarla?”

Each chemical reaction which occurs in the human body requires enzymes and each one of these processes needs a coenzyme. But what are coenzymes? They are vitamins and minerals. Approximately 37 billion, billion chemical reactions occur in the human body every second.

That is why proper nutrition and a balanced diet rich in whole foods with vitamins and minerals is fundamental towards overall health and wellness. The majority of people in the United States are vitamin and/or mineral deficient. But, how do you know if you’re a part of the 90 percent of individuals with enough deficiencies to develop disease? We will discuss the tests you can utilize to find out if you’re vitamin and/or mineral deficient and what you can do about it.

Today we will begin to discuss how the spectrum which medicine currently considers “normal” may not actually be optimal towards your overall health and wellness. These reference ranges can change based on age, gender, physical activity, and more. As a matter of fact, if we were to evaluate an individual’s weight in the United States, it would be considered “normal” to be overweight, simply because 70 percent of the population is overweight. Reference ranges for lab tests today are based on a sick population when we should aspire for optimal well-being.

Then, I will demonstrate how this knowledge can apply to the most basic medical measurements: your vital signs. Everyone knows that when you first visit a doctor, they take your vital signs, including your weight, your blood pressure, your heart rate, and your temperature. However, does your doctor tell you what your results mean? How can you tell if you’re healthy?

The endocannabinoid system's discovery has created debate in its conclusions on human health. Because of its capability to target various therapeutic agents that are in different states of disease has piqued interest for researchers.

Some researchers suggest the endocannabinoid system plays a vital role in cellular homeostasis. This could mean that the health of this system could affect the health of the whole body.

What is the endocannabinoid system and why is it important?

This article reviews the basics of the endocannabinoid system and its role in cardiovascular and neurological health and specifically, endocannabinoid system deficiency and the adverse effects on the other body's systems.

Endocannabinoid System & What It Consists Of

The endocannabinoid system is comprised of two receptors and a series of internally produced compounds. The two main receptors in the endocannabinoid system are the CB1 and CB2 receptors.

Endocannabinoid comes from the fact that cannabinoids from the cannabis plant interact with receptors in the endocannabinoid system. There are many endocannabinoids, the most widely known and studied is;

N-arachidonoylethanolamine (AEA).

AEA increases in times of oxidative stress, inflammation or cell death. Researchers believe that it may be produced as a response to injury when counteracting inflammatory activity. This activity could be the evidence of the systems role in cellular homeostasis.

CB1 and CB2 receptors are found throughout the body. CB1 receptors are primarily found in the nervous system, while CB2 receptors are primarily found in intestinal epithelium cells and immune system cells.

CB1 receptors predominantly interact with THC and other psychoactive compounds from the cannabis plant. This is a logical find because the CB1 receptors are found primarily in the nervous system. This interaction of CB1 receptors and THC could cause certain changes in brain chemistry, which leads to the euphoric feeling produced from cannabis use.

CB2 receptors interact with cannabidiol (CBD) which is a secondary major compound in cannabis. This does not mean that CBD does not interact with CB1 receptors ever, but because these interactions are quite uncommon they are considered unimportant. Because CBD does not have compelling interaction with CB1 receptors, the psychoactive effects from THC are not present.

Both cannabinoid compounds have therapeutic potential. Studies have found these compounds help control chronic inflammation in conditions like IBS (irritable bowel syndrome).

THC use in modulating endocannabinoid system deficiency has been very limited because of its psychoactive properties. Because of this, THC has become rejected in many U.S. states, the U.S federal government, and in conservative countries around the world. Researchers refrain from investigating its therapeutic properties or recommending it, as an alternative medicine.

Cannabinoid Research Marches On Despite THC Affects

CBD contains the same therapeutic properties as THC, without the psychoactive effects. CBD is under extensive research, as a compound that can help with various diseases and their progression. This has led researchers to create synthetic compounds that mimic CBD and its interaction with CB2 receptors.

The endocannabinoid systems role in cardiovascular health and disease.

Depending on the receptors involved cardiovascular health, and the endocannabinoid system's activation could lead to beneficial or conflicting effects.

CB1 receptors have been linked to an increase of cardiovascular disease or cardiovascular incidents.  Incidents include heart attack, atherosclerosis (plaque inside the blood vessels ), stroke, kidney dysfunction and liver problems. Animal models and epidemiological studies have shown these findings.

However, activation of the endocannabinoid system's CB2 receptors may have cardioprotective properties. Certain animal studies show how the use of synthetic cannabinoids interacting with CB2 receptors could beneficial for heart attacks. This comes from their ability to limit infiltration of cells that cause inflammation by CB2 activation.

The Clinical Significance

The difference between CBD and THC:

THC use, as a therapeutic agent could increase risk of cardiovascular incidents from interaction with CB1 receptors. But CBD also interacts with CB2 receptors and is possible that administration of CBD could lead to cardioprotective effects.

Adult neurogenesis, brain health and the endocannabinoid system

Various research reports show neural-progenitor cells produce endocannabinoids in time of injury and stress. This stimulates cell division in the brain, especially in areas like the hippocampus and sub-ventricles. This division is believed to be produced through interaction of endocannabinoids and CB1 receptors. 

Other reports have shown CB1 deficient mice have a decreased ability in neural progenitor cell division when a nervous system injury occurs. This could mean CB1 deficient mice have less of a chance to recover from stroke or other type of brain injury compared to mice with CB1 at normal levels.

AEA, for example, induces astroglial proliferation in mice. Astroglia are star-shaped neurons thought to be extremely important for brain structure and protection. These are found in various areas like the blood brain barrier. Pharmacological stimulation of CB1 using synthetic cannabinoids has lead to neurogenesis or new growth of nervous tissue.

Can Synthetic Cannabinoids Be Beneficial For Brain Health

Synthetic cannabinoids could be beneficial not just for brain injuries, but could also be utilized as an antidepressant. The synthetic cannabinoid HU210 has been used for this purpose from its ability to modulate the endocannabinoid system and increase neural growth.

Recent studies show that CB1-deficient mice tend to suffer from early age related cognitive impairment or a noticeable and measurable decline in cognitive abilities, which include memory and thinking skills. This could be because CB1 deficient mice cannot regenerate cells in the nervous system, making them succumb faster to age related cellular death. But this is a perfect example of endocannabinoid system deficiencies, which could lead to detrimental effects in humans.

Injury Medical Clinic: Stress Management Treatment

Autoimmunity: One of the most common things is to leave the doctor’s office with a diagnosis of an autoimmune disease and no nutritional or lifestyle changing insight. Autoimmune diseases are related to inflammation. Keeping  the inflammation down is the goal with autoimmune attacks. The foods you eat make a huge difference in the frequency and severity of flare-ups. Steady dietary changes can help you reach your optimal self.

Is Autoimmune Disease A Result Of The Collective Perturbations Of The Exposome & Its Impact On The Immunometabolic System? 

The Exposome

Semin Arthritis Rheum. 2018; 47(5): 710‐717.

Exposome Influence On SLE

The Ecology Of The Exposome

Exposome & The Alteration Of “Self”

The Exposome Connections To Autoimmune Diseases Converting Self Into Non‐Self

• Immunometabolic dysfunctions through diet and lifestyle imbalances
• Gut Ecology and the Microbiome
• ViralorBacterialInfections
• Hormones
• Drugs
• Chemicals
• IonizingRadiation
• PsychologicalStress

FEBS Lett. 2017 Oct;591(19):3119‐3134.

Cell. 2018 Jan 11;172(1‐2):22‐40.

Cross‐Talk Among The Endocrine, Immune & Metabolic Systems

Multi‐Organ Network Biology

In Autoimmunity, Warburg Metabolism Is Increased Through Increased Activity Of GAPDH

Science. 2018; 360: 377‐78. Dietary Influence?

Blocking Immune Cell Glycolysis & “Starving” Its Function

Science. 2018; 360: 449‐54.

Ketogenic Diet’s Potential Impact On GAPDH Immunometabolic Regulation

Cell. 2018 Jan 11;172(1‐2):162‐175.

Gut Microbes. 2016;7(1):82‐9.

Front Immunol. 2017 Mar 21;8:311.

Origin Of IL‐17 Producing Th17 Cell

What Is The Relationship Of The Gut Microbiome To Autoimmune Disease?

Science. 2018 Mar 9;359(6380):1097‐98.

Science. 2018 Mar 9;359(6380):1156‐61.

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Int J Mol Sci. 2015 Sep 1;16(9):20841‐58.

Science. 2018 Mar 9;359(6380):1151‐56.

High Fiber Influences On Diabetes In Animal Model

80% Of Patients With Autoimmune Disease Are Female

Why?

Estrogen & Autoimmunity

• The greatest association with autoimmune diseases is the female gender
• 17‐beta estradiol seems to play a role in activating T cells in autoimmune disease
• T cells have ER‐alpha receptors that are activated by 17‐beta estradiol resulting in the production of inflammatory cytokines
• Blocking ER‐alpha receptors may have a beneficial effect on autoimmune activation

Sci Signal. 2018 Apr 17;11(526). piieaap 9415

Eleanor Rogan, PhD IFM Linus Pauling Award Winner

www.JeffreyBland.com

Estrogen & Androgen Metabolism

4‐Hydroxyestrogens & DNA reactivity

Indole‐3‐Carbinol (I3C) Inhibition Of ER‐Alpha

Relationship Of Hepatic Drug Detoxification To Anti‐Nuclear Antibody Development

Biomed Res Int. 2015;2015:194031.

Making Friends With Ourselves: Clinical Implications

• Reduce exposure to agents that activate immunometabolic dysfunction through the exposome
• – Dietary
• – Infection
• – Parasites
• – Xenobiotics
• – Hormone
• – Allergy
• – Specific medications
• – Dysbiosis
• Reduce exposure to DNA damage (radiation, chemicals)
• Support hepatic detoxification
• Implement gastrointestinal restoration program
• Reduce metabolic inflammation and endotoxin
• Reduce psychological stress factors that activate HPA axis

Jeffrey Bland, PhD

Chairman Emeritus & Member, Board of Directors The Institute for Functional Medicine