Chronic Inflammatory Response Syndrome (CIRS) Evaluation and Treatment

Chronic Inflammatory Response Syndrome (CIRS) Evaluation and Treatment

Introduction

When a patient presents to a doctor with many symptoms, has seen many doctors, and has not improved despite many attempts by the most well meaning practitioners, both traditional and alternative/integrative/functional, it is time to consider whether a diagnosis of CIRS may be playing a role in his presentation. However, this decision can be complex. Unless a specific roadmap is followed and a process of deductive reasoning applied to a differential diagnosis, one may find oneself in a quagmire of conflicting information.

What will follow in this essay is a step by step map for health care practitioners to follow in the process of deductive reasoning in the consideration of whether CIRS may be underlying the patient’s presentation. Unless a practitioner follows an evidence-based protocol of carefully developed steps as outlined by Dr Shoemaker and others, one may be tempted to omit or skip specific steps in the diagnostic process thereby reaching conclusions that are not in keeping with the published research. Thus, it is vital to follow the steps exactly so to support or refute the evidence.

Health care practitioners must precede a diagnostic workup for CIRS with the normal workup one employs for chronically ill patients: present history, presenting symptoms, past history, family history, medications, allergies, supplements, surgeries, dental history, toxin exposure, review of systems. A cognitive and mood history is also essential. As a certified functional medicine practitioner, I am most interested in the timeline of illness presentation, as well as any antecedents, mediators, and triggers that may fall outside of the CIRS presentation.

However, if the patient’s symptom clusters point towards a possible diagnosis of CIRS, the diagnosis of CIRS must be included in the differential diagnosis.  It is then incumbent upon the practitioner to enquire as to whether or not there have been any exposures to the possible agents and/or biotoxins that are responsible for initiating this potential diagnosis and if so, to then follow the rest of the diagnostic criteria to establish the diagnosis.  

Questions to ask patients who have been exposed to water damaged buildings include: Do you/did you live in a building with obvious mold visible? Has your home ever been flooded?  Is there any obvious water intrusion? Do you smell musty odors? Does your home have condensation on the windows? Are there any water stains around your light fixtures in the ceilings? Did you feel worse after you moved homes, school, and work place? Has conventional air quality testing revealed mold spores present?

Further questioning includes: Have you had a tick bite, EM rash, severe flu-like illness that persisted after visiting Lyme endemic areas? Have you been exposed or swam in a body of water with an algae bloom? Have you ever been in waters/estuaries where sudden fish kills were reported through direct contact or inhalation of aerosolized or volatized toxins? Have you eaten reef fish and felt ill soon afterwards? Have you ever had a spider bite (brown recluse spider)?

Background Information prior to engaging in the diagnostic criteria

Immune System

The immune system is composed of two major subdivisions: the innate or nonspecific and the adaptive or specific immune system (found only in vertebrates). We are born with innate immune responses intact; we develop adaptive immune systems after birth.

The innate immune system is the body’s primary defense mechanism against invading antigens: the adaptive immune system is summonsed by the innate immune system as a second line of defense provided there are no HLA genetic defects in the individual (74% of the population).

26 % (1 in 4) of the population has an aberrant HLA system that leads to upregulation of the innate immune system with an inability to adequately notify and summons the adaptive immune system.

This defective setup informs the basic underlying issue with CIRS; an aberrant upregulation of the innate immune system due to biotoxin inducing triggers, with a defective adaptive immune response to these inflammatory signals

Innate System

  • Acts almost immediately to infection, the adaptive takes longer to respond
  • Is not specific to a particular antigen and reacts the same way to a variety of infectious agents and inflammagens.
  • Recognizes toxins with pattern recognition receptors
  • Does not provide long-lasting immunity to the host
  • Communicates with the adaptive immune system via macrophages/monocytes and dendritic cells as antigen-presenting cells, the first responders of the innate immune system
  • Recruits immune cells to the site of infection via the use of cytokines and TGF beta-1
  • Activates the complement cascade system to assist in removing antigens
  • Presents toxins to the adaptive immune system naïve lymphocytes called T cells, the lead cells of the adaptive immune system. These inflammatory molecules do not have a specific target and they do not remove biotoxins. Trichothecenes, the biotoxins released from Stachybotrys and Fusarium mold species can slow the maturation rate of dendritic cells, [1] resulting in defective antigen presentation to the adaptive immune system

Both aspects of the immune system have cellular and humoral components.


[1] Hymery N, Sibiril Y, Parent-Massin D. In vitro effects of trichothecenes on human dendritic cells. Toxicol In Vitro. 2006 Sep; 20 (6): 899-909. PMID: 16517116

Adaptive System

  • Provides long term immunity by creating immunological memory after the initial exposure to a specific pathogen or biotoxin
  • Adaptive immunity involves the destruction of foreign pathogens and presentation of their peptide remains to T cells to begin process of antibody production by B cells, and NK cells and cytotoxic T cells. [1]  The T cells teach the B cells to recognize and respond to invading toxins so that, in the future, if re-exposed, antibodies produced by the B cells can mount an appropriate antibody response  
  • In biotoxin illness, due to specific genetic HLA susceptibilities, the adaptive system cannot see the biotoxins presented to them by the innate system and thus cannot produce antibodies to neutralize them. The toxin isn’t recognized as foreign. [2] These toxins have a unique structure called “ionophores” that prevent them being metabolized or excreted. The innate immune system continues to create inflammatory cytokines, leading to dysregulation of multiple systems and thus the CIRS diagnosis 
  • Patients with CIRS have dysfunction of T reg cells which are converted into pathogenic T lymphocytes via the inflammatory cytokine TGF beta-1
  • B cells, the cells of TH 2 immunity, tend to fight infections and inflammagens outside of the cell and produce antibodies
  • T cells, the cells of TH 1 immunity, tend to fight infections and inflammagens within the cell and produce transfer factors. Transfer factors are made in a similar fashion to B cells antibodies [3]

[1] Ryan J, Shoemaker R. Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin. BMC Medical Genomics 2015 8:15

[2] Shoemaker R. Mold Warriors . Otter Bay Books Baltimore pg. 63

[3] Rappaport S. The Evaluation and Treatment of Chronic Inflammatory Response Syndrome. Pg 16

Case Definition of CIRS

Chronic Inflammatory Response Syndrome (CIRS) is a syndrome which was originally described and expanded upon by Dr Ritchie Shoemaker in the late 90s. To date, there are over 1700 scientific articles on this condition. 

CIRS is defined as a multi-symptom, multisystem illness caused by exposure to biotoxins or neurotoxins derived from a biological source. [1]  It is associated with a well-defined set of abnormal biochemical disorders and test results in genetically susceptible individuals.

In a 2013 paper, CIRS was described as a chronic, progressive, multi-system, multi-symptom syndrome characterized by exposure to biotoxins, HLA genetic predisposition, altered innate and adaptive immunity, peripheral hypoperfusion at multiple sites and multiple hypothalamic-pituitary-end organ dysregulations. [2] This inflammatory dysregulation can affect every organ in the body and if left untreated, can become debilitating. Diagnosis begins with a history of symptoms suggestive of CIRS plus a history of exposure to a known trigger. Once these criteria are established, a set of specific diagnostic biomarkers is undertaken to establish the diagnosis. 

Biotoxins are extremely small, fat soluble molecules capable of going from cell to cell through membranes without being carried directly in the blood stream rendering them impossible to find in the blood stream. Biotoxins can enter through inhalation, direct contact with contaminated water, ingestion, tick bites and spider bites. These biotoxins, in genetically susceptible people whose immune system (antibodies) do not recognize and tag them, lead to chronic inflammation and long lasting chronic illness. Biotoxins bind to certain surface receptors, particularly those on white blood cells (macrophages, monocytes and dendritic cells) called antigen presenting cells.

Pattern recognition receptors (PRRs) are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with cell components that are released during cell damage or death. The microbe-specific molecules that are recognized by a given PRR are called pathogen-associated molecular patterns (PAMPs) and include bacterial carbohydrates (such as lipopolysaccharide or LPS, mannose), nucleic acids (such as bacterial or viral DNA or RNA), bacterial peptides (flagellin,


[1] Shoemaker RC, House D, Ryan J, Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health, 2013;5 (3): 396-401

[2] Shoemaker R.C. Ryan JC Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health 5 (3), 396-401

microtubule elongation factors), peptidoglycans and lipoteichoic acids (from Gram-positive bacteria), N-formylmethioninelipoproteins and fungal glucans, mannans, and chitin.

Endogenous stress signals are called damage-associated molecular patterns (DAMPs) and include uric acid and extracellular ATP, among many other compounds.[1]

This binding releases specific amounts of inflammatory molecules, cytokines, complement and TGF beta-1- the innate immune system activation sequence. This inflammation is not specific and cannot remove the biotoxins but result in persistent inflammation and a syndrome now known as CIRS.

Unlike bacterial or viral pathogens, which can be identified in blood work, biotoxins cannot be identified by routine blood tests and therefore one needs to rely on identifying them via the damage they inflict on the immune system, neuropeptide hormones and end-organ hormone systems.

Keith Berndtson MD, describes the structure of biotoxins in his Chronic Inflammatory Response Syndrome essay.[2] For example, cell membranes depend on ion channels to transport potassium, sodium and calcium ions in and out of cells. Biotoxins show the structural forms of amphipathic ionophores, creating ion channels that disrupt cell electrodynamics and hence the battery-like charge, rendering the cell incapable of performing its energy producing functions derived from the ion pumps. They also behave as “rogue” ion channels.

Biotoxins have both water and fat-soluble capacities. Biotoxins nestle on the inner fat-soluble membrane of cells, thus showing a predilection for fatty tissue like the brain, nervous tissue and the autonomic nervous system. Thus, they disrupt cell function without destroying the cell; as opposed to pore-forming toxins which create large holes in cell membranes, which are enough to kill the cell itself.

Cell-signaling is disrupted inside the cell by the disruption in the ion movement. The cell then triggers a defensive response by activating genes that code for inflammatory cytokines, on top of the already overworked innate immune system driven by CIRS. Elevated TGF beta-1 is a sign that the body is over revving from both an innate and an adaptive immune system T cell response.

CIRS biotoxins are first and foremost neurotoxins due to the fatty acid predilection with the brain being a common site, especially if there is porous blood-brain barrier.  Cardiovascular and GI sites are also common organ sites due to the rich nervous innervation and the fact that these biotoxins reside intracellularly in the fatty acid membrane, not accessible in the blood stream. They are difficult to dislodge particularly when the adaptive immune system is not adequately working.

Originally, the case definition criteria included Tier One and Tier Two criteria. All tier-one criteria had to be met and three of the six tier- two criteria had to be met to confirm the condition. As research progressed and deeper insights were gained, Dr Shoemaker updated his case definition in 2006 by including Tier-Three criteria which described the response to successful treatment.

 In 2008, the Government Accountability Office (GAO) issued their case definition, which was largely reliant on the published work of Dr. Shoemaker. It is the definition commonly used today. Dr. Scott McMahon at the 2016 Surviving Mold Conference at Irving, California, recommended that the GAO case definition be used in clinical practice.


[1] https://en.wikipedia.org/wiki/Pattern_recognition_receptor

[2] Berndtson K. Chronic Inflammatory Response Syndrome, 2013

TIER ONE CRITERIA – all three must be met

1. Exposure

The patient must have a story of an exposure to a biotoxin causing illness.

Mold – water damaged buildings (due to faulty construction, defects in ventilation, condensation issues, high humidity, leaky pipes, poor basement designs, flat roofs without adequate ventilation, fake stucco, faulty appliances, poorly ventilated bathrooms, front end loading washing machines) host microbial growth (bacteria, fungi, mycobacteria and actinomycetes) and produce over 30 different toxins and inflammagens (including mannans, beta glucans, hemolysins and proteinases). Toxic metabolic fragments and cell wall fragments from these filamentous molds are the major source of these biotoxins.

Mold is a specific biotoxin producing component of many water damaged buildings. In 2011, the National Institute for Occupational Safety and Health reported that 50 % of buildings have sustained water damage. Indoor fungi such as Stachybotrys, Aspergillus, Acremonium, Penicillium and Chaetomium have been implicated.

The Center for Disease Control (CDC) agrees with these findings, stating in a paper published after Hurricane Katrina and Rita in New Orleans, “Mold, endotoxins and fungal glucans were detected in the environment after Hurricanes Katrina and Rita in New Orleans at concentrations that have been previously associated with health effects.” [1]  Among the sources of biotoxins that can produce CIRS, biotoxins from molds known to grow in water damaged buildings (WDB) account for some 80% of the CIRS-related illness burden.[2]

Lyme disease- Borrelia burgdorferi infections produce a biotoxin (Bbtox1). [3]A history of a tick-bite, an EM rash, followed by a flu-like illness and the use of suitable testing (Elisa plus confirmatory Western Blot) is required to make the diagnosis. Lyme disease and post Lyme treatment syndrome remains a highly contentious area of investigation. Dr Shoemaker’s research showed that up to 21 % of the population is genetically Lyme susceptible, more likely to develop post-Lyme syndrome and less responsive to antibiotics for Lyme disease. They will be more likely to have an upregulated, persistent, inflammatory immune response due to the circulating neurotoxins, in spite of the bacteria being adequately killed by antibiotics.

A 2010 paper showed that Borrelia antigens may bind to pattern recognition receptors of the innate immune system and result in decreased CD 38 and thus decreased dendritic cell activation.[4]  Individuals thus have genetically determined defective protective antibody production and upregulated innate immune systems; they fail to respond to antibiotics, the definition of post-treatment Lyme syndrome (PTLS).


[1] Rao C, Brown C, et al. Applied and Environmental Micro 2007; 73 (5); 1630-1634

[2] Berndtson K. Chronic Inflammatory Response Syndrome. 2013. Pg 3

[3] Cartwright MJ, Martin SE, Donta ST. A novel neurotoxin (Bbtox1) of Borrelia burgdorferi. Meeting of the American Society for Microbiology. 1999 May: Chicago.

[4] Hartiala P, Hytonen J, et al. TLR2 utilization of Borrelia does not induce p38 and IFN-beta autocrine loop-dependent expression of CD38, resulting in poor migration and weak IL-12 secretion of dendritic cells. Journal of Immunology 2010 May 2015;184 (10): 5732 -42.

Invertebrate species producing neurotoxins including dinoflagellates (ciguatera and red tide), Pfiesteria (PEAS), and cyanobacteria- (freshwater blue-green algae Cylindrospermopsis and Microcystis – a genus of freshwater cyanobacteria) exposure. Ciguatera fish poisoning is the most common marine toxin poisoning worldwide with an estimated 50,000-500,000 cases annually. [1] Ciguatoxins are dinoflagellates of the genus Gambierdiscus found in numerous (over 400) reef fish such as barracuda, grouper and snapper with larger and older fish higher up the fish chain being the most toxic.

Poisonous spiders like Brown Recluse and Mediterranean Recluse spiders.


[1] Ryan J, Shoemaker R. Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin. BMC Medical Genomics 2015 8:15

2. Other Diseases

are ruled out via a thorough differential diagnosis workup. Patients with CIRS are often misdiagnosed as having depression, anxiety, PTSD, somatization, Alzheimer’s, Parkinsonism, allergy, ADD/ADHD, fibromyalgia and Chronic Fatigue Syndrome. If treated for these underlying conditions, it will make no difference to their underlying CIRS diagnosis. [1]


[1] Ryan J, Shoemaker RC, RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal polypeptide (VIP)shows a shift in metabolic state and innate immune fluctuations that coincide with healing. Medical Research Archives Vol 4 Issue 7 2016.

3. Symptoms

  1. must be allied with the clinical picture as outlined by Dr. Shoemaker in numerous publications.  

Symptoms associated with CIRS (37 in number) are grouped into 8 organ system categories. Symptoms in at least 4 out of the 8 organ system categories (below) are considered diagnostic.

 The symptoms categories are listed in the table below:

  1. General fatigue and weakness
  2. Muscles – aches, cramps (claw-like cramping of hands and feet), joint pains, morning stiffness, ice-pick pains
  3. General – headache, frequent urination and increased thirst, night sweats, static electricity or shocks, appetite swings.
  4. Eyes – light sensitivity, red eyes, blurred vision, tearing
  5. Respiratory – sinus congestion, cough, shortness of breath
  6. Gastrointestinal – abdominal pain, diarrhoea
  7. Neurological – numbness, tingling, metallic taste, vertigo, temperature regulation, dizziness, tics, atypical seizures, fine motor skill problems
  8. Cognitive – memory loss, concentration difficulties, confusion, learning difficulties, difficulty finding words, disorientation, mood swings, anxiety, panic

These 8 categories are further organized in a questionnaire (below) into 13 symptom clusters. Each cluster has between 1-5 symptoms. The clusters were selected by statisticians in order to maximize predictive capabilities.  A patient presenting with at least 1 symptom in at least 6 of the 13 clusters for more than two weeks, needs to be considered as having the CIRS diagnosis and should have a thorough diagnostic workup. In adults, if symptoms are present in at least 8 symptom clusters, this is considered consistent with biotoxin illness. In children, if symptoms are in 6 symptom clusters, these results are considered positive.

Clinical questionnaire chart

Signs

Signs were not included in the Three Tier categories.

There are many possible clues on physical examination as to the possibility of a CIRS diagnosis:

  1. Red eyes
  2. Tremor – resting.
  3. Cool hands and feet
  4. Discolored hands and feet
  5. Pallor
  6. Weakness in the shoulder extensor muscles
  7. Decreased muscle strength in the arms and forearms
  8. Grip strength and shrugging of shoulders against resistance
  9. Hyper flexibility – Flexibility is tested
  10. A full examination of all systems is to be done, including thyroid, cardiac and respiratory systems[1]

[1] Shoemaker R. Biotoxin Illness Treatment Protocol Pg. 1

TIER TWO CRITERIA – at least three of the following six criteria must be met

1. Abnormal Visual Contrast Sensitivity (VCS)   

http://www.survivingmold.com/store1/online-screening-test

  • In 1997, Dr. Shoemaker and Ken Hudnell published a study demonstrating that patients with exposure to biotoxins showed abnormal VCS results consistent with biotoxin illness. The visual contrast test measures the neurologic function of the optic nerve from the retina to the cortex by measuring the least amount (threshold) of luminescence difference between adjacent areas (contrast) necessary for an observer to detect a visual pattern.
  • The test measures contrast sensitivity for five sizes (spatial frequencies) of light, gray and dark bar patterns (sinusoidal gratings). The VCS eliminates near, far, color, motion and peripheral vision variables.
  • There are spatial frequencies measured amongst healthy individuals which is the curve formed by the highest level of contrast the patient will see, versus the CIRS patients who will have lower contrast sensitivities and their curves will fall below the healthy control line. Higher contrast sensitivity is better.
  • In the presence of biotoxin illness, visual contrast sensitivity decreases. Only rows C and D count for scoring pass or fail. One must see 7 in each eye on C and 6 in each eye on D.  Rows D and C show improvement with clearing of biotoxins. With an intensification reaction to cholestyramine, there will be a fall in column E followed by a fall in column D. [1] A fail in 1 eye and not the other eye, still constitutes a fail.
  • VCS appears to be an early, persistent, highly sensitive, inexpensive and easily measured indicator for biotoxin illness.[2] Only 8 % of people with CIRS will have a normal VCS. Thus, 92 % of people with biotoxin illness will fail the VCS. However, 98 % of patients who fail the VCS test and who have 8 of the symptom clusters will have biotoxin illness.
  • A few people will pass the VCS but still show signs, symptoms, and inflammatory markers suggestive of biotoxin illness such as artists and professional baseball players with extra keen vision. [3] Occupational exposure to solvents, hydrocarbons and petrochemicals can cause a person to fail the VCS test but not have biotoxin illness. This phenomenon is rare.

For accuracy, the following conditions need to be met:

  1. Visual acuity must be better than 20:50.
  2. Patients must wear their corrective eyewear
  3. Lighting must be sufficient
  4. Patients must sit 14 inches away from the screen for visual acuity, 18 inches for contrast sensitivity.[4]

If a patient either passes or fails the VCS test and there is still a high index of suspicion for biotoxin illness based on a history of exposure, symptom cluster analysis and/or signs on physical examination, it is still advisable to proceed with HLA and inflammatory biomarker testing.


[1] Shoemaker R. State of the Art answers to 500 Mold Questions Question 212.

[2] Shoemaker R, Hudnell K. Possible Estuary-Associated Syndrome: Symptoms, Vision and Treatment Environmental Health Perspectives Vol 109. No5 May 2001.

[3] Shoemaker, 2011, June 27, DVD.

[4] Shoemaker R., Letter to St Barnard Parish, 2/22/2006. pg. 8

VCS test results

2. Human Leukocyte Antigen (HLA) Genetic Testing

  • Approximately 24 % of the USA population have HLA gene types that make them susceptible to biotoxin illness i.e.- they do not have the genetic capability to clear biotoxins. The susceptible population makes up 95 % of the CIRS patients. The remaining 5% of CIRS patients do not have this genetic susceptibility. Approximately 76 % of the population is not susceptible to CIRS.
  • HLA refers to the Human Leukocyte Antigen genes on chromosome 6. HLA’s are found on the surface of nearly every cell in the human body. They provide instructions for making a group of related proteins known as the HLA complex which helps the immune system distinguish between the body’s own proteins and proteins made by foreign invaders such as bacteria, viruses, and fungi. This gene encodes for proteins that present foreign antigens to immune cells for removal. The HLA DR test determines ones susceptibility to CIRS plus many other diseases. [1]
  • These HLA DR/DQ encoded proteins are found on antigen presenting cells such as macrophages, B cells and dendritic cells and they present foreign cells from outside the cell to naive T lymphocytes. The T lymphocytes eliminate the antigen and transfer to B lymphocytes the ability to identify the antigen for removal. The structures of the HLA DR molecules are critical to the initial peptide/antigen recognition. The alleles most important for chronic illness expression include DRB1, DQ, DRB3, DRB4, and DRB5.
  • Just as we inherit one red blood cell type from our parent, we also inherit white cell types from our parents. However, the proteins inherited are not just one or two as in red cell proteins; they are many more combinations of proteins into groups resulting in over 50 different HLA types. The chart below will demonstrate which haplotypes are associated with which biotoxin illness susceptibility
  • The following haplotypes are associated with these different biotoxin illnesses.
  • Multi-susceptible:  4/3/53; 11/3/52B; 12/3/52B; 14/5/52B
  • Mold specific: 7/2/53; 7/3/53; 13/6/52A, B or C; 17/2/52A; 18/4/52A
  • Borrelia specific: 15/6/51; 16/5/51
  • Dinoflagellate specific: 4/7/53; 4/8/53
  • MARCoNS susceptible: 11/7/52B
  • MSH low: 1/5
  • Mold- low risk: 7/9/53; 12/7/52B; 9/9/53

[1] Shoemaker RC. Johanning E. Sick Building Syndrome in Water-damaged Buildings: Bioaerosols, Fungi, Bacteria, Mycotoxins and Human Health, pp 66-77, 2005

HLA-DR Patterns

SusceptibilityDRB1DQDRB3DRB4DRB5
Multi-susceptible43 53 
Unable to clear an/all toxins from system11 or 12352B  
 14552B  
Mold72 or 3 53 
Unable to recognize or clear mold toxins13652 A, B, C  
 17252A  
 18*452A  
Chronic Lyme-post Lyme syndrome156  51
Unable to clear Lyme toxins165  51
Dinoflagellates47 or 8 53 
MARCoNS immune system lacks ability to recognize and attack methicillin resistant staph infections11752B  
Low MSH15   

Clinical Observation

  • 4-3-53 – has 12 subtypes DRB1- 0401, -0402 and -0404 are the worst, 3% incidence, the worst RA, malaria, autoimmune hepatitis. Have the highest C4a and TGF beta-1. 0401 is the worst.
  • 11/12-3-52B – 1% incidence, tall, hypermobile, long arm span, good athletes. With free/unbound TGF β-1, they get “sicker quicker” upon exposure.
  • 17-2-52 A,B,C and 7-2-53 haplotypes associated with celiac disease
  • If a Lyme patient does not have the Lyme or multi-susceptible haplotypes there is a higher chance that he will respond to antibiotics alone. 
  • If the patient is not better with antibiotics and he has one of these haplotypes, he will need a biotoxin pathway approach. Taking antibiotics for prolonged periods alone will not fix these patients.
  • Low risk mold HLA types are: 7-9-53; 12-7-52B; 9-9-53;
  • No recognized significance types are: 8-3,4,6. 1-5,6,8

3. Matrix Metallopeptidase 9 (MMP-9) 

Lab Results

Normal range: 85-332 ng/ml; 28.14-109.89 nmol/l

A prechilled SST tube is essential to use. Following the lab draw, the specimen should be immediately centrifuged and frozen. This step will prevent the release of MMP9 from the white blood cells into the blood specimen which can double or triple at room temperature in as little as 30 minutes. Use LabCorp.

  • MMP-9 is an enzyme activated by macrophages inducing inflammatory cytokines of the innate immune system that destroys the basement membrane of endothelial cells. This provides a barrier between the blood and tissue
  • With high MMP-9, as when the immune system is chronically stimulated, the basement membrane is porous, allowing inflammatory compounds/chemokines to penetrate tissues such as muscles, joints, brain, lungs, peripheral and autonomic nervous system.[1]
  • High MMP-9 will increase blood-brain barrier permeability. [2]

[1] Shoemaker RC. Defining Sick Building Syndrome in adults and children in a case -control series as a biotoxin-associated illness: American Journal of Tropical Hygiene and Health; 2005;73 (6):228

[2] Candelario-Jalil E, Thompson J, Taheri S, Grossetete M, et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke. 2011 Mar 31.

  • MMP-9 can contribute to the destruction of connective tissue as seen in arthritis, atherosclerosis and cardiomyopathy.
  • MMP-9 increases lipoprotein a and oxidized LDL
  • MMP-9 correlates with high toxic load, total cytokine load, reflect disease progression, exposure, Herxheimer reaction (with TNF). It is a great marker for hidden cytokine production.
  • Increased in head injury
  • Patient may feel worse with CSM if they have high MMP9.

4. ACTH/Cortisol

Lab Results

Normal Range:

 ACTH:  8-37 pg./ml; 1.76-8.14 pmol/l

 Cortisol: A.M. 4.3-22.4 ug/dl; 3.07-15.99 umol/l

                        P.M. 3.1-16.7 ug/dl; 2.21-11.92 umol/l

Absolute or relative ACTH dysregulations may be seen:

  1. Absolute high: ACTH > 45 or cortisol > 21
  2. Absolute low: ACTH <5 or cortisol <4
  3. Relative:  ACTH was < 10 when cortisol was < 7- two-tiered test
  4. Relative: ACTH was > 15 when cortisol was > 16 –  two-tiered test
  • ACTH and cortisol are hypothalamic-pituitary-end organ dysregulation markers.  ACTH and cortisol measure hypothalamic regulation of the adrenal glands. ACTH is released with the breakdown of POMC. It stimulates the adrenals to release cortisol, a stress hormone.
  • Cortisol release raises blood sugar. Levels are higher in the morning and lower at night. Cortisol levels begin to increase at approx. 6 am in an individual with normal circadian rhythms (i.e. not a shift worker).
  • Cortisol is said to “boot us up – mentally and physically” in the morning.  If higher during the night, this may result in insomnia.
  • When stressed either physiologically or mentally, both cortisol and DHEA rise in tandem. We may adjust to long term stress with higher than average levels of both DHEA and cortisol. However, over time, levels of DHEA may start to decline, followed by cortisol levels. We may also have dysregulated day and night levels of cortisol with low daytime and high night time levels. Daytime fatigue and nighttime insomnia with awakening issues can result. 
  • The normal response of ACTH to cortisol is that if cortisol levels fall, ACTH levels should rise.
  • Both of these may be elevated in the beginning stages of CIRS but later both may be decreased.
  • Having low ACTH in relationship to cortisol is often a common pattern seen in CIRS.
  • Cortisol regulation is lost in 50 % of people with low MSH
  • Early in the CIRS diagnosis, as MSH falls, high ACTH is not associated with many symptoms
  • As ACTH falls, there is a marked rise in symptoms
  • People who are quite ill can have low ACTH and low cortisol levels.  
  • Treating CIRS through the different stages may correct these abnormalities.
  • Adrenal support through lifestyle and/or supplementation may also be needed. This approach, however, is not part of the Shoemaker protocol.

5. Antidiuretic Hormone (ADH) and Osmolality

Lab Results

Normal range:  ADH: 1- 13.3 pg./ml; 0.9 – 12.28pmol/l;

                           Osmolality: 280-300 mOsm/kg.

High serum osmolality – High ADH = normal

Low serum osmolality – Low ADH = normal

High serum osmolality with low ADH = abnormal. Consider treatment with Desmopressin

Absolute or relative ADH dysregulations may be seen:

  1. Absolute high: ADH > 13 or osmolality > 300
  2. Absolute low: ADH <5 or osmolality <275
  3. Relative:  ADH was < 2.2 when osmolality was 292-300 –  two-tiered test
  4. Relative: ADH was > 4 when osmolality was 275-278 –  two-tiered test
  • ADH and osmolality are hypothalamic-pituitary-end organ dysregulation markers
  • Dr. Shoemaker published data showing that up to 80 % of patients with CIRS have dysregulated ADH/osmolality levels.
  • If mold is remediated, biotoxins are bound with CSM, the VCS improves and MARCoNS is eradicated, low ADH will normalize in many cases on its own. Some patients will still require treatment.
  • ADH is a marker of disrupted MSH function. Reduced hypothalamic output of ADH in response to increased osmolarity is associated with reduced VEGF production in response to low microcirculatory oxygen levels. Low ADH is also associated with autistic behaviour and social avoidance behaviour in CIRS patients. [1] [2] 
  • The hypothalamus contains cells called osmoreceptors that respond to serum osmolality.
  • When the serum osmolality is high (body fluids/blood concentrated due to dehydration), the osmoreceptors shrink and release antidiuretic hormone from the posterior pituitary where it is stored. ADH is a 9-amino acid peptide. ADH binds to receptors on cells in the collecting ducts in the kidneys and reabsorbs water. Thus, cells become rehydrated and ADH levels fall.
  • When serum osmolality falls (overhydrated, more water in the blood), the osmoreceptors swell and block ADH release from the posterior pituitary. ADH levels drop and free water is lost in the kidneys.
  • In CIRS patients there is a dysregulation of this mechanism. Most commonly ADH levels are low (they may however be high) and osmolality levels are high (dehydrated); however, they may be low). What is apparent is that the ADH levels and the osmolality levels do not appear to be synchronous with each other as they should be in a healthy non-CIRS patient.

[1] Berndston K. Chronic Inflammatory Response Syndrome pg.  15

[2] Tansey KE, Hill MJ, Cochrane LE, Gill M, et al. Functionality of promotor microsatellites of arginine vasopressor 1A (AVPR1A): implications for autism. Molecular Autism. 2011 Mar 31;2(1):3

  • Patients with CIRS often have increased thirst and increased urination. They are also susceptible to electric shocks from touching door handles. This happening is due to the fact that as salt levels rise in blood due to the dehydration, salt is released onto the skin, through the sweat glands and creates a battery-like effect that increases the electrostatic shock potential. Chloride levels may be higher than cystic fibrosis patients in some cases.
  • Dehydration may also produce migraine like headaches.[1]
  • ADH also affects VIP and MSH levels in the suprachiasmatic nucleus of the hypothalamus. Without these three hormones, the hypothalamic regulation is significantly affected. Patients with low MSH will most often have low levels of ADH.
  • Treatment is to use DDAVP.

[1] Shoemaker R. Biotoxin Illness Treatment Protocol pg. 6

6. Melanocyte Stimulating Hormone (MSH)

Lab Results

Normal Range:  35-81 pg/ml; 206-478.7 pmol/. Run through LabCorp:

  • MSH is one of the most critically supressed neuroregulatory peptide hormones in the dysregulation seen in CIRS patients.
  • MSH is decreased in more than 95 % of patients with CIRS.
  • One of most potent anti-inflammatory compounds in the body; it regulates the innate immune system.
  • Inflammatory cytokines bind to leptin receptors, usually activating MSH and beta endorphins.  MSH would then control leptin. In biotoxin illness, cytokines block leptin receptors, MSH is not made, disrupting nerves, hormones and immune function.
  • MSH is controlled by leptin in the pituitary gland; pro-opiomelanocortin (POMC) is split into three components- alpha-MSH, or adrenocorticotrophin (ACTH) and beta-endorphin. 
  • MSH functions include: melatonin production, immune surveillance of mucous membranes intestinal permeability, nasal pathogen protection), regulates ADH and VIP, reduces inflammation, controls cytokine release in skin and gut, prevents Candida infections, controls pain through endorphin release
  • When abnormal, the result is problems with sleep, pain, gut symptoms, fluid dysregulation due to ADH with increased thirst and increased urination, cortisol dysregulation, fatigue, nasal colonization with MARCoNS, stress management problems, reduced sex hormones.
  • Due to leptin issues, weight gain which does not respond to more exercise and less eating, can be a problem.
  • Low MSH causes dysregulation of T reg cells leading to inflammation and autoimmune disorders
  • MSH has been shown to regulate the inflammatory cytokines (TNF and nitric oxide) found in inflammatory bowel disease.[1]
  • Low MSH associated with anti-gliadin positivity.

Important: Markers of hypothalamic illness include high leptin and osmolality, low MSH, low ADH, ACTH and/or VIP.


[1] Rajora N, alpha MSH Modulates Inflammatory Bowel Disease Peptides Vol 18 Issue 3 pg. 381-385.

TIER THREE CRITERIA

These criteria were based on the 2010 Consensus Report as written by Dr Shoemaker and his research committee. [1]  These criteria are evaluated after treatment has begun and are the final validation of the diagnosis of CIRS.

Improvement in the following areas is required to validate the CIRS diagnosis.

  1. Symptoms and VCS improve with treatment; and
  2. Lab markers (leptin, MMP 9) return to normal levels.

[1] Shoemaker RC, Mark L and McMahon S, Research Committee Report on Diagnosis and Treatment of Chronic Inflammatory Response Syndrome Caused by Exposure to the Interior Environment of Water-Damaged Buildings. Mold Research Committee, Pocomoke 2010

SUMMARY OF THE THREE TIERS CRITERIA FOR DIAGNOSIS OF CIRS:

  • Thus, in summary, with these Shoemaker criteria in mind, three of the Tier-Two criteria in addition to all of the Tier- One criteria must be met to make the preliminary diagnosis of CIRS.
  • Once the diagnosis is made, there are other proteomic, genomic and imaging studies which can be done in order to establish the diagnosis and assist in the treatment protocol.
  • One of the most striking features of the CIRS diagnosis is the absence of the anti-inflammatory neuropeptides vasoactive intestinal peptide (VIP) and melanocyte stimulating hormone (MSH), with the concurrent master immune regulator TGF beta-1 being abnormally increased.[1]
  • Patients should present with at least four out of the eight objective serum markers found in CIRS – TGFB1, VIP, MSH, MMP9, C4a, VEGF, ACTH/cortisol and ADH/osmolality.

[1] Shoemaker R.C. Ryan JC Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health 5 (3), 396-401

Government Accountability Office (GAO) 2008 Case Definition

The GAO issued its case definition in 2008 which became the standard for case definition. The GAO definition focuses exclusively on CIRS from water-damaged buildings and not from other initiating triggers. 

  1. Patient exposed to WDB -verified by presence of musty smells, visible mold or mycological testing.
  2. Multiple symptoms from multiple systems similar to Dr Shoemakers published research.
  3. Lab abnormalities similar to Dr Shoemaker’s lab abnormalities.
  4. Improvement with therapy similar to those found in peer-reviewed published research.

Challenges with CIRS Case Definition

One of the challenges of the CIRS case definition is that it takes more than one visit to confirm the diagnosis, patients need to have labs, need to take their medications, and thus the diagnosis cannot be made on the first visit.

Further Diagnostic Tests

If a patient has a positive exposure history, more than 6 symptom clusters, a positive VCS test, and fulfills the diagnositc criteria of the first 2 tiers, then further confirmatory lab testing must be done to confirm or diprove the CIRS diagnosis.

The following chart gives a visual representation of the biotoxin pathway with some of the lab markers being represented.

Biotoxin pathway

FURTHER BIOMARKERS/IMAGING/TESTS ASSESSED IN CIRS:

  • ERMI            
  • MARCoNS
  • Antigliadin antibodies
  • Androgens
  • Leptin
  • C3a
  • C4a- run through Quest
  • VEGF
  • TGFbeta-1
  • VIP
  • Von Willebrands
  • CD4+CD25+
  • Anti-cardiolipin antibodies
  • PAI-1
  • Pulmonary Function Tests
  • VO2 Max
  • Stress Echocardiogram
  • Neuroquant
  • Genomics

PHYSICIAN ORDER SHEET

Physician order sheet
Physician order sheet

ENVIRONMENTAL RELATIVE MOLDINESS INDEX (ERMI)

  • If water damaged buildings/mold is suspected, an ERMI is essential.
  • Mold illness and CIRS arise from any indoor environment that is damaged by water intrusion. Until recently, there had been no standardized objective methods available to quantify the indoor air mold burden.[1]  Air sampling has come under much criticism due to the fact that it samples air for just a few minutes in time, does not separate all the toxigenic molds into the correct genera, and does not take into account Wallemia. Stachybotrys can often be missed as it is not an airborne mold, being heavy in nature and existing mostly on the ground. Not all molds are toxic to humans and not all “mold is mold.”
  • Dr. Stephen Vesper and his team at the Microbial Exposure Laboratories of the EPA in Cincinnati pioneered the use of Mold Specific Quantitative Polymerase Chain Reaction (MSQPCR), and its application called the Environmental Relative Mold Index (ERMI).[2]  ERMI is an objective, standardized DNA-based method that will identify and quantify molds. ERMI does not measure the DNA of all fungi, but those that carry the highest implications for the relative mold burden in water damaged buildings.
  • There are currently three labs that offer the ERMI test: EMSL Analytical www.emsl.com, Mycometrics www.mycometrics.com and EMLab P&K www.emlab.com. Mycometrics is the most accurate according to Dr Shoemaker and provides both a Swiffer cloth method of detection and offers the HERTSMI-2 score. 
  • The ERMI classifies 36 species of mold into 26 species or clusters associated with WDB (Group 1) and 10 common species/clusters not associated with WDB (Group 2) and commonly found outside.[3]  The number calculated as the ERMI is the sum of the logs of the concentrations of the DNA of the different species. The mold index (ERMI) is the difference between Group 1 and Group 2. The ERMI was calibrated to the specific measurements (3 feet by 6 feet) in the living room and bedroom for 5 minutes and all the national standards reflect measurements from these areas only. Measuring mold in the basement only is not recommended as a first line measurement for these reasons. 

Computerized ERMI values are graphed from the lowest to the highest (see figure below). The ERMI value is typically between -10 (lowest mold levels) and 20 (highest relative mold levels). An


[1] Lin K-T, Shoemaker R.C. Inside Air Quality Filtration News Vol 26, No 3, pg. 32, 2007.

[2] Ibid

[3] Ibid

ERMI above 5 is in the top 75 % of homes for relative mold burden. An ERMI of -4 and below is on the lowest 25 % of homes in the US. 

Mycometrics LLC Report

As Dr. Shoemaker and Dr. Lin point out, the ERMI is a mold index, not a health index.

  • If the ERMI is low and there are people living in the home with positive symptoms for CIRS, that is, exceeding the cut-off criteria, and/or failing the VCS test, the ERMI should be repeated in different areas of the house. An ERMI does not exclude the value of a thorough top to toe visual inspection by a mold indoor specialist.
  • If you are not ill, an ERMI will help determine if your home is safe for visitors who have the mold susceptible gene and who are known to have health effects from moldy buildings
  • If the ERMI is low and no one is ill, one’s sense of security increases. Doing an ERMI is very helpful before one considers buying a new home. 
  • Elevated ERMI test result have been shown to have a positive correlation with lab abnormalities associated with CIRS, symptoms of CIRS, neurotoxicological studies, measurements of abnormal brain metabolites and symptoms of cognitive decline including brain fog, memory deficits and poor executive cognitive functioning. [1] Dr. Shoemaker writes that the high levels of mold translate in genetically susceptible patients into inflammation that reduces blood flow in particular parts of the brain so that it does not work efficiently. Furthermore, if a person is adequately treated but returns to a home with an ERMI above 2, he relapses.
  • In general, an ERMI value greater than 2 is considered unsafe for CIRS patients if the MSH is less than 35 and the C4a is less than 20,000. If the MSH is less than 35 and C4a is greater than 20,000, the ERMI score needs to less than -1.

[1] Ibid

HEALTH EFFECTS ROSTER OF TYPE SPECIFIC FORMERS OF MYCOTOXINS AND INFLAMMAGENS – HERTSMI-2

  • A secondary result can be calculated called a HERTSMI-2. This scoring system is application of the DNA testing shown on ERMI test results.  The new roster is designed to help patients previously sickened by water-damaged buildings and genetically predisposed understand if a given building is safe for occupancy. The roster is based on the results of 738 ERMI consecutive test results with 592 that were over 2 and 146 under 2.
  • This uses values of five specific molds-  Aspergillus penicilloides, Aspergillus versicolor, Chaetomium globosum, Stachybotrys chartarum and Wallemia sebi – from group 1 on ERMI based on 2 criteria:
  • Representative of varied water saturations (60-80%; 80-90%; 90-100%); and
  • Relative risk for enrichment is WDB compared to non-WDB is at least 10.

               A specific scale is used to grade the counts of each of the five species as and added up. 

             10 points are awarded for:

  • Aspergillus penicilloides                >500 spore E/mg
  • Aspergillus versicolor                      >500 spore E/mg
  • Chaetomium globosum                 >125 spore E/mg
  • Stachybotrys chartarum                >125 spore E/mg
  • Wallemia sebi                                    >2500 spore E/mg

             6 points are awarded for    

  • A. penicilloides or A. versicolor   >100
  • Chaetomium or Stachybotrys     >25
  • Wallemia                                             >500

              4 points awarded for   

  • A. penicilloides or A versicolor    >10
  • Chaetomium or Stachybotrys     >5
  • Wallemia   sebi                                  >100

*Any score over 15 is too dangerous for previously sickened patients to occupy.
*Any score under 11 has been safe to date.

* Some individuals may need a HERTSMI-2 score of <8 to not relapse

*Any score 11-15 is borderline. The building must be treated before safety can be assessed. 

Fungal ID/Sample IDSpore E./mg
Aspergillus flavus/oryzaeND
Aspergillus fumigatusND
Aspergillus nigerND
Aspergillus ochraceus<1
Aspergillus penicillioides13
Aspergillus restrictus*<1
Aspergillus sclerotiorumND
Aspergillus sydowiiND
Aspergillus unguis<1
Aspergillus versicolor190
Aureobasidium pullulans140
Chaetomium globosumND
Cladosporium sphaerospermum<1
Eurotium (Asp.) amstelodami9
Paecilomyces variotii<1
Penicillium brevicompactum45
Penicillium corylophilum1
Penicillium crustosum*10
Penicillium purpurogenum<1
Penicillium spinulosum*ND
Penicillium variabile<1
Scopulariopsis brevicaulis/fuscaND
Scopulariopsis chartarum13
Stachybotrys chartarum<1
Trichoderma viride*<1
Wallemia sebi230
Sum of the Logs (Group I):12.61
Acremonium strictum1
Alternaria alternata19
Aspergillus ustusND
Cladosporium cladosporioides 1130
Cladosporium cladosporioides 26
Cladosporium herbarum 63510
Epicoccum nigrum93
Mucor amphibiorum*1
Penicillium chrysogenum26
Rhizopus stolonifer<1
Sum of the Logs (Group II):10.26
ERMI (Group I – Group II):2.35

MULTIPLE ANTIBIOTIC RESISTANCE COAGULASE-NEGATIVE STAPH (MARCoNS)

Lab Test: API-Staph culture

Resistance to two or more distinct classes of antibiotics plus the presence of a biofilm.

  • MARCoNS plus biofilms is identified by a nasopharyngeal culture. Thrives in deep aerobic spaces of nasal cavity.
  • Must use API Staph Isolate to get biofilm forming coagulase negative Staph. This is not a routine nasal culture technique that is only cultured for two days at Quest or LabCorp.
  • Biofilms are slimy polysaccharide matrixes that surround the bacteria, acting as a protective barrier protecting bacteria from the immune system.
  • Dr Shoemaker observed in 1998 that in MSH deficient patients, over 80 % had MARCoNS in the nasopharynx and in MSH normal patients, less than 1 % were positive for MARCoNS. 
  • MARCoNS will result in MSH deficiency.
  • MARCoNS release endotoxin A and B which cleave MSH, rendering it ineffective and thus leading to immune dysregulation.
  • MARCoNS release hemolysins, which disrupt red blood cells and endothelial cell membranes increasing inflammation, coagulation risk, and anti-phospholipid abnormalities.
  •  Low MSH impairs its ability to coordinate dendritic cell responses within gut and respiratory mucous membrane compartments. [1]
  • With low MSH, multiple neuro-immune pathways are impacted leading to dysregulation in ACTH, cortisol, androgens, ADH and osmolality, melatonin (sleep disturbances), endorphins (pain issues.)   In addition, cytokines are stimulated.
  • MSH acts as a guard immune modulator on the skin and mucous membranes and kills fungi and coagulase negative staphylococci. With normal MSH, MARCoNS will not survive. [2]
  • Inadequate treatment of MARCoNS will reduce the efficiency of CSM therapy possibly because of MARCoNS continued effect on MSH.
  • Low MSH patients rarely get better until MARCoNS is treated. Hard to raise MSH with MARCoNS present.
  • With MARCoNS, thick biofilms are made which prevent antibiotics and natural immune function from dealing with the offending organisms.
  • MARCoNS colonization produces no symptoms but dysregulates MSH.
  • MARCoNS can also be isolated from dental cavitations.
  • MARCoNS with low MSH patients have a differential genomic profile than negative MARCoNS patients and low MSH. [3]
  • MARCoNS not to be confused with other coagulase -negative staphylococci that are not antibiotic resistant.

[1] Catania A, Caterina L, Sordi A, et al., The melanocortin system in control of inflammation. The Scientific World Journal 2010; 10:1840-1853.

[2] Shoemaker R. Katz BEG DVD 2013

[3] Shoemaker R. Katz 2013 BEG DVD

Microbiology Dx report
Microbiology Dx report

ANTIGLIADIN- ANTIBODIES (AGA)

Lab results

AGA normal range:  0-19 U

  • Low MSH results in T reg dysregulation, leading to inflammation and possibly autoimmunity
  • Serum IgA and IgG antigliadin antibodies (AGA) are antibodies against gliadin, the protein found in wheat, barley and rye. Some oats is cross-contaminated with gliadin but does not, in and of itself, contain gliadin.
  • AGA is not specific for celiac disease, but it does indicate an inflammatory response to gluten
  • I tend to do the HLA DQ2/DQ8 genes and serum tissue transglutaminase (TTG-IGA) levels to exclude celiac disease.
  • Over 58 % of children with CIRS have elevated AGA levels according to Dr. Shoemaker.

ANDROGEN DEFICIENCY

Lab Results

Normal Range:  DHEA and testosterone: Various ranges for age and gender

  • Abnormal androgens are due to an upregulated aromatase enzyme.
  • Testosterone is often dysregulated and DHEA may be low.
  • Using testosterone is contraindicated in these patients.
  • Due to low VIP and inflammation, testosterone is more rapidly converted into estrogen resulting in high estrogen and low testosterone.
  • One may use DHEA.
  • VIP nasal spray corrects aromatase activity.

LEPTIN

Lab results: LabCorp

Normal ranges: 0.5-13.8 ng/ml; in men

                            1.1-27.7 ng/ml; in women

  • Leptin is a hormone that controls how fat stores fatty acids. If the leptin receptors are disrupted, high levels of leptin will be seen.
  • Leptin regulates the pro-opiomelanocortin (POMC) pathway, thus MSH pathways that also control ADH.
  • Low leptin levels contribute to low MSH, ADH, VIP and ACTH.
  • Leptin outside the brain binds to immune cells and increases inflammatory cytokines. [1]
  • If leptin is high, fatty acids are stored in fat, resulting in weight gain.
  • Leptin is not considered a major marker in the CIRS workup.  
  • Markers of hypothalamic illness include high leptin and osmolality, low MSH, low ADH, ACTH and/or VIP.

[1] Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and periphery. Recent Progress in Hormone Research. 2004; 59: 305-31. PMID: 14749508

C3a

Lab results: Quest

Normal ranges: 55-486 ng/ml;  

  • C3a generated when C4a and C2a are made by activating MASP-2; splitting C4 and C2 creates C4b and C2a thereby activating C3
  • C3a is only activated when the innate immune system is presented with a bacterial cell membrane.
  • If elevated, tick -borne illness must be excluded or diagnosed.
  • Increased C3a can cause anaphylaxis through an upregulated immune response resulting in vasoconstriction, capillary hypoperfusion, increased vascular permeability and WBC release of oxidants, leukotrienes and enzymes.[1]
  • C3a will usually be low unless there is Lyme- usually more acute in nature.
  • C3a elevates within 12 hours of a tick-bite
  • If HLA is Lyme susceptible pattern – 15-6-51; 16-5-51, most likely will need longer than 3 weeks of antibiotics and CIRS can be a distinct possibility.
  • Will need Cholestyramine to remove the biotoxins if inflammatory CIRS markers and positive VCS present.
  • May need statin therapy if C3a persists after antibiotic therapy.

[1] Shoemaker R Biotoxin Illness Treatment Protocol pg. 8

C4a

Lab Results: Quest

Normal Range:  0-2830 ng/ml;

  • If levels are very high, this could be due to delays in shipping, sample not frozen quickly enough or the specimen thawed in transit.
  • C4a is an innate immune system biomarker. If high, it usually means that the innate immune system is in overdrive to PAMPS (pathogen -associated molecular patterns) and that a biotoxin burden is present.
  • Usually results in capillary hypoperfusion of the CNS.
  • C4a is a split product of the mannose binding lectin pathways of the complement system of the innate immune system and predicts the severity of CIRS.
  • C4a has been associated with elevated levels of mannin-binding lectin serine protease 2 (MASP2) in patients with chronic fatigue syndrome.[1]
  • C4a helps the antibodies and phagocytic cells remove infections and toxins from the body.

[1] Sorensen B, Jones JF, Vernon SD, Rajeevan MS. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Molecular Medicine 2009 Jan-Feb; 15 (1-2): 34-42

  • Complement proteins circulate as inactive precursors but when split into active components they amplify the immune response of the membrane attack complex (MAC).[1] MAC kills the outer layer of cells causing cell death.
  • Both C3a and C4a are anaphylatoxins which cause smooth muscle release, can activate mast cells, increase histamine, increase basophils, increase vascular permeability, cause capillary hypoperfusion with resultant cellular hypoxia resulting in reduced mitochondrial function, increase lactate production from glycolysis,  and can increase cognitive dysfunction (memory loss, concentration, word finding difficulties, disorientation, confusion, difficulty integrating new information.) as well as fatigue. [2]
  • Brain fog caused by increased lactate and suppression of the glutamate/glutamine ratio. -increased inhibition versus excitation.
    • When C4a with anaphylatoxin activity stimulates the degranulation of mast cells, vascular permeability ensues, dermatographia can exist on the skin and smooth muscle contractions occur.
    • C4a can causes high lactate levels >1.29 and low glutamate/glutamine ratio <2.19 on MR spectroscopy.
    • If C4a levels are above 20,000 with low MSH levels the individual cannot be in a home with an ERMI above -1.
    • Cognitive functions improve when C4a drops.
    • C4a can be elevated in Lyme disease and SLE.

[1] Rapaport S. Evaluation and Treatment of CIRS pg. 7

[2] Ogata RT, Rosa PA, Zepf NE. Sequence of the gene for murine complement component C4a. The Journal of Biological Chemistry, 1989; 264( 28): 16565-72.

VEGF

Lab results: LabCorp and Quest

Normal Ranges: 31-86 pg./ml

  • VEGF is a marker of capillary hypoperfusion. A low level of skeletal muscle VEGF is associated with decreased muscle endurance.[1]
  • Treat VEGF if less than 31. If high, say 105, it means the innate immune is activated, but does not give the cause.
  • VEGF is high in renal failure and Bartonella infections. [2]
  • Inflammatory cytokines bind to endothelial receptors, which release “glues”- adhesion and integrins.  These hold the white cells together and narrow the capillaries creating hypoxia. This is sensed by regulatory cells which produce a gene controller hypoxia inducible factor (HIF), which produces VEGF.  
  • VEGF is a growth factor which stimulates blood vessel growth in response to HIF and dilates blood vessels in healthy people.

[1] Olfert IM, Howlett RA, Tang K, Dalton ND et al. Muscle specific VEGF deficiency greatly reduces exercise endurance in mice. Journal of Physiology 2009 Apr 15; 587:1755-1767

[2] Kempf VAVolkmann BSchaller MSander CAAlitalo KRiess TAutenrieth IB. Evidence of a leading role for VEGF in Bartonella henselae-induced endothelial cell proliferations. Cell Microbiol. 2001 Sep;3(9):623-32.

  • In biotoxin patients, inflammation and cytokines suppress VEGF, creating persistent capillary hypoperfusion.
  • This result in fatigue, cognitive fallout, muscle aching, and poor recovery from exercise due to anaerobic mitochondrial metabolism.
  • Usually glycolysis and protein are used for energy, taking several days to replenish glycogen.
  • In lactic acid metabolism, due to low VEGF, one obtains only 2 ATP for every glucose molecule, instead of 36 ATP as is normally the case.
  • Early in CIRS, VEGF can be increased, signifying that the body is trying to compensate for low oxygen delivery to tissues.

TRANSFORMING GROWTH FACTOR BETA-1 (TGF beta-1)

Lab results: LabCorp and Quest

Must be double spun plasma with Cambridge to make sure all plasma platelet contamination is gone. Not serum. If result is greater than 40,000, the specimen is likely mishandled.

Normal range:   < 2380 pg/ml; =normal

> 5000 = symptoms appear

                                > 10,000 = restrictive lung disease, tremor, cognitive issues, joint problems may occur

  • TGF beta-1 is a protein that causes cells to change and usually results in innate-adaptive immune system dysregulation. It can either produce or suppress inflammation.
  • It must be addressed vigorously as it represents widespread tissue involvement, most common in people with highly susceptible 11-3-52B and 4-3-53 HLA haplotypes. Limiting mold exposure is crucial to down regulate this biomarker.
  • Elevated levels usually indicate that the body is trying hard to down regulate an overactive T cell adaptive immune system as in allergy (asthma) and autoimmunity (multiple sclerosis) as well as an overactive innate system (CIRS)- both caused by biotoxins in the HLA susceptible host.
  • TGF-beta-1 has a dual function in the innate immune system. If elevated it indicates an overactive immune system and it a key marker of the CIRS severity.
  • If stays high, it can indicate the person is having a difficult time recovering.
  • It helps control the growth and differentiation of cells, cell motility and cell death. In utero, it helps form new blood vessels, regulates muscle and body fat development and wound healing. 
  • It is an inflammatory regulatory cytokine which affects autoimmunity through differential gene activation. It can damage T reg cells CD4+CD2++, which regulate TH1 (autoimmunity), TH2 (allergy), TH17 cells. It converts CD4+CD25++ T reg cells into pathologic T cells, thus activating TH17 (autoimmune system) driven inflammation. Together, TH-17 and T-regulatory cells are responsible for preventing autoimmunity. TGF beta-1 can thus activate or reduce autoimmunity.
  • In the treatment, one must increase the low T reg cells (cellular immunity) and lower TGFB, thus improving humoral immunity.
  • If T reg cells are low <4.66 %, TGF beta will be high > 2,380.
  • VIP will raise T Reg cells (CD4, CD25).
  • TGF beta-1 can cause tissue remodeling in the liver, heart, central nervous system and the kidney.
  • If TGF beta-1 levels are >10,000, this may result in pulmonary remodeling and interstitial, restrictive lung disease (shortness of breath and asthma like symptoms), pulmonary
  • hypertension (where endothelial cells become thick fibroblasts and result in acquired pulmonary hypertension). Pulmonary stress testing can determine VO2 max and pulmonary function testing can look for signs of restrictive lung disease. Stress echocardiogram to estimate pulmonary arterial pressure (the measurement of the tricuspid jet and right atrial pressure) can also be done and which will measure further pulmonary cell transformation
  • High TGF beta-1 associated with joint inflammation
  • High TGF-B-1 may result in neurological diseases (MS), seizures, tremor, Parkinson’s, Autoimmune diseases (lupus, RA, dermatomyositis, ulcerative colitis, positive ANCA, ACLA, scleroderma), learning disabilities, vocal polyps and nasal polyps  and cognitive symptoms.
  • High TGF beta-1 can be seen in HIV, cancer and connective tissue disorders
  • High TGF beta-1, along with low MSH can contribute to GI dysfunction which improves when immune markers are normalized.
  • CD4+CD25++ blood levels = T reg cells. If low, the TGFbeta-1 would expect to be high.
  • VIP will cause T reg cells to increase, but re-exposure to biotoxins will cause them to drop.
  • TGF beta-2 will cause hair loss with increased catagen hair. Growing hair follicles are anagen, rest-phase hair is telogen but dying hair follicles are catagen due to TGF β-1.[1]

[1]Hibino T1Nishiyama T. Role of TGF-beta2 in the human hair cycle  J Dermatol Sci. 2004 Jun;35(1):9-18.

VASOACTIVE INTESTINAL POLYPEPTIDE (VIP)

Lab Results: Quest

Normal range:   23-63 pg/ml

  • No accurate test for VIP at the moment.
  • VIP is a 28-amino acid regulatory neuropeptide, neuro-immune modulator which downregulates cytokine levels with interactions with other peptides: MSH and Vasopressin.
  • It has hypothalamic receptors; it regulates blood flow and distribution.
  • Low levels are associated with capillary hypoperfusion and abnormal pulmonary artery pressure at rest or in response to exercise. [1]
  • It is also made in the nerve endings, gut and pancreas.
  • It can have a positive effect on the entire Biotoxin Pathway.
  • Like MSH, it regulates peripheral cytokine responses and inflammation throughout the body.
  • Low levels found in 98 % of CIRS patients and in less than 10 % of controls.
  • VIP helps reduce pulmonary artery hypertension. If pulmonary artery pressure raised with tricuspid valve regurgitation, one can have shortness of breath, especially with exercise. VIP will help reduce post exertional fatigue and shortness of breath
  • Helps with MCS, releases endorphins, reduces sicker-quicker phenomenon, downregulates MASP2- the enzyme that stimulates cleavage of C4-C4a; the key to reducing “quicker/sicker” phenomenon.
  • VIP induces smooth muscle relaxation in the intestinal tract stimulating water secretion into bile and pancreatic fluid; it can reduce stomach acid and absorption of nutrients from the GI tract. Diarrhea can result.  

[1] Berndtson K. Chronic Inflammatory Response Syndrome. Overview, Diagnosis, and Treatment. Pg.7

  • Restores hormone levels, Vit D 3 levels, decreases aromatase upregulation caused by cytokines thereby restoring estrogen and testosterone levels, corrects ADH/osmolality.
  • Helps restore energy in chronically fatigued patients.
  • Enhances IL-10 production
  • Increases CD4+/CD25+ T reg cells, restoring their numbers and thereby regulated TH 17 autoimmune response. If used appropriately, it will suppress overly active inflammation and will regulate dendritic cells, the cells that mediate between the innate and adaptive immune systems.  Inhibits TGF beta-1. Down regulates cytokines and thus is a down-regulator of inflammation
  • Restores circadian rhythm.
  • It helps treat genomic dysregulation caused by CIRS.
  • VIP assists in treating the brain abnormalities found in NeuroQuant esp. caudate nuclei atrophy.
  • Upregulates VEGF esp. if not responded to Actos or Fish oil 1 spray – alternating nostrils 4 times per day.
  • Dr. Shoemaker published a study in 2013 on VIP used on CIRS-WDB patients which demonstrated the following: [1]
    • refractory symptoms reduced to control levels
    • corrected inflammatory biomarkers -C4a, TGF beta-1, VEGF and MMP 9 and reduced levels to controls
    • raised VIP and MSH, corrected estradiol, testosterone and Vit D levels,
    • corrected T-reg levels,
    • retuned PASP during exercise to normal
    • enhanced quality of life in 100% of patients in the study
  • Dr. Shoemaker found that 100 % of over 500 patients with multiple chemical sensitivities were found to have low VIP.
  • In order to use VIP, need to be out of a moldy building (ERMI less than 2), have a normal VCS and be MARCoNS free.

[1] Shoemaker RC, House D, Ryan J. Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health, 2013; 5 (3) 396-401

CD4+ CD25+

  • No commercial test is currently availablealthough select centres may do the test under special circumstances. 

VON WILLEBRANDS PROFILE

Lab results: Quest

  • Factor VIII activity, von Willebrand Factor antigen, Ristocetin Cofactor, von Willebrand Factor Collagen Binding Assay, von Willebrand Antigen) –as well as coagulase study- PT, PTT, PT/INR –  esp. if history of bleeding with exposure to WDB.
  • Patients with levels of Factor VIII, von Willebrand’ s antigen or Ristocetin associated cofactor either <50 or >150 IU are classified as abnormal for von Willebrand’ s antigen.
  • Blood will be thinner and bleeding will result.
  • Acquired von Willebrand syndrome can be the result of increased C4a resulting in increased bleeding tendencies. Water damaged building avoidance is the first step in treatment as well as using DDAVP.

ANTI-CARDIOLIPIN ANTIBODIES

  • Marker of autoimmunity.

PAI-1

  • A marker of increased blood coagulation.

PULMONARY FUNCTION TESTS

Unusual shortness of breath with post exertional fatigue warrants a workup for pulmonary function and possibly acquired pulmonary hypertension.

  • In CIRS, pulmonary function tests may show a restrictive pattern rather than an obstructive pattern of respiratory difficulties. If restrictive test is shown, proceed to VO2 max.  

VO2 MAX

  • VO2 max testing done on a treadmill may show abnormally low VO2 max, often lower than 20. This reflects capillary hypoperfusion and post exertional fatigue and malaise. High cytokine levels can first raise and then lower VEGF leading to chronic tissue hypoxia. CIRS patients have a lower threshold for hypoxia as a result.
  • Exercise is very helpful for these patients but they must stay below their anaerobic threshold.  If they stay below their anaerobic threshold, glycogen store depletion is prevented. This is determined by performing a cardiopulmonary stress treadmill test.
  • VO2 max > 35 = normal
  • VO2 max < 20 = CIRS patients 
  • VO2 max 12-15 = Stage IV Cardiac failure

STRESS ECHOCARDIOGRAM

This is to be pursued in the patient with unusual shortness of breath, asthma like symptoms and excessive post-exertional fatigue/poor exercise tolerance.

  • A stress echocardiogram will non-invasively measure the tricuspid jet and the right atrial pressure, thus estimating pulmonary arterial pressure (PA) response to exercise.
  • Normally the pulmonary pressure drops with exercise, allowing for increased oxygenation.
  • In CIRS patients, the PA pressure may increase, resulting in reduced oxygen absorbed into blood during exercise and thus poor exercise tolerance
  • A high pressure at rest may be seen, esp. if TGF beta-1 is high and T-reg cells are low. Th-17, induced by high TGF beta-1 will convert T reg cells to pathogenic T cells.
  • Avoid mold, use losartan and use VIP to correct this abnormality.

NEUROQUANT

A Neuroquant MRI is a software addition to an MRI and assists in determining if there are any changes in brain volume and structure according to specific quantifiable determinants in 11 different brain regions.

 Patients with CIRS due to mold exposure have a specific pattern of abnormalities as compared to controls:[1]

  • Forebrain parenchyma increased
  • Cortical gray increased

[1] Shoemaker R, D House R, Ryan J, Structural brain abnormalities in patients with inflammatory illness acquired following exposure to water-damaged buildings,” Center for Research on Biotoxin Associated Illness, Pocomoke

  • Hippocampus increased – although not included in the criteria
  • Caudate decreased – reversible through use of VIP according to Dr. Shoemaker’s clinical experience
  • Pallidum increased

Patients with CIRS due to Lyme neuroborreliosis have the following pattern:[1]

  • Small forebrain parenchyma
  • Small putamen
  • Large thalamus – (isolated post gray matter change)
  • Large cerebellum

Neuroquant also assists in the detection of other nuclei that can be atrophied and is helpful when looking at brain atrophy in dementia Alzheimer’s disease.

In Dr. Shoemaker’s research, no confirmed case of CIRS had less than 5 points and no controls had 3 or more points. One needs to take the average of the two sides to determine the points awarded.


[1] Ibid

 Black = Mold  Red = Lyme1 point2 points
Forebrain>31.9>32.5
Cortical Gray>16.3>17.0
Caudate<0.255<0.235
Pallidum>0.07>0.08
Putamen<0.345<0.335
Right thalamus>0.58>0.60
 AtrophyHypertrophy
Forebrain<29.00>31.9
Cortical Gray<13.50>16.3
Hippocampus<0.255>0.31
Amygdala<0.10>0.14
Caudate<0.255>0.30
Putamen<0.345>0.375
Pallidum<0.055>0.07
Thalamus<0.495>0.58
Cerebellum<3.50>4.55

GENOMICS

www.survivingmold.com/store1/progene-dx

  • PAX genomics allows for measurement of mRNA and miRNA in serum samples so as to assess metabolic patterns of cellular function based on RNA transcription patterns. [1]

A 2016 paper by Dr Shoemaker and James Ryan set out the underlying genomic abnormalities found in white blood cells that can result in someone suffering from a CIRS diagnosis leading to


[1] Berndston K.

  • chronic inflammation. [1] 14 patients who had failed the normal CIRS protocol were investigated genomically while using VIP.
  • This new RNA sequencing focuses on the abnormal gene expression found in the white blood cells of CIRS patients. Several key immune regulators were found to be differentially expressed over the course of the investigation including CD244, CD3D, CD48, CD 52, granzymes, defensins, and the Ikaros family of lymphoid transcription factors.
  • Two families of genes upregulated in CIRS are alpha defensins (these are antimicrobial peptides which keep bacteria in bodies from spreading by using mucosal layer coating inside the gut, airways or nasal passages) and granzymes (these are cytotoxic proteases found elevated in patients with autoimmune disease and infections). [2] These were downregulated with VIP.
  • The Ikaros family of five different zinc finger transcription factors may indicate a decline in lymphocyte proliferation after treatment with VIP.
  • In addition to these down regulated innate immune functions, there was a significant metabolic shift with a downregulation of ribosomal and mitochondrial gene expression possibly indicating a quietening of the overall upregulated immune response. [3] 
  • Patient reporting of CIRS symptoms decreased from a mean of 12.9 to a 3.3 over the duration of the therapy. TGF beta-1 and C4a were significantly lower after VIP therapy. MMP9 was lower post VIP but not significantly and VEGF was unchanged.
  • In addition, ribosomal genes as well as nuclear encoded mitochondria genes were shown to be down regulated after treatment with VIP and this coincided with the abatement of symptoms.  This argues the return to normal function of ribosomal and mitochondrial gene expression.
  • It is a great advance in the treatment of CIRS that both pre- and post-genomic expression patterns can be measured. Added to the measurement of proteomic expression and Neuroquant evaluation pre- and post treatment, the genomic insights add much additional value to quantifying the patients return to normal functioning.
  • Diagrams per Jimmy Ryan presentation at 2016 Surviving Mold conference Irvine, California.

[1] Ryan J, Shoemaker RC, RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal polypeptide (VIP)shows a shift in metabolic state and innate immune fluctuations that coincide with healing. Medical Research Archives Vol 4 Issue 7 2016.

[2] www.survivingmold.com

[3] Ibid.

Before VIP
After VIP
Mitochondrial proteins pre-vip
Mitochondrial proteins post-vip

OTHER LAB TESTS DONE IN CIRS

  • These lab tests are done to rule out other possible illnesses.
  • CBC, Metabolic panel, Lipid panel, C-reactive protein, ESR, ANA, ENA, Thyroid studies with thyroid antibodies, sex hormones (estradiol, progesterone), pregnenolone, cardiolipin antibodies, PTT, Prothrombin time, Thrombin time, d-Dimer, IgE, Immunoglobin panel, protein electrophoresis.
  • If autoimmunity is suspected, check anti-gliadin antibodies, (due to low MSH and dysregulation of T reg cells) anticardiolipin antibodies, lupus anticoagulant, phospholipid.
  • If mast cell activation syndrome is suspected, consider doing serum histamine, serum tryptase, urinary prostaglandin D2, enolase.

Treatment Steps

Stepwise treatment protocol for CIRS

Dr. Shoemaker’s Surviving Mold Protocol involves a number of specific steps:

It must be kept in mind that CIRS is an inflammatory upregulation of the innate immune system and is thus an immune disorder occurring in genetically susceptible individuals. It will not therefore just respond to removal of the initial triggers. The particular triggers do need to be taken into account, but so does the immune dysregulation, the inflammatory markers, the neurohormonal abnormalities, potential autoimmune dysregulation as well as possible coagulation disorders.  

  1. Removal from exposure – monitor home or WDB with ERMI or HERTS-MI-2 testing
  2. Removal of biotoxins with either cholestyramine or Welchol – monitor with VCS
  3. Treat MARCoNS with BEG spray or EDTA- Check API-Staph nasal culture
  4. Begin a gluten free diet if anti-gliadin antibodies present
  5. Correct abnormal androgens – use DHEA-S if indicated
  6. Correction of elevated MMP-9
  7. Correction of low VEGF
  8. Correction of elevated C3a
  9. Correction of elevated C4a
  10. Reduce elevated TGF-beta-1
  11. Treat low VIP
  12. Recheck labs and VCS

STEP 1: REMOVAL FROM EXPOSURE

  • This is the most important step in the treatment process if a diagnosis of CIRS has been established. Attempt to determine the source of the biotoxin exposure; was it from Borrelia spirochete, dinoflagellate food poisoning or ciguatera. A person may be exposed to one or more of these toxins. If the source is identified, every effort must be made to remove the individual from the source of exposure.
  • If water damaged building is the issue and as up to 50 % of all USA homes have some form of water damage, mold exposure and all the corresponding inflammagens are the most frequent source of biotoxin illness. An ERMI test must be done and a visual inspection must be undertaken by a qualified mold/indoor air specialist. The article Inside Indoor Air Quality by Dr. Ritchie Shoemaker and Dr.  King-Teh Lin is a helpful resource.
  • If an ERMI test is positive with a reading >2, the building or home is considered unsafe for occupation with the CIRS diagnosis.  
  • Once a building has been declared unfit for occupation due to the visual inspection and the patient fulfilling the CIRS diagnosis, a sick patient should most often have to be removed from the building and a mold remediation team is called in.
  • One of the challenges for CIRS patients is what to do with belongings as they often have to be removed (clothing, furniture that cannot be adequately wiped down, contents esp. paper and cloth products and personal effects). All porous material should be removed and taken out of the house and discarded. Non-porous items need to be thoroughly and professionally cleaned.
Diagram: Written permission granted by Dr Lynese Lawson
Diagram: Written permission granted by Dr Lynese Lawson
  • Finding someone who can adequately undertake the remediation is often a major problem. An organized approach to the problem is vital but often is not able to be initiated due to the cognitive difficulties many people face with the CIRS diagnosis.
  • Small brief exposures must be avoided due to “sicker, quicker” phenomenon.
  • Patients that I see are given a list of companies that can assist them in their assessment and remediation process. HEPA filters (IQ air and Blue Sense Air filters) are used which can remove particles smaller than 0.3 microns in size. Air purifiers such as the Air Oasis are also used.
  • It is important that remediation efforts are continued until ERMI levels are down to safe levels – ERMI less than 2 or = 2 in patients with MSH <35; ERMI to < or = to – 1 if MSH <35 and C4a >20,000 with HERTSMI-2 < 11.
  • Post remediation testing should occur 3-5 weeks after remediation. One can place black or green garbage bags and collect new dust.

STEP 2: REMOVE TOXINS AND INFLAMMAGENS

Biotoxins must be removed from the body, particularly in a patient with the genetic predisposition to biotoxin illness. These patients cannot recognize the biotoxins and need help in doing so.

Cholestyramine (CSM), a bile acid sequestrant, has a quaternary cation structure that binds negatively charged ionophore biotoxins which possess an anion dipole. The biotoxins are excreted in bile and removed from the body while bound to the CSM, through the GI tract. This excretion prevents enterohepatic recirculation of the biotoxins. A handout should be given and consent obtained.

CSM can also bind industrial chemicals

  • CSM must be taken on an empty stomach away from meals and medications and/or supplements. 
  • Many people start with ¼ teaspoon a day. Take ½ hour before meals and 1 hour after meals, drugs or supplements.
  • Drink 6 –  8 oz. of water with the dose.
  • Juice is often a better mix for this very chalky tasting medication.
  • Side effects include heartburn, GERD, belching, bloating, nausea, bad tastes and/or constipation.
  • Welchol is a second option, although not as effective. There is said to be a 4:1 differential in terms of efficiency for biotoxin removal. CSM has 4 times as many electrically active sites. However, Welchol may be better tolerated but longer to change lab tests in the right direction.
  • These two binding agents are to be taken until the patient either passes the VCS test and/or eradicate MARCoNS.
  • Some patients combine the two meds: CSM twice per day – morning and bedtime and Welchol – lunch and dinner. Avoid the CSM with aspartame additives.
  • Chemically sensitive patients and patients with GI issues and/or food allergies, do better on Welchol.
  • If problems with toxin release or treatment reactions, start with Actos 15-45mg a day, or EPA 2.4 gms DHA 1.8gms for 5 days, then add cholestyramine again.
  • If Leptin <7 use omega 3s.
  • Watch fat-soluble vitamins A, D, E, K as CSM can bind these.
  • Welchol 625- work up to 2 caps three times per day.
  • CSM dosing: 4 -9 grams four times a day. Mix with 6 oz. water or juice. 30 mins before food. Followed by 4-6 oz. water.  
  • Paed. <120 lbs. or less than 18 years old.  Use 60 mg/kg/dose TID with 6 oz. water 30 mins before food.
  • Use Welchol 625 bid (1 tab) if out and about and exposed to mold.
  •  If re-exposed- use Welchol or CSM for 3 days.
  •  Works within a week.
  • Treat constipation with magnesium oxide or citrate powders. Can use 70 % sorbitol (Miralax).
  • Recheck VCS one month after starting treatment and then with each step.
  • When VCS normalized, switch to Welchol 625 mg twice daily if person is out a lot.
  • If at home mostly, no meds used.
  • If treatment fails, consider continued exposure, non-compliance or MARCoNS not adequately treated.   

STEP 3: ERADICATE MARCoNS

If positive for MARCoNS on API-Staph culture and if associated with a biofilm, eradication is important.

BEG spray:

  • Start one month after using CSM
  • Comprised of Bactroban, EDTA, and Gentamycin.
  • Blow nose first.
  • Use for 30 days 2 sprays each nostril 3 times per day in adults, 1 spray alternative nostril in children- seldom need to use
  • The patient may feel worse after starting treatment due to “die-off”.
  • Use low amylose diet, high dose fish oil and Actos if this occurs.
  • Repeat nasal culture to see if eradicated.
  • If symptoms worse after starting, it may imply re-exposure; VCS row D and E will fall and MMP9 will go up
  • If still positive after treatment, consider pet dog as source of reservoir, re-exposure to mold, or a partner with low MSH and MARCoNS
  • Rifampin has been used in the past at 600 mg per day with adults or 10-20 mg/kg/day in children. Start the rifampin the same day as the BEG spray to discourage resistance
  • Rifampin is known to induce multiple enzymes responsible for drug metabolism including cytochrome P450 (CYP)1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and some glucuronidation pathways. In addition, it has been reported to induce the activity of several drug transporters, such as the organic anion transporter and P-glycoprotein.[1] Need to quite careful with anticoagulants and pain medications (may reduce their efficiency).
  • Recent MARCoNS resistance to multiple antibiotics has emerged due to what Dr Shoemaker believes to be the overuse of -azole antifungals.
  • This step is essential if VIP is going to be successful.
  • If symptoms worsen after 1 month, check for re-exposure, recheck VCS and MMP9 levels.
  • If patient better, stop BEG spray, recheck API- Staph nasal culture and VCS.

[1] http://www.pharmacytimes.com/publications/issue/2011/april2011/druginteractions-0411

STEP 4: ELIMINATE GLUTEN IN AGA POSITIVE PATIENTS

  • If positive for AGA, it is imperative they are completely gluten free for at least 3 months.
  • This will reduce GI sources of inflammation
  • The no-amylose diet prescribed during CSM treatment is already gluten free, thus no gluten continues for an additional 3 months assuming that that the VCS corrected.
  • No amylose diet involves eliminating:
  • Grains- wheat, rice, barley, oats, rye – corn appears to be okay as has a natural inhibitor of amylase- no sugar added.  
  • Fruits-all fruit allowed except bananas. Can use fresh fruit juice.
  • Vegetables – all okay except root vegetables grown below the ground (potatoes, yams, radishes, carrots, beets). Garlic and onions are okay.
  • Other foods –  glucose, dextrose, sucrose, maltodextrin, low-fat corn syrup, cereal, chocolate, fast food, soft drinks, commercial fruit juices. Lactose (milk), artificial sweeteners, spices and condiments, diet soft drinks and caffeine drinks are allowed
  • Many patients will have many other possible food issues including but not limited to IgE allergies, IgG sensitivities, oxalate issues, salicylate issues, FODMAPS issues, SIBO issues, high histamine issues etc. These issues are not part of the Shoemaker protocol but need to be taken into account when addressing and treating chronic GI issues. 
  • If AGA is negative after 3 months, reintroduce gluten and keep monitoring for GI symptoms.
  • If patient feels better off gluten, and/or AGA returns as positive, stay off gluten for life.
  • If a patient is known to have celiac disease, it is imperative he follows a strict gluten free diet for life. [1]

[1] Shoemaker RC. Surviving Mold: Life in the Era of Dangerous Buildings. Otter Bay Books. Baltimore 2010.

STEP 5: CORRECT ANDROGENS: DHEA/Testosterone/Androgens and Cortisol

Treatment:

  • DHEA – 25 -75 mg a day- men. 5-25 mg a day -women
  • HCG injections 125 250 mg twice weekly. This raises LH. Not part of Shoemaker protocol
  • VIP nasal spray 4 times per day for 30 days- can stabilize aromatase and rebalance androgens
  • Measure DHEA before treatment and monitor estradiol levels- at least every 3 months
  • Resist using testosterone replacement
  • Do not use aromatase inhibitors with a low-MSH patient<35, this will cause significant deterioration.

STEP 6: CORRECT ADH/OSMOLALITY

Treatment: Desmopressin Acetate (DDAVP)

  • Use DDAVP when osmolality is high>295
  • Use 0.2 mg every other night to verify tolerance and absence of side effects especially if weight gain. Initial correction of ADH can lead to edema and rapid weight gain due to fluid retention.
  • After 5 doses – check serum osmolality, ADH and electrolytes verifying normal sodium and not too low.
  • If symptoms persist, especially on “off days”, use 0.2 mg daily.
  • Check electrolytes and osmolality after 10 days.
  • Some people (especially those with POTS) may need to be on drug daily for indeterminate basis.
  • Some may need it twice daily.
  • ADH abnormalities usually normalizes over time.
  • This treatment may also correct von Willebrand syndrome and help reduce MMP9 (and C4a) levels. Von Willebrands patients need to carry DDAVP to stop nasal hemorrhage.
  • One needs to taper DDAVP when endpoint of normal ADH for a given osmolality is reached. 
  • Children need to use 1-4 sprays based on weight and age.
  • If odd symptoms occur while on treatment, stop treatment and check electrolytes and serum osmolality.
  • Taurine can cause polyuria and Lithium can cause ADH resistance.
  • Symptoms addressed include polyuria, polydipsia, orthostatic hypotension, recurrent headaches and static shocking.

STEP 7: CORRECT ELEVATED MMP-9

Treatment: Actos and/or EPA/DHA Fish oil

  • The goal of therapy is to upregulate PPAR-gamma production and reduce MMP-9 expression.
  • Lowers TNF, leptin, MMP9, PAI-1, and raises low VEGF.
  • If low leptin-less than 7 or less than 18 years, can’t use Actos.
  • If leptin less than 7, use high dose fish oil: EPA 2.4 mg, DHA 1.8 mg daily.
  • If high or normal leptin, use Actos- low carb/amylose, high protein diet.
  • Actos 45 mg once daily for 30 days.
  • If get swollen and hypoglycemic have to stop.
  • Watch kidney function and blood sugar.
  • Actos is also implicated in bladder cancer with long term use.
  • Takes longer to work but is effective.
  • Recheck labs after 30 days.
  • High MMP-9 patients may get worse when starting CSM with Herxheimer reactions.  
  • Herxheimer reaction defined as- symptoms gotten worse, new symptoms arise, reactivation of old symptoms.
  • With an increase in MMP-9 there is worsening in row E of the VCS test.
  • Trental, progesterone, curcumin, glutamine, glutathione and phosphatidyl choline have been anecdotally shown to lower MMP-9- not part of Shoemaker protocol.

Step 8: CORRECT VEGF – Correction of Hypoperfusion

  • The previous steps may have improved VEGF.
  • If not improved, exercise is added to the protocol to increase low VEGF.
  • Graded exercise below anaerobic threshold 7 days per week is recommended.
  • Patients are asked to start very slowly but may end up exercising to a maximum of 45 minutes
  • Suitable routine eventually may include 15 minutes of cardio, 15 minutes of weights, 15 minutes of abdominal exercises.
  • Corrects low VEGF.
  • Procrit and VIP can increase VO2 max.

Step 9: CORRECT ELEVATED C3a

  • Statins show reduction in T cell activation, macrophage infiltration and vascular wall infiltration.
  • Statins inhibit an enzyme HMG-COA reductase that controls the rate of cholesterol production.
  • Must be used with Coenzyme Q10 (CoQ10) – needed by mitochondria to make ATP.
  • Coenzyme Q10 levels can be measured in the serum.
  • Start Coenzyme Q10 150-300 mg for 10 days.
  • Then start statins – Zocor 80 mg day, Pravastatin, Atorvastin, Fluvastin, Rosuvastatin and Lovastatin may all be used.
  • Statins metabolized by Cytochrome P450 3A4.
  • Drugs that inhibit CYT 3A4= Sporonox, Ketoconazole, Erythromycin, Clarithromycin, HIV protease inhibitors, Nefazodone, gemfibrozil, Biaxin, Ketek and Posaconazole.  
  • No large quantities of grapefruit juice.
  • With Lovastatin, do not exceed 20 mg dose if on danazol, diltiazem or verapamil.
  • Monitor liver function, renal function and creatine.
  • May increase cognitive symptoms and raise blood sugars.

Step 10: CORRECT ELEVATED C4a

  • Reduce C4a with erythropoietin (Procrit) 8,000 units twice weekly (Mon and Thurs) for 5-8 doses with baby aspirin. 40,000 units per vial.
  • Higher doses once per week not effective due to short half-life of 1.5 days.
  • Erythropoietin causes tissue remodeling and repair.
  • Informed consent must be signed as there is a black box warning.
  • Most practitioners now use VIP instead of Procrit.  
  • Monitor CBC, iron studies, blood pressure, D-dimer.
  • Use baby aspirin when using Procrit.
  • Check levels of C4a, TGF beta-1, T reg cells and VEGF before each dose to ensure efficiency of treatment.
  • Ensure no polycythemia occurs thus increase risk for thrombus formation.
  • Keep track of symptoms to see if improvement- breathing easier, increased mental clarity.  
  • High C4a can cause decreased cognitive function due to hypoperfusion.
  • Treating C4a can improve cognitive deficits- memory, concentration, word finding, assimilation of new knowledge, confusion, disorientation.
  • Can use VIP 4 sprays a day if cannot use Procrit.
  • High C4a can cause hypoperfusion and increased brain swelling as seen on Neuroquant. Will see high lactate (>1.29) in frontal lobes and hippocampus and low glutamate/glutamine ratio (<2.19). These findings result in cognitive dysfunction and brain fog.
  • Assess cognitive function: if abnormal, do MRI spectroscopy.
  • If MRI abnormal showing low glutamate/glutamine ratio (capillary hypoperfusion) – then use Procrit. [1]
  • Recheck MRI spectroscopy after Procrit = normal G:G, normal lactate and improvement in 6 areas of cognitive functions.

[1] Shoemaker R. Biotoxin Illness Treatment Protocol pg. 10.

Step 11: REDUCE ELEVATED TGF beta -1

  • Every effort must be made to reduce this biomarker as it represents widespread tissue involvement.[1]
  • Losartan can prevent TH17 conversion of T reg cells and thus correct TGF beta-1 levels.
  • Losartan/Cozaar 12.5 mg bid, up to 25-50mg a day.
  • Child dosage is 0.6-0.7 mg/kg/day bid.  
  • VIP also lowers TGF-b1.
  • Use 4 sprays VIP a day if can’t use Cozaar due to low b.p. Patient must meet VIP criteria.  
  • If CD4+CD25++ T reg cells <4.66% and TGF beta -1 >2,380 and blood pressure normal.
  • Treat with Cozaar 25 mg daily- start with 12.5 mg.
  • Increase to 25 mg bid if necessary.
  • Monitor TGFB monthly and blood pressure daily.
  • Transfer Factor may also reduce TGF beta-1. This is not part of the Shoemaker protocol.

[1] Berndston K. pg. 14 

STEP 12: REPLACE LOW VIP

  • If patients have cleared a number of the Dr. Shoemaker biomarkers (see below) but still have signs of capillary hypoperfusion with fatigue, unusual shortness of breath with exertion and post-exertion malaise, a trial of VIP may be the most effective treatment so far in the treatment protocol.
  • Neuroquant findings will also determine suitability of use
  • Patients must be given a VIP handout before treatment.
  • VIP is dispensed in a brown bottle, must be refrigerated in upright position. It can last for 90 days if stored properly.
  • If deficient in VIP, the final step can provide significant relief.
  • Most people will have at least 75% of their symptoms relieved before starting VIP providing all the preceding steps have been done successfully.
  • All prior steps need to be fulfilled prior to use of VIP:
  • MARCoNS must be eradicated
  • VCS must be normal
  • Lipase must be normal
  • No significant exposure can be tolerated- home must have an ERMI of less or equal to 2 or Health Effects Roster Type Species Mycotoxin and Inflammagen test (HERTSMI-2) must be less than or equal to 10
  • Once decision made to use VIP the following steps need to be taken:
  • Patients must be in the office
  • Pre -VIP administration labs: VIP, MSH (this may be one of the last hormones to correct and may need VIP), TGF-beta-1, C4A, VEGF, MMP-9, CD4+/CD25++, Vit D-25-OH, estradiol, total testosterone and lipase should also be measured
  • Baseline stress echo to measure tricuspid regurgitation/ pulmonary artery systolic pressure (PASP) – verify it does not rise over 8 mm during exercise.
  • CIRS patients will often have over 8 mm Hg elevation of PASP- this can result in palpitations and dyspnea not responsive to asthma medication.[1]
  • After bloods are drawn, test spray one dose 50 mcg in one nostril.
  • Patient observed for any symptom improvement.
  • Vital signs (b. p. pulse) followed every 5 minutes for 3 separate occasions. Look for rash.
  • Watch for improvements in shortness of breath, reduced joint pain and improved cognition.
  • Post-VIP 15 minutes, redraw TF beta-1 and C4a levels. If there is a twofold increase, hidden mold may be present.
  • Patient leaves office if they tolerate the second dose.
  • Dosing thereafter is 1 spray 50 mcg 4 times per day for 30 days.
  • Redo stress echo and blood pressure after 30 days. Redo lipase, C4a,TGF beta-1, VCS.
  • Dosage can be increased to 8 sprays or reduced to less than 4 sprays per day. 
  • One needs to watch for pancreatitis and increased lipase levels. Lipase needs to be checked monthly and any signs of abdominal pain need to be noted.
  • If lipase rises, VIP needs to be stopped.
  • One must check for gallbladder issues if lipase remains elevated.
  • If TGF-beta-1 and VCS are stable, lipase is normal and symptoms are improving, VIP can continue for 30 days tapering to twice daily and then discontinued.
  • Check at 6 months when off VIP: lipase, VCS and stress echo for any changes to PASP.
  • Can use VIP for up to 4 years without adverse effects.
  • Patients with MCS and chronic fatigue syndrome may improve over time. CFS patients will have low VIP.
  • Can use Cialis 20 mg 3 times per week if VIP low and poor response to exercise.
  • VIP will increase CD4 + CD25 + FoxP3 and reduce shortness of breath and cognitive problems.
  • However, reduced joint stiffness may be seen in as little as 10 minutes as it causes immediate endorphin release.
  • Improved exercise tolerance will occur as well as overall all symptoms will improve.
  • Tight clenched hands can open and patients able to take a deeper breath on VIP.
  • Immediate pain relief is a huge relief for most patients.
  • Cognitive issues respond more slowly.

[1] Shoemaker R. Biotoxin Illness Treatment Protocol pg. 12.

Re-exposure Protocol

The phrase used by Dr Shoemaker is that patients previously exposed who are re-exposed will become “sicker-quicker” due to the immediate upregulation of immunological markers.

The following steps to be used if re-exposed:

  1. Treat with CSM or Welchol immediately. A VCS is an excellent idea to monitor biotoxin exposure. Measure key labs:  C4a, leptin, MMP-9, TGF beta-1, VEGF, von Willebrands (if bleeding).
  2. Patient to move to safe environment immediately the issue is discovered.
  3. Stay off binders and other meds if patient’s labs and VCS stable

Re-exposure Trial

If it is needed to prove that a certain building is unsafe for occupation, the following protocol can be followed: SEQUENTIAL activation of innate immune elements (SAIIE)

  • After CSM use has ended, draw the following labs: C4a, TGF beta-1, MMP9, leptin, VEGF and CD4+CD25+
  • Stop all treatment meds- CSM and Welchol.
  • Stay away from building for 3 days
  • Document symptoms having been away from the building for 3 days. Do VCS and do same labs as above.
  • Return to the suspicious building for 8 hours on no meds. Record symptoms and redo above labs
  • Return to building for a second 8 hours on the second day. Record symptoms and redraw same labs
  • Return for the 3rd day, document symptoms and obtain labs.
  • Restart medications. Record symptom scores, and VCS. Labs get scored by office.

   VIII Sequential Activation of Innate Immune Elements (SAIIE)[1]


[1] http://www.tequestafamilypractice.com/articles/CIRS_Overview.htm#SAIIE

BASELINEDAY 1DAY 2DAY 3
VCSDeceasingDecreasingDecreasing
C4aIncreasingIncreasingIncreasing
VEGFIncreasingDecreasing (2 to TGF β-1)Decreasing
LeptinStableIncreasingIncreasing
MMP9StableSpikesIncreasing
vWF Factor VIIIDecreasingIncreasingNormalizes
vWF RistocetinNormalDecreasingDecreasing/may bleed on day 3
CD4+CD25+DecreasingDecreasingDecreasing
Compare to baselineC4a, VEGFLeptin, MMP9MMP9, CD’s, VEGF, & symptoms

Scoring the SAIIE;

  • Compare the C4a on day 1 to baseline
    • Compare Leptin on day 2 to baseline
    • Compare MMP9 as average of day 2 and 3 to baseline
    • Compare VEGF to baseline; rise on day 1, fall by day 3
    • Compare symptoms day 3 to baseline.
    • Add the values

 SAIIE Scores;

  • 5 for 100%; 4 for 80%, 3 for 70%, 2 for 60%, and 1 for 50%
    • Controls mean is 6.3
    • Cases mean is 17.9
    • TGF β-1 rapidly changes
    • CD4+CD25+; it drops rapidly.

 What is SAIIE really showing?

  1. Looking at the progression of innate immune responses- extremely sensitive C4a and TGF β-1
    1. Gene activation following receptor resistance (leptin)
    1. Bottom line; this is absolute proof of causation.
    1. A/B/B’/A/B research design.
      1. A Person at baseline
      1. B Intervention fixes them
      1. B’ Stop medicine
      1. A Re-expose
      1. B Intervention fixes them again

   This is demonstrative of:

  1. Pattern recognition; antigen presentation gone awry
    1. Inflammatory responses not controlled, neuropeptides are depleted
    1. Innate immune abnormalities become chronic as a host-response syndrome

Summary

Patients who present with a CIRS diagnosis, at present, have an enormous amount of information to ingest and, on occasion, significant skepticism to overcome. Skepticism usually rises when the patient returns to the primary care provider or specialist, to discuss the diagnostic and therapeutic path that may have been outlined. There is a common saying in life, “what you are not up on, you are usually down on.” Nowhere is this more evident than in the world of medicine. It is not uncommon for medical doctors to dismiss outright any information that is not part of their consensual reality. Even if one is not trained in this area of emerging medicine, it still requires a deep commitment to study the literature, learn the diagnostic and therapeutic criteria for CIRS and apply them to complex multi-symptom, multi system patients who fit the CIRS diagnosis.

At present, the CIRS diagnosis may be dismissed, diminished, misdiagnosed or misunderstood. It may take some time before the full scope and implications of this diagnosis make its way into clinical practice and hence consensual reality. In the meantime, it is incumbent upon practitioners of the CIRS protocol to continue learning the emerging science, particularly the role of genomics in the diagnosis and treatment protocol.

Adequate standards of remediation are another problem many patients frequently encounter. Too often I have heard of patients phoning a mold specialist who does not perform an adequate attic to basement visual inspection of the house but instead does an air sample and proclaims that the home is “mold free.”

Thanks to the recent Consensus Statement on the investigation and remediation of water-damaged buildings in case of CIRS-WD, [1] specific guidelines now exist for patients, practitioners, and indoor air practitioners to follow in cases of those patients with a known CIRS diagnosis.

It will take some time before critical mass is reached and this diagnosis and treatment protocol makes its way into everyday clinical practice. Having worked with the Dr. Shoemaker protocol for over five years, it has been my experience that if a patient is correctly diagnosed and follows the protocol exactly as it has been set out, the possibilities in their returning to good, if not excellent health, are directly proportional to the effort he applies to strictly following the diagnostic and treatment criteria. It is certainly a rewarding moment to witness patient’s symptom scores fall away as he makes progress with the protocol. The protocol does not produce overnight miracles, but at each step of the way, gains are made as the patient’s lives slowly return to normal. It is a wonderful experience to be a part of this transformation.


[1] Schwartz L, Weatherman G, Schrantz M, Spates W, Charlton J, Berndtson K, Shoemaker R. Indoor Environmental Professional Panel of Surviving Mold – Consensus Statement

How Does Time Restricted Eating and Intermittent Fasting Work? Part II

How Does Time Restricted Eating and Intermittent Fasting Work? Part II

Intermittent fasting or IF is a practice involving alternating fasting time and/or calorie restriction with periods of feeding that has proven cellular benefits, metabolic gains and remission or reversal for a variety of symptoms and disease states. Time restricted eating is compressing an eating window to a specific number of hours each day. An example of this would be eating all the day’s food within a 6–8-hour window. 

With the prevalence of obesity and chronic disease impacting our healthspan and quality of life, implementing the practices of intermittent fasting or time restricted eating may prove to be an important lifestyle tool for maintaining health and vitality as we age.

In Part One of this series, I went into detail about how intermittent fasting and time restricted eating works along with the long list of health benefits that have been linked to these lifestyle tools. In today’s article, Part Two takes a more practical view regarding the different ways to structure intermittent fasting and time restricted eating. We will also cover some of the most common questions about the safety and details of these two lifestyle practices. This will essentially be a guide to intermittent fasting and time restricted eating for beginners and experienced fasters alike.

This article covers the following topics:

  • How to intermittent fast
  • How to do time restricted eating
  • Is intermittent fasting and time restricted eating safe?
  • Are these two practices different for men and women?
  • Can you drink coffee or tea?
  • Does intermittent fasting and time restricted eating promote weight loss?
  • Can a ketogenic diet be combined with intermittent fasting and time restricted eating?

By the end of this article, you’ll know if intermittent fasting and time restricted eating are for you and how to get started.

Time restricted eating meal plan hours – 16:8, 18:6, and 20:4

There are many ways to implement a time restricted eating and/or intermittent fasting plan. Let’s look at some of the most popular schedules for time restricted eating and intermittent fasting.

Type of time restricted eating or intermittent fastingExplanationSample scheduleWhat to eat in your windowTips
Time restricted feeding (TRF)Fast for 16 hours overnight and condense meals into an 8-hour windowFinish dinner by 8 pm then fast until 12 pm the next dayRegular dietMay be practiced daily or a few times per week
Time restricted feeding 18:6 (TRF)Fast for 18 hours overnight and condense meals into a 6-hour eating windowFinish dinner by 6 pm and fast until 12 pm the next dayRegular dietMay be practiced daily or a few times per week
Time restricted feeding 20:4 (TRF)Fast for 20 hours overnight and condense meals into a 4-hour eating windowFinish dinner by 6 pm and fast until 2 pm the next dayRegular dietMay be challenging to meet nutrient needs if practiced daily
One Meal A Day (OMAD)Eat only one meal per day and fast for 23 hoursEat between 12 pm and 1pm each dayRegular dietMay be challenging to meet nutrient needs if practiced daily 
Alternate Day Fasting (ADF)24-hour fast every other dayFor example Monday – Fast Tuesday – Eat Wednesday – Fast Thursday – Eat  Regular dietSafe for several months, long-term challenges (1)
5:2 fasting (periodic fasting)24-hour fast 2 days per weekMonday, Tuesday – Eat Wednesday – Fast Thursday, Friday – Eat Saturday – Fast Sunday – EatRegular diet 
Fasting-Mimicking Diet (FMD)5 days of plant-based dietMay be practiced monthly for between 3 and 6 monthsPlant-based diet of 800 to 1000 calories per dayFood available through Prolon or Whole Food FMD program, available through the Hoffman Centre

With so many options, it may be challenging to determine how to start time restricted feeding or intermittent fasting. For example, do you just dive in or do you ease into it more slowly? I recommend starting with either time restricted feeding (TRF) or with the fasting-mimicking diet. (FMD). With that experience, you can then work with your provider or myself to determine if you’d benefit from other practices.

TRF may begin with a simple 12:12 schedule, meaning that you begin fasting overnight and then eat your regular diet within a twelve-hour eating window. For many people this isn’t that much different from their typical pattern, although they may have to be aware of any tendencies for late night snacking. A fast from 8 pm until breakfast at 8 am the following day is a good schedule to start with. Once you have this under your belt, you can expand your fasting window, in increments if needed, to a fourteen-hour fast with a ten-hour eating window. You can then potentially lengthen this to include a fast of sixteen hours or longer.

The fasting-mimicking diet (FMD) is a five-day program, typically practiced once per month for between three and six months, and then one time every 3-4 months as a maintenance program. During the five day fast, you follow a plant-based, calorie-restricted diet. The diet is derived from plant sources like vegetables, nuts, seeds, and fruit. The diet relies on plant foods for protein, olives, coconut and nuts and seeds for healthy fats. The diet constituents are carefully chosen by a nutritional expert. There is a commercially available program involving packaged constituents called ProLon.

With calories restricted to approximately between 750 and 1100 per day, with day one containing the most calories. This represents a réduction in calories of around 50 to 60 percent, this diet is designed to mimic molecular and cellular fasting while increasing patient compliance. The stomach sees food, while the cells see fasting. (2, 3)

The fasting mimicking diet has been clinically studied as a therapy for a variety of conditions including autoimmunity, breast cancer, and metabolic disease such as heart disease and diabetes. Extensive studies in mice have been completed, along with a few human clinical trials.

In the most recent randomized controlled trial from 2021, obese women received either a five-day fasting mimicking diet or their typical diet with a calorie deficit of 500 calories each day. This particular study didn’t indicate a difference in weight between the two groups, but the women following the fasting-mimicking plan showed reduced insulin resistance and improved appetite regulating hormones, along with preserved muscle mass and metabolic rate. (4)

At the Hoffman Centre, Justine leads a whole food fasting-mimicking program which I’ve personally undertaken three times and seen the dramatic results. An additional benefit to this structure is the group dialogue component and support provided throughout the process.

Learn more about this program here

It’s important to note that many fasting trends such as juice fasting don’t have the same benefits and may even have risks. Prolonged fasting of more than two days without food may contribute to electrolyte imbalances, dizziness, exhaustion, and other symptoms, making compliance quite challenging. Both time restricted feeding and the fasting-mimicking diet offer the benefits of fasting with intermittent fasting rules that are easy to follow.

Frequently asked questions

Let’s dive into some of the most common questions that I’m asked about intermittent fasting and time restricted eating, who it’s recommended for and who it’s not recommended for, along with some details to help you feel more confident moving forward.

Are intermittent fasting and time restricted eating safe?

Intermittent fasting and time restricted eating are safe and effective practices for many people. However, it’s important to work with your doctor, especially if you have a medical condition or take any medications. A doctor should look at your medical history, complete a physical exam, and review any laboratory testing. Please however note that your doctor may not be that familiar with these approaches to nutrition nor know the science behind it. Be sure that you are practicing the most well informed kind of patient advocacy and be prepared to educate you doctor on the subject .

While intermittent fasting and time restricted eating might be beneficial in a variety of medical cases, as explained in Part One, there are many cases in which intermittent fasting and time restricted eating are not indicated including:

  • Pregnancy and lactation
  • Anorexia, underweight, or chronic malnutrition
  • Type 1 diabetes or insulin-dependent Type 2 diabetes (as insulin requirements may plummet dramatically requiring a lowering of insulin dosing)
  • Recent stroke or heart attack
  • Pulmonary embolism or deep vein thrombosis
  • Cardiac instability or atrial fibrillation
  • Advanced kidney disease
  • Advanced liver disease
  • Advanced heart disease
  • Porphyria, MCAD
  • Inability to discontinue medications
  • Inability to obtain adequate rest while fasting
  • Active growth, such as with children or adolescents
  • Current fever, cough, or signs of an active infection (5)

Alternatively, if you’re working on any of the following imbalances or disease states, it may be worth discussing intermittent fasting and time restricted eating with your personal doctor or with myself.

  • Excess weight or obesity
  • Elevated cholesterol
  • Elevated blood pressure
  • Cardiovascular disease
  • Metabolic syndrome or type 2 diabetes
  • Lymphoma and other cancers
  • Digestive imbalance, including SIBO
  • Autoimmune disease
  • Dependency or toxicity

Fasting side effects may include fatigue, weakness, headache, dry mouth, menstrual irregularity, memory impairment, muscle pain, constipation, sugar cravings, and brain fog. Be sure to stay well hydrated and avoid strenuous exercise or extreme environments while fasting. Fasting is the ideal time for rest.

Is intermittent fasting and time restricted eating different for men and women?

While much of the initial intermittent fasting research has been conducted on animals and human men, we’re starting to learn more about the unique needs of women when it comes to fasting. Whereas men have similar hormonal patterns from day to day, women’s hormones fluctuate on a monthly cycle and then decline through perimenopause and menopause. You can learn more in my article on hormone replacement therapy.

Women seem to be more sensitive to over-fasting and restricting their food intake too much, too often. They might see imbalances in stress hormones, thyroid hormones, and sex hormones. In extreme cases, too much fasting may lead to amenorrhea or the loss of a woman’s period, especially when percentage body fat drops below a certain percentage. When it comes to intermittent fasting for women, it’s important to note that more fasting isn’t always better. A less-is-more-approach often applies.

And while each woman is different, it’s challenging to provide advice for fasting in women on a worldwide basis. For example, some women with autoimmune disease do very well with implementing intermittent fasting practices, while others might do more poorly. Remember that fasting is a stressor on the body and this can be a good stressor that leads to autophagy, detoxification, and cellular rejuvenation. Yet if the system is already stressed, fasting can sometimes be the straw that breaks the camel’s back. Often, if a woman is exhausted, overwhelmed, and feeling burnt out this isn’t the time to add even more stress.

In a study of obese women, intermittent fasting combined with calorie restriction was shown to reduce weight over a ten-week period. (6) However, many restrictive methods work in the short-term and we may need to learn more about the long-term results of fasting for women.

In another study comparing men and women in a forty-eight-hour fast, it was noted that women tend to accumulate triglycerides in their muscles, while men accumulate these in their livers, although other physiological aspects during the fast were similar. (7) We certainly need more research to further establish the differences related to long-term fasting practices and the different types of intermittent fasting between men and women regarding the potential benefits fasting.

As always with functional medicine, a personalized approach is best. As discussed above, I recommend starting with gentle time restricted feeding or with the fasting-mimicking diet.

Can I drink coffee or tea during fasting hours?

This question about hot drinks usually leads to hot debate! Whether you can drink coffee while intermittent fasting may depend on what works best for you as an individual.

Experts in the fasting field recommend “complete abstinence from all substances except pure water.” (5) Biological fasting is the absence of anything that triggers nutrient-sensing pathways. (3) This certainly means no protein, carbohydrates, or fats, but most likely no vitamins, minerals, or plant compounds either.

While black coffee or tea, doesn’t contain any calories, it does contain caffeine, which can influence the hormones cortisol and insulin. It also contains phytonutrients, the antioxidant compounds that are absorbed and which rely on digestion and metabolism.

So, what can you drink during intermittent fasting? If you want to be a purist, stick to only water during your fasting window then enjoy coffee or tea with your first meal of the day or at any time within your eating window.

After that, you can experiment with plain coffee or tea within your fasting window and see whether it improves, or deters from, your results. Coffee or tea with added fat, such as bulletproof coffee, should be enjoyed during the eating window.

Does intermittent fasting and time restricted eating help with weight loss?

Weight loss is difficult and traditional strategies are largely based on reducing calories and increasing exercise. However, these strategies, especially extreme versions, typically only produce short-term results. Many factors contribute to weight, including hormones, sleep, stress, nutrient levels, toxin exposure, mindset, and so much more. Simply looking at calories doesn’t always address the situation and a short-lived fast may only result in a Band-Aid effect. Yet for some, even a quick boost in hope and confidence that the body can lose stubborn weight can be a catalyst for deeper change. That’s why discussing how to use fasting with a trained professional is key.

Using intermittent fasting and time restricted eating for weight loss might be a solution, or just part of the weight solution, especially for someone who spends the majority of their time in the fed state. Fasting might provide the metabolic balance that will address some of the underlying physiology contributing to weight gain, such as inflammation, elevated insulin, and oxidative stress.

In a review of different types of intermittent fasting, IF produced similar weight loss results to those derived from caloric restriction. 5:2 fasting was similar to restricting daily calories in nine out of eleven studies. In addition, the majority of the weight loss occurred in the first three months before weight hit a plateau and results were similar with different distributions of macronutrients. Time restricted feeding and caloric restriction also seemed similar as far as weight was concerned. (8)

In a long-term study that compared alternate day fasting or ADF with daily calorie restriction in obese adults, weight loss after one year was 6 percent in the ADF group compared to 5.3 percent in the calorie restriction group, so there wasn’t a huge difference. (9)

When examining human studies involving individuals with diabetes, those practicing time restricted feeding as opposed to consuming six small meals per day lost more weight. The studies also showed more results with intermittent fasting in terms of decreasing A1C and blood glucose, which are markers of diabetes, compared to a common recommendation of eating frequent small meals. (10)

The definitive answer to this question regarding the intermittent fasting weight loss diet may not be clear in the science. However, I’ve seen it used successfully in my practice for patients who are good candidates, along with other functional medicine interventions.

Does intermittent fasting and time restricted eating work while following a ketogenic diet?

Ketogenic diets, time restricted eating, and intermittent fasting are often discussed as going hand in hand. Keto, which is an abbreviation for the ketogenic diet, is a high fat, low carbohydrate eating pattern that in its own way mimics the fasting state through the restriction of dietary glucose. The ketogenic diet, time restricted eating, and intermittent fasting all have the potential to increase ketones in the blood that can be used as fuel by the cells instead of them employing glucose. The ketogenic diet combined with time restricted eating and intermittent fasting may also have similar benefits related to a treatment approach to chronic and metabolic diseases.

To answer the question, yes, intermittent fasting and time restricted eating can be combined with a ketogenic diet. Those following a ketogenic diet that are in a state of ketosis, where the body is efficient at turning fat into ketones and using them as fuel, may have a better experience with fasting and fewer negative side effects. Similarly, those with an existing fasting practice might have an easier time transitioning to a ketogenic diet because their metabolism is already primed to use ketones.

So, while intermittent fasting or time restricted eating combined with a keto diet may certainly be an important dietary approach for some people healing from chronic disease or working to promote longevity, it may be too restrictive for others. This is another reason why working with an experienced practitioner can be so helpful. You can dial in your nutrition plan and then have support adjusting, and even expanding, the diet over time.

We all want to remain healthy and high-functioning as we get older, but it’s about more than living a long time. It’s about improving our quality of life. Intermittent fasting is meant to mimic the balance between feast and famine that humans have always experienced throughout history. Regular feasting is a relatively recent development and this excess time in the fed state may deter us from experiencing all of the important health and longevity benefits that come from fasting. The best part about intermittent fasting is that it makes fasting simple, gentle, and fit into modern life.

To learn more about working with me individually or to join our next group fasting-mimicking diet, please contact my office.

References:

  1. Stekovic S, Hofer SJ, Tripolt N, et al. Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans [published correction appears in Cell Metab. 2020 Apr 7;31(4):878-881]. Cell Metab. 2019;30(3):462-476.e6.
  2. Di Francesco, A., Di Germanio, C., Bernier, M., de Cabo, R. A time to fast. Science. 2018;362(6416),770-775.
  3. Hong, K. Intermittent Fasting and Fasting Mimicking: Clinical Applications. Presentation. University of Southern California.
  4. Sadeghian M, Hosseini SA, Zare Javid A, Ahmadi Angali K, Mashkournia A. Effect of Fasting-Mimicking Diet or Continuous Energy Restriction on Weight Loss, Body Composition, and Appetite-Regulating Hormones Among Metabolically Healthy Women with Obesity: a Randomized Controlled, Parallel Trial [published online ahead of print, 2021 Jan 9]. Obes Surg. 2021;10.1007/s11695-020-05202-y.
  5. Goldhamer, A. Can Fasting Save Your life. TrueNorth Health Center.
  6. Klempel MC, Kroeger CM, Bhutani S, Trepanowski JF, Varady KA. Intermittent fasting combined with calorie restriction is effective for weight loss and cardio-protection in obese women. Nutr J. 2012;11:98. Published 2012 Nov 21.
  7. Browning JD, Baxter J, Satapati S, Burgess SC. The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. J Lipid Res. 2012;53(3):577-586.
  8. Rynders CA, Thomas EA, Zaman A, Pan Z, Catenacci VA, Melanson EL. Effectiveness of Intermittent Fasting and Time-Restricted Feeding Compared to Continuous Energy Restriction for Weight Loss. Nutrients. 2019;11(10):2442. Published 2019 Oct 14.
  9. Trepanowski JF, Kroeger CM, Barnosky A, et al. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern Med. 2017;177(7):930-938. doi:10.1001/jamainternmed.2017.0936
  10. Muñoz-Hernández L, Márquez-López Z, Mehta R, Aguilar-Salinas CA. Intermittent Fasting as Part of the Management for T2DM: from Animal Models to Human Clinical Studies. Curr Diab Rep. 2020;20(4):13. Published 2020 Mar 12.

How Does Time Restricted Eating and Intermittent Fasting Work? Part I

How Does Time Restricted Eating and Intermittent Fasting Work? Part I

If you’re interested in living a healthier lifestyle, you’ve probably heard of time restricted eating, or intermittent fasting and the success stories associated with incorporating these practices into your life. Despite living longer these days, the healthspan of many Americans is actually cut short as the average person spends seventeen of their final years living in poor health. This is due to chronic diseases such as diabetes, heart disease, cancer, and Alzheimer’s. In fact, 80 percent of older adults have at least one chronic condition, which is primarily related to their lifestyle.

What if time restricted eating or intermittent fasting could be a solution, one of the tools in the kit, to help combat the underlying factors that contribute to such diseases? Is time restricted eating and intermittent fasting simply a diet trend? Or is there a substantial and credible scientific basis to warrant its therapeutic use?

In this two-part series, we’ll explore these questions, and more.

In Part One we’ll examine the nature of time restricted eating and intermittent fasting, how it works, and the health benefits of both practices.

Part Two will cover methods of fasting and time restricted eating, along with answers to the most commonly asked questions regarding this popular practice.

What are time restricted eating and intermittent fasting?

Time restricted eating, (TRF) and intermittent fasting, also referred to as IF, are often treated as if they are one and the same, but there are actually some major differences between the two.

Time restricted eating involves simply alternating periods of eating with periods of fasting. With TRF, all of your eating is compressed into a 1 -12 hour feeding window. Most hours of the waking day, you’ll spend in a feeding state—say from 8:00 am to 4:00 pm. The other hours, you don’t consume any calories, although you are allowed calorie-less drinks, like water, sparkling water, decaffeinated tea and black coffee. Some people, (known as OMAD’s), eat only one meal a day (OMAD) and fast for 23 hours. 

The term intermittent fasting can be confusing and inaccurate. The term ruffles some researchers feathers because there are many different forms of fasting or restriction. It’s important to distinguish between them. The other problem with the term intermittent fasting is the flexibility around the term “fasting.” Most studies on various intermittent fasting schedules allow up to 700 calories per day on fasting days, while others don’t allow any calories. I want to be very particular about the definitions because I think different forms of fasting and different types of restriction may have different physiologic effects, and by lumping all forms of fasting together, we may dilute such insights.

Intermittent fasting includes the fasting-mimicking diet or FMD, where your intake is restricted to between 750 and 1050 calories (approximately) per day for a five-day period out of the month. This has been shown to mimic some of the physiological benefits of water fasting.

In addition, intermittent fasting also includes alternate day fasting or ADF. With this type of fasting a regular diet is followed for one day followed by a day of fasting. Another option is 5:2, which involves five days of regular eating followed by two fasting days in one week. With each of these methods, the fasting days can feature either a water fast or a calorie-reduced diet.

In contrast, a long-term or prolonged fast is considered more than two days and up to several weeks without food.

As you can see, there are several versions of intermittent fasting in which individuals can engage and that have been explored with scientific research. I’ll cover these in more detail when we discuss an intermittent fasting schedule and how to implement it in Part Two of this series.

How intermittent fasting works

If we take a look back in time to more ancestral or hunter-gatherer ways of eating, feasting was always balanced with famine. There were naturally times of the year when food was abundant and times of the year when food was scarce. The human body has the ability to adapt and thrive in both cases.

With the onset of our modern agricultural system, most of us in the developed world no longer have natural periods of fasting and life is a perpetual feast. We have access to whatever food we desire, grown anywhere in the world, every day. It’s no wonder that rates of obesity are the highest they’ve ever been, leading to inflammation and chronic disease. These days the body’s systems never have an opportunity to rest and reset.

So how exactly does intermittent fasting work? To answer this question, we need to go behind the scenes and into the cell to understand what’s happening on the cellular level, in both the fed state and the fasting state.

When we eat a meal, the body’s system is dedicated to processing food, which places the cell in growth mode. Insulin levels are higher, signaling the cell to grow. More specifically, insulin signals mTOR, meaning mammalian target of rapamycin, which instructs the cell to grow and divide. mTOR also decreases autophagy, the process of cellular recycling, that’s predominant during fasting and important for regular repair and maintenance of the cell. (1)

Autophagy naturally declines with age and decreased autophagy is related to neurodegenerative disease, cardiomyopathy, cancer, metabolic syndrome, suppressed immunity, and signs of aging. Boosting autophagy by means of intermittent fasting methods may help to slow or reverse these changes.

In the fasting state AMPK, or 5’ AMP-activated protein kinase, slows down mTOR. This causes fat breakdown and works to activate autophagy, allowing the body to run on its own stored fuel in the form of fat. AMPK also cleans up and repairs parts of the cell that don’t work, an important process that contributes to healthy aging and preventing diseases such as cancer. (1)

In addition, fasting, intermittent fasting, and calorie restriction down regulates IGF-1, or insulin-like growth factor-1. IGF-1 signaling is important for protein synthesis, as well as blood sugar regulation and growth. Later in life, increased IGF-1 can accelerate the aging process and decreasing it, through methods such as IF or time restricted eating, may increase longevity. Studies in mice indicate that employing different types of intermittent fasting can result in an increased lifespan. (1)

When food is scarce, the body conserves energy by downregulating or decreasing both mTOR and IGF-1, which increases stress resilience and protection on the cellular level. In fact, this can be considered inner rejuvenation, which reduces inflammation and increases autophagy. The results include increased stem cell regeneration and improved immunity, especially during fasts lasting more than a few days or by means of fasting-mimicking. (1)

Decreasing IGF-1 also decreases cellular senescence, in which the cell loses its ability to divide, as measured by telomere length. This process of cellular senescence is caused by underlying factors that produce oxidative stress, changes in the epigenetic gene expression, metabolic dysfunction, and mitochondrial dysfunction and the process is considered irreversible. However, decreasing IGF-1 or mTOR increases sirtuins, via the antiaging molecule NAD+, autophagy, and enables DNA repair. (1)

When the body is in a fed state, cells are highly acetylated so that genes are turned on. This helps cells to survive and proliferate. When these genes are on, the ones that are more related to fat metabolism, stress resistance, and cellular repair are turned down. (1)

This is what happens metabolically throughout a longer fast or a fast-mimicking diet over the course of five days.

  • 12 hours: The body transitions from primarily using glucose as fuel to increasing ketones as the preferred fuel for cells, including cells in the brain. (2) This causes an increase in BDNF, or brain-derived neurotropic factor, which allows for increased brain plasticity and neurogenesis. (1)
  • 18 hours: Ketone levels continue to rise. More ketones lead to a decreased need for glucose and insulin, along with more BDNF.
  • 24 hours: Cells increase autophagy, allowing for recycling and the breakdown of old or broken cellular components. (3)
  • 48 hours: Growth hormone (GH) is five times higher than normal, helping to preserve lean muscle mass, reduce fat, and is important for longevity. (4)
  • 54-72 hours: Insulin sensitivity increases and new stem cells and immune cells form. (5)

In summary, on the cellular level, fasting results in the following:

  • Decreased mTOR
  • Reduced IGF-1
  • Increased AMPK
  • Increased autophagy
  • Greater NAD+ and sirtuins
  • Increased ketones
  • Increased BDNF
  • Increased GH
  • Reduced levels of insulin and blood glucose
  • Decreased cellular senescence
  • Increased fat metabolism
  • Improved resistance to cellular stress
  • Reduced inflammation

Our bodies still need both the fed and fasting state, but in our modern culture the balance strongly favors always being fed. Intentional fasting may be a way to add greater balance to the system by allowing for these natural cellular processes that primarily happen in the fasted state.

Health Benefits of Intermittent Fasting and Time Restrictive Eating

Now that we’ve covered the science of fasting and time restricted eating, the question I’m often asked is whether these practices work in regard to health and longevity. This is an exciting area of study, using a wide variety of animal models, along with increasing numbers of studies in humans, in order to decipher the potential benefits of intermittent fasting and implementing time restricted eating.

Research has indicated a number of positive clinical benefits related to intermittent fasting and time restricted eating

  • Weight loss
  • Changes in body composition/fat loss
  • Improved insulin sensitivity or decreased insulin resistance
  • Reduced oxidative stress
  • Increased cellular autophagy
  • Stem cell regeneration
  • Optimized neurogenesis
  • Enhanced parasympathetic nervous system response
  • Improved gut motility, which is important for conditions like SIBO
  • Reduced heart rate
  • Reduced blood pressure
  • Improved lipid/cholesterol balance
  • Improved cognitive function
  • Improved detoxification
  • Improved physical performance
  • Improved sleep patterns
  • Improved immunity (1,6,7)

Taken together, all these clinical benefits translate into important applications related to longevity and chronic disease reversal. Intermittent fasting results are clearly beneficial for a variety of disease states and populations, including those with cardiovascular disease, diabetes, obesity, dementia, cancer, depression, and a number of other conditions. (6,7)

Intermittent fasting addresses the metabolic root causes that contribute to disease over time. IF and time restricted eating may be an important lifestyle tool, along with diet, physical activity, and stress reduction, that brings health more into balance.

In Part Two of this series on intermittent fasting, we explore the specifics of the different types of intermittent fasting, along with how to implement an intermittent fasting schedule. We’ll then cover some frequently asked questions on the topic and provide details and guidance to get you started.

If you’re looking for more personalized guidance, or are interested in our whole food fasting-mimicking program available through Justine Stenger and the Hoffman Centre for Integrative and Functional Medicine, please contact us for more information.

References:

  1. Hong, K. Intermittent Fasting and Fasting Mimicking: Science and Molecular Mechanisms. Presentation. University of Southern California.
  2. Anton SD, Moehl K, Donahoo WT, et al. Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting. Obesity (Silver Spring). 2018;26(2):254-268.
  3. Alirezaei M, Kemball CC, Flynn CT, Wood MR, Whitton JL, Kiosses WB. Short-term fasting induces profound neuronal autophagy. Autophagy. 2010;6(6):702-710.
  4. Hartman ML, Veldhuis JD, Johnson ML, et al. Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men. J Clin Endocrinol Metab. 1992;74(4):757-765.
  5. Klein S, Sakurai Y, Romijn JA, Carroll RM. Progressive alterations in lipid and glucose metabolism during short-term fasting in young adult men. Am J Physiol. 1993;265(5 Pt 1):E801-E806.
  6. Hong, K. Intermittent Fasting and Fasting Mimicking: Clinical Applications. Presentation. University of Southern California.
  7. Goldhamer, A. Can Fasting Save Your life. TrueNorth Health Center.
  8. Rynders CA, Thomas EA, Zaman A, Pan Z, Catenacci VA, Melanson EL. Effectiveness of Intermittent Fasting and Time-Restricted Feeding Compared to Continuous Energy Restriction for Weight Loss. Nutrients. 2019;11(10):2442. Published 2019 Oct 14.

Mast Cell Activation Syndrome and Excipients

Mast Cell Activation Syndrome and Excipients

Mast cell activation syndrome (MCAS) is a complex disease that I’ve previously written about at length. It’s a multi-faceted condition that can often be frustrating and difficult to manage for both the patient and the provider.

Mast cells are immune cells that function to help your body get rid of what they deem to be harmful compounds. In the presence of a harmful substance, the mast cells release mediators such as histamine, leukotrienes and prostaglandins which help your body to expel the invader.

However, in certain individuals, mast cells can be oversensitive and release large amounts of mediators in response to certain triggers. These include heat, cold, sunlight, certain medications, and certain foods, among other things. These reactions can cause a cascade of symptoms of varying severity, up to and including anaphylactic shock.

Treatment for MCAS involves identification and strict avoidance of your triggers, along with medication therapy and lifestyle changes. Medications that may help with the management of MCAS include H1 and H2 histamine blockers.

However, sometimes these changes alone aren’t enough to help you completely manage your MCAS. You may also struggle to identify what triggers your MCAS reactions.

MCAS is considered ‘idiopathic’ when triggers can’t be identified. If you’re struggling with idiopathic MCAS, this article will be of interest to you.

Common drugs known to trigger MCAS

  • Vancomycin is an antibiotic often used in C. Difficile treatment, which is known to cause ‘Red Man Syndrome’.
  • Morphine and other opiates, with fentanyl and Dilaudid being the opiates that are the most easily tolerated.
  • Aspirin and non-steroidal anti-inflammatories (NSIADS), like Motrin and Advil, are only sometimes a problem as in certain people they can actually act as mast cell inhibitors.
  • Angiotensin converting enzyme inhibitors, known as ACE inhibitors, are drugs used to treat hypertension and can increase bradykinin levels, which in turn activates mast cells.
  • Beta-blockers are used to treat hypertension, anxiety and tachycardia and lower the threshold for mast cell activation, interfering with the efficacy of epinephrine if this is needed for anaphylaxis. A glucagon pen can be used as an alternative if beta-blockers are necessary to treat other conditions.
  • Some local anesthetics, such as benzocaine, procaine, tetracaine, and chloroprocaine, can trigger mast cell activation, although lidocaine is usually well tolerated.
  • Some muscle relaxants like atracurium and succinylcholine can act as triggers, but vecuronium and pancuronium are usually well tolerated.

One relatively recent development in the treatment and management of MCAS involves considering drug and supplement excipients or inactive ingredients, rather than the actual drug itself. Drug formulations vary significantly between brands and there’s mounting evidence to suggest that many people with MCAS may have reactions to certain excipients found in their medications and/or supplements. The same drug or supplement made by different manufactures with different dyes, excipients, or fillers may provoke very different reactions in patients with MCAS. The active drug itself may not be the issue, but the excipients, dyes, and fillers may be the culprit.

In this article, you’ll learn:

  • What excipients are
  • How they can trigger mast cell responses
  • Some of the most common harmful excipients
  • How to tell if you’re having a reaction to an excipient
  • How to identify and avoid excipients that may worsen your MCAS

What are excipients?

Excipients are inactive ingredients found in over-the-counter and prescription medications, as well as in vaccines. These ingredients play a number of different roles in the proper delivery of the active ingredient to the body and many of these roles are absolutely necessary to facilitate the efficacy of the drug. (1)

In fact, most drugs are made mostly of excipients and the active ingredients represent only a small percentage of the drug by weight.

According to Dr. Jill Schofield of the Center for Multisystem Disease, excipients “are supposed to be ‘inert’ and ‘safe,’ but they may cause problematic reactivity in MCAS patients, including anaphylaxis.” (2)

Unfortunately, many excipients pose a risk of reactivity in people with MCAS, so it’s important to fully consider the impact of not only the active ingredients of a drug, but also its inactive ingredients when starting a new medication.

Types of excipients

There are over a thousand known drug excipients and the list grows almost daily, as researchers continue to develop new drugs and drug delivery systems.

Here are some of the main categories of excipients and their role in medications, according to Dr. Schofield:

  • Lubricants: These prevent pills from sticking together in storage, examples being silica and magnesium stearate
  • Binders and fillers: These provide volume to pills and bind ingredients together. Binders and fillers include cellulose and polyethylene glycol.
  • Coatings: These protect pills from damage, make them easier to swallow, and may provide ‘time-release’ or ‘extended-release’ function, examples being shellac and gelatin.
  • Dyes: As you’d expect, these alter the color of medications. Dyes used include FD&C red #5 and FD&C blue #2.
  • Flavourings: These alter the taste of the drug to mask bad-tasting ingredients and improve acceptance of the medication, especially in the case of children. Flavouring examples include sucralose and xylitol.
  • Preservatives:Substances such ascitric acid and retinol palmitate improve the shelf life of medications.

This is just a small sampling of some commonly used excipients. Not only are there hundreds more individual excipients, there are also many more categories of excipients that play different roles in medications.

How can excipients affect MCAS?

Dr. Schofield describes people with MCAS as “canaries in the coal mine.” If you’re unfamiliar with this turn of phrase, it refers to the canaries that were carried by miners deep into mines when they worked. If there were toxic levels of gases present in the mine, the canary would die well before the miners, serving as warning that they needed to get out of the mine.

People with MCAS, like the canaries in the coal mine, are profoundly more sensitive to the chemicals they’re exposed to than other people. Unfortunately, this means that many people with MCAS experience reactivity to one or more drug excipients. These reactions can manifest in the following ways:

  • Fatigue
  • Malaise
  • Gastrointestinal upset, such as abdominal pain, nausea, vomiting, or diarrhea
  • Skin rashes
  • Itchy skin
  • Hives
  • Headache
  • Anxiety
  • Flushing
  • Anaphylaxis
  • Headaches
  • Insomnia

However, this isn’t a complete list of symptoms of excipient reactivity. MCAS is such a complex and individualized disease and symptoms can differ vastly from person to person.

If you’ve been diagnosed with MCAS and have removed your known triggers but are still experiencing symptoms, it may be time to investigate drug and supplement excipients and how they may be affecting you.

What are some of the common harmful excipients?

Some of the most common excipients that people with MCAS are reactive to include alcohol, dyes, and povidone. In fact, according to Dr. Schofield, dyes and alcohol are a great starting point for determining excipient reactivity in MCAS patients, primarily because so many people are reactive to them.

Povidone

Povidone is an extremely common excipient, used as an ingredient in hundreds of drugs. (3) It’s a polymer that’s added to drugs to help disperse the active ingredient evenly throughout a liquid or powder solution. It’s also used as a binder and to help drugs in pill form disintegrate properly. It’s water-soluble, so it’s commonly used in liquid drug solutions as well as in tablets or capsules.

It’s an ingredient in betadine, an antiseptic iodine solution that’s used to prep the skin before medical procedures. According to Lawrence B. Afrin, M.D., if you’ve previously been diagnosed with a betadine allergy, it’s highly likely that you’re actually sensitive to povidone. (4) You see, iodine is absolutely vital for proper body functioning so it’s illogical, and emerging research suggests it’s impossible, to be allergic to iodine (5). Because the only ingredients in iodine solutions like betadine are often water, iodine, and povidone, and it’s highly unlikely that you are allergic to water or iodine, this leaves povidone as the likely culprit.

Dyes

Dyes are ubiquitous in medications, a very common MCAS trigger, and unfortunately serve no purpose beyond an aesthetic one.

Although you may find that you’re only sensitive to one or two dyes, it’s often best to avoid all FD&C dyes when possible. Ferric oxide red and yellow may be better tolerated by people with MCAS, according to Dr. Schofield.

You should note that even white tablets may contain dyes, so you’ll need to check the ingredient list for confirmation.Many drugs have dye-free formulations or, in the case of drugs in capsule form, you can discard the capsule. This is often the only portion of the drug containing the dye and you can then simply take the powder inside.

Alcohol

According to Dr. Schofield, alcohols are an extremely common trigger. They’re commonly added to liquid medications, IV medications, or topical medications, which are applied directly to the skin.

Alcohol has some antiseptic qualities, which is why it’s used to disinfect the skin prior to medical procedures, along with being used as the active ingredient in most hand sanitizers. It’s also used as a solvent, to help suspend the active ingredient evenly throughout a drug, and as a preservative, to extend the shelf life of a drug.

Luckily, tablet or capsule forms of alcohol-containing liquid or IV medications are often alcohol-free. This makes them a potential alternative that wouldn’t cause reactivity.

Although these are some of the most common excipients that MCAS sufferers may react to, theoretically you could have a reaction to any of the hundreds of excipients that are used in medications today. This is why an understanding of how to identify an excipient reaction is of the utmost importance for people with MCAS that suspect they have excipient triggers.

Adhesives

Many adhesives are based in glycerin, which is corn-derived. If people react to corn, they may have problems with standard adhesives. Standard tegaderm adhesive wound dressings may be replaced with Opsite 3000 and the IV 3000 line of adhesive products.

Another product is DuoDerm Extra Thin CGF Dressing. If adhesives can’t be used and a patient needs an IV line, this can be wrapped with guaze, on top of which tape is then fastened. All IV bags should be DEHO free to reduce the risks of mast cells reactions

How to tell if you’re reacting to an excipient

There are several ways to tell if you’re reacting to an excipient in a drug, according to Dr. Schofield.


First and foremost, you should suspect excipient reactivity if you have an unexpected reaction to a drug that you previously tolerated well. In this case, some questions you can ask are:

  • Did you get this from a different pharmacy than usual?
  • Is this drug from a different manufacturer than the one that was well tolerated?
  • Was there a risk for environmental contamination when this drug was compounded?

Next, you should suspect an excipient reaction if you have different reactions to two different medications that are in the same class of drug. For example, loratadine and fexofenadine are two over-the-counter antihistamines that function in similar ways to help manage allergies. If you react differently to these drugs, it may be because one contains an excipient that you’re reacting to.

Additionally, if you experience side effects that aren’t typical for a drug, these side effects may actually be a result of reactivity to one of the excipients in that particular formulation of the drug.

You should also consider an excipient reaction if you react to a drug or supplement within the first few doses of taking a new pill. 

Finally, if you’ve been diagnosed with multiple drug allergies or intolerances, you should strongly suspect excipient reactivity. Particularly if you’ve been diagnosed with an iodine or betadine allergy, this is a strong indicator that you may actually be sensitive to povidone. This is an excipient that’s commonly added to iodine solutions along with a variety of other medications, including those as seemingly harmless as over-the-counter pain medications.

Identifying and avoiding harmful excipients

Identification of excipients to which you’re sensitive will require collaboration between you, your physician, and your pharmacist.

According to Dr. Schofield, once you’re able to identify an excipient that you react to, it should be added to your allergy list. However, you shouldn’t add the medication in which it was found to that list, as it’s likely you’re only sensitive to the specific excipient and not the medication itself.

Luckily, due to the availability of different brands and formulations of drugs, it’s often easier than you expect to find a formulation of your needed medication that doesn’t contain any of your excipient triggers.

However, you’ll need to thoroughly review the ingredient list of all medications you’re prescribed, or purchased over-the-counter, to see if they include any excipients that you’re sensitive to. Dr. Schofield recommends using DailyMed, a service of the U.S. National Library of Medicine that provides detailed information about medication ingredients, including excipients.

You may need to get creative in your avoidance of your excipient triggers. For example, if the tablet form of a medication contains an excipient you’re sensitive to, check to see if there’s a capsule, liquid, or IV form that would be okay for you.

As I already mentioned, if you’re sensitive to dyes, you can often just discard the capsule that contains the dye and still use the powder inside the capsule. You can sprinkle it on top of yogurt or mix it into a drink.

If you find that you’re profoundly sensitive to a certain excipient, you may need to have your medications especially compounded in a ‘clean room’ that poses minimal risk for cross-contamination with your triggers. Your local compounding pharmacist should be intimately involved with the challenges of MCAS and the potential risks of excipient reactivity. Sourcing of the pure powder ingredient in a medication may be necessary. Compounding pharmacies should be accredited with their parent organization, the Pharmacy Compounding Accreditation Board (PCAB).Established in 2007 by eight of the nation’s leading pharmacy organizations, PCAB offers the most comprehensive compliance solution in the industry. This includes the combining, mixing, or altering of drug ingredients to create a medication pursuant to a prescription order for an individually identified patient.

In Canada, most of the compounding pharmacies will use microcrystalline cellulose, known as Avicel, as a filler. This compound is derived from wood pulp and contains strings of glucose molecules strung together. It’s commonly used a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production.The most common form is used in vitamin supplements or tablets or as an alternative binder in compounding medications. Some people may also not tolerate gelatin capsules and are given vegicaps as a substitute. These are composed of hypromellose, short for hydroxypropyl mMethylcellulose (HPMC), a substance that’s prepared from cellulose, which is the main polysaccharide and constituent of wood and all plant structures.

Additionally, excipients aren’t only found in medications. If you’re sensitive to an excipient, you’ll also need to check foods, supplements, cleaning products, cosmetics, and body care products to see if they contain any of your excipient triggers.

Please reach out to me or my team if you need help managing your MCAS or identifying potential triggers or excipient reactivity. My team is extremely experienced with the management of MCAS, and we can help you formulate a plan to identify your potential triggers and remove them so that you can have some relief.

References:

  1. Abrantes CG, Duarte D, Reis CP. An Overview of Pharmaceutical Excipients: Safe or Not Safe? J Pharm Sci. 2016;105(7):2019‐2026. doi:10.1016/j.xphs.2016.03.019 Abstract: https://pubmed.ncbi.nlm.nih.gov/27262205/
  2. Schofield J. The Problem of Excipient Reactivity in MCAS Patients. Lecture from The Center for Multisystem Disease, n.d.
  3. National Center for Biotechnology Information. PubChem Database. Povidone, CID=131751496, https://pubchem.ncbi.nlm.nih.gov/compound/povidone (accessed on May 31, 2020)
  4. Afrin LB. Re: [MASTerMinds] Precautions for Oral Surgeons doing Wisdom tooth extractions in CCI patients? #cci #mcas #dental. Email communication from MASTerMinds listserv. 2020 May 8.
  5. Dewachter P, Mouton-Faivre C. Allergie aux médicaments et aliments iodés : la séquence allergénique n’est pas l’iode [Allergy to iodinated drugs and to foods rich in iodine: Iodine is not the allergenic determinant]. Presse Med. 2015;44(11):1136‐1145. doi:10.1016/j.lpm.2014.12.008

How a Multi-Level Approach to Medicine Can Augment a Cancer Patient’s Treatment

How a Multi-Level Approach to Medicine Can Augment a Cancer Patient’s Treatment

Contrary to mainstream rhetoric, the treatment and prevention of cancer in patients is much more layered than a simple diagnosis and chemo, for example. Things such as past trauma, mold exposure, allergies, and metal toxicity exposure can truly impact how one recovers and even how one reacts to chemo. 

Watch the full video as Dr. Hoffman dives into some of the complexities of a multi-level approach to treatment of cancer in patients. 

Watch the Video

How a Multi-Level Approach to Medicine Can Augment a Cancer Patient’s Treatment

Reference Links

Transcript

Hi everybody. I received an email today from a colleague who is posting his case history on a cancer patient. He detailed the specific oncology issues that had arisen, his approach, and what he believed to be the correct treatment. I was thinking as I was reading this report from an integrative medicine physician about how far integrated medicine, medicine that incorporates many different layers and levels and dimensions of a personal experience, has come. This patient was managed impeccably by her oncologists. Insights were derived from post oncology or peri oncology type issues. When I read through the presentation of my colleague, I was struck by how we can bring so many more diagnostic and therapeutic features to the patient’s experience. When we consider the layers and levels that any individual person brings to the consultation, the history given by my colleague on this patient just touched on a few issues and could have been further expanded upon. I’d like to expand upon the history to provide a road map of how the seven levels, or the seven stages, to health and transformation can be incorporated when thinking of strictly biologically-based medicine.

In his history, he mentioned that this patient had breast cancer. She was treated with chemo and radiation and developed side effects. He went on to mention a few things, such as that she was sensitive, that she had experienced early developmental trauma, that she was a poet and artist, and that she had post chemo fatigue. He also happened to mention that she had a supportive framework, a loving husband, and was very involved in her own patient advocacy. In addition to everything else that he was bringing to the table, he wanted to treat her mast cell activation syndrome. He was looking for further triggers as to why she was still fatigued and anxious, things such as mold exposures or possible Lyme disease. 

In looking through this history, things came to my mind. Whenever there’s a history of early trauma, you have to look upstream to ancestral Inheritance. We know now that individuals carry the experiences of their forefathers. This is well researched and well studied and is now being incorporated into clinical medicine. Whatever the ancestors, particularly the mother, father, and grandparents had emotionally experienced gets epigenetically transferred into the proteomics and metabolomics. This is the cellular expression of that patient’s life that can’t be ignored. Secondly, when a person is born into a dramatic scenario, when they have interrupted bonds between them and their mothers, particularly their mothers in the first ten, twenty even thirty years, there’s a price that’s paid. Particularly if the patient isn’t entrained with the mother’s right prefrontal cortex in an empathic entrainment, one sense of self that inhibits early anxiety and stress or fear doesn’t develop a robust mechanism or the ability to inhibit should anxiety and stressful events arise in the future. So in early developmental trauma, when the child’s developing brain doesn’t entrain with the mother’s development, the mother’s external prefrontal cortex and just a side note, the mother may not have a very robust right prefrontal cortex either, but the child pays a price. They pay a price of potentially a fragile sense of self or even a very undeveloped sense of self and an inability to self regulate.

This is very obviously seen when you do NeuroQuant MRIs or qEEGs. You can see these fingerprints on the qEEG and on the NeuroQuant MRI in the form of increased amygdala size and increased thalamus size. The evidence is there. On a qEEG you can see heightened amplitude of the beta brainwaves, what’s called the anterior cingulate area, and you can see diminished alpha brain waves. You can see these fingerprints of biographical data on biomedical equipment. It’s important to know that. So if somebody has cancer and he’s had a very bad chemo experience with many symptoms post chemo, one does look upstream to any possible inherited trauma from the ancestral realm. One looks at early developmental trauma because all of these get affected through what’s called the HPA axis, the hypothalamic pituitary adrenal axis, in the form of a heightened stress response. The height and stress response can create permeability of gut membranes, mitochondrial membranes, and blood-brain barrier membranes, leading to a flood of potential autoimmune disease and/or inflammatory compounds. So it’s important to take that particular history to look at the brain through a NeuroQuant MRI and to look at the qEEG to see if there are any fingerprints and then therapeutically to assist that individual in self-regulation through various techniques, whether they be inside therapy, m-wave training, vehicle tone stimulators. I always recommend that people get an insight into the underlying dynamics, not just downregulate the biochemical or physiological pathway. 

When there’s early trauma and when there’s early developmental trauma we usually suggest family constellation therapy insight or family constellation workshop to look at the unconscious dynamics of that inheritance. For early developmental trauma, again we use family constellation therapy but sometimes we have to be more advanced. In those cases instead of doing a technique like DNRS, which just downregulates the expression of the anxiety that’s being felt, you need to do more advanced psychological techniques like ISDP. This looks at the defenses the individual developed as a child who wasn’t safe in their environment. They’ve developed the provisional self in order to cope with the slings and arrows of modern life, or just their early life.  So you’ve got to look at the family system that’s inherited, look at early developmental trauma, and the defenses that were developed by that person. Then you’ve got to look at the ego strength and structure of that individual to see if they have a robust sense of self. This determines if they can cope with sometimes what’s required of them to get their physiology and their health back online.

So with oncology and cancer, yes we can give chemo, we do radiation. We do those plus all the natural therapies but if you don’t look further upstream to all these potential mediators that keep a person somewhat off kilter, you don’t complete your healing interrogation and your diagnostic interrogation. So it’s very important to shine your light upstream to look at these potential inherited issues. We know from clinical experience that when you heal at a deeper level, the downstream metabolites and the downstream effects are profound. The body tends to express those consequences of the new images and the new insights and the new narratives in a more cohesive fashion. We say in this work that nobody truly heals until they have a new image or a new narrative or a new story to tell about their past and their present. This is vitally true to understand people who present with extreme complex multi-system illness. It’s never only at level two,which is the physical level. You can do all the most sophisticated functional medicine workups, you can give them every supplement in the book, you can send them to wherever you want to detoxify, or you can do bioidentical hormone therapy. But it doesn’t land in a robust place if that sense of self is fragile, if the ability to self-regulate is poor, if the defenses of the individual are too fortified and won’t allow you in. If a child has had an early experience that keeps them from trusting parental figures, do you think they’re going to trust medical authorities? Unlikely since we’re just external representations of parental figures. No healing occurs without a deep sense of trust. This is deeply profound. I’ve been called out over the years for not taking this seriously and developing an empathic trusting relationship with the patient because if that’s not established you might as well give up the rest of it. It’s not going to occur. Patients will resist your efforts to help them if there’s not an empathic relatedness between you and them whereby you understand their dynamics, you understand the fortifications of the psyche that prevent healing from occurring, and you relate subtly to what they’re asking you to do. Sometimes it takes time to establish a therapeutic alliance and a trusting relationship. If you bulldoze your way in and try to tell somebody what to do who has high resistance, something called projection of will, which means they’re asking you to fix them without any advocacy of their own, you’re in a precarious position and success is very limited.

So in this particular case I was struck by the fact that:

A) she had early trauma 

B) she had heightened anxiety

C) she had post chemo fatigue

And the whole world of post chemo fatigue of course has lots to do with mitochondrial dysfunction. In traditional medicine we’re not taught anything about mitochondrial dysfunction unless it’s a genetically inherited mitochondrial disease. Even in functional medicine you know mitochondrial dysfunction is paid lip service and people are given you know coenzyme q10, carnitine, lipoic acid, vitamin C, magnesium, and so on. But through the work of Robert Naviaux and the cell danger response we know that the mitochondria also need to be approached with a certain elegance, a certain sophistication, a certain patience because you can’t coax a mitochondria back to health by just throwing everything in the kitchen sink at it, hoping it’s going to recover. You have to understand the timelines and the movement through what they call the cell danger response, where there’s an inflammatory response and the mitochondria shut down

to protect the host. Then there’s moving through a healing response, which takes time. Our bone marrow turns over every four months and the mitochondria too have their own timeline, their own seasons so to speak. If you’re interested in the subject I’d suggest you read anything by Robert Naviaux. 

So this patient needed chemo, she had post radiation, post chemo fatigue, she was highly anxious, and wasn’t sleeping but she also had resources and she had some insight into her case. With these issues in mind it’s always important to expand our diagnostic and therapeutic base and try and bring everything to the table, to assist that person moving through their present symptomatology of anxiety fatigue and gut issues. This particular individual had gut issues. You have to do a full functional medicine workup with food sensitivities, gut permeability, hormonal HPA axis assessment, and methylation micelle detoxification. That’s just a given, a basement workup. I was struck by how far we’ve come in the understanding of illness and the fact that illness isn’t something that just requires a therapeutic drug. That concept of n squared, d squared, name of disease, name of drug, is so far advanced. We’ve come so far over the last thirty years in this understanding. Unfortunately the healthcare systems that exist are still very mechanistically based, disease based, which is fine. But when it comes to a true transformative healing experience, all layers, all levels, and interpersonal relatedness with trust are now available to us. It behooves us as therapists and medical personnel and healers if you wish to use that word. We have to do our own work and we have to know how to navigate the nuances and subtleties and levels and layers of a person’s experience and how to read the hidden signs. How to access unconscious dynamics and how to make conscious that which is being asked to be made conscious. Symptoms are often in a person’s life in order to bring to consciousness that which is hidden. It’s been said before that all sickness is homesickness. Even though this could be considered a sort of glib metaphor, especially when somebody’s suffering severely.  It’s been my experience that if you really lean into that possibility, the full potential of the person’s self-expression can be realized through a sensitive, insightful and broad palette of diagnostic and therapeutic insights. So these were my musings on a Sunday afternoon and I just wanted to share those with you. Thank You.

A Discussion About Mold and Mold Exposure with Dr. Bruce Hoffman

A Discussion About Mold and Mold Exposure with Dr. Bruce Hoffman

We discuss how mold and mold exposure can be a trigger for Chronic Inflammatory Response Syndrome (CIRS), and Mast Cell Activation Syndrome (MCAS). We discuss ways to investigate and determine if you have been exposed to mold and what you should do if you suspect mold exposure is affecting your overall health.

To learn more about mold treatment, prevention, and recommendations, visit the Mold Illness section of our Hoffman Centre website.

Watch the Video

A Discussion About Mold and Mold Exposure with Dr. Bruce Hoffman

Reference Links

Transcript

I wanted to talk a bit about mold and mold exposure as a potential cause for chronic ill health. Mold is ubiquitous and, without question, many people are suffering from the effects of mold. Mold triggers Mast Cell Activation Syndrome (MCAS), and many people are suffering from that, which is why I feel that it has to be part of a differential diagnosis for chronic ill health.  

It’s shocking how many people have mold exposure as a trigger and as an ongoing mediator, keeping them in an inflamed state resulting in Chronic Inflammatory Response Syndrome or CIRS. There is a 34-page article on my website describing the diagnosis and treatment of mold illness or CIRS.  

I would recommend the following steps to people who feel they have mold exposure.

Do the CIRS questionnaire found on page 9 of the aforementioned article. You can see if you fulfill the criteria for the potential diagnosis of mold illness. Some of those symptoms are not just for mold illness. Some are more psychiatric based questions that can arise from mold. So, the questionnaire itself isn’t enough but it’s a good start. If you have more than eight symptoms in more than six of the subtypes on the questionnaire, consider mold as a potential differential diagnosis.

The second thing you can do is a visual contrast test. This too can be googled. Dr. Shoemaker’s website has access to a computerized VCS test. Take the test and if you fail it, consider mold as a potential illness or reason for feeling unwell.

Then, of course, the most important consideration is exposure. If you know that you’ve got a basement full of mold or your bathroom or your bedroom has mold on the windows from condensation, you have to consider that in your differential.

Not everybody gets sick from mold. Some people simply get allergy type symptoms,  but some people get true inflammatory response illness (CIRS). It’s been estimated that only 25% of people will have significant illness from mold. However, in my experience it’s more than that. People often downplay how important mold and the mycotoxins produced by mold are in influencing your health. 

So, what is important? Your exposure and your history. Is what you are exposed to visible mold? If it’s not visible, it could be hidden and so you often have to do your own homework and call in a mold inspector to look for the potential sources of mold. So, what can you do to potentially identify a problem? Look up at your pot lights. Is there a brown ring around your pot lights? Do you have buckled baseboards? Do you have black mold on your window frames? Is there mold in the grout in your shower? Do you have a front-end loading washing machine that smells musty? Does your house smell musty? Is there any potential mold in your air-conditioning system? Do you have a food composter in your kitchen? Because a lot of mold grows there. If you aren’t sure, it’s important that you call in a mold inspector, someone who will do a visual inspection and is armed with specific tools such as an infrared camera. Someone who is able to actually measure the dryness or wetness of drywall and put a small hole through drywall if you suspect mold or moisture behind the wall. The inspector will begin the examination of your home in the attic, looking at the insulation and at the condensation potential. Is your upstairs attic vented? A lot of the homes that we built in the Calgary building boom in 2009-2010, including my own by the way, didn’t have venting.  Condensation and wetness were ubiquitous and many people didn’t discover the mold until many years later, so get a good visual inspection. Find somebody to come in and inspect from the attic to the basement, someone who goes inside and outside and looks in multiple areas. If you go online, you’ll see how to do a visual inspection and a lot of it you can do yourself.   

Then you want somebody to do what’s called an ERMI test, which is a mold spore count. You want to do it either through a vacuum collecting dust from carpets or a swiffer cloth collecting dust off the floors. We recommend living rooms and bedrooms first. Some people do it in the basements although it’s not often recommended because a lot of basements are moldy. In my personal experience it’s important to know if your basement is moldy because through your furnace you’ll be pulling in mold through the furnace and pushing it throughout the house. Molds have also traveled from the basement through convection currents when your home heats up and so if the basement is a source, you want to know exactly how bad it is.  

Once you’ve done the visual inspection, once you’ve done ERMI testing looking for mold spores, once you’ve found mold (or not), the next step in the diagnosis is to do what we call the cytokine testing. Those aren’t done in Canadian labs, so we have to send them out. We call them the Shoemaker panel and we measure things like C4a, TGF Beta-1, MMP-9, VEGF, MSH and we do a nasal swab for something called MARCoNS, a coagulase negative staph. Basically, it’s a staph that lives in your nasal passages. It doesn’t produce overt nasal symptoms but can have significant cognitive effects and mitochondrial effects on your symptoms. So, we do those inflammatory markers.  

Recent advances have been very controversial regarding the use of urinary mycotoxin testing. In the original workup by Dr. Shoemaker didn’t believe that urea mycotoxin testing had any role to play in the diagnosis of mold illness. He has personally moved on to transcriptomic testing for definitive diagnosis but many other clinicians do urine mycotoxin testing to determine if there are any toxic mycotoxins of mold in the urine.  This is used quite extensively by the breakaway group that doesn’t adhere strictly to the Shoemaker protocol. There are two schools, which are the Shoemaker purists and then the group that has broken away. Like any good movement, there are always two camps, we can’t get away from that. Support and challenge exists throughout nature, exists throughout medicine, exists throughout clinical diagnosis and treatment.   

So, if you have a symptom profile that was suggested by the questionnaire, if you have a positive VCS test, if you have any signs of mold in your home, if the testing for mold spores in your home is positive, if your urine mycotoxin tests are positive and your Shoemaker labs are very positive, it’s highly likely that mold is playing a role in your illness. You need to find a practitioner who knows how to treat it. The treatment is extensive, requires lots of steps, and has to be followed in a specific sequence otherwise you can overload the detox pathways and get into increased symptom expression and feeling worse, not better.

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A Discussion About Lyme Disease with Dr. Bruce Hoffman

A Discussion About Lyme Disease with Dr. Bruce Hoffman

The diagnosis and care of a patient with Lyme Disease is multifaceted and can be approached from more than one angle. It likely goes without saying that mainstream medicine is taking a much different approach than those in the functional and integrative space. 

In this video, I discuss the importance of looking at the larger history of said patient and how lab testing plays a role in proper diagnosis of Lyme Disease. 

If you are looking for answers regarding your situation, please contact our office today for more information. 

Watch the Video

A Discussion About Lyme Disease, with Dr. Bruce Hoffman

Reference Links

https://hoffmancentre.com/podcast-understanding-symptoms-and-treating-the-whole-person/

Transcript

Good afternoon everybody. I just finished an interview with the CBC (Canadian Broadcasting Corporation) and they wanted to talk about Lyme disease in Canada. We had a good, 20-minute chat that will probably be aired on some CBC broadcast in the fall. 

I was struck by one of the issues that often arises in my practice when I’m asked to treat complex multi-system, multi-symptom patients. They often come in and say, “I’ve got Lyme disease can you help me?” or “I’ve seen five doctors, naturopaths, et cetera, but I’m not better”.  

One of the biggest frustrations has been people believing that there’s one single trigger for their presentation of symptoms. They have one or two positive antibodies on their lab test, are told that’s a positive Lyme marker, and then are told by their medical provider that they should be on a full treatment program. I think that it’s medical malpractice to jump into the diagnosis and treatment of Lyme disease without a considered approach. 

We do know that there are two schools of thought in the standard of Lyme diagnosis. There are the traditional infectious disease specialists, who have very strict criteria for the diagnosis of Lyme disease, rightfully or wrongfully. Then there is a more broad approach to the understanding, diagnosis, and treatment of Lyme disease, which is purported and put forth by a group called ILADS, to which I happen to belong. 

The two schools of thought do not see eye to eye and that continual friction places the patient in the middle, trying to work out what is the best approach. 

Often patients get a diagnosis of Lyme disease from a provider they’ve seen based on the US test. They then get sent by their family doctor to an infectious disease specialist who reads them the riot act and lets them know that the tests are recording too many false positives, that they are irrelevant, that the lab is just trying to make money, or that the labs aren’t standardized. This battle goes back and forth, causes frustration for everyone, and the poor patient sits in the middle, trying to make sense of it all. 

Our aim is to talk about the differences between the two approaches, address the specifics as to why one group is vehemently certain of their position and the other group contests that position and has their own set of criteria for diagnosing and treating, which, based on the data, can’t be invalidated and has to be taken into account.

So here’s my take on patients who believe Lyme may be a trigger without a thorough health history. Lyme disease and co-infections are based on a very thorough clinical history.

I’m not going to go into the specifics of that clinical history, but the doctor or healthcare professional interviewing you must spend a lot of time taking a very specific history as to what symptoms you’re presenting and how you came to this diagnosis.

Just walking in with a positive lab test, whether it be US based or even Canadian based, isn’t good enough. Although with the Canadian test, if it’s positive, there’s a strong likelihood that Lyme disease is playing a role.

The Canadian test has very strict criteria for false positives and negatives, so if you have a positive test in the Canadian lab, it’s very likely that Lyme is an issue. So, I suggest that your practitioner takes a very thorough history and starts to use certain criteria to make the diagnosis.

One, is there history of a visit to an endemic area? Secondly, is there a history of tick bites?  Third, is there history of rashes? The problem is that many times, in fact most times, that history isn’t obtained. But if the history is there, that guides you in a certain direction. Those questions must be asked. Then a full list of symptoms must be taken, to try and differentiate whether your symptoms are specific to Lyme and related co-infections or whether they cross over with other conflicting or added potential causes for illness.

For instance, we know that in Lyme disease patients, after the first thirty days, the disease is characterized particularly in the later stages by migratory polyarthritis, which is joint pain or muscle pain that goes from joint to joint or muscle to muscle. These sorts of symptoms are very diagnostic. There are other things that cause this, but in the context of exposure to tick-borne illness, if those symptoms exist, you want to dig deeper.   

So migratory polyarthritis or muscle pain, those are very big symptoms for Lyme disease. Now for the co-infections, you want to ask very specific things. Do you have night sweats? Do you have day sweats? These occurrences are very specific for Babesia symptomatology. Do you have shortness of breath or “air hunger”? Do your symptoms come and go? Are there a lot of emotionally based symptoms, particularly anxiety as this has been associated with Babesia. You want to ask these very specific things.

Bartonella tends to be more peripheral so you tend to get a lot of pain syndromes such as Neuritis, which is pain in the peripheral nerves. Painful soles of the feet, particularly when you get out of bed in the morning. This is why the history is so important.

Lyme disease is now considered to be a clinical diagnosis based on history and physical examination, not based on a positive lab test. Why? Because you do get false positives and depending on which tests you run, the interpretation of results is highly complex. Unfortunately, due to cost we have the Canadian tests, which are elementary and introductory at best. 

Infectious disease specialists will say that they’re good enough, however, I disagree. When you want to look further and beyond you do have to look at more advanced testing which is, unfortunately, cost prohibitive. Most people can’t afford what’s really needed. I do try and get as many tests as I can across the spectrum of different testing types, including B-cell antibody testing, T-cell testing, PCR testing, plasma testing, and FISH testing. The more tests you can get, and the more that you correlate those tests with the clinical diagnosis in the symptom profile picture, the more you can hone in on the diagnosis of potential Lyme disease.

In Canada, Lyme disease is rising at a very alarming rate due to the migration of ticks and songbirds to the North. There was a study done showing that there are 32 million South American ticks brought north by South American birds every year. That’s a pretty alarming statistic. We know that songbirds are migrating to the North due to global warming and spreading their tick-borne load further and further North, hence the rise in tick-borne illness in Canada.

So, be cautious. Don’t jump to a diagnosis of Lyme disease because you have a positive test. Make sure that you have a very thorough history taken and make sure that the person who’s interviewing you has experience in the diagnosis and in interpreting lab data. The more lab data you have, the better.

Don’t rush ahead and treat yourself for Lyme disease without due caution. It can lead you into the wrong direction and make your immune system and your gut microbiome quite compromised if you treat inappropriately with some of the drugs out there that are available. Just a word of caution. This was covered in a podcast that you can listen to here.

Inflammatory Bowel Disease – Crohn’s Disease and Ulcerative Colitis, Part 1

Inflammatory Bowel Disease – Crohn’s Disease and Ulcerative Colitis

In anticipation of the upcoming Crohn’s and Colitis Summit, I want to share more about inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. This two-part series will be a deep-dive into the root cause of inflammatory bowel disease, along with a comprehensive look at lifestyle changes and functional therapies that may provide relief. This free summit, hosted by Ravi Jandhyala and Mallika Allu of Gut Heal Protocol, will be held September 21st-27th. I will be speaking at the summit, and I encourage you to sign up if you or a loved one has Crohn’s disease or ulcerative colitis.

Inflammatory bowel disease (IBD) comprises a number of different medical conditions. The most significant of these are Crohn’s disease (CD) and ulcerative colitis (UC). These are chronic, immunologically mediated diseases with periods of relapse and remission, in addition to marked variations in mucosal inflammation from near normal in remission to severe ulceration in relapse.

UC affects only the colon with superficial inflammation, whereas CD affects the entire gastrointestinal tract and leads to transmural inflammation, strictures, fistulas, and abscess formation. 

The etiology of IBD is complex, but intricate dynamic interactions between the intestinal microbiome, host genetics, and external environmental factors all play an interrelated role in the development of IBD and its subsequent outcomes. 

The key mechanisms underlying the pathogenesis of these diseases are a genetically susceptible host exposed to external environmental factors, affecting gut microbiome and commensal flora. This results in a dysregulated immune response to different aspects of the gut microflora and increased intestinal permeability.

In this article, you will learn:

  • The etiology (root causes) of IBD, CD, and UC,
  • How the intestinal microbiome and your body’s immune response lead to IBD,
  • And the risk factors that may make you more susceptible to developing CD or UC, or having more severe flare-ups.

In Part 2, I will discuss our current strategies for diagnosing and treating CD and UC.

What causes IBD?


The health of the intestinal microbiome plays a key role in the pathogenesis of CD and UC. In particular, this is related to dysbiosis and reduced diversity of the gut microbiome. It also relates to protective bacteria subpopulations, such as Firmicutes, and an increased representation of potentially pathogenic bacteria, such as enteroinvasive Escherichia coli in subsets of ileal CD. In these conditions, species richness decreases, although some species seem to overgrow and increase in number. 

Both CD and UC are defined by an abnormal immune response, in which the immune system mistakes benign or beneficial cells and bacteria for harmful foreign substances. When this happens, the immune system, through a process known as molecular mimicry, can damage the gastrointestinal tract and produce symptoms of IBD.  UC is primarily a T-helper 2 (Th2) immune cell response, while CD is primarily T-helper 1 (Th1) cell mediated. 

Starting at birth, the cumulative effects of different environmental exposures, combined with a predetermined genetic susceptibility, is thought to cause IBD. It appears that continuous exposure to the collective effect of dynamic environmental factors, referred to as ‘exposome’ by Christopher Wild, affects the incidence of IBD.  Infancy and early childhood influence the formation of the immune system, whereas adult exposures to environmental factors alter established pathways.

Western lifestyles also seem to play a role, indicated by higher number of cases of IBD in Europe and the USA. The condition affects 1.5 million US citizens and 2.2 million people in Europe. There has been a significant increase in the last five years that’s consistent across several distinct ethnic groups and geographic locations. This increase parallels the Westernization or industrialization of an area’s lifestyle

Immigrants moving from low risk to high risk areas tend to assume the qualities of the high-risk areas within a generation or two. In their new location, the risks are much higher than in their low-risk country of origin. There has also been an increase in the number of cases in developing countries in Asia, Eastern Europe, and Northern Africa, as their lifestyles and living environments change. Onset of IBD in young adulthood is characterized by a relapsing and remitting course with frequent hospitalizations or surgery.

  1. Is irritable bowel syndrome a type of IBD?

Irritable Bowel Syndrome (IBS) is considered non-inflammatory and a syndrome, or a group of symptoms, rather than a specific disease. Symptoms of IBS typically include chronic abdominal pain, diarrhea, constipation, or alternating bouts of both of these. People with IBS are also more likely to have other functional disorders such as fibromyalgia and chronic fatigue syndrome (CFS). IBS doesn’t produce the destructive inflammation found in IBD, so it may be considered a less serious condition. However, it can still cause chronic discomfort and affect quality of life. Research suggests that IBS can be caused by stress and the manner in which the brain and gut interact.

Risk factors of IBD


Well known risk factors for IBD include:

  1. Cigarette smoking: reduced risk of UC, increased risk of CD
  2. Appendectomy: reduced risk 
  3. Western diet: increased risk
  4. Stress: increased risk 
  5. Depression: increased risk 
  6. Low vitamin D levels: increased risk
  7. Estrogen replacement therapy: increased risk of UC
  8. Left-handedness: increased risk
  9. Mycobacterium paratuberculosis infection: increased risk of CD

Breast-feeding, appendectomy, and smoking, surprisingly, are all associated with reduced risk of UC. 

The effects of some of the risk factors outlined above appear to differ between CD and UC. Despite shared genetic and immunologic mechanisms, distinct pathways of pathogenesis exist.

There’s a substantial body of research that’s available regarding risk factors, but limited evidence for the treatment of these environmental triggers to modify disease outcomes or prevent relapse. There have only been a few controlled clinical trials for modification of risk factors resulting in an improvement in patient outcomes.

Risk loci, or specific gene locations within your chromosomes that appear to alter IBD risk, highlight several key pathways in pathogenesis. These include the following:

  • Innate immunity
  • Adaptive immune responses
  • Abnormal glycosaminoglycan (GAG) content of the mucosa
  • Maintenance of intestinal barrier function with increased intestinal permeability
  • Pathogen sensing 
  • Endoplasmic reticulum stress
  • Response to oxidative stress
  • Decreased oxidation of short chain fatty acids  
  • Increased inflammatory mediators 
  • Increased sulfide production
  • Decreased methylation
  1. Genetics

Everyone is born with a certain genetic susceptibility to IBD. Following exposure to a Western lifestyle, diet, and certain environmental triggers, a specific threshold is reached and IBD may develop. This explains the low concordance rate in twins, suggesting that genetic influence, while important, is only one piece of the IBD puzzle. The exposome, or the total coherent effect of all environmental factors from birth to death, plays the determining role.  

A positive family history of IBD is the most important risk factor for the development of the condition. Whole genome scans have found susceptibility genes for UC on chromosomes 1 and 4. A concordance rate of 19 percent for UC and 50 percent for CD in monozygotic twins has also been established. 

Genetics have shown 204 distinct genetic risk loci for IBD, with the majority of risk alleles being shared between both diseases. However, 37 CD-specific and 27 UC-specific loci have been identified. Known loci account for only a third of the risk for either disease. 

  1. Childhood exposures

Breast-feeding appears to confer a protective effect on both UC (1.8-fold) and CD (2.2-fold), in keeping with known protective effects for other immune-mediated diseases such as eczema and asthma, allergic rhinitis, and type 1 diabetes. This is thought to be due to protective maternal antibodies and the induction of immune tolerance to specific food antigens and gut microbes.

Antibiotic exposure is associated with an increased risk of adult and pediatric-onset IBD. Exposure during infancy or early childhood is associated with the greatest increase in risk. Use of antibiotics between the ages of five and sixteen, through the effect on the microbiome, appears to increase the incidence 1.6-fold. If antibiotics are used in the first year of life, the risk of CD increases 5.3-fold. 

The strongest risk increase is linked to the use of broad-spectrum penicillin (3.1-fold), pen V (2.9-fold), then cephalosporin (1.9-fold).

It’s been hypothesized that by altering the gut microbiome composition, pathogenic bacteria colonize while the normal process of tolerance, which is crucial for immune development, is disrupted. This leads to an aberrant response of the host immune system to its microflora.

On the other hand, early childhood Helicobacter pylori infection is associated with a decreased risk of CD of 1.7-fold and UC of 1.3-fold. H. pylori increases Fox-3, the transcription factor of T-regulatory cells, which down-regulates the inflammatory response. 

  1. Hygiene

A high hygiene level increases the risk of IBD. Living in an urban environment increases risk by 1.2-fold.

Having a smaller number of siblings increases risk 2.6-fold. The more siblings you have, the lower your risk for IBD.

Sharing a bedroom decreases risk of UC by 2.1-fold and CD by 2.3-fold, while a hot water tap in the home increases the risk of CD by 5-fold.

Animal contact decreases risk of UC and CD, with similar effects seen regarding asthma and eczema.

The implication is that the more hygiene measures employed, the fewer helminths (worms and parasites) you’re exposed to, and therefore less induction of dendritic cells maturation and ability to drive the T-cell immune system occurs. This results in decreased protection against autoimmunity. 

In simpler terms, “germophobes” may be at an increased risk of developing IBD.

  1. Autism

There have been several reports of a link between autism spectrum disorder (ASD) and chronic gastrointestinal (GI) symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia, and focally enhanced gastritis in people with ASD compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability, and unfavourable gut microflora. 

Wakefield et al conducted one of the earliest studies investigating gastrointestinal anomalies in autistic children in 1998. In this study, twelve children with regressive developmental disorders, nine of whom were autistic, were all reported to have abnormal colonoscopies. The most consistent finding was lymphoid nodular hyperplasia (LNH), which was present in nine of the twelve children. This mild to moderate colitis was deemed nonspecific on the basis of not fulfilling criteria for either Crohn’s disease or ulcerative colitis.

Criticism regarding the ‘normalcy’ of LNH in children prompted Wakefield, et al. to perform ileocolonoscopies in 60 children with regressive developmental disorders and compare them with 37 developmentally normal controls. In this trial, ileal LNH was present in 93 percent of affected children in comparison to 14.3 percent of controls (P<0.001). Chronic colitis was detected in 88% of affected children compared with 4.5% of controls. 

Torrente et al. compared the gastric biopsies of 25 autistic children with those of ten normal controls, ten CD patients, and ten children with H. pylori infection. Eleven of the 25 autistic children had a focally enhanced gastritis, while two had mild diffuse gastritis. Immunohistochemistry results demonstrated the pattern of lymphocyte infiltration was most similar to Crohn’s disease, with the exception of a striking predominance of CD8-positive over CD4-positive cells and a marked increase in intra-epithelial lymphocytes. Another highly specific finding among autistic children was a dense, sub-epithelial basement membrane immunoglobulin G deposition, which was absent in the other subgroups.

ASD patients and their caregivers often report improvement in the patient’s condition after following elimination diets. Improvements occur not only in the GI symptoms, but also in behavioural and cognitive problems such as hyperactivity, communication skills, and attentiveness. Interestingly, 36% of children with ASD have a history of cow’s milk and/or soy protein intolerance in infancy. In addition, while studies haven’t indicated an increased incidence of Celiac disease in these individuals, parents have often reported an improvement in their child’s behavioural disturbances when following a gluten-free diet. These benefits haven’t been seen consistently in randomized trials, although a Cochrane review did report a significant reduction in autistic traits on a gluten-free, casein-free diet.

One hypothesis is that ASD may be accompanied by aberrant innate immune responses to dietary proteins, leading to GI inflammation and aggravation of behavioural problems. One study, measuring pro-inflammatory cytokines in response to common dietary proteins, showed a greater than two standard deviations (SD) excess in tumour necrosis factor-alpha and interferon-gamma production in response to gluten and cow’s milk protein among ASD children, when compared with controls. 

A subsequent study confirmed a higher prevalence of elevated tumour necrosis factor-alpha and interleukin-12 production with beta-lactoglobin and alpha-lactoglobin, but not casein, in autistic children and children with non-allergic food hypersensitivity, compared with normal controls. 

Another theory suggests that abnormal intestinal permeability in children with ASD causes them to absorb fragments of incompletely broken-down peptides such as gluten or casein, which cross the blood-brain barrier and act as endogenous opioids. 

The gut microflora has also been targeted as a potential player. There have been anecdotal reports of the onset of autism following broad-spectrum antibiotics, suggesting that disruption of the indigenous flora may lead to colonization by neurotoxin-producing bacteria. Autistic children have been shown to have higher counts and more species of Clostridia than controls matched by age or gender. A small prospective trial demonstrated a significant but transient improvement in autistic features following a course of vancomycin (antibiotic) therapy, with relapses presumed to occur because of persistent spores that proliferate upon discontinuing the medication.

  1. Yeast

The ratios of yeasts in the gut, such as Saccharomyces cerevisiae and Candida albicans, may be significantly altered by IBD. Normally, yeasts and fungi account for less than 0.1% of the total microbiota population. However, there is often a decreased population of S. cerevisiae and increased populations of C. albicans and other Candida yeasts in the guts of people with IBD.

Antibiotic use can result in fungal overgrowth, especially of the Candida yeasts, which may then compete with the bacteria in the gut for survival and growth. This fungal overgrowth can make the host more susceptible to mold illness, paving the way for an immune response that may invoke chronic inflammation, autoimmunity, or IBD.

It appears also that certain components of the cell walls of fungi can trigger immune responses, which may add to the overall exposomeXI.

  1. Gut microbiome

Recent studies have highlighted the association between the gut microbiome and the pathogenesis of IBD. 

Reduced biodiversity of the gut microbiome is apparent even at the onset of diagnosis, before treatment is initiated. CD, especially ileal CD, has been associated with increased frequency of pathogenic bacteria such as enteroinvasive E. coli. There can also be a reduction in the frequency of anti-inflammatory bacterial subgroups, particularly Faecalibacterium prausnitzii. Giving strains of this specific bacteria has resulted in improved outcomes and amelioration of colitis in animal models.

By the time someone reaches adulthood, the immune system has matured and lifestyle factors become more apparent as choices are increased. Adult exposures seem to be involved in changing the already developed immune system. Several environmental factors have been identified as playing a role in IBD development independent of stage of life, previous development of acute bacterial gastroenteritis, geographical location, and vitamin D. 

Bacterial gastroenteritis as a result of Clostridium difficile, Campylobacter, and/or Salmonella infections can increase risk of IBD. The risk of developing IBD increases significantly after bacterial gastroenteritis, especially within the first year. The largest effect is seen with CD, for which there is a 2.9-fold increase, rather than the 2.1-fold for UC. This may be explained by the increase in interleukin-6 (IL6), blockage of T-reg cells, and the activation of self-reactive T-cells, leading to a chronic inflammatory response.

  1. Mycobacterium avium infection

M. avium subspecies paratuberculosis (MAP) infection rates are higher in CD, although a causative link hasn’t been established. Meta-analysis has shown a 7-fold increase in CD in MAP infections, but the timing of this infection couldn’t be ascertained to be a cause of CD and is perhaps merely a bystander. 

  1. Tap water

Drinking tap water lowers the risk of CD 2-fold. It’s been proposed that this might be due to harmless microorganisms triggering regulatory T-cells.  

  1. Flying

Individuals have an increased risk of disease flare following high-altitude flights or after travelling more than 2,000 metres above sea level. Mild hypoxia leads to an increase in IL6 and C-reactive protein (CRP), which are markers of inflammation.

  1. Obesity

An American cohort study showed a 2.5-fold increase in CD in obese women with a body mass index (BMI) greater than 30 kg/m2. 

  1. Smoking 

Smoking confers a 2-fold increase in risk of CD, which is somewhat lessened when stopping smoking, although the pathogenic mechanism remains unknown. 

Smoking is associated with a more aggressive form of CD, more surgery, and an earlier risk of recurrence and re-operation following a bowel resection. Stopping smoking prior to the diagnosis can result in a reduced likelihood of progressing to complicated disease behaviour or the need for surgery. Smoking cessation is also associated with a reduced rate of relapse regarding CD.

With UC, current but not former smokers appear to have some protection, with half the risk of UC in current smokers compared to individuals that have never smoked. Smoking confers a 1.7-fold reduction in risk for UC. 

For former smokers, the risk for both UC and for CD increases by the same amount.

For patients with UC, smoking leads to a more benign disease course with fewer flares, a reduced need for steroids, and lower colectomy rates. Smoking cessation increases the risk, with the effect lasting for up to ten years after quitting smoking. This suggests that smoking only defers the development of UC. Quitting smoking is also associated with flare-ups.

Passive, or second-hand, smoking has a weaker beneficial effect. The mechanism of this different effect between CD and UC is unknown, but is thought to be influenced by the constituents of cigarette smoke having different effects on oxidative stress in mononuclear cells.

Smoking is known to affect the immune system through both cellular and humeral pathways by transforming the synthesis of pro-inflammatory cytokines, altering gut permeability, reducing smooth muscle tone and contractility due to nitrous oxide, and effecting changes in the gut microflora. 

There’s also an interaction between smoking and genetic variants in the CYP2A6/EGLN 2 locus and glutathione transferase enzymes (GSTP1) and risk of CD and UC. Snips in these genes showed significantly different outcomes. 

  1. Appendectomy

There are divergent effects between UC and CD following appendectomy.

When performed before the age of twenty, there’s an increased risk of UC with no effect or only a slightly increased risk of CD. The mechanisms remain unclear, and appendectomy may result in intestinal microbiome alteration with a protective effect on UC. The microbiome composition in the appendix also appears to confer protective effects against UC

  1. Diet 

The role of diet has been problematic to determine. This is due to difficulty in tracking it through the course of a lifetime, different recall between controls and cases, and potential restrictions on diet choices pre-diagnosis based on the nature of the disease. 

Increased fibre of approximately 24 grams was associated with a significant reduction in risk of CD but not UC.   This was related to fruit fibre and not that of vegetables, including cruciferous ones. No association was found between fibre from cereals, whole grains, or legumes. 

Fibre may confer epithelial integrity and reduce translocation of potentially pathogenic bacteria such as enterovirus E. Coli, which may play a role in CD. Fibre activates the aryl hydrocarbon receptor (AhR) expressed in intestinal lymphocytes, which offers protection against environmental antigens.  

A diet high in long-chain n-3 polyunsaturated fatty acids (PUFA) was associated with a reduced risk of UC. CD had no modifiable fat intake risk factors for CD. One large study found omega-3 supplements had no beneficial effects, while a high intake of animal protein revealed a potential association with IBD. Sugar and a high-carbohydrate diet are associated with an increased risk of IBD, while fruits and vegetables seem to have a protective effect.

Alteration of diet can trigger flares in many different types of disease. High fat diets result in expansion of specific bacterial subpopulations that are associated with a pro-inflammatory response, particularly diets high in meats, as well as polyunsaturated omega-6 fats (like those found in industrial seed oils such as soybean oil, corn oil, and canola oil).XVI Elemental diets show improved outcomes in CD, whereas partial and complete enteral nutrition show effects superior to placebo but lower than steroids. 

Elimination diets, such as the specific carbohydrate diet, lectin-free diet, autoimmune paleo, and Whole30, are of particular interest as well, but there is still a lack of strong evidence regarding their efficacy for IBD treatment.

Childhood diet and antibiotic exposure is an important determinant of microbiome composition. Breastfeeding appears to reduce UC risk, but it doesn’t appear that formula-feeding necessarily increases UC risk. Researchers have found that the gut microbiome of both breastfed and formula-fed children changes significantly after the introduction of foods. Therefore, the first foods a child receives (other than breastmilk or formula), and the foods they eat throughout their early childhood, may profoundly affect their gut microbiota composition and affect their IBD risk level.

  1. Glyphosate

Glyphosate is the world’s most widely produced herbicide. It’s the primary toxic chemical in Roundup™ and many other herbicides. As a broad-spectrum herbicide, glyphosate is present in more than 700 different products and used in industries such as agriculture and forestry, and even in the home. 

Glyphosate was introduced in the 1970s to kill weeds by targeting the enzymes that produce the amino acids tyrosine, tryptophan, and phenylalanine. However, the enzymes of many bacteria are susceptible to inhibition by this chemical, so it can also alter the gut flora of many animals. 

Usage of glyphosate significantly increased after the introduction of genetically modified (GMO), glyphosate-resistant crops that grow well despite the presence of this chemical in the soil. In addition, the toxicity of the surfactant polyoxyethyleneamine (POEA), which is commonly mixed with glyphosate, is greater than the toxicity of glyphosate alone. 

In addition, Enlist Duo™, a herbicide product containing a 2,4-dichlorophenoxyacetic acid (2,4-D) salt and glyphosate, was approved for use in Canada and the United States in 2014. This was for use on GMO soybeans and maize, both of which were designed to be resistant to both 2,4-D and glyphosate. 2,4-D has many toxic effects of its own. 

Research has shown that glyphosate disrupts the microbiome in the intestine, causing a decrease in the ratio of beneficial to harmful bacteria. Highly pathogenic bacteria such as Salmonella entritidis, Salmonella gallinarum, Salmonella typhimurium, Clostridium perfringens, and Clostridium botulinum are highly resistant to glyphosate. Unfortunately, however, most beneficial bacteria such as Enterococcus faecalis, Enterococcus faecium, Bacillus badius, Bifidobacterium adolescentis, and Lactobacillus ssp. were found to be moderately to highly susceptible. 

The relationship between the microbiome of the intestine and overall human health is still unclear.

 However, current research indicates that disruption of the microbiome could lead to conditions such as metabolic disorder, diabetes, depression, autism, cardiovascular disease, and autoimmune diseases such as IBD. 

  1. Celiac disease, IBD, and the glyphosate connection

Researchers have found that people with Celiac disease are about 10 times as likely as a control group to have IBD. Conversely, the prevalence of Celiac disease in IBD appears to be comparable with that indicated in controls.

Celiac disease, and more generally, gluten intolerance, is a growing problem worldwide. It’s particularly serious in North America and Europe, where an estimated 5% of the population now suffers from this condition. It’s a multi-factorial disease associated with numerous nutritional deficiencies, as well as reproductive issues and an increased risk of thyroid disease, kidney failure, and cancer. 

It has been proposed by researchers Samsel and Seneff that glyphosate is the most important causal factor in this epidemic. Fish exposed to glyphosate develop digestive problems that are reminiscent of Celiac disease. The condition is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on these particular types of bacteria. 

Characteristics of celiac disease point to impairment in many cytochrome P450 (CYP450) enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit CYP450 enzymes. 

Deficiencies in iron, cobalt, molybdenum, copper, and other rare metals associated with Celiac disease can also be attributed to glyphosate’s strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine, and selenomethionine associated with Celiac disease also match glyphosate’s known depletion of these amino acids. 

Celiac disease patients have an increased risk of developing non-Hodgkin’s lymphoma, which has also been implicated in glyphosate exposure. Reproductive issues associated with Celiac disease, such as infertility, miscarriages, and birth defects, can similarly be linked to glyphosate. 

Glyphosate residues in wheat and other crops have been increasing recently due to the growing practice of crop desiccation just prior to the harvest. The practice of ‘ripening’ sugar cane with glyphosate may also explain the recent surge in cases of kidney failure among agricultural workers in Central America. 

  1. Mast Cell Activation Syndrome (MCAS)

As early as 1980, Dvorak and colleagues reported that mast cells were markedly increased in the ileum of patients with CD. In 1990, Nolte et al. showed the same findings in patients with UC. There were increased numbers of mast cells with associated degranulation products of histamine and tryptase, along with associated increases in cytokines and leukotrienes IL-16. TNF-alpha and substance P have also been found in the mucosa of patients with IBD, particularly when stained with the CD 117 stain. 

According to the latest literature research conducted by Dr. Lawrence Afrin, one of the key researchers in MCAS, mast cells release at least 1,000 mediators of inflammation. This includes, but isn’t limited, to histamine, proteoglycans (heparin and chondroitin sulfate), proteases (tryptase, chymase and carboxypeptidase), eicosanoids, and platelet activating factor (PAF).

Activation of mast cells leads to the release of the eicosanoid arachidonic acid from the phospholipids on the cell membrane. This 20-carbon fatty acid is then rapidly oxidised, along either the cyclooxygenase pathway to form prostaglandin D2 (PGD2) or the lipoxygenase pathway to form leukotriene C4 (LTC4). Histamine triggers the histamine H1 receptor and tryptase, the protease-activated receptor 2 (PAR2).

Therapies aimed at down-regulation of mast cell activity may be important in the treatment of IBD. 

Mast cell cytokines constitute a third category in that they may be both preformed and newly synthesized. These include IL-4, IL-5, IL-6 and TNF-alpha in the nasal mucosa and bronchi, as well as IL-1B, IL-3, IL-8, IL-9, IL-10, IL-13, IL-16, IL-18, IL-25, granulocyte -macrophage colony stimulating factor (GM-CSF), and stem cell factor macrophage chemotactic peptide (MCP)-1, MCP-3, and MCP-4. 

Many factors are known to activate mast cells, and their activation is a crucial step involving pathophysiological changes. These factors include antigens, anti-IgE, substance P, VIP, C5a, C3a, somatostatin, morphine, very low-density lipoprotein, stem cell factor, tryptase, and eosinophil cationic protein, all of which are known to activate mast cells. 

It should be noted that mechanisms of mast cell activation differ with different classes of triggers.

  1. Nutrient deficiencies 

UC patients were found to have lower levels of vitamin A, vitamin E, and carotenoids than those in  controls. This implies that certain nutrient deficiencies may either play a role in the development of UC, or, conversely, are a complication of UC. 

  1. Vitamin D

Vitamin D intake is inversely associated with UC risk, meaning that higher vitamin D intake is linked to a lower UC risk.  Additionally, higher blood levels of vitamin D are associated with reduced risk of CD.

 Patients who increased their blood vitamin D levels had a 1.9-fold protective effect for CD, but not for UC. They also had a lower risk of surgery compared to those who remained vitamin D deficient. Low vitamin D levels are also associated with a higher rate of colon cancer and C. difficile infections.

Vitamin D administration may reduce the risk of IBD relapses. Vitamin D is also known to play a role in the regulation of the innate immune system by activating the TH1 lymphocytes and monocytes. This causes the inflammatory response to be down-regulated. 

  1. Weather and latitude

Incidence of IBD is higher in northern latitudes where people have reduced exposure to ultraviolet (UV) light. The Women’s Health Initiative (WHI) study noted a lower risk for both UC and CD in women in southern latitudes (1.6-fold for UC) compared to those at higher latitudes. Living in southern latitudes appears to be protective, likely due to increased UV light and subsequently higher vitamin D levels.

Warm summers have a protective effect for UC and possibly for CD as well. This is also the case for other inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). This is thought to be due to an increase in microbial diversity, which in turn confers benefit.

  1. Psychological behaviours

IBD has long been associated with neuroticism, dependency, anxiety, and perfectionism. Recent well-designed studies have confirmed that adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with quiescent (dormant) IBD.

The evolving science of psychoneuroimmunology has outlined the mechanisms by which the nervous system can affect immune function at both the systemic and gut mucosal levels. These mechanisms are thought to be due to changes in the hypothalamic-pituitary-adrenal (HPA) axis and alterations in the bacterial mucosal barrier. These occur via mucosal mast cells and mediators, such as corticotrophin releasing factor (CRF). 

To maintain homeostasis, a living organism must constantly adapt at a mental, emotional, molecular, cellular, physiological, and environmental level. Stress is defined as a threat to an organism’s homeostasis. The function of the stress response is to maintain homeostasis through behavioural and biological or physiological adaptations. The stress response involves the complex integration between a series of interconnected regions within the brain. These are the hypothalamus, the amygdala, and the hippocampus. This hub receives inputs from viscera and somatic afferents and from higher cortical structures, including the internal dialogue and mental perceptions of the patient. This in turn, affects the neuroendocrine stress response via two interconnected effector pathways, namely the HPA axis and the autonomic nervous system (ANS).  

Stress stimulates the release of CRF from the hypothalamus, causing the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. This in turn causes the release of cortisol from the adrenal cortex. Stress also activates the descending neural pathways from the hypothalamus to pontomedullary nuclei, which control the autonomic nervous system response. Stimulation of the sympathetic nervous system (fight/flight) causes the release of adrenaline and noradrenaline from the adrenal medulla. This is in addition to supplying the entire gut directly. The parasympathetic vagus nerve and sacral nerves provide parasympathetic input to the upper gut and to the distal colon and rectum. 

The gut has its own nervous supply called the enteric nervous system (ENS), which is innervated by both sympathetic and parasympathetic fibres. This network has been termed the gut-brain axis. The ENS contains 100 million neurons and regulates the motility, the exocrine and endocrine functions, and the microcirculation of the gut. These axes (HPA, ANS, ENS) can then interact directly with the immune system. Psychoneuroimmunology is the study of how behavioural factors and CNS function can influence the immune system, and hence inflammation, at both systemic and local tissue levels.

Nerve fibres of the ANS form close effector junctions with lymphocytes and macrophages in lymph glands, bone marrow, the thymus, the spleen, and mucosa associated lymph tissue. These nerve fibres also release a number of chemicals called neurotransmitters, such as catecholamines, vasoactive intestinal peptides, angiotensin II, neurotensin, somatostatin, and substance P. These are capable of affecting lymphocytes, macrophages, neutrophils, and other inflammatory cells at the neuro-immune cell junction. Lymphocytes and other inflammatory cells also carry receptors for the hormones and neuropeptides of the HPA axis, such as growth hormone, ACTH, corticosteroids, and CRF. 

At high concentrations, cortisol has an immunosuppressive effect, increasing the release of anti-inflammatory proteins and IL-10. Transcription of inflammatory signalling molecules such as IL-6, IL-1, and TNF-α are reduced through transcription factors AP-1 and nuclear factor kappa beta. At lower doses, cortisol has an immune stimulating effect.

Similarly, adrenaline and noradrenaline have mixed effects at different doses on immunity and inflammation. Adrenaline causes an increase in serum IL-6, an increase in lipopolysaccharide (LPS) induced IL-8 and IL-10, and an increase in cytotoxic (cell-killing) T-cells and natural killer (NK) cells.

Chronic sustained stress due to adverse life events, such as bereavement, divorce, and depression, have been shown to reduce the numbers of cluster of differentiation 8 (CD8, a glycoprotein) lymphocytes, NK cells, and macrophages in the blood. However, in addition to immunosuppression, chronic stress with reduced heart rate variability, which is a sign of increased sympathetic tone, has been shown to increase inflammation, showing raised CRP.  

Acute stress causes stimulation of the sympathetic nervous system with a rise in adrenaline and noradrenaline, followed a little later by a rise in cortisol. This leads to an acute episode of immune enhancement with an increase in inflammatory cytokines that are known to be associated with flares of IBD. This includes a rise in cytotoxic CD8 T lymphocytes and NK cells and an increase in their cytolytic activity, in addition to platelet activation and thrombin generation, producing effects of microcirculation ischemia causing thrombosis and microinfarction. This effect is lowered with beta blockers rather than aspirin, suggesting that a stress response or sympathetic activation is at the root of it. 

Psycho-social stressors have long been associated with triggers. Recent and remote stress is associated with an increased incidence of IBD, with recent stress being more significant. When questioned, patients indicated that stress was the trigger for 70% of their flares. Depression feelings were associated with a 2.4-fold increased risk of CD, but not UC. Depression, anxiety, and stress are also associated with increased rates of relapse and surgery for IBD.

The inflammatory response to stress through elevation of IL-6 levels can be changed in mice by administrating antibiotics, suggesting antibiotics exerts their effects through changes in the gut microbiota.

Using medications to treat these conditions appears to have variable effects. People referred for therapy following increased stress due to the diagnosis have reduced rates of relapse, outpatient attendance, and use of steroids or other medications for IBD. 

In summary, stress can play a significant role in immune system dysfunction leading to an inflammatory response, which may trigger new-onset IBD or a flare of existing disease.

  1. Sleep

Both increased and reduced amounts of sleep have been associated with negative health outcomes. Reduced sleep quality was associated with an increased risk of relapse at six months post-remission in CD, supporting an association between poor sleep and gut inflammation. Sleep disturbances in IBD may lead to a 2-fold increase of disease flare. Sleep deprivation also leads to activation of the immune cascade.

  1. Nonsteroidal anti-inflammatory drugs

The use of nonsteroidal anti-inflammatory drugs (NSAIDS) for fifteen days per month increases the risk of UC 1.9-fold and CD 1.6-fold. These figures are increased by greater weekly dosage, and a higher frequency or longer duration of use. NSAIDS lead to inhibition of cyclooxygenase (COX), resulting in a decrease in protective prostaglandins in the gut mucosa, increasing gut permeability. 

  1. Oral contraceptives

Current use of oral contraceptives (OCP) leads to 1.3-fold increased risk of UC. The risk of developing CD with current use of OCP is increased by 1.5-fold. 

  1. Post -menopausal HRT

Post menopausal HRT increases the risk of UC by 1.7-fold, but not CD. It’s been proposed that estrogen modulates gut inflammation by acting on estrogen receptors that are found on gastrointestinal epithelial and immune cells. 

UC is a Th2 mediated illness, and estrogen promotes Th2 cytokines. The same holds true for other Th2 mediated diseases, such as RA and SLE. However, this is not the case with CD, which is a Th1 mediated illness. 

A prospective cohort study (the Women’s Health Study) followed 108,844 postmenopausal American women, with a median age of 54, without a prior history of CD or UC in 1976. The risk of UC appeared to increase with longer duration of hormone use and decrease depending on the time since discontinuation. There was no difference in risk according to the type of hormone therapy used, such as estrogen as opposed to estrogen and progestin. No association was noted between the current use of hormones and the risk of CD. The effect of hormones on the risk of UC and CD was also not modified by age, BMI, or smoking.

  1. Ambient air pollution

On the whole, air pollution exposure wasn’t associated with the incidence of IBD. However, residential exposure to sulfur dioxide and nitrous dioxide gases found in industrialized regions may increase the risk of early-onset UC and CD respectively. 

Living in regions with high sulfur dioxide emissions before the age of 25 increases the chances of UC 2-fold. A high nitrogen dioxide exposure before the age of 23 increases the chance of CD 2.3-fold. Total pollutant emissions correlate significantly with an increased risk of hospitalization in established IBD. Pollutants may also be absorbed and incite the inflammatory process that’s characteristic of IBD.

  1. Physical activity

Researchers have found that women engaging in active physical activity have a 44% reduction in CD risk compared with sedentary women. Physical activity was not associated with risk of UC.

The absolute risk of UC and CD among women in the highest fifth of physical activity levels was at just 8 and 6 events per 100,000 person years. This compares to 11 and 16 events per 100,000 person years among women in the lowest fifth of physical activity. 

Age, smoking, BMI, and cohort didn’t significantly modify the association between physical activity and the risk of UC or CD in these findings. The pathway appears to be mediated through the autophagy (clearing out or recycling of damaged cells) pathway or cell senescence (cell aging).

Summary

There’s a rich body of research showing potential environmental risk factors for the development of IBD. However, there aren’t many high-quality studies showing that environmental changes may have a large effect on disease outcomes. For a large number of possible environmental factors, meta-analyses are not yet available.

Many novel factors are identified by large cohort or case-control studies, but are yet to be reproduced by and validated by independent research groups. Consequently, the level of evidence is somewhat low and caution should be exercised when drawing firm conclusions or making recommendations.

However, individuals with a genetic susceptibility can be cognisant of environmental factors and do their best to lower or delay their genetic expression, as their exposure threshold may not be reached. Being aware of which environmental factors are involved in developmental phases as well as along the course of the disease to increase flares and development of complications, gives the treating physician and patient as advocate the opportunity to make the necessary adjustments along the patient’s timeline.

 This has the effect of lowering the risk of disease expression with a more personalized treatment plan.

In Part 2, I will be reviewing the lab tests that are used to diagnose CD and UC, along with lifestyle changes and treatment options that are often successfully employed in IBD care.

In the meantime, I encourage you to join me at the Crohn’s & Colitis Summit from September 21st-27th, or to contact my office if you are seeking functional and integrative care for your IBD. 

Podcast: Looking at Lyme: Understanding Symptoms and Treating the Whole Person

Looking at Lyme

I was recently interviewed by Sarah Cormode for an episode of Looking at Lyme, an educational podcast created by the Canadian Lyme Disease Foundation, where I highlight the importance of taking an in-depth patient history to understand and document symptoms.

I also discuss several approaches to treating Lyme disease and explain why such a variety of symptoms amongst patients with Lyme disease exists.

Take a listen below.

I was recently interviewed by Sarah Cormode for an episode of Looking at Lyme, an educational podcast created by the Canadian Lyme Disease Foundation, where I highlight the importance of taking an in-depth patient history to understand and document symptoms.

I also discuss several approaches to treating Lyme disease and explain why such a variety of symptoms amongst patients with Lyme disease exists.

People with Lyme disease have a lot of different symptoms, the bacteria attacks the body in so many different ways. Sometimes it attacks the brain, the heart, the joints, you name it. Today I'm looking at Lyme, we're going to dive into functional medicine, we'll look at the body from a holistic perspective and meet a doctor who treats the whole body and the mind.

Getting treated early for acute Lyme disease is critical. Some people find the attach ticks and others might get a bull's eye rash. But that's not always the case. And without these telltale signs, people might not get diagnosed. The longer that you have the disease, the worse it gets, and the harder it is to treat. That's when we need to go to the doctor. So, let's do that. There are very few medical doctors with the expertise of Dr. Bruce Hoffman. He practices functional medicine, and we'll get him to tell us more about that. We reached him at his Calgary clinic. Good morning, Dr. Hoffman.

Good morning to you.

What's the first thing that you look for in a patient who potentially has Lyme disease?

Your patients present to a doctor's office with many symptoms and many complex, interlocking possible what we call in medicine, differential diagnosis. So, they present with a whole host of symptoms. And it's the task of the doctor taking the history to try and work out what may or may not be Lyme disease. And sometimes patients come in with some Lyme test and say they definitively have Lyme disease, or they have positive biomarkers for Lyme disease on some of the tests they've done. But when a closer history is taken, that may not be the case. So, there's quite a lot to really sift through when you're trying to differentiate whether somebody has Lyme disease or not. The most important thing is the symptomatology. You want to take a very definitive history. In my clinic, we use different types of questionnaires to try and determine whether or not Lyme may be a diagnosis. And we also then start to take a very specific history about whether they visited endemic areas, which is somewhat a moot point because Lyme disease is somewhat, you know, it's specific, it's everywhere. If they visit an endemic area, if they've been bitten by a tick, if they've had the rash, which is very uncommon, by the way. But we start to ask the history of exposure, history of tick bite, history of rashes and in a symptom history, looking over the variable symptoms that present with Lyme disease and/or co-infections that come along with Lyme disease. A lot of questions need to be asked, and you've got to sift through them and try and determine if Lyme disease is the primary presenting feature or are there any other coexisting disorders that interlock, like mold exposure, or heavy metal toxicity or food sensitivities? And there's many of them that may interlock with a symptom presentation. So, there's a lot to ask.

Yeah, it sounds like getting that patient history is just so critical. 

History is everything. You know, you've got to take a good history. You can’t have a patient walk in and say I've got Lyme disease, and I go, okay, let's treat you. No, no, you have to stop and really ask very specific questions.

And it also sounds like you mentioned that most of your patients don't ever remember having a tick attached or getting a rash.

You know, the majority don't. I do have a number of patients who went to college in northeast in the United States, and they were out in the fields and in the forests, have a history of tick bite and rash exposure. But I would say that's probably 5% of my population. My patient population, it's very low.

Guess when we spend time in the outdoors, if we check for ticks and do a tick check and actually found one attached, we have something to at least document or same with a rash. If you found one, it'd be a good idea to get a photo of that to share with your doctor.

Absolutely. It would be lovely if we had that cookie cutter you know, clear cut, walked in the woods, got a tick, notices for within three days a high fever, headache, and then the rash. That's so seldom.

It's never that that clear? Is it?

Never. I wish it was easier.

So how critical is it then for people to get diagnosed and treated early?

Oh, if they've been exposed and there's definitely a tick bite. And the symptomatology of high fever, sore neck, chills and joints. If that occurs, you get them on antibiotics while waiting for lab data or getting the tick, if it's discovered, sent off to the lab for analysis. Definitely, I’ll put them on treatment right away. And there's different standards of treatment, depending on which school of thought you belong to. Some schools of thought say, you just need like a brief dose of doxycycline. And others say at least four to six weeks of treatment. It depends on your approach.

Do you have a preference?

Longer term antibiotics, definitely not a short term

Yeah, that was certainly my experience, I had about 10 days of antibiotics, and then all of my symptoms came back afterwards.

Absolutely. If patients have an acute exposure, and they have symptomatology, we do have a baseline laboratory test. And then we repeat it four to eight weeks later to see if there's any rising titers. And we send the tick off for analysis. I usually cover them with antibiotics for at least six weeks. 

Wow. That's great to hear. And so, what is functional medicine?

Well, functional medicine is this emergent system of approaching a patient from a very different point of view. Like my medical training is what we, I don't mean to be derogatory, but it's called the N2D2 method of diagnosis and treatment; name the disease, name the drug. You know, that's how we learned in medical school, we just look at differential diagnoses, what disease or symptom cluster does this person have, and what drug can I pull out to help them. That's the specific training, highly relevant, nothing wrong with it. But now we have this emerging cohort of patients who have this chronic multi system, multi symptom disease profiles, with many interlocking issues. And that model doesn't work. And I tend to see and many people who are outside of the so-called traditional healthcare system tend to see that cohort of patients. Functional medicine attempts to take an upstream history back to what we call antecedents, mediators, and triggers. We go and look upstream to see, first of all, what's your symptom profile now? But, when did you start to feel unwell? One of the most relevant questions I ask a patient is; when did you last feel well, and then you want to take it from there, backwards and forwards. So functional medicine looks backwards as to the timeline, or the potential triggers and inherited factors which may play a role, the triggers what may have triggered the illness, and then what we call mediators, what may be keeping that symptom cluster alive. In conjunction with that we look at, not so much as pathology and disease laboratory tests, but we look at functional laboratory tests. How is the biochemistry and the metabolomics? How are they functioning? Are they optimized? Or are they deficient within a spectrum? Traditional Medicine has a reference range of, you know, negative or positive. Functional medicine optimizes function based on individual susceptibility and genetics. It's a very elegant form of practicing medicine within chemical principles. Just old school sort of, you know, when did you last feel well; what happened and what may have been playing a role. No longer looking at single factors, instead, looking at multiple causative factors as to what keeps this patient still symptomatic. And I can tell you, from my experience, that there is never one reason why a person is not feeling well. There's usually a whole myriad and host of issues from poor sleep, poor diet, early childhood trauma, dental issues, food and gut sensitivities. It is complex, long list of what made you unwell. 

Yeah, absolutely. Why do the symptoms vary so much from one patient to the other?

You mean with Lyme disease specifically?

Yes. with Lyme disease specifically?

Well, while it depends on a whole host of factors, it depends on the individual immune response of the person, the total toxic load, the infectious load, the expression of the Lyme disease spirochaete, with or without co infections, the metabolic and nutritional strength of the individual, the immune competencies, the presence of natural killer cell functions, whether they can suppress the immune response. The fact that Lyme disease goes from different forms; the cellular form to an intracellular form, to a cystic form to a biofilm form then it comes and goes depending on your immune surveillance. There's a lot of reasons why somebody has waxing and waning of symptoms and feels variations in their symptom profile.

Is it possible for someone to have Lyme but not have any symptoms?

You can have positive laboratory testing for Lyme and be asymptomatic. Absolutely, absolutely. But you don't see those people because they feel good.

Yeah, definitely. Do symptoms flare and go dormant normally for some of your patients?

They do. They wax and wane depending on stressors, diet, travel and multiple factors affect the expression of symptomatology. Treatment or no treatment. Some treatments exacerbate the symptomatology quite dramatically. They get what they call the Jarisch Herxheimer reaction (JHR) where you put in a treatment and the patient's symptoms just go through the roof. And so, there's all these variations as to why people wax and wane and get increased symptoms at times. But yeah, we certainly have people with, with no symptoms, who have positive laboratory tests as well.

Dr. Hoffman, are you seeing a larger increase in the number of patients that you suspect to have Lyme disease and other co infections?

Absolutely. Yeah. As you know that the diagnosis of Lyme disease is highly controversial, depending on which school of thought you belong to. Whether you belong to the sort of infectious disease society, the infectious disease group of medicine, or whether you follow the ILADS criteria for the diagnosis and treatment. Those are these two different schools of thought. Now you know, even with that, there's been a tremendous uptake in the diagnosis of Lyme and co-infections due to global warming. The migration of songbirds further north and the spread of ticks deeper into the north because of global warming. It's been estimated, one study showed that the songbird flight path from South America to North America brought up to 32 million tick species. In the yearly migration just northwards from South America. So, there's a there's a huge increase in the diagnosis. For sure.

Yeah, especially for anyone who's living along any kind of migratory bird path.

Absolutely. Yeah, absolutely. And there’s this great Canadian researcher, John Scott, showing us published papers on this issue.

Yes, hopefully, we'll get him on a future podcast as well. I'd love to hear more about his research

Absolutely. Yeah.

So I was fortunate to go to the ILADS conference last year in Boston, and I learned about mast cell activation. And I was just wondering if you could tell me a little bit about that disorder.

Well, Mast Cell Activation Syndrome (MCAS) is a relatively new diagnosis. It's been around for a while. Dr. Lawrence Afrin is one of the leaders in the diagnosis and treatment. He's just recently published, which I co-authored, a criteria for the diagnosis. And the reason why that has been important is because previously at medical school, we learned about systemic mastocytosis, which is an increase in the number of mast cells that create disease processes. But mast cell activation syndrome is an increase in activity without an increase in number. And there are different criteria for the diagnosis. Mast cell activation syndrome is a very, very important concept to keep in mind when seeing patients with chronic systemic illness because you'll see it a lot. I see it a lot. Mast cells or white cells act as vigilante cells to try and protect you from incoming stressors. Whatever they may be, whether it's mental, chemical, environmental, infections or food, they spew out at least 1000, not 200 as one's thought, but more than 1000 mediators of inflammation. One of them is histamines. Everybody knows the histamine is a sort of allergy hive reaction. There are many other mediators of inflammation. People with mast cell activation syndrome have this heightened inflammatory response to ongoing day to day environmental exposures and present with a multitude of symptoms in multiple organ systems. And they travel from doctor to doctor you know, they go to the allergist and the rheumatologist and to the neurologists, but nobody ties the systemic nature of this condition together. So, it's important again to take a thorough history and elicit whether somebody may be presenting with mast cell activation syndrome. Now, interestingly, mold exposures and Lyme disease trigger mast cell activation syndrome. So you often get a cross mapping of symptomatology.

Well, what would be your best advice for someone who suspects that they might have Lyme disease?

Well, it's a very tricky one. Because here's my experience. People often want to believe in a one diagnosis - one treatment approach when they present with complex illness. And it's really doesn't do them any favors to adopt that attitude. Yes, you may have a classic exposure and symptom profile, no question about that. But when you've got chronic illness, and chronic multi system, multi symptom exposures, and you go into a Lyme test with a naturopath or an MD, they send it to the states or even they send it to the Canadian Winnipeg group. And you come back with a positive test, it doesn't mean that the reason for your symptom profile is Lyme. Lyme may be the trigger, but you may have a whole host of underlying issues that are playing a role in your symptom profile. And one of the great tragedies that I see in my practice is people who come to see me, they've got a positive Lyme test and they've been treated for Lyme. But it's really not the key diagnosis, there are 70 other underlying factors that are far more relevant than that positive laboratory test. So, in response to your question is just be extremely discriminatory, when you jump to the diagnosis of Lyme disease as causing your symptoms, it may not be that. It may be there, you may have a positive test. But it doesn't mean that Lyme disease is at the root of it. It may be that it is. But you can't just take a positive test and treat it as if that's it. And I see that 90-95% of the time. They just go get treated for Lyme, but it's not really Lyme that's causing a symptom profile. Sometimes it is, of course it is, but you've got to discriminate.

So it's that combination of diagnostic testing and patient history,

History, history, history. If you're not taking a two-hour history with your patient, a timeline from conception to present, plus even intergenerational issues because we know that you inherit epigenetically family trauma. It is very well studied and well researched. Now, if you're not taking a thorough history, and following the timeline and symptom presentation of that patient, at least a two-hour history, you can't really discriminate on a history basis, whether this patient is suffering from one illness or 15 possible comorbid conditions. You have to take that history, then you back it up with laboratory data. The more laboratory data, the better, which unfortunately and again, with our healthcare system, that sort of privilege and that sort of luxury of a two-hour interview with extensive lab data. It doesn't exist. You have to go outside the healthcare system to get that service, you know, which is a tragedy, but it's the truth.

I couldn't agree more. Thank you so much for your time, Dr. Hoffman.

Thank you so much.

My key takeaway from that conversation was just how important it is that a doctor gets a full patient history. I know that in my case, I had a lot of symptoms and it was really confusing to understand what was going on in my body. That wraps up another podcast. Thank you so much for listening. Stay safe in the outdoors.

Diagnosis of Mast Cell Activation Syndrome – A Global Consensus 2

Diagnosis of Mast Cell Activation Syndrome - A Global Consensus

Please take a look at this newly published peer-reviewed article by Dr. Lawrence Afrin of which I was a co-author, on the revised criteria for the diagnosis of mast cell activation syndrome (MCAS):

Diagnosis of mast cell activation syndrome: a global “consensus-2”

One of the most common difficulties patients seem to face after they have been to our clinic and given a diagnosis of mast cell activation syndrome is when they return to their GP’s or specialists with a description of this syndrome. Traditional medicine is well-schooled in the diagnosis of systemic mastocytosis, a condition characterized by an increased number of mast cells as opposed to MCAS which is a diagnosis arrived at due to the increased activity of mast cells (and not an increase in the actual numbers).

Systemic mastocytosis is most often diagnosed by using a biomarker called tryptase, whereas the diagnosis of MCAS has much broader diagnostic criteria as this article will outline.

For a much more in-depth description of MCAS, please see my treatment page and the following articles:

  1. Treating Mast Cell Activation Syndrome (MCAS)
  2. Mast Cell Activation Syndrome: When You Immune System Runs Rampant
  3. Natural Treatments For Mast Cell Activation Syndrome
  4. Your Ultimate Guide to the Low-Histamine Diet