AUTISM:�

WHAT IS HAPPENING,� WHY,� AND WHAT CAN WE DO ABOUT IT?

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PROF ROBYN COSFORD

ACIIDS SYDNEY

OCTOBER 2025

THE STAGE:

• DISCONNECTION

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HOMO ERECTUS

POST HUMANISM

Homo fattus slouchicus

OBESITY

OBESITY

DIABETES 2000

DIABETES 2021

NEUROPSYCHIATRIC DEATHS

AND AUSTRALIA

DISEASE �BURDEN�VS�HEALTH�EXPENDITURE�

INFANT DEATHS GLOBALLY

OECD 18

• Australia, New Zealand
• Austria, Belgium, Denmark, Finland, France, Germany, Italy, Japan, the Netherlands, Norway, Spain, Sweden, Switzerland,
• United Kingdom, Ireland,
• Canada
• ( Luxemburg, Iceland: OECD 20)

Trends in US Children’s Mortality, Chronic Conditions, Obesity, Functional Status, and Symptoms�

• Statistics from US cf 18 comparator high-income nations OECD18
• 5 nationally representative surveys
• Electronic health records from 10 pediatric health systems (PEDSnet).
• Populations: < 20 years old.
• Sample size ranges: 1623 to 95 677 (surveys), 1 026 926 to 2 114 638 for PEDSnet, 81.9 million to 83.2 million in US, 118.4 million to 121.1 million in the OECD18 (mortality statistics).

(Forrest CB, Koenigsberg LJ, Eddy Harvey F, Maltenfort MG, Halfon N. Trends in US Children’s Mortality, Chronic Conditions, Obesity, Functional Status, and Symptoms. JAMA. 2025;334(6):509–516. doi:10.1001/jama.2025.9855)

CHILD HEALTH MORTALITY USA: 2007-2022

• Infants (<1 year old) 78%
• 1- to 19-year-old individuals 80% more likely to die in US than in OECD18.
• Causes of death difference:
• Infancy <12 mo: prematurity (RR, 2.22) sudden unexpected infant death (RR, 2.39)
• Children 1-19:firearm-related incidents (RR, 15.34), MVA (RR, 2.45)

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CHRONIC DISEASE CHILDREN AGE 3-17: 2011- 2023

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• Prevalence of 3- to 17-year-old individuals with chronic condition:
• From 39.9% to 45.7% (RR, 1.15) within PEDSnet

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• From 25.8% to 31.0% (RR, 1.20) within general population.

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CHRONIC DISEASE CHILDREN AGE 3-17

Increased rates

• Obesity
• Premature thelarche ( 8-11)
• Sleep disorder ( 16-17 yo)
• Limitations in activity
• Physical symptoms
• Depressive symptoms ( 15-18 yo)
• Loneliness ( 12-18yo)

WHICH CONDITIONS?

TRENDS: FROM 1970s

CHRONIC CONDITIONS

WHAT IS AUTISM?

• First described by Leo Kanner (a child psychiatrist at The Johns Hopkins School of Medicine) in 1943, who called it “autistic disorders” (https://www.autismtruths.org/pdf/Autistic%20Disturbances%20of%20Affective%20Contact%20-%20Leo%20Kanner.pdf).
• 11 children: 8 boys: early infancy feeding difficulties, bottle feeding: highly intelligent, distant parents
• American Psychiatric Association (APA) described autistic behavior as “psychotic reactions in children, manifested primarily as autism”
• autism in group “schizophrenic reaction, childhood type” in first version of the Diagnostic and Statistical Manual of Mental Disorders (“DSM-1”, 1952, page 28) (https://www.turkpsikiyatri.org/arsiv/dsm-1952.pdf).

NEURODEVELOPMENTAL DISORDERS:

SUBACUTE ENCEPHALITIS

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NEUROINFLAMMATION

ASD/ADHD/OCD/TD

. Translational Psychiatry 2019 Nov 26;9:318. doi: 10.1038/s41398-019-0631-2

OVERLAPS: OCD, ADHD, ASD

COMORBIDITIES IN ASD

• 42,569 individuals with ASD and 11,389 non-ASD siblings (full and half siblings)
• Majority (74%) at least one comorbidity
• Greater average number of comorbidities than non-ASD siblings.

COMORBIDITIES

• ADHD most common comorbidity
• Affecting> 1 in 3 children with ASD (35.3%),
• cf 1 in 6 (16.8%) among non-ASD siblings.
• Learning disability (23.5%) and intellectual disability (21.7%)
• Sleep disorder
• Encopresis

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1/31 CHILDREN AGED 8 YEARS

2018 vs 2014 BIRTH YEARS

MULTI- HIT HYPOTHESIS

WHY IS IT HAPPENING?

Any disease process, consider:

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1. Predisposing factors
2. Precipitating factors
3. Perpetuating factors

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PREDISPOSING FACTORS

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1. GENETIC:
1. No one gene causative for autism
2. Over 2000 genes
3. Numerous SNPS
4. FHx autoimmune disease

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2. TRANSMITTED:
1. Seminal fluid
2. In utero

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3. PRENATAL:

• Maternal health issues: advanced age (≥35 years), chronic hypertension, preeclampsia, gestational hypertension, and being overweight before or during pregnancy, maternal autoimmunity
• Maternal OC use 
• IVF
• Maternal vaccination
• Maternal toxicity

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PRECIPITATING FACTORS

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2. ANTENATAL:
1. Maternal U/S
2. GDM
3. Preeclampsia
4. Maternal GBS
5. Maternal vaccination
6. Maternal paracetamol use?
7. Maternal air pollution exposure
8. Prematurity

PRECIPITATING FACTORS

3. NATAL FACTORS:

• Caesarian section
• Traumatic delivery

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4. PERINATAL FACTORS

• Neonatal Hep B
• Infant separation
• Vit K injection
• Comp feeding
• Lack of breast feeding ( contact, oligosaccharides, immune, gut microbiotica)
• Formula feeding ( aluminium, casein)

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PRECIPITATING FACTORS

5. FIRST 6 MONTHS

• Early cessation breast feeding
• Introduction of formula
• Recurrent infections
• Paracetamol use
• Antibiotics use
• General anaesthetic
• Routine vaccination schedule
• Toxin exposure
• Air pollution

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PRECIPITATING FACTORS

6. 6MO- 2 YEARS

• Recurrent infections
• Antibiotics
• General anaesthetics
• Paracetamol use
• Routine vaccination schedule
• Early separation from mother
• Introduction of SAD modern western diet
• Refusal of coloured foods; craving sugared, high refined carb, white foods

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PRENATAL, PERINATAL, POSTNATAL:

• Pregnancy and birth-related conditions served as the main exposure variables
• Preterm birth (gestational age of <37 weeks), fetal alcohol syndrome, serious prenatal infection (e.g., German measles), hypoxia at birth, and bleeding into brain during delivery.
• Postnatal exposures included lead poisoning, brain infections such as bacterial meningitis, and encephalitis, and traumatic brain injury requiring hospitalization.

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PERPETUATING FACTORS

PERPETUATING FACTORS: CYCLE

GENETICS

GENOMICS SIGNIFICANT: TWINS

• Siblings of individuals with autism have a prevalence of 2.9% to 3.7%

represents almost a 100-fold increased risk as compared with the general population

• Twin studies have found concordance rates of 36% to 91% between identical twins

• concordance rate of only 1% between dizygotic twins

Over 2000 gene variants have been identified that are associated with autism on some level ��Many hundreds of pathogenic variants (disease causing) yet only a small percentage of children with ASD have pathogenic variants identified on WGS. ��85 pathogenic SNPs found with a frequency of <1/10,000

ASD SNPS �ARE COMMON

• Most of the variants found that predispose to ASD would be considered BENIGN!
• Common (.5-45% of population)
• Variants relate to inflammation, mitochondrial factors, nutrient factors, ability to remove toxicants, immune function, brain scaffolding and plasticity, neurotransmitters,

JILL JAMES: �OXIDATIVE STRESS, METHYLATION

• 360 ASD, 205 controls
• MTHFR: C677C>T, 1298A>C
• GST M1
• COMT 472G>A
• RFC (Reduced folate carrier)
• TCNII ( transcobalamin) 776G>C

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SNPS IN AUTISM 2022

• 12 significant SNPs
• CNTNAP2: rs 2710102, rs7794745
• MTHFR: C677T
• OXTR,
• SLC25A12,
• VDR : rs 731236

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CNTNAP2:

• CNTNAP2 is a member of neurexin superfamily and is a synaptic protein.
• Plays major role in neural development, crucial for neural circuit assembly
• CNTNAP2 mutations may be linked to the abnormal behavior of ASD by altering synaptic neurotransmission, functional connectivity, and neuronal network activity
• it is likely that the rs2710102 and rs7794745 polymorphisms of CNTNAP2 influence the risk of ASD:

MTHFR

• C667T polymorphism of MTHFR  associated with an increased risk of ASD-
• Homozygous and heterozygous
• no significant association between the A1298C polymorphism of MTHFR and ASD risk

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OXTR

• OXTR, a neuropeptide gene
• Oxytocin- important role in a range of human behaviors, including affiliative behavior to social bonding
• 3 SNPs (rs2268491, rs237887, and rs7632287) significantly associated with ASD risk.

SLC25A12

• SLC25A12 encodes mitochondrial aspartate/glutamate carrier of brain
• Calcium-binding solute carrier in inner mitochondrial membrane that is expressed principally in the heart, brain, and skeletal muscle
• Mutant alleles associated with mitochondrial dysfunction
• Higher risk of ASD in individuals with the mutant allele of rs2056202 or rs2292813. 

SLC19A1

• Reduced folate carrier
• Folate transporter -1
• SNP c.80GG associated with reduced folate
• Also carrier protein for MTX

VDR

• Vitamin D plays a significant role in brain homeostasis, neurodevelopment, and immunological modulation
• deficiency has been reported in children with ASD
• vitamin D exerts its effects on genes via VDR gene The
• rs731236 polymorphism of VDR associated with increased risk of ASD

2023:

• ‘Our study summarized research evidence on the genetic variants of ASD and provides a broad and detailed overview of ASD risk genes’.
• C677T and A1298C polymorphisms of MTHFR
• rs2710102 and rs7794745 polymorphisms of CNTNAP2
• rs2254298 polymorphism of OXTR
• rs731236 and rs2228570 polymorphisms of VDR were genetic risk factors.
• rs7975232 polymorphism of VDR was a genetic protective factor for ASD.

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BROADER PERSPECTIVE

SHANK-3 SNPS

• Scaffolding protein densely associated with postsynaptic glutamatergic synapses
• Important part of postsynaptic density (PSD)
• Ability to interact with multiple key synaptic components, including glutamate receptor complexes, anchoring proteins, and actin cytoskeleton
• Critical orchestrator of frontocortical function.
• Modulated by: exercise, light exposure ( melatonin), zinc

CCL-2 rs1024611

• CCL-2 -helps guide immune cell migration towards sites of inflammation and tissue injury.
• Stimulate monocytes to produce superoxide and stimulates further expression of various pro-inflammatory genes.
• Released in response to injury, ischemia
• In neurodegenerative diseases, greater activity of CCL2 leads to increased tissue damage.
• CCL2 binds to CCR2 and this complex is important for gut inflammation in response to dysbiosis.

(Pham MH, Bonello GB, Castiblanco J, et al. The rs1024611 regulatory region polymorphism is associated with CCL2 allelic expression imbalance. PLoS One. 2012;7(11):e49498. doi:10.1371/journal.pone.0049498. )

RS1024611 CCL2, NEUROINFLAMMATION

• SNP associated with higher serum CCL2 levels
• increased susceptibility to variety of diseases such as HIV-1 associated neurological disorders, tuberculosis, and atherosclerosis, cancers, DM
• high CCL2 noted in ASD

ENVIRONMENT

AIR POLLUTION

AIR POLLUTION

• Greatest single environmental health risk worldwide.
• According to the World Health Organization, ambient air pollution prematurely kills 7 million people per year (World Health Organization, 2021)
• Among air pollutants, fine particulate matter (PM_2.5) largest health impact in monetized terms—more than half of global population is exposed to annual-average ambient concentrations exceeding first interim target from the World Health Organization, 35 μg/m³ (Health Effects Institute, 2019).
• within-city emissions are most commonly industry, energy transformation and extraction, and residential and commercial activities
• ie- industry, motor vehicle

AIR POLLUTION, AUTISM

• We found a strong association between maternal exposure to particulate matter (PM) during pregnancy or in the first years of the children’s life and the risk of the ASD.
• This association was found to be stronger with PM_2.5 and less evident with the other pollutants.
• Current evidence suggest that pregnancy is the period in which exposure to environmental pollutants seems to be most impactful concerning the onset of ASD in children.
• Air pollution should be considered among the emerging risk factors for ASD

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PM_{2.5 :}INDUSTRY, CHEMICALS, CARS

COAL FIRED POWERPLANTS AND MERCURY

• Increased risk ASD for increased levels of industrial release
• Independent predictor:
• Reduction risk as further away from coal plants

MERCURY, NEUROTOXICITY

• Maternal mercury exposure: fish, seafood

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• Role of calcium, glutamate dyshomeostasis,

mitochondrial dysfunction

ENVIRONMENTAL:�MERCURY AND ALUMINIUM

• 5: Al, As, Hg, Pb and Tl
• all alien to body
• no known biological purpose
• ingested to various degrees by diet.
• Ethyl mercury received in form of thimerosal in vaccines.
• ligand-type organometallic
• C₂H₅HgS-group directly attached to sodium salicylic acid benzene ring structure that can metabolize to ethyl mercury ion.
• These organo-mercury forms mimic true organic and be transported very efficiently through a placenta.
• Can also be transported through BBB

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HUMAN NOEL: WHALE MEAT

• Human NOAEL levels generally are derived from animal studies in which known dose levels are administered
• Result is expressed in units of grams of toxin consumed per kilogram body mass per day.
• Then, through approximate animal/human models, translated to a human dietary intake
• EPA (US Environmental Protection Agency) and later other agencies chose instead to use extensive data base acquired from a decade’s long study of population of Faeroe Islands, known to live on a high fish (whale meat) diet.
• From observed cases there, that were in fact displaying neurological effects, a dangerously high blood mercury level was assessed directly.
• This was then converted in reverse and scaled to dietary intake

MERCURY TOXICITY

CORD BLOOD

• Pregnant mother’s blood can contain all of these metal neurotoxins and toxins.
• Recent review of more than 100 such studies examined this ratio of mother’s blood to cord blood concentrations
• This not only included 14 metallic compounds but also innumerable toxic organics in environmental circulation.
• Placenta and cord analysis did indicate a fractional barrier transfer possibly reflecting a halving of concentration in the fetal blood level
• Expect that fetal blood, cf mothers, has following approximate percentage ratio:
• for Cd (≈ 17%), Tl (≈ 20%),
• Pb (75%), As (80%), Se (100%),
• High levels apparent for Hg (160%) and Mn (200%).

DEVELOPING FOETAL BRAIN

• Once foetus starts accepting nutrients from the mother via umbilical cord and placenta, growing organs will begin to encounter toxic levels of numerous metals.
• Foetal kidneys and liver remain initial main filters
• Foetus very dependent on its blood/brain barrier.
• Genes to regulate cysteine and glutathione related enzymes and selenoproteins that can bind to any toxin leaking into brain and transport toxins away with p-glycoprotein molecules.
• Strong antioxidants that can control inflammatory reactions and have the capability also for DNA repair.

VULNERABLE MALE BRAIN

• Gender specific effects for:
• Lead, thimerosal/ethylmercury,
• OC: dieldrin,endosulfan, heptachlor
• Air pollution

Less so:

• Mercury vapor, PCB, OP
• mercury vapor, polychlorinated biphenyls (PCBs), and organophosphate

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FEMALES PROTECTED:

NEURODEVELOPMENTAL DISORDERS, PRENATAL CHEMICAL EXPOSURE 2014

• CHARGE STUDY; antenatal exposure
• 1/3 of mothers lived within 1.5 km of an agricultural pesticide application.
• Proximity to OPs at some point during gestation- associated with 60% increased risk for ASD
• higher for third trimester exposures (OR = 2.0),
• second-trimester chlorpyrifos applications (OR = 3.3)
• Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, (ORs ranging from 1.7 to 2.3).

MATERNAL IMMUNE ACTIVATION, ASD 2015

• From 1996 to 2002, total of 101 033 pregnant women recruited to DNBC
• total of 976 DNBC children diagnosed with ASD (1%); 342 had infantile autism (0.4%)
• increased risk of infantile autism after influenza infection (aHR: 2.3).
• �increased risk of ASD (aHR: 1.6) and infantile autism (aHR: 3.2) after febrile episodes lasting ≥7 days.
• increased risk of ASD/infantile autism after use of various antibiotics.
• sulfonamides anytime during pregnancy, penicillin during 2^nd, 3 rd trimesters increased risk of ASD/infantile autism by ~50%.
• macrolides anytime during pregnancy increased risk for infantile autism in the offspring (aHR: 2.2)

POSTNATAL EFFECTS

Post natal risk factors

Internet survey 1741

• Postnatal paracetamol use
• Antibiotic use
• Otitis media
• Early weaning

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School Lunch Testing Program

• September 29, 2022
• Thirty million genetically modified school meals are served daily in America to our children.
• The MAA commissioned testing of 43 school lunch samples shows:
• 10% contained known aviary contraceptive, Nicarbazine.
• 93% contained carcinogenic, endocrine disrupting, and liver disease-causing glyphosate.
• 74% contained at least one of 29 harmful pesticides.
• 4 Veterinary drugs and hormones in 9 school lunch samples at levels up to 130.76 ng/g.
• 100% contained heavy metals at levels up to 6,293 X higher than EPA’s maximum levels allowed in drinking water.
• Majority of samples were abysmally low in nutrients

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School Lunch Testing Program

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September 29, 2022

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Thirty million genetically modified school meals are served daily in America to our children.

The MAA commissioned testing of 43 school lunch samples shows:

• 10% of the samples contained a known aviary contraceptive, Nicarbazine.
• 93% of the school lunch items contained carcinogenic, endocrine disrupting, and liver disease-causing glyphosate.
• 74% of the samples contained at least one of 29 harmful pesticides.
• 4 Veterinary drugs and hormones were found in 9 school lunch samples at levels up to 130.76 ng/g.
• 100% of the school lunch samples contained heavy metals at levels up to 6,293 X higher than the EPA’s maximum levels allowed in drinking water.
• The majority of the samples were abysmally low in nutrients.

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CHILDHOOD VACCINATIONS

VACCINATIONS CDC 1986- 2019

VACCINES OVER TIME: 1967 - 2009

INFECTIOUS DISEASES OVER TIME (USA)

HUMAN DNA IN MMR, HEP A VACINES,�ASD 2015

• fetal DNA fragments persist in vaccine vials
• readily enter the nucleus of human cells
• align with chromosomal “hotspots” located within genes strongly linked to autism.
• correlation between MMR vaccination coverage and autism prevalence in UK, Norway, and Sweden following 1998 “Wakefield” disruption of MMR uptake

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THIMEROSAL TIMELINE

THIMEROSAL TIMELINE

ADDM

• Autism and Developmental Disabilities Monitoring (ADDM) Network
• Most thorough and detailed ongoing ASD surveillance system in United States.
• Established by U.S. CDC in 2000
• Has been conducted in multiple select U.S. regions to provide estimates of ASD prevalence among 8-year-old children.
• Includes information on cognitive ability of a subset of children diagnosed with ASD
• Assigned to one of 3 intelligence quotient (IQ) categories.�IQ < 70 (intellectual disability (ID)),�IQ 71-85 (borderline ID),�IQ > 85 (normal cognitive ability).

I D �VS �ASD PREVALENCE

VACCINE EXCIPIENTS

• Some excipients are added to a vaccine for a specific purpose.
• These include: Preservatives, to prevent contamination. For example, thimerosal.
• Adjuvants, to help stimulate a stronger immune response. For example, aluminum salts.
• Stabilizers, to keep the vaccine potent during transportation and storage. For example, sugars or gelatin.
• Others are residual trace amounts of materials that were used during the manufacturing process and removed. These can include:
• Cell culture materials, used to grow the vaccine antigens. For example, egg protein, various culture media
• Inactivating ingredients, used to kill viruses or inactivate toxins. For example, formaldehyde.
• Antibiotics, used to prevent contamination by bacteria. For example, neomycin.
• A table listing vaccine excipients and media by excipient is published by the Institute for Vaccine Safety at Johns Hopkins University, and can be found at http://www.vaccinesafety.edu/ components-Excipients.htm.

BUT HEY, ITS ALL GOOD!

VACCINE EXCIPIENTS

VACCINE EXCIPIENTS

VACCINE EXCIPIENTS

VACCINE EXCIPIENTS

ALUMINIUM LEVELS:

• ‘The current aluminium threshold of 0.85 mg per dose was set in the mid-20th century based on immunological efficacy - not on toxicological data- and remains in place despite changes in vaccination schedules and cumulative exposure.

• The key documents supporting this limit, which date back to 1947 and 1952, do not evaluate the potential toxicity of ABAs and are, in any case, no longer relevant to the current vaccination schedule.’

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• Based on oral dosage ( vs injected)

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TOXICITY KNOWN

CATCH UP ALUMINIUM

• Based on previous models of whole-body clearance of aluminium hydroxide from vaccines,
• First-ever estimate of pediatric dose limit (PDL) of aluminium hydroxide for CDC vaccination schedule.
• Found repeated instances of acute (whole-body) toxicity resulting from vaccine administration according to schedule recommended by CDC Advisory Committee on Immunization Practices (CDC/ACIP)
• Modelled accumulation and clearance comparing 3 vaccine schedules
• Found - can be expected that children receiving CDC recommended schedule will experience chronic aluminium toxicity (as measured by %AlumTox) during at least 70 % of days up to age of 7 months, 25 %of days up to age 2 years.
• This result did not accommodate for fact that at birth, infants have only 20 % glomerular filtration rate CF two-year olds
• Results were considered conservative

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ORAL VS INJECTED TOXICITY

• Commonly perceived that children receive more aluminium from oral sources than from vaccines
• McFarland et al - infants up to six months are exposed internally to far more aluminium from vaccines (100 % absorption) than from oral exposure (about 0.3 % absorption)
• Contradicting the common misconception that the reverse is true once body weight and pass-through intestinal clearance of aluminium from parenteral sources are considered.
• Aluminium localises to the bone

ALUMINIUM IN CHILDHOOD VACCINES

ALUMINIUM, NEUROTOXICITY

• There has been, since 1985, evidence that aluminium enters the brain;
• localization to the brain is cause for concern for neurodevelopment.
• Intracellular generator ROS
• Induces mitochondrial dysfunction

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• Non-specific conditions associated with aluminium adjuvants include Gulf War Syndrome (Petrik et al); chronic fatigue syndrome, and macrophagic myofasciitis .
• Specific neurological effects likely due to aluminium toxicity/sensitivity in macrophagic myofasciitis
• Mounting evidence of persistence of aluminium with multiple points of toxic impact on immune system components provides additional solid ground for concern over chronic toxicity.

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ALUMINIUM IN AUTISM BRAIN TISSUE:

• Aluminium content of brain tissue in autism was consistently high.
• Mean (SD) aluminium content across all 5 individuals for each lobe were 3.82(5.42), 2.30(2.00), 2.79(4.05) and 3.82(5.17) μg/g dry wt. for the occipital, frontal, temporal and parietal lobes respectively.
• These are some of the highest values for aluminium in human brain tissue yet recorded 
• appeared to be present intracellularly in microglia-like cells and other inflammatory non-neuronal cells in the meninges, vasculature, grey and white matter CF neurones
• IE NEUROINFLAMMATION

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ALUMINIUM IN AD, MS AND AUTISM

• Confirmed that PM aluminium in brain in AD, ASD, MS many times higher than in controls

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BIOLOGICAL PLAUSIBILITY

• Aluminium (Al) is neurotoxic.
• Infants who have received AlAd in vaccines show a higher rate of ASD.
• The behavior of mice changes with Al injection.
• Patients suffering from ASD have higher concentrations of Al in their brains.

BRADFORD – HILL CAUSATION FOR AUTISM

BRADFORD HILL – ALUMINIUM CAUSATIVE

RESIDUAL MERCURY…

• Infanrix Hexa ( Australia) significant, measurable Hg levels
• In all vials/batches tested
• Less than prior to ‘removal ‘ of Hg from vaccines
• Less than ‘established safety levels’
• Av 9.7 ppb

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PARACETAMOL

PARACETAMOL, AUTISM

• Harvard, Mt Sinai
• 46 studies included in analysis.
• 27 studies reported positive associations (significant links to NDDs),
• Higher-quality studies were more likely to show positive associations.
• Overall, majority of studies reported positive associations of prenatal acetaminophen use with ADHD, ASD, or NDDs in offspring,.

PARACETAMOL USE

• Acetaminophen (also known as paracetamol) is currently considered the only pain and fever reducer indicated for use during pregnancy because of the risks of miscarriage or birth defects associated with other analgesics in common use.
• Associations such as the American College of Obstetricians and Gynecology have reassured patients that acetaminophen is safe to take during pregnancy
• Has become first-line medication for fever and pain during pregnancy.
• Estimated that > 60% of women use acetaminophen during pregnancy for headaches and other pain, or fever, with ~ 20% of pregnant women using acetaminophen for > 20 days

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PARACETAMOL HEPATOTOXICITY

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• Second most common cause of liver transplantation worldwide

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• Most common cause of liver failure in USA

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• Cases 500 deaths annually

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PARACETAMOL DETOXIFICATION

PARACETAMOL AND GLUTATHIONE

• Liver metabolizes 89% of acetaminophen via CYP P450
• Leading to saturation of the sulfation and glucuronidation pathways
• Resultant depletion of hepatic glutathione stores.
• Result is production of a toxic, highly reactive compound that causes a cascade of oxidative hepatocyte injury.
• N-acetyl-p-benzoquinoneimine (NAPQI); binds to cysteine groups, depletes glutathione

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• https://www.ncbi.nlm.nih.gov/books/NBK441917/

PARACETAMOL VS ASPIRIN

PARACETAMOL TOXICITY AND �OXIDATIVE STRESS

SELENOPROTEINS:REMINDER:

• From animal studies it is well known that neurotoxic metals can partially cross BBB.
• This is also evident in human brain autopsies that monitor all the neurotoxins and toxins
• Neurotoxins can pass through placenta to fetus and its organs including its brain.
• Mercury pronounced affinity for sulfur , stronger for selenium
• Unlike most metals this is much stronger than that for oxygen.
• Mice- Se can attenuate levels of CH₃Hg⁺ in fetal brain if on an equal or larger atomic basis, reduce toxicity of CH₃Hg⁺ and Hg²⁺ 
• known to be necessary for DNA repair and during pregnancy
• Selenium appears to have general chelating properties in the body and brain due to its involvement in at least 25 selenoproteins and molecules such as selenocysteine that can provide oxidative stress protection
• Demonstrated ( animal studies) protective against Al, As, Pb, Hg Mn toxicity

EXAMPLE SCENARIO

• Genetic predisposition ( glutathione, oxidation, inflammation)
• Maternal amalgums, mercury load, cross transplacentally
• Maternal vaccinations (eg flu vaccine – thimerosal)
• Maternal fever: paracetamol
• Depletion sulphation stores, glutathione – oxidative stress to foetus; dependance on selenoproteins ( deficient in maternal diet)
• Foetus born oxidatively compromised ( low glutathione, low sulphur stores)
• Childhood vaccinations….

PERPETUATION CYCLE:

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METABOLIC AND PHYSIOLOGICAL

MARKERS

OXIDATIVE STRESS, METHYLATION CAPACITY: 2004

• 20 ASD cf 31 controls
• ASD: lower methionine, SAMe, homocysteine, cystathionine, cysteine, total glutathione
• Higher SAH, adenosine, oxidized glutathione
• c/w impaired methylation
• Increased oxidative stress

JILL JAMES: 2006�OXIDATIVE STRESS, METHYLATION

• 360 ASD, 205 controls
• MTHFR: C677C>T, 1298A>C
• GST M1
• COMT 472G>A
• RFC (Reduced folate carrier)
• TCNII ( transcobalamin) 776G>C
• Low: methionine, SAM/SAH, cysteine, glutathione, reduced/oxidized glutathione

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Folate – methionine-transsulphuration Cycle Disruption

• High homocysteine
• Low B12, folate
• Dietary, MTHFR

OXIDATIVE STRESS: REVIEW 2022

• Increased oxidative stress
• Lower antioxidant capacity
• Alterations function SOD, GPx, catalase
• Altered glutathione levels, HCY/Meth metabolism
• Increased inflammation
• Excitoxicity
• Mitochondrial dysfunction
• Immune dysfunction,

BIOMARKERS: systematic review 2019

• Multiple markers
• Maternal, prenatal
• SNPS
• Methylation
• Oxidative stress
• Mitochondrial
• FA metabolism ( mitochondrial)

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Table 3. Summary of quantitative performance of promising biomarkers.

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• Strong biomarkers; > 85%
• Neuroimaging: functional connectivity, cortical surface area
• Methylation – redox
• Human- microbiome RNA
• Autonomic: pupillary light reflex (SNS)

NEUROIMAGING

• 1571 ASD patients and 1651 controls
• ASD patients had smaller putamen, pallidum, amygdala, nucleus accumbens,
• Larger lateral ventricles, and mean intracranial volume

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AUTONOMIC NERVOUS SYSTEM(ANS)�

• Prospective controlled study
• Pupillary reactivity in siblings of children with ASD, low-risk controls 9–10 months old
• Children with an ASD diagnosis at 36 months of age demonstrated a relatively larger pupillary light reflex constriction as infants
• Magnitude of this response associated with symptom severity.

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ANS, ASD: AUTONOMIC HYPERAROUSAL

• ASD group had marginally elevated basal heart rate
• showed decreased heart rate reactivity to social anxiety
• increased RSA reactivity to the social cognition task.
• heart rate reactivity to the social anxiety task was positively correlated with IQ and task performance,
• negatively correlated with generalized anxiety.
• RSA reactivity in the social cognition task was positively correlated with IQ.
• Conclusions
• Our data suggest overall autonomic hyperarousal in ASD and selective atypical reactivity to social tasks.

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RETAINED PRIMITIVE FEAR REFLEXES REVIEW 2022

• Many aspects ASD related to interregional brain functional disconnectivity associated with maturational delays in development of brain networks.
• Delay in brain maturation in some networks may result in increase in cortical maturation and development in other networks
• Leading to developmental asynchrony, unevenness of functional skills and symptoms.
• Close relationship between RPFR and cognitive and motor function in general, ASD in particular
• Indicate that inhibition of RPFRs can effect positive change in ASD.

ANS, GUT-BRAIN AXIS

• Neuro-inflammation and neuro–immune abnormalities are observed within ASD-affected individuals.
• Hypothesis:
• Forms of dysbiosis encountered in ASD-affected individuals could also originate from ANS functioning abnormalities, a common neuro–anatomical alteration underlying ASD.
• Overactivation of sympathetic branch of ANS, (ASD-specific parasympathetic activity deficit)
• Deregulation of gut–brain axis, attenuating intestinal immune and osmotic homeostasis.
• Sets-up dysbiotic state, gives rise to immune and osmotic dysregulation, maintaining dysbiosis in a vicious cycle.

ASD, GUT, ZINC

• Gastrointestinal disorders in 80%,
• Most frequent symptoms; diarrhea, nausea, vomiting, abdominal pain and distension, and gastroesophageal reflux.
• Direct impact on Zn status: involved in mechanisms maintaining homeostasis of the gastrointestinal tract
• In severe Zn deficiency, fecal excretion decreases, intestinal absorption to maintain plasma and tissue levels consequently increases;

ANS, GUT MICROBIOME, ASD

• ANS is part of "gut brain axis"
• consists of an intricate interplay between the gut microbiome, mucosal immune system, enteric nervous system, ANS, and central processes receiving input from the vagus nerve.
• Measurements of gut microbiome and autonomic indices can serve as non-invasive markers of the status of the gut-brain axis in ASD

ORAL AND GUT DYSBIOSIS IN ASD

• Multiple co-occurring conditions, such as gastrointestinal abnormalities, dental/periodontal diseases, and allergies.
• pilot study, first degree-relative matched design combined with high fidelity 16S rRNA (ribosomal RNA) gene amplicon sequencing
• to characterize oral and gut microbiotas of patients with ASD compared to neurotypical individuals

ORAL DYSBIOSIS

• Our analysis detected differences between ASD and control subjects in both their gut and oral microbiomes
• Consistent with prior reports, ASD patients demonstrated a significantly higher gut Firmicutes/Bacteroidetes ratio 

THE WHITE FOOD DIET

• ‘ASD patients tend to have more unhealthy and restricted dietary habits.
• This is consistent with previous studies, showing that up to 79% of children with ASD suffer from feeding-related difficulties or nutritional challenges
• Strong preference for nutrient-poor foods.
• Given the correlation between severity of poor dietary habits and relative abundances of gut microbiome biomarkers, it is conceivable that the unhealthy dietary habits may be driving gut dysbiosis’.

GI FLORA, GUT SYMPTOMS 2011

• Gastrointestinal symptoms (assessed by 6-GSI) strongly correlated with the severity of autism (assessed by ATEC), (r = 0.59, p < 0.001)
• Children with ASD- much lower total SCFA (-27%, p = 0.00002), including lower levels of acetate, proprionate, and valerate;
• difference greater in children with ASD taking probiotics

probably partly due to either

• lower production (less saccharolytic fermentation by beneficial bacteria
• and/or lower intake of soluble fiber)
• and/or greater absorption into body (due to longer transit time
• and/or increased gut permeability).

GUT SYMPTOMS, DYSBIOSIS

• autistic samples displayed relatively low microbial richness and diversity
• Low polysaccharide fermenters – Prevotella -
• Normally, CHO-based diets shift intestinal microbiota towards the Prevotella-rich enterotype.
• Autistic children-significant deficiencies in dissacharide metabolism, eg a low level of lactase activity in upper GI tract.
• Unabsorbed mono- and disaccharides may enter large intestine, cause imbalance of gut environment, where mono- and disaccharides fermenters may outcompete polysaccharide degrading Bacteroidetes species, such as Prevotella

Autism

Retrospective, multi-center (NSW, VIC, & QLD), comparative study of the faecal microbial flora of Autistic Patients and control subjects in, 2004-2005

Butt H.L.¹ Emms T.M.¹, Cosford, R.², Duff, J.³, & Patterson D ⁴.

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Bio21, Molecular Science & Biotechnology Institute, & Bioscreen, University of Melbourne ¹;

Northern Beaches Medical Center, Mona Vale, NSW²; Behavioural Neurotherapy Clinic, Doncaster, VIC³;

Secrenase Medical Center, Runaway Bay, QLD⁴.

PANDAS and the Increased Colonization of Faecal Streptococcus in Patients with Autism

Northern Beaches Care Centre, Narrabeen, School of Biological Sciences, University of Newcastle. NSW, Australia¹.

 Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Parkville, Victoria, Australia².

Bioscreen, Bio21, Institute of Biotechnology and Molecular Science, The University of Melbourne, Parkville, Victoria, Australia³.

Cosford R¹ , McGregor NR² , Butt HL³

(Cosford, 2013 unpublished data)

Method

• Autistic patients (n=39) were compared with age and sex matched non-autistic patients (n=37)
• Investigation included:
• Faecal microbiology
• ASOT ( anti-streptolysin ‘O’ titers)
• Anti-DNase B (antideoxyribonuclease-B) titers
• Anion Gap (serum anion gap)

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(Cosford, 2013)

PANDAS and the Increased Colonization of Faecal Streptococcus in Patients with Autism

Northern Beaches Care Centre, Narrabeen, School of Biological Sciences, University of Newcastle. NSW, Australia¹.

 Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Parkville, Victoria, Australia².

Bioscreen, Bio21, Institute of Biotechnology and Molecular Science, The University of Melbourne, Parkville, Victoria, Australia³.

Cosford R¹ , McGregor NR² , Butt HL³

Cosford, 2013 ( Sydney) unpublished data)

PANDAS and the Increased Colonization of Faecal Streptococcus in Patients with Autism

Northern Beaches Care Centre, Narrabeen, School of Biological Sciences, University of Newcastle. NSW, Australia¹.

 Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Parkville, Victoria, Australia².

Bioscreen, Bio21, Institute of Biotechnology and Molecular Science, The University of Melbourne, Parkville, Victoria, Australia³.

Cosford R¹ , McGregor NR² , Butt HL³

Cosford, 2013 ( Sydney) unpublished data)

Streptococcus & anti-DNase B

• Anti-DNase B
• 27/39 patients tested for anti-DNase B

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• Anti-DNase B titers positively and significantly correlate with the levels of faecal Strepotococcus sp ( p < 0.004)
• Suggesting a direct relationship between faecal streptococcus and pathology

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Negative = < 170 units/mL Positive = > 170 units /mL

(Cosford, 2013)

GUT-BRAIN, B6

• Murine study:
• Key role for gut microbiota in regulation of autism-like social behavior
• By vitamin B₆, dopamine deficiency, loss regulation excitation/inhibition (E/I) balance in the medial prefrontal cortex 

B6, B9, B12: METHYLATION, TRANSSULPHURATION

• Urinary metabolic patterns 60 children with ASD and 60 corresponding controls (age group 3–8, M: F=42:18)
• lower B6, B9, B12 levels
• significant block of cystathione formation with consequent accumulation of homocysteine.
• lower glutathione levels (GSH) -reduction of essential intracellular reducing environment required for normal immune function, detox capacity and redox-sensitive enzyme function.
• Increased 5-MTHF- lower availability of methyl
• significant decrease in urinary methionine and S-adenosyl-L-methionine (SAM) concentrations, major methyl donor.
• Thus reduction in protein and DNA methylation reported in autistic children

IMMUNE:�CEREBRAL FOLATE DEFICIENCY

• autoantibodies against folate receptor (FRA)
• impacting brain pathology and behavioural phenotypes in children with ASD.
• FRAs to be prevalent in up to 70% of children with ASD, including blocking and binding FRAs
• FRA prevalent in pregnancy and in developmental disorders such as autism
• can block folate transport to fetus and ultimately to brain in young children, contributing to the core symptoms of autism

SLC19A1, FRAA

• 227 children with ASD, 156 of whom had CFD.
• FRAA binding in 39.2% of ASD patients, blocking FRAA in 3.5%, and a specific soluble folate receptor in 13.2%.
• The 80GA genotype most common (46.3%)
• homocysteine levels tended to be moderately elevated (upper quartile – 7.0).
• Significant correlations were found between homocysteine levels and vitamins B9, B12, and B6 (p < 0.05)
• between verbal impairments and vitamin B12 (p = 0.043).
• ASD and CFD patients, 80GG genotype was more frequent (p = 0.03) and vitamin B12 levels were elevated (p = 0.021).
• ASD group, correlations 80AA genotype and demyelination (p = 0.020), homocysteine levels and demyelination (p = 0.042).

ASD, MAGNESIUM,ZINC MINERALS

• 1,020 children with ASD and 1,038 healthy children 
• Plasma mass spectroscopy, iron, magnesium, zinc, copper
• Serum magnesium, copper, and zinc levels in children with ASD are significantly lower than in healthy children (both) P. < 0.05).
• Serum magnesium and zinc levels in children with severe ASD significantly lower than with mild-moderate ASD (both) P. < 0.05).
• Serum magnesium levels negatively correlated with total score autism behavior scale and communication ability score ( r =-0.318, 0.282, both P. < 0.001);
• Serum zinc levels negatively correlated with total autism behavioral scale scores, communication ability scores, and somatic movement scores  r =-0.221, -0.270, -0.207, all P. < 0.001).

ZINC IN ASD: REVIEW

• Significant differences in zinc concentrations between ASD and control groups in 23 studies
• 19 (36%) showed lower zinc concentrations in ASD group.
• lower concentrations of Zn in serum, hair, and whole blood for individuals with most serious forms ASD
• related to high concentrations of toxic metals: lead (Pb), barium (Ba), mercury (Hg), and lithium (Li)

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ZINC FUNCTION

• second most abundant mineral in human body
• participates in several metabolic processes
• catalytic functions and as enzymatic, structural, and regulatory cofactors.
• regulatory action in an inflammatory state
• in oxidative stress in concert with metalloproteins, in addition to the elimination of toxic metals together with metallothionein (MT)
• body zinc content in humans is effectively allocated in its largest part in the intracellular environment
• plasma zinc has been more recommended

ZINC IN BRAIN-�SHANK 3

• Zn fundamental role in nervous system, especially during neurodevelopmental phase.
• In this phase, involved in regulation of brain morphogenesis through Zinc Finger proteins (Zinc Finger) and in maturation of oligodendrocytes
• SHANK3 gene- genetic component related to ASD, responsible for expression of proteins that structure postsynaptic region of excitatory neurons.
• Low Zn concentrations reported to affect activity levels in postsynaptic region dependent on ProSAP1/Shank2 and ProSAP2/Shank3
• Zn supplementation can restore Shank3 levels in the postsynaptic region, modulate excitatory synapses, and consequently improve the ASD phenotype

NEUROINFLAMMATION:

• ESR, CRP, ferritin, α-2 globulins, and TNF-α: 51/55 patients at least one IM; most patients (21) had two IMs
• Increased inflammatory cytokines- IL-1β, IL-6, IL-8, TNF-α, (MCP)-1, (TGF)–β1,
• Increased GFAP, NFkB - neuroinflammation and glial M1 activation in CNS  
• Neuron-specific enolase (NSE) elevated in ASD kids tested in our study (40 of 41- 97.5%)
• RELIABLE MARKER BRAIN DAMAGE.

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NSE

• Cytosolic isoenzyme in glycolytic pathway,

critical step for ATP production and neuronal

metabolism 

• In neurons, neuroendocrine cells, neuronal cellular support system, including astrocytes, microglia, oligodendrocytes, and meningeal fibroblasts.  
• Also functions as regulatory protein involved in neuronal growth, cell differentiation, regeneration, repair, inflammation, apoptosis, and cell death. 

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NSE

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• Expression levels fluctuate in response to cellular energy demands
• Upregulated following axonal injury to maintain homeostasis.

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• Like hepatic transaminases:
• Under physiologic conditions, NSE confined intracellularly
• Neuronal injury, BBB disruption lead to release into CSF, serum
• Valuable biomarker for neuronal damage and various neurological diseases

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CLINICALLY

This Photo by Unknown Author is licensed under CC BY-SA

Phenotypical

• Macrocephaly ( Courchesne 2002)
• Prominent frontal lobes, flattened occiput
• Chronic mouth breathers, high arched palate
• Overbite, underdeveloped maxilla
• Marked pallor
• Circumscribed red cheeks
• Either obese very slender
• Hypotonia, ligamentous laxity ( cf ED)
• Retained PFR- Babinski, Moro, spinal galant etc

INVESTIGATIONS

• MBA: anion gap, bicarb, bilirubin ( phosphate)
• T cell subsets, Ig G, Ig A, Ig E
• Iron studies
• B12/folate
• Copper/zinc
• ASOT/ADB
• UOAT; methylation cycle
• Gut profile: Bioscreen, Gi map etc
• Dermal spectroscopy – tissue nutrients ; HMA; urine
• Genetics: SNPS
• Autoantibodies:
• QEEG

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INTERVENTIONS

CONCEPTUAL FRAMEWORK

• Clean environment
• Calm neuroinflammation
• Reduce oxidative stress
• Reduce gut and systemic acidity
• Support methylation/sulphation cycle
• Activate PNS
• Support TH1/TH2 balance
• ‘cover’ specific SNPS
• Correct abnormal gut bacterial patterns
• Mobilise/mop up toxins

LIFESTYLE

1. Air – outside, fresh air, ?filtration; breathing ( mouth breathing)
2. Light: day-night chronobiology- time outside in sunlight; limit/ no screen time/ EMF exposure
3. Water: drinking water; filtered water
4. Sleep: sleep routines, ?melatonin; EMF
5. Movement: exercise ( PNS, BDNF), RPFR exercises
6. Foods:
7. Nutrients;
8. Hub: PNS – stress, ( Sonrise programme), ‘safe’ environments

DIET

• GFCF ( Shattock, Riechelt): gluteomorphin, caseomorphin
• GAPS diet (Mc Bride)
• Paleo diet
• Ketogenic diet

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• Remove refined carbohydrates
• Remove food additives
• Introduce coloured foods

BOVINE MILK

• (Fresian): A1 casein: high proline, requires DPPIV endopeptidase – limited, immunogenic
• Streptococcal mastitis, antibiotics
• Bovine milk folate blocking proteins show epitope homology with human brain FR,
• ? Produce FRAA
• Milk free diets reducing titres blocking antibodies, restore CSF folate in cerebral folate deficiency

Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J.

Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med

(2005) 352:1985–1991.

Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune

disease. Clin Rev Allergy Immunol (2012) 42:102–111.

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FOLATE INTO THE BRAIN:

• 3 possible mechanisms.

1.pharmacologic doses of 5-formyltetrahydrofolate (folinic acid), converts in vivo to physiologically active 5MTHF,enters the cerebrospinal fluid by way of the RFC on choroid epithelial cells.

2.displacement of blocking AA to FR by high level of 5MTHF (approximately 2 μM or greater).

3.diffusion, when plasma level of 5MTHF is very high.

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Me-B12, �FOLINIC ACID

• Methylcobalamin: 75mcg/kg 2xweek
• Folinic acid ( leucovorin) 400 mcg/d

ZINC DYSREGULATION,�SUPPLEMENTATION

• certain studies report that Zn supplementation may improve neurocognitive outcomes in children with ASD
• others find limited or no benefit,
• underscoring the need for more rigorous, large-scale trials to clarify Zn’s therapeutic potential in ASD management 

‘PYRROLURIA’: MAUVE FACTOR�WOODY MCGINNIS 2008

• Mauve Factor" was once mistaken for kryptopyrrole but is the hydroxylactam of hemopyrrole, hydroxyhemopyrrolin-2-one (HPL).
• Treatment with nutrients--particularly vitamin B6 and zinc--reduces urinary excretion of HPL and improves diverse neurobehavioral symptoms in subjects with elevated urinary HPL
• 24-hour urinary HPL correlated negatively with vitamin B6 activity and zinc concentration in red cells (P < .0001)

HB METABOLISM

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• Pyrroles are critical intermediates in heme biosynthesis, with porphobilinogen (PBG) being a key pyrrole formed from δ-aminolevulinic acid (ALA) by ALA dehydratase.
• Normally, PBG is rapidly converted into porphyrins and heme, so does not accumulate or appear in significant amounts in urine
• ALA- PLP ( B6) dependant: formation tetrapyrrole HB from pyrroles
• B6 and zinc deficiencies impair heme synthesis and decrease pyrrole intermediates like PBG.
• There is no good evidence linking them to increased pyrrole production
• Excess pyrroles may correlate with (and purportedly cause) B6 and zinc deficiencies via binding/excretion, but this is not scientifically substantiated and remains debated

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PYRROLES, OXIDATIVE STRESS 2023

• p-N,N-dimethylaminobenzaldehyde (DMAB) with pyrrole moieties been well studied for use as marker of oxidative stress dysregulation ( mauve)
• Both pyrroles and urobilinogen condense the DMAB reaction system (form condensation products) and are quite different.
• Urobilinogen detected in urine forms when gut microflora chemically reduces the bilirubin content of bile acids.
• cf evidence suggests that pyrrole fraction originates from fragmentation of haem by reactive oxygen species (ROS) such as hydrogen peroxide and super and nitrous oxides

OXIDATIVE DAMAGE

SULPHUR, SELENOPROTEINS

• From animal studies it is well known that neurotoxic metals can partially cross BBB.
• This is also evident in human brain autopsies that monitor all the neurotoxins and toxins
• Neurotoxins can pass through placenta to foetus and its organs including its brain.
• Mercury pronounced affinity for sulphur , stronger for selenium
• Unlike most metals this is much stronger than that for oxygen.
• Mice- Se can attenuate levels of CH₃Hg⁺ in foetal brain if on an equal or larger atomic basis, reduce toxicity of CH₃Hg⁺ and Hg²⁺ 
• known to be necessary for DNA repair and during pregnancy
• Selenium appears to have general chelating properties in the body and brain due to its involvement in at least 25 selenoproteins and molecules such as selenocysteine that can provide oxidative stress protection
• Demonstrated ( animal studies) protective against Al, As, Pb, Hg Mn toxicity

VITAMIN A �(COD LIVER OIL), 2000

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• using cod liver oil
• Autism may be a disorder linked to the disruption of the G-alpha protein, affecting retinoid receptors in the brain.
• Natural vitamin A may reconnect the retinoid receptors critical for vision, sensory perception, language processing and attention

BASELINE

• Plant polyphenols, herbs
• Zinc, Magnesium, B6 ( PLP)
• Folate ( folinic), B12 ( methylcobalamin)
• Minerals – selenium, sulphur, broad spectrum
• EFA- cell membranes – cod liver oil ( A, D, W-3)
• Nrf-2 activation/antioxidants
• Probiotics ( D – lactate free)
• Sulphation support: NAC, glutathione, sulphur, molybdenum
• Gut treatment

THANKYOU!

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PROFESSOR ROBYN COSFORD

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