Evidence base for the Management of Sulphate Deficiency.
Sulphate is required for many physiological processes as well as the structure and function of macromolecules. Inadequate supply can inhibit efficient detoxification, increase susceptibility to xenobiotics and alter the metabolism of endogenous biocomponents. Sulphate availability may be affected by various genetic, environmental, dietary and lifestyle influences. Therapeutic strategies used to improve sulphate status therefore have broad implications over a wide range of health problems.
The methodological approach includes: surveying nutritional therapist and supplement companies: interviewing senior educationalists and sulphate researchers: and systematically reviewing primary research. The systematic review method is of a flexible, qualitative design, without meta-analysis, of the primary data relevant to the research question.
Protein foods and supplements may be beneficial for improving sulphate availability when there is a deficiency of sulphur amino acids, otherwise they may elevate homocysteine or cysteine:sulphate ratios. Sulphate compounds including Epsom salts and glucosamine sulphate may be beneficial for directly supplying sulphate while methyl donors, vitamins, minerals and antioxidants may help to support sulphate synthesis. Sulphotransferase function is just as important as sulphate availability so dietary and environmental sulphotransferase inhibitors should be avoided. An anti-inflammatory, nutrient dense, fibre-rich, organic diet should be promoted while exposure to drugs, toxins and chemicals should be avoided.
Further research is required to understand the functions of sulphate, the causes and consequences of deficiency and the effects of a range of nutritional supplements on sulphate availability. Recommendations made for improving sulphate availability should be part of a comprehensive, individually-tailored programme based on a comprehensive understanding of nutritional and biochemical requirements which have been identified though laboratory assessments.
This report aims to identify, evaluate and compare the effectiveness of dietary and nutritional strategies employed to improve sulphate status. Systematic and critical appraisal of the scientific data has been undertaken to help define best-practice solutions and provide clear working methods for the management of sulphate deficiency in nutritional therapy practice.
The sulphate ion is an oxidised form of sulphur metabolised from cysteine. It is required for proper cell growth and development as well as the structural conformation of almost all proteins, including: membranes, tissues, hormones, enzymes, antibodies and neurotransmitters, via disulphide links1-3 .
Sulphation is the transfer of a sulphate group from phosphoadenosine phosphosulphate (PAPS) to a substrate, catalysed by a family of sulphotransferase (ST) enzymes, it is used for:
o the biosynthesis of numerous structural components of membranes and tissues, such as glycosaminoglycans (GAGs), sulpholipids, glycoproteins and cerebroside sulphate 1, 4, 5
o controlling the balance of key pharmacologically active molecules including: dehydroepiandrostenone (DHEA), thyroid hormones, androgenic and oestrogenic steroids, cholecystokinin, gastrin, heparin, catecholamine neurotransmitters and endorphins 1, 6, 7
o biotransformation of endogenous and exogenous compounds, including amines, phenols, xenobiotics and hormones as part of Phase II detoxification reactions.
Sulphate deficiency is thought to disturb the bi-directional signalling system between the gut and brain, via neurotransmitter and endocrine imbalances, as well as gastrointestinal, immune and detoxification functions 7. Although it is beyond the scope of this research project to discuss the influence sulphate status has on health, impaired sulphation has been considered to be a factor in the aetiology of: myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), hyperactivity migraine and depression 8, 9. Inflammatory conditions such as rheumatoid arthritis, food sensitivity, multiple chemical sensitivity (MCS) and autism may also be related to poor sulphation 10, 11. Some of these disorders, including ME, CFS, IBS and MCS, are regarded as having overlapping symptomology which suggests a common aetiology. Elevated plasma cysteine to sulphate ratios have also been found in patients with motor neuron disease, Parkinson’s disease, systemic lupus erythematosus (SLE), and Alzheimer’s disease, when compared to controls without neurodegenerative disorders 12, 13.
Sulphate concentration appears to be a balance between absorption of inorganic sulphate, or its production from cysteine, and sulphate elimination by urinary excretion or its incorporation into substrates of sulphation 10. The causes of sulphate deficiency, which have also not been well defined in the literature, may include:
o Deficiency of sulphur amino acids (SAAs) 14.
o Inability to synthesise and regulate the amino acid cysteine 10.
o Impaired ability to convert cysteine to sulphite 11, using cysteine dioxygenase and requiring iron, NAD(P)H and vitamin B6.
o Impaired ability to convert sulphite to sulphate using sulphite oxidase 10, a molybdenum- and vitamin B2-dependent enzyme 11.
o Increased requirement for sulphate 15.
o Excessive “dumping” of sulphate 3.
Identification and correction of the problem is ideal. The identification of sulphate deficiency – through laboratory tests such as urinary sulphate, organic acid markers, detoxification assessment by acetaminophen conversion, plasma sulphate analysis and amino acid analysis 14 – are an important part of nutritional therapy practice.
There may also be different nutritional approaches from those with an inborn error of metabolism to those who have acquired sulphate imbalances. Although this project focuses on the nutritional therapy strategies which may be used to improve sulphate status, ultimately, the development of a nutritional strategy should be unique to the individual. Health care protocols may be used to guide treatment decisions but professionals are still required to consider the implications in the management of each individual patient, who is likely to have a complex and unique mix of dietary, lifestyle, health, environmental and genetic considerations.
The review method undertaken was based on a systematic review 16,17, without meta-analysis, of the primary data relevant to the research question. A survey of nutritional therapist and supplement companies, as well as interviews with senior educationalists and researchers in this area, have also been undertaken to: promote triangulation of methods, guide the search for primary data, ensure a thorough review and to gain information on current knowledge, practice and nutritional strategies.
See appendix 1 for further information regarding methodology and results.
It has been estimated that approximately 80-90% of sulphate in vivo is formed via oxidation of cysteine 3, 9. Short-term restriction of dietary protein results in lower urinary excretion of sulphate but may not reduce plasma amino acid concentrations, due to a sparing mechanism 18-20. However, the catabolism of methionine to sulphate may be considerably inhibited by protein calorie malnutrition, fasting and low-protein diets due to the decreased availability of SAAs 14,18.
Increased dietary sulphur amino acid (SAA) intake and protein supplementation are indicated for those at risk of SAA deficiency 21. The World Health Organisation (WHO) committee has established a tentative requirement for all SAA’s (mainly methionine) of 13mg/kg per day 22. However, the RDA may underestimate the body’s need for these nutrients, particularly in periods of increased synthesis and in those using acetaminophen 18, 21. 25mg/kg/day of SAA for adults has been recommended 21.
Ratios of methionine to cysteine tend to be higher in animal proteins than plant sources 21. Glutathione is also a source of dietary sulphate and fruits and vegetables contribute to over 50% of dietary glutathione 21.
Glucosamine sulphate, made up of glucose, glutamine and sulphur, is widely used to treat symptoms of osteoarthritis 21, 23. It was identified by the response to the supplement company survey as the ‘best seller’ amongst sulphate supplements that is purchased by the elderly and sports people. Its mechanism of action and benefits may be due to the sulphate group, which is required for glucosaminoglycan (GAG) synthesis rather than glucosamine, which is a substrate for GAGs 21, 23.
Various amino acid supplements are available, either as individual amino acids, or in a number of combinations. N-acetylcysteine (NAC) may be the preferred delivery system for cysteine because it is considered to be more stable and may be better absorbed 21 but more research is required before it can be indicated for sulphate deficiency. Glutathione, taurine, N-acetyl-methionine and inorganic sulphate can all have amino acid bioactivity by sparing the need for dietary methionine or cysteine 21. Without adequate taurine, aldehydes are produced which increase the requirement for the molybdeno-enzyme aldehyde oxidase 24. Methionine loading may increase homocysteine levels 25, 26 and should be avoided if there is a risk of homocysteinuria. Amino acid loading should also be avoided if sulphite oxidase is inhibited as this may lead to a build-up of sulphite.
An amino acid supplementation programme should carefully consider and meet the needs of the individual. Evidence to support their use is minimal and supplementation should only be recommended for short periods of time. Identifying amino acid requirements through screening prior to supplementation is preferential.
MSM is an important volatile component in the sulphur cycle 21 and has been given orally in an attempt to elevate blood sulphate levels 27. Subjects who showed hypersensivity to aspirin, oral antibiotics and other non-steroid anti-inflammatory drugs (NSAID) became drug-tolerant when MSM was given within an hour of ingesting the sensitising drug 21. It is one of the least toxic substances in biology but little is known about the pharmokinetics of MSM in humans 21. Although efficacy has not been demonstrated in terms of appropriate clinical trials, the body of anecdotal evidence is considered to be impressive 27. MSM is also found in certain foods.
Organosulphur compounds, such as isothiocyanates, diallyl sulphide allicin and allicin, are found in garlic, onions and other vegetables 21. These foods should therefore be promoted where appropriate.
Magnesium sulphate (Epsom salts) can be supplemented when sulphite oxidase is deficient 24. Although only 5-25% of inorganic sulphate is absorbed across the gastrointestinal tract 3, 9 it may be absorbed through skin via Epsom salts baths or trans-dermal patches containing crystals of magnesium sulphate 27. Sulphur-containing baths have had a long history of use for the treatment of psoriasis, rheumatic pain, infections and asthma 21. Sulphate levels have been shown to increase after taking baths at a level of 1% Epsom salts 27. Bathing in Epsom salts is considered to be a safe and easy way to increase sulphate levels 27.
A non-randomised trial of 7 healthy men 23 demonstrated that oral glucosamine sulphate also increases serum inorganic sulphate concentrations. As highlighted, it is widely used to treat symptoms of osteoarthritis and its benefits may come from its sulphate group as opposed to glutamine 21, 23.
The same study demonstrated that 1g of sodium sulphate fails to increase serum sulphate concentrations 23. However, in another study of 8 healthy persons 28, 9g of sodium sulphate ingestion did increase serum sulphate concentrations. Differences may be due to dose although large doses of sodium sulphate are an osmotic laxative and small amounts are considered to be well absorbed 23. Further investigation is therefore required.
Chondroitin sulphate is a GAG and is used to treat the symptoms of osteoarthritis. It is believed to promote water retention and elasticity in cartilage and inhibit enzymes that break down cartilage 21 but there appear to be no studies to determine if it affects sulphate availability. Chondroitin sulphate also needs to be degraded by intestinal flora for absorption 18.
Some dietary supplements containing sulphate may therefore be helpful in overcoming sulphate deficiency. However, further research and specific information about the relative bioavailabilities of the different sulphate supplements appears to be lacking and should be investigated.
Supplementing 6gm of ascorbic acid had no apparent effect on serum concentration, urinary excretion and renal clearance of inorganic sulphate, probably because only a small fraction of it is converted to a sulphate conjugate 28.
Cysteine does, however, works synergistically in the body with vitamin C and other antioxidants including selenium, beta-carotene and lipoic acid 22.
The methionine cycle requires methyl donors. Defects in methylation or a deficiency of the cofactors, including vitamin B6, vitamin B12, folic acid, choline and betaine, will impact the transulphuration pathway and the availability of sulphate. One interviewee also highlighted the need to support the energy cycle which supplies material for the methyl cycle.
Cysteine and MSM are methyl donors as well as sulphur donors 10 Methionine is converted to s-adenosylmethionine (SAM) and used by many biochemical pathways as a methyl donor 10. SAM has been proposed as an alternative to N-acetylcysteine in patients after acetaminophen overdose 21 as it prevents glutathione deficiency and mitochondrial dysfunction 29. SAM is a prescription only medication (POM) in the UK and is therefore not a practical option for most nutritional therapists.
Trimethylgycine (betaine) and dimethylglycine are involved in cysteine metabolism 27 but there do not appear to be any studies which have assed their affect on sulphate status.
Dimethyl sulphoxide (DMSO) can scavenge free radicals which are a primary trigger in the inflammatory process. When it enters the body, 15% is converted to MSM 21 which is why it is considered to impact sulphate availability: it does, however, require significantly more research regarding its efficacy.
Organic sulphur compounds are metabolised by the molybdenum-dependent mitochondrial enzyme sulphite oxidase 21. Molybdenum supplementation may therefore help to improve sulphate availability 3. In a study of autistic children, molybdenum supplementation benefited 36% (14/38) of those tested 3. Inborn errors of sulphite oxidase or inhibition of the enzyme by endogenous metabolites may also contribute to sulphate deficiency 3. Diets with low levels of molybdenum in conjunction with a high protein diet may also cause sulphite to accumulate and make it difficult for sulphation to occur 10. Molybdenum supplementation may only provide benefits at low concentrations as toxicity may occur at high concentrations. Molybdate, a molybdenum salt, inhibits sulphate intestinal absorption, renal re-absorption and sulphate incorporation into PAPS at high levels 5. Sulphate and molybdate follow similar metabolic pathways and further research is required to understand the complex metabolic inter-relationship between molybdenum, sulphate, copper, iron, selenium and other minerals.
Research also needs to be conducted regarding the effects of zinc sulphate and ferrous sulphate on sulphate availability. NAC supplementation may increase the requirement for zinc 30. Iron is required for cysteine dioxygenase and magnesium is required for ATP-sulphurylase. The trace mineral boron can bind to vitamin B2, thus making it unavailable for sulphite oxidase 11, and copper antagonises molybdenum and may increase the need for it 24. Excessive copper also impairs SAA utilisation and may increase dietary requirements for SAA 21. Copper levels should therefore be assessed.
SAAs need adequate amounts of pyridoxine (vitamin B6), cyancobalamin (vitamin B12) and folic acid in order to be properly metabolised 22. Supplementation with high doses of B6 and folic acid help to support the methinone cycle and reduce plasma concentrations of homocysteine 25, 26. Glutathione recycling and sulphite oxidase also require vitamin B2 11.
Shattock & Whiteley (27) suggest a balanced multivitamin and mineral supplement to ensure adequate intake levels of vitamins and minerals for those initiating a restrictive diet.
Both SAAs and inorganic sulphur contribute to the common blood sulphate pool 31 but it has been estimated that only 20% of the required supply comes from inorganic sulphate 3. A threshold for absorption of dietary sulphate is ≈0.22g S/d, above which significant amounts spill over into the colonic sulphate pool 31. Dietary sulphate intake above this may need to be avoided as it will mostly be converted to sulphide 31, which is considered to be toxic. A high fibre diet may help to protect the colonic mucosa from hydrogen sulphide 32. Sulphide may be absorbed and converted back to sulphate 31 but the mechanisms for this are not clear and further research is required to fully understand the biology of sulphur in the gastrointestinal tract.
High sulphate foods include some breads, soya flour, dried fruits, brassicas and some sausages, although there is considerable variations of concentrations within the food types 32. Other than in the brassicas, high sulphate levels are due to preservation by sulphuring which correlates with the presence of sulphite 32 which is known to be toxic to the nervous system 21. Beers, ciders and wines were also high in sulphate 32, but alcohol should be avoided as it is partly detoxified by aldehyde oxidase, which uses molybdenum and vitamin B2 11.
In an in vitro control study 33 beetroot, grapefruit, orange, radish and spinach were found to be moderately good inhibitors of dopamine sulphate and pumpkin was found to be a moderately good inhibitor of p-nitrophenol sulphation. They should therefore be restricted, while carrots and royal gala apples, which showed signs of increasing dopamine sulphation, should be promoted. Orange juice, and to a lesser extend grapefruit juice, inhibit phenolsulphotransferases 33 and should also be restricted.
Although casein- and gluten-free diets were identified in the results several times, there appears to be no evidence that their removal directly affects sulphate status. Removing gluten and casein may be beneficial for certain individuals, such as autistic patients, because of their effects on the central nervous system via ‘opiod’ activity 3, 27.
Some foods, like red meats, oily fishes and yeast contain large amounts of purines which should be avoided as they require processing with xanthine dehydrogenase, a molybdenum and vitamin B2 dependent enzyme 11, 24.
Dietary compounds, such as flavonoids, amines and phenols, may affect sulphate availability by either inhibiting the sulphotransferase enzyme directly 10, 33 or by competing for sulphation with promutagens or toxins and exhausting supplies of PAPS 33. Phenol sulphotransferases break down and remove phenols and amines, such as: dopamine, serotonin, tyramine, phenylethylamine, histamine, salicylates, xenobiotics, artificial food colourings, artificial flavourings and some preservatives 34. These may be ingested, produced by the body or produced by microbes and yeasts in the intestines 34. Individuals with reduced sulphotransferase activity are less able to form inactive metabolities of endogenous and exogenous amines (3, 27). Dietary sources of these compounds should therefore be restricted in sulphate deficient individuals 33.
Salicylates are also found in some foods and medications (such as aspirin), as well as perfumes, cosmetics, creams, toothpastes, shampoos, conditioners and cleaning products. Research has found that salicylates suppress the activity of any phenolsulphotransferase enzyme by up to 50% 34. Sulphotransferase function is just as important as sulphate availability for sulphate conjugation, sulphotransferase inhibitors should therefore be avoided.
Sulphiting agents are widely used in the food industry as preservatives. High sulphite levels in the diet are associated with an increase in asthma and allergic reactions in certain individuals 3. The molybdenum-dependent enzyme sulphite oxidase detoxifies sulphite food additives 21. A deficiency in sulphite oxidase or molybdenum may make an individual more sensitive to sulphur containing drugs and compounds 21. Some common food additives are also potent inhibitors of sulphotransferases 35. If sulphotransferase enzymes are inhibited by some additives and sulphite is being provided by other additives, this may cause a significant build up of sulphite, which is known to be toxic.
Chemicals produced from the plastics and detergents industries, such as alkylphenols and bisphenol have oestogenic activity 36. The endocrine-disrupting effects of some plasticisers may be a consequence of modulation of expression of sulphotransferase enzymes which may negatively affect the sulphate supply pathway 36. Much is unknown about the effects of environmental toxic exposure and research is needed to assess the effects of low-dose and multiple exposures. However, due to the number of environmental variables and the complex non-linear system of the body it may be technically impossible to determine the effects of toxin exposure on health.
Gastrin and cholecystokinin (CCK) are more active when sulphated 3. Gastrin is required for the release of secretin and together with CCK they promote the release of digestive enzymes from the pancreas 3. A consequence of sulphate deficiency may therefore be reduced hydrolysis of dietary proteins 3. Protein fermentation may also contribute to formation of sulphide 21. Addition of bromelain or other digestive enzyme supplements may therefore help to support the break down of peptides in the gut 3, 27 and improve availability of SAAs.
Flavonoids, present in red wine and citrus fruit, have been shown to be potent inhibitors of phenolsulphotransferases 3, 33, 37. Phytoestrogens can also inhibit the sulphotransferases that sulphate both oestrogenic steroids and a variety of environmental chemicals, including dietary pro-carcinogens 37. Although there are many health benefits from phytonutrients, excessive intake should be avoided. Strategies for improving sulphate status should also consider reducing exposure to xenooestrogens.
Many exogenous and endogenous compounds, such as amines, phenols, xenobiotics and drugs, are substrates for sulphotransferase enzymes. Liver support supplements were identified by nutritional therapists as helpful, although no research evidence was identified. Milk thistle may be an antioxidant which could help to reduce inflammation and protect the liver from hepatoxins and disease 38, 40 but there do not appear to be any studies which have assessed its influence in sulphate availability or sulphation.
Essential Fatty Acids (EFAs)
EFAs may not have a direct effect on sulphate status: however, ensuring a correct balance may help to reduce inflammation and the production of inflammatory cytokines which inhibit the expression of cysteine dioxygenase 41. Fish oil supplements rather than a diet high in oily fish may help to avoid high levels of dietary purine 11. Ideally, testing for essential fatty acid imbalances should precede supplementation recommendations.
Dietary sulphate can be potentially reduced to sulphide by sulphate-reducing bacteria in the large bowel 31, 32. There is concern that sulphide is toxic to the colonic epithelium 21, 31, 32 and patients with ulcerative colitis may carry more sulphate-reducing bacteria compared to healthy individuals 21. Probiotic bacteria may help to reduce colonic inflammation by enhancing natural and acquired immunity 42. Probiotics should certainly be given when supplementing chondroitin sulphate because it needs to be degraded by intestinal flora for absorption 18. Further research is needed to identify the influence of gut flora on the availability of sulphate from dietary and supplementary sources.
There may be other supplements on the market which were not identified by the research methods of this project. For example, ‘Phenol Assist’™ by Kirkman Laboratories contains a variety of enzymes aiming to assist digestion and helps to reduce phenolic load. There are continuously new nutritional products available and this highlights the need for keeping up-to-date with the products from supplement companies in nutritional therapy practice.
The extracellular sulphate pool in humans is one of the smallest among animal species and is readily depleted by low protein diets or drugs metabolised by sulphation 21, 28. Information concerning the effect of drugs on endogenous inorganic sulphate levels in man is very limited 28. Excessive exposure to foreign chemicals can deplete sulphate stores and lead to chronic illness 14.
Acetaminophen (Paracetamol) is known to reduce serum sulphate levels 23, 28. 40% of this medication is excreted in the urine conjugated with 18. It may be that concomitant use of sulphate supplementation during acetaminophen use may prevent sulphate depletion 28. However, it may also increase the metabolic clearance of the drug, potentially reducing its analgesic potency 21, 23.
Inflammatory conditions and neurological disorders have been linked to high cysteine: sulphate ratios 41. The cytokines tumour necrosis factor–α (TNF-α) and transforming growth factor-β (TGF-β) have been shown to inhibit the expression of cysteine dioxygenase and may therefore modulate sulphate production 41. An anti-inflammatory diet high in fruit and vegetables should therefore be promoted.
The identification of sulphate deficiency and, ideally, the cause of deficiency through laboratory assessments is essential. The needs of an individual with impaired sulphite oxidase activity will be different to the needs of an individual with protein malnutrition. Genetic screening may be considered as individuals with lack of sulphate due to poor gene expression would require longer-term therapeutic strategies. Although it has been important to look at the efficacy of dietary and nutritional strategies used to manage sulphate deficiency, ultimately, the development of a nutritional strategy should be unique to the individual.
Strategies for unknown causes of sulphate deficiency should provide support by working backwards along the sulphate pathway to avoid sulphite, cysteine or homocysteine build-up. Once sulphate deficiency has been identified, the following dietary and nutritional practices may be applied:
Avoid paracetamol and other medications containing acetaminophen.
Promote a nutrient-dense, anti-inflammatory and fibre-rich, organic diet of vegetables and whole grains with moderate intakes of fruit and essential fatty acids. Include only a moderate increase of brassica vegetables such as cabbage, broccoli, sprouts and organosulphur compounds such as garlic and onions as a threshold for absorption of dietary sulphate is ≈0.22g S/d 31. Include MSM foods such as fruit, alfalfa, corn, tomatoes and milk 21. Increase intake of molybdenum-containing foods including: buckwheat, wheat germ, barley oats, lima beans, canned beans, lentils, green beans, liver and sunflower seeds 43.
Remove phenolic foods including: apple juice, citrus fruits and chocolate 27 and avoid food colourants as they possess phenolic groupings 27. It may also be worth avoiding exposure to non-food sources of phenols such as fertilisers, paints, rubber (latex), textiles, adhesives, drugs, paper, soap and wood preservatives. Reduce intake of beetroot, grapefruit, orange, radish, spinach and pumpkin 33. Avoid orange juice, and to a lesser extent grapefruit juice 3, 33. Reduce amine foods such as red wine, coffee, certain cheeses and chocolate 10 and avoid serotonin foods, including bananas 3. Avoid alcohol and avoid high intakes of flavonoids present in red wine and citrus fruits 33, 37.
It is important to maintain a balanced diet, variety, flavour and interest when restricting a number of foods. There has been much debate about the efficacy of programs such as the Feingold diet as restriction of numerous foods has many limitations. There appears to be sufficient evidence to support the avoidance of processed foods containing additives, colouring, flavourings and preservatives, while short-term restriction, limiting intake or food rotation may be considered for other foods.
Avoid high intakes of SAAs as these may elevate homocysteine, or cysteine to sulphate ratios, which may increase risk of inflammatory and neurodegenerative disorders 12, 13, 41.
Epsom salts baths containing 500-600g of magnesium sulphate for a minimum of 12 minutes, 2-3 times per week should be recommended 27.
Test for nutrient status, including molybdenum deficiency and copper overload. Use the results to guide appropriate multivitamin and mineral supplementation. Supplementation should avoid bioflavonoids and high levels of copper. Ensure adequate B vitamins, magnesium, vitamin C and iron.
Molybdenum has low toxicity and supplementation of up to 300mcg per day for at least 4 months should be recommended 43 to support the function of sulphite oxidase. The dosage may be decreased to 100mcg or 200mcg/day after 2 months and stopped completely after 4 months if the patient is asymptomatic 43 to avoid copper toxicity.
Decrease intake of caffeine and high purine foods including: red meats, oily fish, yeast: as well as boron-containing foods including: tomatoes, peppers, apples, pears, peaches, plums, grapes, soya, parsnips, rosehips, hazelnuts, peanuts, and almonds as they may decrease the availability of vitamin B2 and molybdenum and therefore synthesis of sulphate 11.
Avoid supplements containing boron as it can bind to vitamin B2 11 and decrease its availability.
Avoid food additives and preservatives including sulphur dioxide (E220) sulphite or disulphite (E221-E227) 32. Avoid chemicals, plasticisers, pesticides and exposure to foreign chemicals.
Avoid dried fruits and vegetables, bread, English-style sausages, jams, pectin, soya flours, wines and cider as the high concentration of sulphate in these foods is correlated with the presence of sulphite residues 32.
Although MSM was mentioned across all data collection methods, little is known about the pharmokinetics in humans 21 and appropriate clinical trials need to be conducted before supplementation can become a standard or guideline recommendation.
Reduce dietary phytoestogens. Soy is by far the richest source, but they are also found in forage crops, chick peas and other legumes 37. Avoid exposure to xenooestrogens and oestrogenic drugs such as the oral contraceptive pill.
Avoid over-cooked meats as sulphotransferases are required to catalyse the bio-activation of heterocyclic amine pro-carcinogens which are found in overcooked meats 37.
Test for essential fatty acid requirements and supplement appropriately.
Increase intake of probiotic and prebiotic foods such as yoghurt, sauerkraut, artichokes and oats to promote healthy intestinal flora. Supplementing probiotics to promote a healthy gut flora and reduce inflammation may also be considered.
Impaired ability to synthesise and regulate the amino acid cysteine
If an impaired ability to synthesise and regulate the amino acid cysteine has been identified then the above standard practice recommendations still need to be recommended to promote sulphate availability and prevent sulphate loss.
Additionally, B vitamin foods and dietary cysteine from: eggs, meat, dairy produce, grains, oats, corn and beans 21, 22 should be increased and methyl donors, B vitamins and antioxidants may need to be supplemented to support cysteine synthesis and prevent homocysteine build-up.
Deficiency of sulphur amino acids
If a lack of sulphate is due to SAA deficiency then the above standard practice recommendations should also be recommended to promote sulphate availability and prevent sulphate loss. Also ensure dietary protein intake of 25mg/kg/day of SAA for adults 21. Increase dietary intake of methionine by including: eggs, fish, milk, meat, corn, sunflower seeds, oats, cashews, walnuts, almonds and sesame seeds 21, 22. Nuts, coconut milk and avocado may also provide a protein-sparing effect 32.
Add bromelain from pineapple and recommend supplementation with digestive enzymes to support the breakdown of peptides in the gut 3, 27.
Testing amino acid requirements is recommended to be able to supplement them appropriately. Methionine is available as L-methionine and DL-methionine 22. Doses for L and DL-methionine range from 1 to 3 g depending on the condition being treated. Dosages for N-acetyl cysteine (NAC) may vary from 2g-7g daily depending on the condition being treated but cysteine and NAC supplementation are contra-indicated if candidiasis co-exists 44. The maximum safe levels for cysteine supplementation have not been established but doses greater than 7g may be harmful 22 and it should be taken with vitamin C to prevent cysteine from being converted to cystine which may form kidney stones 22 Long-term supplementation with high doses of any single amino acid should however be avoided 22 and further research is required to fully understand their effects on human health.
Stage Practice Action Comment
Sulphate deficiency due to: impaired ability to convert cysteine to sulphite, impaired ability to convert sulphite to sulphate, or other, unknown reasons.
1 Standard Test for sulphate deficiency. If a deficiency has been identified move to stage 2. Tests include:
urinary sulphate, organic acid markers, detoxification assessment by acetaminophen conversion, plasma sulphate analysis or amino acid analysis.
2 Standard Avoid paracetamol Any medication containing acetaminophen
3 Standard Dietary adjustment Promote anti-inflammatory, fibre rich diet of organic foods
Increase: MSM foods, organosulphur compounds, molybdenum foods.
include only a moderate increase of brassica vegetables
Reduce: amines, phenols, flavonoids, ST inhibitors, alcohol, food colourings
Avoid: high intakes of protein and sulphur amino acids
4 Standard Epsom salts baths 500-600g per bath for a minimum of 12 minutes, 2-3 times per week (Waring 2004).
5 Standard Test for nutrient deficiencies and copper toxicity.
6 Standard Use appropriate multivitamin and mineral supplement Avoid bioflavonoids and high levels of copper. Ensure adequate molybdenum, B2, B6, B12, magnesium, folic acid, vitamin C and iron
7 Standard Molybdenum supplementation Up to 300mcg per day for a minimum of 4 months.
Guideline Dietary adjustment Decrease caffeine, high purine foods, high boron foods
Avoid: food additives, preservatives, chemicals, plasticisers, pesticides and exposure to foreign chemicals
Avoid: dried fruits and vegetables, English style sausages, jams, pectin, soya flours, wines and cider
Guideline Supplementation Avoid boron containing supplements
Option Dietary adjustment Reduce: salicylate compounds, dietary phytooestogens, over-cooked meats.
Increase: pre and probiotics
Option Test for essential fatty acid requirements Supplement essential fatty acids appropriately
Option Supplementation Methyl sulphonyl methane (MSM)
Essential fatty acids
Contraindicated Increasing protein intake and amino acid supplementation This may elevate homocysteine or cysteine: sulphate ratio’s which have been noted as risk factors for inflammatory and neurodegenerative disordersPractice Action Comment
Sulphate deficiency due to homocysteineurea – the impaired ability to synthesise and regulate the amino acid cysteine
Stages 1-6 above To promote sulphate availability and prevent loss
Standard Dietary adjustment Increase: B vitamin and cysteine foods
Standard Supplementation B Vitamins
Stage Practice Action Comment
Sulphate deficiency due to deficiency of sulphur amino acids, increased sulphate requirement or sulphate dumping
Stages 1-6 above To promote sulphate availability and prevent loss
Standard Dietary adjustment Increase protein, sulphur amino acid intake and bromelaine
Guideline Test for amino acid requirements
Guideline Supplementation Supplement amino acids appropriately
Further research regarding the causes and consequences of sulphate deficiency are required to develop knowledge and interest in this important area. Without this we may never develop a proper understanding of how to recognise and correct sulphate deficiency appropriately in clinical practice.
There is also a significant lack of research regarding the dietary and nutritional influences on sulphate status. Supplementing: amino acids, methyl donors, antioxidants, fatty acids, digestive enzymes, bioflavonoids, probiotics and liver support such as milk thistle and their effects on sulphate availability needs to be researched. The bioavailabilties of sulphate supplements and their effects on sulphate availability should also be compared.
Unique genetics, individual biochemistry and varying nutritional influences will affect individual nutrient, dietary and supplementation requirements. Evidence-based medicine is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients” 45. Improving sulphate status should focus on preventing sulphate loss as well as increasing sulphate availability. There is sufficient rationale and preliminary evidence to demonstrate the potential benefits of balancing nutrient status, improving sulphate supply and easing the requirement for sulphate.
Sulphate deficiency is likely to be part of a complex metabolic disorder that requires a comprehensive and integrated nutritional strategy which will include the above recommendations as part of an individually tailored programme. Without the results of screening the most clinically effective strategy for overcoming sulphate deficiency may not be determined. Ideally nutrition therapy should focus on evaluating unique genetic susceptibility, individual biochemistry and environmental influences, then understanding function and then implementing an individual strategy to improve health outcomes.
1 Markovich, D., (2001). Physiological Roles and Regulation of Mammalian Sulphate Transporters. Physiological Reviews. 81:1499-1533
2 Percy, A. K., & Yaffe, S. J., (1964). Sulfate metabolism during mammalian development. American Academy of Pediatrics. 33(6);965-974
3 Waring, R. H., Klovrza, L. V., (2000). Sulphur Metabolism in Autism. Journal of Nutritional & Environmental Medicine. 10:25-3
4 Sagawa, K., DuBois, D., Almon, R. R., Murer, H., Morris, M. E., (1998). Cellular Mechanisms of Renal adaptation of Sodium dependent sulphate cotransport to altered dietary sulphate in rats. Pharmacology. 287(3);1056-1062.
5 Klaassen, C. D., & Boles, J. W., (1997). The importance of 3’phosphoadenosine 5’-phosphosulfate (PAPS) in the regulation of sulfation. The FASEB Journal. 11;404-415
6 Pangborne, J., (2000). How does Sulfation work? Nutrition and metabolic newsletter retrieved on 14/6/05 from: http://www.gsdl.com/home/news/nmnewsletter/issue2-2/index.html
7 Hooper, M., (2003). Engaging with multiple chemical sensitivities. Retrieved on 4th November 2006 from http://osiris.sunderland.ac.uk/autoism/hooper2000a.htm
8 Moss, M., Waring, R. H., (2003). The Plasma Cysteine/Sulphate ratio: A possible Clinical Biomarker. Journal of Nutritional and Environmental Medicine. 13(4):215-229.
9 Waring, R., (2001). Autism and ADHD: could diet affect the symptoms? The nutrition practitioner. 3.3;8-10.
10 Bland, J. S., Costarella, L., Levin, B., Liska, D, Lukaczer, D., Schiltz, B., Schmidt, M. A., (1999). Clinical Nutrition: A functional Approach. Washington: Institute for Functional Medicine.
11 Moss, M. A., (2001). Purines, alcohol and boron in the diets of people with chronic digestive problems. Journal of nutritional & Environmental medicine. 11:23-32.
12 McFadden, S., A., (1996). Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulphur-dependent detoxification pathways. Toxicology. 111;43-65.
13 Heafield, M. T., Fearn, S., Steventon, G. B., Waring, R. H., Williams, A. C., Sturman, S.G., (1990). Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson’s and Alzheimer’s disease. Neurosci lett. 2;110:216-20.
14 Bralley, J. A., Lord, R. S., (2001). Laboratory evaluations in molecular medicine. Norcross: The institute for advances in molecular medicine.
15 O’Reilly, B. A., Waring, R. H., (1993). Enzyme and sulphur oxidation deficiencies in autistic children with known food/chemical intolerances. Journal of Orthomolecular Medicine. 8;198-200.
16 Khan, K. S., Glanville, J., Kleijnen, J., (2001). Undertaking Systematic reviews of Research Effectiveness: CRD’s guidelines for those carrying out or commissioning reviews. Retrieved on 4th October 2006 from: http://www.york.ac.uk/inst/crd/report4.htm
17 NHS CRD (1996). Undertaking systematic Review of Research Effectiveness. CRD Guidelines for those carrying out or commissioning reviews. CRD report 4. The University of York.
18 Cordoba, F., Nimni, M. E., (2003). Chondroitin sulfate and other sulfate containing chondroprotective agents may exhibit their effects by overcoming a deficiency of sulfur amino acids. Osteoarthritis and Cartilage. 11(3): 228-230
19 Jourdan, M., Glock, C., Margen, S., Bradfield, R. B., (1980). Sulphate, acid-base, and mineral balances of obese women during weight loss. Am. J. Clinical Nutrition. 33: 236 – 243.
20 Lakshmanan, F.L., Perera, W. D., Scrimshaw, N. S., Young, V. R., (1976). Plasma and urinary amino acids and selected sulfur metabolites in young men fed a diet devoid of methionine and cystine. Am. J. Clinical Nutrition. 29: 1367 – 1371.
21 Parcell, S. W., (2002). Sulfur in human nutrition and applications in medicine – Review: sulfur. Alternative Medicine Review. 7(1).
22 Braverman, E. R.,(2003). The Healing Nutrients within. North Bergen: Basic Health Publications.
23 Hoffer, L. J., Kaplna, L. N., Mazen, J. H., Grigoriu, A. C., Baron, m., (2001). Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metababolism. 50:767-70
24 Moss, M. A., (1995). Effects of molybdenum on pain and general health: a pilot study. Journal of nutritional and environmental medicine. 5: 55-61.
25 Suliman, M. E., Divino Filho, J. C., Barany, P., Anderstam, B., Lindholm, B., Bergstrom, J., (1999). Effects of high-dose folic acid and pyrodoxine on plasma and erythrocyte sulfur amino acids in hemodialysis patients. J Am Soc Nephrol. 10:1287-1296.
26 Suliman ME, Filho JC, Barany P, Anderstam B, Lindholm B, Bergstrom J. (2001). Effects of methionine loading on plasma and erythrocyte sulphur amino acids and sulph-hydryls before and after co-factor supplementation in haemodialysis patients. Nephrol Dial Transplant. 16(1):102-10.
27 Shattock, P., Whiteley, P., (2000). The Sunderland Protocol: A logical sequencing of biomedical interventions for the treatment of autism and related disorders. Retreived on 8th February 2007 from http://osiris.sunderland.ac.uk/autism/The%20Sunderland%20Protocol.pdf
28 Morris. M. E., Levy, G., (1983). Serum Concentration and renal excretion by normal adults of inorganic sulfate after acetaminophen, ascorbic acid or sodium sulfate. Clin Pharmacol Ther. 33:529-36.
29 Song, Z., McClain, C. J., Chen, T., (2004). S-Adenosylmethionine protects against acetaminophen-induced hepatoxicity in Mice. International Journal of Experimental and Clinical pharmacology. 71(4):199-208.
30 Brumas V, Hacht B, Filella M, Berthon G. (1992). Can N-acetyl-L-cysteine affect zinc metabolisms when used as a paracetamol antidote? Agents Actions 36:278–88.
31 Magee, E. A., Curno, R., Edmond, L. M., Cummings, J. H., (2004). Contribution of dietary protein and inorganic sulfur to urinary sulfate: toward a biomarker of inorganic sulfur intake. Am. J. Clinical Nutrition. 80: 137 – 142.
32 Florin, T. H. J., Neale, G., Goretski, S., Cummings, J. H., (1993). The sulphate content of foods and beverages. J. Food Comp Anal. 6:140-51
33 Harris, R. M., Waring, R. H., (1996). Dietary modulation of human platelet phenolsulphotransferase activity. Xenobiotica. 26(12):1241-7
34 Langford, W. S., (2000). To infuse or not to infuse. Retrieved on 28th July from http://trainland.tripod.com/toinfuse.pdf
35 Bamforth, K. J., Jones, A. L., Roberts, R. C., Coughtrie, M. W., (1993). Common food additives are potent inhibitors of human liver 17 alpha-ethinyloestradiol and dopamine sulphotransferases. Biochem Pharmacol. 46(10):1713-20.
36 Turan N, Waring RH, Ramsden DB. (2005). The effect of plasticisers on “sulphate supply” enzymes. Mol Cell Endocrinol. 244(1-2):15-9
37 Kirk, C. J., Harris, R. M., Wood, D. M., Waring, R. H., Hughes. P. J., (2001). Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens? Biochem. Soc. Trans. 29: 209–216.
38 Rotblatt, M., Ziment, I., (2002). Evidence-based herbal medicine. Philadelphia: Hanley & Belfus Inc.
40 Bratman, S., Girman, A. M., (2003). Mosby’s handbook of herbs and supplements and their therapeutic uses. St. Louis: Elsevier Health.
41 Wilkinson, L.J., Waring, R.H., (2002). Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and control of sulphate production. Toxicol In Vitro. 16(4):481-3
42 Bullock, N. R., Booth, J. C., Gibson, G. R., (2004). Comparative Composition of bacteria in the Human Intestinal Microflora During Remission and Active Ulcerative Colitis. Intestinal Microbiol. 5(2): 59-64.
43 Miroff, G., Mowles, R., Pangborn, J. B., Philpot, W. H., Schmitt, W. H., (1991). Molybdenum for candida albicans patients and other problems. Retreived on 3rd April 2007 from: http://www.arthritistrust.org/Articles/Molybdenum%20for%20Candida%20albicans%20Patients.pdf
44 Wain, W. H., Price, M. F., Cawson, R. A., (1975). A re-evaluation of the effect of cysteine on Candida Albicans. Sabouraudia. 13(1):74-82.
45 Sackett, D. L., Rosenberg, W. M. C., Gray, J. A. M., Haynes, R. B., Richardson, W. S., (1996). Evidence based medicine: what it is and what it isn’t. British Medical Journal. 312:71-2.
Key terms were extracted from the survey responses and interview manuscripts and used as secondary search terms in the systematic review. This was done to help minimise researcher bias in searching for, identifying and retrieving primary data from health and medical databases, journals, articles and books.
Databases, journals, articles and books were searched and all details were recorded in comprehensive research registers. Then references from included studies were searched. During the searches all studies with the key search terms in their title were selected and recorded. From the studies selected, only human studies without serious error, which assessed, described or evaluated dietary and nutritional influences on sulphate status, met the inclusion criteria for review.
The methodologies of included studies were assessed, for quality and validity, and graded into the following hierarchy, so that they could be given appropriate weight when drawing conclusions.
I. Evidence provided by one or more randomized, controlled clinical trials including overviews (meta-analyses) of such trials.
II. Evidence provided by observational studies with concurrent controls (e.g., case control or cohort studies), including in vitro studies.
III. Evidence obtained from non-experimental descriptive studies (e.g. comparitive studies, correlation studies and case studies).
IV. Evidence provided by expert opinion (e.g. case reports, literature reviews, surveys).
Each treatment strategy was then graded on the basis of supporting evidence. Grading levels are:
• Standard Practice. Principle for patient management that reflects a high degree of clinical certainty (this requires Class I evidence or overwhelming Class II evidence, without safety issues, and individual key word identification in the results of 20% or more).
• Guideline. Recommendation for patient management that reflects moderate clinical certainty (this requires Class II evidence or a strong consensus of Class III evidence and individual key word identification in the results of 14% or more).
• Practice Option. Strategy for patient management for which the clinical utility is uncertain (Class IV evidence with identification of the individual key word more than once).
• 3 studies were provided by the Nutritional therapists surveyed, of which 2 met the inclusion criteria 11, 24.
• 1 study was provided by a supplement company and it met the inclusion criteria 21.
• 48 studies with interviewees as authors were identified, of which 7 met the inclusion criteria 3, 27, 27, 33, 36, 41.
• 50 articles were searched, 13 studies were selected of which 1 met the inclusion criteria 21.
• 10 books were searched, 46 studies were selected, and none met the inclusion criteria.
• 10 databases were searched, 239 studies were selected and 5 met the inclusion criteria 18, 19, 20, 25, 31.
• References of included studies were searched and 152 studies selected, 6 of which met the inclusion criteria 21, 23, 24, 26, 28, 32, 33.