In my interview with world glutathione expert Dr Jimmy Gutman I accidentally asked a question. that had deeper implications than I realised.
These are excerpts from a recent paper (Sept 28th 2022) nailing the connection between illness and low glutathione.
Low glutathione levels are associated with these 90 + diseases or conditions.
Acetaminophen poisoning / toxicity
Arteriosclerosis (hardening of the arteries)
Chronic Fatigue Syndrome
Coronary artery disease
Epstein Barr Viral Syndrome (EBV)
Free Radical Overload
Heavy Metal Toxicity
Hepatic dysfunction (liver disease)
Some day to be added to the list...
Hypercholesterolemia (high blood cholesterol)
Huntington's Disease/ Huntington's Chorea
Infections (bacterial, viral, fungal)
Inflammatory bowel disease (IBD)
Macular Degeneration (diabetic macular degeneration)
Multiple sclerosis (MS)
Noise Induced Hearing Loss
Obsessive Compulsive Disorder
Polycystic kidney disease
Polycystic ovary syndrome
Primary Billary Cirrhosis
Trichotillomania (Hair Pulling)
Veisalgia (when combined with vitamin C and B1)
There are many more diseases which are not listed above, that are also associated with low glutathione.
To find out more on how to raise glutathione levels naturally, click for more info here.
The Role of Glutathione Metabolism in Chronic Illness Development and Its Potential Use as a Novel Therapeutic Target
Low GSH levels have been associated with many chronic pro-inflammatory conditions, such as metabolic syndrome, cardiovascular, renal, and hepatic disease, as well as neurodegenerative conditions and autoimmune diseases.
Several large prospective studies support this hypothesis by demonstrating that higher GGT levels are correlated with the risk of developing metabolic syndrome and cardiovascular disease in a dose-dependent fashion.
Human and animal trials utilizing GSH augmentation using precursor supplementation in chronic conditions, including metabolic syndrome, cardiovascular disease, hepatic disease, renal disease, and neurodegenerative conditions, were also reviewed.
There is strong evidence that GSH supplementation leads to improved outcomes in all of these chronic conditions.
This review seeks to highlight the role of GSH in chronic disease progression because a simple and cost-effective strategy can be created to screen for, track, and intervene in susceptible patients at the earliest possible time in the disease process.
Such a novel strategy would impact the majority of chronic diseases contributing to the bulk of morbidity and mortality in the Western world, and, thus, even minor benefits across many conditions may substantially impact population-wide health and longevity.
The biochemical role of glutathione as a driver of chronic illness
Low total GSH levels and elevated ratios of oxidized to reduced GSH are common in chronic illnesses as well as advanced age.
While these relationships have been known for years, most literature has overlooked these findings as the predictable result of increased inflammation and oxidative stress similar to other biomarkers such as C-reactive protein (CRP).
Few, if any, studies have explored the possibility of low GSH levels as a potentially important causative driver of disease pathology in itself
GSH is a key thiol antioxidant in the human body which, among its many functions, serves as a major mitochondrial protector, and through this function is linked to many chronic illnesses which make up the bulk of the healthcare burden in Western societies today.
Studies presented in this review show that low GSH levels have a demonstrable correlation to the faster onset of these chronic diseases and increased mortality.
The study above mentions NAC which is basically manmade cysteine.
Most NAC is made from recycled human hair.
NAC can become toxic, having the reverse effect becoming oxidative.
There is a better way of introducing natural highly bioavailable cysteine - more info here.
References to the paper above
Owen JB, Butterfield DA: Measurement of oxidized/reduced glutathione ratio. Methods Mol Biol. 2010, 648:269-77. 10.1007/978-1-60761-756-3_18
Nuhu F, Gordon A, Sturmey R, Seymour AM, Bhandari S: Measurement of glutathione as a tool for oxidative stress studies by high-performance liquid chromatography. Molecules. 2020, 25:4196. 10.3390/molecules25184196
Lutchmansingh FK, Hsu JW, Bennett FI, et al.: Glutathione metabolism in type 2 diabetes and its relationship with microvascular complications and glycemia. PLoS One. 2018, 13:e0198626. 10.1371/journal.pone.0198626
Sekhar RV, McKay SV, Patel SG, Guthikonda AP, Reddy VT, Balasubramanyam A, Jahoor F: Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care. 2011, 34:162-7. 10.2337/dc10-1006
Lapenna D, de Gioia S, Ciofani G, et al.: Glutathione-related antioxidant defenses in human atherosclerotic plaques. Circulation. 1998, 97:1930-4. 10.1161/01.cir.97.19.1930
Ceballos-Picot I, Witko-Sarsat V, Merad-Boudia M, et al.: Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. Free Radic Biol Med. 1996, 21:845-53. 10.1016/0891-5849(96)00233-x
Sian J, Dexter DT, Lees AJ, et al.: Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol. 1994, 36:348-55. 10.1002/ana.410360305
Mischley LK, Standish LJ, Weiss NS, Padowski JM, Kavanagh TJ, White CC, Rosenfeld ME: Glutathione as a biomarker in Parkinson's disease: associations with aging and disease severity. Oxid Med Cell Longev. 2016, 2016:9409363. 10.1155/2016/9409363
Wei Z, Li X, Li X, Liu Q, Cheng Y: Oxidative stress in Parkinson's disease: a systematic review and meta-analysis. Front Mol Neurosci. 2018, 11:236. 10.3389/fnmol.2018.00236
Perricone C, De Carolis C, Perricone R: Glutathione: a key player in autoimmunity. Autoimmun Rev. 2009, 8:697-701. 10.1016/j.autrev.2009.02.020
Kennedy L, Sandhu JK, Harper ME, Cuperlovic-Culf M: Role of glutathione in cancer: from mechanisms to therapies. Biomolecules. 2020, 10:1429. 10.3390/biom10101429
Morris D, Ly J, Chi PT, et al.: Glutathione synthesis is compromised in erythrocytes from individuals with HIV. Front Pharmacol. 2014, 5:73. 10.3389/fphar.2014.00073
Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C: Changes in glutathione content in liver diseases: an update. Antioxidants (Basel). 2021, 10:364. 10.3390/antiox10030364
Ben-Shachar R, Chen Y, Luo S, Hartman C, Reed M, Nijhout HF: The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model. Theor Biol Med Model. 2012, 9:55. 10.1186/1742-4682-9-55
Kaplowitz N: Acetaminophen hepatoxicity: what do we know, what don't we know, and what do we do next?. Hepatology. 2004, 40:23-6. 10.1002/hep.20312
Mak TW, Grusdat M, Duncan GS, et al.: Glutathione primes T cell metabolism for inflammation. Immunity. 2017, 46:675-89. 10.1016/j.immuni.2017.03.019
Hammarström S: Leukotrienes. Annu Rev Biochem. 1983, 52:355-77. 10.1146/annurev.bi.52.070183.002035
Hayden RE, Paniello RC, Yeung CS, Bello SL, Dawson SM: The effect of glutathione and vitamins A, C, and E on acute skin flap survival. Laryngoscope. 1987, 97:1176-9. 10.1288/00005537-198710000-00011
Jain SK, Parsanathan R, Achari AE, Kanikarla-Marie P, Bocchini JA Jr: Glutathione stimulates vitamin D regulatory and glucose-metabolism genes, lowers oxidative stress and inflammation, and increases 25-hydroxy-vitamin D levels in blood: a novel approach to treat 25-hydroxyvitamin D deficiency. Antioxid Redox Signal. 2018, 29:1792-807. 10.1089/ars.2017.7462
Sedlak TW, Paul BD, Parker GM, et al.: The glutathione cycle shapes synaptic glutamate activity. Proc Natl Acad Sci U S A. 2019, 116:2701-6. 10.1073/pnas.1817885116
Bjørklund G, Peana M, Maes M, Dadar M, Severin B: The glutathione system in Parkinson's disease and its progression. Neurosci Biobehav Rev. 2021, 120:470-8. 10.1016/j.neubiorev.2020.10.004
Sharma S, Sehrawat A, Deswal R: Asada-Halliwell pathway maintains redox status in Dioscorea alata tuber which helps in germination. Plant Sci. 2016, 250:20-9. 10.1016/j.plantsci.2016.05.013
Winkler BS, DeSantis N, Solomon F: Multiple NADPH-producing pathways control glutathione (GSH) content in retina. Exp Eye Res. 1986, 43:829-47. 10.1016/s0014-4835(86)80013-6
Dunning S, Ur Rehman A, Tiebosch MH, et al.: Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death. Biochim Biophys Acta. 2013, 1832:2027-34. 10.1016/j.bbadis.2013.07.008
Moreno-Sánchez R, Marín-Hernández Á, Gallardo-Pérez JC, Vázquez C, Rodríguez-Enríquez S, Saavedra E: Control of the NADPH supply and GSH recycling for oxidative stress management in hepatoma and liver mitochondria. Biochim Biophys Acta Bioenerg. 2018, 1859:1138-50. 10.1016/j.bbabio.2018.07.008
Zhang H, Forman HJ, Choi J: Gamma-glutamyl transpeptidase in glutathione biosynthesis. Methods Enzymol. 2005, 401:468-83. 10.1016/S0076-6879(05)01028-1
Lee DS, Evans JC, Robins SJ, et al.: Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2007, 27:127-33. 10.1161/01.ATV.0000251993.20372.40
Ndrepepa G, Colleran R, Kastrati A: Gamma-glutamyl transferase and the risk of atherosclerosis and coronary heart disease. Clin Chim Acta. 2018, 476:130-8. 10.1016/j.cca.2017.11.026
Fine A, McIntosh WB: Elevation of serum gamma-glutamyl transpeptidase in end-stage chronic renal failure. Scott Med J. 1975, 20:113-5. 10.1177/003693307502000309
Akaydın SY, Salihoğlu EM, Güngör DG, Karanlık H, Demokan S: Correlation between gamma-glutamyl transferase activity and glutathione levels in molecular subgroups of breast cancer. Eur J Breast Health. 2020, 16:72-6. 10.5152/ejbh.2019.5147
Pinkham CA, Krause KJ: Liver function tests and mortality in a cohort of life insurance applicants. J Insur Med. 2009, 41:170-7.
Palmier J, Lanzrath BJ: Laboratory and biometric predictors of cancer-related mortality in an insured population. J Insur Med. 2012, 43:162-8.
Monami M, Bardini G, Lamanna C, et al.: Liver enzymes and risk of diabetes and cardiovascular disease: results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism. 2008, 57:387-92. 10.1016/j.metabol.2007.10.015
Paschalis V, Theodorou AA, Margaritelis NV, Kyparos A, Nikolaidis MG: N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione. Free Radic Biol Med. 2018, 115:288-97. 10.1016/j.freeradbiomed.2017.12.007
Prescott LF, Newton RW, Swainson CP, Wright N, Forrest AR, Matthew H: Successful treatment of severe paracetamol overdosage with cysteamine. Lancet. 1974, 1:588-92. 10.1016/s0140-6736(74)92649-x
Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH: Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988, 319:1557-62. 10.1056/NEJM198812153192401
Nabi T, Nabi S, Rafiq N, Shah A: Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: a prospective study. Saudi J Gastroenterol. 2017, 23:169-75. 10.4103/1319-3767.207711
Lee WM, Hynan LS, Rossaro L, et al.: Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009, 137:856-64, 864.e1. 10.1053/j.gastro.2009.06.006
Ozaras R, Tahan V, Aydin S, Uzun H, Kaya S, Senturk H: N-acetylcysteine attenuates alcohol-induced oxidative stress in the rat. World J Gastroenterol. 2003, 9:125-8. 10.3748/wjg.v9.i1.125
Wang ML, Yin XJ, Li XL, et al.: Retrospective analysis of the clinical efficacy of N-acetylcysteine in the treatment of hepatitis B virus related acute-on-chronic liver failure. Front Med (Lausanne). 2021, 8:724224. 10.3389/fmed.2021.724224
Khoshbaten M, Aliasgarzadeh A, Masnadi K, et al.: N-acetylcysteine improves liver function in patients with non-alcoholic fatty liver disease. Hepat Mon. 2010, 10:12-6.
Rani M, Aggarwal R, Vohra K: Effect of N-acetylcysteine on metabolic profile in metabolic syndrome patients. Metab Syndr Relat Disord. 2020, 18:341-6. 10.1089/met.2020.0017
Kumar P, Liu C, Hsu JW, Chacko S, Minard C, Jahoor F, Sekhar RV: Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: results of a pilot clinical trial. Clin Transl Med. 2021, 11:e372. 10.1002/ctm2.372
Alnahdi A, John A, Raza H: Mitigation of glucolipotoxicity-induced apoptosis, mitochondrial dysfunction, and metabolic stress by N-acetyl cysteine in pancreatic β-cells. Biomolecules. 2020, 10:239. 10.3390/biom10020239
Pasupathy S, Tavella R, Grover S, et al.: Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM trial [N-acetylcysteine in acute myocardial infarction]). Circulation. 2017, 136:894-903. 10.1161/CIRCULATIONAHA.117.027575
Marian AJ, Tan Y, Li L, et al.: Hypertrophy regression with N-acetylcysteine in hypertrophic cardiomyopathy (HALT-HCM): a randomized, placebo-controlled, double-blind pilot study. Circ Res. 2018, 122:1109-18. 10.1161/CIRCRESAHA.117.312647
Wu XY, Luo AY, Zhou YR, Ren JH: N-acetylcysteine reduces oxidative stress, nuclear factor‑κB activity and cardiomyocyte apoptosis in heart failure. Mol Med Rep. 2014, 10:615-24. 10.3892/mmr.2014.2292
Cui Y, Narasimhulu CA, Liu L, et al.: N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein. Sci Rep. 2015, 5:16339. 10.1038/srep16339
Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al.: Effectiveness of prevention strategies for contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med. 2016, 164:406-16. 10.7326/M15-1456
Tsai JP, Yang FL, Wang CH, Fang TC, Lee RP, Hsu BG: Effect of intravenous N-acetylcysteine on plasma total homocysteine and inflammatory cytokines during high flux hemodialysis. Tzu Chi Med J. 2010, 22:90-5. 10.1016/S1016-3190(10)60047-X
Thaha M, Yogiantoro M, Tomino Y: Intravenous N-acetylcysteine during haemodialysis reduces the plasma concentration of homocysteine in patients with end-stage renal disease. Clin Drug Investig. 2006, 26:195-202. 10.2165/00044011-200626040-00003
Giannikouris I: The effect of N-acetylcysteine on oxidative serum biomarkers of hemodialysis patients. Hippokratia. 2015, 19:131-5.
Ahmadi F, Abbaszadeh M, Razeghi E, Maziar S, Khoidaki SD, Najafi MT, Lessan-Pezeshki M: Effectiveness of N-acetylcysteine for preserving residual renal function in patients undergoing maintenance hemodialysis: multicenter randomized clinical trial. Clin Exp Nephrol. 2017, 21:342-9. 10.1007/s10157-016-1277-5
Amore A, Formica M, Giacchino F, et al.: N-Acetylcysteine in hemodialysis diabetic patients resets the activation of NF-kB in lymphomonocytes to normal values. J Nephrol. 2013, 26:778-86. 10.5301/jn.5000167
Di Giorno C, Pinheiro HS, Heinke T, Franco MF, Galante NZ, Pacheco-Silva A, Camara NO: Beneficial effect of N-acetyl-cysteine on renal injury triggered by ischemia and reperfusion. Transplant Proc. 2006, 38:2774-6. 10.1016/j.transproceed.2006.08.178
Monti DA, Zabrecky G, Kremens D, et al.: N-acetyl cysteine is associated with dopaminergic improvement in Parkinson's disease. Clin Pharmacol Ther. 2019, 106:884-90. 10.1002/cpt.1548
Adair JC, Knoefel JE, Morgan N: Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology. 2001, 57:1515-7. 10.1212/wnl.57.8.1515
Garg G, Singh S, Singh AK, Rizvi SI: N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging. Can J Physiol Pharmacol. 2018, 96:1189-96. 10.1139/cjpp-2018-0209
Berk M, Copolov D, Dean O, et al.: N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008, 64:361-8. 10.1016/j.biopsych.2008.03.004
Lee TM, Lee KM, Lee CY, Lee HC, Tam KW, Loh EW: Effectiveness of N-acetylcysteine in autism spectrum disorders: a meta-analysis of randomized controlled trials. Aust N Z J Psychiatry. 2021, 55:196-206. 10.1177/0004867420952540
Amrein K, Schnedl C, Holl A, et al.: Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014, 312:1520-30. 10.1001/jama.2014.13204