Oxidative Stress part 2 - Blood Biomarkers

Oxidative stress: Functional Blood Chemistry Clues

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

Oxidative stress affects many different cells and tissues, contributing to a wide variety of diseases. The presence of underlying oxidative stress may be revealed in commonly available blood chemistry panels in which biomarker fluctuations may provide clues to the presence of this underlying “smoldering ember.”

The ODX Oxidative Stress Series

1. Oxidative Stress part 1 - And You Thought You Were Stressed!
2. Oxidative Stress part 2 - Blood Biomarkers: Functional Blood Chemistry Clues
3. Oxidative Stress part 3 - Specialized Markers Provide More Clues
4. Oxidative Stress part 4 - Cardiometabolic Disease & Oxidative Stress
5. Oxidative Stress part 5 - The Cholesterol Connection
6. Oxidative Stress part 6 - Glutathione Inside and Out
7. Optimal - The Podcast: Episode 1 Oxidative Stress

Clinical assessment of oxidative stress risk should begin with a comprehensive history that can reveal exposure to major risk factors, including[1]

• Alcohol consumption
• Chemotherapy drugs
• Cigarette smoke (contains more than 7000 chemicals)
• Plastics, phthalates
• Radiation
• Toxic heavy metals, cadmium, lead, manganese, mercury

A detailed history should help provide a general picture of antioxidant capacity by reviewing diet and supplement intake (e.g. vitamins A, C, E, selenium, phytonutrients, glutathione precursors, etc.). Comprehensive blood chemistry panels should then be reviewed and assessed within the framework of the patient’s exposure, history, and current clinical picture.

Recognizing oxidative stress early in its pathological course can help reduce associated tissue damage and dysfunction and add a valuable tool to every clinician’s toolbox.

General indicators of oxidative stress on a blood chemistry test may include:

• Decreased albumin
• Decreased cholesterol
• Decreased lymphocytes
• Decreased platelets
• Increased globulin
• Increased uric acid
• Increased or decreased bilirubin
• Increased LDL
• Increased ferritin
• Increased inflammatory markers

Albumin

• Serum albumin of less than 3.2 g/dL (32 g/L) was associated with increased oxidative stress and markers of inflammation, including CRP, IL-6, thiol oxidation, and protein carbonyl production in hemodialysis patients.[2]
• Total antioxidant status and albumin levels were significantly lower, and oxidative stress was significantly higher. in a group of 55 chronic ischemic heart failure patients.[3]
• Albumin can account for up to 70% of the antioxidant capacity in the blood, and a low level is associated with inflammation, malnutrition, and liver and kidney disease. Mortality risk increased by 50% for each 0.25 g/dL (2.5 g/L) reduction in serum levels.[4]
• As a potent antioxidant compound, albumin possesses 3-7 times the antioxidant potential of vitamin C, vitamin E, and bilirubin.[5] Therefore, lower albumin can mean reduced antioxidant potential.

Cholesterol

• Intercepts oxidants and produces oxysterol compounds[6]
• Oxidative damage can, in turn, deplete cholesterol and disrupt cell membrane function.[7]
• Hypocholesterolemia (total cholesterol below 160 mg/dL) can reflect malnutrition
• Low HDL-C permits excess oxidative stress
• HDL-C exerts important antioxidant, anti-inflammatory, and anti-atherogenic properties activities that protect against cardiovascular disease.
  • Low serum HDL-C is an independent risk factor for early atherosclerosis and coronary heart disease and is associated with increased oxidative stress[9]

Lymphocytes

• Lymphocytes are susceptible to oxidative damage and increased cell death in the absence of adequate antioxidant protection.
• Lymphocytes represent a double-edged sword because they produce damaging pro-inflammatory and pro-oxidant compounds needed to fight pathogens, yet, in turn, they need adequate antioxidant protection to survive.[10]
• Research on older (41-60 years) versus younger subjects (11-40 years) indicates that antioxidant reserves of reduced glutathione within lymphocytes decline with age, making them even more susceptible to oxidative damage.[11]

Platelets

• Oxidative stress can increase platelet activation and platelet clearance and decrease serum platelet levels.[12]
• Oxidative stress may be a cause or trigger of platelet depletion in immune thrombocytopenia (ITP).[13]
• An increase in reactive oxygen species and platelet activation can lead to a prothrombotic state.[14]
• Chronic spontaneous urticaria was associated with increased platelet oxidative stress evidenced by significantly elevated plasma levels of the oxidative stress marker malondialdehyde (MDA), hs-CRP, and IL-6, as well as significantly reduced levels of platelet superoxide dismutase and glutathione peroxidase.[15]
• Oxidative stress experienced by and perpetrated by platelets is believed to play a role in the pathogenesis of cardiovascular disease and type 2 diabetes.[16]
• Antioxidants such as vitamin C and melatonin were found to inhibit platelet activation following exposure to oxidative stress from ischemia/reperfusion in an in vitro study using blood donated by healthy volunteers.[17]

Globulin

• Evaluation of significantly increased globulin levels may be used to assess an oxidative stress-induced inflammatory response in human studies.[18]
• Increased serum globulin was associated with oxidative stress in hyperthyroid subjects.[19]
• Animal studies also observe increased globulin levels with exposure to oxidative stress, inflammation, and toxins.[20] [21]

Uric acid

• Research suggests that increased uric acid is an important oxidative stress marker.[22]
• In response to oxidative stress, compounds such as uric acid may increase to counter reactive oxygen species and enhance the antioxidant potential of the blood.[23]
• Uric acid may act as an antioxidant in the plasma but may become a pro-oxidant within the cell.[24]

Bilirubin, total

• Bilirubin, produced from the breakdown of heme in red blood cells, may be toxic at high levels but possesses antioxidant properties at physiological levels.[25] [26]
• Accumulating research suggests that bilirubin may protect against oxidative damage and can contribute significantly to the antioxidant potential of the blood.[27]
• As a lipophilic antioxidant, bilirubin may protect against atherosclerosis, as suggested in a meta-analysis of 11 studies.[28]
• Note that total bilirubin may be increased when oxidative stress causes the hemolysis of red blood cells but may be decreased with excessive oxidative stress that consumes antioxidants, including bilirubin.

LDL

• When LDL cholesterol is modified by oxidative stress, it becomes atherogenic. [29]
• Increased LDL-cholesterol was associated with increased levels of the oxidative stress marker malondialdehyde, which, in turn, correlated with an increased atherogenic index and risk of atherosclerosis.[30]
• An LDL cholesterol above 132 mg/dL (3.42 mmol/L) was associated with oxidative stress in young adults.[31]
• Interestingly, one study noted that consumption of red wine enriched with resveratrol with a high-fat fast food meal reduced the oxidative damage to LDL-cholesterol. Therefore, I think we can conclude that we do have a creative and enjoyable way to counter oxidative stress.[32]

Inflammatory markers

• Oxidative stress is believed to be pro-inflammatory and can be associated with markers of inflammation.
• The term oxi-inflamm-aging reflects the close association between oxidative stress, inflammation, and aging. Oxidative stress sets off a perpetual inflammatory response from the immune system, compounding its negative effects on the body. [33]
• A cross-sectional study of 126 CHD-free adults revealed that the oxidative stress marker free oxygen radical test (FORT) was significantly associated with higher levels of hs-CRP.[34]
• Frail and pre-frail elderly were found to have elevated C-reactive protein and elevated F2-IsoPs, reflecting increased inflammation and oxidative stress. Elevations in IL-6 are also observed in disorders associated with oxidative stress, including Alzheimer’s, COPD, and biliary cirrhosis. [35]
• Ischemic stroke is associated with increased oxidative stress and inflammatory markers (e.g. hs-CRP), and decreased erythrocyte glutathione peroxidase and superoxide dismutase activity.[36]
• Synthesis of ferritin is increased during oxidative stress and correlates with a variety of oxidative stress markers, including malondialdehyde and isoprostanes.[37]

Up Next - Oxidative Stress part 3 - Specialized Markers

References

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[2] Danielski, Michael, et al. "Linkage of hypoalbuminemia, inflammation, and oxidative stress in patients receiving maintenance hemodialysis therapy." American journal of kidney diseases 42.2 (2003): 286-294.

[3] Ellidag, Hamit Yasar et al. “Oxidative stress and ischemia-modified albumin in chronic ischemic heart failure.” Redox report : communications in free radical research vol. 19,3 (2014): 118-23.

[4] Sitar, Mustafa Erinç et al. “Human serum albumin and its relation with oxidative stress.” Clinical laboratory vol. 59,9-10 (2013): 945-52.

[5] Ihara, Hiroshi et al. “Antioxidant capacities of ascorbic acid, uric acid, alpha-tocopherol, and bilirubin can be measured in the presence of another antioxidant, serum albumin.” Journal of clinical laboratory analysis vol. 18,1 (2004): 45-9.

[6] Smith, L L. “Another cholesterol hypothesis: cholesterol as antioxidant.” Free radical biology & medicine vol. 11,1 (1991): 47-61.

[7] Butterfield, J D Jr, and C P McGraw. “Free radical pathology.” Stroke vol. 9,5 (1978): 443-5.

[8] Zhang, Zhiying et al. “Evaluation of Blood Biomarkers Associated with Risk of Malnutrition in Older Adults: A Systematic Review and Meta-Analysis.” Nutrients vol. 9,8 829. 3 Aug. 2017,

[9] Karabacak, Mustafa, et al. "Low HDL Cholesterol Situations is Characterised by Elevated Oxidative Stress." Journal of the American College of Cardiology 62.18 Supplement 2 (2013): C181.  

[10] Qasim, Neha, and Riaz Mahmood. “Diminution of Oxidative Damage to Human Erythrocytes and Lymphocytes by Creatine: Possible Role of Creatine in Blood.” PloS one vol. 10,11 e0141975. 10 Nov. 2015,

[11] Gautam, Nandeslu et al. “Age associated oxidative damage in lymphocytes.” Oxidative medicine and cellular longevity vol. 3,4 (2010): 275-82.

[12] Assinger, Alice. “Platelets and infection - an emerging role of platelets in viral infection.” Frontiers in immunology vol. 5 649. 18 Dec. 2014, 

[13] Zhang, Bing, and James L Zehnder. “Oxidative stress and immune thrombocytopenia.” Seminars in hematology vol. 50,3 (2013): e1-4.

[14] Iyer, Krishna S, and Sanjana Dayal. “Platelet antioxidants: A conundrum in aging.” EBioMedicine vol. 47 (2019): 29-30.

[15] Rajappa, Medha et al. “Platelet oxidative stress and systemic inflammation in chronic spontaneous urticaria.” Clinical chemistry and laboratory medicine vol. 51,9 (2013): 1789-94.

[16] El Haouari, Mohammed. “Platelet Oxidative Stress and its Relationship with Cardiovascular Diseases in Type 2 Diabetes Mellitus Patients.” Current medicinal chemistry vol. 26,22 (2019): 4145-4165.

[17] Liu, Demin et al. “Effects and Mechanisms of Vitamin C Post-Conditioning on Platelet Activation after Hypoxia/Reoxygenation.” Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie vol. 47,2 (2020): 110-118. 

[18] Avinash, S S et al. “Advanced oxidation protein products and total antioxidant activity in colorectal carcinoma.” Indian journal of physiology and pharmacology vol. 53,4 (2009): 370-4.

[19] Nandakumar, D N et al. “Activation of NF-kappaB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism: possible role of oxidative stress.” Immunobiology vol. 213,5 (2008): 409-15. 

[20] Javed, Mehjbeen et al. “Multiple biomarker responses (serum biochemistry, oxidative stress, genotoxicity and histopathology) in Channa punctatus exposed to heavy metal loaded waste water.” Scientific reports vol. 7,1 1675. 10 May. 2017, 

[21] Bracht, Adelar et al. “Oxidative changes in the blood and serum albumin differentiate rats with monoarthritis and polyarthritis.” SpringerPlus vol. 5 36. 15 Jan. 2016, 

[22] Glantzounis, G K et al. “Uric acid and oxidative stress.” Current pharmaceutical design vol. 11,32 (2005): 4145-51. 

[23] Ok, Eun Jeong et al. “Association between Serum Uric Acid and Oxidative Stress in Korean Adults.” Korean journal of family medicine vol. 39,5 (2018): 295-299. 

[24] Sautin, Yuri Y, and Richard J Johnson. “Uric acid: the oxidant-antioxidant paradox.” Nucleosides, nucleotides & nucleic acids vol. 27,6 (2008): 608-19. 

[25] Tomaro, María L, and Alcira M del C Batlle. “Bilirubin: its role in cytoprotection against oxidative stress.” The international journal of biochemistry & cell biology vol. 34,3 (2002): 216-20. 

[26] Zelenka, Jaroslav et al. “Intracellular accumulation of bilirubin as a defense mechanism against increased oxidative stress.” Biochimie vol. 94,8 (2012): 1821-7. 

[27] Inoguchi, Toyoshi et al. “Bilirubin as an important physiological modulator of oxidative stress and chronic inflammation in metabolic syndrome and diabetes: a new aspect on old molecule.” Diabetology international vol. 7,4 338-341. 21 Sep. 2016, 

[28] Novotný, Ladislav, and Libor Vítek. “Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies.” Experimental biology and medicine (Maywood, N.J.) vol. 228,5 (2003): 568-71. 

[29] Le, Ngoc-Anh. “Lipoprotein-associated oxidative stress: a new twist to the postprandial hypothesis.” International journal of molecular sciences vol. 16,1 401-19. 26 Dec. 2014, 

[30] Yang, Rui-Li et al. “Increasing Oxidative Stress with Progressive Hyperlipidemia in Human: Relation between Malondialdehyde and Atherogenic Index.” Journal of clinical biochemistry and nutrition vol. 43,3 (2008): 154-8. 

[31] Turkdogan, Kenan Ahmet et al. “Association between oxidative stress index and serum lipid levels in healthy young adults.” JPMA. The Journal of the Pakistan Medical Association vol. 64,4 (2014): 379-81.

[32] Di Renzo, Laura et al. “Changes in LDL Oxidative Status and Oxidative and Inflammatory Gene Expression after Red Wine Intake in Healthy People: A Randomized Trial.” Mediators of inflammation vol. 2015 (2015): 317348.

[33] Liguori, Ilaria et al. “Oxidative stress, aging, and diseases.” Clinical interventions in aging vol. 13 757-772. 26 Apr. 2018,  

[34] Abramson, Jerome L et al. “Association between novel oxidative stress markers and C-reactive protein among adults without clinical coronary heart disease.” Atherosclerosis vol. 178,1 (2005): 115-21.  

[35] Liguori, Ilaria et al. “Oxidative stress, aging, and diseases.” Clinical interventions in aging vol. 13 757-772. 26 Apr. 2018,  

[36] Chehaibi, Khouloud et al. “Correlation of Oxidative Stress Parameters and Inflammatory Markers in Ischemic Stroke Patients.” Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association vol. 25,11 (2016): 2585-2593. 

[37] Kell, Douglas B, and Etheresia Pretorius. “Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells.” Metallomics : integrated biometal science vol. 6,4 (2014): 748-73.