Biomarkers of Inflammation and Oxidation: Homocysteine

Optimal Takeaways

Homocysteine is a potentially harmful amino acid that can build up, cause damage to blood vessels, and promote inflammation, hypertension, cardiovascular disease, and cerebrovascular disease. Insufficiency of vitamins B6, B12, and folate is the most common cause of elevated homocysteine. Increased homocysteine is associated with inflammation and oxidative stress, while low levels may be associated with peripheral neuropathy and metabolic deficits.

Standard Range: 0.00 - 10.30 umol/L

The ODX Range: 5.0 - 7.2 umol/L

Low homocysteine is associated with peripheral neuropathy and disruption of methylation and sulfur metabolism (Pizzorno 2014).

High homocysteine is seen with deficiencies of vitamin B6, B12, and folate), megaloblastic anemia, atherosclerosis, CVD, cerebrovascular disease, peripheral vascular disease, smoking, renal impairment/poor excretion, cystinuria, or inborn errors of methionine metabolism. Drugs that increase homocysteine include nitrous oxide, phenytoin, methotrexate, carbamazepine, and azaribine (Pagana 2021).

Elevated homocysteine is also associated with elevated red cell distribution width (Peng 2017), oxidative stress, inflammation, cardiovascular mortality (Pusceddu 2020), increased risk of cognitive decline and dementia (Smith 2016), migraines (Nolan 2020), arterial stiffness (Kim 2011), sarcopenia, weakness (Lee 2020), hypertension, progression from pre-hypertension to hypertension (Lim 2002), and insufficient intake of fruits and vegetables (Foscolou 2019, Panagiotakos 2005).

Overview

Homocysteine is an intermediary compound involved in methionine metabolism. When not fully processed, homocysteine can build up and contribute to endothelial damage, arterial deposition of LDL, cardiovascular and cerebrovascular disease, peripheral artery disease, and venous thrombosis. Homocysteine levels increase with age and tend to be higher in men, possibly due to greater muscle mass and higher creatinine levels. The most common cause of elevated homocysteine is insufficient vitamins B6, B12, or folate (Pagana 2021).

Elevated homocysteine is considered a risk factor for cardiovascular disease because of its association with atherosclerosis, the promotion of oxidative stress, and its adverse effects on vascular endothelial integrity (Kumar 2017, Ganguly 2015).

Elevated homocysteine is considered an independent risk factor for all-cause mortality, cardiovascular mortality, and shortened telomeres. It impairs antioxidant systems and increases oxidative stress and inflammation in vital tissues such as the heart, brain, and liver, contributing to their pathology. Analysis of the Ludwigshafen Risk and Cardiovascular Health Study revealed that mortality increased significantly as serum homocysteine rose above 9.8 umol/L, even when adjusted for antioxidants vitamin C and alpha- and gamma-tocopherol. Individuals with homocysteine below 9.8 umol/L had significantly lower hs-CRP and IL-6 and significantly longer telomeres. Homocysteine may also be a marker of B6, B12, and folate status (Pusceddu 2020).

Data analyzed from the NHANES III studies suggest that when the highest and lowest quintiles of homocysteine were compared (11.5-98.1 versus 3-6.4 umol/L), the risk of hypertension increased twofold for men and threefold for women with higher homocysteine (Lim 2002).

Ideally, homocysteine should be maintained below 7 umol/L, a level associated with improved cardiovascular function and reduced risk of atherosclerosis and stroke (Travica 2015). However, very low homocysteine may have consequences as well. Under normal metabolic conditions, homocysteine serves as a methyl transfer molecule, sulfur depot, and source of cysteine for glutathione synthesis. Suboptimal homocysteine may compromise glutathione status, facilitate increased oxidative stress, and contribute to pathology such as peripheral neuropathy (Pizzorno 2014).

References

Foscolou, Alexandra et al. “The association between homocysteine levels, Mediterranean diet and cardiovascular disease: a case-control study.” International journal of food sciences and nutrition vol. 70,5 (2019): 603-611. doi:10.1080/09637486.2018.1547688

Ganguly, Paul, and Sreyoshi Fatima Alam. “Role of homocysteine in the development of cardiovascular disease.” Nutrition journal vol. 14 6. 10 Jan. 2015, doi:10.1186/1475-2891-14-6

Kim, Byung Jin et al. “Associations of plasma homocysteine levels with arterial stiffness in prehypertensive individuals.” Clinical and experimental hypertension (New York, N.Y. : 1993) vol. 33,6 (2011): 411-7. doi:10.3109/10641963.2010.549274

Kumar, Avinash et al. “The metabolism and significance of homocysteine in nutrition and health.” Nutrition & metabolism vol. 14 78. 22 Dec. 2017, doi:10.1186/s12986-017-0233-z

Lee, Wei-Ju et al. “Sex-different associations between serum homocysteine, high-sensitivity C-reactive protein and sarcopenia: Results from I-Lan Longitudinal Aging Study.” Experimental gerontology vol. 132 (2020): 110832. doi:10.1016/j.exger.2020.110832

Lim, Unhee, and Patricia A Cassano. “Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994.” American journal of epidemiology vol. 156,12 (2002): 1105-13. doi:10.1093/aje/kwf157

Noland, Diana, Jeanne A. Drisko, and Leigh Wagner, eds. Integrative and functional medical nutrition therapy: principles and practices. Springer Nature, 2020.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Panagiotakos, Demosthenes B et al. “The association between lifestyle-related factors and plasma homocysteine levels in healthy individuals from the "ATTICA" Study.” International journal of cardiology vol. 98,3 (2005): 471-7. doi:10.1016/j.ijcard.2003.12.036

Peng, You-Fan, and Guo-Gang Pan. “Red blood cell distribution width predicts homocysteine levels in adult population without vitamin B12 and folate deficiencies.” International journal of cardiology vol. 227 (2017): 8-10. doi:10.1016/j.ijcard.2016.11.012

Pizzorno, Joseph. “Homocysteine: Friend or Foe?.” Integrative medicine (Encinitas, Calif.) vol. 13,4 (2014): 8-14.

Pusceddu, Irene et al. “Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study.” European journal of nutrition vol. 59,4 (2020): 1399-1411. doi:10.1007/s00394-019-01993-8

Smith, A David, and Helga Refsum. “Homocysteine, B Vitamins, and Cognitive Impairment.” Annual review of nutrition vol. 36 (2016): 211-39. doi:10.1146/annurev-nutr-071715-050947

Travica, Nikolaj, et al. "Integrative Health Check reveals suboptimal levels in a number of vital biomarkers." Advances in integrative medicine 2.3 (2015): 135-140.