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August 19, 2021

Homocysteine: Highs, Lows, and Optimals

In this post, the ODX Research team dives into homocysteine, a silent but deadly biomarker, and provides research-based evidence to a tighter optimal reference range.

Homocysteine: Highs, Lows, and Optimals

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

Elevated homocysteine (Hcy) has been recognized as a risk factor for cardiovascular disease considering its negative effects on vascular endothelial integrity and its promotion of oxidative stress.[1] It is an independent risk factor for atherosclerosis (cerebral, coronary, and peripheral) so excess homocysteine can have harmful consequences throughout the body.[2]

Acceptable levels of Homocysteine have varied over time. In the past, hyperhomocysteinemia, elevated levels of homocysteine in the blood, had been defined as a level above 15 umol/L, with moderate hyperhomocysteinemia being defined as 16-30 umol/L, intermediate 31-100 umol/L, and severe hyperhomocysteinemia above 100 umol/L.[3] However, researchers now recognize that a level of 10 umol/L or above can be considered hyperhomocysteinemia and warrants further assessment. [4]

Unfortunately, again, research does not quickly translate into updated lab reference ranges. Even today, “normal” lab values for the homocysteine range can from 0 to a high of 21.3 umol/L for individuals over 80 years of age.[5]

However, a significant decline in cognitive function was observed when Hcy rose above 11 umol/L, with an 88% increased risk of decline with Hcy of 20 umol/L. Researchers conclude that elevated homocysteine is a “strong modifiable risk factor for vascular dementia and Alzheimer’s.”[6]

Higher than optimal homocysteine has been associated with a variety of negative health outcomes.

Levels of homocysteine previously accepted as “normal” with a mean of 10.5 umol/L, were associated with atherosclerotic regions in the carotid arteries of healthy individuals.[7] Atherosclerosis of the carotid artery is considered a strong predictor for stroke and cardiovascular disease.[8]

In a randomized double-blind placebo-controlled trial of overweight women with vitamin D deficiency, homocysteine levels greater than 10 umol/L were significantly associated with elevated CRP, AST, urea, and creatinine, as well as decreased 25(OH) vitamin D.[9]

In a study of 396 individuals with an average age of 64, homocysteine was considered an independent risk factor for CVD. Levels positively correlated with LDL-C, uric acid, BMI, waist circumference, and blood pressure, and negatively correlated with HDL-C. Homocysteine below 11 umol/L was considered low, and above 14.3 umol/L was considered high in the study.[10]

A tighter range for cutoff values may help predict the risk of cardiovascular morbidity and mortality.   Higher homocysteine was also associated with shorter sleep duration, a potential cardiovascular risk factor. Note Hcy cutoff values from various studies:[11]                          

  • 9.47 umol/L for cardiovascular events
  • 9.74 umol/L associated with short sleep duration
  • 11.84 umol/L for all-cause death
  • > 15 umol/L significantly predicted cardiovascular events

Along with vitamin B6 deficiency, elevated hs-CRP, elevated IL-6, and shortened telomeres, Hcy is considered a marker of oxidative stress and systemic inflammation and contributes to morbidity and mortality. Homocysteine levels of 9.8 umol/L or higher were associated with a 28% greater risk of all-cause mortality, including CVD when compared to those with concentrations below 9.8 umol/L.[12]

A study of 4177 subjects with prehypertension (SBP 120-139 mmHg, DBP 80-89 mmHg) demonstrated an independent association between homocysteine levels and arterial stiffness. Quartiles of Hcy were defined: ≤9.19; 9.20–10.86; 10.87–12.79; and ≥12.80 umol/L.[13]

Brachial-ankle pulse wave velocity, a marker for arterial stiffness, increased progressively as Hcy increased, suggesting an increased risk of progression from prehypertension to hypertension. BMI, waist circumference, serum glucose, uric acid, triglycerides, HDL, and LDL cholesterol differed significantly between quartiles as well.

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 Hcy.[14] Researchers note that the sufficiency of vitamins B6, B12, and folate can influence homocysteine and blood pressure levels.

As we can see from a variety of studies, as homocysteine begins to increase above 9 umol/L, disease risk increases as well. It is important to closely monitor and intervene in those trending toward dysfunction before the disease begins to manifest.

We must not demonize homocysteine completely as it is important as a sulfur depot and a methyl transfer molecule. Low or insufficient homocysteine should be addressed as it may reflect a compromised ability to synthesize glutathione, which will increase the risk of oxidative stress. Low homocysteine may also be associated with peripheral neuropathy.[15]

Researchers have observed a U-shaped curve with regard to homocysteine and elevated blood pressure. The risk of hypertension appeared to increase with increasing homocysteine, but risk also appeared to increase with lower homocysteine, especially in males.[16]

According to Mosby’s guidelines, a homocysteine below 4 umol/L would be considered low.[17]

An optimal goal for homocysteine would be ~ 5 - 7.2 umol/L.


[1] 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

[2] 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

[3] 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

[4] Wang, Yixuan et al. “Homocysteine as a risk factor for hypertension: a 2-year follow-up study.” PloS one vol. 9,10 e108223. 13 Oct. 2014, doi:10.1371/journal.pone.0108223

[5] Labcorp Homocysteine.

[6] 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

[7] Willinek, W A et al. “High-normal serum homocysteine concentrations are associated with an increased risk of early atherosclerotic carotid artery wall lesions in healthy subjects.” Journal of hypertension vol. 18,4 (2000): 425-30. doi:10.1097/00004872-200018040-00011

[8] Zhang, Yanqiu et al. “Features and risk factors of carotid atherosclerosis in a population with high stroke incidence in China.” Oncotarget vol. 8,34 57477-57488. 16 Feb. 2017, doi:10.18632/oncotarget.15415

[9] Al-Bayyari, N et al. “Vitamin D3 reduces risk of cardiovascular and liver diseases by lowering homocysteine levels: double-blinded, randomised, placebo-controlled trial.” The British journal of nutrition vol. 125,2 (2021): 139-146. doi:10.1017/S0007114520001890

[10] Shih, C., Y. Shih, and J. Chen. "The Association Between Homocysteine Levels and Cardiovascular Disease Risk Among Middle-Aged and Elderly Adults in Taiwan." (2020).

[11] Chen, Tien-Yu et al. “Short Sleep Duration Is Associated With Increased Serum Homocysteine: Insights From a National Survey.” Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine vol. 15,1 139-148. 15 Jan. 2019, doi:10.5664/jcsm.7588 [R}

[12] 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

[13] 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

[14] 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

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

[16] Wang, Yixuan et al. “Homocysteine as a risk factor for hypertension: a 2-year follow-up study.” PloS one vol. 9,10 e108223. 13 Oct. 2014, doi:10.1371/journal.pone.0108223

[17] Pagana, Kathleen Deska; Pagana, Timothy J.; Pagana, Theresa N. Mosby's Diagnostic and Laboratory Test Reference - E-Book. Elsevier Health Sciences. 2019..

Tag(s): Biomarkers

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