Homocysteine (Hcy) is not a classic amino acid found in dietary protein. Homocysteine’s only source in humans is the demethylation of s-adenosylmethionine (SAM).
Homocysteine is a major branch point in the methylation pathway. It can be metabolized via two pathways: degraded irreversibly through the transsulfuration pathway or re-methylated back to methionine. These two pathways are greatly affected by vitamin and mineral cofactor availability and enzymatic SNPs. [L]
Transsulfuration is the main route for irreversible Homocysteine disposal. Transsulfuration begins when Homocysteine is converted to cystathionine, using the cystathionine β-synthase enzyme (CBS). This reaction requires nutrient cofactors, such as vitamin B6 and iron.
Alternatively, Homocysteine can be re-methylated back to methionine. [L] Two distinct routes exist for Hcy remethylation. The first reaction is dependent on folate and vitamin B12. The second route for Homocysteine remethylation is independent of folate, but requires betaine. The betaine pathway for Homocysteine remethylation is a salvage pathway when folate metabolism abnormalities are present or in folate deficiency. [L] Under normal conditions, the body will remethylate Homocysteine several times before allowing irreversible transsulfuration. [L]
Whereas SAM-dependent methylation occurs in nearly all tissues, the transsulfuration pathway and Homocysteine remethylation occur primarily in the liver and kidneys. [L]
Homocysteine intracellular concentration is under tight control. As mentioned above, SAH accumulation must be avoided as it can inhibit all methylation reactions. Because of AHCY’s reversible nature, it is mandatory that intracellular Homocysteine concentrations are kept within strict limits. Optimal Homocysteine concentrations in cells are maintained or re-established through folate-dependent remethylation.
Whenever the cellular capacity to metabolize Homocysteine is exceeded, this amino acid will be exported to the extracellular space until intracellular levels are normalized. This results in elevated plasma Homocysteine levels. Exceptions are liver and kidney cells, where Homocysteine can enter the transsulfuration pathway.
Several factors can affect Homocysteine metabolism causing hyperhomocysteinemia. These include B-vitamin deficiencies, impaired renal excretion, advanced age, sex (male), smoking, alcohol, and genetic enzyme deficiencies. [L]
Elevated homocysteine levels have many clinical implications:
- Hyperhomocysteinemia is regarded as a risk factor for non-coronary atherosclerosis and coronary artery disease. Elevated homocysteine enhances vascular smooth-muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis, causing normal endothelium to become more thrombotic. The mechanism may be related to elevations in SAH, due to the reversible nature of Hcy formation. [L] SAH has been shown to be a more sensitive marker in many diseases as previously outlined. [L], [L]
- Diabetes, both type 1 and type 2, initially causes hypohomocysteinemia, due to renal hyperperfusion early in the diabetic nephropathy disease process. This progresses to hyperhomocysteinemia as renal function becomes compromised. [L], [L]
- Elevated homocysteine levels have also been implicated in gastrointestinal disorders such as inflammatory bowel disease and colon cancer. [L], [L] Hyperhomocysteinemia may be partially due to nutrient malabsorption (methyl donor and B-vitamin deficiency). Subsequently, elevated Hcy has been shown to induce inflammatory cytokines and contribute to disease progression. [L]
- Homocysteine can impair bone health by interfering with osteoclast activity. The increased Hcy impairs the cellular and molecular mechanism of bone marrow- derived osteoclasts by causing imbalance between phosphorylation and de-phosphorylation of various protein kinases that modulate bone cell remodeling. [L]
Homocysteinemia contributes to neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases) and mood disorders. [L], [L], [L]
Elevated Hcy increases CNS phosphorylated tau leading to increased neurofibrillary tangle formation, seen in Alzheimer’s dementia. [L]
Hyperhomocysteinemia related to mood disorders may be multifactorial. Elevated Hcy causes elevations in SAH, which interferes
with many methyltransferase reactions involved in neurotransmitter synthesis and metabolism. Hcy may also have direct neurotoxic effects. Research is ongoing regarding the exact mechanisms regarding Hcy and psychiatric disorders. [L], [L]
Possible treatmenet options:
Dietary supplementation with folate, vitamin B12, and SAM has been shown to effectively lower plasma homocysteine levels and improve outcomes. [L], [L], [L]
Additional Note:
When referring to Hcy, the terms ‘homocysteine’ and ‘homocystine’ are used interchangeably. However, the reduced sulfhydryl form is ‘homocysteine,’ while the oxidized disulfide form is ‘homocystine.’ The composite of both forms are routinely described by the term ‘homocysteine. [L]
Most conventional laboratories that offer homocysteine measurement are actually measuring a total of homocystine, homocysteine, and SAH. To note, Genova’s Methylation Panel measures SAH and homocysteine as separate clinically significant entities. Homocystine (an oxidized form of homocysteine) is not measured by Genova. SAH and homocystine levels are negligible as compared to homocysteine, though direct comparisons have not yet been done by Genova.
----------------------
References:
- Schalinske KL, Smazal AL. Homocysteine imbalance: a pathological metabolic marker. Adv Nutr. 2012;3(6):755-762. [L]
- Castro R, Rivera I, Blom HJ, Jakobs C, Tavares de Almeida I. Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inher Metab Dis. 2006;29(1):3-20 [L]
- Stabler SP, Lindenbaum J, Savage DG, Allen RH. Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood. 1993;81(12):3404-3413. [L]
- Williams KT, Schalinske KL. New insights into the regulation of methyl group and homocysteine metabolism. J Nutr. 2007;137(2):311-314. [L]
- Kerins DM, Koury MJ, Capdevila A, Rana S, Wagner C. Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine. Am J Clin Nutr. 2001;74(6):723-729. [L]
- Wagner C, Koury MJ. S-Adenosylhomocysteine - a better indicator of vascular disease than homocysteine. Am J Clin Nutr. 2007;86(6):1581-1585. [L]
- Poirier LA, Brown AT, Fink LM, et al. Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. Metabolism. 2001;50(9):1014-1018. [L]
- Behera J, Bala J, Nuru M, Tyagi SC, Tyagi N. Homocysteine as a pathological biomarker for bone disease. J Cell Physiol. 2017;232(10):2704-2709. [L]
- Gariballa S. Testing homocysteine-induced neurotransmitter deficiency, and depression of mood hypothesis in clinical practice. Age Ageing. 2011;40(6):702-705. [L]
- Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psych. 2008;79(4):368-376. [L]
- Obeid R, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W. Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem. 2009;55(10):1852- 1860. [L]
- Popp J, Lewczuk P, Linnebank M, Cvetanovska G, Smulders Y, Kölsch H. Homocysteine metabolism and cerebrospinal fluid markers for Alzheimer’s disease. J Alzheimers Dis. 2009;18. [L]
- Kevere L, Purvina S, Bauze D, et al. Elevated serum levels of homocysteine as an early prognostic factor of psychiatric disorders in children and adolescents. Schizophr Res Treatment. 2012;2012:373261. [L]
- Hei G, Pang L, Chen X, et al. [Association of serum folic acid and homocysteine levels and 5, 10-methylenetetrahydrofolate reductase gene polymorphism with schizophrenia]. Zhonghua yi xue za zhi. 2014;94(37):2897-2901. [L]
- Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Int Med. 2001;161(5):695-700. [L]
- Plasma Homocyst(e)ine or Homocysteine New Engl J Med. 1995;333(5):325-325. [L]
- DeStefano Vea. Linkage disequilibrium at the cystathionine beta-synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine. Ann Human Genet. 1998;62(6):481-490. [L]
- Turner MA, Yang X, Yin D, Kuczera K, Borchardt RT, Howell PL. Structure and function of S-adenosylhomocysteine hydrolase. Cell Biochem Biophys. 2000;33(2):101-125. [L]
- Cullen CE, Carter GT, Weiss MD, Grant PA, Saperstein DS. Hypohomocysteinemia: a potentially treatable cause of peripheral neuropathology- Phys Med Rehab Clin. 2012;23(1):59-65. [L]
- Ohuchi S, Matsumoto Y, Morita T, Sugiyama K. High-casein diet suppresses guanidinoacetic acid-induced hyperhomocysteinemia and potentiates the hypohomocysteinemic effect of serine in rats. Biosci Biotechnol Biochem. 2008;72(12):3258-3264. [L]
- Kawakami Y, Ohuchi S, Morita T, Sugiyama K. Hypohomocysteinemic effect of cysteine is associated with increased plasma cysteine concentration in rats fed diets low in protein and methionine levels. J Nutr Sci Vitaminol. 2009;55(1):66-74. [L]
- Ho V, Massey TE, King WD. Effects of methionine synthase and methylenetetrahydrofolate reductase gene polymorphisms on markers of one-carbon metabolism. Genes Nutr. 2013;8(6):571- 580. [L]
- Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5(9):3481-3495. [L]
- Gaughan DJ, Kluijtmans LA, Barbaux S, et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis. 2001;157(2):451-456. [L]
- Ueland PM. Choline and betaine in health and disease. J Inher 20. Metab Dis. 2011;34(1):3-15. [L]
- van der Gaag MS, Ubbink JB, Sillanaukee P, Nikkari S, Hendriks HF. Effect of consumption of red wine, spirits, and beer on serum homocysteine. Lancet. 2000;355(9214):1522. [L]
- O’Callaghan P, European Cg, Meleady R, et al. Smoking and plasma homocysteine. Eur Heart J. 2002;23(20):1580-1586. [L]
Keeping track of your medical data and laboratory results while understanding what they mean empowers positive health outcomes.
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- Vitamin B6 or iron deficiency (CBS enzyme cofactors)
- Enzymatic deficiency in MTR/MTRR/BHMT [L], [L], [L]
- Folate deficiency with low choline intake [L]
- Alcohol [L]
- Tobacco [L]
-------------------
Elevated levels are associated with:
– Atherosclerosis and coronary artery disease
– Osteopenia
– Neurodegenerative conditions – Mood disorders
– IBD and colon cancer risk
--------------------
A chronic elevation in homocysteine levels results in a parallel increase in intracellular or plasma SAH, which is a more sensitive biomarker of cardiovascular disease than homocysteine and suggests that SAH is a critical pathological factor in homocysteine-associated disorders. Previous reports indicate that supplementation with folate and B vitamins efficiently lowers homocysteine levels but not plasma SAH levels, which possibly explains the failure of homocysteine-lowering vitamins to reduce vascular events in several recent clinical intervention studies.
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- Unknown clinical significance
- May be a sign of over-methylation, though literature not available
- CBS SNP in the presence of oxidative stress or inflammation [L], [L]
- AHCY deficiency (lack of vitamin B3) [L]
--------------
The clinical implications associated with low homocysteine levels are not well represented in literature. Furthermore, there is no consensus on what constitutes a ‘low level’ or if it is something that needs correcting.
However, because Hcy is used to make glutathione and is remethylated to maintain methionine levels, the theoretical importance of low Hcy exists. Without Hcy, glutathione production is compromised. Excessive oxidative stress may accelerate the transsulfuration pathway toward glutathione production, which can lower Hcy. A SNP in the CBS enzyme accelerates homocysteine transsulfuration, which may result in a low Hcy.
Many ‘methylation experts’ and key opinion leaders teach that low plasma homocysteine leads to disease and can be cancer-producing; therefore it should be corrected. Many recommend protein and sulfur-containing foods, as well as evaluating for excessive oxidative stress and decreasing methyl support. There is currently no literature that has looked at correcting low plasma homocysteine.
Literature is evolving to include low Hcy implications; however, the only literature-based clinical correlation currently available is an association with peripheral neuropathy. [L] There are a few animal studies looking for implications, physiologic impacts, and treatment strategies to correct hypohomocysteinemia, but currently no human studies exist. [L], [L]
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Betaine, Betaine/Choline Ratio, Choline, Cyst(e)ine, Cystathionine, Dimethylglycine (DMG), Glutathione, Glycine, Homocysteine, Met/Sulf Balance Ratio, Methionine, Methylation Balance Ratio, Methylation Index (SAM/SAH Ratio), S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), Sarcosine, Serine, Taurine
