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Thrombosis and Haemostasis Mar 2023Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and... (Review)
Review
Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and deficiencies in vitamin B12 and folate. In contrast, moderate hyperhomocysteinemia (15-30 µmol/L) is a modest predictor of cardiovascular risk. The recognition of homocysteine as a cardiovascular risk factor has been challenged by some but not all randomized clinical trials. We reviewed the main data of this controversy and formulated conclusions to be translated in clinical practice.Homocysteine-lowering trials have been performed in cardiovascular subjects with moderate but not intermediate/severe hyperhomocysteinemia despite the dose-effect risk association. The first meta-analyses found no benefit and led cardiology societies not recommending homocysteine in the assessment of cardiovascular risk. This guideline challenged the need to diagnose and treat the nutritional and genetic causes of intermediate/major hyperhomocysteinemia and was not revised when larger meta-analyses concluded to a reduced risk of stroke. In a recent observational study, 84% of consecutive cardiovascular patients assessed for homocysteine had intermediate or major hyperhomocysteinemia, which was properly assessed in only half of the cases and related to B12 and/or folate deficiency and Addison/Biermer disease in 55% of these cases.In conclusion, revisiting observational studies and clinical trials suggests that cardiovascular patients should be screened for hyperhomocysteinemia, when no other risk factor is found. Patients with intermediate/major hyperhomocysteinemia should be properly assessed and treated for B vitamin deficiencies and inherited disorders according to current guidelines. Further trials are needed to assess the effect of lowering homocysteine according to hyperhomocysteinemia categories at baseline.
Topics: Humans; Cardiovascular Diseases; Hyperhomocysteinemia; Folic Acid; Vitamin B 12; Risk Factors; Homocysteine
PubMed: 36170884
DOI: 10.1055/a-1952-1946 -
Giornale Italiano Di Nefrologia :... Aug 2021Patients with chronic kidney disease or end-stage renal disease experience tremendous cardiovascular risk. Cardiovascular events are the leading causes of death in these... (Review)
Review
Patients with chronic kidney disease or end-stage renal disease experience tremendous cardiovascular risk. Cardiovascular events are the leading causes of death in these patient populations, thus the interest in non-traditional risk factors such as hyperhomocysteinemia, folic acid and vitamin B12 metabolism is growing. Hyperhomocysteinemia is commonly found in CKD patients because of impaired renal metabolism and reduced renal excretion. Folic acid, the synthetic form of vitamin B9, is critical in the conversion of homocysteine to methionine like vitamin B12. Folic acid has also been shown to improve endothelial function without lowering homocysteine, suggesting an alternative explanation for the effect of folic acid on endothelial function. Whether hyperhomocysteinemia represents a reliable marker of cardiovascular risk and cardiovascular mortality or a therapeutic target in this population remains unclear. However, it is reasonable to consider folic acid with or without methylcobalamin supplementation as appropriate adjunctive therapy in patients with CKD. The purpose of this review is to summarize the characteristics of homocysteine, folic acid, and vitamin B12 metabolism, the mechanism of vascular damage, and the outcome of vitamin supplementation on hyperhomocysteinemia in patients with CKD, ESRD, dialysis treatment, and in kidney transplant recipients.
Topics: Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Failure, Chronic; Renal Dialysis; Vitamin B 12
PubMed: 34469084
DOI: No ID Found -
CNS Neuroscience & Therapeutics Feb 2024Homocysteine (Hcy) is an important metabolite in methionine metabolism. When the metabolic pathway of homocysteine is abnormal, it will accumulate in the body and... (Review)
Review
Homocysteine (Hcy) is an important metabolite in methionine metabolism. When the metabolic pathway of homocysteine is abnormal, it will accumulate in the body and eventually lead to hyperhomocysteinemia. In recent years, many studies have found that hyperhomocysteinemia is related to the occurrence and development of Parkinson's disease. This study reviews the roles of homocysteine in the pathogenesis of Parkinson's disease and illustrates the harmful effects of hyperhomocysteinemia on Parkinson's disease.
Topics: Humans; Parkinson Disease; Levodopa; Hyperhomocysteinemia; Homocysteine
PubMed: 37641911
DOI: 10.1111/cns.14420 -
Joint Bone Spine May 2009Bone tissue quality is determined not only by multiple architectural variables, but also by the mechanical properties of collagen type 1. Homocysteinuria is a genetic... (Review)
Review
Bone tissue quality is determined not only by multiple architectural variables, but also by the mechanical properties of collagen type 1. Homocysteinuria is a genetic disease whose manifestations include severe hyperhomocysteinemia and decreased bone strength. The effects of smaller homocysteine elevations on bone tissue are difficult to demonstrate in clinical studies. Studies in animals and in humans suggest that homocysteine may weaken collagen crosslinks and, if present in large amounts, interfere with bone remodeling. Whether routine homocysteine assays should be performed to detect bone frailty remains unclear. In clinical practice, the focus should be on identifying patients with potential causes of homocysteine elevation (e.g., medications), who should then be given vitamin D and folic acid supplementation if needed. This approach may improve not only bone health, but also vascular and general health.
Topics: Animals; Bone Density; Bone Remodeling; Bone and Bones; Disease Models, Animal; Homocysteine; Humans; Hyperhomocysteinemia; Mice; Osteoporosis
PubMed: 19217816
DOI: 10.1016/j.jbspin.2008.11.002 -
Sheng Li Xue Bao : [Acta Physiologica... Dec 2018Homocysteine (Hcy) is an intermediate metabolite of methionine metabolism. Hyperhomocysteinemia (HHcy) is defined as a condition characterized by plasma Hcy level above... (Review)
Review
Homocysteine (Hcy) is an intermediate metabolite of methionine metabolism. Hyperhomocysteinemia (HHcy) is defined as a condition characterized by plasma Hcy level above 16 μmol/L which can result from abnormal Hcy metabolism. HHcy has been confirmed to be related to cardio-cerebrovascular disease, peripheral vascular disorders, neurodegenerative diseases, diabetes, pregnancy-induced hypertension syndrome, liver cirrhosis and kidney diseases. In this review, we summarize the correlation between HHcy and kidney diseases. Elucidating the role of HHcy in kidney diseases may provide a new strategy to prevent and treat kidney diseases.
Topics: Homocysteine; Humans; Hyperhomocysteinemia; Kidney Diseases
PubMed: 30560269
DOI: No ID Found -
Biochimica Et Biophysica Acta May 2016Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10μM). While rare genetic mutations (CBS, MTHFR)... (Review)
Review
Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID). Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range; and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
Topics: Animals; Cognitive Dysfunction; Dementia, Vascular; Disease Models, Animal; Homocysteine; Humans; Hyperhomocysteinemia
PubMed: 26689889
DOI: 10.1016/j.bbadis.2015.11.015 -
Archives of Pathology & Laboratory... Jun 2007Homocysteine, a sulfur-containing amino acid, absent in natural diets, is a metabolic intermediary in transmethylation and transsulfuration reactions. Such reactions are... (Review)
Review
CONTEXT
Homocysteine, a sulfur-containing amino acid, absent in natural diets, is a metabolic intermediary in transmethylation and transsulfuration reactions. Such reactions are essential to normal cellular growth, differentiation, and function. Excess homocysteine is associated with vascular disease and related disorders.
OBJECTIVE
To review homocysteine metabolism, the pathogenesis and classification of hyperhomocysteinemia, and the published literature investigating the association of homocysteine and methylenetetrahydrofolate reductase defects with arterial and venous thromboembolism and related disorders. The role of vitamin supplementation in patients with hyperhomocysteinemia is addressed.
DATA SOURCES
Published medical and scientific literature. Articles addressing the objectives were selected and reviewed. Pertinent studies and conclusions were summarized, grouped, and contrasted.
CONCLUSIONS
The association of hyperhomocysteinemia and arterial and venous thrombosis is controversial. Severe hyperhomocysteinemia is associated with atherosclerosis. The effect of mild hyperhomocysteinemia is less certain. Coinheritance of methylenetetrahydrofolate reductase defects and factor V Leiden is likely to increase the risk of venous thromboembolism. The association of methylenetetrahydrofolate reductase defects combined with no additional thrombophilic risk factors with venous thrombosis is less clear. High doses of folic acid to lower homocysteine levels might not be necessary.
Topics: Homocysteine; Humans; Hyperhomocysteinemia; Methylenetetrahydrofolate Reductase (NADPH2); Thromboembolism
PubMed: 17550314
DOI: 10.5858/2007-131-872-HATAO -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2005Arteriosclerosis and its complications, such as heart attack and stroke, are the major causes of death in developed countries. It was believed that age, hyperlipidemia,... (Review)
Review
Arteriosclerosis and its complications, such as heart attack and stroke, are the major causes of death in developed countries. It was believed that age, hyperlipidemia, hypertension, diabetes and smoking are common risk factors for cardiovascular disease. In addition, overwhelming clinical and epidemiological studies have identified homocysteine (Hcy) as a significant and independent risk factor for cardiovascular disease. In healthy individuals, plasma Hcy is between 5 and 10 micromol/L. One cause of severe hypehomocys- teinemia (HHcy) is the deficiency of cystathionine beta-synthase (CBS), which converts Hcy to cystathionine. CBS homozygous deficiency results in severe HHcy with Hcy levels up to 100 to 500 micromol/L. Patients with severe HHcy usually present with neurological abnormalities, premature arteriosclerosis. It has been reported that lowering plasma Hcy improved endothelial dysfunction and reduced incidence of major adverse events after percutaneous coronary intervention. The mechanisms by which Hcy induces atherosclerosis are largely unknown. Several biological mechanisms have been proposed to explain cardiovascular pathological changes associated with HHcy. These include: (1) endothelial cell damage and impaired endothelial function; (2) dysregulation of cholesterol and triglyceride biosynthesis; (3) stimulation of vascular smooth muscle cell proliferation; (4) thrombosis activation and (5) activation of monocytes. Four major biochemical mechanisms have been proposed to explain the vascular pathology of Hcy. These include: (1) autooxidation through the production of reactive oxygen species; (2) hypomethylation by forming SAH, a potent inhibitor of biological transmethylations; (3) nitrosylation by binding to nitric oxide or (4) protein homocysteinylation by incorporating into protein. In summary, our studies, as well as data from other laboratories support the concept that Hcy is causally linked to atherosclerosis, and is not merely associated with the disease. Although folic acid, vitamin B12 and B6 can lower plasma Hcy levels, the long-term effects on cardiovascular disease risk are still unknown and judgments about therapeutic benefits await the findings of ongoing clinical trials.
Topics: Animals; Atherosclerosis; Cystathionine beta-Synthase; Homocysteine; Humans; Hyperhomocysteinemia; Reactive Oxygen Species
PubMed: 15830093
DOI: No ID Found -
Signal Transduction and Targeted Therapy Mar 2023Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological...
Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (βGPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-βGPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.
Topics: Mice; Animals; Ferroptosis; Hyperhomocysteinemia; Endothelial Cells; Kidney Diseases; Glycoproteins
PubMed: 36907919
DOI: 10.1038/s41392-023-01313-x -
BMC Ophthalmology Oct 2023Folate, a pteroylglutamic acid derivative, participates in fundamental cellular metabolism. Homocysteine, an amino acid, serves as an intermediate of the methionine... (Review)
Review
Folate, a pteroylglutamic acid derivative, participates in fundamental cellular metabolism. Homocysteine, an amino acid, serves as an intermediate of the methionine cycle and can be converted back to methionine. Hyperhomocysteinemia is a recognized risk factor for atherosclerotic and cardiovascular diseases. In recent decades, elevated plasma homocysteine levels and low folate status have been observed in many patients with retinal vascular diseases, such as retinal vascular occlusions, diabetic retinopathy, and age-related degeneration. Homocysteine-induced toxicity toward vascular endothelial cells might participate in the formation of retinal vascular diseases. Folate is an important dietary determinant of homocysteine. Folate deficiency is the most common cause of hyperhomocysteinemia. Folate supplementation can eliminate excess homocysteine in plasma. In in vitro experiments, folic acid had a protective effect on vascular endothelial cells against high glucose. Many studies have explored the relationship between folate and various retinal vascular diseases. This review summarizes the most important findings that lead to the conclusion that folic acid supplementation might be a protective treatment in patients with retinal vascular diseases with high homocysteine or glucose status. More research is still needed to validate the effect of folate and its supplementation in retinal vascular diseases.
Topics: Humans; Folic Acid; Hyperhomocysteinemia; Endothelial Cells; Methionine; Diabetic Retinopathy; Glucose; Homocysteine
PubMed: 37833663
DOI: 10.1186/s12886-023-03149-z