Treatment of mild hyperhomocystinemia in vascular disease patients
Franken DG; Boers GH; Blom HJ; Trijbels FJ; Kloppenborg PW
Department of Medicine, University Hospital Nijmegen, The Netherlands.
Arterioscler Thromb (U.S.) Mar 1994, 14 (3) p465-70.
Mild hyperhomocystinemia is recognized as a risk factor for premature arteriosclerotic disease. A few vitamins and other substances have been reported to reduce blood homocysteine levels, but normalization of elevated blood homocysteine concentrations with any of these substances has not been reported. Therefore, we screened 421 patients suffering from premature peripheral or cerebral occlusive arterial disease by oral methionine loading tests for the presence of mild hyperhomocystinemia. Thirty-three percent of patients with peripheral, and 20 percent of patients with cerebral occlusive arterial disease, were identified with mild hyperhomocystinemia (14 percent of the men, 34 percent of the premenopausal women, and 26 percent of the postmenopausal women). Mildly hyperhomocystinemic patients were administered vitamin B6 250 mg daily. After 6 weeks methionine loading tests were again assessed to evaluate the effect of treatment. Patients with non-normalized homocysteine concentrations were further treated with vitamin B6 250 mg daily and/or folic acid 5 mg daily and/or betaine 6 g daily, solely or in any combination. Vitamin B6 treatment normalized the afterload homocysteine concentration in 56 percent of the treated patients (71 percent of the men, 45 percent of the premenopausal women, and 88 percent of the postmenopausal women). Further treatment resulted in a normalization of homocysteine levels in 95 percent of the remaining cases. Thus, mild hyperhomocystinemia, which is frequently encountered in patients with premature arteriosclerotic disease, can be reduced to normal in virtually all cases by safe and simple treatment with vitamin B6, folic acid and betaine, each of which is involved in methionine metabolism.
Can Lowering Homocysteine Levels Reduce Cardiovascular Risk?
The New England Journal of Medicine, February 2, 1995;332(5):328-329.
Consistent findings have emerged from more than 20 case-control and cross-sectional studies of over 2,000 subjects indicating that patients with stroke and other cardiovascular diseases tend to have higher levels of homocysteine than those without the disease even though most have values within the normal range. In the Physician's Health Study, the 271 men who later had myocardial infarctions had significantly higher mean base-line levels of homocysteine than matched controls who were free of infarction. Men whose homocysteine levels were in the highest 5 percent had three times the risk of myocardial infarction than those with lower levels, even after adjustment for coronary risk factors. The prevalence of carotid-artery stenosis has been shown to be related to increasing plasma levels of homocysteine. One hypothesis regarding homocysteine's effects on cardiovascular disease is that damage stems from a toxic effect by homocysteine on vascular endothelium, which impairs the production of endothelium-derived relaxing factor. Homocysteine may stimulate the proliferation of smooth muscle cells, which is part of atherogenesis. Homocysteine can also act as a thrombogenic agent. The most dramatic elevations of homocysteine, which lead to life threatening vascular abnormalities at a young age, are due to an enzyme defect. Inadequate folic acid intake is the main determinant of homocysteine-related increase in carotid-artery thickening. Folic acid, vitamins B6 and B12, all play an important role in homocysteine metabolism. Homocysteine levels reach a stable low level only when folic acid intakes of approximately 400 ug per day or more are sustained. Folic acid supplements in the range of 1 to 2 mg per day are generally innocuous, and usually are sufficient to reduce or normalize high homocysteine levels, even if the elevation is not due to inadequate folic acid supplementation. When folic acid consumption is high the minor and common genetic variances have no clinical significance. But when folic consumption is marginal the risk may be elevated. In the Physician's Health Study, 5 percent of the controls had plasma homocysteine levels above 15.8 umol/L, the level which is associated with a three-fold increased risk of myocardial infarction. In the older and less highly selected population of the Framingham Heart Study, 21 percent had high levels of homocysteine. The author notes, "Because the weight of evidence is substantial and the intervention appears to be benign, it may be possible to make broad preliminary recommendations based on trials of secondary prevention or disease progression rather than wait for large, expensive and prolonged trials of primary prevention. In the meantime, it will be prudent to ensure adequate dietary intake of folate".
Hyperhomocysteinaemia and end stage renal disease
Journal of Nephrology (Italy), 1997, 10/2 (77-84)
Vascular disease is a major cause of morbidity and mortality in end stage renal failure patients and cannot be explained entirely by the prevalence of traditional risk factors for atherosclerosis. A high plasma homocysteine concentration, which is a risk factor for vascular disease is found in patients with end stage renal disease. The exact cause for the hyperhomocysteinaemia seen in these patients is unknown, al metabolism of homocysteine. High homocysteine concentrations may also be attributable to a deficiency of folate, vitamin B6 or vitamin B12 although, because of supplementation, these vitamins may be present in high concentrations in renal patients. The occurrence of hyperhomocysteinaemia despite high plasma vitamin concentration could be due to altered metabolism or inhibition of intracellular vitamin activity. A number of studies have now established hyperhomocystinaemia to be an independent risk factor for atherosclerosis in patients with end-stage renal disease. Plasma homocysteine concentrations can be reduced by administration of folic acid either alone or combined with vitamin B12 or vitamin B6. The effects of such reduction on vascular risk in renal failure patients needs further study.
High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients.
Kidney Int (UNITED STATES) Jan 1996, 49 (1) p147-52
Hyperhomocysteinemia, an arteriosclerotic risk factor, persists in 75% of dialysis patients despite routine low dose supplementation with the B-vitamin co-factors/substrates for homocysteine (Hcy) metabolism, and normal or supernormal plasma status of these vitamins (Atherosclerosis 114:93, 1995). We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid (15 mg/day), B-6 (100 mg/day), and B-12 (1 mg/day) to the usual daily dosing of 1 mg folic acid, 10 mg B-6, and 12 micrograms B-12, in 27 hyperhomocysteinemic dialysis patients. Total plasma homocysteine was measured at baseline, and after four and eight weeks. Blinded analyses revealed no evidence of toxicity in the group randomized to supraphysiologic dose B-vitamin supplementation. Plasma homocysteine was significantly reduced after both four weeks (-29.8% vs. -2.0%; P = 0.0024) and eight weeks (-25.8% vs. +0.6%; P = 0.0009) of active versus placebo treatment. Also, 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hcy reduced to within the normative range (< 15 mumol/liter). Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients.
Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure.
Miner Electrolyte Metab (SWITZERLAND) 1996, 22 (1-3) p106-9
Moderate hyperhomocysteinemia, a risk factor for premature atherosclerosis, is present in chronic uremic patients. We prospectively evaluated the effects of sequential supplementation with pyridoxine (70 mg/day) and folic acid (10 mg/day) for two 3-month periods in 37 nondialyzed patients (29 males) with creatinine clearance (Ccr) ranging from 10 to 80 ml/min, whose plasma vitamin B12 and folate level was in the normal range. Mean (+/- SD) baseline plasma total homocysteine (Hcy) was 14.9 +/- 5.2, 16.5 +/- 5.1 and 26.1 +/- 12.1 mumol/l (upper limit in 45 healthy controls 14.1 mumol/l) in patients with CCr 40-80, 20-40 and < 20 ml/min, respectively. Following pyridoxine Hcy did not significantly decrease whereas following folic acid Hcy decreased significantly to 9.9 +/- 2.9 (-33% vs. baseline), 10.3 +/- 3.4 (-37%) and 15.4 +/- 5.5 (-40%), respectively (Student's paired t test, p < 0.001) in the 3 groups. We conclude that folate (but not pyridoxine) pharmacologic supplementation is effective in lowering elevated plasma Hcy in chronic renal failure patients, thus suggesting that enhancing the Hcy remethylation pathway may overcome hyperhomocysteinemia in such patients. In view of the potential atherogenic effects of hyperhomocysteinemia, long-term folate supplementation should be considered in uremic patients.
The role of folic acid in deficiency states and prevention of disease.
Swain R.A.; St. Clair L.
Dr. R.A. Swain, Charleston Division, Dept. of Family and Sports Medicine, West Virginia University, 1201 Washington St. East, Charleston, WV 252701 USA
Journal of Family Practice (USA), 1997, 44/2 (138-144)
Folic acid, a water-soluble vitamin, has been used since the 1940s to treat some cases of macrocytic anemia without neurologic disease. Folate deficiency is best diagnosed with red blood cell folate levels along with macrocytosis and/or megaloblastic anemia. In addition to reversing overt deficiency, the vitamin may reduce the incidence of neural tube defects by 45% in women who receive 400 microg per day. It is recommended that all women of childbearing age take 400 microg of folate per day. Elevations in homocysteine levels, a metabolite intimately associated with folate, are also being found with increasing regularity in those with cardiovascular diseases. Homocysteine levels are reduced by folic acid administration. Therefore, there is some biologic plausibility, but not currently direct proof, for the assumption that folate supplements may prevent heart disease, stroke, and peripheral arterial disease. Controlled trials should take place before widespread food supplementation with folate is carried out on a large scale because of the possibility of outbreaks of permanent B12-related neurologic damage in those with undiagnosed pernicious anemia. However, if a patient has a premature cardiovascular event and has minimal risk factors, ordering a test to determine homocysteine level may be advisable, and if elevated, treating with folic acid supplement as long as B12 deficiency does not coexist.
Prevention of neural tube defects.
Gyali ut 2-6, 1966 Budapest Hungary
CNS Drugs (New Zealand), 1996, 6/5 (399-412)
Recent intervention studies have shown that periconceptional supplementation with folic acid-containing multivitamins or pharmacological doses of folic acid alone can reduce the occurrence and recurrence of neural tube defects. This primary preventive method may also reduce the occurrence of other major congenital abnormalities, mainly cardiovascular and urinary tract defects. The underlying biological mechanisms of this protective effect are still not understood, but naturally occurring folates (polyglutamates) or synthetic folic acid (monoglutamate) have a key role. At present, 3 approaches to supplementation with folic acid exist: (i) consumption of a diet that is rich in folate and other vitamins; (ii) periconceptional supplementation; and (iii) fortification of food to ensure appropriate folic acid consumption for all women of childbearing age who are capable of becoming pregnant. The debate over supplementation concerns which vitamins (folic acid-containing multivitamins or folic acid alone?) and what dosages (0.4, 0.8 or 4 to 5 mg/day of folic acid?) are to be given to whom (is it worthwhile differentiating between women at high and low risk?).
Vitamins as homocysteine-lowering agents.
Department of Medicine, County Hospital, S-391 85 Kalmar Sweden
Journal of Nutrition (USA), 1996, 126/4 SUPPL. (1276S-1280S)
Moderate hyperhomocysteinemia is, today, considered an established risk factor for cardiovascular disease. A graded dose-response relationship between plasma homocysteine concentration over its full range and cardiovascular risk strongly supports causality. Therefore, intervention studies with homocysteine-lowering vitamins are needed. This mini review shows that supplementation with folic acid not only markedly reduces elevated plasma homocysteine concentrations but also reduces normal homocysteine concentrations. Folic acid doses of <1 mg/d may be effective. Supplementation with a combination of folic acid and cyanocobalamin will secure full homocysteine-lowering effect and prevent occurrence of vitamin B-12 deficiency during the course of therapy.
Homocysteine: Relation with ischemic vascular diseases.
Piolot A.; Nadler F.; Parez N.; Jacotot B.
Serv. de Med. Int.-Nutr.-Metab., CHU Henri-Mondor, 94010 Creteil Cedex France
Revue de Medecine Interne (France), 1996, 17/1 (34-45)
Homocysteine, a sulfur-containing amino acid, is an intermediate metabolite of methionine. Patients with homocystinuria and severe hyperhomocysteinemia develop premature arteriosclerosis and arterial thrombotic events, and venous thromboembolism. Studies suggest that moderate hyperhomocysteinemia can be considered as an independent risk factor in the development of premature cardiovascular disease. In vitro, homocysteine has toxic effects on endothelial cells. Homocysteine can promote lipid peroxidation and damage vascular endothelial cells. Moreover, homocysteine interferes with the natural anticoagulant system and the fibrinolytic system. Homocysteinemia should be known in patients with premature vascular diseases, especially in subjets with no risk factors. Folic acid, vitamin B6 can lower homocysteine levels.
Drug therapy during pregnancy.
Curr Opin Obstet Gynecol (UNITED STATES) Feb 1992, 4 (1) p43-7
A randomized prospective trial has shown that folic acid started before conception and continued for the first trimester reduces the risk of recurrence of neural tube defects by 72% in women with a previously affected child. Carbamazepine exposure in utero is associated with a 1% risk of spina bifida. Long-term follow-up of antenatal exposure to phenobarbital and carbamazepine in two groups of infants shows no neurologic differences between the two groups. Magnesium sulfate is more effective in prevention of recurrent eclamptic seizures than phenytoin. During pregnancy, the need for thyroxine increases in many women. Vitamin B6 and ginger are both effective for nausea and vomiting in early pregnancy. Low-dose aspirin does not change the course of preeclampsia when it is started after the diagnosis is made. Angiotensin-converting enzyme inhibitors cause significant disturbances of fetal and neonatal renal function. Prophylactic beta-adrenergic agents fail to prevent prematurity in twins. Oral tocolysis with magnesium chloride or ritodrine is no more effective than observation alone. The risk of primary pulmonary hypertension in the newborn after indomethacin tocolysis is increased with prolonged therapy. Lithium causes polyhydramnios from fetal diabetes insipidus in utero. Treatment of Ureaplasma urealyticum infection with erythromycin during pregnancy does not eliminate the organism from the lower genital tract and does not improve perinatal outcome. (21 Refs.)
Clinical rise of a combination containing phosphocreatinine as adjuvant to physiokinesiotherapy
RIABILITAZIONE (ITALY), 1976, 9/2 (51-62)
The authors make a clinical contribution to the therapeutic use of phosphocreatinine, both alone and in combination with vitamin B12, folic acid, vitamin B6 and fructose 1-6 diphosphate. The study was carried out on 24 adult patients of both sexes, suffering from neuromyolesions (paraplegia, hemiparesis, tetraparesis, neuraxitis, myopathy, radiculoneuritis) and presenting, as therapeutic indications, conditions of organic wasting, marked asthenia, cachexia, or the requirement of physical performance and intense muscular effort in connection with the use of kinesitherapy techniques. An analysis of the collected data showed that both phosphocreatinine preparations (the simple form and combined with vitaminic coenzymes) induced significant improvements in the initial symptomatology; no statistically significant difference was observed between the 2 treatments. Particular interest is placed on the finding with regard to the effect on motor re education; in fact, the 2 preparations considered phosphocreatinine influenced this parameter favourably in over half the cases investigated. The drug was excellently tolerated in all the cases studied, from both the clinical point of view and the blood chemistry standpoint. In conclusion, the results obtained make the therapeutic use of phosphocreatinine undoubtedly useful as a valid factor in association with physiokinesitherapy.
Gastrointestinal infections in children
CURR. OPIN. GASTROENTEROL. (United Kingdom), 1994, 10/1 (88-97)
Gastrointestinal infections are common and important in infants and young children, particularly where poor hygiene and living conditions allow the spread of infectious agents. With increasing information about microorganisms that cause these infections and improved methods to detect them, many episodes that were once undiagnosed can now be attributed to previously unrecognized viruses, bacteria, and other pathogens. These advances facilitate better management and will permit more effective control and preventive strategies. This review highlights some recent reports about enterovirulent classes of Escherichia coli, including E. coli O157:H7, which causes the hemolytic-uremic syndrome and hemorrhagic colitis; Campylobacter species and a new Campylobacter-like organism (Arcobacterbutzlerlli Helicobacter pylori; Aeromonas species; and rotavirus. Important new information about intestinal parasites, including Giardia and Cryptosporidium, has emerged that should prove of practical use in diagnosis and management in places where these parasites are prevalent in children, particularly in parts of the world where HIV infection has become established. A newly described organism, so far called coccidian-like or cyanobacterium-like body, has been found in patients with prolonged diarrhea (including travelers and expatriate residents) in several countries; the name Cyclospora cayetanensis has been proposed for this organism. This year's review concludes with a short commentary on some recent reports about risk factors that predispose children to gastrointestinal infections, eg, nutritional status, domestic hygiene, maternal hygiene behavior, and young children gathered in communal facilities like day care centers. Immune function status is also important, and deficiencies of single nutrients such as vitamin A, pyridoxine, folic acid, iron, and zinc may also play a role.
Folic acid supplementation improves erythropoietin response.
Nephron (SWITZERLAND) 1995, 71 (4) p395-400
Therapy with recombinant human erythropoietin (rhEPO) has become most valuable for the treatment of renal anemia in patients with various chronic renal diseases. For the first time this study presents data showing that rhEPO affects the metabolism of folic acid. There were 13 patients enrolled; they suffered from different chronic renal diseases and showed an impaired responsiveness to rhEPO therapy. Before starting rhEPO therapy the mean corpuscular volume of erythrocytes (MCV) was measured; MCV was 90.4 fl. During rhEPO therapy the MCV increased significantly by 14.8 fl (p < 0.05). The developing macrocytic anemia was overcome when folic acid was administered additionally for a mean period of 3.14 +/- 3 months. Hematocrit (Hct) also responded accordingly. Whereas Hct did not increase adequately during the exclusive treatment with rhEPO, an increase in Hct from 23 +/- 3.3 to 30 +/- 4.2% (p < 0.01) was observed after the addition of folic acid. These results are rather remarkable as folic acid serum levels were clearly within the normal range during the whole study period. So it can be concluded that rhEPO therapy results in an increased demand for folic acid. Even if serum concentrations are within the normal range, the administration of folic acid will enhance the effectiveness of rhEPO therapy so that the rhEPO dosage can be reduced.
Megaloblastic anemia in patients receiving total parenteral nutrition without folic acid or vitamin B12 supplementation.
Can Med Assoc J (CANADA) Jul 23 1977, 117 (2) p144-6
Pancytopenia developed in four patients receiving postoperatively total parenteral nutrition (TPN). Symptoms and signs were related mainly to underlying bowel disease. Hematologic abnormalities, first noted from 4 to 7 weeks following institution of TPN, consisted of normocytic anemia (mean decrease in hemoglobin value, 2.2 g/dL), occasional macrocytes being noted, leukopenia (range of leukocyte counts, 1.2 to 3.6 X 10(9) L), some hypersegmented neutrophils being detected, and clinically significant thrombocytopenia (range of platelet counts, 25 to 52 X 10(9)/L). In all patients the bone marrow showed megaloblastic changes, with ring sideroblasts, although pyridoxine was included in the TPN regimens. Serum vitamin B12 values were normal in one patient and at the lower limit of normal in the other two patients in whom it was measured, while serum or erythrocyte folate values, or both, were reduced in three patients. Full hematologic response was observed in the four patients after folic acid replacement therapy; leukocytosis and thrombocytosis were noted in three. Thus, folic acid and possibly vitamin B12 should be added routinely to TPN regimens to prevent deficiency of either substance.
[Is it necessary to supplement with folic acid patients in chronic dialysis treated with erythropoietin?]
Rev Med Chil (CHILE) Jan 1993, 121 (1) p30-5
The need for folate supplementation in patients on chronic hemodialysis receiving erythropoietin (EPO) remains to be determined. Thirty five patients on chronic hemodialysis were studied; of these 10 did not receive EPO nor folic acid, 12 received EPO with folic acid supplementation and the rest only EPO. In these groups, after 9 +/- 2.9 months of treatment, serum olate levels were normal, although higher in those patients supplemented with folate. An additional group of 8 patients, previously supplemented with 2 mg/week of folate, was studied during the first 10 weeks of EPO treatment. In these patients a significant decrease in serum folate was observed from the first to the tenth week (from 18 +/- 29 to 7 +/- 4 ng/ml). Red cell folate had an unexplained raise during the first four weeks and went back to near basal levels during the next weeks. As expected serum ferritin levels decreased at the end of the study period, but remained over 100 ng/ml Red blood cell protoporphyrin remained normal. We thus recommend the measurement of serum and red cell folate levels during the first and tenth weeks of the induction phase of EPO treatment. Also, folic acid supplementation in doses of 2 mg/week is recommended to maintain adequate body stores, specially in extremely anorectic hemodialysis patients or those in whom strict diets without fruits are prescribed.
[Primary prophylaxis against cerebral toxoplasmosis. Efficacy of folinic acid in the prevention of hematologic toxicity of pyrimethamine]
Presse Med (FRANCE) Apr 2 1994, 23 (13) p613-5
OBJECTIVES: Cerebral toxoplasmosis is the most frequent opportunistic infection in patients with acquired immune deficiency syndrome in France. We evaluated the effect of adding folic acid to the standard treatment (including pyrimethamine) on preventing induced cytopenia in order to determine the optimal dose. METHODS: From January to September 1990, pyrimethamine (50 mg 3 times per week) was given as primary prophylaxis against toxoplasmosis to 30 patients who were positive for human immunodeficiency virus (CDC classes II or II, CD4 counts < 200/mm3). The patients were randomly divided into three groups given 5, 25 and 0 mg folic acid 3 times per week. Associated treatments were the same in all patients (zidovudine 600 mg/d, pentamidine isethionate aerosol, 300 mg, once a month). Blood cell counts and lymphocyte subset counts were made on days 0, 30, 90 and 180. RESULTS: Two patients were lost to follow-up and between day 90 and 180, 3 were excluded due to other opportunist infection and 1 due to zidovudine induced anaemia. Between the groups, there was no difference in haemoglobin level or cell counts on day 0. No haematologic toxicity was observed at day 90. Haemoglobin was significantly reduced in the control group (0 mg folic acid) on day 180 (mean haemoglobin on day 180, 13.8, 13.1 and 12.1 g/dl in groups 1, 2 and 3 respectively). No variation in polynuclear neutrophil counts was observed. CONCLUSION: These findings suggest that folic acid has a moderate beneficial effect on preventing haematologic disease in patients treated with pyrimethamine. There was no observed dose effect.
[Myelopathy and macrocytic anemia associated with a folate deficiency. Cure by folic acid]
Ann Med Interne (Paris) (FRANCE) May 1975, 126 (5) p339-48
The authors report a case of myelopathy associated with macrotic anemia. The prior inefficacy of treatment with B1, B6 and B12 vitamins, in spite of a normal Schilling test, suggested the possibility of folate deficiency, the concentration of which was found very low in the serum (1.5 mg/ml). The addition of folic acid to the vitamins already administered without success, was followed by rapid recovery of the anemia and a frank neurological improvement maintained after 10 months follow-up. The rare similar cases observed in the world literature are analysed here. The other neurological manifestations, due to folate deficiency, the etiological circumstances and the methods of diagnosis are recalled.
Acute folate deficiency associated with intravenous nutrition with aminoacid-sorbitol-ethanol: prophylaxis with intravenous folic acid.
Br J Haematol (ENGLAND) Dec 1977, 37 (4) p521-6
Preoperative folate levels were initially normal in 30 patients with gastrointestinal tract disease but fell within 48 h by 60-95% in 20 patients who received intravenous nutrition for 6-12 d with aminoacid-sorbitol-ethanol (ASE). This depression persisted in patients not given folate supplements. Folate levels in 10 control patients not given ASE showed only minimal decline. Haematological changes were reduced to a minimum in 10 patients given 0.5 mg i.v. folic acid daily whilst eight unsupplemented patients showed evidence of megaloblastic haemopoiesis. Three of these eight patients developed thrombocytopenia and/or leukopenia which was fatal in one patient.
Common mutation in methylenetetrahydrofolate reductase: Correlation with homocysteine metabolism and late-onset vascular disease
Circulation (USA), 1996, 94/12 (3074-3078)
Background: Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this mutation in many subjects with and without vascular disease and related it to homocysteine and folate levels. Methods and Results: DNA from 247 older subjects with vascular disease and 594 healthy subjects without vascular disease (in three different control groups) was screened for the MTHFR 677 C-to-T mutation. Within each group, 9% to 17% of the subjects were homozygous for this mutation, and the mutant allele frequency was 31% to 39%. The genotype distributions, homozygote frequencies, and allele frequencies did not differ significantly between the study groups. In the vascular disease subjects, despite significantly lower folate levels in MTHFR homozygotes, there was no significant difference in homocysteine levels among the MTHFR genotype groups. The negative slope of the regression line relating homocysteine and folate was significantly steeper for those with a homozygous MTHFR mutation compared with those without this mutation. Conclusions: Although the thermolabile MTHFR mutation is very common, it does not appear to be a significant genetic risk factor for typical late-onset vascular disease. Because MTHFR homozygotes have increased homocysteine with low folate levels, this mutation may contribute to early-onset or familial vascular disease. The genotype dependence of the folate-homocysteine correlation further suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletiacid therapy.
Homocystinuria: What about mild hyperhomocysteinaemia?
Postgraduate Medical Journal (United Kingdom), 1996, 72/851 (513-518)
Hyperhomocysteinaemia is associate risk of atherosclerotic vascular disease and thromboembolism, in both men and women. A variety of conditions can lead to elevated homocysteine levels, but the relation between high levels and vascular disease is present regardless of the underlying cause. Pooled data from a large number of studies demonstrate that mild hyperhomocysteinaemia after a standard methionine load is present in 21% of young patients with coronary artery disease, in 24% of patients with cerebrovascular disease, and in 32% of patients with peripheral vascular disease. From such data an odds ratio of 13.0 (95% confidence interval 5.9 to 28.1), as an estimate of the relative risk of vascular disease at a young age, can be calculated in subjects with an abnormal response to methionine loading. Furthermore, mild hyperhomo-cysteinaemia can lead to a two- or three-fold increase in the risk of recurrent venous thrombosis. Elevated homocysteine levels can be reduced to normal in virtually all cases by simple and safe treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism. A clinically beneficial effect of such an intervention, currently under investigation, would make large-scale screening for this risk factor mandatory.
Dietary methionine imbalance, endothelial cell dysfunction and atherosclerosis
Nutrition Research (USA), 1996, 16/7 (1251-1266)
Dietary factors can play a crucial role in the development of atherosclerosis. High fat, high calorie diets are well known risk factors for this disease. In addition, there is strong evidence that dietary animal proteins also can contribute to the development of atherosclerosis. Atherogenic effects of animal proteins are related, at least in part, to high levels of methionine in these proteins. An excess of dietary methionine may induce atherosclerosis by increasing plasma lipid levels and/or by contributing to endothelial cell injury or dysfunction. In addition, methionine imbalance elevates plasma/tissue homocysteine which may induce oxidative stress and injury to endothelial cells. Methionine and homocysteine metabolism is regulated by the cellular content of vitamins B6, B12, riboflavin and folic acid. Therefore, deficiencies of these vitamins may significantly influence methionine and homocysteine levels and their effects on the development of atherosclerosis.
Homocysteine, folate, and vascular disease
Journal of Myocardial Ischemia (USA), 1996, 8/2 (60-63)
Current evidence indicates that the genesis of atherosclerotic disease is multifactorial. One of the newly recognized factors that contributes to this process is raised homocysteine blood levels. A variety of atherosclerotic procd by elevated homocysteine levels, including stimulation of smooth muscle cell growth, impairment of endothelial regeneration, oxidation of LDL particles, and thrombogenesis. A generic defect may account for some instances of hyperhomocysteinemia, but the majority of persons with high levels do not have known genetic defects to account for their elevations. Low levels of folic acid, vitamin B12, and pyridoxine appear to underlie most cases of elevated homocysteine levels. Adding folic acid to the diet may reduce homocysteine levels, but a link between increasing folic acid and lower risk of atherosclerotic disease has yet to be demonstrated in clinical trials. However, increasing daily folic acid intake is not unjustified in some patients. Since this may mask B12 deficiency, a supplement of cobalamin, 1 mg/d, has been proposed. In the final analysis, a clinical trial is needed to determine the true significance of hyperhomocysteinemia. Meanwhile, physicians and patients can consider increasing the daily folate intake by eating more oranges, leafy vegetables, wheat products, and cereals.
Hyperhomocysteinemia and venous thromboembolic disease.
Haematologica (ITALY) Mar-Apr 1997, 82 (2) p211-9
BACKGROUND AND OBJECTIVE: In spite of the large number of reports showing that hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and arterial occlusive disease, this metabolite of the methionine pathway is measured in relatively few laboratories and its importance is not fully appreciated. Recent data strongly suggest that mild HHcy is also involved in the pathogenesis of venous thromboembolic disease. The aim of this paper is to analyze the most recent advances in this field. EVIDENCE AND INFORMATION SOURCES: The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition the authors of the present article have been working in the field of mild HHcy as cause of venous thromboembolic disease. STATE OF ART AND PERSPECTIVES: The studies examined provide very strong evidence supporting the role of moderate HHcy in the development of premature and/or recurrent venous thromboembolic disease. High plasma homocysteine levels are also a risk factor for deep vein thrombosis in the general population. Folic acid fortification of food has been proposed as a major tool for reducing coronary artery disease mortality in the United States. Vitamin supplementation may also reduce recurrence of venous thromboembolic disease in patients with HHcy. At the present time, however, the clinical efficacy of this approach has not been tested. In addition, the bulk of evidence indicates that fasting total homocysteine determinations can identify up to 50% of the total population of hyperhomocysteinemic subjects. Patients with isolated methionine intolerance may benefit from vitamin B6 supplementation. Homocysteine-lowering vascular disease prevention trials are urgently needed. Such controlled studies, however, should not focus exclusively on fasting homocysteine determinations and folic acid monotherapy. (127 Refs.)
Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.
Curr Opin Lipidol (UNITED STATES) Feb 1997, 8 (1) p28-34
Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.
[Homocysteine, a risk factor of atherosclerosis]
Arch Mal Coeur Vaiss (FRANCE) Dec 1996, 89 (12) p1667-71
Homocysteine is a sulphurated amino acid which, at high plasma concentrations, predisposes to thrombosis and induces focal arteriosclerosis. These characteristics have been established both in patients with homocystinuria, a genetic disease in which homocysteine accumulates in the blood, and in animals submitted to intravenous infusions of this amino acid. Many recent publications have addressed the problem of whether mild increases in plasma homocysteine predisposed to the development of the usual forms of atherosclerosis. Transverse epidemiological studies have established a correlation between homocysteine levels and atherosclerosis at all its vascular localisations, coronary, carotid and lower limb. Multivariate analysis in several prospective studies have shown plasma homocysteine to be an independent risk factor for cerebrovascular accidents and myocardial infarction. Causes of mild increases in plasma homocysteine are usually dietetic deficiencies in folic acid, vitamin B6 or B12, or genetic by mutation of the methylene-tetrahydrofolate reductase. Renal failure is also associated with a high risk in plasma homocysteine levels. However, the toxicity of homocysteine to the arterial wall at slightly elevated concentration remains speculative.
Hyperhomocysteinemia induced by folic acid deficiency and methionine load--applications of a modified HPLC method.
Clin Chim Acta (NETHERLANDS) Aug 15 1996, 252 (1) p83-93
The increasing possibility that homocysteine might be involved in atherosclerosis in non-homocysteinuric subjects has required the measurement of low concentrations of this aminothiol in biological samples. The procedure described here represents an improvement of different HPLC methods. We utilized an isocratic HPLC system with fluorescence detection of plasma total homocysteine derivatized after reaction with ammonium 7-fluoro-benzo-2-oxa-1,3-diazole-4-sulphonate. With the help of the rapidly eluting internal standard N-acetyl-cysteine, the method ensures very good recovery (approximately 100%), reproducibility and precision (within-assay 2.31%; day-to-day: 2.8%) in the physiological concentration range. This procedure allowed us to validate various animal models of hyperhomocysteinemia such as dietary folic acid deficiency in rat and acute methionine loads in rat and hamster. Using this method, we also confirmed that men have higher plasma total homocysteine levels than women. Due to its simplicity and reliability, our procedure is suitable for routine analysis of total homocysteine and other aminothiols (cysteine, cysteinyl-glycine and glutathione) in biological samples, as required in clinical and research laboratories.
Cas Lek Cesk (CZECH REPUBLIC) May 2 1996, 135 (9) p266-9
Similarly as in other inborn metabolic diseases the cause of hyperhomocysteinaemia are interactions between genetically conditioned changes most frequently due to reduced cystathionine-beta synthase activities and negative factors of the external environment. Negative environmental factors include above all a high dietary animal protein consumption which is the main methionine donor and a low intake of protein of plant origin. Another negative factor is a low intake of foods of plant origin. Fruits and vegetables are among others important sources of folic acid and pyridoxine. Substitution therapy with vitamin preparations is essential in homozygotes and in high risk heterozygotes of cystathionine beta-synthase. This treatment is also necessary during the periconception period in hyperhomocysteinaemic fertile women to reduce the risk of neurotubal defects in their future children. So far investigations are lacking which would provide evidence of a reduced risk of ischaemic heart disease and other cardiovascular diseases in isolated treatment of mildly elevated levels of plasma homocysteine. To elucidate the part played by hyperhomocysteinaemia in hastening of the atherogenetic process further studies are essential, focused on the interaction of elevated homocysteine plasma levels, dyslipoproteinaemias, hyperfibrinogenaemia and other metabolic indicators in this process. (31 Refs.)
Hyperhomocysteinaemia: a role in the accelerated atherogenesis of chronic renal failure?
Neth J Med (NETHERLANDS) May 1995, 46 (5) p244-51
Moderate hyperhomocysteinaemia has recently been established as an independent risk factor for atherothrombotic disease. It might be caused by heterozygosity for cystathionine beta-synthase deficiency, an enzyme involved in the conversion of methionine to cysteine through the transsulphuration pathway or by inherited thermolability of the enzyme which remethylates homocysteine into methionine. In chronic renal failure (CRF) homocysteine levels are significantly elevated at a relatively early stage. The normal kidney possibly plays an important role in homocysteine catabolism, which cannot be performed in CRF. Alternatively, decreased extrarenal catabolism can contribute to the hyperhomocysteinaemia in this disease state. Treatment with folic acid, 5 mg daily, significantly lowers homocysteine levels in chronic renal patients. (45 Refs.)
Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease.
Eur J Clin Invest (ENGLAND) Mar 1995, 25 (3) p176-81
Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin ™, and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL- 1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.
Vitamin status in patients with inflammatory bowel disease
Fernandez-Banares F.; Abad-Lacruz A.; Xiol X.; Gine J.J.; Dolz C.; Cabre E.; Esteve M.; Gonzalez-Huix F.; Gassull M.A.
Department of Gastroenterology, Hospital de Bellvitge 'Princeps
d'Espanya', Barcelona Spain
AM. J. GASTROENTEROL. (USA), 1989, 84/7 (744-748)
The status of water- and fat-soluble vitamins was prospectively evaluated in 23 patients (13 men, 10 women, mean age 33 plus or minus 3 yr) admitted to the hospital with acute or subacute attacks of inflammatory bowel disease. Protein-energy status was also assessed by means of simultaneous measurement of triceps skin-fold thickness, mid-arm muscle circumference, and serum albumin. Fifteen patients (group A) had extensive acute colitis (ulcerative or Crohn's colitis), and eight cases (group B) had small bowel or ileocecal Crohn's disease. Eighty-nine healthy subjects (36 men, 53 women, mean age 34 plus or minus 2 yr) acted as controls. In both groups of patients, the levels of biotin, folate, beta-carotene, and vitamins A, C, and B1 were significantly lower than in controls (p < 0.05). Plasma levels of vitamin B12 were decreased only in group B (p < 0.01), whereas riboflavin was lower in group A (p < 0.01). The percentage of patients at risk of developing hypovitaminosis was 40% or higher for vitamin A, beta-carotene, folate, biotin, vitamin C, and thiamin in both groups of patients. Although some subjects had extremely low vitamin values, in no case were clinical symptoms of vitamin deficiency observed. Only a weak correlation was found between protein-energy nutritional parameters and vitamin values, probably due to the small size of the sample studied. The pathophysiological and clinical implications of the suboptimal vitamin status observed in acute inflammatory bowel disease are unknown. Further studies on long-term vitamin status and clinical outcome in these patients are necessary.
Sulfasalazine inhibits the absorption of folates in ulcerative colitis
Dept. Int. Med., Univ. California, Davis, CA 95616 USA
N. ENGL. J. MED. (USA), 1981, 305/25 (1513-1517)
Folate deficiency, a common occurrence in patients with inflammatory bowel disease, has been ascribed in part to the therapeutic use of sulfasalazine. However, a clear relation between the use of sulfasalazine (salicylazosulfapyridine) and the development of folate malabsorption and deficiency has not been shown. The authors designed studies to evaluate the relation of the use of sulfasalazine to folate malabsorption and deficiency in patients with ulcerative colitis. They compared the incidence of low serum folate levels in patients who were using sulfasalazine and those who were not. In a selected group of patients, the intestinal-perfusion method was used to study the effects of graded concentrations of sulfasalazine at the site of jejunal hydrolysis and luminal disappearance of folates. The data indicate that sulfasalazine inhibits the hydrolysis of polyglutamyl folate and also decreases the absorption of both polyglutamyl and monoglutamyl folates.
The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis
Lashner B.A.; Provencher K.S.; Seidner D.L.; Knesebeck A.; Brzezinski A.
Gastroenterology (USA), 1997, 112/1 (29-32)
Background and Aims: Two case-control studies have shown that folate may protect against neoplasia in ulcerative colitis. This historical cohort study was performed to better define this association. Methods: The records of 98 patients with ulcerative colitis who had disease proximal to the splenic flexure for at least 8 years were reviewed. Documented folate use of at least 6 months was deemed a positive exposure. Results: Of the patients, 29.6% developed neoplasia and 40.2% took folate supplements. The adjusted relative risk (RR) of neoplasia for patients taking folate was 0.72 (95% confidence interval (CI), 0.28-1.83). The dose of folate varied with the risk of neoplasia (RR, 0.54 for 1.0 mg folate; RR, 0.76 for 0.4 mg folate in a multivitamin compared with patients taking no folate). Folate use also varied with the degree of dysplasia (RR for cancer, 0.45; RR for high-grade dysplasia, 0.52; RR for low-grade dysplasia, 0.75 compared with patients with no dysplasia) (P = 0.08). Conclusions: Although not statistically significant, the RR for folate supplementation on the risk of neoplasia is <1 and shows a dose-response effect, consistent with previous studies. Daily folate supplementation may protect against the development of neoplasia in ulcerative colitis.