Severe hyperhomocysteinemia revealing homocystinuria in two young adults with mild phenotype

INTRODUCTION: To the request of total plasma homocysteine determination in the investigation of vascular disease, diagnosis of homocystinuria in young adult patients with mild phenotype is not so rare. EXEGESIS: A 26-year-old man developed embolic cerebral infarction and a 22-year-old woman presented a right renal venous thrombosis one week after delivery. In each case, high concentration of total plasma homocysteine was first found and plasma and urinary amino acids analysis later on directed the diagnosis towards homocystinuria. Finally, reduced skin fibroblast cystathionine beta-synthase activity confirmed the diagnosis of homocystinuria. CONCLUSION: Total plasma homocysteine determination must be determined for screening for hyperhomocysteinemia in young adults with venous thromboembolism without characteristic phenotypic features of homocystinuria.     

Venous thrombosis associated with pernicious anaemia. A report of two cases and review

Since homocystinuria, an inborn metabolism error is complicated by venous thrombosis in about half of the patients, hyperhomocysteinemia has been suspected of favouring thrombosis. Several case-control studies and even meta-analysis have confirmed a link between venous thrombosis and mild hyperhomocysteinemia. Nevertheless, the proper role of homocysteine remains debated. Hyperhomocysteinemia is induced by vitamin B9 or B12 deficiencies in a vast majority of cases. The authors report on two patients with venous thrombosis revealing pernicious anemia and review nine similar cases found in the world literature. The literature concerning the relationships between homocysteine and venous thrombosis is briefly reviewed.     

Homocysteine in the prevention of ischemic heart disease, stroke and venous thromboembolism: therapeutic target or just another distraction?

PURPOSE OF REVIEW: Homocysteine has been proposed as a potentially modifiable risk factor for arterial and venous vascular disease. This notion is supported by a large body of literature derived from observations in patients with rare inborn errors of metabolism associated with homocystinuria, experimental studies, which show that homocysteine promotes atherogenesis and thrombosis and epidemiological studies, which in general suggest a graded and independent relationship between homocysteine and atherothrombotic vascular risk. RECENT FINDINGS: The current review briefly summarizes observational studies with emphasis on new meta-analyses linking homocysteine to ischemic heart disease, stroke, and venous thromboembolism. These data support weak associations between homocysteine and vascular risk. A number of recent large randomized controlled trials failed to demonstrate benefit for homocysteine lowering with B vitamin supplements in the prevention of cardiovascular events and venous thrombosis. These studies, however, may have been insufficiently powered to detect modest but clinically important treatment benefits. Therefore, completion of ongoing large randomized trials is essential. SUMMARY: At present, the status of homocysteine as a target for intervention in the prevention of atherothrombotic arterial and venous disease is uncertain. Current evidence does not support the use of B vitamin supplements to reduce vascular risk. Ongoing large randomized trials will provide further clarity on this subject.     

Hyperhomocysteinemia and thrombosis

It has been known for some time that patients with homocystinuria are at an increased risk for both venous and arterial thrombosis. More recently it has been found that even moderate increases in homocysteine levels are associated with increased risk for deep venous thrombosis, myocardial infarction, cerebral infarction and peripheral vascular disease. It is possible, with the use of folic acid, vitamin B12 and vitamin B6, to correct the elevated homocysteine levels but it has not yet been demonstrated that by doing so the natural history of the disorder is altered.     

Interleukin 8 and venous thrombosis: evidence for a role of inflammation in thrombosis

Elevated plasma levels of interleukin 8 (IL-8) were previously shown to be associated with recurrent venous thrombosis. To assess the risk of venous thrombosis, IL-8 plasma concentrations were measured in patients and control subjects of the Leiden Thrombophilia Study (LETS). This population based case-control study included 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. The risk of venous thrombosis for subjects with elevated IL-8 levels (above 90th percentile of controls) compared with subjects with IL-8 levels below the 90th percentile was increased 1.8-fold (95%CI 1.2-2.8). Adjusted for age and sex, the odds ratio was 1.9 (95%CI 1.3-2.8). IL-8 concentrations were weakly correlated with age, male sex, and concentrations of C-reactive protein, factor VIII coagulation activity and homocysteine, but adjustment for these factors did not substantially affect the association between IL-8 and venous thrombosis. Our results suggest that IL-8 is a risk factor for venous thrombosis.     

Vascular complications of homocystinuria: a retrospective multicenter study

PURPOSE: Arterial or venous thromboses are frequent in patients with homocystinuria. Because severe homocystinuria is rare, prevalence of thrombosis, especially in France, is still unknown. METHODS: Review of the clinical outcome of 37 patients with homocystinuria due to cystathionine-cystathionine beta-synthase deficiency (34) and 5,10-methylenetetrahydrofolate reductase (three) lead us to describe vascular complications occurring in 12 (32%) of them. RESULTS: Venous thromboembolism is the earlier and the most frequent one and is mainly found in untreated late-diagnosed cases. Under specific treatment of homocystinuria, thromboses are rare and always a complication of surgery associated with high thromboembolic risk. Association with factor V Leiden increased the risk of venous thrombosis.     

Homocysteine and venous thromboembolism—Is there any link?

Homocysteine is an intermediary product of methionine metabolism. The level of homocysteine is controlled by two pathways—remethylation and transsulphuration. Elevated homocysteine level may result from deficiency or impaired function of enzymes and cofactors in these pathways. Homocystinuria is a rare genetic disease with extreme hyperhomocysteinemia and is associated with the occurrence of arterial and venous thrombotic events at young age. Therefore, homocysteine has been considered a risk factor for vascular diseases.Plasma homocysteine level is influenced by many factors, genetic as well as environmental. Mild hyperhomocysteinemia is quite common. The role of homocysteine in venous thrombosis has been studied less extensively than its role in arterial diseases and nowadays it seems quite controversial. In vitro, it is possible to demonstrate multiple prothrombotic action of homocysteine. However, the results of epidemiologic studies are not so clear. Most of them found an association of hyperhomocysteinemia with venous thromboembolism (VTE) but the association was quite weak and moreover, it was much weaker in prospective than in retrospective studies. It is not quite clear whether elevated homocysteine level is the cause of thromboembolic event or the consequence of it. It is also possible that hyperhomocysteinemia plays a role in the pathogenesis of VTE only as an additional risk factor in the presence of other thrombophilic disorders.However, some data confirm hyperhomocysteinemia as a risk factor for recurrent VTE. Some smaller studies have also found association of hyperhomocysteinemia with venous thrombosis at unusual sites.Homocysteine level can be lowered by vitamin supplementation, especially with folic acid and vitamin B12. So far, the benefit of lowering homocysteine level in primary and secondary VTE prevention has not been clearly proven.Currently, there is not enough evidence to support the necessity of testing homocysteine level in VTE patients, neither is sufficient evidence of the benefit of vitamin supplementation in mild or moderate hyperhomocysteinemia. Therefore, such testing and supplementation should be performed only in selected cases.     

Hyperhomocysteinaemia in Beh?et's disease.

OBJECTIVE: Arterial and venous thrombosis are among the clinical features of Beh?et's disease (BD), the pathogenesis of which is not completely understood. In this study, we investigated whether hyperhomocysteinaemia, being a well known risk factor for thrombosis, is also a contributive risk factor for the arterial and venous thrombosis of BD. METHODS: Eighty-four patients fulfilling the criteria of the International Study Group for Beh?et's Disease (54 males, 30 females, mean age 36+/-9 yr) were enrolled. All the patients were carefully screened for a history of venous thrombosis and were separated into two groups with respect to thrombosis history. Thirty-six healthy individuals (23 males, 13 females), matched for age and sex with the BD group, were included as a negative control group. Patients were excluded if they had any condition that might affect plasma homocysteine concentration. As methotrexate (MTX) causes hyperhomocysteinaemia, we also included 29 rheumatoid arthritis patients (five males, 24 females) receiving MTX weekly. Fasting plasma homocysteine concentrations were measured by high-performance liquid chromatography. The data were analysed with the chi(2) test and Student's t-test. RESULTS: The highest homocysteine concentrations were found in the MTX group (17.5+/-5.3 micromol/l). Mean plasma homocysteine concentrations in BD patients were significantly higher than in the healthy controls (11.5+/-5.3 vs. 8.8+/-3.1 micromol/l, P<0.001). Among BD patients with a history of thrombosis, 20 of 31 (64%) had hyperhomocysteinaemia, and this was significantly higher than in those without thrombosis (9%). On the other hand, there was no significant difference between patients with non-thrombotic BD and healthy controls (P>0.05). In patients with thrombosis, we found no correlation between the duration of the post-thrombotic period and homocysteine concentration. Among all the variables investigated, only hyperhomocysteinaemia was found to be related to thrombosis. CONCLUSION: Hyperhomocysteinaemia may be assumed to be an independent risk factor for venous thrombosis in BD. Unlike the factor V Leiden mutation, hyperhomocysteinaemia is a correctable risk factor. This finding might lead to new avenues in the prophylaxis of thrombosis in BD.     

Homocysteinemia: depressed plasma serine levels

Plasma serine levels were found to be lower than normal (mean +/- SD, 91 +/- 18 mumol/L, n = 16) in homocystinuria patients with a deficiency of cystathionine B-synthase on folate therapy, compared with healthy adults (121 +/- 25 mumol/L, n = 25, P less than 0.001). Of 13 other patients with elevated plasma total homocysteine, two patients with homocystinuria due to remethylation defects had normal serine levels, while 11 renal transplant recipients with mild elevations of serum creatinine had lower than normal serine levels (100 +/- 28 mumol/L, P less than .05). Treatment of both the pyridoxine responsive and nonresponsive cystathionine B-synthase-deficient patients with betaine, which lowered plasma homocysteine, also normalized plasma serine levels. In the two patients with remethylating defects however, betaine lowered plasma homocysteine levels without changing plasma serine levels. By contrast, treatment of the renal transplant patients with pyridoxine, folic acid, and vitamin B12 (cofactors required for homocysteine metabolism), caused falls in plasma homocysteine levels, with a concurrent decline in plasma serine levels. These findings may be explained in terms of the requirements for serine in homocysteine metabolism, both as a source of methyl carbon atoms in the methylation of homocysteine by N5-methyltetrahydrofolate and as a substrate in the cystathionine B-synthase reaction. During periods of elevated plasma total homocysteine in man, increased amounts of serine may be diverted to lowering plasma homocysteine.     

Homocysteine. The cardiovascular risk factor of the next millennium?

Several epidemiologic studies have demonstrated that hyperhomocysteinemia is a risk factor for arteriosclerosis in coronary, cerebral, peripheral and aortic arteries. This risk is independent of other cardiovascular risk factors, and it is dose related. However, prospective studies show contradictory findings. Hyperhomocysteinemia is also associated with a higher risk of venous thrombosis to which other coagulation disorders, such as factor V Leiden, could contribute. Hyperhomocysteinemia can be due to genetic defects in the enzymes that control homocysteine metabolism, and also to other factors, mainly nutritional (deficiencies in vitamin B6, vitamin B12, or folic acid). Dietary supplements of these vitamins reduce plasma homocysteine levels. Randomized clinical trials are still needed to demonstrate that reducing plasma homocysteine levels will reduce the risk for cardiovascular disease.     

Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects

This overview addresses homocysteine and folate metabolism. Its functions and complexity are described, leading to explanations why disturbed homocysteine and folate metabolism is implicated in many different diseases, including congenital birth defects like congenital heart disease, cleft lip and palate, late pregnancy complications, different kinds of neurodegenerative and psychiatric diseases, osteoporosis and cancer. In addition, the inborn errors leading to hyperhomocysteinemia and homocystinuria are described. These extreme human hyperhomocysteinemia models provide knowledge about which part of the homocysteine and folate pathways are linked to which disease. For example, the very high risk for arterial and venous occlusive disease in patients with severe hyperhomocysteinemia irrespective of the location of the defect in remethylation or transsulphuration indicates that homocysteine itself or one of its “direct” derivatives is considered toxic for the cardiovascular system. Finally, common diseases associated with elevated homocysteine are discussed with the focus on cardiovascular disease and neural tube defects.     

Homocysteine and venous thrombosis: outline of a vitamin intervention trial

In the past years several case-control studies established the association of an elevated plasma homocysteine concentration and the risk of venous thromboembolism. It is still unclear if elevated homocysteine concentrations can cause venous thrombosis. The VITRO (VItamins and ThROmbosis) trial is the first multicenter, randomized, double-blind and placebo-controlled study to evaluate the effect of homocysteine-lowering therapy by means of 5 mg folic acid, 0.4 mg vitamin B12 and 50 mg vitamin B6. The study is a secondary prevention trial in 600 patients who suffered from a first episode of idiopathic deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. There will be 300 hyperhomocysteinemic and 300 normohomocysteinemic patients included, all with an objectivated venous thrombosis. The end point is recurrence of venous thrombosis.     

Myocardial infarction and 5,10-methylenetetrahydro-folate reductase mutation

A 40-year-old woman with previous venous thrombosis in the lower limbs had recurrent myocardial infarction in the early puerperium. The only documented risk factor was an elevated level of plasma homocysteine, associated to a heterozygotic anomaly in the enzyme responsible for its metabolism, 5,10-methylenetetrahydrofolate reductase. The case and approaches to treatment are discussed.     

Hyperhomocysteinemia and deep vein thrombosis in orthotopic heart transplantation: a case report

Homocysteine has been recognized as a risk factor for atherosclerosis and arterial and venous thrombosis. Heart transplant patients have an increased prevalence of hyperhomocysteinemia. High homocysteine levels in transplant patients may promote development of cardiac allograft vasculopathy, but there is minimal information regarding the risk of venous thrombosis. The current case report illustrates the association of increased levels of homocysteine and hypercoagulable syndrome in a 36-year-old heart transplant patient with no previous history of clotting disorder. Both elevated homocysteine levels and extensive venous thrombosis responded promptly to treatment with a folate/B12/B6 vitamin combination and enoxaparin.     

Hyperhomocysteinemia: a risk factor for arterial and venous thrombosis]

Homocysteine is a sulfur-containing amino acid intermediate involved in two metabolic pathways, in the remethylation to methionine and in the transsulfuration to cysteine. Severe hyperhomocysteinemia (> 100 mumol/l) is found in congenital homocystinuria. Moderate (15-30 mumol/l) or intermediate (> 30-100 mumol/l) hyperhomocysteinemia is caused by defects in genes encoding for enzymes of homocysteine metabolism or by inadequate intake of those vitamins that are involved in homocysteine metabolism (folic acid, cobalmin, and vitamin B6). Today, hyperhomocysteinemia should be considered an important risk factor for atherosclerotic vascular and venous thromboembolic diseases. Homocysteine-plasma levels above the 95th percentile were found to be associated with a 2 to 3-fold elevated relative risk for deep-vein thrombosis and pulmonary embolism. Moreover, mild hyperhomocysteinemia has been shown to be associated with a 2 to 4-fold increased relative risk for coronary artery disease, cerebrovascular disease, and peripheral arterial occlusive disease. Several mechanisms have been proposed by which hyperhomocysteinemia contributes to atherogenesis and thrombogenesis. Several studies have shown that hyperhomocysteinemia can be corrected by supplementation of folic acid, cobalamin and vitamin B6. Clinical trials are urgently needed which investigate the preventive effect of supplementation of these vitamins on thrombotic diseases.     

Homocysteine levels in polycythaemia vera and essential thrombocythaemia

Patients with polycythaemia vera (PV) or essential thrombocythaemia (ET) have an increased risk of arterial and venous thromboembolic complications. Since hyperhomocysteinaemia (HHC) is a risk factor for vascular disease, we investigated the frequency of HHC in these disorders and analysed a possible association of elevated plasma homocysteine levels with vascular complications. In the cohort of 134 patients from Vienna (69 female, 65 male, median age 65.5 years, range 21-91 years) with PV (n = 74) or ET (n = 60), plasma homocysteine levels were significantly higher compared to 134 healthy controls. Median homocysteine level was 12.3 micromol/l (range 3.5-48.4 micromol/l) in patients with PV or ET and 8.9 micromol/l (range 4.8-30.5 micromol/l) in normal controls (P < 0. 0001). In addition to the 134 patients from Vienna, 48 patients (28 female, 20 male; median age 66.5 years, range 24-82) from Vicenza with PV (n = 25) or ET (n = 23) were included to evaluate the impact of HHC on the risk of thrombosis. Of 59 patients with HHC (44 from Vienna and 15 from Vicenza) 18 (31%) had a history of arterial and 10 (17%) of venous thrombosis. Of 123 patients with normal homocysteine levels, 30 (24%) had arterial and 16 (13%) had venous thromboses. The difference between the two groups was statistically not significant. Even though mild to moderate HHC occurred in a larger number of patients with PV or ET and thrombosis, it can presently not be regarded as an additional risk factor for thrombosis.     

Antithrombin III activity is not related to plasma homocysteine concentrations

Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low antithrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homocysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.     

Homocysteine: A new cardiac risk factor?

Elevated plasma homocysteine levels have recently been implicated as a new risk factor for coronary artery disease. In this article, homocysteine metabolism, secondary causes of elevated plasma homocysteine, and the potential mechanism of vascular damage in hyperhomocysteinemia are briefly reviewed. The current clinical evidence implicating hyperhomocysteinemia as a risk factor for coronary artery disease, as well as the data regarding the effects of B vitamin supplementation on homocysteine concentrations, are also reviewed. The current recommendation of the authors is to treat patients with known coronary artery disease or those who are considered to be at high risk for coronary artery disease with 400 microg of folate supplementation. Until prospective clinical trial data become available, this approach appears to be a safe and effective way to approach this patient population.     

Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients.

The present study describes 403 patients with thrombosis, from a uniform ethnic and geographical background. Two-hundred-and-seven individuals had suffered mild or moderate stroke and 196 individuals suffered venous thromboembolism. We recorded levels of antithrombin, protein C and protein S, plasminogen and plasma homocysteine, and the presence of the factor V Leiden mutation, the prothrombin 20210G-->A variant, and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism. Controls for the mutation frequencies consisted of Guthrie card blood spots from a cohort of new-born babies. The cumulative prevalence of deficiencies in antithrombin, protein C, protein S or plasminogen was 2.4% in patients with stroke and 11.2% in patients with venous thrombosis. The factor V Leiden mutation was present in 11.1% of patients with stroke and 26.5% of patients with venous thrombosis, compared with 6.6% of controls (n = 4188; P < 0.05 and P < 0.0001, respectively). The prevalence of the prothrombin 20210A variant was 3.1% in patients with venous thrombosis, 1.9% in patients with stroke and 2.0% in controls (n = 500; P > 0.05). Hyperhomocysteinemia was present in 16.0% of patients with stroke and 17.6% of patients with venous thrombosis. The prevalence of the MTHFR 677T/T genotype was no different in patients with stroke (10.6%) and venous thrombosis (8.7%) than in controls (8.3%; n = 1084; P > 0.05); thus, it apparently contributed to thrombosis only via its influence on total plasma homocysteine, which was significantly increased in patients with the T/T genotype (P < 0.001). The MTHFR T/T genotype did not further increase the risk for thrombosis in carriers of the factor V Leiden mutation. Overall, thrombotic events were associated with a known risk factor in 27% of patients with stroke and 55% of patients with venous thrombosis.     

Hyperhomocysteinaemia.

Homocysteine is a sulphur-containing amino acid that is derived primarily from protein of animal origin. Classical homocystinuria is an inherited metabolic disorder that arises from defects in either the re-methylation or trans-sulphuration pathways of homocysteine metabolism and leads to skeletal abnormalities, mental retardation and a high risk of vascular disease. In contrast, moderate hyperhomocysteinaemia is associated with an increased risk of both arterial and venous thrombotic disease but no other abnormalities. This increased risk appears to be independent of other conventional risk factors. Many cases of hyperhomocysteineaemia have been attributed to defects in the enzyme cystathionine-beta-synthase (CBS) but this accounts for less than 1.5% of cases. A thermolabile variant of the enzyme methylenetetrahydrofolate reductase (MTHFR) arises from a C --> T transition at nucleotide 677 in the MTHFR gene resulting in an alanine-to-valine substitution. While the mutation does not appear to be associated with an increased risk of vascular disease, it results in excessively high homocysteine levels in response to a low or low-normal serum folate. Supplementation of the diet with folate, B6 and B12 can reduce homocysteine levels and this is the mainstay of treatment. Supplementation of grain with folate is undertaken in the USA to reduce the risk of neural tube defects in pregnant women. However, by reducing plasma homocysteine levels, it is estimated that this will save up to 50,000 lives per annum.