Homocysteinemia

Description

Hyperhomocysteinemia refers to above-normal concentrations of plasma/serum homocysteine. Plasma/serum homocysteine is the sum of the thiol-containing amino acid homocysteine and the homocysteinyl moiety of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins (Malinow and Stampfer, 1994).

Hyperhomocysteinemia in isolation may be associated with an increased risk of atherosclerosis and recurrent arterial and venous thrombosis usually in the third or fourth decade of life (review by Welch and Loscalzo, 1998).

Homocysteinemia is also a feature of several inherited metabolic disorders, including homocystinuria (236200), due to mutation in the CBS gene (613381), and N(5,10)-methylenetetrahydrofolate reductase deficiency (236250), caused by mutation in the MTHFR gene (607093). Homocysteinemia/homocystinuria and megaloblastic anemia can result from defects in vitamin B12 (cobalamin; cbl) metabolism, which have been classified according to complementation groups of cells in vitro; see cblE (236270) and cblG (250940). See also the various forms of combined methylmalonic aciduria (MMA) and homocystinuria due to disorders of cobalamin: cblC (277400), cblD (277410), and cblF (277380).

Clinical Features

Wilcken and Wilcken (1976) studied methionine loading in males under age 50 with angiographic evidence of ischemic heart disease but free of known risk factor. Of 25 such persons, 7 had peak postmethionine concentrations of homocysteine-cysteine elevated in the heterozygous range, whereas only 1 of 22 controls had such an elevation.

Genest et al. (1991) had estimated that 14% of coronary artery disease patients had familial hyperhomocysteinemia. Other data suggested a relationship to cerebrovascular and peripheral arterial disease. The studies showing elevated basal homocysteine levels as correlated among family members of patients with coronary vascular disease and juvenile venous thrombosis suggested the possibility of an inherited basal mild hyperhomocysteinemia.

Rees and Rodgers (1993) summarized clinical data linking vascular disease with homocysteinemia.

Falcon et al. (1994) determined the prevalence of hyperhomocysteinemia before and 4 hours after methionine load in 80 patients who had had at least one verified episode of venous thromboembolism before the age of 40 years and in 51 healthy control subjects. According to their criteria, hyperhomocysteinemia was found in 15 patients (18.8%) and in 1 control subject (1.9%). Family history for venous thromboembolism was positive in 7 of the 15 patients. Family studies, performed for 8 kindreds, showed that for more than half of the studied probands the abnormality was inherited.

Wu et al. (1994) found hyperhomocysteinemia in at least 12% of 85 families with 2 or more sibs affected by early coronary artery disease.

Boushey et al. (1995) and Motulsky (1996) concluded from a metaanalysis of 27 relevant publications that homocysteine is an independent risk factor for arteriosclerotic vascular disease unrelated to hyperlipidemia, hypertension, diabetes, and smoking. As with cholesterol levels, the risk is graded, i.e., the risk rises with increasing homocysteine levels. They calculated that 10% of the population's risk for coronary artery disease is attributable to elevated homocysteine levels.

In 269 patients with a first, objectively diagnosed episode of deep-vein thrombosis and in 269 healthy controls matched to the patients according to age and sex, den Heijer et al. (1996) measured plasma homocysteine levels and concluded that high plasma homocysteine is a risk factor for deep-vein thrombosis in the general population.

Welch and Loscalzo (1998) reviewed the topic of homocysteine and atherothrombosis beginning with the clinical observations of McCully (1969). By the time of the review, multiple prospective and case-control studies had shown that a moderately elevated plasma homocysteine concentration is an independent risk factor for atherothrombotic vascular disease. They stated that it was not yet clear whether homocysteine itself or a related metabolite or cofactor is primarily responsible for the atherothrombogenic effects of hyperhomocysteinemia in vivo.

In a 2-year prospective study in an Asian Indian population, Narayanasamy et al. (2007) found that 15 (51.7%) of 29 consecutive patients (mean age, 30 +/- 6 years) with central retinal vein occlusion (CRVO) exhibited significantly elevated homocysteine levels compared with those of healthy control subjects. The increased homocysteine level in CRVO cases was associated with decreased methionine and decreased B-12 levels.

Other Features

Recurrent early spontaneous abortion was linked to hyperhomocysteinemia by Steegers-Theunissen et al. (1992) and Wouters et al. (1993). Owen et al. (1997) found hyperhomocysteinemia in 6 of 21 women with unexplained abruptio placentae. They presented data suggesting that homocysteinemia in these women is not caused by a block in the transsulfuration pathway but could be due to defective remethylation of homocysteine into methionine.

Selhub et al. (1995) concluded that high plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid artery stenosis in the elderly.

The Framingham (Massachusetts) Study cohort has been evaluated biennially since 1948. In a sample of 1,092 subjects (mean age, 76 years) from this cohort, Seshadri et al. (2002) analyzed the relation of the plasma total homocysteine level measured at baseline and that measured 8 years earlier to the risk of newly diagnosed dementia on follow-up. They used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E (107741) genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Over a median follow-up period of 8 years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer disease (AD; 104300). The multivariable-adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the log-transformed homocysteine value either at baseline or 8 years earlier. The relative risk of Alzheimer disease was 1.8 per increase of 1 SD at baseline and 1.6 per increase of 1 SD 8 years before baseline. With a plasma homocysteine level greater than 14 micromoles per liter, the risk of Alzheimer disease nearly doubled. Seshadri et al. (2002) concluded that an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer disease.

Axer-Siegel et al. (2004) found an association between an elevated plasma level of homocysteine and exudative neovascular age-related macular degeneration (ARMD; see 603075) but not dry ARMD.

Very high plasma homocysteine levels are characteristic of classic homocystinuria (236200), a rare autosomal recessive disorder accompanied by the early onset of generalized osteoporosis. The increased prevalence of osteoporosis in homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen crosslinking, thereby increasing the risk of osteoporotic fracture. Van Meurs et al. (2004) and McLean et al. (2004) reported findings in the Netherlands and the Framingham (Massachusetts) Study, respectively, suggesting that homocysteine concentration is a strong and independent risk factor for osteoporotic fractures in older persons.

Inheritance

Franken et al. (1996) studied homocysteine levels after fasting as well as after methionine load among 96 family members of 21 postload hyperhomocysteinemic vascular index patients: 6 parents, 27 offspring, 38 sibs, 19 uncles and aunts, and 6 cousins. In 15 of 21 screened families, postload mild hyperhomocysteinemia was established in at least 1 family member. Both fasting and postload hyperhomocysteinemia were observed in 21% of screened family members and 32% of screened family members, respectively. Franken et al. (1996) concluded that both fasting and postload hyperhomocysteinemia are inherited in the majority of instances.

In 306 individuals from 51 Dutch families, den Heijer et al. (2005) found that heritability for homocysteine levels after methionine-loading was greater (67.5%) than that for fasting homocysteine levels (21.6%). However, the heritability of postload homocysteine levels was not strongly affected by the MTHFR C677T genotype (607093.0003), in contrast to fasting homocysteine levels, which were affected. The findings were consistent with a model in which the capacity for methionine handling is dependent on genetically determined enzyme activity.

Clinical Management

Rees and Rodgers (1993) reviewed therapeutic measures for homocysteinemic patients.

Stampfer and Malinow (1995) argued that the 'time is ripe for randomized clinical trials' of folate supplementation. To avoid masking pernicious anemia, the supplement could include oral vitamin B12 in doses that would circumvent the lack of intrinsic factor.

Motulsky (1996) stated 'On the basis of our assessment of the role of folic acid in reduction of raised homocysteine levels, and on the basis of the quantitative effects of homocysteine elevations on the pathogenesis of coronary artery disease, we have calculated that 9% of male and 5.4% of female coronary artery deaths in the United States (approximately 50,000 total deaths/year) could be prevented by fortification of flour and cereal products by using 350 micro g folic acid/100 g food.' (An erratum pointed out that the editorial by Motulsky (1996) stated: '54% of female coronary artery deaths,' whereas the correct figure is 5.4%.)

Wiklund et al. (1996) described results of a double-blind study using N-acetylcysteine (NAC) or placebo on 11 subjects with high plasma lipoprotein(a) levels (greater than 0.3 g/l). Main outcome measures were treatment effects on Lp(a) and plasma amino thiols (homocysteine, cysteine, and cysteinyl glycine). They reported that there was no significant effect on plasma Lp(a) levels with NAC: homocysteine was reduced by 45% (p less than 0.0001), cysteinyl glycine by 24% (p less than 0.0001), and cysteine by 11% (p = 0.0002). Wiklund et al. (1996) noted that the reduction of homocysteine levels seen with NAC was considerable and might be of clinical significance in cases with high plasma homocysteine levels, since even moderately high plasma levels of homocysteine are associated with atherosclerosis and thrombotic events.

Although vitamin supplementation decreases or even normalizes plasma homocysteine concentrations in most cases, prospective, randomized clinical trials will be necessary to determine the effect of vitamin supplementation on cardiovascular morbidity and mortality. The Food and Drug Administration (FDA) recommended that cereal-grain products be fortified with folic acid to prevent congenital neural tube defects. Since folic acid supplementation reduces levels of plasma homocysteine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, Malinow et al. (1998) hypothesized that folic acid fortification of food might reduce plasma homocyst(e)ine levels. To test this hypothesis, they assessed the effects of breakfast cereals fortified with 3 levels of folic acid, as well as the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. The results suggested that folic acid fortification at levels higher than that recommended by the FDA may be warranted for the prevention of atherothrombotic disease.

Schnyder et al. (2001) found that treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduced homocysteine levels and decreased the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. They proposed that this inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty.

Pathogenesis

Fryer et al. (1993) demonstrated that homocysteine can induce tissue factor procoagulant activity in cultured human endothelial cells.

Several reports, including those of Kang et al. (1986) and Chao et al. (1999), indicated a likely role for homocysteine in the pathogenesis of atherosclerosis.

Malinow and Stampfer (1994) reviewed the role of plasma homocysteine in arterial occlusive diseases.

To understand the role of homocysteine in the pathogenesis of atherosclerosis, Tsai et al. (1994) examined the effect of homocysteine on the growth of both vascular smooth muscle cells and endothelial cells at concentrations similar to those observed clinically. As little as 0.1 mM homocysteine caused a 25% increase in DNA synthesis, and homocysteine at 1 mM increased DNA synthesis by 4.5-fold in rat aortic smooth muscle cells. In contrast, homocysteine caused a dose-dependent decrease in DNA synthesis in human umbilical vein endothelial cells. Homocysteine increased mRNA levels of cyclin D1 (168461) and cyclin A (123835) in aortic smooth muscle cells by 3- and 15-fold, respectively, indicating that homocysteine induced the mRNA of cyclins important for the reentry of quiescent smooth muscle cells into the cell cycle. The growth-promoting effect of homocysteine on vascular smooth muscle cells, together with its inhibitory effect on endothelial cell growth, may explain homocysteine-induced atherosclerosis.

Kraus et al. (1986) demonstrated that mean activity of cystathionine synthase (CBS; 613381), which is on chromosome 21, is 166% in cultured fibroblasts from Down syndrome patients compared with controls. Brattstrom et al. (1987) suggested that if cystathionine synthase deficiency is involved in the pathophysiology of arteriosclerosis, Down syndrome patients might be protected against arteriosclerosis. Indeed, Murdoch et al. (1977) found that arteriosclerosis was rare in Down syndrome and referred to this disorder as an 'atheroma-free model.' Brattstrom et al. (1987) likewise found a remarkable freedom from arteriosclerosis in Down syndrome.

In cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, Werstuck et al. (2001) found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol. Mice with diet-induced hyperhomocysteinemia had significantly increased cholesterol and triglycerides in liver, but not plasma, due to increased lipid biosynthesis, not impaired hepatic export of lipids. The findings suggested a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides., which contribute to hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.

Jakubowski et al. (2008) found that patients with homocysteinemia due to MTHFR deficiency or CBS deficiency had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen (134820). N-Hcy-proteins are detrimental by contributing to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals.

Population Genetics

Chandalia et al. (2003) investigated whether Asian Indians have high plasma homocysteine compared with Caucasians in the United States in the era of folate fortification, and whether low vitamin B12 or insulin resistance may account for possible interethnic differences in plasma homocysteine. A total of 227 Asian Indians and 155 Caucasians participated in the study. Asian Indians were found to have significantly higher plasma homocysteine than Caucasians (median of 12.6 and 8.0 micromol/liter, P less than 0.0001, respectively) and lower plasma concentrations of B6 (median 49 vs 70 nmol/liter, P = 0.05, respectively). Plasma folate was relatively high and similar in both ethnic groups. Plasma vitamin B12 was significantly lower in Asian Indians than in Caucasians. Vitamin B12 correlated significantly with plasma homocysteine. When vitamin B12 was between 150 and 379 pmol/liter, the regression curve between vitamin B12 and homocysteine had a significantly different slope in the 2 ethnic groups (P less than 0.05) and Asian Indians had significantly higher homocysteine for any level of vitamin B12. Chandalia et al. (2003) concluded that Asian Indians living in the United States have significant elevation of plasma homocysteine concentrations despite normal plasma folate.

Molecular Genetics

In an editorial, Motulsky (1996) reviewed evidence that polymorphism of the MTHFR gene (C677T; 607093.0003) may be an important factor in atherosclerotic vascular disease.

Polymorphic mutations in the MTHFR and MTR (156570) genes, both of which cause recessively inherited increased homocysteine levels, explain only a small proportion of the observed variation in homocysteine level. To investigate additional genetic influences, Jee et al. (2002) examined environmental, familial, and genetic influences on serum homocysteine levels in 661 family members of 112 probands who underwent elective coronary arteriography. Estimated mean homocysteine levels for the 3 putative genotypes (designated LL, LH, and HH) were 8.0, 10.1, and 15.9 micromol per liter, respectively, with relative frequencies of 56.8%, 37.2%, and 6%, respectively. Analysis suggested the presence of a codominantly expressed major gene, in addition to the effects of the MTHFR C677T mutation. The results of the study supported multifactorial inheritance more strongly than mendelian inheritance alone.

Retinal artery occlusion is a common vision-threatening disease, primarily affecting patients older than 60 years. Because hyperhomocysteinemia has been established as an important risk factor for cardiovascular disease, Weger et al. (2002) investigated whether hyperhomocysteinemia and/or homozygosity for the C677T mutation (607093.0003) in the MTHFR gene were associated with an increased risk for retinal artery occlusion. They found that mean plasma homocysteine levels were significantly higher in patients with retinal artery occlusion compared with normal controls. However, the prevalence of the homozygous genotype of the MTHFR C677T mutation did not differ significantly between patients and controls.

Lange et al. (2010) performed a genomewide association study for plasma homocysteine (Hcy) in 1,786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP), rs7422339 (p = 4.7 x 10(-13)), encodes thr1405 to asn in CPS1 (608307.0006) and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133; 607093.0003) was also highly significant (p = 8.7 x 10(-10)) and explained 1.6% of the trait variation. In a follow-up genotyping of these 2 SNPs in 1,679 CLHNS young adult offspring, the MTHFR C677T SNP was strongly associated (p = 1.9 x 10(-26)) with Hcy and explained 5.1% of the variation in gender-combined offspring. In contrast, the CPS1 variant was significant only in females. Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring. Although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring, there was no significant evidence for an interaction in the mothers. The authors suggested that genetic effects on Hcy may differ across developmental stages.

Nomenclature

Genest et al. (1991) introduced the term 'familial hyperhomocysteinemia.' Hyperhomocysteinemia is sometimes written as hyperhomocyst(e)inemia to emphasize the pathogenetic significance of the sulfhydryl homocysteine as opposed to the disulfide homocystine.

Mudd and Levy (1995) urged use of the term hyperhomocyst(e)inemia to describe the composite of homocysteine-derived moieties usually measured in the plasma in either sulfhydryl or disulfide form, since in speech it is difficult to distinguish 'homocyst(e)ine' from 'homocysteine.' They suggested that an alternative useful in communicating orally is to substitute 'total Hcy' for homocyst(e)ine, spelling out the 'Hcy.' The term 'homocyst(e)ine' with parentheses around the 'e' in the middle of the word is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia.

Animal Model

Nishinaga et al. (1993) presented results from experiments in cultured porcine aortic endothelial cells suggesting that inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the homocysteine-induced endothelial cell perturbation.

To investigate the mechanism whereby folate supplementation protects against heart and neural tube defects, Rosenquist et al. (1996) tested the effects of homocysteine on chick embryos and the effect of added folate. The hypothesis was that homocysteine may be the teratogenic agent, since serum homocysteine increases in folate depletion. Of embryos treated with homocysteine or homocysteine thiolactone, 27% showed neural tube defects. A high frequency of ventricular septal defects and neural tube defects was observed. Also, a ventral closure defect was found in a high percentage of day 9 embryos. The teratogenic dose was shown to raise serum homocysteine to over 150 nmol/ml, compared with a normal level of about 10 nmol/ml. Folate supplementation kept the rise in serum homocysteine to approximately 45 nmol/ml and prevented the teratogenic effect. Rosenquist et al. (1996) concluded that homocysteine per se causes dysmorphogenesis of the heart and neural tube, as well as of the ventral wall.

To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency (236250), Chen et al. (2001) generated Mthfr knockout mice. Plasma total homocysteine levels in heterozygous and homozygous knockout mice were 1.6- and 10-fold higher than those in wildtype littermates, respectively. Both heterozygous and homozygous knockouts had either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appeared normal, whereas the homozygotes were smaller and showed developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.

Troen et al. (2008) found that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. There was also a decrease in brain microglia. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies and with plasma total homocysteine. Feeding mice a methionine-rich diet produced similar but less pronounced effects. The findings suggested that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline.