HOMOCYSTEINE: You Should Understand It!

Homocysteine (HC) was discovered in 1952; however, it was not until 1962 that two cases of elevated HC in urine were described. Two years later, HC was detected in the urine of children with intellectual disability, along with the absence of the CβS enzyme in liver biopsy fragments of children with homocystinuria.

In 1969, the relationship between HC, atherosclerosis, and arterial thrombosis was first described.

It is biologically plausible that high levels of HC can cause brain damage and neuropsychiatric disorders. It is pro-atherogenic and pro-thrombotic, thereby increasing the risk of stroke and potentially having a direct neurotoxic effect. Evidence that HC is a risk factor for cerebral microvascular disease is conflicting but warrants further study. Cross-sectional and some longitudinal studies support the increasing prevalence of stroke and vascular dementia in individuals with hyperhomocysteinemia. Evidence of increasing neurodegeneration is accumulating. The relationship with depression is still experimental, as is its connection with epilepsy. Currently, studies on treatments are needed to put the evidence on a more solid foundation. High-risk patients should also be screened for hyperhomocysteinemia, with treatment focusing on correcting various metabolic pathways.

A meta-analysis involving 27 studies and over 4,000 patients concluded that when HC values are greater than 10 mmol/L, every additional 5 mmol/L increase in circulating homocysteine values is associated with an 80% risk for cardiovascular disease in women, 60% in men, and 50% for cerebrovascular disease, in addition to increasing the risk for peripheral vascular disease by 6.8 times. This increase also corresponds to 20 mg/dL of total cholesterol with a higher probability of acute myocardial infarction.

Fasting homocysteine or homocysteine after methionine overload increases cardiovascular risk similarly to excess cholesterol and smoking. Physicians who experienced recurrent acute myocardial infarctions (AMIs) over five years showed higher homocysteine concentrations than controls, and the risk of AMI was three times greater. Individuals who died from AMI showed higher homocysteine values than controls, and there was a correlation between cardiovascular diseases and hyperhomocysteinemia determined in blood samples from individuals with coronary artery disease (CAD) who suffered fatal and non-fatal AMIs.

The mechanism of vascular injury determined by hyperhomocysteinemia includes endothelial cell damage, vascular smooth muscle growth, increased platelet adhesiveness, increased oxidation of LDL-cholesterol with deposition in the vascular wall, and direct activation of the coagulation cascade with a pro-thrombotic effect.

The fact that homocysteine may be related to neurodegenerative disease is an intriguing finding supported by many lines of evidence. Of 10 cross-sectional studies that examined the association between AD and HC levels, eight reported higher Hcy levels in AD patients compared to controls. Several authors demonstrated a correlation between HC levels and the severity of cognitive deficit, except in very elderly patients.

The report by Clarke et al. deserves special comment. These authors examined 164 AD patients, with histological confirmation in 76 of them, and found that those with baseline HC in the upper two tertiles had significantly more temporal lobe atrophy after three years than those in the lowest tertile. Such results suggest that elevated HC levels may determine the rate of disease progression. A recent cross-sectional Magnetic Resonance Imaging (MRI) study described a similar correlation between high homocysteine levels and cerebral atrophy in healthy elderly individuals, suggesting the possibility that hyperhomocysteinemia is neurotoxic.

Treatment varies according to the underlying cause, which is inexpensive and safe. The biochemical dysfunctions involved in its genesis and elimination should be corrected as per the simplified mechanism shown alongside. Treatment is based on folic acid, pyridoxine, methylcobalamin, betaine, and methionine; however, the minimum effective doses of vitamins have not yet been established. It is up to the PHYSICIAN to define the best strategy through laboratory monitoring.

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