Homocysteine is an amino acid not supplied by the diet that can be converted into cysteine or recycled into methionine, an essential amino acid, with the aid of specific B vitamins. Homocysteine levels vary between men and women with a normal range typically between 5 to 15 micromol/L. Hyperhomocysteinemia is when levels exceed 15 micromol/L. 
When homocysteine levels are greater than normal limits, it signifies that there is a disruption in the metabolism of homocysteine. Elevated levels of homocysteine have been associated with increased cardiovascular, cerebrovascular, and thromboembolic diseases. While there are clear associations between homocysteine and cerebrovascular disease, the evaluation and treatment remain controversial as studies have shown conflicting results in its effect in lowering risks for cardiovascular and cerebrovascular disease. There has been clear evidence that lowering homocysteine levels decreases cardiovascular risks in patients with homocystinuria, a rare autosomal recessive disorder, which can lead to atherosclerotic disease at a young age. Also, some studies have shown that lowering homocysteine levels can be beneficial in slowing the acceleration of brain atrophy. On the other hand, a meta-analysis by the American Heart Association showed that homocysteine-lowering therapies did not have a significant effect in averting stroke  and has a non-significant impact on coronary heart disease.
Homocysteine levels are generally categorized into three groups: moderate (16 to 30 micromol/L), intermediate (31 to 100 micromol/L), and severe (over 100 micromol/L).
Homocysteine is converted to cysteine and methionine by a combination of B vitamins (B12, B6, and folate) and enzymes (Methylene Tetrahydrofolate Reductase: MTHFR). Specifically, homocysteine is converted to methionine by a process known as remethylation with the help of vitamin B12. Methionine can subsequently be broken down to S-adenosyl-methionine to be regenerated to homocysteine. In a reaction called transsulfuration, homocysteine is converted to cysteine catalyzed by pyridoxal-5’-phosphate (PLP) and cystathionine B-synthase. Elevations in homocysteine suggest disruptions in one of the components of this reaction. While there are numerous causes for this condition, one of the most common causes of hyperhomocysteinemia is the inadequate enzyme activity of MTHFR due to genetic defects. Because vitamins play such a crucial role in the biochemistry of homocysteine, any causes of vitamin B12, B6, and folate deficiency (i.e., alcohol use, proton pump inhibitors) can theoretically cause elevated homocysteine. Other diseases that correlate with elevated homocysteine levels include hip fracture, cognitive decline, osteoporosis, chronic kidney disease, hypothyroidism, Alzheimer disease, and schizophrenia.
The estimated prevalence of mild hyperhomocysteinemia is 5% to 7% in the general population. Several studies have shown that it is an independent risk factor for thrombotic disorders (i.e., deep vein thrombosis). It has even been reported that lowering a patient's homocysteine levels by 25% decreases stroke risk by 19%.
Elevated levels of homocysteine can increase the risk of atherosclerosis by causing endothelial layer injury, promoting inflammation, and increasing oxidative stress. However, the exact mechanism is still unknown, and more research needs to be done to identify the pathophysiology. In relation to brain atrophy and cognitive decline, the correlation with elevated homocysteine levels is unclear but has been speculated to be a finding related to vitamin deficiencies. However, in studies, there was no relationship between baseline levels of tHcy and the rate of atrophy in people who were being treated for hyperhomocysteinemia, which suggests that homocysteine is a direct cause of brain atrophy.
There are multiple pathways to which elevated homocysteine levels can lead to schizophrenia. Elevated total homocysteine levels in the third trimester of pregnancy may cause subtle damage to the vasculature of the placenta, which can limit oxygen to the fetus and may have a direct effect on the brain structure of the fetus and thus increase the risk of developing schizophrenia. Homocysteine may also play a role in schizophrenia via effects on the NMDA receptor by initiating oxidative stress, which leads to vascular inflammation.
The pathogenesis of hip fracture and elevated homocysteine levels is speculated to be due to homocysteine interference in collagen cross-linking, which alters the bone matrix and increases the fragility of the bones.
The presentation of hyperhomocysteinemia varies due to the underlying cause and, in some cases, is asymptomatic. Patients presenting with any cardiovascular and cerebrovascular disorders can have elevated homocysteine levels and can be asymptomatic. Also, it is possible that elevated homocysteine levels can be found with those who are vitamin B12, B6, and folate deficiency. In these patients, symptoms could range from fatigue, numbness/tingling to weight loss, and dementia. Some other symptoms/diseases that can present in hyperhomocysteinemia include hip fracture, cognitive decline, osteoporosis, chronic kidney disease, hypothyroidism, Alzheimer disease, and schizophrenia.
The initial evaluation of hyperhomocysteinemia includes a thorough history and physical exam to look for any signs and symptoms of homocystinuria, a rare but deadly disease. In children, it would present as an ectopic lens and developmental delay, whereas in adults, it would manifest as vascular disease. Other signs and symptoms include a family history of homocystinuria, osteoporosis, glaucoma, and retinal detachment, especially in children and young adults. In these patients, homocysteine levels should be obtained.
In patients who do not have signs and symptoms of homocystinuria, the decision to measure homocysteine levels and pursue treatment remains controversial. According to the American Heart Association (AHA), homocysteine levels do not predict cardiovascular disease development. Lowering homocysteine levels does not improve clinical outcomes, nor does it prevent future cardiovascular and thromboembolic diseases with treatment.
On the other hand, some studies showed that lowering the homocysteine level was beneficial. One study was able to show that lowering hyperhomocysteinemia through folic acid supplementation would reduce carotid atherosclerosis progression. In addition, a randomized control study noted that patients who have mild cognitive impairment and received 0.8 mg of folic acid, 0.5 mg of vitamin B12, and 20 mg of B6 for 24 months were noted to have decreased brain atrophy and a slowing of cognitive decline. These patients also had no safety issues while being on this homocysteine-lowering treatment. Therefore, in these patients, a discussion between the clinician and patient is warranted on the risks and benefits of obtaining a homocysteine level.
Several studies have tried to demonstrate the efficacy of vitamin supplementation to reduce cardiovascular and thromboembolic risk. The American Heart Association explained that folic acid supplementation (0.2 to 15 mg/d) could lower homocysteine levels. However, randomized control trials have been controversial in showing cardiovascular risk reduction with folic acid supplementation unless a patient has homocystinuria.
In patients who have homocystinuria with severe hyperhomocysteinemia, homocysteine-lowering treatments with pyridoxine, folic acid, and hydroxocobalamin did reduce cardiovascular risk.
In patients who have hyperhomocysteinemia without homocystinuria, treatment remains controversial. Randomized control trials have not been able to show a reduction in cardiovascular risk for those who lower homocysteine levels using homocysteine-lowering therapies. However, studies have also shown that it can potentially reduce carotid atherosclerosis progression, have mild primary stroke prevention benefits and delay brain atrophy in patients with mild cognitive impairment in patients who have been treated with homocysteine-lowering medications. Therefore, the clinician must have a detailed discussion of the risks and benefits of obtaining and treating an elevated homocysteine level. Compared to the risks, placing a patient on vitamin B supplement that is readily over-the-counter seems to have more benefits.
The differential diagnosis for hyperhomocysteinemia, especially in the setting of homocystinuria (i.e., these patients would have marfanoid habitus and ectopic lens) include Marfan syndrome and sulfite oxidate deficiency syndrome. Differentiating among these conditions is crucial as studies have pointed out their similarities. Obtaining a homocysteine level will distinguish these diseases from homocystinuria. Other conditions where elevated homocysteine levels would be present are hip fracture, cognitive decline, osteoporosis, chronic kidney disease, hypothyroidism, Alzheimer disease, and schizophrenia.
The prognosis of severe hyperhomocysteinemia in the setting of homocystinuria is poor if it is left untreated. For patients who have hyperhomocysteinemia without homocystinuria, the prognosis is difficult to assess as there is not enough research. However, theoretically, there is an increased risk for osteoporosis, schizophrenia, and brain atrophy in specific populations that can increase the morbidity of these patients. Therefore, further research is needed to determine a patient's prognosis when they are diagnosed with elevated homocysteine.
Potential complications of hyperhomocysteinemia in the setting of homocystinuria include retinal detachment, glaucoma, and vascular disease as children or young adults. For patients who have hyperhomocysteinemia without homocystinuria, there is an increased risk for atherosclerotic events. Also, there is an increased risk for hip fractures and brain atrophy for specific populations as well as an increased risk of developing schizophrenia.
Especially for the primary care physician, we believe that it is reasonable to discuss the evaluation of hyperhomocysteinemia, including the controversial nature of the treatment. The first step would be to discuss the patient’s intake of foods with folic acid, vitamin B6, and B12 to see if the patient is meeting the recommended dietary amount for these vitamins. If they are not meeting these requirements, recommendations can be made to increase foods rich in these vitamins such as fruits and vegetables as a portion of the general population does not meet the Recommended Dietary Allowance (RDA) for these nutrients. In addition, education would have to be on a case by case basis based on the patient’s disease. For patients with signs and symptoms of homocystinuria or mild cognitive impairment, the benefits for vitamin B supplementation outweigh the risks; therefore, supplementation is recommended. For all other patients, there is not enough evidence to support the use of homocysteine-lowering treatments across the board.
At this time, it is recommended that only those with signs and symptoms of homocystinuria and mild cognitive impairment are evaluated and treated for hyperhomocysteinemia. [Level 2] This subset of the patient population will most likely benefit from treatment, as demonstrated by randomized control trials. For all other patients, physicians and other healthcare professionals, operating as a cohesive interprofessional team, need to have a discussion with their patients about the risks and benefits of obtaining a homocysteine level. Pharmacists should assist patients in the selection of supplements, recommend appropriate dosing and administration, and check for drug interactions. Dieticians and nutritionists educate patients. Specialty trained nurses in cardiology also provide guidance and arrange referrals and follow up. All these healthcare providers need to contact the clinician if they encounter any issues within their particular discipline. This type of interprofessional collaboration can result in better outcomes for patients with hyperhomocysteinemia. [Level 5]
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