Overview
A disease characterized by elevated levels of homocysteine in the blood due to a variety of causes.
Usually asymptomatic
Pathogenesis is related to genetics, nutrition, lifestyle, age, gender, disease, medications and other factors.
Lifestyle interventions combined with drug therapy
Definition
A disease characterized by elevated levels of homocysteine in the blood due to accumulation of homocysteine in the blood for various reasons.
In China, the “Expert Consensus on the Diagnosis and Treatment of Hyperhomocysteinemia” (2020 Edition), the blood homocysteine level of 15 μmol/L in adults is considered to be the upper limit of normal.
Hyperhomocysteinemia can cause damage to cells, tissues, and organs of the body, and is therefore an independent risk factor and an important risk factor for the development of many chronic diseases.
Hyperhomocysteinemia, like hypertension, hyperlipidemia, and hyperglycemia, is an important indicator of human health risk.
In recent years, the incidence of hyperhomocysteinemia has been increasing year by year, and it has been recognized worldwide as the “fourth highest” after “hypertension, hyperlipidemia and hyperglycemia”.
Incidence
The overall prevalence of the disease in the population is as high as 5%.
Research shows that the average value of blood homocysteine in adults in China is between 13 and 14 μmol/L, which is usually higher in men than in women.
In China, 75% of men and 50% of women over the age of 45 have a blood homocysteine level of more than 10.5 μmol/L.
Causes
Causes
Current research has linked the development of hyperhomocysteinemia to the following factors:
Genetic factors
Studies have shown that there is a genetic predisposition for the disease, which is related to the inactivation of key enzymes in homocysteine metabolism (e.g., MTHIFR, CBS, MS, CBL, betaine homocysteine methyltransferase) due to mutations in genes such as MTHFR C677T, and that the incidence of the disease is higher among people with a family history of homocysteine metabolism.
Nutritional factors and lifestyle
Nutrients such as folic acid, vitamin B12, and vitamin B6 are consumed during homocysteine metabolism.
Poor lifestyle, such as alcohol consumption and smoking, can lead to excessive consumption of folic acid, vitamin B12, and vitamin B6, and an unbalanced diet can lead to low intake of these nutrients, all of which can lead to hyperhomocysteinemia.
Age and gender
It has been found that blood homocysteine levels gradually increase with age.
Homocysteine metabolism is influenced by estrogen, so blood homocysteine levels are generally higher in men than in women, and higher in postmenopausal than premenopausal women.
Diseases and Medications
Certain diseases (e.g., abnormal kidney function, hypothyroidism, severe anemia, severe scleroderma, malignant tumors, etc.) have been found to contribute to elevated blood homocysteine.
In addition, the use of drugs such as methotrexate, antiepileptic drugs (e.g. carbamazepine, sodium valproate, phenytoin sodium, etc.), diuretics (e.g. furosemide, torasemide, etc.), and niacin may also lead to elevated blood homocysteine.
Symptoms
Main Symptoms
Hyperhomocysteinemia by itself usually does not cause any symptoms, but damage to other tissues and organs may cause symptoms.
Complications
Stroke
Hyperhomocysteinemia is an independent risk factor for stroke.
A blood homocysteine value above 10.50 μmol/L increases the risk of stroke by 4.2 times compared to the general population.
Dizziness, headache, hemiparesis, aphasia, convulsions, and impaired consciousness can occur after inducing a stroke.
Dementia
Hyperhomocysteinemia can cause Parkinson’s disease, Alzheimer’s disease, vascular dementia and other dementia diseases.
It may lead to memory loss, intellectual disability, mental behavioral abnormalities and other manifestations.
Cardiovascular disease
Studies have shown that increased blood homocysteine increases the risk of cardiovascular diseases such as coronary heart disease.
Symptoms such as chest tightness, palpitations, chest pain and dyspnea can occur.
High Blood Pressure
High blood homocysteine levels can lead to H-type hypertension.
Dizziness, headache, and elevated blood pressure may occur.
Diabetes Complications
Diabetic patients with hyperhomocysteinemia are more susceptible to macrovascular damage and microangiopathy, and are more likely to develop complications such as diabetic neuropathy, diabetic foot, and diabetic nephropathy.
Symptoms such as limb numbness, sensory abnormalities, limb ulceration and necrosis, oliguria or anuria, and edema may occur.
Chronic kidney disease
Hyperhomocysteinemia is an independent risk factor for the progression of chronic kidney disease.
It can cause manifestations such as edema, oliguria, and anuria.
Osteoporosis
Hyperhomocysteinemia has a harmful effect on the adult bone, which can reduce the bone mass and lead to decreased bone strength, which can easily cause fracture.
Diseases during pregnancy
Hyperhomocysteinemia can lead to pregnancy diseases such as gestational hypertension, gestational diabetes mellitus, placental vasculopathy, and habitual abortion.
Fetal malformations
Hyperhomocysteinemia can directly affect the degree of closure of the neural tube of the fetus, which in turn can lead to fetal malformations.
Male Diseases
Hyperhomocysteinemia may affect spermatogenesis and sperm function leading to infertility, and may also lead to erectile dysfunction in men.
Tumors
It has been found that hyperhomocysteinemia is associated with the development of a variety of malignant tumors such as breast cancer, liver cancer, gastric cancer and lung cancer in the Asian population.
Liver disease
Hyperhomocysteinemia can induce hepatocyte damage and apoptosis, aggravating liver injury.
Symptoms such as loss of appetite, anorexia, nausea and jaundice may occur.
Vitamin deficiency
It can lead to vitamin deficiencies such as folic acid, vitamin B12, and vitamin B6.
Symptoms such as fatigue, mouth sores, developmental abnormalities, and sensory abnormalities can occur [1-3].
Consultation
Department of Medicine
Cardiovascular medicine
Routine physical examination reveals elevated blood homocysteine, or symptoms such as fatigue, mouth sores, developmental abnormalities, and sensory abnormalities, prompt medical consultation is recommended.
Prompt medical consultation is recommended if symptoms of cardiovascular damage such as chest tightness, palpitations, chest pain, dyspnea, and elevated blood pressure occur.
Preparation for medical treatment
Preparation for consultation: registration, preparation of documents, common problems
Tips for Consultation: Registration, Preparation of Documents, Frequently Asked Questions
Blood test is required, so it is recommended to visit the doctor on an empty stomach.
Preparation List
Symptom list
Pay special attention to the time of onset of symptoms and special symptoms.
Are there any symptoms such as fatigue, mouth sores, developmental abnormalities, sensory abnormalities, etc.?
Are there any symptoms such as chest tightness, palpitations, chest pain, dyspnea, elevated blood pressure, etc.?
Are there any symptoms such as dizziness, headache, hemiplegia, aphasia, convulsions, impaired consciousness, etc.?
How long have these symptoms been present?
List of medical history
Is there any history of abnormal renal function, hypothyroidism, severe anemia, severe scleroderma, malignancy, etc.?
Is there any poor lifestyle such as alcohol consumption, smoking, partiality of food, etc.?
Do you have regular medical checkups? What is the previous blood homocysteine level?
Any history of hyperhomocysteinemia in immediate family members such as parents and children?
Checklist
Test results in the last 6 months, which can be brought to the doctor’s office
Laboratory test: blood homocysteine test
Medication List
Medication used in the last 3 months, bring the box or package with you if available
Methotrexate
Antiepileptic drugs: carbamazepine, sodium valproate, phenytoin sodium, etc.
Diuretics: furosemide, torasemide, etc.
Niacin
Diagnosis
Diagnosis is based on
Medical history
May be seen in people with a family history of hyperhomocysteinemia.
Prevalent in people with poor lifestyles such as alcohol consumption, smoking, and predilection for food.
Underlying diseases such as renal dysfunction, hypothyroidism, severe anemia, severe scleroderma, and malignant tumors may have preceded the onset of the disease.
Before the onset of the disease, the patient may have used drugs such as methotrexate, antiepileptic drugs (e.g. carbamazepine, valproate, phenytoin sodium, etc.), diuretics (e.g. furosemide, torasemide, etc.), and nicotinic acid.
Clinical manifestations
Symptoms
Hyperhomocysteinemia itself does not cause any symptoms in adults, and some mild symptoms may occur in children. Symptoms are usually associated with vitamin deficiencies.
Ancillary Tests
Blood homocysteine measurement
is important to confirm the diagnosis of the disease.
The reference value for blood homocysteine ranges from 5 to 15 μmol/L, and 15 μmol/L is the upper limit of normal in the “Expert Consensus on the Diagnosis and Treatment of Hyperhomocysteinemia” (2020 edition).
Blood Vitamin Measurement
Measure serum folate, folic acid, vitamin B12, vitamin B6 levels.
Identify if the deficiency is secondary to hyperhomocysteinemia due to nutritional factors.
Blood amino acid, free carnitine and propionyl carnitine profile
Can confirm the diagnosis of a number of disorders.
Methionine is significantly elevated in patients with homocysteinemia type 1 and hypermethioninemia.
Methylmalonic acidemia combined with homocysteinemia is associated with increased propionylcarnitine and normal or decreased methionine.
Patients with homocysteinemia type 2 have normal propionylcarnitine and normal or decreased methionine.
Urinary organic acids
Urinary methylmalonic acid is significantly increased in patients with methylmalonic acidemia combined with homocysteinemia.
Urinary organic acids were normal in patients with hyperhomocysteinemia type 1 and hypermethioninemia.
Assessment of organ function
Find out how the patient’s cardiovascular and other organs are damaged.
For example, liver and kidney function, eye, electrocardiogram, echocardiogram, brain CT and MRI, and psycho-behavioral assessment.
Genetic analysis
It can clarify the genetic defect of hereditary hyperhomocysteinemia.
Diagnostic criteria, grading
Diagnostic criteria
In the Expert Consensus on the Diagnosis and Treatment of Hyperhomocysteinemia (2020 Edition) formulated in China, the diagnostic criterion is blood homocysteine ≥15μmol/L in adults.
Grading
The Expert Consensus on the Diagnosis and Treatment of Hyperhomocysteinemia (2020 Edition) classifies adult hyperhomocysteinemia into the following 3 grades:
Mild: blood homocysteine levels between 15 and 30 μmol/L.
Moderate: blood homocysteine levels between 30 and 100 μmol/L.
Severe: blood homocysteine levels >100 μmol/L.
Differential diagnosis
The disease can be diagnosed by measuring blood homocysteine levels, and usually no differential is needed.
Treatment
Aim of treatment: Reduce blood homocysteine levels to avoid damage to cells, tissues, and organs of the body.
Principle of treatment: Mainly through lifestyle intervention combined with medication.
General Treatment
Healthy lifestyle intervention
Stop smoking and drinking.
Eat a reasonable diet with plenty of fresh fruits and vegetables and enough vitamins.
Increase exercise.
Medication
Folic acid
Indicated for hyperhomocysteinemia due to folic acid deficiency.
High doses (more than 1mg/d) should be avoided to avoid masking vitamin B12 deficiency and subsequent zinc deficiency.
Folic acid is not effective in hyperhomocysteinemia due to choline and betaine deficiency.
Vitamin B12.
Vitamin B12 alone is not as effective as folic acid in lowering blood homocysteine.
However, in cases of vitamin B12 deficiency or defects in its gene, the dose can be increased or supplemented with methylcobalamin.
Vitamin B6
Vitamin B6 alone is not effective in lowering blood homocysteine. It is often combined with folic acid and vitamin B12 to achieve a significant synergistic effect.
Natural Betaine
Postprandial betaine supplementation is more effective than folic acid in lowering blood homocysteine.
Choline supplementation has been found to result in a decrease in mean fasting blood homocysteine.
Choline
A small portion of choline can be irreversibly converted to betaine in the liver and kidneys.
Studies have found that supplementation with 2.6 g of choline for 2 weeks resulted in an 18% reduction in mean fasting blood homocysteine.
Surgical treatment
Liver transplantation should be considered if the patient’s blood methionine is persistently higher than 800 μmol/L [4-6].
Prognosis
Cure
Simple hyperhomocysteinemia usually returns to normal after early and aggressive treatment, mostly without serious consequences and with a good prognosis.
However, hyperhomocysteinemia is an independent risk factor or an important risk factor for the development of many chronic diseases, and if not actively treated, it is prone to cause stroke, hypertension, coronary heart disease and other diseases with a poor prognosis.
Harmfulness
It can induce stroke, leading to sequelae such as paralysis, limb dysfunction, intellectual disability, and affecting normal life and work.
It can cause Alzheimer’s disease, Parkinson’s disease, vascular dementia and other diseases, affecting intelligence and loss of self-care ability.
It can cause cardiovascular disease, leading to decreased activity tolerance and affecting survival (5-year survival rate of coronary heart disease patients with blood homocysteine higher than 20 μmol/L is less than 65%).
Hyperhomocysteinemia has a significant synergistic effect with hypertension, and the risk of stroke in such patients is four times higher than in patients with hypertension alone.
It can lead to the progression of chronic disease and affect survival (5-year survival of renal dialysis patients is <65% when blood homocysteine is above 37.8 μmol/L, but can exceed 95% if blood homocysteine is below 22.9 μmol/L).
Diabetes mellitus combined with hyperhomocysteinemia will greatly increase the occurrence of uropathic neuropathy, diabetic foot, diabetic nephropathy and other complications, which in turn will affect their normal life, work and prognosis.
It can lead to osteoporosis, which increases the risk of bone mass in daily life.
It can cause pregnancy diseases such as gestational hypertension, gestational diabetes, placental vasculopathy, habitual abortion, etc., which affects the health and life safety of pregnant women and fetuses.
It may increase the risk of giving birth to a fetus with congenital heart disease and other malformations.
Can affect male sperm production, sperm function and erectile function, leading to infertility.
Can increase the risk of breast cancer, liver cancer, stomach cancer, lung cancer and other malignant tumors.
Easily cause or aggravate liver function damage [3,7].
Daily
Daily management
Dietary management
Limit sodium intake, no more than 6g of salt per day.
Eat a low-fat diet and reduce the intake of high-fat foods such as fried foods, animal oil and offal.
Eat more fresh fruits and vegetables rich in vitamins.
Exercise management
Develop a habit of continuous exercise. The type of exercise chosen can be decided according to the physical condition of the exerciser and climatic conditions.
The intensity of exercise varies from person to person, but usually moderate-intensity aerobic exercise is appropriate, and the frequency is usually 3 to 5 times/week, lasting 20 to 60 minutes each time.
People with underlying diseases such as coronary heart disease should exercise under the guidance of a physician.
Lifestyle management
Smokers should strictly quit smoking, and non-smokers should avoid exposure to second-hand smoke.
Limit alcohol intake: Limit alcohol intake: WHO recommends that alcohol intake for men should not exceed 25g/day (i.e., liquor <25-50ml, wine <100-150ml, beer <250-500ml), the less the better, and women should reduce it by half, and do not advocate the drinking of highly potent alcohol.
Disease monitoring
Those with underlying diseases such as hypertension and diabetes should learn how to measure blood pressure and blood glucose correctly, and regularly monitor and record changes in blood pressure and blood glucose.
Follow-up review
Patients with hyperhomocysteinemia should have their blood homocysteine levels monitored on a regular basis (the exact timing of the review should be determined by the specialist according to the patient’s condition), so that the doctor can assess the condition and make timely adjustments to the treatment plan.
Prevention
Adopt good living habits, quit smoking and drinking, pay attention to balanced diet and nutrition, and exercise more.
Have regular medical checkups to detect diseases and treat them promptly.
Suffer from renal dysfunction and injury, hypothyroidism, severe anemia, severe scleroderma, malignant tumors and other diseases, or use of methotrexate, nitric oxide, antiepileptic drugs, diuretics, nicotinic acid and other drugs should be supplemented with appropriate amounts of folic acid and vitamins B6 and B12 [8-10].