I. What every physician needs to know.

Hyper-homocystenemia, also known as homocystinuria, is a syndrome of elevated levels of plasma homocysteine with manifestations in almost all body systems, most notably an increased risk of arterial and venous thrombotic events and premature development of cardiovascular disease. Elevated levels result from genetic defects in enzymes of methionine metabolism or vitamin (folic acid, B6 and B12) deficiencies, but often a combination of the two.

Hematologic manifestations result from a proposed mechanism of vascular endothelium damage, disrupting release of nitric oxide and platelet activation. The severe form of disease results from homozygous enzyme deficiency and presents with highly elevated blood levels and a distinguishable syndromic picture, as described below. If left untreated, it is a slowly progressive, multiorgan disorder.

The less severe forms can result from minor or heterozygous enzyme defects or vitamin deficiencies and is often asymptomatic. Management decisions are based on homocysteine blood levels and relative increased risk of thromboembolic events.

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II. Diagnostic Confirmation: Are you sure your patient has hyper-homocysteinemia?

While a positive urine nitroprusside test is inexpensive and relatively sensitive, diagnosis requires measurement of fasting quantitative amino acids and total plasma homocysteine levels. Disease classifications that determine management priorities are as follows:

  • Severe (classic homocystinuria) – plasma level greater than 100 micromole/Liter (μmol/L)

  • Moderate – plasma level 30-100 μmol/L

  • Mild – plasma level 15-30 μmol/L

Genetic testing is required to identify the specific genetic defect responsible for the elevated plasma levels, but this rarely affects immediate management while inpatient and can be performed outpatient.

A. History Part I: Pattern Recognition:

The majority of patients often present to an adult hospitalist with a picture similar to other thrombophilias. The most common venous thromboembolic event (VTE) is deep venous thrombosis (DVT) of lower extremity, which may lead to pulmonary embolization.

Personal history often includes recurrent DVTs or arterial thrombosis at a young age (<50 years old), including myocardial infarction, cerebral vascular accident, and peripheral vascular disease. Female patients may also have a history of multiple miscarriages or pregnancy complications, including intrauterine growth restriction, fetal demise, abruption, or early severe pre-eclampsia. They may also have a family history of recurrent thrombosis or thrombophilia.

Patients with severely elevated levels present with a genetic syndromic picture that differ slightly depending on the enzymatic defect present. Many are identified as children and become more severe with age if left untreated. Listed below are the more common defects and their syndromic picture:

Cystathionine β-synthase (CBS) deficiency (“classic” homocystinuria)

  • Vascular – arterial and venous thromboembolic events (major cause of morbidity and mortality)

  • Ocular – ectopia lentis (occurs between 4 and 12 years of age), myopia, blindness secondary to glaucoma, optic atrophy, retinal detachment

  • Skeletal (Marfanoid) – elongated and thinned bones, genu valgum, pectus malformation, scoliosis, osteoporosis

  • Neurologic – mental retardation (if untreated), cerebrovascular thrombosis, seizures, various psychiatric and personality disorders

Methylenetetrahydrofolate reductase (MTHFR) deficiency (folate-dependent homocystinuria) – may resemble subacute combined degeneration seen in vitamin B12 deficiency –

  • Neurologic (predominate) – psychomotor retardation, seizures, abnormal gait, and psychiatric disturbances

  • Vascular – arterial and venous thromboembolic events

  • Ocular – ectopia lentis

Transcobalamin II deficiency (TC-II) –

  • Hematologic – pancytopenia, macrocytosis

  • Metabolic – methylmalonic acidemia, ketoacidosis

  • Mucocutaneous – stomatitis

Lysosomal B12 translocase deficiency (Cbl F) –

  • Hematologic – macrocytosis

  • Metabolic – methylmalonic acidemia

  • Mucocutaneous – stomatitis

Cobalamin reductase (Cbl C and Cbl D) deficiency –

  • Hematologic – pancytopenia

  • Neurologic – mental retardation

Methionine synthase (Cbl G) and methyltransferase reductase (Cbl E) deficiency –

  • Vascular – vaso-occlusive phenomena

  • Hematologic – macrocytosis

  • Neurologic – developmental delay, spasticity, dystonia

B. History Part 2: Prevalence:

Hyper-homocysteinemia is present in among 5-10% of the general population, and in approximately 10-25% of patients presenting with a spontaneous single venous thromboembolism. The clinical significance of these elevated levels, however, is highly debated. Testing should be considered for individuals presenting with recurrent VTE, VTE in uncommon sites, VTE during pregnancy or while on oral contraceptives (OCP)/hormone replacement therapy (HRT).

Severely elevated levels are most often due to enzymatic deficiencies. Some of the genetic defects only produce a state of elevated homocysteine when concomitant with vitamin deficiency. Below are listed the most common causes of elevated levels of total plasma homocysteine:

Severe inherited hyper-homocysteinemia
  • 1 in 60,000 to 1 in 300,000 live births.

  • More commonly homozygous mutation in methylenetetrahydrofolate reductase (MTHFR) or cystathionine β-synthase (CBS) deficiency.

  • Often asymptomatic unless deficient in folate, resulting in an exaggerated hyperhomocysteinemic response.

  • Rarely caused by errors in cobalamin (vitamin B12) metabolism.

Mild to moderate inherited hyper-homocysteinemia
  • Most commonly C677T polymorphism in MTHFR gene, but may be due to heterozygous mutation in MTHFR and CBS deficiencies.

  • Heterozygous C677T – normal homocysteine blood levels.

  • Homozygous C677T – mild to moderate hyper-homocysteinemia with concomitant folate deficiency.

Acquired hyper-homocysteinemia
  • Vitamin B6 deficiency – patients on isoniazid

  • Folate and Vitamin B12 deficiency – alcoholics and pregnant women

  • Renal failure

  • Diabetes mellitus

  • Hypothyroidism

  • Malignancy

  • Pernicious anemia

  • Psoriasis

  • Inflammatory bowel disease

  • Medications – methotrexate, theophylline, phenytoin

C. History Part 3: Competing diagnoses that can mimic hyper-homocysteinemia.

Due to the pleiotropic nature of this disorder, presentation is highly variable. Below is listed differential diagnoses for some of the most common presentations:


Malignancy (most common acquired hypercoagulable state), myeloproliferative syndromes, antiphospholipid antibodies (APA), heparin-induced thrombocytopenia, activated protein C resistance, factor V Leiden thrombophilia, prothrombin G20210A mutation, natural anticoagulant deficiencies (antithrombin, protein C, and protein S).

Ectopia lentis

Downward dislocation differentiates from Marfan’s syndrome, which predominately dislocates upward.

Marfanoid habitus

Although patients often have overlapping features with Marfan’s syndrome, they do not have true arachnodactyly, hypermobility of joints or other cardiac abnormalities seen in the latter disorder. Marfanoid habitus can also be seen in MEN 2B syndrome.

D. Physical Examination Findings.

Physical findings may vary with syndromic presentation. Many patients with milder disease do not have any identifiable abnormalities on physical exam.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The priorities of immediate management are based on clinical picture and hematologic profile, however detection of homocysteine may provide an etiology and indicate whether further outpatient work-up is required.

  • Urine nitroprusside test – positive also for cystinuria, but can be falsely negative.

  • Total plasma homocysteine (tHcys) – determined by high-performance liquid chromatography (HPLC), measures both homocysteine moieties of homocysteine, the homocysteine component of the mixed disulfide form, and protein-bound homocysteine (90%).

  • Blood methionine levels (met) – unreliable in early stages of disease, and useful only for detecting more severe pyridoxine-nonresponsive patients.

  • Urine methylmalonic acid (MMA) – utilized to diagnose methylmalonic aciduria and exclude other cobalamin defects

See Table I.

Table I.
Class Hcys met MMA
CBS deficiency Elevated Elevated
MTHFR deficiency Elevated Reduced
TC-II Elevated/Normal Reduced/Normal +/-
Cbl-F Elevated/Normal Unknown +/-
Cbl C and Cbl D Elevated/Normal Reduced/Normal +
Cbl G and Cbl E Elevated Reduced/Normal

Genetic testing or enzyme assayed from liver or fibroblasts can isolate specific genetic defect, but are often not required in patient.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging tests are required to characterize hyper-homocysteinemia. However, contrast venography or duplex ultrasound can be useful in detecting deep vein thromboses. In addition, all age- and gender-appropriate cancer screenings are required to evaluate for malignancy as underlying cause of hypercoagulability.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Genetic testing for specific mutation, such as C677T mutation in MTHFR is costly and rarely influences immediate management, thus is rarely appropriate in an inpatient setting. In addition, misinterpretation may lead to misuse of antithrombotic drugs in the absence of overt hypercoagulability. Measurement of homocysteine levels and monitoring for clinical manifestations should be emphasized.

Methionine challenge tests were once used to diagnose patients with suspected hyper-homocysteinemia and normal fasting serum homocysteine levels. The prognostic value of this test is debatable.

Screening healthy women with no personal or family history of VTE for hyper-homocysteinemia prior to initiation of OCP or HRT is not cost-effective. The relative risk of thromboembolism increases dramatically with hyper-homocysteinemia, but the absolute risk is still low.

III. Default Management.

Management should depend on the presenting complaint. In patients with acute thrombosis, anticoagulation should be started immediately. Lifetime anticoagulation is not warranted for asymptomatic patients (relative risk of single VTE being only 2-4). Prophylaxis may be considered for patients in a high-risk situation, such as a major orthopedic surgery.

In the general population, interventional studies have shown limited benefit on morbidity or mortality from cardiovascular disease by lowering homocysteine levels. This paired with the cost of laboratory test recommends against routine screening. The American Heart Association (AHA) recommends a healthy, balanced diet to provide adequate folate and B12. Supplementation should only be necessary if diet does not provide the recommended daily values.

In patients with severe homocystinuria, oral folic acid and pyridoxine supplementation has been shown to reduce plasma methionine and homocysteine levels, but this may not reverse hypercoagulability or improve cardiovascular morbidity and mortality completely. Although exact minimally effective doses have not been determined, low dose folate (0.8 milligrams/day [mg/day]) and pyridoxine (250-500 mg/day) maximally reduces homocysteine levels. Normalization of levels may been seen at 2 weeks, but usually take between 4 to 6 weeks. Dosage should be increased incrementally to achieve reduction in blood levels because high vitamin levels can be toxic.

Patients not responsive to oral pyridoxine (approximately 50%) may require betaine treatment (6 grams/day [g/day] in divided doses) and a very low-protein (<5-10 mg/day) diet, supplemented with methionine-free amino-acids. Some patients, such as those with MTHFR deficiency, may require much larger doses of betaine (12-150 millgram/kilogram/day [mg/kg/day]) to lower plasma homocysteine levels and raise methionine levels. With adequate control, many patients can have a normal life expectancy.

A. Immediate management.

In patients with an acute thromboembolic event should undergo anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular weight heparin followed by oral warfarin therapy. There is no data to suggest that a course beyond 3 to 6 months is necessary. Experts disagree whether the presence of thrombophilias should alter management of VTE.

Oral pyridoxine and folate supplementation can be started immediately to lower plasma homocysteine levels, but maximal reduction may not be seen for weeks.

B. Physical Examination Tips to Guide Management.

Patients should have standard screening for bleeding events while on anticoagulation. Low-level vitamin supplementation should not require any additional monitoring.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Total plasma homocysteine levels can be periodically monitored for patients on vitamin therapy, but there is no evidence that controlling these levels alters clinical course. Levels should be monitored at 8 weeks to assess response to therapy and modulate dosage if necessary. If levels remain high, levels may need to be checked 2 to 3 times annually. Levels should be monitored primarily on an outpatient basis.

Recent literature has challenged that free plasma homocysteine may have greater predictive and prognostic value, but evidence is very limited.

D. Long-term management.

Long-term anticoagulation is most often unnecessary. Most recurrent VTEs occur within 1-3 years of initial event and annual rate declines after that, conversely the risk of anticoagulation-related major bleeding increases with age. The risks and benefits of long-term anticoagulation should be seriously considered before initiation.

Long-term supplementation with folate, B6, and B12 may help prevent recurrence of VTE and arterial thrombosis although data is limited. Dosing as below:

  • Folate: 0.8 mg/day by mouth (PO), low dose supplementation

  • Pyridoxine (B6): 250-500 mg/day PO, low dose supplementation

  • Betaine: 6 g/day PO, divided in divided doses

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Renal failure can elevate homocysteine levels, sometimes 4 times greater than normal values, and produce false-positive results for total plasma homocysteine. This may contribute to accelerated atherosclerosis in these patients. Whether this is due to impaired metabolism or impaired excretion is unknown, however levels are reduced with dialysis. Management should focus on treating renal insufficiency. If levels remain elevated once renal insufficiency is resolved, then vitamin supplementation may be required.

In stable kidney transplant recipients and patients with end stage renal disease, large randomized control trials have failed to show an impact on major clinical outcomes despite significant reductions in plasma homocysteine levels.

B. Liver Insufficiency.

Increased levels of homocysteine have been found in patients with cirrhosis and have been associated with more severe disease and worse graft and patient survival after transplantation. No causal relationship has been established, and thus there is no recommended change in standard management.

C. Systolic and Diastolic Heart Failure

Observational studies have found an association between elevated levels and worse prognosis in chronic heart failure, but no practical clinical protocols have been established. For now, routine screening in this population is not recommended.

D. Coronary Artery Disease or Peripheral Vascular Disease

As stated above, the American Heart Association (AHA) does not currently recognize hyper-homocysteinemia as a major modifiable risk factor for cardiovascular disease although some meta-analyses have shown that approximately 10% of the risk for coronary artery disease in the general population is attributable to elevated homocysteine levels. There may be a role for screening in patients with early onset atherosclerosis.

Additionally, up to a third of patients with cerebrovascular and peripheral vascular disease were found to have hyper-homocysteinemia after a methionine challenge test, and there may also be a graded relationship between homocysteine levels and carotid stenosis.

All these findings suggestion an association with hyper-homocysteinemia; however, a recent Cochrane systematic review demonstrated no reduction in myocardial infarction, stroke, or death from any cause with homocysteine-lowering therapies. There are an insufficient number of studies to provide recommendations for patients with peripheral vascular disease. Therefore, supplementation should only be necessary if diet does not provide the recommended daily value.

E. Diabetes or other Endocrine issues

As with coronary-artery disease, there is extensive literature on the presence of hyper-homocysteinemia in many endocrine disorders, such as diabetes and hypothyroidism. However, the impact of these findings on management is highly debated. High dose B-vitamin supplementation in patients with diabetic nephropathy should be avoided and has been associated with decreased glomerular filtration rate (GFR) and increased cardiovascular events.

F. Malignancy

Hyper-homocysteinemia can be seen in patients with breast, ovarian, pancreatic cancers, and acute lymphoblastic leukemia (ALL). After treatment of primary disease, especially in patients for ALL, levels decrease dramatically.

Some studies have found a link between elevated levels of homocysteine and increased risk of cervical dysplasia. No recommendations for increased surveillance have been made.

Although some studies have suggested an association with homocysteine-lowering interventions and increased incidence of some malignancies – mainly colorectal cancers – a recent Cochrane systematic review demonstrated no such association.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Elevated levels have been seen in patients with pernicious anemia, however the risk for vascular events is unclear. As in other disease states, effect on management is highly debatable.

J. Hematologic or Coagulation Issues

Patients with known hyper-homocysteinemia and a high-risk situation, such as prolonged immobility, are strong candidates for prophylaxis, such as intermittent compression devices (ICDs), heparin, or warfarin therapy. The risk of bleeding should be heavily weighed against the minor benefits of more aggressive therapy.

The use of OCPs and HRT is controversial in patients with hyper-homocysteinemia due to increased risk of thrombotic events. While some studies support an interaction between thrombophilias and the use of OCPs or HRT in increasing the risk for VTE, no relationship with hyper-homocysteinemia was seen.

K. Dementia or Psychiatric Illness/Treatment

In a recent Cochrane systematic review, long-term folic acid and B12 supplementation improved cognitive function in healthy older people with high homocysteine levels. Further studies are needed to further investigate this association and establish specific recommendations for hyper-homocysteinemia screening and supplementation.

There are no recommended changes in standard management in patients with a psychiatric disorder not resulting from underlying hyper-homocysteinemia.

L. Pregnancy

Elevated levels of homocysteine may predispose to thromboembolic events in this population, however universal screening in pregnancy is not justified. Homocysteine levels are often lower during pregnancy, possibly resulting from increased blood volume, decreased albumin levels, and use of pre-natal vitamins containing folic acid, which may result in false negative tests. Aggressive anticoagulation is often contraindicated in this population.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Sign-out should be similar to other patients with thrombophilia and patients on anticoagulation.

B. Anticipated Length of Stay.

Length of stay depends on severity of presenting disorder and may not be affected by presence of elevated levels of homocysteine.

C. When is the Patient Ready for Discharge.

Patients are ready for discharge when thromboembolic event has been identified and proper anticoagulation has been initiated. Thrombophilia testing, monitoring and long-term treatment in an outpatient setting should be adequate for most patients.

D. Arranging for Clinic Follow-up

Inpatient lab results may be transient or falsely negative or positive, so if a thrombophilia is expected, arrange follow-up in 4-6 weeks with a thrombosis specialist. Any patient who is pregnant or considering pregnancy should see an internist with interest in obstetric medicine or perinatologist for assessment of VTE risk.

1. When should clinic follow up be arranged and with whom.

  • Thrombosis specialist

  • Geneticist for family testing and counseling if a severe form is identified

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Genetic testing and monitoring of homocysteine levels can be best performed on an outpatient basis and are often not required prior to discharge.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Genetic testing and total plasma homocysteine levels may be required at clinic visit, depending on severity of disorder.

E. Placement Considerations.

Most patients will not require special placement. Patients with severe mental disability or incapacitating psychiatric or neurologic disorders may require special arrangements or adequate social support. Functional assessment may be required by social work.

F. Prognosis and Patient Counseling.

Approximately half of untreated patients with severe hyper-homocysteinemia will develop a thromboembolic event prior to the age of 30, and disease-related mortality can be up to 20 percent. Without any cohort studies of asymptomatic patients, estimates of absolute risk for VTE are unknown. Patients should be educated on how to identify thrombotic events and the importance of seeking early medical intervention.

Due to the increased risk of VTE, all patients should be counselled on smoking cessation, weight control, adequate hydration and avoidance of prolonged immobility by early ambulation post-operatively, and frequent ambulation or use of graduated compression stockings during flights and long car rides.

Patients should receive nutritional counseling on how to ensure adequate intake of folic acid, B6 and B12 vitamins. Good sources of folate include breakfast cereals and fortified grain products, lentils, asparagus, spinach and most beans. Good sources of B6 include breakfast cereals and fortified grain products, potatoes, bananas, garbanzo beans (chickpeas), and chicken. Good sources of B12 include dairy products, organ meats (such as liver), beef and some fish.

Patients with severe pyridoxine-unresponsive disorders may require additional counseling on a low-protein diet. Specialist consultation with a nutritionist may be required.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

There are no core indicator standards and documentation required for hyper-homocysteinemia.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

All age-appropriate prophylaxis for patients with thrombophilic disease should be followed. If specific dietary restrictions are necessary, a nutritionist should be consulted.

What's the evidence?

Andras,, A,, Stansby, G,, Hansrani,, M., G., Stansby. “Homocysteine lowering interventions for peripheral arterial disease and bypass grafts.”. Cochrane Database of Systematic Reviews. 2013. (Although there are no changes in management recommendations, this is the most up-to-date and comprehensive review of the literature on this topic. Referenced studies have been removed from the list of citations.)

Bhanji, RA,, Ma, M,, Bain, VG,, Montano-Loza, AJ. “Hyperhomocysteinemia is associated with severity of cirrhosis and negative impact after liver transplantation.”. Liver International. 2015.

Boushey, CJ,, Beresford, S,, Omenn, GS,, Motulsky, G. “A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.”. JAMA: The Journal of the American Medical Association. vol. 274. 1995. pp. 1049-1057.

den Heijer, M,, Lewington, S,, Clarke, R.. “Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies.”. Journal of thrombosis and haemostasis. vol. 3. 2005. pp. 292-299.

Heinz, J,, Kropf, S,, Domrose, U,, Westphal, S. “B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease: Results of a Randomized Controlled Trial.”. Circulation. vol. 121. 2010. pp. 1432-1438.

House, AA,, Eliasziw, M,, Cattran, DC,, Churchill, DN. “Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.”. Jama. vol. 303. 2010. pp. 1603-9.

Kang, A,, Nigwekar, SU,, Perkovic, V,, Kulshrestha, S. “Interventions for lowering plasma homocysteine levels in kidney transplant recipients.”. Cochrane Database of Systematic Reviews. vol. 5. 2015. (Although there are no changes in management recommendations, this is the most up-to-date and comprehensive review of the literature on this topic. Referenced studies have been removed from the list of citations.)

Li,, D,, Zhou,, M,, Peng, X,, Sun, H.. “Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism, and risk of retinal vein occlusion: an updated meta-analysis.”. BMC Ophthalmology. vol. 14. 2014. pp. 147

Martí-Carvajal,, AJ,, Solà,, I,, Lathyris,, D.. “Homocysteine-lowering interventions for preventing cardiovascular events.”. The Cochrane Database of Systematic Reviews. vol. 1. 2015. (Although there are no changes in management recommendations, this is the most up-to-date and comprehensive review of the literature on this topic. Referenced studies have been removed from the list of citations.)

Malouf, Rand, Evans, JG.. “Folic acid with or without vitamin B for the prevention and treatment of healthy elderly and demented people.”. The Cochrane Library. vol. 2. 2009.

McCully, KS. “Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.”. The American journal of pathology. vol. 56. 1969. pp. 111-128.

Mudd, SH,, Skovby, F,, Levy, HL,, Pettigrew, KD. “The natural history of homocystinuria due to cystathionine beta-synthase deficiency.”. American journal of human genetics. vol. 37. 1985. pp. 1-31.

Ray, JG.. “Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease.”. Archives of internal medicine. vol. 158. 1998. pp. 2101-2106.

Vasan, RS,, Beiser, A,, D’Agostino, RB,, Levy, D. “Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction.”. JAMA. vol. 289. 2003. pp. 1251-7.

van Oijen, MGH,, Claessen, BEPM,, Clappers, N,, van Schaik, A. “Prognostic Value of Free Plasma Homocysteine Levels in Patients Hospitalized With Acute Coronary Syndrome.”. The American Journal of Cardiology. vol. 102. 2008. pp. 135-139.

Wu, O,, Robertson, L,, Twaddle, S,, Lowe, G. “Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis.”. British Journal of Haematology. vol. 131. 2005. pp. 80-90.

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