Homocysteine Testing
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This policy governs when measurement of plasma homocysteine is considered medically necessary or experimental/investigational for Aetna members; it applies to ordering and coverage decisions for homocysteine testing.
No material clinical or coverage changes in this revision.
Coverage Criteria
inv-01: Medically Necessary
Covered when ANY one of the following indications is documented:
Document rationale and relevant B12/holotranscobalamin or methylmalonic acid results as applicable.
Document absence of common local risk factors (eg, hypertension, glaucoma, diabetes) when ordering selective thrombophilia testing.
Order plasma and/or urine Hcy and plasma amino acids for newborns or at‑risk siblings immediately after birth when hyper-methioninemia is confirmed.
Measurement may augment thrombophilia assessment and could influence anticoagulation duration when other thrombophilias are present; an elevated Hcy alone typically does not change management.
inv-02: Experimental and Investigational / Not Medically Necessary
Not covered — Aetna considers homocysteine testing experimental and investigational for all other indications, including but not limited to:
Evidence is observational or inconsistent; effectiveness not established.
Randomized trials and guideline statements do not support routine screening or management based on Hcy for these indications.
List is not exhaustive; these uses are considered investigational per policy.
inv-03: Testing in thrombosis evaluation
Covered when used as part of a targeted thrombosis evaluation in selected patients:
An elevated Hcy alone generally does not alter management but may augment risk assessment when other thrombophilias are present and could influence anticoagulation duration; document clinical context and prior tests.
inv-04: Testing related to fracture/osteoporosis risk
Covered in research settings or specific high‑risk clinical contexts:
Evidence is mixed; benefit of vitamin therapy was shown in a selected elderly post‑stroke hemiplegic cohort but is not established for general fracture prevention.
inv-05: Cardiovascular disease and stroke — routine screening
Not indicated for routine screening of asymptomatic individuals for cardiovascular disease or stroke:
Multiple large RCTs and systematic reviews failed to demonstrate clinical benefit from homocysteine‑lowering interventions despite reductions in biochemical levels; USPSTF and editorial guidance do not recommend routine screening.
inv-06: Use of percent change in tHcy to monitor folic acid therapy (research/selected populations)
Use in research or select trial-derived contexts to monitor treatment effect:
This metric may serve as an indicator of treatment efficacy in research settings or selected hypertensive populations but is not an established routine clinical monitoring standard; findings require confirmation.
inv-07: Retinal vein occlusion — selective testing
Selective testing may be considered in atypical retinal vein occlusion presentations:
Routine testing in all RVO patients is not recommended; document absence of common risk factors (eg, hypertension, glaucoma, diabetes) when ordering selective thrombophilia testing.
inv-08: Cardiovascular disease risk prediction
Observational data support Hcy as an adjunctive risk marker but not for routine screening:
Evidence is observational; further trials are needed before recommending routine clinical use for risk reclassification.
inv-09: Situations where Hcy testing may be appropriate
Consider Hcy testing in the following targeted clinical situations when documentation supports the indication:
Testing should be targeted and documented; routine inclusion in pregnancy thrombophilia panels is discouraged.
Refer to UpToDate and ACOG guidance cited in policy.
Document prior obstetric history and rationale for ordering.
This policy explicitly excludes the use of homocysteine testing for management of MTHFR abnormalities and lists numerous clinical conditions and screening uses as not covered. Examples include assessment of autism, cardiovascular disease or stroke risk, cognitive impairment/dementia, depression, Down syndrome, fracture risk, Gaucher's disease, HELLP syndrome, lung transplant candidates, Meniere's disease, migraine, movement disorders, multiple sclerosis, polycystic ovary syndrome, premature ovarian failure, primary carnitine deficiency, recurrent pregnancy loss, retinal artery/branch vein occlusion, in‑vitro fertilization planning, management of celiac disease or inflammatory bowel disease, pulmonary hypertension, and monitoring of methotrexate or other specific therapies.
Routine measurement of homocysteine to screen asymptomatic men and women with no history of coronary heart disease (CHD) for the prevention of CHD events is not supported. The USPSTF found insufficient evidence to recommend screening, and systematic reviews and randomized trials of B‑vitamin supplementation that lowered homocysteine did not demonstrate reduced cardiovascular events, so routine population screening is not endorsed.
The American College of Obstetricians and Gynecologists (ACOG, 2014) does not recommend screening with MTHFR mutation analyses or fasting homocysteine levels when evaluating inherited thrombophilias in pregnancy, citing lack of association between MTHFR C677T polymorphism and adverse pregnancy outcomes.
There is insufficient evidence to support routine homocysteine testing for a wide range of conditions. The policy specifically lists acquired thrombophilia, autism, Down syndrome, Gaucher's disease, HELLP syndrome, Meniere's disease, methotrexate therapy monitoring, response to vitamin B‑12 therapy, movement disorders, primary carnitine deficiency, and pulmonary hypertension among indications lacking sufficient evidence for routine testing.
Homocysteine measurement is not recommended as part of routine thrombophilia screening in pregnancy. UpToDate and ACOG guidance advise against including homocysteine testing or MTHFR polymorphism testing in standard pregnancy thrombophilia panels.
In the provided sections there are no additional explicit coverage exclusions beyond those enumerated elsewhere in the policy; routine and investigational uses are addressed in the Experimental/Not Medically Necessary and Not Covered sections.
Testing for cardiovascular disease or stroke risk and many other diagnostic or monitoring uses is not supported as routine care. The policy cites randomized trials and systematic reviews showing that lowering homocysteine with B‑vitamin therapy did not reduce cardiovascular events, and therefore routine Hcy testing for CVD/stroke risk assessment or to guide B‑vitamin therapy is not recommended.
The use of homocysteine testing for routine cardiovascular risk assessment in asymptomatic individuals without specific clinical indications is not supported by the evidence and is considered not medically necessary. Major guideline reviews and randomized trial data do not support population‑level screening or routine use to prevent ischemic stroke or CHD events.
Routine homocysteine testing for age‑related macular degeneration (ARMD) or retinal vein occlusion (RVO) is not supported. Systematic reviews and meta‑analyses report heterogeneity and possible publication bias, and the evidence is insufficient to recommend routine investigation or treatment based on homocysteine levels for these ocular conditions.
Routine homocysteine testing for all patients with retinal vein occlusion is not recommended. The policy supports selective testing in young patients or those with atypical presentations and thrombosis history, but routine use as a standard component of thrombophilia screening in pregnancy or for all RVO cases is discouraged until a clear role and impact on treatment are established.
The sections provided do not contain explicit language using the phrase 'not medically necessary' for every listed item; instead, the policy characterizes many indications as experimental and investigational or not covered based on insufficient evidence and cites relevant guideline conclusions.
Covered Indications and Use Cases
inv-67: Assessment of borderline vitamin B12 deficiency when results will impact management
Covered when results will affect clinical management:
Document how the result will change management and consider corroborating tests (eg, methylmalonic acid, holo‑transcobalamin).
inv-68: Assessment of central retinal vein occlusion with prior thrombosis, family history of thrombosis, or age <56 without strong arteriosclerotic risk factors
Covered selectively for CRVO when thrombotic predisposition is suspected:
Document atypical presentation, absence of common local risk factors, and rationale for thrombophilia testing.
inv-69: Assessment of homocystinuria due to cystathionine beta synthase deficiency (newborn screening only when hyper-methioninemia confirmed)
Covered for diagnostic confirmation in newborns/at‑risk siblings when screening abnormality present:
Measure plasma amino acids and Hcy in at‑risk siblings immediately after birth to enable early diagnosis and treatment.
inv-70: Assessment of idiopathic venous thrombo-embolism, recurrent VTE, thrombosis at age <45, or thrombosis at an unusual site
Covered when part of evaluation for concerning VTE presentations:
Document clinical context; elevated Hcy alone is a relatively weak thrombosis risk factor but may augment assessment when combined with other thrombophilias.
inv-71: Investigation of selected patients with venous thromboembolism (idiopathic, recurrent, young age, unusual site) — Measurement may augment assessment when other thrombophilias are present and could influence duration of anticoagulation.
Measurement may augment thrombophilia evaluation when results could influence management:
Document all relevant thrombophilia testing and clinical decision implications.
inv-72: Assessment in high-risk fracture populations or research protocols evaluating homocysteine–fracture relationships
Covered in selected high‑risk fracture research or clinical protocols:
Use in research or narrowly defined clinical contexts; not established for routine fracture risk screening.
inv-73: Investigational or selected use in neurological disorders (e.g., MS) to explore associations with pHcy
Investigational clinical use to explore associations where implications for management are uncertain:
Consider only in research settings or when findings would meaningfully inform care.
inv-74: Newborn/at-risk sibling testing for homocystinuria when hypermethioninemia is confirmed
Covered for newborns and at‑risk siblings when screening indicates metabolic disorder:
Document newborn screening results and prompt confirmatory testing.
inv-75: Evaluation of women with a history of recurrent miscarriage — testing Hcy, antiphospholipid antibodies and factor V Leiden is justified
Covered as part of targeted recurrent miscarriage workup when clinically justified:
Document obstetric history and rationale; follow related policy CPB 0348 as applicable.
inv-76: Investigation of retinal artery/ocular ischemic syndromes when hypercoagulable state suspected
Covered when systemic hypercoagulable state is suspected in ocular ischemic syndromes:
Consider concurrent testing (eg, CRP, lipid profile, creatinine) and document the clinical rationale.
inv-77: Selected thrombophilia evaluation in young patients or those with unexpected retinal vein occlusion and personal/family thrombosis history
Covered selectively in atypical young retinal vein occlusion presentations:
Panel testing may include factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, protein C/S, and antithrombin III; document atypical presentation.
inv-78: Adjunct to cardiovascular risk assessment in research or select clinical contexts
Investigational adjunct for cardiovascular risk assessment in research or select contexts only:
Observational data show improved reclassification metrics, but routine clinical use is not established.
inv-79: Evaluation for hypercoagulable state in young patients with central retinal vein occlusion, especially with bilateral disease or personal/family history of thrombosis.
Consider homocysteine as part of a selective thrombophilia panel in young CRVO patients:
Document patient age, bilateral involvement, prior thrombosis, and family history; include other thrombophilia tests as indicated.
inv-80: Research or investigational use as a biomarker for diabetic nephropathy/retinopathy and pre-eclampsia risk where associations have been reported but evidence certainty is low.
Investigational biomarker uses supported only in research settings due to low certainty:
Not established for routine clinical screening; consider only in research protocols.
inv-81: Exploratory biomarker for COVID-19 severity in patients with diabetes/obesity based on small observational data.
Exploratory applications in preliminary observational data only:
Consider only in research contexts; clinical utility unproven.
inv-82: Investigational or diagnostic measurement of homocysteine in association with a wide range of conditions — lists references for each condition studied
Investigational uses across a broad range of conditions — evidence insufficient to support routine clinical use:
References cited in policy document list the studies; clinical utility is uncertain for most indications.
Coding and Definitions
| 83090 | Homocysteine |
| D51.0 - D51.9 | Vitamin B12 deficiency anemia |
| D81.818 | Other biotin-dependent carboxylase deficiency |
| D81.819 | Biotin-dependent carboxylase deficiency, unspecified |
| E53.8 | Deficiency of other specified B group vitamins |
| E72.10 - E72.11 E72.19 | Disturbances of sulphur-bearing amino-acid metabolism |
| H34.8110 - H34.8192 | Central retinal vein occlusion |
| I26.01 - I26.99 | Pulmonary embolism |
| I81 | Portal vein thrombosis |
| I82.0 - I82.91 | Other venous embolism and thrombosis |
| C16.0 - C16.9 | Malignant neoplasm of stomach |
| D68.51 - D68.69 | Primary or other thrombophilia |
| E10.10 - E13.9 | Diabetes mellitus |
| G30.0 - G30.9 | Alzheimer's disease |
| G35 | Multiple sclerosis |
| G43.001 - G43.919 | Migraine |
| H81.01 - H81.09 | Meniere's disease |
| I27.0, I27.20 - I27.29 | Pulmonary hypertension |
| K90.0 | Celiac disease |
| N96 | Habitual aborter |
Provider Actions and Authorization
Prior authorization for CPT 83090
Prior authorization may be required for CPT 83090. Coverage for CPT 83090 (homocysteine) is limited to tests meeting the medically necessary selection criteria — verify the indication matches policy criteria prior to authorization.
- Affected code: CPT 83090
Required clinical indication / Indications not listed may be denied
Document the clinical indication at the time of order. Testing for indications not listed as medically necessary may be denied; if ordering for an unlisted indication, include supporting clinical rationale in the record.
- Required clinical indication must meet a medically necessary indication
- If ordering for non-covered indications, document rationale
Document vitamin evaluation or trials when testing to guide therapy
When ordering Hcy testing to evaluate possible vitamin deficiency or to guide vitamin therapy, document prior assessment or trials of appropriate vitamin supplementation and monitored Hcy response when applicable (e.g., assessment of borderline vitamin B12 deficiency where results will impact management).
- Document prior vitamin evaluation or therapeutic trial when relevant
- Record how test results will change management
ACOG / specialty guidance on MTHFR and homocysteine testing in pregnancy
Follow ACOG guidance and specialty guidance: do not routinely screen for MTHFR polymorphisms or fasting homocysteine levels in pregnancy as part of inherited thrombophilia evaluation; MTHFR/homocysteine screening is not recommended.
- Do not order MTHFR mutation analyses or fasting homocysteine as routine screening in pregnancy
Retinal vein occlusion testing limitation and documentation
Retinal vein occlusion: routine testing for homocysteine and other thrombophilia markers is not recommended for all patients. Consider selective testing in young patients (<56 years), bilateral/unexpected CRVO, or when personal or family history suggests a hypercoagulable state and after excluding common risk factors (e.g., hypertension, glaucoma, diabetes).
- Document absence of common CRVO risk factors (hypertension, glaucoma, diabetes) when ordering Hcy testing for retinal vein occlusion
- Selective testing supported for young patients, bilateral CRVO, or personal/family thrombosis history
Limit routine cardiovascular screening and document indication
Clinical guidance and evidence recommend against routine measurement of homocysteine for cardiovascular or arterial disease risk screening in asymptomatic individuals; routine screening may be denied. Document clinical indication if testing is ordered for cardiovascular concerns.
- Routine cardiovascular or stroke risk screening with Hcy is not supported and may be denied
- If ordered for cardiovascular reasons, document specific clinical justification
UpToDate guidance on when to perform Hcy testing
UpToDate guidance: do not perform homocysteine testing as part of routine thrombophilia screening in pregnancy; perform hypercoagulable workup (including homocysteine) only in patients with personal or family history suggesting hypercoagulable state or young patients without arteriosclerotic risk factors.
- Avoid Hcy testing as routine in pregnancy thrombophilia screening
- Consider Hcy testing in thrombophilia workup when personal/family history or young patients without arteriosclerotic risk factors
No step therapy specified; consider verification of nutritional deficiency
There are no explicit step therapy requirements specified for homocysteine testing in this policy. Consider verification of nutritional deficiencies (e.g., B12/folate) or alternative evaluations prior to testing when clinically appropriate.
- No step therapy specified in policy
- Consider verifying B12/folate deficiency or alternative tests before ordering Hcy
Actions when a hereditary thrombophilia is identified
If a hereditary thrombophilia is identified, refer to hematology and consider anticoagulation and family screening as clinically appropriate to reduce the risk of future thrombotic episodes.
- Refer to hematology for identified hereditary defects
- Consider anticoagulation and family member screening
Policy history and review dates
Policy history and review dates are provided in the policy header; check the policy record for last review and next review dates when validating coverage rules.
- Effective date: 08/08/2008
- Last review: 10/26/2023
- Next review: 08/22/2024
Ordering Requirements
Ordering must document a covered clinical indication; no clinician restriction stated
Order homocysteine testing only when the requisition documents one of the covered clinical indications; no restriction on ordering clinician type is specified in the cited text.
- Ensure the order includes the covered indication (e.g., selected thrombophilia evaluation, newborn confirmation of homocystinuria after hyper-methioninemia).
- No specific specialist-only ordering requirement is stated.
Order Hcy as part of targeted diagnostic evaluation or to monitor vitamin therapy
Order homocysteine testing when it is part of a targeted diagnostic evaluation (e.g., thrombosis workup) or when monitoring response to vitamin therapy in specific patients; document the clinical rationale and prior treatments/results.
- Use Hcy testing to augment evaluation in idiopathic, recurrent, young-age, or unusual-site VTE when it may influence management.
- When monitoring vitamin therapy, record supplementation history and measured changes in Hcy.
Order Hcy testing for newborns/at-risk siblings after confirmed hypermethioninemia
For homocystinuria evaluation, order Hcy (plasma and/or urine) when newborn screening indicates hypermethioninemia and for at-risk siblings immediately after birth; document amino acid and Hcy results to support diagnosis and early treatment.
- Aim to maintain pHcy below 11 micromol/L in treated newborns.
- Measure plasma amino acids and Hcy promptly in at-risk siblings to enable early intervention.
Order Hcy (with APS and FVL) in evaluation of recurrent miscarriage — document history
Testing for homocysteine, antiphospholipid antibodies, and factor V Leiden is justified in women with a history of recurrent miscarriage based on the literature cited; document the clinical history to support ordering.
- Provide details of recurrent pregnancy losses and prior evaluations when ordering these tests.
- ACOG guidance on inherited thrombophilias should be considered when testing in pregnancy.
Order Hcy for selective thrombophilia workup in young/atypical CRVO patients
Order homocysteine testing for selective thrombophilia workup in young or atypical retinal vein occlusion patients (e.g., age <50–56, bilateral disease, prior thrombosis, family history); document the atypical presentation and absence of common risk factors.
- Include documentation of prior negative evaluations for hypertension, glaucoma, diabetes, and other local risk factors.
- Specify age and family/personal thrombosis history to support targeted testing.
Targeted ordering for young CRVO patients — document indications and prior negative evaluations
Ordering should be targeted by clinicians evaluating young CRVO patients or those with suggestive personal/family history; include documentation of the indication and prior negative evaluation of common risk factors.
- Testing is recommended only when common CRVO risk factors are absent and clinical features suggest hypercoagulability.
- Document bilateral disease, age, and thrombosis history as applicable.
No ordering provider restrictions stated
No ordering clinician restrictions (such as specialist-only ordering) are specified in the provided policy text.
Frequency Limits
Not Covered / Limitations
Testing for many indications listed as experimental and investigational is designated as not covered. This includes routine cardiovascular disease or stroke risk assessment, management of MTHFR abnormalities, and numerous neurologic, reproductive, ophthalmologic, and other conditions noted in the policy's exclusions and not‑covered lists.
Population‑wide or routine cardiovascular homocysteine screening in asymptomatic individuals without specific risk factors or clinical indications is considered not covered, reflecting USPSTF and systematic review findings that do not support benefit from such screening.
Routine investigation and treatment of elevated total homocysteine (tHcy) in retinal vein occlusion cannot be recommended due to study heterogeneity and possible publication bias; therefore routine testing and treatment in this context are not supported.
Routine homocysteine testing for a wide range of conditions listed as having insufficient evidence is not covered. The policy identifies numerous conditions (see exclusions) where routine Hcy measurement is not supported by current evidence.
Routine homocysteine testing as part of pregnancy thrombophilia screening is not covered; UpToDate guidance recommends avoiding homocysteine measurement and MTHFR testing in routine pregnancy thrombophilia evaluations.
Within the provided excerpts there are no additional explicit statements listing individual tests or indications as categorically not covered beyond the Experimental/Not Medically Necessary and Not Covered sections already summarized.
Background and Definitions
Homocysteine (Hcy) is a sulfur‑containing amino acid formed from methionine and metabolized via vitamin‑dependent pathways: B12/folate‑dependent remethylation or B6‑dependent transsulfuration. Plasma tHcy is measured fasting and reported in micromoles per liter.
Key Definitions
Background and Evidence Summary
In biochemical terms, homocysteine levels are influenced by B‑vitamin cofactors (folate, B12, B6) and genetic enzyme defects. Typical reference considerations note a normal plasma Hcy around ~12 micromol/L with a desirable level <10 micromol/L, and elevations categorized as moderate (15–30 μmol/L), intermediate (31–100 μmol/L), or severe (>100 μmol/L).
The document lists numerous references associating homocysteine measurement with a wide range of conditions and research contexts. These citations support the policy's discussion of investigational uses and include studies and reviews on coronary heart disease/stroke risk, multiple sclerosis, polycystic ovary syndrome, osteoporosis/fracture risk, recurrent pregnancy loss, homocystinuria, IVF planning, retinal artery/vein occlusion, diabetic microvascular disease, pre‑eclampsia, COVID‑19 hematologic complications, and many other conditions.
Revision History
Policy reviewed (Last Review date recorded).
Policy became effective on this date.
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