Thursday, August 28, 2025

MOLDX Proposes Two LCDs: Thrombophilia Testing, Liver Disease Steatosis Risk

MolDx has released two proposed LCDs, DL40238 for genetic testing for hereditary thrombophilia, and DL40187 for risk stratification of metabolic dysfunction with steatotic liver disease.

The liver LCD has been released for all 4 MolDx MACs, the thrombophilia one for 3 MolDx MACs (not WPS, so their comment period will lag).  

Comment periods for the proposals in release run August 28 to October 12, 2025.

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LIVER

The liver LCD 40187 is here.  Note that MASLD has replaced NASH.

It has a request letter from Margaret Connelly, LabCorp (9/2023), for the risk test NIS4.    There is also a request from Hilary Imai, Siemens (7/2024), for the ELF test.

The five main criteria proposed are, guideline-based suspicion of MASLD, initial risk testing with non-molecular or non-proteomic test (e.g. FIB4), liver stiffness is "indeterminate or not performed," and results will aid management (referal, Rx).  There are 46 references.

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THROMBOPHILIA

The thrombophilia LCD 40259 was internally generated.  

The patient has a venous thromboembolism with certain risk factors.  In addition, genetic testing will guide management eg anticoagulation, contains defined minimum genetic content, and does not contain improperly validated content that would "reasonably expect" misuse.  There are 45 references.

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AI CORNER

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Direct AI output.  Do not quote without checking details. Chat GPT 5.

Here’s a structured expert-level review of the two new proposed MolDX LCDs you provided.

1. DL40187 – Biomarker Testing for Risk Stratification in MASLD/MASH

Scope and Coverage

  • This LCD covers molecular and proteomic biomarker tests used for risk stratification of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH).

  • MASLD/MASH terminology is aligned with recent AASLD guidance, replacing the older NAFLD/NASH labels.

  • Tests considered include proteomics assays (e.g., ELF test) and molecular biomarker panels (e.g., NIS4, multi-analyte assays with algorithmic analysis).

Coverage Criteria

  • Applies to adults with MASLD/MASH where:

    1. FIB-4 (initial clinical risk tool) suggests intermediate/high risk.

    2. Imaging (VCTE, MRE) is indeterminate or not performed.

    3. Test results will guide management (biopsy, drug eligibility, specialist referral).

    4. Test is not repeated within 12 months or after biopsy.

    5. Analytical and clinical validity must be shown in peer-reviewed studies.

    6. Algorithm validation must be independent of the development cohort.

    7. A MolDX Technical Assessment must be completed.

Evidence Base

  • Justifies policy via:

    • High prevalence of MASLD (35–48% in U.S. adults, higher in T2D and Hispanic populations).

    • Increasing progression to cirrhosis and liver transplant.

    • Recent FDA approval of resmetirom (March 2024) for F2–F3 MASH fibrosis, creating immediate demand for non-biopsy diagnostic stratification tools.

  • ELF test and NIS4 specifically discussed, including AUROC values and comparative performance to elastography.

Billing Guidance (DA60205)

  • Limits to 1 test per 12 months.

  • Requires DEX Z-Code® submission.

  • Accepts CPT codes 81479, 81517, 81599, 0003M, 0166U, etc..

Comment Period

  • Open August 28, 2025 – October 12, 2025 (per LCD posting).

External Requests

  • Labcorp (Sept 18, 2023): Requested LCD for NIS4 blood test to identify at-risk NASH.

  • Siemens Healthineers (July 1, 2024): Requested LCD for ELF test, citing FDA De Novo clearance (2021), guideline endorsement, and disruption due to MolDX Z-code billing enforcement.

2. DL40259 – Genetic Testing for Hereditary Thrombophilia

Scope and Coverage

  • Defines coverage for hereditary thrombophilia testing via LDTs, FDA-cleared, or FDA-approved tests.

  • Includes single variant (familial) or NGS-based multi-gene panels.

  • Focused on germline testing (not somatic or acquired thrombophilias).

Coverage Criteria
Genetic testing covered when ALL are true:

  1. Patient has VTE in specific contexts:

    • VTE associated with major transient or hormonal risk factors (where anticoagulation duration is uncertain).

    • Cerebral or splanchnic venous thrombosis where short-term therapy is standard, but test result may support extended therapy.

  2. Test will directly guide anticoagulation management.

  3. Test includes minimum content with well-established evidence (per 2023 ASH Thrombophilia Testing Guidelines).

  4. No extra genetic content of unclear clinical validity.

  5. No conflict with repeat germline testing rules.

  6. Must complete MolDX Technical Assessment.

Evidence Base

  • Notes VTE incidence (~1–1.5/1000 person-years) and 30% 10-year recurrence risk.

  • Recognizes genetic contribution (up to 60% heritability), with Factor V Leiden and prothrombin 20210G>A most common.

  • However, emphasizes risks of overdiagnosis, inappropriate anticoagulation, and bleeding.

  • Cites 2023 ASH Guidelines, which recommend against routine thrombophilia testing in most clinical scenarios, allowing conditional use only when it would alter management.

Billing Guidance (DA60294)

  • Codes: 81240 (prothrombin), 81241 (Factor V Leiden), 81479.

  • Requires DEX Z-Code™.

  • Broad set of ICD-10 VTE/embolism codes included.

Comment Period

  • Open August 28, 2025 – October 12, 2025 (parallel to MASLD LCD).

External Requests

  • No external request letters identified in your documents; this appears internally initiated by MolDX based on ASH guidelines and utilization concerns.

3. Comparison of DL40187 (MASLD) vs. DL40259 (Thrombophilia)

Common Features

  • Both are MolDX LCDs with draft billing/coding articles attached.

  • Both restrict testing frequency (no repeats without justification).

  • Both require DEX Z-Codes and MolDX Technical Assessments.

  • Both have the same public comment window: Aug 28 – Oct 12, 2025.

Key Differences

  • Clinical Area:

    • DL40187 addresses liver disease risk stratification in a growing population with new drug eligibility implications.

    • DL40259 addresses genetic thrombophilia in VTE patients, a narrower but clinically high-stakes population.

  • Evidence Drivers:

    • MASLD LCD is motivated by new FDA-approved therapies (resmetirom) and the clinical need for non-biopsy fibrosis risk tools.

    • Thrombophilia LCD is driven by guideline caution (ASH 2023), emphasizing that most thrombophilia tests lack clinical utility in routine care.

  • Industry Requests:

    • MASLD LCD arose from external manufacturer requests (Labcorp for NIS4, Siemens for ELF) dating back to 2023–2024.

    • Thrombophilia LCD appears MAC-initiated, with no external sponsor request.

  • Policy Stance:

    • MASLD LCD is expansive, creating a pathway for multiple biomarker assays if they meet MolDX validity standards.

    • Thrombophilia LCD is restrictive, limiting coverage only to scenarios where test results meaningfully guide anticoagulation management.

✅ In summary:

  • DL40187 (MASLD/MASH) is a coverage-enabling policy shaped by industry requests and clinical innovation.

  • DL40259 (Thrombophilia) is a coverage-restricting policy aligned with guideline skepticism about routine use.

  • Together, they illustrate MolDX’s dual role: expanding access where strong clinical/economic rationale exists, while curbing low-value or over-used genetic testing.

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Is the workup for venous thromboembolism and suspected thrombophilia primarily Factor V genetics or are other genes routinely needed?

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The workup for venous thromboembolism (VTE) and suspected inherited thrombophilia is broader than just Factor V Leiden.

Here’s the usual approach in clinical practice:

1. Factor V Leiden

  • The most common inherited thrombophilia in Caucasian populations.

  • Testing is usually by PCR for the G1691A mutation.

2. Prothrombin Gene Mutation (G20210A)

  • The second most common genetic risk factor.

  • Like Factor V Leiden, usually tested by PCR.

3. Other Genetic Factors

  • Antithrombin deficiency, Protein C deficiency, and Protein S deficiency are considered inherited thrombophilias, but these are generally tested functionally (activity/antigen assays), not primarily by gene sequencing.

  • Genetic confirmation is possible but not routinely ordered unless there is a strong family history or atypical lab results.

4. Non-genetic Workup

  • Testing for antiphospholipid syndrome (lupus anticoagulant, anticardiolipin antibody, anti-β2 glycoprotein I antibody) is often included in the evaluation because it is an acquired cause of thrombosis.

  • Homocysteine and MTHFR mutations are no longer routinely recommended, as they don’t strongly predict VTE risk in most patients.

5. Practical Clinical Use

  • Most “routine” thrombophilia panels ordered after a first unprovoked clot typically include:

    • Factor V Leiden

    • Prothrombin G20210A

    • Protein C activity

    • Protein S activity

    • Antithrombin activity

    • Antiphospholipid antibody panel

  • Full next-generation sequencing panels (with multiple rare gene variants) are not routine outside research or very unusual cases.

✅ Summary:
The primary genetic tests are Factor V Leiden and Prothrombin G20210A. 

Protein C, Protein S, and Antithrombin are tested functionally rather than genetically. Other genes are not routinely needed. Workup is broadened depending on age of onset, family history, recurrence, and unusual clot location.

Would you like me to put together a table of “core” vs “optional/rarely indicated” tests for suspected thrombophilia? That way you’d have a quick reference.