Coverage Policy Manual
Policy #: 2013038
Category: Laboratory
Initiated: November 2013
Last Review: November 2023
  Galectin Measurement
Description:
Galectins are a family of lectins which include 15 members and are characterized by a galactose-specific carbohydrate recognition domain (CRD), with an affinity for beta-galactosides. A characteristic of galectins is to mediate recognition of N-acetyl-lactosamine-containing glycoproteins located at the cell surface and within the extracellular matrix. The function of galectins in modulating the immune system and regulating cell growth has been well documented.  Galectins are known to carry out intra- and extracellular functions, including inhibition of chronic inflammations, angiogenesis, immune response and cancer cell migration. (Yu, 2012)
 
The following is a list of known and putative functions and biological activities of galectins toward cells in the immune system (Cummings, 2009):
 
Galectin-1
involved in Treg cell function and enhances Treg formation
conflicting results in effects on T-cell viability
mediates adhesion of thymocytes to thymic epithelium
induces apoptosis in CD4+ CD8+  double positive thymocytes
induces shift in Th1 response to Th2 (decreases IFN-γ, increases IL-5)
reduces TNF-α, IL1β, IL-12, IL-2 and IFN-γ
increases IL-10 production in both naive and activated T cells
inhibits mast cell degranulation
reduces pathology-associated graft-versus-host disease,
Con A-induced hepatitis, experimental allergic encephalomyelitis, myasthenia gravis and rheumatoid arthritis
reduces acute inflammatory responses
expression in endothelial cells up-regulated by activation
induces apoptosis-independent phosphatidylserine (PS) exposure (Ca++-dependent) in neutrophils
inhibits chemotaxis of neutrophils
inhibits extravasation of neutrophils
activates NADPH-dependent respiratory burst in neutrophils
induces maturation of dendritic cells
 
Galectin-2
induces T-cell apoptosis under some conditions
decreases IFN-γ and TNF-α while increasing IL-10 and IL-5
involved in the pathogenesis of atheroma formation
induces apoptosis-independent PS exposure (Ca++-dependent) of neutrophils
 
Galectin-3
blocks apoptosis of T cells when overexpressed intracellularly
endogenously involved in T-cell viability
extracellularly induces apoptosis of T cells
promotes adhesion of thymocytes to thymic epithelium
enhances Th2 immune responses
enhances adhesion of naïve T cells to DCs
binds TCR, reducing TCR mediated T cell activation
inhibits IL-5 production in eosinophils
induces mast cell degranulation independent of antigen-mediated IgE stimulation
exacerbates Th2 immune responses (asthma)
expressed on surface of macrophages (also called Mac-2 antigen)
enhances phagocytosis of macrophages
enhances respiratory burst of macrophages
enhances LPS-induced IL-1β secretion of macrophages
inhibits apoptosis (intracellularly)
blocks IL-4-induced survival of activated B cells
favors plasma cell differentiation
exhibits an anti-apoptotic role in B-cell lymphomas
expression induced in dendritic cells by T. cruzi infection
enhances pro-inflammatory cytokine release in endothelial cells
expression up-regulated in tumor endothelial cells
induces chemotaxis of neutrophils
enhances extravasation of neutrophils
activates NADPH-dependent respiratory burst of neutrophils
induces activation of neutrophils
induces release of IL-8 of neutrophils
medicates interaction of neutrophils with laminin and fibronectin (both directly and indirectly)
enhances leukocyte adhesion to endothelium
 
Galectin-4
induces IL-6 production in T cells
induces apoptosis-independent PS exposure (Ca++-independent) of neutrophils
 
Galenctin-7
intracellular expression induces apoptosis of tumor cells
extracellularly can inhibit growth of cells
 
Galectin-8
activates Rac-1 in T cells
activates NADPH-dependent respiratory burst of neutrophils
modulates integrin-mediated neutrophil adhesion of neutrophils
 
Galectin-9
induces apoptosis in thymocytes and T cells
induces selective loss of CD4+ Th1 cells
induces selective loss of CD8+ T cells
induces eosinophil chemotaxis, activation, superoxide generation
induces moderate degranulation of eosinophil
expression in endothelial cells induced by virus infection
induces maturation of dendritic cells
 
Galectin-10
highly expressed in eosinophils (Charcot-Leyden crystal protein) involved in Treg function
 
 
Galectin-12
intracellular expression induces apoptosis of tumor cells can cause cell cycle arrest and growth suppression
 
The most widely reported use of galectin-3 is as a marker of cardiac fibrosis where a higher concentration is associated with increased risk for heart failure and mortality..
 
Limitations of Testing: Levels of galectin-3 in blood may be increased in patients with certain forms of advanced cancer and other conditions associated with organ fibrosis. Galectin-3 results should be interpreted with caution in such patients. Presence of human antimouse antibodies (HAMA) or rheumatoid factor (RF) may interfere with the galectin-3 assay, which could cause falsely elevated results. The galectin-3 assay should not be used in patients with known HAMA or RF. Galectin-3 results should be interpreted with caution in patients with a history of therapeutic use of murine monoclonal antibodies (IgG) or their fragments or in those who have known autoimmune disorders.
 
Specimens with high levels of γ-globulins (>2.5 g/dL) may cause false elevation in results. Galectin-3 results from patients with diseases associated with hyperglobulinemia, such as multiple myeloma, should be interpreted with caution.
There is a CPT code for galectin-3 – 82777.  The measurement of other galectins would be billed with 84999 until other specific codes are developed.
 
 
Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The measurement of galectin-3, or any other galectin, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the measurement of galectin-3, or any other galectin, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Regulatory: The FDA approved the BGM Galectin-3™ (ELISA) on Nov 17, 2010 (K093758) for use in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure (HF).   Other laboratories may be measuring Galectin-3, as well as other galectins, using "laboratory-developed tests" or "LDTs" , tests by laboratories, developed in-house, for use by the laboratory entity itself. In this case, the laboratory may purchase reagents from outside suppliers (or create them itself), and then develop its own proprietary test to use within the laboratory. The laboratory never sells the test kit to other laboratories, hospitals or doctors; rather, it only offers the testing service to them and performs this test, when ordered, in-house. These tests do not typically go through the FDA ap­proval or clearance process.
 
There are multiple articles about the use of Galectin 3 as a biomarker for cardiac fibrosis in patients with heart failure but opinions about its usefulness vary.
 
Lopez-Andres et al., 2012, et al reported a substudy of the CARE-HF study, 260 patients who had measurements of extracellular cardiac matrix (ECCM) modeling with galactic-3, N-terminal propeptides of type I and III procollagens (PINP and PIIINP) type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1).  The authors hoped to determine, in patients with heart failure and cardiac dyssynchrony, whether ECCM biomarkers are influenced by cardiac resynchronization therapy and can predict cardiovascular outcomes and response to CRT.  They determined increased glalectin-3 and PIIINP, and low MMP-1 are associated with adverse long-term cardiovascular outcomes but did not predict response to CRT.  CRT did not favourably affect serum concentrations of ECCM markers.  
 
Weir et al., 2013, looked at galectin-3 to determine if it is related to LV remodeling after acute myocardial infarction in 100 patients.  Galectin-3 correlated significantly with certain biomarkers involved in extracellular matrix turnover, but no definite relationship of LV remodeling was identified.  “Whether galectin-3 plays a pathological role in remodeling remains unclear but merits further study.”
 
Gullestad et al., 2012, reported 1462 patients, > 60 years, with systolic ischemic heart failure, randomized to 10 mg/d rosuvastatin or placebo.  In the unadjusted analysis galectin-3 was associated with all considered end points except for hospitalization for worsening HF.  In a multivariate analysis galectin-3 was significantly associated with the primary end point as well as all cause, cardiovascular mortality, sudden death and the coronary end point.  When N-terminal pro-brain natriuretic peptide was added to the model glaectin-3 association with the end points was markedly attenuated and no longer significant.  The authors concluded: Galectin-3 is not associated with outcome in older patients with advanced chronic systolic HF of ischemic etiology when adjusting for N-terminal pro-brain natriuretic peptide and may therefore have limited use in the prognostication of elderly patients with systolic HF in clinical practice.
 
Lok et al., 2012, concluded the prognostic value of galectin-3 is independent of severity of HF, as assessed by NT-proBNP, may potentially be useful in the management of such patients (> 60 years in NYHA class III, predominantly male, were characteristics of 232 patients reported).
 
van der Velde et al,. 2013, concluded repeated measurements of galectin-3 provided important and significant prognostic value in identifying patients with HF at elevated risk for subsequent HF morbidity and mortality.  Galectin-3 was measured at baseline and at 3 months in 1392 patients in the CORONA trial and at baseline and at 6 months in 324 patients in the COACH trial.  
 
Shah et al., 2010, reported on 115 patients who had presented to the ER with acute dyspnea who had galectin-3 measurement and detailed echocardiographic studies.  Higher galectin-3 levels were associated with tissue Doppler E/E(a) ratio, a lower RV fractional area change, higher RV systolic pressure, and more severe mitral or tricuspid regurgitation.  Dyspneic patients with HF and galectin-3 levels above the median value had a 63% mortality while those with galectin-3 less than the median value had a 37% mortality.  
 
The American College of Cardiology Foundation/American Heart Association (ACCF/AHA), in a 2013 update of their Heart Failure Guidelines (Yancy, 2013) stated the use of biomarkers of myocardial fibrosis (galectin-3) could provide additive risk stratification giving it a Class of Recommendation IIb.  This recommendation means the benefit ≥ risk, that additional studies with broad objectives is needed.  Galectin-3  measurement may be considered but it was not specifically recommended.
 
There are ongoing studies of the measurement of galectins in metastatic cancer, for the diagnosis of goiter, in cardiovascular disease as well as studies of the use of glalectin as a therapeutic agent in malignancies.  (www.clinicaltrials.gov )
 
2014 Update
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through October 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
2018 Update
A literature search was conducted through October 2018.  There was no new information identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
82777Galectin 3
84999Unlisted chemistry procedure
References: Bayes-Genis A, de Antonio M, et al.(2012) Head-to-head comparison of two myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 vs, Galectin-3. J Am Coll Cardiol, 2013; Sep 16 [Epub ahead of print].

Cummings RD, Liu FT.(2009) Galectin, Chap 33. Essentials of Glycobiologu, 2nd edtition. Cold Spring Harbor Laboratory Press.

de Boer RA, Lok DJ, et al.(2011) Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med, 2011; 43:60-8.

Felker GM, Fiuzat M, et al.(2012) Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail, 2012; 5:72-8.

Gullestad L, Ueland T, et al.(2012) Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Eur Heart J, 2012; 33:2290-6.

Gullestad L, Ueland T, et al.(2012) The predictive value of galectin-3 for mortality and cardiovascular events in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Am Heart J, 2012; 164:878-83.

Ho JE, Liu C, et al.(2012) Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community J Am Coll Cardiol, 2012; 60:1249-56.

Lok DJ, van der Meer P, et al.(2010) Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol, 2010; 99:323-8.

Lopez-Andres N, Rossignol P, et al.(2012) Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail, 2012; 14:74-81.

Shah RV, Chen-Tournoux AA, et al.(2010) Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure. Eur J Heart Fail, 2010; 12:826-32.

Tang WH, Shrestha K, et al.(2011) Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol, 2011;108:385-90.

van der Velde AR, Gullestad L, et al.(2013) Prognostic value of changes in galectin-3 levels over time in patients with heart failure: data for CORONA and COACH. Circ Heart Fail, 2013; 6:219-26.

Weir RA, Petrie CJ, et al.(2013) Galectin-3 and cardiac function in survivors of acute myocardial infarction. Circ Hear Failure, 2013; 6:492-8.

Yancy CY, Jessup M, et al.(2013) 2013 ACCF/AHA guideline for the management of heart failure. J Am Coll Cardiol, 2013; 62:e147-239 [Epub ahead of print].

Yu Y.(2012) Galectin-3: a new target for tumor immunotherapy. http://www.omicsgroup.org/journals/galectin-3-a-new-target-for-tumor-immunotherapy-2168-9431-2-e116.pdf .
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.