Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness

Vineesh Indira Chandran; Charlotte Wilhelmina Wernberg; Mette Munk Lauridsen; Maria Kløjgaard Skytthe; Sofie Marchsteiner Bendixen; Frederik Tibert Larsen; Camilla Dalby Hansen; Lea Ladegaard Grønkjær; Majken Storm Siersbæk; Tina Di Caterino; Sönke Detlefsen; Holger Jon Møller; Lars Grøntved; Kim Ravnskjaer; Søren Kragh Moestrup; Maja Sofie Thiele; Aleksander Krag; Jonas Heilskov Graversen

doi:10.1002/hep.32620

Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness

Vineesh Indira Chandran, Charlotte Wilhelmina Wernberg, Mette Munk Lauridsen, Maria Kløjgaard Skytthe, Sofie Marchsteiner Bendixen, Frederik Tibert Larsen, Camilla Dalby Hansen, Lea Ladegaard Grønkjær, Majken Storm Siersbæk, Tina Di Caterino, Sönke Detlefsen, Holger Jon Møller, Lars Grøntved, Kim Ravnskjaer, Søren Kragh Moestrup, Maja Sofie Thiele, Aleksander Krag, Jonas Heilskov Graversen^*

^*Corresponding author for this work

Department of Clinical Medicine - Department of clinical biochemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

24 Citations (Scopus)

Abstract

Background and Aims: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. Approach and Results: We collected cross-sectional, clinical data including liver biopsies from a derivation (n = 48) and a validation cohort (n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84–0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77–0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning (p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Conclusions: Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

Original language	English
Journal	Hepatology
Volume	77
Issue	2
Pages (from-to)	558-572
Number of pages	15
ISSN	0270-9139
DOIs	https://doi.org/10.1002/hep.32620
Publication status	Published - Feb 2023

Keywords

Biomarkers
Biopsy
Cross-Sectional Studies
Humans
Liver Cirrhosis/pathology
Liver/pathology
Membrane Glycoproteins
Non-alcoholic Fatty Liver Disease/complications
Receptors, Immunologic

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10.1002/hep.32620Licence: CC BY-NC-ND

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Indira Chandran, V., Wernberg, C. W., Lauridsen, M. M., Skytthe, M. K., Bendixen, S. M., Larsen, F. T., Hansen, C. D., Grønkjær, L. L., Siersbæk, M. S., Caterino, T. D., Detlefsen, S., Møller, H. J., Grøntved, L., Ravnskjaer, K., Moestrup, S. K., Thiele, M. S., Krag, A., & Graversen, J. H. (2023). Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness. Hepatology, 77(2), 558-572. https://doi.org/10.1002/hep.32620

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title = "Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness",

abstract = "Background and Aims: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. Approach and Results: We collected cross-sectional, clinical data including liver biopsies from a derivation (n = 48) and a validation cohort (n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84–0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77–0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning (p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Conclusions: Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.",

keywords = "Biomarkers, Biopsy, Cross-Sectional Studies, Humans, Liver Cirrhosis/pathology, Liver/pathology, Membrane Glycoproteins, Non-alcoholic Fatty Liver Disease/complications, Receptors, Immunologic",

author = "{Indira Chandran}, Vineesh and Wernberg, {Charlotte Wilhelmina} and Lauridsen, {Mette Munk} and Skytthe, {Maria Kl{\o}jgaard} and Bendixen, {Sofie Marchsteiner} and Larsen, {Frederik Tibert} and Hansen, {Camilla Dalby} and Gr{\o}nkj{\ae}r, {Lea Ladegaard} and Siersb{\ae}k, {Majken Storm} and Caterino, {Tina Di} and S{\"o}nke Detlefsen and M{\o}ller, {Holger Jon} and Lars Gr{\o}ntved and Kim Ravnskjaer and Moestrup, {S{\o}ren Kragh} and Thiele, {Maja Sofie} and Aleksander Krag and Graversen, {Jonas Heilskov}",

year = "2023",

month = feb,

doi = "10.1002/hep.32620",

language = "English",

volume = "77",

pages = "558--572",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

Indira Chandran, V, Wernberg, CW, Lauridsen, MM, Skytthe, MK, Bendixen, SM, Larsen, FT, Hansen, CD, Grønkjær, LL, Siersbæk, MS, Caterino, TD, Detlefsen, S, Møller, HJ, Grøntved, L, Ravnskjaer, K, Moestrup, SK, Thiele, MS, Krag, A & Graversen, JH 2023, 'Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness', Hepatology, vol. 77, no. 2, pp. 558-572. https://doi.org/10.1002/hep.32620

Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness. / Indira Chandran, Vineesh; Wernberg, Charlotte Wilhelmina; Lauridsen, Mette Munk et al.
In: Hepatology, Vol. 77, No. 2, 02.2023, p. 558-572.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness

AU - Indira Chandran, Vineesh

AU - Wernberg, Charlotte Wilhelmina

AU - Lauridsen, Mette Munk

AU - Skytthe, Maria Kløjgaard

AU - Bendixen, Sofie Marchsteiner

AU - Larsen, Frederik Tibert

AU - Hansen, Camilla Dalby

AU - Grønkjær, Lea Ladegaard

AU - Siersbæk, Majken Storm

AU - Caterino, Tina Di

AU - Detlefsen, Sönke

AU - Møller, Holger Jon

AU - Grøntved, Lars

AU - Ravnskjaer, Kim

AU - Moestrup, Søren Kragh

AU - Thiele, Maja Sofie

AU - Krag, Aleksander

AU - Graversen, Jonas Heilskov

PY - 2023/2

Y1 - 2023/2

N2 - Background and Aims: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. Approach and Results: We collected cross-sectional, clinical data including liver biopsies from a derivation (n = 48) and a validation cohort (n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84–0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77–0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning (p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Conclusions: Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

AB - Background and Aims: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. Approach and Results: We collected cross-sectional, clinical data including liver biopsies from a derivation (n = 48) and a validation cohort (n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84–0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77–0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning (p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Conclusions: Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

KW - Biomarkers

KW - Biopsy

KW - Cross-Sectional Studies

KW - Humans

KW - Liver Cirrhosis/pathology

KW - Liver/pathology

KW - Membrane Glycoproteins

KW - Non-alcoholic Fatty Liver Disease/complications

KW - Receptors, Immunologic

UR - http://www.scopus.com/inward/record.url?scp=85134038246&partnerID=8YFLogxK

U2 - 10.1002/hep.32620

DO - 10.1002/hep.32620

M3 - Journal article

C2 - 35712786

AN - SCOPUS:85134038246

SN - 0270-9139

VL - 77

SP - 558

EP - 572

JO - Hepatology

JF - Hepatology

IS - 2

ER -

Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness

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