Panel of 10 serum metabolites shows promise in the non-invasive detection of advanced fibrosis

ObjectiveNon-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis.DesignThis is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling.ResultsIn the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively.ConclusionA combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.

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Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-91560-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yotsawat Pomyen ◽

Anuradha Budhu ◽

Jittiporn Chaisaingmongkol ◽

Marshonna Forgues ◽

Hien Dang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Treatment Effectiveness ◽

Data Types ◽

Serum Metabolites ◽

Non Invasive ◽

Metabolic Genes ◽

Tissue Metabolites

AbstractTreatment effectiveness in hepatocellular carcinoma (HCC) depends on early detection and precision-medicine-based patient stratification for targeted therapies. However, the lack of robust biomarkers, particularly a non-invasive diagnostic tool, precludes significant improvement of clinical outcomes for HCC patients. Serum metabolites are one of the best non-invasive means for determining patient prognosis, as they are stable end-products of biochemical processes in human body. In this study, we aimed to identify prognostic serum metabolites in HCC. To determine serum metabolites that were relevant and representative of the tissue status, we performed a two-step correlation analysis to first determine associations between metabolic genes and tissue metabolites, and second, between tissue metabolites and serum metabolites among 49 HCC patients, which were then validated in 408 additional Asian HCC patients with mixed etiologies. We found that certain metabolic genes, tissue metabolites and serum metabolites can independently stratify HCC patients into prognostic subgroups, which are consistent across these different data types and our previous findings. The metabolic subtypes are associated with β-oxidation process in fatty acid metabolism, where patients with worse survival outcome have dysregulated fatty acid metabolism. These serum metabolites may be used as non-invasive biomarkers to define prognostic tumor molecular subtypes for HCC.

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Simple non-invasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease

Gastroenterology Report ◽

10.1093/gastro/gou034 ◽

2014 ◽

Vol 2 (4) ◽

pp. 276-280 ◽

Cited By ~ 28

Author(s):

E. B. Tapper ◽

K. Krajewski ◽

M. Lai ◽

T. Challies ◽

R. Kane ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Advanced Fibrosis ◽

Alcoholic Fatty Liver ◽

Non Invasive ◽

Alcoholic Fatty Liver Disease

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P1045 : Ultra-high-field MR-spectroscopy in NAFLD as non-invasive in-vivo tool for monitoring changes in fat and energy metabolism with potential identification of NASH and advanced fibrosis by saturation transfer technique

Journal of Hepatology ◽

10.1016/s0168-8278(15)31243-5 ◽

2015 ◽

Vol 62 ◽

pp. S739-S740 ◽

Cited By ~ 3

Author(s):

S. Traussnigg ◽

C. Kienbacher ◽

M. Gajdošík ◽

L. Valkovič ◽

H. Hofer ◽

...

Keyword(s):

Energy Metabolism ◽

Mr Spectroscopy ◽

High Field ◽

Advanced Fibrosis ◽

Saturation Transfer ◽

Ultra High Field ◽

Non Invasive ◽

High Field Mr

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Among simple non-invasive scores, Pro-C3 and ADAPT best exclude advanced fibrosis in Asian patients with MAFLD

Metabolism ◽

10.1016/j.metabol.2021.154958 ◽

2021 ◽

pp. 154958

Author(s):

Liang-Jie Tang ◽

Hong-Lei Ma ◽

Mohammed Eslam ◽

Grace Lai-Hung Wong ◽

Pei-Wu Zhu ◽

...

Keyword(s):

Advanced Fibrosis ◽

Non Invasive ◽

Asian Patients

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Screening for non-alcoholic fatty liver disease in type 2 diabetes using non-invasive scores and association with diabetic complications

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000904 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000904 ◽

Cited By ~ 7

Author(s):

Stefano Ciardullo ◽

Emanuele Muraca ◽

Silvia Perra ◽

Eleonora Bianconi ◽

Francesca Zerbini ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fatty Liver ◽

Diabetic Complications ◽

Fatty Liver Disease ◽

European Association ◽

Advanced Fibrosis ◽

Alcoholic Fatty Liver ◽

Non Invasive ◽

Alcoholic Fatty Liver Disease

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is prevalent in patients with type 2 diabetes. Here, we estimate the proportion of patients with type 2 diabetes that should be referred to hepatologists according to the European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) Guidelines and evaluate the association between non-invasive biomarkers of steatosis and fibrosis and diabetic complications.Research design and methodsThis is a retrospective analysis of type 2 diabetes patients who attended on a regular basis our diabetes clinic between 2013 and 2018 (n=2770). Steatosis was assessed using Fatty Liver Index (FLI), Hepatic Steatosis Index and NAFLD Ridge Score and fibrosis using NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI) and AST/alanine aminotransferase (ALT) ratio. Outcome measures were altered albumin excretion rate (AER), chronic kidney disease (CKD) and cardiovascular disease (CVD).ResultsThe prevalence of advanced fibrosis varied from 1% (APRI) to 33% (NFS). The application of the guidelines using a sequential combination of FLI and FIB-4 would lead to referral of 28.3% of patients when using standard FIB-4 cut-offs, while this number dropped to 13.4% when age-adjusted FIB-4 thresholds were applied. A higher prevalence of altered AER was associated with liver steatosis (FLI: OR: 3.49; 95% CI 2.05 to 5.94, p<0.01), whereas liver fibrosis was associated with CKD (FIB-4: OR: 6.39; 95% CI 4.05 to 10.08, p<0.01) and CVD (FIB-4: OR: 2.62; 95% CI 1.69 to 4.04, p<0.01).ConclusionsWhile specific fibrosis scores identify different proportion of patients with advanced fibrosis, the use of age-adjusted FIB-4 cut-offs leads to a drop in gray-zone results, making referrals to hepatologists more sustainable. Interestingly non-invasive biomarkers were consistently associated with a different pattern of diabetic complications.

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