Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyNoninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease
Section snippets
Currently Available Noninvasive Methods and Their Limitations
Noninvasive methods rely on 2 different approaches: a “biological” approach based on the quantification of biomarkers in serum samples or a “physical” approach based on the measurement of liver stiffness, using either ultrasound- or magnetic resonance–based elastography techniques. Although these approaches are complementary, they are based on different rationales. Liver stiffness corresponds to a genuine and intrinsic physical property of liver parenchyma, whereas serum biomarkers indicate
Serum Biomarkers
Several steatosis scores have been proposed for the detection of steatosis, including the SteatoTest,13 Fatty Liver Index,14 Hepatic Steatosis Index,15 lipid accumulation product,16 the Index of NASH,17 and the NAFLD Liver Fat Score.18 Their diagnostic performances have been summarized in a recent review.19 Although SteatoTest, Fatty Liver Index NAFLD Liver Fat Score, lipid accumulation product, and Hepatic Steatosis Index have been validated independently,20, 21, 22, 23 their diagnostic
Serum Biomarkers
Many serum biomarkers have been investigated for the diagnosis of NASH 64 but cytokeratin (CK)-18 is by far the one that has been the most widely investigated. CK-18 fragments come from apoptosis of hepatocytes accomplished by the enzyme caspase 3 and can be measured in serum by immunoassay. The M30 enzyme-linked immunosorbent assay measures the caspase-cleaved K18 fragments and detects apoptosis, which is a hallmark of steatohepatitis, whereas the M65 enzyme-linked immunosorbent assay detects
Serum Biomarkers
The diagnostic performances of serum biomarkers have already been summarized in several reviews78, 64, 103 and, therefore, will not be detailed here. Briefly, as for nonpatented tests, a recent meta-analysis (based on 64 studies in 13,046 NAFLD patients) comparing BARD, APRI, FIB-4, and NAFLD fibrosis score (NFS) for diagnosing advanced fibrosis reported summary AUROCS of 0.76, 0.77, 0.84, and 0.84, respectively.104 With an APRI threshold of 1.0 and 1.5, the sensitivities and specificities for
Use in Clinical Practice
In patients with suspected NAFLD (presence of steatosis on ultrasound or abnormal liver tests [transaminases/γ-glutamyltransferase] in patients with risk factors such as obesity, type 2 diabetes, or metabolic syndrome), noninvasive tests can be used in clinical practice for risk stratification. Whatever the approach, serum biomarkers or elastography, each modality is most reliable in excluding the presence of advanced fibrosis. As shown in Figure 1, the choice of noninvasive tools to be used
Special Populations and Controversies
Patients with type 2 diabetes mellitus are known to be at increased risk for NAFLD and advanced fibrosis. Noninvasive screening strategies for NAFLD, NASH, or advanced fibrosis have been proposed in diabetic patients, including the use of routinely available clinical variables,133 TE,134, 135 MRE,52 or combination of TE and ELF.136 It is noteworthy that most studies on noninvasive tests in NAFLD patients have not been stratified for the presence of diabetes. Several recent studies suggested
Prognosis
Several recent studies have shown the ability of liver stiffness, measured using TE,107 or serum biomarkers107, 142, 143 to predict clinical decompensation as well as survival in patients with NAFLD. A meta-analysis144 based on 17 studies in 7058 patients with chronic liver diseases (mainly related to viral hepatitis) has shown that baseline liver stiffness, measured using TE, was associated significantly with risk of hepatic decompensation (6 studies; relative risk [RR], 1.07; 95% CI,
Future Directions
There is a wealth of data that are informing clinicians regarding the utility and limitations of each of the diagnostic modalities in the assessment of NAFLD. However, further advances are needed to refine clinical management and more accurate identification of patients at risk for fibrosis progression and those who need to be treated in the setting of a clinical trial without subjecting them to a liver biopsy evaluation. The key research priorities in the field are listed in Table 5.
Conclusions
Significant progress has been made regarding the noninvasive assessment of liver disease in patients with NAFLD. Use of noninvasive tests should be tailored according to the setting (primary heath care, tertiary referral center, trial) and clinical needs (screening, staging of fibrosis, follow-up). Regarding detection and grading of steatosis, MRI-PDFF is the most accurate method but appears better suited for assessment and follow-up of selected patients in clinical trials, whereas conventional
Acknowledgments
Author contributions: Laurent Castera contributed to drafting and writing of the manuscript and to critical revision for important intellectual content. Mireen Friedrich-Rust contributed to drafting and writing of the manuscript and to critical revision for important intellectual content. Rohit Loomba contributed to drafting and writing of the manuscript and to critical revision for important intellectual content.
References (168)
- et al.
Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation
Gastroenterology
(2017) - et al.
Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease
Gastroenterology
(2015) - et al.
Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD
J Hepatol
(2017) - et al.
Liver ultrasound elastography: an update to the world federation for ultrasound in medicine and biology guidelines and recommendations
Ultrasound Med Biol
(2018) - et al.
Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease
Dig Liver Dis
(2010) - et al.
Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors
Gastroenterology
(2009) - et al.
Noninvasive diagnosis of nonalcoholic fatty liver disease and quantification of liver fat using a new quantitative ultrasound technique
Clin Gastroenterol Hepatol
(2015) - et al.
Controlled attenuation parameter (CAP): a novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes
Ultrasound Med Biol
(2010) - et al.
Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis
J Hepatol
(2017) - et al.
Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD
Eur J Radiol
(2012)
Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography
Gastroenterology
Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease
Gastroenterology
Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease
Clin Gastroenterol Hepatol
A comparison of hepatic steatosis index, controlled attenuation parameter and ultrasound as noninvasive diagnostic tools for steatosis in chronic hepatitis B
Dig Liver Dis
Heritability of hepatic fibrosis and steatosis based on a prospective twin study
Gastroenterology
Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial
J Hepatol
Agreement between magnetic resonance imaging proton density fat fraction measurements and pathologist-assigned steatosis grades of liver biopsies from adults with nonalcoholic steatohepatitis
Gastroenterology
Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib
J Hepatol
Magnetic resonance imaging proton density fat fraction associates with progression of fibrosis in patients with nonalcoholic fatty liver disease
Gastroenterology
Role of imaging-based biomarkers in NAFLD: Recent advances in clinical application and future research directions
J Hepatol
Non-invasive assessment of non-alcoholic fatty liver disease: clinical prediction rules and blood-based biomarkers
J Hepatol
Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients
Clin Gastroenterol Hepatol
Effect of lectin-like oxidized LDL receptor-1 polymorphism on liver disease, glucose homeostasis, and postprandial lipoprotein metabolism in nonalcoholic steatohepatitis
Am J Clin Nutr
Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers
J Hepatol
Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease
J Hepatol
An apoptosis panel for nonalcoholic steatohepatitis diagnosis
J Hepatol
Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese
Gastroenterology
Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
J Lipid Res
Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal
J Hepatol
A population-based study on the prevalence of NASH using scores validated against liver histology
J Hepatol
Noninvasive detection of nonalcoholic steatohepatitis using clinical markers and circulating levels of lipids and metabolites
Clin Gastroenterol Hepatol
Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes
Hepatology
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). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease
J Hepatol
The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases
Hepatology
Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies
Clin Gastroenterol Hepatol
Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis
Hepatology
Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis
J Hepatol
EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, Update 2017 (Long Version)
Eur J Ultrasound
Critical comparison of elastography methods to assess chronic liver disease
Nat Rev Gastroenterol Hepatol
The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis
Comp Hepatol
The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population
BMC Gastroenterol
A simple index of lipid overaccumulation is a good marker of liver steatosis
BMC Gastroenterol
Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
J Gastroenterol Hepatol
Non-invasive diagnosis of hepatic steatosis
Hepatol Int
Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data
PLoS One
Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease
Aliment Pharmacol Ther
External validation of the fatty liver index and lipid accumulation product indices, using 1H-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals
Eur J Endocrinol
Fatty liver index and mortality: the Cremona study in the 15th year of follow-up
Hepatology
Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis
Hepatology
Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD
Liver Int
Cited by (0)
Conflicts of interest The authors disclose the following: Laurent Castera: speaker bureau of AbbVie, Echosens, Intercept, Gilead, and Sirtex. Advisory boards for Allergan, Gilead, MSD, Pfizer, and Servier. Mireen Friedrich-Rust: speaker honorarium from Echosens, Siemens. Advisory board for Toshiba. Research support for Echosens, Supersonic, and Siemens. Rohit Loomba: grants from Allergan, BMS, Boehringer Ingleheim, Eli Lily, Galectin, Galmed, GE, Genfit, Gilead, Intercept, Janssen, Madrigal, NGM, Prometheus, Siemens, Shire, Pfizer, advisory committees for Arrowhead Research, Conatus, Galmed, Gemphire, Gilead, Intercept, NGM, and Cirius. Consultant for Bird Rock Bio, BMS, Coh Bar, Celgene, Civi Bio, Conatus, Enanta, Gilead, GRI Bio, Ionis, Metacrine, NGM, Receptos, Sanofi, Salix, Kowa, and Median technologies. Co-founder of Liponexus Inc.
Funding Rohit Loomba is supported in part by grant R01-DK106419-01 from the National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Health. Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institute of Health under Award P42ES010337.