Gastroenterology

Gastroenterology

Volume 156, Issue 5, April 2019, Pages 1264-1281.e4
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease

https://doi.org/10.1053/j.gastro.2018.12.036Get rights and content

Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.

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.

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    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.

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