Noninvasive Methods of Assessing Nonalcoholic Fatty Liver Disease: What the Clinician Needs to Know
Authors: Dawn M. Torres, Stephen A. Harrison
Journal: Clinical Gastroenterology and Hepatology (2013)

Nonalcoholic fatty liver disease (NAFLD) has become recognized as a worldwide problem, approaching epidemic status in parts of the Western world. Current prevalence estimates for NAFLD range from 30% to 75%, depending on ethnicity, body mass index (BMI), and the presence of diabetes mellitus.1Torres D.M. Williams C.D. Harrison S.A. Features, diagnosis and treatment of nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2012; 10: 837-858Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar Significant necroinflammation with or without fibrosis on liver biopsy is required to diagnose nonalcoholic steatohepatitis (NASH). Data suggest that 10% to 30% of NAFLD patients meet the criteria for NASH, with an overall prevalence ranging from 3%2Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology.Gastroenterology. 2012; 142: 1592-1609Abstract Full Text Full Text PDF PubMed Scopus (1431) Google Scholar up to 25%, depending on the population studied.3Williams C.D. Stengel J. Asike M.I. et al.Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle aged population utilizing ultrasound and liver biopsy: a prospective study.Gastroenterology. 2011; 140: 124-131Abstract Full Text Full Text PDF PubMed Scopus (1727) Google Scholar, 4Targher G. Bertolini L. Padovani R. et al.Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease in type 2 diabetic patients.Diabetes Care. 2007; 30: 1212-1218Crossref PubMed Scopus (820) Google Scholar Natural history data suggest that although overall NAFLD patients are at an increased risk for developing type 2 diabetes and cardiovascular disease, patients with biopsy-proven isolated fatty liver have very little risk of progressing to cirrhosis and hepatic decompensation.5Adams L.A. Lymp J.F. St. Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (2411) Google Scholar, 6Angulo P. Diagnosing steatohepatitis and predicting liver-related mortality in patients with NAFLD: two distinct concepts.Hepatology. 2011; 53: 1792-1794Crossref PubMed Scopus (48) Google Scholar Alternatively, patients with NASH and fibrosis are at significant risk of disease progression.7Adams L.A. Sanderson S. Lindor K.D. et al.The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.Hepatology. 2005; 42: 132-138Abstract Full Text Full Text PDF Scopus (793) Google Scholar All NAFLD patients are at risk for hepatocellular carcinoma, although this risk appears greatest in those with advanced fibrosis and cirrhosis.8White D.L. Kanwal F. El-Serag H.B. Association between nonalcoholic fatty liver disease and risk for hepatocellular carcinoma, based on systematic review.Clin Gastroenterol Hepatol. 2012; 12: 1342-1359Abstract Full Text Full Text PDF Scopus (583) Google Scholar The high prevalence of NAFLD coupled with the need for liver biopsy to differentiate NASH from not-NASH presents the clinician with several potential dilemmas. Despite the fact that patients with isolated fatty liver have a very low probability of progressing to cirrhosis or hepatic decompensation, they still should be identified given the association of NAFLD with other conditions resulting in decreased survival. Typically, patients will be identified by the incidental finding of hepatic steatosis on abdominal imaging or a mild asymptomatic increase of serum aminotransferase levels on routine testing in the absence of other chronic liver disease, particularly alcohol-related. Once a patient has been identified as having NAFLD, the next clinical decision is whether to perform a liver biopsy to establish a diagnosis of NASH. It is unreasonable to perform a biopsy on every patient with NAFLD because liver biopsies are invasive, expensive, subject to sampling error, and, rarely, associated with severe complications such as hemorrhage or even death. However, liver biopsy is currently the best available way to identify the histopathologic features of NASH that have been shown to correlate with disease progression. NASH with advanced fibrosis on liver biopsy has greater clinical implications than NASH with no or minimal fibrosis. Noninvasive testing is needed to identify NAFLD patients as a whole, but even more importantly to identify patients with NASH, and specifically those with advanced fibrosis. Noninvasive methods that have been used to date include radiographic studies, laboratory tests, and scoring systems that combine clinical and laboratory data to predict the presence of NAFLD, NASH, or fibrosis.9Adams L.A. Feldstein A.E. Non-invasive diagnosis of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.J Dig Dis. 2011; 12: 10-16Crossref PubMed Scopus (82) Google Scholar An ideal test would be easy to obtain, of low cost, and have appropriately high sensitivity and specificity to answer the desired question: NAFLD vs no NAFLD, NASH vs not-NASH, and mild fibrosis vs advanced fibrosis. A test that could be repeated over time to monitor disease progression or response to therapeutic intervention would be even more desirable. Table 1 summarizes the tests investigated to date to answer each of these clinical questions.Table 1Noninvasive Tests for NAFLD, NASH, and Advanced FibrosisNAFLD vs non-NAFLDNASH vs not-NASHNo/minimal fibrosis vs advanced fibrosisRadiologyUltrasonographyComputed tomographyMagnetic resonance imagingNashTest (Biopredictive, Paris, France)RadiologyTransient elastographyMagnetic resonance elastographyAcoustic radiation force impulse elastographyShearWave elastographyFatty liver indexPalekar testFIB-4Steatotest (Biopredictive, Paris, France)Shimada testFibrotestLipid accumulation productCK-18 (cleaved vs uncleaved)European Liver FibrosisNASH DiagnosticsNAFLD fibrosis scorePIIINPAST/ALT ratioCK-18 + FGF-21BARD scoreCK-18 + sFasHyaluronic acidPentraxin-3BAATALT, alanine aminotransferase; AST, aspartate aminotransferase; BARD, BMI, AST/ALT ratio, diabetes; BAAT, BMI, ALT, age, triglycerides; FGF-21, fibroblastic growth factor; FIB-4, fibrosis 4; PIIINP, terminal peptide of procollagen-III; sFas, soluble Fas. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; BARD, BMI, AST/ALT ratio, diabetes; BAAT, BMI, ALT, age, triglycerides; FGF-21, fibroblastic growth factor; FIB-4, fibrosis 4; PIIINP, terminal peptide of procollagen-III; sFas, soluble Fas. The question of NAFLD vs no NAFLD is the focus of the investigation by Koehler et al10Koehler E.M. Schouten J.N.L. Hansen B.E. et al.External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study.Clin Gastroenterol Hepatol. 2013; 11: 1201-1204Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar in this issue of Clinical Gastroenterology and Hepatology in which the Fatty Liver Index (FLI) was compared with abdominal ultrasound (US) to identify patients with NAFLD in a large elderly Caucasian population from The Netherlands. An advantage of the FLI is that it is easily obtained using readily available clinical variables including BMI, waist circumference, triglycerides, and γ-glutamyltransferase. The FLI previously has been shown to have good accuracy in detecting NAFLD, in a relatively small study (n = 216 + 280), with a receiver operator characteristic of 0.84 (95% confidence interval, 0.81–0.87).11Bedogni G. Bellentani S. Miglioli L. et al.The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastro. 2006; 6: 33Crossref PubMed Scopus (1801) Google Scholar The current study of 2652 predominantly elderly Caucasians (mean age, 76 ± 6.0 y) appears to confirm good diagnostic accuracy of FLI for NAFLD using US as the surrogate gold standard with a receiver operator characteristic of 0.813 (95% confidence interval, 0.797–0.830). Although the FLI outperformed the Homeostatic Model Assessment of Insulin Resistance, waist circumference, BMI, γ-glutamyltransferase, and lipid accumulation product in diagnostic accuracy, the absence of comparative liver biopsy specimens in this study is notable because US is a good but imperfect test for hepatic steatosis, with a reported sensitivity of 60% to 94% and a specificity of 66% to 97%.12Saverymuttu S.H. Joseph A.E. Maxwell J.D. Ultrasound scanning in the detection of hepatic fibrosis and steatosis.BMJ. 1986; 292: 13-15Crossref PubMed Scopus (720) Google Scholar, 13Graif M. Yanuka M. Baraz M. Blank A. et al.Quantitative estimate of attenuation in ultrasound video images: correlation with histology in diffuse liver disease.Invest Radiol. 2000; 35: 319-324Crossref PubMed Scopus (174) Google Scholar, 14Palmentieri B. de Sio I. La Mura V. et al.The role of bright echo liver pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.Dig Dis. 2006; 38: 485-489Scopus (273) Google Scholar In addition, US is less accurate in the setting of morbid obesity and in diagnosing mild (<10%) steatosis. In a study of 100 potential living donors for liver transplant, US detected only 55% of patients with 10% to 19% steatosis on liver biopsy.15Ryan C.K. Johnson L.A. Germin B.I. Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation.Liver Transp. 2002; 8: 1114-1122Crossref PubMed Scopus (279) Google Scholar This calls into question the reported high sensitivity (91.5%) of FLI for predicting the absence of NAFLD because patients with mild steatosis may have been overlooked by US. Although this study suggests an alternative to US when screening for NAFLD, and answers the question of NAFLD or no NAFLD fairly effectively, it does not address the other subsequent clinical dilemmas: NASH or no NASH, and advanced or minimal fibrosis. The investigators do intimate that FLI can be associated with "severity" of fatty liver on US using the scale of no fatty liver, mild fatty liver, or moderate-to-severe fatty liver.10Koehler E.M. Schouten J.N.L. Hansen B.E. et al.External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study.Clin Gastroenterol Hepatol. 2013; 11: 1201-1204Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar However, US and, for that matter, FLI are not designed to answer the question of disease severity because the amount of fat does not predict disease severity or prognosis.16Machado M.V. Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal.J Hepatol. 2013; 58: 1007-1019Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar Strengths of this study included the large cohort of patients and the ease of obtaining the FLI based on readily available clinical data. The finding of an NAFLD prevalence of 34.9% is on par with other prevalence data and offers a measure of external validity to the findings of this study despite its limitations. The investigators concluded that the FLI may be used as a screening tool to decide who should undergo US, referencing another study of 2075 middle-aged Caucasians followed up for 15 years, in which FLI was associated independently with overall, cardiovascular, and cancer-related mortality.17Calori G. Lattuada G. Ragogna F. et al.Fatty liver index and mortality: the Cremona study in the 15th year of follow-up.Hepatology. 2011; 54: 145-152Crossref PubMed Scopus (211) Google Scholar However, if this test is truly accurate in diagnosing NAFLD, then undergoing US would be an unnecessary next step. Nevertheless, a possible future application of the FLI score would be to identify NAFLD and then apply a noninvasive scoring system to determine the patients who are at greatest risk of NASH and/or advanced fibrosis. This application of sequential testing would require an investigation in an initial cohort with subsequent validation in a large prospective cohort, with liver biopsy as the reference gold standard before it can be applied to clinical practice. Promising noninvasive tests currently under investigation include elastography-based radiology studies to evaluate liver stiffness/fibrosis and biomarker tests such as cytokeratin-18 (cleaved or uncleaved), a marker of hepatic apoptosis used to identify patients with NASH. It is important to note that individual biomarker tests such as cytokeratin-18 have not held up to strict validation in predicting an individual's likelihood of having NASH, but scoring systems using combinations of radiographic, clinical, laboratory, and biomarkers have shown promise as tools for distinguishing both NASH vs not-NASH, as well as early vs advanced fibrosis.18Adams L.A. George J. Bugianesi E. et al.Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease.J Gastroenterol Hepatol. 2011; 26: 1536-1543Crossref PubMed Scopus (137) Google Scholar, 19Dowman J.K. Tomlinson J.S. Newsome P.N. Systematic review: the diagnosis and stage of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.Aliment Pharmacol Ther. 2011; 33: 525-540Crossref PubMed Scopus (251) Google Scholar Another approach would be to use a scoring system to rule out or rule in advanced fibrosis and refer to liver biopsy those individuals who are in an intermediate probability range. These tests may have wide clinical application as they become cheaper and easier to obtain, although further validation in large prospective trials is required. In summary, the FLI score appears to be a reasonable modality to predict hepatic steatosis, although it is notable that the recently published tri-society guidelines do not recommend screening for NAFLD, even in high risk populations such as those with diabetes mellitus. Future studies using the FLI score plus another noninvasive surrogate test could further the clinical utility of this test and help clinicians decide who should undergo liver biopsy. External Validation of the Fatty Liver Index for Identifying Nonalcoholic Fatty Liver Disease in a Population-based StudyClinical Gastroenterology and HepatologyVol. 11Issue 9PreviewWe aimed to validate the fatty liver index (FLI), an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and γ-glutamyltransferase. We calculated its ability to identify fatty liver disease from any cause or nonalcoholic fatty liver disease (NAFLD) in a large population of white elderly persons. Full-Text PDF