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Non-Invasive Imaging Modalities in Nonalcoholic Fatty Liver Disease: Where Do We Stand?

| Hepatology Download as | PDF
Authors:
Somaya Albhaisi
Disclosure:

The author has declared no conflicts of interest.

Received:
30.11.18
Accepted:
18.02.19

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Liver biopsy is the gold standard for diagnosis and staging of fibrosis in patients with NAFLD; however, it is invasive, costly, and may be associated with morbidity and even mortality, so is not suitable for screening the large number of individuals who are at risk of, or have, NAFLD.  Therefore, there has been tremendous focus on finding non-invasive diagnostic modalities,  including imaging. New imaging modalities are emerging and may potentially replace biopsy. This review discusses the different non-invasive imaging modalities for the assessment of NAFLD.

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in developed countries.1 It is defined as the presence of at least 5% of hepatic steatosis on histology or imaging in absence of significant alcohol use and other secondary causes of steatosis.2 NAFLD has been clinically associated with metabolic disorders such as obesity, diabetes, and dyslipidaemia. It consists of a wide spectrum of clinico-pathologic presentations ranging  from simple steatosis to nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC).3-6 The top three leading causes of death in patients with NAFLD, in descending order, are cardiovascular disease, cancer, and liver disease.3 Therefore, early identification of this disease is paramount.

The gold standard for diagnosis of NASH is liver biopsy; however, this is invasive, costly, and risks complications.7 Thus, biopsy is not practical for the screening or monitoring of NAFLD.8,9 Non-invasive diagnostic techniques, such as serum biomarkers and imaging studies, have emerged. Imaging, in particular, has gained importance in the non-invasive diagnosis of hepatic steatosis.

IMAGING IN NAFLD/NASH

Ultrasonography

Ultrasonography is the most commonly used imaging modality for evaluating hepatic steatosis.

Ultrasound (US) is accepted as an initial screening for fatty liver because it is safe, widely available, well tolerated, and inexpensive.10-13 It also plays a key role in ruling out focal liver lesions and characterising them.14 There are numerous sonographic features of steatosis, such as the ‘echogenicity’ of the liver relative to the adjacent right kidney, hepatomegaly, and blunting of liver structures. Recent studies suggest that fatty infiltration of the liver can change the Doppler waveform of the hepatic veins.15,16 The degree of steatosis can be subjectively scored as mild, moderate, and severe, or, as reported in some studies, by using ordinal US scores.17,18

In a large meta-analysis of patients with suspected or known liver diseases, the reported sensitivity and specificity of US in distinguishing moderate-to-severe fatty liver from the absence of steatosis, was 85% (80–89%) and 93% (87–97%), respectively. Nevertheless, US lacks the sensitivity for detection of liver fat and is considered inaccurate in differentiating fibrosis from steatosis or quantifying the fat accumulation. US can only detect steatosis if the liver fat content is above 12.5–20.0%.9 Another major weakness of US is its operator dependency. Numerous factors can affect the sonographic features besides hepatic steatosis, such as obesity, renal disease, equipment-related factors, operator dependency, and the qualitative interpretation. Consequently, US has limited accuracy, repeatability, and reproducibility for diagnosis and evaluation of the degree of hepatic steatosis.20-23 Such limitations may be at least partially overcome by semi-quantitative indices, which are correlated with metabolic derangements and histological features in various liver diseases, notably including NAFLD both in adults and in children.24,25 Despite its undisputed limitations, US remains a first-line option technique in the investigation of NAFLD.26

Computed Tomography

X-ray CT uses the density of liver to spleen ratio to detect hepatic steatosis. NAFLD is typically an incidental finding on CT that is being performed for another indication. CT has fallen out of favour for diagnosis of hepatic steatosis for multiple reasons, including exposure to ionising radiation and lack of accuracy and reliability, especially for the detection of small fractions of fatty infiltration.27 Moreover, it has been demonstrated that CT attenuation values vary significantly between different manufacturers’ scanners and image processing techniques.28

Magnetic Resonance Imaging

Magnetic resonance (MR) spectroscopy (MRS) is reportedly the most accurate method for the quantification of steatosis,29,30 but its use is currently limited to research. MRS may be better than histology in assessing longitudinal changes in liver fat content, and is also safe; however, it is expensive and not widely available (Box 1).31

Box 1: Relative cost of current available non-invasive techniques for liver steatosis assessment.

CT: computed tomography; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; US: ultrasonography.

Magnetic Resonance Elastography

Magnetic resonance elastography (MRE) is the MR equivalent of transient elastography that is considered among the final options to assess hepatic fibrosis in patients with NAFLD. It uses a modified phase-contrast method to image the propagation of the shear wave in the liver parenchyma. MRE has demonstrated excellent diagnostic accuracy and ability to exclude significant fibrosis. Studies have shown that MRE has a sensitivity and specificity of 98% and 99%, respectively, for detecting all grades of fibrosis.32,33 When coupled with MRI, MRE can be helpful for the screening of HCC. Another advantage is that MRE accuracy is not affected by obesity or cirrhosis. Since the measured liver area is large on MRE, it can avoid potential sampling errors.  On the other hand, MRE may be inaccurate in inflammatory conditions and iron overload. MRE may not be practical for routine screening of NAFLD patients because it is costly, time-consuming, and not readily available. The best indication for MRE may be in morbidly obese patients who fail US-based elastography or need detailed liver imaging.

Magnetic Resonance Spectroscopy

(MRS) is the gold standard for quantification of fat in the liver,34  therefore it can accurately diagnose NAFLD.35 MRS measures the chemical composition of tissue based on proton signals frequency. Most of the identifiable peaks are derived from water and fat, and the fat signal fraction, also known as proton density fat fraction (PDFF) can be calculated.34,36 Therefore, MRS is considered the most sensitive and accurate non-invasive method of quantifying liver fat.30,31,36 MRS has important limitations that preclude its widespread use.37 MRS is time-consuming, not readily available, and requires additional equipment and special expertise.

Vibration-Controlled  Transient Elastography

Vibration-controlled transient elastography (VCTE), also known as Fibroscan® (Echosens,  Paris, France), is the most commonly used elastography method.38 VCTE is a non-invasive point-of-care method of assessing liver fibrosis by using an US-based technology for estimation of liver stiffness measurement (LSM).39,40  VCTE was originally validated for use mainly in the setting of viral hepatitis.41,42 Studies have shown robust VCTE quality criteria in patients with NAFLD, which include a minimum of 10 measurements that are used to obtain  the median LSM and the interquartile range.  Two probes are now available: the M-probe and the XL-probe. The latter probe has been introduced due to the high failure rate of VCTE in obese patients.43,44  XL-probes possess a deeper focal length, increased amplitude, and lower  shear wave frequency; therefore, they are more reliable in obese patients.45 A multicentre prospective study by Siddiqui et al.46 on NAFLD patients who underwent VCTE found that the diagnostic accuracy of VCTE in differentiating fibrosis stages was lower than previously reported by Tapper et al.47

Controlled Attenuation Parameter

The controlled attenuation parameter (CAP) is a novel tool for the assessment of hepatic steatosis available as an adjunct to VCTE.48 Based on studies, CAP relies on an M-probe of Fibroscan; therefore, it shares the same limitations as VCTE.43 The first study that assessed its performance in patients with chronic liver diseases has reported that CAP was able to accurately detect steatosis ≥11%, ≥33%, and ≥66% with an area under the curve of the receiver operating characteristic (AUROC) of 0.91, 0.95, and 0.89, respectively.49 Nevertheless, a meta-analysis by Karlas et al.50 suggested that CAP does not provide accurate reliable quantification of liver fat. Another meta-analysis of studies using the M-probe has suggested optimal cut-offs of 248 (237–261) dB/m, 268 (257–284) dB/m, and 280 (268–294) dB/m, respectively, for detection of steatosis.51 Others have proposed an optimal cut-off of 288 dB/m.52 The differences in proposed cut-offs can be explained by the variation in BMI and diabetes prevalence in heterogeneous populations, the use of M-probe, and the small sample size in most studies. A multicentre study in NAFLD patients using the XL-probe reported that CAP had an AUROC of 0.76 for detecting steatosis >5% and a 96% positive predictive value.53 Only two studies have performed a head-to-head comparison of CAP with US, showing that the performance of CAP for detecting and grading liver steatosis was higher than that of US; however, the rate of overestimation was significantly higher for CAP than for US (30.5% versus 12.4%; p<0.05).54 Overall, CAP is a useful technique for the rapid quantification of steatosis, but it still needs to be better validated with the XL-probe in patients with NAFLD.

Acoustic Resonance Forced Impulse Imaging and Shear Wave Elastography

Acoustic resonance forced impulse imaging (ARFI) is integrated into a conventional  US device and relies on elastography to estimate the LSM in shear wave speed. Shear wave elastography (SWE) adapts US imaging to evaluate liver stiffness. SWE can perform measurements over a wide range of frequencies and regions and thereby reduce sampling errors. SWE may be considered a screening test for patients with mild fibrosis stages according to Cassinotto et al.55 and Leung et al.;56 however, further studies are needed to confirm its applicability to patients with NAFLD. In general, SWE and ARFI are more reliable compared to VCTE in the assessment of liver fibrosis, but the utility of their use in NAFLD is yet to be confirmed as data are currently limited. The quality criteria for the application of ARFI or SWE are limited; thus, further studies are needed to establish those criteria and to define the role of ARFI and SWE in NAFLD so their readings can  be standardised.

Discussion

US is not sensitive but is highly specific for detection of moderate-to-severe hepatic steatosis. MRI–PDFF/MRE is considered the gold standard to quantify liver fat due to its high diagnostic accuracy; however, it may not be routinely available and is expensive. It may be used when other tests fail and can otherwise be reserved for clinical studies. CAP readings can be highly reliable if the interquartile range is <30 db/m.57 It becomes less accurate with a dynamic range of liver fat; therefore, it is not reliable in differentiating closely related steatosis stages.42 CAP, when combined with VCTE, may be helpful in screening obese patients for NAFLD. Elastography has gained wide acceptance. The most validated imaging modality in NAFLD is VCTE, which can be performed as a point-of-care test. It is best used to exclude significant fibrosis; however, VCTE is less accurate for low stages of fibrosis. SWE or ARFI may be useful for risk stratification of patients with NAFLD. Imaging in NAFLD is an area of increasing research focus. Further studies are needed to evaluate and quantify the relationship between imaging modalities and clinical status in NAFLD.

Non-invasive imaging methods, together with serum-based biomarkers, can be used as part of targeted screening strategies for NAFLD in primary care settings to improve specialist  referral. There is a need for an integrated management plan for NAFLD between primary and secondary care, with robust pathways for subsequent referrals. The absence of well-defined referral strategies can potentially result  in missing a substantial proportion of the  population at risk.58

CONCLUSION

The non-invasive assessment of NAFLD has progressed significantly. It is important to tailor the choice of non-invasive tests to the setting (primary care, tertiary referral centre, or clinical trial) and clinical needs (screening, staging of fibrosis, or follow-up). Although various imaging techniques are available, US remains the first line technique to be adopted in the evaluation  of NAFLD. MRI–PDFF is the most accurate  method for detection and grading of steatosis, but it is neither routinely available nor affordable, making it strictly used in research. Until now, there is no imaging modality that can reliably  discriminate NASH from simple steatosis.  Imaging can help with the identification of advanced fibrosis and, therefore, the appropriate referral for a liver biopsy. The combination of serum markers and liver stiffness, measured using transient elastography, can identify NAFLD patients at a high risk of  liver-related complications.

References
Jimba S et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005;22(9):1141-5. Chalasani N et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-57. Bang KB, Cho YK. Comorbidities and metabolic derangement of NAFLD. J Lifestyle Med. 2015;5(1):7-13. Cho Y et al. Transient elastography-based liver profiles in a hospital-based pediatric population in Japan. PLoS One. 2015;10(9):e0137239. Byrne CD, Targher G. NAFLD: A multisystem disease. J Hepatol. 2015;62(1 Suppl):S47-64. Smits MM et al. Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: Results of a US national survey in three ethnic groups. J Gastroenterol Hepatol. 2013. 28(4):664-70. Rockey DC et al. Liver biopsy. Hepatology. 2009;49(3):1017-44. Castera LV et al. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):666-75. Chalasani N et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012;107(6):811-26. Palmentieri B et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis. 2006;38(7):485-9. Ricci C et al. Noninvasive in vivo quantitative assessment of fat content in human liver. J Hepatol. 1997;27(1):108-13. Roldan-Valadez E et al. Imaging techniques for assessing hepatic fat content in nonalcoholic fatty liver disease. Ann Hepatol. 2008;7(3):212-20. Saverymuttu SH et al. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed). 1986;292(6512)13-5. Delahaye J et al. Doppler ultrasonography devices, including elastography, allow for accurate diagnosis of severe liver fibrosis. Eur J Radiol. 2018;108:133-9. von Herbay A et al. Association between duplex doppler sonographic flow pattern in right hepatic vein and various liver diseases. J Clin Ultrasound. 2001;29(1):25-30. Dietrich CF et al. Hepatic and portal vein flow pattern in correlation with intrahepatic fat deposition and liver histology in patients with chronic hepatitis C. AJR Am J Roentgenol. 1998;171(2):437-43. Ballestri S et al. Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. Liver Int. 2012;32(8):1242-52. Hamaguchi M et al. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol. 2007;102(12):2708-15. Bril F et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015;35(9):2139-46. van Werven JR et al. Assessment of hepatic steatosis in patients undergoing liver resection: Comparison of US, CT, T1-weighted dual-echo MR imaging, and point-resolved 1H MR spectroscopy. Radiology. 2010;256(1):159-68. Strauss S et al. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. AJR Am J Roentgenol. 2007;189(6):W320-3. Fishbein M et al. Hepatic MRI for fat quantitation: Its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol. 2005;39(7):619-25. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013;58(5):1007-19. Liu HK et al. Novel ultrasonographic fatty liver indicator can predict hepatitis in children with non-alcoholic fatty liver disease. Front Pediatr. 2018;6:416. Yang KC et al. Association of non-alcoholic fatty liver disease with metabolic syndrome independently of central obesity and insulin resistance. Sci Rep. 2016;6:27034. Leoni S et al. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World J Gastroenterol. 2018;24(30):3361-73. Park SH et al. Macrovesicular hepatic steatosis in living liver donors: Use of CT for quantitative and qualitative assessment. Radiology. 2006;239(1):105-12. Birnbaum BA et al. Multi-detector row CT attenuation measurements: Assessment of intra- and interscanner variability with an anthropomorphic body CT phantom. Radiology. 2007;242(1):109-19. Cowin GJ et al. Magnetic resonance imaging and spectroscopy for monitoring liver steatosis. J Magn Reson Imaging. 2008;28(4):937-45. Szczepaniak LS et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288(2):E462-8. Schwenzer NF et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol. 2009;51(3):433-45. Iijima H et al. Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis. Hepatol Res. 2007;37(9):722-30. Singh S et al. Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: A diagnostic accuracy systematic review and individual participant data pooled analysis. Eur Radiol. 2016;26(5):1431-40. Reeder SB et al. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging. 2011;34(4):729-49. Wong VW et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: A population study with paired proton-magnetic resonance spectroscopy. J Hepatol. 2015;62(1):182-9. Tang A et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis. Radiology. 2013;67(2):422-31. Dulai PS et al. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J Hepatol. 2016;65(5):1006-16. Afdhal NH et al. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: A United States multicenter study. Clin Gastroenterol Hepatol. 2015;13(4):772-9. Petta S et al. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values. Hepatology. 2017;65(4):1145-55. Park CC et al. 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. 2017;152(3):598-607. Boursier J et al. A new combination of blood test and fibroscan for accurate non-invasive diagnosis of liver fibrosis stages in chronic hepatitis C. Am J Gastroenterol. 2011;106(7):1255-63. Osakabe K et al. Reduction of liver stiffness by antiviral therapy in chronic hepatitis B. J Gastroenterol. 2011;46(11):1324-34. de Ledinghen V et al. Controlled attenuation parameter (CAP) for the diagnosis of steatosis: A prospective study of 5323 examinations. J Hepatol. 2014;60(5):1026-31. Foucher J et al. Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations. Eur J Gastroenterol Hepatol. 2006;18(4):411-2. de Ledinghen V et al. Diagnosis of liver fibrosis and cirrhosis using liver stiffness measurement: Comparison between M and XL probe of FibroScan®. J Hepatol. 2012;56(4):833-9. Siddiqui MS et al. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019;17(1):156-63 e2. Tapper EB et al. The performance of vibration controlled transient elastography in a US cohort of patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2016;111(5):677-84. Myers RP et al. Controlled Attenuation Parameter (CAP): A noninvasive method for the detection of hepatic steatosis based on transient elastography. Liver Int. 2012;32(6):902-10. Dietrich CF et al. EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, Update 2017 (Long Version). Ultraschall Med. 2017;38(4):e48. Karlas T et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017;66(5):1022-30. Ferraioli G et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: Liver. Ultrasound Med Biol. 2015;41(5):1161-79. Friedrich-Rust M et al. Critical comparison of elastography methods to assess chronic liver disease. Nat Rev Gastroenterol Hepatol. 2016;13(7):402-11. Hamilton G et al. In vivo characterization of the liver fat (1)H MR spectrum. NMR Biomed. 2011;24(7):784-90. Xu L et al. A comparison of hepatic steatosis index, controlled attenuation parameter and ultrasound as noninvasive diagnostic tools for steatosis in chronic hepatitis B. Dig Liver Dis. 2017;49(8):910-7. Cassinotto C et al. Non-invasive assessment of liver fibrosis with impulse elastography: Comparison of supersonic shear imaging with ARFI and FibroScan®. J Hepatol, 2014;61(3):550-7. Leung VY et al. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: Comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology. 2013;269(3):910-8. Caussy C et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018;67(4):1348-59. Tsochatzis EA, PN Newsome. Non-alcoholic fatty liver disease and the interface between primary and secondary care. Lancet Gastroenterol Hepatol. 2018;3(7):509-17.