Getting closer to a point-of-care diagnostic assessment in patients with chronic liver disease: Controlled attenuation parameter for steatosis
Authors: Annalisa Berzigotti
Journal: Journal of Hepatology (2014)

Controlled attenuation parameter (CAP) for the diagnosis of steatosis: A prospective study of 5323 examinationsJournal of HepatologyVol. 60Issue 5PreviewControlled attenuation parameter (CAP) evaluated with transient elastography (FibroScan®) is a recent method for non-invasive assessment of steatosis. Its usefulness in clinical practice is unknown. We prospectively investigated the determinants of CAP failure and the relationships between CAP and clinical or biological parameters in a large cohort of consecutive patients. Full-Text PDF In a worldwide scenario of pandemic obesity and metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) is exponentially increasing. NAFLD per se has become the most frequent cause for referral for chronic liver disease evaluation (CLD) and an increasing cause of hepatocellular carcinoma and end-stage liver disease requiring liver transplantation in developed countries [1Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231Crossref PubMed Scopus (4291) Google Scholar, 2Charlton M.R. Burns J.M. Pedersen R.A. Watt K.D. Heimbach J.K. Dierkhising R.A. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.Gastroenterology. 2011; 141: 1249-1253Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar]. Fatty liver (steatosis) can be also found in patients with CLD of other aetiologies, since some CLD are themselves steatogenic (chronic hepatitis C virus – HCV infection; alcoholic liver disease), and since the metabolic syndrome can be superimposed to other liver diseases. Detection of hepatic steatosis in CLD patients is relevant for several reasons. Just to cite some, NAFLD is a well recognized co-factor accelerating the progression of CLD [[3]Leandro G. Mangia A. Hui J. Fabris P. Rubbia-Brandt L. Colloredo G. et al.Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data.Gastroenterology. 2006; 130: 1636-1642Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar] and reduces the likelihood of sustained virological response in patients with HCV [[4]Poynard T. Ratziu V. McHutchison J. Manns M. Goodman Z. Zeuzem S. et al.Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C.Hepatology. 2003; 38: 75-85Crossref PubMed Scopus (549) Google Scholar]. Furthermore, in patients undergoing liver resection NAFLD independently increases the risk of postoperative complications and death [[5]de Meijer V. Kalish B.T. Puder M. Ijzermans J.N. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection.Br J Surg. 2010; 97: 1331-1339Crossref PubMed Scopus (196) Google Scholar]. Finally, in the setting of liver transplantation the presence of macrovesicular steatosis in the graft increases the 1-year risk of graft failure [[6]Spitzer A.L. Lao O.B. Dick A.A. Bakthavatsalam R. Halldorson J.B. Yeh M.M. et al.The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment.Liver Transpl. 2010; 16: 874-884Crossref PubMed Scopus (255) Google Scholar]. Therefore, an accurate method to detect and quantify liver steatosis would be extremely useful and as such it has been subject of research in the last 10 years. The presence of fat within the liver tissue modifies its physical properties, making it visible by appropriate imaging techniques. The most sensitive and most accurate imaging method to assess fatty liver so far is magnetic resonance spectroscopy, that is able to diagnose steatosis when involving ⩾5% of hepatocytes [[7]Machado 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 (301) Google Scholar]. Regrettably, this technique cannot be used routinely given its high cost, and certainly it cannot be used as a point-of-care method to guide a rapid decision making in clinical practice. Liver ultrasound (US) is accepted as the first line imaging technique to screen for liver steatosis given its low cost, safety and wide availability. US is accurate in detecting steatosis if this involves at least 20% of hepatocytes [[8]Dasarathy S. Dasarathy J. Khiyami A. Joseph R. Lopez R. McCullough A.J. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study.J Hepatol. 2009; 51: 1061-1067Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar], gives results in real time and can be used as a point-of-care method, and allows mirroring changes in hepatic fat content over time. However, US assessment has substantial well-known limitations [[7]Machado 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 (301) Google Scholar]: it relies upon a qualitative or at most upon a semi-quantitative assessment, it is operator-dependent (meaning that it requires a specific expertise), and it has a limited applicability in case of morbid obesity. Furthermore, the accuracy of US in diagnosing steatosis in patients with pre-existent CLD might be reduced by the presence of fibrosis, and has not been adequately assessed. Controlled attenuation parameter (CAP) is a recently developed non-invasive technique that might overcome some of these limitations. CAP measures the degree of ultrasound attenuation due to hepatic fat at the standardized frequency of 3.5 MHz taking advantage of a technology named vibration-controlled elastography (VCTE™) implemented on FibroScan® (Echosens, Paris, France) [[9]Sasso M. Beaugrand M. de Ledinghen V. Douvin C. Marcellin P. Poupon R. 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; 36: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar]. The software provides a numerical value that is operator-independent and can be obtained by operators without experience in medical imaging simultaneously to LS measurement. CAP values range from 100 to 400 dB/m, and the final result is the median value of 10 valid measurements (note that CAP is calculated simultaneously with valid LS measurements) [[9]Sasso M. Beaugrand M. de Ledinghen V. Douvin C. Marcellin P. Poupon R. 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; 36: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar]. CAP values correlated well with the amount of steatosis assessed by liver biopsy in previous studies from different countries [9Sasso M. Beaugrand M. de Ledinghen V. Douvin C. Marcellin P. Poupon R. 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; 36: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar, 10de Ledinghen V. Vergniol J. Foucher J. Merrouche W. Le B.B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.Liver Int. 2012; 32: 911-918Crossref PubMed Scopus (304) Google Scholar, 11Friedrich-Rust M. Romen D. Vermehren J. Kriener S. Sadet D. Herrmann E. 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; 81: e325-e331Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 12Masaki K. Takaki S. Hyogo H. Kobayashi T. Fukuhara T. Naeshiro N. et al.Utility of controlled attenuation parameter measurement for assessing liver steatosis in Japanese patients with chronic liver diseases.Hepatol Res. 2013; ([Epub ahead of print])https://doi.org/10.1111/hepr.12094Crossref PubMed Scopus (53) Google Scholar, 13Myers R.P. Pollett A. Kirsch R. Pomier-Layrargues G. Beaton M. Levstik M. et al.Controlled attenuation parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography.Liver Int. 2012; 32: 902-910Crossref PubMed Scopus (261) Google Scholar, 14Sasso M. Tengher-Barna I. Ziol M. Miette V. Fournier C. Sandrin L. et al.Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): validation in chronic hepatitis C.J Viral Hepat. 2012; 19: 244-253Crossref PubMed Scopus (172) Google Scholar, 15Chon Y.E. Jung K.S. Kim S.U. Park J.Y. Park Y.N. Kim D.Y. et al.Controlled attenuation parameter (CAP) for detection of hepatic steatosis in patients with chronic liver diseases: a prospective study of a native Korean population.Liver Int. 2014; 34: 102-109Crossref PubMed Scopus (129) Google Scholar]; values >215 dB allowed the detection of fatty infiltration ⩾10% of hepatocytes with a sensitivity over 90% in a recent study [[10]de Ledinghen V. Vergniol J. Foucher J. Merrouche W. Le B.B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.Liver Int. 2012; 32: 911-918Crossref PubMed Scopus (304) Google Scholar], while the CAP cut-off associated with significant steatosis (>33% of hepatocytes) varied among studies but was invariably >250 dB [9Sasso M. Beaugrand M. de Ledinghen V. Douvin C. Marcellin P. Poupon R. 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; 36: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar, 10de Ledinghen V. Vergniol J. Foucher J. Merrouche W. Le B.B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.Liver Int. 2012; 32: 911-918Crossref PubMed Scopus (304) Google Scholar, 11Friedrich-Rust M. Romen D. Vermehren J. Kriener S. Sadet D. Herrmann E. 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; 81: e325-e331Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 12Masaki K. Takaki S. Hyogo H. Kobayashi T. Fukuhara T. Naeshiro N. et al.Utility of controlled attenuation parameter measurement for assessing liver steatosis in Japanese patients with chronic liver diseases.Hepatol Res. 2013; ([Epub ahead of print])https://doi.org/10.1111/hepr.12094Crossref PubMed Scopus (53) Google Scholar, 13Myers R.P. Pollett A. Kirsch R. Pomier-Layrargues G. Beaton M. Levstik M. et al.Controlled attenuation parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography.Liver Int. 2012; 32: 902-910Crossref PubMed Scopus (261) Google Scholar, 14Sasso M. Tengher-Barna I. Ziol M. Miette V. Fournier C. Sandrin L. et al.Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): validation in chronic hepatitis C.J Viral Hepat. 2012; 19: 244-253Crossref PubMed Scopus (172) Google Scholar, 15Chon Y.E. Jung K.S. Kim S.U. Park J.Y. Park Y.N. Kim D.Y. et al.Controlled attenuation parameter (CAP) for detection of hepatic steatosis in patients with chronic liver diseases: a prospective study of a native Korean population.Liver Int. 2014; 34: 102-109Crossref PubMed Scopus (129) Google Scholar]. Furthermore, CAP values were not influenced by the presence of fibrosis or cirrhosis. These results were certainly promising, but were obtained in relatively small, selected populations (<150 cases), preventing to conclude what is the real applicability of the technique in detecting steatosis, and which factors may cause uncertainty on CAP results. In this number of Journal of Hepatology, de Ledinghen and colleagues [[16]Ledinghen V.D. Vergniol J. Capdepont M. Chermak F. Hiriart J.B. Cassinotto C. et al.Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations.J Hepatol. 2014; 60: 1026-1031Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar] provide interesting data expanding the knowledge of this new method in CLD. CAP performance was evaluated in a large prospective study including 5323 consecutive patients with CLD of various etiologies in whom the metabolic profile and LS by FibroScan® were also estimated. A subgroup of 440 patients (of whom 52% had steatosis, being this severe in 15%) simultaneously underwent liver biopsy. In this subset CAP confirmed an excellent diagnostic accuracy for steatosis detection, with an adjusted AUROC of 0.914 (95% CI 0.90–0.93). Taken together, the results of this [[16]Ledinghen V.D. Vergniol J. Capdepont M. Chermak F. Hiriart J.B. Cassinotto C. et al.Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations.J Hepatol. 2014; 60: 1026-1031Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar] and previous studies [9Sasso M. Beaugrand M. de Ledinghen V. Douvin C. Marcellin P. Poupon R. 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; 36: 1825-1835Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar, 10de Ledinghen V. Vergniol J. Foucher J. Merrouche W. Le B.B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.Liver Int. 2012; 32: 911-918Crossref PubMed Scopus (304) Google Scholar, 11Friedrich-Rust M. Romen D. Vermehren J. Kriener S. Sadet D. Herrmann E. 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; 81: e325-e331Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 12Masaki K. Takaki S. Hyogo H. Kobayashi T. Fukuhara T. Naeshiro N. et al.Utility of controlled attenuation parameter measurement for assessing liver steatosis in Japanese patients with chronic liver diseases.Hepatol Res. 2013; ([Epub ahead of print])https://doi.org/10.1111/hepr.12094Crossref PubMed Scopus (53) Google Scholar, 13Myers R.P. Pollett A. Kirsch R. Pomier-Layrargues G. Beaton M. Levstik M. et al.Controlled attenuation parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography.Liver Int. 2012; 32: 902-910Crossref PubMed Scopus (261) Google Scholar, 14Sasso M. Tengher-Barna I. Ziol M. Miette V. Fournier C. Sandrin L. et al.Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): validation in chronic hepatitis C.J Viral Hepat. 2012; 19: 244-253Crossref PubMed Scopus (172) Google Scholar, 15Chon Y.E. Jung K.S. Kim S.U. Park J.Y. Park Y.N. Kim D.Y. et al.Controlled attenuation parameter (CAP) for detection of hepatic steatosis in patients with chronic liver diseases: a prospective study of a native Korean population.Liver Int. 2014; 34: 102-109Crossref PubMed Scopus (129) Google Scholar], demonstrate that CAP allows a precise and reliable non-invasive diagnosis of liver steatosis in patients with CLD, and indicates that a "one-shot study" using the same equipment that gives results in real time can be used to diagnose both steatosis and fibrosis in this population. CAP has the additional advantage of being quantitative. In the whole study population, factors independently associated with CAP values indicating significant steatosis (>33% of hepatocytes) were male gender, age >55 years, BMI, presence of metabolic syndrome, and alcohol abuse. Notably, while male gender and age >55 years increased by about 30% the risk of showing a CAP value of either 250–300 dB or >300 dB, obesity, metabolic syndrome and alcohol abuse (variables epidemiologically associated with a more severe fatty liver [[17]Nascimbeni F. Pais R. Bellentani S. Day C.P. Ratziu V. Loria P. et al.From NAFLD in clinical practice to answers from guidelines.J Hepatol. 2013; 59: 859-871Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar]) were more strongly associated with values of CAP >300 dB. LS >6 kPa was also associated with high CAP values independent of the features of metabolic syndrome and alcohol abuse. This finding was not further analyzed, but is somehow disturbing since it implies either that a common factor can explain increases in both CAP and LS (such as can occur in patients with HCV-related CLD inducing both steatosis and fibrosis) or that false positive results of CAP might be observed in patients with increased LS. Additional data are required to clarify this issue. Technical failure of the method (observed in 7.7% of cases) was also significantly associated with age >55 years, BMI, presence of metabolic syndrome, and with female gender. These results are not surprising considering that technical failures of LS with the standard M FibroScan® probe, that is used for CAP measurement, occur more often in such patients [[18]Castera L. Foucher J. Bernard P.H. Carvalho F. Allaix D. Merrouche W. et al.Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.Hepatology. 2010; 51: 828-835PubMed Google Scholar]. Clearly, a CAP algorithm for the FibroScan® XL probe, specifically designed for obese population, would be welcome. Several other questions remain to be answered. The first regards the generalizability of the findings of de Ledinghen and colleagues [[16]Ledinghen V.D. Vergniol J. Capdepont M. Chermak F. Hiriart J.B. Cassinotto C. et al.Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations.J Hepatol. 2014; 60: 1026-1031Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar] to primary care population, in which it is important to detect NAFLD since it is an independent predictor of cancer, cardiovascular disease, and mortality from any cause [[17]Nascimbeni F. Pais R. Bellentani S. Day C.P. Ratziu V. Loria P. et al.From NAFLD in clinical practice to answers from guidelines.J Hepatol. 2013; 59: 859-871Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar]. Studies targeting the general population are still scarce, but recent data confirm that CAP correlates with the features of metabolic syndrome in this setting [19Carvalhana S. Leitao J. Alves A.C. Bourbon M. Cortez-Pinto H. How good is controlled attenuation parameter and fatty liver index for assessing liver steatosis in general population: correlation with ultrasound.Liver Int. 2013; ([Epub ahead of print])https://doi.org/10.1111/liv.12305Crossref PubMed Scopus (71) Google Scholar, 20Yilmaz Y. Ergelen R. Akin H. Imeryuz N. Noninvasive detection of hepatic steatosis in patients without ultrasonographic evidence of fatty liver using the controlled attenuation parameter evaluated with transient elastography.Eur J Gastroenterol Hepatol. 2013; 25: 1330-1334Crossref PubMed Scopus (32) Google Scholar]. The second question, to be addressed both in patients with CLD and in the general population, regards which CAP cut-off should be used to correctly identify the presence of liver steatosis and to estimate its amount. Given the well known limitations of liver biopsy (limited sampling of the liver, implying a risk of over- or underestimating steatosis even with morphometric analysis), studies comparing CAP with magnetic resonance spectroscopy, that gives a quantitative measure of fat content in the whole liver and is probably more accurate than biopsy [[7]Machado 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 (301) Google Scholar], would be of great value. Future studies should also focus on assessing whether CAP is able to accurately mirror changes in steatosis over time. This would be important to consider CAP a reliable biomarker for assessing the effectiveness of new treatments for NAFLD in clinical trials. A final issue regards how CAP compares with other non-invasive methods available in this field. Up to date conflicting results have been obtained in studies comparing CAP to serum indices of steatosis (Steatotest™ [BioPredictive, Paris, France], FLI and Hepatic Steatosis Index) [10de Ledinghen V. Vergniol J. Foucher J. Merrouche W. Le B.B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography.Liver Int. 2012; 32: 911-918Crossref PubMed Scopus (304) Google Scholar, 13Myers R.P. Pollett A. Kirsch R. Pomier-Layrargues G. Beaton M. Levstik M. et al.Controlled attenuation parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography.Liver Int. 2012; 32: 902-910Crossref PubMed Scopus (261) Google Scholar, 16Ledinghen V.D. Vergniol J. Capdepont M. Chermak F. Hiriart J.B. Cassinotto C. et al.Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations.J Hepatol. 2014; 60: 1026-1031Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 19Carvalhana S. Leitao J. Alves A.C. Bourbon M. Cortez-Pinto H. How good is controlled attenuation parameter and fatty liver index for assessing liver steatosis in general population: correlation with ultrasound.Liver Int. 2013; ([Epub ahead of print])https://doi.org/10.1111/liv.12305Crossref PubMed Scopus (71) Google Scholar]. Data comparing CAP with US in the general population are also inconclusive: although in one study CAP was able to detect steatosis in patients with normal US, suggesting that it might be more accurate [[20]Yilmaz Y. Ergelen R. Akin H. Imeryuz N. Noninvasive detection of hepatic steatosis in patients without ultrasonographic evidence of fatty liver using the controlled attenuation parameter evaluated with transient elastography.Eur J Gastroenterol Hepatol. 2013; 25: 1330-1334Crossref PubMed Scopus (32) Google Scholar], in another study both methods had a similar, good accuracy for the diagnosis of steatosis [[19]Carvalhana S. Leitao J. Alves A.C. Bourbon M. Cortez-Pinto H. How good is controlled attenuation parameter and fatty liver index for assessing liver steatosis in general population: correlation with ultrasound.Liver Int. 2013; ([Epub ahead of print])https://doi.org/10.1111/liv.12305Crossref PubMed Scopus (71) Google Scholar]. Analogous comparisons between these two point-of-care methods are lacking in patients with CLD, and should be performed in order to design diagnostic algorithms useful to correctly and non-invasively diagnose steatosis and its severity. CIBERehd is funded by Instituto de Salud Carlos III. The author declared that she does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.