Assessment of Fibrosis by Transient Elastography Compared With Liver Biopsy and Morphometry in Chronic Liver Diseases
2008; Elsevier BV; Volume: 6; Issue: 9 Linguagem: Inglês
10.1016/j.cgh.2008.02.038
ISSN1542-7714
AutoresGrace Lai‐Hung Wong, Vincent Wai‐Sun Wong, Paul Cheung‐Lung Choi, Anthony W.H. Chan, Richard Hoi–Leong Chum, Henry Kai–Wing Chan, Kenneth Ka–Ki Lau, Angel Mei‐Ling Chim, Karen Ka–Lam Yiu, Francis K.L. Chan, Joseph J.�Y. Sung, Henry Lik‐Yuen Chan,
Tópico(s)Hepatitis B Virus Studies
ResumoBackground & Aims: Liver stiffness measurement (LSM) with transient elastography (Fibroscan) can accurately diagnose advanced liver fibrosis, but its performance in early liver fibrosis is less satisfactory. We aimed to study the diagnostic performance of LSM for histologic bridging fibrosis and cirrhosis in various chronic liver diseases and to investigate the effects of liver fibrosis distribution on LSM. Methods: We prospectively studied consecutive patients with chronic liver diseases undergoing liver biopsy and transient elastography examinations. Morphometric analysis was performed to evaluate the distribution of liver fibrosis. Results: One hundred thirty-three patients (50% chronic hepatitis B, 14% chronic hepatitis C, and 24% nonalcoholic fatty liver disease) were studied. Morphometric analysis revealed a higher correlation between LSM and pericellular fibrosis (r = 0.43) than periportal (r = 0.21) or perivenular fibrosis (r = 0.25). Area under receiver operating characteristic curve (ROC) of LSM for bridging fibrosis was 0.87 (95% confidence interval, 0.81–0.93) and for cirrhosis was 0.89 (95% confidence interval, 0.83–0.94). Higher LSM was associated with higher serum ALT level. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM. The area under ROC curve of LSM for cirrhosis was lower among patients who had ALT above the upper limit of normal (0.86) as compared with that of patients with normal ALT levels (0.93, P = .03). Conclusions: Transient elastography can diagnose severe fibrosis because of its good correlation with pericellular fibrosis. Transient elastography might overestimate liver fibrosis when ALT is elevated. Background & Aims: Liver stiffness measurement (LSM) with transient elastography (Fibroscan) can accurately diagnose advanced liver fibrosis, but its performance in early liver fibrosis is less satisfactory. We aimed to study the diagnostic performance of LSM for histologic bridging fibrosis and cirrhosis in various chronic liver diseases and to investigate the effects of liver fibrosis distribution on LSM. Methods: We prospectively studied consecutive patients with chronic liver diseases undergoing liver biopsy and transient elastography examinations. Morphometric analysis was performed to evaluate the distribution of liver fibrosis. Results: One hundred thirty-three patients (50% chronic hepatitis B, 14% chronic hepatitis C, and 24% nonalcoholic fatty liver disease) were studied. Morphometric analysis revealed a higher correlation between LSM and pericellular fibrosis (r = 0.43) than periportal (r = 0.21) or perivenular fibrosis (r = 0.25). Area under receiver operating characteristic curve (ROC) of LSM for bridging fibrosis was 0.87 (95% confidence interval, 0.81–0.93) and for cirrhosis was 0.89 (95% confidence interval, 0.83–0.94). Higher LSM was associated with higher serum ALT level. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM. The area under ROC curve of LSM for cirrhosis was lower among patients who had ALT above the upper limit of normal (0.86) as compared with that of patients with normal ALT levels (0.93, P = .03). Conclusions: Transient elastography can diagnose severe fibrosis because of its good correlation with pericellular fibrosis. Transient elastography might overestimate liver fibrosis when ALT is elevated. See editorial on page 958. Progressive liver fibrosis is the natural wound-healing response to parenchymal injury in almost all chronic liver diseases. It might eventually result in liver cirrhosis and its various complications including hepatocellular carcinoma. Liver fibrosis might progress in the absence of elevated liver enzymes in nonalcoholic fatty liver disease (NAFLD).1Hui A.Y. Wong V.W. 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Van Hecke A. et al.Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics.Nat Med. 2004; 10: 429-434Crossref PubMed Scopus (375) Google Scholar were developed to diagnose significant fibrosis and cirrhosis with accuracies of 51%–84% and 79%–87%, respectively. However, most of these fibrosis markers have been evaluated only in chronic hepatitis C patients, and only a few of them have been reproduced by other investigators. Transient elastography (Fibroscan; Echosens, Paris, France) is a rapid, noninvasive, and reproducible method18Fraquelli M. Rigamonti C. Casazza G. et al.Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.Gut. 2007; 56: 968-973Crossref PubMed Scopus (693) Google Scholar of measuring liver stiffness. Liver stiffness measurement (LSM) has been shown to be a reliable tool to detect early liver cirrhosis in chronic hepatitis B,19Ganne-Carrié N. Ziol M. de Ledinghen V. et al.Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.Hepatology. 2006; 44: 1511-1517Crossref PubMed Scopus (432) Google Scholar, 20Foucher J. Chanteloup E. Vergniol J. et al.Diagnosis of cirrhosis by transient elastography (Fibroscan): a prospective study.Gut. 2006; 55: 403-408Crossref PubMed Scopus (1028) Google Scholar, 21Marcellin P. de Ledinghen B. Dhumeaux D. et al.Non-invasive assessment of liver fibrosis in chronic hepatitis B using Fibroscan.Hepatology. 2005; 42: 715A-716AGoogle Scholar chronic hepatitis C,20Foucher J. Chanteloup E. Vergniol J. et al.Diagnosis of cirrhosis by transient elastography (Fibroscan): a prospective study.Gut. 2006; 55: 403-408Crossref PubMed Scopus (1028) Google Scholar, 22Ziol M. handra-Luca A. 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Adhoute X. et al.Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate.Aliment Pharmacol Ther. 2006; 23: 1621-1628Crossref PubMed Scopus (71) Google Scholar The accuracy of LSM was also unaffected by hepatic steatosis.26Yoneda M. Fujita K. Inamori M. et al.Transient elastography in patients with nonalcoholic fatty liver disease (NAFLD).Gut. 2007; 56: 1330-1331Crossref PubMed Scopus (201) Google Scholar In most previous studies, LSM has very good correlation with advanced liver fibrosis but less satisfactory results with milder liver fibrosis because of uncertain reasons. Patients of the previous studies were mostly white, and only a small proportion had chronic hepatitis B. The use of transient elastography for white NAFLD patients might be limited by obesity, but its use in the leaner Chinese NAFLD patients has not been evaluated.27Kettaneh A. Marcellin P. Douvin C. et al.Features associated with success rate and performance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: a prospective study of 935 patients.J Hepatol. 2007; 46: 628-634Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar In this study, we aimed to assess the accuracy of LSM to detect severe liver fibrosis in a prospective cohort of patients with chronic liver diseases. To better understand the factors affecting the performance of LSM, we investigated the relationship of LSM and the distribution of liver fibrosis as determined by image and morphometric analysis, which is a reproducible and accurate tool to quantify fibrosis in different parts of the liver.28Hui A.Y. Liew C.T. Go M.Y. et al.Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B.Liver Int. 2004; 24: 611-618Crossref PubMed Scopus (48) Google Scholar We prospectively recruited consecutive adult patients with chronic liver diseases who were clinically indicated for liver biopsy examination in our hospital in 12 months from July 2006–June 2007. The indications of liver biopsy were identifying the etiology of liver disease and assessing the severity of liver fibrosis and inflammation before treatment. We excluded patients who were chronic drinkers (with regular consumption of at least 20 g of alcohol weekly), and who had decompensated liver disease, complications of liver cirrhosis, previous liver surgery, or liver transplantation. Viral hepatitis B and C infections were diagnosed by positive serology tests for serum HBsAg and anti-HCV antibodies, respectively. NAFLD was diagnosed by ultrasonography and histology after exclusion of other possible etiologies of fatty liver.29Chan H.L. de Silva H.J. Leung N.W. et al.How should we manage patients with non-alcoholic fatty liver disease in 2007?.J Gastroenterol Hepatol. 2007; 22: 801-808Crossref PubMed Scopus (73) Google Scholar Autoimmune liver disease and primary biliary cirrhosis were diagnosed with standard serologic and histologic criteria.30Krawitt E.L. Autoimmune hepatitis.N Engl J Med. 2006; 354: 54-66Crossref PubMed Scopus (708) Google Scholar, 31Kaplan M.M. Gershwin M.E. Primary biliary cirrhosis.N Engl J Med. 2005; 353: 1261-1273Crossref PubMed Scopus (1012) Google Scholar The study protocol was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee, and all patients gave written informed consent before being enrolled into the study. All patients received comprehensive clinical and laboratory assessment at the time of liver biopsy. Anthropometric parameters including body weight, body height, hip circumference, and waist circumference were measured. Overweight was defined as body mass index (BMI) ≥23 kg/m2 and obesity as BMI ≥25 kg/m2 according to the Asian and Chinese criteria.32World Health Organisation, International Association for the Study of Obesity, International Obesity Task ForceThe Asia-Pacific perspective: redefining obesity and its treatment. Health Communications, Sydney2000Google Scholar Metabolic syndrome was defined according to the International Diabetes Federation criteria.33International Diabetes Federation: The IDF consensus worldwide definition of the metabolic syndromehttp://www.idf.org/webdata/docs/Metabolic_syndrome_definition.pdfDate: 2007Google Scholar Percutaneous liver biopsy was performed by using the 18-gauge Temno needle (Cardinal Health, Dublin, OH). Liver histology was assessed by pathologists specialized in liver diseases (P.C.L.C., A.W.H.C.) without knowledge of the clinical data. Their interobserver agreement was 0.93 for fibrosis staging and 1.0 for the presence of stage 2 fibrosis or above. A liver sample was considered adequate if it was longer than 15 mm and contained 6 portal tracts or more. Liver biopsy specimens were prepared with hematoxylin-eosin stain, Masson trichrome stain, Prussian blue stain, reticulin stain, orcein stain, and periodic acid–Schiff stain for histologic assessment. For patients with viral hepatitis, liver fibrosis and necroinflammatory activity were evaluated semiquantitatively according to the METAVIR scoring system as follows34Bedossa P. Poynard T. An algorithm for grading of activity in chronic hepatitis C.Hepatology. 1996; 24: 289-293Crossref PubMed Google Scholar: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis and few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis. METAVIR activity score was defined as A0, none; A1, mild; A2, moderate; and A3, severe. The histologic grading and staging of NAFLD followed the criteria of Brunt et al35Brunt E.M. Janney C.G. Di Bisceglie A.M. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.Am J Gastroenterol. 1999; 94: 2467-2474Crossref PubMed Scopus (3105) Google Scholar as follows: macrovesicular steatosis was graded from 0–3, necroinflammatory activity was graded from 0–3, and fibrosis was staged from 0–4 (stage 0, absence of fibrosis; stage 1, pericellular or portal; stage 2, pericellular and portal/periportal; stage 3, septal or bridging fibrosis; and stage 4, cirrhosis). Cholestatic liver disease was staged according to the score of Ludwig et al.36Ludwig J. Dickson E.R. McDonald G.S. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).Virchows Arch A Pathol Pathol Anat. 1978; 379: 103-112Crossref Scopus (646) Google Scholar Hepatic steatosis was expressed as percentage of fat in the histology slides. Bridging fibrosis was defined as METAVIR or Brunt fibrosis score ≥3, and liver cirrhosis was defined as METAVIR or Brunt fibrosis score of 4. Cirrhosis was classified as macronodular if many nodules were greater than 3 mm in diameter.37Anthony P.P. Ishak K.G. Nayak N.C. et al.The morphology of cirrhosis: recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization.J Clin Pathol. 1978; 31: 395Crossref PubMed Scopus (387) Google Scholar LSM was performed within 4 weeks from the liver biopsy examination by using transient elastography according to the instructions and training provided by the manufacturer. Details of the technical background and examination procedure have been previously described.20Foucher J. Chanteloup E. Vergniol J. et al.Diagnosis of cirrhosis by transient elastography (Fibroscan): a prospective study.Gut. 2006; 55: 403-408Crossref PubMed Scopus (1028) Google Scholar Ten successful acquisitions were performed on each patient. The success rate was calculated as the ratio of the number of successful acquisitions over the total number of acquisitions. The median value was kept as representative of the liver elastic modulus. The LSM was considered reliable only if 10 successful acquisitions were obtained, with interquartile range ≤30% of LSM and success rate >60%. The liver stiffness was expressed in kilopascals (kPa). A higher kPa reflected a stiffer liver and more severe liver fibrosis. Three officially trained operators (G.L.H.W., A.M.L.C., and K.K.L.Y.) who had performed at least 50 measurements before this study were responsible to perform the LSM, because operators with this kind of experience were found to have the best success rate and reproducibility in LSM.18Fraquelli M. Rigamonti C. Casazza G. et al.Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.Gut. 2007; 56: 968-973Crossref PubMed Scopus (693) Google Scholar No treatment for the chronic liver disease was given during the 4-week period between liver biopsy examination and the LSM. Morphometric analysis was used for the quantitative assessment of fibrosis in the liver biopsy.28Hui A.Y. Liew C.T. Go M.Y. et al.Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B.Liver Int. 2004; 24: 611-618Crossref PubMed Scopus (48) Google Scholar Liver sections stained with 0.1% picrosirius red for collagen were subjected to morphometric analysis by 3 independent investigators (R.H.L.C., H.K.W.C., and K.K.K.L.) who were blind to the histologic score of the liver biopsies. We used a computerized image analysis system composed of a photomicroscope (Axioplan 2) and digital camera (Axiocam) (Carl Zeiss Microscopy, Oberkochen, Germany) and the Bioquant Nova Prime software (Bioquant Image Analysis Corporation, Nashville, TN; see Appendix for details). We determined the areas of collagen in different zones of the liver by morphometric analysis. The areas of fibrosis or collagen were quantified in 3 different zones in mm2: portal-periportal area (periportal), pericellular space (pericellular), and around the centrolobular venous area (perivenular). At least 5 periportal fields, 5 perivenular fields, and 15 random fields of pericellular were captured on digitalized images at a final magnification of 400×. Lumens, sinusoids, and any other parts of the liver tissue that contained no collagen were excluded from the measurement. The mean areas per periportal, pericellular field, and perivenular were calculated before further analyses. Twenty-five biopsy specimens of different fibrosis stages were randomly selected for morphometric analyses by all 3 investigators to assess interobserver agreement. Statistical analysis was performed by Statistical Package for Social Science (version 11.5; SPSS Inc, Chicago, IL). Continuous variables were expressed in mean ± standard deviation or median (range) as appropriate. Qualitative and quantitative differences between subgroups were analyzed with χ2 or Fisher exact test for categorical parameters as appropriate and Mann–Whitney test for continuous parameters. Linear regression analysis was used to identify factors associated with higher LSM. Interobserver agreement on morphometric analysis was evaluated by the intraclass correlation coefficient, which corresponded to the real agreement. Spearman rank correlation coefficient was used to analyze the correlations between morphometric scores and the histologic (METAVIR and Brunt) fibrosis scores. Pearson correlation coefficient was used to test the correlations between morphometric scores and LSM. Z values calculated with the formulas by Steiger38Steiger J.H. Tests for comparing elements of a correlation matrix.Psychol Bull. 1980; 87: 245-251Crossref Scopus (3338) Google Scholar were used to compare the correlation coefficients from the analyses between morphometric scores and LSM. The overall accuracy of LSM in diagnosing histologic bridging fibrosis and cirrhosis was calculated with the receiver operating characteristic (ROC) curve and its 95% confidence intervals (CIs). Areas under ROC were compared by the test of DeLong et al.39DeLong E.R. DeLong D.M. Clarke-Pearson D.L. Comparing the areas under two or more correlated receiver operating characteristic curves: a non-parametric approach.Biometrics. 1988; 44: 837-845Crossref PubMed Scopus (13934) Google Scholar All statistical tests were two-sided. Statistical significance was taken as P < .05. One hundred eighty-two patients underwent liver biopsy within the study period; 133 (73%) patients fulfilled the criteria for data analysis. Thirty-seven patients were excluded because of inadequate liver biopsy samples size (<1.5 cm and/or 23 kg/m2)124 (68%)89 (67%)35 (71%).56 Obesity (BMI >25 kg/m2)80 (44%)60 (45%)20 (41%).60 Metabolic syndrome46 (25%)36 (27%)10 (20%).36Biochemical Albumin (g/L)43 ± 443 ± 443 ± 5.82 Bilirubin (μmol/L)17 ± 4914 ± 1225 ± 93.20 Alkaline phosphatase (IU/L)96 ± 6391 ± 56110 ± 77.17 ALT (×ULN)1.4 ± 1.41.5 ± 1.61.3 ± 1.1.95Histology Length (mm)16 ± 317 ± 213 ± 4<.001 No. of portal tracts7 ± 37 ± 24 ± 2<.001 Steatosis (%)16 ± 2416 ± 2317 ± 26.18 Viral hepatitis patients No. of patients1158728 METAVIR activity score1 (0–3)1 (0–3)1 (0–3).99 METAVIR fibrosis score3 (0–4)3 (0–4)2 (0–4).09 F010 (9%)4 (5%)6 (21%) F113 (11%)9 (10%)4 (14%) F227 (24%)22 (25%)5 (18%) F321 (18%)17 (20%)4 (14%) F444 (38%)35 (40%)9 (32%) NAFLD patients No. of patients443410 Brunt NI score1 (0–2)0 (0–2)0 (0–2).20 Brunt fibrosis score1 (0–4)1 (0–4)1 (0–4).84 022 (50%)17 (50%)5 (50%) 19 (21%)7 (21%)2 (20%) 22 (4%)2 (6%)0 33 (7%)3 (8%)0 48 (18%)5 (15%)3 (30%) Bridging fibrosis83 (45%)63 (47%)20 (41%).27 Cirrhosis58 (32%)42 (32%)16 (33%).51 Macronodular cirrhosis39 (21%)32 (24%)7 (14%).32NI, necroinflammation.a Comparison was performed between study cases and excluded cases.b Etiologies of chronic liver diseases were classified as chronic hepatitis B, chronic hepatitis C, chronic hepatitis B and C coinfection, NAFLD, autoimmue hepatitis, primary biliary cirrhosis, and cholestatic liver disease. Other etiologies included hepatitis B and C coinfection, autoimmue hepatitis, primary biliary cirrhosis, and cholestatic liver disease. Open table in a new tab NI, necroinflammation. Overall, LSM ranged from 3.3–48.0 kPa (median, 7.7 kPa). The mean number of measurements per patient was 12 ± 3. A total of 170 of 182 (93%) patients had 10 successful acquisitions and a success rate of at least 60%, with median interquartile range of 15% (1%–30%). On morphometric analysis, the interobserver agreement was excellent, with intraclass correlation coefficients for pericellular, periportal, and perivenular fibrosis of 0.988, 0.990, and 0.993 respectively (all P < .001) among the 3 independent investigators. Overall, the correlation of LSM and pericellular fibrosis on morphometry (r = 0.43, P < .001; Figure 1A) was better than that for periportal fibrosis (r = 0.21, P = .026; Z value 2.2, P = .03; Figure 1B) and perivenular fibrosis (r = .25, P = .007; Z value 3.6, P < .001; Figure 1C) but not the overall fibrosis (r = .32, P= .001; Z value 1.6, P = .11). The correlation of LSM and pericellular fibrosis was also better in patients with more severe fibrosis (F3–4; r = .55, P < .001) than those with mild fibrosis (F0–2; r =0.02, P = .9; Z value 3.6, P < .001). Because pericellular fibrosis indicated more advanced fibrosis than periportal and perivenular fibrosis, we further analyzed the association of LSM with histologic bridging fibrosis and cirrhosis. Figure 2 shows the box plots of liver stiffness for each fibrosis stage. For viral hepatitis patients with severe fibrosis (F3–4) and cirrhosis (F4), median liver stiffness was 10.2 kPa (4.8–36.8 kPa) and 11.6 kPa (6–36.8 kPa), respectively. For NAFLD patients with severe fibrosis (Brunt stage 3–4) and cirrhosis (stage 4), median liver stiffness was 11.1 kPa (6.8–48 kPa) and 20.9 kPa (10.4–48 kPa), respectively. The area under the ROC curves of LSM for bridging fibrosis and cirrhosis were 0.87 (95% CI, 0.81–0.93; P < .001) and 0.89 (95% CI, 0.83–0.94; P < .001), respectively (Figure 3). The prediction of cirrhosis by LSM seemed better than that of bridging fibrosis, although it did not reach statistical significance (DeLong test, P = .24). On the basis of the LSM distribution according to fibrosis stage and ROC curves, a cutoff value of 8.4 kPa was associated with very high sensitivity (93%) and negative predictive value (96%) for cirrhosis (with specificity of 79% and positive predictive value of 67%). On the other hand, a LSM cutoff value of 13.4 kPa was associated with high specificity (95%) and positive predictive value (77%) for cirrhosis (with sensitivity of 41% and negative predictive value of 78%; Table 2).Figure 3ROC curves of LSMs for (A) bridging fibrosis (area under curve [AUC], 0.87; 95% CI, 0.81–0.93; P < .001) and (B) liver cirrhosis (AUC, 0.89; 95% CI, 0.83–0.94; P < .001).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Diagnostic Performances of LSM for Cirrhosis With Respect to Different LSM Cutoff Values and Serum ALT LevelsLSM cutoff values ALT8.4 kPa13.4 kPaAll<1× ULN≥1× ULNAll<1× ULN≥1× ULNNo. of patients13371621337162Sensitivity (%)939096412555Specificity (%)799263959693Positive predictive value (%)678258777180Negative predictive value (%)969696787779Diagnostic accuracy (%)839274777679Likelihood ratio for positive test67472324617
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