Transient elastography in chronic liver diseases of other etiologies

4 Post Meeting A.I.S.F. Unmet Clinical Needs in Hepatology: New and upcoming diagnostic tools" Transient elastography in chronic liver diseases of other etiologies Dr. Vincenza Calvaruso Gastroenterologia & Epatologia, Di.Bi.M.I.S., University of Palermo, Italy vcalvaruso@libero.it

Fibrosis in Chronic Liver Diseases Development of severe fibrosis and cirrhosis is a common outcome of chronic liver diseases The degree of liver fibrosis is important in the prognosis and management of patients with viral and non-viral liver disease There have been many efforts to develop noninvasive methods that can substitute liver biopsy in the measurement of liver fibrosis Transient elastography (TE) by Fibroscan is a noninvasive method for the assessment of liver fibrosis TE has high accuracy and reproducibility in predicting bridging fibrosis and cirrhosis in patients with HCV chronic hepatitis

Patients in which liver fibrosis assessment is clinically relevant, but routine liver biopsy is controversial Patients with Non-alcoholic fatty liver disease (NAFLD) and borderline ALT values Patients with metabolic syndrome and signs of liver disease Children with asymptomatic chronic liver disease Alcoholic liver disease (ALD) Patients with biliary liver disease Patients with Drug Induced Liver Injury (DILI) Thalassemia patients with and without HCV infection

Non-alcoholic fatty liver disease (NAFLD) NAFLD is one of the most common chronic liver diseases worldwide, with a prevalence of about 20%-30% Angulo, Hepatology 2010; Based on 13,369 examinations, liver stiffness measurements (LSM) are uninterpretable in nearly 20% of cases. The principal reasons are obesity and, particularly, increased waist circumference Casterà et al., Hepatology 2010;

LSM in viral and non viral liver diseases CHC n = 51 CHB n = 11 NAFLD n = 17 PBC n = 20 AIH n = 15 Obara et al.: J Gastroenterol 2008

Performance of TE in patients with HCV chronic hepatitis and non viral chronic liver disease Obara et al.: J Gastroenterol 2008

Diagnostic performance in predicting liver fibrosis (F 2) Obara et al.: J Gastroenterol 2008

Correlation between TE and histological features in 97 patients with NAFLD p = 0.1912 p = 0.0063 p < 0.001 Yoneda et al.: Dig. Liv. Dis 2008

TE correlates with histology in patients with NAFLD Liver stiffness Mild (F 1) Moderate (F 2) Severe (F 3) Cirrhosis (F = 4) Cut-off values(kpa) 5.9 6.7 9.8 17.5 Yoneda et al. Dig. Liv. Dis 2008 AUROC values 0.93 0.87 0.90 0.99

French Cohort (128 patients) Chinese Cohort (118 patients) Liver stiffness accuracy Moderate (F 2) Severe (F 3) Cirrhosis (F = 4) Cut-off values(kpa) 7.0 8.7 10.3 Liver stiffness was not affected by AUROC values 0.84 0.93 0.95 hepatic steatosis, necroinflammation, or body mass index Sensitivity 79.2 83.9 92.0 Specificity 75.9 83.2 87.8

TE failure and discordance results in patients with NAFLD 10.2% failure to obtain 10 valid LSM acquisitions Significant higher BMI (35.6 vs 28.0 kg/m2, P < 0.001) and waist circumference (114 vs 94 cm, P < 0.001) in patients who failed LSM acquisitions Discordance of at least two stages between TE and histology was observed in 33 (13.4%) patients By multivariate analysis, liver biopsy length less than 20 mm and F0-2 disease were associated with discordance Wong et al. Hepatology 2010

Algorithm for clinical practice Wong et al.: Hepatology 2010

Reliability of TE for the detection of fibrosis in NAFLD p = 0.001 Liver stiffness accuracy Cut-off values (kpa) (F 2) (F 3) (F = 4) 7.0 8.0 10.5 Sensitivity (%) 76 65 78 Specificity (%) 80 80 96 Diagnostic accuracy 78 70 80 In NAFLD, the BMI and AST were significant predictors of severe fibrosis whereas LSM was not significant in the regression model Gaia et al.: J Hepatol 2011

Misdiagnosis of the fibrotic stage assessed by TE in patients with chronic viral hepatitis or NAFLD Gaia et al.: J Hepatol 2011

Distribution of liver stiffness values according to the different stages of fibrosis in 169 NAFLD patients assessed by liver biopsy Liver stiffness accuracy (F 2) (F 3) Cut-off values (kpa) 7.25 8.75 Sensitivity (%) 69.1 75.8 Specificity (%) 70.5 77.9 AUROC 0.794 0.870 23 patients (13.6%) failed to obtain 10 valid LSM acquisitions They had higher BMI (35.7±6.3 versus 29.1±4.1 kg/m2, P < 0.001) No significantly different prevalence of significant and severe fibrosis Petta et al. submitted

False-positive and false negative cases of significant fibrosis by TE according to BMI Petta et al. submitted

False-positive and false negative cases of severe fibrosis by TE according to BMI Petta et al. submitted

Accuracy of TE for the Diagnosis of Fibrosis in Pediatric Nonalcoholic Steatohepatitis F 1 AUROC: 0.97 Cut-off: 5.1 kpa F 2 AUROC: 0.99 Cut-off: 7.4 kpa F 3 AUROC: 1.00 Cut-off: 10.2 kpa Nobili et al. Hepatology 2008

147 patients with ALD F 3 AUROC: 0.94 Cut-off: 11.6 kpa F = 4 AUROC: 0.97 Cut-off: 22.7 kpa

Sequential LSM analysis before and after normalization of AST in 50 patients with ALD during alcohol detoxification Mueller S et al. WJG 2010

Sequential LSM analysis before and after normalization of AST in 50 patients with ALD during alcohol detoxification Mueller S et al. WJG 2010

Assessment of Biliary Fibrosis by TE in Patients with PBC and PSC Corpechot, et al. Hepatology 2006

TE performance in Patients with PBC and PSC Liver stiffness accuracy Cut-off values (kpa) Sensitivity (%) (F 2) (F 3) (F = 4) 7.3 9.8 17.3 84 91 93 Specificity (%) 87 90 95 AUROC 0.92 0.95 0.96 Corpechot, et al. Hepatology 2006

TE to assess hepatic fibrosis in primary biliary cirrhosis F 3 AUROC: 0.86 Cut-off: 14.7 kpa Sensitivity: 56% Specificity: 100% F = 4 AUROC: 0.96 Cut-off: 15.6 kpa Sensitivity: 88% Specificity: 98% Gomez Dominguez et al. APT 2007

TE and iron overload in patients with thalassaemia major 56 patients (45 adults and 11 children) with β-thalassemia major and liver biopsy 23 HCV-RNA positive 30 HCV-RNA negative Di Marco V, Calvaruso V et al. BJH 2009

TE and iron overload in patients with thalassaemia major 115 patients with β-thalassemia major (TM) (59) or intermedia (TI) (56) underwent TE by Fibroscan Histologic data were obtained in 14 cases. Liver iron concentration was assessed by atomic absorption spectrometry and T2* magnetic resonance. Significantly higher value of TE In patients with TM than TI In the 4 patients who underwent liver biopsy, a significant positive correlation was observed between liver stiffness and fibrosis stage (r = 0.73, P = 0.003) Severe fibrosis is diagnosed with a sensitivity of 60% and a specificity of 89%, whereas cirrhosis is detected with a sensitivity of 100% and a specificity of 92% Fraquelli M et al American J of Hematol et al. 2010

LSM by TE predicts early recovery from acute hepatitis Variable HAV (11) HBV (34) HCV (23) DRUGS (20) P value Age (mean, SD) 33.1± 17.1 45.3 ± 15.4 48.3 ± 14.4 36.8± 18.8 N.S. Gender (% males) 6 (55%) 28 (82%) 17 (74%) 12 (60%) N.S. ALT (U/L) 1,222 ±1,117 2,131 ±1,459 1,083 ± 660 1,368 ± 1,428 0.115 Bilirubin (mg/dl) 3.01 ± 2,7 10.0 ± 7.0 4.4 ± 5.4 8.2 ± 8.4 0.211 GGT (IU/L) 206 ± 261 279 ± 443 360 ± 295 244 ± 162 0.758 Alc. Fosf. (IU/L) 179 146 158 153 PLT ( 236.234 ± 62.856 243,135±102,456 226,987 233,765± 84,987 INR 1.03 1.10 1.09 ± 0.16 1.08 N.S. Albumin (g/dl) 4.59 4.26 4.21 4.05 N.S. N.S. Liver Stiffness (kpa) 7.5 ± 2.8 16.9 ±11.1 12.9 ± 7.5 12.5 ± 6.4 0.042 Di Marco V, Calvaruso V et al, GUT, 2011

Kinetics of LSM during the clinical course of DILI Di Marco V, Calvaruso V et al, GUT, 2011

Predictors of early recovery (ALT normal at 4 th weeks) by logistic regression analysis in 88 patients with acute hepatitis Predictor Univariate Analysis OR (95%CI) p value Multivariate Analysis OR (95% CI) p value Age yrs Sex Male vs. female Etiology ALT U/L Bilirubin- Stiffness-kPa 1,001 (0,968-1,035) 0.941-1,408 (0,346-5,726) 0.632-1,244 (0,771, 2,008) 0.372-0,999 (0,998 1,000) 0.029 0,999 (0,998-1,000) 0.058 0,987 (0,904 1,078) 0.779-0,825 (0,706-0,964) 0.015 0,846 (0.729-0.981) 0.027 Di Marco V, Calvaruso V et al, GUT, 2011

TE in patients with chronic heart failure Fibroscan seems to be unreliable in patients with congestive heart failure TE assesed before and after recompensation in 10 patients with congestive heart failure. Median initial LSM: 40.7 kpa (suggested liver cirrhosis) After a recompensation LSM decreased in all 10 patients down to a median of 17.8kPa Millonig G et al. J Hepatol 2010 Among 24 patients with heart failure, median liver stiffness significantly decreased during hospitalization (p < 0.003). Colli A et al. Radiology 2010

LSM by TE does not correlate with liver and heart RMN T2* and left cardiac function in patients with thalassaemia major fibroscan fibroscan 22 20 18 16 14 12 10 8 6 4 2 0 5 10 15 20 25 22 20 fibroscan 18 16 14 12 10 8 6 4 2 0 10 20 30 40 50 T2fegato T2cuore 18 16 14 12 10 8 6 4 2 30 40 50 60 70 80 FE SX 22 P = 0.234 P = 0.331 P = 0.327 fibroscan 20 22 20 P = 0.185 18 16 14 12 10 8 6 4 2 0 20 40 60 80 100 v.telesistolico indicizzato sin (ml/m²) Calvaruso V, Borsellino Z et al.submitted

Correlation between TE and right cardiac function index in patients with thalassaemia major fibroscan 22 20 18 16 14 12 10 8 6 4 2 P = 0.05 22 20 18 16 14 12 10 8 6 4 2 P = 0.05 30 40 50 60 70 80 10 20 30 40 50 60 70 80 FE dx v._telesistolico_indicizzato_dx fibroscan TE values are higher in patients with lower right heart function These data suggest that TE could reflect an increase of central venous pressure. Calvaruso V, Borsellino Z et al. submitted

Conclusion 1: TE in NAFLD LSM is clinically useful in staging liver fibrosis in NAFLD LSM is not affected by steatosis and necroinflammation in NAFLD patients High BMI and visceral obesity are associated to TE invalid measurement The use of the recently introduced XL probe in obese patients may reduce the unreliability of the test Discordance observed between TE and histology is high in these patients TE achieves the best performance for the diagnosis of cirrhosis

Conclusion 2: TE in other etiologies In biliary disorders data are not sufficient to assess the real role of TE In patients with beta-thalassemia liver iron overload does not influence the LSM suggesting that TE is a reliable tool to assess liver fibrosis Interesting data are emerging on the influence of central venous pressure on LS