- Email: [email protected]
Novel multiparametric magnetic resonance elastography (MRE) protocol accurately predicts NAS score for NASH diagnosis
POSTER PRESENTATIONS SP-72.0%) and for TE was 9.5 (SN-82.5%, SP-81.1%) for diagnosing advanced fibrosis.
in the multivariable logistic regression model. The only statistically significant factor was the iron overload ( p values: iron overload 0.006, genotype 0.966). Conclusions: The risk of liver fibrosis is associated with the iron overload in patients with TM. There is no additional independent impact of the genotype. Male gender increases the risk of liver fibrosis independent from iron overload. larger studies needed to confirm association. SAT-464 Novel multiparametric magnetic resonance elastography (MRE) protocol accurately predicts NAS score for NASH diagnosis A.M. Allen1, M. Yin2, S.K. Venkatesh2, T. Mounajjed3, T.A. Kellogg4, M.L. Kendrick4, T.J. McKenzie4, K. Glaser5, V.S. Shah1, R.L. Ehman2. 1 Gastroenterology and Hepatology; 2Radiology; 3Pathology; 4Surgery; 5 Mayo Clinic, Rochester, United States E-mail: [email protected]
Conclusions: Liver stiffness measurement by TE followed by Fib-4 has the best diagnostic characteristics for evaluating advanced liver fibrosis in NAFLD patients. The feasibility and affordability should determine the choice of non-invasive tests for assessment of advanced fibrosis in NAFLD patients. SAT-463 Risk of liver fibrosis in patients with Thalasemia major; a tertiary center experience A.A. Alomairi1, S.A. Albusafi2, M.K. Alkhabouri3, S.F. Daar4, H. Aldhuhli5. 1Internal Medicine; 2Gastroentrology; 3Hematology; 4 Thalasemia Unit Hematology; 5Radiology, SQUH, Aseeb, Oman E-mail: [email protected] Background and Aims: Transfusion dependant thalasemia major (TM) is associated with liver fibrosis. The aim of the study is to assess risk of liver fibrosis in patients with TM. Methods: 96 patients were included, All those patients underwent elastography to assess for significant liver fibrosis (cut of value of 7.8 KPa). The genotyping was done using ARMS-hot start-PCR technique and iron overload was assessed using the average serum ferritin in the 5 years prior to the liver fibrosis assessment. Association was tested using Chi-squared test and adjustment using multivariable logistic regression. Results: The median age was 26 years (Interquartile range [IQR]: 22– 30), 45% males. The median ALT, AST, albumin and total bilirubin were 30 U/L (IQR: 18–64), 30 U/L (IQR: 18–46), 46 g/L (IQR: 44–48) and 21 µmol/L (IQR: 14–32) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1293 µg/L (IQR: 753– 2715) and 6.7 mg/gdw (IQR: 3.5–16.1) respectively. The TM genotypes were homozygous IVS-I, 5 (G-C) in 39 patients, homozygous codon 44 (−C) in 19 patients, double heterozygous IVS-I, 5 (G-C)/25 bp deletion in 5 patients and others (≤3 patients each) in 25 patients . Hepatitis C and hepatitis B serology was positive in 37% and 1% of the patients, respectively. The proportion of patients with a significant fibrosis as assessed by elastography was 59%. In the multivariable logistic regression model with ferritin and gender, both the male gender (OR of 3.0, P value of 0.0188) and ferritin (OR of 1.0004, p value of 0.0036) were statistically significant independent predictors of liver fibrosis. The proportion of patients with fibrosis in the homozygous IVS-I, 5 (G-C) group was 58% compared to 52% in all other genotypes and the difference was not statistically significant (odds ratio of 1.3 with a p value of 0.6652). The impact of the genotype remained non-significant after adjustment of iron overload
Background and Aims: The lack of a reliable, noninvasive method to diagnose nonalcoholic steatohepatitis (NASH) remains a major unmet need in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance elastography (MRE) is the most accurate noninvasive biomarker of liver fibrosis. We aimed to determine the diagnostic performance of a multiparametric MRE protocol (the “Hepatogram”) for the detection of NAFLD activity score (NAS) components, using novel mechanical properties that detect early parenchymal viscoelastic changes in NASH. Methods: The model was developed in animal studies and validated in humans. In both models, multifrequency 3D MRE was used to assess mechanical properties that correlate with hepatocyte ballooning and inflammation, while MRI proton density fat fraction (MRI PDFF) was used to quantify steatosis. Liver biopsies were obtained for histologic grading of steatosis, lobular inflammation and ballooning, and NAS was calculated based on the NASH CRN criteria. Pairwise comparisons (nonparametric Dunn method for joint ranking) were performed for imaging parameters among different grades of inflammation, ballooning and steatosis. The imaging parameters were included into predictive regression models which were tested with ROC analyses using NAS score as a continuous output. Ceiling operations were used to predict NAS score for NASH classifications. Results: The preclinical model included 64 mice: 36 with NAFLD/ NASH (fed a fast food diet and fructose water) and 28 controls. The clinical model included 51 human subjects: 38 obese (22 NAFLD and 16 NASH) and 13 healthy volunteers. From the complex shear modulus output generated by MRE at multiple mechanical frequencies, the parameters that best correlated with individual NAS components were selected. The damping ratio (loss modulus/ storage modulus) correlated with lobular inflammation, while the complex shear modulus magnitude correlated with hepatocellular ballooning. The fat fraction obtained from MRI PDFF best correlated with steatosis ( p <0.05 for all parameters). These 3 parameters were fit into a generalized linear model which successfully distinguished each NAS score with excellent accuracy (AUROC >0.89 for all) Figure 1. Misclassifications in distinguishing steatohepatitis (NAS ≥3) from NAFLD (NAS <3) occurred in 2/64 mice and 3/51 human subjects. Conclusions: This preliminary data shows that the Hepatogram can accurately predict NAS score and represents a promising alternative to liver biopsy for NASH diagnosis and monitoring.
Journal of Hepatology 2017 vol. 66 | S543–S750
S659
POSTER PRESENTATIONS other populations. This cohort is being followed longitudinally with further data analysis planned to establish whether abnormalities are progressive and correlate with clinical end points of chronic liver disease. SAT-466 The clinical utility of non-invasive tests in cirrhosis: results of decision analysis modelling A. Majumdar1, S. Campos1, M. Pinzani1, E.A. Tsochatzis1. 1Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, United Kingdom E-mail: [email protected]
SAT-465 Acoustic radiation force imaging the Fontan liver – feasibility and reproducibility D. Zentner1, K. Phan1, R.N. Gibson2, S. Sood3, L. Grigg1, A.J. Nicoll4. 1 Cardiology Department; 2Department of Radiology; 3Department of Gastroenterology and Hepatology, Royal Melbourne Hospital; 4 Department of Gastroenterology, Eastern Health, Melbourne, Australia E-mail: [email protected] Background and Aims: Adults with a Fontan circulation may be at risk of developing liver fibrosis. Time since Fontan surgery is thought to be a risk factor, but how to monitor fibrosis progression remains uncertain. Biochemistry and imaging do not follow the same rules as in other liver injury. Most imaging modalities resemble cirrhosis and transient elastography (TE) readings are affected by raised venous pressures, so different thresholds need to be determined. Many are anticoagulated, and increased venous pressure makes biopsy high risk, yet remains the only way to confidently diagnose cirrhosis in this population. Our aim was to examine TE via Acoustic Radiation Force Imaging (ARFI) to determine its utility, and if left lobe readings may be more useful than standard right lobe readings. Methods: ARFI was performed in 33 adults (female = 20; aged 28 (22–32.5) years) with a Fontan circulation (atriopulmonary n = 16, lateral tunnel n = 2, extracardiac n = 15). ARFI was measured by 2 experienced sonographers, with 10 measures in the right lobe (RL) (n = 33) and in the left lobe (LL) (n = 21). Results: In these adults, a median (IQR) of 22 (15.5–27) years post Fontan operation, ARFI revealed (1) similar results (m/sec) for different liver lobes and sonographers (RL: 2.25 (1.62–2.94) and 2.04 (1.73–2.53); LL: 2.04 (1.74–2.93) and 2.54 (1.97–2.85); (2) acceptable interobserver variability (Bland Altman plot) between sonographers: mean difference 0.02 (limits of agreement: −0.5–0.5) (RL) and 0.04 (limits of agreement −0.3–0.4) (LL) with (3) acceptable readings (defined as interquartile range/median <0.3 m/s) obtained in the LL in 13 (62%) and 12 (57%) patients, and in the RL in 19 (56%) and 26 (79%) patients by the sonographers. There was no correlation with time since Fontan, and no difference in ARFI results between the AP and other Fontan types. A statistically significant difference was seen in ARFI between patients with and without nodularity on ultrasound ( p = 0.04). Conclusions: ARFI may be a screening measure of hepatic fibrosis in adults with a Fontan circulation. Results obtained in the different lobes are similar, suggesting that dual lobe assessment may not offer further clinical utility. The quality of readings appears less than in S660
Background and Aims: The performance of non-invasive tests (NITs) is usually expressed as statistical metrics (eg. AUROCs) that do not determine if a test is fit for clinical practice. No minimal performance criteria currently exist for the use of NITs as opposed to liver biopsy (LB). The aims of this study were to establish minimal diagnostic accuracy criteria for NITs to diagnose cirrhosis when compared to LB in terms of mortality and to determine the clinical utility of existing NITs in this scenario. Methods: A decision tree was constructed to determine the probability of death using LB or a NIT to diagnose cirrhosis in asymptomatic patients. Potential test outcomes were true/false positives and true/false negatives with different associated followup and mortality. Input data were from structured Medline and PubMed searches. LB sensitivity and specificity was fixed at 95% and 100% (no false positives) to reflect sampling variability. Pooled diagnostic accuracy for NITs were from a recent systematic review and meta-analysis. A hypothetical cohort of 10,000 patients was used with a time horizon of 2 years. Cirrhosis prevalences of 5%, 20% and 50% were tested. The minimal diagnostic accuracy for an NIT to diagnose cirrhosis where the mortality rate is equal to LB was termed MNIT. Decision curve analysis (DCA) was used to express the net benefit of using tests across a range of threshold probabilities (Pt). Pt is the chance of a correct diagnosis that a clinician/patient is willing to accept to undertake a test. A hospitalisation rate of 3% for LB was added to the DCA. Results: The performance of other NITs across prevalence is given in the table. Only transient elastography (TE) was fit for practice at a prevalence of 5%, but was suboptimal at higher cirrhosis prevalences. In the DCA (Figure), TE provided the highest net benefit at prevalence of 5%. At cirrhosis prevalence of 20% and 50%, the sensitivity and specificity of the MNIT was higher than that of TE and exceeded >90%. Conclusions: TE can be used as a screening tool to diagnose cirrhosis in a low prevalence of cirrhosis setting. NITs should be used with caution where the prevalence of cirrhosis is high.
Decision Tree Mortality (%) Cirrhosis Prevalence 5%
20%
50%
Test
Sensitivity (%)
Specificity (%)
NIT
LB
MNIT TE FIB-4 APRI MNIT TE FIB-4 APRI MNIT TE FIB-4 APRI
90 89 84 75 94 89 84 75 94 89 84 75
67 89 71 78 94 89 71 78 97 89 71 78
0.47 0.47 0.49 0.52 1.58 1.63 1.70 1.9 3.81 3.97 4.12 4.39
0.47 0.47 0.47 0.47 1.58 1.58 1.58 1.58 3.81 3.81 3.81 3.81
Journal of Hepatology 2017 vol. 66 | S543–S750
Fit for practice
Yes Yes No No Yes No No No Yes No No No
in the multivariable logistic regression model. The only statistically significant factor was the iron overload ( p values: iron overload 0.006, genotype 0.966). Conclusions: The risk of liver fibrosis is associated with the iron overload in patients with TM. There is no additional independent impact of the genotype. Male gender increases the risk of liver fibrosis independent from iron overload. larger studies needed to confirm association. SAT-464 Novel multiparametric magnetic resonance elastography (MRE) protocol accurately predicts NAS score for NASH diagnosis A.M. Allen1, M. Yin2, S.K. Venkatesh2, T. Mounajjed3, T.A. Kellogg4, M.L. Kendrick4, T.J. McKenzie4, K. Glaser5, V.S. Shah1, R.L. Ehman2. 1 Gastroenterology and Hepatology; 2Radiology; 3Pathology; 4Surgery; 5 Mayo Clinic, Rochester, United States E-mail: [email protected]
Conclusions: Liver stiffness measurement by TE followed by Fib-4 has the best diagnostic characteristics for evaluating advanced liver fibrosis in NAFLD patients. The feasibility and affordability should determine the choice of non-invasive tests for assessment of advanced fibrosis in NAFLD patients. SAT-463 Risk of liver fibrosis in patients with Thalasemia major; a tertiary center experience A.A. Alomairi1, S.A. Albusafi2, M.K. Alkhabouri3, S.F. Daar4, H. Aldhuhli5. 1Internal Medicine; 2Gastroentrology; 3Hematology; 4 Thalasemia Unit Hematology; 5Radiology, SQUH, Aseeb, Oman E-mail: [email protected] Background and Aims: Transfusion dependant thalasemia major (TM) is associated with liver fibrosis. The aim of the study is to assess risk of liver fibrosis in patients with TM. Methods: 96 patients were included, All those patients underwent elastography to assess for significant liver fibrosis (cut of value of 7.8 KPa). The genotyping was done using ARMS-hot start-PCR technique and iron overload was assessed using the average serum ferritin in the 5 years prior to the liver fibrosis assessment. Association was tested using Chi-squared test and adjustment using multivariable logistic regression. Results: The median age was 26 years (Interquartile range [IQR]: 22– 30), 45% males. The median ALT, AST, albumin and total bilirubin were 30 U/L (IQR: 18–64), 30 U/L (IQR: 18–46), 46 g/L (IQR: 44–48) and 21 µmol/L (IQR: 14–32) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1293 µg/L (IQR: 753– 2715) and 6.7 mg/gdw (IQR: 3.5–16.1) respectively. The TM genotypes were homozygous IVS-I, 5 (G-C) in 39 patients, homozygous codon 44 (−C) in 19 patients, double heterozygous IVS-I, 5 (G-C)/25 bp deletion in 5 patients and others (≤3 patients each) in 25 patients . Hepatitis C and hepatitis B serology was positive in 37% and 1% of the patients, respectively. The proportion of patients with a significant fibrosis as assessed by elastography was 59%. In the multivariable logistic regression model with ferritin and gender, both the male gender (OR of 3.0, P value of 0.0188) and ferritin (OR of 1.0004, p value of 0.0036) were statistically significant independent predictors of liver fibrosis. The proportion of patients with fibrosis in the homozygous IVS-I, 5 (G-C) group was 58% compared to 52% in all other genotypes and the difference was not statistically significant (odds ratio of 1.3 with a p value of 0.6652). The impact of the genotype remained non-significant after adjustment of iron overload
Background and Aims: The lack of a reliable, noninvasive method to diagnose nonalcoholic steatohepatitis (NASH) remains a major unmet need in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance elastography (MRE) is the most accurate noninvasive biomarker of liver fibrosis. We aimed to determine the diagnostic performance of a multiparametric MRE protocol (the “Hepatogram”) for the detection of NAFLD activity score (NAS) components, using novel mechanical properties that detect early parenchymal viscoelastic changes in NASH. Methods: The model was developed in animal studies and validated in humans. In both models, multifrequency 3D MRE was used to assess mechanical properties that correlate with hepatocyte ballooning and inflammation, while MRI proton density fat fraction (MRI PDFF) was used to quantify steatosis. Liver biopsies were obtained for histologic grading of steatosis, lobular inflammation and ballooning, and NAS was calculated based on the NASH CRN criteria. Pairwise comparisons (nonparametric Dunn method for joint ranking) were performed for imaging parameters among different grades of inflammation, ballooning and steatosis. The imaging parameters were included into predictive regression models which were tested with ROC analyses using NAS score as a continuous output. Ceiling operations were used to predict NAS score for NASH classifications. Results: The preclinical model included 64 mice: 36 with NAFLD/ NASH (fed a fast food diet and fructose water) and 28 controls. The clinical model included 51 human subjects: 38 obese (22 NAFLD and 16 NASH) and 13 healthy volunteers. From the complex shear modulus output generated by MRE at multiple mechanical frequencies, the parameters that best correlated with individual NAS components were selected. The damping ratio (loss modulus/ storage modulus) correlated with lobular inflammation, while the complex shear modulus magnitude correlated with hepatocellular ballooning. The fat fraction obtained from MRI PDFF best correlated with steatosis ( p <0.05 for all parameters). These 3 parameters were fit into a generalized linear model which successfully distinguished each NAS score with excellent accuracy (AUROC >0.89 for all) Figure 1. Misclassifications in distinguishing steatohepatitis (NAS ≥3) from NAFLD (NAS <3) occurred in 2/64 mice and 3/51 human subjects. Conclusions: This preliminary data shows that the Hepatogram can accurately predict NAS score and represents a promising alternative to liver biopsy for NASH diagnosis and monitoring.
Journal of Hepatology 2017 vol. 66 | S543–S750
S659
POSTER PRESENTATIONS other populations. This cohort is being followed longitudinally with further data analysis planned to establish whether abnormalities are progressive and correlate with clinical end points of chronic liver disease. SAT-466 The clinical utility of non-invasive tests in cirrhosis: results of decision analysis modelling A. Majumdar1, S. Campos1, M. Pinzani1, E.A. Tsochatzis1. 1Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, United Kingdom E-mail: [email protected]
SAT-465 Acoustic radiation force imaging the Fontan liver – feasibility and reproducibility D. Zentner1, K. Phan1, R.N. Gibson2, S. Sood3, L. Grigg1, A.J. Nicoll4. 1 Cardiology Department; 2Department of Radiology; 3Department of Gastroenterology and Hepatology, Royal Melbourne Hospital; 4 Department of Gastroenterology, Eastern Health, Melbourne, Australia E-mail: [email protected] Background and Aims: Adults with a Fontan circulation may be at risk of developing liver fibrosis. Time since Fontan surgery is thought to be a risk factor, but how to monitor fibrosis progression remains uncertain. Biochemistry and imaging do not follow the same rules as in other liver injury. Most imaging modalities resemble cirrhosis and transient elastography (TE) readings are affected by raised venous pressures, so different thresholds need to be determined. Many are anticoagulated, and increased venous pressure makes biopsy high risk, yet remains the only way to confidently diagnose cirrhosis in this population. Our aim was to examine TE via Acoustic Radiation Force Imaging (ARFI) to determine its utility, and if left lobe readings may be more useful than standard right lobe readings. Methods: ARFI was performed in 33 adults (female = 20; aged 28 (22–32.5) years) with a Fontan circulation (atriopulmonary n = 16, lateral tunnel n = 2, extracardiac n = 15). ARFI was measured by 2 experienced sonographers, with 10 measures in the right lobe (RL) (n = 33) and in the left lobe (LL) (n = 21). Results: In these adults, a median (IQR) of 22 (15.5–27) years post Fontan operation, ARFI revealed (1) similar results (m/sec) for different liver lobes and sonographers (RL: 2.25 (1.62–2.94) and 2.04 (1.73–2.53); LL: 2.04 (1.74–2.93) and 2.54 (1.97–2.85); (2) acceptable interobserver variability (Bland Altman plot) between sonographers: mean difference 0.02 (limits of agreement: −0.5–0.5) (RL) and 0.04 (limits of agreement −0.3–0.4) (LL) with (3) acceptable readings (defined as interquartile range/median <0.3 m/s) obtained in the LL in 13 (62%) and 12 (57%) patients, and in the RL in 19 (56%) and 26 (79%) patients by the sonographers. There was no correlation with time since Fontan, and no difference in ARFI results between the AP and other Fontan types. A statistically significant difference was seen in ARFI between patients with and without nodularity on ultrasound ( p = 0.04). Conclusions: ARFI may be a screening measure of hepatic fibrosis in adults with a Fontan circulation. Results obtained in the different lobes are similar, suggesting that dual lobe assessment may not offer further clinical utility. The quality of readings appears less than in S660
Background and Aims: The performance of non-invasive tests (NITs) is usually expressed as statistical metrics (eg. AUROCs) that do not determine if a test is fit for clinical practice. No minimal performance criteria currently exist for the use of NITs as opposed to liver biopsy (LB). The aims of this study were to establish minimal diagnostic accuracy criteria for NITs to diagnose cirrhosis when compared to LB in terms of mortality and to determine the clinical utility of existing NITs in this scenario. Methods: A decision tree was constructed to determine the probability of death using LB or a NIT to diagnose cirrhosis in asymptomatic patients. Potential test outcomes were true/false positives and true/false negatives with different associated followup and mortality. Input data were from structured Medline and PubMed searches. LB sensitivity and specificity was fixed at 95% and 100% (no false positives) to reflect sampling variability. Pooled diagnostic accuracy for NITs were from a recent systematic review and meta-analysis. A hypothetical cohort of 10,000 patients was used with a time horizon of 2 years. Cirrhosis prevalences of 5%, 20% and 50% were tested. The minimal diagnostic accuracy for an NIT to diagnose cirrhosis where the mortality rate is equal to LB was termed MNIT. Decision curve analysis (DCA) was used to express the net benefit of using tests across a range of threshold probabilities (Pt). Pt is the chance of a correct diagnosis that a clinician/patient is willing to accept to undertake a test. A hospitalisation rate of 3% for LB was added to the DCA. Results: The performance of other NITs across prevalence is given in the table. Only transient elastography (TE) was fit for practice at a prevalence of 5%, but was suboptimal at higher cirrhosis prevalences. In the DCA (Figure), TE provided the highest net benefit at prevalence of 5%. At cirrhosis prevalence of 20% and 50%, the sensitivity and specificity of the MNIT was higher than that of TE and exceeded >90%. Conclusions: TE can be used as a screening tool to diagnose cirrhosis in a low prevalence of cirrhosis setting. NITs should be used with caution where the prevalence of cirrhosis is high.
Decision Tree Mortality (%) Cirrhosis Prevalence 5%
20%
50%
Test
Sensitivity (%)
Specificity (%)
NIT
LB
MNIT TE FIB-4 APRI MNIT TE FIB-4 APRI MNIT TE FIB-4 APRI
90 89 84 75 94 89 84 75 94 89 84 75
67 89 71 78 94 89 71 78 97 89 71 78
0.47 0.47 0.49 0.52 1.58 1.63 1.70 1.9 3.81 3.97 4.12 4.39
0.47 0.47 0.47 0.47 1.58 1.58 1.58 1.58 3.81 3.81 3.81 3.81
Journal of Hepatology 2017 vol. 66 | S543–S750
Fit for practice
Yes Yes No No Yes No No No Yes No No No