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Non-invasive estimation of HVPG by combined structural and hemodynamic evaluation of portal hypertension using quantitative magnetic resonance imaging
Accepted Manuscript Editorial Editorial: Non-invasive estimation of HVPG by combined structural and hemodynamic evaluation of portal hypertension using quantitative magnetic resonance imaging Sudhakar Kundapur Venkatesh, Rohit Loomba PII: DOI: Reference:
S0168-8278(16)30509-8 http://dx.doi.org/10.1016/j.jhep.2016.09.007 JHEPAT 6263
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
22 August 2016 14 September 2016
Please cite this article as: Venkatesh, S.K., Loomba, R., Editorial: Non-invasive estimation of HVPG by combined structural and hemodynamic evaluation of portal hypertension using quantitative magnetic resonance imaging, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.09.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Venkatesh et al.
Editorial: Non-invasive estimation of HVPG by combined structural and hemodynamic evaluation of portal hypertension using quantitative magnetic resonance imaging 1
Sudhakar Kundapur Venkatesh and Rohit Loomba 1
2,3
Department of Radiology, Mayo Clinic, Rochester, MN 55905
2
NAFLD Research Center, University of California, San Diego, La Jolla 92093 Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla 92093. 3
Corresponding author Sudhakar Kundapur Venkatesh Professor of Radiology Department of Radiology Mayo Clinic, 200 First Street SW, Rochester Minnesota 55905 Phone: +15072841728 Fax: +15072842405 Email: [email protected] Electronic word count: 1000 Number of figures and tables: 0 Conflicts of interest: None Financial Disclosure: None Author contribution Drafting of the manuscript: SKV, RL Critical revision of the manuscript for important intellectual content: SKV, RL Final approval of the manuscript: SKV, RL
1
Venkatesh et al.
Non-invasive quantitative assessment of portal hypertension is a major unmet need in the field of liver disease. Currently, hepatic venous pressure gradient (HVPG) is the gold standard for quantitative assessment of portal hypertension. HVPG of 6 mmHg or higher is considered diagnostic for the presence of portal hypertension. HVPG of 10 mm Hg or higher is considered diagnostic for the presence of clinically significant portal hypertension (CSPH). Higher the HVPG, greater the risk of incident variceal bleeding, hepatic decompensation, hepatocellular carcinoma, and liver related mortality. Therefore, HVPG is well-accepted as an important surrogate biomarker or endpoint for showing reduction in the risk of liver related mortality. Furthermore, it is now increasingly being utilized as a surrogate endpoint in the assessment of treatment response of anti-fibrotic therapies in patients with cirrhosis. However, HVPG is invasive and requires expertise in measuring the HVPG that may not be available in routine clinical setting. Therefore, non-invasive, quantitative and accurate estimation of HVPG will greatly advance the field and has been an important area of investigation. Several non-invasive approaches have been studied and these approaches have shown variable association in estimating HVPG. Imaging techniques are on the forefront for evaluation of HVPG. Simple techniques such as the Doppler ultrasound and computed tomography (CT) are limited by their poor sensitivity and reproducibility. In addition, CT has fallen out of favor due to the risk of exposure to ionizing radiation. Therefore, Magnetic resonance imaging (MRI) is emerging as the preferred imaging technique for chronic liver disease and portal hypertension because it provides anatomical, structural and quantitative information with specialized sequences and with better diagnostic test accuracy than ultrasound and CT and with no risk of exposure to ionizing radiation. Currently Elastography techniques are preferred non-invasive methods to evaluate liver fibrosis [1]. Previous studies with vibration controlled transient elastography (VCTE) [2, 3] have shown a significant correlation between liver stiffness measurements (LSM) with HVPG. However, the correlation is less striking in patients with CSPH,[2, 4] . Spleen stiffness is useful for prediction of HVPG and studies continue to emerge with variable results [5, 6]. Magnetic resonance Elastography (MRE) shows correlation of liver stiffness with HVPG [7] and spleen stiffness of >10kPa [8] can reliably predict CSPH. Recent data on 3D MRE is also emerging suggesting that it may even have higher diagnostic accuracy than 2D MRE for assessment of advanced fibrosis [9]. However, further multicenter studies are awaited to validate the reproducibility of 2D MRE and 3D MRE in assessment of portal hypertension. MRE is generally considered superior than ultrasound-based methods such as acoustic radiation forced imaging (ARFI) and VCTE [10, 11]. In this issue of Journal of Hepatology, Palaniyappan N, et al [12] conducted a welldesigned pilot study including 30 patients with chronic liver diseases using MRI-based methods for non-invasive assessment of portal hypertension. They demonstrated that combined quantitative information including liver structure and hemodynamic changes can be helpful in evaluating portal hypertension. Their study showed an excellent correlation between HVPG and liver T1 and splenic artery velocity. This correlation was present even in CSPH cohort. The authors then validated their results in a small cohort of 10 patients confirming the reproducibility of the results derived from the training cohort. An interesting outcome of the study was that the ELF score and LSM with VCTE did not correlate significantly with HVPG in patients with CSPH. This phenomenon of divergence between the serum based biomarker, ELF, and liver stiffness based imaging-biomarker, VCTE suggests that these methods are not able to capture all of the factors that may contribute to portal hypertension. It is plausible that VCTE is not good at predicting the contribution of
2
Venkatesh et al.
severity of the extra hepatic and splenoportal axis hemodynamic variability on portal hypertension. However, it is possible that the T1 relaxation time is likely to measure the effects of increased collagen content within the liver, leading to increased stiffness, a property assessed by Elastography techniques also. Moreover, the reason for a higher degree of correlation between Liver T1 and HVPG still remains to be mechanistically illustrated. Whether sinusoidal congestion leads to increased liver T1 remains to be confirmed but has important implications as this technique may be limited in cases of congestive hepatopathy and BuddChiari syndrome. The authors also did not study the effect of inflammation as recent publication from their group did demonstrate influence of inflammation and iron on liver T1 measurements [13]. The major advantage of application of the liver T1 relaxation assessment technique is that it does not require an additional hardware set up. Finally, it is plausible that T1 relaxation of the liver would provide additive information to MRE, and together, they would provide a more comprehensive or complementary assessment of CSPH and/or assessment of treatment response. Both methods are limited by general limitations of MR methods including MR scanner bore constraints, presence of metallic implants, claustrophobia and extreme iron overload. Although the authors claim that T1 mapping is performed with no breath-hold sequence, but respiratory triggered sequences require consistent breathing pattern. Studies in patients with advanced chronic liver disease who may have erratic breathing can result in lower diagnostic accuracy and may prolong scan times There is quite a bit of computation that needs to be done to derive the estimated HVPG including obtaining liver T1 values by drawing regions of interest (however the reproducibility is excellent), histogram analysis, obtaining cross-sectional area of splenic artery and computing the flow velocity required for the formula. This is in contrast to simple manual or automated drawing of region of interest on stiffness maps with elastography methods [14]. The excellent correlation of liver T1 alone with HVPG is promising for a single parameter to be evaluated thereby simplifying the process. These initial proof-of-concept results provide stimulus for further studies in this direction. Further multicenter studies are needed to validate these findings in order to establish the utility of Liver T1 relaxation in the assessment of CSPH detection as well as its role in the assessment of treatment response in anti-fibrotic trials.
References [1] Dulai PS, Sirlin CB, Loomba R. 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. [2] Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007;45:1290-1297. [3] Bureau C, Metivier S, Peron JM, Selves J, Robic MA, Gourraud PA, et al. Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease. Alimentary Pharmacology & Therapeutics 2008;27:1261-1268.
3
Venkatesh et al.
[4] Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. Journal of Hepatology 2012;56:696-703. [5] Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Takabatake H, et al. Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness. Radiology 2016;279:609-619. [6] Elkrief L, Rautou PE, Ronot M, Lambert S, Dioguardi Burgio M, Francoz C, et al. Prospective comparison of spleen and liver stiffness by using shear-wave and transient elastography for detection of portal hypertension in cirrhosis. Radiology 2015;275:589-598. [7] Ronot M, Lambert S, Elkrief L, Doblas S, Rautou PE, Castera L, et al. Assessment of portal hypertension and high-risk oesophageal varices with liver and spleen three-dimensional multifrequency MR elastography in liver cirrhosis. Eur Radiol 2014;24:1394-1402. [8] Talwalkar JA, Yin M, Venkatesh SK, Rossman PJ, Grimm RC, Manduca A, et al. Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension. American Journal of Roentgenology 2009;193:122-127. [9] Loomba R, Cui J, Wolfson T, Haufe W, Hooker J, Szeverenyi N, et al. Novel 3D Magnetic Resonance Elastography for the Noninvasive Diagnosis of Advanced Fibrosis in NAFLD: A Prospective Study. Am J Gastroenterol 2016;111:986-994. [10] Cui J, Heba E, Hernandez C, Haufe W, Hooker J, Andre MP, et al. Magnetic resonance elastography is superior to acoustic radiation force impulse for the Diagnosis of fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease: A prospective study. Hepatology 2016;63:453-461. [11] Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016;150:626-637.e627. [12] Palaniyappan N, Cox E, Bradley C, Scott R, Austin A, O'Neill R, et al. Non-invasive assessment of Portal Hypertension Using Quantitative Magnetic Resonance Imaging. J Hepatol 2016. [13] Hoad CL, Palaniyappan N, Kaye P, Chernova Y, James MW, Costigan C, et al. A study of T₁ relaxation time as a measure of liver fibrosis and the influence of confounding histological factors. NMR Biomed 2015;28:706-714. [14] Dzyubak B, Venkatesh SK, Manduca A, Glaser KJ, Ehman RL. Automated liver elasticity calculation for MR elastography. J Magn Reson Imaging 2016;43:1055-1063.
4
S0168-8278(16)30509-8 http://dx.doi.org/10.1016/j.jhep.2016.09.007 JHEPAT 6263
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
22 August 2016 14 September 2016
Please cite this article as: Venkatesh, S.K., Loomba, R., Editorial: Non-invasive estimation of HVPG by combined structural and hemodynamic evaluation of portal hypertension using quantitative magnetic resonance imaging, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.09.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Venkatesh et al.
Editorial: Non-invasive estimation of HVPG by combined structural and hemodynamic evaluation of portal hypertension using quantitative magnetic resonance imaging 1
Sudhakar Kundapur Venkatesh and Rohit Loomba 1
2,3
Department of Radiology, Mayo Clinic, Rochester, MN 55905
2
NAFLD Research Center, University of California, San Diego, La Jolla 92093 Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla 92093. 3
Corresponding author Sudhakar Kundapur Venkatesh Professor of Radiology Department of Radiology Mayo Clinic, 200 First Street SW, Rochester Minnesota 55905 Phone: +15072841728 Fax: +15072842405 Email: [email protected] Electronic word count: 1000 Number of figures and tables: 0 Conflicts of interest: None Financial Disclosure: None Author contribution Drafting of the manuscript: SKV, RL Critical revision of the manuscript for important intellectual content: SKV, RL Final approval of the manuscript: SKV, RL
1
Venkatesh et al.
Non-invasive quantitative assessment of portal hypertension is a major unmet need in the field of liver disease. Currently, hepatic venous pressure gradient (HVPG) is the gold standard for quantitative assessment of portal hypertension. HVPG of 6 mmHg or higher is considered diagnostic for the presence of portal hypertension. HVPG of 10 mm Hg or higher is considered diagnostic for the presence of clinically significant portal hypertension (CSPH). Higher the HVPG, greater the risk of incident variceal bleeding, hepatic decompensation, hepatocellular carcinoma, and liver related mortality. Therefore, HVPG is well-accepted as an important surrogate biomarker or endpoint for showing reduction in the risk of liver related mortality. Furthermore, it is now increasingly being utilized as a surrogate endpoint in the assessment of treatment response of anti-fibrotic therapies in patients with cirrhosis. However, HVPG is invasive and requires expertise in measuring the HVPG that may not be available in routine clinical setting. Therefore, non-invasive, quantitative and accurate estimation of HVPG will greatly advance the field and has been an important area of investigation. Several non-invasive approaches have been studied and these approaches have shown variable association in estimating HVPG. Imaging techniques are on the forefront for evaluation of HVPG. Simple techniques such as the Doppler ultrasound and computed tomography (CT) are limited by their poor sensitivity and reproducibility. In addition, CT has fallen out of favor due to the risk of exposure to ionizing radiation. Therefore, Magnetic resonance imaging (MRI) is emerging as the preferred imaging technique for chronic liver disease and portal hypertension because it provides anatomical, structural and quantitative information with specialized sequences and with better diagnostic test accuracy than ultrasound and CT and with no risk of exposure to ionizing radiation. Currently Elastography techniques are preferred non-invasive methods to evaluate liver fibrosis [1]. Previous studies with vibration controlled transient elastography (VCTE) [2, 3] have shown a significant correlation between liver stiffness measurements (LSM) with HVPG. However, the correlation is less striking in patients with CSPH,[2, 4] . Spleen stiffness is useful for prediction of HVPG and studies continue to emerge with variable results [5, 6]. Magnetic resonance Elastography (MRE) shows correlation of liver stiffness with HVPG [7] and spleen stiffness of >10kPa [8] can reliably predict CSPH. Recent data on 3D MRE is also emerging suggesting that it may even have higher diagnostic accuracy than 2D MRE for assessment of advanced fibrosis [9]. However, further multicenter studies are awaited to validate the reproducibility of 2D MRE and 3D MRE in assessment of portal hypertension. MRE is generally considered superior than ultrasound-based methods such as acoustic radiation forced imaging (ARFI) and VCTE [10, 11]. In this issue of Journal of Hepatology, Palaniyappan N, et al [12] conducted a welldesigned pilot study including 30 patients with chronic liver diseases using MRI-based methods for non-invasive assessment of portal hypertension. They demonstrated that combined quantitative information including liver structure and hemodynamic changes can be helpful in evaluating portal hypertension. Their study showed an excellent correlation between HVPG and liver T1 and splenic artery velocity. This correlation was present even in CSPH cohort. The authors then validated their results in a small cohort of 10 patients confirming the reproducibility of the results derived from the training cohort. An interesting outcome of the study was that the ELF score and LSM with VCTE did not correlate significantly with HVPG in patients with CSPH. This phenomenon of divergence between the serum based biomarker, ELF, and liver stiffness based imaging-biomarker, VCTE suggests that these methods are not able to capture all of the factors that may contribute to portal hypertension. It is plausible that VCTE is not good at predicting the contribution of
2
Venkatesh et al.
severity of the extra hepatic and splenoportal axis hemodynamic variability on portal hypertension. However, it is possible that the T1 relaxation time is likely to measure the effects of increased collagen content within the liver, leading to increased stiffness, a property assessed by Elastography techniques also. Moreover, the reason for a higher degree of correlation between Liver T1 and HVPG still remains to be mechanistically illustrated. Whether sinusoidal congestion leads to increased liver T1 remains to be confirmed but has important implications as this technique may be limited in cases of congestive hepatopathy and BuddChiari syndrome. The authors also did not study the effect of inflammation as recent publication from their group did demonstrate influence of inflammation and iron on liver T1 measurements [13]. The major advantage of application of the liver T1 relaxation assessment technique is that it does not require an additional hardware set up. Finally, it is plausible that T1 relaxation of the liver would provide additive information to MRE, and together, they would provide a more comprehensive or complementary assessment of CSPH and/or assessment of treatment response. Both methods are limited by general limitations of MR methods including MR scanner bore constraints, presence of metallic implants, claustrophobia and extreme iron overload. Although the authors claim that T1 mapping is performed with no breath-hold sequence, but respiratory triggered sequences require consistent breathing pattern. Studies in patients with advanced chronic liver disease who may have erratic breathing can result in lower diagnostic accuracy and may prolong scan times There is quite a bit of computation that needs to be done to derive the estimated HVPG including obtaining liver T1 values by drawing regions of interest (however the reproducibility is excellent), histogram analysis, obtaining cross-sectional area of splenic artery and computing the flow velocity required for the formula. This is in contrast to simple manual or automated drawing of region of interest on stiffness maps with elastography methods [14]. The excellent correlation of liver T1 alone with HVPG is promising for a single parameter to be evaluated thereby simplifying the process. These initial proof-of-concept results provide stimulus for further studies in this direction. Further multicenter studies are needed to validate these findings in order to establish the utility of Liver T1 relaxation in the assessment of CSPH detection as well as its role in the assessment of treatment response in anti-fibrotic trials.
References [1] Dulai PS, Sirlin CB, Loomba R. 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. [2] Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007;45:1290-1297. [3] Bureau C, Metivier S, Peron JM, Selves J, Robic MA, Gourraud PA, et al. Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease. Alimentary Pharmacology & Therapeutics 2008;27:1261-1268.
3
Venkatesh et al.
[4] Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. Journal of Hepatology 2012;56:696-703. [5] Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Takabatake H, et al. Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness. Radiology 2016;279:609-619. [6] Elkrief L, Rautou PE, Ronot M, Lambert S, Dioguardi Burgio M, Francoz C, et al. Prospective comparison of spleen and liver stiffness by using shear-wave and transient elastography for detection of portal hypertension in cirrhosis. Radiology 2015;275:589-598. [7] Ronot M, Lambert S, Elkrief L, Doblas S, Rautou PE, Castera L, et al. Assessment of portal hypertension and high-risk oesophageal varices with liver and spleen three-dimensional multifrequency MR elastography in liver cirrhosis. Eur Radiol 2014;24:1394-1402. [8] Talwalkar JA, Yin M, Venkatesh SK, Rossman PJ, Grimm RC, Manduca A, et al. Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension. American Journal of Roentgenology 2009;193:122-127. [9] Loomba R, Cui J, Wolfson T, Haufe W, Hooker J, Szeverenyi N, et al. Novel 3D Magnetic Resonance Elastography for the Noninvasive Diagnosis of Advanced Fibrosis in NAFLD: A Prospective Study. Am J Gastroenterol 2016;111:986-994. [10] Cui J, Heba E, Hernandez C, Haufe W, Hooker J, Andre MP, et al. Magnetic resonance elastography is superior to acoustic radiation force impulse for the Diagnosis of fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease: A prospective study. Hepatology 2016;63:453-461. [11] Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, et al. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016;150:626-637.e627. [12] Palaniyappan N, Cox E, Bradley C, Scott R, Austin A, O'Neill R, et al. Non-invasive assessment of Portal Hypertension Using Quantitative Magnetic Resonance Imaging. J Hepatol 2016. [13] Hoad CL, Palaniyappan N, Kaye P, Chernova Y, James MW, Costigan C, et al. A study of T₁ relaxation time as a measure of liver fibrosis and the influence of confounding histological factors. NMR Biomed 2015;28:706-714. [14] Dzyubak B, Venkatesh SK, Manduca A, Glaser KJ, Ehman RL. Automated liver elasticity calculation for MR elastography. J Magn Reson Imaging 2016;43:1055-1063.
4