Role of MRI in Detection of Minimal Hepatic Encephalopathy

Hepatic Encephalopathy Clinical Trial

Official title:

Role of Magnetic Resonance Imaging in Detection of Minimal Hepatic Encephalopathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04131205
• Other study ID #: HepaticEncephalopathy
• Status: Recruiting
• Start date: June 1, 2019
• Est. completion date: June 1, 2023

Study information

• Verified date: October 2019
• Source: University Medical Centre Ljubljana
• Contact: Gasper Zupan, M.D.
• Phone: 0038615437826
• Email: gasper.zupan[@]mf.uni-lj.si
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Introduction Liver cirrhosis (LC) is irreversible fibrosis of the liver (1) and it remains a public health problem. One of the complications of the cirrhosis is hepatic encephalopathy (HE) which is defined as brain dysfunction caused by liver insufficiency. Pathophysiological mechanisms of HE are complex and multifactorial. Recognition of beginning stages of HE, such as minimal HE (mHE) is of most importance.

Objectives and originality of the project Diagnosis of mHE can be challenging, time-consuming and, at least to some extent, subjective. This project will assess the role of magnetic resonance (MR) in mHE diagnosis with emphasis on multimodal imaging technique. With advanced magnetic resonance (MR) techniques, in-vivo detection of intracellular water content, estimation pH and metabolites levels with millimolar concentrations can be easily performed. This will offer to explore possible pathophysiological mechanisms of HE and to evaluate the results from previous, studies that were mainly performed on animal models or cell cultures.

By our best knowledge, multimodal MR approach as the investigators propose in this application has not been yet performed. The investigators will use advanced MR techniques which are currently not available in the clinical setting and require multicenter collaboration.

Methods The investigators will include 10-20 patients of both genders with hyperammonemia and mHE and 10-20 patients of both genders with HE. Diagnosis of HE will be made based on results of validated neuropsychiatric test. Age-matched and gender-matched control group with no gastrointestinal, neurological or psychiatric complaints and normal levels of ammonia in the blood. Patients with mHE/HE will be included from outpatient clinic of the Department of gastroenterology, University Medical Centre (UMC) Ljubljana. Healthy controls (HC) will be invited to join via internet advertisement. Contraindications for HC will include gastrointestinal (emphasis on liver disease), neurological or psychiatric complaints. Grade of mHE/HE will be classified according to West-Haven (WH) classification. Patients with different degree of liver cirrhosis, which will be scored with the Child-Pugh (CP) score, and with no contraindications for MR (e.g. presence of metal in body) will be included. Blood levels of liver enzymes and ammonia will be measured in all participants. MR scanning will include: T1- and T2-weighted MR, MRS (MEGA-PRESS and PRESS) in two voxels: striatum and cerebellum. Location will be double-checked by voxel position screenshots. Analysis, with voxel-positioning error compensation will be performed in Gannet (www.gabamrs.com). Moreover, high resolution diffusion weighted imaging (DWI), diffusion kurtosis imaging (DKI), quantitative susceptibility mapping (QSM) will be performed in brain as well. Liver QSM will be executed to assess iron load.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: June 1, 2023
• Est. primary completion date: June 1, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Known liver disease/cirrhosis

Exclusion Criteria:

• Pregnancy, non compatible material with MRI

Related Conditions & MeSH terms

• Brain Diseases
• Hepatic Encephalopathy
• Liver Cirrhoses
• Liver Cirrhosis

Intervention

Diagnostic Test:
• Magnetic Resonance Imaging
We will assess the role of magnetic resonance (MR) in mHE diagnosis with emphasis on multimodal imaging technique

Locations

Country	Name	City	State
Slovenia	Department of Gastroenterology and Hepatology, University Medical Centre Ljubljana	Ljubljana

Sponsors (4)

Lead Sponsor	Collaborator
University Medical Centre Ljubljana	Johns Hopkins University, Medical University of Graz, University of Ljubljana, Faculty of Medicine

Country where clinical trial is conducted

Slovenia, 

References & Publications (30)

Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology. 2006 Oct;44(4):788-94. Review. — View Citation

American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014 Sep;61(3):642-59. doi: 10.1016/j.jhep.2014.05.042. Epub 2014 Jul 8. Review. Erratum in: J Hepatol. 2015 Oct;63(4):1055. — View Citation

Bartolic M, Vovk A, Šuput D. Effects of NH(4)CL application and removal on astrocytes and endothelial cells. Cell Mol Biol Lett. 2016 Aug 23;21:13. doi: 10.1186/s11658-016-0011-3. eCollection 2016. — View Citation

Binesh N, Huda A, Bugbee M, Gupta R, Rasgon N, Kumar A, Green M, Han S, Thomas MA. Adding another spectral dimension to 1H magnetic resonance spectroscopy of hepatic encephalopathy. J Magn Reson Imaging. 2005 Apr;21(4):398-405. — View Citation

Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013 Mar;58(3):593-608. doi: 10.1016/j.jhep.2012.12.005. Review. — View Citation

Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodés J. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999 May;30(5):890-5. — View Citation

Chavarria L, Alonso J, García-Martínez R, Simón-Talero M, Ventura-Cots M, Ramírez C, Torrens M, Vargas V, Rovira A, Córdoba J. Brain magnetic resonance spectroscopy in episodic hepatic encephalopathy. J Cereb Blood Flow Metab. 2013 Feb;33(2):272-7. doi: 10.1038/jcbfm.2012.173. Epub 2012 Nov 21. — View Citation

Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999 Feb;9(2):179-94. — View Citation

Elwir S, Rahimi RS. Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. J Clin Transl Hepatol. 2017 Jun 28;5(2):142-151. doi: 10.14218/JCTH.2016.00069. Epub 2017 May 4. Review. — View Citation

Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21. — View Citation

Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11050-5. — View Citation

Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002 Jan 31;33(3):341-55. — View Citation

Fischl B, Salat DH, van der Kouwe AJ, Makris N, Ségonne F, Quinn BT, Dale AM. Sequence-independent segmentation of magnetic resonance images. Neuroimage. 2004;23 Suppl 1:S69-84. — View Citation

Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999 Feb;9(2):195-207. — View Citation

Fischl B, Sereno MI, Tootell RB, Dale AM. High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp. 1999;8(4):272-84. — View Citation

Fischl B, van der Kouwe A, Destrieux C, Halgren E, Ségonne F, Salat DH, Busa E, Seidman LJ, Goldstein J, Kennedy D, Caviness V, Makris N, Rosen B, Dale AM. Automatically parcellating the human cerebral cortex. Cereb Cortex. 2004 Jan;14(1):11-22. — View Citation

Foerster BR, Conklin LS, Petrou M, Barker PB, Schwarz KB. Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy. AJNR Am J Neuroradiol. 2009 Sep;30(8):1610-3. doi: 10.3174/ajnr.A1652. Epub 2009 Jun 9. — View Citation

Ge PS, Runyon BA. Treatment of Patients with Cirrhosis. N Engl J Med. 2016 Aug 25;375(8):767-77. doi: 10.1056/NEJMra1504367. Review. — View Citation

Geissler A, Lock G, Fründ R, Held P, Hollerbach S, Andus T, Schölmerich J, Feuerbach S, Holstege A. Cerebral abnormalities in patients with cirrhosis detected by proton magnetic resonance spectroscopy and magnetic resonance imaging. Hepatology. 1997 Jan;25(1):48-54. — View Citation

Harris AD, Saleh MG, Edden RA. Edited (1) H magnetic resonance spectroscopy in vivo: Methods and metabolites. Magn Reson Med. 2017 Apr;77(4):1377-1389. doi: 10.1002/mrm.26619. Epub 2017 Feb 2. Review. — View Citation

Hassan EA, Abd El-Rehim AS, Seifeldein GS, Shehata GA. Minimal hepatic encephalopathy in patients with liver cirrhosis: magnetic resonance spectroscopic brain findings versus neuropsychological changes. Arab J Gastroenterol. 2014 Sep-Dec;15(3-4):108-13. doi: 10.1016/j.ajg.2014.09.003. Epub 2014 Nov 11. — View Citation

Häussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, Gerok W, Hennig J. Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology. 1994 Nov;107(5):1475-80. — View Citation

Laubenberger J, Häussinger D, Bayer S, Gufler H, Hennig J, Langer M. Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology. 1997 May;112(5):1610-6. — View Citation

Lee JH, Seo DW, Lee YS, Kim ST, Mun CW, Lim TH, Min YI, Suh DJ. Proton magnetic resonance spectroscopy (1H-MRS) findings for the brain in patients with liver cirrhosis reflect the hepatic functional reserve. Am J Gastroenterol. 1999 Aug;94(8):2206-13. — View Citation

Long LL, Li XR, Huang ZK, Jiang YM, Fu SX, Zheng W. Relationship between changes in brain MRI and (1)H-MRS, severity of chronic liver damage, and recovery after liver transplantation. Exp Biol Med (Maywood). 2009 Sep;234(9):1075-85. doi: 10.3181/0903-RM-118. Epub 2009 Jun 22. — View Citation

Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 2018 Feb;38 Suppl 1:2-6. doi: 10.1111/liv.13682. Review. — View Citation

Mechtcheriakov S, Schocke M, Kugener A, Graziadei IW, Mattedi M, Hinterhuber H, Vogel W, Marksteiner J. Chemical shift magnetic resonance spectroscopy of cingulate grey matter in patients with minimal hepatic encephalopathy. Neuroradiology. 2005 Jan;47(1):27-34. Epub 2005 Jan 18. — View Citation

Miese F, Kircheis G, Wittsack HJ, Wenserski F, Hemker J, Mödder U, Häussinger D, Cohnen M. 1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy. AJNR Am J Neuroradiol. 2006 May;27(5):1019-26. — View Citation

Ochoa-Sanchez R, Rose CF. Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease. J Clin Exp Hepatol. 2018 Sep;8(3):262-271. doi: 10.1016/j.jceh.2018.08.001. Epub 2018 Aug 18. Review. — View Citation

Oeltzschner G, Butz M, Baumgarten TJ, Hoogenboom N, Wittsack HJ, Schnitzler A. Low visual cortex GABA levels in hepatic encephalopathy: links to blood ammonia, critical flicker frequency, and brain osmolytes. Metab Brain Dis. 2015 Dec;30(6):1429-38. doi: 10.1007/s11011-015-9729-2. Epub 2015 Sep 11. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Structural and Functional Changes in Brain Structures with Magnetic Resonance Imaging	GABA levels and other neurotransmitters with respect to the tissue water signal and corrected for tissue composition.	2 hours