Patent Application: US-201515302693-A

Abstract:
the present invention relates to methods for assessing or obtaining an indication of vascular pressure associated with organs or visceral tissues of the body by using mri imaging methods . the invention particularly relates to methods for assessing or obtaining an indication of portal hypertension using magnetic resonance t1 , or t1 and t2 * relaxometry , and t1 , t2 and / or t2 * mapping of the liver or spleen .

Description:
the present invention is further illustrated by the following examples , in which parts and percentages are by weight and degrees are celsius , unless otherwise stated . it should be understood that these examples , while indicating preferred embodiments of the invention , are given by way of illustration only . from the above discussion and these examples , one skilled in the art can ascertain the essential characteristics of this invention , and without departing from the spirit and scope thereof , can make various changes and modifications of the invention to adapt it to various usages and conditions . thus , various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description . such modifications are also intended to fall within the scope of the appended claims . the disclosure of each reference set forth herein is incorporated herein by reference in its entirety . liver and spleen t1 and t2 * mapping using mri can help in the evaluation of portal pressure the accumulation of liver fibrosis leads to increased hepatic vascular resistance and portal hypertension . once portal hypertension is established in the context of liver disease , the patient is at risk of complication including , variceal bleeding , ascites , encephalopathy and renal dysfunction . furthermore the degree of portal hypertension has important prognostic implications in many clinical situations including alcoholic hepatitis , ( rincon et al . ( 2007 )), liver cirrhosis , ( ripoll et al . ( 2005 )) and recent variceal bleeding ( patch et al . ( 1999 )). portal pressure is usually assessed by measuring the hepatic vein pressure gradient ( hvpg ), which is invasive , costly and requires high expertise . non invasive ways to assess portal hypertension have the potential to revolutionise the care of patients with liver disease as they would allow widespread use and repeated measurements to assess the progression / regression of portal hypertension over time . a novel mri technique has been developed for imaging the liver and spleen based on the following hypothesis : 1 . the spleen parenchyma undergoes changes which may be assessed using mri ( t1 and t2 * mapping ) and which may indicate the severity of portal hypertension . 2 . the severity of liver fibrosis as measured by liver t1 mapping would reflect the severity of portal hypertension . a prospective study was conducted to assess the mr method in the evaluation of patients with portal hypertension due to chronic liver disease . the designated reference standard was the hepatic vein pressure gradient . patients with suspected liver cirrhosis who were due to have a liver biopsy as part of their clinical care were invited to have their biopsy through the trans - jugular route with portal pressure assessment at the time of the biopsy . patients with portal vein thrombosis and with contra - indications to mr scanning were excluded . eleven patients were recruited in the study period ( july 2013 - march 2014 ). the patients attended for an mri scan prior to their biopsy . all mr scans were performed in oxford , uk , with the patient lying supine in a 3 tesla system ( tim trio , siemens healthcare , germany ). patients attended for their scans having fasted for at least 4 hours . transverse t1 and t2 * maps of the abdomen were acquired and t1 and t2 * measurements were documented for the liver and spleen . a t1 relaxation time map was acquired using the shortened modified look locker inversion recovery ( shmolli ) sequence ( piechnik et al , j cardiovasc magn reson ) in a transverse plane through the liver and the spleen . a subject - dependent frequency adjustment was carried out during end - expiration . the shmolli sequence samples the t1 recovery curve using single - shot steady state free precession ( ssfp ) acquisitions using the following parameters : tr 2 . 14 ms , te 1 . 07 ms , flip angle of 35 °, field - of - view optimised per patient , acquisition matrix 192 × 134 − 160 , depending on patient , with grappa acceleration of 2 with 24 reference lines , yielding a typical interpolated voxel size 0 . 9 × 0 . 9 × 8 mm . images were acquired 200 ms after the ecg r - wave and the total time for each ssfp acquisition between 169 and 197 ms , depending on the number of phase encoding steps . the variable acquisition parameters fall in the ranges used in myocardial t1 mapping at 1 . 5 t , with associated inter - individual coefficient of variation for normal myocardial t1 of 2 . 2 %, ( piechnik et al , j cardiovasc magn reson ) well within the inter - subject coefficient of variation measured in normal volunteers here of 7 %. a multi - gradient - echo acquisition with rf spoiling is used to calculate a t2 * map of the liver . the same field - of - view as in the t1 mapping sequence is used , with a matrix size of 192 × 128 − 160 , depending on patient , slice thickness of 3 mm and 2 × grappa acceleration , with the same 200 ms delay after the r - wave before acquisition . the image is acquired in nine segments with a tr of 26 . 5 ms and flip angle of 20 °. echo times are selected as far as possible such that the signals from fat and water are in phase ( te = 2 . 46 , 7 . 38 , 12 . 30 , 17 . 22 and 22 . 14 ms ). fat - saturation and a double - inversion - recovery black blood preparation are used . a single region of interest ( roi ) was selected for each patient . there were 4 considerations in the choice of the roi : ( a ) as each acquisition generates an r 2 map for the fit of signal intensity to the exponential recovery curve the roi was chosen in an area where r 2 was ≧ 99 % ( which was the case in all patients ), ( b ) the roi was placed approximately halfway between the porta hepatis and the liver surface in order to avoid interference from the fluid filled structures in the porta hepatis and subcutaneous tissue or air close to the liver surface , ( c ) the roi was placed so as to avoid visible bile ducts and blood vessels , ( d ) the roi was placed in an area that corresponded to good quality images in the t2 * map in order to allow t1 and t2 * quantification in the same roi . fig1 illustrates the process of choosing an roi for the liver . the choice of the roi for the spleen followed the same principles as described above for the liver . the roi placement in the spleen was less complicated as the spleen is smaller , and more homogeneous than the liver . it also has no blood vessels running through its parenchyma and the step of avoiding blood vessels and bile ducts as described above for the liver ( step ( d ) above ) did not apply to the spleen . data were analysed by physicians blinded to the clinical information , using software tools available on the scanner console . for each patient one roi was selected for the liver and one roi for the spleen and mean t1 and t2 * were recorded for each . the assessment of the portal pressures was performed by a consultant interventional radiologist specialising in hepatobiliary procedures . the procedures were carried out with the patient in the supine position , under conscious sedation , after an overnight fast . after injection of local anaesthetic in the skin , a vascular catheter was inserted through an introducer into the right internal jugular vein under ultrasound guidance . this catheter was advanced into the right atrium and then the hepatic vein to measure the right atrial pressure and free hepatic vein pressure ( fhvp ) respectively . the catheter was then further advanced into the wedged position where the hepatic wedge pressure ( hwp ) was taken . the hepatic vein pressure gradient was calculated as the difference between the fhvp and the hwp . the hepatic vein pressure gradient was used to classify portal hypertension according to this schema : hvpg & lt ; 5 mmhg : no portal hypertension , hvpg 6 - 9 mmhg : pre - clinical portal hypertension , hvpg & gt ; iommhg : clinically significant portal hypertension , hvpg & gt ; 12 mmhg : severe portal hypertension pearson &# 39 ; s correlation and linear regression analysis was used to check for associations between variables . summary data for each of the hvpg categories were calculated and the mann whitney test was used to test for differences between the groups . we found a highly significant association both between the hvpg ( r = 0 . 83 ; p = 0 . 003 , r 2 = 0 . 69 ) and the hwp ( r = 0 . 88 ; p = 0 . 0009 ; r 2 = 0 . 77 ) and the spleen t1 relaxation time ( fig2 ). significant differences in the spleen t2 * were found between those patients with a hvpg & gt ;“ 10 mmhg ( median 37 . 2 ms ; iqr 30 . 2 - 76 . 2 ) and those with a hvpg & lt ; 10 mmhg ( median 22 . 9 ms ; iqr 14 . 6 - 24 . 5 ; p = 0 . 036 ; fig3 ). we found a statistically significant association both between the hvpg ( r = 0 . 63 ; p = 0 . 049 , r 2 = 0 . 40 ) and the hwp ( r = 0 . 68 ; p = 0 . 029 ; r 2 = 0 . 47 ) and the liver t1 relaxation time ( fig4 ). spleen t1 and t2 * mapping can be used to help in the assessment of liver fibrosis . changes in the severity of liver disease can result in structural and other changes in the spleen . this is particularly true for the late stages of liver disease , when portal hypertension is established . the spleen becomes engorged with portal venous blood and can be enlarged . this can be picked up on clinical examination or by using routine ultrasound scans . however , it is not known if the spleen undergoes any changes in the early stages of liver fibrosis . we hypothesised that our mr techniques for measuring spleen t1 and t2 * are very sensitive and may be able to detect early changes in the spleen that occur before portal hypertension is established . a prospective study of a new diagnostic mr method to evaluate the severity of liver fibrosis was conducted . the designated reference standard was histological assessment of liver fibrosis . from march 2011 to march 2014 , patients referred for liver biopsy in oxford were invited to take part in the study . patients with contraindications for mr scanning and patients that were found to have an increased amount of iron in their spleen were excluded . a patient was considered to have an increased spleen iron if the measured t2 * value was less than 19 ms . patients attended for an mri scan prior to their liver biopsy . the mri procedure for the acquisition and recording of liver t1 and t2 * and spleen t1 and t2 * is the same as described in example 1 . in addition , an algorithm was used to correct the liver t1 values for the amount of iron present to produce the corrected t1 metric ( ct1 ; banerjee et al , j hepatol ). the ishak score ( ishak et al , j hepatol ) was used for the histological assessment of liver fibrosis . in this score fibrosis is scored on a scale from 0 ( no fibrosis ) to 6 ( severe fibrosis ; cirrhosis ). in clinical practice patients can be subdivided into 3 groups according to their ishak score . ( ishak 0 - 2 : no or mild fibrosis ; ishak 3 - 4 : moderate fibrosis ; ishak 5 - 6 advanced fibrosis ). spearman &# 39 ; s correlation coefficient was used to test for associations between the ishak stages and spleen t1 and the sum of spleen t1 and liver ct1 . one way analysis of variance ( anova ) with bonferroni &# 39 ; s correction was used to test for differences between the spleen t1 and spleen t2 * of those with ishak 0 - 2 , ishak 3 - 4 and ishak 5 - 6 . in patients with a low amount of iron in their spleen ( spleen t2 *& gt ; 19 ms ), there was a highly significant association between the spleen t1 and the degree of liver fibrosis assessed by histology ( r s = 0 . 69 ; p & lt ; 0 . 000 ; fig5 ). the mean spleen t1 values of patients with severe ( ishak 5 - 6 ), moderate ( ishak 3 - 4 ) and no or mild fibrosis ( ishak 0 - 2 ) were 1439 ms , 1352 ms and 1278 ms respectively . one way anova with bonferroni &# 39 ; s correction showed significant differences between ishak 5 - 6 and ishak 0 - 2 and ishak 3 - 4 ( fig6 and table 1 ). there was a highly significant correlation between the sum of spleen t1 and liver ct1 with the ishak fibrosis score ( r s = 0 . 72 ; p & lt ; 0 . 0001 , fig7 ). the correlation of the sum was stronger than the correlation of spleen t1 and ishak score ( r s = 0 . 69 ; p & lt ; 0 . 0001 ; fig5 ) or between liver ct1 and ishak ( r s = 0 . 61 , p & lt ; 0 . 0001 ; data not shown ). liver vascular congestion can result from liver venous outflow tract obstruction or from any cause of increased central venous pressure ( e . g . right heart failure , congestive heart failure , constrictive pericarditis , obstruction in the intra - thoracic inferior vena cava ). vascular congestion in the liver manifest as liver sinusoidal dilatation which is detected on liver biopsies . we hypothesised that liver t1 and corrected t1 would be higher in patients who have sinusoidal dilatation on liver biopsies , compared to patients without . pairs of patients with the same ishak stage and the same underlying liver disease aetiology were identified from the cohort of patients in the studies of examples 1 and 2 . the liver t1 and corrected t1 values of the patient pairs were compared to establish if the presence of sinusoidal dilatation had any impact on the observed measurements . we found that the presence of sinusoidal dilatation leads to an increase in the liver t1 and corrected t1 . fig8 illustrates a comparison between two patients with hepatitis c and mild fibrosis ( ishak 1 ), where one doesn &# 39 ; t have sinusoidal dilatation ( top row , panels a and b ) the other does ( bottom row , panels d and c ). fig9 illustrates the same situation in two patients with primary sclerosing cholangitis . in both scenarios , the patient where sinusoidal dilatation is present has higher liver t1 and ct1 measures . example of how to assess central venous pressure using imaging of the liver the liver is directly connected to the heart via the hepatic veins and the inferior vena cava . any pathological process that leads to an increased central venous pressure can result in increased liver vascular congestion . increases in central venous pressure can be seen in right heart failure , congestive heart failure , constrictive pericarditis and congenital heart disease . other causes of liver vascular congestion include liver veno - occlusive disease and venous outflow tract obstruction . over the long term , liver vascular congestion from any cause can lead to the accumulation of fibrosis and the development of cirrhosis and liver failure . a way of assessing liver congestion non - invasively would allow clinicians to monitor both the progression of the underlying condition causing liver congestion ( e . g . right heart failure ), but also the direct effect on the liver . liver t1 and t2 * mapping and the corrected t1 metric may be used to assess liver vascular congestion and studies are designed to test this in the context of right heart failure . patients who are having routine clinical investigations for the evaluation of central venous pressure and right heart function are recruited . patients have a liver mri for t1 and t2 * mapping and measurement of liver ct1 in addition to their clinically indicated investigations which may include echocardiography , cardiac mri and cardiac catheter studies . association between parameters of central venous pressure and right heart function measured on echocardiography , cardiac mri and cardiac catheter studies and liver t1 and ct1 are tested . 1 . right ventricular diameter 2 . pulmonary artery pressure 3 . presence and degree of tricuspid regurgitation 1 . right ventricular ejection fraction 2 . right ventricular end systolic and end diastolic volume 3 . right ventricular end systolic and end diastolic diameter 1 . right atrial pressure 2 . pulmonary artery pressure 3 . pulmonary wedge pressure 4 . right ventricle end systolic and end diastolic pressure 5 . right ventricle end systolic and end diastolic volume 6 . the difference between the lv end diastolic pressure and the hepatic wedge pressure . banerjee , r ., m . paviides , et al . “ multiparametric magnetic resonance for the noninvasive diagnosis of liver disease .” j . hepatol . 2014 january ; 60 ( 1 ): 69 - 77 . bohte , a . e ., a . de niet , et al . “ non - invasive evaluation of liver fibrosis : a comparison of ultrasound - based transient elastography and mr elastography in patients with viral hepatitis b and c .” eur radiol 24 ( 3 ): 638 - 48 . bosch , j ., j . g . abraldes , et al . 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( 2007 ). “ prognostic value of hepatic venous pressure gradient for in - hospital mortality of patients with severe acute alcoholic hepatitis .” aliment pharmacol ther 25 ( 7 ): 841 - 8 . ripoll , c , r . banares , et al . ( 2005 ). “ influence of hepatic venous pressure gradient on the prediction of survival of patients with cirrhosis in the meld era .” hepatology 42 ( 4 ): 793 - 801 . varghese , t ., j . a . zagzebski , et al . “ elastographic imaging using a handheld compressor .” ultrason imaging . 2002 january ; 24 ( 1 ): 25 - 35 .