Original Research
Gastrointestinal Imaging
July 2009

Feasibility of In Vivo MR Elastographic Splenic Stiffness Measurements in the Assessment of Portal Hypertension

Abstract

OBJECTIVE. Liver stiffness is associated with portal hypertension in patients with chronic liver disease. However, the relation between spleen stiffness and clinically significant portal hypertension remains unknown. The purposes of this study were to determine the feasibility of measuring spleen stiffness with MR elastography and to prospectively test the technique in healthy volunteers and in patients with compensated liver disease.
MATERIALS AND METHODS. Spleen stiffness was measured with MR elastography in 12 healthy volunteers (mean age, 37 years; range, 25-82 years) and 38 patients (mean age, 56 years; range, 36-60 years) with chronic liver disease of various causes. For patients with liver disease, laboratory findings, spleen size, presence and size of esophageal varices, and liver histologic results were recorded. Statistical analyses were performed to assess all measurements.
RESULTS. MR elastography of the spleen was successfully performed on all volunteers and patients. The mean spleen stiffness was significantly lower in the volunteers (mean, 3.6 ± 0.3 kPa) than in the patients with liver fibrosis (mean, 5.6 ± 5.0 kPa; range, 2.7-19.2 kPa; p < 0.001). In addition, a significant correlation was observed between liver stiffness and spleen stiffness for the entire cohort (r2 = 0.75; p < 0.001). Predictors of spleen stiffness were splenomegaly, spleen volume, and platelet count. A mean spleen stiffness of 10.5 kPa or greater was identified in all patients with esophageal varices.
CONCLUSION. MR elastography of the spleen is feasible and shows promise as a quantitative method for predicting the presence of esophageal varices in patients with advanced hepatic fibrosis.

Introduction

The development of portal hypertension in chronic liver disease is related to architectural changes caused by progressive hepatic fibrosis. These changes include formation of regenerative nodules and intrahepatic shunting of arterial blood flow [1]. Splenomegaly also is a common finding in patients with advanced hepatic fibrosis and portal hypertension [2], but the relation between splenomegaly and portal hypertension remains poorly understood. To our knowledge, a consistent relation between spleen size and portal venous pressure has not been identified [3-5] despite evidence of increased splenic red pulp blood volume from congestion by blood in affected patients [6]. Additional changes in the morphologic features of the spleen have been found in patients with cirrhosis. These changes include hyperplasia of splenic histiocytes [6], lengthening of arterial terminals [7], increased white pulp volume [8], and even fibrosis between splenic trabeculae [9]. However, the in vivo importance of these alterations and their contribution to clinically significant portal hypertension remain unknown.
The ability to measure liver tissue elasticity, or stiffness, in vivo has been of great clinical relevance in the treatment of patients with chronic liver disease. Both ultrasound-based transient elastography [10] and MR elastography (MRE) [11-14] have been found useful in the detection of advanced hepatic fibrosis, including occult cirrhosis based on liver stiffness measurements. Previous studies with ultrasound-based transient elastography have shown a systematic association between liver stiffness and portal hypertension assessed with quantitative pressure measurements [15, 16]. In contrast, liver stiffness has been inconsistently associated with the formation of esophageal varices [17]. Because of the relation between splenomegaly and esophageal varices in some patients with cirrhosis, we hypothesized that spleen stiffness may have a unique association with esophageal varices given the anatomic relation between the spleen and the portal vein. Furthermore, it would be expected that spleen stiffness would increase with the development of cirrhosis and esophageal varices. Therefore, we sought to assess the feasibility of measuring spleen stiffness with MRE in human subjects with and those without evidence of chronic liver disease, including compensated cirrhosis.
Fig. 1 Diagram shows system for application of shear waves to abdomen for MR elastography of liver. Acoustic pressure waves (60 Hz) are generated by active audio driver located away from magnetic field of MRI unit and transmitted through flexible tube to passive pneumatic driver placed over anterior body wall. Inset shows left coronal view of location of passive pneumatic driver (circle) with respect to liver. (Adapted with permission from [14])

Materials and Methods

Patient Population

The study was approved after review by the institutional review board. Individual patients undergoing clinical evaluation and therapy for chronic liver disease at our institution between January 2005 and January 2007 were eligible for study participation. Inclusion criteria were age older than 18 years, percutaneous liver biopsy within 1 year of study enrollment, and a diagnosis of compensated cirrhosis supported by findings at histologic examination of the liver or compatible clinical and imaging findings. Exclusion criteria were a history of hepatocellular carcinoma or cholangiocarcinoma, a history of liver resection or transplantation, and absolute contraindications to MRI, including presence of an aneurysm clip, a deep brain stimulator, metallic foreign bodies, a cardiac pacemaker, an implantable defibrillator, a ventriculoperitoneal shunt, or a vagal nerve stimulator. Recruitment was performed by contact letter and a combination of prospective subject identification and recall of patients who had undergone liver biopsy or clinical evaluation within the preceding 12 months.
Healthy volunteers were recruited prospectively to act as controls. Inclusion criteria for the controls were age 18 years or older, no history of chronic liver disease, and normal serum liver enzyme levels during testing at physical examination for employment purposes. Both oral and written consent were obtained from all volunteers and patients after the nature of the procedure had been fully explained to them.

MR Elastographic Technique

All MRE experiments were performed with a 1.5-T whole-body imager (Signa, GE Healthcare) with a transmit-receive body coil (Fig. 1). All volunteers and patients were imaged in the supine position with a 19-cm-diameter 1.5-cm-thick cylindric passive longitudinal shear wave driver placed against the anterior body wall. The driver was placed over the right lobe of the liver on the chest wall below the breast. Continuous longitudinal vibrations at 60 Hz were generated by means of variation of acoustic pressure waves transmitted from an active driver device through a vinyl tube (2.5-cm inside diameter, 7.6-m length).
A 2D gradient-echo MRE sequence was used to acquire axial wave images with the following parameters: TR/TE, 50/23; continuous sinusoidal vibration, 60 Hz; field of view, 32-42 cm; matrix size, 256 × 64; flip angle, 30°; slice thickness, 10 mm; four evenly spaced phase offsets; four pairs of 60-Hz trapezoidal motion-encoding gradients with zeroth and first-moment nulling along the through-plane direction. Two spatial presaturation bands were applied on each side of the selected slice to reduce motion artifacts from blood flow. The total acquisition time was 40 seconds, split into four periods of suspended respiration. To obtain a consistent position of the liver and spleen for each phase offset, individual subjects were asked to hold their breath at the end of expiration [14, 18, 19].

MRE

The liver and spleen slices obtained at MRE were 10-mm thick, and each slice was obtained within the mid portion of the liver and spleen, respectively. MRE images of the liver and spleen were obtained by processing the acquired images of propagating shear waves with a previously described local frequency estimation inversion algorithm [20]. The local frequency estimation algorithm combines local estimates of instantaneous spatial frequency over several scales to provide robust estimates of stiffness. A gaussian bandpass filter was applied to the original wave data to remove low-frequency wave information caused by longitudinal waves and bulk motion and to remove high-frequency noise. The cutoff frequencies of the bandpass filter were chosen carefully to be far from the dominant spatial frequencies observed in the liver data. The high-end spatial frequency cutoff value was 1.25 cm-1, which corresponds to stiffness values of less than 0.5 kPa. The low-end cutoff value was 0.08 cm-1, which corresponds to stiffness values greater than 100 kPa. Before applying the local frequency estimation inversion algorithm, we used eight motion direction filters evenly spaced between 0° and 360° and combined in a weighted leastsquares method to improve the performance of the algorithm because complex interference of shear waves from all directions can produce areas with low-shear displacement amplitude.
All of the steps in processing were applied automatically, without human intervention, to yield quantitative images of tissue shear stiffness in kilopascals. We use the designation “shear stiffness” rather than “shear modulus” to indicate that the measurements can include a viscous component, although this component was likely to be very small at the low driving frequency used. The elastograms were analyzed by measurement of mean shear stiffness within a large, manually specified region of interest that included an entire cross-sectional image of hepatic parenchyma (excluding major blood vessels such as hepatic veins, main portal veins, and branches with a width greater than 8 mm) or spleen. MRE interpretation was performed by blinded readers without knowledge of the clinical information.

Data Collection

One investigator abstracted relevant demographic and clinical information from electronic medical records. Variables of interest for patients with chronic liver disease included age, sex, body mass index (weight in kilograms divided by height squared in meters), cause of chronic liver disease, presence or absence of compensated cirrhosis according to clinical criteria, results of laboratory tests including serum platelet and leukocyte counts, presence or absence of splenomegaly (defined by craniocaudal length ≥ 12 cm measured with ultrasound), spleen volume measured with MRI, presence or absence of esophageal varices, fibrosis stage at histologic examination of the liver per formed with accepted techniques [21-23], mean liver stiffness measurement at MRE, and mean spleen stiffness measurement at MRE. The method used for calculating spleen volume entailed linear inter polation to identify 2.5-mm slices from avail able images. The area for each slice was determined manually and excluded large arteries and veins seen on anatomic images. Volume was calculated as the summation of all slice volume areas. For healthy volunteers, the variables age, sex, body mass index, mean liver stiffness mea sure ment, and mean spleen stiffness measurement were recorded.
Fig. 2A 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR images show anatomic findings.
Fig. 2B 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR images with superimposed wave image data in liver and spleen show that shear wavelength for both liver and spleen is higher in patients with cirrhosis (E and H) than in healthy volunteer (B).
Fig. 2C 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR elastograms show that mean spleen stiffness of fibrotic livers (F and I) is much higher than that of normal liver (C) (11.5 ± 1.1 kPa and 19.6 ± 3.3 kPa vs 3.6 ± 0.4 kPa). Mean liver stiffness is also higher in patients with cirrhosis (8.3 ± 1.5 kPa and 18.9 ± 2.9 kPa) than in healthy volunteer (2.1 ± 0.3 kPa).
Fig. 2D 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR images show anatomic findings.
Fig. 2E 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR images with superimposed wave image data in liver and spleen show that shear wavelength for both liver and spleen is higher in patients with cirrhosis (E and H) than in healthy volunteer (B).
Fig. 2F 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR elastograms show that mean spleen stiffness of fibrotic livers (F and I) is much higher than that of normal liver (C) (11.5 ± 1.1 kPa and 19.6 ± 3.3 kPa vs 3.6 ± 0.4 kPa). Mean liver stiffness is also higher in patients with cirrhosis (8.3 ± 1.5 kPa and 18.9 ± 2.9 kPa) than in healthy volunteer (2.1 ± 0.3 kPa).
Fig. 2G 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR images show anatomic findings.
Fig. 2H 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR images with superimposed wave image data in liver and spleen show that shear wavelength for both liver and spleen is higher in patients with cirrhosis (E and H) than in healthy volunteer (B).
Fig. 2I 28-year-old healthy volunteer (A-C) and 46-year-old patient (D-F) and 54-year-old patient (G-I) with cirrhosis. MR elastograms show that mean spleen stiffness of fibrotic livers (F and I) is much higher than that of normal liver (C) (11.5 ± 1.1 kPa and 19.6 ± 3.3 kPa vs 3.6 ± 0.4 kPa). Mean liver stiffness is also higher in patients with cirrhosis (8.3 ± 1.5 kPa and 18.9 ± 2.9 kPa) than in healthy volunteer (2.1 ± 0.3 kPa).

Statistical Analysis

Continuous variables were expressed as mean ± SD or median as appropriate. Categoric variables were expressed as proportion or percentage. Mean spleen stiffness values were compared between patients and healthy volunteers by use of a Kruskal-Wallis test followed by a non parametric Dunnett test with control. Comparisons between mean spleen stiffness values in patients with mild fibrosis (fibrosis score, 0-2) and those with severe fibrosis (fibrosis score, 3-4) were performed with the same methods as for the patient-control comparison. The correlation between mean spleen and mean liver shear stiffness values was assessed with Spearman's correlation coefficient technique. Univariate logistic regression analysis was performed to identify predictors of spleen stiffness and esophageal varices. All statistical analyses were performed with JMP 6.0 Statistical Discovery software (SAS Institute).

Results

Feasibility of In Vivo Spleen Stiffness Measurement in Healthy Volunteers

Twelve healthy volunteers (three women, eight men; mean age, 37 years; range, 25-82 years), participated in this study. Excellent shear wave illumination was seen throughout the liver and spleen in all of these subjects (Figs. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, and 2I). Calculation of mean spleen stiffness was possible in all subjects. The mean spleen stiffness value for healthy subjects was 3.6 ± 0.3 kPa.
Fig. 3 Graph shows good correlation between mean liver and mean spleen stiffness values among healthy volunteers and patients with varying stages of chronic liver disease (r2 = 0.75; p < 0.001).

Feasibility of In Vivo Spleen Stiffness Measurement in Patients With Chronic Liver Disease

Thirty-eight patients (19 women, 19 men; mean age, 56 years; range, 21-75 years) with chronic liver disease consented to undergo MRE. The mean body mass index was 29.7 ± 5.5. Major causes of chronic liver disease included chronic hepatitis C (20%), nonalcoholic fatty liver disease (20%), alcoholic liver disease (11%), autoimmune hepatitis (11%), and primary biliary cirrhosis (11%). The histologic stage of fibrosis was 0 in 32% of patients, I in 5%, II in 5%, III in 13%, and IV in 45% of patients. The average Model for End-Stage Liver Disease score was 6 (range, 6-7).
Excellent shear wave illumination throughout the liver and spleen was found in all patients examined (Figs. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, and 2I). Calculation of mean spleen stiffness also was possible for all patients. For the entire group of patients with varying degrees of chronic liver disease, the mean spleen stiffness value was 5.6 ± 5.0 kPa (range, 2.7-19.2 kPa). The difference in mean spleen stiffness between patients with chronic liver disease and healthy subjects was statistically significant (p < 0.001).

Relation Between Mean Spleen and Liver Stiffness Values

Assessed by stage of fibrosis, the mean spleen stiffness value increased systematically (p = 0.0007) in patients with chronic liver disease (6.0 kPa for stage 0, 4.4 kPa for stage I, 5.4 kPa for stage II, 9.0 kPa for stage III, and 10.5 kPa for stage IV). For both healthy subjects and patients with liver disease, a significant linear correlation between mean liver and spleen stiffness values was observed (Fig. 3) (r2 = 0.75; p< 0.001). Higher spleen stiffness values also were found for patients with cirrhosis and collateral splenic varices (n = 7) compared with patients with cirrhosis and no collateral splenic varices (n = 10) (11.2 kPa vs 9.9 kPa; p = 0.2). There was no significant correlation between mean liver or spleen stiffness value and age, sex, or body mass index in either patient subgroup.

Association Between Mean Spleen Stiffness Value and Esophageal Varices in Patients with Compensated Cirrhosis

Among patients with histologic or clinical evidence of compensated cirrhosis (n = 17), the mean liver stiffness value was 8.1 ± 2.3 kPa (range, 3.6-12.0 kPa). The frequency of splenomegaly was 65%, and the mean spleen volume in these subjects was 518 ± 302 cm3 (range, 196-1,236 cm3). The mean serum platelet count was 135,000/mm3; nine patients (53%) with cirrhosis had serum platelet counts less than 140,000/mm3. All 17 patients with cirrhosis underwent diagnostic esophagogastroduodenoscopy before MRE, and esophageal varices were detected in seven of the 17 patients (41%). Small esophageal varices were found in five patients, and large varices were detected in two patients. The average time between esophagogastroduodenoscopy and MRE was 10 months (range, 1 day-37 months).
The mean spleen stiffness value among patients with compensated cirrhosis and esophageal varices was 12.6 ± 2.0 kPa. At univariate analysis, splenomegaly (p = 0.003), mean spleen stiffness (p = 0.03), and serum platelet count (p = 0.05) were identified as potential variables associated with the presence of esophageal varices. No association was observed between mean liver stiffness value (p = 0.63) or mean spleen volume (p = 0.14) and the presence of esophageal varices. All of the patients with esophageal varices had a mean spleen stiffness of 10.5 kPa or greater.

Discussion

In this preliminary study, we found it feasible to use MRE to measure in vivo spleen stiffness in patients with chronic liver disease and in healthy persons. In addition to observing that spleen stiffness increases with higher degrees of hepatic fibrosis, we found a strong linear relation between liver and spleen stiffness values in the entire cohort. Furthermore, a preliminary observation suggested that a mean spleen stiffness value of 10.5 kPa or greater in the presence of compensated cirrhosis was associated with esophageal varices in all cases.
The anatomic features and microcirculation of the spleen are well characterized [7, 24]. Splenic tissue is composed primarily of red pulp tissue and lesser degrees of white pulp. Within the red pulp, blood is received by the penicillar arterioles, which open directly into venous sinuses and trabecular veins. Blood exits through the splenic vein into the splanchnic venous circulation. White pulp is composed of a central artery surrounded by lymphoid tissue. Penicillar arterioles originate from the central arteries outside the white pulp and drain into venous sinuses and the red pulp. In this study, healthy subjects were observed to have a consistently narrow range of spleen stiffness values. Spleen stiffness was unrelated to age, sex, or body mass index. It could be expected that the spleen in healthy adults retains its elasticity throughout life, as is observed with spleen volume measured with cross-sectional imaging techniques [25-27]. However, the effect of normal tissue architecture on the dynamic or elastic properties of splenic tissue over time remains unknown.
A greater mean spleen stiffness value was found in patients with chronic liver disease than in healthy subjects. Mean spleen stiffness also was observed to increase significantly as the degree of hepatic fibrosis increased. The greatest values were found among patients with histologic stages III and IV hepatic fibrosis. In chronic liver disease, the spleen has been found to undergo architectural and dynamic circulatory alterations, including pulp hyperplasia, congestion from increased blood flow, and even fibrosis [6-10, 24]. These findings have led to hypotheses implicating portal venous hypertension as a cause of the morphologic changes of cirrhosis. Results to date suggest that portal venous pressure remains within physiologic values until architectural changes from bridging (stage III) fibrosis occur [28]. Whether local alterations in splenic hemodynamics preceding the development of clinically significant portal hypertension are responsible for increased spleen stiffness re mains speculative.
Despite the association between splenomegaly and portal hypertension, to our knowledge previous studies have not shown a consistent relation between splenomegaly and quantitative portal venous pressure measurements [2-5]. Mean splenic blood flow at Doppler ultrasound examinations [5, 29] has not correlated with portal venous pressure. Furthermore, an inverse relation between splenic arterial blood flow and hepatic venous pressure gradient (HVPG) at CT has been reported [30]. The finding of increased splenic blood flow, however, supports the hypothesis that splenic hemodynamics are not characterized by passive congestion alone [24, 31]. Increased phagocytic cell mass within the spleen, which corresponds to volumetric growth in patients with chronic liver disease, may also play a role in determining tissue stiffness [32].
A relation has been found between liver stiffness measurements at ultrasound-based transient elastography and clinically significant portal hypertension assessed with HVPG [15, 16, 33]. A strong relation between an HVPG less than 10 mm Hg and liver stiffness is consistent with mild to moderate degrees of liver fibrosis [15, 16]. However, there has been less than robust correlation between liver stiffness value and the presence of esophageal varices in patients with cirrhosis [17]. Similarly, our preliminary results did not show a statistically significant relation between mean liver stiffness value and the presence of esophageal varices. We did, however, observe a statistically significant relation between mean spleen stiffness and the presence of esophageal varices. At a mean spleen stiffness value of 10.5 kPa or greater, we had a 100% rate of detection of esophageal varices in patients with compensated cirrhosis. This observation remained independent of serum platelet count, including values less than 140,000/mm3, which is known to have modest utility as a predictor of the presence of esophageal varices [34]. Although liver stiffness measurement appears to capture the effect of elevated intrahepatic vascular resistance from advanced fibrosis [35], it is possible that spleen stiffness provides additional information about hemodynamic alterations within the splenic and splanchnic arterial circulations as portal venous pressure increases over time.
We excluded patients with decompensated cirrhosis (including the complications of jaundice, hypoalbuminemia, and ascites) because the pretest probability of identifying esophageal varices related to portal hypertension is high in the evaluation of these patients. In contrast, there is great interest in knowing whether spleen stiffness measurements can aid in identifying which patients with compensated liver disease (including cirrhosis) are at risk of esophageal varices. In turn, esophagogastroduodenoscopy may be reserved for patients at higher risk and be appropriately deferred for patients at low risk. Future studies are expected to include patients with decompensated cirrhosis.
Our study had limitations. Mean liver and spleen stiffness measurements were performed in 2D on cross-sectional images of all subjects. Greater accuracy in tissue stiffness measurement may be possible with 3D wave analysis at MRE, which is awaited. Correlation between mean spleen stiffness and portal venous pressure measurement with HVPG was not performed in this preliminary study. Based on preliminary results suggesting a relation between spleen stiffness and esophageal varices, measurement of HVPG and comparison with spleen and liver stiffness are being pursued. The varying intervals between esophagogastroduodenoscopy and MRE in some patients were quite long, which could have resulted in misclassification of patients in terms of indentifying esophageal varices based on spleen stiffness measurement. Future studies will attempt to include patients in whom both assessments are performed within a narrower time interval. Finally, our results concerning the predictive utility of mean spleen stiffness in the detection of esophageal varices in patients with compensated cirrhosis remain preliminary. We did not examine the performance of other noninvasive methods of detection of esophageal varices, such as the ratio of platelet count to spleen diameter, which has some evidence of external validity among independent samples [36].
We conclude that our results show the feasibility of MRE for spleen stiffness measurement in healthy persons and patients with chronic liver disease. Among patients with advanced fibrosis and compensated cirrhosis, mean spleen stiffness may have a role in improving selection of patients for endoscopic screening for detection of esophageal varices. Further studies are needed to define the feasibility and diagnostic performance of mean spleen stiffness measurement in clinical practice.

Footnotes

This study was supported by the National Institutes of Health grants RR024151 (J. A. Talwalkar) and EB01981 (R. L. Ehman).
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Address correspondence to R. L. Ehman.

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Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: 122 - 127
PubMed: 19542403

History

Submitted: December 5, 2007
Accepted: February 2, 2009

Keywords

  1. esophageal varices
  2. liver fibrosis
  3. MR elastography
  4. portal hypertension
  5. spleen stiffness

Authors

Affiliations

Jayant A. Talwalkar
Advanced Liver Diseases Study Group, Department of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN.
Meng Yin
Center for Advanced Imaging Research, Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
Sudhakar Venkatesh
Center for Advanced Imaging Research, Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
Present address: Department of Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Phillip J. Rossman
Center for Advanced Imaging Research, Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
Roger C. Grimm
Center for Advanced Imaging Research, Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
Armando Manduca
Center for Advanced Imaging Research, Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
Anthony Romano
Naval Research Laboratory, Washington, DC.
Patrick S. Kamath
Advanced Liver Diseases Study Group, Department of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN.
Richard L. Ehman
Center for Advanced Imaging Research, Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.

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