MRE Application Monograph_addons

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MR-TouchMR Elastography

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Table of contentsHealthymagination Source

MR Elastography Healthymagination Validation . . . . . . . . . . . . . . . . . . . . oxford Analytica . . . . . . . . . . . . . . . . . . . . 3

MR-Touch Fact Sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Healthymagination . . . . . . . . . . . . . . . . . 5

Whitepaper

Healthymagination white paper (traditional format) . . . . . . . . . . . . . . . . . Healthymagination . . . . . . . . . . . . . . . . . 7

Signapulse white paper (Signapulse format) . . . . . . . . . . . . . . . . . . . . . . . . Signapulse supplement . . . . . . . . . . . . 20

ProductLaunch/Technology Source

MR-Touch teaser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . product Brief . . . . . . . . . . . . . . . . . . . . . . 30

A new Touch for MR imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Fall 2008 . . . . . . . . . . . . . . . 33

MR Elastography / MR-Touch story board . . . . . . . . . . . . . . . . . . . . . . . . . . RSnA 2009 . . . . . . . . . . . . . . . . . . . . . . . . 35

The Sound Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Spring 2010 . . . . . . . . . . . . 36

PatientManagementImpact

changing patient Management with MR Elastography . . . . . . . . . . . . . . Signapulse Fall 2009 . . . . . . . . . . . . . . . 41

changing patient Management – patient perspective . . . . . . . . . . . . . . . Signapulse Fall 2009 . . . . . . . . . . . . . . . 44

MRE Helps Guide patient Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Fall 2009 . . . . . . . . . . . . . . . 45

Clinicalcases

case Review compendium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Fall 2010 . . . . . . . . . . . . . . . 46

MRE Strengthens practice Service line . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Fall 2010 . . . . . . . . . . . . . . . 53

Evaluating liver Fibrosis without Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Fall 2010 . . . . . . . . . . . . . . . 55

CostEffectiveness

preliminary Threshold Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iSpoR European congress 2010 . . . . 58

Scenario Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Fall 2010 . . . . . . . . . . . . . . . 60

The facts and reimbursement figures that appear in articles in this monograph were true and accurate at the time of the article’s original publication and reflect national averages . Healthcare providers should always independently investigate and consider reimbursement rates and other factors in their own area .

Accelerating Adoption

Current Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Signapulse Spring 2011 . . . . . . . . . . . . . . . 64

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Oxford Analytica Ltd.

Registered Address: 5 Alfred Street Telephone: +44 (0) 1865 261600 Registered in England: No. 1196703 Oxford Fax: +44 (0) 1865 242018 VAT No.: GB 533 1281 76 OX1 4EH E-Mail: [email protected] England

Potential 15% total cost savings when 67% of MREs are

used as a triage for liver biopsies

97% negative predictive value in

distinguishing normal from

fibrotic liver iii

Completely non-invasive test

resulting in higher patient comfort

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Oxford Analytica Ltd.

Registered Address: 5 Alfred Street Telephone: +44 (0) 1865 261600 Registered in England: No. 1196703 Oxford Fax: +44 (0) 1865 242018 VAT No.: GB 533 1281 76 OX1 4EH E-Mail: [email protected] England

i Carlson JJ, Kowdley KV, Sullivan SD, Ramsey SD, Veenstra DL: “An evaluation of the potential cost-effectiveness of non-invasive testing strategies in the diagnosis of significant liver fibrosis,” Journal of Gastroenterology and Hepatology 24, 2009.

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GE Healthcare Fact Sheet

M R - T o u c h

MR-TouchFact Sheet

WhatchallengesdoesMR-Touchaddressandwhatsolutionsdoesitcreate?

chronic liver disease and cirrhosis are major public health problems worldwide . in 2004, these conditions were associated with nearly 40,000 deaths and a cost of at least $1 .4 billion for medical services in the U .S . alone .1,2

liver biopsy is the current standard of care for detecting hepatic fibrosis, but its invasive nature limits its value to use as a screening tool for a large population . There are also limitations with the technique that include poor acceptance by patients, measurement errors, and cost .3,4 current noninvasive alternatives to liver biopsy are serum-based testing,5 which is not reliable for detecting early disease, and transient ultrasound elastography,6 which has technical limitations in patients with obesity and conditions such as ascites .

MR-Touch uses the MR Elastography (MRE) technique to provide diagnostic information without the discomfort and risk of complications due to invasive procedures, enabling more frequent evaluation when closer monitoring is needed .

Whatarethemainbenefitsofthetechnology?

By creating a vivid visual representation of liver tissue stiffness, MRE helps radiologists deliver a more confident diagnosis . Both comprehensive and noninvasive, the technique can appeal to patients and referring physicians, and can help expand the role of radiology into new areas .

HowdoesMREwork?

MRE, a technique developed by Richard Ehman, MD, and colleagues at Mayo clinic (Rochester, Mn), uses low-frequency mechanical waves to probe the elastic properties of tissue . These mechanical waves are generated in the body through an external acoustic driver, which are then imaged using a special phase-contrast MR sequence .

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Fact Sheet

M R - T o u c h

Using a sophisticated mathematical algorithm, the mechanical wave data collected by the MR is then used to generate an “elastogram,”—a diagnostic image that depicts tissue stiffness .

HowdoesMREtechnologyimprovecareanddecreasecosts?

Improvedquality:MRE is noninvasive and provides a color-coded visual representation of tissue stiffness overlaid on the anatomy . Mechanical properties of the liver tissue has been strongly correlated with the extent of fibrosis .7 MRE technology also improves quality of care due to its attractiveness for use in early diagnosis .

Diagnosticvalue: Sampling variability appears to be one of the major limitations of liver biopsy .3 Even though small biopsy specimens may be sufficient for diagnostic purposes in certain situations, the possibility that sampling variability exists must be recognized, so that the absence of key findings does not rule out a suspected diagnosis . By showing information about liver stiffness over one or more cross sections of the entire liver, MR elastography provides a more comprehensive view than before available .

Patientcomfort: pain and bleeding are the most common complications of liver biopsy, occurring in up to 84% of patients .3

MRE does not use contrast or ionizing radiation and provides a completely noninvasive test of liver tissue elasticity, thus resulting in greater patient comfort than invasive tests .

Reducedcost: Given the novelty of the MRE technology, peer-reviewed academic or medical literature evaluating the potential cost-effectiveness of this noninvasive testing strategy in the diagnosis and management of liver fibrosis is currently limited . At this stage, there is no way to predict the willingness of payers to cover the procedure and the level of reimbursement .

As a new technology, MRE is currently not reimbursed with its own cpT code* . if MRE is not reimbursed any more than a typical abdominal MRi scan, the reimbursement for a valid MRE scan would be similar to the 2010 national Medicare average payment rate for an abdominal MRi, i .e . $628 (cpT code 74183) .

carlson et al . used data originally reported by Wong et al . and adjusted for inflation using the consumer price index to arrive at an estimated cost of liver biopsy of $1,255 .8,9

MRE has high predictive value in distinguishing stiffness associated with normal liver tissue .10 if one assumes that the cost of a liver biopsy is $1,255** and the cost of an MRE would be $628, then MRE would lower costs by at least 15% if it successfully avoids approximately two-thirds of unnecessary biopsies .

** Figures associated with US rates of reimbursement . not globally applicable .

** When procedure-related morbidities are included, the true cost of a biopsy could be several times higher than the reported average cost

©2010 General Electric company – All rights reserved .

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1 . Kim WR, Brown RS Jr, Terrault nA, et al . Burden of liver disease in the United States: summary of a workshop . Hepatology 2002; 36:227–242 .

2 . Shaheen nJ, Hansen RA, Morgan DR, et al . The burden of gastrointestinal and liver diseases, 2006 . Am J Gastroenterol . 2006;101:2128–2138 .

3 . Rockey Dc, celdwell SH, Goodman ZD, et al . liver Biopsy . American Association for the Study of liver Disease (AASlD) position paper, 2009 .

4 . Bravo AA, Sheth SG, cehopra S . liver biopsy . n Engl J Med . 2001; Feb 15;344(7):495-500 .

5 . Smith Jo, Sterling RK . Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis c . Aliment pharmacol Ther . 2009; Sept 15;30(6):557-76 .

6 . Stebbing J, Farouk l, panos G, et al . A Meta-analysis of Transient Elastography for the Detection of Hepatic Fibrosis . J clin Gastroenterol . 2009; Sept 9 .;44(3):214-219

7 . Yeh Wc, li pc, Jen YM, et al . Elastic modulus measurements of human liver and correlation with pathology . Ultrasound Med Biol 2002;28:467-474 .

8 . carlson JJ, Kowdley KY, Sullivan SD, Ramsey SD, Veenstra Dl . An evaluation of the potential cost-effectiveness of non-invasive testing strategies in the diagnosis of significant liver fibrosis . J Gastroenterol Hepatol . 2009 May;24(5):786-91 .

9 . Wong J, Bennet W, Koff R, et al . pretreatment evaluation of chronic hepatitis c: Risk, Benefits, and costs . JAMA . 1998 Dec 23-30; 280(24):2088–93 .

10 . Yin M, TalWalkar JA, Glaser KJ, et al . Assessment of Hepatic Fibrosis with Magnetic Resonance Elastography . clin Gastroenterol and Hepatol . 2007;5(10):1207-1213 .

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GE Healthcare White paper

h e a l t h y m a g i n a t i o n M R E


Background

chronic liver disease and cirrhosis are major public health problems worldwide . in 2004, these conditions were associated with nearly 40,000 deaths and a cost of at least $1 .4 billion for medical services in the U .S . alone .1,2 These figures are expected to increase due to aging, obesity, and end-stage liver disease caused by chronic hepatitis c . The major biological process responsible for clinical liver disease is progressive hepatic fibrosis .

liver biopsy is the current gold standard for detecting hepatic fibrosis . There are, however, limitations with the technique, which include poor acceptance by patients, measurement errors, and cost .3,4 current non-invasive alternatives to liver biopsy are limited to serum-based testing,5 which is not reliable for detecting early disease, and transient ultrasound elastography,6 which has technical limitations in patients with obesity and conditions such as ascites .7,8

Magnetic Resonance ElastographyThe promise of better outcomes and lower costs

Vinod S . palathinkara, phD, lloyd Estkowski, and David W . lee, phD

GE Healthcare

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Magneticresonanceelastography(MRE)

Magnetic resonance elastography (MRE), a technique developed by Richard Ehman, MD, and colleagues at Mayo clinic (Rochester, Mn), uses low-frequency mechanical waves to probe the elastic properties of tissue . These mechanical waves are generated in the body through an external acoustic driver, which are then imaged using a special phase- contrast MR sequence . Using a sophisticated mathematical algorithm, the mechanical wave data collected by the MR is then used to generate

“elastograms” – diagnostic images that depict a relative stiffness of tissues .

MRE gives referring physicians a powerful new option for liver assessment . it is a new tool that provides diagnostic information without the discomfort and risk of complications due to invasive procedures, enabling more frequent evaluation when closer monitoring is needed . By creating a visual representation of liver tissue stiffness, MRE helps radiologists deliver a more confident diagnosis at a lower cost than previous techniques .

Both comprehensive and non-invasive, MRE can appeal to patients and referring physicians and can help expand the role of radiology into new areas . More than anything else, MRE holds the promise of better outcomes at lower costs to the healthcare system .

PatientmanagementwithMRE

Multiple studies have shown that when added to a conventional MRi exam of the abdomen, MRE can provide additional information that clinicians need to improve the management of their patients with chronic liver disease . The long-term benefit is in using the information downstream to better utilize liver tests and procedures, and enhance the quality of patient care .

MRE provides additional assessment of liver disease beyond routine lab and imaging tests, so that the patients can be more appropriately referred for further diagnosis options such as biopsy . Because liver biopsy is invasive, some patients with suspected liver disease may decline the procedure . As a result, some patients with significant liver disease are not properly identified as eligible candidates for appropriate treatment . MRE can enable referring physicians to assess more patients who may need liver biopsy and to identify patients who present tissue stiffness that is symptomatic of fibrosis .

MRE could be a particularly useful tool for physicians to manage patients afflicted with hepatitis B and c, which can often lead to liver injury . Since MRE identifies tissue with elevated liver stiffness, and advanced fibrosis or cirrhosis leads to increased liver stiffness, patients with either type of liver disease can still be evaluated and monitored . MRE could be a better-tolerated, noninvasive method to risk-stratify patients who may have symptoms typical of fibrosis, such as elevated liver stiffness . MRE can also be used to evaluate the need for biopsies or to conduct that first biopsy in the future when evidence typical of hepatic fibrosis first presents on MRE .

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Figure 1 (all images below): Typical MR elastograms of normal volunteer and patients .

Images courtesy of Dr. Richard Ehman, The Mayo Clinic

Elastogram on volunteer patient is shown (right) and corresponding anatomic image (left) . in the elastogram, relative stiffness is shown on a color scale, ranging from softest (purple) to hardest (red) . For reference, a dashed outline has been superimposed on the elastogram to indicate the approximate location of the liver note that the stiffness of normal liver tissue is very low and similar to that of adipose tissue . The spleen is usually considerably stiffer than other tissues, as shown by the corresponding red areas .

A 61-year-old with elevated serum liver tests and nonalcoholic fatty liver disease . in this case of advanced liver fibrosis, the elastogram shows that the liver is much stiffer than subcutaneous tissues and overall stiffness of the liver . The heterogeneity of the stiffness of the liver is also increased (compared to volunteer in images shown above) .

A 61-year-old with hepatitis c, cirrhosis, and hepatocellular carcinoma .The oval outline in the anatomic image (left) shows the location of the hepatocellular carcinoma . The elastogram (right) shows a corresponding area of high stiffness in the right lobe of the liver (red arrow), as well as an area of very high stiffness in the left lobe of the liver (green arrow) that is consistent with advanced fibrosis .

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ClinicalvalueofMRE

Yin et al . evaluated the diagnostic performance of an optimized MRE protocol for assessing hepatic fibrosis among patients with diverse causes of chronic liver disease and in normal individuals . The summary of mean values and variance of liver stiffness from the 35 normal volunteers and 48 patients with chronic liver disease is shown in Figure 2 .

The mean liver stiffness value for normal individuals was 2 .20 ± 0 .31 kilopascal (kpa) (range, 1 .77–2 .85 kpa) . For the entire group of patients with varying degrees of chronic liver disease, the mean liver stiffness value was 5 .80 ± 2 .57 kpa (range, 2 .76–12 .01 kpa) . When assessed by stage of fibrosis, the mean liver stiffness value increased systematically with an excellent correlation between histologic fibrosis and shear stiffness obtained with MR elastography (R2 = 0 .94, p < 0 .001) (see Figure 2) . Further comparisons between the normal volunteers and the patient groups showed significantly higher

mean liver stiffness values by fibrosis groups of F0–1–2, F3, and F4 compared with normal volunteers (p < 0 .0001) (see Figure 3) . Between the mild (F0–1–2) and severe (F3–4) fibrosis groups, the authors also found significant differences in mean liver stiffness measurements (p < .05) (see Figure 3) .

This study’s results supported the hypothesis that MRE is effective for distinguishing normal, soft-liver tissue from stiff fibrotic-liver tissue with a very high negative predictive value . The severity of increased stiffness was shown to allow moderate to severe fibrosis to be distinguished non-invasively from mild fibrosis .

it is important to assess the accuracy of MRE in relation to the accuracy of liver biopsy . A review of the available data on the accuracy of needle liver biopsy to define the stage of fibrosis reveals that significant sampling and interpretive error affects the diagnostic accuracy of liver biopsy . needle liver biopsy evaluates only about 1/50,000 of the volume of the liver, so it may be


Figure 2: Mean liver shear stiffness measurements for normal volunteers and patients .

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0(35) (14) (6) (5) (5) (18)

Mea

n liv

er s

tiffn

ess

(kPa

)

Chronic liver diseaseNormal

StageF0

StageF1

StageF2

StageF3

StageF4

y = .1631 e 0.2374x

r = 0.94432

Mean liver stiffness increases with the increased fibrosis stage in patients . Shown is a summary of the mean shear stiffness measurements of the liver for the 35 normal volunteers and the 48 patients divided into the five different fibrosis stages, which are indicated as F0, F1 . . . F4 . liver stiffness is significantly higher in patients than in the control group . The error bar for each group also illustrates the standard errors for each group . An exponential function fit well to the liver stiffness data with an r2 value of 0 .94 .

Chart from Yin et al., Gastroenterology and Hepatology, 2007.

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affected by substantial sampling error .10 Autopsy and laparoscopy studies that have evaluated the accuracy of liver biopsy for staging fibrosis and diagnosing cirrhosis have clearly shown that cirrhosis is missed on a single blind liver biopsy in 10% to 30% of cases .11,

12, 13, 14, 15 The majority of this error is due to the under-staging of disease . Both the size of the biopsy and number of biopsies taken have a major effect on accuracy . Abdi et al . report that the correct diagnosis of cirrhosis with a single biopsy increased from 80% to 100% when three specimens were analyzed .16 Similarly, in a study that evaluated the agreement between three biopsies taken at a single setting, Maharaj reported that cirrhosis was identified in all three biopsies in only 50% of the cases .17

Rocky et al . suggest that sampling variability appears to be one of the major limitations of liver biopsy .3 in a study of 124 patients with chronic

HcV infection who underwent laparoscopy-guided left and right lobe liver biopsies, 33% of cases had discordant results by at least one histological stage . A smaller but substantial proportion of biopsies were discordant by at least two stages . Similarly, a single liver biopsy specimen may fail to distinguish steatohepatitis from simple steatosis and may mis-stage the disease by one, or less frequently, two stages if the specimen is much smaller than 2 cm . The authors caution that although even small biopsy specimens may be sufficient for diagnostic purposes in certain situations, the possibility that sampling variability exists must be recognized, so that the absence of key findings does not rule out a suspected diagnosis . By showing information about liver stiffness over one or more cross sections of the entire liver, MRE provides a more comprehensive view than before available .


Normal

Live

r st

iffne

ss (k

Pa)

Chronic liver disease

Kruskal WallisDunnett’s Test

a=0.5

NormalStage 0Stage 1Stage 2Stage 3Stage 4Li

ver

patie

nt

14

12

10

8

6

4

2

00 1 2 3 4

P < .0001*

P < .0001*

P < .0001*NormalFO-1-2F3-4

Figure 3: Mean liver shear stiffness at different fibrosis stages .

liver stiffness increases significantly with increased fibrosis extent as determined by liver biopsy examination . in the left diagram, significant differences (*) were observed in the liver stiffness between the normal control group and patient groups F0–1–2, F3, and F4 . The p values all are less than .0001 . The ci diamonds are shown for each group . in the right diagram, a significant difference also was observed between the mild fibrosis groups (F0 –1–2) and the severe fibrosis groups (F3– 4) . The p value is less than .05 . The center and the radius of the three circles indicate the mean and SD of the normal, F0–1–2, and F3–4 fibrosis groups . The data were analyzed with a Kruskal–Wallis test followed by the Dunnett test .

Chart from Yin et al., Gastroenterology and Hepatology, 2007.

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ImprovedpatientcomfortandsafetywithMRE

According to Rocky et al ., pain is the most common complication of liver biopsy, occurring in up to 84% of patients .3 The most important complication of a liver biopsy is bleeding . Severe bleeding requires hospitalization and increases the likelihood of transfusion or even radiological intervention or surgery . Such bleeding has been estimated to occur in between 1 in 2500 to 1 in 10,000 biopsies . less severe bleeding, defined as that sufficient to cause pain or reduced blood pressure, but not requiring transfusion or intervention, occurs in approximately 1 in 500 biopsies . Mortality after liver biopsy is usually related to hemorrhage and is very uncommon . The most commonly quoted mortality rate is approximately 1 in 10,000 to 1 in 12,000 .18, 19

MRE does not use contrast or ionizing radiation and provides a completely non-invasive test of liver tissue elasticity, thus resulting in high patient comfort . According to Ehman et al ., the vibration used in MRE has amplitude that is very small (typically less than 0 .1 mm) and does not cause discomfort to the patient .20

Figure 4: Major complications of liver biopsy .

Complications Risk

Any pain 1:4

Significant pain 1:10–1:20

Bleeding 1:100

Bile leak 1:1,000

Death 1:10,000– 1:12,000

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h e a l t h y m a g i n a t i o n

Healthcaresystemcosts

carlson et al . use data originally reported by Wong et al . and adjusts for inflation using consumer price index to arrive at an estimated cost of liver biopsy of $1,255,* but this estimate is based on cost rather than charge and does not include all expenses associated with the test . it also understates the true costs of a liver biopsy because it excludes procedure-related morbidities .7, 21 Myers et al . use administrative databases from a large canadian Health Region to identify percutaneous liver biopsies performed between 1994 and 2002 .22 The study found that between 1994 and 2002, 3627 patients had 4275 liver biopsies . Thirty-two patients (0 .75%) had significant biopsy related complications .† pain requiring admission (0 .51%) and bleeding (0 .35%) were most common . Six patients (0 .14%) died; all had malignancies . The median direct cost of a hospitalization for complications was $4579 canadian (range $1164-$29,641) .

As a new technology, MRE is currently not reimbursed as a standalone test with its own cpT code . Because the acquisition time for MRE is very short, the technique can be readily included in the protocol for an already-indicated abdominal MRi exam with little impact on the typical examination time of 30 to 45 minutes . if the entire cost of such an exam is attributed to the MRE procedure, then a conservative estimate of the cost of the MRE would be equivalent to the 2010 national Medicare average payment amount

for abdominal MRi, i .e ., $628 (cpT code 74183) . At this stage, there is no way to predict the willingness of payers to cover an MRi examination conducted solely to perform MRE .

To better quantify the costs associated with MRE and liver biopsy, a decision- analytic model comparing diagnostic costs was constructed .23 A targeted literature review was conducted and, in addition, a leading hepatologist and pathologist were consulted to identify the appropriate procedure codes associated with liver biopsy . The study assumed that MRE would be reimbursed≠ using cpT-4 code 74181 (magnetic resonance [e .g ., proton] imaging, abdomen; without contrast material[s]) . All appropriate allowable charges were assigned to the identified procedure codes using the 2010 Medicare physician Fee Schedule . please note that all costs discussed here are US-based costs and are not globally applicable . Based on the model, the cost of a guided liver biopsy was $1,424 (ultrasound $164, surgical $881, pathology $347, laboratory $32) and the cost of an MRE (without contrast) was $946 (hospital setting) or $666 (non-hospital setting) .

Given the novelty of MRE technology, peer-reviewed academic/medical literature evaluating the potential cost-effectiveness of this non-invasive testing strategy in the diagnosis and management of liver fibrosis is not yet available . nevertheless, scenario-based analysis of published comparisons of patients who had both biopsy and MRE is illustrative and insightful .

*Figures associated with US rates of reimbursement . not applicable globally .

†Significant complications were identified by reviewing medical records of patients hospitalized within seven days of a biopsy and those with a diagnostic code indicative of procedural complications .

≠MRE is currently not reimbursed on its own cpT code .

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Scenarioanalysis

Huwart et al . performed a blind comparison of MRE and liver biopsy for non-invasive staging of liver fibrosis and reported histopathologic staging of liver fibrosis according to the METAViR scoring system as the reference .24 The study analyzed 96 patients for whom both MRE and liver biopsy were performed (see Figure 5) . it should be noted that the initial sample had 141 patients from whom liver biopsy specimens were collected, but only 127 liver biopsy specimens were suitable for fibrosis staging . This suggests that approximately 10% of the samples from a biopsy specimen may be unsuitable for staging .

We consider three scenarios as a hypothetical example to illustrate the costs of performing MRE for evaluation of liver disease . in scenario 1, we assume that liver biopsy is 100% accurate and that the discrepancy in staging between MRE and liver biopsy is entirely due to the errors in MRE . From a cost perspective, this would mean that at some time, these patients would need some follow-up to get a definitive diagnosis . Since we are using biopsy as the reference standard, the cost for the follow-up would be assumed to be the cost of a biopsy .

Figure 5: Flow diagram of patients who underwent liver biopsy and MRE (Huwart et al .) .

Elevatedliver enzymes

Biopsy (96)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome

Misclassification Follow-up(24)


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Huwart et al . report that when comparing results from MRE and biopsy, 24 of 96 (25%) were misclassified in their stage of fibrosis . Based on the reported sensitivity and specificity of MRE techniques, this misclassification is unusually high . nevertheless, since biopsy is the reference standard, we assume that 25% of patients who underwent MRE would eventually require further evaluation, probably with a biopsy . We do not consider how one would identify the patients who are misclassified and ignore the impact on the outcome or the additional treatment costs due to misclassification . our attempt here is to illustrate a methodology that can provide directional information on costs to explore potential for cost reduction, rather than to establish or estimate actual cost differentials .

in scenario 1, we assume that biopsy is 100% accurate and all samples are good enough to make a diagnosis . We consider this as a worst-case scenario for MRE . The authors highlight the fact that liver biopsy is not an optimal reference examination and that they do not know if the reported discordant results between MRE and histopathology were caused by problems of inadequate biopsy sampling .* The authors also report that the two pathologists who reviewed the biopsy specimen were initially in agreement only on 81 of the 96 samples . nevertheless, since biopsy is the reference standard, we have to assume that it provides clinically accepted basis for comparison .


Biopsy (96)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome


Figure 6: Hypothetical examples of direct costs of MRE and liver biopsy for scenario 1 .


*in 26 of the 96 samples, the biopsy specimen was less than 25 mm .

Scenario1

Biopsy is 100% accurate; all samples are suitable .

costs for procedures:

Biopsy = 96 x $1424 = $136,704

MRE = 96 x $946 + 24 x $1424

= $123,100

cost differential = $13,604 , or 10% less than biopsy

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As reported by Huwart et al ., 14 of 141 samples were unsuitable for diagnosis . Even though there are many studies that recommend a minimum sample length of 25 mm, the study reports that 23% of the samples were less than 25 mm in length . Thus the scenario that a few biopsy samples would be unsuitable is realistic . in scenario 2, we assume that to get 96 good samples, one would need to do 10% more samples (105 .6 biopsies) . This assumption does not imply that these patients would undergo an immediate repeat biopsy . The cost of this may result in an increased cost of diagnosis per person .


Biopsy (105.6)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome


Unsuitable sample (9.6)

Figure 7: Hypothetical example of direct costs of MRE and liver biopsy for scenario 2 .


Scenario2

Biopsy is 100% accurate, but 10% samples are unsuitable .


Biopsy = 96 x $1424 + 9 .6 x 1424

= $136,704 + $13,670

= $150,374

MRE = $123,100 + 2 .4 x $1424 = $126,518

cost differential = $23,856, or 16% less than biopsy

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in scenario 3, we take into account biopsy leading to a misclassification . More than questioning the accuracy of the biopsy, this is reflective of the fact that biopsy is a sampling technique . Studies report biopsy mis-staging to be in the range of 10% to 33% . in this case, we assume 20% mis-staging . if 20% of biopsy samples are mis-staged, then the discordances between MRE and biopsy may decrease . However, for simplicity, we still assume that the discordance between MRE and biopsy would not change .

Conclusion

MRE is non-invasive and provides tissue stiffness information for the entire liver . it avoids the discomfort and risk of complications associated with other invasive procedure . in addition, elastograms that overlay tissue stiffness images over the anatomy avoid sampling error and provide richer information that could assist in diagnosis . Studies show that the technique has excellent sensitivity in depicting the elevated stiffness associated with hepatic fibrosis . Stiffness of normal liver tissue is very soft and comparable to that of subcutaneous fat . Studies have also shown that hepatic steatosis, a common condition, does not have a significant influence on liver stiffness and therefore does not confound the elastographic findings observed in fibrosis . in summary, the evidence supports the use of MRE as a triaging option for liver biopsy . The accuracy and the noninvasive nature of the technology offer the promise that MRE could improve outcomes, potentially at lower costs .

Follow-up


Biopsy (105.6)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome



(19.2)

Figure 8: Hypothetical examples of direct costs of MRE and liver biopsy for scenario 3 .


Scenario3

Biopsy is only 80% accurate, but MRE still has 25% misclassifications .


Biopsy = $136,704 + 0 .2 x 96 x $1424

= $136,704 + $27,341

= $164,045

MRE = $123,100


11

18

References1 Kim, W .R ., et al . Burden of liver disease in the United States: summary of a workshop . Hepatology 36, 227–242 (2002) .2 Shaheen, n .J ., et al . The burden of gastrointestinal and liver diseases . Am J Gastroenterol 101, 2128–2138 (2006) .3 Rockey, D .c ., et al . liver biopsy . American Association for the Study of liver Disease (AASlD), position paper, 2009 .4 Bravo, A .A ., et al . liver biopsy . N Engl J Med 344(7), 495-500 (2001) .5 Smith, J .o ., Sterling, R .K . Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis c . Aliment Pharmacol Ther 30(6), 557-76 (2009) .6 Stebbing, J ., et al . A meta-analysis of transient elastography for the detection of hepatic fibrosis . J Clin Gastroenterol 44(3), 214-9 (2010) .7 carlson, J .J ., et al . An evaluation of the potential cost-effectiveness of non-invasive testing strategies in the diagnosis of significant liver fibrosis .

J Gastroenterol Hepatol 24(5), 786-91 (2009) .8 Talwalkar, J .A . Elastography for detecting hepatic fibrosis: options and considerations . Gastroenterology 359(1), 299-302 (2008) .9 Yin, M, . et al . Assessment of hepatic fibrosis with magnetic resonance elastography . clin Gastroentero 5(10), 1207-1213 (2007) .10 Afdhal, n .H ., nunes, D . Evaluation of liver fibrosis: a concise review . Am Gastroentero, 99(6), 1160-74 (2004) .11 Bruguera, M ., et al . A comparison of the accuracy of peritoneoscopy and liver biopsy in the diagnosis of cirrhosis . Gut 15, 799-800 (1974) .12 poniachik, J ., et al . The role of laparoscopy in the diagnosis of cirrhosis . Gastrointest Endosc 43, 568-71 (1996) .13 pagliaro, l ., et al . percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis . Dig Dis Sci, 28, 39-43 (1983) .14 olsson, R ., et al . Sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis . J Clin Pathol 48, 933-5 (1995) .15 Angelucci, E ., et al . needle liver biopsy in thalassemia: analyses of the diagnostic accuracy and safety in 1184 consecutive biopsies . Br J Haematol 89, 757-61 (1995) .16 Abdi, W ., et al . Sampling variability on percutaneous liver biopsy . Arch Intern Med 15, 329-35 (1979) .17 Maharaj, B ., et al . Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver . Lancet 1, 523-5 (1986) .18 perrault, J ., et al . liver biopsy: complications in 1000 inpatients and outpatients . Gastroenterology 74, 103-106 (1978) .19 McGill, D .B ., et al . A 21-year experience with major hemorrhage after percutaneous liver biopsy . Gastroenterology 99, 1396-1400 (1990) .20 Ehman, E .c ., et al . Vibration safety limits for magnetic resonance elastography . Phys Med Biol 53(4), 925-935 (2008) .21 Wong, J ., et al . pretreatment evaluation of chronic hepatitis c: risk, benefits, and costs . JAMA 280, 2088–93 (1998) .22 Myers, R .p ., et al . Utilization rates, complications and costs of percutaneous liver biopsy: a population-based study including 4275 biopsies . Liver Int, 705-12 (2008) .23 DeKoven, M . cost comparison: liver biopsy versus abdominal MRi . Memo to GE Healthcare from iMS Health incorporated . May 25, 2010 .24 Huwart, l ., et al . Magnetic resonance elastography for the non-invasive staging of liver fibrosis . Gastroenetrology, 135(1), 32-40, (2008) .

19

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201

Background

chronic liver disease and cirrhosis are major public health problems worldwide . in 2004, these conditions were associated with nearly 40,000 deaths and a cost of at least $1 .4 billion for medical services in the U .S . alone .1,2 These figures are expected to increase due to aging, obesity, and end-stage liver disease caused by chronic hepatitis c . The major biological process responsible for clinical liver disease is progressive hepatic fibrosis .

liver biopsy is the current gold standard for detecting hepatic fibrosis . There are, however, limitations with the technique, which include poor acceptance by patients, measurement errors, and cost .3,4 current non-invasive alternatives to liver biopsy are limited to serum-based testing,5 which is not reliable for detecting early disease, and transient ultrasound elastography,6 which has technical limitations in patients with obesity and conditions such as ascites .7,8

The promise of better outcomes and lower costs Vinod S. Palathinkara, PhD, Lloyd Estkowski, and David W. Lee, PhD GE Healthcare

A GE Healthcare MR publication • Autumn 2010

W H i T E p A p E RM A G n E T i c R E S o n A n c E E l A S T o G R A p H Y

21

Magneticresonanceelastography(MRE)

Magnetic resonance elastography (MRE), a technique developed by Richard Ehman, MD, and colleagues at Mayo clinic (Rochester, Mn), uses low-frequency mechanical waves to probe the elastic properties of tissue . These mechanical waves are generated in the body through an external acoustic driver, which are then imaged using a special phase-contrast MR sequence . Using a sophisticated mathematical algorithm, the mechanical wave data collected by the MR is then used to generate “elastograms” – diagnostic images that depict relative stiffness of tissues .

MRE gives referring physicians a powerful new option for liver assessment . it is a new tool that provides diagnostic information without the discomfort and risk of complications due to invasive procedures, enabling more frequent evaluation when closer monitoring is needed . By creating a visual representation of liver tissue stiffness, MRE helps radiologists deliver a more confident diagnosis at a lower cost than previous techniques .

Both comprehensive and non-invasive, MRE can appeal to patients and referring physicians and can help expand the role of radiology into new areas . More than anything else, MRE holds the promise of better outcomes at lower costs to the healthcare system .

MRE Supplement • Autumn 20102

W H i T E p A p E R M A G n E T i c R E S o n A n c E E l A S T o G R A p H Y

22

PatientmanagementwithMRE

Multiple studies have shown that when added to a conventional MRi exam of the abdomen, MRE can provide additional information that clinicians need to improve the management of their patients with chronic liver disease . The long-term benefit is in using the information downstream to better utilize liver tests and procedures, and enhance the quality of patient care .

MRE provides additional assessment of liver disease beyond routine lab and imaging tests, so that the patients can be more appropriately referred for further diagnosis options such as biopsy . Because liver biopsy is invasive, some patients with suspected liver disease may decline the procedure . As a result, some patients with significant liver disease are not properly identified as eligible candidates for appropriate treatment . MRE can enable referring physicians to assess more patients who may need liver biopsy and to identify patients who present tissue stiffness that is symptomatic of fibrosis .

MRE could be a particularly useful tool for physicians to manage patients afflicted with hepatitis B and c, which can often lead to liver injury . Since MRE identifies tissue with elevated liver stiffness, and advanced fibrosis or cirrhosis leads to increased liver stiffness, patients with either type of liver disease can still be evaluated and monitored . MRE could be a better-tolerated, noninvasive method to risk-stratify patients who may have symptoms typical of fibrosis, such as elevated liver stiffness . MRE can also be used to evaluate the need for biopsies or to conduct that first biopsy in the future when evidence typical of hepatic fibrosis first presents on MRE .

Howelastographyworks

The image is captured in as little as 14 seconds, or one breath hold, in three steps:

A special MRi technique images minute displacements of the tissue that result from wave propagation .

A simple, drum-like driver generates acoustic waves within the tissue of interest .

An advanced mathematical technique generates maps of tissue stiffness, known as “elastograms” .

A GE Healthcare MR publication • Autumn 2010 3


23

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inic

Figure1. (all images below): Typical MR elastograms of normal volunteer and patients .

Elastogram on volunteer patient is shown (right) and corresponding anatomic image (left) . in the elastogram, relative stiffness is shown on a color scale, ranging from softest (purple) to hardest (red) . For reference, a dashed outline has been superimposed on the elastogram to indicate the approximate location of the liver note that the stiffness of normal liver tissue is very low and similar to that of adipose tissue . The spleen is usually considerably stiffer than other tissues, as shown by the corresponding red areas .

A 61-year-old with elevated serum liver tests and nonalcoholic fatty liver disease . in this case of advanced liver fibrosis, the elastogram shows that the liver is much stiffer than subcutaneous tissues and overall stiffness of the liver . The heterogeneity of the stiffness of the liver is also increased (compared to volunteer in images shown above) .

A 61-year-old with hepatitis c, cirrhosis, and hepatocellular carcinoma .The oval outline in the anatomic image (left) shows the location of the hepatocellular carcinoma . The elastogram (right) shows a corresponding area of high stiffness in the right lobe of the liver (red arrow), as well as an area of very high stiffness in the left lobe of the liver (green arrow) that is consistent with advanced fibrosis .



24A GE Healthcare MR publication • Autumn 2010 5


ClinicalvalueofMRE

Yin et al . evaluated the diagnostic performance of an optimized MRE protocol for assessing hepatic fibrosis among patients with diverse causes of chronic liver disease and in normal individuals .9 The summary of mean values and variance of liver stiffness from the 35 normal volunteers and 48 patients with chronic liver disease is shown in Figure 2 .

The mean liver stiffness value for normal individuals was 2 .20 ± 0 .31 kilopascal (kpa) (range, 1 .77–2 .85 kpa) . For the entire group of patients with varying degrees of chronic liver disease, the mean liver stiffness value was 5 .80 ± 2 .57 kpa (range, 2 .76–12 .01 kpa) . When assessed by stage of fibrosis, the mean liver stiffness value increased systematically with an excellent correlation between histologic fibrosis and shear stiffness obtained with MR elastography (R2 = 0 .94, p < 0 .001) (see Figure 2) . Further comparisons between the normal volunteers and the patient groups showed signifi-cantly higher mean liver stiffness values by fibrosis groups of F0–1–2, F3, and F4 compared with normal volunteers (p < 0 .0001) (see Figure 3) . Between the mild (F0–1–2) and severe (F3–4) fibrosis groups, the authors also found significant differences in mean liver stiffness measurements (p < .05) (see Figure 3) .

This study’s results supported the hypothesis that MRE is effective for distinguishing normal, soft-liver tissue from stiff fibrotic-liver tissue with a very high negative predictive value . The severity of increased stiffness was shown to allow moderate to severe fibrosis to be distinguished non-invasively from mild fibrosis .

it is important to assess the accuracy of MRE in relation to the accuracy of liver biopsy . A review of the available data on the accuracy of needle liver biopsy to define the stage of fibrosis reveals that significant sampling and interpretive error affects the diagnostic accuracy of liver biopsy . needle liver biopsy evaluates only about 1/50,000 of the volume of the liver, so it may be affected by substantial sampling error .10 Autopsy and laparoscopy studies that have evaluated the accuracy of liver biopsy for staging fibrosis and diagnosing cirrhosis have clearly shown that cirrhosis is missed on a single blind liver biopsy in 10% to 30% of cases .11,12,13,14,15 The majority of this error is due to the under-staging of disease . Both the size of the biopsy and number of biopsies taken have a major effect on accuracy . Abdi et al . report that the correct diagnosis of cirrhosis with a single biopsy increased from 80% to 100% when three specimens were analyzed .16 Similarly, in a study that evaluated the agreement between three biopsies taken at a single setting, Maharaj reported that cirrhosis was identified in all three biopsies in only 50% of the cases .17

Mean liver stiffness increases with the increased fibrosis stage in patients . Shown is a summary of the mean shear stiffness measurements of the liver for the 35 normal volunteers and the 48 patients divided into the five different fibrosis stages, which are indicated as F0, F1 . . . F4 . liver stiffness is significantly higher in patients than in the control group . The error bar for each group also illustrates the standard errors for each group . An exponential function fit well to the liver stiffness data with an r2 value of 0 .94 .

Figure2. Mean liver shear stiffness measurements for normal volunteers and patients .

10

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Mea

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ess

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)

Chronic liver diseaseNormal

StageF0

StageF1

StageF2

StageF3

StageF4

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25

liver stiffness increases significantly with increased fibrosis extent as determined by liver biopsy examination . in the left diagram, significant differences (*) were observed in the liver stiffness between the normal control group and patient groups F0–1–2, F3, and F4 . The p values all are less than .0001 . The ci diamonds are shown for each group . in the right diagram, a significant difference also was observed between the mild fibrosis groups (F0 –1–2) and the severe fibrosis groups (F3– 4) . The p value is less than .05 . The center and the radius of the three circles indicate the mean and SD of the normal, F0–1–2, and F3–4 fibrosis groups . The data were analyzed with a Kruskal–Wallis test followed by the Dunnett test .

Normal

Live

r st

iffne

ss (k

Pa)

Chronic liver disease

Kruskal WallisDunnett’s Test

a=0.5

NormalStage 0Stage 1Stage 2Stage 3Stage 4Li

ver

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nt

14

12

10

8

6

4

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00 1 2 3 4

P < .0001*

P < .0001*

P < .0001*NormalFO-1-2F3-4

Figure3. Mean liver shear stiffness at different fibrosis stages .

Char

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Gas

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Complications Risk

Any pain 1:4

Significant pain 1:10–1:20

Bleeding 1:100

Bile leak 1:1,000

Death 1:10,000– 1:12,000

Figure4. Major complications of liver biopsy .

Rocky et al . suggest that sampling variability appears to be one of the major limitations of liver biopsy .3 in a study of 124 patients with chronic HcV infection who underwent laparoscopy-guided left and right lobe liver biopsies, 33% of cases had discordant results by at least one histological stage . A smaller but substantial proportion of biopsies were discordant by at least two stages . Similarly, a single liver biopsy specimen may fail to distinguish steatohepatitis from simple steatosis and may mis-stage the disease by one, or less frequently, two stages if the specimen is much smaller than 2 cm . The authors caution that although even small biopsy specimens may be sufficient for diagnostic purposes in certain situations, the possibility that sampling variability exists must be recognized, so that the absence of key findings does not rule out a suspected diagnosis . By showing information about liver stiffness over one or more cross sections of the entire liver, MRE provides a more comprehensive view than before available .

ImprovedpatientcomfortandsafetywithMRE

According to Rocky et al ., pain is the most common complication of liver biopsy, occurring in up to 84% of patients .3 The most important complication of a liver biopsy is bleeding . Severe bleeding requires hospitalization and increases the likelihood of transfusion or even radiological intervention or surgery . Such bleeding has been estimated to occur in between 1 in 2500 to 1 in 10,000 biopsies . less severe bleeding, defined as that sufficient to cause pain or reduced blood pressure, but not requiring transfusion or intervention, occurs in approximately 1 in 500 biopsies . Mortality after liver biopsy is usually related to hemorrhage and is very uncommon . The most commonly quoted mortality rate is approximately 1 in 10,000 to 1 in 12,000 .18,19

MRE does not use contrast or ionizing radiation and provides a completely non-invasive test of liver tissue elasticity, thus resulting in high patient comfort . According to Ehman et al ., the vibration used in MRE has amplitude that is very small (typically less than 0 .1 mm) and does not cause discomfort to the patient .20

MRE Supplement • Autumn 2010 6


26



carlson et al . use data originally reported by Wong et al . and adjusts for inflation using consumer price index to arrive at an estimated cost of liver biopsy of $1,255,* but this estimate is based on cost rather than charge and does not include all expenses associated with the test . it also understates the true costs of a liver biopsy because it excludes procedure-related morbidities .7, 21 Myers et al . use administrative databases from a large canadian Health Region to identify percutaneous liver biopsies performed between 1994 and 2002 .22 The study found that between 1994 and 2002, 3627 patients had 4275 liver biopsies . Thirty-two patients (0 .75%) had significant biopsy related complications .† pain requiring admission (0 .51%) and bleeding (0 .35%) were most common . Six patients (0 .14%) died; all had malignancies . The median direct cost of a hospitalization for complications was $4579 canadian (range $1164 – $29,641) .

As a new technology, MRE is currently not reimbursed as a standalone test with its own cpT code . Because the acquisition time for MRE is very short, the technique can be readily included in the protocol for an already-indicated abdominal MRi exam with little impact on the typical examination time of 30 to 45 minutes . if the entire cost of such an exam is attributed to the MRE procedure, then a conservative estimate of the cost of the MRE would be equivalent to the 2010 national Medicare average payment amount for abdominal MRi, i .e ., $628 (cpT code 74183) . At this stage, there is no way to predict the willingness of payers to cover an MRi examination conducted solely to perform MRE .

To better quantify the costs associated with MRE and liver biopsy, a decision-analytic model comparing diagnostic costs was constructed .23 A targeted literature review was conducted and, in addition, a leading hepatologist and pathologist were consulted to identify the appropriate procedure codes associated with liver biopsy . The study assumed that MRE would be reimbursed≠ using cpT-4 code 74181 (magnetic resonance [e .g ., proton] imaging, abdomen; without contrast material[s]) . All appropriate allowable charges were assigned to the identified procedure codes using the 2010 Medicare physician Fee Schedule . please note that all costs discussed here are US-based costs and are not globally applicable . Based on the model, the cost of a guided liver biopsy was $1,424 (ultrasound $164, surgical $881, pathology $347, laboratory $32) and the cost of an MRE (without contrast) was $946 (hospital setting) or $666 (non-hospital setting) .

Given the novelty of MRE technology, peer-reviewed academic/medical literature evaluating the potential cost-effectiveness of this non-invasive testing strategy in the diagnosis and management of liver fibrosis is not yet available . nevertheless, scenario-based analysis of published comparisons of patients who had both biopsy and MRE is illustrative and insightful .

*Figures associated with US rates of reimbursement . not applicable globally .

† Significant complications were identified by reviewing medical records of patients hospitalized within seven days of a biopsy and those with a diagnostic code indicative of procedural complications .

≠MRE is currently not reimbursed on its own cpT code .

A GE Healthcare MR publication • Autumn 2010 7

27

Scenarioanalysis

Huwart et al . performed a blind comparison of MRE and liver biopsy for non-invasive staging of liver fibrosis and reported histopathologic staging of liver fibrosis according to the METAViR scoring system as the reference .24 The study analyzed 96 patients for whom both MRE and liver biopsy were performed (see Figure 5) . it should be noted that the initial sample had 141 patients from whom liver biopsy specimens were collected, but only 127 liver biopsy specimens were suitable for fibrosis staging . This suggests that approximately 10% of the samples from a biopsy specimen may be unsuitable for staging .

We consider three scenarios as a hypothetical example to illustrate the costs of performing MRE for evaluation of liver disease . in scenario 1, we assume that liver biopsy is 100% accurate and that the discrepancy in staging between MRE and liver biopsy is entirely due to the errors in MRE . From a cost perspective, this would mean that at some time, these patients would need some follow-up to get a definitive diagnosis . Since we are using biopsy as the reference standard, the cost for the follow-up would be assumed to be the cost of a biopsy .

Huwart et al . report that when comparing results from MRE and biopsy, 24 of 96 (25%) were misclassified in their stage of fibrosis . Based on the reported sensitivity and specificity of MRE techniques, this misclassification is unusually high . nevertheless, since biopsy is the reference standard, we assume that 25% of patients who underwent MRE would eventually require further evaluation, probably with a biopsy . We do not consider how one would identify the patients who are misclassified and ignore the impact on the outcome or the additional treatment costs due to delay in misclassification . our attempt here is to illustrate a methodology that can provide directional information on costs to explore potential for cost reduction, rather than to establish or estimate actual cost differentials .

Figure5. Flow diagram of patients who underwent liver biopsy and MRE (Huwart et al .) .


Biopsy (96)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome




28A GE Healthcare MR publication • Autumn 2010 9


in scenario 1, we assume that biopsy is 100% accurate and all samples are good enough to make a diagnosis . We consider this as a worst-case scenario for MRE . The authors highlight the fact that liver biopsy is not an optimal reference examination and that they do not know if the reported discordant results between MRE and histopathology were caused by problems of inadequate biopsy sampling .* The authors also report that the two pathologists who reviewed the biopsy specimen were initially in agreement only on 81 of the 96 samples . nevertheless, since biopsy is the reference standard, we have to assume that it provides clinically accepted basis for comparison .

As reported by Huwart et al ., 14 of 141 samples were unsuitable for diagnosis . Even though there are many studies that recommend a minimum sample length of 25 mm, the study reports that 23% of the samples were less than 25 mm in length . Thus the scenario that a few biopsy samples would be unsuitable is realistic . in scenario 2, we assume that to get 96 good samples, one would need to do 10% more samples (105 .6 biopsies) . This assumption does not imply that these patients would undergo an immediate repeat biopsy . The cost of this may result in an increased cost of diagnosis per person .


Biopsy (96)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome


Figure6. Hypothetical examples of direct costs of MRE and liver biopsy for scenario 1 .

*in 26 of the 96 samples, the biopsy specimen was less than 25 mm .

Scenario1



Biopsy = 96 x $1424 = $136,704

MRE = 96 x $946 + 24 x $1424

= $123,100


Figure7. Hypothetical example of direct costs of MRE and liver biopsy for scenario 2 .


Biopsy (105.6)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome



Scenario2

Biopsy is 100% accurate, but 10% samples are unsuitable .


Biopsy = 96 x $1424 + 9 .6 x 1424

= $136,704 + $13,670

= $150,374

MRE = $123,100 + 2 .4 x $1424 = $126,518


29

in scenario 3, we take into account biopsy leading to a misclassification . More than questioning the accuracy of the biopsy, this is reflective of the fact that biopsy is a sampling technique . Studies report biopsy mis-staging to be in the range of 10% to 33% . in this case, we assume 20% mis-staging . if 20% of biopsy samples are mis-staged, then the discordances between MRE and biopsy may decrease . However, for simplicity, we still assume that the discordance between MRE and biopsy would not change .

Conclusion

MRE is non-invasive and provides tissue stiffness information for the entire liver . it avoids the discomfort and risk of complications associated with other invasive procedure . in addition, elastograms that overlay tissue stiffness images over the anatomy avoid sampling error and provide richer information that could assist in diagnosis . Studies show that the technique has excellent sensitivity in depicting the elevated stiffness associated with hepatic fibrosis . Stiffness of normal liver tissue is very soft and comparable to that of subcutaneous fat . Studies have also shown that hepatic steatosis, a common condition, does not have a significant influence on liver stiffness and therefore does not confound the elastographic findings observed in fibrosis . in summary, the evidence supports the use of MRE as a triaging option for liver biopsy . The accuracy and the noninvasive nature of the technology offer the promise that MRE could improve outcomes, potentially at lower costs .


Follow-up


Biopsy (105.6)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome



(19.2)

Scenario3



Biopsy = $136,704 + 0 .2 x 96 x $1424

= $136,704 + $27,341

= $164,045

MRE = $123,100


References

1 Kim, W .R ., et al . Burden of liver disease in the United States: summary of a workshop . Hepatology 36, 227–242 (2002) .

2 Shaheen, n .J ., et al . The burden of gastrointestinal and liver diseases . Am J Gastroenterol 101, 2128–2138 (2006) .

3 Rockey, D .c ., et al . liver biopsy . American Association for the Study of liver Disease (AASlD), position paper, 2009 .

4 Bravo, A .A ., et al . liver biopsy . N Engl J Med 344(7), 495-500 (2001) .

5 Smith, J .o ., Sterling, R .K . Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis c . Aliment Pharmacol Ther 30(6), 557-76 (2009) .

6 Stebbing, J ., et al . A meta-analysis of transient elastography for the detection of hepatic fibrosis . J Clin Gastroenterol 44(3), 214-9 (2010) .

7 carlson, J .J ., et al . An evaluation of the potential cost-effectiveness of non-invasive testing strategies in the diagnosis of significant liver fibrosis . J Gastroenterol Hepatol 24(5), 786-91 (2009) .

8 Talwalkar, J .A . Elastography for detecting hepatic fibrosis: options and considerations . Gastroenterology 359(1), 299-302 (2008) .

9 Yin, M, . et al . Assessment of hepatic fibrosis with magnetic resonance elastography . clin Gastroentero 5(10), 1207-1213 (2007) .

10 Afdhal, n .H ., nunes, D . Evaluation of liver fibrosis: a concise review . Am Gastroentero, 99(6), 1160-74 (2004) .

11 Bruguera, M ., et al . A comparison of the accuracy of peritoneoscopy and liver biopsy in the diagnosis of cirrhosis . Gut 15, 799-800 (1974) .

12 poniachik, J ., et al . The role of laparoscopy in the diagnosis of cirrhosis . Gastrointest Endosc 43, 568-71 (1996) .

13 pagliaro, l ., et al . percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis . Dig Dis Sci, 28, 39-43 (1983) .

14 olsson, R ., et al . Sampling variability of percutaneous liver biopsy in primary sclerosing cholangi-tis . J Clin Pathol 48, 933-5 (1995) .

15 Angelucci, E ., et al . needle liver biopsy in thalassemia: analyses of the diagnostic accuracy and safety in 1184 consecutive biopsies . Br J Haematol 89, 757-61 (1995) .

16 Abdi, W ., et al . Sampling variability on percutaneous liver biopsy . Arch Intern Med 15, 329-35 (1979) .

17 Maharaj, B ., et al . Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver . Lancet 1, 523-5 (1986) .

18 perrault, J ., et al . liver biopsy: complications in 1000 inpatients and outpatients . Gastroenterology 74, 103-106 (1978) .

19 McGill, D .B ., et al . A 21-year experience with major hemorrhage after percutaneous liver biopsy . Gastroenterology 99, 1396-1400 (1990) .

20 Ehman, E .c ., et al . Vibration safety limits for magnetic resonance elastography . Phys Med Biol 53(4), 925-935 (2008) .

21 Wong, J ., et al . pretreatment evaluation of chronic hepatitis c: risk, benefits, and costs . JAMA 280, 2088–93 (1998) .

22 Myers, R .p ., et al . Utilization rates, complications and costs of percutaneous liver biopsy: a population-based study including 4275 biopsies . Liver Int, 705-12 (2008) .

23 DeKoven, M . cost comparison: liver biopsy versus abdominal MRi . Memo to GE Healthcare from iMS Health incorporated . May 25, 2010 .

24 Huwart, l ., et al . Magnetic resonance elastography for the non-invasive staging of liver fibrosis . Gastroenetrology, 135(1), 32-40, (2008) .



Sound diagnosis has a new look.

GE Healthcare

MRElastography—apictureofconfidenceToday, a new technique known as MR elastography can capture a compelling visual image of the liver, using sound waves to detect the stiffness of tissue that can indicate liver disease .

HowelastographyworksThe image is captured in as little as 14 seconds, or one breath hold, in three steps:

A special MRi technique images minute displacements of the tissue that result from wave propagation .

A simple, drum-like driver generatesacoustic waves within the tissueof interest .

An advanced mathematical technique generates maps of tissue stiffness, known as “elastograms .”

30

31

IntroducingMR-TouchMR-Touch, a new visual palpation device from GE Healthcare, is the first commercial product for MR elastography .*

conventional MR liver image of normal liver

conventional MR liver image with liver disease

new MR-Touch elastogram of a normal liver

new MR-Touch elastogram with liver disease

* Available on the optima MR450w (pictured here) .

ForReferringPhysicians:A sound alternative

MR-Touch gives referring physicians a powerful new option for liver assessment . its non-invasive examination will help to minimize discomfort and reduce the potential risk of infection, while enabling more frequent evaluation when closer monitoring is needed .

ForRadiologists: A sound diagnosis

By creating a profound visual represen tation of liver tissue stiffness, MR-Touch helps radiologists deliver a more confident diagnosis . At the same time, it helps expand the role of radiology into new areas .

ForAdministrators:A sound investment

MR-Touch enables diagnostic procedures at a lower cost than previous techniques . Both comprehensive and non-invasive, the technique can appeal to patients and referring physicians, helping to drive additional procedures, referrals, and revenue .

soft

hard

It sounds like the future. But it is here today.While MR elastography is an innovative technology, an investment in MR-Touch can bring immediate clinical value to organizations dedicated to clinical excellence .

For patients, clinicians and administrators, MR-Touch represents a sound choice today — no matter how you look at it .

GE Healthcare 3000 north Grandview Waukesha, Wi 53188 USA

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3348 SignapUlSE • Spring 2008

on few occasions, medical advancements bring together the new with the old . This is the case with MR-Touch . More than just an a new pulse sequence, MR-Touch, is an MR elastogra-phy (MRE) technique that brings together advanced MR imag-ing with the age-old clinical skill of touch palpation .

MR-Touch provides an imaging counterpart to the physical examination technique called palpation . For centuries, clinicians have used simple touch to assess the mechanical properties of tissue, and this has served as an incredibly powerful diagnostic tool to detect diseases . MR-Touch allows physicians to assess these same tissue properties at a much higher sensitivity than can be achieved by palpation and in regions of the body that are inaccessible to palpation .

MRelastography–whatisit?

invented at Mayo clinic (Rochester, Mn), MRE is a technology that employs low frequency mechanical sound waves in combination with MRi to probe the mechanical properties of tissue . The technique is implemented as a software and hardware upgrade to a conventional MR scanner and can be easily included in standard MRi protocols .

During MRE acquisition, mechanical waves in the range of 40 Hz to 200 Hz are generated in the tissues of interest using a compact, nonmetallic MR compatible acoustic driver device that is placed in contact with the body . The vibration causes no discomfort and has an amplitude that is typically less than 0 .1 mm, falling well within established safety limits for vibration exposure .1 A special phase-contrast MRi sequence is used to image the pattern of propagating mechanical waves within the body . This sequence is capable of depicting waves with amplitudes as small as the wavelength of light .2 Advanced software algorithms are then used to automatically process the wave information to create “elastograms,” which represent tissue stiffness on a color scale .

The special cyclic motion sensitizing gradients that are used for wave imaging can be potentially incorporated into virtually any MR pulse sequence, including spin echo, gradient echo, and echo-planar methods . The MRE sequence is also compatible with parallel-imaging and motion artifact reduction techniques such as gradient moment nulling and spatial pre-saturation .

Advances in medicine come about in a variety of ways: new technologies that allow clinicians to visualize body structures and functions they’ve never seen before, novel therapies that bring new hope to patients, and basic advances in the understanding of the molecular basis of disease that offer physicians new capabilities in prediction and prevention of illness .

A new Touch for MR imaging

i S S U E S p o T l i G H T M R E l A S T o G R A p H Y

3449A GE Healthcare MR publication • Autumn 2008

Figure1: MR elastography is used here to characterize the relative stiffness in soft tissue . Toprow: conventional MR images of two different individuals . Centerrow: Mechanical waves are generated in the upper abdomen with an acoustic driver device and imaged with the MRE technique . Bottomrow: The wave information is processed to generate “elastograms,” showing the stiffness of tissue . The patient on the right has elevated tissue stiffness, consistent with moderately advanced liver disease . The patient on the left has a normal liver stiffness appearance .

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Figure2: Left: conventional MR image shows a mass in the liver . Center: Mechanical waves are imaged in the liver, using an MRE sequence . Right: The wave information is processed to generate an elastogram, which indicates that the mass (arrow) is very hard, consistent with a malignant tumor .

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Discussion

With the advent of MRi, radiologists learned to understand the basic T1, T2, and proton density contrast provided by this modality and how it could be used to depict anatomy and characterize tissues . Yet that was just the beginning . over the years, researchers have introduced techniques for imaging many new properties including, chemical shift, flow, diffusion, perfusion, and BolD contrast, yielding powerful new diagnostic applications .

MRE provides a different type of contrast – tissue stiffness . initial exploration of this new capability has focused on diseases that are already known to cause local changes in tissue stiffness . MRE is a non-invasive, pain free procedure . The addition of MRE to a standard MRi protocol enhances the comprehensive nature of the diagnostic exam . countless other applications remain to be explored .3

At Mayo clinic, Richard Ehman, MD, and colleagues have been evaluating MRE to non-invasively measure tissue stiffness (Figure 1) . Dr . Ehman and his group are also exploring many other applications of MRE (Figure 2) .

in recent years, researchers have become more aware of the profound way in which the mechanical environment of tissue affects the behavior of cells . Abnormal tissue stiffness is now thought to contribute to the development of many diseases . MRE provides access to a new, largely unexplored, set of imaging biomarkers that await investigation . n

References:

1 . Ehman Ec, Rossman pJ, Kruse SA, et al . Vibration safety limits for magnetic resonance elastography . phys Med Biol 2008;53(4):925-935 .

2 . Muthupillai, R ., D .J . lomas, p .J . Rossman, et al . Magnetic resonance elastography by direct visualization of propagating acoustic strain waves . Science, 1995 . 269(5232): p . 1854-1857 .

3 . Talwalker JA, Yin M . MR Elastography inspires new wave of hepatic imaging . Diagnostic imaging 2008; 30(8):20-27 .

4 . Venkatesh SK, Yin M, Glockner JF, et al . MR elastography of liver tumors: preliminary results . American Journal of Roentgenology . 2008;190:1534–40 .

Lloyd Estkowski, MR manager for Body Applications at GE Healthcare, contributed to this article.

M R E l A S T o G R A p H Y i S S U E S p o T l i G H T

35

GE Healthcare

Drop a pebble in a pool of water Drop a pebble in a pool of gel

Wave Length

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New Touch in MR Imaging – extension of diagnosing by Touch

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Shear waves generated by external acoustic driver.

Shear waves transmitted to tissue by passive driver.

Inversion algorithm used to convert wave images into stiffness map

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MEG gradient synchronized with external acoustic vibrations

Shear waves captured using phase contrast gradients GRE with modified cyclic motion-encoding gradients

Motion Synthesis

MR-Touch - Implementation

MR Elastography - Concept

3663A GE Healthcare MR publication • Spring 2010

The Sound Diagnosisno matter how you look at it, MR Elastography can provide new information and options – and it’s here today

By Vinod S. Palathinkara, PhD, Lloyd Estkowski, and David W. Lee, PhD

While MR Elastography (MRE) is an innovative technology, an investment in MRE can bring immediate clinical value to patients . MRE gives referring physicians a powerful new option for liver assessment . it is a new tool that provides diagnostic informatioin without the discomfort and risk of complications due to invasive procedures, enabling more frequent evaluation when closer monitoring is needed . By creating a vivid visual representation of liver tissue stiffness, MRE helps radiologists deliver a more confident diagnosis . MRE enables diagnostic procedures at a lower cost than previous techniques . Both comprehensive and non-invasive, the technique can appeal to patients and referring physicians,

and can help expand the role of radiology into new areas . More than anything else, MRE holds the promise of better outcomes at lower costs to the overall healthcare system .

chronic liver disease and cirrhosis are major public health problems worldwide . in 2004, these conditions were associated with nearly 40,000 deaths and a cost of at least $1 .4 billion for medical services in the U .S . alone .1,2 These figures are expected to increase due to aging, obesity, and end-stage liver disease caused by chronic hepatitis c infection . The major biological process responsible for clinical liver disease is progressive hepatic fibrosis .


is effective for distinguishing normal, soft-liver tissue from stiff fibrotic liver tissue with a very high negative predictive value . The severity of increased stiffness was shown to allow moderate to severe fibrosis to be distinguished non-invasively from mild fibrosis .

it is important to assess the accuracy of MRE in relation to the accuracy of liver biopsy . A review of the available data on the accuracy of needle liver biopsy to define the stage of fibrosis reveals that significant sampling and interpretive error affects the assessment of liver biopsy . needle liver biopsy assesses only about 1/50,000 of the volume of the liver and so it may be affected by substantial sampling error .9 Autopsy and laparoscopy studies that have evaluated the accuracy of liver biopsy for staging fibrosis and diagnos-ing cirrhosis have clearly shown that cirrhosis is missed on a single blind liver biopsy in 10% to 30% of cases .10,11,12,13,14 The

Figure1. Mean shear stiffness measurements of the liver for normal volunteers and patients at different fibrosis stage

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liver biopsy is the current gold standard for detecting hepatic fibrosis . There are, however, limitations with the technique that include poor acceptance by patients, measurement errors, and cost .3,4 current non-invasive alternatives to liver biopsy are serum-based testing,5 which is not reliable for detecting early disease, and transient ultrasound elastography,6 which has technical limitations in patients with obesity and conditions such as ascites . 21

MRE, a technique developed by Richard Ehman, MD, and colleagues at Mayo clinic (Rochester, Mn), uses low-frequen-cy mechanical waves to probe the elastic properties of tissue . These mechanical waves are generated in the body through an external acoustic driver, which are then imaged using a special phase-contrast MR sequence . Using a sophisticated mathematical algorithm, the mechanical wave data collected by the MR is then used to generate an

“elastogram,” – a diagnostic image that depicts tissue stiffness .

in its spirit of bringing the latest technology to clinicians, in July 2009, GE Healthcare commercially launched MR-Touch, an MR-Elastography (MRE) application, available on the optima MR450w and Signa HDxt systems . GE Healthcare is currently working to expand its availability to other 1 .5T systems .

ClinicalvalueofMRE

Yin et al . evaluated the diagnostic performance of an optimized MR elastography protocol for assessing hepatic fibrosis among patients with diverse causes of chronic liver disease and in normal individuals .8 The summary of mean values and variance of liver stiffness from the 35 normal volunteers and 48 patients with chronic liver disease are shown in Figure 1 .

When assessed by stage of fibrosis, the mean liver stiffness value increased systematically with excellent correlation between histologic fibrosis and shear stiffness obtained with MR elastography (R2 = 0 .94, p < 0 .001) (Figure 1) . The study results supported the hypothesis that MR elastography

MRE has the potential to significantly reduce cost as a triage for liver biopsy .

T E c H n i c A l i n n o V A T i o n M A G n E T i c R E S o n A n c E E l A S T o G R A p H Y


complications Risk

Death 1:10,000 – 1:12,000

Bleeding 1:100

Bile leak 1:1,000

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Significant pain 1:10 – 1:20

Figure2.Major complications of liver biopsy3,18,19

majority of this error is due to the under-staging of disease . Both the size of the biopsy and number of biopsies taken have a major effect on accuracy . Abdi et al . report that the correct diagnosis of cirrhosis with a single biopsy increased from 80% to 100% when three specimens were analyzed .15 Similarly, in a study that evaluated the agreement between three biopsies taken at a single setting, Maharaj reported that cirrhosis was identified in all three biopsies in only 50% of the cases .16

Rockey et al . suggest that sampling variability appears to be one of the major limitations of liver biopsy .17 in a study of 124 patients with chronic HcV infection who underwent laparoscopy-guided left and right lobe liver biopsies, 33% of cases had discordant results by at least one histological stage . A smaller but substantial proportion of biopsies were discordant by at least two stages . Similarly, a single liver biopsy specimen may fail to distinguish steatohepatitis from simple steatosis and may mis-stage the disease by one (or less frequently), two stages if the specimen is much smaller than 2 cm . The authors caution that although even small biopsy specimens may be sufficient for diagnostic purposes in certain situations, the possibility that sampling variability exists must be recognized, so that the absence of key findings does not rule out a suspected diagnosis . By showing infor-mation about liver stiffness over one or more cross sections of the entire liver, MR elastography provides a more comprehensive view than before available .

PatientcomfortofMRE

According to Rockey et al ., pain is the most common complication of liver biopsy, occurring in up to 84% of patients .3 The most important complication of liver biopsy is bleeding . Severe bleeding requires hospitalization, has an increased likelihood of transfusion or radiological intervention, or surgery . less severe bleeding is defined as that sufficient to cause pain or reduced blood pressure, but not requiring transfusion or intervention . Mortality after liver biopsy is usually related to hemorrhage and is very uncommon .

MRE does not use contrast or ionizing radiation and provides a completely non-invasive test of liver tissue elasticity, thus

resulting in high patient comfort . According to Ehman at al ., the vibration has amplitude in abdominal tissue that is very small (typically less than 0 .1 mm), and does not cause discomfort .18


Given the novelty of the MRE technology, peer-reviewed academic or medical literature evaluating the potential cost-effectiveness of this non-invasive testing strategy in the diagnosis and management of liver fibrosis is currently limited . There is, however, evidence to suggest that MRE has the potential to lower the overall costs in the management of liver diseases .

carlson et al . used data originally reported by Wong et al . and adjusts for inflation using consumer price index to arrive at an estimated cost of liver biopsy of $1,255*, but this estimate understates the true costs of a liver biopsy because it excludes procedure-related morbidities .7,19 Myers et al . used administrative databases from a large canadian Health Region to identify percutaneous liver biopsies performed between 1994 and 2002 .20 The study found that between 1994 and 2002, 3,627 patients had 4,275 liver biopsies . Thirty-two patients (0 .75%) had significant biopsy related complications . The median direct cost of a hospitalization for complications was $4,579 canadian (range $1,164-$29,641) .

As a new technology, MRE is currently not reimbursed with its own cpT code* . Because the acquisition time is very short, the addition of MRE for liver evaluation into a conventional MRi examination protocol adds very little to the typical examination time of 30 to 45 minutes . if MRE is not reimbursed any more than a typical abdominal MRi

in liver biopsies, the absence of key findings does not rule out a suspected diagnosis .

*Figures associated with US rates of reimbursement . not globally applicable .

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1 . Kim WR, Brown RS Jr, Terrault nA, et al . Burden of liver disease in the United States: summary of a workshop . Hepatology 2002; 36:227–242

2 . Shaheen nJ, Hansen RA, Morgan DR, et al . The burden of gastrointestinal and liver diseases, 2006 . Am J Gastroenterol . 2006;101:2128–2138 .

3 . Rockey Dc, celdwell SH, Goodman ZD, et al . liver Biopsy . American Association for the Study of liver Disease (AASlD) position paper, 2009 .

4 . Bravo AA, Sheth SG, cehopra S . liver biopsy . N Engl J Med . 2001; Feb 15;344(7):495-500 .

5 . Smith Jo, Sterling RK . Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis c . Aliment Pharmacol Ther . 2009; Sept 15;30(6):557-76 .

6 . Stebbing J, Farouk l, panos G, et al . A Meta-analysis of Transient Elastography for the Detection of Hepatic Fibrosis . J Clin Gastroenterol . 2010 Sept 9 .;44(3):214-219

7 . cerlson JJ, Kowdley KY, Sullivan SD, Ramsey SD, Veenstra Dl . An evaluation of the potential cost-effectiveness of non-invasive testing strategies in the diagnosis of significant liver fibrosis . J Gastroenterol Hepatol. 2009 May;24(5):786-91 .

8 . Yin M, TalWalkar JA, Glaser KJ, et al . Assessment of Hepatic Fibrosis with Magnetic Resonance Elastography . Clin Gastroenterol and Hepatol. 2007;5(10):1207-1213 .

9 . Afdhal nH, nunes D: Evaluation of liver Fibrosis: A concise Review . Am J Gastroenterol. 2004 Jun;99(6):1160-74

10 . Bruguera M, Bordas JM, Mas p, et al . A comparison of the accuracy of peritoneoscopy and liver biopsy in the diagnosis of cirrhosis . Gut 1974; 15:799-800 .

11 . poniachik J, Bernstein DE, Reddy KR, et al . The role of laparoscopy in the diagnosis of cirrhosis . Gastrointest Endosc. 1996;43:568-71 .

12 . pagliaro l, Rinaldi F, ceraxi A, et al . “percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis . Dig Dis Sci. 1983;28:39-43 .

13 . olsson R, Hagerstrand i, Broome U, et al . Sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis . J Clin Pathol. 1995;48:933-5 .

14 . Angelucci E, Baronciani D, lucarelli G, et al . needle liver biopsy in thalassemia: Analyses of the diagnostic accuracy and safety in 1184 consecutive biopsies . Br J Haematol. 1995;89:757-61 .

15 . Abdi W, Millan Jc, Mezey E . Sampling variability on percutaneous liver biopsy . Arch Intern Med. 1979;15:329-35 .

16 . Maharaj B, Maharaj RJ, leary Wp, et al . Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver . Lancet. 1986:1:523-5 .

17 . Rockey Dc, celdwell SH, Goodman ZD, nelson Rc, Smith AD . liver Biopsy . American Association for the Study of liver Disease (AASlD) position paper, 2009 .

18 . Ehman Ec, Rossman pJ, Kruse SA, et al . Vibration safety limits for magnetic resonance elastography . Phys Med Biol. 2008;53(4):925-935 .

19 . Wong J, Bennet W, Koff R, et al . pretreatment evaluation of chronic hepatitis c: Risk, Benefits, and costs . JAMA. 1998 Dec 23-30; 280(24):2088–93 .

20 . Myers Rp, Fong A, Shaheen AAM . Utilization rates, complications and costs of percutaneous liver biopsy: a population-based study including 4275 biopsies . Liver Int. 2008 May;28(5):705-12 .

21 . Talwalker JA . Elastography for detecting hepatic fibrosis: options and considerations . Gastroenterology . 2008 Jul; 35(1):299-302 .


scan, the reimbursement for a valid MRE scan would be similar to the 2010 national Medicare average payment rate for an abdominal MRi, i .e . $628 (cpT code 74183) . At this stage, there is no way to predict the willingness of payers to cover the procedure and the level of reimbursement .

MRE has the potential to significantly reduce cost as a triage for liver biopsy . The information MRE provides could be used to assess if and when a patient should undergo liver biopsy . if one assumes that the cost of a liver biopsy is $1,255 and the cost of an MRE would be $628, then MRE would lower costs by at least 15% if it successfully avoids approxi-mately two-thirds of unnecessary biopsies (Figure 3) . Yin et al . showed that MRE has high predictive value in distinguish-ing stiffness associated with normal liver tissue .8 Even though liver biopsy is accurate in identifying fibrosis, due to its basis as a sampling technique, absence of evidence of fibrosis from biopsy does not rule out fibrosis . MRE may also be a useful tool that helps guide clinicians in localizing the area of biopsy . if MRE achieves a 65% success rate in triaging, it would reduce the total costs by approximately 15% . With a negative-predictive value8 of 97% (95% ci, 83 .8%-99 .8%), the threshold of 65% for MRE is far less than the combined true positive, false positive, and false negative rates for MRE .

Conclusion

MRE is non-invasive and provides tissue stiffness information for the entire liver and avoids the discomfort and risk of complications associated with other invasive procedures . in addition, elastograms avoid sampling errors and provide

MRE is effective for distinguishing stiffness . . . with very high negative-predictive value .

Figure3.comparison of direct costs when MRE is used in triaging for biopsy

100 Patients

Liver Biopsy:$1,255

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MRE: $628 65%

Liver Biopsy:$1,255

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richer information that could assist in diagnosis . Studies show that the technique has excellent sensitivity in differentiating stiffness associated with normal liver tissue and fibrotic tissue . Stiffness of normal liver tissue is comparable to that of subcutaneous fat; studies have also not reported any influence of steatosis on tissue stiffness . in summary, the evidence supports the use of MRE as a triaging option for liver biopsy . The accuracy, lower costs, and the noninvasive nature of the technology offer the promise that MRE could improve outcomes at lower costs . n

T E c H n i c A l i n n o V A T i o n M A G n E T i c R E S o n A n c E E l A S T o G R A p H Y

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4118 SignapUlSE • Autumn 2009

chronic liver disease is a major problem worldwide and causes tens of thousands of deaths each year in the United States . An important diagnostic task in assessing patients with suspected liver disease is to detect the presence of hepatic fibrosis, which can often be treated if diagnosed early enough before it progresses to irreversible cirrhosis . The current practice for diagnosing liver fibrosis is needle biopsy . liver biopsy is, however, relatively expensive compared to magnetic resonance imaging (MRi) .1

Hepatic fibrosis is known to increase the stiffness of the liver tissue . Richard Ehman, MD, and colleagues at Mayo clinic (Rochester, Mn), have developed a technique for noninvasively measuring liver tissue stiffness – Magnetic Resonance Elastography (MRE) . This technology, licensed by Mayo clinic, is now being introduced by GE Healthcare . The first commercial MRE application, called MR-Touch, is innovative imaging technology that is available on the optima™ MR450w 1 .5T system .

changing patient Management With MR Elastography

c l i n i c A l V A l U E l i V E R i M A G i n G


Dr. Richard L. Ehman

Richard Ehman, MD, is professor of radiology at the Mayo clinic and serves as a member of the Mayo clinic Board of Governors .

He divides his time between clinical practice, education, and research . His main clinical activity is Magnetic Resonance imaging . His research program is focused on developing new imaging technologies . Dr . Ehman has been principal investigator of several niH grants, holds more than 30 US and foreign patents for his inventions, and has authored more than 200 publications in the scientific literature . He was awarded the Gold Medal of the international Society for Magnetic Resonance in Medicine in 1995 for his research contributions, an honorary Doctor of Science Degree by the University of Saskatchewan in 2000, and the outstanding Researcher Award of the Radiological Society of north America in 2006 .

Dr . Ehman has served as chair of the Radiology and nuclear Medicine Study Section of the niH, and is currently a member of the Advisory council of the national institute of Biomedical imaging and Bioengineering of the niH . He is an Associate Editor of Magnetic Resonance in Medicine, and a member of the editorial boards of several other journals . He served as president of the international Society for Magnetic Resonance in Medicine in 2002-2003 .

MR-Touch employs low frequency sound waves in combination with MRi to probe tissue stiffness . There are three steps to the process: generating acoustic waves within the tissue of interest; imaging the micron level displacements of the tissue that result from wave propagation using a special MRi technique with oscillating motion-sensitizing gradients; and generating maps of the tissue stiffness, known as

“elastograms,” using a mathematical technique developed by Mayo clinic physicians and researchers .

MRE of the liver can be accomplished in an acquisition that lasts only 15 seconds and is easily added to a standard MRi examination of the abdomen . A simple, drumlike acoustic driver is placed in contact with the body . A flexible tube is connected to a driver device outside the scan room that generates low-frequency sound waves in the range of 40 to 90 Hz . The vibration should not cause discomfort and has an amplitude that is typically less than 0 .1 mm, which falls well within established safety limits for vibration exposure .2

in a 2007 publication, the Mayo clinic team reported hepatic fibrosis could be detected with high sensitivity and specificity using the information provided by MRE .3 The team’s findings indicate that MR elastography has a promising ability to help discriminate between tissue stiffness consistent with mild, moderate, and severe fibrosis .

other research groups have reported similar results .4 These studies have also compared the performance of MRE to a method for ultrasound-based measurement of liver stiffness, called transient elastography .5 MRE had a higher rate of technical success compared with ultrasound-based elastography and higher sensitivity and specificity for identifying variations in tissue stiffness consistent with early stages of hepatic fibrosis .4 Unlike ultrasound-based elastography, MRE can be performed successfully in overweight patients and it depicts stiffness in a cross-sectional image of the liver, so it is less likely to be affected by sampling error .6

Figure1. Elastogram on volunteer patient is shown (right) and corresponding anatomic image (left) . in the elastogram, relative stiffness is shown on a color scale, ranging from softest (purple) to hardest (red) . For reference, a dashed outline has been superimposed on the elastogram to indicate the approximate location of the liver . note that the stiffness of normal liver tissue is very low and similar to that of adipose tissue . The spleen is usually considerably stiffer than other tissues, as shown by the corresponding red areas .

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Dr. Jayant A. Talwalkar

Jayant A . Talwalkar, MD, M .p .H ., is associate professor of Medicine, Miles and Shirley Fiterman center for Digestive Diseases, center for Advanced imaging Research, Mayo clinic in Rochester, Mn . Dr . Talwalkar received his MD from the University of illinois in 1993 and completed residency training in internal Medicine at the Mayo clinic in 1996, fellowship training in Gastroenterology at the Brigham and Women’s Hospital in 1999, and advanced training in Hepatology and liver Transplantation at the Mayo clinic in 2000 . He joined the Mayo clinic staff in 2000 . He is a member of editorial boards for Gastroenterology, Hepatology, and liver Transplantation, and is currently chair of the practice Guidelines committee for the American Association for the Study of liver Diseases . Dr . Talwalkar is also the principal investigator of several niH grants related to epidemiologic and imaging aspects of acute and chronic liver disease .

Many conditions can result in progressive hepatic fibrosis . Globally, one of the most important causes of liver disease is chronic hepatitis c infection, which is estimated to affect as many as 170 million people worldwide . While the condition has minimal effects on most individuals, a subset (approximately 25%) develop hepatic fibrosis . MRE has a role in identifying patients with diseases associated with liver stiffness, as they may benefit from antiviral therapy .

A rising problem in developed countries is fatty liver disease, linked to obesity and Type 2 diabetes, now affecting as much as one-third of the US population .7 While fatty liver disease has a benign course in many patients, a subset of people develop steatohepatitis which can lead to progressive liver fibrosis and end stage liver failure .

Researchers are exploring many other applications of MRE, including the potential applications of this new imaging modality for evaluating the brain, heart, breast, and musculoskeletal system .

Conclusion

MRE offers a new type of contrast in MRi, depicting the mechanical properties of tissues . Due to the very short acquisition time, MRE can be included in standard abdominal MRi protocols with minimal impact on exam time . n

References:1 . Taouli B, Ehman Rl, Reeder SB . Advanced MRi Methods for

Assessment of chronic liver Disease . AJR 2009;193:14-27 .

2 . Ehman Ec, Rossman pJ, Kruse SA, et al . Vibration safety limits for magnetic resonance elastrography . phys Med Biol 2008;53(4):925-935 .

3 . Yin M, Talwalkar JA, Glaser KJ, et al . Assessment of hepatic fibrosis with magnetic resonance elastography . clin Gastroenterol Hepatol 2007;5(10):1207-1213 .

4 . Huwart l, Sempoux c, Vicaut E, et al . Magnetic resonance elastography for the noninvasive staging of liver fibrosis .Gastroenterology . 2008 Jul;135(1):32-40

5 . castera l, Vergniol J, Foucher J, et al . prospective comparison of transient elastography, FibroTest, ApRi, and liver biopsy for the assessment of fibrosis in chronic hepatitis c . Gastroenterology 2005; 128:343–350

6 . Talwalkar JA . Elastography for detecting hepatic fibrosis: options and considerations . Gastroenterology 2008; 135:299–302

7 . Ehman Rl . Science to practice: MR Elastography of steatohepatitis in fatty liver disease . Radiology 2009; 253: 1-3 .

Figure2. A 61-year-old with elevated serum liver tests and nonalcoholic fatty liver disease . in this case of advanced liver fibrosis, the elastogram shows that the liver is much stiffer than subcutaneous tissues and overall stiffness of the liver . The heterogeneity of the stiffness of the liver is also increased (compared to volunteer in Figure 1) .

Figure3. A 61-year-old with hepatitis c, cirrhosis, and hepatocellular carcinoma . The oval outline in the anatomic image (left) shows the location of the hepatocellular carcinoma . The elastogram (right) shows a corresponding area of high stiffness in the right lobe of the liver (red arrow), as well as an area of very high stiffness in the left lobe of the liver (green arrow) that is consistent with advanced fibrosis .



are slim when pBc and infection “overlap,” doctors were determined to perform a second transplant . it was unsuc-cessful, and on June 29, 2006, Sarah lost her battle with pBc at only 47 years of age .

Before Sarah died, Deb promised that her sister’s story would help others . “Sarah was a huge patient advocate up until her last breath,” remembers Deb . “She still holds the

torch . Sarah is not able to communi-cate anymore, so i am continuing her work and giving her a voice .”

Hopeonthehorizon

While watching cnn one day, Deb saw a story about Mayo clinic trials of magnetic resonance elastography (MRE) – a technology much like a magnetic resonance imaging (MRi) scan that uses a drum over the area to be examined . The drum generates sound waves that move through stiff and supple tissue at different rates . A computer analyzes the difference, showing what’s healthy and what’s not on a color scale .

Deb decided to fight for the opportu-nity to access MRE . After speaking with Dr . Jayant Talwalkar at the Mayo clinic and telling him about her sister Sarah, Dr . Talwalkar invited Deb to come in for an MRE . He even wrote letters to her insurance company to get partial coverage for the test, as it was still not FDA cleared . in 2007, Deb had

the MRE and saw the condition of her liver for the first time in the almost 10 years she had been battling the disease .

Up until 1998, life had its normal ups and downs for Deb Sobel, who spoke often with her sister, Sarah Jane Kiley, via telephone . They talked about everything from family and politics to business and real estate . However, that was the year their lives – and their conversations – would change forever .

Sarah was diagnosed via a biopsy with primary Biliary cirrhosis (pBc), a rare autoimmune liver disease . Three months after Sarah’s diagnosis, Deb also had a biopsy and was diagnosed with the same disease .

Deciding to seek a second opinion, Deb and Sarah sought out Dr . Marshall Kaplan at new England Medical center in Boston . The doctor confirmed the sisters’ diagnoses, but he also did something that no other doctor had done: He encouraged them to be patient advocates for the rare, little-known disease .

Advocatingforchange

Sarah needed no further encouragement, becoming very involved in the pBc support network . She also became a strong advocate for the pBcers organization and the American liver Foundation, helping hundreds to find the healthcare she so strongly believed they deserved .

“Sarah ran with it and became a full-fledged advocate for helping others with the disease,” explains Deb . “She treated each person she encountered as family .”

After eight years of campaigning for pBc patient rights, Sarah’s condition had become so advanced that she underwent a liver transplant at the cleveland clinic in 2006 . Unfortunately, Sarah devel-oped an infection called pseudomonas, a bacteria, and the transplant was not successful . While the chances of survival

Before Sarah Jane Kiley lost her battle with pBc, she encouraged people to take responsibility for their own health .

The picture That paints a Thousand Words But left a patient Speechless

MRE revealed the extent and distribution of fibrosis in Deb Sobel’s liver .



Gettingthewholepicture

“Seeing my liver and the state of the disease for the first time was a very powerful, emotional moment – it left me speechless,” recalls Deb . “MRE painted a true picture of the pBc progression . i used to be mad at my liver, but then i felt bad for it and decided to protect and take care of it as much as possible .”

While pBc can not be reversed, Deb feels strongly that MRE will help her manage the disease and she is thankful that MRE enabled her doctors to pinpoint the true state of the pBc – as biopsies, she says, can be hit or miss . Knowing exactly what is going on with her body is empowering .

“There are 100,000 women in the United States diagnosed with pBc who could benefit greatly from the MRE technology . it might not have saved Sarah’s life, but it could have helped,” maintains Deb . “i want to carry on the advocacy started by my sister to help women get this test .”

Deb’s passion is further fueled by Sarah’s two daughters who could carry a hereditary component (the disease has a 95% female hereditary component) . She would like to

ensure that her nieces can have the test to track any possibility of the disease and if necessary, begin a management plan .

Sarah and Deb’s efforts will be rewarded soon . As mentioned on the previous pages, GE Healthcare is collaborating with the Mayo clinic to be the first to bring MRE to hospitals and clinics, commercially introduced as MR-Touch .

“i think it’s phenomenal that patients will now have the opportunity to manage their pBc,” continues Deb . “We need to get the word out that GE is making the test possible nationwide, and i hope all hospitals and clinics make the decision to get it .”

For more information about pBc and MRE, and to find out how you can help spread the word, visit the following Web sites:

• pbcers .org

• www .mayoclinic .com/health/magnetic-resonance- elastography/MM00718

• www .liverfoundation .org

Jayant Talwalkar, MD, hepatologist at the Mayo clinic, uses MRE as part of his evaluation in assessing patients with known or suspected chronic liver disease to help determine whether or not a patient should undergo an invasive liver biopsy . “MRE provides additional assessment of liver disease beyond routine lab and imaging tests,” he explains, “so we can more appropriately refer for biopsy .”

Dr . Talwalkar believes the test enables him to assess more patients who may need liver biopsy, and identify patients who are likely to have fibrosis . Because liver biopsy is invasive, some patients with suspected liver disease may decline the procedure . As a result, in some cases, patients with significant liver disease are not properly identified as eligible candidates for appropriate treatment .

The test is particularly useful for patients afflicted with Hepatitis B and c, which can often lead to liver injury .

Since MRE identifies tissue with elevated liver stiffness, and advanced fibrosis or cirrhosis leads to increased liver stiffness, patients with either type of liver disease can still be evaluated and monitored .

“MRE is a better tolerated, noninvasive method to risk-stratify patients who may have symptoms typical of fibrosis, such as elevated liver stiffness,” he explains, “and we can evaluate the need for biopsies, or wait to conduct that first biopsy in the future when evidence typical of hepatic fibrosis first presents on MRE .”

MRE, says Dr . Talwalkar, can provide additional information that clinicians need to improve the management of their patients with chronic liver disease . “our long term goal is to use the information downstream, to better utilize liver tests and procedures and enhance the quality of patient care .”

MRE Helps Guide patient Management



MRE in clinical practice: case Review compendiumMR Elastography (MRE) is a non-invasive method for evaluating tissue elasticity utilizing special phase encoding sequences with an MR system . previously, a physician used palpation, a subjective technique limited to tissue of interest close to the surface, to find and evaluate pathological changes in the targeted tissue . GE launched MR-Touch, its commercial implementation of MRE, in July 2009 .

initially, MRE was used in conjunction with biopsy and other techniques . As physicians become more experienced with MRE in the clinical setting, their confidence in the information obtained with MRE grows stronger . MRE is now routinely used in clinical practice for the evaluation of liver disease at several sites worldwide . The cases reviewed here are collected from sites across the world and illustrate the clinical value of MRE in the evaluation of liver tissue due to many liver diseases .

SitescontributingMREcases

San Diego, cA

Baltimore, MD

Madison, Wi

Yamanashi, Japan

Seoul, Korea

compiègne, France

Singapore

St . paul, Mn

SitescurrentlyusingMRE

Scottsdale, AZ

San Diego, cA

Jacksonville, Fl

Rochester, Mn

Houston, TX

cambridge, United Kingdom

new Delhi, india

SitespendingMREimplementation

Seongnam, Korea

San Bernardino, cA

Dallas, TX

Milwaukee, Wi

pittsburgh, pA

paris, France

Hong Kong



Dr. Russell N. Low

Figure1. (a) MR image from December 2008, initial post-liver transplantation MR . (b) March 2009, liver biopsy shows mild fibrosis .

Figure2.(a) MR image from December 2009, (b) MRE at this time shows stiffness levels consistent with moderate to marked fibrosis .

Figure3. MRE images from March 2010, stiffness levels consistent with marked liver fibrosis . MRE on right suggests recurrent hepatitis c .

Contributor:RussellN.Low,MD,MedicalDirectorSharpandChildren’sMRICenter,SanDiego,CA

Case1: A 55-year-old man with rising liver function tests; two years post liver transplantation . The patient had many MR exams that show mild Splenomegaly and a normal appearing liver .

MREFinding: The elastogram showed abnormal liver stiffness that is consistent with fibrosis from reinfection with hepatitis c . Results were confirmed by liver biopsy .

SitespendingMREimplementation

Seongnam, Korea

San Bernardino, cA

Dallas, TX

Milwaukee, Wi

pittsburgh, pA

paris, France

Hong Kong


a

a

a

b

b

b


Dr. Susanne Bonekamp

Contributor:SusanneBonekamp,DVM,PhD,ResearchAssociateintheDivisionofClinicalMRI,DepartmentofRadiology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD

Case1: A 50-year-old female patient with hepatitis c and HiV co-infection . patient received biopsy 89 days after MRE (as part of a research study) .

MREFinding: Elastogram is consistent with that of mild fibrosis . Biopsy showed steatosis, inflammation, and mild fibrosis (F1) .

Case2: A 47-year-old male patient with hepatitis c and HiV co-infection . patient received biopsy 48 days after MRE (as part of a research study) .

Figure4a. MRi with color coded wave . Figure4b. MRi with elastogram .

Figure5a. MRi magnitude image . Figure5b. MRi with elastogram .

MREFinding: Elastogram shows stiffness consistent with that of severe fibrosis (METAViR F4), 5–30% macrovascular fat, and mild necroinflammatory activity (overall MHAi=6) .



Dr. Utaroh Motosugi

Figure6a. Arterial-phase image of gadoxetic acid-enhanced MRi .

Figure6b. Hepatocyte-phase after gadoxetic acid-administration .

Figure6c. MRE .

Contributor:UtarohMotosugi,MD,PhD,AssistantProfessor,DepartmentofRadiology,UniversityofYamanashi,Yamanashi,Japan

Case1: A 52-year-old female with clinically suspected primary biliary cirrhosis for seven years . Blood exam showed elevated Alp, anti-mitochondria antibody, and igM .

Alkaline phosphatase (Alp): 712 iU/l (normal range: 100-248) anti-mitochondria antibody: > 320 (normal range: < 20) igM: 311 mg/dl (normal range: 35-225) Total bililbin: 0 .6 mg/dl (normal range: 0 .3-1 .3)

MREFinding: Based on the MRE, the mean stiffness for the region of interest did not indicate the onset of liver fibrosis . The planned biopsy to confirm liver fibrosis was deemed unnecessary and postponed .

Case2: An 81-year-old male without history of liver disease: HBs-Ag (-), HcV-Ab (-), non-alcohol drinker, and no history of fatty liver disease .

Dynamic MRi using gadoxetic acid; Slight hypervascularity on arterial-phase image in the hepatic dome with subsequent hypointensity, suggesting hepatocellular carcinoma (Hcc) .

MREFinding: MRE showed mean stiffness consistent with liver cirrhosis, which gave the radiologist more confidence in the diagnosis of Hcc .

Figure7.



Dr. Jeong Ming Lee

Contributor:JeongMingLee,MD,AssociateProfessor,SeoulNationalUniversityHospital,Seoul,Korea

Case1: A 14-year-old with glycogen storage disease . conventional MRi is not able to show definite changes of fibrosis .

MREFinding: Elastogram indicates liver stiffness consistent with significant fibrosis . pathology reveals F3 fibrosis .

Case2: A 69-year-old male Hepatocellular carcinoma (Hcc) with central necrosis .

Figure8.

Figure10.

Figure11.

Figure9.

MREFinding: Elastogram shows elevated liver stiffness for the tumor and liver parenchyma, consistent with stage 1 fibrosis (F1) . pathology confirmed that this tumor was grade iii Hcc, and the liver showed no evidence of severe fibrosis .



Dr. Scott Reeder

Contributor:ScottReeder,MD,PhD,AssociateProfessor,SectionChiefofMRI,DepartmentofRadiology,UniversityofWisconsin-Madison,Madison,WI

Case1:A 27-year-old male with increased AlT (241) and AST (79) and a BMi of 27kg/m2

MREFinding: The MRE stiffness is normal; chemical shift based imaging with T2* correction shows marked dropout of signal on the opposed phase image demonstrating the presence of severe steatosis; R2* map (=1/T2*) shows a normal T2* (27ms) . The biopsy shows severe steatosis and no fibrosis or inflammation, and therefore the biopsy is concordant with MRE . in this case, MRE successfully differentiated (the tissue stiffness) between isolated steatosis and steatohepatitis .

Figure12.Marked dropout of signal on the opposed phase image demonstrates the presence of severe steatosis .

Figure13.(a) T2 with fat sat, (b) in phase, (c) elastrogram

Case2: A 10-year-old pediatric patient with abdominal pain .

MREFinding: MRE study shows highly elevated stiffness . chemical shift based imaging with T2* correction and long T2* (40ms) is consistent with steatosis and edema . overall, the combined findings of MRE and chemical shift based imaging fit a clinical picture of acute steatohepatitis from non-alcoholic fatty liver disease . These findings were confirmed with biopsy that demonstrated severe steatohepatitis with severe bridging and pericellular fibrosis, most consistent with nonalcoholic fatty liver disease .


a b c


Figure14.

Dr. Sabine F. Bensamoun

Dr. Fabrice Charleux

Contributors:SabineF.Bensamoun,MD,PhD,ResearcherCNRSintheBiomechanicsandBioengineeringLaboratoryattheUniversityofTechnologyofCompiègne,Compiègne,FranceandFabriceCharleux,MD,MRIradiologist,DepartmentofRadiology,PolyclinicSt.Côme,Compiègne,France

Case1: A 54-year-old, female, alcoholic . Fibroscan and Fibrometer revealed a liver fibrosis stage F4 .

MREFinding: The mean stiffness for the region of interest was consistent with that of stage F4 liver fibrosis, thus confirming the diagnosis . The patient was placed in detoxification therapy during three weeks .

Acknowledgement

The editor sincerely acknowledges the support and encouragement of Richard Ehman, MD, The Mayo clinic, and Adrian Knowles and Vinod palathinkara, phD, from GE Healthcare in developing this case review . n



St . paul Radiology, p .A . (SpR) is a large sub-specialized radiology group with an emphasis on abdominal imaging, including liver, pancreas, biliary mass characterization, cT and MR enterography for crohn’s disease and cT colonography . in the Fall of 2009, SpR introduced MRE to the hepatology community in the Minneapolis and St . paul metropolitan area . The early introduction of MRE to the community practice is the result of a partnership between MRE’s pioneer, Richard Ehman, MD, Mayo clinic Rochester, and SpR’s peter Wold, MD, and Armen Kocherian, phD .

prior to MRE, only end stage hepatic fibrosis (i .e ., cirrhosis) was detected via ultrasound, cT or MRi, Dr . Wold explains . “With MRE we can now detect subclinical hepatic fibrosis and help the hepatologist triage the patient appropriately, and this sets us apart from other practices in the area,” he adds .

SpR’s commitment to liver imaging caught the attention of Minnesota Gastroenterology, p .A . (MnGi), the area’s largest provider of gastroenterology services . in Spring 2010, MnGi created a dedicated liver clinic that offers ultrasound-based Hcc screening and asked SpR to provide professional

services . MR elastography has gained gradual acceptance by MnGi’s hepatologists as an effective non-invasive tool for evaluating hepatic fibrosis . According to Dr . Wold, “MRE has solidified our imaging practice’s liver service line and has made a positive contribution to the care of patients with chronic liver disease . The continued referrals and increasing volumes indicate to me that MRE is helping the hepatologist treat their patients .”

coleman Smith, MD, FRAcp, hepatologist with MnGi, agrees with Dr . Wold’s assessment that an elastogram offers a prognosis of the patient’s disease that helps him clarify patient management . “MRE also allows us to more carefully select the patients who should consider biopsy,” he adds MRE is also useful to gain knowledge of a patient’s fatty liver disease in situations where there is no other course of action—specifically patients who refused biopsy or have contraindications, Dr . Smith explains . “With MRE, we can determine if they have just fat in the liver or if fat has led to scarring or fibrosis, which can potentially lead to cirrhosis .”

MRE in clinical practice: MRE Strengthens practice Service line



Dr. Peter B. Wold

Dr. Coleman Smith

Case1.

Case2.

Contributors:PeterB.Wold,MD,BodyImagingSection,St.PaulRadiology,andColemanSmith,MD,HepatologySectionHead,MinnesotaGastroenterology,P.A.,St.Paul,MN

Case1: A 43-year-old man with elevated lFTs and positive HcV anti-body is referred for hepatology consult . Additional testing showed non-detectable HcV viral load . positive HcV antibody consistent with either false positive or spontaneous clearance of HcV infection .

MREFinding: MRE is consistent with mild to moderate fibrosis . Diffuse hepatic steatosis also present at out-of-phase gradient MRi (middle) .

clinical data and MRi suggest nonalcoholic steatohepatitis (nASH) possibly complicated by fibrosis . liver biopsy ordered to exclude more advanced liver disease . pathology results revealed moderate steatosis, mild necroinflammatory activity, and moderate hepatic fibrosis . Biopsy confirms nASH complicated by fibrosis as suggested by MRE .

Case2: A 57-year-old man with chronic HcV and stage i-ii hepatic fibrosis diagnosed at biopsy four years prior presents for hepatology consultation with question of recanalized umbilical vein at recent ultrasound . if present, a recanalized umbilical vein would be an indication to screen endoscopically for esophageal varices .

MREFinding: MRE yields liver stiffness consistent with stable stage i-ii fibrosis . liver morphology is normal and there are no manifestations of portal hypertension at MRi (middle) .


55SignapUlSE • Autumn 2010

By Sudhakar K Venkatesh, MD, FRCR, Department of Diagnostic Imaging and Seng Gee Lim, MD, FRACP, Department of Gastroenterology and Hepatology, National University Health System

MRE in clinical practice: Evaluating liver Fibrosis without Biopsy

Introduction

The management of chronic hepatitis B and c involves identifying patients at risk of disease progression as not all patients develop complications of liver disease . Guidelines on patient selection for therapy rely on the presence of liver inflammation and fibrosis . liver inflammation can be evaluated through the use of serum tests . The gold standard for diagnosis of liver fibrosis is liver biopsy .

liver biopsy has potential complications and consequently patients are often anxious and prefer to avoid this invasive procedure . chronic hepatitis is treated with antiviral therapy . Many patients with minimal or no fibrosis defer therapy due to the high expense and known side effects of antiviral treatment, but opt for therapy if they have advanced fibrosis . Some patients may also want to know their degree of fibrosis as a general indicator of prognosis . in these cases, the confirmation and accurate staging of disease is necessary .

The traditional gold standard to diagnose and stage chronic liver disease is liver biopsy and consensus groups recommend the routine performance of liver biopsy prior to the initiation of antiviral therapy for chronic hepatitis .1,2 However, the study by Andriulli et al of 535 patients with viral hepatitis3 showed that knowledge of the grade and stage of chronic hepatitis were considered of value by the treating physician in only approximately 60% of cases, and antiviral treatment was not changed in 81% of patients . in another study, Saadeh et al show that while biopsy provided useful information regarding staging, prognosis, and treatment decisions, the biopsy did not yield new diagnoses in patients with chronic hepatitis .4

liver biopsy is associated with pain in 30%, severe complications in three per 1,000, and death in three per 10,000 patients .5 in addition, sampling variability is one of the major limitations of liver biopsy . Recent studies suggest that biopsy is approximately 80% accurate in staging liver fibrosis and may even miss advanced fibrosis of cirrhosis in 30% of patients .6 This implies that patients with chronic hepatitis who are candidates for antiviral therapy face a decision to undergo a procedure for which there is much apprehension, a finite complication rate, personal and societal costs, and the potential for inaccurate information on disease staging or a missed diagnosis .

A new option for evaluating liver fibrosis is MR Elastography (MRE) . MRE non-invasively measures liver stiffness by employing low frequency sound waves in combination with MRi to generate “elastograms .” Elastograms are maps of tissue stiffness shown on a color scale ranging from soft to hard .

The following study describes the initial experience of non-invasive evaluation of liver fibrosis with MRE in patients who refused or had contraindications for liver biopsy .

ClinicalStudy

Thirty-eight patients with chronic hepatitis B (HBV) who refused or had contraindications to liver biopsy underwent an MRE of the liver . liver fibrosis was suspected in 85% of patients; 15% were receiving treatment and referred from other centers for confirmation of liver fibrosis . The patients’ mean age was 57 years . liver function tests were abnormal in 25% and normal in 75% of patients . Due to perceived unacceptable risk, 90% of the patients refused liver biopsy, while liver biopsy was contraindicated in 10% .

18



Dr. Sudhakar K. Venkatesh

Sudhakar K . Venkatesh, MD, FRcR, is Assistant professor of Diagnostic Radiology, national University Health System, Singapore . He graduated from Bangalore University in 1994 and completed residency training in Radiodiagnosis at the University of Delhi in 1997 and fellowship training in Radiodiagnosis at SGpGiMS, lucknow, india in 2000 . He completed his clinical fellowship at national University Hospital in 2002 and was awarded Fellowship of the Royal college of Radiologists (FRcR), london, UK in 2003 . in 2004, he joined the national University Hospital (nUH) . Dr . Venkatesh also completed a one year research fellowship (2006-2007) in MR Elastography at the Mayo clinic (Rochester, Mn) . Dr . Venkatesh’s research interests are in liver diseases, specifically non-invasive imaging such as MRi . Dr . Venkatesh is the principal investigator of a research project for establishing normal liver stiffness in Asian subjects with MRE and its utility in the diagnosis of liver fibrosis and differentiation of focal liver lesions .

Method

MRE was performed at the end of a routine MRi liver study on a 1 .5T MR scanner (GE Healthcare, HDx 15 .0) . The MRE exam involves a liver MRE sequence with four axial sections of 10mm thickness through the largest axial cross section of the liver . Mean stiffness was calculated by placing a region of interest (Roi) on automatically generated stiffness maps excluding liver edges and major vessels .

Results

MRE was successful in all but one patient who had high liver iron content . one experienced radiologist performed the evaluation of the stiffness maps . literature reports were used as guidance for differentiating elevated liver stiffness representative of significant fibrosis . Using MRE, 55% of the patients had liver stiffness indicating fibrosis and 42% of the patients had normal liver stiffness .

Management

liver stiffness from MRE and serum viral DnA levels were considered for management decisions . Among the patients suspected of liver fibrosis, 45% had normal liver stiffness and low serum viral DnA levels and did not receive treatment . Another 16% of patients with mildly elevated liver stiffness and low viral DnA serum levels also received no antiviral therapy and were followed up with regular serum viral DnA and liver function tests . The remaining 38% of patients with elevated liver stiffness and high viral DnA levels received antiviral treatment . Among the six patients who were on antiviral therapy, MRE confirmed fibrosis in four patients and treatment was continued . in two patients with normal liver stiffness, antiviral therapy was stopped in one patient with no detectable serum viral DnA levels while treatment was continued in the other patient with high serum viral DnA levels .

The patients are currently undergoing clinical follow up .

case oneA 67-year-old male with 30-year history of chronic hepatitis B had HBV load <1000 copies/ml . liver function tests were normal . The patient refused percutaneous liver biopsy .

MREFinding

The mean stiffness of the liver was consistent with the absence of fibrosis . The patient is now on regular follow-up .

19


57SignapUlSE • Autumn 2010

Dr. Seng Gee Lim

Seng Gee lim, MD, FRAcp, is Associate professor of Medicine and consultant hepatologist at the national University Health System, Singapore . He also serves as head of the Division of Gastroenterology at nUH and coordinator of the liver research group and is on the editorial boards of liver international, Gastrohep .com, and Medscape . Dr . lim graduated in 1980 from Monash Medical School, Australia, completed his fellowship at the Alfred Hospital and was a clinical Research Fellow at the Royal Free Hospital, london from 1989-1993 . He joined nUH in 1995 . Dr . lim’s current research interests are molecular biology and immunology of hepatitis, hepatitis B natural history, clinical outcomes, and quality of life issues including investigating hepatitis B lifecycle events . Dr . lim is also the principle investigator in multiple clinical trials of new hepatitis B treatments .

AboutthefacilityThe national University Hospital (nUH), a member of the national University Health System (nUHS), is a tertiary specialist hospital that provides advanced, leading-edge medical care and services . Equipped with state-of-the-art facilities as well as dedicated and well-trained staff, the nUH is a major referral center that delivers tertiary care for a wide range of medical and dental specialties including cardiology, Gastroenterology & Hepatology, obstetrics & Gynecology, oncology, ophthalmology, pediatrics and orthopedic Surgery . it is the principal teaching hospital of the nUS Yong loo lin School of Medicine .

1 . national institute of Health consensus Development conference panel statement: management of hepatitis c . Hepatology 1997;26(suppl 1):2S-10S .

2 . European Association for the Study of the liver . consensus statement . EASl international consensus conference on hepatitis c . J Hepatol 1999;30:956-61 .

3 . Andruilli A, Festa V, leandro G, Rizzetto M, and AiGo members, “Usefulness of liver biopsy in the evaluation of patients with elevated AlT values and serological markers of hepatitis viral infection—An AiGo study”, Dig . Dis . Sci . 2001; 46:1409-15 .

4 . Saadeh S, cammell G, carey WD, et al . “The role of liver biopsy in chronic hepatitis c”, Hepatology 2001:33:196-200

5 . piccinino F, Sagnelli E, pasquale G, et al . complications following percutaneous liver biopsy: a multicenter retrospective study on 68,276 biopsies . J Hepatol1986;2:165–73 .

6 . Afdhal, nH, “Staging liver fibrosis: Time to abandon liver biopsy?”, http://www .natap .org/2005/HcV/080905_01 .htm

case TwoA 67-year-old female with chronic hepatitis B presented with high HBV viral load . The patient was allergic to local anesthesia (lignocaine) .

MREFinding

The mean stiffness for the Roi was consistent with that of fibrosis . Antiviral therapy was started without confirmation by liver biopsy .

case ThreeA 58-year-old male with chronic hepatitis B and high HBV load refused liver biopsy .

MREFinding

The mean stiffness of the liver was consistent with that of severe cirrhosis . Antiviral treatment was started one week after MRE .

Summary

For initiation of antiviral treatment, liver stiffness with MRE and viral DnA load influenced clinical decision for antiviral treatment . For patients on antiviral treatment, elevated liver stiffness was interpreted as fibrosis present and antiviral treatment was continued . liver function tests did not influence decision in the majority of patients .

liver MRE provides clinicians useful information for detection of liver fibrosis or confirmation of cirrhosis in the management of patients with chronic liver disease . n

20


58

Introduction

liver biopsy is the most specific test to assess the nature and severity of liver diseases .1 While often considered the reference standard, liver biopsy can yield false-negative results in nearly one-third of cases2,3 and is characterized by a morbidity rate of 3% and a mortality rate of 0 .03% .2 As such, noninvasive methods are being developed as a means for detecting liver fibrosis . Magnetic Resonance Elastography (MRE) is a promising noninvasive technique for evaluating tissue stiffness and liver tissue characterization .4

This study estimated the accuracy needed for MRE to be cost-neutral, as compared to liver biopsy, from a US Medicare perspective .

Methods

We conducted a targeted literature review to identify the full range of services that accompany both a liver biopsy and MRE . A leading hepatologist and pathologist were consulted in order to identify the appropriate procedure codes associated with both modalities . We assumed that MRE would be reimbursed using cpT-4 code 74181 (Magnetic resonance [eg, proton] imaging, abdomen; without contrast material[s]) .5

payment amounts were assigned to the identified procedure codes using the Medicare 2010 physician Fee Schedule, the Medicare 2010 Hospital outpatient prospective payment System,6 and the Medicare 2010 clinical laboratory Fee Schedule . payment rates were subsequently stratified into both payer and patient responsibility, based upon patient out-of-pocket responsibility .

The payment amounts were incorporated into a decision-analytic model that compared the costs for patients with suspected liver fibrosis via two scenarios: 1) biopsy or 2) MRE followed by biopsy when the MRE test was positive . We assumed MRE negative predictive values (npV) of 0 .8, 0 .9 and 0 .95 and patients with a false-negative MRE would ultimately receive a biopsy .

Results

The cost of an ultrasound-guided liver biopsy in the hospital setting, from the US Medicare payer perspective, is $1,443 .68 (ultrasound: $120 .96; surgical: $730 .97; pathology: $271 .10; laboratory: $25 .54; evaluation and management: $295 .11 (Table 1) .

MRE cost Effectiveness: preliminary Threshold Assessment

LiverBiopsyCosts ProfessionalFee FacilityFee Total

Ultrasound $23 .67 $97 .29 $120.96

Surgical (i .e ., biopsy) $79 .38 $651 .59 $730.97

pathology $128 .18 $142 .92 $271.10

laboratory $25 .54 $25.54

physician Evaluation and Management

$127 .59 $167 .52 $295.11

Total $384.36 $1059.32 $1443.68

*cost to Medicare program (80% of allowable charge) excluding cost sharing

By David W. Lee, PhD, Vinod Palathinkara, PhD, GE Healthcare and Mitch DeKoven, IMS Health

Table1:Liverbiopsycosts*


H E A lT H E c o n o M i c S B E Y o n D T H E S c A n


The cost of an MRE (without contrast) in the hospital setting, from the US Medicare payer perspective is $723 .87 while in the non-hospital setting it is $533 .03 . (Table 2)

As shown in Figure 1, MRE potentially saves cost in the hospital setting if the test-negative rate is greater than 63%, 56%, and 53% for npVs of 0 .8, 0 .9, and 0 .95, respectively . in a non-hospital setting, MRE can reduce diagnostic costs when more than 46%, 41%, and 39% of patients have negative MRE results for the corresponding npV values (0 .8, 0 .9, and 0 .95) .

Conclusions

The cost of liver biopsy is substantial as compared to MRE . As a triaging tool, MRE offers the potential to reduce costs of evaluating liver fibrosis . cost saving potential increases with MRE’s negative predictive value and negative test rate . n

Editor’s Note: This study was presented as a poster at the ISPOR 13th Annual European Congress held in Prague, Czech Republic, on November 6 to 9, 2010.

*cost to Medicare program (80% of allowable charge) excluding cost sharing

Table2:MRECosts*

HospitalSetting Non-HospitalSetting

CostCategory ProfessionalFee FacilityFee Total ProfessionalFeeOnly

imaging $58 .89 $349 .53 $408.42 $360 .27

Kidney Function tests $20 .34 $20.34 $20 .34

physician Evaluation and Management

$127 .59 $167 .52 $295.11 $152 .42

Total $206.85 $517.05 $723.87 $533.03

References

1 . Bravo AA, Sheth SG, chopra S . liver Biopsy . n Engl J Med . Feb 15, 2001;344(7):495-500 .

2 . piccinino F, Sagnelli E, pasquale G, Giusti G . complications following percutaneous liver biopsy: a multicentre retrospective study on 68,276 biopsies . J Hepatol 1986;2:165-173 .

3 . poniachik J, Bernstein DE, Reddy KR, et al . The role of laparoscopy in the diagnosis of cirrhosis . Gastrointest Endosc 1996;43:568-571 .

4 . Venkatesh SK, Yin M, Glockner JF, Takahashi n, Araoz pA, Talwalkar JA, Ehman Rl . MR Elastography of liver Tumors: preliminary Results . AJR 2008;190:1534-1540 .

5 . American Medical Association . current procedural Terminology . 2010 professional Edition .

6 . Medicare Hospital outpatient prospective payment

Figure1:MRE vs . liver biopsy—cost neutral comparison; shows MRE test negative rates needed for MRE to be cost-neutral for selected MRE negative predictive values .

70%

60%

50%

40%

30%

20%

10%

0%0.8 0.9 0.95

NegativePredictiveValue(NPV)

MRE

Tes

tNeg

ativ

eRa

te

Hospital setting

non-hospital setting

B E Y o n D T H E S c A n H E A lT H E c o n o M i c S

60


Biopsy (96)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome


Given the novelty of MRE, peer-reviewed academic/medical literature on direct evaluation of potential cost-effectiveness of the technique in the diagnosis and management of liver fibrosis is not yet available . nevertheless, indirect comparisons based on studies that compare stiffness measured using MRE and biopsy results can provide insights . A scenario analysis based on a peer reviewed literature comparing observations of a patient who had both biopsy and MRE is illustrated here .

MRE is currently not reimbursed as a stand-alone test with its own cpT code . Because the acquisition time for MRE is very short, the technique can be readily included in the protocol for an already indicated abdominal MRi exam with little impact of the typical examination time of 30 to 45 minutes . if the entire cost of such an exam is attributed to the MRE procedure, then a conservative estimate of the cost of MRE would be equivalent to the 2010 national Medicare

average payment amount for abdominal MRi, i .e . $628 (cpT code 74183) . At this stage, there is no way to predict the willingness of payers to cover an MRi examination conducted solely to perform MRE .

To better quantify the costs associated with MRE and liver biopsy, a decision-analytic model comparing diagnostic costs was constructed .1 A targeted literature review was conducted and a leading hepatologist and pathologist were consulted to identify the appropriate procedure codes associated with liver biopsy . The study assumed that MRE would be reimbursed* using cpT-4 code 74181 (magnetic resonance [e .g ., proton] imaging, abdomen; without contrast material[s]) . All appropriate allowable charges were assigned to the identified procedure codes using the 2010 Medicare physician Fee Schedule . All costs discussed here are US-based and are not globally applicable . Based on the model, the cost of a guided liver biopsy is $1,424 (ultrasound $164,

Figure1. Flow diagram of patients who underwent liver biopsy and MRE (Huwart et al .) .

MRE cost Effectiveness: A Scenario AnalysisBy Vinod S. Palathinkara, PhD, and David W. Lee, PhD, GE Healthcare

*MRE is currently not reimbursed on its own cpT code .



surgical $881, pathology $347, laboratory $32) and the cost of an MRE (without contrast) is $946 (hospital setting) or $666 (non-hospital setting) .

ScenarioAnalysis

Huwart et al, performed a blind comparison of MRE and liver biopsy for non-invasive staging of liver fibrosis and reported histopathologic staging of liver fibrosis according to the METAViR scoring system as the reference .2 The study analyzed 96 patients who underwent both MRE and liver biopsy (Figure 1) . it should be noted that the initial sample had 141 patients from whom liver biopsy specimens were collected, but only 127 liver biopsy specimens were suitable

for fibrosis staging . This suggests that approximately 10% of the samples from a biopsy specimen may be unsuitable for staging .

We consider three scenarios as a hypothetical example to illustrate the costs of performing MRE for evaluation of liver disease . in scenario 1, we assume that liver biopsy is 100% accurate and the discrepancy in staging between MRE and liver biopsy is entirely due to the errors in MRE . From a cost perspective, this would mean that at some point in time, these patients would require follow-up for a definitive diagnosis . Since we are using biopsy as the reference standard, the cost for the follow-up is assumed to be the cost of a biopsy .


Biopsy (96)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome



Scenario1



Biopsy: 96 x $1,424 = $136,704

MRE: 96 x $946 + 24 x $1,424 = $123,100


Figure3. Hypothetical example of direct costs of MRE and liver biopsy for scenario 2 .


Biopsy (105.6)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome



Scenario2

Biopsy is 100% accurate, but 10% of samples are unsuitable .


Biopsy: 96 x $1,424 + 9 .6 x 1,424

= $136,704 + $13,670

= $150,374

MRE: $123,100 + 2 .4 x $1,424 = $126,518


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Follow-up


Biopsy (105.6)

MRE (96)

F0(22)

F1-2(41)

F3-4(33)

Conforming outcome

Outcome



(19.2)

Scenario3



Biopsy: $136,704 + 0 .2 x 96 x $1,424

= $136,704 + $27,341

= $164,045

MRE: $123,100


Huwart et al, report that in comparing results from MRE and biopsy, 24 of 96 (25%) were misclassified in their stage of fibrosis . Based on the reported sensitivity and specificity of MRE techniques, this misclassification is unusually high . nevertheless, since biopsy is the reference standard, we assume that 25% of patients who underwent MRE would eventually require further evaluation and likely receive a biopsy . We do not consider how one would identify the misclassified patients and ignore the impact on the outcome or the additional treatment costs due to delay in misclassification . our attempt here is to illustrate a methodology that can provide directional information on costs to explore potential for cost reduction rather than to establish or estimate actual cost differentials .

in scenario 1, we assume that biopsy is 100% accurate and all samples are sufficient for diagnosis . This is also considered a worst-case scenario for MRE . The study’s authors highlight the fact that liver biopsy is not an optimal reference examination and that they do not know if the reported discordant results between MRE and histopathology were caused by problems of inadequate biopsy sampling* . The authors also report that the two pathologists who reviewed the biopsy specimen were initially in agreement for 81 of the 96 samples . nevertheless, since biopsy is the reference standard, we assume it provides a clinically accepted basis for comparison .

As reported by Huwart et al, 14 of 141 samples were unsuitable for diagnosis . While many studies recommend a minimum sample length of 25mm, the study reports that 23% of the samples were less than 25mm in length . Thus the scenario that a few biopsy samples would be unsuitable is realistic .

in scenario 2, we assume that to obtain 96 good samples, one would need to do 10% more samples (105 .6 biopsies) . This assumption does not imply that these patients would undergo an immediate repeat biopsy . The cost of this may result in an increased cost of diagnosis per person .

in scenario 3, we take into account a biopsy leading to a misclassification . More than questioning the accuracy of the biopsy, this is reflective of the fact that biopsy is a sampling technique . Studies report biopsy mis-staging to be in the range of 10 to 33% . if we assume 20% of biopsy samples are mis-staged, then the discordances between MRE and biopsy may decrease . However, for simplicity, we still assume that the discordance between MRE and biopsy will not change .

Summary

We have illustrated a scenario-based analysis to compare potential cost differentials of MRE with other techniques that provide similar information . no recommendation on the likelihood of any scenario is being made . As the three scenarios show, the cost differentials for MRE (over biopsy) can range from 10% to 25% lower than direct biopsy costs . The key assumptions that determine the actual cost savings are accuracy of biopsy, sample suitability of biopsy, and accuracy of MRE . n

References

1 . DeKoven, M, “cost comparison: liver Biopsy versus Abdominal MRi”, Memo to GE Healthcare from iMS Health incorporated; May 25, 2010 .

2 . Huwart, l, Sempoux, c, Vicaut, E, Salameh, n, Annet, l, Danse, E, peeters, F, Ter Beek, lc, Rahier J, Sinkus, R, Horsmans, Y, and Van beers, BE, “Magnetic Resonance Elastography for the non-invasive staging of liver fibrosis”, Gastroenetrology, 135(1): 32-40, July 2008 .

*in 26 of the 96 samples, the biopsy specimen was less than 25mm .


H E A lT H E c o n o M i c S B E Y o n D T H E S c A n

GE Healthcare

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l i v E R d i S E A S E i S S u E S p o t l i G H t

name of author

info about clinic, etc.

Liver disease includes Hepatitis B, Hepatitis C, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and alcoholic liver disease. As the obesity rate rises—about one-third of adults in the uS were obese in 20081— the disease is tied to a greater prevalence of NAFLD.

Globally, 350 million people are infected with Hepatitis B, causing 500,000 deaths yearly, and 170 million have Hepatitis C.2 According to Jayant A. talwalker, Md, hepatologist at the Mayo Clinic (Rochester, MN), if no treatment is provided for the management of Hepatitis chronic C, then cirrhosis and hepatocellular carcinoma will almost double, decompensated cirrhosis will more than double, and liver-related deaths will triple.3

to better understand the current state of non-invasive evaluation of liver diseases, GE Healthcare recently hosted a roundtable discussion of radiologists and hepatologists regarded as clinical experts on liver disease evaluation and management. the purpose was to explore non-invasive imaging techniques for diagnosing chronic liver disease, fibrosis, and cirrhosis—all leading causes of death worldwide.

Hepatic fibrosis, or a stiffening of the liver, occurs with liver disease and impacts the organ’s normal function. Hepatic fibrosis is potentially reversible with early intervention and adequate treatment. if left untreated, fibrosis often leads to cirrhosis which permanently scars the liver, cannot be treated, and is associated with high mortality. Also, fibrosis is a known pathogenic of portal hypertension and hepato-cellular carcinoma (HCC)—the fourth-leading cause of cancer death worldwide—and can be a marker for the development of both diseases.

Current trends in Non-invasive Evaluation of Liver Diseases

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70 SignaPULSE • Spring 2011

i s s u e s p o t l i g h t l i v e r d i s e a s e

Economically, Hepatitis C is the underlying cause for one-third (approximately 1,000) of all liver transplants at a cost of $280,000 (USD) per procedure. The lifetime cost of Hepatitis C without transplant is estimated at $100,000 per individual.4

Assessing liver disease—background

Alaninie transaminase (ALT) and aspartate transaminase (AST) are sensitive indicators of liver damage or injury from different types of disease, yet these enzyme levels are not a precise indicator of liver damage or prognosis. Both tests indicate only the presence of liver disease, not staging, and cannot be used to guide treatment. According to Dr. Talwalker, normal ALT values do not always indicate mild liver disease.

Three serum tests help evaluate overall liver function. Serum albumin measures how well the liver is producing the protein albumin; serum bilirubin determines how well the liver clears a blood waste product, bilirubin; and, prothrombin time (INR) measures the clotting time of plasma as an increase in prothrombin time may indicate liver damage. As with ALT/AST, these tests are also not conclusive for staging liver disease.

Currently, the gold standard for confirming a clinical diagnosis and assessing the severity of necroinflammation is liver biopsy. Biopsy is also used to evaluate possible concomitant disease processes and assess fibrosis and therapeutic intervention.

“The primary goal of biopsy is to differentiate state 1–2 from stage 2–3 and to diagnose cirrhosis,” explains John R. Lake, MD, professor of Medicine and Surgery, University of Minnesota Medical School, “in order to determine whether there is an indication for treatment.” He adds that making a diagnosis of cirrhosis can also have important implications, such as screening for HCC and dosing antivirals.

Dr. Lake explains that although biopsy is the gold standard, it is costly (ranges from $1,500 to $2,000 USD) and poses risks to patients, namely moderate pain in 20% and hospitalization in 1 to 3%. It has a mortality rate of .01%, which increases to 0.4% in patients with cancer.

The procedure is also associated with potential sampling errors and subjective histology grading. Fewer than 11 portal tracts may be linked with sampling errors—one study found fibrosis stage discordance in 33% of cases.5 Pathology skill sets also vary widely. Another study found 20% of fibrosis and cirrhosis are understaged with the size of biopsy being a likely culprit.6 As a result, second opinions are often required.

Figure 1. Epidemiology of Hepatitis B—prevalence of HBsAg carrier state.

>8%

2–8%

2%

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“A real problem for liver biopsy is the ability to detect small changes in regression of fixed, fibrous lesions over the short time intervals associated with most controlled clinical trials,” adds Jeong Min lee, Md, department of Radiology, Seoul National university Hospital.

Higher incidences of chronic liver disease coupled with the complications and potentially unreliable biopsy results has led to increased interest in non-invasive methods for screening and diagnosis. dr. lake believes that non-invasive determination of fibrosis stage coupled with patient preference will further accelerate the decline in the need for liver biopsy.

Non-invasive options for chronic liver disease management

Hepatologists are interested in diagnosing chronic liver disease before its endpoint—cirrhosis—says Robert J. Fontana, Md, Medical director of the liver transplant program and Clinic, university of Michigan Medical Center. While diagnosis

can be made for Hepatitis B, Hepatitis C, and alcoholic fatty liver, NAFld—which affects 20% of the population—cannot be conclusively diagnosed via biopsy.

“until we have effective treatments [for fatty liver disease], the value of the biopsy is limited,” he explains. in general, he says, clinicians tend to understage fibrosis and cirrhosis via biopsy. Knowing the extent of fibrosis is an important yet complicated clinical question.

While blood tests have been available for many years, they are not abnormal until the patient has cirrhosis, dr. Fontana says. Specifically, ASt/Alt provide a moderate correlation with staging, but are not specific.

the ideal non-invasive test for monitoring chronic liver disease would be simple, readily available, inexpensive, and reproducible, he adds. Additionally, it must provide accurate prediction of the full spectrum of disease severity, be sensitive to treatment effects, and be useful in tracking disease progression.

10 to 20

5 to 10

2 to 5

1 to 2

0 to 1

Figure 2. Worldwide HCv prevalence.

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Serum fibrosis markers

In chronic liver disease, the physiologic process includes inflammation, cell death, and the collagen deposits in the liver. Serum fibrosis markers (SFM) detect dynamic changes in the liver. Dr. Fontana cautions that SFM are dependent upon the rate of production and clearance, and currently are not liver specific. He cautioned that using a single analyzed serum marker is likely to be inconclusive. Studies have determined that combining serum markers with other tests—such as blood tests, transient ultrasound, or MRI—would provide a more conclusive result.

Ideal non-invasive test for monitoring chronic liver disease

Simple

Readily available

Inexpensive

Reproducible

Accurate prediction of the full-spectrum of disease severity

Sensitive to treatment effects

Useful in tracking disease progression

A large prospective study7 of 1,000 patients sponsored by NIH presented “a great opportunity to evaluate serum markers as a predictive of disease progression at the same time,” says Dr. Fontana. The study’s authors found the best model for predicting disease severity was the combination of albumen, bilirubin, INR, and YKL-40. However, Dr. Fontana and co-authors determined the results, while sufficient for research, were not yet ready for clinical practice.

According to Dr. Fontana, serum marker tests available today have a very high negative predictive value but poor positive predictive value and require further refinement to increase their accuracy. Biochemical indices have limited sensitivity and specificity to replace biopsy in most patients. While proteomics and glycoproteomics may provide new markers, they require prospective, cross-sectional, and longitudinal studies for clinical use. However, Dr. Fontana believes that with additional study, SFM combined with other non-invasive testing may prove most useful in diagnostic and management algorithms.

“This area of research is not complete,” he explains, “and there is still discovery work and validation that needs to be done.” He is buoyed by the potential to utilize several different studies together—blood test, serum marker, and a radiology test—to conclusively diagnosis fibrosis and to reduce the number of patients who undergo biopsy.

“The question, ‘which one is best?’ is the wrong approach,” Dr. Fontana says. It will be through a combination of these tests that clinicians determine the course of clinical management.

Transient and ultrasound elastography

Transient elastography and ultrasound elastography measure the speed of ultrasound propagation through the liver. The wave may be generated through mechanical vibration (transient elastography) or through an ultrasound source (ultrasound elastography).

By controlling vibration and energy and applying an algorithm, transient elastography calculates the stiffness of the region of interest (ROI). Typically, the ROI is 2.5 to 6.5 cm below the skin, 10 x 40 mm with limited visualization.

While similar to transient elastography, ultrasound elastography utilizes an acoustic shear wave. The region of interest can be anywhere—it is not limited to a finite depth—and provides direct visualization with an ROI of 5 x 10 mm. Results are directly measured (m/s).

Robert P. Myers, MD, MSc (Epid), Associate Professor, Liver Unit, Division of Gastroenterology, University of Calgary, notes that transient elastography may potentially also be used to detect complications of cirrhosis and steatosis, while ultrasound elastography can capture other data

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during the same session (e.g. masses, portal hypertension, fatty liver, etc.). ultrasound elastography is readily available, relatively inexpensive, has no reported failures, and can provide rapid, “real time” assessment of fibrosis.

However, both techniques suffer from limited sensitivity for intermediate stages and end results are influenced by factors other than fibrosis, adds dr. Myers. transient elastography equipment is expensive—roughly five times the cost of ultrasound elastography—which could lead to limited availability. in approximately 5% of cases, the

technique may fail, especially in patients who are obese, although dr. Myers notes a new probe for obese patients has been trialed. With transient ultrasound, stiffness values are disease-dependent and exam success is influenced by a number of factors, making reproducibility fair at low-liver stiffness values, he adds. ultrasound elastography also suffers from sensitivity to fibrosis changes over time and poses many unresolved issues that require additional validation for clinical efficacy.

Performance of MR Elastography in difficult situations

Normal Biopsy stage F1 Biopsy stage F2 Biopsy stage F3 Biopsy stage F4

Liver fibrosis

(Imag

es c

ourt

esy

of M

ayo

Clin

ic,

Roch

este

r, M

N)

Figure 3. MRE images concordant with stiffness and consistent to stages of fibrosis.

Figure 4. MRE images in difficult to evaluate situations: obese patient with BMi = 40.7.

Figure 5. MRE images in difficult to evaluate situations: patient with ascites.

MR Elastography

Compared to transient and ultrasound elastography, MR Elastography (MRE) uses shear waves to assess the stiffness of the liver. According to Richard l. Ehman, Md, professor of Radiology, Mayo Clinic, MRE adds approximately five minutes (with the scan taking 15 sec) to a conventional 30 minute MR abdomen exam.

A study that compared the diagnostic performance of MRE, transient ultrasound, and ASt blood tests to biopsy samples

found MRE to be 94% concordant, transient ultrasound 84% concordant, and ASt blood test 70% concordant.8 Additionally, MRE is not impacted by obesity (high BMi) or the presence of ascites as is the case with transient and ultrasound elastography. Also, the presence of steatosis does not affect liver stiffness with MRE. in several studies, explains dr. Ehman, MRE demonstrated the ability to identify steatohepatitis before the onset of fibrosis—an important indicator for treatment.

Shear stiffnessSoft Hard

0 2 4 6 8


0 2 4 6 8


0 2 4 6 8

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When compared to DWI and morphologic MR, MRE is shown to have higher sensitivity and specificity than either conventional MR technique.9

According to Dr. Ehman, MRE is a reliable, non-invasive test for assessing hepatic fibrosis. It could be easily added to standard abdominal MRI protocols.

Conclusion

Based on the strengths and weakness of the different options for liver disease evaluation, the panel did not find one technology superior to another for all applications.

However, the panel was confident that non-invasive staging of fibrosis would lead to the decline in the need for liver biopsy and that patient acceptance of these non-invasive techniques would accelerate the decline.

For use as a screening tool, a technique may be preferred due to its availability, cost, and examination time. Another technique may be used as a diagnostic tool based on its robustness, accuracy, and reproducibility. Further work is expected on defining the biologic and clinical implications of alterations in liver stiffness following therapy and how each technique fits within a clinical algorithm. n

References:

1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and Trends in Obesity Among US Adults, 1999-2008. JAMA 2010;303(3):235-241.

2. Disease Burden from Viral Hepatitis A, B, and C in the United States. Centers for Disease Control. Available at: http://www.cdc.gov/hepatitis/PDFs/disease_burden.pdf; and World Health Organization, available at http://www.who.int/whosis/whostat/en/index.html

3. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 2003; 9:331-338.

4. Available at: http://www.epidemic.org/theFacts/theEpidemic/USHealthCareCosts/

5. Regev A, Bergo M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. AJG 2002;97:2614-2618

6. Bedossa P, Dargere D, Paradis V. Sampling Variability of Liver Fibrosis in Chronic Hepatitis C.Hepatology 2003;38(6):1449-1457.

7. Fontana RJ, Dienstag JL, Bonkovsky HL, et al. Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C. Gut2010;59:1401-1409 doi:10.1136

8. Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008;135(1):299-302

9. Venkatesh SK, Teo LLS, Ang BWL, Ehman RL. Non-invasive detection of liver fibrosis: Comparison of MR Elastography with diffusion weighted MR imaging. European Congress of Radiology 2010, Vienna, Austria, March 4–8, 2010.

Photo L to R. Row 1: Vinod Palathinkara, PhD, and Ersin Bayram, PhD, GE Healthcare; Don Rockey, MD, UT Southwestern; Jim Davis, PhD, Jeff Hersch, MD, PhD, Karthik Kuppusamy, PhD, and Tom Verghese, PhD, GE Healthcare. Row 2: John R. Lake, MD, University of Minnesota; Coleman Smith, MD, Minnesota Gastroenterology PA; Jacques Coumans, PhD, GE Healthcare. Row 3: Robert J. Fontana, MD, University of Michigan; Richard K. Sterling, MD, Virginia Common-wealth; Jeong Min Lee, MD, Seoul National University Hospital; Grzegorz W. Telega, MD, Children’s Hospital of Wisconsin. Row 4: Peter Wold, MD, Saint Paul Radiology; Jayant A. Talwalkar, MD, Mayo Clinic; Robert P. Myers, MD, University of Alberta (Canada); Richard L. Ehman, MD, Mayo Clinic. Row 5: Keyur Patel, MD, Duke University; Hugo E. Vargas, MD, Mayo Clinic—Scottsdale; Dennis Meister, GE Healthcare. Row 6: Joanna Jobson, MSEE, MBA, and Jean Brittain, PhD, GE Healthcare.

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