Determination of Normal Liver Stiffness by MR Elastography in Children
Phase: NA
Conditions: Liver Diseases
Sponsor: Children's Hospital Medical Center, Cincinnati

 
Determination of Normal Liver Stiffness by 
MR Elastography in Children 
 
 
NCT03235414 
April 18, 2019 

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Normal Liver Stiffness in Children by MRE – Version 4.0 – Apr 18,2019
DETERMINATION OF NORMAL LIVER STIFFNESS BY MR ELASTOGRAPHY IN 
CHILDREN
1. ABSTRACT: 
MR elastography (MRE) is playing a growing role in the non-invasive diagnosis and 
monitoring of liver disease in the pediatric population. There is, however, little data 
specific to the use of this technique in children with existing data and techniques largely 
extrapolated from adult studies. Existing studies suggest that liver stiffness values may 
be different between children and adults [Etchell, Xanthakos]. As such there is an unmet 
need for uniquely pediatric data in both healthy and diseased cohorts. To address the 
need for such data, we plan a multi-site, prospective study of healthy pediatric (<18 
years of age) volunteers to determine normal liver stiffness measured by MR 
elastography across the range of MRI equipment.
2. PURPOSE OF STUDY: 
The primary purpose of this study is to determine normal liver stiffness values (and 
associated normal ranges) as measured by MR elastography for two pediatric age 
groups.
Secondary purposes of this study include:
1. To assess for cross-platform (different MRI vendors) variability in normal MRI 
liver stiffness values.
2. To assess for cross-field strength (1.5T vs. 3T) variability in normal MRI liver 
stiffness values.
3. To assess for sex-related (male vs. female) differences in normal MRI liver 
stiffness values.
3. BACKGROUND: 
Pediatric chronic liver disease encompasses both inherited and sporadic diseases, all of 
which have the potential to progress to liver fibrosis and may ultimately require liver 
transplantation due to cirrhosis or development of hepatocellular carcinoma. Non-
alcoholic fatty liver disease (NAFLD) is rapidly eclipsing other causes of liver disease in 
the pediatric population and is now the second most common indication for liver 
transplantation in the adult population [Vos].
MR elastography is becoming increasingly available, and, alongside ultrasound 
elastography, is playing a growing role in the non-invasive diagnosis and monitoring of 
liver disease. There is an increasing body of literature demonstrating the diagnostic 
efficacy of MR elastography in adult patients. Studies at both 1.5 and 3T have 
demonstrated significant positive correlation between MRI liver stiffness and pathologic 
grades of liver fibrosis and significant predictive accuracy for discriminating significant 
from little to no fibrosis in a variety of disease states [Yin, Yoshimitsu, Kim]. MR 
elastography currently has advantages over other tissue elastographic techniques. 
These advantages include the ability to evaluate the liver in its entirety, ability to 
characterize tissue composition in terms of fat and iron content, and standardization 

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across manufacturer platforms, since the vast majority elastography hardware and 
software currently comes from a single company (Resoundant Inc.; Rochester, MN).
While MR elastography is being used in pediatric and young adult patients and is 
particularly attractive in this population due to its non-invasive nature (cf biopsy), the 
body of literature supporting its use in this population is relatively small. To date, the 
only uniquely pediatric study of MR elastography that has explored diagnostic 
performance of the technique is a study of 35 subjects, mean age of 13 years, with 
suspected liver disease who underwent both MRE and liver biopsy [Xanthakos]. That 
study by Xanthakos et al. found that a cut-off of 2.71 kPa provided optimal sensitivity 
(88%) and specificity (85%) for distinguishing F0-F1 (no to little) from F2-F4 (moderate 
to severe) fibrosis. Of note, this cut-off is lower than the mean stiffness values 
previously reported for F2 fibrosis in adult studies (3.87±1.85 kPa) raising the possibility 
that both normal and pathologic liver stiffness may differ between pediatric and adult 
patients (3). Importantly, there were no subjects without liver disease in this study by 
Xanthakos et al. to define normal liver stiffness values.
There is one prior study of healthy pediatric patients that included 35 subjects (24 
between ages 5-14 years and 11 between ages 15-18 years)[Etchell]. That study 
demonstrated that normal liver stiffness values were lower for healthy pediatric subjects 
than for healthy adult subjects (2.2 vs. 2.6 kPa). The authors also found a slight 
significant correlation between age and liver stiffness (r=0.38) but failed to demonstrate 
a difference in liver stiffness between subjects ≤14 years of age versus >14 years of 
age. While this prior study provides some information about normal liver stiffness in the 
pediatric population, it has key limitations. First, this study was performed with 
nonstandard multi-frequency MR elastography. One of the frequencies that was utilized 
(56 Hz) is close to the standard 60 Hz MR elastography utilized for clinical MRE, but 
differences in frequency utilized to measure tissue stiffness are known to influence liver 
stiffness measurements and thus normative data from this study may not apply to MR 
elastography performed with manufacturer standard technique. Second, the subjects 
imaged in this study were not fasting at the time of MR imaging. There are conflicting 
data regarding the effect of fasting (or lack thereof) on measured liver stiffness with 
some studies showing a stiffening effect of increased post-prandial splanchnic blood 
flow [Hines, Lemoine, Yin]. Third, while the subjects included in this study had no 
“known history of liver disease” MR fat fractions were not measured and serum liver 
function tests were not checked to confirm liver health. Finally, all examinations in this 
prior study were performed on a single manufacturer MR platform and at a single field 
strength, possibly limiting generalizability across other platforms.
MR elastography is a rapidly evolving technique and sequence improvements are 
constantly being developed. Additionally, new MRI techniques for assessment of diffuse 
liver disease are constantly being developed. At CCHMC only, additional imaging data 
will be acquired for exploratory aims related to these newer techniques.
4. STUDY DESIGN: 
Study aims and hypotheses are as follows:

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Normal Liver Stiffness in Children by MRE – Version 4.0 – Apr 18,2019
Primary aim/hypothesis – To determine normal liver stiffness values (and associated 
normal ranges) as measured by MR elastography for two pediatric age groups. We 
hypothesize that normal liver stiffness as measured by MR elastography will differ 
between the two pediatric age groups, increasing with increasing age.
To achieve the primary aim, MR elastography will be performed in up to 104 healthy 
children, somewhat evenly divided (approximately 48 each) into two age groups (7-
˂12years, 12-˂18years). Means, standard deviations and 95% confidence intervals for 
normal liver stiffness will be calculated for each age group and values will be compared 
across groups.
Multi-site secondary aims and hypotheses are as follows:
1. To assess cross-platform variability in normal MRI liver stiffness values. We 
hypothesize that there will be no significant difference in mean normal liver 
stiffness values obtained on three different vendor platforms (GE, Philips, 
Siemens).
2. To assess for cross-field strength variability in normal MRI liver stiffness values. 
We hypothesize that there will be no significant difference in mean normal liver 
stiffness values obtained at 1.5T versus 3T.
3. To assess for sex-related (male vs. female) differences in normal MRI liver 
stiffness values. We hypothesize that there will be no sex-related differences in 
normal liver stiffness measured by MR elastography.
To achieve secondary aim #1, subject recruitment will be stratified across sites with 
approximately 32 subjects in each age group being imaged on each of the different 
vendor platforms (GE, Philips, Siemens). To achieve secondary aim #2, subject 
recruitment will be stratified across 1.5T and 3T magnets with approximately 48 
subjects in each age group being imaged at each of the different field strengths. To 
achieve secondary aim #3, approximately equal numbers of male and female subjects 
will be recruited in each of the two age groups.
CCHMC exploratory aims and hypotheses are as follows:
1. To determine normal corrected T1 (cT1) values for two pediatric age groups. We 
hypothesize that there will be no significant difference in mean cT1 values 
between age groups or between field strengths.
Overall research strategy:
We propose to conduct a multi-institutional study of normal liver stiffness values in 
pediatric subjects with no known history of liver disease. The requirement for multiple 
sites relates to the need to acquire normative stiffness values on each of the three 
major MRI vendor platforms to assess for unexpected cross-platform variability in liver 
stiffness. CCHMC has Philips MRI scanners (1.5 and 3T) equipped with MR 
elastography but does not have access to GE or Siemens MRI scanners in a research 
environment. Massachusetts General Hospital (MGH) has an elastography capable GE 
scanner (1.5T), Children’s Hospital of Philadelphia (CHOP) has elastography-capable 
GE and Siemens scanners (3T), and Mallinckrodt Institute of Radiology (MIR) has an 

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elastography-capable Siemens scanner (1.5T). This human study protocol will be 
submitted for approval to the Institutional Review Board at CCHMC. CCHMC will serve 
as the lead site. CHOP, MGH and MIR may choose to submit to their IRB or to rely on 
the CCHMC IRB.
Power calculation relevant to SA1: Determine normal liver stiffness values (and 
associated normal ranges) as measured by MR elastography for three pediatric age 
groups: Based on the standard deviation of normal liver stiffness measurements in the 
study by Etchell et al. (SD=0.3 kPa) and the confidence intervals from a study of healthy 
adult livers by Lee et al. (95% CI ~±0.1 kPa), we calculate that a sample size of n=18 is 
needed in each group to achieve 2-sided 95% confidence intervals with a distance from 
the mean to the limits that is equal to 0.15 kPa for each group [Etchell, Lee]. This 
sample size also provides 80% power to detect an effect size (Cohen’s d) of 0.67 
between the two age groups. Given the prior study findings of a correlation between 
subject age and liver stiffness, we will recruit into two subject age groups (7-˂12years, 
12-˂18years). Based on prior published and unpublished MRI studies of “healthy 
volunteers” at CCHMC, we expect up to 25% of “healthy subjects” recruited for this 
study will have unsuspected liver disease manifest as abnormalities in liver function 
tests or liver fat fraction values greater than 5% by MRI proton density fat fraction 
(PDFF) (12). Therefore, we will increase recruitment targets by 25% over the levels 
required to achieve adequate statistical power. Thus, approximately 24 subjects will be 
recruited to each group at each field strength for a total study recruitment of n= up to 
104.
MR imaging:
All imaging will be performed using multi-channel phased-array torso coil. MR 
elastography will be performed utilizing the manufacturer product MRE sequence 
(generally 2D gradient recalled echo at 1.5T and 2D spin echo echo-planar imaging at 
3T) and the manufacturer standard 60 Hz frequency. For the GRE sequence, driver 
amplitude will be adjusted based on patient weight (no adjustment required for SE-EPI). 
Per standard protocol, four axial slices will be acquired through the bulk of the central 
liver. PDFF sequences will be performed per manufacturer recommended settings. 
Total imaging time will be less than 15 minutes per examination and will be 
accomplished with approximately six breath holds.
Sequences acquired will include:
1.
3-plane localizer
2.
MR elastography (manufacturer recommended)
3.
PDFF sequence
4.
Axial T2-weighted single-shot fast spin-echo (anatomic sequence)
Driver amplitude will be adjusted as follows for the GRE sequence:
GRE:
Patient weight
Amplitude
40-49 kg
40%
50-59 kg
50%

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60-69 kg
60%
70-79 kg
70%
80-89 kg
80%
90-99 kg
90%
100+ kg
100%
Additional sequences will be acquired at CCHMC only. These will extend the total 
imaging time to up to 30 minutes and add additional breath holds.
5.
Corrected T1
MR exam post-processing:
All PDFF and MR elastography images will be processed both locally and centrally at a 
single site (CCHMC) by a single trained observer to ensure uniformity in post-
processing technique. Post-processing will be performed as previously described with 
placement of single large regions of interest in the right hepatic lobe (12). Central MR 
elastography data will be post-processed using MRE Lab (Mayo Clinic, Rochester, MN) 
and PDFF data will be post-processed using Philips Intellispace (Philips Healthcare, 
Best, The Netherlands).
De-identified cT1 data acquired at CCHMC only will be sent to Perspectum Diagnostics 
for analysis.
5. DURATION: 
18 months: 1 year for subject accrual, 6 months for analysis and write-up
6. SELECTION & RECRUITMENT OF PARTICIPANTS: 
Healthy pediatric subjects without a known history of liver disease will be recruited via 
advertising through established hospital channels (e.g. email) and posted flyers and/or 
posters at each of the study sites. Based on prior studies of normal subjects at CCHMC, 
we anticipate no difficulty recruiting the required number of subjects for this study. For a 
prior study of pancreatic function in normal subjects that required MRI and placement of 
an intravenous catheter, 142 responses expressing interest in participating in the study 
were received within 4 days of study announcement.
For each age group, MRI vendor and field strength, approximately half the recruited 
subjects will be male and half will be female. CCHMC will recruit a total of 32 subjects 
(16 male, 16 female), CHOP will recruit up to 40 subjects (approximately 20 male, 20 
female), and MIR and MGH will each recruit a total of 16 subjects (8 male, 8 female).
Inclusion criteria:
1.
Age 7-less than 18 years of age
2.
No documented history of liver disease
3.
English speaking*
Exclusion criteria:
1.
NPO less than 4 hours

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2.
Body mass index < 10th or > 85th percentile for age
3.
Documented history of liver disease
4.
Pregnancy
5.
Inability to lie still for duration of the MRI 
6.
Inability to breath hold for the duration of the 15-20 second MR elastography 
sequence
7.
Standard contraindication to MRI (implanted hardware, etc.)
8.
Requirement of sedation or general anesthesia for MRI
9.
Abnormality of any prior measured liver function test**
10.
Any prior liver fat fraction > 5% by MRI PDFF**
*English speaking has been included as an inclusion criterion as successful 
performance of an MRE examination requires following detailed and repeated breath 
hold instructions. This is a multicenter study and interpreter services are not uniformly 
available in the imaging research environment across participating institutions.
**Research results meeting this exclusion will eliminate subjects  from population 
analysis
7. PROCESS OF OBTAINING CONSENT: 
Participants will be screened in advance of enrollment by study personnel to determine 
baseline eligibility for participation. Once eligibility has been confirmed, written informed 
consent will be obtained in person at the time of the research visit.
Written informed consent will be obtained in person from parents/guardians of subjects 
<18 years of age. In addition to parent/guardian informed consent, assent will be 
obtained from all subjects ≥11. Consent or assent may be obtained by study personnel 
inclusive of the PI, Co-Is or clinical research coordinator(s).
8. STUDY PROCEDURES: 
To confirm “healthy status” and the absence of liver disease, subjects will be weighed 
and measured (height and waist circumference) prior to the research MRI.
Subjects will be surveyed about liver health using a survey created with the assistance 
of the study hepatologist and medical records (if available) will be reviewed to exclude 
documented liver disease (ATTACHMENT A).
Subjects will also undergo a research venous blood draw to confirm absence of 
elevation of markers of liver health inclusive of: AST, ALT, GGT, alkaline phosphatase, 
total and direct bilirubin. This research blood draw will require 2.5 mL of venous blood 
and will occur prior to or following the research MRI. At CCHMC the research blood 
draw will occur in the Schubert Research Center by SRC nursing staff. In addition, the 
research MRI will include a PDFF sequence to measure liver fat fraction in all subjects 
to identify previously unknown fatty liver disease.
Study visit structure (single visit):
1.
Intake survey and anthropomorphic measurements

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2.
MRI safety screening
3.
Research MRI exam
4.
Research blood draw
Drugs, Devices, and Biologics:
MR elastography equipment consists of an active and a passive driver system. The 
passive driver is connected to the active driver in the equipment room by a wave-guide 
with a hollow plastic tube. The active driver generates low amplitude (60 Hz) vibrations 
which are passed via pneumatic pressure to the passive driver. The initiation and 
cessation of the vibrations are controlled by the MR pulse sequence programmed and 
embedded as part of the scanner software. All MRE pulse sequences and hardware to 
be used for this study are sold as product by the MR vendors or an aftermarket 
company (Resoundant, Inc.) and all are FDA approved.
The other MRI sequences to be utilized in this study (anatomic, PDFF) are FDA 
approved sequences sold as product by the MRI hardware vendors.
9. DATA ANALYSIS/METHODS: 
All PDFF and MR elastography images will be processed both locally and centrally at a 
single site (CCHMC) by a single trained observer to ensure uniformity in post-
processing technique. Post-processing will be performed as previously described with 
placement of single large regions of interest in the right hepatic lobe (12). Central MR 
elastography data will be post-processed using MRE Lab (Mayo Clinic, Rochester, MN) 
and PDFF data will be post-processed using Philips Intellispace (Philips Healthcare, 
Best, The Netherlands).
De-identified cT1 data acquired at CCHMC only will be sent to Perspectum Diagnostics 
for analysis.
Descriptive statistics will be utilized to describe the characteristics of each subject group 
(age, sex, scanner manufacturer, field strength). Normal liver stiffness for each age 
group will be summarized as mean ± std with range and 95% confidence interval also 
provided. Two sample t-test or one-way analysis of variance (ANOVA) will be used to 
assess for differences in liver stiffness between age groups and between different 
groups of categorical variables (sex, scanner manufacturer, field strength). The 
correlation between liver stiffness and continuous variables will be assessed by using 
Pearson on Spearman correlation coefficients as appropriate. Multiple linear regression 
models will be utilized to evaluate the association between liver stiffness and the 
predictor variables adjusting for all other covariates. Box plots will be generated to 
visually illustrate the results from the group comparisons mentioned above.  All 
analyses will be performed using SAS version 9.4. A p-value less than 0.05 will be 
considered statistically significant for all inference testing.
10. FACILITIES and PERFORMANCE SITES: 
Research blood draws will occur in the Schubert Research Clinic. All other study 
procedures will occur in the CCHMC Imaging Research Center (IRC).

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11. POTENTIAL BENEFITS: 
There are no direct benefits to study participants. This research, however, is critical for 
our understanding of normal MRE values in children which are relevant to the diagnosis 
of disease utilizing MRE. Therefore this research has potential future benefit to children 
with known or suspected liver disease.
12. POTENTIAL RISKS, DISCOMFORTS, INCONVENIENCES AND PRECAUTIONS: 
There are no known risks from having an MRI or from use of the sequences being 
investigated for appropriately screened patients. However, some people are 
claustrophobic and may become anxious, fearful, or nervous in the scanner. Should 
participants become uncomfortable at any time the scan will be stopped immediately. 
Should any previously unknown risks related to having an MR examination be identified 
during the course of this study, that information will be relayed from individual site PIs to 
the lead PI at CCHMC and participants will be informed of those risks.
A board-certified radiologist will review the MRI exam.  Any unexpected finding requiring 
further medical evaluation will be shared with the participant and/or the participant’s 
physician.  For any finding deemed not related to the study there will be no further follow-up 
by the study team.  The research MRI exam will be identified by a number assigned as a 
part of the research study and will not become a part of the participant’s permanent medical 
record.  
There are no specific risks to pregnant patients from having the short MRI examination 
as part of this study.
Research blood draws may be associated with transient mild discomfort and the 
potential for mild bruising or fainting.
There is minimal risk of loss of confidentiality through study participation (see PRIVACY 
AND CONFIDENTIALITY BELOW).
13. RISK/BENEFIT ANALYSIS: 
This study is minimal risk with no direct benefit to study participants. The primary risks 
relate to physical discomfort (blood draw, possibly MRI) and potential loss of 
confidentiality.
14. DATA SAFETY & MONITORING: * 
No formal data safety monitoring board will be appointed for this minimal risk study. 
Adverse events related to study procedures will be monitored by site PIs/study 
coordinators, recorded and reported to the overall study PI (CCHMC).
15. PRIVACY and CONFIDENTIALITY: 
Each subject will be assigned a site-specific study ID number. Password-protected 
tables will be maintained at each study site that link the study ID number to the medical 
record number. This table will be maintained on a secure server or in a locked file 
cabinet, as appropriate. Identifying data will be saved in a password-protected 

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spreadsheets at the individual study sites. Any data that are extracted from the 
database and used for research will be subject to standard data protection practices. 
Only de-identified patient data (including study ID numbers) and de-identified imaging 
data will be transmitted from the individual study sites to CCHMC for central analysis. 
Only de-identified patient data will be shared with Perspectum Diagnostics.
16. COST OF PARTICIPATION: * 
There will be no cost to study participants. Study charges will be covered by grant 
support.
17. PAYMENT FOR PARTICIPATION:
Subjects will receive $50 for participation to cover time and expenses.
18. REFERENCES:
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in Pediatric Subjects Than in Adults and Increase with Age: A Multifrequency MR 
Elastography Study. Radiology. 2016:160252.
2. Hines CD, Lindstrom MJ, Varma AK, Reeder SB. Effects of postprandial state 
and mesenteric blood flow on the repeatability of MR elastography in 
asymptomatic subjects. J Magn Reson Imaging. 2011;33(1):239-44.
3. Kim D, Kim WR, Talwalkar JA, Kim HJ, Ehman RL. Advanced fibrosis in 
nonalcoholic fatty liver disease: noninvasive assessment with MR elastography. 
Radiology. 2013;268(2):411-9.
4. Lee DH, Lee JM, Han JK, Choi BI. MR elastography of healthy liver parenchyma: 
Normal value and reliability of the liver stiffness value measurement. J Magn 
Reson Imaging. 2013;38(5):1215-23.
5. Lemoine M, Shimakawa Y, Njie R, et al. Food intake increases liver stiffness 
measurements and hampers reliable values in patients with chronic hepatitis B 
and healthy controls: the PROLIFICA experience in The Gambia. Aliment 
Pharmacol Ther. 2014;39(2):188-96.
6. Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN Clinical Practice Guideline 
for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: 
Recommendations from the Expert Committee on NAFLD (ECON) and the North 
American Society of Pediatric Gastroenterology, Hepatology and Nutrition 
(NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319-34.
7. Xanthakos SA, Podberesky DJ, Serai SD, et al. Use of magnetic resonance 
elastography to assess hepatic fibrosis in children with chronic liver disease. J 
Pediatr. 2014;164(1):186-8.
8. Yin M, Glaser KJ, Talwalkar JA, Chen J, Manduca A, Ehman RL. Hepatic MR 
Elastography: Clinical Performance in a Series of 1377 Consecutive 
Examinations. Radiology. 2016;278(1):114-24.
9. Yin M, Talwalkar JA, Glaser KJ, et al. Dynamic postprandial hepatic stiffness 
augmentation assessed with MR elastography in patients with chronic liver 
disease. AJR Am J Roentgenol. 2011;197(1):64-70.

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10.Yoshimitsu K, Mitsufuji T, Shinagawa Y, et al. MR elastography of the liver at 3.0 
T in diagnosing liver fibrosis grades; preliminary clinical experience. Eur Radiol. 
2016;26(3):656-63.