Association between novel MRI-estimated pancreatic fat and liver histologydetermined steatosis and fibrosis in nonalcoholic fatty liver

disease
N. S. Patel,* M. R. Peterson, D. A. Brenner, E. Heba, C. Sirlin, and R. Loomba
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SUMMARY
Background

Ectopic fat deposition in the pancreas and its association with hepatic steatosis
have not previously been examined in patients with biopsy-proven non-alcoholic
fatty liver disease (NAFLD).

Aim

To quantify pancreatic fat using a novel magnetic resonance imaging (MRI)

technique and determine whether it is associated with hepatic steatosis and/or
fibrosis in patients with NAFLD.

Methods

This is a cross-sectional study including 43 adult patients with biopsy-proven NAFLD

who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy
assessment was performed using the NASH-CRN histological scoring system, and
liver and pancreas fat quantification was performed using a novel, validated MRI
biomarker; the proton density fat fraction.

Results

The average MRI-determined pancreatic fat in patients with NAFLD was 8.5% and
did not vary significantly between head, body, and tail of the pancreas. MRIdetermined pancreatic fat content increased significantly with increasing histologydetermined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in

grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with
histology-determined liver fibrosis than in those without fibrosis (11.2% in stage 0
fibrosis vs. 5.8% in stage 12 fibrosis, and 6.9% in stage 34 fibrosis, P = 0.013).
Pancreatic fat did not correlate with age, body mass index or diabetes status.

Conclusions

In patients with NAFLD, increased pancreatic fat is associated with hepatic

steatosis. However, liver fibrosis is inversely associated with pancreatic fat content.
Further studies are needed to determine underlying mechanisms to understand if
pancreatic steatosis affects progression of NAFLD.

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INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) affects approximately 2030% of the adult
population in the western world and is becoming increasingly prevalent
worldwide.1, 2 It is well established that obesity, insulin resistance and other
components of metabolic syndrome are risk factors for the development of
NAFLD.3, 4

Obesity and metabolic syndrome are also associated with ectopic fat deposition in
other organs including the pancreas. This ectopic fat deposition in the pancreas
may trigger lipotoxicity in the pancreas.5 In the liver, this process of ectopic fat
deposition in the setting of metabolic syndrome may lead to cytokine-mediated
inflammation, lipotoxicity and oxidative stress resulting in hepatocellular injury,
inflammation and steatosis. This results in progressive liver disease termed as nonalcoholic steatohepatitis (NASH).6, 7 NASH may lead to cirrhosis, end-stage liver
disease and hepatocellular carcinoma, and is one of top three indications of liver
transplantation in the United States.810

In the pancreas, it has been suggested that fat accumulation, in the setting of
metabolic syndrome, may lead to a similar process that is termed as non-alcoholic
steatopancreatitis (NASP).11 Other clinical implications of pancreatic steatosis
include -cell dysfunction, exocrine dysfunction, increased risk of post-operative
fistula in patients undergoing pancreatic surgery, increased risk of dissemination
and mortality in co-existent pancreatic cancer and potentially greater severity of
episodes of acute pancreatitis.1217 Therefore, emerging data suggest that
pancreatic steatosis may have long-term clinical implications.

Recent studies have shown that pancreatic steatosis has a risk factor profile that is
similar to that seen in NAFLD including advanced age, obesity and insulin
resistance.1824 However, the association between novel magnetic resonance
imaging (MRI)-determined pancreatic fat content and histology-determined
steatosis grade in patients with biopsy-proven NAFLD has not been previously
studied. Previous studies have utilised imaging to assess pancreatic fat. In this
study, we utilised an advanced chemical shift-based gradient-echo MRI technique
that measures the proton-density-fat-fraction (PDFF), a standardised and
reproducible quantitative marker of fat content in tissue.25 Older MRI techniques
assessing steatosis are limited by T1 bias, T(2)* decay and multi-frequency signalinterference effects of protons in fat. This technique corrects for the above limiting
factors and provides a more accurate assessment of steatosis content using the
PDFF measurement.2629 MRI-PDFF of pancreas has not been specifically compared
with liver biopsy in adult patients with NAFLD. In this study, we aim to determine
whether MRI-PDFF of the pancreas is associated with liver histology-determined
steatosis and/or fibrosis in adults with NAFLD.

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METHODS
Study design and patient population

This is a cross-sectional analysis of a prospective cohort study including 43 adult

patients with biopsy-proven NAFLD who underwent clinical evaluation, physical
examination, biochemical testing and MRI. All patients were diagnosed with NAFLD
based on liver biopsy as well as exclusion of other causes of liver disease (as
detailed in the following section). All patients provided written informed consent to
participate in the study and the study was approved by the University of California
at San Diego institutional review board. All patients underwent a standard history
and physical examination, biochemical testing and MRI examination at UCSD. They
all also underwent an alcohol history assessment by completing the AUDIT and
Skinner Lifetime Drinking questionnaires.

Inclusion criteria

Inclusion criteria included an age greater than 18 years, evidence of NAFLD on liver
biopsy as assessed by the NASH-CRN histological scoring system (please see Liver
histology assessment sub-section) and serum alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) levels above the upper limit of normal (19 U/L or
more for women and 30 U/L or more for men).

Exclusion criteria

Exclusion criteria included significant systemic illnesses, use of steatogenic

medications, decompensated liver disease indicated by a Child-Pugh score greater
than 7 points, or alcohol intake of more than 30 g per day in the previous 10 years
or greater than 10 g per day in the previous 1 year. Subjects were also excluded if
there was any evidence of other forms of liver disease, including other biopsy
findings, a positive hepatitis B surface antigen, hepatitis C viral RNA, or
autoimmune serologies, alpha-1 antitrypsin deficiency, haemochromatosis genetic
testing, or low ceruloplasmin. In addition, patients with any known history or
imaging findings concerning for hepatic malignancy or pancreatic malignancy were
also excluded.

Clinical evaluation

After meeting inclusion and exclusion criteria, patients underwent a routine history
and physical examination in a research clinic. Body weight, height and vital sign
measurements were obtained and standard blood testing was performed, including
measurement of ALT, AST, alkaline phosphatase, gamma-glutamyl transpeptidase
(GGT), total bilirubin, direct bilirubin, albumin, fasting glucose and insulin,
haemoglobin A1c (HbA1c), lipid panel, free fatty acids (FFA) and C-reactive protein
(CRP). Homeostatic model of insulin resistance (HOMA-IR) was calculated as the
product of fasting insulin and glucose divided by a correction factor of 405.

Liver histology assessment

All patients underwent liver biopsies within 6 months prior to inclusion in the study,
which were scored by a single liver pathologist (MP) using the NASH-CRN
histological scoring system.30 Biopsies were performed untargeted for the purpose
of evaluating for diffuse liver disease. Liver biopsy assessment included the
following variables: degree of steatosis (on a scale of 03), lobular inflammation (0
3), and hepatocellular ballooning (02). The sum of steatosis, lobular inflammation
and hepatocellular ballooning scores were added to determine the NAFLD activity
score (NAS) that ranges from 0 to 8. The liver fibrosis was staged from 0 to 4. The
pathologist was blinded to the clinical as well as the radiological data. As noted in
the inclusion criteria, patients were included in the study with a diagnosis of NAFLD
based on a liver steatosis grade of 1 or greater. All patients also had histological
evidence of either lobular inflammation or hepatocellular ballooning.

MRI protocol

To determine pancreatic fat content, we used a previously described advanced

chemical shift-based gradient-echo MRI technique that measures the PDFF.28 It
acquires multiple echo sequences at different times when fat and water signals are
nominally in phase or out of phase with each other. Data from each echo time are
passed into an algorithm that estimates and corrects T2* effects, models the fat
signal as a superposition of multiple frequency components, and estimates fat and
water proton densities from which the fat content is calculated. A magnitude-based
technique was applied to echo sequences to avoid phase errors, which can
adversely affect fat quantification.31, 32 This algorithm is applied to the source
images using custom analysis software developed at the UCSD Liver Imaging Group
to generate a PDFF parametric map depicting fat quantity and distribution
throughout the pancreas and liver. This method provides a more direct measure of
liver fat content than prior MR techniques that relied on measurements of the image
signal fat-fraction.33 It has been shown to accurately measure liver fat fraction
when compared with the magnetic resonance spectroscopy (MRS) technique34 and
reliably measures pancreatic fat content when compared with other MRI imaging
techniques.35

This technique was used to measure liver as well as pancreatic fat in this study.
Images were obtained with a slice thickness of 8 mm without interslice gaps. To
measure MRI-determined liver steatosis, 3 regions of interest (ROIs) 300400 mm2
in area were placed in each of the nine liver segments on the PDFF parametric map.
This technique has been described in detail previously in patients with NAFLD and
has been shown to correlate well with histology-determined steatosis.36, 37

To measure pancreatic fat, 12 ROIs of 100 mm2 in area were placed in the head,
body and tail of the pancreas in each slice of the PDFF parametric map, with each
ROI at least 10 mm apart as shown in Figure 1. To minimise contamination from
volume averaging with extra-pancreatic adipose tissue, we placed ROIs in the head,
body and tail of the pancreas, making sure that the ROIs were surrounded by
pancreatic tissue not only within the imaging plane, but also on the slice above and
slice below. The head of the pancreas was defined as the area of the pancreas to
the anatomic right of the superior mesenteric vein. The body was defined as the
anatomic right half of the remaining pancreatic tissue and the tail was defined as
the anatomic left half of the remaining pancreatic tissue. The mean of all ROIs in
each part of the pancreas was calculated to determine the average fat fraction in
the head, body and tail, respectively, while the mean of all ROIs in the entire
pancreas determined the overall pancreatic fat fraction.

Figure 1
Figure 1
Measurement of pancreatic fat using MRI PDFF. A single source image of a magnetic
resonance image (MRI) gradient echo sequence of the abdomen is shown. Source

image was obtained with a slice thickness of 8 mm. Regions of interest (ROIs) 100
mm2 in area ...
A single resident physician who was trained in this method of MRI analysis
performed the measurements. The physician was blinded to clinical and histological
data and was under the supervision of the radiology investigator (CS). These
findings were cross-validated by an independent radiology investigator who was
blinded to the prior pancreatic fat fraction maps.

Sample size estimation

We hypothesised that pancreatic fat would positively correlate with histologydetermined steatosis grade in the liver. We would need a sample size of at least 40
to have an alpha of 0.05 with a power of 80% (or higher) requiring an effect size of
0.38 or higher.

Statistical analysis

The two-tailed t-test was used for comparison of continuous variables across
groups, while the Chi-squared test was used for comparisons of categorical
variables. Patients were stratified according to steatosis grade on liver biopsy and
the mean and standard error values were calculated for demographic, biochemical,
histological and MRI PDFF results. Statistical analyses with t-tests were performed
between the grade 1 and grade 3 steatosis groups. Paired t-tests were used to
compare MRI PDFF across different regions of the pancreas. All statistical analyses
were performed using Excel and SPSS software packages. A P-value <0.05 was
considered statistically significant.

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RESULTS
Demographic and biochemical data by liver steatosis grade

Forty-three patients with biopsy-confirmed NAFLD were enrolled in this study

between 1/2010 and 4/2011. All patients received an MRI and liver biopsy within 6
months each other, with a mean (standard error) time interval of 42.9 days (6.9)
between studies. Liver biopsy occurred before MRI in 74.4% of patients (32 of 43).
Ten patients had grade 1 steatosis on liver histology, 21 patients had grade 2
steatosis and 12 patients had grade 3 steatosis based on NASH CRN criteria.
Demographic and biochemical data for these patients are shown in Table 1
segmented by liver histology steatosis grade. Patients ranged from 22 to 66 years

of age and included 24 men and 19 women. There was no statistically significant
difference in age and body mass index (BMI) across steatosis grades. Patients with
grade 1 steatosis were significantly more likely to have diabetes than those with
grade 3 steatosis (60.0% vs. 25.0%, P = 0.016). There was no statistically
significant difference across steatosis grades in biochemical data, including AST,
ALT, glucose, insulin, triglycerides, total cholesterol, low-density lipoprotein (LDL),
high-density lipoprotein (HDL), FFA, CRP, Hgb A1c, alkaline phosphatase, total
bilirubin, direct bilirubin and HOMA-IR. Pancreatic fat measured by MRI PDFF did not
significantly correlate with BMI (R2 = 0.019) or age (R2 = 0.015) in this cohort of
patients with NAFLD. In addition, there was no significant difference in average MRIdetermined pancreatic fat fraction between patients with diabetes (7.9%, n = 15)
and those without (8.8%, n = 28) in this population of patients with biopsy-proven
NAFLD.

Table 1
Table 1
Demographic and biochemical characteristics of patients with NAFLD by steatosis
grade
MRI-determined pancreatic fat across regions of the pancreas

The mean (standard error) MRI-determined pancreatic fat was 8.5 (1.0)%. The
mean pancreatic fat content did not vary significantly between the head, body and
tail of the pancreas, as shown in Figure 2.

Figure 2
Figure 2
MRI-determined pancreatic fat across regions of the pancreas. Mean magnetic
resonance image (MRI) proton density fat-fraction (PDFF) is shown for the head,
body and tail of the pancreas. Overall mean MRI PDFF was calculated as the mean
of all regions ...
Association between MRI-determined pancreatic fat and histology-determined liver
steatosis grade

MRI-determined pancreatic fat content increased significantly with increasing

histology-determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2;
13.0% in grade 3 (P = 0.004) (Figure 3). Similarly, MRI-determined liver fat content
increased significantly with increasing histology-determined hepatic steatosis grade;
9.4% in grade 1; 15.8% in grade 2; 22.1% in grade 3 (P < 0.0001) (Figure 3).

Figure 3
Figure 3
MRI-determined pancreatic and liver fat across histology-determined steatosis
grade. Mean pancreas and liver fat percentage measured by magnetic resonance
image (MRI) proton density fat-fraction (PDFF) are shown according to steatosis
grade. Grade 1, ...
Patients with a higher histology-determined NAFLD activity score (NAS) also had
significantly higher pancreatic fat content. The mean MRI-determined pancreatic fat
content for subjects with an NAS <5 points was 6.4% (n = 22), while it was 10.6%
(n = 21) for those with an NAS 5 points (P = 0.03).

Association between MRI-determined pancreatic fat and histology-determined liver

fibrosis stage

MRI-determined pancreatic fat content was significantly higher in patients without

evidence of fibrosis on liver biopsy than in those with fibrosis (P = 0.013) as shown
in Figure 4. The mean MRI PDFF of the pancreas was 11.2% in 19 patients with no
fibrosis (grade 0), 5.8% in 13 patients with mild fibrosis (grade 1a, 1b or 2) and
6.9% in 11 patients with advanced fibrosis (grade 3 or 4).

Figure 4
Figure 4
MRI-determined pancreatic fat across histology-determined fibrosis grade. Mean
pancreas fat percentage measured by magnetic resonance image (MRI) proton
density fat-fraction (PDFF) is shown according to fibrosis stage grouped by no
fibrosis (stage 0), ...
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DISCUSSION
Main findings

In this pilot study, utilising a novel MRI-technique that allows the non-invasive
quantification of pancreatic fat in a cohort of well-characterised patients with
biopsy-proven NAFLD, we demonstrate that pancreatic steatosis is common in
patients with NAFLD, and pancreatic fat content positively correlates with liver
histology-determined steatosis grade. Furthermore, the MRI-determined pancreatic
fat content is higher in patients who had increased NAFLD activity score (NAS 5)
on liver histology. Finally, we also found that pancreatic fat content is lower in
NAFLD patients who had advanced fibrosis. In summary, these findings suggest that

steatosis accumulation in patients with NAFLD is probably also occurring in other

organs including the pancreas as shown in this pilot study. It is also likely that
pathophysiological changes that occur in the liver due to fat deposition also occur in
other organs in which fat accumulation is occurring.

These finding suggest that perhaps a similar mechanism may be involved in

steatosis of the liver and pancreas. Similar to risk factors for NAFLD, prior studies
have also established that obesity, age and insulin resistance are associated with
pancreatic steatosis.18, 19, 21, 23, 24, 38 Pancreatic fat accumulation results in cell dysfunction, which may also contribute to hepatic steatosis.39 The correlation
between pancreatic and hepatic steatosis was highlighted recently in 36 healthy
participants using MRI. Sijens et al. found that unlike kidney fat content, MRI fat
content of the liver and pancreas are coupled and correlate with BMI in healthy
patients.22 In an autopsy study, Van Geenen et al. recently compared postmortem
liver and pancreatic histology in 80 patients without known pancreatic or liver
disease and noted that pancreatic fat correlated with histology-determined NAS,
suggesting that pancreatic fat may play a role in the pathogenesis of NASH.40 It
should be noted, however, that death may lead to inflammatory changes in the fat
cells of the pancreas. Therefore, an autopsy study may not be a reliable indicator of
in vivo changes in pancreatic and liver fat content in humans.

No correlation with BMI, age or diabetes was noted in our cohort of patients with
NAFLD, which differs from findings in prior studies. This may be explained by the
fact that prior studies focused on healthy patients without known liver disease. In
contrast, all patients in this study had NAFLD, 93.0% were overweight (BMI >24.9
kg/m2) and 67.1% were obese (BMI >29.9 kg/m2). Although only 14 of 43 patients
had diabetes, 64.3% of the remaining patients were pre-diabetic (A1c >5.7). In
addition, the role of diabetes is unclear, as Saisho et al. reported no association
between pancreatic fat and diabetes in a postmortem analysis of 1886 adults.20

One of the concerns with measuring pancreatic fat is the need for non-invasive
testing as a biopsy cannot be performed on living subjects to evaluate pancreatic
fat, inflammation and fibrosis. Some prior studies have relied on postmortem
histological analysis of the pancreas1820, 40, 41; however, inflammatory changes
with death can make this analysis unreliable as noted previously. Ultrasonography
has also been used, but provides a relatively insensitive measure of fat content.24,
42, 43 More recently, various MRI and MRS techniques have been used to measure
pancreatic fat.12, 13, 23, 38 We chose to use a novel chemical shift-based gradientecho MRI technique to measure PDFF because of its improved accuracy over
traditional techniques and because it has been validated in measuring fat content
non-invasively in human tissue.28, 34, 35, 44 A second concern is the uneven
accumulation of fat in the pancreas, which differs from the relatively homogenous
steatosis of the liver in NAFLD. Focal accumulation of fat in the pancreas,
particularly in the tail and anterior aspect of the head, has previously been
described using ultrasonography, computed tomography (CT) and MRI

techniques.42, 4548 Li et al. used a similar MRI technique as was used in our study
to measure fat content in the head, body and tail of the pancreas in healthy
subjects and noted no significant different in fat content across regions.23 Our
results are consistent with Li and colleagues and showed that there was no
significant difference in fat content between the head, body and tail of the
pancreas.

In our study, patients with histology-determined liver fibrosis had significantly less
pancreatic fat than those without evidence of liver fibrosis. It is possible that
pancreatic steatosis may have a similar mechanism of causing fibrosis in the
pancreas as the development of liver fibrosis in patients with NASH. Therefore, the
reduced degree of pancreatic steatosis in these patients may be related to
increased pancreatic fibrosis. Although the concept of pancreatic fibrosis in nonalcoholics has not been studied extensively, Pitchumoni et al. noted that fibrosis
was present in 29% of nonalcoholics in a postmortem analysis.49 Our study did not
use histology or imaging techniques to evaluate fibrosis of the pancreas; however, it
has been established previously that lower liver steatosis is associated with greater
liver fibrosis in patients with NAFLD.37 In addition, obesity and pancreatic steatosis
have been shown to result in increased cytokine production and fibrosis in the
pancreas in studies in which mice were fed a high fat diet.50, 51

With the increasing prevalence of NAFLD worldwide, pancreatic steatosis will

probably also become increasingly common. Pancreatic fat may induce local effects
in the liver that affect the progression of NAFLD. Clinicians performing endoscopic
ultrasounds have noted a significant prevalence of pancreatic steatosis24 and many
of these patients may have undiagnosed NAFLD; however, there is little information
to guide what clinical management, if any, is required in these patients. There are
no data about pancreatic fat in patients with biopsy-proven NAFLD, and this study
fills that gap. This study illustrates that there is a strong association between
pancreatic fat and liver steatosis. In addition, it suggests that steatosis and
lipotoxicity may lead to fibrosis of the pancreas as well as the liver.

Strengths and limitations

The major strengths of this study include the use of an MRI technique that has been
well validated to measure fat content in the liver, histological assessment of the
liver, a patient population exclusively comprised of subjects with biopsy-proven
NAFLD and detailed biochemical and demographic data. As mentioned previously,
no prior studies have reviewed pancreatic fat in patients with biopsy-proven NAFLD.
In addition, measuring pancreatic fat in all anatomic areas of the pancreas allowed
for detailed measurements and confirmation of the homogenous nature of fat
distribution in the pancreas. Both the pathologist and radiologist were blinded to the
clinical data, and radiology or pathology data respectively. However, we
acknowledge following limitations of the study. We did not have a control and it is

neither feasible nor ethical to obtain a biopsy of the pancreas to confirm pancreatic
steatosis, and evaluate for changes in co-existent pancreatic fibrosis. In addition, we
do not have longitudinal data to help clarify whether pancreatic steatosis affects the
progression of NAFLD. We also acknowledge that an MRI slice thickness of 8 mm
may not provide optimal spatial resolution for measurement of fat in the pancreas.
We adopted the spectral model of fat derived from human liver in vivo by Hamilton
et al.52 While the spectral model of fat in human pancreatic tissue is likely to be
similar to that in liver tissue, this has not yet been experimentally verified. A
refinement for future studies will be the integration, if possible, of a spectral model
of fat derived from human pancreas in vivo. Finally, there was a small time interval
on average of 42.9 days between liver biopsy and MRI assessment in this study,
which could theoretically allow for a change in patient behaviour or management
before both studies were completed.

Implications for future research

Additional studies need to be performed to further describe the relationship

between fat accumulation in the liver and pancreas. Longitudinal analysis would
provide insight into the progression of NAFLD and how it relates to the progression
of pancreatic steatosis. In this study, we used a 2-dimensional (2D) MRI technique
to estimate PDFF. 3-dimensional (3D) techniques have also been developed for
estimating PDFF in the liver.53 It is likely that these 3D techniques could also be
applied for estimating PDFF in human pancreas in future studies. One potential
advantage of 3D imaging for measuring pancreatic fat is that it may allow
acquisition of thinner slices, which would reduce potential contamination from
through-plane volume averaging with extrahepatic adipose tissue.

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CONCLUSIONS
MRI-determined pancreatic fat correlates with histology-determined liver steatosis
grade in patients with NAFLD. Pancreatic steatosis appears relatively homogenous
in patients with NAFLD. Further studies are needed to examine whether the
systemic effects and clinical consequences associated with ectopic fat deposition in
various organs, including the liver and pancreas, lead to either one common end
point such as cardiovascular disease or lead to end organ damage in each of these
organs independent of each other. Future studies are also needed to determine
whether pancreatic fat increases the risk of incident pancreatic exocrine or
endocrine insufficiency, or progressive pancreatic fibrosis.

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Supplementary Material

Supplemnetary figure

Figure S1. MRI-determined pancreatic fat across regions of the pancreas. Individual
subject and mean magnetic resonance image (MRI) proton density fat-fraction
(PDFF) is shown for the head, body and tail of the pancreas. Overall mean MRI PDFF
was calculated as the mean of all regions of interest (ROIs) in the pancreas. Head,
body and tail definitions are described in detail in the methods section. Paired twotailed t-test showed no statistical difference in MRI PDFF between regions of the
pancreas.

Click here to view.(67K, pptx)

supplementary figure legend

Click here to view.(15K, docx)

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Acknowledgments
Declaration of funding interests: The study was conducted at the Clinical and
Translational Research Institute, University of California at San Diego. RL is
supported in part by the American Gastroenterological Association (AGA)
Foundation Sucampo ASP Designated Research Award in Geriatric
Gastroenterology and by a T. Franklin Williams Scholarship Award; Funding provided
by: Atlantic Philanthropies, Inc, the John A. Hartford Foundation, the Association of
Specialty Professors, and the American Gastroenterological Association and grant
K23-DK090303, and by the UCSD Digestive Diseases Research Development Center,
US PHS grant #DK080506, and P30CA23100-27.

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Footnotes
Guarantor of the article: Rohit Loomba.

Author contributions: Niraj Patel was involved in analysis and interpretation of data,
statistical analysis, drafting of the manuscript and critical revision of the
manuscript. Michael Peterson, David A. Brenner and Claude Sirlin were involved in
critical revision of the manuscript. Elhamy Heba was involved in analysis of data
and critical revision of the manuscript. Rohit Loomba was involved in the study
concept and design, analysis and interpretation of data, drafting of the manuscript,
critical revision of the manuscript, obtained funding, study supervision. All authors
approved the final version of the manuscript.

Declaration of personal interests: None.

SUPPORTING INFORMATION:

Additional Supporting Information may be found in the online version of this article:

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