Gastroenterology
Volume 138, Issue 4 , Pages 1346-1356.e3, April 2010

Trunk Fat Is Associated With Increased Serum Levels of Alanine Aminotransferase in the United States

  • Constance E. Ruhl

      Affiliations

    • Social & Scientific Systems, Inc., Silver Spring, Maryland
    • Corresponding Author InformationReprint requests Address requests for reprints to: Constance E. Ruhl, MD, PhD, Social & Scientific Systems, Inc., 8757 Georgia Avenue, 12th Floor, Silver Spring, MD 20910. fax: 301-628-3201
    • ,
  • James E. Everhart

      Affiliations

    • National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

Received 10 November 2009; accepted 30 December 2009. published online 11 January 2010.

Article Outline

Background & Aims

Liver injury is associated with obesity and related measures, such as body mass index (BMI) and waist circumference. The relationship between liver injury and body composition has not been evaluated in a population-based study.

Methods

Using data from a US population-based survey, we examined the contributions of body composition, measured by dual-energy x-ray absorptiometry (DXA), to increased serum alanine aminotransferase (ALT) activity among 11,821 adults without viral hepatitis. Trunk fat, extremity fat, trunk lean, and extremity lean mass were divided by height squared and used to categorize subjects into quintiles; logistic regression odds ratios (OR) were calculated for increased ALT.

Results

Increased ALT was associated with higher measures of fat and lean mass (P < .001) after adjustment for alcohol consumption and other liver injury risk factors in separate models for each DXA measure. Trunk fat was associated with increased ALT (P ≤ .001) in models also including any 1 of the other 3 measures. Extremity fat was independently inversely associated among women (P < .001). Trunk and extremity lean mass were not independently related to increased ALT. In models that contained all 4 DXA measures, the OR (95% confidence interval [CI]) for increased ALT for the highest, relative to lowest, quintile of trunk fat/height squared was 13.8 (95% CI: 5.4−35.3) for men and 7.8 (95% CI: 3.9−15.8) for women. When BMI, waist circumference, and trunk fat were considered together, only trunk fat remained independently associated with increased ALT.

Conclusions

Trunk fat is a major body composition determinant of increased ALT, supporting the hypothesis that liver injury can be induced by metabolically active intraabdominal fat.

Keywords: Alanine aminotransferase, Body composition, Dual-energy x-ray absorptiometry, National Health and Nutrition Examination Survey

Abbreviations used in this paper: BMI, body mass index, CI, confidence interval, DXA, dual-energy x-ray absorptiometry, NHANES, National Health and Nutrition Examination Survey, OR, odds ratio

 

See editorial on page 1244.

Obesity is an important risk factor for liver injury. A central fat distribution may be more important than total adipose mass.1, 2 In the general population, liver injury has been associated with anthropometric measures, such as body mass index (BMI) and waist circumference.3 Although this relationship is presumed to be determined by fat mass, a limitation of BMI and other anthropometric measures is that they reflect both fat and lean mass. The relationship of liver injury with body mass components using actual measures of body composition, such as dual x-ray absorptiometry (DXA), has not been evaluated in a population-based study. We examined the individual and relative contributions of body composition, measured with DXA, to elevated serum alanine aminotransferase (ALT) among US adults without evidence of chronic viral hepatitis in a national population-based sample.

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Materials and Methods 

The National Health and Nutrition Examination Survey (NHANES) is conducted in the United States by the National Center for Health Statistics of the Centers for Disease Control and Prevention and since 1999 has been a continuous annual survey.4 It consists of a cross-sectional interview, examination, and laboratory data collected from a complex multistage, stratified, clustered probability sample representative of the civilian, noninstitutionalized population with oversampling of persons aged 60 years and older, African Americans, and Hispanics. The survey was approved by the Centers for Disease Control and Prevention Institutional Review Board, and all participants provided written informed consent to participate. The current analysis utilized data collected from 1999 through 2004, the 6 years of performance of DXA body composition measurements.

Refrigerated serum samples were shipped weekly to testing laboratories. From 1999 to 2001, serum ALT activity was assayed by a Hitachi model 917 multichannel analyzer (Roche Diagnostics, Indianapolis, IN) at the Coulston Foundation, Alamogordo, NM and from 2002 to 2004 by a Beckman Synchron LX20 (Beckman Coulter Inc., Fullerton, CA) at Collaborative Laboratory Services, LLC, Ottumwa, IA.5, 6, 7, 8 ALT activity distributions did not differ between the Coulston Foundation Laboratory and Collaborative Laboratory Services.9 ALT was considered abnormal if >95th percentile among US adults not at high risk for liver injury (negative for viral hepatitis B and C, alcohol consumption ≤2 drinks per day, BMI <25 kg/m2, waist circumference ≤102 cm among men and ≤88 cm among women, no doctor-diagnosed diabetes, and hemoglobin A1C ≤6.7% [95th percentile among all US adults]). These cutoffs were 44 IU/L for men and 31 IU/L for women.

Arm, leg, and trunk fat mass and lean soft-tissue mass were measured by DXA using a Hologic QDR 4500A fan-beam densitometer (Hologic Inc., Bedford, MA); Hologic Discovery software version 12.1 was used for analysis of the scans.10, 11, 12 The NHANES 1999–2004 Multiple Imputation Data Files, as released by the National Center for Health Statistics, were used for this analysis (see Statistical Analysis section for additional information).4, 13 Height was measured using a stadiometer.14 Arm and leg fat summed to extremity fat mass, while arm and leg fat-free mass minus bone mineral content summed to extremity lean tissue mass. We calculated 4 body composition indices by dividing trunk and extremity fat masses and trunk and extremity lean soft-tissue masses (kg) by height (m) squared. These index measures accounted for variation in fat and lean mass due to variation in height and are analogous to BMI (kg/m2).12, 15, 16, 17 Body composition indices and waist circumference (cm) were categorized as quintiles because they were not normally distributed and because extreme values could exert undue influence if coded as continuous variables.

Factors known or thought to be related to elevated ALT or body composition were included as covariates in multivariate analyses: age (years), gender, ethnicity (non-Hispanic white, non-Hispanic black, Mexican American, other), cigarette smoking (never, former, <1 pack/day, ≥1 pack/day), alcohol consumption (drinks/day; 0, <1, 1–2, >2), glucose status (abnormal if doctor-diagnosed diabetes or elevated hemoglobin A1C), and serum total cholesterol concentration (mg/dL). Among a subgroup of participants who attended a morning examination after an overnight fast, concentrations of plasma glucose (mg/dL), serum C-peptide (nmol/L), and serum triglycerides (mg/dL) were determined.3

Of 20,228 sampled persons age 20 years and older, 14,213 (70%) were examined. We excluded participants positive for serum hepatitis B surface antigen or positive or indeterminate for hepatitis C antibody (n = 379), missing viral hepatitis serology (n = 867), pregnant women (n = 711), highly variable imputed or missing DXA data (n = 244), missing height (n = 115), or missing serum ALT activity (n = 76). The analysis sample, therefore, consisted of 11,821 participants. Of the 11,821 participants, 2579 had some or all imputed DXA data. Measures of insulin resistance have been shown to be strongly related to elevated ALT,3 but were only available for a subgroup of participants. Therefore, a secondary analysis of 5331 participants randomly assigned to be examined in the morning after an overnight fast excluded 907 who missed the morning examination or who fasted <8 or >24 hours.

Statistical Analysis 

Missing DXA data, due to no scan or an invalid scan, were nonrandom (ie, more frequent with greater age, BMI, weight, and height), which could lead to biased population estimates if simply excluded from analyses. Therefore, missing DXA data were imputed by the National Center for Health Statistics using multiple-imputation methodology.11, 13 Five versions of imputed values were generated randomly and independently, resulting in 5 complete data sets of measured and imputed values. Imputation introduces extra variability because the imputed values are plausible replacements, but not the true values. Therefore, each of the 5 data sets was analyzed separately and the results combined. The variability across the 5 analyses reflects the additional variability due to imputation. For the current analysis, multiply imputed DXA data were analyzed using the built-in option (MI_COUNT = x in the PROC statement, where x is the number of data sets) found in SUDAAN software (SUDAAN User's Manual, Release 10.0, 2008; Research Triangle Institute, Research Triangle Park, NC).

Because of gender differences in ALT levels and body composition, separate analyses were conducted for men and women. Mean body composition indices were compared by categories of participant characteristics and in people with and without abnormal ALT activity using a t-test. To further examine the relationship of elevated ALT with body composition indices, the prevalence of elevated ALT was compared among body composition index quintiles. Multivariate logistic regression analysis (SUDAAN, PROC RLOGIST, SUDAAN User's Manual, Release 10.0, 2008; Research Triangle Institute) was then used to calculate OR estimates and 95% CIs for elevated ALT, while controlling for effects of other factors related to abnormal ALT activity. ORs were computed for each body composition index quintile relative to the lowest quintile by categorizing these indices as indicator variables. The trend in ORs across quintiles of body composition indices was tested by treating these indices as ordinal variables of 5 levels. Interaction between body composition indices was tested by categorizing indices as tertiles in order to have adequate cell sizes and including interaction terms in models.

Because body composition measures are correlated, analyses were conducted using both standard multivariate logistic regression and the residual method, which removes the potentially distorting effect of collinearity of 2 highly correlated variables, such as body composition measures.18 In the residual method, models contained 1 body composition index and the residual of a second body composition index (the variable of interest) that was regressed on the first in an initial step. Body composition indices were treated as ordinal variables of 5 levels for analyses using the residual method.

An analysis was also conducted of the relationship of elevated ALT with BMI and waist circumference to evaluate whether DXA measures were better predictors of abnormal ALT than were BMI and waist circumference. Multivariate analyses were conducted among participants examined in the morning after an overnight fast to adjust for fasting plasma glucose and serum C-peptide and triglyceride concentrations. In addition, an analysis was performed to examine whether DXA measures explained gender and race/ethnicity differences in prevalence of elevated ALT. Body composition indices were treated as continuous variables for this analysis.

Multivariate analyses excluded persons with missing values for any factor included in the model. A P value of <.05 indicated statistical significance. All analyses utilized sample weights that accounted for unequal selection probabilities and nonresponse. All variance calculations took into consideration the design effects of the survey using Taylor series linearization.19 Analyses were conducted using SUDAAN software (SUDAAN User's Manual, Release 10.0, 2008; Research Triangle Institute). When using the sample weights, this software enables the strata and primary sampling unit pairings from the sample design to also be used in estimating variances and testing for statistical significance. As advised by the NHANES sponsor,20 such consideration of the complex sample design is necessary to accurately determine the precision and statistical significance of any statistic.

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Results 

Mean (standard deviation) body composition indices for the 5903 men and 5918 women included in the analyses are shown in Table 1 (first row for men and women); ranges and quintile cut points are shown in Table 3, Table 4 (footnote). Fat mass tended to increase in middle age, while lean mass tended to decrease in older age (Table 1). Among men, non-Hispanic blacks had lower fat and lean trunk mass and higher extremity lean mass than either non-Hispanic whites or Mexican Americans (Table 1). Among women, blacks had higher levels of all body composition measures than whites, while Mexican Americans had higher levels of fat and lean trunk mass than whites (Table 1). All body composition measures were higher with elevated glucose concentration and lower with greater alcohol consumption among both men and women (Table 1). Former smokers had higher fat and lean trunk mass among both men and women, while current smokers tended to have lower levels of all body composition measures (Table 1).

Table 1. Body Measure Indices and Waist Circumference by Characteristics among Men and Women
CharacteristicFat (kg/m2)Lean (kg/m2)BMI (kg/m2)Waist Circumference (cm)
TrunkExtremityTrunkExtremity
Men (n=5903)
All4.3(1.9)3.5(1.4)9.5(1.4)8.6(1.3)28.0(5.5)99.6(14.7)
Age (y)
20-393.7(1.9)3.4(1.5)9.3(1.3)8.7(1.4)27.2(5.6)94.9(15.0)
40-594.6(1.9)a3.6(1.3)a9.7(1.4)a8.7(1.3)28.8(5.4)a102.2(13.8)a
60+4.9(1.8)ab3.6(1.2)a9.5(1.3)ab8.0(1.2)ab28.2(4.9)ab104.5(12.8)ab
Race-ethnicity
NHW4.4(1.9)3.6(1.3)9.5(1.4)8.5(1.3)28.1(5.4)101.0(14.4)
NHB3.7(2.1)a3.5(1.7)9.3(1.5)a9.3(1.6)a28.0(6.5)95.8(16.6)a
Mex-Am4.3(1.7)b3.4(1.2)a9.5(1.2)b8.5(1.1)b27.9(4.8)97.0(12.7)a
Other4.0(1.7)abc3.2(1.2)ab9.2(1.4)ac8.4(1.4)b27.0(5.1)abc95.0(14.2)a
Glucose status
Normal4.2(1.8)3.5(1.3)9.4(1.3)8.6(1.3)27.7(5.3)98.7(14.2)
Abnormald5.8(2.3)a4.1(1.6)a10.4(1.6)a8.8(1.5)a31.3(6.5)a109.8(15.7)a
Smoking
Never4.3(1.9)3.6(1.4)9.5(1.4)8.8(1.4)28.2(5.5)99.3(14.8)
Former4.7(1.9)a3.7(1.3)9.7(1.3)a8.6(1.3)a28.8(5.3)a103.2(13.8)a
<1 pack/day3.8(1.9)ab3.2(1.4)ab9.3(1.4)ab8.4(1.3)a26.8(5.4)ab95.4(14.7)ab
≥1 pack/day3.8(1.8)ab3.2(1.2)ab9.4(1.3)b8.2(1.2)abc26.6(5.1)ab97.2(14.3)abc
Alcohol intake (drinks/day)
04.8(2.2)3.8(1.6)9.7(1.6)8.6(1.5)29.1(6.4)103.5(16.2)
<14.2(1.9)a3.5(1.3)a9.4(1.3)a8.6(1.3)27.8(5.3)a98.8(14.7)a
1-23.9(1.5)ab3.2(1.0)ab9.3(1.1)a8.5(1.1)ab27.1(4.3)ab97.4(11.9)ab
>24.0(1.8)a3.3(1.2)ab9.4(1.3)a8.4(1.2)ab27.3(5.0)a98.5(13.5)a
Women (n=5918)
All5.6(2.6)5.8(2.2)8.1(1.3)6.7(1.3)28.2(7.0)93.1(15.6)
Age (y)
20-395.0(2.7)5.5(2.2)8.0(1.2)6.9(1.3)27.4(7.1)89.3(15.8)
40-595.9(2.7)a6.0(2.3)a8.3(1.4)a6.8(1.4)29.0(7.3)a94.7(15.9)a
60+5.9(2.1)a5.9(2.0)a8.0(1.1)b6.4(1.2)ab28.2(5.9)ab96.5(13.8)ab
Race-ethnicity
NHW5.5(2.6)5.7(2.1)8.1(1.3)6.6(1.2)27.8(6.8)92.6(15.6)
NHB6.1(2.8)a6.8(2.6)a8.4(1.4)a7.9(1.5)a31.4(7.9)a98.6(16.6)a
Mex-Am6.1(2.4)a5.7(1.9)b8.4(1.3)a6.7(1.2)ab29.0(6.5)ab93.9(14.5)b
Other5.4(2.3)bc5.4(1.9)abc7.9(1.2)bc6.6(1.2)b27.4(6.1)bc90.4(14.3)bc
Glucose status
Normal5.4(2.5)5.7(2.2)8.0(1.2)6.7(1.3)27.8(6.8)92.1(15.1)
Abnormald7.5(2.8)a6.6(2.5)a9.1(1.4)a7.3(1.6)a32.7(7.6)a106.5(16.0)a
Smoking
Never5.5(2.6)5.8(2.2)8.0(1.3)6.8(1.3)28.2(6.9)92.6(15.4)
Former5.9(2.6)a6.0(2.2)8.2(1.3)a6.7(1.3)28.8(7.0)a95.2(15.9)a
<1 pack/day5.3(2.7)b5.5(2.3)ab8.1(1.3)6.8(1.4)27.7(7.3)b92.0(16.2)b
≥1 pack/day5.4(2.5)b5.4(2.0)ab8.2(1.3)a6.6(1.3)27.6(6.7)b93.2(15.4)
Alcohol intake (drinks/day)
06.1(2.7)6.1(2.3)8.3(1.4)6.8(1.4)29.5(7.4)96.5(16.2)
<15.3(2.5)a5.7(2.2)a8.0(1.2)a6.7(1.3)a27.7(6.8)a91.5(15.4)a
1-25.0(2.2)ab5.1(1.7)ab7.8(1.0)ab6.4(1.1)ab26.3(5.6)ab91.1(13.6)a
>24.6(1.9)ab4.8(1.6)ab7.6(1.0)ab6.4(1.1)ab25.5(5.2)ab88.7(12.9)a

NOTE. Values are mean (standard deviation).

BMI, body mass index; NHB, non-Hispanic black; NHW, non-Hispanic white; Mex-Am, Mexican American.

aP < .05 compared with 1st listed category.

bP < .05 compared with 2nd listed category.

cP < .05 compared with 3rd listed category.

dDoctor-diagnosed diabetes or hemoglobin A1C > 6.8% (95th percentile).

Relationship of ALT to Body Measurements 

The prevalence (± standard error of mean) of elevated ALT was 11.1% (± 0.56%) among men and 10.1% (± 0.36%) among women. Means of all body composition measures were higher with elevated ALT compared with normal ALT among both men and women (P < .001 for all comparisons) (Table 2). Likewise, unadjusted prevalence of elevated ALT increased across quintiles of all body measures among men and women (Table 3, Table 4). The association of elevated ALT with individual body measures of BMI, waist circumference, and the 4 compositions was evaluated in logistic regression analyses (Table 5). An increased odds of higher ALT was seen with increasing quintiles of all body measures among men and women in both unadjusted models (P value for trend <.001 for all comparisons) and after adjusting for alcohol consumption and other liver injury risk factors (P value for trend <.001 for all comparisons). Of the 4 DXA measures, the relationship was strongest with trunk fat, especially among men. The higher risk of elevated ALT with greater trunk fat among men in the multivariate-adjusted analysis (OR = 11.6 comparing highest to lowest quintile) than unadjusted analysis (OR = 7.1) was primarily the result of adjusting for age.

Table 2. Body Measure Indices and Waist Circumference by Serum Alanine Aminotransferase (ALT) Statusa Among Men and Women
MenWomen
ALT (IU/L)bDifference95% CI of differenceALT (IU/L)bDifference95% CI of difference
Body measure≤44 (n = 5286)>44 (n = 617)≤31 (n = 5281)>31 (n = 637)
Trunk fat (kg/m2)4.2(1.9)5.3(1.9)1.10.93–1.35.4(2.5)6.7(2.8)1.20.95–1.5
Extremity fat (kg/m2)3.4(1.3)4.0(1.4)0.600.50–0.705.7(2.2)6.2(2.3)0.490.23–0.75
Trunk lean (kg/m2)9.4(1.3)10.1(1.4)0.740.60–0.888.0(1.2)8.6(1.4)0.580.45–0.72
Extremity lean (kg/m2)8.5(1.3)9.2(1.4)0.660.53–0.796.7(1.3)7.1(1.3)0.380.26–0.51
BMI (kg/m2)27.6(5.3)30.8(5.7)3.22.7–3.627.9(6.9)30.7(7.3)2.82.0–3.5
Waist circumference (cm)98.8(14.4)106.3(14.8)7.56.1–8.992.4(15.5)99.2(16.0)6.85.3–8.3

ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval.

aP < .001 for all comparisons.

bValues are mean (standard deviation).

Table 3. Prevalence of Elevated Serum Alanine Aminotransferase (ALT)a by Body Measure Quintileb Among Men (n = 5903)
Quintilec
Body measure1st2nd3rd4th5th
Trunk fat3.5(0.59)6.9(0.75)12.3(1.3)12.8(1.2)20.4(1.7)
Extremity fat5.1(0.70)8.9(0.93)9.6(1.1)13.6(1.3)18.5(1.3)
Trunk lean5.1(0.70)7.4(0.96)9.9(0.88)12.9(1.4)20.4(1.6)
Extremity lean5.3(0.69)8.8(0.87)8.5(0.96)13.5(1.4)19.6(1.6)
BMI3.9(0.54)6.6(0.93)10.4(0.98)14.7(1.5)20.2(1.4)
Waist circumference3.9(0.57)9.2(1.0)10.1(1.1)14.1(1.3)18.4(1.5)

NOTE. Values are % (standard error).

BMI, body mass index.

a>44 IU/L.

bP < .001 for all comparisons.

cQuintile definitions for body measure indices (kg/m2) and waist circumference (cm), respectively, were as follows: for trunk fat, 0.47–<2.6, 2.6–<3.6, 3.6–<4.5, 4.5–<5.7, and 5.7–16.1; for extremity fat, 0.85–<2.5, 2.5–<3.0, 3.0–<3.6, 3.6–<4.4, and 4.4–15.3; for trunk lean, 4.8–<8.4, 8.4–<9.1, 9.1–<9.6, 9.6–<10.5, and 10.5–18.8; for extremity lean, 3.9–<7.5, 7.5–<8.2, 8.2–<8.8, 8.8–<9.5, and 9.5–18.2; for BMI, 16.0–<23.7, 23.7–<26.1, 26.1–<28.5, 28.5–<31.7, and 31.7–65.0; and for waist circumference, 62.4–<87.5, 87.5–<95.1, 95.1–<101.8, 101.8–<110.8, and 110.8–173.4.

Table 4. Prevalence of Elevated Serum Alanine Aminotransferase (ALT)a by Body Measure Quintileb Among Women (n = 5918)
Body measureQuintilec
1st2nd3rd4th5th
Trunk fat4.3(0.75)7.3(0.79)9.4(0.90)12.7(1.2)16.7(1.1)
Extremity fat7.7(0.72)7.0(0.95)11.0(0.94)12.3(0.93)12.3(1.1)
Trunk lean5.2(0.80)7.3(1.0)9.5(1.2)12.0(1.2)16.5(1.2)
Extremity lean6.0(0.78)8.4(0.88)10.2(1.1)11.4(1.1)14.4(1.2)
BMI5.4(0.74)6.9(0.84)10.2(0.85)12.1(1.0)15.9(1.0)
Waist circumference4.1(0.75)7.2(0.89)12.2(1.2)10.8(0.99)15.7(1.0)

NOTE. Values are % (standard error).

a>31 IU/L.

bP < .001 for all comparisons.

cQuintile definitions for body measure indices (kg/m2) and waist circumference (cm), respectively, were as follows: for trunk fat, 0.67–<3.3, 3.3–<4.6, 4.6–<5.9, 5.9–<7.5, and 7.5–18.2; for extremity fat, 0.79–<4.0, 4.0–<4.9, 4.9–<5.9, 5.9–<7.3, and 7.3–20.6; for trunk lean, 3.9–<7.0, 7.0–<7.6, 7.6–<8.2, 8.2–<9.0, and 9.0–14.8; for extremity lean, 3.5–<5.7, 5.7–<6.2, 6.2–<6.8, 6.8–<7.7, and 7.7–15.4; for BMI, 12.0–<22.4, 22.4–<25.3, 25.3–<28.6, 28.6–<33.4, and 33.4–66.4; and for waist circumference, 58.5–<79.1, 79.1–<87.4, 87.4–<95.7, 95.7–<105.8, and 105.8–157.7.

Table 5. The Relationshipa of Elevated Serum Alanine Aminotransferase (ALT)b With Body Measure Indices (kg/m2) and Waist Circumference (cm) Among Men and Women
MenWomen
Body measure quintileUnadjusted (n = 5903)Multivariate-adjustedc (n = 5590)Body measure quintileUnadjusted (n = 5918)Multivariate-adjustedc (n = 5496)
ORd95% CIORd95% CIORd95% CIORd95% CI
Trunk fat
< 2.61.0 1.0 <3.31.0 1.0
2.6–<3.62.11.4–3.12.31.5–3.63.3–<4.61.81.2–2.71.91.2–3.0
3.6 –<4.53.92.6–5.94.83.2–7.24.6–<5.92.31.5–3.62.51.6–4.0
4.5–<5.74.12.5–6.65.63.5–9.25.9–<7.53.32.0–5.33.52.1–5.8
≥5.77.14.9–10.311.67.9–16.9≥7.54.53.0–6.74.63.0–7.1
Extremity fat
<2.51.0 1.0 <4.01.0 1.0
2.5–<3.01.81.2–2.71.81.2–2.84.0–<4.90.900.63–1.30.890.62–1.3
3.0–<3.62.01.4–2.82.11.4–3.04.9–<5.91.51.2–1.91.51.1–1.9
3.6–<4.42.91.9–4.43.01.9–4.85.9–<7.31.71.3–2.21.71.3–2.3
≥4.44.23.1–5.65.13.6–7.3≥7.31.71.2–2.31.71.2–2.3
Trunk lean
<8.41.0 1.0 <7.01.0 1.0
8.4–<9.11.50.98–2.31.61.0–2.57.0–<7.61.40.87–2.41.50.89–2.5
9.1–<9.62.11.4–3.02.21.4–3.27.6–<8.21.91.2–3.12.01.2–3.2
9.6–<10.52.81.9–4.02.92.0–4.38.2–<9.02.51.6–3.82.61.7–3.9
≥10.54.83.4–6.85.74.0–8.2≥9.03.62.4–5.43.62.3–5.6
Extremity lean
<7.51.0 1.0 <5.71.0 1.0
7.5–<8.21.71.2–2.51.51.0–2.25.7–<6.21.50.96–2.21.51.0–2.3
8.2–<8.81.71.2–2.41.40.94–2.06.2–<6.81.81.2–2.82.01.3–3.0
8.8–<9.52.82.0–4.02.41.7–3.46.8–<7.72.01.4–3.02.31.6–3.4
≥9.54.33.1–6.14.02.8–5.8≥7.72.71.9–3.73.22.2–4.7
BMI
<23.71.0 1.0 <22.41.0 1.0
23.7–<26.11.81.1–2.81.91.1–3.122.4–<25.31.30.88–2.01.30.87–2.0
26.1–<28.52.81.9–4.32.92.0–4.425.3–<28.62.01.4–2.92.11.4–3.0
28.5–<31.74.22.9–6.34.73.1–7.028.6–<33.42.41.6–3.62.51.7–3.8
≥31.76.24.4–8.97.75.5–10.7≥33.43.32.3–4.83.42.3–4.9
Waist circumference
<87.51.0 1.0 <79.11.0 1.0
87.5–<95.12.51.6–3.92.81.7–4.679.1–<87.41.81.1–2.91.91.2–3.2
95.1–<101.82.81.8–4.33.62.3–5.687.4–<95.73.22.0–5.23.62.2–6.0
101.8 –<110.84.12.9–5.96.04.1–8.995.7–<105.82.81.9–4.33.22.0–5.0
≥110.85.63.8–8.29.36.0–14.2≥105.84.32.8–6.64.93.1–7.8

BMI, body mass index; CI, confidence interval; OR, odds ratio.

aP value for trend <.001 for all body composition measures in both unadjusted and multivariate-adjusted analyses.

b>44 IU/L for men or >31 IU/L for women.

cAdjusted for ethnicity, age (6 categories, ordinal), glucose status (doctor-diagnosed diabetes, elevated hemoglobin A1C), serum total cholesterol, cigarette smoking, and alcohol consumption.

dCalculated from logistic regression analysis.

Analysis was performed for the combined effect of body composition measures on elevated ALT. In multivariate-adjusted models, including trunk fat and 1 of the other 3 body composition indices, higher trunk fat remained strongly associated with elevated ALT (P ≤ .001 for all comparisons) among both men and women (data not shown). Among women, an independent inverse relationship emerged with extremity fat. The OR (95% CI) comparing the 2nd through 5th quintiles, respectively, relative to the 1st quintile were 0.51 (95% CI: 0.34–0.78), 0.56 (95% CI: 0.38–0.83), 0.45 (95% CI: 0.29–0.69), and 0.27 (95% CI: 0.16–0.47) (P value for trend <.001). Among men, an inverse relationship with extremity fat also appeared after adjustment for trunk fat, but did not reach statistical significance. The ORs (95% CIs) comparing the upper quintiles relative to the lowest quintile among men were 0.79 (95% CI: 0.43–1.5), 0.58 (95% CI: 0.33–1.0), 0.59 (95% CI: 0.30–1.2), and 0.55 (95% CI: 0.27–1.1) (P value for trend = .13). Trunk lean mass was of borderline statistical significance among men (P = .050) and women (P = .071). Extremity lean mass was not independently related to ALT among either men or women (P > .10).

When all 4 body composition indices were included in multivariate-adjusted models, higher trunk fat remained independently associated with elevated ALT among both men (Figure 1A) and women (Figure 1B). Compared with the lowest quintile, the OR for elevated ALT among men in the highest quintile of trunk fat was 13.8 (95% CI: 5.4–35.3), and among women it was 7.8 (95% CI: 3.9–15.8). Among women, extremity fat was inversely associated with elevated ALT with adjustment for trunk fat (Figure 1B). Thus, compared with the lowest quintile, women in the highest quintile were only one-quarter as likely to have an elevated ALT (OR = 0.24; 95% CI: 0.14–0.42). However, this relationship was found only among women with the highest degree of trunk fat (Figure 2) (test for interaction P = .043). Among men, an inverse relationship with extremity fat was also found, but was not statistically significant comparing the highest to lowest quintile, OR = 0.52 (95% CI: 0.26–1.1) (Figure 1A). Trunk lean and extremity lean mass were not independently related to ALT among either men or women. To address the possible effect on ALT measurement of impaired renal function, an additional analysis excluded 1220 participants with moderately or severely decreased glomerular filtration rate (defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2).21 There was little effect on the relationship of elevated ALT with body composition indices among either men or women (data not shown). To evaluate the possible confounding effect of potentially hepatotoxic medications used more often in the overweight and obese, an additional analysis was conducted among 5120 participants not taking prescriptions medications. Elevated ALT remained strongly associated with higher trunk fat among both men and women and inversely related to higher extremity fat among women (data not shown).

  • View full-size image.
  • Figure 1. 

    (A) Multivariate-adjusted odds ratio (OR) for elevated alanine aminotransferase (ALT) comparing upper relative to lowest body composition index quintile and adjusting for all 3 other measures among men. (B) Multivariate-adjusted OR for elevated ALT comparing upper relative to lowest body composition index quintile and adjusting for all 3 other measures among women. (C) Multivariate-adjusted OR for elevated ALT comparing upper relative to lowest quintile of trunk fat, body mass index (BMI), and waist circumference and adjusting for the other 2 measures among men. (D) Multivariate-adjusted OR for elevated ALT comparing upper relative to lowest quintile of trunk fat, BMI, and waist circumference and adjusting for the other 2 measures among women.

Having established that elevated ALT was most strongly associated with trunk fat, we considered its effect on the association of BMI and waist circumference with elevated ALT. When trunk fat, BMI, and waist circumference were included together in multivariate-adjusted models, higher trunk fat remained independently associated with elevated ALT among both men (P = .002) (Figure 1C) and women (P = .011) (Figure 1D), but BMI and waist circumference were not (P value for trend >.10 for all comparisons). However, women in the highest 3 quintiles of waist circumference were more likely to have ALT elevation than women in the lower 2 quintiles (OR = 1.2, 95% CI: 0.95–1.4).

Because body composition measures are strongly correlated, relationships were further evaluated in analyses containing trunk fat and the residual of one of the other measures regressed on trunk fat (Table 6). This enabled us to examine the information contained in each of the other 3 body composition indices that was not accounted for by trunk fat. As with analyses using standard multivariate logistic regression, trunk fat remained the dominant body composition measure among both men and women. The residual of extremity fat was inversely related to elevated ALT among women (P = .001) and men (P = .002). The residuals of BMI and waist circumference were not independently related to elevated ALT among men or women.

Table 6. The Relationship of Elevated Serum Alanine Aminotransferase (ALT)a With Trunk Fat Mass Index and Residuals of Body Measure Indices (kg/m2) and Waist Circumference (cm) Regressed on Trunk Fat Among Men and Women in Multivariate-Adjustedb Analysis Using the Residual Method
Men (n = 5590)Women (n = 5496)
ORc95% CIP valueORc95% CIP value
Trunk fatd1.71.6–1.9<0.0011.41.3–1.5<0.001
Body measure residual
Extremity fat0.870.80–0.950.0020.860.79–0.940.001
Trunk lean1.10.99–1.20.0821.10.98–1.20.13
Extremity lean1.00.94–1.10.450.980.90–1.10.70
BMI1.00.91–1.10.910.940.86–1.00.15
Waist circumference0.970.90–1.10.541.10.98–1.20.11

BMI, body mass index; CI, confidence interval; OR, odds ratio.

a>44 IU/L in men or >31 IU/L in women.

bAdjusted for ethnicity, age (6 categories, ordinal), glucose status (doctor-diagnosed diabetes, elevated hemoglobin A1C), serum total cholesterol, cigarette smoking, and alcohol consumption.

cCalculated from logistic regression analysis; per quintile increase in trunk fat and per quintile increase in residuals for the other measures.

dModels contained trunk fat and the residual of one of the other body measures. The odds ratio for trunk fat was unchanged regardless of which body measure residual was included in the analysis.

A secondary analysis was conducted among a random subgroup of 5331 participants examined in the morning after an overnight fast, adjusting for fasting plasma glucose and serum triglyceride and C-peptide concentrations, in addition to the factors adjusted for in the main analysis. Among men in the morning fasting sample, the association of elevated ALT with trunk fat was reduced modestly with adjustment for these other factors. The OR (95% CI) comparing the highest relative to lowest trunk fat quintile was 6.1 (95% CI: 2.8–13.7) (Supplementary Table 1) as compared with 11.6 (95% CI: 7.9–16.9) in the main analysis (Table 5). Among women the association of abnormal ALT with trunk fat was attenuated, primarily by C-peptide concentration. The OR (95% CI) comparing the highest relative to lowest trunk fat index quintile was 2.6 (95% CI: 1.0–6.4) (Supplementary Table 2) as compared with 4.6 (95% CI: 3.0–7.1) in the main analysis without adjustment for C-peptide (Table 5).

Finally, analyses were performed to examine whether trunk fat explained gender and race/ethnicity differences in prevalence of elevated ALT. For the analysis of gender, the same cut point for elevated ALT was used for both men and women (>38 IU/L, defined similarly to the cut points for men and women individually by using the 95th percentile among US adults not at high risk for liver injury). In multivariate analysis using the same cut point for elevated ALT for both men and women, the OR for ALT elevation was 3.1 (95% CI: 2.7–3.6) for men relative to women, which increased to 4.5 (95% CI: 3.7–5.4) with adjustment for trunk fat (Supplementary Table 3). Compared with non-Hispanic white men, the OR for elevated ALT was 0.66 (95% CI: 0.47–0.92) for non-Hispanic black men and 2.0 (95% CI: 1.5–2.6) for Mexican-American men. Adjustment for trunk fat attenuated the lower risk among black men (OR = 0.75; 95% CI: 0.53–1.1), but not the higher risk among Mexican-American men (Supplementary Table 3). Compared with non-Hispanic white women, the OR for elevated ALT was 0.52 (95% CI: 0.38–0.72) for non-Hispanic black women and 2.0 (95% CI: 1.5–2.6) for Mexican-American women. Adjustment for trunk fat had little effect on these relationships (Supplementary Table 3).

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Discussion 

The main finding of this large, national, population-based study was a strong association of higher trunk fat mass index (trunk fat mass/height squared) with abnormal ALT activity. This relationship was found among both men and women and was independent of extremity fat, trunk lean, and extremity lean mass, BMI, waist circumference, and of other liver injury risk factors. A measure of insulin resistance attenuated but did not eliminate the relationship among women. In an analysis of an earlier NHANES, an elevated ALT was associated with a central fat distribution as measured by anthropometric indicators, such as waist circumference or waist-to-hip circumference ratio.3 Waist-to-hip circumference ratio is considered to be a measure of upper vs lower body adiposity. However, circumferences are influenced by both fat and lean mass and a higher waist-to-hip circumference ratio may reflect both increased upper body fat and decreased lower body fat. DXA provides a more direct and accurate measurement of total and regional (ie, trunk, arm, leg) fat and lean body mass. In clinical and epidemiologic studies, hepatic steatosis has been associated with abdominal adiposity22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 with few exceptions.35, 36 This relationship was found among both men and women and obese and nonobese persons. In most studies using imaging methods to measure abdominal fat, intraabdominal fat, but not subcutaneous abdominal fat, was associated with liver fat.22, 24, 25, 28, 30, 31, 32, 33, 34 The relationship of liver injury with greater trunk fat is therefore likely attributable to the visceral adipose component. It has been hypothesized that visceral fat releases potentially hepatotoxic fatty acids and adipokines into the portal vein, where they exert a first-pass effect on the liver.22, 37 Visceral adipose tissue lipolysis is also less sensitive to insulin suppression than other fat depots.38

Despite the strength of the relationship of trunk fat with abnormal ALT, it did not explain the higher prevalence of elevated ALT among men compared with women. In fact, because women tend to have higher trunk fat and lower ALT than men, the relationship of ALT with male gender was strengthened by this adjustment. Trunk fat partially explained the lower prevalence of abnormal ALT among non-Hispanic black men compared with non-Hispanic white men, but not the higher prevalence among Mexican-American men or any race/ethnic differences among women.

An unexpected finding was a relationship of decreased extremity fat with elevated ALT after adjusting for trunk fat. Extremity or leg fat mass measured by DXA has been shown to be inversely associated with metabolic risk factors independent of trunk fat.39, 40, 41, 42, 43, 44, 45, 46 Higher peripheral fat has also been reported to be favorably related to coronary atherosclerosis42, 47 and peripheral arterial stiffness.48, 49 Nonalcoholic fatty liver is associated with dyslipidemia, glucose intolerance, and insulin resistance, and has been considered to be the liver manifestation of the metabolic syndrome.50, 51, 52 However, little is known about the relationship of peripheral fat mass with liver injury. In a clinical study of French patients referred for overweight/obesity, ALT was independently related positively to trunk fat mass and inversely to leg fat mass among men and women.53 Among Chinese patients, low femoral subcutaneous fat was associated with ultrasound-diagnosed fatty liver independent of visceral fat and abdominal subcutaneous fat among women, but not men.54 The metabolism of adipose tissue differs based on its central or peripheral location. Lipoprotein lipase activity is higher in leg fat compared with trunk fat, resulting in decreased fatty acid turnover.55, 56 Uptake and storage of free fatty acids by femoral adipose tissue could lead to protection of other organs, such as the liver from exposure to fatty acids and ectopic fat deposition.53

As reported previously, limitations of using NHANES to study liver injury are reliance on serum measures to estimate liver injury. Liver biopsies cannot be conducted on the general population, and imaging was not performed. Therefore, a single serum liver enzyme activity was relied upon as a marker for liver injury.3, 57, 58 Inevitably, participants were included in the elevated ALT group who would not have been had repeat ALT measurements been available. Several limitations of DXA should be appreciated. Trunk fat measured by DXA does not differentiate between subcutaneous and visceral adipose tissue and parenchymal fat, including that in the liver. Thus, abdominal fat measurements by DXA are not necessarily comparable to adipose tissue measurements by computed tomography or magnetic resonance imaging. In addition, soft-tissue composition can only be determined on pixels free of bone. In the arm and leg, the percentage of bone-free pixels is lower than in the trunk, which may have resulted in less accurate measures of extremity soft-tissue composition. For a number of larger and older participants, multiple imputation methods were used to adjust for their missing DXA data. An additional limitation of this study is its cross-sectional design. The current results do not necessarily indicate that reduction of trunk fat will reduce liver injury. Factors in common, such as insulin resistance, could be more significant. These limitations are balanced by the benefits of a large, national, population-based sample, particularly the avoidance of ascertainment bias that occurs in clinical studies of selected patients, and the ability to generalize the results to the US population. Despite the limitations mentioned here, a major strength of the study was the use of DXA, a relatively accurate and precise method to estimate body fat and lean soft-tissue mass components.

These results in the US population indicate that trunk fat is the major body composition determinant of elevated ALT activity. They support the hypothesis that liver injury can be induced by metabolically active intraabdominal fat.

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Acknowledgments 

The authors thank Zhongyu Fang for programming support and assistance with creation of tables and Danita Byrd-Holt for consultation on SUDAAN programming using multiply imputed data and the residual method.

Author contributions: CER: study concept and design, statistical analysis and interpretation of data, drafting of manuscript; JEE: study concept and design, statistical analysis and interpretation of data, critical revision of manuscript for important intellectual content.

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Supplementary material 

Supplementary Table 1. The Relationship of Elevated Serum Alanine Aminotransferase (ALT)a With Body Composition Indices (kg/m2) and Waist Circumference (cm) Among Men in the Morning Fasting Sample
Body measure quintilePrevalence of elevated ALT (%)Unadjusted (n = 2665)Multivariate-adjustedb (n = 2543)
ORc95% CIP value for trendORc95% CIP value for trend
Trunk fat <.001 <.001
<2.62.71.0 1.0
2.6–<3.67.32.81.4–5.6 2.10.96–4.7
3.6–<4.511.84.82.4–9.4 3.11.5–6.4
4.5–<5.714.25.93.0–11.9 3.31.5–7.3
≥5.725.612.36.5–23.3 6.12.8–13.7
Extremity fat <.001 .002
<2.55.41.0 1.0
2.5–<3.07.81.50.84–2.6 0.920.50–1.7
3.0–<3.610.72.11.3–3.5 0.970.52–1.8
3.6–<4.415.83.32.0–5.4 1.60.89–2.8
≥4.421.84.83.3–7.1 1.71.1–2.7
Trunk lean <.001 <.001
<8.45.51.0 1.0
8.4–<9.16.91.30.69–2.4 0.830.43–1.6
9.1–<9.69.41.81.1–3.0 0.960.55–1.7
9.6–<10.514.52.91.8–4.7 1.40.80–2.5
≥10.524.75.73.4–9.4 2.11.2–3.7
Extremity lean <.001 .005
<7.55.81.0 1.0
7.5–<8.29.01.60.83–3.1 1.20.59–2.3
8.2–<8.87.91.40.79–2.5 0.740.40–1.4
8.8–<9.516.53.22.0–5.2 1.70.95–2.9
≥9.522.84.82.8–8.1 1.90.99–3.7
BMI <.001 <.001
<23.74.51.0 1.0
23.7–<26.16.31.40.74–2.7 0.940.52–1.7
26.1–<28.58.21.91.1–3.2 0.910.53–1.6
28.5–<31.718.84.92.9–8.3 2.31.3–4.2
≥31.723.76.64.3–10.0 2.31.4–3.7
Waist circumference <.001 <.001
<87.54.01.0 1.0
87.5–<95.17.21.91.0–3.4 1.10.53–2.3
95.1–<101.812.83.51.9–6.4 2.11.0–4.1
101.8–<110.815.64.42.8–7.0 2.41.3–4.3
≥110.822.46.93.8–12.4 3.01.4–6.1

BMI, body mass index; CI, confidence interval; OR, odds ratio.

a>44 IU/L.

bAdjusted for ethnicity, age (6 categories, ordinal), fasting glucose, serum total cholesterol, cigarette smoking, alcohol consumption, c-peptide deciles, and fasting serum triglycerides deciles.

cCalculated from logistic regression analysis.

Supplementary Table 2. The Relationship of Elevated Serum Alanine Aminotransferase (ALT)a With Body Composition Indices (kg/m2) and Waist Circumference (cm) Among Women in the Morning Fasting Sample
Body measure quintilePrevalence of elevated ALT (%)Unadjusted (n = 2666)Multivariate-adjustedb (n = 2504)
ORc95% CIP value for trendORc95% CIP value for trend
Trunk fat <.001 .042
<3.33.61.0 1.0
3.3–<4.66.41.80.80–4.2 1.70.67–4.1
4.6–<5.911.03.31.6–6.9 2.61.0–6.4
5.9–<7.510.93.31.4–7.6 1.90.69–5.2
≥7.5317.05.52.6–11.4 2.61.0–6.4
Extremity fat .010 .96
<4.07.71.0 1.0
4.0–<4.96.70.860.46–1.6 0.790.41–1.5
4.9–<5.99.01.20.72–2.0 0.960.57–1.6
5.9–<7.313.31.81.0–3.3 1.20.59–2.3
≥7.312.01.60.90–2.9 0.850.44–1.6
Trunk lean <.001 .060
<7.04.71.0 1.0
7.0–<7.66.11.30.61–2.9 1.30.61–2.9
7.6–<8.28.82.00.97–4.0 1.70.77–3.6
8.2–<9.011.12.61.2–5.5 1.70.72–4.0
≥9.017.64.42.3–8.5 2.20.94–5.1
Extremity lean <.001 .018
<5.74.41.0 1.0
5.7–<6.26.71.60.70–3.6 1.50.68–3.3
6.2–<6.810.82.71.3–5.6 2.41.2–4.7
6.8–<7.711.32.81.3–5.9 2.21.0–4.9
≥7.715.54.01.9–8.4 2.51.1–5.9
BMI <.001 .15
<22.45.21.0 1.0
22.4–<25.36.01.20.57–2.4 1.10.53–2.4
25.3–<28.69.31.90.94–3.7 1.50.68–3.3
28.6–<33.413.02.71.4–5.5 1.60.74–3.5
≥33.415.53.41.7–6.7 1.60.70–3.7
Waist circumference <.001 .15
<79.13.71.0 1.0
79.1–<87.47.32.00.97–4.3 1.70.74–4.0
87.4–<95.712.03.51.6–7.7 2.71.1–6.7
95.7–<105.88.62.41.2–5.1 1.30.55–3.2
≥105.816.45.12.4–10.6 2.40.96–6.0

BMI, body mass index; CI, confidence interval; OR, odds ratio.

a>31 IU/L.

bAdjusted for ethnicity, age (6 categories, ordinal), fasting glucose, serum total cholesterol, cigarette smoking, alcohol consumption, c-peptide deciles, and fasting serum triglycerides deciles.

cCalculated from logistic regression analysis.

Supplementary Table 3. The Relationship of Elevated Serum Alanine Aminotransferase (ALT)a With Gender or Race/Ethnicity Adjusted for Trunk Fat Mass Index
UnadjustedMultivariate-adjustedb
ORc95% CIP value for trendORc95% CIP value for trend
Relationship with gender (men vs women)
Not adjusted for trunk fat3.53.0–4.0<.0013.12.7–3.6<.001
Adjusted for trunk fat4.84.1–5.8<.0014.53.7–5.4<.001
Relationship with race/ethnicity
Men
NHB vs NHW
Not adjusted for trunk fat0.660.50–0.88.0060.660.47–0.92.015
Adjusted for trunk fat0.770.57–1.0.0950.750.53–1.1.11
Mex-Am vs NHW
Not adjusted for trunk fat2.41.8–3.2<.0012.01.5–2.6<.001
Adjusted for trunk fat2.61.9–3.5<.0012.01.5–2.6<.001
Women
NHB vs NHW
Not adjusted for trunk fat0.540.40–0.74<.0010.520.38–0.72<.001
Adjusted for trunk fat0.470.34–0.65<.0010.470.34–0.65<.001
Mex-Am vs NHW
Not adjusted for trunk fat2.21.7–2.7<.0012.01.5–2.6<.001
Adjusted for trunk fat2.01.6–2.5<.0011.81.4–2.4<.001

BMI, body mass index; CI, confidence interval; Mex-Am, Mexican-American; NHB, non-Hispanic black; NHW, non-Hispanic white; OR, odds ratio.

a>38 IU/L for analyses of the relationship with gender; >44 IU/L in men or >31 IU/L in women for analyses of relationships with ethnicity.

bAdjusted for ethnicity, age (6 categories, ordinal), glucose status, serum total cholesterol, cigarette smoking, and alcohol consumption.

cCalculated from logistic regression analysis.

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 This article has an accompanying continuing medical education activity on page e12. Learning Objective: Upon completion of reading this article, successful learners will be able to explain the relationships of body composition measures with elevated ALT activity in the US population.

 Conflicts of interest The authors disclose no conflicts.

 Funding This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN267200700001G).

PII: S0016-5085(10)00005-3

doi:10.1053/j.gastro.2009.12.053

Refers to article:

  • April CME Exam 2 Questions , 25 February 2010

    Gastroenterology April 2010 (Vol. 138, Issue 4, Page e12)

  • Trunk Fat as a Determinant of Liver Disease , 24 February 2010

    Jacquelyn J. Maher
    Gastroenterology April 2010 (Vol. 138, Issue 4, Pages 1244-1246)

Gastroenterology
Volume 138, Issue 4 , Pages 1346-1356.e3, April 2010

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