- Email: [email protected]
Short Sleep Duration Is Associated With Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease
Accepted Manuscript Short Sleep Duration is Associated with Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease Donghee Kim, MD, PhD, Hwa Jung Kim, MD, PhD, Clete A. Kushida, MD, PhD, Nae-Yun Heo, MD, PhD, Aijaz Ahmed, MD, W. Ray Kim, MD
PII: DOI: Reference:
S1542-3565(17)31057-1 10.1016/j.cgh.2017.08.049 YJCGH 55429
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 29 August 2017 Please cite this article as: Kim D, Kim HJ, Kushida CA, Heo N-Y, Ahmed A, Kim WR, Short Sleep Duration is Associated with Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.08.049. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Short Sleep Duration is Associated with Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease
MD, PhD1, Aijaz Ahmed, MD1, W. Ray Kim, MD1 1
RI PT
Donghee Kim, MD, PhD1, Hwa Jung Kim, MD, PhD2, Clete A Kushida, MD, PhD3, Nae-Yun Heo,
SC
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford,
CA United States 2
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Department of Preventive Medicine, Ulsan University College of Medicine, Seoul, South Korea
3
Division of Sleep Medicine, Stanford Hospital and Clinics, Redwood City, CA, United States
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DK and HJK contributed equally to this work.
Short Title: Association of Sleep Deprivation with NAFLD
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Correspondence: W. Ray Kim, MD Division of Gastroenterology and Hepatology Stanford University School of Medicine 300 Pasteur Drive Stanford, California 94304 Telephone: 650-725-6511 Fax: 650-723-5488. E-mail: [email protected]
ACCEPTED MANUSCRIPT 2
List of Abbreviations: ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; NHNAES, National Health and Nutrition Examination Survey; US FLI, US fatty liver index.
Word count: 744 Disclosure: No relevant conflicts of interest exist.
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Number of tables: 1 Table
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Grant Support: This work was supported in part by a grant from the National Institute of
Diabetes, Digestive and Kidney Disease (DK-34238 and DK-92336). The funding organization
M AN U
played no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. Keywords: sleep duration; sleep quality; alanine aminotransferase; fatty liver. Authors Contributions:
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Donghee Kim: study concept and design, acquisition of data, analysis and interpretation of data, drafting manuscript, and approval of final draft manuscript. Hwa Jung Kim: acquisition of data, analysis and interpretation of data, statistical analysis, drafting manuscript, and approval of
EP
final draft manuscript. Clete A Kushida: interpretation of data, critical revision of the manuscript for important intellectual content, and approval of final draft manuscript. Nae-yun Heo:
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acquisition and interpretation of data and approval of final draft manuscript. Aijaz Ahmed: interpretation of data, critical revision of the manuscript for important intellectual content, and approval of final draft manuscript. W. Ray Kim: study concept and design, interpretation of data, obtained funding, critical revision of the manuscript for important intellectual content, and approval of final draft manuscript.
ACCEPTED MANUSCRIPT 3
Introduction The proportion of adults in the United States (US) who report sleeping ≤ 6 hours per night rose from 22.3% in 1985 to 29.2% in 2012 despite recommendations that adults maintain
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sleep duration ≥ 7 hours for optimal health.1,2 Sleep deprivation increases metabolic risks known to be associated with nonalcoholic fatty liver disease (NAFLD). We studied the
SC
association between duration and quality of sleep and indicators of NAFLD in the US general
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population.
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Methods Out of the 22,692 adult (> 20 years) participants in the National Health and Nutrition
RI PT
Examination Survey (NHANES) for 2005-2012, subjects with significant alcohol consumption, viral hepatitis, pregnancy or malignancy, or with missing data (n=1,654) on sleep
duration/quality, serum alanine aminotransferase (ALT), viral hepatitis were excluded. The final
SC
study sample consisted of 17,245 adults. NHANES divided sleep duration into ≤ 5, 6, 7, 8, and ≥ 9 hours per night. Sleep quality, available only in NHANES 2005-2006 and 2007-2008, was
M AN U
categorized into good, moderate and poor.
The primary outcome variable was serum ALT > 30 U/L for men and > 19 for women.3 The secondary outcome variable was the US fatty liver index (USFLI), which consisted of age, race-ethnicity, waist circumference, gamma glutamyltransferase, fasting glucose, and insulin,
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with a threshold of 30 to diagnose NAFLD.4 Given the sampling design of NHANES, appropriate sample weights (primary sampling unit, strata, and weighting) were used to reconstitute population level data for the entire US. The association between sleep duration/quality and
EP
abnormal ALT was examined using the multivariable logistic regression analyses using SAS 9.2
AC C
(SAS institute, Cary, NC, USA) and STATA 13.0 (StataCorp, College Station, TX, USA).
ACCEPTED MANUSCRIPT 5
Results The NHANES data projected that 15.9% US adults slept for ≤ 5 hours a night, 23.8% for 6
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hours, 27.1% for 7 hours, 26.3% for 8 hours and 7.0% for ≥ 9 hours. In descriptive analyses (Table 1), certain variables (e.g., diabetes, hypertension, blood levels of glucose and
triglycerides, education, and socio-economic status) had a U- or inverse U-shaped association
SC
with sleep duration, whereas others (e.g., body mass index, waist circumference) showed a linear relationship, with progressively shorter sleep duration associated with poor outcomes.
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Serum ALT activities belonged in the latter group (P for trend <.001).
In multivariable analyses, shorter sleep duration had progressively higher odds of abnormal ALT. For example, compared to the reference group with sleep duration of ≥ 9 hours, those with sleep duration of ≤ 5 hours were 35% more likely to have abnormal ALT. In contrast,
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sleep quality showed no association. In sensitivity analyses incorporating insulin resistance and fasting triglycerides, using different ALT cut off values, or incorporating serum C-reactive protein levels, the effects of sleep duration on ALT remained unchanged. Finally, sleep duration
EP
was significantly associated with NAFLD as defined by USFLI: adults who slept ≤ 5 hours were 45%
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higher odds of having NAFLD compared to those who slept ≥ 9 hours (P for trend = .001).
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Discussion Approximately 70.1 million US adults sleep for ≤ 6 hours in 2012, compared to 38.6
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million in 1985.1 Based on these data, we estimate 32 million sleep-deprived Americans have abnormal ALT and 28.6 million NAFLD. As we excluded major etiologies of chronic liver disease, abnormal ALT seen in these data is likely linked to NAFLD. Despite limitations related to missing
SC
data, we believe this is a robust, US population-based analysis about sleep health and NAFLD. Prior studies, including a recent meta-analysis, reported inconsistent or non-significant
M AN U
associations.5
These associations may be driven by obesity-related insulin resistance and proinflammatory milieu associated with poor sleep.6, 7 In addition, sleep deprivation has been hypothesized to disrupt the hypothalamic-pituitary-adrenal axis, which may contribute to
TE D
NAFLD.8 However, it is also possible that sleep duration has an independent association with serum ALT in subjects with or without NAFLD or other chronic liver disease. For example, some of the metabolic abnormalities commonly associated with NAFLD have a U-shaped relation with
EP
sleep (i.e, longer duration sleep being unhealthy), whereas the relation between sleep duration and ALT was linear. The association between long sleep duration and metabolic disorders may
AC C
be represent residual confounding or reverse causation, highlighting the limitation of this observational study – firm causal relationship may not be inferred and prospective interventional studies are needed to confirm the association.2 In summary, optimal sleep duration (≥ 7 hours) is associated with lower likelihood of abnormal ALT and NAFLD, independent of metabolic risk factors. Improving sleep health may provide a novel opportunity for intervention in patients with abnormal ALT and/or NAFLD.
ACCEPTED MANUSCRIPT 7
References
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EP
TE D
M AN U
SC
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1. Ford ES, Cunningham TJ, Croft JB. Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep. 2015;38(5):829-32. 2. Consensus Conference P, Watson NF, Badr MS, et al. Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. J Clin Sleep Med. 2015;11(8):931-52. 3. Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology. 2009;136(2):477-85 e11. 4. Ruhl CE, Everhart JE. Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey. Aliment Pharmacol Ther. 2015;41(1):65-76. 5. Shen N, Wang P, Yan W. Sleep Duration and the Risk of Fatty Liver Disease: A Systematic Review and Meta-analysis. Sci Rep. 2016;6:31956. 6. Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14(4):402-12. 7. Liu R, Liu X, Zee PC, et al. Association between sleep quality and C-reactive protein: results from national health and nutrition examination survey, 2005-2008. PloS one. 2014;9(3):e92607. 8. Balbo M, Leproult R, Van Cauter E. Impact of sleep and its disturbances on hypothalamopituitary-adrenal axis activity. Int J Endocrinol. 2010;2010:759234.
ACCEPTED MANUSCRIPT
§§
Table 1. Association of various characteristics of NHANES participants with sleep duration (n=17,245 ) Sleep Duration
≤5 hours (n=2,739)
6 hours (n=4,104)
7 hours (n=4,669)
8 hours (n=4,530)
≥9 hours (n=1,203)
45.5 ± 17.0 48.5 ± 1.14 32.6 ± 0.97 13.3 ± 0.73
45.1 ± 15.5 52.3 ± 0.98 28.5 ± 0.88 9.7 ± 0.65
45.2 ± 14.7 50.4 ± 0.83 25.5 ± 0.76 7.0 ± 0.51
46.3 ± 17.1 46.2 ± 0.80 28.9 ± 1.03 9.4 ± 0.52
47.9 ± 21.1 39.2 ± 1.47 32.0 ± 1.66 11.5 ± 1.00
7.10 ± 0.80 6.73 ± 1.00 57.42 ± 2.42 20.82 ± 1.69 7.93 ± 0.88
8.48 ± 0.94 5.35 ± 0.72 65.92 ± 1.96 13.23 ± 1.18 7.01 ± 0.62
8.31 ± 0.91 5.09 ± 0.67 72.87 ± 1.67 7.11 ± 0.68 6.63 ± 0.63
10.29 ± 1.00 5.16 ± 0.65 69.43 ± 1.84 8.73 ± 0.73 6.39 ± 0.75
9.74 ± 1.39 4.72 ± 0.91 69.93 ± 2.31 9.80 ± 1.18 5.82 ± 0.79
48.0 ± 1.39 30.8 ± 1.25 21.2 ± 0.89 29.7 ± 8.69 96.0 ± 28.9 76.7 ± 0.95 57.1 ± 1.34 19.1 ± 1.07 196.5 ± 47.2 147.0 ± 151.9 51.3 ± 17.3 106.6 ± 37.0 5.70 ± 1.23 26.0 ± 20.1
54.4 ± 1.15 23.4 ± 1.02 22.2 ± 0.71 28.8 ± 7.22 95.2 ± 24.7 83.2 ± 0.97 64.1 ± 1.32 14.0 ± 0.83 196.3 ± 40.2 133.4 ± 103.9 52.1 ± 15.4 104.9 ± 32.3 5.57 ± 0.91 25.3 ± 10.8
58.4 ± 1.04 16.4 ± 0.82 25.2 ± 0.82 28.1 ± 6.15 94.3 ± 21.1 85.1 ± 0.94 69.2 ± 0.93 10.5 ± 0.67 197.2 ± 37.9 128.0 ± 93.5
57.9 ± 1.13 17.9 ± 0.82 24.2 ± 0.97 27.9 ± 7.19 93.4 ± 24.0 81.2 ± 0.95 64.1 ± 1.17 14.9 ± 0.90 196.7 ± 41.5 132.2 ± 98.2
54.4 ± 1.93 24.3 ± 1.76 21.2 ± 1.62 27.7 ± 8.47 90.9 ± 29.7 75.5 ± 1.69 55.8 ± 2.04 18.9 ± 1.69 193.5 ± 43.7 136.4 ± 93.3
53.2 ± 14.4 103.2 ± 25.8 5.48 ± 0.76 25.2 ± 13.3
53.4 ± 16.2 105.0 ± 31.7 5.56 ± 0.94 25.1 ± 10.8
52.9 ± 16.4 105.6 ± 34.7 5.58 ± 1.00 24.9 ± 10.5
26.1 ± 18.6
25.8 ± 16.3
25.5 ± 18.8
24.8 ± 14.9
23.8 ± 18.6
32.6 ± 66.1
27.2 ± 31.0
24.9 ± 25.4
26.5 ± 32.8
25.0 ± 26.5
86.4 ± 80.7 0.465 ± 0.897
78.5 ± 68.3 0.400 ± 0.763
75.2 ± 67.8 0.339 ± 0.674
74.3 ± 67.6 0.364 ± 0.631
80.5 ± 96.5 0.512 ± 0.977
1.17 (0.971.40) 1.27 (0.961.67)
1.15 (0.951.39) 1.00 (0.761.31)
Reference
1.15 (0.911.45) 1.12 (0.921.38) 0.86 (0.641.16)
1.22 (0.941.58) 1.11 (0.911.35) 0.88 (0.661.18)
Reference
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*
HDL-cholesterol (mg/dL) Fasting glucose (mg/dL) HbA1C* (%) * Aspartate aminotransferase (IU/L) * Alanine aminotransferase (IU/L) * Gamma glutamyltransferase (IU/L) * Fasting Insulin (pmol/L) CRP (mg/dL) (n=13,027)
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§
Descriptive Data * Age (years) * Gender (male, %) Hypertension* (%) * Diabetes (%) * Ethnicity (%) Mexican American Other Hispanic Non-Hispanic white Non-Hispanic black Asian/Other * Smoking (%) Never Ex-smoker Current smoker * 2 Body mass index (kg/m ) * Waist circumference (cm) * High education (%) * Married status (%) * Poverty (%) Total cholesterol* (mg/dL) * Triglyceride (mg/dL)
Multivariable Analyses, OR (95% CI) Association with Abnormal ALT 1.35 (1.111,24 (1.061.65) 1.46) Association with NAFLD 1.45 (1.081.33 (1.041.95) 1.70) Sensitivity Analyses (association with abnormal ALT), OR (95% CI) Incorporate insulin resistance 1.35 (1.011.22 (0.96and triglycerides 1.80) 1.54) Incorporate serum CRP 1.30 (1.051.20 (1.011.60) 1.44) Utilize higher NHANES-defined 1.16 (0.840.93 (0.69ALT cut-off (M > 40, F > 31) 1.62) 1.25)
Reference
Reference Reference
ACCEPTED MANUSCRIPT
§
Data are expressed as the mean ± SD or proportion ± SE
§§
There were 1,654 patients with missing data who were excluded from the analysis. Excluded subjects were similar in age, sex, and smoking status to those included. However, they were more likely to non-white, less well educated, single and poor compared to those in the analysis.
*
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p < 0.05 (at least one of the five groups being significantly different from the rest) by the chi-square or the analysis of variance test as appropriate
The multivariable model included age, sex, ethnicity, education level, marital status, economic status, body mass index, waist circumference, smoking status, diabetes, hypertension, and total cholesterol.
SC
The multivariable model included age, sex, education level, married status, economic status, smoking status, diabetes, hypertension, cholesterol level, and triglycerides. NAFLD is defined by US fatty liver index (USFLI), which is calculated by USFLI = (e
-0.8073 * non-Hispanic black + 0.3458 * Mexican
American + 0.0093 * age + 0.6151* loge (gamma glutamyltranferase) + 0.0249 * waist circumference + 1.1792 * loge (insulin) + 0.8242 * loge (glucose) – 14.7812
-
)/ (1+ e
0.8073 * non-Hispanic black + 0.3458 * Mexican American + 0.0093 * age + 0.6151* loge (gamma glutamyltranferase) + 0.0249 * waist circumference + 1.1792 * loge (insulin) + 0.8242 * loge (glucose) – 14.7812
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) * 100.
Analyses for fasting glucose, triglyceride, and insulin concentrations, for USFLI and for insulin resistance were limited to 8,419 participants who were examined after an overnight fast of a minimum of 8 hours.
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Abbreviations: HDL, high density lipoprotein; CRP, C-reactive protein, ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio; CI, confidence interval.
PII: DOI: Reference:
S1542-3565(17)31057-1 10.1016/j.cgh.2017.08.049 YJCGH 55429
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 29 August 2017 Please cite this article as: Kim D, Kim HJ, Kushida CA, Heo N-Y, Ahmed A, Kim WR, Short Sleep Duration is Associated with Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.08.049. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Short Sleep Duration is Associated with Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease
MD, PhD1, Aijaz Ahmed, MD1, W. Ray Kim, MD1 1
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Donghee Kim, MD, PhD1, Hwa Jung Kim, MD, PhD2, Clete A Kushida, MD, PhD3, Nae-Yun Heo,
SC
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford,
CA United States 2
M AN U
Department of Preventive Medicine, Ulsan University College of Medicine, Seoul, South Korea
3
Division of Sleep Medicine, Stanford Hospital and Clinics, Redwood City, CA, United States
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DK and HJK contributed equally to this work.
Short Title: Association of Sleep Deprivation with NAFLD
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Correspondence: W. Ray Kim, MD Division of Gastroenterology and Hepatology Stanford University School of Medicine 300 Pasteur Drive Stanford, California 94304 Telephone: 650-725-6511 Fax: 650-723-5488. E-mail: [email protected]
ACCEPTED MANUSCRIPT 2
List of Abbreviations: ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; NHNAES, National Health and Nutrition Examination Survey; US FLI, US fatty liver index.
Word count: 744 Disclosure: No relevant conflicts of interest exist.
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Number of tables: 1 Table
SC
Grant Support: This work was supported in part by a grant from the National Institute of
Diabetes, Digestive and Kidney Disease (DK-34238 and DK-92336). The funding organization
M AN U
played no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. Keywords: sleep duration; sleep quality; alanine aminotransferase; fatty liver. Authors Contributions:
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Donghee Kim: study concept and design, acquisition of data, analysis and interpretation of data, drafting manuscript, and approval of final draft manuscript. Hwa Jung Kim: acquisition of data, analysis and interpretation of data, statistical analysis, drafting manuscript, and approval of
EP
final draft manuscript. Clete A Kushida: interpretation of data, critical revision of the manuscript for important intellectual content, and approval of final draft manuscript. Nae-yun Heo:
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acquisition and interpretation of data and approval of final draft manuscript. Aijaz Ahmed: interpretation of data, critical revision of the manuscript for important intellectual content, and approval of final draft manuscript. W. Ray Kim: study concept and design, interpretation of data, obtained funding, critical revision of the manuscript for important intellectual content, and approval of final draft manuscript.
ACCEPTED MANUSCRIPT 3
Introduction The proportion of adults in the United States (US) who report sleeping ≤ 6 hours per night rose from 22.3% in 1985 to 29.2% in 2012 despite recommendations that adults maintain
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sleep duration ≥ 7 hours for optimal health.1,2 Sleep deprivation increases metabolic risks known to be associated with nonalcoholic fatty liver disease (NAFLD). We studied the
SC
association between duration and quality of sleep and indicators of NAFLD in the US general
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EP
TE D
M AN U
population.
ACCEPTED MANUSCRIPT 4
Methods Out of the 22,692 adult (> 20 years) participants in the National Health and Nutrition
RI PT
Examination Survey (NHANES) for 2005-2012, subjects with significant alcohol consumption, viral hepatitis, pregnancy or malignancy, or with missing data (n=1,654) on sleep
duration/quality, serum alanine aminotransferase (ALT), viral hepatitis were excluded. The final
SC
study sample consisted of 17,245 adults. NHANES divided sleep duration into ≤ 5, 6, 7, 8, and ≥ 9 hours per night. Sleep quality, available only in NHANES 2005-2006 and 2007-2008, was
M AN U
categorized into good, moderate and poor.
The primary outcome variable was serum ALT > 30 U/L for men and > 19 for women.3 The secondary outcome variable was the US fatty liver index (USFLI), which consisted of age, race-ethnicity, waist circumference, gamma glutamyltransferase, fasting glucose, and insulin,
TE D
with a threshold of 30 to diagnose NAFLD.4 Given the sampling design of NHANES, appropriate sample weights (primary sampling unit, strata, and weighting) were used to reconstitute population level data for the entire US. The association between sleep duration/quality and
EP
abnormal ALT was examined using the multivariable logistic regression analyses using SAS 9.2
AC C
(SAS institute, Cary, NC, USA) and STATA 13.0 (StataCorp, College Station, TX, USA).
ACCEPTED MANUSCRIPT 5
Results The NHANES data projected that 15.9% US adults slept for ≤ 5 hours a night, 23.8% for 6
RI PT
hours, 27.1% for 7 hours, 26.3% for 8 hours and 7.0% for ≥ 9 hours. In descriptive analyses (Table 1), certain variables (e.g., diabetes, hypertension, blood levels of glucose and
triglycerides, education, and socio-economic status) had a U- or inverse U-shaped association
SC
with sleep duration, whereas others (e.g., body mass index, waist circumference) showed a linear relationship, with progressively shorter sleep duration associated with poor outcomes.
M AN U
Serum ALT activities belonged in the latter group (P for trend <.001).
In multivariable analyses, shorter sleep duration had progressively higher odds of abnormal ALT. For example, compared to the reference group with sleep duration of ≥ 9 hours, those with sleep duration of ≤ 5 hours were 35% more likely to have abnormal ALT. In contrast,
TE D
sleep quality showed no association. In sensitivity analyses incorporating insulin resistance and fasting triglycerides, using different ALT cut off values, or incorporating serum C-reactive protein levels, the effects of sleep duration on ALT remained unchanged. Finally, sleep duration
EP
was significantly associated with NAFLD as defined by USFLI: adults who slept ≤ 5 hours were 45%
AC C
higher odds of having NAFLD compared to those who slept ≥ 9 hours (P for trend = .001).
ACCEPTED MANUSCRIPT 6
Discussion Approximately 70.1 million US adults sleep for ≤ 6 hours in 2012, compared to 38.6
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million in 1985.1 Based on these data, we estimate 32 million sleep-deprived Americans have abnormal ALT and 28.6 million NAFLD. As we excluded major etiologies of chronic liver disease, abnormal ALT seen in these data is likely linked to NAFLD. Despite limitations related to missing
SC
data, we believe this is a robust, US population-based analysis about sleep health and NAFLD. Prior studies, including a recent meta-analysis, reported inconsistent or non-significant
M AN U
associations.5
These associations may be driven by obesity-related insulin resistance and proinflammatory milieu associated with poor sleep.6, 7 In addition, sleep deprivation has been hypothesized to disrupt the hypothalamic-pituitary-adrenal axis, which may contribute to
TE D
NAFLD.8 However, it is also possible that sleep duration has an independent association with serum ALT in subjects with or without NAFLD or other chronic liver disease. For example, some of the metabolic abnormalities commonly associated with NAFLD have a U-shaped relation with
EP
sleep (i.e, longer duration sleep being unhealthy), whereas the relation between sleep duration and ALT was linear. The association between long sleep duration and metabolic disorders may
AC C
be represent residual confounding or reverse causation, highlighting the limitation of this observational study – firm causal relationship may not be inferred and prospective interventional studies are needed to confirm the association.2 In summary, optimal sleep duration (≥ 7 hours) is associated with lower likelihood of abnormal ALT and NAFLD, independent of metabolic risk factors. Improving sleep health may provide a novel opportunity for intervention in patients with abnormal ALT and/or NAFLD.
ACCEPTED MANUSCRIPT 7
References
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EP
TE D
M AN U
SC
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1. Ford ES, Cunningham TJ, Croft JB. Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep. 2015;38(5):829-32. 2. Consensus Conference P, Watson NF, Badr MS, et al. Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. J Clin Sleep Med. 2015;11(8):931-52. 3. Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology. 2009;136(2):477-85 e11. 4. Ruhl CE, Everhart JE. Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey. Aliment Pharmacol Ther. 2015;41(1):65-76. 5. Shen N, Wang P, Yan W. Sleep Duration and the Risk of Fatty Liver Disease: A Systematic Review and Meta-analysis. Sci Rep. 2016;6:31956. 6. Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14(4):402-12. 7. Liu R, Liu X, Zee PC, et al. Association between sleep quality and C-reactive protein: results from national health and nutrition examination survey, 2005-2008. PloS one. 2014;9(3):e92607. 8. Balbo M, Leproult R, Van Cauter E. Impact of sleep and its disturbances on hypothalamopituitary-adrenal axis activity. Int J Endocrinol. 2010;2010:759234.
ACCEPTED MANUSCRIPT
§§
Table 1. Association of various characteristics of NHANES participants with sleep duration (n=17,245 ) Sleep Duration
≤5 hours (n=2,739)
6 hours (n=4,104)
7 hours (n=4,669)
8 hours (n=4,530)
≥9 hours (n=1,203)
45.5 ± 17.0 48.5 ± 1.14 32.6 ± 0.97 13.3 ± 0.73
45.1 ± 15.5 52.3 ± 0.98 28.5 ± 0.88 9.7 ± 0.65
45.2 ± 14.7 50.4 ± 0.83 25.5 ± 0.76 7.0 ± 0.51
46.3 ± 17.1 46.2 ± 0.80 28.9 ± 1.03 9.4 ± 0.52
47.9 ± 21.1 39.2 ± 1.47 32.0 ± 1.66 11.5 ± 1.00
7.10 ± 0.80 6.73 ± 1.00 57.42 ± 2.42 20.82 ± 1.69 7.93 ± 0.88
8.48 ± 0.94 5.35 ± 0.72 65.92 ± 1.96 13.23 ± 1.18 7.01 ± 0.62
8.31 ± 0.91 5.09 ± 0.67 72.87 ± 1.67 7.11 ± 0.68 6.63 ± 0.63
10.29 ± 1.00 5.16 ± 0.65 69.43 ± 1.84 8.73 ± 0.73 6.39 ± 0.75
9.74 ± 1.39 4.72 ± 0.91 69.93 ± 2.31 9.80 ± 1.18 5.82 ± 0.79
48.0 ± 1.39 30.8 ± 1.25 21.2 ± 0.89 29.7 ± 8.69 96.0 ± 28.9 76.7 ± 0.95 57.1 ± 1.34 19.1 ± 1.07 196.5 ± 47.2 147.0 ± 151.9 51.3 ± 17.3 106.6 ± 37.0 5.70 ± 1.23 26.0 ± 20.1
54.4 ± 1.15 23.4 ± 1.02 22.2 ± 0.71 28.8 ± 7.22 95.2 ± 24.7 83.2 ± 0.97 64.1 ± 1.32 14.0 ± 0.83 196.3 ± 40.2 133.4 ± 103.9 52.1 ± 15.4 104.9 ± 32.3 5.57 ± 0.91 25.3 ± 10.8
58.4 ± 1.04 16.4 ± 0.82 25.2 ± 0.82 28.1 ± 6.15 94.3 ± 21.1 85.1 ± 0.94 69.2 ± 0.93 10.5 ± 0.67 197.2 ± 37.9 128.0 ± 93.5
57.9 ± 1.13 17.9 ± 0.82 24.2 ± 0.97 27.9 ± 7.19 93.4 ± 24.0 81.2 ± 0.95 64.1 ± 1.17 14.9 ± 0.90 196.7 ± 41.5 132.2 ± 98.2
54.4 ± 1.93 24.3 ± 1.76 21.2 ± 1.62 27.7 ± 8.47 90.9 ± 29.7 75.5 ± 1.69 55.8 ± 2.04 18.9 ± 1.69 193.5 ± 43.7 136.4 ± 93.3
53.2 ± 14.4 103.2 ± 25.8 5.48 ± 0.76 25.2 ± 13.3
53.4 ± 16.2 105.0 ± 31.7 5.56 ± 0.94 25.1 ± 10.8
52.9 ± 16.4 105.6 ± 34.7 5.58 ± 1.00 24.9 ± 10.5
26.1 ± 18.6
25.8 ± 16.3
25.5 ± 18.8
24.8 ± 14.9
23.8 ± 18.6
32.6 ± 66.1
27.2 ± 31.0
24.9 ± 25.4
26.5 ± 32.8
25.0 ± 26.5
86.4 ± 80.7 0.465 ± 0.897
78.5 ± 68.3 0.400 ± 0.763
75.2 ± 67.8 0.339 ± 0.674
74.3 ± 67.6 0.364 ± 0.631
80.5 ± 96.5 0.512 ± 0.977
1.17 (0.971.40) 1.27 (0.961.67)
1.15 (0.951.39) 1.00 (0.761.31)
Reference
1.15 (0.911.45) 1.12 (0.921.38) 0.86 (0.641.16)
1.22 (0.941.58) 1.11 (0.911.35) 0.88 (0.661.18)
Reference
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*
HDL-cholesterol (mg/dL) Fasting glucose (mg/dL) HbA1C* (%) * Aspartate aminotransferase (IU/L) * Alanine aminotransferase (IU/L) * Gamma glutamyltransferase (IU/L) * Fasting Insulin (pmol/L) CRP (mg/dL) (n=13,027)
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§
Descriptive Data * Age (years) * Gender (male, %) Hypertension* (%) * Diabetes (%) * Ethnicity (%) Mexican American Other Hispanic Non-Hispanic white Non-Hispanic black Asian/Other * Smoking (%) Never Ex-smoker Current smoker * 2 Body mass index (kg/m ) * Waist circumference (cm) * High education (%) * Married status (%) * Poverty (%) Total cholesterol* (mg/dL) * Triglyceride (mg/dL)
Multivariable Analyses, OR (95% CI) Association with Abnormal ALT 1.35 (1.111,24 (1.061.65) 1.46) Association with NAFLD 1.45 (1.081.33 (1.041.95) 1.70) Sensitivity Analyses (association with abnormal ALT), OR (95% CI) Incorporate insulin resistance 1.35 (1.011.22 (0.96and triglycerides 1.80) 1.54) Incorporate serum CRP 1.30 (1.051.20 (1.011.60) 1.44) Utilize higher NHANES-defined 1.16 (0.840.93 (0.69ALT cut-off (M > 40, F > 31) 1.62) 1.25)
Reference
Reference Reference
ACCEPTED MANUSCRIPT
§
Data are expressed as the mean ± SD or proportion ± SE
§§
There were 1,654 patients with missing data who were excluded from the analysis. Excluded subjects were similar in age, sex, and smoking status to those included. However, they were more likely to non-white, less well educated, single and poor compared to those in the analysis.
*
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p < 0.05 (at least one of the five groups being significantly different from the rest) by the chi-square or the analysis of variance test as appropriate
The multivariable model included age, sex, ethnicity, education level, marital status, economic status, body mass index, waist circumference, smoking status, diabetes, hypertension, and total cholesterol.
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The multivariable model included age, sex, education level, married status, economic status, smoking status, diabetes, hypertension, cholesterol level, and triglycerides. NAFLD is defined by US fatty liver index (USFLI), which is calculated by USFLI = (e
-0.8073 * non-Hispanic black + 0.3458 * Mexican
American + 0.0093 * age + 0.6151* loge (gamma glutamyltranferase) + 0.0249 * waist circumference + 1.1792 * loge (insulin) + 0.8242 * loge (glucose) – 14.7812
-
)/ (1+ e
0.8073 * non-Hispanic black + 0.3458 * Mexican American + 0.0093 * age + 0.6151* loge (gamma glutamyltranferase) + 0.0249 * waist circumference + 1.1792 * loge (insulin) + 0.8242 * loge (glucose) – 14.7812
M AN U
) * 100.
Analyses for fasting glucose, triglyceride, and insulin concentrations, for USFLI and for insulin resistance were limited to 8,419 participants who were examined after an overnight fast of a minimum of 8 hours.
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Abbreviations: HDL, high density lipoprotein; CRP, C-reactive protein, ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio; CI, confidence interval.