Depression Is Associated With Non-alcoholic Fatty Liver Disease Among Adults in the United States

Donghee Kim; Eric R. Yoo; Andrew A. Li; Sean P. Tighe; George Cholankeril; Stephen A. Harrison; Aijaz Ahmed


Aliment Pharmacol Ther. 2019;50(5):590-598. 

In This Article

Materials and Methods

Study Design and Data Sources

This study represents an analysis of the recent five 2-year cycles of the continuous National Health and Nutrition Examination Survey (NHANES) data from 2007-2008 to 2015-2016. NHANES data employ a multi-staged, stratified and clustered probability sampling design to acquire a nationally representative sample of the non-institutionalised civilian population in the US.

Among 29,208 adult (≥20 years in age) individuals in the NHANES 2007-2016 survey, 96.4% (n = 28 154) underwent laboratory examinations at a mobile examination centre. Of these, we excluded 3439 individuals with the following: significant alcohol consumption (defined by > 30 grams per day in men and >20 g/d in women), viral hepatitis (defined by positive serum hepatitis C antibody and/or positive serum hepatitis B surface antigen), steatogenic medication use for more than 6 months (such as amiodarone, corticosteroids, methotrexate, tamoxifen and valproate) and pregnancy. We also excluded 2443 individuals for whom questionnaire results on depression, data on serum aminotransferase, body mass index (BMI), platelet and albumin were not available. Among 22 272 eligible individuals, final samples included 10 484 individuals who underwent laboratory tests after an overnight fast of a minimum of 8 hours (Figure 1).

Figure 1.

Flow diagram of participants in the study

Center for Disease Control and Prevention's Institutional Review Board approved the original survey, and all individuals reviewed and signed a full informed consent. The study was exempted by the Institutional Review Board at our institution because the dataset was completely de-identified.

Clinical and Laboratory Evaluations

Methods used for clinical and laboratory evaluations have been described in detail elsewhere.[3,19] The NHANES database included a detailed questionnaire which covered demographic and lifestyle information including depression and physical activity, anthropometric measures, and a comprehensive laboratory examination. Race/ethnicity was categorised as non-Hispanic white, Hispanic (Mexican American, Other Hispanic), non-Hispanic black, or Asians/other. We dichotomized education as lack of high school graduation vs high school graduation. We categorised marital status as being married or cohabitating with a partner vs others. Family income-to-poverty ratio, which was used as a proxy for socioeconomic status, was categorised as ≤0.99 = below poverty; 1.00 and above = at or above poverty. Poverty was defined as participants below poverty by family income-to-poverty ratio. We defined hypertension as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg and/or treatment with anti-hypertensive medication. We defined diabetes mellitus as fasting plasma glucose levels ≥ 126 mg/dl and/or the use of hypoglycaemic agents or insulin. Insulin resistance was examined using the homoeostasis model assessment of insulin resistance (HOMA-IR), as described previously.[20] We identified current smokers as subjects who reported ongoing cigarette use in individuals who had smoked at least 100 cigarettes in their lifetime. We calculated alcohol consumption using self-reported data on the amount and frequency of alcohol use, as previously described.[21] Physical activity was categorised according to the 2008 Physical Activity Guidelines for Americans (adults engage in ≥150 minutes/week of moderate-intensity aerobic activity per week, 75 minutes/week of vigorous-intensity aerobic activity per week, or an equivalent combination).[22] We categorised physical activity as sedentary (no activity regarding moderate or vigorous activity per week), intermediate and physically active who met guideline.[22]

Definition of NAFLD and Advanced Fibrosis

For definitions of NAFLD and advanced fibrosis, we utilised previously mentioned methods.[3] Briefly, we defined NAFLD using the US Fatty Liver Index (USFLI), Hepatic Steatosis Index (HSI) and Fatty Liver Index (FLI) in the absence of other causes of chronic liver disease and use of steatogenic medication. These indices have been validated previously and used in epidemiologic studies.[23–29] We calculated the USFLI using the following equation: USFLI = (e−0.8073 * non-Hispanic black + 0.3458 * Mexican American + 0.0093 * age + 0.6151* loge (gamma glutamyltransferase) + 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 glutamyltransferase) + 0.0249 * waist circumference + 1.1792 * loge (insulin) + 0.8242 * loge (glucose) – 14.7812) * 100.[26] We calculated HSI by using the following equation: HSI = 8 * (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] ratio) + BMI (+2, if female; +2, if diabetes).[23] We utilised the published cut-off of 36 to define presence of NAFLD.[23] As FLI formula requires fasting triglycerides, analyses using FLI included a subgroup of 8668 individuals with available fasting triglycerides. We calculated FLI according to the published equation:

We have added this limitation in the Discussion2.2 section as below: FLI = (e0.953 * ln(triglycerides) + 0.139 * BMI + 0.718 * ln(GGT) + 0.053* waist circumference – 15.745)/(1 + e0.953 * ln(triglycerides) + 0.139 * BMI + 0.718 * ln(GGT) + 0.053* waist circumference – 15.745)*100.[27]

Regarding advanced fibrosis, Fibrosis-4 (FIB-4) score was calculated by the published equation: FIB-4 = (Age [years] * AST [U/L])/(platelet [109/L] * (ALT [U/L])1/2).[30] Individuals with NAFLD were categorised into three groups, including those with low (FIB-4 < 1.30), intermediate (FIB-4 1.30-2.67) and high probability for advanced fibrosis (FIB-4 > 2.67).[30] We defined advanced fibrosis as having the high probabilities for advanced fibrosis calculated using FIB-4 score.

Definition of Depression

NHANES assessed depressive symptoms and functional impairment using the Patient Health Questionnaire (PHQ-9), which constitutes a 9-item questionnaire about the frequency of depressive symptoms over the past 2 weeks (Table S1).[31,32] Each of the nine symptoms was scored by a 4-point response scale ranging from 0 to 3 (0 = not at all, 1 = several days, 2 = more than half the days, 3 = nearly every day). The sum-score of the PHQ-9 questionnaire was calculated by summing the nine items together, resulting in a variable ranging between 0 and 27.[31,32] A PHQ-9 score ≥ 10 (defined as depression_PHQ-9) have been validated for a clinical diagnosis of major depression with a sensitivity and specificity of 88%.[33] We also defined depression with medication (depression_med) as individuals with major depression using PHQ-9 score and/or the use of antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, phenylpiperazine antidepressants, tetracyclic antidepressant, serotonin and norepinephrine reuptake inhibitors and miscellaneous antidepressants) if PHQ-9 score was ≥ 1 at least.[14] Functional impairment due to depression was assessed with the question as follow: "If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with people?", graded 4-point response scale ranging from 0 to 3 (0 = not difficult at all, 1 = somewhat difficult, 2 = very difficult, 3 = extremely difficult).[31] Functional impairment was dichotomized by merging the two lower (0 or 1) and the two higher values (2 or 3), indicating that it was very or extremely difficult to carry out normal activities due to depression.[31,33,34]

Statistical Analysis

Due to the complex sample design applied by NHANES, we used appropriate sample weights for fasting participants to reconstitute representative population-level data for the entire US.[35] We provided frequencies of categorical variables and the means ± standard errors of the continuous variables. We compared baseline characteristics using the Chi-squared test for categorical variables or linear regression for continuous variables. We also performed multivariable logistic regression to identify an independent association of depression with NAFLD and advanced fibrosis after consideration of other potential demographic and clinical confounders. We performed all data analyses using STATA 15.0 (StataCorp, College Station, Texas) utilising Taylor series linearisation.