Association of anxiety and depression with chronic liver diseases in patients with noncardiac chest pain: A cross-sectional study

Abstract

Causes of chest pain can vary from benign to life-threatening conditions, and in many cases not necessary of cardiac origin. A possible reason for noncardiac chest pain could be anxiety or depression caused by chronic liver diseases. The aim of this study was to investigate the association of anxiety and depression with chronic liver disease in patients with noncardiac pain.
Patients with chest tightness or pain referred for treadmill exercise testing were recruited from a regional hospital in southern Taiwan. Medical records of the patients were used to define the presence and type of chronic liver disease. Multiple logistic regression analyses were conducted to assess the association of anxiety and depression with chronic liver disease.
A total of 2537 patients with liver function test results and abdominal sonography data were analyzed, and 1965 patients showed a negative treadmill exercise testing. The mean age of these 1965 patients was 51.9 years and 54.2% were male. The prevalence of alcoholic liver disease, hepatitis B, hepatitis C, and fatty liver disease was 10.6%, 10.9%, 3.7%, and 27.0%, respectively. Results from multiple logistic regression analyses showed that the risk of anxiety (adjusted odds ratio [aOR] = 1.83, P < .001) and depression (aOR = 1.85, P < .001) was significantly higher in patients with alcoholic liver disease. Anxiety was significantly higher in patients with fatty liver disease (aOR = 1.30, P = .031), and the risk of depression was significantly higher in patients with chronic hepatitis C (aOR = 2.18, P = .005).
In conclusion, in patients with noncardiac chest pain, alcoholic liver disease was significantly associated with anxiety and depression, while those with fatty liver and chronic hepatitis C were associated with anxiety and depression, respectively. Clinicians should be vigilant to these correlations in their practice.

Full text

Observational Study
1
Medicine®
Association of anxiety and depression with
chronic liver diseases in patients with
noncardiac chest pain
A cross-sectional study
Rei-YeuhChang, MD, MSca,b, SheriHsueh-Hua Ho, MDc, Han-LinTsai, MDa, MalcolmKoo, PhDd,e,*
Abstract
Causes of chest pain can vary from benign to life-threatening conditions, and in many cases not necessary of cardiac origin. A
possible reason for noncardiac chest pain could be anxiety or depression caused by chronic liver diseases. The aim of this study
was to investigate the association of anxiety and depression with chronic liver disease in patients with noncardiac pain.
Patients with chest tightness or pain referred for treadmill exercise testing were recruited from a regional hospital in southern
Taiwan. Medical records of the patients were used to define the presence and type of chronic liver disease. Multiple logistic
regression analyses were conducted to assess the association of anxiety and depression with chronic liver disease.
A total of 2537 patients with liver function test results and abdominal sonography data were analyzed, and 1965 patients
showed a negative treadmill exercise testing. The mean age of these 1965 patients was 51.9 years and 54.2% were male.
The prevalence of alcoholic liver disease, hepatitis B, hepatitis C, and fatty liver disease was 10.6%, 10.9%, 3.7%, and 27.0%,
respectively. Results from multiple logistic regression analyses showed that the risk of anxiety (adjusted odds ratio [aOR] = 1.83,
P < .001) and depression (aOR = 1.85, P < .001) was significantly higher in patients with alcoholic liver disease. Anxiety was
significantly higher in patients with fatty liver disease (aOR = 1.30, P = .031), and the risk of depression was significantly higher in
patients with chronic hepatitis C (aOR = 2.18, P = .005).
In conclusion, in patients with noncardiac chest pain, alcoholic liver disease was significantly associated with anxiety and
depression, while those with fatty liver and chronic hepatitis C were associated with anxiety and depression, respectively. Clinicians
should be vigilant to these correlations in their practice.
Abbreviations: ALT = alanine aminotransferase, aOR = adjusted odds ratio, AST = aspartate aminotransferase, C-CBI =
Chinese version of the Copenhagen Burnout Inventory, DAA = direct-acting antivirals, ECG = electrocardiography, g = gram,
HADS = Hospital Anxiety and Depression Scale, HBsAg = hepatitis B surface antigen, HCV = hepatitis C virus, HDL-C = high-
density lipoprotein cholesterol, HRmax = maximum age-predicted heart rate, LDL-C = low-density lipoprotein cholesterol, MET =
metabolic equivalent of task, NAFLD = nonalcoholic fatty liver disease, NASH = nonalcoholic steatohepatitis, NHANES = National
Health and Nutrition Examination Survey, OR = odds ratio, PSQI = Pittsburgh Sleep Quality Index, RNA = ribonucleic acid, SD =
standard deviation, TNF-α = tumor necrosis factor-alpha.
Keywords: anxiety, chronic liver diseases, depression, nonischemic chest pain
1. Introduction
Anxiety and depression are common complaints among out-
patient settings,[1] including patients who present with chest
pain. A cross-sectional study of 250 patients referred for
evaluation of chest pain found that the prevalence of anxiety
and depressive symptoms were 42% and 31%, respectively.[2]
A prospective cohort study of 500 low- to moderate-cardiac
risk emergency department patients showed that depression
was a signicant independent predictor of 30-day chest pain
recurrence, regardless of signicant cardiac ischemia on
stress testing.[3] Causes of chest pain can vary from benign to
life-threatening conditions, and in many cases are not neces-
sarily of cardiac origin. The prevalence of noncardiac chest
pain was estimated to be more than 50% of all chest pain cases
presenting at the emergency department.[4] In patients without
cardiac disease, chest pain can be caused by psychological and
psychiatric factors.[5]
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are
available from the corresponding author on reasonable request.
a Division of Cardiology, Department of Internal Medicine, Ditmanson Medical
Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan, b Min-Hwei Junior
College of Health Care Management, Tainan City, Taiwan, c Sheri Hsueh-Hua Ho
Family Medicine Clinic, Irvine, CA, d Graduate Institute of Long-term Care, Tzu Chi
University of Science and Technology, Hualien City, Hualien, Taiwan, and e Dalla
Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
* Correspondence: Malcolm Koo, PhD, Graduate Institute of Long-term Care, Tzu
Chi University of Science and Technology, Hualien City, Hualien 970302 Taiwan
(e-mail: m.koo@utoronto.ca).
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to
download, share, remix, transform, and buildup the work provided it is properly
cited. The work cannot be used commercially without permission from the journal.
How to cite this article: Chang R-Y, Hsueh-Hua Ho S, Tsai H-L, Koo M.
Association of Anxiety and Depression with Chronic Liver Diseases in
Patients with Noncardiac Chest Pain: A Cross-Sectional Study. Medicine
2022;101:31(e29620).
Received: 1 January 2022 / Received in final form: 21 April 2022 / Accepted:
4May 2022
http://dx.doi.org/10.1097/MD.0000000000029620

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Chang et al. • Medicine (2022) 101:31 Medicine
In the basic theory of traditional Chinese medicine, the Qi
of the body ows in a continuous and circular way through a
system consisting of 12 meridians. Of these, the liver meridian
is considered to be associated with psychological and blood-re-
lated problems. The main functions of the liver meridian include
smoothing the ow of blood and energy to the whole body;
regulating bile secretion and store blood; connecting with the
tendons, nails, and eyes.[6] Imbalance in the liver meridian is
associated with not only diseases of the liver as dened by the
organ anatomy, but emotional changes, such as anger and bit-
terness, as well as a number of psychosomatic disorders, such as
depression, anxiety, and insomnia. However, few studies have
specically explored whether anxiety and depression were asso-
ciated with different types of chronic liver disease. It is plausible
that one of the reasons for noncardiac chest pain is anxiety or
depression, which is in turn caused by chronic liver diseases.
Hence, the aim of this study was to investigate the association
of anxiety and depression with various chronic liver disease in
patients referred for treadmill exercise testing due to chest tight-
ness or pain.
2. Methods
2.1. Study design and study population
A cross-sectional study design was used to recruit patients with
chest tightness or pain referred for treadmill exercise testing at
a regional hospital in southern Taiwan between January 2015
and February 2018. Patients who had an implanted pacemaker
or atrial brillations were excluded. In addition, those with con-
traindications for the stress test were excluded.
The study protocols were approved by the Institutional
Review Board of Chia-Yi Christian Hospital, Taiwan (CYCH-
IRB No. 2019058). All patients provided written informed
consent.
2.2. Treadmill exercise testing
After supine and standing electrocardiography (ECG), heart
rate, and blood pressure were obtained, symptom-limited tread-
mill exercise testing using the standard Bruce protocol was con-
ducted (GE T-2000 treadmill, CardioSoft diagnostic software
version 5.20, Marquette ECG analysis program, GE Medical
Systems IT, Inc., Milwaukee, USA). Blood pressure was measured
using a Suntech 4240 monitor (Suntech Medical Instruments,
Raleigh, NC) from the left brachial artery. Patients were encour-
aged to achieve a goal of 85% of the maximum age-predicted
heart rate (HRmax) (beats/min). Functional capacity was esti-
mated based on a range of speeds and grades of the treadmill
and was expressed in metabolic equivalent of task. ECG, heart
rate, and blood pressure were recorded at each stage of exercise,
peak exercise, and every minute in the recovery phase up to 6
minutes. A positive ischemic ST-segment response was dened
as the horizontal or downsloping ST-segment depression of
>1 mm below baseline taken 80 ms after the J-point.
2.3. Clinical measurement
An electronic medical chart review was conducted to obtain
measurements of liver function and reports of abdominal sonog-
raphy of the patients who had completed the treadmill exercise
test. Only patients with liver function measurement and abdom-
inal sonography within 2 years prior to or after the date of the
treadmill exercise test were included in this study.
Elevated serum aminotransferases were dened as alanine
aminotransferase (ALT) > 44 U/L or aspartate aminotransferase
(AST) > 37 U/L in men and ALT or AST > 31 U/L in women.
The possible causes of chronic liver disease were classied as
the following 4 types: (1) alcoholic liver disease was dened as
alcohol consumption of 10 g/day or more in women and 20 g/
day or more in men during 1 year and the presence of elevated
aminotransferases or fatty liver change or cirrhotic changes by
abdominal sonography; (2) chronic hepatitis B was dened by
the presence of hepatitis B surface antigen (HBsAg); (3) chronic
hepatitis C was dened by the presence of antihepatitis C virus
(HCV) antibody and/or HCV-RNA; and (4) fatty liver disease,
including nonalcoholic steatohepatitis (NASH) and nonalco-
holic fatty liver disease (NAFLD), was dened as fatty liver
change by abdominal sonography with or without elevated ami-
notransferases and in the absence of any of the causes of chronic
liver diseases listed earlier.
Body weight and body height of the patients were measured
before the treadmill exercise test. Data on HbA1c, total choles-
terol, triglycerides, high-density lipoprotein cholesterol (HDL-
C), low-density lipoprotein cholesterol (LDL-C), hemoglobin,
hematocrit, and medication use were also obtained from the
electronic medical records.
2.4. Questionnaires
The patients were asked to complete a questionnaire on the
history of diseases (including hypertension, diabetes mellitus,
coronary artery disease, hyperlipidemia, chronic obstructive
pulmonary disease, renal disease, and liver disease), smoking,
drinking, exercise, self-perceived health status, sleep quality, job
stress, anxiety, and depression.
Smoking and alcohol use were dened as daily use in the past
month. Exercise was dened as engaging in physical activity at
least 3 days a week for more than 30 minutes each time. Sleep
quality over the previous 1-month period was assessed using
the Pittsburgh Sleep Quality Index. A Pittsburgh Sleep Quality
Index global score of >5 was dened as poor sleep quality.[7]
Hospital Anxiety and Depression Scale (HADS) was used to
assess anxiety and depression status. The HADS is a well-vali-
dated screening tool initially designed to assess the psychologi-
cal distress of medically ill patients,[8] and it has been extensively
used in clinical settings and research.[9] The scale is composed of
2 7-item subscales for measuring anxiety and depression. Item
responses are recorded on a 4-point Likert-type scale (0–3) with
a total score ranging from 0 to 21 points for each subscale. A
cutoff score of >8 in each subscale is indicative of anxiety and
depression, respectively.
In addition, job stress was assessed using the work-related burn-
out subscale of the Chinese version of the Copenhagen Burnout
Inventory (C-CBI). The subscale consists of 7 questions based
on a 5-point Likert response scale of 100 (always), 75 (often),
50 (sometimes), 25 (seldom), and 0 (never/almost never). The
mean score for the subscale was further categorized into quar-
tiles for subsequent data analysis. Scores of <45, 45 to 60, >60
were dened as mild, moderate, and severe levels, respectively.
For patients who were not working, they were assigned to a “not
working” category.[10] In the present study, the Cronbach alpha
coefcient for the work-related burnout subscale was 0.871.
2.5. Statistical analysis
Continuous and categorical variables were expressed as mean
with standard deviation and number with percentage. Analysis
of variance and Chi-square test were used to compare the
demographic and clinical characteristics of the study patients
with the results of treadmill exercise testing and with differ-
ent chronic liver diseases. Multiple logistic regression analyses
with a backward elimination procedure based on the likelihood
ratio test were conducted to assess the association of anxiety
and depression with chronic liver disease. All statistical analyses
were performed using IBM SPSS Statistics for Windows, Version
27.0.1.0 (IBM Corp., Armonk, NY). A 2-tailed P value of <.05
was considered statistically signicant.

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Chang et al. • Medicine (2022) 101:31 www.md-journal.com
3. Results
A total of 2825 patients completed the treadmill exercise test
and 2537 patients with liver function test results and abdominal
sonography data were analyzed. Table1 shows the demographic
and clinical factors according to myocardial ischemia by the
results of treadmill exercise testing. A total of 1965 patients
(77.4%) showed a negative result, 428 patients (16.9%) showed
positive myocardial ischemia, and 144 patients (5.7%) were
unable to gain 85% of the maximal aged-predicted heart rate.
There were signicant differences among the 3 groups in age,
hypertension, type 2 diabetes mellitus, coronary artery disease,
smoking, exercise, depression, self-perceived health status, and
work stress.
Table2 shows the demographic and clinical data of patients
with different liver diseases and without liver disease. Age, sex,
body mass index, hypertension, type 2 diabetes mellitus, hyper-
lipidemia, smoking, alcohol use, depression measured by HADS,
work-related burnout, ALT, AST, total cholesterol, triglycerides,
HDL-C, LDL-C, gamma-glutamyltransferase, hemoglobin,
hematocrit, direct-acting antivirals (DAA)-HBV, interferon-α,
and benzodiazepine use were signicantly different among the
5 groups of patients.
Table3 shows the results of multiple logistic regression analy-
ses for anxiety and depression. First, the risk of anxiety (adjusted
odds ratio [OR] = 1.83, P < .001) and depression (adjusted OR
= 1.85, P < .001) was signicantly higher in patients with alco-
holic liver disease. Second, the risk of anxiety was signicantly
higher in patients with fatty liver disease (adjusted OR = 1.30, P
= .031). The risk of depression was only marginally associated
with fatty liver disease (adjusted OR = 1.26, P = .091). Third,
the risk of depression was signicantly higher in patients with
chronic hepatitis C (adjusted OR = 2.18, P = .005). The risk
of anxiety and depression was not signicantly associated with
hepatitis B.
4. Discussion
Anxiety and depression are common in patients with chronic dis-
eases.[11] However, their risk of these mental conditions has not
been fully explored in different types of chronic liver diseases. In
Table 1
Demographic and clinical factors between patients according to the results of treadmill exercise testing for myocardial ischemia
(N = 2537).
Variable
Treadmill exercise testing for myocardial ischemia
P
Mean (standard deviation) or number (%)
Negative Positive Inconclusive
1965 (77.4) 428 (16.9) 144 (5.7)
Age 51.9 (11.9)* 56.1 (10.9)† 54.7 (11.7)† <.001
Sex, male 1065 (54.2) 245 (57.2) 77 (53.5) .496
Body mass index .129
Normal or underweight 742 (37.8) 148 (34.6) 41 (28.5)
Overweight 602 (30.6) 144 (33.6) 47 (32.6)
Obese 621 (31.6) 136 (31.8) 56 (38.9)
Hypertension 625 (31.8)* 185 (43.2)† 68 (47.2)† <.001
Type 2 diabetes mellitus 224 (11.4)* 79 (18.5)† 43 (29.9)‡ <.001
Coronary artery disease 239 (12.2)* 81 (18.9)† 39 (27.1)† <.001
Hyperlipidemia 333 (16.9) 93 (21.7) 26 (18.1) .064
Smoking 340 (17.3)* 65 (15.2)* 42 (29.2)† .001
Alcohol use 351 (17.9) 61 (14.3) 27 (18.8) .180
Exercise 620 (31.6)* 167 (39.0)† 41 (28.5)*,† .006
Anxiety 1101 (56.0) 218 (50.9) 80 (55.6) .157
Depression 493 (25.1)* 79 (18.5)† 47 (32.6)* .001
Sleep quality, PSQI > 5 216 (11.0) 38 (8.9) 21 (14.6) .147
Self-perceived health status <.001
Very good or good 220 (11.2)* 50 (11.7)* 8 (5.6)*
Fair 1202 (61.2)* 247 (57.7)* 64 (44.4)†
Poor or very poor 543 (27.6)* 131 (30.6)* 72 (50.0)†
Work stress .012
Mild 964 (78.4)* 198 (82.5)*,† 55 (75.3)†
Moderate 176 (14.3)* 31 (12.9)* 11 (15.1)*
Severe 90 (7.3)* 11 (4.6)* 7 (9.6)*
Not working 735 (37.4)* 188 (43.9)† 71 (49.3)†
Treadmill exercise test
Resting heart rate, beats/min 71.0 (11.4)* 70.3 (10.9)* 66.1 (11.1)† <.001
Peak heart rate, beats/min 154.3 (14.1)* 148.5 (17.3)† 125.0 (16.7)‡ <.001
Resting SBP, mm Hg 123.2 (18.3)* 128.7 (18.8)† 123.9 (20.0)* <.001
Resting DBP, mm Hg 74.0 (12.4) 74.2 (12.7) 73.9 (11.9) .933
Maximum SBP, mm Hg 165.2 (26.4)* 168.3 (26.9)* 155.7 (29.4)† <.001
Maximum DBP, mm Hg 80.5 (14.4)* 79.1 (15.7)* 75.5 (14.0)† <.001
MET 9.7 (1.9)* 9.0 (1.9)† 9.3 (8.6)*,† <.001
Electrocardiogram findings
APC 93 (4.7)* 20 (4.7)*,† 14 (9.7)† .028
VPC 249 (12.7)* 35 (8.2)† 17 (11.8)*,† .034
Af 2 (0.1) 1 (0.2) 0 (0.0) .705
SVT 8 (0.4) 1 (0.2) 0 (0.0) .656
VT 3 (0.2) 2 (0.5) 0 (0.0) .355
Af = atrial fibrillation, APC = atrial premature complex, DBP = diastolic blood pressure, MET = metabolic equivalent of task, PSQI = Pittsburgh Sleep Quality Index, SBP = systolic blood pressure, SVT =
supraventricular tachycardia, VPC = ventricular premature complex, VT = ventricular tachycardia.

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Chang et al. • Medicine (2022) 101:31 Medicine
this cross-sectional study of 2537 patients with chest tightness
or pain referred for treadmill exercise testing, 1965 (77.4%) of
them were tested to be negative for myocardial ischemia. Of these
1965 patients, 47.7% had no chronic liver disease. Multiple logis-
tic regression analysis showed that alcoholic liver disease was sig-
nicantly and independently associated with both anxiety and
depression. In addition, fatty liver disease was signicantly and
independently associated with anxiety, whereas chronic hepatitis
C was signicantly and independently associated with depression.
Chronic alcohol consumption and dependence are associated
with an increased risk of developing many healthy problems,
including liver disease, psychiatric disease, cardiovascular dis-
eases, neurologic disease, and malignant neoplasms. Moreover,
the effect of alcohol consumption on coronary artery disease,
hypertension, and stroke is presented as a J-shape dose-re-
sponse relationship.[12] A meta-analysis of 156 studies showed
that the risk of coronary artery disease decreased by 20% with
the consumption of 0 to 20 g/day of alcohol, and the protective
Table 2
Demographic and clinical data of patients with and without different chronic liver diseases (N = 1965).
Variable
Number (%) or mean (SD)
P
All patients,
Patients classified by chronic liver disease
Alcoholic liver disease Chronic hepatitis B Chronic hepatitis C Fatty liver disease Normal
1965 (100) 209 (10.6) 215 (10.9) 72 (3.7) 531 (27.0) 938 (47.74)
Age, yr 51.9 (11.9) 49.2 (9.8) 51.4 (9.4) 56.7 (9.2) 54.4 (11.2) 50.9 (13.1) <.001
Sex, male 1065 (54.2) 188 (90.0) 142 (66.0) 25 (34.7) 272 (51.2) 438 (46.7) <.001
Body mass index <.001
Normal or underweight 742 (37.8) 61 (29.2) 83 (38.6) 28 (38.9) 141 (26.6) 429 (45.7)
Overweight 602 (30.6) 65 (31.1) 65 (30.2) 26 (36.1) 181 (34.1) 265 (28.3)
Obese 621 (31.6) 83 (39.7) 67 (31.2) 18 (25.0) 209 (39.4) 244 (26.0)
Hypertension 625 (31.8) 64 (30.6) 73 (34.0) 28 (38.9) 202 (38.0) 258 (27.5) <.001
Type 2 diabetes mellitus 224 (11.4) 16 (7.7) 29 (13.5) 11 (15.3) 87 (16.4) 81 (8.6) <.001
Coronary artery disease 239 (12.2) 19 (9.1) 33 (15.3) 6 (8.3) 74 (13.9) 107 (11.4) .139
Hyperlipidemia 333 (16.9) 42 (20.1) 34 (15.8) 14 (19.4) 113 (21.3) 130 (13.9) .004
Smoking 340 (17.3) 90 (43.1) 38 (17.7) 13 (18.1) 55 (10.4) 144 (15.4) <.001
Alcohol use 351 (17.9) 206 (98.6) 34 (15.8) 5 (6.9) 0 (0.0) 106 (11.3) <.001
Exercise 620 (31.6) 60 (28.7) 69 (32.1) 25 (34.7) 179 (33.7) 287 (30.6) .611
Sleep quality, PSQI > 5 216 (11.0) 18 (8.6) 20 (9.3) 13 (18.1) 68 (12.8) 97 (10.3) .103
HADS, anxiety 1101 (56.0) 129 (61.7) 124 (57.7) 40 (55.6) 299 (56.3) 509 (54.3) .380
HADS, depression 493 (25.1) 67 (32.1) 55 (25.6) 26 (36.1) 130 (24.5) 215 (22.9) .014
Self-perceived health status .149
Very good or good 543 (27.6) 49 (23.4) 57 (26.5) 29 (40.3) 146 (27.5) 262 (27.9)
Fair 1202 (61.2) 136 (65.1) 140 (65.1) 39 (54.2) 318 (59.9) 569 (60.7)
Poor or very poor 220 (11.2) 24 (11.5) 18 (8.4) 4 (5.6) 67 (12.6) 107 (11.4)
Work-related burnout <.001
Mild 964 (49.1) 134 (64.1) 106 (49.3) 26 (36.1) 248 (46.7) 450 (48.0)
Moderate 176 (9.0) 22 (10.5) 23 (10.7) 6 (8.3) 37 (7.0) 88 (9.4)
Severe 90 (4.6) 7 (3.3) 11 (5.1) 2 (2.8) 28 (5.3) 42 (4.5)
Not working 735 (37.4) 46 (22.0) 75 (34.9) 38 (52.8) 218 (41.1) 358 (38.2)
eGFR, mL/min/1.73m2108.3 (29.8) 106.6 (26.5) 105.6 (29.5) 111.3 (26.8) 107.5 (31.1) 109.6 (30.0) .375
ALT 43.7 (116.8) 58.3 (104.1) 76.3 (316.3) 65.2 (101.0) 44.7 (51.7) 29.5 (27.9) <.001
AST 41.4 (139.5) 61.7 (161.7) 74.3 (349.1) 54.4 (82.3) 34.1 (34.6) 28.5 (31.2) .006
HbA1c 6.6 (1.6) 6.5 (2.2) 6.6 (1.4) 6.3 (1.1) 6.8 (1.6) 6.5 (1.5) .269
Total cholesterol 206.2 (42.1) 207.2 (45.6) 193.1 (45.7) 207.5 (38.7) 208.9 (41.1) 207.2 (40.7) .006
Triglycerides 177.0 (169.4) 239.6 (285.5) 162.9 (157.9) 160.2 (149.8) 184.9 (146.5) 159.5 (142.7) <.001
HDL-C 54.5 (15.5) 50.4 (14.4) 52.1 (15.9) 55.7 (14.6) 53.3 (14.3) 57.0 (16.4) <.001
LDL-C 128.2 (33.7) 130.0 (36.1) 121.8 (32.5) 130.8 (31.9) 132.5 (32.4) 126.0 (34.2) .021
Glucose 110.9 (36.0) 111.2 (34.6) 111.5 (31.5) 112.7 (27.6) 114.2 (39.9) 108.0 (35.0) .176
Gamma-glutamyltransferase 114.4 (359.8) 308.3 (765.5) 70.2 (103.8) 77.8 (107.8) 95.7 (222.1) 30.9 (42.4) .015
Hemoglobin 14.3 (1.7) 15.2 (1.5) 14.7 (1.4) 14.0 (1.7) 14.4 (1.6) 13.9 (1.7) <.001
Hematocrit 42.2 (4.2) 44.2 (4.3) 43.4 (3.5) 41.6 (4.2) 42.6 (4.1) 41.3 (4.1) <.001
Medications
β-Blockers 485 (24.7) 46 (22.0) 56 (26.0) 16 (22.2) 139 (26.2) – .231
Corticosteroids 81 (4.1) 12 (5.7) 5 (2.3) 5 (6.9) 22 (4.1) – .615
DAA-HCV 2 (0.1) 0 (0) 1 (0.5) 1 (1.4) 0 (0) – .054
DAA-HBV 4 (0.2) 0 (0) 4 (1.9) 0 (0) 0 (0) – .004
Interferon-α1 (0.1) 0 (0) 0 (0) 1 (1.4) 0 (0) – .047
Levodopa 2 (0.1) 1 (0.5) 0 (0) 0 (0) 0 (0) – .591
Methyldopa 1 (0.1) 0 (0) 0 (0) 0 (0) 0 (0) – >.999
Benzodiazepines 140 (7.1) 12 (5.7) 13 (6.0) 12 (16.7) 49 (9.2) – .009
H2-blocker 19 (1.0) 3 (1.4) 2 (0.9) 0 (0) 8 (1.5) – .085
Tamoxifen 1 (0.1) 0 (0) 0 (0) 0 (0) 1 (0.2) – .687
Verapamil 17 (0.9) 3 (1.4) 4 (1.9) 1 (1.4) 3 (0.6) – .522
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DAA-HBV = direct-acting antiviral therapy for hepatitis B virus, DAA-HCV = direct-acting antiviral therapy for hepatitis C virus, eGRF
= estimated Glomerular filtration rate, HADS = Hospital Anxiety and Depression Scale, HbA1c = glycosylated hemoglobin, HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein
cholesterol, PSQI = Pittsburgh Sleep Quality Index, SD = standard deviation.

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Chang et al. • Medicine (2022) 101:31 www.md-journal.com
effect of alcohol was up to 72 g/day, although, the level of alco-
hol consumption was related to an increased risk of liver dis-
ease.[13] However, the risk of development of coronary artery
disease was found to increase when alcohol consumption was
more than 89 g/day.[14] The reduction in coronary artery disease
from moderate alcohol intake may be mediated by increased
brinolysis because alcohol polyphenols can modulate endo-
thelial cell brinolytic protein (t-PA, u-PA, PAI-1, u-PAR, and
Annexin-II) expression at the cellular, molecular, and gene levels
to increase brinolytic activity.[15] This can, in turn, decrease the
acute atherothrombotic consequences (e.g., plaque rupture) of
myocardial infarction. Conversely, activation of the sympathetic
nervous system with heavy alcohol consumption might explain
the associated increase in coronary artery disease.[16]
Chronic alcohol dependence is related to mood disorders
because of the psychoactive properties of alcohol. Depression
and anxiety are the most frequent symptoms that precede and
succeed alcohol abuse. Based on the data from the National
Inpatient Sample 2011 in the United States, the prevalence
of anxiety disorder (8.84% vs 7.54% vs 7.91%), depression
(3.96% vs 2.12% vs 3.21%) were signicantly higher among
hospitalized patients with alcohol liver disease compared with
chronic liver diseases not caused by alcohol, and patients with-
out liver diseases.[17] Moreover, in a study of 143 alcohol depen-
dents of either East Indian ancestry or African ancestry, and
109 controls matched by age, sex, and ethnicity, 39% of the
participants of East Indian ancestry and 37% of participants
of the African ancestry had alcohol dependence combined with
major depression caused by alcohol or drug use. The severity of
depression was signicantly associated with the severity of alco-
hol dependence.[18] In addition, a study on 1767 patients from
various specialized treatment settings in 8 European countries
showed that high levels of alcohol consumption (mean level
of daily ethanol intake of 141.1 g) existed with comorbidities
of alcohol consumption, including liver problems of 19.6%,
depression of 43.2%, and anxiety of 50.3%.[19]
In this study, fatty liver disease was found to be signicantly
and independently associated with anxiety (adjusted OR = 1.30).
A study on 878 patients with chronic liver disease recruited at
an outpatient liver center from a tertiary care medical center
showed that those with NAFLD had a signicantly higher prev-
alence of depression (27.2%) than patients with hepatitis B
(3.7%) or that reported for the general population (2–5%).[20]
In addition, a study of 36 patients with histologic evidence of
NASH on liver biopsy and 36 matched controls found that
patients with NASH had a signicantly increased risk of both
lifetime major depressive disorder (OR = 3.8, P = .018) and
lifetime generalized anxiety disorder (OR = 5.0, P = .005).[21]
Moreover, the risk of depression increased in proportion to the
severity of ultrasonographically detected NAFLD (mild fatty
liver: adjusted OR = 1.14 and moderate to severe fatty liver:
adjusted OR = 1.32) in 112,797 Korean adults participating in
the Kangbuk Samsung Health Study cohort.[22] A recent retro-
spective cohort study of 39,742 adult patients also revealed an
increased risk of anxiety disorder (adjusted hazard ratio = 1.23,
P < .001) and depression (adjusted hazard ratio = 1.21, P <
.001) in patients with NAFLD.[23] Although the exact mecha-
nism between NAFLD and anxiety disorder is still unknown,
there are a few possible explanations. First, the correlation of
NAFLD with obesity and diabetes mellitus,[24] both of which
have been strongly associated with depression symptoms, could
be another explanation. Nevertheless, the signicant association
between fatty liver disease and anxiety observed in the present
study was independent of body mass index and diabetes mel-
litus, suggesting that there are other underlying mechanisms.
Second, the association might be explained by their shared
pathogenesis mediated by the immune-inammatory, oxidative
and nitrosative stress pathways.[25]
Table 3
Multiple logistic regression analysis of anxiety and depression in patients with different chronic liver diseases.
Variable Anxiety Depression
Adjusted odds ratio (95% CI) P Adjusted odds ratio (95% CI) P
Chronic liver disease
Normal 1.00 1.00
Alcoholic liver disease 1.83 (1.31–2.57) <.001 1.85 (1.29–2.64) <.001
Chronic hepatitis B 1.27 (0.92–1.76) .146 1.22 (0.84–1.76) .292
Chronic hepatitis C 1.00 (0.60–1.68) .993 2.18 (1.26–3.78) .005
Fatty liver disease 1.30 (1.02–1.64) .031 1.26 (0.96–1.66) .091
Age, yr 0.97 (0.96–0.98) <.001 0.97 (0.96–0.98) <.001
Sex
Male 1.00
Female 1.43 (1.16–1.76) <.001
Body mass index
Normal or underweight 1.00
Overweight 0.77 (0.61–0.98) .032
Obese 0.77 (0.60–0.97) .029
Exercise 0.66 (0.51–0.86) .002
Sleep quality, PSQI > 5 1.46 (1.05–2.02) .024 2.43 (1.76–3.35) <.001
Self-perceived health status
Very good or good 1.00 1.00
Fair 1.87 (1.37–2.56) <.001 1.84 (1.15–2.94) .011
Poor or very poor 4.29 (3.01–6.11) <.001 3.09 (1.90–5.04) <.001
Work-related burnout
Mild 1.00 1.00
Moderate 2.63 (1.80–3.85) <.001 2.99 (2.10–4.25) <.001
Severe 8.73 (3.94–19.38) <.001 5.50 (3.39–8.91) <.001
Not working 1.43 (1.14–1.80) .002 1.61 (1.24–2.10) <.001
Other variables included in the model evaluation: alcohol use, ALT, AST, coronary artery disease, eGFR, HbA1c, HDL-C, hematocrit, hemoglobin, hyperlipidemia, hypertension, LDL-C, smoking, total
cholesterol, treadmill exercise test results, triglycerides, and type 2 diabetes mellitus.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, CI = confidence interval, eGFR = estimated glomerular filtration rate, HbA1c = glycosylated hemoglobin, HDL-C = high-density
lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol, PSQI = Pittsburgh Sleep Quality Index.

6
Chang et al. • Medicine (2022) 101:31 Medicine
HCV infection is a worldwide problem and is one of the major
causes of chronic liver diseases. The global prevalence is about
2% to 3%, and more than 0.35 million people die of HCV-
related conditions each year.[26] HCV infection is associated with
chronic hepatitis, cirrhosis, hepatic failure, and hepatocellular
carcinoma. HCV infection is also associated with psychiatric dis-
orders, including alcohol abuse, drug abuse, and depression.[27]
Findings from the National Health and Nutrition Examination
Survey (NHANES 2005–2010) showed that only chronic hepa-
titis C, but not chronic hepatitis B, alcohol-related liver disease,
or nonalcoholic fatty liver disease, was strongly associated with
depression.[28] The prevalence of depressive symptoms among
patients with HCV infection was found to be between 21% and
58.6%.[29] The prevalence of depression in patients with HCV
was about 1.5 to 4.0 times higher than the general population.[30]
The mechanism of high prevalence of depression among
patients with HCV infection may be multifactorial. First, direct
HCV neuroinvasion of HCV is possible. HCV-RNA has been
detected in the brain of chronically infected patients with neuro-
psychiatric disorders.[31] Second, chronic HCV infection is asso-
ciated with systemic and brain inammation.[32] Higher TNF-α
plasma levels in HCV infection patients could lead to depressive
symptoms.[33] Third, immune activation of serotoninergic activ-
ity could be associated with depression in patients with HCV
infection.[34]
The standard therapy for HCV infection is antiviral therapy
with long-acting peginterferon alpha, oral ribavirin, and DAA-
HCV therapy. Depression is one of the most common side effects
of antiviral therapy. A meta-analysis revealed that a quarter of
patients with HCV infection who started to receive interferon
and ribavirin therapy would develop a major depressive epi-
sode.[35] In addition, in a cohort of 91 patients with hepatitis C,
the incidence of major depression and any depressive disorder
during DAA-HCV therapy was found to be 13% and 46.3%,
respectively.[36] Nevertheless, in the present study, one of the 102
patients with HCV infection had received DAA-HCV therapy
and 1 patient with HCV infection received both DAA-HCV
and interferon therapy. Both of them did not have depression.
Therefore, DAA-HCV and interferon did not appear to be the
cause of depression in our study.
This study has some limitations. The cross-sectional design
precluded the determination of causal relationships between
chronic liver disease, anxiety, and depression. Second, the sever-
ity of chronic liver disease is not available. Third, the precise
level of alcohol consumption was not available, which precluded
the analysis of whether a dose-response relationship exists.
5. Conclusions
Findings from this study showed that in patients with noncar-
diac chest pain, alcoholic liver disease was signicantly asso-
ciated with anxiety and depression, while those with fatty
liver and chronic hepatitis C were associated with anxiety and
depression, respectively. Clinicians should be vigilant to these
correlations in practice.
Author contributions
Conceptualization: R.-Y.C., H.-L.T., and S.H.-H.H.; methodol-
ogy: R.-Y.C.; formal analysis: R.-Y.C. and M.K.; investigation:
R.-Y.C.; writing – original draft: R.-Y.C.; writing – review &
editing: M.K., R.-Y.C., H.-L.T., and S.H.-H.H. All authors have
read and agreed to the published version of the manuscript.
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