Journal of Trace Elements and Minerals 2 (2022) 100035

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Journal of Trace Elements and Minerals

journal homepage: www.elsevier.com/locate/jtemin

The effect of zinc supplementation on mental health in overweight/obese

patients with non-alcoholic fatty liver disease: A randomized, double-blind,
placebo-controlled trial
Mojdeh Fathi a, Pezhman Alavinejad b, Zahra Haidari c, Reza Amani a,∗
a
Department of Clinical Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
b
Alimentary Tract Research Center, Ahvaz Imam Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
c
Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran

a r t i c l e i n f o a b s t r a c t

Keywords: Background: Zinc deficiency is common in patients with non-alcoholic fatty liver disease (NAFLD) and evidence
Zinc supplement indicates the role of zinc as an antioxidant and improvement in insulin resistance in obesity and type 2 dia-
Mental health betes. The aim of this study was to investigate the effects of zinc supplementation on mental health among
Non-alcoholic fatty liver
overweight/obese patients with NAFLD.
Depression
Methods: Fifty- seven overweight/obese subjects with confirmed non-alcoholic fatty liver disease (NAFLD) were
Anxiety
Stress randomly allocated to treatment (30 mg/day supplement) or placebo groups under a calorie restricted diet for
12 weeks. Mental health was assessed using a valid 21-item questionnaire, the Depression, Anxiety, and Stress
Scale (DASS-21). Anthropometric measurements, food assessment, and mental health were assessed at the first,
6th, and 12th weeks. Serum zinc was assessed at the beginning and end of the intervention.
Results: A total of 50 participants completed the study. Serum zinc deficiency was significantly compensated in the
treatment group (P<0.05). Although the DASS-21 depression, anxiety, and stress scores decreased significantly
during the intervention, after adjusting for confounder factors, no significant differences were seen between the
two groups. After 12 weeks, only waist circumference decreased significantly in the treatment group compared
to the placebo group (P<0.05).
Conclusions: The study showed daily intake of 30 mg of zinc elemental improves zinc deficiency and waist circum-
ference in patients with NAFLD. However, further clinical trial studies with a longer duration, dose-dependent
and considering gender and severity of mood disorders are needed to clarify the effect of zinc supplementation on
depression, anxiety, and stress in overweight/obese patients with NAFLD [IR.MUI.RESEARCH.REC.1399.071].

Introduction Oxidative stress and Inflammation-induced liver fat accumulation,

Many evidence indicates a close relationship between obesity and
mental disorders [1,2]. Effects of metabolic disorders as inside risk fac-
tors of emotional impairments and also the role of emotional disorders
on obesity and lifestyle have been indicated [3]. Recently, the extra-
hepatic effects of non-alcoholic fatty liver disease (NAFLD) on mental
disorders have been investigated. Metabolic risk factors among patients
with NAFLD such as type 2 diabetes mellitus, lipid profile disorders as
well as obesity have been suggested as risk factors for central nervous
system (CNS) disorders such as developing Alzheimer, mild cognitive
impairment, and dementia(1). In this regard, many clinical trial studies
investigated different dietary patterns on mental health status among
overweight or obese individuals with or without mood disorders [2,4,5].
lipid peroxidation and, insulin resistance have been suggested as origi-
nal factors in developing NAFLD [6]. Evidence has also been indicated
the extrahepatic role of oxidative stress, inflammation, and dysbiosis
on the CNS [7,8]. Additionally, the liver as a part of the gut-brain axis
plays a pivotal role in hemostasis of components which can transfer into
the BBB and affect brain function, such as inflammatory factors and ce-
ramide. As a result, it is not surprising that the mental health of NAFLD
patients with obesity is worse than that of obese individuals. It has been
estimated that about to 30% of patients with NAFLD have major de-
pressive disorder (MDD) [9]. Chronic stress resulted in increasing of
developing depression or anxiety. Indeed, it is reported 85% of patients
with depression display also symptoms of anxiety [10]. While relation of
depression and fatty liver seems plausible in experimental and interven-

∗
Corresponding author at: Department of Clinical Nutrition, School of Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan,
Iran.
E-mail address: r_amani@nutr.mui.ac.ir (R. Amani).

https://doi.org/10.1016/j.jtemin.2022.100035
Received 18 June 2022; Received in revised form 16 November 2022; Accepted 16 November 2022
Available online 25 November 2022
2773-0506/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
M. Fathi, P. Alavinejad, Z. Haidari et al.
tional studies [11,12], results of observational studies are controversial
[9,13,14].
Evidence indicated zinc deficiency through the hypothalamic–
pituitary–adrenal axis causes susceptibility to stress and vice versa,
stress conditions lead to zinc deficiency [15,16]. Animal model studies
have also shown that resistance to antidepressant treatments is lower in
patients with lower serum zinc levels [17,18]. Results of a meta-analysis
showed serum levels of zinc approximately 0.12 μg/mL is lower in de-
pressed subjects than in normal subjects [19]. Zinc has also been shown
in some experimental studies to regulate antioxidant, neurotransmit-
ter systems, neurotrophic factors, and neuronal precursor cells [20,21].
Therefore, the objective of this clinical trial study is to evaluate the effect
of zinc supplementation on mood status in overweight or obese patients
with NAFLD.
Material and methods
Participants
The Medical Ethics Committee at the Isfahan University of Medical
Sciences approved the present study under the registration cod number
IR.MUI.RESEARCH.REC.1399.071. The study was conducted in accor-
dance with the Declaration of Helsinki between Jun 2020 and Decem-
ber 2020. Before the current study, in order to investigate the feasibility
2
Journal of Trace Elements and Minerals 2 (2022) 100035
Fig. 1. summary of patient flow diagram.
of the DASS questionnaire among patients with NAFLD, we conducted
a pilot study as part of the Ph.D. thesis of MF which was registered in
the Iranian Registry of Clinical Trials (IRCT NO: 20181005041238N1).
Participants were selected from overweight/ obese patients with NAFLD
referred to the gastroenterology clinic of the Ahvaz Imam Educational
Hospital. All participants signed the informed consent.
Inclusion criteria: adult (18–65 year), body mass index (BMI) be-
tween 25 and 35 kg/m2, waist circumference (WC > 94 cm for men and
> 80 cm for women) [21], grade 1 or 2 NAFLD. Exclusion criteria: a
clinical history of chronic diseases (diabetes, hepatic or kidney dysfunc-
tion, major cardiovascular diseases, cancer, malabsorption, hormonal
disturbances), pregnant or lactating women, smoking and drinking alco-
hol habits, used any supplements (zinc or other supplements), adhered
to any special diet or highly physically active (> 3 h/week) over the
past 3 months as well as not taking more than 10% of the zinc supple-
ment. Patients with major neural disorder (such as Alzheimer, multiple
sclerosis, Parkinson et cetera) were excluded.
Dietary weight loss protocol
56 overweight/obese patients with NAFLD participated in a 12-week
randomized, double-blind, placebo-controlled trial. At the first of inter-
vention, after randomization, each participant received a personalized
diet plan containing 55% carbohydrate, 30% fat, and 15% protein with
M. Fathi, P. Alavinejad, Z. Haidari et al. Journal of Trace Elements and Minerals 2 (2022) 100035

Table 1
Baseline demographics, clinical, laboratory data.

Variable Zinc supplementation Placebo p-value

Male (%) 17 (68) 15 (60) 0.556

Education (%) 0.01
≤12 7(28) 15(60)
High school diploma 5(20) 3(12)
Bachelor degree or higher 13(52) 7(28)
Age (year) 39.44 ± 10.54 40.68 ± 9.87 0.670
Duration history of NAFLD 0.037
< 1 year 13 (52) 20 (80)
≥1 year 12 (48) 5(20)
Steatosis N (%) 0.208
Normal (grade = 0) 0 0
Mid (grade = 1) 9 ((36) 5 ((20)
Moderate (grade = 2) 16 ((64) 20 ((80)
Serum zinc (𝜇g/dL) 63.56 ± 10.47 64.48 ± 22.04 0.852
BMI (kg/m2) 31.23 ± 3.03 31.47 ± 3.85 0.813
Waist circumference (cm) 106.58 ± 8.95 107.18 ± 10.11 0.825
Hip circumference (cm) 108.58 ± 5.31 109.20 ± 5.79 0.695
Body fat (%) 42.11 ± 9.64 40.80 ± 10.08 0.639
Activity (met- H/week) 33.74 ± 4.48 34.54 ± 4.25 0.541
Energy intake (kcal) 2723.40 ± 568.64 2773.41 ± 832.13 0.805
Depression N (%) 0.248
Normally 13 (52%) 14 (56%)
Mild 3 (12%) 4 (16%)
Moderate 4 (16%) 5 (20%)
Severe and extremely severe 5 (20%) 2 (8%)
Anxiety N (%) 0.266
Normally 6 (24%) 8 (32%)
Mild 2 (8%) 3 (12%)
Moderate 5 (20%) 6 (24%)
Severe and extremely severe 12 (48%) 8 (32%)
Stress N (%) 0.909
Normally 3 (12%) 2 (8%)
Mild 6 (24%) 7 (28%)
Moderate 2 (8%) 4 (16%)
Severe and extremely severe 14 (56%) 12 (48%)

Quantitative variables are reported as mean ± SD and p-values obtained from

independent- sample t-test. Qualitative variables are reported as number (percent-
ages) and p-values obtained from the chi square test. Qualitative variables are re-
ported as number (percentages). p-values obtained from the chi square test. Abbre-
viations: BMI: Body mass index.

500–1000 kcal/day energy restriction targeting 0/5–1 kg weight loss
per week. A trained dietitian followed the adherence to the diet (assess-
ment food recalls and weight loss at least 3% of body weight during the
study) and supplementation (taking > 90% of the supplements) in each
visit and by phone call.
Supplementation
By considering blinding conditions, simultaneously with the weight
loss diet, one group received daily 220 mg zinc gluconate (as 30- mg
elemental zinc), and the other received a placebo for 12-weeks. Either
zinc supplement or placebo was exactly the same and made and packed
by Dineh Pharmacy Company, Tehran, Iran.
Measurement and assessment
The body weight, waist circumference, hip circumference, lean body
mass, fat mass, 24-h food recall and physical activity were assessed at
first, 6th week, and 12th week.
At the beginning and end of the intervention, after 12- h of fast-
ing, participants were asked for blood collecting and ultrasonography.
Serum zinc was measured using the assay kit (Bionik, Iran) based direct
colorimetric technique [15]. (the detail of measurements are presented
in the previous study) [16].
Depression, anxiety and, stress was assessed using a self-reported 21-
itemes questionnaire (DASS-21) that there are seven questions in each
subscale (depression, anxiety and, stress). The questionnaire was con-
ducted for all participants in each visit. For each item was considered
score ranging from 0 “Did not apply to me at all - NEVER” to 3 “Applied
to me very much, or most of the time - ALMOST ALWAYS”. The degree
of severity of emotional states was determined using multiplication by
two the DASS-21 sub-scale and categorization to yield equivalent scores
ranging from normal to extremely severe. Previous studies reported high
reliability of the questionnaire with a Cronbach’s alpha coefficient 0.84
and high convergent validity and internal consistency [17].
Statistical analysis
All statistical analyses were performed using SPSS version 21 (SPSS
Inc., Chicago, IL, USA). Q–Q plot and skewness of the data were explored
to evaluate data distribution. Data was presented as mean ± standard
deviation (SD) and frequency (percentage) as appropriate. Independent
sample t-tests or chi-squared tests were used to compare variables be-
tween two groups. Assessments of differences over time within groups
were made by repeated measure ANOVA. Changes from baseline ad-
justed for baseline measurement were explored using repeated measure
ANCOVA. A P < 0.05 was considered statistically significant.
Results
Among 141 participants who were screened, 56 subjects were eli-
gible. Four participants in the treatment group and two participants in
the placebo did not continue the study for personal reasons and entirely

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M. Fathi, P. Alavinejad, Z. Haidari et al. Journal of Trace Elements and Minerals 2 (2022) 100035

Table 2 Table 3
Anthropometric measurements in the both groups. Dietary zinc intakes status and serum zinc in the both groups.

Variable Zinc supplementation Placebo p-value b p-value c Variable Zinc supplementation placebo group p-value

Weight (kg) Zinc intake(μg) 0.187

0 week 92.42 ± 12.19 91.01 ± 11.60 0.587 0.168 0week 11.60± 1.90 11.69 ± 2.00
6th week 90.11 ± 11.83 87.74± 10.6 6th week 11.17± 1.62 10.75 ± 1.58
12th week 87.64 ± 11.82 86.16 ± 10.59 12th week 10.61± 1.40 10.49± 1.42
p-Value a <0.001 <0.001 p-valuea 0.003 <0.001
BMI (kg/m2) Serum zinc(μg/dL) <0.001
0 week 31.23± 3.03 31.47 ± 3.85 0.920 0.266 Before 63.56 ± 10.47 64.48 ± 22.04
6th week 30.45 ± 2.94 30.32 ± 3.36 After 103.64 ± 15.85 66.12 ± 22.08
12th week 29.63± 3 29.81 ± 3.68 p-valuea <0.001 0.259
p-Value a <0.001 <0.001
Waist circumference (cm) Values are mean ± SD. Within group analyses were done using paired t-
0 week 106.58 ± 8.95 107.18 ± 10.11 0.593 0.042 tests or repeated measure ANOVA. Between group analyses were done
6th week 103.18 ± 8.29 105.04 ± 9.86 using ANCOVA (adjusted for baseline value) and repeated measure
12th week 101.88 ± 8.12 103.58 ± 9.51 ANOVA, where needed.
p-Value a <0.001 <0.001 Pa : within group Pb : between group.
Hip circumference (cm)
0 week 108.58 ± 5.31 109.20 ± 5.79 0.85 0.102
6th week 107.06 ± 4.52 107.46 ± 5.21
12th week 106.18 ± 4.15 105.95 ± 4.92 rotrophic Factor (BDNF) in the hippocampus and cortex [18–23]. Ev-
p-Value a <0.001 <0.001 idence also showed cortisol, a depressive hormone, leads to zinc defi-
FM (%) ciency through active Zinc14, metallothionine and transfer zinc in to the
0week liver and adipose tissue. Finally zinc deficiency results in decreasing neu-
6th week 42.11 ± 9.64 40.80 ± 10.08 0.535 0.933
12th week 39.14 ± 8.92 37.58 ± 9.15
rogenesis and neural plasticity as well as mood disorder [24–27]. Since
p-Value a 36.80 ± 8.14 34.97 ± 8.77 the liver is a main responsible for zinc hemostasis in the body and also
<0.001 <0.001 oxidative stress deteriorates the zinc serum levels, so zinc deficiency is
LBM (%) obvious in patient with NAFLD. [28–31]. In the other hand, both copper
0 week 31.86 ± 4.78 31.93 ± 3.70 0.579 0.589
and zinc are needed for SOD. Since the bioavailability of zinc and copper
6th week 33.87 ± 3.92 34.82 ± 4.04
12th week 35.41 ± 3.82 36.18 ± 4.33 is linked to each other, the ratio between the two is vital for keeping this
p-Value a <0.001 <0.001 enzyme functioning optimally. In this line, a significant enhancement of
serum levels and the ratio of serum copper to zinc has been indicated in
Values are reported as mean ± SD and p-values obtained from Repeated mea-
a previous study [32]. Therefore, it seems that the major concern about
sure ANOVA.
Abbreviations: FM: fat mass; LBM: lean body mass; Pa: within group P b: be-
NAFLD patients lies in zinc status. Consistence previous studies, in the
tween group Pc: time∗ group. present study, despite of adequate dietary zinc intake, the serum lev-
els of zinc were lower than the normal (< 70 𝜇g/dL) in both groups at
the beginning of the intervention. Indeed, several observational studies
50 overweight ( n = 19) and obese (n = 31) participants completed the reported mood disorders in patients with NAFLD [33–35].
study (25 subjects in each group) (Fig. 1). Because of various methodological studies such as dose and type of
Baseline demographics, characteristics and prevalence of depression, supplementation, duration of study, as well as different target popula-
anxiety and stress of the subjects are presented in Table 1. The mean age tions, the results of zinc supplementation on mood status are inconclu-
of participants was 40.06 ± 10.12. There were no significant differences sive [36,37]. A meta-analysis review found that zinc supplementation
in demographic and baseline characteristics between the two groups significantly improved depressive symptoms only in people with a clin-
except history duration of NAFLD and education (P<0.05). There was ical diagnosis of major depression who were receiving antidepressant
no significant difference in severity of baseline DASS depression, anxiety therapy, not in healthy people or people with other major depression
and, stress scores between the two groups. [37]. Siwek et al. demonstrated effect of zinc supplementation on ef-
After 12 weeks, all anthropometric parameters did not significant ficacy and speed of antidepressant treatments in individuals with de-
differences between the groups except waist circumference decreased pression [37]. Siwek et al. demonstrated that the effect of zinc sup-
significantly in the treatment group compared with the placebo group plementation on the efficacy and speed of antidepressant treatments in
(P<0.05) (Table 2). individuals with depression [38]. A previous trial study showed zinc
At the beginning of intervention, the mean serum level of zinc was supplementation (10 mg ZnO /d for 5 d/wk) on depression and anxi-
lower than the normal level (< 70 𝜇g/dL) in both groups. After zinc ety in school-aged children for six months had only a significant effect
supplementation, the mean serum level of zinc increased significantly in children with zinc deficiency [39]. At the beginning of the interven-
and reached to the normal levels (P<0.05) (Table 3). tion, based on the DASS score in the moderate’ to ‘extremely severe’
Repeated-measures ANOVAs revealed a significant decrease in the range, the percent of depression, anxiety, and, stress were 32%, 62%
DASS-21 depression, anxiety and, stress score in the two groups and, 64%, respectively. Cerebrovascular alteration, neuroinflammation,
(P<0.05). At the end of the intervention, after adjusting education and and brain insulin resistance have been suggested in CNS manifestations
the history duration of NAFLD, and also baseline factors, the DASS-21 in patients with NAFLD/NASH. Additionally, High prevalence of cardio-
depression (Fig 2A), anxiety (Fig 2B) and, stress (Fig 2C) score did not vascular disease in patients with serious mental disorders have been at-
statistically difference between the two groups. tributed to some biological mechanisms such as oxidative stress, inflam-
mation, hypothalamic-pituitary adrenal (HPA) axis dysregulation, lipid
Discussion profile disorder, and increased platelet reactivity [40]. In this study, al-
though insulin resistance and oxidative stress improved significantly in
The present study evaluates the effect of zinc supplementation on the treatment group, no significant difference was seen in DASS score
mood status in overweight/obese patients with NAFLD under weight and also other anthropometric and metabolic factors between the two
loss diet. Zinc is involved in several parts of the nervous system such as groups [16]. Considering the protective effects of copper in cardiovas-
the regulation of neurotransmitters and synaptic transmission, modula- cular disease have been illustrated in some previous studies, the results
tion of voltage-gated ion channels, and production Brain-Derived Neu- of the study can be attributed to the copper status after zinc supplemen-

4
M. Fathi, P. Alavinejad, Z. Haidari et al. Journal of Trace Elements and Minerals 2 (2022) 100035

Fig. 2. A: Comparison Depression, Anxiety and Stress score in zinc supplementation versus placebo group at baseline, week 6 and 12 after intervention., Fig. 2B:
Comparison Anxiety score in zinc supplementation versus placebo group at baseline, week 6 and 12 after intervention, Fig 2C: Comparison Stress score in zinc
supplementation versus placebo group at baseline, week 6 and 12 after intervention.

tation. It is suggested that the appropriate proportion of copper and zinc longer durations, and does dependent are warranted to determine the
should be evaluated in future studies [41]. effect of zinc supplementation in NAFLD patients with different intensi-
All stress, anxiety, and depression scores decreased during the inter- ties of mood disorders, from mild to extremely severe.
vention in all participants except one participant in the placebo group
who had a minimum score for stress, depression, and anxiety at the
Ethics approval and consent to participate
beginning of the intervention. At the end of the intervention, 30- mg el-
emental zinc supplementation did not have significant effects on mood
The Medical Ethics Committee at the Isfahan University of Medical
outcomes in the adjusting models that were controlled for education
Sciences approved the present study under the registration cod number
and the history duration of NAFLD, and also baseline factors in over-
IR.MUI.RESEARCH.REC.1399.071.
weight/obese patients with NAFLD. Consist of previous studies, it seems
that the improvement in mood status can be attributed to the dietary
weight loss [42,43]. Consent for publication

Strengths and limitations All participants signed the informed consent.

The present study is the first clinical trial to evaluate the effect of Data availability statement
zinc supplementation on mood disorders in patients with NAFLD. How-
ever, allowing for the severity of stress, depression, and anxiety, further The datasets analyzed in this study are accessible by the correspond-
long-term and dose-dependent clinical trials are needed to clarify the ing author on any reasonable request.
influence of zinc supplementation on the mood status of patients with
NAFLD. It is suggested that serum levels of hormonal and metabolomic
factors related to mood disorders will be investigated. Funding/support

This work was supported by the Vice Chancellor for Research of Is-
Conclusion
fahan University of Medical Sciences, Iran under Grant number 16902.
There is an ethical statement.
The present study showed although 30 mg elemental zinc supple-
ment compensated serum levels of zinc deficiency in overweight/obese
patients with NAFLD, did not significant effect on the mood outcomes Declarations of Competing Interest
in these patients. It seems weight loss diet prompts an improvement
in depression, anxiety, and stress status. Studies of larger sample sizes, None.

5
M. Fathi, P. Alavinejad, Z. Haidari et al.
CRediT authorship contribution statement
Mojdeh Fathi: Conceptualization, Methodology, Software, Writing
– review & editing, Investigation. Pezhman Alavinejad: Visualization.
Zahra Haidari: Software, Data curation. Reza Amani: Supervision, In-
vestigation, Conceptualization, Methodology, Writing – original draft.
Acknowledgments
We would like to appreciate all patients who kindly contributed in
the study.
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