Psychological factors associated with NAFLD/NASH- a ......Psychological factors associated with...
Transcript of Psychological factors associated with NAFLD/NASH- a ......Psychological factors associated with...
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Abstract. – OBJECTIVE: Nonalcoholic fat-ty liver disease (NAFLD) represents one of the most common chronic liver diseases world-wide. So far, the pathogenesis of NAFLD and its more severe variant nonalcoholic steatohep-atitis (NASH) is yet unclear, with many mecha-nisms being proposed as possible causes. This article aims to review the psychological factors associated with NAFLD/NASH.
MATERIALS AND METHODS: Three main ca-tegories of factors have been investigated: emo-tional, cognitive and behavioral. Five electronic databases were searched, limited to studies pu-blished in the English language, during the pe-riod 2005-2015: PubMed, Thomson ISI – Web of Science, Scopus, ProQuest, and ScienceDirect.
RESULTS: Results indicated the most relevant emotional factors to be depression and anxiety. The areas of investigation for cognitive func-tioning concern those contents and processes related to the ability to initiate and maintain life-style changes. The most important behavioral factors identified are physical activity, nutrition/food intake and substance consumption: coffee, alcohol, cigarettes.
CONCLUSIONS: Some of the factors identi-fied act as protective factors, other as vulnera-bility factors. NAFLD/NASH may be considered a cognitive-behavioral disease, the most effec-tive management being lifestyle changes, with emphasis on diet and exercise.
Key WordsNonalcoholic fatty liver disease (NAFLD), Nonalco-
holic steatohepatitis (NASH), Cognitive factors, Behav-ioral factors, Emotional factors.
Introduction
Nonalcoholic fatty liver disease (NAFLD) re-presents one of the most common chronic liver diseases worldwide. NAFLD is an umbrella term used to name a condition identified in 1981 in pre-
gnant women1. The term was introduced in 1986 to describe a spectrum of diseases ranging from a simple benign fatty liver (hepatic steatosis) to nonalcoholic steatohepatitis (NASH), to progres-sive fibrosis and cirrhosis2.
Chronologically, the nonalcoholic steatohepa-titis (NASH) was coined before NAFLD, in 1980, by Ludwig et al3. They described the pattern of li-ver injury observed in a group of patients treated at Mayo Clinic. It refers to a condition of fat accu-mulating in the liver, due to causes different from excessive alcohol consumption (less than 20 g per day) or any other specific causes of hepatic stea-tosis3. Most of these patients were obese women, thus associating from the very beginning NASH with one of the most debilitating conditions of the present time-obesity3. Of all the patients affected by NAFLD, only those with histologic evidence of steatohepatitis are shown to progress to fibro-sis or cirrhosis4. Some studies5 show between 10%-29% of patients with NASH will develop cirrhosis within a 10-year period, underlying the importance of prevention and early treatment. The most important histologic feature of NAFLD is the accumulation of triacylglycerols and diacyl-glycerols in hepatocytes6. Visceral fat provides most of the triglycerides leading to steatosis offering a possible explanation for the cases of generally lean individuals, centrally obese, who develop NAFLD7.
Although the world-wide prevalence has not yet been determined, rates of 10-24% were esti-mated in various general populations8. The pre-valence of NAFLD increases significantly, up to 74% in obese individuals8. In the United States alone, this condition represents over 75% of the chronic liver disease1.
NAFLD is reported among all racial and ethnic groups. Hispanics have the highest prevalence of NAFLD, 45%. For the non-Hispanic whites, pre-valence was estimated to be 33%, while for the
European Review for Medical and Pharmacological Sciences 2016; 20: 5081-5097
B. MACAVEI1, A. BABAN1, D.L. DUMITRASCU2
1Department of Psychology, Babes-Bolyai University, Cluj-Napoca, Romania12nd Medical Clinic, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania
Corresponding Author: Adriana Baban, Ph.D; e-mail: [email protected]
Psychological factors associated with NAFLD/NASH: a systematic review
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African Americans 24%1. In China9, the commu-nity prevalence of nonalcoholic fatty liver disease was estimated at a relatively lower rate of 15%. In India, the prevalence of NAFLD is around 9% to 32% in the general population, with higher preva-lence in overweight or obese individuals10. Women tend to develop the disease later than men (in the sixth decade of life vs. the fourth), the condition being more frequent in male than female1. NAFLD is a disease affecting people regardless of age; it has been reported1 in children as young as 2. So-me studies8 indicate 2.6% of children are affected, with higher rates in case of obese child population ranging from 22.5% to 52.8%.
The pathogenesis of NAFLD is not yet fully clarified. It might be multifactorial, with many mechanisms as possible causes; among the most important are insulin resistance, oxidative stress, apoptosis, and adipokines7,11. Based on available data from clinical, experimental and epidemio-logical studies, there is now a consensus that primary NAFLD is the hepatic manifestation of the metabolic syndrome11,12.
Insulin resistance, mostly in the context of extra weight and obesity, generates higher levels of hepatic free fatty acid (FFA); this condition facilitates the development of NAFLD6. FFA oxidation leads to the generation of toxic reactive oxygen species resulting in hepatic injury and inflammation. As a consequence, the initiation and progression of fibrosis are likely to follow6.
Associated ConditionsNAFLD has been associated with many other
conditions, among them obesity and visceral fat, diabetes mellitus, hyperlipidemia, and hypotha-lamic-pituitary dysfunction8. Some studies show that obese pregnant women can pass on their metabolic phenotype to their children. In turn, early childhood obesity predicts the development of nonalcoholic fatty liver disease later on13. In adolescence, a range of liver problems are as-sociated with greater rates of weight-for-height change between 1-10 years, mediated by concur-rent body fatness14. Other researches underline that overweight and obesity lead to increased quantities of hepatic-free fatty acids, generating an environment appropriate for the development of NAFLD6. As such, the prevalence of NAFLD in obese persons can go as high as 74%8.
An independent risk factor for the develop-ment of NAFLD was identified in dietary fructose6.
Steatosis can also come as a consequence of multiple rare genetic conditions, which influen-
ce the liver processing of nutrients and lipids. Mutations that contribute to either an increase in lipid synthesis/uptake or a decrease in hy-drolysis/export (e.g., glycogen storage diseases, ATGL defects, or very-low-density lipoproteins mutations) were associated with NAFLD15. Some other conditions associated with NAFLD include parental nutrition, acute starvation, abdominal surgery, use of several drugs (e.g. amiodarone, tamoxifen, glucocorticoids, synthetic estrogens, diltiazem, aspirin, methotrexate, highly active antiretroviral therapy), hepatitis C, HIV and me-tabolic disorders16,17.
A complication of hepatic steatosis, the no-nalcoholic steatohepatitis (NASH) is proven to be associated with cardiovascular diseases and malignancy. In a study of biopsy-proven NASH18, the main causes of death in patients were cardio-vascular disease and malignancy. Also, studies19 show both hepatic steatosis and the more aggres-sive NASH are associated with type 2 diabetes mellitus.
Methods
Psychological Risk and Protective factors for NASH/NAFLD
A systematic review was conducted in an attempt to answer the question “Which are the most important psychological factors (emotional, behavioral and cognitive) associated with NASH/NAFLD?”.
Five electronic databases were searched, limi-ted to studies published in the English language, during the period 2005-2015: PubMed, Thomson ISI - Web of Science, Scopus, ProQuest, and ScienceDirect.
The search terms used were nonalcoholic ste-atohepatitis along with each of the following: (1) “psychological risk factors”, (2) “psycholo-gical factors”, (3) “psychological predictors”, (4) “behavioral factors”, (5) “emotional factors”, (6), “affective factors”, (7) “cognitive factors”, (8) “resilience factors”, (9) “anxiety”, (10) “de-pression”.
Studies published in a peer-reviewed journal from January 2005 to December 2015, whi-ch evaluated risk and resilience psychological factors associated with NAFLD/NASH were included in this review. These conditions were selected because of the shared common elemen-ts regarding their biological and psychological mechanisms.
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Inclusion CriteriaAt least one psychological factor associated with
NASH/NAFLD was included in each study co-gnitive, emotional/affective or behavioral. Studies were specifically designed to investigate the asso-ciation of risk and protective factors with NAFLD/NASH manifestations. Studies were clinical trials, single-case experiments, cohort trials, or surveys.
Exclusion CriteriaNon-English language studies were excluded.
Also, studies conducted on animals, and children or adolescents (age <18) were excluded. Studies focusing on treatment or different forms of inter-vention to change factors contributing to the on-set or exacerbation of NAFLD/NASH symptoms
were not included. Also, studies focusing prima-rily on factors other than the psychological ones targeted (e.g., obesity, hypertension, age, low bir-th weight, coronary artery disease, metabolic risk factors, pain, impaired glucose tolerance, type 2 diabetes, cirrhosis) were excluded.
Results
A total of 4583 abstracts were initially identified by using the ten established search combinations in the five databases. Of these abstracts, 107 met the search criteria and were later analyzed about exclusion criteria. In Figure 1, we detail the process by which 29 final articles were selected for analysis.
Figure 1. Articles included and excluded in the final analysis.
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Emotional/Affective FactorsDepression and anxiety were the two emotio-
nal factors mostly investigated in relationship to NAFLD/NASH.
Depression is currently one of the leading causes of death and disability in the general adult population, and expected to become the second leading cause of disability in all age groups by 202020. In a foreword by Deborah Wan, president of World Federation of Mental Health issued for the 20th Anniversary of World Mental Health Day in October 2012 it is specified that unipolar depressive disorders were the third leading cause of the global burden of disease in 2004 and will move into the first place by 203021. It is also the most common mental disorder in patients with chronic conditions22. It is yet unclear if chronic conditions lead to depression, or major depres-sion constitutes a risk factor for chronic illnesses. The relationship could be both ways. However, in an attempt to clarify this issue, Pattern et al23 proved that a set of different conditions characte-rized particularly by pain, inflammation and/or autonomic reactivity (e.g., arthritis, peptic ulcer, migraines) has a higher incidence in people with major depression.
There were several studies discussing the role of depression and anxiety in relationship to NAFLD/NASH, in which clear associations between emotional symptoms and liver disease symptoms could be identified.
Stewart et al24 explored possible associations between anxiety, depression, personality factors, readiness for behavior change and weight outco-mes in 58 overweight or obese participants with NAFLD. Anxiety and depression, as well as cognitive complaints, were considered psycho-logical symptoms and were assessed using the Brief Symptom Inventory. Although mean scores for anxiety, depression and cognitive dysfunction were in the average range, these symptoms were significantly more frequent than in the general population. Also, depression, low conscientiou-sness, and high neuroticism were associated with higher weight at 6-month follow-up.
The study of Youssef et al25 explored the association of depression and anxiety with the severity of histological features of NAFLD in 567 patients. Results indicate that depression is signi-ficantly associated with more severe hepatocyte ballooning in a dose-dependent manner. Patients with subclinical depression had 2.1 times higher likelihood of having more severe hepatocyte bal-looning grade than patients without depressive
symptoms. Also, patients with clinical depres-sion had 3.6 times higher likelihood of having more severe hepatocyte ballooning grade when compared to the non-depressed individuals. In conclusion, there seems to be a dose-dependent association between severity of depressive symp-toms and severity of hepatocyte ballooning. The-se associations were not supported for anxiety symptoms.
Some studies26 suggest emotional problems like anxiety and depression could influence the progression of chronic liver diseases, among whi-ch NAFLD/NASH. Elwing et al26 compared pa-tients diagnosed with nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD, to ma-tched controls without a liver disease in regards to emotional disorders. Major depressive disorder and generalized anxiety disorder diagnoses were established based on the DSM-IV criteria; they preceded the diagnosis of liver disease. The au-thors concluded that major depressive disorder, as well as generalized anxiety disorder, appeared more frequently in patients with NASH and were associated with more advanced liver histological abnormalities.
Also, patients with chronic hepatitis C and NAFLD seem to have a higher prevalence of depression than patients with hepatitis B and the general population27. In this study, depression was self-reported and confirmed by the history of prescription medication. The main factors independently associated with depression in NAFLD were hypertension, smoking, history of lung disease, being female and non-Afri-can-American27.
Depression seems to be associated not just wi-th NAFLD, but also with other liver diseases. The prevalence of depression in hepatitis C patients is known to be high, ranging from 20% to 60%27. In a recent investigation of the relationship betwe-en liver diseases, major depression and suicide attempts, Le Strat et al29 found that participants with a liver disease were 2.2 times more likely to have major depression, after adjustment for a number of socio-demographical, medical and behavioral factors (e.g., age, sex, race, marital status, educational level, past history of cardio-vascular disorder or heart attack, hypertension, arthritis, average volume of alcohol consumed daily and smoking status). Liver diseases were associated with both major depression and suicide attempts among adults in the community29.
Other studies could not find a clear asso-ciation between NAFLD/NASH in particular
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and major depression, although there is a pro-ven pattern of relations between liver diseases and depression. Upon examination of four chronic liver diseases (i.e., chronic hepatitis C, chronic hepatitis B, alcohol-related liver disease, and nonalcoholic fatty liver disease), the authors of a 2013 study30 concluded that chronic hepatitis C alone had a strong asso-ciation with depression.
Another investigation by Surdea-Blaga and Dumitrascu31 provided results indicating there are no differences when comparing the scores of depression, anxiety, or distress in women with NASH and women with viral hepatitis. In this research depression, anxiety and distress scores were not statistically different in patients with NAFLD and normal LST as compared with pa-tients with NASH and elevated LST.
In conclusion, at the moment there are a rela-tively small number of studies investigating the relationship between NAFLD and depression. Results are conflicting and some confounders like obesity and diabetes mellitus may be worth investigating. Also, designing further studies wi-th relevant control groups and more valid forms of measurement for emotional problems might be of help in clarifying the issue.
Concerning the relationship between anxiety and NAFLD, the data collected in several investi-gations indicate it is similar to that found in the case of depression. In the 2013 study by Youssef et al25, subclinical and clinical anxiety was no-ted in 45% and 25% of patients with NAFLD, respectively. Another paper26 reported that ge-neralized anxiety disorder is overrepresented in NASH subjects and is associated with more ad-vanced liver histological abnormalities. The 2011 investigation by Surdea-Blaga and Dumitrascu31 found no differences in anxiety among patients with NAFLD and normal LST and patients with NAFLD and elevated LST as well as patients with viral hepatitis.
Other more specific emotions, like fear of falling, also play a part in the evolution of NAFLD32. Fear of falling highly influences the involvement in physical activity, which is cen-tral to NAFLD management32. Self-efficacy, expressed as confidence to perform, seems to be involved as a possible mechanism underlying the fear of falling.
Although the relationship between liver di-seases and anger received less attention, a stu-dy conducted by the Duke University Medical Center researchers deserves consideration33. The
team found that healthy people prone to anger, hostility and mild to moderate depressive symp-toms produce higher levels of C-reactive protein (CRP), known to promote cardiovascular disease and stroke. CRP is a substance involved in plaque development and plaque’s clogging up of arte-ries, and is produced by the liver in response to inflammation. Moreover, another team of Israeli researchers34 found that elevation of liver enzy-mes correlate with higher CRP concentrations that could be indicative of a worsening of liver disease. Starting from these conclusions, further researches should attempt to investigate the pos-sible role of anger, hostility, and depression as possible contributors to liver inflammation.
In summary, the relationship between NAFLD/NASH and emotional problems like depression and anxiety, in particular, is receiving more and more attention, as some correlation between these conditions begins to emerge. However, results are mixed and further studies might benefit from de-signs specifically elaborated to clarify causality.
Cognitive FactorsSome cognitive factors relevant to patients’
ability to engage in necessary lifestyle changes were also investigated in relationship to NAFLD/NASH.
Frith et al32 assessed two of the cognitive fac-tors relevant to the uptake of physical exercise in patients with NAFLD: confidence to exercise and perceived benefits of exercise. They concluded that confidence to exercise (i.e., the belief one can engage in and complete physical exercises) was significantly lower in NAFLD patients when compared to the primary biliary cirrhosis (PBC) patients and comparable to that of alcoholic li-ver disease (ALD) patients. However, patients in all three groups had similar levels of exercise expectations, thus understanding the benefits of working out. Consequently, although the NAFLD patients understand the importance to exercise, they seem to lack the confidence to engage in physical activity.
In individuals with NAFLD, ratings of percei-ved exertion (RPE) were related to the level of physical activity in adulthood35. Ratings of per-ceived exertion refer to perception of effort and are defined by sensations of effort, constraints, discomfort and fatigue one feels when engaging in physical activity. The way people assess their feelings of physical stress, effort and fatigue while doing exercises influences further involve-ment in such activities and regulation of effort.
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Therefore, in patients with NAFLD, the way they perceive exertion depends on the glucose level, as well as self-reported physical activity. As such, because RPE can stimulate or deter a person to engage in exercises, it could be used to prescribe appropriate physical activities for patients with NAFLD.
Stewart et al24 brought further evidence suggesting that overweight/obese NAFLD pa-tients have a readiness to change consistent mostly with the pre-contemplation and con-templation stages of the Stages of Change Model36. Only about 10% of their 58 patients sample were either preparing to or were acti-vely making lifestyle changes, an important requirement for the management of NAFLD. These conclusions were further supported by the results of a 2013 study by Centis et al37. In a sample of 138 NAFLD patients, the authors found that in case of physical activity about 50% of subjects could be classified in either pre-contemplation or contemplation stages. In case of diet, no subjects were classified in the pre-contemplation phase, 36% were in the contemplation phase, while 64% were distri-buted in determination to change, actions for changing and changed maintenance phases. Such findings suggest that, for reasons that could involve various thoughts and cognitions (i.e., information scarcity, personal beliefs, low self-efficacy beliefs, etc.) NAFLD patien-ts have little motivation for changing their diet or engaging in physical activity.
Some studies found cognitive dysfunction (e.g., memory impairment, attention deficit, etc.) to be significantly more frequent in the overwei-ght/obese NAFLD population than in the general population24. However, in a study by Felipo et al38 only a small number of patients with NASH, a more advanced form of NAFLD, could be clas-sified as having mild cognitive impairment asso-ciated with hyperammonemia and inflammation. None of the patients with NAFLD showed any cognitive impairment. Further data are needed to clarify whether NAFLD patients are at risk for cognitive dysfunction.
In summary, for NAFLD patients, the most relevant areas of investigation for cognitive fun-ctioning concern those contents and processes related to the ability to initiate and maintain lifestyle changes. The cognitive mechanisms underlying dietary behaviors and engagement in physical activity are some of the most important targets for further investigation.
Behavioral Factors
Physical ActivityThe level of physical activity seems to be af-
fected in patients with NAFLD. Elliott et al39 as-sessed the extent of impairment in daily activity patients diagnosed with NAFLD and ALD have when compared with healthy controls. Results in-dicate all liver disease patients experience signi-ficant difficulties in their daily activities, across eight domains of physical functioning: dressing, arising, eating, walking, hygiene, reach, grip, and activity. In case of NAFLD patients, age, fatigue, autonomic dysfunction, and cognitive difficulty are associated with worsening functional difficul-ty. The impairment appears to persist in time, and was observed over a 3 year period in this study.
Koehler et al40 found that total physical acti-vity was associated with NAFLD in an elderly population. Also, Oni et al41 indicated that people with higher levels of physical activity had lower odds of having NAFLD. The association was maintained independentely of obesity and the metabolic syndrome.
Although the overall level of physical activity seems to be important in NAFLD, Kistler et al42 brought evidence supporting that it is the inten-sity of physical exercise that is associated with the severity of NAFLD. The authors suggest that intensity of exercise may be more important than duration or total volume. Results presented in this particular study indicate that neither moderate intensity exercise, nor total exercise per week was associated with NASH or stage of fibroses. It ap-pears that vigorous physical exercise is beneficial to NAFLD to a much higher extent than physical activity in general.
Conversely, reduced physical activity seems to impact NAFLD in a negative manner. Hua et al43 found that elderly day nappers had a significantly higher prevalence of NAFLD. Longer habitual day napping was associated in a dose-dependent manner with NAFLD.
In summary, intense physical exercise may act as a protective factor against the debut and aggravation of NAFLD symptoms.
Food Intake/DietImproper food intake, low on nutrients and
high in saturated fat and carbohydrates seems to be a significant risk factor for NAFLD/NASH. Some investigations have attempted to assess the impact of different foods and nutrients on liver functioning.
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Yu et al44 explored the role of dietary choline – found in eggs, soy foods, red meat, fish and ve-getables – in relation to NAFLD. Lack of choline is known to stimulate liver fat accumulation. Conversely, higher dietary choline intake seems to be associated with lower risk of NAFLD in normal-weight Chinese women.
Zelber-Sagi et al45 concluded that the inta-ke of soft drinks and meat was significantly associated with an increased risk for NAFLD. Also, the NAFLD patients appear to have a tendency to consume lower quantities of fish rich in omega-3. Body mass index (BMI), waist circumference and percent dietary fat intake proved to be independent nutritional risk factors for NAFLD46. Most NAFLD pa-tients presented a significantly high intake of meats, fats, sugars, legumes (beans), and vegetables and a low consumption of cereals, fruits, and dairy products compared with the recommendations47. Low nutrient food intake seems to be relatively common in NAFLD patients.
Kim et al48, indicated that NAFLD patien-ts consumed more low-nutrient food, and more high-sodium food than HBV (hepatitis B virus) patients. Also, NAFLD patients ingested fewer calories from fruits than chronic viral hepatitis patients.
In women, vitamin K and vegetable intakes were shown to have a beneficial effect on lowe-ring the NAFLD risk. In men, low intakes of vi-tamin C, Vitamin K, folate, omega-3 fatty acids, nuts and seeds were associated with a high risk for developing NAFLD49.
Musso et al50 showed that subjects with NAFLD had lower vitamins A and E intakes than control subjects. Nitrotyrosine and adipo-nectin concentrations and vitamin A intake in-dependently predicted alanine aminotransferase concentrations in NAFLD patients and liver hi-stology in a subgroup of biopsy-proven NASH subjects.
According to Kang et al51, in NAFLD patients, the metabolic syndrome is associated with more carbohydrate and less fat intake and greater hi-stological severity.
In summary, in the development of NAFLD and the severity of symptoms, poor nutrition seems to play a central role and needs further investigation.
Substance Consumption: Coffee, Alcohol, Smoking
Some pretty usual lifestyle habits seem to develop as protective factors against the onset of NAFLD. As such, greater consumption of coffee has been associated with a significantly reduced prevalence of cirrhosis in patients with chronic liver disease. Walton et al52 indicated that patients with cirrhosis drank significantly less coffee than those without cirrhosis. Moreover, some studies identified an increased activity of the autophagy-lysosomal pathways in mice fed caffeine, inferring a biochemical explanation for the protective role of caffeine1.
In regards to coffee consumption, it is yet unclear if the beneficial effect is due to coffee in itself or just the caffeine component.
Alcohol represents another frequently used substance that has been investigated in relation to NAFLD. Kwon et al53 concluded that patients who used alcohol moderately had a decrease in the histological severity of NAFLD. Other studies have shown that moderate wine drinking (i.e., one glass of wine per day) was correlated with a decreased prevalence of suspected NAFLD54. When comparing nondrinkers and moderate drinkers with NAFLD, data show lower rates of steatohepatitis in the moderate drinkers55.
In summary, moderate alcohol consumption (especially wine) may have favorable effects on patients with NAFLD or at risk for NAFLD.
Contrary to the effect of coffee consumption and moderate alcohol drinking, smoking seems to have a detrimental effect on the evolution of NAFLD. Not only does active smoking contri-bute to the exacerbation of symptoms, but also passive smoking appears to negatively influence liver functioning. Liu et al56 showed that passive smoking during childhood and adulthood was associated with a 25% increase in the risk for NAFLD. The combination of active smoking and body mass index (BMI) was also associated with a high risk for NAFLD. In a 2012 study, Koehler et al40 proved that pack years of smoking, as well as other variables, were associated with NAFLD. Smoking also influences the severity of NAFLD. A study by Zein et al57 indicated smoking history to be associated with advanced liver fibrosis in NAFLD patients.
In summary, cigarette smoking may aggravate fatty liver.
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ical
dep
ress
ion
was
a
ssoc
iatio
n of
dep
ress
ion
not
ed in
53%
, clin
ical
a
nd a
nxie
ty w
ith se
verit
y
d
epre
ssio
n w
as n
oted
o
f his
tolo
gica
l fea
ture
s
i
n 14
%, s
ubcl
inic
al an
xiet
y o
f NA
FLD
.
w
as n
oted
in 4
5% a
nd
c
linic
al an
xiet
y w
as n
oted
in
25%
of s
ubje
cts.
S2
1.
Wei
nste
in A
A,
878
patie
nts w
ith c
hron
ic
Com
paris
ons w
ere
Emot
iona
l: de
pres
sion
Pa
tient
s with
NA
FLD
and
hep
atiti
s C h
ave
a hi
gher
pre
vale
nce
e
t al (
2011
) l
iver
dis
ease
. 207
of a
ll
con
duct
ed u
sing
the
of d
epre
ssio
n th
an h
epat
itis B
pat
ient
s and
the g
ener
al p
opul
atio
n.
p
atie
nts (
23.6
%) w
ere
M
ann-
Whi
tney
test
and
For N
AFL
D, i
ndep
ende
nt p
redi
ctor
s of d
epre
ssio
n w
ere
the
dia
gose
d w
ith d
epre
ssio
n
Kru
skal
-Wal
lis te
st.
p
rese
nce o
f hyp
erte
nsio
n, sm
okin
g, h
istor
y of
lung
dise
ase,
(N
AFL
D 2
7.2%
, hep
atiti
s C
Reg
ress
ion
mod
els w
ere
b
eing
fem
ale
and
non
–Afr
ican
- Am
eric
an.
2
9.8%
, hep
atiti
s B 3
.7%
). u
sed
to id
entif
y
ind
epen
dent
pre
dict
ors
o
f dep
ress
ion.
Table
I.
Stud
ies s
elec
ted
to b
e re
view
ed.
Con
tinue
d
Psychological factors associated with NAFLD/NASH: a systematic review
5089
Stu
dy
Au
thors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
S2
2.
Surd
ea-
63 p
atie
nts w
ith N
AFL
D,
Gro
ups c
ompa
red
usin
g Em
otio
nal:
depr
essi
on,
No
diff
eren
ces i
n an
xiet
y, d
epre
ssio
n or
dis
tress
scor
es c
ould
be
B
laga
T a
nd
38
of th
em fe
mal
e.
AN
OVA
, Man
n-W
hitn
ey
anx
iety
f
ound
bet
wee
n fe
mal
es w
ith N
AFL
D a
nd fe
mal
es w
ith v
iral
D
umitr
ascu
D
The
dia
gnos
is o
f liv
er
(ba
sed
on d
ata
h
epat
itis.
(
2011
) s
teat
osis
was
est
ablis
hed
dis
trib
utio
n).
N
o re
latio
n co
uld
be su
ppor
ted
betw
een
NA
FLD
and
dep
ress
ion
bas
ed o
n ab
dom
inal
C
orre
latio
ns u
sing
Pea
rson
o
r anx
iety
.
u
ltras
ound
and
the
aspe
ct
and
Spe
arm
an c
oeffi
cien
ts.
of l
iver
par
ench
yma.
S24.
Fr
ith J,
23
0 no
n-al
coho
lic fa
tty
Coh
ort s
tudy
. Thr
ee
Cog
nitiv
e: c
onfid
ence
U
nder
stan
ding
the
bene
fits o
f phy
sica
l act
ivity
was
sim
ilar i
n al
l
et a
l (20
10)
liv
er d
isea
se –
NA
FLD
, d
iffer
ent g
roup
s (N
AFL
D,
to
exer
cise
, t
hree
gro
ups.
Con
fiden
ce to
exe
rcis
e w
as si
gnifi
cant
ly lo
wer
in
1
10 a
lcoh
olic
live
r dis
ease
A
LD, P
BC
) wer
e
und
erst
andi
ng th
e t
he N
AFL
D g
roup
. Fea
r of f
allin
g w
as si
mila
r in
the
NA
FLD
– A
LD a
nd 9
7 pr
imar
y
com
pare
d in
rega
rds t
o b
enefi
ts o
f exe
rcis
e a
nd P
BC
gro
ups,
and
high
er in
the
ALD
gro
up.
bili
ary
cirr
hosi
s – P
BC
f
acto
rs p
erta
inin
g to
Em
otio
nal:
fear
A
lthou
gh th
ey u
nder
stan
d th
e be
nefit
s of p
erfo
rmin
g ph
ysic
al
sub
ject
s wer
e in
clud
ed.
eng
agem
ent i
n ph
ysic
al
of f
allin
g a
ctiv
ities
, pat
ient
s with
NA
FLD
lack
the
confi
denc
e ne
cess
ary
e
xerc
ise
(lack
of
a
nd a
re a
frai
d of
falli
ng.
c
onfid
ence
, poo
r
In N
AFL
D, f
ear o
f fal
ling
was
inde
pend
ently
ass
ocia
ted
with
und
erst
andi
ng o
f the
inc
reas
ing
diffi
culty
eng
agin
g in
phy
sica
l act
ivity
.
ben
efits
of e
xerc
isin
g,
B
oth
fear
of f
allin
g an
d co
nfide
nce
are
mod
ifiab
le th
roug
h
fea
r of f
allin
g).
p
sych
olog
ical
inte
rven
tion.
S28
. El
win
g JE
, 36
non
alco
holic
stea
to-
A m
ultiv
aria
te m
odel
Em
otio
nal:
anxi
ety
Maj
or d
epre
ssiv
e di
sord
er a
nd g
ener
aliz
ed a
nxie
ty d
isor
der a
re
et a
l (20
06)
hep
atiti
s (N
ASH
) pat
ient
s i
ncor
pora
ting
a nu
mbe
r a
nd d
epre
ssio
n m
ore
freq
uent
in N
ASH
subj
ects
and
are
ass
ocia
ted
with
mor
e
a
nd 3
6 m
atch
ed c
ontro
ls
of p
oten
tial r
isk
fact
ors
a
dvan
ced
liver
his
tolo
gica
l abn
orm
aliti
es.
wer
e us
ed.
for
NA
SH w
as u
sed
to
a
sses
s ind
epen
dent
eff
ects
of m
ajor
dep
ress
ive
d
isor
der a
nd g
ener
aliz
ed
a
nxie
ty d
isor
der o
n
sev
erity
of h
isto
logi
cal
fi
ndin
gs.
C
ogni
tive
fact
ors
S
2.
Wei
nste
in A
A,
Con
veni
ence
sam
ple
of 5
1 O
bser
vatio
nal a
naly
tical
C
ogni
tive:
per
cept
ion
In in
divi
dual
s with
NA
FLD
, rat
ings
of p
erce
ived
exe
rtio
n (R
PE)
e
t al (
2016
) s
ubje
cts d
iagn
osed
with
s
tudy
. Spe
arm
an ra
nk su
m
of e
ffor
t dur
ing
w
ere
rela
ted
to a
met
abol
ic fa
ctor
(fas
ting
gluc
ose
leve
l), a
nd a
N
AFL
D o
r Chr
onic
c
orre
latio
ns w
ere
p
hysi
cal a
ctiv
ity
life
styl
e fa
ctor
(lev
el o
f phy
sica
l act
ivity
in a
dulth
ood)
. Rat
ings
h
epat
itis C
, age
51.
1 ±
8.8
p
erfo
rmed
. Gro
ups w
ere
o
f per
ceiv
ed e
xert
ion
refe
r to
perc
eptio
n of
eff
ort,
whi
ch is
a
yea
rs, 3
5% fe
mal
e.
com
pare
d us
ing
anal
ysis
pow
erfu
l reg
ulat
or o
f eff
ort.
o
f var
ianc
e.
Table
I (
Con
t.).
Stu
dies
sele
cted
to b
e re
view
ed.
Con
tinue
d
B. Macavei, A. Baban, D.L. Dumitrascu
5090
Stu
dy
Au
thors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
S3
. St
ewar
t KE,
58
ove
rwei
ght/o
bese
A
ssoc
iatio
ns b
etw
een
Cog
nitiv
e: re
adin
ess
Dep
ress
ion,
low
con
scie
ntio
usne
ss, a
nd h
igh
neur
otic
ism
wer
e
et a
l (20
15)
par
ticip
ants
with
NA
FLD
. d
epre
ssio
n, a
nxie
ty,
for
beh
avio
ur c
hang
e,
ass
ocia
ted
with
hig
her w
eigh
t at 6
-mon
th fo
llow
-up.
Of a
ll th
e
per
sona
lity
fact
ors
cog
nitiv
e dy
sfun
ctio
n p
atie
nts,
only
10.
4% w
ere
activ
ely
wor
king
on
or p
repa
ring
to
(ex
., low
cons
cient
ious
ness
, Em
otio
nal:
depr
essi
on,
cha
nge,
alth
ough
all
rece
ived
nut
ritio
nal e
duca
tion
and
n
euro
ticis
m),
read
ines
s a
nxie
ty
gui
danc
e. R
eadi
ness
for c
hang
e w
as n
ot fo
und
to p
redi
ct
f
or b
ehav
ior c
hang
e an
d
s
ubse
quen
t cha
nge
in w
eigh
t.
wei
ght o
utco
mes
in
Co
gniti
ve d
ysfu
nctio
n sy
mpt
oms (
e.g., m
emor
y pr
oble
ms,
atte
ntio
n
NA
FLD
pat
ient
s wer
e
pro
blem
s) w
ere
signi
fican
tly m
ore
freq
uent
in th
e N
AFL
D
e
xplo
red.
sam
ple
than
in th
e ge
nera
l pop
ulat
ion.
C
ompa
red
to th
e ge
nera
l pop
ulat
ion,
dep
ress
ion
and
cogn
itive
dys
func
tion
in p
artic
ular
wer
e sig
nific
antly
mor
e fr
eque
nt in
the
NA
FLD
sam
ple.
S1
3.
Cen
tis E
, 13
8 N
AFL
D p
atie
nts
Logi
stic
regr
essi
on
Cog
nitiv
e: st
age
of
Phys
ical
act
ivity
– 5
0% w
ere c
lass
ified
in e
ither
pre
-con
tem
plat
ion
e
t al (
2013
) (
73%
mal
e, a
ge 1
9-73
). a
naly
sis
cha
nge,
mot
ivat
ion
or c
onte
mpl
atio
n st
ages
.
D
iagn
osis
con
firm
ed b
y
Die
t – 0
% w
ere
clas
sifie
d in
the
pre-
cont
empl
atio
n ph
ase,
36%
liv
er b
iops
y in
64
case
s
w
ere
in th
e co
ntem
plat
ion
phas
e. 6
4% w
ere
dist
ribut
ed in
(
stea
tohe
patit
is 4
7%)
det
erm
inat
ion,
act
ion
and
mai
nten
ance
pha
ses.
NA
FLD
p
atie
nts h
ave
little
read
ines
s to
lifes
tyle
cha
nges
and
mot
ivat
ion
w
ith re
gard
to d
iet a
nd p
artic
ular
ly p
hysi
cal a
ctiv
ity.
S1
5.
Felip
o V,
29
pat
ient
s with
sim
ple
Gro
ups c
ompa
red
usin
g C
ogni
tive:
cog
nitiv
e Fi
ve o
ut o
f 11
NA
SH p
atie
nts,
with
out l
iver
cir
rhos
is, w
ere
e
t al (
2012
) s
teat
osis
(NA
FLD
) A
NO
VA. C
orre
latio
n d
efici
ts/im
pair
men
t
cla
ssifi
ed a
s hav
ing
mild
cog
nitiv
e im
pair
men
t ass
ocia
ted
with
and
11
with
stea
tohe
patit
is
anal
ysis
was
per
form
ed.
h
yper
amm
onem
ia a
nd in
flam
mat
ion.
(N
ASH
). A
ll N
ASH
N
one
of th
e pa
tient
s with
NA
FLD
show
ed c
ogni
tive
impa
irm
ent.
pat
ient
s pre
sent
ed
hep
atic
fibr
osis
.
S
24.
Frith
J,
230
non-
alco
holic
fatty
C
ohor
t stu
dy. T
hree
C
ogni
tive:
con
fiden
ce
Und
erst
andi
ng th
e be
nefit
s of p
hysi
cal a
ctiv
ity w
as si
mila
r in
e
t al (
2010
) l
iver
dis
ease
– N
AFL
D,
diff
eren
t gro
ups (
NA
FLD
, t
o ex
erci
se,
all
thre
e gr
oups
. Con
fiden
ce to
exe
rcis
e w
as si
gnifi
cant
ly lo
wer
110
alc
ohol
ic li
ver d
isea
se
ALD
, PB
C) w
ere
u
nder
stan
ding
i
n th
e N
AFL
D g
roup
. Fea
r of f
allin
g w
as si
mila
r in
the
NA
FLD
– A
LD a
nd 9
7 pr
imar
y
com
pare
d in
rega
rds t
o
the
ben
efits
a
nd P
BC
gro
ups,
and
high
er in
the
ALD
gro
up.
bili
ary
cirr
hosi
s PB
C
fac
tors
per
tain
ing
to
of e
xerc
ise
Alth
ough
they
und
erst
and
the
bene
fits o
f per
form
ing
phys
ical
sub
ject
s wer
e in
clud
ed.
eng
agem
ent i
n ph
ysic
al
Emot
iona
l: a
ctiv
ities
, pat
ient
s with
NA
FLD
lack
the
confi
denc
e ne
cess
ary
e
xerc
ise
(lack
of
fea
r of f
allin
g a
nd a
re a
frai
d of
falli
ng.
c
onfid
ence
, poo
r
In N
AFL
D, f
ear o
f fal
ling
was
inde
pend
ently
ass
ocia
ted
with
u
nder
stan
ding
of t
he
i
ncre
asin
g di
fficu
lty e
ngag
ing
in p
hysi
cal a
ctiv
ity.
b
enefi
ts o
f exe
rcis
ing,
Bot
h fe
ar o
f fal
ling
and
confi
denc
e ar
e m
odifi
able
thro
ugh
f
ear o
f fal
ling)
.
psy
chol
ogic
al in
terv
entio
n.
Table
I (
Con
t.).
Stu
dies
sele
cted
to b
e re
view
ed.
Con
tinue
d
Psychological factors associated with NAFLD/NASH: a systematic review
5091
Stu
dy
Au
thors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
Beh
avio
ral f
acto
rs –
Phy
sica
l act
ivity
S1
. O
ni E
T,
5,74
3 he
alth
y B
razi
lian
Mul
tivar
iate
logi
stic
B
ehav
iora
l: ph
ysic
al
NA
FLD
pre
vale
nce
was
low
er a
t hig
her l
evel
s of r
epor
ted
e
t al (
2015
) s
ubje
cts,
43 ±
10
year
s old
, re
gres
sion
was
use
d a
ctiv
ity
phy
sica
l act
ivity
. Sub
ject
s with
hig
h ph
ysic
al a
ctiv
ity h
ad lo
wer
79%
men
. NA
FLD
was
t
o ev
alua
te a
ssoc
iatio
n
o
dds o
f hav
ing
NA
FLD
. The
ass
ocia
tion
was
mai
ntai
ned
diag
nose
d usin
g ultr
asou
nds.
bet
wee
n N
AFL
D, p
hysic
al
i
ndep
ende
nt o
f obe
sity
and
met
abol
ic sy
ndro
me.
I
n the
tota
l stu
dy p
opul
ation
, a
ctiv
ity a
nd o
ther
risk
NA
FLD
pre
vale
nce
was
f
acto
rs (o
besit
y, m
etab
olic
3
6% (2
,075
subj
ects)
. s
yndr
ome)
.
S7
. H
ua Q
, O
f 6,9
98 p
artic
ipan
ts,
Cro
ss-s
ectio
nal s
tudi
es o
f B
ehav
iora
l: ha
bitu
al
Day
-nap
pers
wer
e fou
nd to
hav
e a si
gnifi
cant
ly h
ighe
r pre
vale
nce
e
t al (
2014
) a
ged
40-7
5 ye
ars,
6,43
8
the
com
mun
ity p
opul
atio
n
day
nap
ping
o
f NA
FLD
. Lon
ger d
ay n
appi
ng w
as a
ssoc
iate
d in
a d
ose-
elig
ible
par
ticip
ants
wer
e
in C
hina
.
dep
ende
nt m
anne
r with
NA
FLD
.
i
nclu
ded.
A
ssoc
iatio
n be
twee
n th
e
It
appe
ars t
hat i
nflam
mat
ory
cyto
kine
s may
be
a lin
k be
twee
n
dur
atio
n of
hab
itual
day
day
nap
ping
and
NA
FLD
.
nap
ping
and
NA
FLD
in
a
n el
derly
pop
ulat
ion.
Lo
gist
ic re
gres
sion
mod
els
wer
e us
ed.
S1
2.
Ellio
tt C
, 22
4 no
n-al
coho
lic fa
tty
Gro
ups w
ere
com
pare
d B
ehav
iora
l: fu
nctio
nal
Peop
le d
iagn
osed
with
NA
FLD
and
ALD
exp
erie
nce
signi
fican
t
et a
l (20
13)
liv
er d
isea
se (N
AFL
D),
u
sing
anal
ysis
of v
aria
nce,
im
pair
men
t d
iffic
ultie
s in
thei
r dai
ly a
ctiv
ities
whe
n co
mpa
red
with
nor
mal
107
alc
ohol
ic li
ver
and
the
Kru
skal
-Wal
lis
c
ontro
ls. F
unct
iona
l im
pair
men
t app
ears
to p
ersi
st o
ver t
ime
dis
ease
(ALD
) and
100
t
est.
Mul
tiple
line
ar
(
eval
uate
d ov
er a
3 y
ear p
erio
d).
con
trols
wer
e in
clud
ed.
reg
ress
ion
was
als
o
45%
(101
) of t
he N
AFL
D
per
form
ed to
det
erm
ine
pat
ient
s wer
e w
omen
t
he a
ssoc
iatio
n be
twee
n
(
age
59 ±
13)
. f
unct
iona
l im
pair
men
t
a
nd d
isea
se se
verit
y.
S1
7.
Koe
hler
EM
, 2,
811
part
icip
ants
, mea
n
Logi
stic
regr
essi
on
Beh
avio
ral:
smok
ing
Tota
l phy
sica
l act
ivity
, pac
k ye
ars o
f sm
okin
g, a
ge, a
s wel
l as
e
t al (
2012
) a
ge 7
6.4
± 6.
0 ye
ars.
ana
lysi
s was
use
d to
h
abits
, phy
sica
l o
ther
var
iabl
es w
ere
asso
ciat
ed w
ith N
AFL
D.
Pre
vale
nce
of N
AFL
D
ass
ess a
ssoc
iatio
ns
act
ivity
Th
e pr
eval
ence
of N
AFL
D d
ecre
ases
with
adv
anci
ng a
ge in
the
was
35.
1%.
bet
wee
n co
-var
iabl
es
e
lder
ly.
a
nd se
verit
y of
NA
FLD
.
S19.
K
istle
r KD
, 81
3 ad
ults
, 302
mal
es a
nd
Ret
rosp
ectiv
e an
alys
is o
n B
ehav
iora
l: ph
ysic
al
Nei
ther
mod
erat
e in
tens
ity e
xerc
ise,
nor
tota
l exe
rcis
e pe
r wee
k
et a
l (20
11)
511
fem
ales
with
bio
psy-
d
ata
was
con
duct
ed.
act
ivity
was
ass
ocia
ted
with
NA
SH o
r sta
ge o
f fibr
oses
.
p
rove
n N
AFL
D w
ere
G
roup
s wer
e co
mpa
red
D
ata
supp
ort a
n as
soci
atio
n of
vig
orou
s phy
sica
l exe
rcis
e w
ith
i
nclu
ded.
Mea
n ag
e 48
. u
sing
ana
lysi
s of v
aria
nce,
t
he se
verit
y of
NA
FLD
. Res
ults
sugg
est i
nten
sity
of e
xerc
ise
K
rusk
al-W
allis
test
, and
may
be
mor
e im
port
ant t
han
dura
tion
or to
tal v
olum
e.
Man
n-W
hitn
ey te
st.
M
ultin
omia
l log
istic
reg
ress
ion
was
als
o us
ed.
Table
I.
Stud
ies s
elec
ted
to b
e re
view
ed.
Con
tinue
d
B. Macavei, A. Baban, D.L. Dumitrascu
5092
Stu
dy
Au
thors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
S2
9.
Kan
g H
, 91
pat
ient
s with
NA
FLD
, Pa
tient
s with
met
abol
ic
Beh
avio
ral:
alim
enta
ry P
atie
nts w
ith m
etab
olic
synd
rom
e co
nsum
ed m
ore
carb
ohyd
rate
s
et a
l (20
06)
31
patie
nts (
34%
) had
s
yndr
ome
wer
e co
mpa
red
hab
its, f
ood
inta
ke
and
less
fat c
ompa
red
with
thos
e w
ithou
t met
abol
ic sy
ndro
me.
met
abol
ic sy
ndro
me.
w
ith th
ose
with
out
Beh
avio
ral:
phys
ical
To
tal d
aily
cal
orie
s, pr
otei
n co
nsum
ptio
n, a
nd p
hysi
cal a
ctiv
ity
met
abol
ic sy
ndro
me.
a
ctiv
ity
wer
e si
mila
r for
the
two
grou
ps. M
etab
olic
synd
rom
e in
pat
ient
s
The
con
trib
utio
n of
with
NA
FLD
is a
ssoc
iate
d w
ith m
ore
carb
ohyd
rate
and
less
fat
d
iffer
ent f
acto
rs (e
.g.,
int
ake
and
grea
ter h
isto
logi
c se
verit
y.
die
tary
com
posi
tion,
phy
sica
l act
ivity
) to
N
AFL
D se
verit
y w
as
als
o es
timat
ed.
B
ehav
iora
l fac
tors
– F
ood
inta
ke/d
iet
S5
. Y
u D
, 56
,195
Chi
nese
wom
en a
nd T
he a
ssoc
iatio
n be
twee
n B
ehav
iora
l: al
imen
tary
Hig
her d
ieta
ry c
holin
e in
take
cou
ld b
e as
soci
ated
with
low
er ri
sk
et a
l (20
14)
men
, 40-
75 y
ears
of a
ge.
cho
line
inta
ke a
nd
hab
its, f
ood
inta
ke
of N
AFL
D in
nor
mal
-wei
ght C
hine
se w
omen
.
N
AFL
D w
as a
sses
sed
by
NA
FLD
was
exp
lore
d.
s
elf-
repo
rt of
a p
hysi
cian
St
ratifi
ed a
naly
sis
dia
gnos
is.
sug
gest
ed a
pot
entia
l
eff
ect m
odifi
catio
n by
o
besi
ty st
atus
in w
omen
.
S6.
Han
JM
, 34
8 K
orea
n ad
ult s
ubje
cts
The
asso
ciat
ion
betw
een
Beh
avio
ral:
alim
enta
ry I
n w
omen
, vita
min
K a
nd v
eget
able
inta
kes w
ere
show
n to
hav
e
et a
l (20
14)
par
ticip
ated
. NA
FLD
was
se
vera
l ris
k fa
ctor
s h
abits
, foo
d in
take
a
ben
efici
al e
ffec
t on
low
erin
g th
e N
AFL
D ri
sk
dia
gnos
ed b
y ul
tras
ound
. (
indi
vidu
al n
utrie
nts
In
men
, low
inta
kes o
f vita
min
C, V
itam
in K
, fol
ate,
om
ega-
3
or w
hole
food
gro
ups)
fat
ty a
cids
, nut
s and
seed
s wer
e as
soci
ated
with
a h
igh
risk
for
a
nd N
AFL
D w
as
d
evel
opin
g N
AFL
D
e
xplo
red.
S9.
Mar
inho
96
non
-alc
ohol
ic fa
tty
Cos
s-se
ctio
nal s
tudy
; B
ehav
iora
l: al
imen
tary
Mos
t pat
ient
s exc
eede
d th
e re
com
men
datio
ns fo
r ene
rgy
inta
ke
Fer
olla
S,
liv
er d
isea
se p
atie
nts.
gro
ups c
ompa
red
with
h
abits
, foo
d in
take
a
nd sa
tura
ted
fat.
e
t al (
2013
) M
edia
n pa
tient
age
53
t
-test
and
Man
n-W
hitn
ey
Th
e pa
tient
s pre
sent
ed a
sign
ifica
ntly
hig
h in
take
of m
eats
, fat
s,
y
ears
. 77%
of s
ubje
cts
U te
st. C
hi-s
quar
e te
st
s
ugar
s, le
gum
es (b
eans
), an
d ve
geta
bles
and
a lo
w
wer
e w
omen
. 67.7
%
or F
ishe
r’s e
xact
test
wer
e
con
sum
ptio
n ce
real
s, fr
uits
, and
dai
ry p
rodu
cts c
ompa
red
of p
artic
ipan
ts w
ere
obes
e.
used
to c
ompa
re p
ropo
rtio
ns.
with
the
reco
mm
enda
tions
.
A
ll pa
tient
s und
erw
ent
The
poss
ible
role
of n
utrie
nt d
efici
enci
es in
the
deve
lopm
ent o
f
a
bdom
inal
ultr
asou
nd,
N
AFL
D n
eeds
furt
her i
nves
tigat
ion.
bio
chem
ical
test
s,
d
ieta
ry e
valu
atio
ns, f
ood
int
ake,
ant
hrop
omet
ric
e
valu
atio
ns.
Table
I (
Con
t.).
Stu
dies
sele
cted
to b
e re
view
ed.
Con
tinue
d
Psychological factors associated with NAFLD/NASH: a systematic review
5093
Stu
dy
Au
thors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
S1
8.
Sath
iara
j E,
98 su
bjec
ts w
ith st
eato
sis
Mul
tiple
logi
stic r
egre
ssio
n B
ehav
iora
l: al
imen
tary
BM
I, w
aist
circ
umfe
renc
e an
d pe
rcen
t die
tary
fat i
ntak
e pr
oved
e
t al (
2011
) a
nd 1
02 c
ontro
ls w
ere
a
naly
sis w
as p
erfo
rmed
h
abits
, foo
d in
take
t
o be
inde
pend
ent n
utrit
iona
l ris
k fa
ctor
s for
NA
FLD
.
inc
lude
d. P
reva
lenc
e of
t
o pr
edic
t the
die
tary
risk
m
etab
olic
synd
rom
e w
as
fac
tors
in N
AFL
D
4
4.9%
am
ong
NA
FLD
c
ases
and
25.
5% a
mon
g
c
ontro
ls.
S23.
K
im C
H,
233
subj
ects
, age
52.
5 ±
NA
FLD
pat
ient
s wer
e B
ehav
iora
l: al
imen
tary
NA
FLD
and
HC
V p
atie
nts c
onsu
med
mor
e hi
gh-fa
t mea
t tha
n
et a
l (20
10)
10
year
s wer
e in
clud
ed.
com
pare
d w
ith c
hron
ic
hab
its, f
ood
inta
ke
HBV
pat
ient
s.
3
1.8%
wer
e di
agno
sed
v
iral h
epat
itis p
atie
nts
N
AFL
D a
nd H
CV
pat
ient
s con
sum
ed m
ore
low
-nut
rient
food
,
w
ith N
AFL
D, 4
8.1%
wer
e
in re
gard
to fo
od in
take
.
and
mor
e hi
gh-s
odiu
m fo
od th
an H
BV p
atie
nts.
dia
gnos
ed w
ith h
epat
itis C
M
ultiv
aria
te a
naly
sis
A
lso,
NA
FLD
pat
ient
s con
sum
ed le
ss c
alor
ies f
rom
frui
ts th
an
v
irus
(HC
V),
and
20.2
%
and
uni
varia
te a
naly
sis
c
hron
ic v
iral h
epat
itis p
atie
nts.
had
hep
atiti
s B v
irus (
HBV
). w
ere
perf
orm
ed.
S27.
M
usso
G,
64 n
on-o
bese
non
-dia
betic
N
AFL
D a
nd c
ontro
l B
ehav
iora
l: al
imen
tary
Per
sons
with
NA
FLD
had
low
er v
itam
ins A
and
E in
take
s tha
n
et a
l (20
08)
pat
ient
s with
NA
FLD
s
ubje
cts w
ere
com
pare
d
hab
its, v
itam
in in
take
c
ontro
l sub
ject
s.
a
nd 7
4 co
ntro
l sub
ject
s i
n re
gard
s to
food
inta
ke.
N
itrot
yros
ine
and
adip
onec
tin c
once
ntra
tions
and
vita
min
w
ithou
t liv
er d
isea
se.
A in
take
inde
pend
ently
pre
dict
ed a
lani
ne a
min
otra
nsfe
rase
con
cent
ratio
ns in
NA
FLD
pat
ient
s and
live
r his
tolo
gy in
a
s
ubgr
oup
of 2
9 su
bjec
ts w
ith b
iops
y-pr
oven
non
alco
holic
ste
atoh
epat
itis.
S26.
Ze
lber
-Sag
i S,
349
Isra
eli p
artic
ipan
ts,
Surv
ey, c
ross
-sec
tiona
l B
ehav
iora
l: al
imen
tary
Int
ake
of so
ft dr
inks
and
mea
t was
sign
ifica
ntly
ass
ocia
ted
with
e
t al (
2007
) 5
2.7%
mal
e, m
ean
age 5
0.7
stu
dy. A
ssoc
iatio
ns
hab
its, f
ood
inta
ke
an
incr
ease
d ris
k fo
r NA
FLD
.
±
10.
4, 3
0.9%
dia
gnos
ed
bet
wee
n di
etar
y ha
bits
Als
o, th
e N
AFL
D p
atie
nts h
ave
a te
nden
cy to
war
d lo
wer
inta
ke
with
pri
mar
y N
AFL
D.
and
pri
mar
y N
AFL
D
o
f fish
rich
in o
meg
a-3.
wer
e ex
plor
ed.
S29.
K
ang
H,
91 p
atie
nts w
ith N
AFL
D,
Patie
nts w
ith m
etab
olic
B
ehav
iora
l: al
imen
tary
Pat
ient
s with
met
abol
ic sy
ndro
me
cons
umed
mor
e ca
rboh
ydra
tes
e
t al (
2006
) 3
1 pa
tient
s (34
%) h
ad
syn
drom
e w
ere
com
pare
d h
abits
, foo
d in
take
a
nd le
ss fa
t com
pare
d w
ith th
ose
with
out m
etab
olic
synd
rom
e.
m
etab
olic
synd
rom
e.
with
thos
e w
ithou
t B
ehav
iora
l: ph
ysic
al
Tota
l dai
ly c
alor
ies,
prot
ein
cons
umpt
ion,
and
phy
sica
l act
ivity
m
etab
olic
synd
rom
e.
act
ivity
w
ere
sim
ilar f
or th
e tw
o gr
oups
.
The
con
trib
utio
n of
Met
abol
ic sy
ndro
me
in p
atie
nts w
ith N
AFL
D is
ass
ocia
ted
with
d
iffer
ent f
acto
rs (e
.g.,
mor
e ca
rboh
ydra
te a
nd le
ss fa
t int
ake
and
grea
ter h
isto
logi
c
die
tary
com
posi
tion,
sev
erity
.
phy
sica
l act
ivity
) to
N
AFL
D se
verit
y w
as
a
lso
estim
ated
.
Table
I (
Con
t.).
Stu
dies
sele
cted
to b
e re
view
ed.
Con
tinue
d
B. Macavei, A. Baban, D.L. Dumitrascu
5094
Stu
dy
Au
thors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
Beh
avio
ral f
acto
rs –
Sub
stan
ce c
onsu
mpt
ion:
cof
fee,
alc
ohol
, sm
okin
g
S4.
K
won
HK
, 77
pat
ient
s with
NA
FLD
M
ultiv
aria
ble
anal
ysis
B
ehav
iora
l: lif
etim
e M
oder
ate
lifet
ime
alco
hol c
onsu
mpt
ion
seem
s to
have
a
e
t al (
2014
) d
iagn
osed
by
biop
sy.
sho
wed
an
asso
ciat
ion
alc
ohol
con
sum
ptio
n p
rote
ctiv
e ef
fect
on
the
hist
olog
ical
seve
rity
of li
ver d
isea
se
F
ifty-
two
patie
nts h
ad a
b
etw
een
alco
hol
a
mon
g N
AFL
D p
atie
nts.
his
tory
of r
egul
ar a
lcoh
ol
con
sum
ptio
n, a
ge a
nd
con
sum
ptio
n.
dis
ease
seve
rity.
S
8.
Wal
ton
HB
, 28
6 pa
tient
s atte
ndin
g th
e N
orm
al c
ontro
ls w
ere
Beh
avio
ral:
alim
enta
ry P
atie
nts w
ith c
irrh
osis
dra
nk si
gnifi
cant
ly le
ss c
offe
e th
an th
ose
et a
l (20
13)
liv
er o
utpa
tient
dep
artm
ent
com
pare
d w
ith c
hron
ic
hab
its, c
offe
e in
take
w
ithou
t cir
rhos
is.
at t
he R
oyal
Infir
mar
y
liv
er d
isea
se p
atie
nts
Th
ere
wer
en’t
signi
fican
t diff
eren
ces i
n th
e am
ount
of c
offe
e
o
f Edi
nbur
gh p
artic
ipat
ed
(non
-alc
ohol
ic fa
tty li
ver
d
runk
by
liver
pat
ient
s and
the
cont
rol g
roup
s.
i
n th
e st
udy.
The
con
trol
dis
ease
and
alc
ohol
Cof
fee
drin
king
is a
ssoc
iate
d w
ith a
redu
ced
prev
alen
ce o
f
g
roup
was
form
ed o
f 100
r
elat
ed li
ver d
isea
se)
c
irrh
osis
in p
atie
nts w
ith c
hron
ic li
ver d
isea
se.
ort
hope
dic
outp
atie
nts
and
120
med
ical
stud
ents
.
95 p
atie
nts w
ere
diag
nose
d
w
ith c
irrh
osis
.
S
11.
Liu
Y,
8580
subj
ects
, 269
1 m
en,
Com
mun
ity b
ased
surv
ey
Beh
avio
ral:
smok
ing
The
com
bina
tion
of a
ctiv
e sm
okin
g an
d bo
dy m
ass i
ndex
(BM
I)
et a
l (20
13)
age
40
and
olde
r. N
AFL
D
in C
hina
. h
abits
(act
ive
and
w
as a
ssoc
iate
d w
ith th
e hi
ghes
t obs
erve
d od
d ra
tio fo
r NA
FLD
.
p
reva
lenc
e w
as 2
9.4%
pas
sive
smok
ing)
In
nev
er sm
okin
g w
omen
, pas
sive
smok
ing
duri
ng c
hild
hood
and
in
neve
r sm
oker
s, 34
.2%
a
dulth
ood
was
ass
ocia
ted
with
a 2
5% in
crea
se in
the
risk
for
in
form
er sm
oker
s, 27
.8%
N
AFL
D.
in
light
smok
ers,
30.8
%
in
mod
erat
e sm
oker
s,
4
3.5%
in h
eavy
smok
ers.
S16
. D
unn
W,
251
lifet
ime
non-
drin
kers
M
ultip
le o
rdin
al lo
gist
ic
Beh
avio
ral:
alco
hol
Whe
n co
mpa
red
to n
on-d
rink
ers,
mod
est d
rink
ers h
ad lo
wer
e
t al (
2012
) w
ere
com
pare
d to
331
r
egre
ssio
n w
as u
sed
to
con
sum
ptio
n o
dds o
f hav
ing
a di
agno
sis o
f NA
SH, l
ower
odd
s for
fibr
osis
m
odes
t dri
nker
s with
d
eter
min
e as
soci
atio
ns
a
nd b
allo
onin
g he
pato
cellu
lar i
njur
y.
bio
psy-
prov
en N
AFL
D
bet
wee
n al
coho
l
con
sum
ptio
n an
d se
verit
y
o
f NA
FLD
/NA
SH
S17
. K
oehl
er E
M,
2,81
1 pa
rtic
ipan
ts, m
ean
Logi
stic r
egre
ssio
n an
alysis
B
ehav
iora
l: sm
okin
g To
tal p
hysi
cal a
ctiv
ity, p
ack
year
s of s
mok
ing,
age
, as w
ell a
s
et a
l (20
12)
age
76.
4 ±
6.0
year
s. w
as u
sed
to a
sses
s h
abits
, phy
sica
l o
ther
var
iabl
es w
ere
asso
ciat
ed w
ith N
AFL
D.
Pre
vale
nce
of N
AFL
D
ass
ocia
tions
bet
wee
n co
- a
ctiv
ity
The
prev
alen
ce o
f NA
FLD
dec
reas
es w
ith a
dvan
cing
age
in th
e
w
as 3
5.1%
. v
aria
bles
and
seve
rity
eld
erly
.
of N
AFL
D.
Table
I (
Con
t.).
Stu
dies
sele
cted
to b
e re
view
ed.
Con
tinue
d
Psychological factors associated with NAFLD/NASH: a systematic review
5095
Conclusions
Primarily associated with insulin resistance, NAFLD is actually considered the hepatic manifesta-tion of the metabolic syndrome58,59. The pathogenesis of NAFLD and the more severe NASH is yet unclear. So far, it appears multifactorial, with many mechani-sms being proposed as possible causes.
Our study attempted to identify some of the emo-tional, cognitive and behavioral factors associated with the evolution of NAFLD/NASH. The results of our analysis are limited, in part due to the lack of con-ceptual clarity in some of the studies reviewed, the very diverse samples used and the various methods of collecting and analyzing the resulting data.
Some investigations suggest that emotional factors like anxiety and depression could influen-ce the progression of chronic liver diseases, but further research is needed to establish the type and the causes of such a relationship.
For NAFLD patients, the most relevant areas of investigation for cognitive functioning concern those contents and processes related to the ability to initiate and maintain lifestyle changes. The co-gnitive mechanisms underlying dietary behaviors and engagement in physical activity are some of the most important targets for further investigation.
Intense physical exercise may act as a protective factor against the debut and aggravation of NAFLD symptoms. In the evolution of NAFLD, poor nutri-tion seems to play a central role and needs further in-vestigation. Some studies show there is an improve-ment in insulin resistance and hypertransaminasemia following hypocaloric diets in NAFLD patients60.
Contrary to the effect of coffee consumption and moderate alcohol drinking, smoking may have a detrimental effect on NAFLD evolution.
In conclusion, some of the factors identified act as protective factors, other as vulnerability factors. NAFLD/NASH may be considered a cognitive-behavioral disease, the most effective management being lifestyle changes, with em-phasis on diet and exercise.
Conflict of interestThe Authors declare that they have no conflict of interests.
References
1) Hassan K, BHalla V, El REgal ME, a-KadER HH. Non-alcoholic fatty liver disease: a comprehensive re-view of a growing epidemic. World J Gastroenter-ol 2014; 20: 12082-12101. St
ud
y A
uth
ors
, Sa
mple
char
acte
rist
ics
Met
hod
Psy
cholo
gic
al
Res
ult
s
ye
ar
(N
o, ag
e, g
end
er,
fa
ctors
d
iag
nosi
s)
id
enti
fied
S2
0.
Zein
CO
, 10
91 su
bjec
ts w
ere i
nclu
ded
The
anal
ysis
use
d cr
oss-
B
ehav
iora
l: Sm
okin
g hi
stor
y w
as a
ssoc
iate
d w
ith a
dvan
ced
liver
fibr
osis
in
et a
l (20
11)
dia
gnos
ed w
ith N
AFL
D.
sec
tiona
l dat
a. B
ivar
iate
s
mok
ing
habi
ts
NA
FLD
pat
ient
s. In
sum
mar
y, c
igar
ette
smok
e m
ay a
ggra
vate
Of t
he to
tal n
umbe
r,
ana
lysi
s was
per
form
ed
f
atty
live
r.
6
3% (6
87) w
ere
fem
ale.
t
o de
term
ine
asso
ciat
ions
Mea
n ag
e 49
± 1
1.9
bet
wee
n sm
okin
g an
d
the
dis
ease
seve
rity
in
N
AFL
D p
atie
nts.
S2
5.
Dun
n W
, 7,
211
nond
rink
ers a
nd
Surv
ey, c
ross
-sec
tiona
l B
ehav
iora
l: al
coho
l Th
e pr
eval
ence
of N
AFL
D is
sign
ifica
ntly
low
er in
mod
est w
ine
e
t al (
2008
) 9
45 m
odes
t win
e dr
inke
rs
stud
y. A
ssoc
iatio
ns
con
sum
ptio
n d
rink
ers w
hen
com
pare
d to
non
drin
kers
.
w
ere
incl
uded
in th
e st
udy.
be
twee
n al
coho
l
con
sum
ptio
n an
d N
AFL
D
wer
e ex
plor
ed.
Table
I (
Con
t.).
Stu
dies
sele
cted
to b
e re
view
ed.
B. Macavei, A. Baban, D.L. Dumitrascu
5096
2) scHaffnER f, THalER H. Nonalcoholic fatty liver dis-ease. Prog Liver Dis 1986; 8: 283-298.
3) ludwig J, Viggiano TR, Mcgill dB, oH BJ. Nonal-coholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434-438.
4) TEli MR, JaMEs of, BuRT ad, BEnnETT MK, day cP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1714-1719.
5) aRgo cK, caldwEll sH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13: 511-531.
6) aTTaR BM, Van THiEl dH. Current concepts and management approaches in nonalcoholic fatty liver disease. Scientific World Journal 2013; 2013: 1-10.
7) PascHos P, PalETas K. Non alcoholic fatty liver dis-ease and metabolic syndrome. Hippokratia 2009; 13: 9-19.
8) sass da, cHang P, cHoPRa KB. Nonalcoholic fatty liver disease: a clinical review. Dig Dis Sci 2005; 50: 171-180.
9) fan Jg, faRREll, gc. Epidemiology of non-alcohol-ic fatty liver disease in China. J Hepatol 2009; 50: 204-210.
10) dusEJa a. Nonalcoholic fatty liver disease in India – a lot done, yet more required! Indian J Gastro-enterol 2010; 29: 217-225.
11) KiM cH, younossi ZM. Nonalcoholic fatty liver dis-ease: a manifestation of the metabolic syndrome. Cleve Clin J Med 2008; 75: 721-728.
12) MaRcHEsini g, BRiZi M, BiancHi g, ToMassETTi s, Bugia-nEsi E, lEnZi M, MccullougH aJ, naTalE s, foRlani g, MElcHionda n. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-1850.
13) BRuMBaugH dE, fRiEdMan JE. Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 2014; 75: 140-147.
14) andERson El, HowE ld, fRasER a, callaway MP, saTTaR n, day c, Tilling K, lawloR da. Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in ado-lescence: the ALSPAC study. J Hepatol 2014; 61: 626-632.
15) HooPER aJ, adaMs la, BuRnETT JR. Genetic deter-minants of hepatic steatosis in man. J Lipid Res 2011; 52: 593-617.
16) adaMs la, lindoR Kd. Nonalcoholic fatty liver dis-ease. Ann Epidemiol 2007; 17: 863-869.
17) duVnJaK M, lERoTić i, BaRšić n, ToMašić V, ViRoVić-JuKić l, VElagić V. Pathogenesis and management issues for non-alcoholic fatty liver disease. World J Gastroenterol 2007; 13: 4539-4550.
18) sofi f, casini a. Mediterranean diet and non-alco-holic fatty liver disease: New therapeutic option around the corner? World J Gastroenterol 2014; 20: 7339-7346.
19) cusi K. Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2009; 16: 141-149.
20) REMicK Ra. Diagnosis and management of depres-sion in primary care: a clinical update and review. CMAJ 2002; 167: 1253-1260.
21) wan d. Depression: A Global Crisis World Men-tal Health Day. Foreword to the 20th Anniversa-ry of World Mental Health Day. World Federation of Mental Health 2012; 1-32. http://www.who.int/mental_health/management/depression/wfmh_paper_depression_wmhd_2012.pdf
22) KaTon w, ciEcHanowsKi P. Impact of major depres-sion on chronic medical illness. J Psychosom Res 2002; 53: 859-863.
23) PaTTEn sB, williaMs JV, laVoRaTo dH, Modgill, g, JETTE, n, EliasZiw M. Major depression as a risk factor for chronic disease incidence: longitudi-nal analyses in a general population cohort. Gen Hosp Psychiatry 2008; 30: 407-413.
24) sTEwaRT KE, HallER dl, saRgEanT c, lEVEnson Jl, PuRi P, sanyal aJ. Readiness for behaviour change in non-alcoholic fatty liver disease: implications for multidisciplinary care models. Liver Int 2015; 35: 936-943.
25) youssEf na, aBdElMalEK Mf, BinKs M, guy cd, oME-nETTi a, sMiTH ad, diEHl aM, suZuKi a. Associations of depression, anxiety, and antidepressants with histological severity of nonalcoholic fatty liver dis-ease. Liver Int 2013; 33: 1062-1070.
26) Elwing JE, lusTMan PJ, wang Hl, clousE RE. De-pression, anxiety and nonalcoholic steatohepati-tis. Psychosom Med 2006; 68: 563-569.
27) wEinsTEin aa, KallMan PRicE J, sTEPanoVa M, PoMs lw, fang y, Moon J, nadER f, younossi ZM. De-pression in patients with nonalcoholic fatty liver disease and chronic viral hepatitis B and C. Psy-chosomatics 2011; 52: 127-132.
28) asnis gM, dE la gaRZa Rn 2nd. Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment ap-proaches. J Clin Gastroenterol 2006; 40: 322-335.
29) lE sTRaT y, lE foll B, duBERTRET c. Major depression and suicide attempts in patients with liver disease in the United States. Liver Int 2015; 35: 1910-1916.
30) lEE K, oTgonsuREn M, younosZai Z, MiR HM, younossi ZM. Association of chronic liver disease with de-pression: a population-based study. Psychoso-matics 2013; 54: 52-59.
31) suRdEa-Blaga T, duMiTRascu d. Depression and anxi-ety in nonalcoholic steatohepatitis: is there any as-sociation? Rom J Intern Med 2011; 49: 273-280.
32) fRiTH J, day cP, RoBinson l, EllioTT c, JonEs dE, nEw-Ton Jl. Potential strategies to improve uptake of exercise interventions in non-alcoholic fatty liver disease. J Hepatol 2010; 52: 112-116.
33) suaREZ Ec. C-reactive protein is associated with psychological risk factors of cardiovascular dis-ease in apparently healthy adults. Psychosom Med 2004; 66: 684-691.
34) KERnER a, aViZoHaR o, sElla R, BaRTHa P, ZindER o, MaRKiEwicZ w, lEVy y, BRooK gJ, aRonson d. Asso-ciation between elevated liver enzymes and C-re-active protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome. Arterioscler Thromb Vasc Biol 2005; 25: 193-197.
35) wEinsTEin aa, EscHEiK c, oE B, KallMan PRicE JK, gERBER lH, younossi ZM. Perception of effort during activity in patients with chronic hepatitis c and nonalcoholic fatty liver disease. PM R 2016; 8: 28-34.
Psychological factors associated with NAFLD/NASH: a systematic review
5097
36) PRocHasKa Jo, diclEMEnTE cc. The transtheoretical approach: Towards a systematic eclectic frame-work. Homewood, IL: Dow Jones Irwin. 1984.
37) cEnTis E, MoscaTiEllo s, BugianEsi E, BEllEnTani s, fRacanZani al, calugi s, PETTa s, dallE gRaVE R, MaRcHEsini g. Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver dis-ease. J Hepatol 2013; 58: 771-777.
38) fEliPo V, uRios a, MonTEsinos E, Molina i, gaRcia-ToR-REs Ml, ciVERa M, dEl olMo Ja, oRTEga J, MaRTi-nEZ-Valls J, sERRa Ma, cassinEllo n, wassEl a, JoRda E, MonToliu c. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis 2012; 27: 51-58.
39) EllioTT c, fRiTH J, day cP, JonEs dEJ, nEwTon Jl. Functional impairment in alcoholic liver disease and non-alcoholic fatty liver disease is significant and persists over 3 years of follow-up. Dig Dis Sci 2013; 58: 2383-2391.
40) KoEHlER EM, scHouTEn Jn, HansEn BE, Van RooiJ fJ, HofMan a, sTRicKER BH, JanssEn Hl. Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J Hepatol 2012; 57: 1305-1311.
41) oni ET, KalaTHiya R, anEni Ec, MaRTin ss, BlaHa MJ, fEldMan T, agaTsTon as, BluMEnTHal Rs, concEicao Rd, caRValHo Ja, sanTos, Rd, nasiR K. Relation of physical activity to prevalence of nonalcoholic fat-ty liver disease independent of cardiometabolic risk. Am J Cardiol 2015; 115: 34-39.
42) KisTlER Kd, BRunT EM, claRK JM, diEHl aM, sallis Jf, scHwiMMER JB, nasH cRn REsEaRcH gRouP. Physi-cal activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liv-er disease. Am J Gastroenterol 2011; 106: 460-468.
43) Hua Q, Hang w, Min d, Huili w, Huacong d. As-sociations between longer habitual day napping and non-alcoholic fatty liver disease in an elderly Chinese population. PLoS One 2014; 9: e105583.
44) yu d, sHu Xo, Xiang yB, li H, yang g, gao yT, ZHEng w, ZHang X. Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liv-er in normal-weight Chinese women. J Nutr 2014; 144: 2034-2040.
45) ZElBER-sagi s, niTZan-KalusKi d, goldsMiTH R, wEBB M, BlEndis l, HalPERn Z, oREn R. Long term nutri-tional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 2007; 47: 711-717.
46) saTHiaRaJ E, cHuTKE M, REddy My, PRaTaP n, Rao Pn, REddy dn, RagHunaTH M. A case-control study on nutritional risk factors in non-alcoholic fatty liver disease in Indian population. Eur J Clin Nutr 2011; 65: 533-537.
47) MaRinHo fERolla s, aBREu fERRaRi Tc, PEREiRa liMa Ml, oliVEiRa REis T, caMPos TaVaREs JR. w, MElo couTo of, ViEiRa TEXEiRa Vidigal P, fausTo Ma, alVEs cou-To c. Dietary patterns in Brazilian patients with non-alcoholic fatty liver disease: a cross-section-al study. Clinics 2013; 68: 11-17.
48) KiM cH, KallMan JB, Bai c, PawlosKi l, gEwa c, aR-salla a, saBaTElla ME, younossi ZM. Nutritional
assessments of patients with non-alcoholic fatty liver disease. Obes Surg 2010; 20: 154-160.
49) Han JM, Jo an, lEE sM, BaE Hs, Jun dw, cHo yK, suK KT, yoon JH, aHn sB, cHo yJ, KiM sw, Jang Ec. Associations between intakes of individual nutri-ents or whole food groups and non-alcoholic fatty liver disease among Korean adults. J Gastroen-terol Hepatol 2014; 29: 1265-1272.
50) Musso g, gaMBino R, Bo s, uBERTi B, BiRoli g, Pa-gano g, cassadER M. Should nonalcoholic fatty liver disease be included in the definition of met-abolic syndrome? A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects. Diabetes Care 2008; 31: 562-568.
51) Kang H, gREEnson JK, oMo JT, cHao c, PETERMan d, andERson l, foEss-wood l, sHERBondy Ma, conJEE-VaRaM Hs. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol 2006; 101: 2247-2253.
52) walTon HB, MasTERTon gs, HayEs Pc. An epidemi-ological study of the association of coffee with chronic liver disease. Scott Med J 2013; 58: 217-222.
53) Kwon HK, gREEnson, JK, conJEEVaRaM Hs. Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease. Liver Int 2014; 34: 129-135.
54) dunn w, Xu R, scHwiMMER JB. Modest wine drinking and decreased prevalence of suspected nonal-coholic fatty liver disease. Hepatology 2008; 47: 1947-1954.
55) dunn w, sanyal aJ, BRunT EM, unalP-aRida a, donoHuE M, MccullougH aJ, scHwiMMER JB. Mod-est alcohol consumption is associated with de-creased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J. Hepatol 2012; 57: 384-391.
56) liu y, dai M, Bi y, Xu M, li M, wang T, Huang f, Xu B, ZHang J, li X, wang w, ning g. Active smoking, passive smoking, and risk for nonalcoholic fatty liver disease (NAFLD): a population-based study in China. J Epidemiol 2013; 23: 115-121.
57) ZEin co, unalP a, colVin R, liu yc, MccullougH aJ, nonalcoHolic sTEaToHEPaTiTis clinical REsEaRcH nET-woRK. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol 2011; 54: 753-759.
58) gasBaRRini g, VERo V, MiElE l, foRgionE a, HERnan-dEZ aP, gREco aV, gasBaRRini a, gRiEco a. Nonal-coholic fatty liver disease: defining a common problem. Eur Rev Med Pharmacol Sci 2005; 9: 253-259.
59) TRaPPoliERE M, Tuccillo c, fEdERico a, di lEVa a, ni-osi M, d’alEssio c, caPasso R, coPPola f, d’auRia M, loguERcio, c. The treatment of NAFLD. Eur Rev Med Pharmacol Sci 2005; 9: 299-304.
60) allER R, dEluis da, iZaola o, dE la fuEnTE B, Ba-cHilliER R. Effect of a high monounsaturated vs high polyunsaturated fat hypocaloric diets in non-alcoholic fatty liver disease. Eur Rev Med Phar-macol Sci 2014; 18: 1041-1047.