Non-alcoholic fatty liver disease in patients with chronic
plaque psoriasis
q
Paolo Gisondi
1,*,#, Giovanni Targher
2,#, Giacomo Zoppini
2, Giampiero Girolomoni
11Section of Dermatology, Department of Biomedical and Surgical Science, University of Verona, Piazzale A. Stefani 1, 37126 Verona, Italy 2Section of Endocrinology, Department of Biomedical and Surgical Science, University of Verona, Verona, Italy
Background
/
Aims
: Non-alcoholic fatty liver disease (NAFLD) and chronic plaque psoriasis are both associated with
metabolic syndrome and increased risk of incident cardiovascular disease. We assessed the frequency and characteristics
of NAFLD in patients with chronic plaque psoriasis.
Methods
: One hundred and thirty consecutive patients with chronic plaque psoriasis and 260 apparently healthy controls
matched for age, sex and body mass index were enrolled. NAFLD was diagnosed by abdominal ultrasound after excluding
other secondary causes of chronic liver disease.
Results
: The frequency of NAFLD was remarkably greater in psoriasis patients than in controls (47%
vs
. 28%;
p
< 0.0001). Patients with psoriasis and NAFLD (
n
= 61) were more likely to have metabolic syndrome and had higher
serum C-reactive protein concentrations and greater severity of psoriasis according to the Psoriasis Area and Severity
Index (PASI) score (14.2 ± 12.6
vs
. 9.6 ± 7.4;
p
< 0.01) than those with psoriasis alone (
n
= 69). In a subgroup of psoriasis
patients (
n
= 43), those with NAFLD (
n
= 21) also had significantly higher serum interleukin-6 and lower serum
adiponec-tin levels. Notably, in multivariate regression analysis, NAFLD was associated with higher PASI score independently of
age, gender, body mass index, psoriasis duration, and alcohol consumption.
Conclusions
: NAFLD is frequent in patients with chronic plaque psoriasis – affecting up to nearly half of these patients –
and is strongly associated with psoriasis severity. Early recognition of NAFLD by radiological imaging tests in this group
of patients is warranted.
Ó
2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Keywords
: Psoriasis; Non-alcoholic fatty liver disease; Metabolic syndrome; Adiponectin; IL-6
1. Introduction
Psoriasis is a complex, chronic, inflammatory skin
disease, frequently associated with abdominal obesity,
type 2 diabetes, insulin resistance and dyslipidemia –
components that characterize metabolic syndrome
[1–5]
. The prevalence of psoriasis is estimated to be
between 2% and 3% of the general population of the
Europe and North America, with men and women
equally affected
[1]
.
Non-alcoholic fatty liver disease (NAFLD),
compris-ing a spectrum of conditions rangcompris-ing from simple
steato-sis to steatohepatitis (NASH) and cirrhosteato-sis, is now
regarded as the hepatic manifestation of metabolic
syn-drome, and represents the most common cause of
0168-8278/$36.00Ó2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.jhep.2009.04.020
Received 11 February 2009; received in revised form 27 April 2009; accepted 29 April 2009; available online 27 May 2009
Associate Editor: C.P. Day q
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.
*
Corresponding author. Tel.: +39 045 8122547; fax: +39 045 8300521.
E-mail address:paolo.gisondi@univr.it(P. Gisondi). # These authors contributed equally to this work.
Abbreviations: NAFLD, non-alcoholic fatty liver disease; PASI, psoriasis area and severity index; BMI, body mass index; CRP, C-reactive protein; IL-6, interleukin-6.
www.elsevier.com/locate/jhep Journal of Hepatology 51 (2009) 758–764
abnormal serum liver enzymes in Western countries,
affecting up to one-third of the general population
[6–9]
.
Considering that metabolic syndrome and the
under-lying insulin resistance are common features of both
psoriasis and NAFLD, it is likely that both entities
may coexist within the same patient. This is an
impor-tant issue, which may have clinical implications in
plan-ning preventive and therapeutic strategies. The possible
association of NAFLD with psoriasis deserves particular
attention in view of the implications for
screening/surveil-lance strategies of the growing number of NAFLD
patients. To our knowledge, however, there is currently
a paucity of information on the association between
pso-riasis and primary NAFLD. A single case report
previ-ously reported that NASH might be the underlying
cause of chronic liver disease in psoriasis patients, who
had been treated with drugs with little or no liver toxicity,
such as retinoids and phototherapy
[10]
.
Thus, the aim of this study was to assess the
fre-quency and characteristics of NAFLD in a large sample
of consecutive patients with chronic plaque psoriasis.
2. Patients and methods
2.1. Participants
One hundred and thirty out-patients with chronic plaque psoriasis who consecutively attended the dermatology clinic of the University Hospital of Verona over a period of 6 months (from January to June 2008) were enrolled. Patients who had any clinical evidence of malig-nancy, cirrhosis or other secondary causes of chronic liver disease (i.e., alcohol abuse, viral hepatitis, autoimmune hepatitis, current use of potentially hepato-toxic medications such as methotrexate, tumor necrosis factor antagonists, amiodarone or chemotherapics) were excluded. The control group, recruited from hospital staff member and relatives, consisted of 260 apparently healthy controls, who were randomly selected in a 2:1 ratio to be matched for age, sex and body mass index (BMI) to psoriasis patients.
2.2. Anthropometric, clinical and laboratory variables
BMI was calculated as weight in kilograms divided by the square of height in meters. Waist circumference was measured with a steel mea-suring tape to the nearest 0.1 cm at the high point of the iliac crest at minimal respiration. Information on daily alcohol consumption, smoking status and use of medications was obtained from all partici-pants by a standardized questionnaire[11]. In particular, alcohol con-sumption was assessed on the basis of the self-reported number of drinks consumed per day. The following amounts of alcoholic bever-ages were considered 1 drink: 330 ml beer (containing5% of alcohol), 150 ml wine (containing12% of alcohol), and 40 ml strong alcohol (containing50% of alcohol). Overall, most patients with psoriasis were non-drinkers (n= 77; 59%) or drank only minimally (62 drinks per day;n= 33; 25%), whereas15% of them drank 3–4 drinks per day. The self-reported number of drinks consumed per day was similar in the control group (zero drinks/day: 63%;62 drinks/day: 22%;P3drinks/day: 15%). None of participants admitted to drinking more than 4 drinks per day. Hypertension was diagnosed if the participant was taking anti-hypertensive medications, reported being told by a physician that they have high blood pressure, or the average of three blood pressure readings was P140/90 mmHg. Participants were defined as having diabetes mellitus when they were taking hypoglycemic medications, had a fasting plasma glucose concentrationP7 mmol/l or when a physician had ever told them that they had diabetes.
Metabolic syndrome was diagnosed by the Adult Panel Treatment (ATP) III definition. In accordance with this definition[12], a person was classified as having the syndrome if he/she had at least three of the following 5 risk abnormalities: (1) waist circumference < 102 cm in men or >88 cm in women, (2) fasting glucoseP5.6 mmol/l or on treatment, (3) triglyceridesP1.7 mmol/l, (4) HDL < 1.0 mmol/l in men and <1.29 mmol/l in women or on treatment, and (5) blood pressureP130/85 mmHg or on treatment.
Venous blood was drawn in the morning after an overnight fast. Serum liver enzymes, lipids and other biochemical blood measure-ments were determined by standard laboratory procedures (DAX 96, Bayer Diagnostics, Milan, Italy). Normal ranges for serum amino-transferase levels in our laboratory were 10–35 U/L for females and 10–50 U/L for males, respectively. Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald’s equation (i.e., total cho-lesterol minus high-density lipoprotein chocho-lesterol minus triglycerides divided by 5). Circulating levels of C-reactive protein (CRP) were mea-sured by a nephelometric assay on a Behring Nephelometer II. Serol-ogy for viral hepatitis B and C was assessed in all participants. Serum adiponectin (B-Bridge International, San Jose, CA) and ultra-sensitive interleukin (IL)-6 (Invitrogen Corp., Carlsbad, CA, USA) were mea-sured in duplicate by commercially available ELISA kits in stored serum samples from a subgroup of psoriasis patients (n= 43).
The diagnosis of psoriasis was made clinically by the same derma-tologist and disease severity was assessed using the Psoriasis Area and Severity Index (PASI)[1–3]. The PASI evaluates the degree of ery-thema, thickness, and scaling of psoriatic plaques, and estimates the extent of involvement of each of these components in four separate body areas (head, trunk, upper and lower extremities). A PASI score P10 is considered to be indicative of clinically relevant disease severity [1]. The presence of psoriatic arthritis was diagnosed according to the criteria proposed by the ClASsification criteria for Psoriatic Arthritis (CASPAR) Study group[13].
Hepatic ultrasonography scanning was performed in all partici-pants by an experienced radiologist, who was blinded to participartici-pants’ details. The diagnosis of hepatic steatosis was made on the basis of characteristic sonographic features, i.e., evidence of diffuse hyper-ech-ogenicity of liver relative to kidneys, ultrasound beam attenuation and poor visualization of intra-hepatic structures[6,7]. Liver ultrasonogra-phy has a sensitivity of90% and a specificity of95% in detecting moderate and severe steatosis, but its sensitivity is reduced when hepa-tic fat infiltration upon liver biopsy is less than 33%[6–9]. A semi-quantitative sonographic scoring for the degree of hepatic steatosis was not available in our study.
2.3. Statistical analysis
All analyses were performed using the STATA (version 10.0 Stata-Corp LP, College Station, TX) and Graph-Pad (version 4.0, El Cami-no Real, San Diego, CA) software packages. Data are expressed as means ± SD or percentages. Skewed variables (i.e., triglycerides, C-reactive protein, adiponectin and IL-6) were logarithmically trans-formed to improve normality prior to analysis. Statistical analyses included the unpaired-ttest (for continuous variables), and thev2-test with Yates’s correction for continuity (for categorical variables). The independence of the association of NAFLD with the severity of psori-asis (estimated by PASI score that was included as the dependent
Table 1
Baseline clinical characteristics of the study population. Psoriasis
patients
Control subjects pValue
n 130 260
Gender (male/female) 89/41 180/80 NSa Age (years) 51.2 ± 13.4 51.2 ± 8 NSa Body mass index (kg/m2) 27.5 ± 5.1 26.7 ± 3.2 NSa Metabolic syndrome (%) 28 26 0.61 Data are expressed as means ± SD or percentages. NS, not significant.
variable) was assessed by multivariate forward stepwise regression analysis. In the fully adjusted regression model age, gender, psoriasis duration, alcohol consumption, BMI or presence of metabolic syn-drome were also included as baseline covariates. In light of the well-known association between alcohol drinking and liver injury, we repeated all the analyses described above after excluding participants who were light to moderate drinkers. Values atp< 0.05 were consid-ered statistically significant.
3. Results
By study design, gender distribution, age and BMI
did not significantly differ between psoriasis patients
and matched healthy controls (
Table 1
). Moreover, the
frequency of the ATP III-defined metabolic syndrome
was similar between the groups. Notably, the frequency
of ultrasound-diagnosed NAFLD was remarkably
greater in psoriasis patients than in matched control
subjects (
Fig. 1
). Similar results were found when the
analysis was limited to participants who were
non-drinkers (37%
vs.
21%;
p
< 0.01).
The baseline characteristics of psoriasis patients
strat-ified by NAFLD status are shown in
Table 2
. Patients
with psoriasis and NAFLD were older, more obese,
more likely to be male and had greater frequency of
hypertension than their counterparts without NAFLD.
They also had higher levels of serum triglycerides,
CRP and liver enzymes – although the vast majority
of NAFLD patients, i.e.,
80% had serum ALT
concen-trations within the reference range. Psoriasis duration,
the presence of psoriatic arthritis, smoking history,
pro-portion of type 2 diabetes, plasma HDL cholesterol and
LDL cholesterol levels did not significantly differ
between the groups. Notably, compared with psoriasis
patients without NAFLD, those with NAFLD had a
more severe degree of psoriasis according to PASI score
(mean ± SD:
14.2 ± 12.6
vs.
9.6 ± 7.4;
p
< 0.01,
respectively). Accordingly, the frequency of NAFLD
was remarkably greater in psoriasis patients with PASI
score
P
10 (n
= 71) compared with those with PASI
score <10 (n
= 59) (
Fig. 2
). Almost identical results were
found when participants who were light-moderate
drinkers were excluded from analysis. In particular,
plasma
CRP
concentrations
(6.0 ± 4.1
vs.
2.1 ±
1.2 mg/l) and PASI score (13.1 ± 11
vs. 5.2 ± 7.1)
remained significantly higher (p
< 0.01 or less) in
patients with psoriasis and NAFLD than in those with
psoriasis alone. Psoriasis patients with NALFD also
had lower serum levels of adiponectin (7.8 ± 3.3
vs.
10.9 ± 2.7
l
g/ml;
p
= 0.002) and higher levels of IL-6
(1.18 ± 0.76
vs.
0.59 ± 0.40 pg/ml;
p
= 0.003) (
Fig. 3
).
In multivariate forward stepwise regression analysis
(
Table 3
), the presence of NAFLD was the only
Psoriasis patients Controls0 20 40 60 80 100
N
A
F
LD
p
rev
al
en
c
e
(%
)
Fig. 1. Prevalence of NAFLD in psoriasis patients (n= 130) and in age-, sex-, and BMI-matched healthy controls (n= 260). P< 0.0001 for difference between the groups.
Table 2
Clinical and biochemical characteristics of patients with chronic plaque psoriasis grouped by the non-alcoholic fatty liver disease (NAFLD) status. With NAFLD (n= 61) Without NAFLD (n= 69) pValue
Gender (% male) 80 58 <0.01
Age (years) 51 ± 12 48 ± 14 <0.001
Body mass index (kg/m2) 29.6 ± 5.4 25 ± 5.3 <0.001
Psoriasis duration (years) 22.1 ± 14.5 21.1 ± 14.6 0.72
Psoriatic arthritis (%) 33 37 0.33
Current smokers (%) 36 29 0.36
Type 2 diabetes (%) 16 7 0.14
Hypertension (%) 69 26 <0.001
Metabolic syndrome (%) 50 3 <0.001
Fasting glucose (mmol/l) 5.8 ± 1.6 5.7 ± 2.2 0.59
LDL cholesterol (mmol/l) 3.65 ± 0.6 3.49 ± 0.7 0.21 HDL cholesterol (mmol/l) 1.41 ± 0.4 1.46 ± 0.6 0.30 Triglycerides (mmol/l) 1.70 ± 1.3 1.15 ± 0.8 <0.01 C-reactive protein (mg/l) 5.6 ± 3.8 2.0 ± 1.3 <0.001 AST (U/l) 28 ± 7 24 ± 10 0.09 ALT (U/l) 36 ± 30 26 ± 11 <0.01 GGT (U/l) 48 ± 40 25 ± 15 <0.001
Data are expressed as means ± SD or percentages. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl-transferase; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.
significant predictor of higher PASI score,
indepen-dently of age, sex, BMI, duration of psoriasis and
alcohol consumption.
4. Discussion
NAFLD is now regarded as the hepatic manifestation
of metabolic syndrome and represents the most common
cause of abnormal liver function tests among adults in
the United States and Europe
[7]
. The NAFLD
preva-lence has been estimated to be in the 20–30% range in
the general population in various countries and is
almost certainly increasing
[6–9]
. Accordingly, a huge
number of individuals are at risk of developing
advanced liver disease. There is now growing evidence
suggesting that NAFLD may be also linked to increased
risk of future cardiovascular events independently of
conventional risk factors and metabolic syndrome
com-ponents
[14,15]
. Psoriasis is a chronic, inflammatory,
immune-mediated skin disease. Both innate and
adap-tive immunity are crucial in the initiation and
mainte-nance of psoriatic plaques. Type 1 CD8
+and type 17
CD4
+T-lymphocytes and their products, including
interferon-
c
, tumor necrosis factor (TNF)-
a
, IL-17 and
IL-22 are essential to disease expression
[16]
. Of
emerg-ing concern is the relationship between psoriasis and
cardiovascular diseases. Although no excess
cardiovas-cular risk seems to exist for patients with mild psoriasis,
moderate and severe disease is associated with a relative
risk of almost three
[17–19]
. In part, this association is
due to the over-representation of established
cardio-metabolic risk factors in the psoriatic population
[1–
3,20,21]
, but evidence indicates that psoriasis
per se
may be an independent risk factor for cardiovascular
morbidity and mortality
[19,22]
. Potential underlying
mechanisms may include the presence of platelet
hyper-reactivity, hyper-homocysteinemia and increased
levels of CRP and other pro-inflammatory cytokines
[23–26]
.
The present study has shown, for the first time, that
the frequency of NAFLD – as diagnosed by patient
his-tory, blood sampling and characteristic sonographic
fea-tures – in patients with chronic plaque psoriasis is
remarkably greater than that in non-psoriasis control
subjects, who were matched for age, gender and BMI.
Notably, the two groups resulted also comparable for
the presence of metabolic syndrome, possibly because
with NAFLD
without NAFLD
0 5 10 15 20
A
d
iponec
ti
n (
μ
g/m
l)
with NAFLD
without NAFLD
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
IL
-6
(n
g
/m
l)
A
B
Fig. 3. Serum adiponectin (A) and IL-6 (B) levels in psoriasis patients with and without NALFD. Adiponectin and IL-6 levels were measured in 21 patients with NAFLD and 22 patients without NAFLD, respectively. Differences between the groups were significant withp= 0.003 (A) and p= 0.002 (B).
PASI <10
PASI
≥
10
0 20 40 60 80 100NA
FL
D pre
va
le
n
c
e
(
%
)
Fig. 2. Prevalence of NAFLD in psoriasis patients stratified by disease severity using the Psoriasis Area and Severity Index (PASI). PASI <10, 59 patients; PASIP10, 71 patients.P< 0.01 for difference between the groups.
Table 3
Independent predictors of psoriasis severity as estimated by the Psoriasis Area and Severity Index.
Independent variables Standardized beta coefficients
pValue PASI score Age (years) 0.051 0.25
Gender (malevs. female) 0.070 0.82 Body mass index (kg/m2) 0.144 0.28 Psoriasis duration (years) 0.010 0.89 Alcohol intake (yesvs. no) 0.126 0.39 NAFLD (yesvs. no) 0.192 0.038 n, 130.
they were matched for BMI. In addition, none of our
psoriasis patients was treated with methotrexate,
TNF-a
antagonists or other potentially hepato-toxic
medica-tions. Another major finding of this study was that
NAFLD was associated with the severity of psoriasis
independently of potential confounders such as age,
gender,
BMI,
psoriasis
duration
and
alcohol
consumption.
Although the study does not allow us to ascertain the
directionality of the association between NAFLD and
psoriasis, it could be speculated that pro-inflammatory
cytokines and other factors that are overproduced in
patients with psoriasis likely contribute to the
develop-ment of insulin resistance
[27]
, and that psoriasis
patients with highest insulin resistance are the ones
who get NAFLD. A leading role in the development
of inflammation, insulin resistance and NAFLD in
pso-riasis patients is likely to be played by increased visceral
adipose tissue, possibly through its multiple secreted
fac-tors, such as free fatty acids, hormones, and
adipocyto-kines
[7,8,15]
. However, it is also possible to hypothesize
that NAFLD might actively contribute to the severity of
psoriasis through the release of pathogenetic mediators
from the inflamed liver, including increased reactive
oxygen species, elevated CRP, IL-6 and other
pro-inflammatory cytokines. Importantly, several studies
have shown that these potential mediators of vascular
and skin injury are remarkably higher in patients with
NAFLD than in those without
[28–35]
. The systemic
release of pro-inflammatory/pro-atherogenic mediators
from the steatotic liver is also one of the underlying
mechanisms by which NAFLD may contribute to
accel-erated atherogenesis
[14,15]
. Adiponectin is an
adipo-cyte-specific secretory protein with anti-diabetic and
anti-inflammatory properties. Indeed, several studies
found that plasma adiponectin is lower in
insulin-resis-tant states, such as obesity and type 2 diabetes, and is
associated with increased risk of cardiovascular events
[36,37]
. Lower adiponectin has been also found in
psori-asis patients with moderate-severe disease
[37]
. IL-6 is a
pro-inflammatory cytokine, which is known to be
asso-ciated with abdominal obesity, type 2 diabetes,
hyper-tension and insulin resistance
[38]
. IL-6 induces the
synthesis of CRP by the liver and, along with TNF-
a
,
may alter insulin sensitivity via the insulin signaling
pathway
[38]
. Obese psoriatic patients have higher
serum IL-6 levels than normal-weight psoriatic patients
or control subjects
[37]
. Moreover, it has been reported
an inverse association between serum IL-6 and
adipo-nectin in obese psoriatic patients
[39]
.
Overall, these findings might have important clinical
implications. Our results indicate that NAFLD is a
com-mon condition in patients with chronic plaque psoriasis,
affecting up to nearly half of these patients, and that
patients with psoriasis and NAFLD are more likely to
have metabolic syndrome and a more severe degree of
skin disease than those with psoriasis alone. This
strongly suggests that psoriasis patients should be
rou-tinely screened for NAFLD given the potentially
pro-gressive
nature
of
the
liver
disease,
and
that
consideration should be given to referring patients to a
hepatologist for further evaluation. The presence of
NALFD should be taken into consideration when
choosing therapy, as some anti-psoriatic drugs are
potentially hepato-toxic. In particular, psoriasis patients
with type 2 diabetes are at high risk of developing liver
fibrosis during methotrexate treatment
[40]
. Indeed, it
may well be that psoriasis patients with NAFLD are
those at greater risk of developing more severe liver
dis-ease during methotrexate treatment. Moreover, the
identification of NAFLD in psoriasis patients might be
also useful for a better stratification of overall
cardio-vascular risk.
Our study has several strengths, including the large
number of participants, the complete nature of the
data-set, the ability to adjust for multiple confounders, the
exclusion of psoriasis patients treated with potentially
hepato-toxic medications, and the ultrasound diagnosis
of NAFLD in all participants.
However, this study has some limitations. First, the
cross-sectional study design precludes the establishment
of causal or temporal relationships between NAFLD
and psoriasis. Prospective studies will be required to
resolve these issues. Second, the diagnosis of NAFLD
was based on ultrasonography and exclusion of other
secondary causes of chronic liver disease, but was not
confirmed by liver biopsy. It is known that none of the
radiological features can distinguish between NASH
and other forms of NAFLD, and that only liver biopsy
can assess the severity of damage and the prognosis
[6–
8]
. However, we believe that liver biopsy would have
been unethical to perform in our psoriasis patients since
most of them had normal serum liver enzymes.
More-over, liver ultrasonography is by far the commonest
way of diagnosing NAFLD in clinical practice.
Ultraso-nography has a good sensitivity and specificity in
detect-ing moderate and severe steatosis, but this sensitivity is
reduced when hepatic fat infiltration upon biopsy is less
than 33%
[6–8]
. Thus, although some non-differential
misclassification of NAFLD on the basis of ultrasound
is likely (some of the psoriasis patients could have
underlying
NAFLD,
despite
normal
serum
liver
enzymes and a negative ultrasound), this limitation
would serve to attenuate the magnitude of our effect
measures towards null; thus, our results can probably
be considered as conservative estimates of the
relation-ship between NAFLD and psoriasis. Finally, it is known
that self-reporting of alcohol consumption may be
unre-liable and often underestimates the true risk. However,
after excluding those participants who were
light-to-moderate drinkers, the main results of this study
remained unchanged.
In conclusion, our findings suggest that NAFLD is
frequent in never-treated patients with chronic plaque
psoriasis and is associated with psoriasis disease
sever-ity. Future investigation is required to determine the
most appropriate diagnostic and treatment strategies
for these patients.
Acknowledgement
This work was supported by Ministero della Salute,
and Ministero dell’Istruzione, Universita` e Ricerca
Sci-entifica (Programmi di Ricerca SciSci-entifica di Rilevante
Interesse Nazionale [PRIN]).
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