Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis q

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1 Journal of Hepatology 51 (2009) Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis q Paolo Gisondi 1, *,#, Giovanni Targher 2,#, Giacomo Zoppini 2, Giampiero Girolomoni 1 1 Section of Dermatology, Department of Biomedical and Surgical Science, University of Verona, Piazzale A. Stefani 1, Verona, Italy 2 Section 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 < ). 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 adiponectin 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 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.: ; fax: 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. 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), comprising a spectrum of conditions ranging from simple steatosis to steatohepatitis (NASH) and cirrhosis, is now regarded as the hepatic manifestation of metabolic syndrome, and represents the most common cause of /$36.00 Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 P. Gisondi et al. / Journal of Hepatology 51 (2009) abnormal serum liver enzymes in Western countries, affecting up to one-third of the general population [6 9]. Considering that metabolic syndrome and the underlying 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 important issue, which may have clinical implications in planning preventive and therapeutic strategies. The possible association of NAFLD with psoriasis deserves particular attention in view of the implications for screening/surveillance strategies of the growing number of NAFLD patients. To our knowledge, however, there is currently a paucity of information on the association between psoriasis and primary NAFLD. A single case report previously 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 frequency 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 malignancy, 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 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 measuring 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 participants by a standardized questionnaire [11]. In particular, alcohol consumption was assessed on the basis of the self-reported number of drinks consumed per day. The following amounts of alcoholic beverages were considered 1 drink: 330 ml beer (containing 5% of alcohol), 150 ml wine (containing 12% of alcohol), and 40 ml strong alcohol (containing 50% of alcohol). Overall, most patients with psoriasis were non-drinkers (n = 77; 59%) or drank only minimally (62 drinks per day; n = 33; 25%), whereas 15% 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%; P3 drinks/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 concentration P7 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 glucose P 5.6 mmol/l or on treatment, (3) triglycerides P 1.7 mmol/l, (4) HDL < 1.0 mmol/l in men and <1.29 mmol/l in women or on treatment, and (5) blood pressure P 130/85 mmhg or on treatment. Venous blood was drawn in the morning after an overnight fast. Serum liver enzymes, lipids and other biochemical blood measurements were determined by standard laboratory procedures (DAX 96, Bayer Diagnostics, Milan, Italy). Normal ranges for serum aminotransferase levels in our laboratory were U/L for females and U/L for males, respectively. Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald s equation (i.e., total cholesterol minus high-density lipoprotein cholesterol minus triglycerides divided by 5). Circulating levels of C-reactive protein (CRP) were measured by a nephelometric assay on a Behring Nephelometer II. Serology 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 measured 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 dermatologist and disease severity was assessed using the Psoriasis Area and Severity Index (PASI) [1 3]. The PASI evaluates the degree of erythema, 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 participants by an experienced radiologist, who was blinded to participants details. The diagnosis of hepatic steatosis was made on the basis of characteristic sonographic features, i.e., evidence of diffuse hyper-echogenicity of liver relative to kidneys, ultrasound beam attenuation and poor visualization of intra-hepatic structures [6,7]. Liver ultrasonography has a sensitivity of 90% and a specificity of 95% in detecting moderate and severe steatosis, but its sensitivity is reduced when hepatic fat infiltration upon liver biopsy is less than 33% [6 9]. A semiquantitative sonographic scoring for the degree of hepatic steatosis was not available in our study 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 Camino 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 transformed to improve normality prior to analysis. Statistical analyses included the unpaired-t test (for continuous variables), and the v 2 -test with Yates s correction for continuity (for categorical variables). The independence of the association of NAFLD with the severity of psoriasis (estimated by PASI score that was included as the dependent Table 1 Baseline clinical characteristics of the study population. Psoriasis Control subjects p Value patients n Gender (male/female) 89/41 180/80 NS a Age (years) 51.2 ± ± 8 NS a Body mass index (kg/m 2 ) 27.5 ± ± 3.2 NS a Metabolic syndrome (%) Data are expressed as means ± SD or percentages. NS, not significant. a Matched variables.

3 760 P. Gisondi et al. / Journal of Hepatology 51 (2009) NAFLD prevalence (%) 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 syndrome were also included as baseline covariates. In light of the wellknown association between alcohol drinking and liver injury, we repeated all the analyses described above after excluding participants who were light to moderate drinkers. Values at p < 0.05 were considered statistically significant. 3. Results Psoriasis patients Controls Fig. 1. Prevalence of NAFLD in psoriasis patients (n = 130) and in age-, sex-, and BMI-matched healthy controls (n = 260). P < for difference between the groups. 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 nondrinkers (37% vs. 21%; p < 0.01). The baseline characteristics of psoriasis patients stratified 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 concentrations within the reference range. Psoriasis duration, the presence of psoriatic arthritis, smoking history, proportion 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 P10 (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 ± 2.7 lg/ml; p = 0.002) and higher levels of IL-6 (1.18 ± 0.76 vs ± 0.40 pg/ml; p = 0.003) (Fig. 3). In multivariate forward stepwise regression analysis (Table 3), the presence of NAFLD was the only 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) p Value Gender (% male) <0.01 Age (years) 51 ± ± 14 <0.001 Body mass index (kg/m 2 ) 29.6 ± ± 5.3 <0.001 Psoriasis duration (years) 22.1 ± ± Psoriatic arthritis (%) Current smokers (%) Type 2 diabetes (%) Hypertension (%) <0.001 Metabolic syndrome (%) 50 3 <0.001 Fasting glucose (mmol/l) 5.8 ± ± LDL cholesterol (mmol/l) 3.65 ± ± HDL cholesterol (mmol/l) 1.41 ± ± Triglycerides (mmol/l) 1.70 ± ± 0.8 <0.01 C-reactive protein (mg/l) 5.6 ± ± 1.3 <0.001 AST (U/l) 28 ± 7 24 ± ALT (U/l) 36 ± ± 11 <0.01 GGT (U/l) 48 ± ± 15 <0.001 Data are expressed as means ± SD or percentages. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.

4 P. Gisondi et al. / Journal of Hepatology 51 (2009) NAFLD prevalence (%) Table 3 Independent predictors of psoriasis severity as estimated by the Psoriasis Area and Severity Index. Independent variables Standardized p Value beta coefficients PASI score Age (years) Gender (male vs. female) Body mass index (kg/m 2 ) Psoriasis duration (years) Alcohol intake (yes vs. no) NAFLD (yes vs. no) PASI <10 PASI 10 n, 130. Fig. 2. Prevalence of NAFLD in psoriasis patients stratified by disease severity using the Psoriasis Area and Severity Index (PASI). PASI <10, 59 patients; PASI P10, 71 patients. P < 0.01 for difference between the groups. significant predictor of higher PASI score, independently of age, sex, BMI, duration of psoriasis and alcohol consumption. Adiponectin (μg/ml) IL-6 (ng/ml) A B with NAFLD with NAFLD without NAFLD without NAFLD 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 with p = (A) and p = (B). 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 prevalence 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 components [14,15]. Psoriasis is a chronic, inflammatory, immune-mediated skin disease. Both innate and adaptive immunity are crucial in the initiation and maintenance 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 emerging concern is the relationship between psoriasis and cardiovascular diseases. Although no excess cardiovascular 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 cardiometabolic 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 history, blood sampling and characteristic sonographic features 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

5 762 P. Gisondi et al. / Journal of Hepatology 51 (2009) they were matched for BMI. In addition, none of our psoriasis patients was treated with methotrexate, TNFa antagonists or other potentially hepato-toxic medications. 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 development 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 psoriasis patients is likely to be played by increased visceral adipose tissue, possibly through its multiple secreted factors, such as free fatty acids, hormones, and adipocytokines [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 proinflammatory 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 accelerated atherogenesis [14,15]. Adiponectin is an adipocyte-specific secretory protein with anti-diabetic and anti-inflammatory properties. Indeed, several studies found that plasma adiponectin is lower in insulin-resistant 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 psoriasis patients with moderate-severe disease [37]. IL-6 is a pro-inflammatory cytokine, which is known to be associated with abdominal obesity, type 2 diabetes, hypertension 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 adiponectin in obese psoriatic patients [39]. Overall, these findings might have important clinical implications. Our results indicate that NAFLD is a common 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 routinely screened for NAFLD given the potentially progressive 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 disease during methotrexate treatment. Moreover, the identification of NAFLD in psoriasis patients might be also useful for a better stratification of overall cardiovascular risk. Our study has several strengths, including the large number of participants, the complete nature of the dataset, 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. Moreover, liver ultrasonography is by far the commonest way of diagnosing NAFLD in clinical practice. Ultrasonography has a good sensitivity and specificity in detecting 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 relationship between NAFLD and psoriasis. Finally, it is known that self-reporting of alcohol consumption may be unreliable and often underestimates the true risk. However, after excluding those participants who were light-tomoderate drinkers, the main results of this study remained unchanged.

6 P. Gisondi et al. / Journal of Hepatology 51 (2009) In conclusion, our findings suggest that NAFLD is frequent in never-treated patients with chronic plaque psoriasis and is associated with psoriasis disease severity. 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, Università e Ricerca Scientifica (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale [PRIN]). References [1] Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370: [2] Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res 2006;298: [3] Gisondi P, Tessari G, Conti A, Piaserico S, Schianchi S, Peserico A, et al. 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