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Abstract
Background: Psoriasis is a chronic, immune mediated inflammatory condition of the skin and imbalance in inflammatory mediators could result in insulin resistance, metabolic syndrome and facilitate the occurrence and progression of Non-alcoholic fatty liver disease (NAFLD).
Objectives:
Primary objectives:
Keywords: BMI (body mass index), BSA (Body surface area), chronic plaque psoriasis, dyslipidemia, FBS (fasting blood sugar), fatty liver, fibroscan, IL1- β, IL-6, liver fibrosis, LFT (liver function test), NAFLD (Non-alcoholic fatty liver disease), PASI (Psoriasis area severity index), serum insulin level, TNF- α (Interleukins), Th-1, transaminitis, waist circumference (WC)
Introduction 
Psoriasis is a chronic, immune-mediated inflammatory condition of the skin with variable prevalence ranging from 0.1% to 11.8%.[1] Recent studies have linked psoriasis to obesity and metabolic syndrome, both of which are risk factors for the development of non-alcoholic fatty liver disease (NAFLD).[2],[3] There is a possible role of chronic, low-grade inflammation in the pathogenesis of NAFLD in patients with psoriasis. Both psoriasis and NAFLD are associated with increased levels of pro-inflammatory adipokines (TNF-α, IL-6), hepatokines and decreased levels of adiponectin (anti-inflammatory adipokine). This imbalance in inflammatory mediators could result in insulin resistance and facilitate the occurrence and progression of NAFLD. Presence and severity of psoriasis correlated with presence and severity of NAFLD risk and vice versa.[4]
Objectives
Primary objective
To study the frequency of NAFLD in cases of chronic plaque psoriasis and controls.To study the interleukin levels in cases of chronic plaque psoriasis and controls.Secondary objectives
To study the BMI, lipid profile, waist circumference, FBS (fasting blood sugar), PPBS (post prandial blood sugar) and serum insulin in cases and controlsTo study the association of age, duration of psoriasis, PASI (psoriasis area severity index), BSA (body surface area) involved, BMI (body mass index), lipid profile, obesity, waist circumference, FBS (fasting blood sugar), PPBS (post prandial blood sugar) and serum insulin levels with NAFLD in patients of chronic plaque psoriasis.To correlate serum levels of IL1-β, IL6 and TNF-α with NAFLD in patients of chronic plaque psoriasis. Methods and Materials This was hospital-based, observational study from November 2018 to March 2020. This study was approved by a thesis review board, Lady Hardinge Medical College, Delhi, India. Fifty patients aged ≥18 years, both males and females, with chronic plaque psoriasis of duration ≥6 months with or without psoriatic arthritis and 30 age- and sex-matched controls, with non-inflammatory and non-infectious conditions presenting to Dermatology OPD of Lady Hardinge Medical College (a tertiary care centre Delhi, North India) were included in the study. Psoriasis was diagnosed clinically, and the severity of psoriasis was assessed on the basis of PASI and BSA involved. Patients with exclusive nail psoriasis, scalp psoriasis, palmoplantar psoriasis and guttate psoriasis were excluded. All subjects with excessive alcohol consumption (>14 drinks weekly for males and >7 drinks weekly for females, 1 standard drink contains 14 gram of pure alcohol),[5] smoking >10 pack-years, pregnancy and lactation, HBsAg, HCV antibody and HIV were excluded. All the known cases of diabetes, dyslipidemia, hypertension, Wilson's disease, primary biliary cirrhosis, hepatocellular carcinoma and patients taking oral drugs associated with fatty liver (methotrexate, tamoxifen, corticosteroid and acitretin) in the last 3 months were also excluded to minimize confounding factors of NAFLD.
In all subjects, BMI, waist circumference and blood pressure were measured. PASI and BSA were calculated in cases. Dyslipidemia, hypertension, diabetes and BMI were categorized using NCEP ATP III recommendations, JNC VIII classification, WHO 2006 recommendations and Asian guidelines of BMI, respectively. Waist circumference cut-off points were 102 cm in men and 88 cm in women.[6] Serum levels of IL1- β, IL6, and TNF-α were analysed by ELISA in all subjects. Serum lipids and blood sugar were measured by Beckman-Coulter's fully automated AU series analyser. Fasting serum Insulin was measured by E-CLIA (raised if >25 μIU/mL)). Viral markers (HBsAg, HCV antibody and HIV) were done in all subjects by ELISA. NAFLD was diagnosed by high-frequency B-mode ultrasound, LFT and fibroscan (UTS Fibroscan 402). B-mode ultrasound provided the grades of fatty liver into grade 1, grade 2 and grade 3.[7] Transaminitis was diagnosed by abnormalities of LFT (normal reference levels of total serum bilirubin 0.0–2.0 mg/dL, direct bilirubin was 0.0–0.2 mg/dL, serum ALT <34 IU/L in females and <45 IU/L in males, serum AST <31 IU/L in females and <35 IU/L in males) and raised AST/ALT ratio. Grading of liver fibrosis was done as F0 <5.6 kPa, F1-5.7–6.9 kPa, F2-7.0–8.6 kPa, F3-8.7–10.2 kPa, F4 - >10.3 kPa.[8] SPSS software (V23) was used in the study analysis. Continuous variables were expressed in mean (SD), and categorical variables were expressed in numbers and percentages. T-test, Chi-square test, Fischer's Exact, Mann-Whitney U test and Wilcoxon test were used for analysis. The association of NAFLD with psoriasis and various risk factors were assessed by univariate regression analysis. Statistical significance was assumed at a P value of <0.05.
Observations and Results Both cases and controls belonged to the 4th decade and had male predominance. The male to female ratio in the case group was 1.9:1 and in the control group was 1.7:1 [Table 1]. In some cases, mean ± SD duration of psoriasis was 6.76 ± 5.66 years and mean BSA ± SD involved was 14.98 ± 19.36%. Seventeen (34%) cases had BSA involvement ≥10% indicating severe psoriasis. Mean PASI of cases was 4.85 ± 5.05. Eleven (22%) cases had PASI ≥10 indicating severe psoriasis. Twenty-eight (56.0%) cases and two (6.6%) controls had NAFLD with statistically significant differences. There was a significant difference between cases and controls in terms of high waist circumference, dyslipidemia, serum insulin, interleukin levels, fatty liver, transaminitis, fibroscan score, liver fibrosis and spectrum of NAFLD with all parameters being higher in cases [Table 1] and [Table 2]. Mean age of presentation of cases with NAFLD and cases without NAFLD was 41.00 ± 11.78 years and 37.86 ± 14.41 years, respectively. The prevalence of NAFLD showed a direct association with increasing age besides the 7th decade as shown in [Table 2]. Patients of psoriasis with NAFLD had a female predominance of 12 (70.6%), while psoriatic patients without NAFLD had a male predominance of 17 (51.5%). There was a significant association of NAFLD in psoriatic patients with increasing duration of psoriasis, BMI ≥23 kg/m2, high waist circumference, BSA involved, deranged lipid profile, high LDL levels, high total cholesterol levels and a number of risk factors as shown in [Table 3] and [Table 4]. Although, there was increased number of cases of NAFLD in patients of psoriasis with high levels of IL1 – β, IL – 6, TNF-α, FBS and increasing PASI but the association was not significant [Table 4] and [Table 5]. There was non-significant positive correlation of IL1 – β with PASI (rho 0.060, P value 0.681) and BSA (rho 0.010, P value 0.937). Similarly, non-significant positive correlation of IL-6 with PASI (rho 0.220, P value 0.131) and BSA (rho 0.170, P value 0.170) was found. Weak negative but not significant correlation of TNF-α with PASI (rho 0.130, P value 0.381) and BSA (rho 0.180, P value 0.0213) was found.
Table 3: Clinical characteristics of psoriatic cases with NAFLD vs without NAFLD
Table 4: Biochemical characteristics of cases of chronic plaque psoriasis with NAFLD vs without NAFLD
Table 5: Interleukin levels in cases of chronic plaque psoriasis with NAFLD vs without NAFLD Discussion Similar to the study done by Awosika et al.,[9] insulin resistance, high waist circumference and dyspildemia were found in cases of psoriasis in the present study. In our study, significantly high serum IL1-β, IL-6 and TNF-α were found in cases whereas, Grossman et al.[10] found increased IL-6 in cutaneous lesions of psoriasis and Pirowska et al.[11] found significantly higher levels of TNF-α in cases vs controls.
Out of 80 subjects, 30 (37.5%) had NAFLD. Among cases 28 (56.0%) and among controls 2 (6.6%) had NAFLD and the difference was statistically significant (P = <0.001) with a larger proportion of NAFLD in psoriatic patients. Narayanasamy et al.[12] found 113/250 (45.2%) psoriatic patients with NAFLD while it was 17.4% vs 7.9% in cases vs controls in a study by Madanagobalane et al.[13] In a case control study by Awosika et al.,[9] NAFLD was more prevalent in patients with psoriasis vs controls (21.2% vs. 7.8%). Gisondi et al.[14] also reported a greater frequency of NAFLD in psoriatic patients than in controls with a significant difference (47% vs. 28%; P < 0.0001). In a study from Italy by Miele et al.,[15] 84 (59.2%) patients received a clinical diagnosis of NAFLD. They had done a liver biopsy along with LFT and ultrasonography (USG) to diagnose NAFLD. Liver biopsy is a gold standard tool with the highest efficacy to diagnose NAFLD which might be a possible explanation for the high prevalence of the same in this study. In an old age (>55 years) population-based study from the Netherlands, prevalence of NAFLD was 46.2% in patients with psoriasis compared to 33.3% in controls that was statistically significant. They had also done liver biopsies apart from USG and LFT to detect NAFLD.[16] In a study from Iran by Abedini et al.,[17] prevalence of NAFLD was significantly higher in the psoriatic group compared with the controls (65.6% vs. 35%, P < 0.01, OR = 3.53). In a study from the USA by Roberts et al.,[18] the overall prevalence of NAFLD was 47% and prevalence of NASH was 22% in those who underwent biopsy and prevalence of NAFLD in patients with psoriasis was maximum among Caucasian (71%).
In the present study, 17 (34.0%) cases and 2 (6.7%) controls had fatty liver with a significant difference. Maximum of 11 (64.7%) cases and 2 (100%) controls had grade 1 fatty liver. In a case-control study by Awosika et al.,[9] odds ratio (95 Cl) of fatty liver was 2.63 (0.51–13.6) which was higher in our study [Table 5]. In an Indian study by Narayanasamy et al.,[12] 113/250 (45.2%) cases had fatty liver which is higher as compared to our study (34%). In a South Indian case-control study, fatty liver was found in 35.73% patients that is approximately similar to our study.[13] In our study, 9/28 (32.1%) cases had transaminitis and 19/28 (67.9%) cases had non-transaminitis NAFLD. None of the controls had transaminitis. In a study by Narayanasamy et al.,[12] 110/250 (44%) cases had elevated ALT; among them 9 (3.6%) were HBsAg positive and 1 (0.4%) case was HCV antibody positive. In a South Indian case-control study, 82.4% of patients with psoriasis and NAFLD had transaminitis. The possible explanation for the increased prevalence of transaminitis is the inclusion of cases with HBsAg, HCV antibody, alcohol intake and hepatotoxic drug intake.[13] There was a significant difference between the cases and controls in terms of the distribution of grades of fibroscan and the presence of liver fibrosis. 11/18 (61.1%) patients of psoriasis with NAFLD had fibroscan grade F1 scores similar to the study by Narayanasamy et al.[12] In our study, although comparatively higher but non-significant levels of TNF-α, IL-6 and IL-1 β were found in patients with NAFLD vs without NAFLD. Roberts et al.[18] also reported similar results about TNF-α and IL-1 β besides IL-6 that was significantly associated with NAFLD in cases of psoriasis. Significant association of IL-6 in psoriasis patients with NALFD was also found in the study by de Oliveira et al.[19] and Gisondi et al.,[14] but they did not correlate NAFLD with PASI.
Association of NAFLD with Various Risk Factors: The prevalence of NAFLD was directly associated with increasing age. Male to female ratio in cases of psoriasis with NAFLD was 16/12 and in cases of psoriasis without NAFLD was 17/5. Out of 33 male cases of psoriasis 16 (48%) had NAFLD, while out of 19 female cases of psoriasis 12 (70.6%) had NAFLD. Male predominance in cases with psoriasis with NAFLD had been observed in most of the studies in contrast to our study.[12],[13] Increased proportion of cases of NAFLD was found with increasing duration of psoriasis (P = 0.029) similar to the findings of Narayanasamy et al.[12] The mean BMI of psoriatic patients in cases with NAFLD was 25.77 ± 3.31 kg/m2 and in cases without NAFLD was 22.08 ± 3.63 kg/m2, and the difference was statistically significant (P = 0.001). Significantly increased proportion of patients of psoriasis was found to have NAFLD with increasing BMI especially with overweight and obese patients i.e., BMI ≥23 kg/m2 [23 (69.7%) psoriatic cases with NAFLD vs10 (30.3%) psoriatic cases without NAFLD; P = 0.009]. The association of NAFLD in psoriatic patients with high BMI had been reported in many studies.[9],[12],[14] The association of high waist circumference with NAFLD was significant (P = 0.014) overall and in females (P = 0.009), while it was not significant in males (P = 0.288). In a study by Pongpit et al.,[20] odds ratio in cases of NAFLD with high waist circumference was 1.24 (95% CI: 1.11–1.38; P = 0.0002), which was higher in our study [Box 1].
Narayanasamy et al.[12] and Roberts et al.[18] also reported significantly increased waist circumference in cases of psoriasis with NAFLD. There was a higher but non-significant association of pre-hypertension found with NAFLD in psoriatic patients. No data is available about the association of pre-hypertension with NAFLD in psoriatic patients but both non-significant and significant association of hypertension with NAFLD in psoriatic patients is reported.[12],[14] More number of cases with NAFLD were observed with increasing BSA involved (P = 0.004) except BSA between 30–49% because these patients had normal BMI with low risk factors. Increased but non-significant proportion of cases with NAFLD were found with increasing PASI. Both significant and non-significant association of PASI in psoriatic patients with NAFLD has been reported.[13],[14] Non-significant association of psoriatic cases with NAFLD was found with FBS, PPBS had impaired glucose tolerance. There was a significant association of psoriatic cases with NAFLD with a deranged lipid profile (P = 0.003), high total cholesterol (P = 0.013) and high LDL levels (0.035). Significant association of NAFLD in cases of psoriasis with high triglyceride levels,[12] raised triglyceride and VLDL levels,[9] raised triglyceride and total cholesterol levels,[19] high LDL, total cholesterol, triglyceride and low levels of HDL[13] has been reported. A similar significant association of psoriatic cases with NAFLD has also been found with high total cholesterol levels.[17]
Cases with NAFLD had a significantly higher number of risk factors than cases without NAFLD (P = <0.001). Prussick et al.[4] reviewed that common link in the pathogenesis of psoriasis and NAFLD was low grade inflammation which in turn is the product of common risk factors such as obesity, insulin resistance, pro-inflammatory cytokines, dyslipidemia, hypertension, stress and genetic susceptibility.
Conclusion Significantly increased interleukin levels and their weak positive correlation with the severity of psoriasis (PASI, BSA) in patients of chronic plaque psoriasis explains the possible role of inflammation in the causation of psoriasis. Screening of comorbidities such as dyslipidemia, insulin resistance, and increased waist circumference in cases of psoriasis may be considered. Association of NAFLD with diabetes and hypertension was not possible because the same was excluded as both conditions may precipitate NAFLD. Hence the association of NAFLD with metabolic syndrome was not possible. Also, a lack of standardization in diagnostic methods of NAFLD has been found. Although many recent advancements have been done in the development of non-invasive testing for NAFLD liver biopsy is the gold standard for establishing a diagnosis of NAFLD. There is non-uniformity in the cut-off value of the fibroscan score as well. Association of inflammatory markers IL1-β, IL-6 and TNF-α with NAFLD and the association of NAFLD with PASI and BSA involved in patients of psoriasis was done in the present study. The preliminary findings in the present study indicate a significant association of NAFLD with increasing duration of psoriasis, high waist circumference, high BSA involved, high BMI, obesity, dyslipidemia, high serum LDL and total cholesterol levels in chronic plaque psoriasis patients. A low glycemic, high polyunsaturated fatty acid diet, exercise, quitting smoking and avoiding hepatotoxic medications were recommended to all psoriatic patients to prevent complications and manage psoriasis effectively. For hypertensive and dyslipidemic patients, low salt, low-fat diet and frequent monitoring of blood pressure, blood sugar and lipid profile was advised. Timely screening and correction of these comorbidities should be included in the management of chronic plaque psoriasis patients for preventing long-term metabolic complications of NAFLD. This is an observation hospital-based study with less number of subjects hence, population-based large prospective studies are required.
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Conflicts of interest
There are no conflicts of interest.
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