Serum adipokine profile in Indian men with nonalcoholic steatohepatitis: Serum adiponectin is paradoxically decreased in lean vs. obese patients

Diabetes & Metabolic Syndrome: Clinical Research & Reviews 3 (2009) 198–203

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Original paper

Serum adipokine profile in Indian men with nonalcoholic steatohepatitis: Serum adiponectin is paradoxically decreased in lean vs. obese patients Madhusudana Girija Sanal a,b, Shiv K. Sarin b,a,* a b

Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India Department of Gastroenterology, GB Pant Hospital, New Delhi, India

A R T I C L E I N F O

A B S T R A C T

Keywords: Nonalcoholic fatty liver disease Paradoxical decrease of serum adiponectin in lean Resistin Leptin TNF-a Adipose tissue dysfunction Inappropriate secretion of adipokines Thrifty phenotype

Background: Asian Indians are known to be more insulin resistant for the same degree of weight gain. It is therefore likely that the adipokine profile in nonalcoholic fatty liver disease (NAFLD) in Asian Indian population could be different from the Western subjects. Aims: To study the serum adiponectin, resistin, leptin and TNF-a profile in NAFLD and cryptogenic cirrhosis patients. Subjects and methods: Body mass indices, insulin resistance and serum adipokine levels were studied in 56 patients; 10 with fatty liver, 30 with nonalcoholic steatohepatitis (NASH) and 16 with cryptogenic cirrhosis. Eighteen healthy controls were also included. Results: Patients in general were obese compared to controls (mean BMI 26.9  4.5 vs. 22.6  2.5, respectively, p < 0.0001). In patients with NASH, adiponectin levels were lower than controls (5.4  3 mg/ml vs.7.2  2.9 mg/ml, p = 0.037). Insulin Resistance as assessed by homeostasis model assessment (HOMA) was higher in obese than lean, NAFLD patients (HOMA IR obese, median = 2.8, range = 0.8–16.3 and lean: median = 1.05, range = 0.51–2.75, p = 0.003). Lean NAFLD patients had adiponectin levels lower than obese patients (3  1 mg/ml vs.6.7  3.8 mg/ml respectively, p = 0.003). Serum resistin levels were higher in NAFLD patients (3.7  3 ng/ml) than controls (2.1  1.7 ng/ml, p = 0.007). This difference was significant even when cirrhotic patients were excluded (3.4  2.7 ng/ml, p = 0.036). Serum leptin levels were raised in cryptogentic cirrhosis compared to NASH (p = 0.03). All adipokines tested were raised in cirrhotic patients compared to NAFLD and controls. Conclusions: A significant reduction in serum adiponectin and increase in serum resistin levels were observed in NAFLD patients, more so in lean than obese NAFLD. This paradoxical decrease of serum adiponectin as well as low frequency of insulin resistance in lean NAFLD suggests a possible different etiology for this subset of patients. ß 2009 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction Accumulation of 5–10% extra fat in liver by weight in the absence of alcohol abuse (consumption of alcohol >20 g/day) is defined as nonalcoholic fatty liver disease (NAFLD). It has a spectrum extending from simple steatosis to steatosis with inflammation to cirrhosis of the liver. It is a major cause of morbidity and has been considered as the hepatic component of metabolic syndrome. The metabolic syndrome is an evolving health problem not only in the developed but also the developing world due to life style changes and dietary habits as a result of a rapid socioeconomic transition. High blood pressure, cholesterol

* Corresponding author at: Department of Gastroenterology, GB Pant Hospital, New Delhi 110002, India. Tel.: +91 11 23232013. E-mail address: [email protected] (S.K. Sarin).

and obesity are associated with it [1–3]. It is predicted that by 2030 India would have an estimated 79.4 million diabetics [4]. Adipokines, the hormones secreted by the adipose tissue, such as adiponectin, leptin, resistin, TNF-a and interleukin-6 have an important role in the development of insulin resistance and NAFLD [2,5]. Adiponectin is an insulin sensitizing hormone with antiinflammatory action. It is found to be protective against steatosis and inflammation of liver [6]. Hypoadiponectinemia is a feature of NAFLD and adiponectin level correlates negatively with the hepatic fat and insulin resistance [7,8]. Resistin is an adipokine associated with insulin resistance and has pro-inflammatory action [5,9]. Resistin can selectively impair insulin action on glucose production. Resistin infusion in mice can result in severe hepatic insulin resistance [10]. Leptin plays a role in appetite regulation and adaptation to reduced energy availability [9,11]. Leptin is directly involved in hepatic fibrogenesis through hepatic stellate cell activation [12]. However, the role of leptin in NAFLD is debatable

1871-4021/$ – see front matter ß 2009 Diabetes India. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dsx.2009.07.012

M.G. Sanal, S.K. Sarin / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 3 (2009) 198–203

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[13,14]. TNF-a is an adipokine that impairs insulin signaling and is pro-inflammatory and might play an important role in the pathogenesis of NAFLD [5,7]. We have earlier shown that serum TNF levels are raised in patients with NASH and they are significantly reduced after treatment with inhibitor of TNF-a, such as pentoxyfylline [15]. The fact that the histological changes also regress after treatment with pentoxyfylline, is a further proof of the pathogenic role of this adipokine [16]. There is limited data where all these adipokines have been evaluated together in a given characterized population. Moreover, it is presumed that Indians differ from the population in the West genotypically, phenotypically as well as in relation to their dietary habits and lifestyle which may make them more vulnerable to metabolic syndrome and NAFLD [17–20]. However, there is no detailed study of serum adipokines in the Indian patients with NAFLD. Due to various biological phenomenon, hormonal variations, we included only male patients in our study. Furthermore, in our previous studies, majority of the patients had been males [15,16,21].

Blood collected from patients with over night fasting was used to measure the levels of adiponectin, insulin, resistin and TNF-a. The blood plasma level of adiponectin, TNF-a, leptin and resistin was determined with commercial immuno-assay kits (Biosource, Belgium). Serum insulin was assayed using radio immuno-assay.

2. Subjects and methods

2.2. Anthropometric and laboratory evaluations

Male patients attending the out patient department of the GB Pant Hospital, India, who fulfilled the criteria for fatty liver or NASH and cryptogenic cirrhosis were screened for inclusion in the study. Inclusion criteria: Age: 18–75 years, ultrasound with diffusely echogenic liver, with normal or elevated ALT (>1.5 times upper limit of normal), and liver histology showing steatosis with or without lobular necro-inflammatory activity, Mallory hyaline and fibrosis. For the diagnosis of NASH, raised ALT and histological injury was considered essential. The severity of histological lesions were graded according to Brunt et al. [23] Exclusion criteria: Alcohol abuse (>20 g/day), evidence of viral or autoimmune hepatitis, Wilson’s disease, haemochromatosis, primary biliary cirrhosis and biliary obstruction and presence of any severe systemic illness like congenital cardiac disease, chronic renal failure, chronic obstructive pulmonary disease and malignancies. Patients who were on treatment with hepatotoxic drugs or drugs known to alter lipid or carbohydrate metabolism, within the prior 6 months were excluded from the study. Fatty liver and NASH patients were picked up on detection of fatty liver on a routine abdominal ultrasonography or a CT examination or an abnormal liver function test (with ALT raised >1.5 times the upper normal values for 6 months or more); usually done on routine screening or for some unrelated cause. Ultrasound scan was repeated in these patients to reconfirm a diffusely hyperechoic pattern suggestive of fatty liver. We used ultrasound scanning which is quite sensitive in detecting fatty liver [22], clinical and biochemical findings alone especially in fatty liver due to ethical concerns. A detailed clinical assessment was done on every patient. Laboratory investigations included a complete hemogram, serum aminotransferases, total proteins, albumin, alkaline phosphatase, bilirubin, HBsAg, anti-HBe, anti-HCV, auto antibodies (anti-nuclear, anti-mitochondrial, anti-smooth muscle antibodies), serum iron profile, ceruloplasmin, serum cholesterol, HDL, LDL, triglycerides, fasting blood sugar and oral glucose tolerance test (in non-diabetic) and serum creatinine. The criteria for enrolling ‘cryptogenic’ cirrhosis included the evidence of cirrhosis (on clinical radiological, biochemical and or histopathlogical criteria) and absence of all known etiological causes of cirrhosis except NASH, i.e. absence of markers of HBV, HCV, autoimmune, metabolic and alcoholic liver disease. We thus grouped our study subjects into three categories—(i) fatty liver with persistently normal ALT (fatty liver), (ii) fatty liver with persistently raised ALT (NASH) and, and (iii) cryptogenic cirrhosis. We had 10, 30 and 16 patients in the first, second and third groups, respectively.

All subjects underwent a thorough clinical, anthropometric and biochemical investigation. BMI was calculated as weight in kilograms divided by the square of height in meters. A BMI between 25 and 29.9 was taken as ‘‘overweight’’, and greater than or equal to 30 as ‘‘obese’’, according to the standard definition of WHO [24]. We however, followed in this study the modified proposal for classification of weight by BMI in adult Asians by WHO [20] according to which BMI between 18.5 and 22.9 was taken as normal, 23 as over weight (23–24.9 at risk, 25–29.9 Obese 1 and 30 Obese 2). We classified subjects having a BMI less than 23 as lean and those having a BMI equal to or greater than 23 as overweight/obese. The components of the metabolic syndrome (MS) were classified according to the modified form of Adult Treatment Plan-III with an adjustment in the waist circumference by lowering the cut-off to 90 cm and 80 cm respectively for men and women to suit the Asian population [25,26]. The diabetic status was assessed according to the criteria of the American Diabetes Association [27] and Insulin Resistance was assessed by homeostasis model assessment (HOMA) [28]. (HOMAIR = [fasting blood glucose (mmol/l)  fasting insulin m (IU/ml)]/ 22.5).

Liver biopsy was done in 25 of the 30 patients who had a fatty liver with raised ALT. The biopsies were evaluated by two pathologists (P.S. and V.M.) according to the criteria proposed by Brunt et al. [23]. Controls: Eighteen men, with no evidence of any disease except for two who had mild to moderate hypertension but were not under treatment, were taken as healthy controls (age range: 25–67 years). The patients as well as controls were explained about the study protocol and a written informed consent was obtained. The protocol of the study was approved by the institutional ethics committee. 2.1. Estimation of serum adipokines and insulin

2.3. Statistical analysis The data was analyzed using standard statistical techniques using Microsoft Excel (MS Office 2003, Microsoft Corporation, USA) and ‘Microstat’ (Ecosoft Inc., 1984) and SPSS 11 for Windows (SPSS Inc.). Levene’s test was done to assess the homogeneity-ofvariance of variables in groups under study. Unpaired (2 tail) Student’s t-test was performed to find any significant difference between the two groups, assuming equal or unequal variance as determined by the Levene’s test. Mann–Whitney U-test was used when the Assumptions for Student’s t-test were suspect. Tamhane’s T2 test or Kruskal–Wallis test was done to compare multiple means as the assumptions behind the standard ANOVA were suspect. Spearman’s rho correlation was used to establish association between the variables. Chi-square test/Fishers’ exact test was used to compare proportions, whichever appropriate. 3. Results 3.1. Clinical profile of the study population The prevalence of diabetes, hypertension and obesity was significantly higher in the patient group with reference to the

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Fig. 1. The patient groups when compared to control shows significant difference in the frequency of Metabolic Syndrome defined according to the modified ATP-III criteria for Asian population (p < 0.001, Pearson Chi-square test).

Table 1 Anthropometrical, clinical and laboratory measurements in patients and controls.

N Age (years) BMI (kg/m2) Obese (BMI > 25) Waist circumference (cm) Systolic BP (mmHg) Diastolic BP (mmHg) Hypertension FBS (mg/dl) Diabetes mellitus Fasting insulin (mU/ml) HOMA-IR ALT (U/l) AST (U/l) HDL–cholesterol (mg/dl) Triglycerides (mg/dl)

Control

Patients

p

18 44 (8) 22.6 (2.5) 5.5 (1) 84 (6.6) 118 (8) 84.8 (8) 5.5 (1) 84 ( 8) 0 5.8 (2.2–16.4) 1.3 (0.4–3.4) 25 (6) 22 (5) 47 (7) 130 (64–173)

56 43 (14) 26.9 (4.5) 35 (62.5) 94.6 (12) 127 (10) 104(42) 25 (14) 104 ( 42) 26.7(15) 13 (2.6–80.3) 2.7 (0.51–36) 61 (45) 51 (42) 38 (6) 144 (58–980)

– 0.7 <0.001 <0.001 <0.001 0.001 <0.001 0.001 0.001 <0.001 0.006 <0.001 <0.001 <0.001 <0.001 0.04

Results expressed as mean (standard deviation) or median (range) or percentage (actual number).

control group. The patient groups when compared to control shows significant difference in the frequency of Metabolic Syndrome defined according to the modified ATPIII criteria for Asian population (p < 0.001, Pearson Chi-square test) (Fig. 1). About 25% of the patients and equal proportion of controls

Fig. 2. Bars represent the mean adipokine values. Values above a bar cluster is the p value pertaining to the corresponding category obtained by Kruskal–Wallis Test. Adiponectin in mg/ml, leptin in ng/ml and TNF-a in pg/200 ml, resistin in ng/ml.

belonged to the poor socioeconomic class (manual laborers, farmers or partly unemployed). A comparison of the anthropometric, clinical and biochemical data of the patients vs. controls are summarized in Table 1 and the comparison between the patient-groups are summarized in Table 2. Cirrhosis patients were older, more obese and insulin resistant than patients with fatty liver and NASH (Table 2). 3.2. Serum adiponectin in NAFLD and cryptogenic cirrhosis Serum adiponectin was decreased in NASH with reference to the controls (NASH 5.36  3 mg/ml, controls 7.2  2.9 mg/ml, p = 0.037) while cryptogenic cirrhosis patients had adiponectin level raised among all categories (cirrhosis 10.2  5.8 mg/ml, p = 0.003) (Fig. 2). Serum adiponectin correlated positively with HOMA-IR (r = 0.42, p = 0.006) and correlated negatively with ALT (r = 0.35, p = 0.007) (Table 3). 3.3. Serum leptin in NAFLD and cryptogenic cirrhosis Serum leptin levels were raised in cryptogentic cirrhosis in comparison with ‘fatty liver’, NASH and controls. The difference between cirrhosis and NASH was significant (median = 8.5, range: 0.5–44 ng/ml and median = 3.4 ng/ml, range: 1–19.7, respectively, p = 0.03) but there was no difference between cirrhosis and ‘fatty liver’ (fatty liver: mean 4.7  1.8, median 5.0, range: 1.4–7.4 ng/ml)

Table 2 Anthropometrics, clinical and laboratory measurements in patients groups.

N Age (years) BMI (kg/m2) Waist (cm) Sys.BP (mmHg) Dia.BP (mmHg) FBS (mg/dl) HOMA-IR Insulin (mU/l) Triglycerides (mg/dl) HDL (mg/dl) ALT (U/l) AST (U/l)

‘Fatty liver’

NASH

Cirrhosis

p

10 46 (13.6) 26.6 (4) 96.7 (13) 130.8 (18) 83 (6) 102.6 (31) 1.93 (0.94–16.3) 8.3 (4.3–56) 137 (80–266) 40.4(5) 30 (14–47) 25 (14–32)

30 34.7 (9.3) 26.4 (4) 91.9 (11) 125 (8) 82 (5) 102.7 (51) 2.6 (0.5–12.1) 12.5 (2.6–50) 160 (64–980) 37.9(6) 65 (46–221) 45 (21–290)

16 56.6 (10) 28.5 (4) 98.3 (12.7) 128 (7) 85 (6) 107.1 (29) 5.2 (2.7–36.4) 23.7 (12–80.3) 103 (58–206) 38 (6) 38 (16–96) 42 (26–127)

– <0.001A 0.2A 0.18A 0.3A 0.18A 0.94A 0.021KW 0.026KW 0.06KW 0.5A <0.001KW <0.001KW

Results expressed as mean (standard deviation) or median (range). A ANOVA. KW Kruskal–Wallis test.

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Table 3 Correlation between adipokines with anthropometrical and biochemical parameters. BMI

Waist

Systolic BP

HDL

TG

Insulin

IR

ALT

AST

Adiponectin

ns

ns

ns

ns

0.29 0.01

0.4 0.005

0.42 0.006

0.35 0.007

ns

Leptin

0.58 <0.001

0.6 <0.001

ns

ns

0.32 0.02

0.44 0.003

0.43 <0.004

ns

ns

Resistin

Ns

ns

ns

ns

ns

ns

ns

0.35 0.01

ns

TNF-a

0.23 0.07

ns

0.27 0.046

ns

ns

0.35 0.02

0.32 0.03

ns

0.26 0.05

Results expressed as correlation coefficient (Spearman-Rho, non-parametric ‘r’) and ‘p’ value. ns = not significant.

or NASH and ‘fatty liver’ (Fig. 2). There was no significant difference in the BMI among patient groups. In patient population serum leptin correlated positively with BMI, waist circumference, insulin and HOMA-IR negatively with triglycerides (Table 3). 3.4. Serum resistin in NAFLD and cryptogenic cirrhosis Serum resistin was increased in the patient population (3.7  3 ng/ml) than the controls (2.1  1.7 ng/ml, p = 0.007) but the difference was significant even when cirrhosis patients were excluded (3.4  2.7 ng/ml, p = 0.036) (Fig. 2). Serum resistin did not differ significantly among the patient groups. In patients there was no significant correlation between serum resistin and BMI, waist circumference, HDL or triglycerides. Serum resistin showed a positive but non-significant correlation with HOMA-IR (r = 0.14, p = 0.3) (Table 3). 3.5. Serum TNF-a in NAFLD and cryptogenic cirrhosis Serum TNF-a was significantly elevated in cryptogenic cirrhosis and NASH with reference to ‘fatty liver’ or controls (cirrhosis median 49.9 (5.6–300), NASH median 31 (9.9–288), ‘fatty liver’ median 21.5 (4.8–242), controls 0.65 (0.1–10.8) pg/ml, p < 0.001 by K–W) (Fig. 2). Among patients, serum TNF-a showed a positive correlation with blood pressure, serum insulin, HOMA-IR and AST (Table 3). 3.6. Serum adiponectin is decreased in lean NAFLD Based on BMI, all patients except cryptogenic cirrhosis were grouped into two (i) lean (BMI < 23), (ii) over weight (BMI  23).

Fig. 3. Serum adiponectin-lean vs. over weight NAFLD patients.

The mean serum levels of all adipokines studied were decreased in lean–(lean vs. over weight: adiponectin 3.0  1 mg/ml vs. 6.7  3.8 mg/ml, p = 0.003; resistin 2.4  2.1 ng/ml vs. 3.6  2.8 ng/ ml, p = 0.29; leptin 2.9  1.7 ng/ml vs. 5.1  4.4 pg/ml, p = 0.18 and TNF-a median: 24 (4.8–41) vs. 31.8 (6–288), p = 0.09). Serum adiponectin is negatively correlated with obesity but here in lean NAFLD serum adiponectin is paradoxically reduced (Fig. 3). The lean NAFLD is significantly less insulin resistant than their counter parts (HOMA-IR: lean median = 1.05, range = 0.51–2.75; over weight: median = 2.8, range = 0.8–16.3, p = 0.003; serum insulin: lean mean 5.6  3.2, over weight mean 17.3  13.1, median: 13.1, range: 4.3–56, p < 0.001). 4. Discussion The present study is first of its kind from the Indian subcontinent; highlighting the role of adipokines in the pathogenesis of NAFLD. We observed a decreased concentration of adiponectin in NASH with reference to the controls though it was statistically significant. Interestingly, the lean NAFLD patients had adiponectin levels lower than over weight patients. This is a previously unreported observation. Serum resistin levels were significantly increased in the patient population than controls. This difference was significant even when cirrhotic patients were excluded. Serum leptin levels were raised in cryptogentic cirrhosis in comparison with ‘fatty liver’, NASH and controls. Fatty liver patients were older by a decade to NASH patients and cirrhosis patients. As expected, the patients in general, were markedly obese than the controls. Obese NAFLD patients (BMI  23, n = 32) were more insulin resistant than lean (BMI < 23, n = 8) patients (HOMA-IR: over weight: mean = 4.4  3.8 median = 2.8, range = 0.8–16.3 and lean: mean = 1.3  0.74, p = 0.003). We hypothesize that the observed paradoxical decrease of serum adiponectin as well as low insulin resistance in lean NAFLD is due to a different pathogenic process. Kagansky et al. [29] reported NAFLD as a common finding in octogenarians (and hence benign) in comparison with the general population. The ‘fatty liver’ patients were older than NASH and had higher serum adiponectin and probably the higher values of serum adiponectin might have protected these patients from progressing of NASH. There are several reports about the protective effects of adiponectin in NAFLD. It has been reported that administration of recombinant adiponectin in ob/ob mice reduces hepatomegaly and steatosis and attenuates inflammation in both alcoholic and nonalcoholic fatty liver [6]. The beneficial effects of rosiglitazone in NAFLD may be due to its effect on adiponectin gene expression [30]. Some recent reports suggest an upregulation of adiponectin in acute liver failure in response to inflammation which could be a negative feed back mechanism to raised pro-inflammatory cytokines [31].

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We observed an increase in serum adiponectin and other adipokines in cryptogenic cirrhosis. Raised adiponectin level in advanced liver fibrosis was reported before [32] and our study is in agreement with the same in our study population of cryptogenic cirrhosis. The higher adiponectin levels could be due to reduced hepatic extraction rather than a feed back response to inflammation. Serum resistin level was elevated in ‘fatty liver’, NASH and cirrhosis in comparison with the controls but was statistically significant even when cirrhosis patients were excluded. Our patient population has high level of insulin resistance than the controls. The possibility that resistin has a role in the pathogenesis of fatty liver cannot be excluded. Serum leptin levels increase with obesity and reduced leptin function as a signal of negative energy balance [9,11]. Leptin induces hepatic fibrogenesis through stellate cell activation and is important in induction of fibrosis in response to chronic liver injury in animal models [12]. Though the role of leptin in NAFLD is debated in man [13,14]; we have observed elevated levels of leptin in all patient groups, this could be due to relatively high BMI in patients vs. controls. In cirrhosis patients, at least partly it could be due to decreased hepatic leptin clearance. However whether the elevated leptin played any role in the progression of steatosis to fibrosis in these patients remains elusive. TNF-a is a pro-inflammatory adipokine, which plays a central role in insulin resistance [5]. TNF-a is raised in all patient groups and its levels correlate with insulin resistance and serum ALT levels. The serum TNF-a was significantly elevated even in ‘fatty liver’ and might suggest a role in NAFLD pathogenesis independent of its pro-inflammatory effect. Hypoadiponectinemia is a feature of NAFLD and contributes to necroinflammatory forms of NAFLD [7]. All studies so far uniformly agree that adiponectin is negatively correlated with BMI and adipose tissue mass [33,34,7,8]. However we observed a paradoxical decrease in serum adiponectin levels in lean NAFLD patients in comparison with their over weight counter parts. There lean NAFLD subset also had a significantly lower HOMA-IR and serum insulin level. These findings might suggest an altogether different etiopathology for this subset of NAFLD. It is known that inherited (e.g. hereditary lipodystrophy) or acquired defects in adipose tissue is associated with ectopic fat distribution and steatosis [35,36]. So lean NAFLD might represent a subset of NAFLD where defects in adipose tissue development, secretion and ‘adipose tissue-liver communication’ takes a major role in the pathogenesis [3]. Chronic malnourishment is very prevalent in the Indian subcontinent. Perhaps chronic malnourishments over generations have favored thrifty genotypes making Indians more prone to hazardous effects of obesity. Alternatively, fetus of a malnourished woman might adapt itself for a thrifty life during the intrauterine life. After birth, once these individuals are exposed to calorie rich diet, they will develop IR early compared to normal individuals for the same weight gain. This is in accordance with the thrifty phenotype hypothesis by Barker [37,38], which proposes that environmental factors are the dominant cause of type 2 diabetes. Extending this hypothesis the adipose tissue of the developing fetus would be adapted for malnourishment. But after birth once these individuals are exposed to a calorie rich diet the maladapted adipose would respond by inappropriate secretion of adipokines compared to normal individuals. This dysfunctional adipose tissue would in turn tip off ‘energy homeostasis signaling mechanisms’ resulting in fatty liver and insulin resistance. This indicates the illeffects of rapid socioeconomic changes and the hazards of fast spreading Western food culture in the developing world. In conclusion, we observed an increase in serum adiponectin, resistin and leptin in cryptogenic patients with reference to other patient groups as well as controls. The serum adiponectin level was decreased in NASH compared to the controls. There was a decrease

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