Authored by Golam Mustafa
Abstract
Objective: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excessive triglyceride accumulation in the hepatocytes. NAFLD describes a spectrum of clinicopathological changes extending from simple steatosis through non-alcoholic steatohepatitis (NASH) to fibrosis. Aim of the study was to assess the correlation of serum adiponectin with severity of NAFLD.Methods: It was an observational, cross sectional study. Fifty patients who fulfilled the inclusion criteria of NAFLD were included in the study; they were studied with liver histology and serum adiponectin level. Correlation of serum adiponectin with non- NASH, NASH and stages of liver fibrosis was analyzed.
Result: Mean age was 38.0±9.4 years with range from 20 to 59 years with female predominance (62%). Serum adiponectin level was 9.09±3.68 microgram/mL in patients with non-NASH(n=17), and it was 4.90±2.34 microgram/mL in those with NASH(n=33). Serum adiponectin was 6.57±3.84 microgram/mL in 38 patients with fibrosis score 1; it was 5.51±1.84 microgram/mL in 10 patients with fibrosis score 2; and it was 5.59±1.08 microgram/mL in 2 patients with fibrosis score 3.
Conclusion: Serum adiponectin level decreased in patients with NASH than in patients not having NASH, and it is also reduced in patients with advanced hepatic fibrosis.
Keywords: NAFLD; NAS; Adiponectin; NASH
Introduction
Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excessive triglyceride accumulation in the hepatocytes. It is a hepatic manifestation of metabolic syndrome [1]. The prevalence of NAFLD in India above 20 years age was 18.9% [2]. The prevalence of NAFLD increased with increased age. Obesity, diabetes mellitus (DM), insulin resistance (IR) are predisposing factors for NAFLD. Although NAFLD is more common in subject with obesity and diabetes mellitus (DM), it also occurs in lean and non-diabetic subject [3,4,5]. Non obese was 25.6% among NAFLD patient in Bangladesh. About 53.1 % of non-obese NAFLD cases were NASH [6].NAFLD consists of a wide spectrum of conditions, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which can progress to cirrhosis and hepatocellular carcinoma (HCC). The prevalence of NASH is 42.4% among NAFLD patients in Bangladesh [7]. The contrasting clinical course of NASH vs non-NASH fatty liver (NNFL) indicates that these two conditions diverge early in the course of NAFLD. A progression to cirrhosis is usually preceded by longstanding histological NASH and is infrequent during NNFL. Overall, 37.5% of normal serum Alanine Aminotransferase (ALT) group had NASH or advanced fibrosis, whereas 53% of elevated ALT had NASH or advanced fibrosis [8].
NASH is a common cause of “cryptogenic” cirrhosis, which accounts for 10%-20% of all cirrhosis cases [9]. The pathogenesis of NAFLD is the “multi-hit hypothesis” with metabolic syndrome playing a major role, due to insulin resistance and the proinflammatory process mediated by different proteins and immune components [10]. Adiponectin also known as adipocyte complement related protein of 30kDa (ACRP30), is a protein that is a product of the adipose tissue-specific transcript-1 (apM1) gene [11]. Adiponectin is induced during adipocyte differentiation, and its secretion is stimulated by insulin and binds to two different receptors termed AdipoR1 and AdipoR2. AdipoR1 is found primarily in skeletal muscle whereas AdipoR2 is primarily found in hepatic tissue [12].
Adiponectin is a fat-derived hormone that circulates at relatively high concentrations in the serum [13] also derived from the placenta in pregnancy. This adipocytokine is believed to mediate insulin action in insulin-sensitive tissues, such as the liver and the muscles, in both humans and animals [14]. Especially in the liver, adiponectin stimulates glucose utilization and fatty acid oxidation by activating the adenosine monophosphate-activated protein kinase, thus mediating hepatic insulin action [15,16]. There are increasing data in the literature indicating that the serum adiponectin correlated with Homeostatic model assessment (HOMA) (Pearson correlation coefficient r = -0.544, P=0.001).
Adiponectin concentration was negatively associated with higher stages of fibrosis (one-way analysis of variance, P=0.007), and was not associated with NAFLD activity score. Low serum adiponectin levels in NAFLD patients are suggestive of advanced fibrosis. Therefore, assessment of serum adiponectin levels may be useful in clinical follow-up [17]. The pathological committee of the NASH clinical research network designed and validated a histological feature scoring system that address the spectrum of lesions of NAFLD and proposed Nonalcoholic fatty liver disease Activity Score (NAS) for use of clinical trial.
The scoring system comprises steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and a separate fibrosis staging (0-4). The proposed NAS is the sum of steatosis, lobular inflammation and hepatocellular ballooning score. NAS of ≥5 correlated with diagnosis of NASH and biopsy with scoring of 3-4 suggestive of NASH and less than 3 were diagnosed as non- NASH fatty liver [18]. Other pathological findings such as Mallory denk bodies or perisinusoidal fibrosis can make the diagnosis even stronger. Fibrosis Stage evaluated separately from NAS; Stages F0, F1, F2 were considered early fibrosis and Stage F3, F4 were considered to be advanced fibrosis [19]. As NASH, fibrosis and cirrhosis is a histological diagnosis, liver biopsy is needed to establish or rule it out definitively. However, it is not practical to do biopsy in every patient with suspected NAFLD. Therefore, a noninvasive marker that can signify the presence or absence of NASH and/or fibrosis is highly demanding.
NAFLD and Adiponectin
NAFLD has a multifactorial disorder associated with obesity, insulin resistance, type 2 diabetes and dyslipidemia. Moreover, genetic mutations also play a role in predisposition to the development and progression of NAFLD [20]. Especially in the liver, adiponectin stimulates glucose utilization and fatty acid oxidation by activating the adenosine monophosphate-activated protein kinase, thus mediating hepatic insulin action 15,16. Adiponectin also manifests anti-inflammatory action by neutralizing tumor necrosis factor-alpha13 and antifibrotic action by inhibiting hepatic stellate cell proliferation and migration [21]. It was found that serum adiponectin levels in patients with NAFLD ranged between 0.4 and 13.2 μg/mL, which is lower compared with normal values (5 to 30 μg/mL) and is consistent with the findings of other investigators in patients with NAFLD [22]. Objective of the study was to correlate serum adiponectin level with severity of nonalcoholic fatty liver disease (NAFLD).NAFLD
It is reported that almost 10% to 20% of individuals with NAFLD have NASH and 10%-15% of individual with NASH progress to cirrhosis [23]. The prevalence of NASH is 42.4% among NAFLD patients in Bangladesh [7]. Longitudinal studies with serial biopsies have shown that approximately one-third of NASH patients develop advanced fibrosis (stage 3 or 4 fibrosis) over the course of 5-10 years from the time of the initial diagnosis [24,25]. Although it is usually relatively slow, the progression to cirrhosis can occur in as little as 2-3 years.NASH
Is a common cause of “cryptogenic” cirrhosis, which accounts for 10%-20% of all cirrhosis cases [9]. Among patients diagnosed with NASH related cirrhosis, the risk of developing portal hypertension (a major complication) is 17%, 23% and 52% at 1, 3 and 10 years, respectively. Among the patients with early-stage of NASH, the overall mortality over 10-15 years is approximately 10%-12%, being significantly higher in the NASH vs the NNFL patients, compared to the general population. The risk of developing decompensated cirrhosis is 5%-10%, and that of hepatocellular cancer is 1%-2%. There is a ten-fold increased risk of cirrhosis relative to the general population [26].Methods
It was an observational cross-sectional study carried out in the department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, during the period from July’2016 to August’2017. Ethical Clearance was approved by the Institutional Review Board (IRB). Sixty-five patients with ultrasonographic evidence of fatty infiltration of the liver attending the outpatient and inpatient department of Hepatology, BSMMU were initially selected. Those with significant alcohol intake (consumption of more than 14 units /week in women and more than 21 units /week in men), history of taking drugs that may cause fatty liver (e.g., tamoxifen, sodium valproate, amiodarone, MTX, corticosteroid), known or overt case of any other liver diseases (e.g., Chronic hepatitis B, chronic hepatitis C, Autoimmune liver disease, Haemochromatosis, Wilson’s disease, Primary biliary cirrhosis), pregnancy, and other co-morbid conditions (e.g., chronic obstructive pulmonary disease, chronic kidney disease, cardiac failure) were excluded from the study. Of the initially included patients, fifty patients (those who have given informed written consent, and those who fulfilled the inclusion criteria) of age 20 to 50 years, with Nonalcoholic fatty liver disease (NAFLD) were finally included.Study procedure
Included patients were advised to do serum sampling for complete blood count (CBC), fasting blood sugar (FBS), blood sugar 2 hours after breakfast (BS 2hrs ABF), Bilirubin, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Prothrombin Time (PT), Thyroid Stimulating Hormone (TSH), Fasting lipid profile, HBsAg (ELISA), Anti HBc (Total) & Anti-HCV (ELISA), Serum ferritin, Serum ceruloplasmin, and antinuclear antibody (ANA). The degree of insulin resistance (IR) was determined by the homeostatic model assessment (HOMA) using the formula, HOMA-IR = (FPI × FPG)/22.5. Patients with HOMA >1.78 were considered insulin resistant [28].They were hospitalized for liver biopsy after adequate counseling. Percutaneous liver biopsy was done for each patient following standard procedure. Following biopsy, liver tissue, preserved in 10% formol saline, was sent to a Pathologist for NAS & fibrosis score. On the morning of liver biopsy, 3 ml of venous blood sample was drawn to determine serum adiponectin level. Serum adiponectin levels were determined by an enzyme-linked immunosorbent assay (ELISA) kit (Quintikine) obtained from R&D Systems (Wiesbaden-Nordenstadt, Germany).
The histological diagnosis of NAFLD (NNFL & NASH) was based on NAFLD Activity Score (NAS), and stages of fibrosis were evaluated by fibrosis score. All other biochemical tests were performed using conventional automated analyzers within the Biochemistry Laboratory at BSMMU. All biochemical analyses were performed in a “blinded” manner.
Data processing and data analysis
Data were collected using structured questionnaire. The statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS) version 23.0 for Windows (SPSS Inc., Chicago, Illinois, USA). The mean values were calculated for continuous variables. The quantitative observations were indicated by frequencies and percentages. Chi-Square test was used to analyze the categorical variables, shown with cross tabulation. Student t-test was used for continuous variables. ANOVA test was used to analyze the continuous variables, shown with mean and standard deviation. Pearson’s and spearman’s correlation coefficients were used to test the relationship between the groups. Sensitivity and specificity were calculated by using the area under the receiver operating characteristic (ROC) curves. P value of <0.05 was taken as significant.
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