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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 41  |  Issue : 4  |  Page : 327-335

Serum leptin and ghrelin concentrations in chronic hepatitis C genotype-4 patients with steatosis: their effect on the response to antiviral therapy


1 Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Diagnostic Radiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission13-Aug-2013
Date of Acceptance01-Sep-2013
Date of Web Publication1-Feb-2014

Correspondence Address:
Mohamed S Abd El Gawad
Department of Internal Medicine, Mansoura University Faculty of Medicine, Elgamaa street, Mansoura City
Egypt
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DOI: 10.4103/1110-1415.126198

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  Abstract 

Background
The precise pathogenic mechanisms of steatosis among patients with chronic hepatitis C (CHC) still remain largely unknown. Recent evidences identified various adipokines and gut hormones as relevant modulators of the pathophysiology of liver fibrosis and steatosis progression. We assessed whether pretreatment serum leptin and ghrelin concentrations differ in steatotic patients infected with hepatitis C virus (HCV) genotype-4 and whether these concentrations are associated with response to antiviral treatment.
Participants and methods
This study was conducted on 50 patients with CHC genotype-4 and steatosis and 25 age-matched healthy participants as a control group. Patients were treated with Peg-interferon and ribavirin for 48 weeks, independent of virologic response. Serum HCV-RNA concentrations were measured before the initiation of treatment and at weeks 12, 24, and 48 during the treatment. The genotype was determined using INNO-LIPA HCV assays, and serum leptin and ghrelin concentrations were measured using enzyme-linked immunosorbent assay. Biopsy specimens were scored according to the Ishak system, and steatosis was graded as mild, moderate, or severe.
Results
We found high insulin resistance and serum leptin concentrations and low plasma ghrelin concentrations at baseline in patients with CHC compared with the healthy controls (P = 0.000). Serum leptin levels tend to increase (P = 0.023), whereas plasma ghrelin levels tend to decrease (P = 0.004) as the grade of steatosis worsens. Plasma ghrelin at baseline showed significant negative correlations with insulin resistance and leptin. However, we did not find any correlations between leptin, ghrelin, insulin resistance, hepatic fibrosis, and hepatic steatosis with viral load. Sustained virological response (SVR) was achieved in 28 patients (56%) and was associated with a lower grade of liver steatosis (P = 0.013), milder fibrosis (P = 0.002), low value of insulin resistance (P = 0.001), lower leptin levels (P = 0.005), and higher ghrelin levels (P = 0.001), whereas patients who did not achieve SVR (nonresponder) had significantly higher leptin and lower ghrelin concentrations at baseline, with significant difference as the severity of steatosis worsened.
Conclusion
Increased serum leptin before treatment may predict non-SVR, whereas increased ghrelin may predict SVR. Ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy.

Keywords: Chronic hepatitis C, ghrelin, hepatic steatosis, HOMA-IR, leptin, sustained virological response


How to cite this article:
Abd El Gawad MS, Hakim H, Elrakhawy MM, El Masry EI. Serum leptin and ghrelin concentrations in chronic hepatitis C genotype-4 patients with steatosis: their effect on the response to antiviral therapy. Tanta Med J 2013;41:327-35

How to cite this URL:
Abd El Gawad MS, Hakim H, Elrakhawy MM, El Masry EI. Serum leptin and ghrelin concentrations in chronic hepatitis C genotype-4 patients with steatosis: their effect on the response to antiviral therapy. Tanta Med J [serial online] 2013 [cited 2020 Jun 6];41:327-35. Available from: http://www.tdj.eg.net/text.asp?2013/41/4/327/126198


  Introduction Top


Persistent hepatitis C virus (HCV) infection is widespread; it affects millions of people worldwide and induces a range of chronic liver diseases [1] . Egypt has the highest countrywide prevalence of HCV in the world; about 12-15% of total population are infected [2] with HCV genotype-4 (HCV-4), accounting for the overwhelming majority of HCV infections [1] .

HCV infection increases oxidative stress, tissue damage, and proinflammatory cytokine secretion, all of which contribute to progressive fibrosis, cirrhosis, cancer, and liver failure [3] . Recent data suggest a close relationship between HCV infection and metabolic syndrome [4] . It is possible that HCV infection causes fatty liver disease, a precursor of hepatic steatosis, which is a recognized component of metabolic syndrome, causing wide adipocytokines changes and impaired glucose metabolism leading to increased prevalence of insulin resistance (IR) and type 2 diabetes [5] . This association is important because several studies have shown that the presence of IR is associated with increased rates of fibrosis [6] and lower rates of rapid and sustained response to antiviral therapy. However, the mechanisms of metabolic syndrome-induced interferon (IFN) resistance are not completely understood [1] .

Leptin is an adipokine that contributes to the pathogenesis of liver steatosis [7] . In patients with chronic hepatitis C (CHC), higher serum leptin concentrations have been associated with the presence of steatosis [8] . Although no clear correlation has been observed between leptin concentrations and the extent of steatosis [9] , a recent study reported that high serum leptin concentrations correlated with more severe steatosis, lower viremia, and a lower antiviral response [10] .

Leptin, a product of the obese (ob) gene, is mainly expressed in the adipose tissue, although it is expressed in other organs, including the liver. Leptin plays an important role in the regulation and metabolism of body fat and may induce IR, increase fatty acid concentrations in the liver, and enhance lipid peroxidation [7],[11] . Leptin may act as an immunomodulator, inducing the release of cytokines such as tumor necrosis factor (TNF)-α, IFN-γ, interleukin (IL)-18, and tumor growth factor (TGF)-β1, thus promoting liver steatosis and fibrosis [7] .

Ghrelin is a peptide that acts as an endogenous ligand of the growth hormone secretagogue receptor [12] . Ghrelin is involved in energy metabolism, food intake, and glucose homeostasis [12],[13] . Recent studies have assessed whether ghrelin acts as an independent signal of adiposity or as a downstream mediator of leptin, affecting energy balance [14] .

Little is known about plasma ghrelin concentrations in patients with CHC and steatosis or the effects of ghrelin concentration on treatment response. We therefore assessed whether pretreatment serum leptin and ghrelin concentrations differ in steatotic patients infected with HCV-4 and whether these concentrations are associated with response to antiviral treatment.


  Participants and methods Top


Participants

The participants investigated in this study were randomly withdrawn from the Outpatient Clinics of Internal Medicine Hospital, Mansoura University Hospitals and Mansoura Health Insurance Hospital (Mansoura, Egypt). They included 50 patients with CHC genotype-4 and 25 apparently healthy age-matched participants (who had donated blood) as a control group. All participants gave written informed consent to participate in the study, and the investigations conformed with the principles outlined in the Declaration of Helsinki. The study protocol was approved by the local ethics committee of the hospital.

Inclusion criteria were adult patients of both sexes (27-66 years old), diagnosed within the previous 6 months, positive for HCV-RNA in serum [by real-time (RT)-PCR assay], with evidence of chronic hepatitis and steatosis supported by liver biopsy and elevated alanine aminotransferase activity (>40 and <400 IU/l). The control group included adult individuals negative for HCV-RNA.

Patients with decompensated cirrhosis, other causes of chronic liver disease, Schistosomal coinfection, autoimmune hepatitis, a history of intravenous drug abuse or alcohol consumption, diabetes, thyroid disorders, chronic renal failure, serious psychiatric disorders, HIV or HBV coinfection, or hepatocellular carcinoma and patients using hepatotoxic drugs, herbal medications, or immunosuppressive agents were excluded. None of these patients had previously received antiviral treatment or steatosis-inducing therapy.

Patients were treated with either Peg-IFN-α-2a 180 mcg/week or Peg-IFN-α-2b 1.5 mcg/kg/week and ribavirin (1000 or 1200 mg/day for body weight ≤75 or >75 kg, respectively) for 48 weeks, independent of virologic response. Patients who did not achieve undetectable HCV-RNA or with a decrease in 2 logs of HCV-RNA at week 12 as compared with baseline (early virological response) were considered nonresponders but included in the study. All patients were clinically, hematologically, and biochemically evaluated at weeks 2, 4, 8, 12, 24, and 48 after the start of treatment.


  Materials and methods Top


In addition to investigations needed to fulfill the selection criteria, all individuals included in this study were subjected to the following.

Medical history

Complete history was taken with special reference to risk factors for liver diseases, such as previous HCV exposure in surgical wards, blood transfusions, dental therapy, needle stick injury, history of HCV in the spouse, and intravenous injection.

Physical examination

Complete medical examination was performed with particular focus on the manifestations of hepatitis, such as jaundice, hepatomegaly, and tenderness in the right hypochondrium. BMI was calculated as body weight in kilograms divided by the square of height in meters (kg/m 2 ). Abdominal ultrasonography was performed in all patients.

Histopathological investigations

Liver biopsy specimens were formalin fixed and paraffin embedded then sectioned and stained (hematoxylin and eosin) for routine histopathological examination. Grading and staging of chronic hepatitis was performed according to Modified Knodell's Score [15] . Steatosis was quantified as the percentage of hepatocytes that contained fat droplets and graded using a three-tier scale: grade 1/mild (1-33%), 2/moderate (33-66%), and 3/severe (>66%). Fibrosis stage (F) was scored as F0 (absent), F1 (portal fibrosis), F2 (portal fibrosis with few septa), F3 (septal fibrosis), and F4 (cirrhosis).

Laboratory investigations

Venous blood samples were collected in the morning after 12-h overnight fast from all patients and controls. Each blood sample was divided into three aliquots, one aliquot was left to coagulate for 30 min, then centrifuged at 3000 rpm for 15 min to separate serum and the other two were transferred to two tubes containing EDTA, one for complete blood count and the other centrifuged at 3000 rpm for 15 min to obtain plasma. Serum and plasma aliquots were immediately labeled and stored at -70°C until laboratory investigations were performed.

(1) Plasma glucose, serum alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, albumin, total bilirubin levels, cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured using Coobas Integra 400 plus (Roche Diagnostic, Germany). Platelet count was measured in all patients and controls using Sysmex KX-21 Analyzer (Germany).

(2) Serum insulin levels were estimated by enzyme immunoassay using Medgenix-Ins-EASIA kit (BioSource, Belgium). IR was calculated on the basis of fasting levels of plasma glucose and serum insulin, according to the homeostasis model assessment (HOMA) method. Calculation for the HOMA model followed a standard protocol: insulin resistance (HOMA-IR) = fasting glucose (mmol/l) × fasting insulin (mIU/ml)/22.5 [16] .

(3) Serum leptin was measured using commercially available ELISA kit (Diagnostic Biochem, Canada).

(4) Human plasma ghrelin was measured using a commercially available EIA kit (Phoenix Pharmaceuticals Inc., Belmont, California, USA), which measures total circulating ghrelin concentrations.

Viral markers

ELISA assays

0Sera of all patients and controls were tested for HBsAg, anti-HBc, and anti-HCV antibodies by ELISA using third generation kits (DiaSorin, Italy), according to the manufacturer's instructions.

Quantitation of HCV-RNA in serum

HCV-RNA was quantitated in all patients' serum samples at baseline and then at weeks 12, 24, and 48 after antiviral treatment using RT-PCR. Primers and RT-PCR reagents were supplied from Stratagene (Qiagen, USA).

HCV genotyping

HCV genotype was determined using INNO-LiPAII and III versant Kit (Innogenetics, Ghent, Belgium) according to the manufacturer's directions.

Statistical analysis

Symmetrically distributed continuous variables were summarized as a mean ± SD or median and interquartile ranges. Categorical variables were presented as frequency and percentage. Comparisons between groups were made using the Mann-Whitney U-test or the Student t-test for continuous variables and the χ΂ or the Fisher exact probability test for categorical data. ANOVA test was used to compare leptin, ghrelin, and HOMA-IR with different stages of hepatic steatosis and fibrosis. Spearman rank correlation was used to quantify the association between continuous or ordered categorical variables. Multiple linear regression analysis was used to model the association between baseline ghrelin and other covariates. A probability value of less than 0.05 was considered statistically significant. SPSS software for Windows version 17 (SPSS Inc., Chicago, Illinois, USA) was used to perform all analyses.


  Results Top


Our study included 50 patients infected with HCV-4 and 25 healthy age-matched participants as a control group. The mean age was 44.8 ± 10.4 years (range 27-66 years) and the mean BMI was 25.1 ± 4.53 kg/m 2 (range 19.4-35.2 kg/m 2 ); 37 (74%) patients were male and 13 (26%) were female. Their clinical, histologic, and baseline laboratory parameters are detailed in [Table 1]. [Table 2] showed HOMA-IR, leptin, and ghrelin with respect to the hepatic fibrosis score and hepatic steatosis grade in CHC patients. Steatosis grade at baseline was significantly higher as leptin concentrations and HOMA-IR increased (P = 0.023 and 0.005, respectively) and ghrelin concentrations decreased (P = 0.004) [Figure 1] and [Figure 2].
Figure 1:

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Figure 2:

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Table 1: Clinical, histologic, and baseline laboratory parameters of CHC patients and healthy controls

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Table 2: HOMA-IR, leptin, and ghrelin with respect to the hepatic fibrosis score and hepatic steatosis grade in CHC patients

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After treatment by combination therapy with PEGylated IFN and weight-adjusted ribavirin for 48 weeks, the mean serum leptin levels and HOMA-IR were (at baseline 16.4 ± 10.4 and 2.67 ± 1.49 ng/ml, respectively) significantly decreased (at the end of follow-up 12.4 ± 7.52 ng/ml, P=0.031; 2.13 ± 1.02 ng/ml, P = 0.037, respectively), whereas plasma ghrelin levels (at baseline 556 ± 146 pg/ml) were significantly increased (at the end of follow-up 616±139 pg/ml, P = 0.046).

A total number of 28 patients (56%) achieved sustained virological response (SVR = responder); they had significantly lower histologic stage of fibrosis with liver disease (P = 0.002) and lower grade of steatosis in liver biopsy (P = 0.013). In addition, they had lower HOMA-IR (P = 0.001) compared with the 22 (44%) patients who did not achieve SVR (nonresponder). Leptin concentrations were significantly lower in responder compared with nonresponder both at baseline (P = 0.005) and at the end of follow-up after treatment (P = 0.000), but we did not observe a statistically significant difference between leptin concentrations at baseline and at the end of follow-up among responder (P = 0.10) as well as nonresponder (P = 0.095). Serum ghrelin concentrations were significantly higher in responder, both at baseline (P = 0.001) and at the end of follow-up (P = 0.000), compared with nonresponder. In addition, we observed higher ghrelin concentrations but did not reach a statistically significant difference between responder (P = 0.059) and nonresponder (P = 0.20) at baseline and at the end of follow-up [Table 3]. Serum leptin at baseline showed significant positive correlations with age and HOMA-IR [Figure 3] whereas plasma ghrelin at baseline showed significant negative correlations with HOMA-IR [Figure 4] and serum leptin [Table 4]. There were no significant correlations between leptin (P = 0.380), ghrelin (P = 0.086), IR (P = 0.095), hepatic fibrosis (P = 0.560), and hepatic steatosis (P = 0.280) with viral load. By multiple linear regression analysis, HOMA-IR was found to be independently associated with plasma ghrelin levels (P = 0.000) [Table 5].
Figure 3:

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Figure 4:

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Table 3: Clinical, histologic, and laboratory parameters of responders and nonresponders CHC patients with respect to HCV therapy

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Table 4: Correlations of HOMA-IR, leptin, and ghrelin with clinical, histologic, and laboratory parameters in CHC patients

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Table 5: Multiple linear regression analysis for factors associated with plasma ghrelin in patients with CHC

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  Discussion Top


The precise pathogenic mechanisms of steatosis among patients with CHC still remain largely unknown. Recent evidences appeared elucidating some of the cellular and molecular mechanisms linking obesity and IR with liver fibrosis progression, identifying various adipokines and gut hormones as relevant modulators of the pathophysiology of liver injury and repair [17] .

We assessed whether pretreatment serum leptin and ghrelin concentrations differ in steatotic patients infected with HCV-4 and whether these concentrations are associated with response to antiviral treatment. We also evaluated the correlations between pretreatment serum leptin and ghrelin concentrations and liver histology and metabolic factors. Our results are similar with observations made by other investigators [18] , suggesting a possible involvement of adipocytokines such as leptin and ghrelin in disease progression among patients with CHC [19],[20] .

Leptin is a putative link between HCV infection and steatosis [21] . Although a high incidence of hyperleptinemia has been observed in HCV infected patients with liver steatosis [22] , the underlying mechanism promoting this effect remains undefined. Leptin may increase IR and fatty acid concentrations in the liver, leading to enhanced lipid peroxidation and promoting steatosis. Leptin may also induce the release of cytokines such as TNF-α, IFN-γ, IL-18, and TGF-β1, which are involved in the pathogenesis of both liver steatosis and fibrosis [20] . In steatosis, activated hepatic stellate cells, but not quiescent cells, can express leptin [23] . However, the results of involvement of leptin in hepatic steatosis and fibrosis are not equivocal [18] .

Although, many studies were demonstrated profibrogenic role of leptin [24],[25] , others did not reveal any role of leptin in determining severity of steatosis and fibrosis in patients with CHC [26] . Similarly to other investigators [18],[25] , we found high serum leptin concentrations and high IR at baseline in patients with CHC compared with healthy controls. We also observe that there is difference in serum concentrations of leptin in relation to liver fibrosis and steatosis severity and progression, as serum leptin levels tend to increase as the grade of steatosis worsens, suggesting that leptin increases during infection as a part of the host immune response, and may contribute to the development of steatosis.

However, Cua et al. [27] found that IR and liver injury in hepatitis C are not associated with virus-specific changes in adipocytokines. Nkontchu et al. [17] found that IR but not serum leptin levels predicts the outcome of HCV. In addition, other studies reported that the structural and nonstructural proteins of HCV may directly cause steatosis by provoking oxidative stress [28],[29] . Alternatively, the viral core protein may target the microsomal triglyceride transfer protein activity, modifying very low-density lipoprotein assembly in and secretion by hepatocytes [30] . The core protein may also affect the cytoplasmic domain of members of the TNF receptor family or act directly on the mitochondria, leading to increased oxidative stress and lipid peroxidation. They also found that the grade of steatosis was correlated with higher viral load at baseline, and this was in agreement with the direct 'steatogenic' effect of HCV [28] . However, in this study, we did not observe any correlations between viral load and the grade of steatosis.

Although ghrelin is important in food intake, energy balance, and regulation of the growth hormone releasing mechanism [13] , its role in hepatic disease has not been extensively evaluated to date. Increased serum ghrelin concentrations have been reported in patients with cirrhosis and hepatocellular carcinoma, suggesting that this adipokine may be involved in the anorexia-cachexia syndrome during the terminal stages of liver diseases [31] . Data on ghrelin concentrations in patients with CHC are limited [32] .

This study demonstrated low plasma ghrelin concentrations in patients with CHC and negative correlations between plasma ghrelin and hepatic fibrosis and steatosis. In addition, we found negative correlations between ghrelin with HOMA-IR and leptin. These results are in agreement with the results of previous studies [20],[33] that demonstrated low plasma ghrelin concentrations, which tend to decrease more as the grade of steatosis increase in patients with CHC, indicating that ghrelin may prevent or reduce steatosis by negatively regulating leptin [20] . In addition, Moreno et al. [33] found that, in patients with chronic liver diseases and CHC, plasma ghrelin levels decreased in those with advanced fibrosis, ghrelin gene hepatic expression correlated with expression of fibrogenic genes, and polymorphisms in the ghrelin gene (-994CT and -604GA) influenced the progression of liver fibrosis; thus, ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy [33] . In contrast to our results, other investigators did not find any significant difference in plasma ghrelin concentrations and correlations with the grade of steatosis among patients with CHC [18] .

In this study, similar to the large clinical trials on antiviral therapy using Peg-IFN and ribavirin [34] , SVR was achieved in 56% of patients. In addition, we found that antiviral therapy produces significant changes in HOMA-IR, leptin, and ghrelin levels. At baseline, HOMA-IR and serum leptin were significantly lower in patients with SVR (responders) compared with nonresponders and continued to decrease but did not reach statistically significant levels at the end of follow-up. In addition, responder had significantly lower hepatic fibrosis score and steatosis grade compared with nonresponder, whereas plasma ghrelin concentrations were significantly higher in responders than in nonresponders and continued to increase but did not reach statistically significant levels at the end of treatment.

We confirmed previous observation of the role of HOMA-IR and fibrosis score as predictive factors of therapy-induced viral eradication [35] . These findings are in accordance with the data that showed insulin sensitivity improvement during IFN treatment restricted to patients with SVR [36] . Similarly, two papers demonstrated, respectively, leptin levels reduction during antiviral therapy [37] and leptin decrease during IFN treatment only in virological responders [38] . Khattab et al. [37] showed that antiviral therapy produces significant changes in IR and leptin levels. At the end of follow-up, HOMA-IR and leptin were lower in patients with SVR but remained unchanged in patients who did not response or relapsed.

In addition, Pavlidis et al. [20] found that responders had lower serum leptin and higher plasma ghrelin concentrations at baseline compared with nonresponders and that ghrelin concentration increased to significant levels at the end of treatment, indicating that ghrelin may prevent or reduce steatosis by negatively regulating leptin. This may enhance the likelihood of SVR, as responders also have lower baseline leptin concentrations. However, ghrelin may be also considered as an independently acting factor on the basis of the finding that responders with moderate and severe steatosis had low ghrelin concentrations at baseline and that these concentrations were increased significantly after treatment. In contrast, no significant differences were observed in nonresponders, and there were no correlations with leptin concentrations.


  Conclusion Top


Serum leptin levels increased and plasma ghrelin levels decreased in patients with CHC as the grade of steatosis worsens. Increased serum leptin before treatment may predict non-SVR, whereas increased ghrelin may predict SVR. Ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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[Pubmed] | [DOI]



 

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