Saudi Journal of Gastroenterology
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ORIGINAL ARTICLE Table of Contents   
Year : 2006  |  Volume : 12  |  Issue : 2  |  Page : 68-72
The role of leptin in non-alcoholic fatty liver disease


1 Department of hepatology,gastroenterology and infectious disease, Faculty of medicine, Banha, Zagazig University, Egypt
2 Department of physiology,King Saud University., Saudi Arabia
3 Department of liver transplantation, King Faisal specialist hospital,Riyadh, Saudi Arabia
4 Division of gastroenterology, department of medicine, king saud University, Riyadh, Saudi Arabia

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Date of Submission11-Jul-2005
Date of Acceptance23-May-2006
 

   Abstract 

Background: The role of steatosis in the pathogenesis of chronic liver disease (CLD) is now believed to form part of a continuum in non-alcoholic fatty liver disease (NAFLD). One of the unconventional areas in which leptin is now receiving great attention is liver diseases. Several published studies indicate that circulating leptin is increased in patients with cirrhosis, chronic HCV, and non-alcoholic steatohepatitis (NASH). Aims: the present study aims to assess serum leptin levels in patients with NAFLD with and without HCV infection, and to correlate it with the biochemical markers and histopathology of liver diseases. Patients and Methods: the present study included 67 Saudi subjects divided into 3 age and sexmatched groups. Group A: 22 patients with DM (8 males and 14 females, mean age 44 ± 12.9 years). Group B: 20 patients with chronic HCV infection (7 males and 13 females, mean age 48.9 ± 14.1 years). Group C: 25 control healthy volunteers (15 males and 10 females, mean age 40.7 ± 12.6 years). Serum leptin, C-peptide, and insulin levels were measured by radioimmunoassay. Liver biopsy was done for the HCV group only. Results: Patients with chronic HCV infection had significantly lower mean ± SD serum leptin levels (25.6 ± 37.2 ng/mL) compared with the diabetic and control groups, 55.7 ± 59.0 and 81.8 ± 41.7 ng/mL (p = 0.002 and p = 0.046 respectively). However, in the HCV group, leptin levels did not differ significantly as regard steatosis grade, and fibrosis stage. Steatosis in the HCV group patients correlated with the body mass index and hyperglycemia, but not with leptin levels. Serum leptin correlated positively with serum insulin and C-peptide levels in both the HCV and diabetic groups, but not in the control group). Conclusion: Serum leptin can't be used as a non-invasive marker for the predication of steatosis and fibrosis in patients with NAFLD.

Keywords: Leptin, NAFLD

How to cite this article:
Elbadawy RA, Eleter EA, Helmy A, Al Ghamdi AS, Al-Mofleh I, Al Faleh FZ, Al Freihi H, Al-Amri S. The role of leptin in non-alcoholic fatty liver disease. Saudi J Gastroenterol 2006;12:68-72

How to cite this URL:
Elbadawy RA, Eleter EA, Helmy A, Al Ghamdi AS, Al-Mofleh I, Al Faleh FZ, Al Freihi H, Al-Amri S. The role of leptin in non-alcoholic fatty liver disease. Saudi J Gastroenterol [serial online] 2006 [cited 2019 Jan 24];12:68-72. Available from: http://www.saudijgastro.com/text.asp?2006/12/2/68/27848


Non alcoholic fatty liver disease (NAFLD), a commonhealth problem world-wide, ranges from simple fatty liverto non alcoholic steatohepatitis (NASH) with subsequentcirrhosis[1],[2]. The exact prevalence of NASH is not knownbecause of its indolent and silent course. The pathogenesis ofNASH is yet to be clearly elucidated, but the most prevailinggeneral theory is the two "hit-hypothesis" proposed by Bacon,1994.3 The first "hit" is thought to be an accumulation of fat(steatosis), especially fatty acids and triglycerides within theliver cell followed by cellular adaptations and altered signalingpathways that lead to increased oxidative stress on the cell,i.e., the second "hit", possibly secondary to environmentaland/or genetic factors with subsequent apoptosis or morelikely cellular necrosis[3].

In patients with chronic hepatitis C virus (HCV) infection,the presence of steatosis is a common histological finding, andis supposed to be due to both host and viral factors[4]. Hostrelatedfactors such as high body mass index (BMI), diabetesmellitus, and dyslipidemia[5],[6], in addition to virus-relatedfactors such as genotype, hepatitis G virus coinfection[7], andHCV viral load[8] have all been associated with the developmentof steatosis in patients with chronic HCV infection. Indeed,some studies found steatosis more often in patients infectedwith genotype 3a,[9],[10] although this is not universal[5]. Also,a relationship between hepatic steatosis and BMI was onlyfound in patients infected with genotype 1[11].

Leptin, a 16-KD peptide hormone that is releasedpredominantly from adipocytes, has been shown to be involvedin peripheral insulin resistance and strongly related to bodyfat composition. Leptin secretion is pulsatile and follows acircadian rhythm with levels up to 30% higher at night. Thus,single time point measurements may not accurately reflecttrue leptin concentration[12]. Leptin is an important regulatoryhormone of energy and homeostasis and may play a role inthe development of hepatic steatosis, and has been detectedin activated liver stellate cells[13],[14],15] as well as sinusoidalcells[15],[16]. Several studies showed that circulating leptin levelsincrease in cirrhosis and obesity[12],[17]. This hormone is thoughtto promote insulin resistance and alter insulin signaling inhepatocytes resulting in increasing hepatocellular fatty acidproduction[12]. Leptin may have a role in the regulation of fatdeposition, fibrogenesis, and inflammation in patients withNAFLD[16],[18].

The aims of the present study were to assess serum leptinlevel in NAFLD (Diabetic patients and chronic HCV) Saudipatient and correlate it with biochemical markers of liverdisease as well as its relation to liver biopsy in HCV patients.


   Patients and Methods Top


Patients: The present study was carried out on 42 Saudipatients subdivided into 22 patients with diabetes mellitus(DM; Group A) and 20 patients with chronic HCV infection(Group B). The control group included 25 age and sexmatchedhealthy volunteers (Group C).

Inclusion and exclusion criteria: Patients with orwithout elevated liver enzymes diagnosed by abdominalultrasonography to have fatty liver assessed according toTreiper et al., 2005 were included[19]. All cases were clinicallyand ultrasongraphically compensated, i.e., no ascites orbleeding. Subjects known to have hepatitis B with or withouthepatitis D, autoimmune liver disease, alcoholic liver disease,malignant liver disease, drug-induced liver disease, or thosewith hepatocellular failure were excluded from the study.


   Methods Top


All patients and control subjects underwent thoroughclinical examination, laboratory investigations includingcomplete blood count, viral hepatitis markers, and autoimmunescreening, liver function tests, renal profile, lipid profile, andfasting blood glucose, and abdominal ultrasound examination.Liver biopsy was done only to the HCV group and wasscored according to Brunt (1999)[20]. Height and weight weredetermined at baseline, and BMI was calculated as weight (inkg) /height (in m2). Informed consent was obtained from allsubjects, and the study was approved by the local researchCommittee.

Serum leptin, insulin and C-peptide assays: Serum sampleswere collected from all subjects and stored immediately at-70 ºC till the time of the assay. Serum leptin was assayed byradioimmunoassay (Linco Research, Inc.). Serum insulin andserum C-peptide levels were determined by radioimmunoassay(Phadeseph Insulin RIA from Linco Research, Inc.) andcompetitive immunoassay (Linco Research, Inc.) respectively.All assays were performed in duplicate.


   Statistical analysis Top


Continuous variables were summarized as mean ± standarddeviation (SD). Groups were compared using unpaired t-testand one-way analysis of variance (ANOVA) as appropriate.Categorical variables were compared with fisher's exact test orx2 test. Independent predictors identified by multiple ordinalregression for steatosis and by binary logistic regression forinflammation and fibrosis. The association between numericvariables was tested by Pearson's correlation coefficient.Comparison between each 2 groups was done by Levene'stest for equality of variance. A probability (p) value of <0.05was taken as significant value.


   Results Top


All groups were matched regarding age and body massindex (BMI). [Table - 1] shows the demographic data of thegroups, and the relation of serum leptin with laboratoryparameters and age, using one-way ANOVA test. There isstatistical significant difference between the studied groups asregard fasting blood sugar (FBS), serum leptin, serum insulin,leptin/BMI ratio, and ALT levels.

[Table - 2] shows comparison between each 2 groups regardingthe mean serum leptin level using Levene's test for equalityof variance. There is significant difference between group A& group B, and between group B and group C (CI 95%). Nostatistical significant difference between group A&C.

[Table - 3] shows the relation between mean serum leptin levelsand the stages of liver fibrosis and steatosis as determinedin liver biopsy. In the HCV group (Group B, n= 20), serumleptin levels did not show any statistical significant differenceregarding steatosis grade. Also, there was no significantdifference between patients with fibrosis grade ≥ 2 versus thosewith minimal or no fibrosis. Steatosis > 1 versus steatosis < 1as regards the level of leptin.

[Table - 4] shows the correlation coefficient (r) between serumleptin and different variables among the three studied groups.There is a statistically significant correlation between serumleptin levels and serum C-Peptide and Insulin levels in theHCV and diabetic groups, but not in the control group. Also,serum leptin levels correlated positively with the age only inthe HCV group.


   Discussion Top


The present study demonstrates that patients with chronicHCV infection have significant hypoleptinemia comparedwith diabetic and healthy control subjects. In addition, thelack of correlation between serum leptin levels and steatosisor fibrosis suggests that leptin can't be used as a predictor ofthese pathological changes in HCV patients. Further studiesin bigger groups of patients are needed to confirm thesefindings.

Obesity has been recognized as a risk factor the developmentof chronic liver disease caused by a variety of etiologiesincluding chronic HCV infection, alcohol, and NAFLD[2],[3],[4].These conditions have been associated with high serum leptinlevels indicating leptin insensitivity or resistant. However,5-10% of obese individuals may have relatively low leptinlevel suggesting decreased production in this group[15],[16].However, in the present study the mean serum leptin level inHCV infected patients was lower than that in the diabetic andhealthy control groups. This has also been shown by otherstudies[12],[17],[21]. This low serum leptin level may be explainedby the presence of negative energy balance secondary to viralpersistence and worsening liver function[17].

In normal humans, the circulating levels of leptin are higherin women than in men (15 ± 82 & 7.2 ± 4.1) respectively[4],[22].In addition, leptin production from adipocytes is affected byglucose and fat metabolism, and its concentration decreaseswith fasting and increases with food consumption. Moreover,leptin release has a circadian rhythm[12]. There may also bedifferences in the expression of bound and free leptin levelsin patients with HCV infection, and most immunoassays donot separate binding components, but rather measure totalleptin[21],[23]. Therefore, single measurements, sex-mismatch, andthe non-differentiation free and bound leptin can complicateinterpretation of these data. Also, a multivariate analysisis necessary to reduce the bias caused by this confoundingvariable.

We were unable to find any significant relationship betweenserum leptin levels and steatosis or fibrosis in the HCV group.Indeed, leptin has previously been shown to be associated withsteatosis and fibrosis in non-obese patients with NASH[24]. Themechanism by which leptin promotes steatosis and fibrosisremains unclear. Leptin could regulate body weight throughincreasing energy expenditure and decreasing food intake[25]and, consequently, would correlate with BMI, percentagebody fat[26], and insulin activity modulation[27]. It has beensuggested that leptin induces insulin resistance and increasesfatty acid concentrations in the liver while enhancing lipidperoxidation[28] and promoting steatosis. Also, it should benoted that leptin perfusion in the portal circulation in ratsinduced hypertriglyceridemia and contributed to hepaticsteatosis by increasing free fatty acids in the liver[29]. On theother hand, leptin could induce hepatic steatosis and fibrosisvia the stimulated release of cytokines such as tumor necrosisfactor-α, interferon-γ, interferon-18, and tumor growth factor-β1[30],[31],[32]. Recently, a link between HCV infection and leptinmetabolism has been proposed. Bound leptin, but not the nonboundfraction, was found to be higher in chronic HCV patientsthan in control subjects, and the concentrations decreasedin sustained responders to antiviral therapy compared tononresponders[33] In chronic HCV, obesity has been associatedwith steatosis development and fibrosis progression[9],[10],[11],[34].Therefore, leptin could be a link between these factors.

Garwieh et al, 2004 looked at the potential diagnosticaccuracy of leptin in differentiating between patients withbland steatosis and NASH in cohort of 10 patients with simplesteatosis and 10 patients with NASH, the result of level ≥40 ng/ml and resistant level ≥ 1.1 ng/ml has a sensitivity of100%, a specificity of 90%, and a negative predictive value of100% in differentiating patients with NASH form those withbland steatosis[35].

The present study has few potential limitations includingthe small number of patients included in each group makingtype-2 error playing a substantial role in the obtained results.Also, the presence of higher fasting blood glucose levels inthe patients with chronic HCV infection makes it difficult todetermine the exact role of leptin in HCV infection alone in thepathogenesis of the associated pathological changes especiallysteatosis and fibrosis. Also, the confinement of liver biopsyto the chronic HCV group makes it difficult to draw positiveconclusions from the current study. Therefore, a long-termprospective study to assess of the complex dynamic processthat exists between serum leptin, hepatic steatosis and hepaticinjury in patients with and without chronic HCV infection iswarranted. This can highlight whether a therapeutic role ofleptin exists.

In conclusion, according to the results of the present study,there was a state of significant hypoleptinemia in patientswith chronic HCV infection as compared to the diabetic andhealthy control groups. Also, there was no correlation betweensteatosis grades or the stages of fibrosis and leptin levels inthe HCV group. Therefore, serum leptin level can't be used asa predictor for the histological grading or staging in patientswith HCV infection.

 
   References Top

1.Brunt EM. Non alcoholic steatohepatitis: definition and pathology. Semin liver Dis 2001; 21: 3-16.  Back to cited text no. 1  [PUBMED]  
2.Patton HM, Behling C, Patel K. Steatosis in chronic hepatitis C. Hepatology 2002; 36: 349 (abstract).  Back to cited text no. 2    
3.Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri B. Non alcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 1103-1109.  Back to cited text no. 3    
4.Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002; 36: 729-736.  Back to cited text no. 4  [PUBMED]  
5.Czaja AJ, Carpenter HA, Santrach PJ, Moore B. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol 1998; 29: 198-206.   Back to cited text no. 5    
6.Hourigan LF, Macdonald GA, Purdie D, Whitehall V, Shorthouse C, Clouston A. Fibrosis in chronic hepatitis C correlates with body mass index and steatosis. Hepatology 1999; 29: 1215-1219.  Back to cited text no. 6    
7.Petrik J, Guella L, Wight DG, Pearson G, Hinton J, Parker H. Hepatic histology in hepatitis C virus carriers coinfected with hepatitis G virus. Gut 1998; 42: 103-106.  Back to cited text no. 7    
8.Adinolfi LE, Gambardella M, Andreana A, Tripodi M, Utili. Steatosis accelerates the progression of liver damage of chronic hepatitis C and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33: 1358-1364.  Back to cited text no. 8    
9.Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997; 25: 735-739.  Back to cited text no. 9  [PUBMED]  
10.Adinolfi LE, Utili R, Ruggiero G. Body composition and hepatic steatosis as precursors of fibrosis in chronic hepatitis C patients. Hepatology 1999; 30: 1530.  Back to cited text no. 10  [PUBMED]  
11.Jonsson JR, Hourigan LF, Purdie D. Body composition and hepatic steatosis as precursor of fibrosis in chronic hepatitis C patients. Hepatology 1999; 30: 1530-1531.  Back to cited text no. 11    
12.Testa R, Franceschini R, Giannini E, Cataldi A, Botta F, Fasoli A et al. Serum leptin levels in patients with chronic viral hepatitis or liver cirrhosis. J Hepatol 2000; 33: 33-37.  Back to cited text no. 12    
13.Potter JJ, Womack L, Mezey E, Anania F. Transdifferentiation of rat hepatic stellate cells results in leptin expression. Biochem Biophys Res Commun 1998; 244: 178-82.  Back to cited text no. 13    
14.Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 2002; 36: 403-409.  Back to cited text no. 14    
15.Saxena NK, Ikeda K, Rockey DC, Friedman S, Anania F et al. Leptin in hepatic fibrosis; Evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 2002; 35: 762-767.  Back to cited text no. 15    
16.Brunt EM. Non alcoholic steatohepatitis: Definition and pathology. Semin Liver Dis 2001; 21:3-16.  Back to cited text no. 16  [PUBMED]  
17.Friedman JM, Halaas JL. Leptin and the regrulation of body weight in mammals. Nature 1998; 395: 3633-3670.  Back to cited text no. 17  [PUBMED]  
18.Kaplan LM. Leptin obesity and liver disease. Gastroenterology 1998; 115: 997-1001.  Back to cited text no. 18  [PUBMED]  
19.Treiber G, Csepregi A, Klauck S, Simple, low-cast, and noninvasive quantification of steatosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2005; 128 (suppl 2): A-543.  Back to cited text no. 19    
20.Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander- Tetri R, Bacon B et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94: 2467-2474.  Back to cited text no. 20    
21.Romero-Gomez M, Castellano B, Grand L, Irles J, Cruz M, Nogales M et al. Serum leptin level correlate with hepatocyte steatosis in chronic hepatitis C. Am J Gastroenterol 2003; 98: 1135-1141.  Back to cited text no. 21    
22.Couillard C, Mauriege P, Prud'homme D, Nadeau A, Tremblay A, Bauchard C et al. Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia 1997; 40: 1178-84.  Back to cited text no. 22    
23.Hui JM, Kench J, Farrell GC, Lin R, Samarasinghe D, Liddle C et al. Genotype specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenteral Hepatol 2002; 17: 873-881.  Back to cited text no. 23    
24.Uygun A, Kadayifci A, Yesilova Z, Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2000; 95: 3584-3589.  Back to cited text no. 24  [PUBMED]  
25.Ockenga J, Bischoff SC, Tillmann HL, Erdil A, Yaman H, Saka M et al. Elevated bound leptin correlates with energy expenditure in cirrhotics. Gastroenterology 2000; 119: 1656-1662.  Back to cited text no. 25    
26.Considine RV, Sinha MK, Heiman ML. Serum immunoreactive J Hepatol 2001; 34: 314-320.  Back to cited text no. 26    
27.Cohen B, Novick D, Rubinstein M. Modulation of insuline by leptin. Science 1996; 274: 1185-1188.  Back to cited text no. 27  [PUBMED]  
28.Paradis V, Mathurin P, Kollinger M. In situ detection of lipid peroxidation in chronic hepatitis C: correlation with pathological features. J Clin Pathol 1997; 50: 401-406.  Back to cited text no. 28    
29.Roden M, Anderwald C, Furnsinn C, Lvaldhausl W, Lohninger A. Effects of shortterm leptin exposure on triglyceride deposition in rat liver. Hepatology 2000; 32: 1045-1049.  Back to cited text no. 29    
30.Powell EE, Edwards-Smith CJ, Hay JL. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000; 31: 828-833.  Back to cited text no. 30    
31.Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura Tm Takei Y. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001; 34: 288-297.   Back to cited text no. 31    
32.Faggioni R, Jones-Carson J, Reed DA, Leptin-deficient (ob/ ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18. Proc Natl Acad Sci USA 2000; 97: 2367-2372.  Back to cited text no. 32    
33.Widjaja A, Wedemeyer H, Tillmann HL, Dinarello C, Freingold K, Gronfeld. Hepatitis C and the leptin system: bound leptin levels are elevated in patients with hepatitis C and decrease during antiviral therapy. Scand J Gastroenterol 2001; 36: 426-431.  Back to cited text no. 33    
34.Clouston AD, Jonsson JR, Purdie DM, Macdonald G, Pendeya N, Shorthouse et al. Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation. J Hepatol 2001; 34: 314-320.  Back to cited text no. 34    
35.Garwieh S, Rodo B, Lindor M. Adipokine levels are predictive of histology in patients with NASH. Hepatology 2004; 40: 237A (abstract).  Back to cited text no. 35    

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Correspondence Address:
Reda A Elbadawy
Department of hepatology, gastroenterology and infectious disease, Faculty of medicine, Banha, Zagazig University
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.27848

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    Tables

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

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