Serum lipids and chronic hepatitis C genotype 4: interaction and significance

Transcription

1 ORIGINAL ARTICLE Serum lipids nd chronic heptitis C genotype 4., 2012; 11 (1): Jnury-Februry, Vol. 11 No.1, 2012: Serum lipids nd chronic heptitis C genotype 4: interction nd significnce Mhmoud A. Khttb,* Mohmmed Eslm,* Myd M. Aly,* Mohmmed Shtt,* Yousef I. Mous,* Heshm Abd-Alhlim,* Hnn Aly,** Yehi Shker* * Deprtment of Internl Medicine, Mini University, Mini, Egypt. **Deprtment of Internl Medicine, Beni-Suif University, Beni-Suif, Egypt. ABSTRACT Bckground & im. Metbolic bnormlities re common in chronic heptitis C infection (CHC). However, the genotypic differences of these disrrngements in ptients infected with CHC genotype 4 (HCV-4) nd its ssocition with liver histology nd virl lods remin unknown. Mteril nd methods. We consecutively enrolled 183 HCV-4 ptients nd 106 helthy mtched controls; to compre metbolic profiles nd ssess pttern of ssocition of HCV RNA levels s well s histologicl fctors with the serum lipid profile. Results. HCV-4 infection is ssocited with higher homeostsis model ssessment of insulin resistnce (HOMA-IR) index, despite tht, fvourble lipid pttern, consisting of n elevtion in HDL- C nd reduction in serum cholesterol (TC), LDL-C nd triglyceride (TG) levels, in comprison with norml mtched dults. Significnt fibrosis ws independently ssocited with HOMA-IR, portl/periportl inflmmtion grde, serum cholesterol nd ge. Univrite ssocition ws elucidted between lower LDL-C nd TC nd Metvir ctivity score nd between higher TG nd TC nd stetosis. In multivrite nlysis, severe heptitis ctivity, milder heptic fibrosis, nd triglyceride levels re ssocited with higher HCV RNA levels. Conclusion. HCV-4 is ssocited with wide metbolic chnges. A proportionl reltionship is found between serum lipid profiles nd heptitis C virl lod nd liver histology in ptients with HCV-4. Key words. Lipids. Heptitis C virus. Genotype 4. Inflmmtion. Fibrosis. Virl lod. INTRODUCTION Chronic heptitis C (CHC) virus infects ~ 170 million individuls worldwide, nd heptitis C genotype 4 (HCV-4) is the cuse of ~ 20% of this number. 1 HCV-4 is common in the Middle Est nd in Afric, where it is responsible for 80% of HCV infections, nd hs recently spred to severl Europen countries. 1,2 Egypt hs the highest prevlence of HCV worldwide (15%) 2 nd the highest prevlence of HCV-4, which is responsible for more thn 90% of infections. 2 HCV remins mjor helth concern throughout the world. As the popultion exposed to Correspondence nd reprint request: Mhmoud Aboelneen Khttb M.D., Ph.D. Deprtment of Medicine Division of Gstroenterology nd Heptology, Mini University Mini 61111, Egypt Tel.: , Fx: E-mil: mkhttbmed@hotmil.com Mnuscript received: My 09, Mnuscript ccepted: August 20, heptitis C ges, the morbidity relted to this disese is lso incresing. HCV infection cn be considered not only s virl disese but lso s specil type of metbolic disese. CHC intercts with lipid metbolism leding to stetosis, impirs glucose metbolism leding to insulin resistnce (IR) nd type 2 dibetes (T2DM), nd is ssocited with n incresed risk of crotid therosclerosis. 3,4 Accumulting clinicl nd experimentl evidence indicte tht there is significnt cross tlk between HCV nd host lipid metbolism. There is incresing evidence to indicte tht the virus uses the host lipoprotein mchinery for its life cycle nd dissemintion. Recently owing to the dvnces in in vitro model for HCV propgtion, it hs been demonstrted tht lipid fctors re linked to HCV RNA repliction. 5 The lipid rfts, scffold for HCV RNA repliction, is mde minly by cholesterol nd sphingolipid, 6 nd the lipid droplet, n orgnelle for the storge of neutrl lipids, is criticl for producing infectious viruses. 7 An interction between HCV infection nd B -lipoprotein metbolism is lso

2 38 Khttb MA, et l., 2012; 11 (1): noted in clinicl cses. 8 These dt suggest how molecules trgeting lipid metbolism could improve HCV therpy. 9 Different HCV genotypes re shown to hve different ssocitions with heptic stetosis. In prticulr, in ptients infected with genotype 3, stetosis is mostly virus-induced nd often severe, correltes with intrheptic virl lod, nd resolves fter successful ntivirl therpy. 10,11 In contrst, in ptients infected with genotype 1, 4 stetosis is minly ssocited with host metbolic fctors nd correltes with body mss index (BMI) nd centrl diposity. 12 Moreover, recent clinicl dt suggest tht HCV ssocited IR is genotype-dependent (1 nd 4). 13 Tking these lines of evidence together, we hypothesized tht there exist genotypic differences on the ssocition of lipid profiles nd HCV. Unfortuntely, HCV-4 hs simply not been the subject of widespred reserch nd, the differentil ssocition of lipid profiles with HCV virl lod nd histology between genotypes 4 infections remin lrgely unknown nd deserves to be studied. We therefore conducted this prospective study to determine the serum lipid profile in ptients with chronic HCV-4 infection, nd to detect if there is ny correltion between serum lipid levels nd virl lod, HCV genotype or liver histology. MATERIAL AND METHODS Eligible ptients This prospective study ws conducted between August 2009 nd July One hundred eighty three eligible CHC nd one hundred six mtched helthy voluntries were enrolled in this study. Eligible ptients were nive dults ged 18 yers or older who hd CHC bsed on the presence of nti-hcv nd detectble serum HCV-RNA for 6 months or more, in combintion with liver biopsy obtined within 12 months of enrollment with findings comptible with CHC using the Metvir score. 14 All ptients were infected with HCV-4. The exclusion criteri dopted in this study were ptients with T2DM dignosed ccording to the Americn Dibetes Assocition clssifiction criteri; 15 ptients with other cuses of liver disese, concomitnt heptitis B virus, or humn immunodeficiency virus nd Schistosom co-infection; ptients with utoimmune diseses, such s utoimmune heptitis; ptients with lcohol intke > 40 g/dy in the lst 6 months before the liver biopsy. Ptients who hd clinicl evidence of heptic decompnstion, ptient who hve received ntivirl tretment nd those were tking ny lipid lowering gents. Informed consent The study protocol ws pproved by the Institutionl Ethics Committee of prticipting centers, nd ll ptients gve informed consent to prticipte in this study. The study ws conducted in ccordnce with the ethicl guidelines of the Declrtion of Helsinki nd Interntionl conference on Hrmoniztion Guidelines for Good Clinicl Prctice. Clinicl nd lbortory ssessment The following dt were collected t the time of liver biopsy: gender, ge, dily lcohol intke in the pst 6 months (g/dy), route of HCV trnsmission, body mss index (BMI), wist circumference. BMI ws clculted s weight divided by the squre of the height (kg/m²). Overweight ws defined s BMI in the rnge of kg/m² nd obesity s BMI 30 kg/m². Wist circumference ws mesured to the nerest 0.5 cm t the shortest point below the lower rib mrgin nd the ilic crest. Lbortory tests. On the morning of the liver biopsy, venous blood ws drwn fter 12 h overnight fst to determine the serum levels of fsting blood glucose, triglyceride (TG), totl cholesterol (TC), low density lipoprotein (LDL- C), high-density lipoprotein (HDL-C), lbumin, sprtte trnsminse (AST), lnine trnsminse (ALT), gmm-glutmyl trnspeptidse (GGT) levels, complete blood count, nd differentil count, interntionl normlized rtio, insulin, C-peptide, nd diponectin were collected. Serum fsting blood glucose, lbumin, TG, TC, LDL-C, HDL-C, AST, ALT, nd GGT ws mesured using n uto nlyzer (Hitchi 7250, Specil; Hitchi, Tokyo, Jpn) ccording to the mnufcturer s instructions. Serum insulin nd C-peptide were determined by electrochemiluminescence immunossy (Elecsys 2010; Roche Dignostics, Indinpolis, Indin, USA). Insulin resistnce ws then clculted in ll ptients by the homeostsis model for the ssessment of IR (HOMA-IR) using the stndrd formul: HOMA-IR = fsting insulin (µu/ml) x fsting glucose (mmol/l)/22.5. The serum diponectin levels were mesured in duplicte by Luminex xmap technology using multiplex ssy (Linco Reserch, St. Chrles, MO). The men vlues of duplicte

3 Serum lipids nd chronic heptitis C genotype 4., 2012; 11 (1): mesurements were used in the nlyses. Heptitis B surfce ntigen nd nti-hcv were ssyed with commercil kits (Abbott Lbortories, North Chicgo, IL, USA). Virologicl ssys Serum HCV RNA ws ssessed by using Abbottm2000 (lower limit of detection 12 IU/mL). Genotyping of HCV ws performed using either line probe ssy or reverse hybridiztion (InnoLip; Innogenetics, Genetics, Gent, Belgium). All smples were tested in triplicte. Histopthology Liver biopsy specimens were nlyzed by single experienced pthologist who ws blinded to the clinicl nd biologicl dt. Liver biopsy specimens not less thn 15 mm in length or the presence of t lest 10 complete portl trcts were required. Necroinflmmtion nd fibrosis were ssessed using the Metvir score13. Necroinflmmtion ctivity (A) ws grded s A0 (bsent), A1 (mild), A2 (moderte), or A3 (severe). Fibrosis stge (F) ws scored s F0 (bsent), F1 (portl fibrosis), F2 (portl fibrosis with few sept), F3 (septl fibrosis), nd F4 (cirrhosis). Stetosis ws ssessed s the percentge of heptocytes contining mcrovesiculr ft droplets. It ws grded s follows: 0 (bsent, < 5% ). 1 (moderte, 5-30%). 2 (severe, > 30 %). We chose to split them into two ctegories tht reflect the bsence (or miniml mount) vs. the presence of lrger mounts of stetosis. 16 Cse controls Helthy volunteers. One hundred six pprently helthy volunteers were enrolled s controls fter written informed consent ws obtined. All hd norml liver tests, negtive serology for chronic virl heptitis nd no history of liver disese or T2DM. Sttisticl nlyses Symmetriclly distributed continuous vribles were summrized s men ± stndrd devition (SD). The medin nd interqurtile rnges were used for skewed continuous vribles. Ctegoricl vribles were presented s frequency nd percentge. The bseline chrcteristics of the HCV-infected ptients were compred with mtched controls by unpired t-test or Mnn-Whitney test for continuous vribles nd by Chi squred test for ctegoricl vribles. Spermn rnk correltion ws used to quntify the ssocition between continuous or ordered ctegoricl vribles. The differences in group distributions ssessed using the Wilcoxon rnk sum or Kruskl-Wllis tests. In regression models, TG, HDL-C nd TC were trnsformed to the nturl logrithm (ln) scle to chieve normlity. Multiple ordinl regression with stepwise vrible selection ws used to identify the independent predictors of stetosis, portl/periportl inflmmtion nd the fibrosis stge (ordered ctegoricl vribles). Liner regression ws used to ssess the significnce of ssocitions between vribles with HCV RNA levels. Stepwise liner regression nlysis (bckwrd) ws performed to exmine the ssocition between HCV RNA levels nd lipid profiles. SPSS softwre for Windows version 12 (SPSS Inc., Chicgo, IL) ws used to perform ll nlyses. Two tiled tests with 5% level of significnce were used throughout. RESULTS Demogrphic, biochemicl nd metbolic chrcteristics of HCV-infected ptients The demogrphic, biochemicl, metbolic nd histologicl chrcteristics of 183 ptients with chronic HCV-4 re detiled in tble 1. The men ge ws 43.7 ± 3.7 yers (rnge yers), the men BMI ws 26.4 ± 1.8 kg/m² (rnge kg/m²) nd the men wist/hip rtio ws 0.89 ± Lipid profile nd insulin resistnce Ptients were bsolutely comprble with controls ccording to ge, sex nd BMI. Significntly higher levels of ll mrkers of IR including the insulin (p = ), C- peptide (p = ) nd HOMA-IR (p = ) were noted in the HCV-4 cohort (Tble 1). While serum TC (143.7 ± 18.3 vs ± 13.2; p = ), TG (94.8 ± 18.3 vs ± 22.9; p = ) nd LDL-C (103.1 ± 9.5 vs ± 11.4; p = ) were significntly lower in HCV-4 ptients compred with controls, with

4 40 Khttb MA, et l., 2012; 11 (1): Tble 1. Chrcteristics of ptients chroniclly infected with HCV. Vrible Ptient (n = 183) Control (n = 106) p vlue Men ge (yers) 43.7 ± ± Mle/femle sex 140 (76.5%) / 43 (23.4%) 80 (75.4%) / 26 (24.5%) 0.2 Men BMI (kg/m²) 26.4 ± ± Systolic blood pressure (mmhg) ± ± Distolic blood pressure (mmhg) 78.5 ± ± Wist/hip rtio 0.89 ± ± Pltelet (x 10 9 /L) ± ± Hemoglobin (g/dl) 13.5 ± ± Totl diponectin (µg/l) 15.8 ± ± Albumin (g/l) 4.1 ± ± ALT (U/L) 42.7 ± ± Fsting glucose (mmol/l) 5.32 ± ± AST (U/L) 46.6 ± ± Insulin (µu/ml) 11.5 ± ± C-peptide (Pmol/L) 1.4 ± ± HOMA-IR 2.4 ± ± Triglycerides(mg/dL) 94.8 ± ± HDL-C (mg/dl) 47.9 ± ± LDL-C (mg/dl) ± ± Cholesterol (mg/dl) ± ± Virl lod (log 10 ) ± Stetosis 82 (44.8%) Absent or Mild 62 (33.8%) Moderte 39 (21.3%) Severe Histopthologicl ctivity (Metvir score) F1 88 (48.08%) F2 47 (25.6%) F3 32 (17.4) F4 16 (8.7%) Metvir ctivity grde Mild (A1) 105 (57.3%) Modrte (A2) 56 (30.6) Severe (A3) 22 (12.02%) n elevtion in HDL-C (47.9 ± 6.9 vs ± 3.7; p = ) compred with the controls (Figure 1). Totl diponectin were significntly higher mong cses thn mong controls (15.8 ± 1.06 µg/l vs. 9.6 ± 2.5 µg/l; p < ) (Tble 1). Liver histology Complete histologicl nlysis for portl/periportl inflmmtory grde, nd fibrosis stge were vilble in ll cses. Fibrosis ws stge 1 in 88 (48.08%), stge 2 in 47 (25.6%) nd stge 3 in 32 (17.4%). Cirrhosis (stge 4 fibrosis) ws present in 16 (8.7%) ptients. Inflmmtion were mild A1 in 105 (57.3%), moderte A2 in 56 (30.6%) nd severe 22 (12.02%). 82 ptients (44.8%) exhibit no or mild stetosis; moderte nd severe stetosis ws present in 101 subjects: moderte in 62 (33.8%) nd severe in 39 (21.3%). Fctors ssocited with the severity of histologicl lesions in chronic HCV-4 infection Fctors ssocited with the severity of histologicl chnges (heptic stetosis, portl/periportl inflmmtion nd fibrosis) were ssessed using univrite nd multivrite models (Tbles 2, 3, 4). Input vribles for the initil univrite nlysis included ge, sex, BMI, WHR, virl lod, stetosis,

5 Serum lipids nd chronic heptitis C genotype 4., 2012; 11 (1): nd portl/periportl inflmmtory grdes, fibrosis stge, fsting blood glucose, insulin, HOMA-IR, diponectin, nd lipid profiles (such s TG, TC, LDL-C, HDL-C). Ptients with significnt stetosis hd higher BMI, HOMA vlues, serum triglyceride levels, cholesterol level, elevted systolic hypertension, elevted distolic hypertension, lrger wist/hip rtio nd Cholesterol HDL-C LDL-C Triglycerides HCV+ptients Helthy control Figure 1. Serum lipid levels (mg/dl) in ptients with chronic heptitis C virus (HCV) vs. helthy donors. TC: totl cholesterol. HDL-C: high-density lipoprotein cholesterol. LDL-C: low-density lipoprotein cholesterol. TG: triglycerides. lower serum diponectin levels thn those with mild or bsent stetosis (p < 0.05). By multiple ordinl regression nlysis, higher stetosis mount were positively nd independently ssocited with BMI (OR; 1.5, 95% CI: ; p = 0.03) nd HOMA-IR (OR; 2.2, 95% CI: 1.2-4; p = 0.011), wheres negtive independent correltion ws observed with serum levels of diponectin (OR; 2.8, 95% CI: ; p = 0.01) (Tble 4). Ptients with severe inflmmtion hd higher ge, BMI, HOMA vlues, serum diponectin levels, Log HCV/Fitted vlue r = 0.32; p = Log10 (triglyceride) Figure 2. Reltionship between triglyceride (TG) nd heptitis C virus (HCV) RNA levels. Tble 2. Univrite nd multivrite nlyses for the fctors ssocited with severe inflmmtion in ptients with heptitis C virus genotype 4 (HCV-4). Vrible Inflmmtion p-vlue OR (95%CI) p-vlue A0- A1 (n = 105) A2, A3 (n = 78) Men ge (yers) ± ± ( ) 0.01 Mle/femle (%) 78 (74.2%) / 27 (25.7 %) 62 (79.4) / 16 (20.5%) 0.3 Men BMI (kg/m 2 ) ± ± ( ) 0.01 Distolic blood pressure (mmhg) 78.6 ± ± Wist/hip rtio 0.90 ± ± Pltelet (x 10 9 /L) ± ± Hemoglobin (g/l) 13.9 ± ± Totl diponectin (µg/l) ± ± Albumin (g/l) 4.3 ± ± ALT (U/L) ± ± Fsting glucose (mmol/l) 4.21 ± ± AST (U/L) 41.8 ± ± Insulin (µu/ml) ± ± C-peptide (Pmol/L) 1.46 ± ± HOMA-IR 1.76 ± ± ( ) 0.02 Triglycerides(mg/dL) 96.7 ± ± HDL-C (mg/dl) 43.3 ± ± LDL-C (mg/dl) ± ± Cholesterol (mg/dl) ± ±

6 42 Khttb MA, et l., 2012; 11 (1): Tble 3. Univrite nd multivrite nlyses for the fctors ssocited with severe fibrosis (Metvir score > F2) in ptients with heptitis C virus genotype 4 (HCV-4). Vrible Fibrosis p-vlue OR (95%CI) p-vlue F1, F2 (n = 135) F3, F4 (n = 48) Men ge (yers) 40.5 ± ± ( ) Mle/femle (%) 105 (77.7%) / 30 (22.2%) 35(72.9%) / 13 (27.08%) 0.3 Men BMI (kg/m 2 ) ± ± Systolic blood pressure (mm/hg) ± ± Distolic blood pressure (mm/hg) 79.2 ± ± Wist/hip rtio 0.91 ± ± Pltelet (X 10 9 /L) ± ± Hemoglobin (g/dl) 13.8 ± ± Totl diponectin (µg/l) 12.6 ± ± Albumin (g/l) 4.3 ± ± ALT (U/L) 42.7 ± ± Fsting glucose (mmol/l)) 4.2 ± ± AST (U/L) 44.3 ± ± Insulin (µu/ml) ± ± C-peptide (Pmol/L) 1.3 ± ± HOMA-IR 2 ± ± ( ) Triglycerides (mg/dl) ± ± HDL-C (mg/dl) 42.9 ± ± LDL-C (mg/dl) ± ± Cholesterol (mg/dl) ± ± ( ) 0.01 Stetosis (Absent or 63 (46.6%)/ 19 (39.5%)/ 0.07 mild vs. moderte or severe) 72 (53.3%) 29 (60.4 %) Necroinflmmtory score 95 (70.3%) 10 (20.8%) ( ) (A1, A2, A3)(%) 37 (27.4%) 19 (39.5 %) 3 (2.2 %) 19 (39.5 %) AST, ALT nd lrger wist/hip rtio nd lower LDL-C nd cholesterol level thn those with mild heptic inflmmtion (p < 0.05). By multiple ordinl regression nlysis, ge, BMI, HOMA-IR were independently predicting incresing grdes of portl/ periportl inflmmtion (Tble 2). Ptients with severe fibrosis hd higher ge, BMI, HOMA vlues, serum diponectin levels, lrger wist/hip rtio, more severe heptitis ctivity nd lower HDL-C nd cholesterol level thn those with mild heptic fibrosis (p < 0.05). By multiple ordinl regression nlysis, HOMA-IR, portl/periportl inflmmtion grde, serum cholesterol nd ge were independently predicted severity of the stge of fibrosis (Tble 3). Vribles ssocited with HCV virl lod Using Spermn s rnk correltion nlysis, significnt indirect direct reltionships were found between the nturl logrithm (ln) of TG nd log 10 virl level (r = 0.32, p = 0.01) (Figure 2). Univrite nlysis between demogrphic, biochemicl vribles nd HCV RNA levels ws done. Stepwise liner regression nlyses were performed to exmine the ssocition between HCV RNA levels nd lipid profiles. The probble correltes of HCV virl lod nd lipid profiles (such s TG, TC, LDL, HDL), fsting blood glucose, HOMA-IR index, heptic inflmmtion score, heptic fibrosis score, heptic stetosis score, PLT, AST, ALT, ge, sex, nd BMI) were selected in stepwise pproch nd included into the multivrite models fter djustment for HOMA-IR index, ge, gender, nd BMI. The nlysis showed tht more severe heptitis ctivity, milder heptic fibrosis nd TG level (p < 0.05) were significntly ssocited with higher HCV RNA levels (Tble 5). DISCUSSION Although in vitro nd in vivo studies hve demonstrted the ssocitions between lipid/glucose/ insulin metbolism nd HCV infection, nd rised ssumptions for potentil benefit of lipid-lowering drugs in the control of HCV repliction, 4,17-18 little is known bout the differentil ssocition of lipid

7 Serum lipids nd chronic heptitis C genotype 4., 2012; 11 (1): Tble 4. Univrite nd multivrite nlyses for the fctors ssocited with heptic stetosis in ptients with heptitis C virus genotype 4 (HCV-4). Vrible Stetosis Stetosis OR (95%CI) p-vlue Absent or mild Moderte or severe (n = 82) (n = 101) Men ge (yers) 41.4 ± ± Mle/Femle (n, %) 62 (75.6%) / 20 (24.3%) 78 (77.2%) / 23 (22.7%) 0.7 Men BMI (kg/m 2 ) 22.8 ± ± ( ) 0.03 Systolic blood pressure (mm/hg) ± ± Distolic blood pressure (mm/hg) 78.4 ± ± Wist/hip rtio 0.90 ± ± Pltelet (x 10 9 /L) ± ± Hemoglobin (g/dl) 13.7 ± ± Totl diponectin (µg/l) 16.4 ± ± ( ) 0.01 Albumin (g/l) 4.3 ± ± ALT (U/L) 46.7 ± ± Fsting glucose (mmol/l) 4.2 ± ± AST (U/L) 47.1 ± ± Insulin (µu/ml) ± ± C-peptide (Pmol/L) 1.1 ± ± HOMA-IR 1.6 ± ± (1.2-4) Triglycerides(mg/dL) 76.1 ± ± HDL-C (mg/dl) 43.6 ± ± LDL-C (mg/dl) ± ± Cholesterol (mg/dl) ± ± Virl lod ± ± Tble 5. Multivrite nlysis identifying fctors ssocited with HCV RNA levels in 183 chronic heptitis C ptients. Prmeter estimte s.e. p vlue Age (yers) Sex (M vs. F) BMI (kg/m²) HOMA-IR log diponectin (µg/ml) Log 10 (PLT) (K/µL) ln (TG) (mg/dl) ln LDL-C (mg/dl) ln HDL-C (mg/dl) Ln Cholesterol (mg/dl) Metvir ctivity Metvir fibrosis Stetosis Constnt profiles with HCV virl lod, HCV-induced liver dmge nd stetosis between genotypes 4 infections. This study shows in single popultion, tht chronic HCV-4 infection is ssocited with glucose intolernce nd, despite tht, fvourble lipid pttern, consisting of n elevtion in HDL-C nd reduction in TC, LDL-C nd TG, in comprison with norml dults mtched for ge nd sex. This combintion of fvorble lipids nd dibetes is unusul, s the conventionl metbolic syndrome, constelltion of risk fctors for therosclerosis, includes, mong others, n therogenic lipid profile, glucose intolernce nd IR. 19 Whether the protective effect of hypolipidemi seems to be not counterblncing the effect of IR in the pthogenesis of therosclerosis mong HCV infected individuls, s higher grdes of crotid intiml thickness ws reported in HCV ptients compring with helthy mtched control. 20 These findings re in line with previous reports in other HCV genotypes A decrese in TG levels hs been previously described mong subjects with chronic HCV-4 infection, in comprison with mt-

8 44 Khttb MA, et l., 2012; 11 (1): ched control. 24 The mechnisms by which HCV infection my lower serum TC re still specultive nd my include, mong others, the binding of HCV prticles to HDL-C, LDL-C nd very low density lipoprotein (VLDL) 25,26 nd the impired heptocytic ssembly of VLDL through inhibition of the microsoml trnsfer protein 27 or through depletion of the intr heptocyte intermedite ftty cids s mevlonic 28 cids nd gernylgernyl lipid required for HCV RNA repliction nd formtion of HCV core proteins. 28 In vitro nd in vivo dt suggest tht sttins, the widely used cholesterol-lowering drugs, my inhibit HCV RNA repliction by depletion of gernylgernyl lipids. 5,9 Considering the ssocitions between liver histology nd lipid profiles in HCV-4 ptients, the univrite nlysis show close reltionship mong ge, BMI, HOMA vlues, serum diponectin levels, lrger wist/hip rtio, more severe heptitis ctivity nd lower HDL-C nd cholesterol level with dvnced heptic fibrosis. HOMA-IR, portl/periportl inflmmtion grde, serum cholesterol nd ge were independently ssocited with severe fibrosis. Univrite ssocition ws elucidted between heptic inflmmtion nd lower TC nd LDL-C levels nd with higher ge, BMI, HOMA vlues, serum diponectin levels, AST, ALT nd lrger wist/hip rtio. Age, BMI nd HOMA-IR were independently correlted with the grdes of portl/periportl inflmmtion. These findings re consistent with other findings from both non-hcv-infected 29 nd chroniclly HCV-infected groups 21,22 tht hve ssocited liver disese with lower levels of HDL-C nd TC. A higher grding score mens more severe inflmmtion, elevted serum levels of cytokines nd hypocholesterolemi, through reduction of LDL-C. 30 Upon tht, the inverse reltionship between liver disese nd non-tg lipid profile mesures my reflect the disruption of lipid nd lipoprotein metbolism becuse of liver dmge, either by host fctors (e.g. poor nutrient intke or excess loss of body weight) or ttributed to chronic HCV infection which use the host lipoprotein mchinery for its life cycle. 31 In contrst, nlysis of fctors ssocited with severe stetosis showed tht stetosis ws ssocited with higher BMI, HOMA vlues, serum triglyceride levels, cholesterol level, elevted systolic hypertension, elevted distolic hypertension, lrger wist/hip rtio nd lower serum diponectin levels. Stetosis ws positively nd independently ssocited with BMI nd HOMA-IR, wheres negtive independent correltion ws observed with serum levels of diponectin. These findings re in line with our previous dt tht stetosis is posited to occur becuse of metbolic chnges in HCV-4 infection, nd follows the sme pttern s those infected with genotype In trnsgenic mouse model, the HCV core protein ws found to inhibit MTP ctivity; this enzyme plys key rte-limiting role in VLDL ssembly. 26 Thus, its inhibition would led to the ccumultion of TG otherwise uploded onto VLDL, nd the morphologicl counterprt of this would be heptocyte stetosis. This mechnism is supported by two epidemiologicl studies, which found inverse reltionships between stetosis nd TC, TG, nd polipoprotein B levels in genotype 3-infected group, but not in genotype 1. 8,22 Tken together, the findings indicte tht in ptients with HCV-4 stetosis is ssocited with the presence of host metbolic risk fctors for stetosis (such s obesity, IR nd hyperlipidemi), which is ssocited with more progression of liver disese. With increse the severity of heptic inflmmtion nd fibrosis the elevted serum levels of cytokines re ssocited with hypolipidemi. Another finding of this study ws the correltion between HCV virl lod nd TG levels, the ltter of which is minly present in VLDL, nd thus strengthened the hypothesis tht HCV infection cn directly link to lipid metbolism in the clinicl setting. This is relevnt to findings from in vitro work bout the proposed biologicl mechnisms nd lipid involvement in HCV entry, repliction nd secretion from heptocytes. 26,32-35 Our results my imply possible ssistnt role of these lipid fctors on HCV- 4 virions life cycle. The erdiction of HCV genotype 1 ws ssocited with elevtion of serum TC levels bove bseline. 36 No similr dt re vilble in HCV-4. This study hs undoubtedly some limittions. Given the cross-sectionl nture of this nlysis, it is not possible to infer custion or temporlity of reltionships between lipid profile nd liver disese mesures. Further studies with longitudinl design nd pired controls re needed to elucidte possible cusl reltionships. CONCLUSION This cross sectionl study hs shown tht in single popultion, chronic HCV infection is ssocited with glucose intolernce nd, despite tht, fvourble lipid pttern, consisting of n elevtion in HDL-C nd reduction in TC, LDL-C nd TG, nd elucidted ssocitions between lipid profile mesures nd both HCV- RNA levels nd liver disese in-

9 Serum lipids nd chronic heptitis C genotype 4., 2012; 11 (1): jury. These findings strengthened the hypothesis tht HCV infection directly links to metbolic derngements but differently mong HCV genotypes in the clinicl setting. Further studies re required to clrify the temporl reltion with ntivirl tretment nd the clinicl impliction of these findings. DISCLOSURE OF CONFLICT OF INTEREST Finncil support: None. Potentil competing interests: None. REFERENCES 1. World Helth Orgniztion. Heptitis C. Fct Sheet Number 164, Revised October Avilble from: [Accessed 13 October 2010]. 2. Khttb MA, Ferenci P, Hdziynnis SJ, Colombo M, Mnns MP, Almsio PL, Estebn R, et l. Mngement of heptitis C virus genotype 4: Recommendtions of An Interntionl Expert Pnel. J Heptol 2011; 54: Ishizk Y, Ishizk N, Tkhshi E, Unum T, Tood E, Hshimoto H, Ngi R, et l. Assocition between heptitis C virus core protein nd crotid therosclerosis. Circ J 2003; 67: Eslm M, Khttb MA, Hrrison SA. Insulin resistnce nd heptitis C: n evolving story. Gut 2011; 60: Kpdi SB, Chisri FV. Heptitis C virus RNA repliction is regulted by host gernylgernyltion nd ftty cids. Proc Ntl Acd Sci USA 2005; 102; Iked M, Kto N. Life style-relted diseses of the digestive system: cell culture system for the screening of ntiheptitis C virus (HCV) regents: suppression of HCV repliction by sttins nd synergistic ction with interferon. J Phrmcol Sci 2007; 105: Miynri Y, Atsuzw K, Usud N, Wtshi K, Hishiki T, Zys M, Brtenschlger R, e t l. Lipid droplet is n importnt orgnelle for heptitis C virus production. Nt Cell Biol 2007; 9: Serfty L, Andreni T, Girl P, Crbonell N, Chzouillères O, Poupon R. Heptitis C virus induced hypobetlipoproteinemi: possible mechnism for stetosis in chronic heptitis C. J Heptol 2001; 34: Bder T, Fzili J, Mdhoun M, Aston C, Hughes D, Rizvi S, Seres K, et l. Fluvsttin inhibits heptitis C repliction in humns. Am J Gstroenterol 2008; 103: Poynrd T, Rtziu V, McHutchison J, Mnns M, Goodmn Z, Zeuzem S, Younossi Z, et l. Effect of tretment with peginterferon or interferon lph-2b nd ribvirin on stetosis in ptient infected with heptitis C. Heptology 2003; 38: Hui JM, Kench J, Frrell GC, Lin R, Smrsinghe D, Liddle C, Byth K, et l. Genotype-specific mechnisms for heptic stetosis in chronic heptitis C infection. J Gstroenterol Heptol 2002; 17: Khttb MA, Abdel-Ftth ME, Eslm M, Abdelleem A, Abdelleem RA, Shtt M, Ali A, et l. Heptic stetosis in genotype 4 chronic heptitis C ptients: impliction for therpy. J Clin Gstroenterol 2010; 44: Moucri R, Asselh T, Czls-Htem D, Voitot H, Boyer N, Ripult MP, Sobesky R, et l. Insulin resistnce in chronic heptitis C: ssocition with genotypes 1 nd 4, serum HCV RNA level, nd liver fibrosis. Gstroenterology 2008; 134: Bedoss P, Poynrd T. An lgorithm for the grding of ctivity in chronic heptitis C. The METAVIR Coopertive Study Group. Heptology 1996; 24: Americn Dibetes Assocition. Dignosis nd clssifiction of dibetes mellitus. Dibetes Cre 2004; 27(Suppl. 1): s5-s Brunt EM, Jnney CG, Di Bisceglie AM, Neuschwnder-Tetri BA, Bcon BR. Nonlcoholic stetoheptitis: proposl for grding nd stging the histologicl lesions. Am J Gstroenterol 1999; 94: Hrrison SA, Rossro L, Hu KQ, Ptel K, Tillmnn H, Dhliwl S, Torres DM, et l. Serum cholesterol nd sttin use predict virologicl response to peginterferon nd ribvirin therpy. Heptology 2010; 52: Negro F, Snyl AJ. Heptitis C virus, stetosis nd lipid bnormlities: clinicl nd pthogenic dt. Liver Int 2009; 29(Suppl. 2): Expert Pnel on Detection, Evlution, nd Tretment of High Blood Cholesterol in Adults. Exec. Summry of the Ntionl Cholesterol Eduction Progrm (NCEP) Expert Pnel on Detection, Evlution nd Tretment of High Blood Cholesterol in Adults (Adult Tretment Pnel III). JAMA 2001; 285: Aslm F, Alm M, Lkkis NM. Heptitis C nd crotid therosclerosis: retrospective nlysis. Atherosclerosis 2010; 209(2): Sigris D, Christofidou M, Theochris GJ, Pgoni N, Ppdimitriou C, Lekkou A, Thomopoulos K, et l. Serum lipid pttern in chronic heptitis C: histologicl nd virologicl correltions. J Virl Hept 2006; 13: Rmchrrn D, Whed AS, Conjeevrm HS, Evns RW, Wng T, Belle SH, Yee LJ. Serum lipids nd their ssocitions with virl levels nd liver disese severity in tretment-nïve chronic heptitis C type 1-infected cohort. J Virl Hept 2011; 18: e144-e Petit JM, Benichou M, Duvillrd L, Jooste V, Bour JB, Minello A, Verges B, et l. Heptitis C virus-ssocited hypobetlipoproteinemi is correlted with plsm virl lod, stetosis, nd liver fibrosis. Am J Gstroenterol 2003; 98: Mrzouk D, Sss J, Bkr I, El Hosseiny M, Abdel-Hmid M, Rekcewicz C, Chturvedi N, et l. Metbolic nd crdiovsculr risk profiles nd heptitis C virus infection in rurl Egypt. Gut 2007; 56: Thomssen R, Bonk S, Thiele A. Density heterogeneities of heptitis C virus in humn ser due to the binding of betlipoproteins nd immunoglobulins. Med Microbiol Immunol 1993; 182: Thomssen R, Bonk S, Propfe C, Heermnn KH, Köchel HG, Uy A. Assocition of heptitis C virus in humn ser with B-lipoprotein. Med Microbiol Immunol 1992; 181: Perlemuter G, Sbile A, Letteron P, Von G, Topilco A, Chrétien Y, Koike K, et l. Heptitis C virus core protein inhibits microsoml triglyceride trnsfer protein ctivity nd very low density lipoprotein secretion: model of virl-relted stetosis. FASEB J 2002; 16: 185e Goldstein JL, Brown MS. Regultion of the mevlonte pthwy. Nture 1990; 343: Kotronen A, Westerbck J, Bergholm R, Pietiläinen KH, Yki-Järvinen H. Liver ft in the metbolic syndrome. J Clin Endocrinol Metb 2007; 92: Hrdrdottir I, Grunfeld C, Feingold KR. Effects of endotoxin nd cytokines on lipid metbolism. Curr Opin Lipidol 1994; 5: Sherlock S, Jmes D. Diseses of the Liver nd Biliry System. 10th Ed. London, UK: Blckwell Science Ltd; 1997.

10 46 Khttb MA, et l., 2012; 11 (1): Ye J. Relince of host cholesterol metbolic pthwys for the life cycle of heptitis C virus. PLoS Pthog 2007; 3: e von Hhn T, Rice CM. Heptitis C virus entry. J Biol Chem 2008; 283: Fnning L, Kenny E, Sheehn M, Cnnon B, Whelton M, O Connell J, Collins JK, et l. Virl lod nd clinicopthologicl fetures of chronic heptitis C (1b) in homogeneous ptient popultion. Heptology 1999; 29: Gstminz P, Cheng G, Wielnd S, Zhong J, Lio W, Chisri FV. Cellulr determinnts of heptitis C virus ssembly, mturtion, degrdtion nd secretion. J Virol 2007; 82: Lnge CM, von Wgner M, Bojung J, Berg T, Frnik H, Hssler A, Srrzin C, et l. Serum lipids in Europen chronic HCV genotype 1 ptients during nd fter tretment with pegylted interferon--2 nd ribvirin. Eur J Gstroenterol Heptol 2010; 22: