| The Impact of Diet on Liver Fibrosis and on Response to Interferon Therapy in Patients With HCV-Related Chronic Hepatitis |
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Saturday, 14 March 2009 10:05
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The Impact of Diet on Liver Fibrosis and on Response to Interferon Therapy in Patients With HCV-Related Chronic Hepatitis Posted 01/21/2009 Authors: Carmela Loguercio, MD; Alessandro Federico, MD; Mario Masarone, MD; Roberto Torella, MD; Marcello Persico, MD Abstract and Introduction Abstract Background and Aims: A deranged metabolic status and alcohol intake may trigger induction and progression of chronic hepatitis C virus (HCV) liver disease. The aim of this study was to evaluate whether dietary composition affects the severity of liver damage and response to therapy in patients with HCV-related chronic hepatitis. Methods: We enrolled 1,084 patients with biopsy-proven HCV-related chronic hepatitis (432 treated with interferon plus ribavirin) and 2,326 healthy subjects in this prospective study conducted in a university hospital. Dietary habits were recorded in enrolled individuals, and their alcohol consumption was evaluated with a questionnaire (AUDIT). Body mass index, and plasma levels of blood glucose, nitrogen, creatinine, cholesterol, and triglycerides were also measured. All individuals underwent routine liver tests and HCV genotyping. Results: At study onset, there were no differences in metabolic status or alcohol consumption between patients and controls. About 50% of each group was overweight, and about 60% consumed alcohol. Patients and controls had similar dietary habits. Intake of carbohydrates, lipids and polyunsaturated fatty acids, and alcohol consumption were independent factors of liver damage at histology (logistic regression analysis). Some dietary components (unsaturated fatty acids, iron, zinc, vitamin A, and niacin) and alcohol intake differed significantly (P < 0.05 and P 0.01, respectively; univariate analysis) between responders and nonresponders to interferon therapy. Genotype, age, body mass index, steatosis, and fibrosis were independent predictors of therapy outcome (P < 0.02; multivariate analysis). Conclusions: The severity of HCV-related chronic hepatitis depends on a variety of factors. Our results show that dietary composition is related to the extent of liver damage. Although traditional risk factors independently affected treatment response, some dietary components were associated with nonresponse to therapy in our patients. This suggests that HCV patients may benefit from instructions regarding their diet. Introduction Viral and host factors regulate the progression of chronic hepatitis and the response to therapy in patients with HCV-related chronic hepatitis, which has been termed a metabolic disease.[1-6] Recent years have seen a surge of interest in complementary food and chemopreventers to treat various liver diseases including cirrhosis.[7-13] Diet influences body mass index (BMI), iron content in the liver, insulin, enzyme activities, substrate reserves, and metabolic pathways in hepatocytes, and many foods have been reported to exert protective or toxic effects on the liver in animal models and humans.[14-20] Moreover, imbalanced diets were found to affect the development and progression in a group of patients with nonalcoholic steatohepatitis.[21] However, to our knowledge, there are no data about the relationships between diet and liver damage in patients with HCV-related chronic hepatitis. We undertook the present prospective study to evaluate the effect of diet on the severity of liver damage and on the response to antiviral therapy in patients with HCV-related chronic hepatitis. Patients and Methods Patients Informed written consent was obtained from each subject and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. We prospectively enrolled patients affected by HCV from Southern Italy referred to our Department between 2002 and 2005. Excluded from the study were patients with chronic HBV and HIV infection, decompensated cirrhotics, and patients with such other clinically relevant associated diseases as decompensated diabetes, kidney diseases, pulmonary diseases, collagen diseases, tumors. A total of 1,084 patients with HCV-related chronic hepatitis were enrolled in the study. Of these, 408 patients had well compensated Child A cirrhosis and 432 were naive patients (including chronic hepatitis and Child A cirrhosis) who had undergone antiviral therapy. HCV genotypes were collected before starting antiviral treatment. As a control group, we studied 2,326 apparently healthy blood donors who were negative for HCV antibody and hepatitis B surface antigen (HBsAg), and had normal liver tests. The 1,084 patients with chronic liver disease underwent a liver biopsy, which was scored according to Ishak et al..[22] Steatosis was graded as absent (0), mild (<33%, 1), moderate (>33% and ?66%, 2), or severe (>66%, 3).[23] The subgroup of patients, in whom interferon (IFN) therapy was indicated, received pegylated-IFN + ribavirin and were treated for 48 (in genotype 1-4 patients) or 24 wk (in genotype 2-3 patients) according to current guidelines.[24] The virological response to therapy was assessed by HCV-RNA measurements at baseline, at 12 and 48 wk of treatment, and 24 wk after treatment ended. Based on qualitative HCV-RNA results, the patients were defined either sustained virological responders (SVRs) (no detectable HCV-RNA after 24/48 wk of treatment and 6 months thereafter) or non-responders (NRs) (viral breakthrough, and virological nonresponse, with persistence of HCV-RNA at the end of treatment). Treatment was discontinued in virological nonresponders at week 12 of therapy, based on a positive quantitative HCV-RNA test.[25] Methods Patients and controls with a BMI between 25 kg/m2 (for men) and 24 kg/m2 (for women) and 29.9 kg/m2 were considered overweight (determined as kg/m2, and those with a BMI ?30 kg/m2 were considered obese. Plasma levels of blood glucose, nitrogen, creatinine, cholesterol, triglycerides after 12 h of fasting (routine kits) were measured, and patients and controls underwent routine liver tests. Dietary habits were recorded for all enrolled subjects. For this purpose, we used the Winfood Software 2.0 package (Medimatica s. r. l., Martinsicuro, Italy) program, which has previously been used to assess alimentary history.[26,27] On the basis of the quantities and qualities of foods consumed, the program elaborates the energy intake and the percentage of macronutrients and micronutrients, and calculates the elements in each food. Proteins are reported as animal and vegetal proteins. Carbohydrates are divided in soluble and amide, lipids in saturated, polyunsaturated, monounsaturated fatty acids, and cholesterol. The complete elaboration of intakes shows the list of diet components, the ratio among components and calories, and the subdivision in breakfast, lunch, and dinner. We recorded the food intake of a complete week, including working days and the weekend. T The dietary examination was randomly repeated in a large number of subjects (202 patients and 334 controls, equally distributed in men and women) to evaluate variability. Data collected were similar in all interviews (Concordance: k = 0 ). The data were compared with the tables of food consumption and recommended dietary intakes of the Italian National Institute of Nutrition and Food Composition Database in Italy.[28,29] Alcohol use was evaluated with a standardized precodified questionnaire (complete AUDIT test).[30] We considered as constant a continuous daily alcohol intake in the last 3 yr at least. The quantity of daily alcohol intake was calculated based on a drink that corresponds to about 12 g of pure ethanol.[31] RNA Preparation and HCV RNA Determination All steps were carried out under RNase-free conditions. The polymerase chain reaction (PCR) procedure was used to determine HCV RNA. Sera were rapidly (within 30 min of blood drawing) frozen at -20ºC. RNA was extracted according to Chomczynsky and Sacchi,[32] and c-DNA was derived. To identify HCV-RNA, a nested PCR was performed using primers that expanded the highly conserved 5' noncoding genomic region. Carryover PCR contamination was avoided by applying the measures suggested by Kwok and Higuchi.[33] Hcv Genotyping To classify the HCV genotypes, serum PCR products were hybridized to type- and subtype-specific probes 1a, 1b, 2a, 2b, and 3a. The probes had to fulfill two main criteria: no more than two mismatches compared with the corresponding published sequences of the same subtype, and they had to differ by three or more mismatches compared with published sequences of other types and subtypes. The only exception is probe 2b, which had only two mismatches compared with the corresponding sequence of type 3a.[34] Statistics Data were considered significant at P < 0.051. Continuous normally distributed variables were summarized as mean ± standard deviation (SD) and categorical variables as frequency and percentage. Variance analysis (ANOVA) was used to evaluate the differences among means and the c2 test for the differences of percentages among groups. The degree of association between continuous, normally distributed variables was assessed by Pearson's correlation test. Spearman rank correlations were also used to assess the significance of associations between ordinal or continuous predictor variables and liver histology (inflammation, steatosis, fibrosis). Univariate logistic regression was used to quantify the association among all clinical and laboratory variables and the histological findings or the response to therapy. Using the univariate predictors as input variables, multiple logistic regression, performed with forward stepwise selection of variables, identified the independent predictor of liver steatosis, grading, and staging as well as response to therapy. The adjusted odds ratios (OR) for the association of liver histology and response to therapy with each category of alimentary history were calculated by multiple logistic regression analysis.[35] In the model, liver histology (inflammation, steatosis or fibrosis) and the response to treatment were outcome variables, whereas the amount of daily food intake, expressed both as total calories and as single components, as well as alcohol intake, age, BMI, HCV genotypes and viremia, and metabolic parameters were the independent variables. For OR estimates, the condition of absence or of normality of each parameter was the reference category (OR = 1). Data handling and analyses were performed with the Statistical Package for Social Sciences (SPSS 13.0; SPSS Inc., Chicago, IL). Results Table 1 shows the baseline demographic and metabolic data of the HCV-positive patients and controls. The BMI did not differ between the two groups. The prevalence of alterations in plasma lipid profiles (hypercholesterolemia and/or hypertriglyceridemia) ranged between 15% and 40%, and there were no differences between the two groups or between men and women (data not shown). Table 2 and Table 3 , respectively, show the intake of micronutrients and macronutrients in patients and controls together with the daily amounts recommended in Italy. We found no differences in nutrient intake between the HCV-positive patients and the control group. However, within each group there were some differences, albeit not significant, related to gender. In both groups, total calorie intake was inversely correlated with age P < 0.01). The intake of animal proteins, carbohydrates, and lipids was directly related to plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (P < 0.01); BMI was related with gamma-glutamyltranspeptidase (?GT) and blood glucose (P < 0.01) (data not shown). Alcohol was constantly consumed by 60% of liver patients and controls ( Table 4 ). There was no difference in the daily intake of alcohol between HCV patients and controls (median: 46 g and 50 g, respectively, range 10-100 g). Moreover, 48% of men affected by HCV continued to consume >40 g alcohol/day (see Table 4 ). We next divided patients according to the presence/absence of liver cirrhosis, and found no difference between the groups or between men and women (data not shown). Liver Histology At liver histology, 58% of patients were affected by steatosis, which was mild in 15%, moderate in 33%, and severe in 10% of cases. The results of the univariate analysis of the association of histology with demographic, dietary, and biochemical parameters in our HCV patients is shown in Table 5 (significant associations are reported in boldface). Alcohol intake was significantly correlated with fibrosis (P < 0.001) and histological steatosis (P < 0.05). Moreover, the variables significantly associated with fibrosis or steatosis were predictive of more severe grading, staging, and steatosis, except for alcohol that was inversely associated with grading. We next included the variables significantly associated with histological parameters in a multivariate analysis. The results showed that the only factors predictive of liver damage, calculated by using the histological scores as continuous variables, were age, BMI, and fasting blood glucose levels. The OR were: age >50 yr versus steatosis: OR 2.7 (0.8-3.4); versus inflammation: OR 4.3 (2.5-11.7); versus fibrosis: OR 7.5 (3.5-18.0). BMI > 25 versus steatosis: OR 1.5 (0.8-2.3); versus inflammation: OR 0.4 (0.2-0.9); versus fibrosis: OR 3.6 (2.1-10 ). Blood glucose versus steatosis: OR 1.3 (0.2-2.7); versus inflammation: OR 0.4 (0.1-0.9); versus fibrosis: OR 1.9 (0.9-2.7). Lastly, we carried out a logistic regression analysis with the components of diet as continuous variables and with all the variables that were significantly related to staging, grading, or steatosis. We adjusted for the confounding effects of age (?50 yr vs >50) and BMI (<25 vs?25), and found that alcohol was the independent factor most closely related to liver damage (OR 4.6; 95% CI 2.7-10. ( Table 6 ). RESPONSE TO IFN. The univariate analysis of epidemiological, nutritional, and histological factors in relation to the response to antiviral treatment is shown in Table 7 . Besides the association between gender, age, genotype, and fibrosis, also obesity, some nutrients, and alcohol consumption were significant. At multivariate analysis, age, BMI, steatosis, fibrosis, and HCV genotypes were independent predictors of the outcome to therapy in our HCV-infected patients (Table). Discussion Dietary components have been implicated in deranged liver function in physiological conditions[36,37] and in patients with liver diseases.[20,22,26,38] Our study, carried out on a large number of HCV patients and controls, demonstrates that dietary intake affects liver histology, and indirectly, response to treatment. In fact, at univariate and multivariate analysis, a high intake of calories, carbohydrates, and lipids was associated with more severe fibrosis. This finding illustrates that diet is an important factor in the management of patients affected by HCV. Interestingly, HCV patients did not seem to adhere to a so-called healthy diet. Indeed, both patients and controls exceeded the daily recommended doses of total proteins, carbohydrates, and lipids. Even more surprisingly, both groups consumed a similar amount of alcohol. Moreover, the number of heavy drinkers (> 40 g/day) was similar in the two groups. Alcohol affects HCV by enhancing oxidative stress and HCV replication[38] and increases insulin resistance in obese individuals by interfering with the traffic of lipids between adipose tissue and liver.[39] It stimulates the production of inflammatory cytokines that in turn affect and are affected by insulin resistance in a vicious circle, and finally, by activating transcriptional factors, alcohol accelerates the progression to fibrosis in HCV-infected patients.[40-42] We found that a high intake of PUFA was associated with a higher degree of steatosis, and that a higher intake of lipids and carbohydrates was associated with fibrosis. Similar associations were found in animals with alcohol-induced liver damage and/or experimental NASH,[43-46] and in patients with NAFLD[47, 48]. It is noteworthy that obesity[49] and diabetes[50] have been found to be risk factors for hepatocellular carcinoma in case-controlled studies. Taken together, the foregoing data suggest a synergistic mechanism whereby alcohol, diet and HCV alter the metabolism of lipids and carbohydrates, which in turn, results in liver damage. The viral characteristics (RNA, viremia, genotype) are important in determining the outcome of treatment with IFN and ribavirin in HCV-positive patients.[51] Also host characteristics seem to be important in establishing the clinical management of patients with HCV-related chronic hepatitis.[1-4,52] Furthermore, weight reduction has been shown to reduce steatosis and abnormal liver enzymes and improve fibrosis in patients with chronic hepatitis C.[53] Here we report the novel finding that, in a large population of HCV-positive patients, several dietary components were related to the severity of liver damage, and that BMI and staging negatively affected the response to therapy in patients affected by hepatitis C. This suggests that educational programs aimed at correcting the overall lifestyle of liver disease patients should be part of the therapeutic strategy of these patients. The simple recommendation of a low calorie, low fat diet may not be effective in an era in which attention is focused on natural products, including such foods as complementary or chemopreventive drugs.[36] Our finding that alcohol intake was similar in patients and controls might indicate that physicians, including hepatologists, do not consider this aspect sufficiently important, and consequently do not advise their patients to abstain from drinking. Because frequent contacts with medical professionals during treatment has been associated with reduced alcohol intake,[54] we suggest the HCV patients undergo regular counseling about this issue in order to improve their awareness of alcohol-related problems. Globalization of dietary habits, which has been well discussed in recent years,[55] seems to be related to the emerging problem of obesity[56] also in our regions, formerly taken as an example of a correct diet. Besides being a cardiovascular risk,[57] obesity is also an important factor of liver damage in hepatitis C.[23,41,49,53] In conclusion, we show that, besides alcohol consumption, an unbalanced diet is an important factor of hepatitis C evolution and nonresponse to antiviral treatment. Specific nutritional education and severe alcohol restrictions might, synergistically, improve the response to antiviral therapy. Acknowledgements C Loguercio: study planning and paper drafting; A Federico: study conducting; Masarone: study conducting and paper drafting; C Del Vecchio Blanco: study planning; R Torella: study planning; M Persico: study planning and paper drafting. 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Clinical implications of obesity with specific focus on cardiovascular disease: A statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: Endorsed by the American College of Cardiology Foundation. Circulation 2004;110:2952-67. Carmela Loguercio, MD,1 Alessandro Federico, MD,1 Mario Masarone, MD,1 Roberto Torella, MD,1 Camillo Del Vecchio Blanco, MD,1 and Marcello Persico, MD1 1Department of Internal Medicine and Hepatogastroenterology, Second University of Naples, Naples, Italy Am J Gastroenterol. 2008;103(12):3159-3166. ©2008 Blackwell Publishing http://www.medscape.com/viewarticle/585010 Add this page to your favourite Social Bookmarking websites;         
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