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Fatigue & Hypermetabolism in HCV:
high HCV RNA may cause fatigue & interferon appears to reduce fatigue
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"Resting energy expenditure in chronic hepatitis C"
Journal of Hepatology 2000; 33: 623_627
Thierry Piche1, Ste _phane M. Schneider1, Albert Tran1, Sylvia Benzaken2, Patrick Rampal1 and Xavier He _buterne1 1Department of Hepatogastroenterology and Nutrition and 2Department of Immunology, Archet Hospital, University of Nice_Sophia Antipolis, France
"...we have demonstrated that abnormally elevated resting energy expenditure is present in chronic hepatitis C, that it is certainly related to HCV itself, and that interferon therapy normalizes hypermetabolism in responders.... Three months of IFN therapy reduced REE/FFM in responders ......On the other hand, no significant improvement in REE/FFM was shown in non_responders. Hypermetabolism may be responsible for chronic fatigue, which is frequently encountered in chronic hepatitis C.... As increased REE (resting energy expenditure) was correlated with the virus load but not with histological status or ALT activity, hypermetabolism might be a direct result of HCV replication rather than the consequence of hepatic inflammation..... Such findings have also been reported in patients infected by HIV.... the underlying mechanisms of increased REE in response to chronic virus infection remain largely speculative, but may involve the release of cytokines in plasma.... Metabolic assessment may be part of the many tools (biological and histological) used to provide more information about the efficacy of IFN therapy...."
"......This study revealed the existence of a marked increase in energy expenditure in patients with CHC that may be related to HCV itself. This is supported by the fact that (a) REE/FFM (resting energy expenditure/fat_free mass) was significantly higher in patients than in healthy controls, (b) REE/FFM was positively correlated with the virus load, (c) REE/FFM normalized in responders to IFN therapy, and (d) no patient had liver cirrhosis....... Hypermetabolism might be a direct result of HCV replication rather than the consequence of hepatic inflammation....."
INTRODUCTION
Increased energy expenditure has been reported in 16_34% of cirrhotic patients (1,2) in association with body weight loss (3). As a consequence, it has been suggested that hypermetabolism is of pathophysiologic importance in liver disease (4). However, whether increased resting energy expenditure (REE) is a constant feature of liver cirrhosis or not remains controversial (5). Selberg et al. (6) have shown that hypermetabolism may predict a poor clinical outcome in patients undergoing liver transplantation, suggesting that nutritional assessment (i.e. measurement of energy expenditure) may be of clinical value in liver disease. Induction of a hypermetabolic/hypercatabolic status by chronic viral infection has been well documented in human immunodeficiency virus (HIV) infection. In clinically stable patients, a positive correlation has been found between increased resting energy expenditure (REE) and weight loss (7). Mulligan & Tai (8) were the first to observe a significant correlation between the viral load of 36 HIV_infected patients and the REE adjusted for fat_free mass (FFM), suggesting that antiretroviral control for treatment of hypermetabolism can improve nutritional status. Hepatitis C virus (HCV) infection, a major cause of chronic hepatitis, leads to cirrhosis in 20% of all patients (9), and thus constitutes an important public health problem. Weight loss and fatigue are common in the natural history of chronic hepatitis C (CHC) and have been observed at all stages of infection (10). However, the underlying mechanisms of such disturbances have not yet been elucidated and it is not known whether chronic virus C infection affects energy expenditure. We therefore hypothesized that a hypermetabolic status develops in patients with CHC. In clinical practice, interferon alpha_2a (IFN) is the treatment of choice in chronic hepatitis C (11). However, whether IFN therapy may affect REE in HCV infection is still unknown. The aims of the present study were: (a) to assess REE in patients chronically infected with HCV without liver cirrhosis, and (b) to determine the effects of IFN therapy on REE.
ABSTRACT
Background/Aims: Hypermetabolism is considered to be of clinical interest in liver disease and in several chronic viral infections. Whether resting energy expenditure (REE) increases during chronic hepatitis C is not known. Our aims were: (a) to determine the metabolic state of patients with chronic hepatitis C, and (b) to evaluate the effects of interferon therapy on REE.
Methods: Forty_seven patients and 20 controls were studied. Sixteen patients failed to respond to interferon and 12 patients stopped the treatment during the first 2 months for various reasons. The 19 responders all received 1 year of interferon. REE (indirect calorimetry) and fat_free mass (FFM, bioelectric impedance analysis) were evaluated before (day 0) and after 90, 180, and 360 days of interferon. The virus load was evaluated in patients before treatment.
Results: On day 0, REE expressed as a ratio of FFM (REE/FFM) was higher in patients than in controls (129.2/14.7 vs 117.9/9.6 kJ kgFFMa1 24 ha1, p-0.01), and was positively correlated with the viral load (r_0.45, p_0.01).
On day 90, REE/FFM had significantly decreased in responders but it did not decrease in non_responders (p-0.01). In responders, REE/FFM on days 180 and 360 was similar to that of the controls.
Conclusions: Chronic hepatitis C induces hypermetabolism that is normalized by interferon therapy in responders. The underlying mechanisms of chronic hepatitis C_induced hypermetabolism and its clinical relevance remain to be determined.
AUTHOR DISCUSSION
This study revealed the existence of a marked increase in energy expenditure in patients with CHC that may be related to HCV itself. This is supported by the fact
that (a) REE/FFM was significantly higher in patients than in healthy controls, (b) REE/FFM was positively correlated with the virus load, (c) REE/FFM normalized
in responders to IFN therapy, and (d) no patient had liver cirrhosis.
A number of methodological issues merit consideration. The design of our study reflected clinical practice, with IFN being discontinued if serum ALT and
viremia levels had not returned to normal after 3 months of treatment. Therefore, only responders received 1 year of IFN therapy. It is well established that REE reflects FFM or, more accurately, the metabolically active body cell mass (16). As expected, we found a significant correlation between REE and FFM in both patients and controls. Although there is no gold standard for the measurement of body composition in humans, bioelectric impedance analysis is now recognized as a sufficient and precise method for use in clinical investigations (17). FFM, total body water, and body cell mass can thus be routinely evaluated with a readily available single frequency bioelectric impedance analyzer (15). As extracellular fluids are included, the technique should be used when the degree
of hydration remains stable, as was the case in all our patients and controls. As liver cirrhosis is reportedly responsible for hypermetabolism whatever the underlying mechanism of fibrosis (3), we did not include patients with liver cirrhosis in the present study. Nicotine (18) and alcohol (19) are known to increase REE. However, there was no difference in tobacco and alcohol
consumption between patients and controls (data not shown). Furthermore, all subjects had abstained from eating, drinking, or smoking during the 12 h prior to metabolic investigations. Plasma C_reactive protein and thyroid function tests were also normal in patients. Finally, as we did not evaluate food intake in
this study, we cannot make any statement on any possible adaptation by patients during the treatment.
Given the evidence that the virus load is an important factor for initiation of antiviral treatment, investigations were warranted on the relation between this
variable and the degree of hypermetabolism. As increased REE was correlated with the virus load but not with histological status or ALT activity, hypermetabolism might be a direct result of HCV replication rather than the consequence of hepatic inflammation. Such findings have also been reported in patients infected by HIV (8). In the latter, the underlying mechanisms of increased REE in response to chronic virus infection remain largely speculative, but may involve the release of cytokines in plasma (20). Indeed, cytokines such as tumor necrosis factor alpha (TNFa) and interleukin 1_b are known to affect energy metabolism, and are responsible for the clinically observed nutritional
effects of critical injury: hypermetabolism, anorexia, protein catabolism, and altered fat and glucose metabolism (21,22). Mention must also be made of the
potential role of catecholamines and other catabolic hormones as mediators in the pathogenesis of CHC_induced hypermetabolism (23). A reduction in energy
expenditure is a well_established occurrence in adults who reduce their body weight, because of the loss of lean body mass (24). However, in our patients, body weight and FFM were not significantly affected by IFN, and no correlation was found between variations in body weight and in REE/FFM during IFN therapy.
Despite the small number of patients studied, our data indicate that IFN therapy significantly reduced the degree of hypermetabolism in responders. The dramatic decline of both virus load and REE/FFM observed
in responders at day 90 is in accordance with the correlation observed between the virus load and REE/FFM at day 0. On the other hand, no significant
improvement in REE/FFM was shown in non_responders. Thus, it is tempting to speculate that HCV itself is responsible for hypermetabolism and that
metabolic assessment is useful in CHC. What, if any, is the clinical relevance of this hypermetabolism in CHC patients? Unlike HIV patients, who are both hypermetabolic and hypercatabolic, CHC patients do not seem to be at short_term risk for malnutrition, as there were no changes in their FFM before and after 1 year of follow_up. Hypermetabolism may be responsible for chronic fatigue, which is frequently encountered in chronic hepatitis C. Metabolic assessment may be part of the many tools (biological and histological) used to provide more information about the efficacy of IFN therapy. Further investigations with a large series of patients are required to assess the pathophysiologic and prognostic values of CHC_induced hypermetabolism.
In conclusion, we have demonstrated that abnormally elevated resting energy expenditure is present in chronic hepatitis C, that it is certainly related to HCV
itself, and that interferon therapy normalizes hypermetabolism in responders. Our data suggest that metabolic characterization may be of use in chronic hepatitis
C in a strategy that yet has to be defined.
RESULTS
Resting energy expenditure before IFN therapy
In patients, REE was significantly higher than PEE (6280+/_1046 vs 6004+/_966 kJ 24 h»1; p 0.01). In controls, REE and PEE (predicted energy expenditure) were not significantly different (5983+/_9834 vs 6075 861 kJ 24 h»1 NS). REE was correlated with FFM both in patients (r1/20.87, p<0.0001) and controls (r1/20.88, p 0.0001).
In patients, REE/FFM was significantly higher than in controls (129.2+/_14.6 vs 117.9 9.6 kJ kg FFM»1 24 h»1; p<0.01). A significant correlation was also found between REE/FFM and the 1/log10_transformed viral load (r1/2 0.45, p1/20.01). However, REE/FFM was not correlated with either the Knodell score (r1/20.06, p1/2 0.7) or ALT activity (r1/20.2, p1/20.1).
In the 19 responders to IFN, REE was significantly higher than PEE (6424+/_802 vs 6094 842 kJ 24 h»1; P<0.01) and REE/FFM was significantly increased
compared to the controls (129.4 15.4 vs 117.9 9.6 kJ kg FFM»1 24 h»1; p<0.01). REE/FFM was not significantly different between responders and non_responders.
Resting energy expenditure during IFN therapy
Three months of IFN therapy reduced REE/FFM in responders (129.4+/_15.4 vs 122.5+/_13.5 at days 0 and 90, respectively; p<0.05), whereas REE/FFM was not modified in non_responders. In responders treated for 1 year, REE/FFM at days 180 and 360 was not significantly different from that of the controls,
suggesting normalization of increased REE (119.5+/_15.1 and 121.9+/_12.6 kJ kg FFM»1 24 h»1 in responders at days 180 and 360, respectively, vs
117.9+/_9.6 kJ kg FFM»1 24 h»1 in controls; NS). No statistically significant modifications were observed in body weight or FFM during IFN therapy.
Materials and Methods
Subjects and study design
Eligible patients were aged 18_70 years and had compensated liver disease due to CHC. None of them were cirrhotic. The diagnosis of CHC was based on the association of: (a) an elevation of serum alanine aminotransferase (ALT) over 35 IU/l (upper normal limit) for 6 months or longer, (b) the presence of anti_HCV antibodies confirmed by a recombinant immunoblot assay, (c) the presence of HCV viremia, and (d) the exclusion of other causes of chronic liver disease (alcoholism, chronic hepatitis B, Wilson's disease, hepatotoxic drugs, hemochromatosis, a_1 antitrypsin deficiency, autoimmune chronic active hepatitis). Patients with evidence of dehydration or overhydration or any other acute or chronic disease liable to cause hypermetabolism (including patients infected with human immunodeficiency virus) were excluded from the study.
Forty_seven consecutive patients (26 females, 21 males, mean age 44.7+/_12.4 years) with CHC were enrolled over a 4_month period. After undergoing a liver biopsy, all patients were given 3 MU of IFN subcutaneously 3 times a week for 1 year. No patient had liver cirrhosis.
Patients were followed monthly for serum ALT and every 3 months for thyroid stimulating hormone levels. Response to IFN was defined at day 90 when negative viremia and normal ALT values were associated. At this time, 19 patients with both normal ALT values and negative HCV viremia were considered as responders, and were treated up to day 360. Sixteen patients had elevated ALT values and positive HCV viremia at the same time. These patients were defined as non_responders to IFN and their treatment was discontinued. Twelve
patients were withdrawn from treatment between months 2 and 3 for the following reasons: depression (n1/24), relapse of drug abuse (n1/23), non compliance with treatment (n1/23), and retraction after previous informed consent (n1/22). No patient had both elevated ALT values and negative HCV viremia, or vice versa.
Twenty healthy volunteers similar to the patients in age, body mass index, and sex ratio formed the control group (mean age 43.0+/_3.3 years; 11 females, 9 males).
REE and body composition were assessed at day 0 (both in controls and patients), after 90 days of IFN (in patients), and after 180 and 360 days of IFN (in responders only).
Informed consent was obtained from all patients and controls, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Human Research Committee of the University of Nice_Sophia Antipolis.
Virological evaluation
Anti_HCV antibodies were detected by a third_generation enzyme immunoassay (HCV EIA 3.0, Abbott Laboratories, North Chicago, IL, USA). Positive cases were confirmed with a recombinant immunoblot assay (RIBA_3, Ortho Diagnostic Systems, Raritan, NJ, USA). HCV_RNA was detected in sera by an RT_PCR technique (Amplicor, Roche Diagnostic Systems, Branchburg, NJ, USA). Levels of viremia were determined by quantitative PCR (Monitor, Roche Diagnostic
Systems, Branchburg, NJ, USA). Virus load were expressed as 1/log10 copies/ml.
Histological evaluation
Liver biopsy specimens were fixed in Bouin's solution and embedded in paraffin for routine staining with hematoxylin_eosin_saffron. All specimens were examined by the same pathologist and were evaluated by a previously validated scoring system, the Knodell score (12).
Body composition
FFM was measured by bipolar bioelectrical impedance analysis with an alternating electric current (50 mA) at two frequencies: 1 MHz and 5 kHz, as previously described and validated by Boulier et al. (13). The portable impedance analyzer (IMP BO 1, L'impulsion, Caen, France) was equipped with a microprocessor; a computer was used to calculate impedance and body composition. Measurements were taken in the morning, in the conditions described hereafter. The subjects had been supine for 30 min, arms relaxed at the sides but not touching the body. Two non_oxidizing stainless needles were inserted subcutaneously: one on the anterointernal side of a foot, the other in the first intermetacarpal space of the dorsal aspect of the contralateral hand. FFM was expressed in kilograms.
Resting energy expenditure
REE was measured in the Functional Explorations Unit of the Archet Hospital in the morning, after a 12_h overnight fast, and at least 48 h after the last injection of IFN. Participants were instructed to abstain from alcohol consumption (including alcohol_containing products and drugs) and smoking for 12 h. After a 30_min rest in the supine position, measurements were taken in a semi_recumbent position using a ventilated_hood, open_circuit indirect calorimeter
(Deltatrac, Datex Instruments, Helsinki, Finland). After equilibrium was reached (10_20 min), respiratory exchanges were monitored continuously over a 30_min period; data were obtained every minute and averaged over the 30 min. The system was checked weekly by burning ethanol under standard conditions, and calibrated immediately before each measurement with two standard gases. REE was calculated from the oxygen consumption rate and carbon dioxide production rate, using the modified Weir formula (14). Predicted energy expenditure (PEE) was calculated using Cunningham's prediction equation (15), as follows: PEE1/24.18À[3701(21.6ÀFFM)], where PEE is expressed in kilojoules per 24 h. REE was also expressed as a ratio of FFM (REE/FFM) in kilojoules per kilogram of FFM and per 24 h.
Statistical analysis
All numerical results are expressed as means SD. The Mann_Whitney test was used to compare the REE/FFM of patients and controls. Repeated measurements in the same group of patients were compared by analysis of variance (ANOVA), and p_values were considered significant after Bonferroni correction. Correlation study between HCV viral load and REE/FFM was performed by linear regression. HCV viral load was expressed as 1/log10 copies/ml to achieve a normal distribution. A p_value of <0.05 was considered significant. Statistical analysis was performed with the Statview 4.0.1 software package (Brain Power Inc., Calabasas, CA, USA).
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