Alcohol and Alcoholism Advance Access originally published online on October 7, 2006
Alcohol and Alcoholism 2006 41(6):593-597; doi:10.1093/alcalc/agl077
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LIPID PEROXIDATION AND SERUM CYTOKINES IN ACUTE ALCOHOLIC HEPATITIS
1 Servicios de Medicina Interna, 2 Servicio de Laboratorio, Hospital Universitario, and 3 Departamento de Fisiología, Facultad de Medicina, Universidad de La Laguna, Tenerife, Canary Islands, Spain
* Author to whom correspondence should be addressed at: Servicio de Medicina Interna' Hospital Universitario, Ofra s/n, Tenerife, Canary Islands, Spain; Tel.: +34 922 678600; E-mail egonrey{at}ull.es
(Received 2 July 2006; in revised form 20 July 2006; accepted 25 July 2006)
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ABSTRACT |
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Aims: Increased exposure of Kupffer cells to intestinal-borne Gram-negative bacteria enhances the metabolism and leads to cytokine production by these cells. Activation of Kupffer cells increases free radical release, which may, in turn, enhance cytokine secretion, creating a positive feedback loop, which contributes to liver inflammation. Cytokines act on T cells, inducing their proliferation and secretion of additional interleukins. Lipid peroxidation products (malondialdehyde; MDA) form adducts with proteins and acetaldehyde, triggering a T cell immune response. Controversy exists about the predominance of either Th-1 or Th-2 cellular responses. We performed the present study in order to analyse the cytokine pattern in patients with acute alcoholic hepatitis, its relation to MDA and the relation between all these parameters and liver function and prognosis. Subjects and methods: The study included 53 male alcoholics, 47 followed up for a median time of 32 months, during which 17 of them died. We measured serum MDA, tumour necrosis factor-alpha, interferon gamma (IFNG) and interleukins (IL) 4, 6, 8, and 10. Results: MDA levels were raised in cirrhotics and non-cirrhotics with alcoholic hepatitis, maintaining a relationship with bilirubin and Maddrey index, and with mortality in the univariate analysis. Both IFNG and IL-4 were raised in our patients compared with controls, as well as IL-8, and IL-6, but IL-10 were below the detection limit in the majority of cases, especially in cirrhotics. Using a Cox regression model, Maddrey index displaced MDA in the survival analysis. Conclusions: Our data lend support to the hypothesis that activation of both Th-1 and Th-2 cell subsets take place. MDA levels are raised in alcoholics with alcoholic hepatitis and are closely related to liver function derangement and to survival, although this is displaced by Maddrey index using Cox regression model.
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INTRODUCTION |
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Cytokines mediate the inflammatory response, exerting their multiple actions in an autocrine, paracrine and endocrine manner (Balkwill and Burke, 1989
). After extensive research mainly performed in the last 15 years, there is little doubt concerning the outstanding role of cytokines in the development of chronic alcoholic liver disease (Bird et al., 1990; Khoruts et al., 1991; Sheron et al., 1993; Bird, 1994; Huang et al., 1996; Fujimoto et al., 2000), so this disease can be considered as an inflammatory condition. Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-6, are directly involved in the pathogenesis of alcoholic hepatitis (Yin et al., 1999). Although ethanol directly induces hepatocytes to secrete IL-8 (Shiratori et al., 1993), it is currently recognized that endotoxin activates Kupffer cells by binding to toll-like receptors (Nanji, 2002). Cytokines released by these cells initiate the cascade of events, which ultimately leads to the development of hepatocyte necrosis, recruitment of neutrophils and immune cells, and liver fibrosis. During this process, increased free-radical production aggravates the scenario (Kono et al., 2000; Poli 2000; Loguercio and Federico, 2003), enhancing cytokine production and creating a positive feedback loop. In chronic alcoholics, induction of the microsomal ethanol oxidizing system (MEOS) also contributes to increased free-radical production (Cederbaum, 1991). Free radicals peroxidate lipids, including cell membrane components, and form adducts with acetaldehyde and proteins (Tuma, 2002) thus leading to increased hepatocyte damage and triggering an immune response (Stewart et al., 2004) which may involve Th-1 and Th-2 lymphocytes, although there is some controversy about this. Prognostic value of several cytokines in alcoholic liver disease has been assessed by several authors, (Rodríguez-Rodríguez et al., 1995; McClain et al., 2004), but the relationship of enhanced lipid peroxidation and liver function derangement and prognosis has been less frequently analysed, as well as the relationship between Th-1 and Th-2 cytokine patterns and lipid peroxidation. Based on these facts we performed the present study in order to analyse the cytokine pattern in acute alcoholic hepatitis, its relation with lipid peroxidation products (malondialdehyde; MDA) and the relationship between all these parameters and liver function and prognosis. |
METHODS |
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Patients and controls
Fifty-three alcoholic men, consecutively admitted to the hospitalization unit of the Internal Medicine Service, entered the study. Ethanol intake was assessed by recall and calculated as follows: grams of ethanol = volume of beverage (cm3) x strength (v/v, as %) x 0.8. All the patients were drinkers of more than 50 g ethanol/day (193 ± 94 g/day) during more than 10 years (27.7 ± 9.9 years). Mean age was 46.36 ± 9.22 years and age range 30–73 years. Based on clinical grounds, including laboratory evaluation liver ultrasound, scintigraphy, and liver biopsy in doubtful cases (only 5 patients), we classified our patients in cirrhotics (20 patients, aged 51.10 ± 10.56 years) and non-cirrhotics (33 patients, aged 43.48 ± 7.02 years (Table 1). The control group was composed of 18 healthy sanitary workers, drinkers of <10 g ethanol day.
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Forty-seven patients were followed up for a median period of 32 months (interquartile range, 18–44 months). During this period, 17 died. The relationship between ILs and MDA, all of them classified in quartiles and tertiles and survival was analysed by means of Kaplan–Meyer curves and log-rank test. A Cox regression analysis was also performed including interleukins, MDA, classic parameters of liver function, including Maddrey's index (Maddrey et al., 1978
), and nutritional parameters.
Cytokines and biochemical parameters
Blood samples were taken at 8.00 a.m. in fasting conditions, immediately frozen at –80°C. The following parameters were determined:
TNF-alpha by immunometric chemiluminiscent assay (intra-assay variation coefficient ranging 4–6.5%, interassay variation coefficient ranging 2.6–3.6%, recovery 92–112%, Diagnostic Products Corporation (DPC), Los Angeles, CA, USA); IL-6, by chemiluminiscent assay (interassay variation coefficient ranging 5.3–7.5%, recovery = 85–104%, DPC, Los Angeles, CA, USA); IL-4, by enzyme-linked immunosorbent assay (ELISA); (inter- and intra-assay coefficient of variation <10%; sensitivity <2 pg/ml; recovery = 101%, Bender MedSystems Diagnostics GmbH, Vienna, Austria); IL-8, by chemiluminiscent assay (interassay variation coefficient ranging 5.3–7.5%, DPC, Los Angeles, CA, USA); IL-10, by enzyme immunometric assay (sensitivity = 3 pg/ml, inter- and intra-assay coefficient of variation ranging from 3.9 to 7.3%; recovery ranging from 86 to 94%; DPC, Los Angeles, CA, USA); interferon gamma (IFNG), by ELISA (inter- and intra-assay coefficient of variation 0.3–10.7%; sensitivity <1.5 pg/ml; recovery = 90–112%, Bender MedSystems Diagnostics GmbH, Vienna, Austria). In addition, patients underwent routine laboratory evaluation. (Table 1).
The study protocol was approved by the local ethical committee of our Hospital and conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
Lipid peroxidation (LPX) products
Serum MDA levels, referred to as thiobarbituric acid-reactive substance (TBARS), were measured according to the method described by Kikugawa et al. (1992). A volume sample of 0.2 ml of plasma was added to 0.2 ml of H3PO4 (0.2 M) and the colour reaction was initiated by the addition of 25 µl of 0.11 M thiobarbituric acid (TBA) solution. Samples were placed in a 90°C heating block for 45 min. After the samples were cooled, the TBARS (pink complex colour) were extracted with 0.4 ml of n-butanol. Butanol phase was separated by centrifugation at 6000x g for 10 min. Aliquots of the n-butanol phase were placed in a 96 well plate and read at 535 nm in a microlate spectrophotometer reader (Benchmark Plus, Bio-Rad, Hercules, CA, USA). The calibration curve was prepared with authentic MDA standards ranging from 0–20 µM. The intra-and interassay CV were 1.82 and 4.01, respectively.
Statistics
The Kolmogorov–Smirnov test was used to test normality, a condition not fulfilled by most of the cytokines analysed. Therefore, non-parametric tests, such as Mann–Whitney's U-test and Kruskall–Wallis (KW) were used to analyse between group differences in these parameters. Spearman's correlation analysis was used to compare quantitative parameters. Relationships between cytokines and MDA (classified in tertiles or quartiles) with survival were analysed using log-rank test and Kaplan–Meier curves. Multivariate Cox regression analysis was used to discern which parameters yield prognostic value.
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Results |
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Results are compiled in Table 2 and Figs 1–2. In Table 2 we compare the values of ILs between cirrhotics and non-cirrhotics,and between cirrhotics, non-cirrhotics and controls by means of the KW test or variance analysis when appropriate. We can see that differences between the three groups are statistically significant for all the ILs except for TNF-alpha. However, among the ILs, only IFNG (P = 0.043), and in an almost significant way, IL-8 (P = 0.053) showed differences between cirrhotics and non-cirrhotics. Indeed, IL-8 showed inverse correlations with prothrombin activity (rho = –0.34, P = 0.024) and serum albumin (rho = –0.45, P = 0.003), and a direct one with Maddrey index (rho = 0.41, P = 0.006). Although differences between cirrhotics and non-cirrhotics were not statistically significant, inverse correlations were also observed between TNF-alpha and serum albumin (rho = –0.44, P = 0.003) and IL-6 and serum albumin (rho = –0.40, P = 0.01). In the cirrhotic subgroup, IL-6 was also related to Pugh's score (r = 0.55, P = 0.02). We failed to find, however, any relation between bilirubin and interleukins.
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In contrast, significant differences were observed between cirrhotics and non-cirrhotics regarding serum MDA, and very close relationships were observed between serum bilirubin and serum MDA (r = 0.85, P < 0.001, Fig. 1), between Maddrey index and serum MDA (r = 0.60, P < 0.001), and prothrombin activity and serum MDA (r = –0.48, P < 0.001).
Regarding survival analysis, besides the Maddrey index (log-rank test = 14.65, P = 0.002), only serum malondialdehyde values were significantly related to survival, Fig. 2, log-rank test = 4.58 (P = 0.03) when patients with serum MDA in the first tertile were compared with those of the other two tertiles. However, when survival was assessed using the Cox regression model, only Maddrey index (
2 = 11.36), amount of ethanol consumption (2 = 5.28) and age (2 = 11.5), in this order, were independently related to survival, all the other parameters (ILs, MDA, withdrawal syndrome at admission, infection at admission, leukocyte count, C reactive protein, and serum albumin) being excluded.
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DISCUSSION |
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In our study we have clearly shown that levels of MDA at admission, although estimated as TBARS, are raised in patients affected by alcoholic hepatitis, especially in cirrhotics. It is important to keep in mind that TBARS concentration not only reflects MDA levels, but also several other compounds derived from oxidation (Del Rio et al., 2005
). Therefore, spectrophotometric detection of TBARS overestimates the results. More accurate and improved detection methods have yielded healthy plasma MDA values in the range 0.1–1 nmol/ml (Karatas et al., 2002; Del Rio et al., 2005). The slightly higher mean MDA values of our controls (1.31 ± 0.74 nmol/ml) may reflect the commented overestimation, but they are clearly lower than the results observed among alcoholics. Moreover, the elevation of MDA is closely correlated with liver function derangement, especially with serum bilirubin and Maddrey's index. These results are not surprising, given the outstanding role of MDA in the formation of protein adducts and hybrid adducts with acetaldehyde, which perpetuates hepatocyte damage and promotes fibrogenesis (Tuma, 2002). MDA adducts trigger a potent immune response (Stewart et al., 2004), at least in 36% of alcoholics. Although the main source of cytokines are Kupffer cells, activated by endotoxin via toll-like receptors, activated T cells also secrete cytokines, which contribute to liver damage. Therefore, MDA adducts are responsible, at least in part, for T-cell activation and cytokine production. However, variable immune responses to antigens formed as a result of ethanol metabolism may explain in part the variable inter-individual susceptibility to alcohol and the inter-individual variability of the severity of alcoholic liver disease. In our study, only IFNG, and, to a lesser extent, IL-8 –in full accordance with other studies (Sheron et al., 1993), seem to keep a parallel behaviour with MDA, showing a significantly more intense alteration in cirrhotics than in non-cirrhotics. In this sense, our results are in disagreement with those reported by Spahr et al. (2004), who found normal IFNG values but raised TNF, which correlated with the severity of liver injury. IFNG is the main cytokine released during a Th-1 response, whereas IL-4 is the main cytokine released during a Th-2 response. Some authors found an expanded Th-2 population in alcoholic liver disease (De Lazzari et al., 2002), but other authors report increased Th-1 responses (Song et al., 2001). In our study, cytokines derived from both kinds of T cells are raised in patients compared with controls. Moreover, a significant relationship was observed between the two main cytokines produced by each T-cell subtype, i.e. IFNG and IL-4 (rho = 0.40, P = 0.008), supporting the hypothesis that stimulation of T cells affects both cell subtypes.
We found markedly raised IL-8 levels, in relation to liver function derangement. As in our study, raised IL-8 levels have also been found by other authors (Hill et al., 1993; Huang et al., 1996) in relation to liver function impairment and survival. Peroxidized fatty acids, but not ethanol, seem to stimulate IL-8 release by peripheral blood monocytes (Jayatilleke and Shaw, 1998), but we failed to find a relationship between MDA and IL-8 (only a trend, rho = 0.27, P = 0.09). In any case the relationship between IL-8 and other pro-inflammatory cytokines, such as IL-6, with liver dysfunction fits well with the inflammatory nature of alcoholic hepatitis.
Some authors have found raised IL-10 levels in acute alcoholic hepatitis, but insufficient to modulate TNF-alpha cytotoxicity (Naveau et al., 2005). In our study, most IL-10 values were below the detection limits in cirrhotics, slightly raised in non-cirrhotics, and also slightly raised in controls. Although these results are in agreement with those of Nanji et al. (1999), these authors also found decreased IL-4 levels, something opposite to our findings. Taïeb et al. (2000) also found low IL-10 levels and decreased production of IL-10 by monocytes from patients with alcoholic hepatitis. Other authors have found that the increase in IL-10 is insufficient to counteract the enhanced production of pro-inflammatory cytokines (Naveau et al., 2005). In our study, the decrease in anti-inflammatory interleukin levels also supports the importance of inflammation in alcoholic hepatitis.
Interestingly, in recent times, it is said that IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction (El-Assal et al., 2004), an observation in contrast with the relationship observed by others between IL-6 and liver damage (Sheron et al., 1991; Hill et al., 1992; Fujimoto et al., 2000), and even with the results of our study: Il-6 was raised in patients compared to controls, it was associated with liver function parameters, such as serum albumin, and also, a direct relationship was observed between serum IL-6 and C reactive protein (rho = 0.46, P = 0.002) and TNF-alpha (rho = 0.47, P = 0.002). The elevation of TNF, produced both by liver and adipose tissue in alcoholics (Lin et al., 1998) is a nearly universal finding (Bird et al., 1990), also reported by our group in another study more than 10 years ago (Rodríguez-Rodríguez et al., 1995), and plays a key role in the progression of liver injury via the TNF-R1 pathway (Yin et al., 1999). However, data in the present study do not lend strong support to these well known effects: TNF values were only slightly raised in cirrhotics, the relationships with liver function tests were relatively weak (only with albumin), and although a relation was found between TNF and C reactive protein (rho = 0.38, P = 0.01), TNF was not related to mortality. This (relative) lack of concordance with other studies is not easily explainable. Perhaps, it is in relation with the short half-life of TNF. In some other studies dealing with alcoholic hepatitis TNF levels were normal (Fujimoto et al., 2000).
Given the close correlation between MDA and Maddrey index and other liver function parameters, the relationship observed between MDA levels and mortality is not surprising. It is, however, remarkable, that MDA levels at admission are related with short/medium-term mortality. Although we did not measure MDA adducts, perhaps the stimulation of the immune system, which ultimately perpetuates liver injury, may explain, at least in part, this relationship.
In summary, we found raised MDA levels in our patients, associated with liver function impairment and with mortality. We also found that cytokines derived from both Th-1 and Th-2 cell subtypes are raised in patients with acute alcoholic hepatitis, except for IL-10, which is undetectable in the majority of cases. However, the relationships between cytokines and MDA are not significant, suggesting that, inflammation and lipid peroxidation are not parallel occurrences in acute alcoholic hepatitis. This finding is in accordance with the current knowledge regarding the relative roles of cytokines and lipid peroxidation in the pathogenesis of alcoholic hepatitis. Although increased TNF production by activated macrophages may lead to enhanced production of oxygen radicals and lipid peroxidation, increased activity of MEOS, which becomes induced by chronic ethanol consumption but is independent of the cytokine network, plays a major role in lipid peroxidation.
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