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Bacterial Translocation in HIV-Infected Patients With HCV Cirrhosis: Implication in Hemodynamic Alterations and Mortality - 'more profound inflammatory state in those HIV-HCV patients with decompensated cirrhosis....inflammation predicts mortality in these patients'
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JAIDS Journal of Acquired Immune Deficiency Syndromes:
15 April 2011
"it can be stated that the increased LBP levels detected in HIV-infected patients with HCV-related decompensated liver cirrhosis can be attributed either to the influence of portal hypertension or/and liver insufficiency.......Microbial translocation has been correlated with markers of systemic immune activation. Endotoxin signalling triggers a cascade that leads to production of proinflammatory cytokines, such as TNF-a and IL 6, and to systemic immune activation.9,10 We found that the serum levels of these cytokines were elevated in HIV-infected patients.....When the overall HIV-infected patients were considered, the concentrations of sCD14, sTNFRI, and IL-6 were significantly higher in those with increased LBP (>8.1 mg/mL) than in those with normal LBP....Having observed the existence of a more profound inflammatory state in those HIV-HCV patients with decompensated cirrhosis, the possible influence of proinflammatory cytokines on the mortality of these patients was studied.....In the multivariate analysis, the factors that predicted survival were Child-Pugh index, a CD4 T-cell count lower than 200 cells per cubic millimeter, plasma aldosterone, and serum IL-6 concentrations (Table 4, Fig. 1).......The objective of this work is to analyze the influence of portal hypertension on intestinal permeability in HIV-infected patients with HCV-related cirrhosis, and the prognostic significance of consequent macrophage activation. Therefore, in these patients, we have studied the serum concentration of LBP (intestinal permeability [measured by lipopolysaccharide-binding protein (LBP) serum levels]), the consequences of macrophage activation (soluble CD14 receptor and pro-inflammatory cytokines), the association of these markers with the consequences of peripheral vasodilation (plasma renin activity and aldosterone concentration), and their implication in prognosis.....In conclusion, increased intestinal permeability, as measured by serum LBP levels, observed in patients with HIV infection, is significantly higher in patients with decompensated liver cirrhosis. We can state that, in addition to previously described markers (immunodepression, liver function scores), the consequences of hemodynamic alterations (plasma aldosterone concentration) and monocyte-derived inflammatory molecules are prognostic markers in HIV-infected patients with decompensated HCV-related liver cirrhosis.
Percentages of patients showing LBP concentration higher than the established cut-off value were as follows: 15% (n = 3) of HIV-monoinfected patients; 20% (n = 4) of HIV/HCV patients coinfected with compensated cirrhosis; and 86% (n = 43) of patients with decompensated cirrhosis.
Early HIV infection is consistently associated with a rapid, dramatic, and largely irreversible depletion of mucosal CD4 T cells, followed by activation-induced cell death responsible for the subsequent depletion of peripheral blood CD4+ T cells.25 Thus, it not was surprising that LBP concentrations were higher in those with a lower CD4+ T cell at diagnosis of HIV infection, as this reflected a more prolonged course of HIV infection and higher intestinal lymphocyte depletion."
de Oca Arjona, Montserrat Montes MD*; Marquez, Mercedes PhD*; Soto, Maria Jose MD, PhD*; Rodriguez-Ramos, Claudio MD, PhD; Terron, Alberto MD; Vergara, Antonio MD; Arizcorreta, Ana MD, PhD*; Fernandez-Gutierrez, Clotilde MD, PhD; Giron-Gonzalez, Jose Antonio MD, PhD*
From the *Internal Medicine Department, Hospital Universitario Puerta del Mar, Cadiz, Spain; Gastroenterology Department, Hospital Universitario Puerta del Mar, Cadiz, Spain; Department of Internal Medicine, Hospital SAS de Jerez, Spain; Department of Internal Medicine, Hospital Puerto Real, Cadiz, Spain; and Department of Microbiology, Hospital Universitario Puerta del Mar, Cadiz, Spain.
Abstract
Objective: Analysis of the influence of portal hypertension on intestinal permeability in HIV-infected patients with hepatitis C virus (HCV)-related cirrhosis and of the prognostic significance of consequent macrophage activation.
Methods: Twenty HIV-monoinfected patients, 70 patients with HIV-HCV coinfection, 20 of them with compensated and 50 with decompensated cirrhosis, and 20 healthy controls were evaluated for intestinal permeability [measured by lipopolysaccharide-binding protein (LBP) serum levels], macrophage activation [soluble CD14, soluble tumour necrosis factor receptor 55 Kd, and interleukin 6 (IL-6)], and activation of the rennin-angiotensin-aldosterone axis. Patients with decompensated cirrhosis were monitored for a median period of 429 days to analyze the prognostic factors implicated in survival.
Results: Patients with decompensated cirrhosis show increased LBP levels compared with HIV-monoinfected patients. Patients with increased LBP concentration showed elevated soluble CD14, soluble tumour necrosis factor receptor 55 Kd, and IL-6 levels. Twenty-two patients died, from liver-related causes, during the follow-up, and 2 more underwent liver transplantation. Child-Pugh index, CD4 T-cell count, plasma aldosterone and serum IL-6 concentrations independently predicted liver-related mortality.
Conclusions: Increased intestinal permeability, as measured by serum LBP levels, observed in patients with HIV infection is significantly higher in patients with decompensated liver cirrhosis. Proinflammatory cytokines (IL-6) are prognostic markers of HIV-HCV-coinfected patients with decompensated cirrhosis.
INTRODUCTION
Hepatitis C virus (HCV)-related liver disease follows an accelerated course in patients with HIV coinfection.1-6
The intestinal mucosal tissue is an early target organ of HIV.7,8 The disruption of gut epithelial integrity and the subsequent microbial translocation has been linked to systemic immune activation. It has been suggested that the activation of the immune system can play a fundamental role in the accelerated course of liver damage in HCV-HIV patients.9 Once in the circulation, endotoxin promotes the hepatic synthesis of lipopolysaccharide-binding protein (LBP), a plasma protein that enhances the binding of lipopolysaccharide (LPS) to the CD14 monocyte receptor molecule associated with a Toll-like receptor. Endotoxin signalling triggers a cascade that leads to production of proinflammatory cytokines, such as tumour necrosis factor (TNF)-a and interleukin-6.10 Both have been implicated in the increased peripheral vasodilatation observed in advanced phases of liver cirrhosis.11-13
Although it is possible to analyze the intestinal permeability by measuring the serum concentration of LPS, determination of LBP, the serum levels of which are positively correlated with those of LPS, is more reliable because the half-life of LBP is longer. It has been used previously for this reason.10
An increased permeability of the intestinal barrier has been also detected in non-HIV-infected patients with cirrhosis and ascites.14 Furthermore, a significant association has been established between markers of intestinal permeability, such as serum LBP concentration, hemodynamic derangement, incidence of bacterial infections, and death, in non-HIV-infected patients.15,16
The combined effect of increased intestinal permeability in HIV-infected patients with decompensated HCV-related liver disease has not been studied until now. The objective of this work is to analyze the influence of portal hypertension on intestinal permeability in HIV-infected patients with HCV-related cirrhosis, and the prognostic significance of consequent macrophage activation. Therefore, in these patients, we have studied the serum concentration of LBP, the consequences of macrophage activation (soluble CD14 receptor and pro-inflammatory cytokines), the association of these markers with the consequences of peripheral vasodilation (plasma renin activity and aldosterone concentration), and their implication in prognosis.
DISCUSSION
The present work has analyzed the intestinal permeability in HIV-infected patients with and without HCV-related liver cirrhosis. In agreement with previous studies,8,24 HIV-infected patients had greater intestinal permeability compared with healthy controls. Furthermore, our results support the existence of an evenly increased alteration in the intestinal barrier in those HIV-infected patients in whom decompensated liver cirrhosis is present.
We observed that LBP concentration, as a marker of intestinal permeability, was associated with a decreased CD4+ T-cell count at HIV diagnosis and with currently detectable HIV RNA. Early HIV infection is consistently associated with a rapid, dramatic, and largely irreversible depletion of mucosal CD4 T cells, followed by activation-induced cell death responsible for the subsequent depletion of peripheral blood CD4+ T cells.25 Thus, it not was surprising that LBP concentrations were higher in those with a lower CD4+ T cell at diagnosis of HIV infection, as this reflected a more prolonged course of HIV infection and higher intestinal lymphocyte depletion.
Specifically, the alteration in the intestinal barrier is not secondary to the absence of HAART therapy. Patients with liver cirrhosis had received this therapy less frequently, and consequently, the percentage of patients with undetectable HIV load was lower in this group, according to previous data.26,27 However, although the proportion of patients with compensated cirrhosis receiving HAART was similar to that of those with decompensated liver disease, only in the former group were LBP levels significantly elevated compared with HIV-monoinfected patients. The absence of HIV replication control, either by nonadherence or by resistance to antiretrovirals, was the parameter clearly associated with increased LBP levels, and not the absence or presence of HAART.
We also noted a significant association between LBP concentration and the Child-Pugh score, an index which includes parameters indicative of liver function (serum concentrations of albumin and bilirrubin, prothrombin activity, encephalopathy), and of portal hypertension (ascites). Although it is generally accepted that the presence of decompensations of cirrhosis is associated with a significant increase in portal pressure,28 no direct measurement of portal pressure, such as the hepatic venous pressure gradient, was performed in the present study. Thus, it can be stated that the increased LBP levels detected in HIV-infected patients with HCV-related decompensated liver cirrhosis can be attributed either to the influence of portal hypertension or/and liver insufficiency.
Microbial translocation has been correlated with markers of systemic immune activation. Endotoxin signalling triggers a cascade that leads to production of proinflammatory cytokines, such as TNF-a and IL 6, and to systemic immune activation.9,10 We found that the serum levels of these cytokines were elevated in HIV-infected patients, with a pattern similar to that observed with LBP as follows: both sTNFRI and IL-6 concentrations were higher in HIV-infected patients when compared with healthy controls and even higher in those patients with decompensated cirrhosis. Moreover, a significant correlation was detected between serum levels of LBP and proinflammatory cytokines.
After proving the existence of a significant inflammatory state in HIV-HCV patients with decompensated cirrhosis, we analyzed the possible influence of proinflammatory cytokines on the mortality of these patients. In the present study, survival was influenced by liver function indices (Child-Pugh score) and by the immunosuppression level, findings previously detected in other series,3,4,6 and by haemodynamic markers and macrophage-derived parameters. The absence of evidence of prognostic capability for LBP levels may be explained because this molecule is not directly involved in changes in liver pathology or in hemodynamic alterations; rather, its effects are mediated by secretion of proinflammatory cytokines.
In advanced phases of the natural history of liver cirrhosis, peripheral vasodilatation with decreased circulatory volume and activation of vasoactive components (renin-angiotensin-aldosterone, norepinephrine, and vasopressin) has been detected.23,29-31 The independent influence of plasma aldosterone concentration on survival found here, indicating the presence of a more profound hemodynamic alteration, supports the view that effective hypovolemia is also important in HCV-related decompensated cirrhosis in HIV-coinfected patients.
Moreover, IL-6 levels have an independent prognostic capability in the multivariate analysis. TNF-a and IL-6, possibly acting through nitric oxide-independent mechanisms, play a role in the hemodynamic alterations and mortality in cirrhosis.11,13,32-34 In fact, our study revealed that serum levels of IL-6 correlate with measures of vasoactive response (plasma renin activity and aldosterone concentration) to vasodilation. In line with this, some studies have reported the role of proinflammatory cytokines in the pathogenesis of hepatic encephalopathy, the main cause of death in HIV/HCV-coinfected patients with liver cirrhosis.35,36
In conclusion, increased intestinal permeability, as measured by serum LBP levels, observed in patients with HIV infection, is significantly higher in patients with decompensated liver cirrhosis. We can state that, in addition to previously described markers (immunodepression, liver function scores), the consequences of hemodynamic alterations (plasma aldosterone concentration) and monocyte-derived inflammatory molecules are prognostic markers in HIV-infected patients with decompensated HCV-related liver cirrhosis.
RESULTS
Baseline Characteristics of the Study Population
The characteristics of the patients and healthy controls included in the study are summarized in Table 1. Seventy HIV-infected patients of the different groups were receiving HAART. HAART regimes were based on 2 nucleosides and either protease inhibitors, efavirenz or another nucleoside, without significant differences between HIV-monoinfected and HIV-HCV-coinfected patients, either with or without decompensated cirrhosis.
In the group of HIV-HCV-coinfected patients with decompensated cirrhosis, ascites was the most common liver decompensation [31 (62%) patients] and was complicated with spontaneous bacterial peritonitis in only 1 case. Seven individuals (14%) showed portosystemic encephalopathy as the first hepatic decompensation; 6 patients (12%) presented portal hypertensive gastrointestinal bleeding and 6 (12%) patients nonobstructive jaundice.
Microbial Translocation: Serum Levels of LBP
Serum concentrations of LBP were significantly elevated in HIV-monoinfected patients when compared with healthy controls, and even higher in those with decompensated cirrhosis. However, LBP concentration was similar in HIV-monoinfected patients and in those with compensated cirrhosis (Table 2).
Patients were categorized in function of the serum levels of LBP, the cut-off value being the highest serum level of LBP observed in healthy controls (8.1 mg/mL) (this value also represents the mean LBP concentration plus 3 standard deviations, in healthy controls). Percentages of patients showing LBP concentration higher than the established cut-off value were as follows: 15% (n = 3) of HIV-monoinfected patients; 20% (n = 4) of HIV/HCV patients coinfected with compensated cirrhosis; and 86% (n = 43) of patients with decompensated cirrhosis.
When HIV-infected patients of the different groups were categorized in function of LBP level, it was evident that significantly increased LBP concentrations were detected in those with a CD4+ T-cell count lower than 200 cells per milliliter at HIV diagnosis and in those with currently detectable HIV RNA load. Moreover, when only those patients with liver cirrhosis were considered, increased LBP levels were observed in those with a Child-Pugh score higher than 9 (Child-Pugh stage C) (Table 3).
Macrophage-Derived Molecules
A pattern similar to that found with LBP concentration was observed when serum levels of sCD14, sTNFRI, and IL-6 were analyzed (Table 2).
When the overall HIV-infected patients were considered, the concentrations of sCD14, sTNFRI, and IL-6 were significantly higher in those with increased LBP (>8.1 mg/mL) than in those with normal LBP [sCD14, 9411 (5360-10714) vs. 5582 (3660-9739) ng/mL, P = 0.004; sTNFRI, 527 (282-1121) vs. 261 (201-354) pg/mL, P < 0.001; IL6, 18 (9-41) vs. 7 (3-15) pg/mL, P = 0.003]. Moreover, significant correlations were observed between LBP concentration and that of sCD14 (r = 0.260, P = 0.027), sTNFRI (r = 0.481, P < 0.001), and IL-6 (r = 0.443, P < 0.001).
Haemodynamic Modifications
Measurement of mean blood pressure and analysis of the renin-angiotensin-aldosterone axis was performed in cirrhotic patients. Whereas mean blood pressure was similar in compensated and decompensated cirrhotic patients [81 (73-92) versus 84 (69-97) mmHg, P = 0.855], both PRA and PAC were significantly higher in patients with decompensated compared with those with compensated cirrhosis [PRA, 1.8 (0.3-6.6) vs. 0.8 (0.1-2.1) ng/ml.h, P < 0.001; PAC, 28.9 (13.6-70.3) vs. 15.0 (10.3-26.9) ng/dL, P < 0.001].
A correlation analysis was performed to analyze the possible association between proinflammatory cytokines and hemodynamic modifications. Concentrations of sTNFRI and of IL-6, but not those of LBP and sCD14, were significantly correlated with PRA (sTNFRI, r = 0.307, P = 0.010; IL-6, r = 0.414, P = 0.005) and PAC (sTNFRI, r = 0.392, P = 0.012; IL-6, r = 0.382, P = 0.010). Likewise, Child-Pugh score was positively and significantly correlated with concentrations of both hormones (PRA, r = 302, P = 0.041; PAC, r = 0.496, P = 0.005).
Because the detectability of HIV load (either by resistance to prescribed antiretrovirals or because the patient has not complied) influences the serum level of LBP, macrophage-derived molecules and hemodynamic parameters were analyzed in patients, distributed in function of the presence or absence of undetectability (independently of the presence or absence of previous decompensations) (see Table, Supplemental Digital Content 1, http://links.lww.com/QAI/A137). Significantly lower levels of macrophage-derived molecules and PRA and PAC values were detected in patients with undetectable HIV load.
Follow-Up and Analysis of Mortality
Having observed the existence of a more profound inflammatory state in those HIV-HCV patients with decompensated cirrhosis, the possible influence of proinflammatory cytokines on the mortality of these patients was studied.
HIV-HCV-coinfected patients with decompensated cirrhosis were followed-up for a median period of 429 (126-1075) days. HAART was indicated for all patients, although a maintained compliance was obtained in only 90% (n = 45) of them. Twenty-four patients (48%) died during the follow-up period. In 22 (44%) individuals, the cause of death was liver-related. Hepatic encephalopathy was the leading cause of mortality, accounting for 11 deaths (22%). Other causes of death were portal hypertensive gastrointestinal bleeding, 4 cases (8%); hepatorenal failure, 4 cases (8%); spontaneous bacterial peritonitis, 2 cases (4%); hepatocellular carcinoma, 1 case (1.9%). Sepsis by infections not related with liver cirrhosis was the cause of death of 2 patients (4%). In addition, 2 patients (4%) received a liver transplant. There were 2 patients lost in the follow-up and they were considered as dead.
The cumulative probability of survival at 1 and 2 years was 64% and 44%, respectively. The differential characteristics between patients who died and those who survived are presented in Table 4. In the multivariate analysis, the factors that predicted survival were Child-Pugh index, a CD4 T-cell count lower than 200 cells per cubic millimeter, plasma aldosterone, and serum IL-6 concentrations (Table 4, Fig. 1).
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