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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Background  Endotoxaemia is commonly seen in cirrhotic patients with ascites and this may be associated with increased portal pressure.

Aim  To investigate the effect of intestinal decontamination on liver haemodynamics in alcohol-related cirrhotic patients with ascites.

Methods  We included 30 patients. At day 0, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed. Patients received rifaximin (1200 mg/day) for 28 days. At day 29, systemic and splanchnic circulation endotoxin levels were determined and HVPG measurement performed again.

Results  Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45(0–3.1) vs. 0.7(0–2.7), < 0.0001] and splanchnic circulation [1.8(0–3.4) vs. 0.8(0–2.1), < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (= 0.001) was not noted at day 29 (= 0.137). HVPG measurement was possible in 28 patients. Median (range) HVPG values were 18 mmHg (12.7–26.3) on day 0 vs. 14.7 mmHg (7–20) on day 29 (< 0.0001). HVPG decreased after rifaximin in 23, remained stable in two and increased in three patients.

Conclusion  Hepatic venous pressure gradient values decreased significantly after intestinal decontamination with rifaximin in patients with alcohol-related decompensated cirrhosis and this might have been achieved through significant reduction of plasma endotoxin levels.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Cirrhotic patients have multiple defects in their immune defence including deficiencies in serum and ascitic fluid complement levels, reticuloendothelial system (RES) function and ascitic fluid opsonic activity.1 Furthermore, in the setting of cirrhosis, patients are predisposed to intestinal bacterial overgrowth, intestinal dysmotility and increased intestinal permeability, all leading to an increase in bacterial translocation and increased endotoxaemia.2, 3 In accordance with this, higher concentrations of endotoxin have been detected in both the portal and systemic circulation of patients with chronic liver disease.4 The impairment of liver function and the presence of porto-systemic shunts lead to a leakage of endotoxin through the liver into the systemic circulation and the levels of endotoxaemia have been correlated with the severity of liver disease.5, 6

Cirrhotics with bacterial translocation and endotoxaemia manifest haemodynamic derangement, with lower systemic vascular resistance, higher cardiac output and lower mean arterial pressure.7 Moreover, endotoxins may increase portal pressure by increasing vascular resistance, which may be promoted through the cytokine-stimulated intrahepatic release of endothelin and cyclo-oxygenase products.8–10

The increase in portal pressure is the most important factor leading to the development of complications of portal hypertension. A threshold increase of 10–12 mmHg in the portal pressure gradient (most commonly evaluated in clinical practice by its equivalent, the hepatic venous pressure gradient or HVPG) has been shown to be the critical factor for the development and rupture of oesophageal varices.11 There is also evidence that a reduction of >20% in HVPG from baseline12 or in an absolute value of <12 mmHg is associated with a very low risk of bleeding.13

Previous studies have shown that selective intestinal decontamination with norfloxacin reduces serum endotoxin concentrations and partially reverses the hyperdynamic circulatory state in cirrhotic patients; however, HVPG was not significantly affected.14, 15

Rifaximin is another antibiotic, derivative of rifamycin, that is virtually unabsorbed after oral administration, exhibits broad spectrum antimicrobial activity against both aerobic and anaerobic gram-positive and gram-negative micro-organisms within the gastrointestinal tract and has been used on a long-term basis in cirrhotic patients for the treatment of hepatic encephalopathy.16 No study has so far examined the effect of rifaximin on liver haemodynamics.

Therefore, we conducted a prospective study to investigate the effect of intestinal decontamination with rifaximin on regional haemodynamics (hepatic venous pressure gradient, HVPG) in alcohol-related patients with ascites.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Patients

The study was conducted from October 2004 to February 2007 at the second Department of Gastroenterology of ‘Evangelismos’ Hospital. The study protocol conformed to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of the hospital. All participants gave written informed consent.

Inclusion criteria were: age between 25 and 80 years, alcohol-related decompensated cirrhosis and presence of ascites. Exclusion criteria were: presence of hepatitis B surface antigen or antibody to hepatitis C virus, gastrointestinal bleeding, hepatic encephalopathy, abstinence from alcohol less than 6 months, bacterial infection, treatment with non-absorbable antibiotics in the preceding 14 days, presence of hepatocellular carcinoma (HCC), portal vein thrombosis, very serious disease that makes HVPG measurement unethical, known allergy to rifaximin and refused informed consent. Presence of ascites was based on clinical findings and confirmed with abdominal ultrasound. Diagnosis of cirrhosis was based on clinical findings (splenomegaly, ascites and/or oesophageal varices), imaging studies (abdominal ultrasound and/or computed tomography and/or magnetic resonance imaging) and laboratory findings or on liver biopsy. The severity of cirrhosis was graded according to Pugh’s classification. All recruited patients attended the liver clinic on a regular basis and had prolonged periods of abstinence from alcohol, as determined by corroborative history and random plasma alcohol determinations. Bacterial infection was ruled out by clinical history, physical examination, chest X-ray, differential and total white blood cell count, urine analysis and culture, blood culture (aerobic and anaerobic), white cell count and culture of ascitic fluid.

Study design

On the first day of the study after cleaning the skin twice with 70% alcohol and iodine tincture, brachial vein was cannulated with a 3-French, 5-cm catheter (Cook, Sydney, Australia) to collect blood samples for measurement of endotoxin. Following this, the patient was subjected to HVPG measurement as described below. During HVPG measurements, blood samples for endotoxin measurement were collected again from the hepatic vein immediately after its catheterization. In both instances, blood for endotoxin measurement was collected into pyrogen free syringes. Following HVPG measurement, all patients received intestinal decontamination for 28 days with rifaximin (1200 mg/d).

On day 29, patients were admitted again at our department and the above mentioned steps were repeated; i.e. blood samples were once again collected (from the brachial vein and the hepatic vein during HVPG measurement). In patients receiving b-blockers, treatment was discontinued 3 days before HVPG measurement.

Plasma endotoxin assay

Blood samples were collected into pyrogen-free tubes containing heparin (BD Vacutainer Systems, Belliver industrial Estate, Plumouth UK) and then centrifuged at 3000 r/min for 15 min at 4 °C. Plasma was kept refrigerated at −20 °C until assayed.

For the determination of lipopolysaccharide (LPS), plasma samples were diluted 1:10 with pyrogen-free water (Cambrex Bio Science, Rockland, USA) and then incubated for 10 min at 75 °C to remove plasma inhibitors. LPS were then measured by the QCL-1000 LAL assay (Cambrex Bio Science, Rockland, USA, lower detection limit 0.1 EU/mL). All measurements were performed twice and the mean of the two observations was applied.

HVPG measurement

All patients underwent femoral hepatic vein catheterization for the measurement of HVPG. Under fluoroscopic control and through the right femoral vein, the catheterization of the hepatic vein was achieved by using a guide catheter (Cobra 2, 8F, Boston scientific, MN USA) and a guide wire (0.035/145, Boston Scientific, Miami USA). Through this introducer set, an occlusion balloon catheter (OB 8.5/5/65, Boston Scientific, Cork Ireland) was then inserted into the hepatic vein. Pressure measurements were taken in the wedged (WHVP) and free (FHVP) position by inflating and deflating the balloon. The occluded position of the catheter was checked by the absence of reflux after injection of 2 mL of contrast medium. The catheter was connected to a highly sensitive pressure transducer (Transducer Transpac 4, Abbot, Sligo, Republic of Ireland), which was attached to a monitor (Life Scope 9, Nihon-Kohden, Tokyo, Japan). Calibrations were performed before each measurement.

Portal pressure was estimated as the difference between WHVP and FHVP. Each measurement was recorded in triplicate and printed for re-review. The HVPG reported is the mean of the three measurements. During the procedure, oxygen saturation was monitored by pulse oximetry.

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Data are expressed as median (range). Quantitative variables were compared using the Wilcoxon matched pairs test. Correlation was performed by using Spearman correlation coefficient. A P value of less than 0.05 was considered statistically significant. All statistical analyses were performed using spss 11.0 for Windows (SPSS Inc. Chicago, IL, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Forty eight patients fulfilled the inclusion criteria. Eighteen patients were excluded because of infection (= 6), refused informed consent (= 5), HCC (= 3), portal vein thrombosis (= 2) and known allergy to rifaximin (= 2). Thirty of the patients (25 men-5 women) were finally included in the study. The mean (SD) age was 63.5 (9.82) years. Twelve patients (40%) were Child-Pugh B and 18 (60%) Child-Pugh C. Eight patients were on b-blockers (3 with small and 5 with large varices). The characteristics of the study population are presented in Table 1.

Table 1.   Clinical characteristics of the patients at the time of initial admission (= 30)
  1. * Values are expressed as median (range).

Gender (M/F), n25/5
Age (years)*63.5 (42–80)
Child-Pugh (A/B/C), n0/12/18
Child-Pugh score9.5 (7–13)
MELD score17 (11–27)
Varices (absent/small/large), n5/16/9
Ascites (absent/small/large), n0/14/16
History of encephalopathy (Y/N), n3/27
Bilirubin (mg/dL)2.3 (0.9–7.2)
Albumin (g/L)2.9 (1.2–4.2)
Prothrombin time (sec)16.75 (12–22)
Mean arterial pressure at baseline (mmHg)84.8 (74.2–101.6)
Heart rate at baseline (beats/min)74 (58–92)

Endotoxin

Plasma endotoxin levels were higher in patients with severe liver dysfunction and there was a significant correlation between the plasma endotoxin levels and the Child-Pugh score (= 0.009), (Figure 1a). There was also a significant correlation between plasma endotoxin levels and the MELD score (= 0.025). Median (range) plasma endotoxin levels decreased significantly after four weeks of Rifaximin administration [1.45 (0–3.1) vs. 0.7 (0–2.7), < 0.0001]. Twenty five patients had lower endotoxin levels on day 29 as compared to day 0 (Figure 2a).

image

Figure 1.  (a) Correlation between plasma endotoxin levels (blood received from brachial vein) and Child-Pugh score on day 0 (= 30, rs=0.47, = 0.009). (b) Correlation between plasma endotoxin levels (blood received from hepatic vein) and Child-Pugh score on day 0 (= 28, rs = 0.52, = 0.005).

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image

Figure 2.  (a) Individual changes in plasma endotoxin levels (blood received from brachial vein) before and after 4 weeks of rifaximin administration (< 0.0001). (b) Individual changes in plasma endotoxin levels (blood received from hepatic vein) before and after 4 weeks of rifaximin administration (< 0.0001).

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Blood samples for measurement of endotoxin were collected from the hepatic vein in 28 patients. Endotoxin levels in the hepatic vein significantly correlated with the severity of liver disease as estimated by the Child-Pugh score (= 0.005), (Figure 1b). Once again, a significant correlation between hepatic vein endotoxin levels and the MELD score was noted (= 0.022). Median (range) endotoxin levels in the hepatic vein decreased significantly after 4 weeks of Rifaximin administration [1.8 (0–3.4) vs. 0.8 (0–2.1), < 0.0001]. Endotoxin levels were reduced in 25 out of 28 patients on day 29 (Figure 2b).

Moreover, endotoxin levels (median, range) on day 0 were significantly higher in the blood received from the hepatic vein compared with those in the blood received from the brachial vein [1.8 (0–3.4) vs. 1.45 (0–3.1), = 0.001]. However, after 4 weeks of Rifaximin administration, this difference became not significant [0.8 (0–2.1) vs. 0.7 (0–2.7), = 0.137].

Hepatic vein pressure gradient (HVPG)

HVPG measurement was achieved in 28 patients, as in two patients hepatic vein catheterization was not possible. HVPG values at day 0 significantly correlated with Child-Pugh score (= 0.007), (Figure 3), as well as the MELD score (= 0.013). Median (range) HVPG values were 18 mmHg (12.7–26.3) on day 0 vs. 14.7 mmHg (7–20) on day 29 and the difference was statistically significant (< 0.0001). HVPG decreased after rifaximin in 23 patients, remained stable in two and increased in 3 patients (Figure 4). The median percentage of HVPG decrease was 19.57% (range, 14.56% - 44.75%). The decrease in HVPG was observed in patients independently of the use of b-blockers (= 0.7).

image

Figure 3.  Correlation between hepatic vein pressure gradient (HVPG) and Child-Pugh score on day 0 (= 28, rs = 0.50, = 0.007).

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image

Figure 4.  Individual changes in hepatic vein pressure gradient (HVPG) before and after 4 weeks of rifaximin administration (< 0.0001).

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The difference in HVPG values (HVPG values on day 0 – HVPG values after 28 days of rifaximin administration) significantly correlated with the difference in hepatic vein endotoxin values (hepatic vein endotoxin levels on day 0 – hepatic vein endotoxin levels 28 days after rifaximin administration) (= 0.023), (Figure 5).

image

Figure 5.  Correlation between the difference in hepatic vein pressure gradient (d-HVPG, mmHg) and the difference in hepatic vein endotoxin levels (d-endotoxin, EU/mL) after 4 weeks of rifaximin administration (= 28, rs = 0.42, = 0.023).

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Systemic haemodynamics

Mean arterial pressure increased significantly after 4 weeks of rifaximin administration from 84.8 mmHg (range:74.2–101.6) to 98.9 mmHg (range:75.7–118.4), < 0.05. Heart rate decreased after rifaximin, but not significantly [from 74 (range:58–92) to 71 (54–95), = 0.185].

Adverse events

Overall patient compliance was excellent. One patient complained of abdominal pain and one patient experienced self-limited diarrhoea. No patient was withdrawn from the trial due to an undue adverse effect. No complications attributed to hepatic vein catheterization occurred.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

In our study, we investigated the potential role of intestinal decontamination on liver haemodynamics in 30 patients with alcoholic cirrhosis and we found a significant decrease in HVPG values as well as a significant improvement of endotoxaemia.

Previous studies have shown that cirrhotic patients have increased endotoxin concentrations in the peripheral blood with a substantially significant gradient among endotoxin levels between portal and peripheral blood, suggesting that the bowel could be the source of endotoxin.6, 7 Altered small bowel motility, bacterial overgrowth in the small intestine and increased intestinal permeability all have been associated with increased bacterial translocation and endotoxaemia in cirrhotics.17 Experimental studies found that bacterial translocation is increased in cirrhotic rats after the development of ascites and might be a major contributor to the development of spontaneous infections in cirrhosis.2 Moreover, in humans, bacterial overgrowth has been demonstrated in one third of alcoholic cirrhotics, especially those with ascites and severe liver dysfunction.5, 18

In this study, we included cirrhotic patients with the above characteristics (alcohol-related cirrhosis, development of ascites, severe liver failure) and we verified that endotoxin levels were significantly higher in the portal compared with the systemic circulation. We chose to exclude patients with active alcohol ingestion because alcoholism has been associated with increased intestinal permeability and endotoxaemia.19 Alcohol abstinence was assessed during close follow-up of all included patients at the hepatology outpatient clinic of our Unit. In accordance with previous studies, the endotoxin concentrations were strongly associated with the severity of liver disease as estimated by the Child-Pugh score as well as the MELD score.

The results of our study clearly demonstrate that intestinal decontamination with rifaximin results in a significant reduction in mean endotoxin levels. We chose rifaximin, a derivative of rifamycin, which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis because it is a highly efficient and safe antibiotic, with a broad spectrum of action identical to that of rifamycins and an intestinal absorption of only 0,007% of the administered dose.16 It has a potential advantage over norfloxacin, as it has better activity against gram-positive organisms. This is very important because the chronic use of norfloxacin has been shown to increase gram-positive flora, gram-positive translocation and gram-positive peritonitis in an animal model of cirrhosis.20

Following rifaximin administration, we demonstrated a significant reduction in endotoxin levels in the splanchnic circulation (as estimated by blood received from the hepatic vein) as well as in the systemic circulation (as estimated by blood received from the brachial vein). Furthermore, the significant difference in endotoxin levels between the splanchnic and systemic circulation noted on day 0, was not seen on day 29 after administration of the study drug. These results further support the hypothesis of intestinal source of endotoxin and highlight the effectiveness of rifaximin in the selective suppression of intestinal bacterial flora. Similar to previous reports15, we also found a significant improvement in systemic haemodynamics as reflected by the increase in mean arterial pressure, although this was not the main aim of our study.

In this study, we have shown for the first time that intestinal decontamination by rifaximin resulted in a significant reduction in HVPG. HVPG decreased by a mean of 3.12 mmHg, supporting the hypothesis that bacterial products contribute to the hyperdynamic circulation and portal hypertension in cirrhosis. In a previous study,7 the investigators did not find any correlation between HVPG and endotoxaemia. However, they included patients with acute exacerbation of chronic hepatitis as well as patients with compensated cirrhosis and this may have influenced their results. In another study,14 the administration of norfloxacin had no effect on HVPG and hepatic blood flow in cirrhotic patients, although it significantly reduced the lipopolysaccharide (LPS)-binding protein (LBP) levels in patients with elevated levels of this protein. On the other hand, in a recent study,15 selective intestinal decontamination with norfloxacin in 14 patients with alcoholic cirrhosis, significantly diminished serum endotoxin levels and decreased HVPG, but not significantly. However, it must be emphasized that HVPG was measured in only 10 patients, while only 6 of them had a portal pressure that would have increased the risk for gastrointestinal bleeding (HVPG >10 mmHg). Thus, the small sample and the characteristics of the patients may have inversely affected the achievement of a significant difference.

In our study, we recruited patients with severe decompensation of liver disease and most of them had initially high values of HVPG. In patients receiving b-blockers, drug was discontinued before HVPG measurement to avoid potential influence in the HVPG values. HVPG decreased after 4 weeks of rifaximin administration in the vast majority of our study population. Most importantly, HVPG decreased by a median of 19.57% and this may have important clinical implications as it could result in a reduction in the probability of complications from portal hypertension.21 A weakness of our study is that we did not include a control placebo group, which would have probably strengthened our data as regards the significant decrease in HVPG after rifaximin administration. The inclusion of a placebo arm is theoretically important since in a previous study on alcoholic cirrhotic patients, HVPG decreased spontaneously during follow-up.22 However, the first follow-up measurement of HVPG in that study was performed after one year, whereas we observed this difference after only 28 days of therapy. Moreover, our patients abstained from alcohol for at least 6 months and we believe that in this case, a spontaneous decrease in HVPG is rather unlikely.

The mechanism by which rifaximin alters hepatic hemodynamics in patients with alcohol-related cirrhosis remains speculative. In cirrhosis and in response to endotoxin, there is increased release of TNF-α, interleukin (IL)-1 and IL-6.23 Moreover, monocytes are spontaneously activated by enteric bacterial products to produce TNF-α and contribute significantly to elevated serum TNF-α.24 It has been previously shown that cirrhotics with high TNF-α concentrations in mesenteric lymph nodes (suggesting bacterial translocation) had a higher cardiac index and higher portal pressure.25 In rats with portal hypertension, inhibition of TNF-α production was accompanied by amelioration of the hyperdynamic syndrome and reduction in the portal pressure.26 Furthermore, both endotoxin itself and cytokines released in response to it are potent stimuli for the production of endothelin-1 (ET-1), which may act in combination with cyclooxygenase products to increase portal venous resistance during endotoxaemia.8, 27 In the cirrhotic liver, there is greater induction of vasoconstrictors over vasodilatory forces after lipopolysaccharide (LPS) injection. There is a compromised ability to upregulate sufficient vasodilatory forces to counterbalance the constrictive effect of ET-1 following increases in endotoxaemia, thus leading to increased intrahepatic resistance.28 These data suggest that endotoxaemia can exacerbate the hemodynamic alterations in cirrhosis, leading to further worsening of portal hypertension.

The ability of rifaximin to alter selectively the microenvironment of the intestine could be beneficial for the prevention of bacterial translocation, the reduction in endotoxin concentration in the splanchnic and systemic circulation and the amelioration of liver hemodynamics in cirrhotic patients.

In conclusion, intestinal decontamination with rifaximin decreased significantly the HVPG values in patients with alcohol-related decompensated cirrhosis and this might have been achieved through significant reduction in plasma endotoxin levels. These preliminary data clearly support the need for randomized controlled clinical trials to investigate further the efficacy of long-term antibiotics administration in the prevention of complications of portal hypertension.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Statistical analysis
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References
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    Vorobioff J, Groszmann RJ, Picabea E, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996; 111: 7019.
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