SEARCH

SEARCH BY CITATION

To the Editor:

We read with great interest the article by Nolan regarding the pathogenetic role of intestinal endotoxin in the development of liver injury.1 Increased circulating levels of gut-derived endotoxin2 and specific sensitivity to endotoxin have been shown in cirrhosis,3 which could worsen further hepatic impairment. However, the effects of changing gut flora on liver function in patients with cirrhosis remain unclear. Treatment with synbiotics improved the Child-Pugh class as a result of significant improvements in serum bilirubin and albumin levels and in prothrombin activity.4 Additionally, probiotics reduced endotoxemia and improved the Child-Pugh score, although not significantly, in patients with compensated cirrhosis.5 Finally, treatment with paromomycin and neomycin for 3-6 months significantly improved serum albumin levels6 and the Child-Pugh score, mainly because of a decreased incidence of ascites and encephalopathy,7 respectively.

Herein, we present preliminary data on the effects of rifaximin, a virtually unabsorbable antibiotic with broad-spectrum antimicrobial activity and an excellent safety profile8 on endotoxemia and liver function and disease severity in 9 liver transplant candidates with alcoholic cirrhosis (male, n = 7; mean age = 56 ± 6 years; Child-Pugh class B/C: 5/4). All patients abstained from alcohol for at least 1 year before inclusion. Plasma endotoxin levels were detected by the Limulus amebocyte lysate chromogenic endpoint assay (Hycult Biotech, Uden, The Netherlands). Clinical infection, upper gastrointestinal bleeding, and use of antibiotics or prebiotics 6 weeks before or during the study were exclusion criteria. Patients were evaluated after an 8-week observational period and after an 8-week course of rifaximin (1,200 mg/day).

All measures remained unchanged during the observational period. Rifaximin significantly reduced plasma endotoxin levels, together with a significant increase in serum albumin levels and significant decreases in serum total bilirubin levels and international normalized ratio. Child-Pugh and model for end-stage liver disease scores decreased significantly after treatment (Table 1).

Table 1. Plasma Endotoxin Levels and Measures of Liver Function and Disease Severity Evaluated Before and After Rifaximin Treatment in Patients With Decompensated Cirrhosis
 BaselineEnd of Observational Period (Week 8)End of Rifaximin Treatment (Week 16)
  • Data are expressed as means ± standard error.

  • Encephalopathy before entry was controlled with lactulose/lactitole. The MELD score was calculated according to the formula of the United Network for Organ Sharing (UNOS) available at www.unos.org. For the estimation of Child-Pugh score in the present series: INR substituted prothrombin time prolongation (<1.7, 1 point; 1.71-2.2, 2 points); encephalopathy was scored 1 point when never having occurred and 2 points when suppressed with medication; ascites was scored with 2 when suppressed with diuretics and 3 when refractory.

  • Abbreviations: INR, international normalized ratio; MELD, model for end-stage liver disease.

  • a

    P < 0.01 versus Baseline.

  • b

    P < 0.01 versus observational period.

  • c

    P < 0.001 versus Baseline.

  • §

    P < 0.001 versus observational period.

Plasma endotoxin levels (EU/mL)3.14 ± 1.233.32 ± 1.051.62 ± 0.85ab
Ascites (suppressed by medication/refractory)8/18/18/1
Encephalopathy (none/suppressed by medication)4/54/54/5
Serum albumin (g/dL)3.21 ± 0.083.14 ± 0.063.45 ± 0.06ab
Serum albumin improved (yes/no) 1/87/2ab
INR1.66 ± 0.091.7 ± 0.071.51 ± 0.07ab
INR improved (yes/no) 1/87/2ab
Serum total bilirubin (mg/dL)2.17 ± 0.162.24 ± 0.11.72 ± 0.13c§
Serum total bilirubin improved (yes/no) 2/78/1ab
Serum alanine aminotransferase (U/L)56 ± 457 ± 452 ± 6
Serum aspartate aminotransferase (U/L)48 ± 548 ± 646 ± 4
Serum creatinine (mg/dL)1.18 ± 0.091.17 ± 0.051.13 ± 0.07
Child-Pugh score8.7 ± 0.49 ± 0.58.1 ± 0.5ab
Child-Pugh score improved (yes/no) 0/97/2c§
MELD score16 ± 1.216.2 ± 1.113.7 ± 1c§
MELD score improved (yes/no) 0/99/0c§

In conclusion, intestinal decontamination by rifaximin could be a feasible, safe approach to prevent endotoxin-induced liver injury and improve liver function and disease severity in patients with decompenstaed cirrhosis. The present findings should be confirmed in a placebo-controlled trial.

References

  1. Top of page
  • 1
    Nolan JP. The role of intestinal endotoxin in liver injury: a long and evolving history. HEPATOLOGY 2010; 52: 1829-1835.
  • 2
    Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic, and peripheral blood in patients with cirrhosis. HEPATOLOGY 1988; 8: 232-236.
  • 3
    Pérez del Pulgar S, Pizcueta P, Engel P, Bosch J. Enhanced monocyte activation and hepatotoxicity in response to endotoxin in portal hypertension. J Hepatol 2000; 32: 25-31.
  • 4
    Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. HEPATOLOGY 2004; 39: 1441-1449.
  • 5
    Lata J, Novotny I, Prıbramska V, Jurankova J, Fric P, Kroupa R, et al. The effect of probiotics on gut flora, level of endotoxin, and Child-Pugh score in cirrhotic patients: results of a double-blind randomized study. Eur J Gastroenterol Hepatol 2007; 19: 1111-1113.
  • 6
    Tarao K, Iwamura K. Effect of long-term administration of paromomycin sulfate on the level of serum albumin and gamma-globulin in human cirrhosis. Tokai J Exp Clin Med 1983; 8: 349-357.
  • 7
    Madrid AM, Hurtado C, Venegas M, Cumsille F, Defilippi C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am J Gastroenterol 2001; 96: 1251-1255.
  • 8
    Koo HL, DuPont HL. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr Opin Gastroenterol 2010; 26: 17-25.

Georgios N. Kalambokis M.D.*, Epameinondas V. Tsianos M.D., Ph.D., F.E.B.G., A.G.A.F.*, * 1st Division of Internal Medicine and Hepato-Gastroenterology Unit University Hospital, Ioannina, Greece.