Our study has shown for the first time that erythromycin can be employed as a feasible HE treatment in cirrhotic patients. The drug has been used as an antibiotic for almost five decades and as a prokinetic for more than ten years, even in ICU patients, pregnant women and children. Its antibiotic and prokinetic effects appear to be very promising in patients with HE and cirrhosis. Our results showed significant reductions of the hospitalization duration and also of the ALT levels in patients that have been treated with erythromycin.
The use of a placebo in severe cases of HE is unjustified, and in HE treatment trials comparisons with disaccharides as controls are not adequate [7, 21]. Thus, the comparison with another antibiotic enabled the correlation of our results with many other studies. We emphasize that the control group received the maximum secure doses of neomycin .
The most prevalent cause of cirrhosis was alcohol and the major precipitating factors were dehydration and hyponatremia, as found in other similar trials [19, 22]. Most of the patients had persistent HE, and among these subjects we had some difficulty to determine the precipitating factor involved, as mentioned by other authors . Besides the fact that MELD scores and Child-Pugh classifications were high, they were not correlated with the total in-hospital days, while the MELD score seems not to be associated with HE severity, as reported by other authors evaluating the renal function in similar patients . This particular discrepancy between HE severity and MELD score appears to account for the low rates of liver transplantation in these patients, and could contribute to the high mortality rates caused by HE.
HE index and HE grade showed similar results, because neither ammonia levels determination nor common psychometric testing were helpful for HE grading, as already noticed by other authors [20, 25, 26]. As the sample was composed by many patients with severe HE, they could not collaborate properly to be submitted to other specific exams. The only way to quantify their treatment response was the clinical findings according to the West Haven criteria.
In relation to applicability, our sample was formed by subjects with more severe HE than in other studies (nine patients with HE grade 2, nine with grade 3 and two with grade 4), which is an important concern in HE trials. The option of using a new drug requires a close observation of these patients and the possibility of antibiotic switch in case of infections. Also of interest are the hospitalization duration as the study endpoint and its correlations with clinical and laboratory variables. Thus, the correlation of the number of in-hospital days with HE grade, IEH, GSC and CRP showed simple clinical aspects that could to estimate the time of HE recovery during which these patients are treated with antibiotics. Since the median in-hospital stay obtained in our trial was 5.6 days, very similar to the value found in an observational North American survey, our results would be reproducible in clinical practice .
The high correlation obtained between CRP levels and the total in-hospital days corroborates the impact of the systemic inflammatory status not only at the moment of hospital arrival, but also as an indicator of HE regression during the treatment with antibiotics. This finding is new and can be used to check the response to the treatment. Another study correlates the CRP levels with encephalopathy occurrence in cirrhotic patients, and many others have described the relevance of inflammation in HE neural physiopathology [24, 27, 28]. Nevertheless, this is the first time that CRP levels are correlated with the hospitalization duration. The role of inflammatory cytokines in affecting the blood–brain barrier and increasing the ammonia diffusion in astrocytes was also well described by other authors . By associating these reports with our findings, we postulate that the CRP reduction must be a clinical target during antibiotic treatment in HE when the values obtained are high.
As also described previously, the selective decontamination of the small intestine in these patients promotes the recovery of motility and the control of bacterial products released in the blood [10, 30]. Consequently, the use of prokinetics, antibiotics or probiotics can be indicated as a direct treatment against SIBO and gut dysmotility . Erythromycin is a drug that combines the prokinetic and antibiotic effects to enable synergistic action in the treatment of HE. Our trial did not measure direct findings of intestinal bacterial overgrowth, but the ALT reduction can be considered an indirect indicator of the role of erythromycin in preventing the release of these bacterial products into the portal vein. According to previous studies, these patients have an increase in production and absorption of intestinal bacterial products, which can lead to a continuous flux of lipopolysaccharides and other toxic materials to the portal vein. In the liver, these substances are recognized by Kuppfer cells and thus trigger the release of tumor necrosis factor (TNF), which together with other products of these cells, leads to hepatocyte lesion [32, 33]. Given that continuous hepatocyte injuries are a source of ALT elevations, we hypothesize that the decrease in the efflux of bacterial products to the liver and the control in systemic inflammation caused by them may have been the key to achieving the promising results obtained by erythromycin in this trial. To avoid inter-laboratory fluctuations, we use the differences between the final and initial ALT and CRP levels as indirect tools to document these plausible mechanisms, which could be the reason for the improvement in hepatic function obtained in other studies by the long term use of antibiotics and prokinetics in cirrhotic patients .
Not only SIBO must be discussed as an oligosymptomatic cause of HE, but other bacterial infections in cirrhotic patients might be important, as Helicobacter pylori infection. H. pylori infection can produce high blood ammonia concentration in these patients, and the eradication of this pathogen may be helpful for treatment and prevention of HE . In this study, the subjects were not submitted to H. pylori tests, but the role of erythromycin could be important in infected patients. In contrast, neomycin is probably useless against bacterial infections in the stomach.
Motility disturbances are clearly associated to cirrhosis, but the subjects evaluated in this study were not submitted to motility exams. Some patients could have a better effect of erythromycin than others, and this information is important in view of future uses of erythromycin in patients with HE. According to the good results obtained with prokinetics in cirrhotic patients, erythromycin must be evaluated in other studies about this condition [10–12].
Hence, given that antibiotics are already considered the best options for HE treatment and that the new drugs are still not useful in clinical practice, our proposal is very attractive because erythromycin is well known, easy to administer and less expensive than other treatments . We hope that new studies can confirm the security profile of this dosage in cirrhotic patients.