Probiotics in the Prevention of Hepatocellular Carcinoma in Cirrhosis

Background. The main risk factor for the development of hepatocellular carcinoma (HCC) is cirrhosis of any etiology, with an annual risk between 1 and 6%, being currently the leading cause of death in patients with cirrhosis and the third cause of death for cancer in the world. In our country there is little information about the incidence of HCC in this population. It has been shown that there is a change in the gut microbiome (set of genetic material of microorganisms that make up the intestinal bacterial flora) as the severity of the cirrhosis progresses. This change in the microbiome has been associated with clinical decompensation events of cirrhosis. However, there are no previous studies in the world that demonstrate an impact of the change of the microbiome in cirrhosis as a precursor to the development of HCC. Our team has compared the profile of the microbiome in patients with cirrhosis with and without HCC. We observed that patients with HCC present changes in the phylum Firmicutes, genus Fusobacterium and change in the bacteroides / prevotella ratio. This pattern was associated with a pro-inflammatory profile. In murine models, it has been postulated that modulation of the gut microbiome through the use of probiotics could have a clinical role in the prevention of HCC development. This research project aims to answer the following question: in patients with cirrhosis, does the nutritional supplement with probiotics prevent HCC development? Objective: To compare the incidence of HCC through intervention with probiotics in cirrhosis. Methods: A randomized, double-blind, placebo controlled trial of probiotics in patients with Child Pugh A-B cirrhosis at 3-year follow-up. Likewise, the type of microbiome found as a predictor of the risk of HCC development will be evaluated. It will include 280 patients, 140 in each branch. Basal blood and stool samples will be obtained and every 6 months. The typing and quantification of the microbiome in samples of fecal matter will be carried out by amplifying a specific region (V3-V4) of the bacterial 16s rRNA gene. Likewise, the presence of endotoxins (LPS) and cytokines (IL6, TNF alpha) in plasma will be determined to analyze the immune environment and the expression of the TLR4 receptor in mononuclear cells.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* signed Informed Consent (CI), obtained before carrying out any specific procedure of the study
* Clinical or histological diagnosis of cirrhosis
* Child Pugh A or B
* Presence of clinical signs of portal hypertension: esophagogastric varices or hypertensive gastropathy or edematous ascitic syndrome or encephalopathy.

Exclusion Criteria:

* History of hepatocellular carcinoma prior to randomization
* Solid organ transplant.
* Immunosuppressive treatment.
* Previous treatment (during the last 6 months prior to the inclusion of the study) or current with pre or probiotics.
* Current antibiotic treatment for any reason.
* Active alcoholism: alcohol consumption in the last 3 months prior to randomization.
* History or current history of other neoplasms.
* Major surgical intervention or serious traumatic injury in the 28 days prior to randomization.
* Unstable angina (angina symptoms at rest, recently started angina, or within the last 3 months of randomization) or myocardial infarction in the 6 months prior to randomization.
* Uncontrolled cardiac arrhythmia, valvular heart disease.
* Infection grade\> 2 in progress, according to the NCA CTCAE criteria, version 4.0.
* Inflammatory bowel disease including ulcerative colitis and Crohn's disease.
* Celiac Disease.
* Diarrhea secondary to any germ or commensal, including Clostridium difficile diarrhea within 6 months prior to randomization.
* Any malabsorption disorder.
* Chronic renal failure with hemodialysis requirement.
* Known hypersensitivity to any of the study drugs, to the study drug classes or to the excipients of its formulation.
* Pregnancy or breast feeding.