Alcoholic Liver Disease, Liver Cirrhosis, Alcoholic, Liver Fibrosis, Probiotics
Conditions
Keywords
Food for special medical purposes, Gut and liver axis
Brief summary
Investigators wishes to influence the gut microbiota in patients with alcoholic liver disease in a randomized controlled clinical trial. The investigators hypothesize that the alcohol-related dysbiosis seen in these patients can be changed and disease progression haltered by modulating microbiota with probiotics during 24 weeks.
Detailed description
Chronic alcohol overuse is associated with increased gut permeability and in addition, the intestinal microbiota changes qualitatively (dysbiosis) and quantitatively (bacterial overgrowth) in alcoholic liver disease in favour of a microbiota with increased invasive potential. As a consequence, an increased load of bacterial products is transported to the liver leading to inflammation and fibrogenesis. This cross talk between the intestinal microbiota and the liver constitute a gut-liver axis, which is increasingly recognized as key mechanism in the progression of liver disease and pathogenesis of liver related complications. The investigators hypothesize that the gut microbiota and its metabolites are major drivers of fibrosis in human liver disease and that modulating the intestinal flora by Profermin® (a food for special medical purposes) will modulate the alcohol related dysbiotic signatures in the microbiota which may halter disease progression by reducing activity of hepatic stellate cells. Dietary supplements that alter the microbiome towards a more beneficent type may improve liver inflammation and thus be a better alternative than supplements that simply add nutrients. Investigators expect that the trial will provide proof-of-concept for a sustainable dietary strategy in liver fibrosis. Examples of biopsies which did not meet quality criteria for reliable histological reading, led to inclusion of 16 extra patients. In total we included 56 patients to ensure an adequate number of participants with valid liver biopsy data for assessment of the primary endpoint and intention-to-treat analysis.
Interventions
DIETARY_SUPPLEMENTProfermin Plus, FSMP, probiotics
Participants will have to supply their normal intake with Profermin Plus, FSMP, Prbiotics product twice every day for 24 weeks. The product Profermin Plus® has changed its name to ReFerm®. The content of the product is unchanged. The change occurred after the clinical part of the study was completed.
DIETARY_SUPPLEMENTFresubin, dietary supplement
Participants will have to supply their normal intake with the control product, Fresubin, dietary supplement twice every day for 24 weeks.
Sponsors
Region of Southern Denmark
Odense Patient Data Explorative Network
University of Southern Denmark
Nordisk Rebalance A/S
Odense University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Masking description
Pathologist will perform outcome assessment blinded
Intervention model description
Patients will be randomized 1:1 to receive Profermin Plus® versus a general FSMP, Fresubin®, for 24 weeks.
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Prior or ongoing harmful alcohol intake defined as an average of ≥24g alcohol/day for women and ≥36g/d for men for ≥ 5 year. * Outpatients with compensated advanced chronic alcohol-related liver disease, defined as stable patients with: 1. liver stiffness ≥15 kPa and asymptomatic and/or 2. New liver biopsy (\<6months) with at least F3 fibrosis (kleiner) and/or 3. Liver biopsy older that 6 months with liver stiffness ≥10 kPa * Understand and speak Danish written and orally * Informed consent
Exclusion criteria
* Hospitalised * Moderete or severe Ascites, determined from imaging diagnostics * High-risk varices needing interventional treatment (endoscopy, TIPS) * Child-Pugh C score * MELD-Na ≥15 * Lactose intolerance * Coeliac disease * Irritable bowel syndrome defined by ROME III criteria * Antibiotic treatment the prior 3 months * Treatment with nutritional drinks, probiotics or prebiotics within the last 3 months * The investigator judge that the patient would not be compliant with trial medicine * Pregnancy * Known liver disease other than alcoholic, of any aetiology * Severe malnutrition * Malignancy - except spino- or basocellular skin cancer. Patients with prior malignant disease are allowed if cancer-free for at least one year * Recent infectious gastroenteritis (for the last 6 weeks)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic stellate cell activity | 24 weeks | Attenuation of liver hepatic stellate cell activity, defined as the proportion of patients with a 10% or more reduction in activated hepatic stellate cells, measured by a-smooth muscle actin (a-SMA) stain quantification of liver biopsies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic inflammation | 24 weeks | Evaluated by hepatic inflammation markers and metabolites |
| Alfa-smooth muscle actin concentration | 24 weeks | Reduction in circulating a-smooth muscle actin concentration |
| Hepatic venous pressure gradient (HVPG) | 24 weeks | Reduction in portal pressure measured by the HVPG in unit mmhg |
| Reduction in non-invasive fibrosis markers | 24 weeks | Reduction in Ultrasound shear wave elastography (transient and 2-dimensional) (kPa) |
| Reduction in non-invasive fibrosis marker | 24 weeks | APRI score |
| Markers of liver inflammation | 24 weeks | Reduction in circulating markers of liver inflammation (cytokeratin-18 degradation products M30 and M65) |
| Improvement of liver histological lesions | 24 weeks | Improvement in semiquantitative liver histological lesions that fulfil at least one of two criteria: * At least one stage of liver fibrosis improvement according to the Kleiner fibroses classification (0-4), with no worsening of hepatic inflammatory activity * Complete resolution of hepatic inflammatory activity, with no worsening of fibrosis. \[Worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning. Resolution defined as ballooning=0 and lobular inflammation=0-1\] |
| Improvement in gut dysbiosis | 24 weeks | Defined as: * Improved taxonomy, defined as increased relative abundance of species characteristic of healthy individuals and decreased relative abundance of species characteristic of cirrhosis and severe alcoholic liver disease * Increase in gut microbial richness |
| Hepatic a-SMA activity | 24 weeks | Reduction in hepatic a-SMA activity |
| Lipid profile | 24 weeks | Improvement of lipid profile defined as: Rising HDL, decrease in triglycerids, LDL and total cholesterol |
| Any changes in non-invasive markers of steatosis | 24 weeks | Controlled Attenuation Parameter(CAP) and ultrasonographic steatosis assessment (bright liver echo pattern) |
| Individual domains of NAS scoring systemt | 24 weeks | Any changes in individual domains of the NAS scoring system (fibrosis 0-4, steatosis 0-3, lobular inflammation 0-2, portal inflammation 0-1, ballooning 0-2) or in collagen proportionate area (%) |
| Metabolic changes | 24 weeks | Water soluble metabolites in circulation will be evaluated with metabolomics |
| Changes in circulating cytokines | 24 weeks | Cytokines related to cardiovascular disease and inflammation will be analysed |
| Changes in hepatic macrophage activity | 24 weeks | Changes in digital imaging analysis of hepatic CD163 expression in liver biopsies |
| Changes in intestinal fibrosis markers | 24 weeks | C4M generated by decomposition of type 4 collagen |
| Changes bile acids | 24 weeks | Changes in bile acids will be measured in both stool and circulation |
| Liver vein outflow of microbial products | 24 weeks | Change in Liver vein outflow of microbial products |
Countries
Denmark
Outcome results
None listed