Non-Alcoholic Fatty Liver Disease
Conditions
Keywords
non alcoholic fatty liver disease, NAFLD, synbiotic, gut microbiota, intervention, RCT (Randomized Clinical Trial), biomarkers
Brief summary
Non-alcoholic fatty liver disease (NAFLD) is a liver condition in which fat builds up in the liver not caused by alcohol. The liver is an organ that is not designed to build up fat. NAFLD is common in people who have too much body fat in their abdomen or who have diabetes (high blood sugar), but does not always exist with these conditions. NAFLD can also occur in thin people too. NAFLD can be harmful to the liver and may cause the liver to fail over time. NAFLD may also cause adult (or type 2) diabetes and also heart disease. In people who already have diabetes, NAFLD can cause glucose (sugar) levels to be too high. Our intestines (guts) contain healthy bacteria and some harmful bacteria (bugs). This balance of healthy and harmful bugs is essential for the normal workings of our intestine to digest food. Providing these bacteria do not leak out into the blood they do not cause harm. If the balance of healthy to harmful bugs is upset, the harmful can cause problems and leak out into the blood. Because the liver is connected to the intestine by blood vessels the harmful bacteria can get to the liver and cause problems. These bacteria can cause the liver and the body to build up too much fat and might cause NAFLD and obesity. In this study, we will test the effects of a supplement (synbiotic) taken during the day, that contains a mixture of 'good' healthy bacteria (probiotic) and a sugar (prebiotic) that is not broken down and absorbed into the blood. We will test whether the synbiotic supplement has beneficial effects on the NAFLD liver condition and on factors linked to too much body fat, diabetes and heart disease.
Detailed description
We will recruit people with NAFLD who have been diagnosed as part of their NHS (National Health Service) care with having this condition. At present there is no treatment for this condition. Purpose and design: We are asking the research question: Does the modulation of gut microflora with a synbiotic improve non-alcoholic fatty liver disease and the related risk factors for heart disease and type 2 diabetes? Presently there is no treatment for this liver condition. Research evidence suggests that a synbiotic supplement might be beneficial for this condition. To address this research question we want to undertake a randomised double blind placebo controlled trial recruiting people who have been diagnosed with NAFLD.
Interventions
DIETARY_SUPPLEMENTSynbiotic
The synbiotic to be used is fructo-oligosacharide with a degree of polymerization \< 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).
DIETARY_SUPPLEMENTMaltodextrin
Sponsors
National Institute for Health Research, United Kingdom
University Hospital Southampton NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Both men and women * Age \> 18 years * Liver fat diagnosed on normal clinical grounds including in most cases liver assessed by Kleiner scoring system to classify severity, with no known aetiological factors for underlying liver disease (e.g. exclusion of hepatitis A, B & C, primary biliary cirrhosis, autoimmune hepatitis, haemochromatosis). Last liver biopsy will be within 3 years of recruitment to the study. * Liver fat diagnosed by ultrasound, CT or magnetic resonance imaging (MRI) in patients who also have either diabetes and/or features of the metabolic syndrome, without evidence of known aetiological factors for underlying liver disease (e.g. exclusion of hepatitis A, B & C, primary biliary cirrhosis, autoimmune hepatitis, haemochromatosis). * Alcohol consumption ≤ 14 units / week for women ≤ 21 units / week for men.
Exclusion criteria
* Alcohol consumption \> 15 units /week for women and \> 22 units /week for men. * Decompensated acute or chronic liver disease. * A history of viral hepatitis, diarrhoea, diverticulosis, irritable bowel syndrome, inflammatory bowel diseases, coeliac disease (seropositivity for anti-endomysial immunoglobulin A antibodies; immunoglobulin A (IgA) EMA). * Previous bariatric or other abdominal surgery. * Continuous use of antibiotics that may change gut microflora, probiotics, or antisecretory drugs capable of causing achlorhydria within the 2 months preceding enrolment, or evidence of immunoglobulin A or immunoglobulin deficiency (both of which produce confounding effects during assessments of intestinal permeability and small intestinal bacterial overgrowth).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Liver Fat | baseline and 12 months | Change in liver fat percent was calculated as the percent liver fat at the end of the study, minus the percent of liver fat prior to the intervention. Change in liver fat percent ranged from -60.6% (good) to + 33.7% (bad). |
| Change in Enhanced Liver Fibrosis Score (ELF) | baseline and 12 months | Change in Enhanced Liver Fibrosis score (ELF) was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis. Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad). |
| Change in NAFLD Fibrosis Score | baseline and 12 months | Change in NAFLD Fibrosis Score (NFS) was calculated as the NFS score at the end of the study, minus NFS score prior to the intervention (at baseline). A decrease in the NFS score was considered good because it reflected a decrease in liver fibrosis, and an increase in NFS score was considered bad, as it reflected an increase in liver fibrosis. Change in NFS scores ranged from -2.07 (good) to + 1.75 (bad) |
| Change in Bifidobacterium Spp. | baseline and 12 months | The change in percent of Bifidobacteria spp was computed as the percent of Bifidobactera spp at the end of the study minus the percent of Bifidobacteria prior to the intervention (at baseline). A positive change in percent (e.g +0.1 to 7.0%) in Bifidobacteria spp. was considered good and a negative change in percent (e.g. -0.1 to -0.5%) in Bifidobacteria spp. considered bad. (Minimum = -0.5% (bad) and Maximum = +7.0% (good)). |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Synbiotic Fructo-oligosaccharide with a degree of polymerization \< 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization \< 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day). | 45 |
| Maltodextrin 4 grams of maltodextrin daily.
Maltodextrin | 44 |
| Total | 89 |
Baseline characteristics
| Characteristic | Synbiotic | Maltodextrin | Total |
|---|---|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 12.4 | 51.6 years STANDARD_DEVIATION 13.1 | 50.8 years STANDARD_DEVIATION 12.6 |
| Bifidobacterium spp. | 0.8 percentage | 0.6 percentage | 0.8 percentage |
| ELF score | 6.9 units on a scale STANDARD_DEVIATION 0.4 | 6.9 units on a scale STANDARD_DEVIATION 0.3 | 6.9 units on a scale STANDARD_DEVIATION 0.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 44 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| NAFLD fibrosis score | -1.3 units on a scale STANDARD_DEVIATION 1.3 | -1.2 units on a scale STANDARD_DEVIATION 1.3 | -1.2 units on a scale STANDARD_DEVIATION 1.3 |
| percentage liver fat | 26.9 percentage | 22.9 percentage | 25 percentage |
| Region of Enrollment United Kingdom | 45 Participants | 44 Participants | 89 Participants |
| Sex: Female, Male Female | 14 Participants | 17 Participants | 31 Participants |
| Sex: Female, Male Male | 31 Participants | 27 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 49 |
| other Total, other adverse events | 35 / 55 | 30 / 49 |
| serious Total, serious adverse events | 6 / 55 | 6 / 49 |
Outcome results
Primary
Change in Bifidobacterium Spp.
The change in percent of Bifidobacteria spp was computed as the percent of Bifidobactera spp at the end of the study minus the percent of Bifidobacteria prior to the intervention (at baseline). A positive change in percent (e.g +0.1 to 7.0%) in Bifidobacteria spp. was considered good and a negative change in percent (e.g. -0.1 to -0.5%) in Bifidobacteria spp. considered bad. (Minimum = -0.5% (bad) and Maximum = +7.0% (good)).
Time frame: baseline and 12 months
Population: numerical difference between baseline measurement and 12 month measurement
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Synbiotic | Change in Bifidobacterium Spp. | 1.72 percentage of fecal Bifidobacterium spp |
| Maltodextrin | Change in Bifidobacterium Spp. | -0.02 percentage of fecal Bifidobacterium spp |
p-value: <0.001Beta-diversity indexes
Primary
Change in Enhanced Liver Fibrosis Score (ELF)
Change in Enhanced Liver Fibrosis score (ELF) was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis. Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad).
Time frame: baseline and 12 months
Population: numerical difference between baseline measurement and 12 month measurement
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Synbiotic | Change in Enhanced Liver Fibrosis Score (ELF) | 0.12 units on a scale |
| Maltodextrin | Change in Enhanced Liver Fibrosis Score (ELF) | 0.13 units on a scale |
p-value: 1Regression, Linear
Primary
Change in Liver Fat
Change in liver fat percent was calculated as the percent liver fat at the end of the study, minus the percent of liver fat prior to the intervention. Change in liver fat percent ranged from -60.6% (good) to + 33.7% (bad).
Time frame: baseline and 12 months
Population: numerical difference between baseline measurement and 12 month measurement
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Synbiotic | Change in Liver Fat | -3.8 percentage of liver fat |
| Maltodextrin | Change in Liver Fat | -6.0 percentage of liver fat |
Comparison: A total sample size of 100 participants, with a 14% drop out during the study and 43 participants in each group completing the study provided 85% power to detect a difference of 40% in liver fat (in the treatment arm compared with the placebo), using a power calculation test with a 0.05 two-sided significance level. For change in liver fat percentage (and other secondary outcomes), ANCOVA will also be undertaken to assess effect sizes in the intervention group and placebo.p-value: =0.05Regression, Linear
p-value: <0.001Regression, Linear
Primary
Change in NAFLD Fibrosis Score
Change in NAFLD Fibrosis Score (NFS) was calculated as the NFS score at the end of the study, minus NFS score prior to the intervention (at baseline). A decrease in the NFS score was considered good because it reflected a decrease in liver fibrosis, and an increase in NFS score was considered bad, as it reflected an increase in liver fibrosis. Change in NFS scores ranged from -2.07 (good) to + 1.75 (bad)
Time frame: baseline and 12 months
Population: numerical difference between baseline measurement and 12 month measurement
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Synbiotic | Change in NAFLD Fibrosis Score | -1.3 units on a scale |
| Maltodextrin | Change in NAFLD Fibrosis Score | -1.2 units on a scale |
p-value: 0.8Regression, Linear