Fructose is a Metabolic and Inflammatory Pathogenic Factor in Metabolic Dysfunction-associated Steatohepatitis (MASH)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 72
- 试验地点
- 4
- 主要终点
- Change in plasma glutamate concentration
研究概览
简要总结
MASLD (Metabolic dysfunction-associated steatotic liver disease) is a condition where fat builds up in the liver. It is the most common cause of liver disease worldwide. In some people, the fat can irritate the liver (inflammation) and cause damage. This is a more serious condition called MASH (Metabolic dysfunction-associated steatohepatitis). People with MASH more at risk of liver cirrhosis (advanced scarring in the liver) and liver cancer.
It is not fully understood why MASLD becomes MASH, or why this happens in some people but not in others. However, it is known that our diet plays a role. Research shows a diet high in a type of sugar called fructose might make MASLD worse. Fructose is found in fruit, honey and table sugar, and lots of processed food and drinks. The body deals with fructose differently to other sugars, which is why fructose may be a problem. Although scientists have studied the effects of fructose in healthy people, no studies so far have included people with MASH, so it is not known if fructose might make the condition worse.
To answer this question, the researchers will conduct a four-week randomised, double-blind study to compare the effects of fructose with another sugar called glucose in 36 people with MASH, 18 people with 'simple' MASLD, and 18 controls without liver disease. Participants will follow a low-sugar diet and, after 14 days on this diet, they will add either a glucose or fructose supplement for another 14 days. Participants will attend 3 study visits, where blood, urine, stool, and saliva samples will be taken. The main question is whether fructose causes more inflammation in people with MASH compared to those with MASLD, or people without liver disease. The researchers will also investigate how fructose affects liver fat content, the gut microbiota, and other processes relevant to MASLD/MASH.
详细描述
Overview of the study:
This is a four-week randomised double-blind parallel-arm food supplement intervention study that will determine the effect of fructose on metabolism in people with MASH, compared to people with simple steatosis, or controls without liver disease. The study will involve consent (visit 0A) and screening (visit 0B), followed by two study stages (see Figure 1), where participants will undergo study visits and procedures as detailed in Table 1. Each participant will attend for a total of up to 5 study visits: consent (visit 0A) and screening (visit 0B); Baseline (visit 1); pre-intervention (visit 2); post-intervention (visit 3). Consent (visit 0A) and screening (visit 0B) visits may be combined into one visit if feasible and the participant would like to do so. Otherwise, visits will be conducted on separate days as close together as practical for the participant and research team (ideally no more than 3-4 weeks). Visits 1 to 3 will each last approximately 8 hours, at which participants will consume a test meal and have hourly blood samples taken via a cannula for approximately 6h.
A subset of participants (maximum of n=24; n=12 MASH; n=12 steatosis/control) will be invited to take part in an optional sub-study. This will involve the same study visits and procedures as the main study but will additionally measure how glucose or fructose is metabolised in the postprandial state by addition of a small amount of glucose/fructose stable isotope tracer (13C6-fructose or 13C6-glucose) to the metabolic test meal. Participants will also provide breath samples at hourly intervals during the 6h feeding period.
There will be no change to routine patient care for MASH and MASLD participants during the study period. Any clinically significant results emerging from study participation will be shared with participants' GP or care team.
Description of the study intervention:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
Both participants and members of the research team will be blinded to the intervention allocation (fructose or glucose). The randomisation list will be maintained by an independent researcher with no role in conducting the research.
入排标准
- 年龄范围
- 45 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Able and willing to give written informed consent
- •Age 45-65 at consent
- •HbA1c < 48 mmol/mol
- •Overweight and stage I obesity using BMI thresholds adjusted for ethnicity:
- •23.0kg/m2 - 32.4kg/m2 in South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean populations
- •25kg/m2 - 34.9kg/m2 in White populations
- •MASH Patients:
- •Clinical diagnosis of MASH and F2 - F3 fibrosis:
- •Liver biopsy within 12 months of baseline
- •History of histologically-diagnosed MASH with current evidence of fatty liver, AST>20 and Fibroscan CAP≥248 dB/m and stiffness 9.5kPa -14kPa
- •FAST score >0.67
- •Patients with steatosis:
- •defined by Fibroscan CAP≥248dB/m and stiffness <7.9kPa.
- •Healthy controls:
- •defined by Fibroscan CAP<248dB/m and stiffness <7.9kPa.
排除标准
- •Unwilling or unable to give consent
- •Age <45 or >65
- •Any form of diabetes mellitus
- •Currently pregnant
- •Known fructose intolerance or food allergy
- •Diagnosis of cirrhosis or Fibroscan stiffness >14kPa
- •Current Child-Pugh B/C or episode of decompensation in last year
- •Non-MASLD liver disease known to participant (including viral hepatitis, auto-immune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, haemochromatosis, sarcoidosis, cystic fibrosis, sickle cell disease)
- •Regular alcohol intake > 14 units a week for females and >21 units a week for males (participant-reported)
- •Smoking, vaping or use of nicotine-containing products within the last month
- •Taking prohibited medication:
- •Probiotic or antibiotic use within last 4 weeks (Note: participants will be considered eligible if they have undergone a 4-week washout from probiotics or 4-weeks after discontinuing antibiotic use)
- •any oral steroids within the last 6 weeks
- •current, or within 3 months, use of immunosuppressive medication
- •Amiodarone, nitrofurantoin, or anti-fungals within 3 months
- •Use of anti-obesity medication - orlistat or GLP-1 receptor agonist-containing treatments within 6 months
- •Use of vitamin E, pioglitazone or other medication for MASH including current or within 3 months enrolment in clinical trial unless documented to have been on placebo
- •History of malignancy (except basal cell carcinoma), or medication for malignancy within the last 2 years
- •Any major organ transplant (excluding corneal or hair)
- •Clinical diagnosis of chronic kidney disease 3 or above, or of heart failure (NYHA 3 or 4)
- •COPD requiring home oxygen
- •Known eating disorder (e.g. anorexia nervosa) or severe mental illness (e.g. schizophrenia)
- •Investigator opinion that study is unsuitable for patient
研究组 & 干预措施
Glucose supplementation
Participants will consume 100 g/day of glucose powder administered as two 50g sachets, dissolved in water in addition to following a low-sugar diet
干预措施: glucose (Dietary Supplement)
Fructose supplementation
Participants will consume 100 g/day of fructose powder administered as two 50g sachets, dissolved in water in addition to following a low-sugar diet
干预措施: fructose (Dietary Supplement)
结局指标
主要结局
Change in plasma glutamate concentration
时间窗: Changes from baseline to week 2
Difference in the fructose-induced changes in plasma glutamate concentration in patients with MASH and fibrosis compared to patients with simple steatosis (without fibrosis) or healthy controls.
次要结局
- Markers of immunity(Changes from baseline to week 2)
- Markers of cell function(Changes from baseline to week 2)
- Urine metabolome(Changes from baseline to week 2)
- Plasma glucose(Changes from baseline to week 2)
- Plasma triglycerides(Changes from baseline to week 2)
- Serum insulin(Changes from baseline to week 2)
- Oral metabolites(Changes from baseline to week 2)
- Markers of inflammation(Changes from baseline to week 2)
- De novo lipogenesis(Changes from baseline to week 2)
- Gut hormones(Changes from baseline to week 2)
- Oral microbiome(Changes from baseline to week 2)
- Plasma metabolome(Changes from baseline to week 2)
- Serum insulin(Changes from baseline to week 2)
- De novo lipogenesis(Changes from baseline to week 2)
- Gut hormones(Changes from baseline to week 2)
- Urine metabolome(Changes from baseline to week 2)
- Liver function markers(Changes from baseline to week 2)
- Oral metabolites(Changes from baseline to week 2)
- Plasma glucose(Changes from baseline to week 2)
- Plasma triglycerides(Changes from baseline to week 2)
- Markers of cell function(Changes from baseline to week 2)
- Oral microbiome(Changes from baseline to week 2)
- Markers of inflammation(Changes from baseline to week 2)
- Markers of immunity(Changes from baseline to week 2)