Fructose is a Metabolic and Inflammatory Pathogenic Factor in Metabolic Dysfunction-associated Steatohepatitis (MASH)

Summary

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.

Eligibility

Inclusion Criteria:

* 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:

Either:

Liver biopsy within 12 months of baseline

Or:

• History of histologically-diagnosed MASH with current evidence of fatty liver, AST\>20 and Fibroscan CAP≥248 dB/m and stiffness 9.5kPa -14kPa

Or:

• 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.

Exclusion Criteria:

* 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

Conditions4

Browse More Trials