Fatty Liver Disease (MASLD): A Metabolic Perspective

For decades, fatty liver was treated as an incidental finding on an ultrasound, mentioned in a report and then forgotten. That attitude has changed. Fatty liver disease is now recognised as one of the most common chronic diseases in the world, closely tied to insulin resistance and type 2 diabetes, capable in some people of progressing to cirrhosis and liver cancer, and strongly associated with cardiovascular disease. In 2023 it was also given a new name, reflecting a better understanding of what drives it.

A new name

An international consensus process involving liver societies worldwide replaced the terms non alcoholic fatty liver disease and non alcoholic steatohepatitis with new terminology.

The change moved away from defining the disease by what it is not, the absence of alcohol, towards what drives it, metabolic dysfunction. It also removed terms some patients found stigmatising. Most people previously diagnosed with non alcoholic fatty liver disease meet the new criteria.

How common it is

Global estimates suggest that around 3 in 10 adults have steatotic liver disease, with higher rates in people with obesity and type 2 diabetes, in whom a majority may be affected. Prevalence is rising with the global increase in obesity and diabetes. It also occurs in people with normal BMI, particularly in populations prone to visceral fat accumulation, and increasingly in children and adolescents.

Why it develops

Fat accumulates in the liver when the supply of fatty acids, from fat tissue, from the diet and from new fat made in the liver itself, exceeds the liver’s ability to burn or export it. Insulin resistance drives increased release of fatty acids from fat tissue and, paradoxically, continued fat synthesis in the liver. High intake of sugar, particularly fructose from sweetened drinks, and refined carbohydrate increases new fat production. Excess energy intake, inactivity, genetic factors such as variants in the PNPLA3 gene, and alcohol all contribute.

What happens over time

Most people with MASLD have simple steatosis and never develop serious liver disease. A minority develop MASH, in which inflammation and injury drive fibrosis, scarring of the liver. Fibrosis can progress to cirrhosis, liver failure and hepatocellular carcinoma. Studies following patients over many years found that the stage of fibrosis was the strongest predictor of liver related outcomes and death.

2 facts are essential for practitioners. First, cardiovascular disease, not liver disease, is the leading cause of death in people with MASLD, reflecting the shared metabolic drivers. Second, MASLD strongly increases the risk of developing type 2 diabetes, and people with diabetes have a higher risk of progressive liver disease.

Recognising and assessing it

Suspicion

MASLD should be suspected in people with obesity, type 2 diabetes, prediabetes, metabolic syndrome or abnormal liver tests, and in people with steatosis on imaging.

Liver tests are unreliable

ALT and AST are often normal in MASLD, including in people with advanced fibrosis. A normal ALT does not exclude disease or significant fibrosis.

Risk stratification

The key clinical question is whether a person has significant fibrosis. Current liver society guidance recommends a stepwise approach.

1. FIB 4, a score calculated from age, AST, ALT and platelet count. A score below 1.3 suggests low risk of advanced fibrosis; higher scores warrant further assessment. The score is less reliable in people under 35 and over 65, with adjusted interpretation in older adults.
2. Elastography, such as vibration controlled transient elastography, which measures liver stiffness, or specialised blood tests, to refine risk in those with indeterminate or high FIB 4 scores.
3. Referral to hepatology for those at higher risk.

Other causes

Assessment should consider alcohol intake, viral hepatitis, medicines, iron overload, autoimmune liver disease and other causes of steatosis or liver injury.

Treatment

Weight loss

Weight loss is the most effective treatment. In a prospective study of people with biopsy proven steatohepatitis, weight loss of 7 to 10 percent or more was associated with resolution of steatohepatitis in most participants and regression of fibrosis in many. Smaller amounts of weight loss reduce liver fat.

Diet

Reducing energy intake, sugar sweetened drinks, refined carbohydrates and ultra processed foods, and adopting a Mediterranean style pattern, are supported by evidence. Coffee consumption is associated with lower risk of liver fibrosis in observational studies.

Physical activity

Both aerobic and resistance exercise reduce liver fat, even without significant weight loss.

Alcohol

Alcohol should be minimised, and avoided in people with significant fibrosis.

Cardiometabolic risk

Treating diabetes, blood pressure and lipids reduces cardiovascular risk. Statins are safe in MASLD and should not be withheld because of mildly raised liver enzymes.

Medicines

Specific medicines for MASH with fibrosis have become available in some countries in recent years, and glucose lowering medicines such as GLP 1 receptor agonists and pioglitazone have shown liver benefits in trials. Vitamin E has shown benefit in steatohepatitis in people without diabetes in a trial, with safety considerations. These treatments are prescribed and monitored by specialists.

A functional perspective

On the functional medicine matrix, MASLD sits at the crossroads of energy, biotransformation and transport. The timeline often reveals weight gain, increased sugar or alcohol intake, inactivity or a new medicine. Mediators frequently include sugar sweetened drinks, late evening eating, short sleep and sleep apnoea. The plan addresses these drivers while ensuring appropriate risk stratification and medical care.

An illustrative case

A 52 year old woman with type 2 diabetes has an ultrasound showing a fatty liver, with normal liver enzymes. She has been told it is common and not a concern. Her FIB 4 score, calculated from routine blood tests, is 1.9, indeterminate. Elastography shows increased liver stiffness suggesting moderate fibrosis, and she is referred to hepatology.

Her plan targets weight loss through a structured dietary programme with a dietitian, eliminating sugary drinks, reducing alcohol to zero and a walking and strength programme. Her diabetes treatment is reviewed by her physician, who switches to a medicine with evidence for liver benefit. A year later she has lost 9 percent of her body weight, her liver stiffness has improved and her HbA1c is lower. A condition once dismissed as incidental turned out to need, and respond to, active management.

From incidental finding to clinical priority

MASLD is common, often silent and, in a minority, serious. Stratifying risk rather than relying on liver enzymes, recognising its role as a marker of cardiometabolic risk and supporting substantial weight loss and lifestyle change can prevent progression and, in many cases, reverse it.