The End of “Fatty Liver”

It won’t be news to you that the disease that we used to refer to as NAFLD is now MASLD: the term Metabolic dysfunction-associated steatotic liver disease now replaces the older term: non-alcoholic fatty liver disease (NAFLD). The change in terminology is more than just words: it reflects our changing understanding of this common and multifactorial steatotic liver disease.

Defining Metabolic-Dysfunction Associated Liver Disease

Metabolic-Dysfunction Associated Steatotic Liver Disease (MASLD): These are patients who have steatotic liver disease (at least 5%) and one metabolic associated risk factors [figure 1], no other causes for liver disease, and no or low-risk alcohol consumption. While not part of diagnostic criteria, there is an association between MASLD and other conditions, including Obstructive Sleep Apnoea, Polycystic Ovarian Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.

Metabolic-Dysfunction and Alcohol Associated Liver Disease (MetALD): Patients with steatotic liver disease, one metabolic associated risk factor [figure 1], no other causes for liver disease, and moderate alcohol consumption. Moderate alcohol consumption is defined as 140-350g alcohol per week for female patients and 210-420g per week for male patients.

MASH (Metabolic-Dysfunction Associated Steatohepatitis) was previously known as NASH. Patients have histological features of hepatocellular injury and inflammation. Fibrosis may or may not be present on biopsy.

MASH cirrhosis: Patients with cirrhosis with a history or evidence of MASH or MASLD.

What should every doctor who looks after patients with metabolic risk factors know about MASLD?

Patients are usually asymptomatic, so a degree of clinical suspicion is needed. It is also common, estimated to be present in up to 30% of the global population has MASLD. MASLD is also found in patients without obesity.

Signs of liver disease are often not present on examination. While there may be a degree of hepatomegaly in some patients with MASLD, this is often not clinically appreciable and evident only on imaging.

While some patients with MASLD may have elevated ALT, AST, and Alkaline Phosphatase, others may have enzymes within normal limits. The presence of persistently elevated liver enzymes, without any other identifiable cause, particularly in patients with diabetes or obesity, should raise clinical suspicions of MASLD. Thrombocytopaenia and neutropaenia are typically associated with cirrhosis.

Laboratory results can also be used to calculate the FIB-4 score. FIB-4 scores have the advantage of being readily accessible in a variety of settings. The score can be calculated using Age in years, AST, ALT, and Platelet count. [Figure 2] However, studies have found it less reliable in patients <35 or >65 years of age, and in patients with hypertension, type 2 diabetes, and obesity.

MASLD may be seen incidentally on abdominal imaging done for other reasons. When imaging specifically for evaluation of MASLD is needed, there is now increasing availability of Vibration-Controlled Transient Elastography. Also known as Fibroscan, it is painless and non-invasive. As the shear wave is passed through the liver, the speed at which it returns is converted into a liver stiffness score, which correlates to liver scarring and fibrosis.

Treatment

For many patients with MASLD, the cornerstone of treatment is lifestyle interventions.

Alcohol Abstinence: There is no safe amount of alcohol that can be recommended to patients with chronic steatotic liver disease.

Tobacco: Patients with MASLD who smoke should be encouraged and supported to quit smoking as smoking is associated with increased risk of fibrosis.

Nutrition: Gradually making changes to adopt a Mediterranean diet (or a Mediterranean-informed diet) has been associated with improved outcomes. Patients should be encouraged to reduce consumption of ultra-processed foods. Patients may benefit from referral to registered dietitian to help improve diet. Moderate coffee should be encouraged in patients who tolerate or enjoy coffee: In some studies, patients who consumed 3 cups of coffee per day had improvement in MASLD. To minimise sleep disturbance, this should be consumed in the earlier part of the day, at least 8 hours before bedtime.

There is no evidence for the use of supplements or nutraceuticals in MASLD.

Exercise: is an essential part of treatment for patients MASLD. Muscle mass has a reciprocal relationship with MASLD. Patients should be prescribed individualised exercise programmes, ideally including a mixture of strength and cardio, for a minimum of 150 minutes per week. It is important to counsel patient that studies have found that the reduction of intrahepatic lipids in response to exercise is independent of any weight loss. Due to lived experience, many patients may get discouraged with therapeutic exercise programmes if they can’t see results on the scale.

Weight loss of between 5 -10% should be targeted for patients with MASLD who are above a healthy weight when BMI is adjusted for ethnicity.

We know from studies that patients struggle to implement prescribed lifestyle interventions, and to sustain lifestyle changes. More awareness of these challenges as well as expert, long-term multi-disciplinary support to make long-term therapeutic lifestyle changes is needed.

Patients may also need assessment to exclude any other associated metabolic conditions, including obstructive sleep apnoea and chronic kidney disease. Optimising control of co-morbidities such as hypertension, dyslipidaemia, and diabetes, if present, is important. In patients with suspected significant liver disease, where the diagnosis is uncertain, or those with advanced fibrosis, referral to expert hepatology services may be indicated for further assessment.

Prognosis for patients with MASLD is variable. While around half of patients with MASLD will have stable disease, up to 1/3 of patients will have progressive fibrosis. Complications from progressive MASLD include cirrhosis, hepatocellular cancer, and increased all-cause mortality; mortality risk increases with MASLD severity.

Looking to the Future: Pharmaceutical interventions

Resmetirom is an oral thyroid hormone receptor-β (THR-β) agonist. In March 2024, it was approved for use by the FDA in the US under accelerated approval for the treatment of adults with MASH with moderate to advanced liver fibrosis, no cirrhosis. In studies, this new drug reduced hepatic fat content, improved liver enzymes and non-invasive markers of liver fibrogenesis, and improved liver stiffness scores. Studies also found a reduction in serum lipids, including LDL cholesterol. Resmetirom is under regulatory review in the EU.

Semaglutide – Emerging evidence suggests that treatment with the now-familiar GLP-1a medication may be associated with improvement in intrahepatic lipid deposits and fibrosis in patient with MASLD. The ESSENCE trial (Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis) is an ongoing 5-year, phase 3, randomised, multicentre trial in 2 parts evaluating the effect of semaglutide in patients with MASH and stage 2 or stage 3 fibrosis on biopsy.

Why Awareness of MASLD is important for your Patients

I’m not a hepatologist. Patients are referred for ongoing support managing chronic health conditions. Despite the prevalence of MASLD among my patients: they never present with complaints about their livers. If you are also not-a-hepatologist, that’s probably true for your practice as well. That is because MASLD is, in most cases, a silent disease. And this has special significance for patients with obesity: MASLD is present in between 65-85% of patients with obesity (the incidence increasing with increasing stage/class of obesity). This becomes especially relevant in the context of the updated obesity definitions put forward in the Lancet in January 2025. The new evidence-based definitions:

CLINICAL OBESITY: A CHRONIC, SYSTEMIC DISEASE STATE DIRECTLY CAUSED BY EXCESS ADIPOSITY

PRECLINICAL OBESITY: A CONDITION OF EXCESS ADIPOSITY WITHOUT CURRENT ORGAN DYSFUNCTION OR LIMITATIONS IN DAILY ACTIVITIES BUT WITH INCREASED FUTURE HEALTH RISK.

The paper states that the purpose of this new diagnostic framework is to reduce healthcare costs, and should be used to prioritise access to care.

Did you know? In studies of patients living with Type 2 diabetes mellitus and unknown MASLD status, 14% were found to have fibrosis and 3 – 6% were found to have cirrhosis.

I have seen at least 3 young patients with MASH cirrhosis in the previous year. I mean that not just in our professional use of the word “young” (the “young” patient being any patient younger than the doctor) but in that generally lower risk age groups of 3rd and 4th decade. The important thing to note was that the patients had no complaints or symptoms.

Access to care for patients with obesity, with or without complications, is already problematic, not just in Ireland but globally. The concern here is that MASLD is among those complications of obesity that can be clinically subtle – subfertility, pre-diabetes/T2DM, dyslipidaemia, hypertension, and OSA. Without a clinician’s reasonable clinical suspicion, the complications can remain unrecognised in early stages, and the patient classified as “pre-clinical.”

An Even Better Future: Prevention

The risk factors for MASLD include diets high in processed foods and a sedentary lifestyle. In Ireland, ~91% of deaths are due to non-communicable disease. While this article has focused on adult patients, it is estimated that MASLD is present in 5 – 10% of the paediatric population, making it the most common liver disease in children; it is almost always detected incidentally. MASLD and MASH are multifactorial diseases: the aetiology an interplay of genetic, environmental, and lifestyle factors. Addressing the modifiable risk factors is essential. Effective preventative health strategies at to reduce tobacco and alcohol use, reduce consumption of ultra-processed foods, improve nutrition, and increase physical activity should be prioritised, both for best patient outcomes and least healthcare costs.

Written by Dr Kate McCann, Lifestyle Medicine, Beacon Consultants Clinic

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