Metabolic dysfunction-associated steatotic liver disease (MASLD): Primary Care (Guidelines)

MET-ALD is the new name for patients with MASLD whose alcohol intake is above recommended levels, but below the thresholds associated with pure Alcohol related Liver Disease (ALD).

MASLD typically occurs in those who are overweight or obese with one or more feature of metabolic dysfunction. Known and unknown genetic mutations confer risk, and contribute to lean MASLD, which can occur in people with normal or mildly raised BMI.

Features of metabolic dysfunction include:

• Prediabetes OR Type 2 DM
• BP >130/85mmHg, OR antihypertensive therapy
• Plasma triglycerides ≥1.70mmol/L (or relevant local upper limit of normal), OR lipid lowering therapy
• HDL cholesterol ≤1.0mmol/L (male) or 1.3mmol/L (female) (or relevant local upper limit of normal)

As more of Scotland’s population are either overweight (2 in 3) or obese (almost 1 in 3), more individuals are at risk of MASLD. In the absence of significant weight loss, hepatic steatosis (excess fat in the liver) is the norm in those with centripetal obesity, and common in those who are overweight. However, the rate of development of significant fibrosis (scarring) of the liver due to MASLD is slow, and the minority develop cirrhosis (the most severe scarring of the liver).

Whilst development of cirrhosis is associated with an increased risk of liver related morbidity and mortality, death from other causes still predominate. In particular, people with MASLD are at high risk of premature death from cardiovascular disease and non-hepatic malignancies. Whilst it is important to identify and refer those at risk of more severe hepatic complications, this should take place in the context of holistic care, which manages cardiovascular risk (including smoking cessation) and encourages participation in age and gender appropriate cancer screening.

In addition, many patients with MASLD have significant co-morbidities and the decision to investigate, refer to secondary care, or monitor FIB-4 should incorporate a Realistic-Medicine approach that always considers the likelihood of benefit to the patient.

This national pathway is a pragmatic guideline that gives advice on primary care identification and management of MASLD, together with guidance for secondary care pathways and the interface between the two.

Intelligent LFTs (iLFTs) are available in some health boards and incorporate a liver screen, BMI and alcohol history to identify patient’s likely underlying liver diagnosis, and the need for secondary care referral. Where available, these guidelines should not replace iLFTs as the initial investigation of choice.

Recommend repeat FIB-4 in 3 years.

FIB-4 threshold for re-referral

MASLD typically occurs in patients who are overweight / obese and who typically have at least one feature of cardiometabolic dysfunction.

Make a diagnosis in those who fit this phenotype and:

• Have typical LFT abnormalities
• Have a negative non-invasive liver screen for other causes
• An absence of alcohol excess, drinking ≤ 14 units/week (see also Met-ALD)

Features of cardiometabolic dysfunction:

• Prediabetes or Type 2 DM
• BP >130/85 mmHg or antihypertensive treatment
• Plasma triglycerides ≥ 1.70 mmol/L or lipid lowering therapy
• HDL cholesterol ≤ 1.0/1.3 mmol/L (m/f) or lipid lowering therapy

• ALT levels within the upper end of the normal range (>30 u/L) may be associated with liver injury. The reference ranges having been defined from healthy populations prior to recognition of the impact of obesity/steatosis on the liver.
• Alkaline phosphatase may also be mildly elevated in MASLD.
• If GGT also elevated (suggesting biliary origin), then request an ultrasound (US) to exclude biliary disease/infiltrative process.
• DO NOT routinely request US for patients with isolated raised ALT/AST and low risk FIB-4 score.

Amongst patients with isolated raised transaminases in NHS Tayside, ultrasound identified no cancers, and all patients with US evidence of cirrhosis had elevated FIB-4 scores.

A negative non-invasive liver screen:

Assuming MASLD as the cause for MASLD, due to the presence of obesity / metabolic syndrome risks missing other treatable causes of liver disease, and a liver screen is necessary for all patients.

In MASLD the liver screen is typically negative for specific conditions, however the following non-specific findings may be present:

• Raised IgA (also raised in ALD)
• Mildly elevated ferritin, with normal fasting transferrin saturation
  
  • Check HFE gene to screen for haemochromatosis if fasting transferrin saturation elevated
• Low titre anti-nuclear / anti-smooth muscle antibodies (ANA/SMA).
  • If normal IgG, then less likely to be of significance

A standard non-invasive liver screen may vary between health boards, but at a minimum, should rule out viral hepatitis, haemochromatosis and screen for autoimmune liver disease.

See sample liver screen, below. 

An absence of alcohol excess:

• Discuss average number of days per week on which alcohol consumed, along with what is drunk.
• Calculate average weekly alcohol intake in units (calculator).
• Avoid vague descriptive terms such as 'social', 'light', 'moderate', 'heavy'.

See: Abnormal liver blood results referral pathway (Over 16’s)

• Repeat LFTs and FBC
  
  • Include AST to calculate FIB-4, if not part of routine LFTs
  • Include GGT, if ALP elevated and not part of routine LFTs
• Blood Borne Virus Screen:
  
  • Hepatitis B Surface Antigen (HBsAg), Hepatitis C antibody (Anti-HCV).
  • If from a high prevalence country or relevant risk factors, also offer HIV testing.
• Ferritin / Transferrin Saturation
• Liver Autoantibodies and Anti-Nuclear Antibody (ANA)
• Immunoglobulins
• Alpha-1-Antitrypsin
• Caeruloplasmin (<50 only)

If GGT not included in standard LFTs: then check if ALP raised (if GGT normal consider bone causes)
If AST not included in standard LFTs: then check to allow FIB-4 calculation.

Ferritin/Transferrin saturation

Ferritin is often mildly elevated in MASLD / MetALD, as well as other liver conditions causing hepatic inflammation and causes systemic inflammation.

A normal ferritin excludes haemochromatosis as the cause of abnormal LFTs, however a raised level may be for numerous reasons. Transferrin saturation is a better screening test for haemochromatosis, however may be falsely elevated if non-fasting samples are obtained.

A raised transferrin saturation, particularly if fasting, should trigger HFE gene testing for genetic haemochromatosis.

Liver autoantibodies

Autoimmune liver disease is associated with a variety of antibodies, including antinuclear antibody (ANA) as well as more liver specific autoantibodies such as anti-mitochondrial (AMA), anti-smooth muscle (SMA), anti-liver-kidney-microsomal (LKM) and anti-liver cytosol antibodies.

Low titre antibodies are relatively common in MASLD. Normal levels of immunoglobulins can help to judge the likelihood of significance and should be tested if positive antibodies are encountered and not already performed.

Diagnose MET-ALD in patents meeting the MASLD criteria who drink:

• > 14 units/week of alcohol BUT
• < 44 (female) / < 53 (male) units of alcohol per week.

Assess fibrosis using the FIB-4 score, using formula below or an online calculator:

• FIB-4 is not reliable in patients <35 years old, consider serum fibrosis test (ELF test) where available
• Refer if ≥9.8
• Consider referral (after liver screen) in under 35 year olds if LFT abnormality persists (3 months).

• A score of less than 1.30 (2.0 if ≥ 65 years) makes significant fibrosis unlikely and correlates with a low risk of liver related and all-cause mortality in the medium term
• Conversely, elevated levels and progression from low to high risk, correlate with increased risk of liver related and all-cause mortality.

If available, serum ELF can further risk stratify those with elevated FIB-4 scores, reducing the number needing referral by over 30%.

If FIB-4 score is low risk, then manage in primary care. Where clinically appropriate, reassess FIB-4 score after 3 years. Changes in FIB-4 score correlate with increased and decreased risk of liver related events.

The FIB-4 score (like all non-screening tests) is not 100% specific. Applying it to people not at risk of liver disease will result in an unacceptably high false positive rate.

• Use only in those with type 2 diabetes, or obesity/overweight plus metabolic dysfunction and raised AST/ALT, using 30 as the upper limit of normal.

Where available, the ELF (Enhanced Liver Fibrosis) Test should be used in those with a positive FIB-4 score, to more accurately predict those likely to have advanced fibrosis. Those with a value of <9.8 may be managed in primary care with interval FIB-4 testing at 3 years and follow up ELF testing if this remains above the age appropriate threshold.

Increased echogenicity, suggestive of steatosis (increased fat), is a common finding on ultrasound, more so with increasing BMI. Ultrasound however lacks specificity, particularly for mild steatosis, and should not be used in isolation to rule out MASLD.

If features of steatosis are encountered on a scan requested for other reasons, consider screening for other metabolic syndrome features, including a LFT check (if not already performed), calculating FIB-4 if meets criteria for MASLD.

Splenomegaly is common in patients with MASLD and, in contrast with other chronic liver disease, does not correlate with advanced fibrosis/cirrhosis. The presence of splenomegaly should not alter the threshold for referral.

Other investigations

If not undertaken, patients should be screened for metabolic dysfunction associated conditions:

• Screen for and treat hypertension.
• Screen for Diabetes
• Check fasting blood glucose/lipids.
• Calculate the ASSIGN score and start preferred statin at standard dose if > 20.

Where ELF not available:

• Patients under the age of 35
• Patients between 35 and 65 years old with a FIB-4 > 1.30
• Patients above 65 years with a FIB-4 > 2.0

Where ELF available:

• Patients under the age of 35 with ELF ≥ 9.8
• Patients between 35 and 65 years old with a FIB-4 > 1.30 and ELF ≥ 9.8
• Patients above 65 years with a FIB-4 >2.0 and ELF ≥ 9.8

Consider the appropriateness of referral in the context of other life limiting co-morbidities/frailty.

In those not referred, offer appropriate lifestyle advice, as per below, and where appropriate consider a repeat FIB-4 after 3 years.

Recommend repeat FIB-4 in 3 years.

FIB-4 threshold for re-referral

No specific drug therapy is currently licensed for MASLD, however given their effect on weight loss, patients with diabetes should be considered for GLP-1 receptor agonists according to local prescribing guidelines.

In due course prescribing guidance may allow for GLP-1 receptor agonists to be used in patients with obesity and co-morbidities, including MASLD.

Frame lifestyle changes as long-term changes to maintain/preserve health and well-being rather than quick fixes.

Weight loss

10% body weight loss leads to resolution of steatosis in MASLD, prevents worsening of fibrosis and leads to improvement of fibrosis in the majority of patients.

• Weigh patients and set them a target weight of 90% of their current weight
• Discuss that patients who weight themselves regularly are more likely to achieve and maintain weight loss and avoid weight gain.
• Recommend calorie deficit of 600 kcal/day, e.g. 1,900 kcal for men and 1,400 kcal for women
  
  • Discuss the calorie content of alcohol, and that reducing or removing (as appropriate) alcohol reduces calorie intake and risk of fibrosis progression. See Drink Aware: Unit and calorie calculator (see below)
  • Slimming clubs offer a means of combining calorie restriction alongside regular weigh-ins and are may be more effective than self-guided efforts.
  • Refer to locally available weight loss initiatives, as appropriate.
  • There is no evidence that one diet is superior to another for resolution of MASLD, however a Mediterranean diet is associated with a reduction in cardiovascular disease and, in the context of MASLD, may be recommended.

See Healthy weight (Guidelines)

Alcohol

Intake should be accurately assessed as outlined above.

• Discuss that alcohol and obesity are synergistic in causing liver damage
• Low to moderate alcohol use is associated with an increased risk of significant fibrosis amongst patients with MASLD. In those with cirrhosis, alcohol intake within recommended limits (<14units/week) is associated with an increased risk of liver morbidity / mortality compared with abstinence, including an increased risk of hepatocellular carcinoma.
• For patients with MASLD
  
  • Elevated FIB-4 score: Recommend abstinence 
  • For low risk FIB-4: Recommend abstinence / minimisation to reduce calorie intake, aid weight loss and reduce the risk of progression.
• For patients with MetALD
  
  • Elevated FIB-4 score: Recommend abstinence 
  • For low-risk FIB-4: Recommend at a minimum a reduction < 14units/week and discuss the benefits of abstinence / minimisation to reduce calorie intake, aid weight loss and reduce the risk of progression

Exercise

Encourage patients to increase exercise as able.

• Exercise reduces the risk of cardiovascular disease, improves mental health and can help towards weight loss.
• Any increase in activity is beneficial. Discuss what current activity patients take part in and how they may increase this.
• Discuss WHO recommendations.
  
  • A minimum of 150 minutes (ideally 300) of moderate-intensity activity per week or 75 minutes of vigorous activity per week
  • Muscle-strengthening exercises should be done involving all major muscle groups on 2 or more days per week
  • Those with poor mobility should perform physical activity to enhance balance and prevent falls, 3 or more days per week.
  • Discuss that whilst exercise / activity improves health and may help with weight loss, most people cannot achieve exercise levels necessary to achieve 10% body weight loss.

See: V2 Metabolic dysfunction associated steatotic (MASLD): Secondary Care (Guidelines)

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