Section 1: Meet Clare

Clare is a 53-year-old lady with a 4-year history of type 2 diabetes. She attends her practice diabetes clinic with the following results:

• BMI 31.2 kg/m².
• Blood pressure 144/78 mmHg.
• HbA_1c 52 mmol/mol (6.9%).
• eGFR 73 mL/min/1.73 m².
• Total cholesterol 5.6 mmol/L; non-HDL cholesterol 4.6 mmol/L.
• Alanine aminotransferase (ALT) 83 IU/L (normal range 0–45 IU/L).
• Alkaline phosphatase (ALP) 103 IU/L (normal range 40–130 IU/L).
• Gamma-glutamyl transpeptidase (GGT) 81 IU/L (normal range 0–75 IU/L).
• Bilirubin 16 IU/L (normal range 0–21 IU/L).
• Albumin 42 g/L (normal range 35–50 g/L).

Medication: metformin 1 g twice daily; ramipril 5 mg once daily.

Non-smoker; alcohol 4–8 units/week.

Background diabetic retinopathy; no other diabetes complications.

What is the most likely cause of Clare’s elevated liver function tests?

Section 2

Given Clare’s type 2 diabetes, obesity, lack of hepatotoxic medication and low alcohol consumption, metabolic dysfunction-associated steatotic liver disease (MASLD) would seem the most likely diagnosis explaining the disturbed liver function tests (LFTs). Up to 70% of people with type 2 diabetes have co-existing MASLD (Younossi and Henry, 2024).

There is currently a transition in nomenclature from non-alcoholic fatty liver disease (NAFLD) to MASLD (Eslam et al, 2020; Rinella and Sookoian, 2024). This case study uses the new terminology; however, NAFLD is the term used in the majority of previous research and literature.

Section 3: What is MASLD?

The drive to reclassify NAFLD as MASLD comes from the desire to define fatty liver disease by positive criteria rather than depending on the exclusion of other liver disease, and in particular consumption of excess alcohol (Eslam et al, 2020; Rinella and Sookoian, 2024).

MASLD defines a population with fat accumulation in the liver identified by blood tests, imaging or histology (biopsy) with at least one of the five following cardiometabolic risk factors (Rinella et al, 2023):

• Overweight/obesity: BMI ≥25 kg/m² (≥23 kg/m² in high-risk ethnicities) or waist circumference >94 cm (males) or >80 cm (females).
• Impaired glucose tolerance (insulin resistance) – any of the following:
  • Fasting blood glucose ≥5.6 mmol/L.
  • 2-hour post-load glucose ≥7.8 mmol/L.
  • HbA_1c ≥39 mmol/mol (5.7%).
  • Type 2 diabetes or on treatment for type 2 diabetes.
• Hypertension: blood pressure ≥130/85 mmHg, or on antihypertensive medication.
• Triglycerides ≥1.7 mmol/L.
• HDL cholesterol ≤1.0 mmol/L (males) or ≤1.3 mmol/L (women), or on lipid-lowering medication.

Possible causes of fatty liver disease

• MASLD
• MASLD + increased alcohol intake.
• Alcohol-associated liver disease.
• Genetic liver disease (e.g. haemochromatosis).
• Drug-induced liver disease.
• Infectious liver disease (e.g. hepatitis C).

Aside from her blood test results, what other information might you seek to help rule out other possible causes of Clare’s elevated LFTs?

Section 4

Further useful information would include:

• History of right upper quadrant pain suggestive of gallstone disease.
• History of jaundice or unexplained fever suggestive of biliary disease.
• Risk factors for hepatic viral infection (ask sensitively!) – country of origin with high prevalence of hepatitis, intravenous drug use, sexual transmission, blood transfusions.
• Past history of malignancy – possible metastatic spread to liver.

Clare has no history of gallstone disease and no symptoms of pain, fever or jaundice. She does not have risk factors for viral hepatitis and has no previous history of cancer. These negative findings increase the likelihood that the cause of her abnormal LFTs is MASLD.

To repeat, Clare’s LFTs are as follows:

• Alanine aminotransferase (ALT) 83 IU/L (normal range 0–45 IU/L).
• Alkaline phosphatase (ALP) 103 IU/L (normal range 40–130 IU/L).
• Gamma-glutamyl transpeptidase (GGT) 81 IU/L (normal range 0–75 IU/L).
• Bilirubin 16 IU/L (normal range 0–21 IU/L).
• Albumin 42 g/L (normal range 35–50 g/L).

Is the pattern of Clare’s disturbed LFTs characteristic of MASLD?

Section 5

Yes. Elevated aminotransferase levels – ALT and AST (aspartate aminotransferase) – are commonly the LFTs affected in MASLD, with smaller rises in other liver enzymes, notably GGT.

Elevated LFTs are often the first indication of MASLD, which is frequently asymptomatic. In people with type 2 diabetes, MASLD is the most common cause of abnormal LFTs (NICE, 2023).

• Early in MASLD: rise in ALT > AST.
• As MASLD progresses: AST:ALT ratio rises.
• AST:ALT ratio >1 likely to indicate more severe liver disease.
• Marked elevation of GGT, although not specific, is seen in alcoholic liver disease.
• Elevation of ALP and bilirubin is suggestive of intrahepatic cholestasis.

How reliable do you think LFTs are in identifying MASLD?

Section 6

Not very. Around half of people with MASLD will have normal LFTs; thus, it is a screening tool with low sensitivity (a high level of false negatives) (Byrne et al, 2018). It is also the case that, while LFTs are more likely to be raised in advanced liver disease, the degree of elevation of transaminases does not accurately indicate the degree of liver damage or fibrotic change (Newsome et al, 2018).

Waist circumference is suggested as a better indicator of cardiometabolic risk and MASLD than BMI. Why is this?

Section 7

It is intra-abdominal fat (visceral fat) that is associated with MASLD, insulin resistance and risk of type 2 diabetes. This central adiposity is more accurately assessed by measuring waist circumference and calculating waist:height ratio rather than relying on BMI (NICE, 2025).

Clare’s waist circumference of 94 cm (>80 cm in women is raised) and height of 165 cm generates a waist:height ratio of 0.57, consistent with increased central adiposity.

What other non-invasive investigation could help confirm Clare’s diagnosis of MASLD?

Section 8

An ultrasound scan of the liver would be a good, non-invasive imaging technique for Clare to identify steatosis (excess fat) in the liver. It would also usefully help exclude other significant liver pathology, such as gallstones, hepatic tumours and metastatic disease (NICE, 2016).

A normal ultrasound scan does not, however, exclude the diagnosis of MASLD and nor does it accurately identify fibrosis or predict the likelihood of disease progression. Compared to liver biopsy, the gold-standard investigation, ultrasound has a sensitivity of 85% and a specificity of 91% for detecting moderate steatosis (Byrne et al, 2018).

With the finding of fat on liver ultrasound, additional blood tests, including aspartate aminotransferase (AST) and platelet count, can be requested to enable calculation of fibrosis risk via the Fib-4 calculator (see Section 15).

Clare’s ultrasound scan shows increased hepatic echogenicity consistent with a diagnosis of MASLD.

What important clinical concerns does a diagnosis of MASLD raise for Clare?

Section 9

Simple steatosis in MASLD can progress to the inflammatory condition of steatohepatitis (metabolic dysfunction-associated steatohepatitis – MASH, formerly known as NASH), and subsequently fibrosis can develop in some people, leading to cirrhosis of the liver. Complications of cirrhosis include variceal bleeding (e.g. haematemesis from oesophageal varices), hepatic encephalopathy, hepatic failure and hepatocellular carcinoma. MASLD is also linked to an increase in extrahepatic malignancies, notably those of gastrointestinal origin, including oesophageal, stomach, pancreatic and colorectal cancers (Powell et al, 2021).

There is a strong association between MASLD and increased risk of cardiovascular disease (CVD), including myocardial infarction, ischaemic stroke, atrial fibrillation and heart failure (Targher et al, 2020). CVD is the leading cause of death in people with MASLD and commonly precedes advanced forms of liver disease (Younossi and Henry, 2024).

Thus, we need to ascertain where Clare lies on the spectrum of MASLD and also to assess her cardiovascular risk profile.

Clare has co-occurring MASLD and type 2 diabetes. Why is this of particular clinical concern?

Section 10

Progression from steatosis to MASH, and beyond this to cirrhosis and hepatocellular carcinoma, are all more likely to occur, and at an accelerated rate, in people with type 2 diabetes compared to those without diabetes (Powell et al, 2021; Younossi and Henry, 2024).

The co-morbidity of MASLD and type 2 diabetes also increases cardiovascular risk to a level greater than in either condition alone (Younossi and Henry, 2024). Furthermore, the presence of MASLD worsens microvascular outcomes (nephropathy and retinopathy) in type 2 diabetes. MASLD is also considered to be an independent risk factor for chronic kidney disease (Byrne and Targher, 2020).

How would you explain the diagnosis of MASLD to Clare?

Section 11

You should explain to Clare that the liver blood tests and ultrasound scan indicate that she has MASLD – an accumulation of excess fat in the liver, usually considered significant when fat accounts for more than 5% of liver weight.

Even though she has no symptoms, it is important Clare understands that managing MASLD is important because it can progress to more advanced forms of liver disease, such as cirrhosis, and it has consequences for conditions outside the liver, in particular cardiovascular disease (Cusi et al, 2024).

What would be your position in screening people with MASLD for type 2 diabetes and vice versa?

Section 12

There is clear advice that if MASLD is identified in a person who has not been diagnosed with type 2 diabetes then they should be tested for diabetes (Byrne et al, 2018). Conversely, however, routine screening for MASLD in people with type 2 diabetes is not currently recommended despite its high prevalence, although this has been proposed by some authorities (EASL, EASD and EASO, 2024).

What readily available blood tests, other than transaminases, might indicate advanced liver disease?

Section 13

Failing liver synthetic function is reflected in low albumin levels and rising liver international normalised ratio (INR) – due to reduced levels of anticoagulants. A falling platelet count is also consistent with liver damage (Newsome et al, 2018).

Clare’s normal albumin level and platelet count are reassuring that she does not have advanced liver disease.

Why is an assessment of Clare’s degree of liver fibrosis important?

Section 14

The severity of fibrosis in MASLD is strongly predictive of morbidity and mortality (Vilar-Gomez et al, 2018). An assessment of fibrosis will help determine the level of intervention necessary and the need for referral to hepatology.

How could you make an assessment of Clare’s risk of liver fibrosis from primary care?

Section 15

An assessment of liver fibrosis can be made in primary care using validated fibrosis score calculators (Srivastava et al, 2019). In the case of MASLD, these tools are applicable if ALT is raised; ultrasound findings would be supportive and there should be an absence of excess alcohol consumption and any other chronic liver condition. Two commonly used tools are:

• Fib-4 score: needs age, ALT, AST and platelet count. Available at: https://liver.org.au/health-professionals/fib-4-calculator/
• NAFLD fibrosis score: additionally incorporates albumin, diabetes status and BMI. Available at: https://www.mdcalc.com/calc/3081/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score

The fibrosis score allows risk stratification and helps to decide future management (Newsome et al, 2018):

• A low fibrosis score (e.g. Fib-4 <1.3, or < 2.0 in those aged over 65) indicates a low risk of advanced fibrosis, allowing management of MASLD in primary care with lifestyle advice and management of cardiovascular risk.
• Higher Fib-4 scores suggesting advanced fibrosis would require further investigation (see Section 16) and/or referral to hepatology.

It is worth noting that the cause of steatotic liver disease may be multifactorial. Thus, for example,  MASLD and excess alcohol consumption may contribute to liver pathology simultaneously. The Fib-4 calculator can still be applied in these circumstances to assess fibrosis risk.

Clare’s Fib-4 score indicates a low risk of advanced fibrosis, with a recommendation to repeat the test in 3 years.

Do you know of any further investigations that assess the degree of liver fibrosis?

Section 16

Quantification of fibrosis can estimated using:

• An ELF (enhanced liver fibrosis) test, which measures three serum biomarkers. This potentially could be undertaken in primary care depending on local arrangements (NICE, 2016).
• Fibroscan (transient elastography) – a measure of liver stiffness.
• Liver biopsy – used sparingly because it is a risky, invasive procedure.

What are the key aims in in managing Clare’s MASLD?

Section 17

Firstly, the aim is to attenuate progression of hepatic steatosis to steatohepatitis and onward to cirrhosis. Secondly, it is to reduce Clare’s risk of CVD. The co-morbidity of type 2 diabetes amplifies the progression of MASLD and confers a high risk of cardiovascular events and heart failure (Cusi et al, 2024).

What lifestyle advice would you offer Clare in managing her MASLD?

Section 18: Lifestyle advice for MASLD management

Lifestyle advice overlaps substantially with that of managing type 2 diabetes. Weight loss is central to managing Clare’s MASLD, with the degree of weight loss correlating with improvement in LFTs. Reduced steatosis is apparent with 5% or more weight loss, MASH improvement with 5–10% weight loss and fibrosis regression with >10% weight loss (Vilar-Gomez et al, 2015). Weight loss also leads to improved glycaemic control and reduction of cardiovascular risk. Setting a target weight loss may be helpful, but if this is not achieved it should not be viewed as failure but, rather, an opportunity to learn and move on.

Dietary advice offered to Clare should be individualised, with the aim of losing weight and being consistent with controlling glycaemia (i.e. avoidance of simple sugars and restriction of unrefined carbohydrates) (NICE, 2025). The Mediterranean diet has been demonstrated to lower liver fat (even in the absence of weight loss) as well as reducing CVD and benefitting glycaemic control (Ryan et al, 2013).

Encourage Clare to exercise regularly; this can reduce liver fat, improve glycaemic control and benefit cardiovascular health (Romero-Gómez et al, 2017). NICE NG246 recommends daily moderate-intensity exercise of around an hour a day (NICE, 2025).

Pragmatically, Clare should choose a diet that is acceptable to her and an exercise pattern that is achievable and sustainable.

Referral to local lifestyle programmes could be discussed with Clare. The Pathway to Remission programme offered by NHS England, which targets weight loss through dietary calorie restriction supported by exercise and counselling, would be available for Clare given her type 2 diabetes and BMI (Bakhai, 2023).

Clare should avoid excess alcohol (national recommendations suggest not more than 14 units of alcohol per week spread over at least 3 days, with complete avoidance of alcohol in pregnancy), as this aggravates steatosis and accelerates liver disease progression (Hart et al, 2010). In advanced liver disease such as cirrhosis, alcohol should be avoided altogether. If possible, other drugs (including over-the-counter products) with the potential to be hepatotoxic should be avoided.

How would you help Clare reduce her cardiovascular risk?

Section 19

A healthy diet, exercise, weight loss and control of hypertension are central issues in managing Clare’s cardiovascular risk. Smoking cessation is crucial in appropriate cases.

Use the QRISK calculator to calculate Clare’s level of cardiovascular risk and offer statin therapy as necessary. A diagnosis of MASLD does not preclude use of statins, and there is evidence that statins can improve aminotransferase levels (Eslami et al, 2013).

If aminotransferase levels are more than three-times the upper limit of normal, seek specialist advice before initiating a statin. After commencing statin therapy, recheck LFTs within 3 months (Wainwright et al, 2015). NICE NG49 advises only to consider statin discontinuation if liver enzymes have doubled from baseline (NICE, 2016).

Over the longer term, management of hyperglycaemia is also important in reducing cardiovascular risk.

Clare’s 10-year QRISK3 score is 15%. After discussion, atorvastatin 20 mg once daily is commenced.

Can any medications for hyperglycaemia benefit MASLD?

Section 20: Medications with effects on MASLD

Whilst no medications are licensed for the treatment of MASLD, there is evidence that some diabetes medications can benefit MASLD (Genua and Cusi, 2024).

Pioglitazone has been demonstrated to have beneficial effects on steatosis, steatohepatitis and fibrosis of the liver, despite its propensity to cause weight gain (Cusi et al, 2016; Musso et al, 2017). NICE NG49 recommends consideration of pioglitazone for adults with advanced liver fibrosis in a specialist setting, whether or not diabetes is present (NICE, 2016).

Randomised controlled trials with the GLP-1 receptor agonists, notably liraglutide and semaglutide, which induce substantial weight loss, have shown improvements in steatosis and hepatosteatosis and reductions in progression of liver fibrosis versus placebo, again whether or not diabetes is present (Newsome et al 2021; Patel Chavez et al, 2022). The dual GIP/GLP-1 receptor agonist tirzepatide has also been shown to improve hepatic steatosis (Gastaldelli et al, 2022).

The SGLT2 inhibitors facilitate weight loss and reduction of fat mass. Research is ongoing but there is evidence that they can improve liver enzymes, reduce hepatic steatosis and, possibly, benefit fibrosis (Genua and Cusi, 2024). A recent trial demonstrated that dapagliflozin was a safe and effective treatment for MASH and fibrosis in people with MASLD, whether or not they had type 2 diabetes (Lin et al, 2025).

Importantly for people with MASLD and type 2 diabetes, pioglitazone, GLP-1 receptor agonists and SGLT2 inhibitors all reduce cardiovascular risk.

Metformin may improve survival in fibrosis and hepatocellular carcinoma (Hazlehurst et al, 2016). Sulfonylureas, DPP-4 inhibitors and insulin, however, do not appear to offer any specific benefits in people with type 2 diabetes and MASLD (Cusi et al, 2024).

What other means of weight loss might benefit Clare’s MASLD?

Section 21

Bariatric surgery for people with type 2 diabetes and obesity can result in large weight reductions, with remission of type 2 diabetes and resolution of MASLD (Bower et al, 2015; Lee et al, 2019).

Can you summarise the circumstances that would lead you to refer Clare to a hepatologist?

Section 22

Triggers for referral to a hepatologist are suggested below (NICE, 2016).

• Marked elevation of LFTs.
• Sudden deterioration in LFTs.
• Clinical signs of advanced liver disease.
• High score from fibrosis calculator.
• High ELF score.
• Uncertain diagnosis of liver disease.

Individuals with MASLD who have advanced fibrosis will require assessment for and management of portal hypertension complications (gastrointestinal variceal bleeding, hepatic encephalopathy, splenomegaly, ascites, hepato-renal syndrome) and surveillance for hepatocellular carcinoma.