Metabolic liver disease – what you need to know and do
Metabolic risks including central obesity, raised blood pressure and hyperglycaemia are now recognised as major contributing factors in the development of liver disease, which is itself a risk factor for cardiovascular disease
Liver disease is becoming increasingly common in the UK, with government statistics indicating that it is now the third leading cause of death. Around 10,000 liver disease-related deaths occur each year, with approximately two thirds of those being in men, and many of them occurring prematurely.1 However, liver damage is often asymptomatic and liver function blood tests may be normal, even when damage is present. As a result, the diagnosis of liver disease may not be made until the damage is established and even irreversible. There are many different types and causes of liver disease but in this article, the focus will be on metabolic dysfunction associated liver disease (MASLD) and metabolic associated steatotic hepatitis (MASH). Metabolic liver disease and increased alcohol intake (MetALD) is also briefly covered here.
THE PATHOPHYSIOLOGY OF MASLD, MASH and MetALD
The liver has a range of different functions within the body, including the synthesis of protein, cholesterol, bile and clotting factor, metabolism of drugs and other substances, supporting immunity, detoxification, and storage of vitamins, iron and copper.2 Almost 90% of liver disease, is caused by preventable risk factors including alcohol, obesity and hepatitis B and C. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the new terminology for a condition where there is evidence of hepatic steatosis (fatty liver) plus at least one other metabolic risk factor.3 MASLD was previously referred to as non-alcoholic fatty liver disease (NAFLD). MASLD is considered to be present if at least 5% of liver cells (hepatocytes) are infiltrated with triglyceride-laden fat. MASLD is specifically associated with metabolic risk factors, rather than being related to alcohol intake or other causes, such as infection. It is thought that as many as a quarter of the global population has MASLD, with the condition being even more prevalent (around 55%) in people with type 2 diabetes (T2D).4 Men are at higher risk than women and age plays a role too, with the condition being most common in the 40–65 years age group. Ethnicity can also affect risk, with people from Hispanic and Asian backgrounds being at highest risk while black people are generally at lowest risk.4
Metabolic risk factors include central obesity and over 90% of people with a BMI greater than 30 kg/m2 or an increased waist circumference have been found to have MASLD. Other metabolic risk factors include a systolic blood pressure of 130 mmHg or higher, a diastolic BP of 85 mmHg and above, an HbA1c of 42mmol/mol or higher, a raised triglyceride level of >1.7mmol/L or more, or a low HDL-C below 1.0 mmol/L.5
Although the prognosis for people with MASLD is generally good, a small number will go on to develop metabolic dysfunction associated steatohepatitis (MASH), where inflammation of the fat-infiltrated liver cells is seen. MASH was previously known as non-alcoholic steatohepatitis (NASH). People with MASH are at increased risk of liver fibrosis and having liver fibrosis significantly increases an individual’s future risk of developing liver cirrhosis. Up to 4% of people with MASLD will develop cirrhosis and this, in turn is associated with an increased risk of hepatocellular carcinoma (HCC).4 The level of fibrosis is closely associated with mortality, but the main cause of death in people with MASLD will be cardiovascular disease.
IDENTIFYING PEOPLE AT RISK OF DISEASE
Certain populations are known to be more likely to develop MASLD and MASH, as indicated above. Key risk factors include:
- A BMI of >25 kg/m2 (23kg/m2 in high-risk ethnicities)
- A waist circumference of 94cm+ in men (90cm+ in high-risk ethnicities) or a waist measurement of 80cm+ in women
- People with, or at increased risk of, T2D
T2D is now recognised as a condition which is linked to cardiovascular complications and much of the management of T2D focuses on reducing this risk through a combination of lifestyle interventions and medication such as SGLT2 inhibitors, GLP-1 RAs and statins.6,7 MASLD has also been shown to increase cardiovascular risk, potentially as a result of its association with other cardiovascular risk factors including T2D, hypertension, dyslipidaemia, and chronic kidney disease.8 There is some evidence that liver fibrosis is an important CVD risk factor, as well as being a marker for poor liver-related outcomes, including portal hypertension with associated oesophageal varices and haemorrhage, liver failure, hepatocellular carcinoma and sepsis.4,9 However, a recent study has indicated that liver disease, even in the absence of metabolic risk factors, increases cardiorenal metabolic risk.10
MAKING THE DIAGNOSIS
People with liver disease are at risk of increased morbidity and mortality with respect to the heart, liver and kidneys, so it is essential to ensure that they are identified and offered support to reduce future risk. People in the groups identified above can be prioritised for assessment of liver function tests, although it is important to remember that these are often not abnormal. Liver function blood tests may include measuring levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (some laboratories will only measure one or the other), bilirubin, which may be raised in advanced disease, albumin, which may be low, gamma GT (GGT) and creatine kinase. Renal function should be assessed as there is a link between chronic liver disease and chronic kidney disease, and HbA1c and lipids measured because of the link with diabetes and cardiovascular risk. Low platelets and a deranged clotting profile are associated with advanced liver fibrosis. ALT levels are usually considered to be abnormal if they are more than twice the upper limit of normal (ULN). If the ratio of the AST to the ALT is more than 2, this suggests alcoholic liver disease, whereas a ratio of less than 1.0 suggests non-alcoholic liver disease.8 Transient changes may be seen during episodes of acute illness, which is why repeat tests over 3 months are recommended by NICE.4 NICE recommends that MASLD should be suspected in people with risk factors for the condition and who have elevated ALT levels of up to 3 times the ULN which have been present for at least three months and where the ALT exceeds AST levels.4 GGT levels can be 2-3 times greater than the ULN in most people with MASLD. Other blood tests that might be carried out could include iron studies (ferritin and transferrin saturation if haemochromatosis is suspected), an autoimmune and hepatitis screen and immunoglobulin levels. High autoantibodies may indicate autoimmune liver disease while low levels may be seen in MASLD.4 Any blood abnormalities should be taken as an indication to take a robust history and consider the range of possible causes. These include medication, specifically nonsteroidal anti-inflammatory drugs, amiodarone, corticosteroids, diltiazem, methotrexate, and tamoxifen. Other causes include infections, polycystic ovarian syndrome, thyroid dysfunction, coeliac disease (via a tTG-IgA blood test) and weight loss, both intentional and through disorders of nutrition.4 An ultrasound scan may help to confirm the presence of steatosis, but it should be noted that both the blood tests and the scan can appear normal, even in those with MASLD. Scans depend on the presence of fat in at least a third of hepatocytes to identify MASLD, are operator dependent, and may be technically difficult in people who are obese, which is one of the risk factors for the condition. NICE does not, therefore, recommend routine ultrasound scans to diagnose MASLD, stating that it is usually an incidental finding.4
Symptoms of MASLD and MASH may include fatigue and/or right upper quadrant pain, but these are often absent. Further assessment will include noting any history (or family history) of cardiovascular disease, T2D, hypertension or autoimmune disorders. The individual’s BMI, BP, waist circumference and alcohol intake should be recorded, and all blood tests reviewed. A cardiovascular risk assessment should be carried out, and QRisk 3 is now recommended as the most appropriate risk assessment tool. As this has not yet been amalgamated into practice systems (and it is worth requesting system providers to address this as a matter of urgency) clinicians will need to go to www.qrisk.org to carry out the risk assessment. A new risk assessment tool, QRisk 4, has been developed but is not currently available, and it does not include MASLD or MASH as a cardiovascular risk factor so clinicians will need to consider the additional cardiovascular risk that comes from having one of these conditions.11 It is then recommended to assess the risk of fibrosis using a risk assessment tool such as the NAFLD score test (www.nafldscore.com) which uses age, BMI, blood glucose, platelet count, albumin, and the AST to ALT ratio to score the risk of advanced liver fibrosis. A score greater than minus1.455 is positive. The FIB-4 test (https://www.mdcalc.com/calc/2200/fibrosis-4-fib-4-index-liver-fibrosis) can also be used and is based on the individual’s age, LFTs and platelets. For people with low FIB-4 scores (<1.3) the advice would be to manage risk factors and review 2-yearly. In people age 65+, scores of <2.0 are considered acceptable. Intermediate scores (1.3 to 3.25) warrant further investigations, which might include a Fibroscan or an Enhanced Liver Fibrosis (ELF) blood test. With the ELF test a score of 10.51 or above suggests advanced liver fibrosis. The ELF test has been shown to outperform liver biopsy as a prognostic and monitoring test for chronic liver disease and is safer and cheaper. However, people with high fibrosis scores on any test may need a diagnostic liver biopsy as there is an increased likelihood of cirrhosis in this group.4
CASE STUDY: GARY
Gary, age 54, has a BMI of 36 kg/m2 and was diagnosed with T2D a year ago. His latest blood results showed an HbA1c of 54mmol/mol, and a non-HDL-cholesterol of 2.3mmol/L. There was an incidental finding of abnormal liver function. His eGFR was reported as >90ml/min, and his albumin creatinine ratio was <0.7mg/mmol. A clinic BP reading was 142/83 mmHg and his QRisk 3 score was calculated to be over 10%. He is treated with metformin, an SGLT2 inhibitor and atorvastatin 20mg.
Gary was asked to monitor his BP at home, and he was subsequently diagnosed with stage 1 hypertension. His liver function tests were repeated in three months and continued to be abnormal with no other causes of liver disease identified. He was diagnosed with MASLD. His FIB-4 score was 2.4, and as a result he was referred for a scan to assess his liver pathology.
MANAGING MASLD THROUGH LIFESTYLE CHANGE
The main focus when managing MASLD is to address lifestyle issues as these will improve cardiometabolic risk factors. People with MASLD should have the diagnosis explained to them, along with the possible implications of the diagnosis for liver and cardiovascular health. These messages need to be balanced with positive support for behaviour change based around weight and cardiovascular risk management. Recommendations should centre on what the individual feels able to do in order to lose weight, with the focus being on dietary interventions but including a reminder about the value of increasing physical activity for both weight and for holistic well-being. NICE highlights the Mediterranean diet as an appropriate option for people living with MASLD.4 MASLD is recognised to be a non-alcohol-related liver condition, where daily alcohol consumption is less than 2.5 units per day for women, and less than 3.75 units per day for men. Nonetheless, people diagnosed with MASLD should be advised to limit their alcohol intake to national recommended limits (14 units per week). Regular reviews should be offered, as although metabolic risk factors are a key feature of the diagnosis of MASLD, if they do not already have hypertension, chronic kidney disease, impaired glucose regulation, and/or T2D, there is an increased risk of developing these problems once a diagnosis of MASLD has been made.4 If excess alcohol intake is a factor, it is referred to as MetALD and support should be given to address hazardous drinking habits through specialist referral.
PHARMACOLOGICAL MANAGEMENT
There are no licensed pharmacological interventions for MASLD and MASH at the time of writing, but NICE recommends lipid lowering therapy (statins) if liver function tests are below 3 times the ULN.4 NICE points out that statin treatment is associated with improvements in steatosis, inflammation and fibrosis. Hypertension should be treated in line with the NICE hypertension guidelines.12 For those with T2D, management will focus on lipid, BP and glycaemic control, and cardiovascular risk reduction.7 Cardiovascular disease is the most common cause of death in people with MASLD, so all measures should be put in place to reduce risk once the diagnosis has been made. As obesity drives the metabolic changes of MASLD, weight loss is key, and newer weight loss treatments such as the GLP-1 RAs (e.g. semaglutide) and the GLP-1 RA/GIP tirzepatide, can be initiated in people with liver disease in line with their relevant licences. Beyond these drug treatments, there is increasing evidence for pioglitazone and SGLT2 inhibitors. However, none of these drugs is licensed for MASLD or MASH. Studies have also identified other potential therapies for MASLD and MASH including probiotics, herbal medicines e.g., pegbelfermin, vitamins – B12, C and D, biologics and bariatric surgery.13 NICE supports the off-label use of pioglitazone and vitamin E supplementation in non-diabetic patients with advanced liver fibrosis but recommends that they are only prescribed in secondary care.4 NICE also mentions obeticholic acid for MASH, but states that this should also be reserved for specialist use. Bariatric surgery has been shown to lead to the resolution of steatosis in 66% of patients, and of fibrosis in 40% patients but is not widely available on the NHS.4
REVIEWS
There are no specific QOF indicators for MASLD or MASH, but the various risk factors will have set criteria which are required to meet QOF requirements. These include hypertension, diabetes and lipid management. NICE recommends that patients with MASLD and MASH are reviewed at least annually with blood tests, cardiovascular risk assessment and management, and fibrosis risk calculations being carried out at each review. This should not cause a high level of extra work as many of those patients with, or at risk of, MASLD and MASH will already be on general practice disease registers.
CASE STUDY: HELEN
Helen is a 63-year-old teacher who has recently had an episode of right upper quadrant pain. She has no past medical history and no family history of note and she considers herself to be generally fit and well. Her blood tests showed an HbA1c of 43mmol/mol, a total cholesterol of 4.2mmol/L, an HDL-C of 1.0mmol/L and triglycerides of 2.3mmol/L. Her renal and liver function tests were within normal range. She has a BMI of 32 kg/m2 and her average home BP is 137/86 mmHg. She reports having an occasional glass of wine at social events and has never smoked. An abdominal ultrasound scan showed an incidental finding of steatosis (fatty liver) with no other pathology.
Based on the ultrasound report and her metabolic profile, Helen is diagnosed with MASLD. The FIB-4 calculation reveals a low score so the practice nurse has recommended that the focus should be on lifestyle interventions, especially weight management, as she has non-diabetic hyperglycaemia. Her QRisk 3 score identified that statins were indicated, and after discussing the diagnosis of MASLD and the associated liver and cardiovascular risks, Helen was keen to start a statin. She was offered the standard yearly review but was encouraged to attend the local weight management group for ongoing support. She was asked to have her lipids checked in 8-12 weeks, and her HbA1c monitored every 6-12 months.
WHEN TO REFER
NICE states that a referral to a specialist should be made if there is a high risk of advanced liver fibrosis or if there are signs of advanced liver disease, such as jaundice, spider naevi, palmar erythema, ascites, encephalopathy, hepatomegaly or splenomegaly.4 A referral should also be made if there is any uncertainty about the diagnosis. Management of risk factors such as obesity, hypertension, insulin resistance and dyslipidaemia should fall within the scope of general practice, but specific issues such as failure to respond to antihypertensive treatment or suspected familial hypercholesterolaemia, should also be referred. If specialist weight management services are required, e.g., for initiation of a GLP-1 RA in someone without T2D, a referral should be made in line with local policy and availability.
SUMMARY
MASLD and MASH are increasingly common disorders with associated risks to liver health and cardiovascular wellbeing. Cardiometabolic risk factors should be identified and addressed in people with, or at risk of MASLD and MASH, with interventions targeted to the individual’s risk. Lifestyle changes are key, with weight management central to reducing future risk. Statins should be considered in people with a CVD risk score of 10% even in the presence of MASLD, as the benefits are likely to outweigh the risks in many people. Other potential pharmacological interventions are available to secondary and tertiary care but remain unlicensed.
REFERENCES
1. Office for Health Improvement and Disparities. Liver disease profile, April 2024 update. https://www.gov.uk/government/
statistics/liver-disease-profile-april-2024-update/liver-disease-profile-april-2024-update
2. Kalra A, Yetiskul E, Wehrle CJ, et al. Physiology, Liver; Updated May 2023. StatPearls https://www.ncbi.nlm.nih.gov/books/NBK535438/
3. American Association for the Study of Liver Diseases. New MASLD Nomenclature; 2024 https://www.aasld.org/new-masld-nomenclature#introducing-masld-and-metald
4. NICE Clinical Knowledge Summaries. Non-alcoholic fatty liver disease (NAFLD); 2023 https://cks.nice.org.uk/topics/non-alcoholic-fatty-liver-disease-nafld/
5. British Society of Gastroenterology. Diagnosis, assessment and management of NAFLD; 2020 https://bsg.org.uk/web-education/nafld-%E2%80%93-diagnosis,-assessment-and-management
6. NICE NG28. Type 2 diabetes in adults: management; 2022. https://www.nice.org.uk/guidance/ng28
7. Davies MJ, Aroda VR, Collins BS, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes care 2022;45(11):2753–2786. https://doi.org/10.2337/dci22-0034
8. Chen L, Tao X, Zeng M, et al. Clinical and histological features under different nomenclatures of fatty liver disease. J Hepatol 2024;80(2):E64-E66 https://www.journal-of-hepatology.eu/article/S0168-8278(23)05075-4/fulltext
9. Johnston MP, Patel J, Byrne CD. Update on cardiovascular risk in nonalcoholic fatty liver disease. Current opinion in Cardiology 2021;36(4): 478–486. https://doi.org/10.1097/HCO.00000000000861
10. Roca-Fernandez A, Banerjee R, Thomaides-Brears H, et al. (2023). Liver disease is a significant risk factor for cardiovascular outcomes – A UK Biobank study. J Hepatol 2023;79(5):1085–1095. https://doi.org/10.1016/j.jhep.2023.05.046
11. Hippisley-Cox J, Coupland CAC, Bafadhel M, et al. (2024) Development and validation of a new algorithm for improved cardiovascular risk prediction. Nat Med 2024;30:1440–1447 https://doi.org/10.1038/s41591-024-02905-y
12. NICE NG136. Hypertension in adults: diagnosis and management; 2023 https://www.nice.org.uk/guidance/ng136
13. Zhang CY, Liu S, Yang M. Treatment of liver fibrosis: Past, current, and future. World J Hepatol 2023;15(6):755–774. https://doi.org/10.4254/wjh.v15.i6.755
