Metabolic dysfunction–associated fatty liver disease: an update

SUMMARY

Metabolic dysfunction–associated fatty liver disease (MAFLD) affects 1 in 3 Australian adults and is an under-recognised but growing cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation.

There is a major role for primary care in MAFLD prevention, diagnosis and management.

Adults with obesity, type 2 diabetes or other metabolic risk factors should be assessed for MAFLD.

Liver ultrasound is the recommended first-line test for diagnosing hepatic steatosis (fat accumulation in hepatocytes).

Management of MAFLD includes noninvasive testing for liver fibrosis, addressing health risk behaviours and comorbidities, and hepatocellular carcinoma surveillance in those with liver cirrhosis.

 

Introduction

Metabolic dysfunction–associated fatty liver disease (MAFLD) is defined as hepatic steatosis (fat accumulation in hepatocytes) on imaging or liver biopsy, in addition to one of: overweight or obesity; type 2 diabetes; or metabolic dysregulation in those with lean or healthy weight. Metabolic dysregulation is defined as the presence of at least 2 of the following risk factors: central obesity, hypertension, dyslipidaemia, pre-diabetes and/or insulin resistance).¹ The nomenclature change from non-alcoholic fatty liver disease (NAFLD) was made to better reflect the role of metabolic risk factors, to allow for coexisting liver disease (e.g. from harmful alcohol), and to be less stigmatising.^1,2 Metabolic dysfunction–associated steatotic liver disease (MASLD) has been proposed as an alternative term to further mitigate this stigmatisation.³

MAFLD is the most common liver condition worldwide, being present in more than one-third of the global population.⁴ MAFLD affects 1 in 3 Australian adults, is associated with increasing incidence of cirrhosis and hepatocellular carcinoma (HCC),^5,6 and is a common indication for liver transplantation.^7,8 In people with type 2 diabetes, obesity or 2 or more metabolic risk factors, the prevalence of MAFLD is greater than 50%. Despite the high prevalence, MAFLD is under-recognised in Australia due to a lack of public and clinician awareness, related, in part, to an historic paucity of clinical guidelines.^7,9 This review follows a recently published consensus statement by the Gastroenterological Society of Australia (GESA) on MAFLD, summarised in Adams et al. 2025.^7,10

 

Underlying pathophysiology

Although risk factors for MAFLD are well recognised, what causes fat accumulation in liver cells is not well understood. Metabolic dysfunction and insulin resistance are upstream drivers.^7,11 Cytokines and inflammatory mediators produced by steatotic liver cells are thought to cause hepatocyte damage, as well as renal and cardiac injury, through oxidative stress and upregulation of inflammatory and fibrotic pathways.^7,12 MAFLD is therefore pathophysiologically related to other metabolic-associated disorders, including cardiovascular and chronic kidney disease.^7,12

Inflammation, secondary to hepatic steatosis, is referred to as steatohepatitis and, if persistent, leads to liver injury and hepatic fibrosis. Fibrosis is quantified on liver biopsies from 0 (no fibrosis) to 4 (cirrhosis). Advanced fibrosis (stage 3 or 4) is associated with increased liver-related and all-cause mortality.¹³ The progression of liver fibrosis in people with MAFLD is relatively slow. The average time to progress one fibrosis stage in those with no (F0) or minimal (F1) fibrosis is 10 years. However, a minority of people can progress more rapidly, with 6 to 15% of those with F0 or F1 fibrosis progressing to advanced fibrosis (F3 or F4) within 5 years.^7,14 The prevalence of advanced fibrosis among people with MAFLD in Australia ranges from 3 to 7.6%.^7,15

 

Diagnosis of MAFLD

Who to assess

All adults with obesity, type 2 diabetes or at least 2 metabolic risk factors should be assessed for MAFLD.⁷ Abnormal liver function tests may prompt the need to consider MAFLD as a possible diagnosis but are neither sensitive nor specific for its presence and MAFLD can be present in people with normal liver function tests.¹⁶

How to assess

Liver ultrasound is the recommended first-line test for diagnosing hepatic steatosis.⁷ Ultrasound is relatively inexpensive, accessible, and has reasonably good diagnostic performance to detect steatosis, with 82% sensitivity and 80% specificity for detecting those with fat accumulation in at least 5% of hepatocytes histologically, a commonly accepted threshold for diagnosis on liver biopsy.^7,17 However, ultrasound has lower sensitivity with lower levels of steatosis and with elevated body mass index (BMI), and is operator dependent.⁷ Magnetic resonance imaging of the liver is the most accurate imaging modality¹⁸ but is expensive and has limited availability.

Other causes of steatosis

People with steatosis on ultrasound should be assessed for other causes of fatty liver – particularly alcohol, medications and viral hepatitis – with history and targeted serological testing as appropriate (Table 1).⁷ Harmful alcohol use is a common issue in primary care and alcohol-related fatty liver disease develops in 90% of people who drink more than 40 g of alcohol (4 standard drinks) per day over a sustained period.¹⁹ In this group, 8 to 20% will develop cirrhosis. The National Health and Medical Research Council guidelines recommend healthy adults should drink no more than 10 standard drinks per week and no more than 4 standard drinks in any one day.²⁰ Despite these recommendations, it is recognised that any alcohol consumption is potentially harmful and people with cirrhosis should avoid alcohol because of the increased risk of HCC and liver decompensation.⁷ Medications that can cause steatosis include corticosteroids, methotrexate and amiodarone. Methotrexate and amiodarone can also result in steatohepatitis and progressive liver injury, including cirrhosis.²¹ Hepatitis C virus genotype 3 can also cause steatosis.

Table 1 Assessing for secondary causes of hepatic steatosis and derangement of liver function tests

Who	Assessment
1. All people with steatosis	Metabolic risk factors Alcohol history Medication history [NB1]
2. People with steatosis + raised ALT [NB2]	Hepatitis B serology (sAb, sAg, cAb) Hepatitis C Ab (or PCR/viral load if known prior history)
3. People with abnormal LFTs (for over 6 months) with ALT predominance (guided by risk factor profile and clinical presentation)	Autoimmune markers (ANA, ASMA, ASLA, ALKMA, IgG, TFT, coeliac serology) Iron studies [NB3] Copper overload (ceruloplasmin) Alpha-1 antitrypsin level
Ab = antibody; ALKMA = anti-liver kidney microsomal antibody; ALT = alanine aminotransferase; ANA = anti-nuclear antibody; ASMA = anti-smooth muscle antibody; ASLA = anti-soluble liver antigen; cAb = core antibody; LFT = liver function test; PCR = polymerase chain reaction; sAb = surface antibody; sAg = surface antigen; TFT = thyroid function NB1: Culprit medications include corticosteroids, methotrexate, amiodarone and drugs that cause weight gain. NB2: Raised ALT is above 35 U/L for women, above 40 U/L for men. NB3: An elevated ferritin (above 200 ng/mL in women, above 300 ng/mL in men), and transferrin saturation (above 45% should prompt HFE genotype testing for hereditary haemochromatosis [homozygous C282Y mutation in HFE gene]).

In people with elevated serum transaminases (alanine aminotransferase [ALT] above 35 U/L for women and above 40 U/L for men) assessment for risk factors for hepatitis B and hepatitis C, and evaluation for iron overload, should be undertaken (Table 1).⁷ Testing should include hepatitis B serology (surface antibody, surface antigen, core antibody),hepatitis C antibody testing (with reflex viral load testing) and serum iron studies. An elevated serum ferritin (above 200 nanogram/mL in women and above 300 nanogram/mL in men) and transferrin saturation (over 45%) should prompt HFE genotype testing. Hereditary haemochromatosis, which affects approximately 1 in 200 Australians, is predominantly caused by homozygous C282Y mutations in the HFE gene.

 

Management of MAFLD

Following diagnosis of MAFLD, the next steps are to determine the risk for liver fibrosis, address health risk behaviours and comorbidities, and monitor for HCC where indicated.

Assessment of liver fibrosis

Identifying those with MAFLD and advanced liver fibrosis is important to facilitate early intervention and prevent progressive liver disease. Specific noninvasive fibrosis tests are recommended and are particularly useful in excluding advanced fibrosis, with further confirmatory tests required for people with higher risk or indeterminate results.

The recommended first-line test is the fibrosis-4 (FIB-4) index (Figure 1).⁷ This low-cost test incorporates age, aspartate aminotransferase (AST), ALT and platelet count, and can be easily performed using an online FIB-4 calculator or by pathology providers. A low-risk score (less than 1.3) has a negative predictive value of 95 to 97%, illustrating the utility in excluding advanced fibrosis.⁷ The FIB-4 index should not be used in people younger than 35 years due to low accuracy, and a higher low-risk score cut-off (less than 2.0) is recommended for people older than 65 years.^7,22 FIB-4 scores may be falsely elevated in people with thrombocytopenia from non-hepatic causes (e.g. excess alcohol- or immune-related) or in acute hepatitis, so its use in these scenarios should be avoided.⁷

A high-risk FIB-4 score (greater than 2.7) indicates an increased risk of advanced liver fibrosis, and these patients should be referred for liver specialist assessment.

In people with an indeterminate FIB-4 score (1.3 to 2.7), a second-line assessment should be performed.⁷ One option is liver elastography with FibroScan or ultrasound – both have comparable diagnostic performance (using a cut-off of less than 8 kPa to exclude advanced fibrosis).²³ Serum liver fibrosis tests, such as a Hepascore or the enhanced liver fibrosis (ELF) test, are alternatives and are more accurate than FIB-4 but are not available through all pathology providers and can incur out-of-pocket costs for patients.⁷

In those with an indeterminate FIB-4 score and no available second-line test, it is recommended to provide advice on healthy living and liver health risks and repeat the FIB-4 assessment after 6 months; or refer to a clinician with expertise in liver disease.⁷

People with a low-risk score (less than 1.3), or with a low-risk second-line result after an indeterminate FIB-4 score, are recommended to undergo repeat testing in 1 to 3 years.⁷ Keeping accurate records of people with MAFLD and embedding repeat fibrosis testing in routine clinical practice is therefore important.

Liver biopsy is the definitive technique for identifying advanced fibrosis, but is invasive, expensive and difficult to access. Standard liver function tests are inaccurate, and ultrasound and computed tomography (CT) lack sensitivity for determining advanced fibrosis and cirrhosis.^16,24

Managing health risk behaviours and comorbidities

Potential risk factors and complications from MAFLD should be appropriately assessed and managed as required (Figure 1).

Weight loss is associated with clinical benefit in people with MAFLD, including improved histological parameters, with the greatest benefit in those who achieve at least 10% loss of body weight.²⁵ Monitoring weight, BMI and/or waist circumference should occur annually, with intervention if required as per the Australian Obesity Management Algorithm.^7,26 Weight loss following bariatric surgery in people with MAFLD and obesity is associated with a reduction in cirrhosis, HCC, liver-related deaths and major cardiovascular events.²⁷

There is a bidirectional association between MAFLD and type 2 diabetes. MAFLD is associated with increased risk of type 2 diabetes and monitoring should occur according to current Australian guidelines, using the Australian Type 2 Diabetes Risk Assessment Tool.⁷ In people with MAFLD, type 2 diabetes is associated with fibrosis progression,²⁸ and both type 2 diabetes and higher HbA1c are associated with hepatic decompensation.²⁹

Cardiovascular disease is the most common cause of death among people with MAFLD.^30,31 Assessment and monitoring of cardiovascular risk should be performed according to current Australian guidelines using the Australian cardiovascular risk calculator.⁷ Statins are safe for people with MAFLD, including those with compensated cirrhosis, and should be prescribed if clinically indicated.⁷

Baseline assessment for coexisting chronic kidney disease, as per Kidney Health Australia guidelines, and screening for obstructive sleep apnoea, using tools such as the STOP-BANG questionnaire, should also be considered for people with MAFLD.⁷

Hepatocellular carcinoma surveillance

People with cirrhosis due to MAFLD are at risk of developing HCC with an annual incidence of over 3.5%.³² Surveillance of people with cirrhosis should therefore be performed 6-monthly with liver ultrasound. In addition, adding serum alpha fetoprotein (AFP) testing increases the sensitivity of surveillance and is also recommended, although this has less consensus in guidelines.^10,33 The annual risk of incident HCC for non-cirrhotic people with MAFLD is less than 0.05% and surveillance is not recommended.^7,32

Emerging therapies

There are currently no drugs specifically approved for MAFLD in Australia. Resmetirom is an oral, liver-directed thyroid hormone receptor beta-selective agonist that is the first medication for MAFLD to receive US Food and Drug Administration (FDA) approval in stage 2 or 3 liver fibrosis.³⁴ Similarly, semaglutide has also recently been approved by the FDA based on a phase 3 trial demonstrating resolution of steatohepatitis in 63% of participants and improvement in fibrosis in 37%.³⁵ Other drugs have been shown to improve liver histology and other clinical biomarker outcomes, including efruxifermin (a fibroblast growth factor 21 analogue).³⁶ These treatments, where available globally or through clinical trials, are reserved for those at higher risk of liver-related complications, namely those with moderate to advanced fibrosis and steatohepatitis.

 

Key practice points

Key diagnosis and management practice points are highlighted in Box 1.

 

Conclusion

MAFLD has a large and increasing burden of disease and should be assessed for in all adults with obesity, type 2 diabetes or multiple metabolic risk factors. Liver ultrasound is the recommended first-line test and, if steatosis is identified, noninvasive testing for liver fibrosis should be offered. Management of MAFLD should include addressing health risk behaviours and comorbidities, and HCC surveillance in those with liver cirrhosis.

This article was finalised on 5 March 2026.

Conflicts of interest: Richard O’Halloran has no conflicts declared.

Leon Adams was the co-chair of the Gastroenterological Society of Australia (GESA) consensus statement for the assessment of MAFLD in primary care and is on the GESA Liver Executive Committee. Leon is on advisory boards for Novo Nordisk, CSL Behring, Pfizer, Novartis, Roche Diagnostics and is a co-applicant on a patent for Hepascore. He was an investigator in a data linkage study determining the prevalence and outcomes of MAFLD and metabolic dysfunction–associated steatohepatitis (MASH) in primary care that received funding from Novo Nordisk for the data linkage component.

Gary Deed is Chair of the Royal Australian College of General Practitioners (RACGP) Diabetes Specific Interest Group, contributed to the GESA MAFLD consensus statement, and is a member of the Heart Foundation Lipid Guidelines Expert Committee. Gary has received funding from Sanofi for international travel to a committee meeting on type 1 diabetes guidelines. He has also received funding from AstraZeneca, Abbott, Boehringer Ingelheim, Dexcom, GSK, Lilly, MSD, Novartis, Novo Nordisk, Sanofi and CSL Seqirus for education and advisory board membership, and funding from Abbott, Healthed, GPCE, Limbic and the RACGP for education.

John Lubel is a board member of GESA and contributed to the GESA MAFLD consensus statement.

This article is peer reviewed.

 

References

1. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73:202-9.
2. Eslam M, Sanyal AJ, George J, International Consensus P. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020;158:1999-2014 e1.
3. Younossi ZM, Alqahtani SA, Alswat K, Yilmaz Y, Keklikkiran C, Funuyet-Salas J, et al. Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease. J Hepatol 2024;80:419-30.
4. Lim GEH, Tang A, Ng CH, Chin YH, Lim WH, Tan DJH, et al. An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors Between MAFLD vs NAFLD. Clin Gastroenterol Hepatol 2023;21:619-29 e7.
5. Adams LA, Roberts SK, Strasser SI, Mahady SE, Powell E, Estes C, et al. Nonalcoholic fatty liver disease burden: Australia, 2019-2030. J Gastroenterol Hepatol 2020;35:1628-35.
6. Farrell AM, Magliano DJ, Shaw JE, Thompson AJ, Croagh C, Ryan MC, et al. A problem of proportions: estimates of metabolic associated fatty liver disease and liver fibrosis in Australian adults in the nationwide 2012 AusDiab Study. Sci Rep 2022;12:1956.
7. Adams LA, Kemp WW, Muller KR, Powell EE, Roberts SK, Bertot LC, et al. Assessment of metabolic dysfunction-associated fatty liver disease in primary care: a consensus statement summary. Med J Aust 2025;223:268-76.
8. Wong RJ, Singal AK. Trends in Liver Disease Etiology Among Adults Awaiting Liver Transplantation in the United States, 2014-2019. JAMA Netw Open 2020;3:e1920294.
9. Patel PJ, Banh X, Horsfall LU, Hayward KL, Hossain F, Johnson T, et al. Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis. Intern Med J 2018;48:144-51.
10. MAFLD Consensus Statement Working Group. Recommendations for the assessment of metabolic dysfunction-associated fatty liver disease (MAFLD) in primary care: a consensus statement. Gastroenterological Society of Australia; 2024. [cited 2026 Mar 5]
11. Roberts SK, Majeed A, Glenister K, Magliano D, Lubel JS, Bourke L, et al. Prevalence of non-alcoholic fatty liver disease in regional Victoria: a prospective population-based study. Med J Aust 2021;215:77-82.
12. Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, Mathew RO, Khan SS, et al. A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association. Circulation 2023;148:1636-64.
13. Sanyal AJ, Van Natta ML, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N Engl J Med 2021;385:1559-69.
14. Le P, Payne JY, Zhang L, Deshpande A, Rothberg MB, Alkhouri N, et al. Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies. Clin Gastroenterol Hepatol 2023;21:1154-68.
15. Armstrong MJ, Houlihan DD, Bentham L, Shaw JC, Cramb R, Olliff S, et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J Hepatol 2012;56:234-40.
16. Gawrieh S, Wilson LA, Cummings OW, Clark JM, Loomba R, Hameed B, et al. Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels. Am J Gastroenterol 2019;114:1626-35.
17. Ballestri S, Mantovani A, Byrne CD, Lonardo A, Targher G. Diagnostic accuracy of ultrasonography for the detection of hepatic steatosis: an updated meta-analysis of observational studies. Metabolism and Target Organ Damage 2021;1:7.
18. Wang XM, Zhang XJ, Ma L. Diagnostic performance of magnetic resonance technology in detecting steatosis or fibrosis in patients with nonalcoholic fatty liver disease: A meta-analysis. Medicine (Baltimore) 2018;97:e10605.
19. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Primers 2018;4:16.
20. National Health and Medical Research Council. Australian guidelines to reduce health risks from drinking alcohol. Canberra; 2020.
21. Liebe R, Esposito I, Bock HH, Vom Dahl S, Stindt J, Baumann U, et al. Diagnosis and management of secondary causes of steatohepatitis. J Hepatol 2021;74:1455-71.
22. McPherson S, Hardy T, Dufour JF, Petta S, Romero-Gomez M, Allison M, et al. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. Am J Gastroenterol 2017;112:740-51.
23. Cassinotto C, Boursier J, Paisant A, Guiu B, Irles-Depe M, Canivet C, et al. Transient Versus Two-Dimensional Shear-Wave Elastography in a Multistep Strategy to Detect Advanced Fibrosis in NAFLD. Hepatology 2021;73:2196-205.
24. Hetland LE, Kronborg TM, Thing M, Werge MP, Junker AE, Rashu EB, et al. Suboptimal diagnostic accuracy of ultrasound and CT for compensated cirrhosis: Evidence from prospective cohort studies. Hepatol Commun 2023;7.
25. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015;149:367-78 e5; quiz e14-5.
26. Markovic TP, Proietto J, Dixon JB, Rigas G, Deed G, Hamdorf JM, et al. The Australian Obesity Management Algorithm: A simple tool to guide the management of obesity in primary care. Obes Res Clin Pract 2022;16:353-63.
27. Aminian A, Al-Kurd A, Wilson R, Bena J, Fayazzadeh H, Singh T, et al. Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis. JAMA 2021;326:2031-42.
28. Huang DQ, Wilson LA, Behling C, Kleiner DE, Kowdley KV, Dasarathy S, et al. Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study. Gastroenterology 2023;165:463-72 e5.
29. Huang DQ, Noureddin N, Ajmera V, Amangurbanova M, Bettencourt R, Truong E, et al. Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis. Lancet Gastroenterol Hepatol 2023;8:829-36.
30. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol 2021;75:1284-91.
31. Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet 2021;397:2212-24.
32. Orci LA, Sanduzzi-Zamparelli M, Caballol B, Sapena V, Colucci N, Torres F, et al. Incidence of Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-analysis, and Meta-regression. Clin Gastroenterol Hepatol 2022;20:283-92 e10.
33. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology 2018;154:1706-18 e1.
34. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med 2024;390:497-509.
35. Sanyal AJ, Newsome PN, Kliers I, Ostergaard LH, Long MT, Kjaer MS, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med 2025;392:2089-99.
36. Noureddin M, Rinella ME, Chalasani NP, Neff GW, Lucas KJ, Rodriguez ME, et al. Efruxifermin in Compensated Liver Cirrhosis Caused by MASH. N Engl J Med 2025;392:2413-24.