Appendix. Delphi round agreement on the recommendations of the present clinical practice guidelines

Recommendation/statement	Consensus
Definition, prevalence and natural course
The incidental finding of steatosis should prompt assessment of the potential aetiology of SLD, alongside tests for the presence of advanced fibrosis, as this could determine the risk of liver-related and/or cardiovascular outcomes and appropriate care (LoE 3, strong recommendation).	100%
MASLD, ALD and MetALD are the most common causes of SLD, but other causes such as drug-induced liver disease and monogenic SLD should be considered, depending on the context (LoE 3, strong recommendation).	98%
General population-based screening for SLD is not advised (LoE 3, strong recommendation).	95%
While the presence of steatotic liver in the general population is not independently associated with liver-related outcomes, the stage of liver fibrosis and persistently elevated liver enzymes are associated with liver-related outcomes (LoE 3).	98%
Type 2 diabetes and obesity (particularly abdominal obesity) are the metabolic diseases with the strongest impact on the natural history of MASLD, including progression to MASLD/MASH-advanced fibrosis, cirrhosis and hepatocellular carcinoma (LoE 2).	98%
Males aged >50 years, postmenopausal women, and individuals with multiple cardiometabolic risk factors are at increased risk of progressive fibrosis and the development of cirrhosis and its complications (LoE 2).	95%
Accumulating evidence shows that alcohol consumption and metabolic risk factors have modifying effects on the onset and progression of chronic liver disease which are independent and can be synergistic (LoE 2).	96%
The presumed beneficial health effects of moderate alcohol consumption are inconsistent across studies and emerging evidence does not support a protective effect of light to moderate amounts of alcohol, particularly in individuals with cardiometabolic risk factors (LoE 3).	100%
The amount, pattern and history of alcohol intake should be documented in all individuals with SLD (LoE 3, strong recommendation).	100%
Alcohol intake may be qualitatively and quantitatively assessed by validated instruments and/or specific biomarkers in individuals with SLD (Table 5) (LoE 3, open recommendation).	97%
Individuals with SLD, particularly those with moderate or high alcohol intake, should be discouraged from consuming alcohol (LoE 3, strong recommendation).	91%
All alcohol consumption should be stopped completely and permanently in individuals with advanced fibrosis or cirrhosis (LoE 3, strong recommendation).	100%
Prevention
In the general population, non-pharmacological measures should be recommended to prevent the development of MASLD and its complications, including hepatocellular carcinoma, and preventive measures should be reinforced in high-risk groups (LoE 3, strong recommendation).	96%
Screening, case-finding, diagnosis and monitoring
Healthcare providers may consider case-finding strategies for MASLD with liver fibrosis in individuals with cardiometabolic risk factors (Table 3), abnormal liver enzymes, and/or radiological signs of hepatic steatosis (LoE 3, weak recommendation).	91%
Healthcare providers should look for MASLD with liver fibrosis either in individuals with (A) type 2 diabetes or (B) abdominal obesity and ≥1 additional metabolic risk factor(s) (Table 3) or (C) abnormal liver function tests (LoE 3, strong recommendation).	89%
Early diagnosis of fibrosis and subsequent appropriate management can potentially prevent progression to cirrhosis and its complications and may justify screening in these populations at risk (LoE 3).	95%
In adults with MASLD, non-invasive scores based on combinations of blood tests or combinations of blood tests with imaging techniques measuring mechanical properties and/or hepatic fat content should be used for the detection of fibrosis since their diagnostic accuracy is higher than standard liver enzyme testing (alanine [ALT] and aspartate aminotransferase [AST]) (LoE 2, strong recommendation).	97%
In adults with MASLD, a multi-step approach is recommended (detailed in Figure 2 and below): First, an established non-patented blood-based score such as FIB-4 should be performed. Thereafter, established imaging techniques such as liver elastography are recommended as a second step to further clarify the fibrosis stage if fibrosis is still suspected or in high-risk groups (LoE 2, strong recommendation).	100%
Tests of specific collagen-related blood constituents (e.g. ELF) may serve as an alternative to imaging to identify advanced liver fibrosis (LoE 2, open recommendation).	86%
Clinical care pathways may be adopted based on the sequential application of non-invasive scores and imaging tests in adults with MASLD or at-risk individuals, recognising that most adults with MASLD are seen at non-hepatology settings (LoE 2, weak recommendation).	98%
Blood biomarker-derived scores and elastography should be used to exclude advanced fibrosis, while elastography is better suited to predict advanced fibrosis (LoE 2, strong recommendation).	92%
None of these non-invasive methods can assess relevant microscopic features of MASLD such as ballooning or lobular inflammation (LoE 2).	96%
Some blood biomarker-based scores may help to identify individuals with MASH at risk of disease progression (LoE 3).	89%
Blood biomarker-derived scores and elastography can help in risk stratification for clinical outcomes, as observational studies have identified thresholds related to liver-related outcomes and mortality (LoE 3).	100%
In most cases, liver biopsy is not required for clinical management of individuals with MASLD; however, liver biopsy is still required for the definite diagnosis of steatohepatitis and can help to rule out alternative causes of liver disease (LoE 1).	100%
In adults with MASLD, sequential assessment with non-invasive tools may assist in ruling out fibrosis progression (LoE 3, weak recommendation).	95%
In adults with MASLD, non-invasive tools can help predict the risk of overall and liver-related events and mortality (LoE 2, weak recommendation).	97%
Clinicians in specialised centres may consider assessing the genetic risk profile (e.g. PNPLA3 p.I148M variant and/or polygenic risk scores) for personalising risk stratification, but this concept should be evaluated in larger prospective studies (LoE 3, open recommendation).	92%
Genetic risk variants can be evaluated in clinical studies for stratification of disease risk progression and sub-phenotyping of MASLD (LoE 2, open recommendation).	98%
Clinicians can consider referring individuals with a strong family history of severe disease in first degree relatives or early presentation with a severe phenotype, especially in the absence of metabolic triggers (and/or e.g. in individuals with normal body weight), for the evaluation of coexisting, treatable, genetic causes of liver disease by next-generation sequencing approaches (LoE 4, open recommendation).	90%
Clinicians should assess associated comorbidities (e.g., type 2 diabetes, dyslipidaemia, hypertension, kidney disease, sleep apnoea, polycystic ovary syndrome) and cardiovascular risk in adults with MASLD (LoE 2, strong recommendation).	100%
At initial diagnosis of MASLD and at regular follow-up intervals, laboratory tests and physical examinations for related comorbidities are recommended (Table 7) (LoE 2, strong recommendation).	100%
Adults with MASLD should be encouraged to participate in extrahepatic cancer screening according to current guidelines, based on their exposure to obesity and type 2 diabetes as risk factors for extrahepatic malignancies (LoE 3, strong recommendation).	96%
Assessment of insulin resistance (e.g., using the homeostasis model assessment of insulin resistance [HOMA-IR] or estimates derived from the oral glucose tolerance test) may be considered to clarify metabolic dysfunction in adults with (suspected) MASLD and without an established diagnosis of type 2 diabetes (LoE 3, weak recommendation).	92%
In adults with non-cirrhotic MASLD or MASH in the absence of severe fibrosis (i.e. those with fibrosis stage <F3) assessed by non-invasive markers or liver biopsy, surveillance for early detection of hepatocellular carcinoma is currently not recommended (LoE 3, weak recommendation).	86%
In adults with non-cirrhotic MASLD or MASH in the presence of severe fibrosis (F3) assessed by non-invasive markers or liver biopsy, surveillance may be considered based on an individual risk assessment (LoE 4, weak recommendation).	95%
According to current guidelines, hepatocellular carcinoma monitoring programmes should be applied to individuals with MASLD-related cirrhosis (LoE 3, strong recommendation).	100%
Risk stratification can help in optimising strategies for monitoring individuals at higher risk of hepatocellular carcinoma (Table 8) (LoE 4, weak recommendation).	100%
As ultrasound-based surveillance has a low sensitivity for detection of hepatocellular carcinoma at an early-stage, particularly in adults with MASLD cirrhosis and obesity, alpha-fetoprotein (AFP) measurement can be combined with ultrasound in individuals at high risk (LoE 3, open recommendation).	93%
Cross-sectional imaging by MRI may be undertaken in selected adults at high risk with persistent poor visualisation at ultrasound, particularly in individuals with dysplastic or regenerative nodules (LoE 3, open recommendation).	100%
Treatment of MASLD: General considerations
In adults with MASLD and advanced fibrosis or cirrhosis, regression of fibrosis has been associated with a reduced risk of liver-related outcomes (LoE 2).	95%
Improvement in disease activity and resolution of steatohepatitis have been associated with regression of fibrosis (LoE 2).	98%
Reduction of steatosis has been associated with histological improvements (particularly necro-inflammation) in some pharmacological intervention studies (LoE 2).	98%
Since improved mortality has not been demonstrated for any of these treatment-induced histological changes, further long-term follow-up studies are needed to demonstrate that halting disease progression and/or reduction of steatosis, resolution of steatohepatitis or regression of fibrosis translate into a reduced risk of clinical outcomes (LoE 3).	95%
Non-invasive tests have been linked with histologically assessed treatment response, but the most appropriate non-invasive test may depend on the type of intervention and patient-related factors (LoE 2).	100%
Longitudinal changes in non-invasive test results have been correlated with changes in the risk of adverse outcomes on a cohort or population level (LoE 3).	92%
In the setting of randomised controlled trials and depending on the mode of intervention, changes of non-invasive markers (e.g., MRI-PDFF relative reduction by ≥30%, ALT reduction by ≥17 U/L) have been associated with resolution of steatohepatitis (LoE 2).	98%
Liver biopsy is not suited for monitoring disease evolution or response to therapy in routine clinical practice due to its invasiveness and procedure-related limitations (LoE 5).	95%
At the individual level, non-invasive tests may be repeatedly used to assess fibrosis progression in a tailored fashion but may provide limited information about treatment response (LoE 5, weak recommendation).	95%
In individual cases and in clinical trials, liver biopsy can be used to monitor disease progression or response to treatment (LoE 1, open recommendation).	100%
Given the multidirectional connections between MASLD and cardiometabolic comorbidities, a multidisciplinary approach is recommended to ensure all components are appropriately targeted to improve both liver-related and extrahepatic outcomes (LoE 3, strong recommendation).	100%
Treatment of MASLD: Non-pharmacological therapy
In adults with MASLD, dietary and behavioural therapy-induced weight loss should be recommended to improve liver injury, as assessed histologically or non-invasively (LoE 1, strong recommendation).	100%
In adults with MASLD and overweight, dietary and behavioural therapy-induced weight loss should aim at a sustained reduction of ≥5% to reduce liver fat, 7-10% to improve liver inflammation, and ≥10% to improve fibrosis (LoE 2, strong recommendation).	100%
Further follow-up studies are needed to determine the long-term effectiveness of dietary and behavioural therapy-induced weight loss (including its magnitude) on clinical liver-related outcomes and liver-related mortality (LoE 3).	100%
In adults with MASLD, improving diet quality (similar to the Mediterranean dietary pattern), limiting the consumption of ultra-processed food (rich in sugars and saturated fat) and avoiding sugar-sweetened beverages should be recommended to improve histologically or non-invasively assessed liver injury (LoE 2, strong recommendation).	95%
There is little evidence that improving diet quality beneficially impacts clinical liver-related outcomes (LoE 3).	93%
In adults with MASLD, physical activity and exercise should be recommended to reduce steatosis, tailored to the individual’s preference and ability (preferably >150 min/week of moderate or 75 min/week of vigorous-intensity physical activity) (LoE 1, strong recommendation).	97%
In comparison to the well-documented cardiometabolic benefits, there is less robust evidence for benefits of physical activity and exercise on histological outcomes, non-invasively assessed liver damage/fibrosis and liver-related clinical outcomes (LoE 5).	96%
In normal-weight adults with MASLD, diet and exercise interventions should be recommended to reduce liver fat (LoE 3, strong recommendation).	100%
In normal-weight adults with MASLD there is currently no evidence regarding the beneficial effect of diet and/or exercise on liver histology, fibrosis and liver-related clinical outcomes (LoE 5).	92%
In adults with MASLD, nutraceuticals cannot be recommended since there is insufficient evidence of their effectiveness in reducing histologically/non-invasively assessed liver damage/fibrosis and liver-related outcomes in MASLD, nor of their safety (LoE 2, open recommendation).	98%
In adults with MASLD, coffee consumption has been associated with improvements in liver damage and reduced liver-related clinical outcomes in observational studies (LoE 4).	95%
Treatment of MASLD: Pharmacological therapy
If approved locally and dependent on the label, adults with non-cirrhotic MASH with significant liver fibrosis (stage ≥2) should be considered for treatment with resmetirom as a MASH-targeted therapy, as this treatment demonstrated histological efficacy on steatohepatitis and fibrosis in a large phase III registrational trial with an acceptable safety and tolerability profile (LoE 2, strong recommendation).	88%
Treatment with resmetirom, if approved locally, may be considered for individuals with MASLD who are non-cirrhotic and with documentation of either: (A) advanced fibrosis; (B) at-risk steatohepatitis with significant fibrosis (by liver biopsy, when available, or by non-invasive panels validated for that purpose); or (C) risk of adverse liver-related outcomes (e.g., by elastography- or biomarker-defined thresholds) (LoE 3, open recommendation).	89%
No MASH-targeted pharmacotherapy can currently be recommended for adults with MASH at the cirrhotic stage (LoE 5, weak recommendation).	95%
Given the lack of robust demonstration of histological efficacy on steatohepatitis and liver fibrosis derived from large phase III trials and potential long-term risks, vitamin E cannot be recommended as a MASH-targeted therapy (LoE 2, weak recommendation).	100%
For individuals with MASLD undergoing therapy with resmetirom, data on sustainability of histological benefits, individual prediction of response, liver-related outcomes and long-term safety are currently not available (LoE 5).	100%
In the absence of a formal demonstration of histological improvement in large, well conducted, phase III trials, glucagon-like peptide 1 receptor agonists (GLP1RA) cannot currently be recommended as MASH-targeted therapies (LoE 5, strong recommendation).	98%
GLP1RAs are safe to use in MASH (including compensated cirrhosis) and should be used for their respective indications, namely type 2 diabetes and obesity, as their use improves cardiometabolic outcomes (LoE 2, strong recommendation).	98%
Where available, pioglitazone is safe to use in adults with non-cirrhotic MASH but given the lack of robust demonstration of histological efficacy on steatohepatitis and liver fibrosis in large phase III trials, pioglitazone cannot be recommended as a MASH-targeted therapy (LoE 2, weak recommendation).	88%
There is insufficient evidence to recommend the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors or metformin as MASH-targeted therapies; however, they are safe to use in MASLD and should be used for their respective indications, namely type 2 diabetes, heart failure and chronic kidney disease (LoE 3, strong recommendation).	100%
In case of substantial weight loss induced by GLP1RAs, a hepatic histological benefit could be expected, although this has not been extensively documented so far (LoE 2).	98%
There is insufficient evidence to support using any other glucose-lowering drug class as MASH-targeted therapies (LoE 5).	100%
Non-incretin-based weight-loss agents are not recommended as MASH-targeted therapies (LoE 5, strong recommendation).	98%
Treatment of MASLD: Surgical and endoscopic therapy
In adults with non-cirrhotic MASLD who have an approved indication, bariatric surgery should be considered because it can induce long-term beneficial effects on the liver and is associated with remission of type 2 diabetes and improvement of cardiometabolic risk factors (LoE 3, strong recommendation).	98%
In adults with MASLD-related compensated advanced chronic liver disease/compensated cirrhosis who have an approved indication, bariatric surgery can be considered but careful evaluation (indication, type of surgery, presence of clinically significant portal hypertension) by a multidisciplinary team with experience in bariatric surgery in this particular population is required (LoE 4, weak recommendation).	100%
Metabolic/bariatric endoscopic procedures require further validation as MASH-targeted therapy and cannot currently be recommended (LoE 4, weak recommendation).	100%
End-stage liver disease and liver transplantation
In adults with MASH cirrhosis, it is recommended that dietary and lifestyle recommendations be adapted to the severity of liver disease, nutritional status and the presence of sarcopenia/sarcopenic obesity (LoE 2, strong recommendation).	100%
In adults with sarcopenia, sarcopenic obesity or decompensated cirrhosis, it is recommended that a high-protein diet is provided, as well as a late-evening snack (LoE 2, strong recommendation).	93%
Moderate weight reduction can be suggested in adults with compensated cirrhosis and obesity, with an emphasis on high protein intake and physical activity to maintain muscle mass and reduce the risk of sarcopenia (LoE 3, weak recommendation).	100%
Metformin can be used in adults with compensated cirrhosis and preserved renal function but should not be used in adults with decompensated cirrhosis, especially when there is concomitant renal impairment, because of the risk of lactic acidosis (LoE 3, strong recommendation).	100%
Sulfonylureas should be avoided in adults with hepatic decompensation because of the risk of hypoglycaemia (LoE 4, weak recommendation).	98%
GLP1 receptor agonists can be used in adults with Child-Pugh class A cirrhosis, according to its indication (LoE 2, weak recommendation).	98%
SGLT2 inhibitors can be used in adults with Child-Pugh class A and B cirrhosis (LoE 4, weak recommendation).	92%
Statins can be used in adults with chronic liver disease, including those with compensated cirrhosis; they should be used in adults according to cardiovascular risk guidelines to reduce cardiovascular events (LoE 1, strong recommendation).	98%
Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) ≤15 kPa plus platelet count ≥150 × 109/L may be used to rule out clinically significant portal hypertension (CSPH) in adults with MASLD (LoE 3, weak recommendation).	95%
If CSPH is present, non-selective beta-blockers may be started unless contraindicated (LoE 3, weak recommendation).	97%
In adults with compensated advanced chronic liver disease but LSM ≥20 kPa and/or platelet count <150 × 109/L, an upper gastrointestinal endoscopy should be performed to screen for varices unless they already fulfil the criteria to initiate non-selective beta-blockers (LoE 3, strong recommendation).	98%
The threshold of LSM ≥25 kPa to rule in CSPH is only applicable to non-obese (BMI <30 kg/m2) adults with MASLD; while obesity can confound LSM, current evidence is insufficient to suggest the optimal non-invasive test to rule in CSPH in adults with MASLD and obesity (LoE 3).	97%
Adults with MASLD are at increased risk for major cardiovascular events in the pre-, peri- and post-transplant phase (LoE 2).	100%
Adults with MASLD who are candidates for liver transplantation should be evaluated by a multidisciplinary team for cardiovascular and metabolic comorbidities to mitigate the risk of major cardiovascular events in the pre-, peri- and post-transplant phase (LoE 3, strong recommendation).	100%
A comprehensive screening for comorbidities in adults with MASLD before liver transplantation (Table 11), including a stepwise and risk-adjusted cardiac work-up algorithm (Fig. 5), may help to optimise management of adults with MASLD before, during and after liver transplantation (LoE 5, weak recommendation).	100%
Adults with obesity and end-stage MASLD listed for liver transplantation should undergo therapeutic interventions aimed at weight reduction without worsening sarcopenia as this will improve peri-operative outcomes (LoE 3, strong recommendation).	98%
Implementation of dietary modification and supervised physical exercise should be the first line management approach with the objective of reducing BMI <40 kg/m2 and ideally <35 kg/m2 (LoE 1, strong recommendation).	100%
In adults with end-stage MASLD listed for liver transplantation, pharmacological weight-loss strategies may be considered after careful risk-benefit assessment (e.g. presence of sarcopenia, liver function impairment) (LoE 4, weak recommendation).	86%
In adults with compensated cirrhosis and without clinically significant portal hypertension, sleeve gastrectomy prior to liver transplantation may be considered as an alternative option to dietary or pharmacological weight loss (LoE 3, open recommendation).	97%
In case of decompensated cirrhosis, bariatric surgery is contraindicated and needs to be discussed in the context of considering liver transplantation (LoE 4, open recommendation).	100%
Weight loss and optimised treatment of comorbidities before transplantation may confer a benefit in terms of cardiovascular morbidity, as well as long-term survival and reduced recurrence of severe MASLD after liver transplantation (LoE 3).	100%
In adults transplanted for MASLD-related end-stage liver disease, there is a high risk of recurrence of MASLD after liver transplantation, especially in adults with several metabolic risk factors (LoE 3).	100%
Adults transplanted for MASLD-related end-stage liver disease are also at risk of cardiovascular events and kidney disease which can negatively impact long-term survival (LoE 2).	100%
No specific issues related to MASLD are known to alter choice of medication or target values; the risk of recurrence of severe, fibrotic steatohepatitis reinforces the need to obtain optimal control of cardiometabolic risk factors (LoE 5).	100%
The benefit of controlling weight and obesity-related comorbidities on recurrence of MASLD post-liver transplant and on progression to advanced fibrosis is expected but needs to be demonstrated in dedicated trials (LoE 5).	100%
In adults transplanted for MASLD-related end-stage liver disease, therapeutic interventions to control obesity and related cardiometabolic complications are recommended (LoE 3, strong recommendation).	100%
After liver transplantation, standard non-pharmacological dietary and lifestyle interventions should be universally implemented; pharmacological management of hypertension, type 2 diabetes and lipid disorders should be implemented according to general clinical guidelines (LoE 3, strong recommendation).	100%
GLP1 receptor agonists may be considered to control weight and obesity-related comorbidities, although specific trials in transplant recipients are needed (LoE 5, weak recommendation).	100%