Corrigendum. Multidisciplinary clinical practice guideline on the management of metabolic hepatic steatosis

Abstract

Metabolic hepatic steatosis (MetHS) is a clinically heterogeneous, multisystemic, dynamic, and complex disease, whose progression is one of the main causes of cirrhosis and hepatocarcinoma. This clinical practice guideline aims to respond to its main challenges, both in terms of disease burden and complexity. To this end, recommendations have been proposed to experts through the Delphi method. The consensus was optimal in recommendations regarding type 2 diabetes as a risk factor (1.5.1, 4.5.1), in which cases early detection of MetHS should be carried out (4.5.2). Its results also emphasize the importance of the use of non-invasive tests (FIB-4, NFS, HFS) for the exclusion of significant fibrosis in patients with suspected MetHS (2.3.1, 2.3.3). Diagnosis should be carried out through the sequential combination of non-invasive indices and transient elastography by FibroScan® for its risk stratification (2.3.3). A nearly unanimous consensus was reached regarding the role of early prevention in the impact on the quality of life and survival of patients (5.1.2), as well as on the effectiveness of the Mediterranean diet and physical exercise in relation to the improvement of steatosis, steatohepatitis and fibrosis in MetHS patients (5.2.2) and on the positive results offered by resmiterom and semaglutide in promoting fibrosis regression (5.4.1). Finally, a great consensus has been reached regarding the importance of multidisciplinary management in MetHS, for which it is essential to agree on multidisciplinary protocols for referral between levels in each health area (6.2.1), as well as ensuring that referrals to Hepatology/Digestive and Endocrinology or Internal Medicine services are effective and beneficial to prevent the risk of disease progression (6.2.3, 6.3.1).

Resumen

La esteatosis hepática metabólica (EHmet) es una enfermedad clínicamente heterogénea, multisistémica, dinámica y compleja, cuyo progreso es una de las causas principales de cirrosis y hepatocarcinoma. La presente guía de práctica clínica pretende dar respuesta a los principales desafíos que presenta, tanto en su carga de enfermedad como en su complejidad. Para ello se han propuesto una serie de recomendaciones consensuadas mediante el método Delphi. El consenso resultó óptimo en las recomendaciones relativas a la diabetes tipo 2 como factor de riesgo (1.5.1, 4.5.1), en cuyos casos se debe llevar a cabo una detección precoz de EHmet (4.5.2). Destaca la importancia del uso de pruebas no invasivas (FIB-4, NFS, HFS) para la exclusión de fibrosis significativa en pacientes con sospecha de EHmet (2.3.1, 2.3.3). El diagnóstico debe ser llevado a cabo a través de la combinación secuencial de índices no invasivos y elastografía transitoria mediante FibroScan® para una correcta estratificación del riesgo (2.3.3). Se ha alcanzado un consenso casi unánime en el papel de la prevención precoz en el impacto en la calidad de vida y supervivencia de los pacientes (5.1.2), así como en la efectividad de la dieta mediterránea y el ejercicio físico en relación con la mejoría de la esteatosis, la esteatohepatitis y la fibrosis en pacientes con EHmet (5.2.2) y en los resultados positivos ofrecidos por resmiterom y semaglutida para promover la regresión de la fibrosis (5.4.1). Finalmente, se ha alcanzado un gran consenso en la importancia del manejo multidisciplinar de EHmet, para el cual es esencial consensuar protocolos multidisciplinares de derivación entre niveles en cada área sanitaria (6.2.1), así como que las derivaciones a los servicios de hepatología/digestivo y endocrinología o medicina interna resulten efectivas y beneficiosas para prevenir el riesgo de progresión de la enfermedad (6.2.3, 6.3.1).

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a biologically and clinically heterogeneous disease defined by the accumulation of fat in the liver. It is considered the liver component of a group of diseases associated with metabolic dysfunction¹ in the absence of alcohol use.

From a histological point of view, MASLD ranges from simple steatotic liver disease (steatosis without inflammation) and steatohepatitis (steatosis, inflammation and ballooning with varying degrees of fibrosis) to cirrhosis and hepatocellular carcinoma. Approximately 80% of patients with MASLD have simple steatotic liver disease, which progresses to more advanced forms of the disease in about 20% of patients. It is, therefore, one of the most common causes of cirrhosis and hepatocellular carcinoma.²

MASLD is a multisystem disease; in patients who have developed significant liver disease, and particularly in those with liver cirrhosis, the mortality risk is related to the liver disease, but in the rest of patients diagnosed with MASLD, the mortality risk is related to cardiovascular events and cancer, both hepatic and extrahepatic.³

The aim with these clinical practice guidelines is to address the main challenges posed by this disease: its huge burden and complexity, and its dynamism and heterogeneity. We thus need to develop non-invasive tools for diagnostic management and risk stratification, while at the same time creating multidisciplinary teams to ensure the care we provide covers all aspects of the disease.

Methods

We have followed the Delphi method throughout the development of this consensus, by selecting experts in MASLD belonging to the nine Spanish scientific societies involved in the management of the disease: AEEH, SEEN, SEMFYC, SEMI, SEPD, SEMERGEN, SEEDO, SED and SEMG. We designed an initial questionnaire with PICO (population, intervention, comparator and outcomes) questions, which were answered taking into account the scientific evidence available for each of the four items. This questionnaire was submitted to two iterative rounds. In the first, the experts responded to the initial questionnaire in full, and the organising team compiled, analysed and summarised the responses, identifying patterns, consensus and areas of disagreement. Based on the disagreements, a new questionnaire was generated and completed in a second round. The new questionnaire contained a reformulation of the questions, enabling discrepancies to be explored and validating the points of consensus. This helped reach an optimal degree of consensus among the participants. It is important to note that reaching a consensus did not mean obtaining unanimous responses, but rather that the organisers perceived the existence of general agreement on the key points related to the consensus.

The first round was carried out in AEEH's RedCAP and the second round in Google Forms®, given the lower volume of recommendations to be evaluated.

Once the responses from the working group were obtained, we carried out a qualitative and quantitative analysis of the degree of agreement. We arbitrarily established that an excellent level would be between 90% and 100% and an optimal level between 75% and 90%. Recommendations with agreement below 75% were evaluated in the second round (Table 1).

Table 1.

Relationship between the degree of consensus, degree of recommendation and level of evidence of each of the proposed recommendations.

Recommendation	Degree of consensus	Degree of recommendation	Level of evidence
1.1.1. In Spanish, the use of the term "esteatosis hepática metabólica" [metabolic hepatic steatosis] and its acronym "EHmet" are recommended	93.3%	Strong	4
1.1.2. in English, the term metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended	93.3%	Strong	4
1.2.1. Screening for MASLD is recommended in patients with risk factors and especially those at risk of developing steatohepatitis and fibrosis (diabetes, obesity, high blood pressure, metabolic syndrome, or kidney or cardiovascular disease) regardless of transaminase levels	95.8%	Strong	1
1.3.1. We recommend that patients with suspected liver disease be investigated for the presence of MASLD, as MASLD is the most common cause of chronic liver disease in industrialised countries	91.7%	Strong	2
1.3.2. We recommend investigating the stage of liver fibrosis, as fibrosis is the variable that independently predicts the progression of the damage, the development of complications and long-term mortality	96.7%	Strong	2
1.4.1. We recommend taking into account the characteristics of the disease in the day-to-day approach to its management, as MASLD is a heterogeneous, complex, dynamic disease, modulated by genetics, metabolic disorders and the gut-liver axis	96.7%	Strong	2
1.5.1. We recommend investigating for diabetes and alcohol consumption, as they are associated with an increased risk of fibrosis progression, liver decompensation and liver cancer	97.4%	Strong	2
2.1.1. For all patients with suspected MAFLD, non-invasive testing is recommended to stratify their risk	98.3%	Strong	2
2.1.2. The use of the serum indices Hepatitis Steatosis Index (HSI) and Fatty Liver Index (FLI) is recommended for the detection of steatosis	91.7%	Weak	3
2.1.3. We recommend not to taking into account the normality of transaminases, as it does not correlate with the diagnosis or severity of MASLD	91.7%	Strong	1
2.1.4. The use of ultrasound is recommended as the imaging test of choice for the study of chronic liver disease, although its sensitivity is limited for the detection of MASLD	92.5%	Strong	2
2.1.5. When available, the Controlled Attenuated Parameter (CAP) is recommended to quantify steatotic liver disease	84.2%	Weak	2
2.1.6. We recommend using proton density fat fraction by magnetic resonance imaging (PDFF-MRI) as the reference test to quantify steatotic liver disease	92.5%	Strong	2
2.2.1. Further studies are recommended to validate the impact of serum markers of steatohepatitis on clinical practice	96.7%	Strong	4
2.3.1. The use of serum fibrosis indices is recommended as a first approach for the exclusion of significant fibrosis in patients with suspected MASLD, especially in those with risk factors such as diabetes, immune-mediated diseases, obesity and metabolic syndrome	98.3%	Strong	2
2.3.2. The use of non-invasive methods such as FIB-4, NFS and HFS is recommended, as they are validated in the population with MASLD and have a high diagnostic efficiency, although FIB-4 is the most used	92.5%	Strong	2
2.3.3. We recommend the sequential combination of non-invasive indices, such as FIB-4/NFS/HFS and transient elastography (TE) or ELF, as they have demonstrated high diagnostic and risk stratification capacity	96.7%	Strong	2
3.1.1. The use of lipidomics- or proteomics-based approaches as screening tools is not recommended, as they do not improve the diagnostic performance of FIB-4	71%	Strong	2
3.1.2. We recommend validating the OWLiver diagnostic algorithm in the Spanish population as a one-step diagnostic method, as it has been validated in the NIMBLE project for the diagnosis of steatohepatitis, and included in the MASEF biomarker for the diagnosis of steatohepatitis at risk of progression in a single step	81.6%	Strong	2
3.1.3. We recommend that further studies be conducted to validate the utility of the SomaScan proteomic algorithm SomaSignal for the detection of advanced liver fibrosis in MASLD before its implementation in clinical practice	85.5%	Strong	2
3.2.1. The use and availability of non-invasive methods for the detection of MASLD with liver fibrosis, such as FIB-4 and VCTE, is recommended in primary care and other healthcare units for patients at risk of MASLD	93.3%	Strong	1
3.2.2. The use of a combination of diagnostic methods such as FIB-4 together with second-line methods such as transient elastography or ELF is recommended, as it is a validated, cost-effective strategy, and should be available in clinics that treat patients at high risk for MASLD	93.3%	Strong	1
4.1.1. We recommend investigating MASLD in patients at cardiovascular risk, as MASLD is associated with an increase in non-fatal cardiovascular disease	91.7%	Strong	2
4.1.2. We recommend intensifying cardiovascular risk prevention in patients with MASLD, with special emphasis on patients who are young at diagnosis and those with advanced fibrosis	87.5%	Strong	1
4.3.1. We recommend intensifying cardiovascular and extrahepatic cancer prevention in patients with MASLD without cirrhosis, as there is a higher mortality rate associated with higher cardiovascular risk and the development of extrahepatic cancer	96.7%	Strong	2
4.3.2. We recommend intensifying the prevention of liver decompensation and hepatocellular carcinoma in patients with MASLD and cirrhosis, as in patients with cirrhosis, mortality risk is associated with the development of hepatocellular carcinoma and complications of liver cirrhosis	88.3%	Strong	1
4.4.1. In patients with MASLD without fibrosis, assessment every three years with non-invasive methods of fibrosis indices (FIB-4, HFS; NFS) is recommended	85.8%	Weak	2
4.4.2. In patients with significant fibrosis (≥ F2) assessment is recommended every year	92.5%	Weak	2
4.4.3. In patients with advanced fibrosis (F3-F4), hepatoportal ultrasound is recommended every six months to screen for hepatocellular carcinoma (HCC) and the development of portal hypertension	87.5%	Strong	1
4.5.1. Early detection of MASLD is recommended in all individuals with type 2 diabetes	95.8%	Strong	1
4.5.2. Monitoring for the development of diabetes in patients with MASLD is recommended, as individuals without diabetes with MASLD and significant fibrosis show an increased risk of developing type 2 diabetes	95.8%	Weak	2
4.5.3. We recommend monitoring for the development of hypertension, as normotensive individuals with MASLD and significant fibrosis show an increased risk of developing hypertension	81.7%	Weak	2
4.6.1. Early diagnosis of MASLD is recommended in all people with obesity	94.2%	Strong	1
4.6.2. We recommend assessing nutritional status in all patients with MASLD, especially those on the liver transplant waiting list	94.2%	Strong	1
4.6.3. In patients with obesity and MASLD, we recommend assessing comorbidities such as insulin resistance, polycystic ovary syndrome and obstructive sleep apnoea-hypopnoea syndrome	87.5%	Strong	1
5.1.1. We recommend that therapeutic goals pursue the regression of fibrosis with the consequent positive impact on prognosis	96.6%	Strong	3
5.1.2. We recommend that a reduction in the rate of hepatocellular carcinoma (HCC) development, early detection and prevention of progression to cirrhosis and liver decompensation be considered as objectives with a high impact on patient quality of life and survival	99.2%	Strong	4
5.2.1. Lifestyle modification with a low-calorie Mediterranean diet and moderate aerobic physical exercise is recommended with the goal of weight loss	93.3%	Strong	1
5.2.2. We recommend promoting 10% loss of body weight through lifestyle changes, with diet and exercise, as this is accompanied by an improvement in steatotic liver disease, steatohepatitis and fibrosis in patients with MASLD	98.3%	Strong	2
5.2.3. We recommend that the macronutrient content of the diet focus on limiting the intake of ultra-processed products, saturated and trans fats, sugary drinks and alcohol	97.5%	Strong	3
5.2.4. We recommend following a Mediterranean-style diet	97.5%	Strong	2
5.2.5. We recommend doing regular physical exercise, both aerobic and resistance, moderate physical activity, 30−60 min a minimum of 3−5 times a week, as this works together in tandem with a balanced diet to achieve the planned goals of changes in body composition and cardiometabolic and liver health	96.6%	Strong	2
5.3.1. To treat hyperglycemia, we recommend considering drugs with a beneficial effect on MASLD (GLP-1 receptor agonist, pioglizatone, SGLT-2 inhibitor)	86.6%	Strong	3
5.3.2. We recommend considering adding drugs with cardiovascular benefits, such as GLP-1RA, SGLT2 inhibitors and pioglitazone	89.1%	Strong	3
5.3.3. The use of statins is recommended to treat dyslipidaemia associated with the aim of reducing cardiovascular risk	98.3%	Strong	3
5.4.1. The use of drugs that promote fibrosis regression such as resmetirom and semaglutide is recommended when available	96.7%	Strong	1
5.4.2. Drugs used in the management of comorbidities such as statins, metformin or vitamin E are not recommended for the purpose of improving fibrosis, as they have not demonstrated efficacy in the regression of fibrosis unequivocally	99.2%	Strong	3
5.4.3. Pioglitazone is recommended for the treatment of MASLD in patients with diabetes without liver cirrhosis, risk of heart failure or grade 2 obesity	93.3%	Strong	4
6.1.1. In all patients with MASLD, a detailed medical history is recommended to rule out comorbidities, as well as other causes of disease such as viral hepatitis or haemochromatosis	97.5%	Strong	1
6.1.2. Universal access for primary care physicians to steatosis and fibrosis calculators, abdominal ultrasound, direct laboratory determination of fibrosis indices, and transient elastography is recommended for stratifying the risk of MASLD-fibrosis	87.4%	Strong	3
6.1.3. We recommend that patients with transient elastography values ≥8 kPa or ELF > 9.8 be referred to hepatology to rule out advanced fibrosis and initiate screening for hepatocellular carcinoma and portal hypertension	95.8%	Strong	1
6.1.4. Vaccination against hepatitis A and B is recommended for patients with MASLD	82.4%	Weak	3
6.1.5. Initial assessment for cardiometabolic risk and extrahepatic cancer is recommended to design a personalised care and monitoring plan according to the risk	89.1%	Strong	2
6.2.1. It is recommended that multidisciplinary referral protocols be agreed on between levels in each health area	97.5%	Weak	4
6.2.2. Referral to endocrinology or internal medicine is recommended for people with type 2 diabetes with poor metabolic control (HbA1c > 8.5%) and/or severe complications of diabetes (target organ damage), severe obesity, treatment-resistant hypertension, SAHS and severe dyslipidaemia, as well as acute complications of diabetes after optimised treatment in primary care	84.9%	Strong	3
6.3.1. Referral to gastroenterology/hepatology is recommended for all patients at risk of disease progression, i.e., patients with steatohepatitis and significant fibrosis or advanced fibrosis, as well as all patients with advanced chronic liver disease	95.8%	Strong	3
6.3.2. Screening of at-risk patients using non-invasive, methods in two steps is recommended (FIB-4/NFS/HFS + ELF/OWLiver/VCTE), as it is cost-effective through reducing the disease burden in hepatology units and therefore healthcare expenditure	85.7%	Strong	2
6.3.3. We recommend referring to hepatology for accurate evaluation of liver damage and assessment of the risk of progression, as well as promoting early intervention in complications by optimising treatment	95.8%	Strong	3
6.4.1. In cases of low risk of fibrosis, re-assessment using non-invasive markers is recommended every 2−3 years, and in cases of significant fibrosis, annual follow-up is recommended	95.8%	Strong	3
6.4.2. In cases of cirrhosis, follow-up every six months is recommended to assess the progression of portal hypertension and screening for hepatocarcinoma	98.3%	Strong	3
6.4.3. In all cases, screening for and monitoring of comorbidities is recommended, as well as promoting smoking cessation and avoiding alcohol consumption, recommending moderate aerobic physical exercise and a healthy diet, and reinforcing adherence to treatment	97.5%	Strong	1
6.5.1. We recommend that the minimum core members of the multidisciplinary team be the primary care physician and nurse, the internal medicine specialist, the endocrinologist and the gastroenterologist or hepatologist. The first three are key for prevention and identifying people at risk for MASLD and their assessment, including estimating fibrosis risk, and managing risk factors and associated comorbidities. The hepatologist should be responsible for further assessment of liver disease and management of advanced liver disease. Depending on the needs, available resources and the organisation, other healthcare professionals may form part of these teams.	89.9%	Strong	4
6.5.2. The multidisciplinary approach requires that the roles of all healthcare professionals be explained and the patient's reference clinical representative be identified. Systematic meetings on clinical and organisational content should also be planned.	96.6%	Strong	4

Concept and definition of metabolic dysfunction-associated steatotic liver disease

Since the early 2000s, various proposals have been made to change the international name of this disease. Until 2020, in the absence of a general consensus, non-alcoholic fatty liver disease (NAFLD) was the name in common use. In recent years, the term “metabolic dysfunction-associated fatty liver disease” (MASLD) has gained ground to highlight the importance of metabolic risk factors in the development and progression of liver disease, even among patients with other liver diseases.⁴ The proposal for this new name was motivated by the need for a non-exclusive definition, as the term "non-alcoholic" overemphasises the lack of alcohol consumption. The aim is also to avoid the stigma of the word fatty and, last of all, give importance to metabolic dysfunction as a central part of the pathogenesis, which is underestimated in the current definition.⁵ The proposed name in Spanish, "esteatosis hepática metabólica" (EHmet) (literally, "metabolic hepatic steatosis"), was defined in a consensus conference of the Asociación Española para el Estudio del Hígado (AEEH) [Spanish Association for the Study of the Liver].⁶ The term "steatotic liver disease" (SLD) would be translated into Spanish as "esteatosis hepática" (literally "hepatic steatosis) or "hígado graso" [fatty liver], which would cover the entire spectrum of disease from MASLD to alcoholic liver disease (ALD). From this, the term metabolic and alcohol-related/associated liver disease (Met-ALD) was coined, which combines the two aetiologies.⁷

Recommendation 1.1.1: in Spanish, we recommend the use of the term "esteatosis hepática metabólica" [metabolic hepatic steatosis] and its acronym EHmet (level of evidence [LoE]: 4; degree of recommendation: strong; degree of consensus: 93.3%).

Recommendation 1.1.2: in English, the use of the term metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended (LoE: 4; degree of recommendation: strong; degree of consensus: 93.3%).

What is the prevalence of metabolic dysfunction-associated steatotic liver disease and which populations are at higher risk?

It is estimated that between 17% and 46% of European adults suffer from MASLD, the average being 25–30 %. MASLD affects people of all ages, including children.⁸ The condition is directly related to calorie intake, lack of physical activity and obesity. The prevalence of MASLD is therefore very high in people who have these risk factors. Steatohepatitis occurs in 20–25 % of people with MASLD (1.5–6.5 % of the general population). Advanced fibrosis occurs in 1.5% of the general adult population and up to 15% of people with type 2 diabetes (T2DM). The prevalence is 70% in patients with T2DM, 90% in those with grade 3 obesity, 60–70 % in those with grade 2 obesity and 50–60 % in people with high blood pressure or hyperlipidaemia.⁹ Of those with MASLD, 20–25 % have a standard body weight, and its worldwide geographical distribution places around 25% in Malaysia or Pakistan and more than 50% in Austria, Mexico and Sweden. The prevalence of MASLD increases with age, and its association with genetic variants and ethnicity has been noted. It tends to affect more individuals carrying the GG genotype of the PNPLA3 gene and those of Asian and Hispanic origin, and its prevalence is much lower in individuals of African origin. For all of the above, early detection of MASLD is currently recommended in patients at risk, and more specifically in those at risk of developing steatohepatitis and/or fibrosis.¹⁰ These risk categories include two large groups: 1) people with chronic abnormal liver biochemistry (over six months); and 2) people with T2DM, individuals with overweight/obesity, subjects with metabolic syndrome and those with cardiovascular disease, even with normal liver biochemistry.¹¹ Patients with type 1 diabetes mellitus (T1DM) could be another target population, but it is too early to make a clear recommendation, unless it is associated with obesity or other risk factors such as those listed above.

Recommendation 1.2.1: screening for MAFLD is recommended in patients with risk factors and especially those at risk of developing steatohepatitis and fibrosis (diabetes, obesity, high blood pressure, metabolic syndrome or kidney or cardiovascular disease), regardless of transaminase levels (LoE: 1; degree of recommendation: strong; degree of consensus: 95.8%).

Concepts of prevalent chronic liver disease and significant liver fibrosis

MASLD has become a major public health problem worldwide, and specifically also in Spain, where it is estimated to affect 25% of the population.^12,13 The importance of assessing the degree of fibrosis lies in its perception as a variable with the greatest impact on damage progression, the development of complications and long-term mortality. Significant fibrosis is understood as that equal to or greater than F2 in the liver biopsy and/or greater than 8 Kpa in liver elastography using Fibroscan®.

Although the exact prevalence of fibrosis in the general population is not known, a very recent study which combines data from a large population and a cohort of patients diagnosed with MASLD by liver biopsy, estimates that the prevalence of MASLD with significant fibrosis and cirrhosis in the Spanish adult population is 2.03% (95% CI: 0.29–5.98) and 0.70% (95% CI: 0.10–4.95), respectively.¹⁰ Being male, central obesity and having T2DM, high triglyceride levels, low HDL cholesterol and elevated aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT) are independently associated with increased liver stiffness. It has also been concluded that men over 50 years of age, postmenopausal women and people with multiple cardiometabolic risk factors make up the population at greatest risk of progressive fibrosis and the development of cirrhosis and its complications.

Recommendation 1.3.1: we recommend that patients with suspected liver disease be investigated for the presence of MASLD, as MASLD is the most common cause of chronic liver disease in industrialised countries (LoE 2; degree of recommendation: strong; degree of consensus: 91.7%).

Recommendation 1.3.2: we recommend investigating the stage of liver fibrosis, as fibrosis is the variable that independently predicts the progression of the damage, the development of complications and long-term mortality (LoE 2; degree of recommendation: strong; degree of consensus: 96.7%).

Pathogenesis of metabolic dysfunction-associated steatotic liver disease. Why does fat accumulate in the liver? Why does fibrosis occur?

MASLD is a heterogeneous, complex, dynamic disease modulated by genetics, metabolic disorders and the gut-liver axis. It comprises a heterogeneous group of conditions characterised by the accumulation of fat in the liver. Simple steatotic liver disease is defined by the presence of excess fat, typically macrovesicular in at least the 5% of hepatocytes. Steatotic liver disease is closely linked to being overweight, obesity, metabolic syndrome and insulin resistance. Therefore, MASLD can be considered the hepatic expression of metabolic syndrome.^14,15

In states of insulin resistance, ectopic fat deposition (visceral fat) occurs with a progressive accumulation of triglycerides in hepatocytes. Triglycerides are not hepatotoxic in themselves, but in some patients this excess liver fat evolves into steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH]), which is characterised by the presence of hepatocellular damage in the form of ballooned hepatocytes (necrosis), predominantly lobular inflammation and fibrosis. Fibrosis, which is initially pericellular, can progress to bridging fibrosis and cirrhosis, which is a risk factor for the development of hepatocellular carcinoma. Fat accumulation in hepatocytes can induce metabolic stress, oxidative stress and endoplasmic reticulum stress (lipotoxicity). The lipotoxicity of triglycerides accumulated in hepatocytes, together with the activation of the innate immune system, are the main pathogenic mechanisms of MASLD, and lead to the recruitment of macrophages, dendritic cells and lymphocytes, which contribute to perpetuating a chronic inflammatory and profibrotic state. In turn, injury or death of hepatocytes releases cellular signals to try to repair the liver damage, which leads to inflammation, vascular remodelling, fibrogenesis and accumulation of hepatic epithelial cells.¹⁶

Genetic, epigenetic and environmental factors have been described that may generate a predisposition to the development of MASLD. Studies in twins suggest that hereditary factors explain up to half of the interindividual differences in the prevalence of steatohepatitis and cirrhosis.¹⁷ Some polymorphisms in genes that regulate the lipid content of adipocytes (PNPLA3 I148 M, TM6SF2) promote liver damage.¹⁸ Epigenetic factors, such as over- or under-nutrition during pregnancy, can lead to overexpression of genes related to energy metabolism, predisposing to obesity, metabolic syndrome and metabolic liver disease. These same factors can alter the microbiome and lead to a proinflammatory state due to increased intestinal permeability, as well as the production of lipopolysaccharides and other cytokines and hepatotoxic factors.¹⁹

Recommendation 1.4.1: we recommend taking into account the characteristics of the disease in the day-to-day approach to its management, as MASLD is a heterogeneous, complex, dynamic disease, modulated by genetics, metabolic disorders and the gut-liver axis (LoE: 2; degree of recommendation: strong; degree of consensus: 96.7%).

What factors influence the rates of progression of fibrosis and hepatic decompensation?

The rates of progression of fibrosis and hepatic decompensation vary according to the underlying severity of the disease, as well as genetic, environmental and individual determinants and associated comorbidities.⁷ A study by Vilar-Gómez found that in patients with advanced fibrosis the risk of progression to decompensation was increased in those suffering from diabetes, as well as in those with moderate alcohol consumption, and inversely with fatty infiltration in the liver.²⁰ A recently conducted study of 2,227 individuals with MASLD, of whom 9% reported low alcohol consumption and 14% moderate alcohol consumption (below 30 g of alcohol per day in men and 20 g of alcohol per day in women), showed that moderate alcohol consumption is independently associated with significant fibrosis and steatohepatitis at risk of progression.²¹

Recommendation 1.5.1: we recommend investigating for diabetes and alcohol consumption, as they are associated with an increased risk of fibrosis progression, liver decompensation and liver cancer (LoE 2; degree of recommendation: strong; degree of consensus: 97.4%).

Detection of metabolic dysfunction-associated steatotic liver disease

How to detect the presence of metabolic dysfunction-associated steatotic liver disease?

Normal transaminase levels are not, in isolation, related to the stage of MASLD. A recent systematic review showed that 90% of patients with cirrhosis would not have been diagnosed using the usual liver profile tests.²²

Ultrasonography is the imaging test of choice for the detection of MASLD due to its wide availability, low cost and safety. However, its main limitations are its limited sensitivity for the detection of mild steatotic liver disease (it does not detect steatosis if it is < 30%) or in individuals with a poor acoustic window due to obesity, and its inability to differentiate between simple steatotic liver disease and steatohepatitis. Even so, it is part of the assessment of every patient with suspected liver disease. Its specificity is excellent (>90%) in the presence of signs of portal hypertension (intra-abdominal collateral circulation, splenomegaly) and/or liver surface nodularity, even in compensated patients.²³

Various serological indices have been developed to predict the existence of steatotic liver disease, including the Fatty liver index (FLI), triglyceride glucose index, NAFLD-Liver Fat Score, Hepatic Steatosis Index (HSI), and SteatoTest, among others (these four can be calculated at https://www.mdapp.co/hepatology/). The most widely used and best validated are the HSI and the FLI.²⁴ FLI values below 30 allow steatotic liver disease to be ruled out with a likelihood ratio of 0.2, while FLI values greater than or equal to 60 allow steatotic liver disease to be inferred with a likelihood ratio of 4.3.

An HSI of less than 30 indicates that MASLD can be ruled out (with a negative likelihood ratio of up to 0.186), while an HSI of 36 or more indicates that MASLD is present (with a positive likelihood ratio starting at 6.069). Diagnostic reliability is satisfactory with areas under the curve of 0.80−0.92, with a high positive predictive value (99%) and acceptable sensitivity (61–80%). Their main limitation lies in their inability to distinguish between different degrees of steatosis. The Controlled Attenuated Parameter (CAP) included in Fibroscan® allows the detection of steatotic liver disease with high certainty when the result is >258−262 dB/m, and should be corrected upwards in patients with diabetes or obesity.²⁵ Proton density fat fraction by magnetic resonance imaging (PDFF-MRI) is the reference test to assess steatotic liver disease in MASLD, as it has demonstrated superiority over liver biopsy and quantification of fatty infiltration.²⁶

Recommendation 2.1.1: for all patients with suspected MASLD, we recommend non-invasive tests to stratify their risk (LoE: 2; degree of recommendation: strong; degree of consensus: 98.3%).

Recommendation 2.1.2: the use of serum indices HSI and FLI is recommended for the detection of steatotic liver disease (LoE: 3; degree of recommendation: weak; degree of consensus: 91.7%).

Recommendation 2.1.3: we recommend not taking into account the normality of transaminases, as it does not correlate with the diagnosis or severity of MASLD (LoE: 1; degree of recommendation: strong; degree of consensus: 91.7%).

Recommendation 2.1.4: the use of ultrasound is recommended as the imaging test of choice for the study of chronic liver disease, although its sensitivity is limited for the detection of MASLD (LoE: 2; degree of recommendation: strong; degree of consensus: 92.5%).

Recommendation 2.1.5: when available, it is advisable to use CAP to quantify steatotic liver disease (LoE: 2; degree of recommendation: weak; degree of consensus: 84.2%).

Recommendation 2.1.6: we recommend using proton density fat fraction by magnetic resonance imaging (PDFF-MRI) as reference test to quantify steatotic liver disease (LoE: 2; degree of recommendation: strong; degree of consensus: 92.5%).

How to detect steatohepatitis?

Non-invasive detection of MASLD is an unmet need, as results have not been robust enough to date to displace liver biopsy as the main detection method. Serum markers evaluated to predict the presence of steatohepatitis are related to the pathophysiological pathways of the disease (apoptosis/cell death, inflammation and oxidative stress). The most studied is fragmented cytokeratin 18, a degradation product of hepatocyte apoptosis.²⁷ Other markers studied include fibroblast growth factor 21 (FGF21) and adiponectin. However, these have demonstrated very low diagnostic accuracy. Oxidative stress and inflammation markers such as interleukin 6 (IL-6) and tumour necrosis factor−〈 (TNΦ〈) have also been studied. Metabolomics-based studies allowed a Spanish group to develop the OWLiver Test, which differentiates steatohepatitis from simple steatotic liver disease with good sensitivity and specificity (ROC greater than 0.8 in patients with diabetes and obesity). The limitations of use in other ethnic groups and in patients with uncontrolled diabetes have recently been resolved by incorporating transaminases and glycated haemoglobin (HbA1c) into the previous diagnostic algorithm.²⁸ Imaging biomarkers based on magnetic resonance imaging such as DeMILI (NASH-MRI) have similarly reported promising results.²⁹ Metabolomics tests such as OWLiver® and MRI-based imaging markers-DeMILI show good correlation with biopsy for the diagnosis of steatohepatitis.

However, the gold standard in the diagnosis of steatohepatitis continues to be liver biopsy.

Recommendation 2.2.1: further studies are recommended to validate the impact of serum markers of steatohepatitis in clinical practice (LoE: 4; degree of recommendation: strong; degree of consensus: 96.7%).

How to detect fibrosis?

Liver fibrosis has traditionally been classified according to four levels of histological severity: F1 mild fibrosis; ≥F2 significant fibrosis; ≥F3 advanced fibrosis; and F4 liver cirrhosis. Fibrosis is an independent factor influencing prognosis, as well as the progression of liver disease, cardiovascular risk and all-cause mortality.³⁰

Serum markers of liver fibrosis

• a)

  Indirect markers related to liver function, such as albumin, bilirubin, AST and ALT. Among them are fibrosis-4 (FIB-4), NAFLD Fibrosis Score (NFS) and Hepamet Fibrosis Score (HFS).

• b)

  Direct markers, which are components of the extracellular matrix, such as hyaluronic acid, matrix metalloproteinases and collagen subtypes.³¹ The most representative is Enhanced Liver Fibrosis (ELF).

The most studied and validated clinical-analytical indices are FIB-4, NFS and HFS. The HFS, recently developed here in Spain, has shown a significantly higher diagnostic odds ratio than the FIB-4 and NFS to rule out and/or diagnose advanced fibrosis, regardless of the presence or absence of diabetes, BMI and age group,³² and fewer patients with indeterminate results (20% vs 30%). The combined use of HFS, NFS and FIB-4 enables the correct exclusion of patients without advanced fibrosis, which is why they are the methods of choice in primary care or in non-hepatology clinics. Patients in the grey area (combined index >0 but <3, in other words with one or two methods abnormal) may benefit from a second non-invasive method such as ELF or OWLiver, which would help define which patients are at risk of advanced fibrosis.

Image-based fibrosis markers

• a)

  Vibration-controlled transient elastography (VCTE, Fibroscan®) with controlled attenuation parameter (CAP) measurement can assess steatosis and fibrosis simultaneously.³³ Transient elastography (TE) has demonstrated great diagnostic utility for the prediction of advanced fibrosis/liver cirrhosis and has demonstrated its cost-effectiveness in primary care. When liver biopsy is used as the reference standard, TE provides high sensitivity and negative predictive values for the detection of cirrhosis greater than 95%.³⁴ The recommended TE cut-off points to rule out advanced fibrosis and cirrhosis vary from 8 to 13 kPa, depending on the underlying aetiology.³⁵ It should be noted that the medium-term risk of liver events in patients with TE below these parameters is very low (for MASLD, the five-year risk of liver event with FibroScan® <12 kPa is 0.3%).³⁶

• b)

  Ultrasound-based: acoustic radiation force impulse elastography and shear wave elastography. The main theoretical advantages of these techniques (which are incorporated into conventional ultrasound devices) compared to TE by FibroScan® are the higher success rate in obese patients and the ability to assess liver morphology in the same examination.

Some authors have proposed strategies that combine serum markers with TE.³⁷ The sequential combination reduces the area of uncertainty and maintains good sensitivity and specificity³⁸; the combination of FIB-4 or NFS with ELF is among the recommendations of the United Kingdom's National Institute for Health and Care Excellence for the diagnosis of advanced fibrosis in patients with NAFLD.³⁹

Recommendation 2.3.1: the use of serum fibrosis indices is recommended as a first approach to rule out significant fibrosis in patients with suspected MASLD, especially in those with risk factors such as diabetes, immune-mediated diseases, obesity and metabolic syndrome (LoE: 2; degree of recommendation: strong; degree of consensus: 98.3%).

Recommendation 2.3.2: the use of non-invasive methods such as FIB-4, NFS and HFS is recommended, as they are validated in the population with MASLD and have a high diagnostic efficiency, although FIB-4 is the most used (LoE: 2; degree of recommendation: strong; degree of consensus: 92.5%).

Recommendation 2.3.3: we recommend the sequential combination of non-invasive indices, such as FIB-4/NFS/HFS and TE or ELF, as they have demonstrated high diagnostic and risk stratification capacity (LoE: 2; degree of recommendation: strong; degree of consensus: 96.7%).

Diagnosis

What role do omics and metabolomics play in the diagnosis of metabolic dysfunction-associated steatotic liver disease?

Metabolomics studies have shown alterations in the amino acid profile, in lipid species, including circulating fatty acids, triglycerides, phospholipids and bile acids,⁴⁰ as well as in metabolites derived from the gut-liver axis, such as short-chain fatty acids, bile acids and aromatic amino acids. These have emerged as potential biomarkers as they play a role in modulating the pathological process of MASLD.^41–43

The OWLiver diagnostic algorithm has been validated in the NIMBLE project for the diagnosis of MASLD and in the new MASEF biomarker combining OWLiver, BMI and AST/ALT for the diagnosis of steatohepatitis at risk of progression.^44,45 A diagnostic capacity of 0.76 (95% CI: 0.72−0.79) was demonstrated in an estimation cohort of 790 patients and 0.79 (95% CI: 0.75−0.83) in a validation cohort of 565 cases.⁴⁶ Furthermore, the one-step screening strategy with the OWLiver Panel has high accuracy in detecting steatohepatitis and steatohepatitis at risk of progression in subjects at high risk of MASLD.⁴⁷

SomaScan's SomaSignal proteomic algorithm has been validated for the detection of advanced liver fibrosis in MASLD. In patients with significant fibrosis (>F2) no superiority of omics-based methods has been demonstrated compared to available methods such as FIB-4 (AUROC ranging from 0.61 [95% CI: 0.54−0.67] for CAP-VCTE and 0.81 [0.75−0.86] for SomaSignal, similar to FIB-4). In patients with advanced fibrosis (>F3) SomaSignal (AUC 0.90 [95% CI: 0.86−0.94]) demonstrated excellent performance with an NNT of 4 (95% CI: 4–5),⁴⁸ data which coincide with those reported by Sanyal et al.⁴⁹

Recommendation 3.1.1: the use of lipidomics- or proteomics-based approaches as screening tools is not recommended, as they do not improve the diagnostic performance of FIB-4 (LoE 2; degree of recommendation: strong; degree of consensus: 71%).

Recommendation 3.1.2: the OWLiver diagnostic algorithm should be validated in the Spanish population as a one-step diagnostic method, as it has been validated in the NIMBLE project for the diagnosis of steatohepatitis and included in the MASEF biomarker for the diagnosis of steatohepatitis at risk of progression in a single step (LoE: 2; degree of recommendation: strong; degree of consensus: 81.6%).

Recommendation 3.1.3: it is advisable to promote new studies to validate the utility of the SomaScan proteomic algorithm SomaSignal for the detection of advanced liver fibrosis in MASLD before its implementation in clinical practice (LoE 2; degree of recommendation: strong; degree of consensus: 85.5%) Table 1.

What tests should be available to primary care and other specialities caring for patients at high risk for metabolic dysfunction-associated steatotic liver disease?

Primary care is the gateway for patients into the healthcare system, allowing patients at risk for MASLD to also be treated by endocrinologists, internal medicine specialists, dermatologists, psychiatrists, cardiologists, neurologists or rheumatologists. The techniques that should be available at this level of care have to be able to diagnose steatotic liver disease and stratify the risk of advanced fibrosis. For diagnosis, liver ultrasound should be used to rule out hyperechoic liver and non-invasive methods for steatotic liver disease, such as the "fatty liver index" (FLI).⁵⁰ In addition, first-line non-invasive methods for early detection of liver fibrosis⁵¹ such as FIB-4, NAFLD fibrosis score and HFS should be confirmed by measuring liver stiffness (VCTE transient elastography) or through biochemical analysis using ELF.

According to the NASH-PI study,⁵¹ the use of VCTE in primary care is cost-effective, as it reduces the level of expenditure and patient referrals. Therefore, Fibroscan should be available in primary care health centres and/or in other healthcare units that deal with high-risk patients.⁵² Confirmation methods such as liver biopsy, magnetic resonance imaging (MRI) or omics-based methods will be reserved for care in gastroenterology and hepatology units.

Recommendation 3.2.1: the use and availability of non-invasive methods for the detection of MASLD with liver fibrosis such as FIB-4 and VCTE in primary care and other care units for patients at risk of MASLD is recommended (LoE: 1; degree of recommendation: strong; degree of consensus: 93.3%).

Recommendation 3.2.2: the use of a combination of diagnostic methods such as FIB-4 together with second-line methods such as transient elastography or ELF is recommended, as it is a validated, cost-effective strategy and should be available in clinics that treat patients at high risk for MASLD (LoE: 1; degree of recommendation: strong; degree of consensus: 93.3%).

Complications

Are cardiovascular events increased in patients with metabolic dysfunction-associated steatotic liver disease?

Patients with MASLD have a higher mortality rate compared to the rest of the population.⁵³ The main cause of death is cardiovascular disease (CVD).⁵⁴ It is not yet clear whether the increased risk of CVD is due to the metabolic disorders associated with MASLD or whether MASLD poses an additional risk independently. A meta-analysis including 34,043 individuals with NAFLD (MASLD) followed for a median of 6.9 years showed that MASLD was associated with a 64% increased risk of CVD after adjusting for cardiovascular risk factors (CVRF).⁵⁵ This finding has recently been challenged in a large observational study of 18 million European adults, in which no association between MASLD and CV events was found in a primary care setting.⁵⁶ However, there are contradictory results on the relationship between MASLD and cardiovascular mortality, with results in favor^57–59 and against.^60,61 These conflicting results may be attributed to several factors, including heterogeneity in the studied populations, prevalence of CVRF, age at MASLD diagnosis, modality of MASLD diagnosis, duration of follow-up, and stage of fibrosis, as the positive association may be limited to patients with advanced fibrosis.^59,61 Patients diagnosed at a younger age would have a less promising clinical profile, with a greater loss of life expectancy and a worse long-term prognosis compared to older patients.

The association of MASLD and CVD has been assessed in a cohort of patients diagnosed with MASLD without underlying CVD, based on the Swedish National Patient Registry (1987–2016), of 10,023 patients, matched 10:1 in age, gender and municipality with individuals from the general population (n = 96,313). The risk of CVD was 2.6 times higher in patients with MASLD than in controls, higher for non-fatal CVD (HR = 3.71). Life expectancy was, on average, 2.8 years less than controls, with the greatest loss of life years when diagnosed between the ages of 40 and 60.⁶²

Recommendation 4.1.1: we recommend investigating MASLD in patients at cardiovascular risk, as MASLD is associated with an increase in non-fatal cardiovascular disease (LoE: 2; degree of recommendation: strong; degree of consensus: 91.7%).

Recommendation 4.1.2: it is advisable to intensify cardiovascular risk prevention in patients with MASLD, with special emphasis on patients who are young at diagnosis and those with advanced fibrosis (LoE: 1; degree of recommendation: strong; degree of consensus: 87.5%).

How does metabolic dysfunction-associated steatotic liver disease influence the prevalence of liver and extrahepatic cancers?

The prevalence and incidence of hepatocellular carcinoma (HCC) is increasing worldwide in direct relation to the increase in the prevalence and incidence of MASLD. MASLD increases the incidence of both liver cancers, especially HCC, and extrahepatic cancers.⁶³ Although liver cirrhosis is the main factor related to the development of HCC, the risk of liver cancer is increased in patients with MASLD without cirrhosis. In fact, in patients with HCC recruited over 12 years, there was a significant number of patients with MASLD without cirrhosis (F0-F2).⁶⁴ The incidence of hepatocellular carcinoma in patients with MASLD without liver cirrhosis is higher compared to other aetiologies of liver disease. The presence of T2DM has been estimated to double the risk of HCC and increase the risk of death from HCC 1.5-fold, while the presence of metabolic syndrome along with T2DM increases the risk of HCC 5-fold. Lastly, obesity (BMI > 30 kg/m²) doubles the risk of HCC, while a BMI > 35 kg/m² quadruples the risk.^65,66

The risk of extrahepatic cancer is also higher, and an increase has been seen in cancer of the uterus (RR = 2.3; 95% CI: 1.4–4.1), stomach (RR = 2.3; 95% CI: 1.3–4.1), pancreas (RR = 2.0; 95% CI: 1.2−3.3) and colon (RR = 1.8; 95% CI: 1.1–2.8).⁶⁷ A recent retrospective study found a statistically significant relationship among gastrointestinal cancers, but not with genitourinary or lung cancers.⁶⁸ A large meta-analysis was also recently carried out of 10 cohort studies with 182,202 middle-aged individuals (24.8% with MASLD) and 8,485 incident cases of extrahepatic cancers at different sites during a median follow-up of 5.8 years. In it, NAFLD was significantly associated with a 1.5- to 2-fold increased risk of developing gastrointestinal cancers (oesophageal, stomach, pancreatic or colorectal cancer). Furthermore, NAFLD was associated with an approximately 1.2- to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary tract cancers.⁶⁹

What is the main cause of death in metabolic dysfunction-associated steatotic liver disease?

Death in patients with MASLD is associated with the development of cardiovascular complications, complications of liver cirrhosis and tumours.⁷⁰ In a 4-year prospective study of 1,773 adults with MASLD, the presence of advanced F3 and F4 fibrosis was found to be associated with an increased risk of complications from cirrhosis and higher mortality rates.⁵¹ Patients with F3 had a higher risk of developing cardiovascular events and extrahepatic cancer, while patients with F4 suffered higher mortality rates from liver causes.⁷¹ CVD-related death is particularly associated with coronary artery disease, myocardial dysfunction and hypertrophy, aortic valve sclerosis and cardiac arrhythmias.^70,72

Recommendation 4.3.1: we recommend intensifying cardiovascular and extrahepatic cancer prevention in patients with MASLD without cirrhosis, as there is a higher mortality rate associated with higher cardiovascular risk and the development of extrahepatic cancer (LoE 2; degree of recommendation: strong; degree of consensus: 96.7%).

Recommendation 4.3.2: It is advisable to intensify the prevention of liver decompensation and hepatocellular carcinoma in patients with MASLD and cirrhosis, as in patients with cirrhosis, mortality risk is associated with the development of hepatocellular carcinoma and complications of liver cirrhosis (LoE: 1; degree of recommendation: strong; degree of consensus: 88.3%).

How often should we monitor for liver and/or extrahepatic complications?

In patients with MASLD, periodic evaluation for progression to significant fibrosis and cirrhosis is indicated. Patients with mild fibrosis (liver fibrosis indices by non-invasive methods [NIM] below the fibrosis cut-off point) should be managed in primary care and NIM should be repeated every three years. Patients with significant fibrosis should be assessed every 12 months or every six months if they show advanced fibrosis (F3) for early diagnosis of progression to cirrhosis or the development of portal hypertension or hepatocellular carcinoma.^73,74 Cardiovascular risk should be assessed annually in all patients with MASLD and every six months in those with advanced fibrosis.⁷⁵

The participation of patients with MASLD in all available early cancer detection or population screening programmes should be encouraged, with special emphasis on gastrointestinal and genitourinary cancer, as currently only those for colorectal, breast, and cervical cancer are established.

Recommendation 4.4.1: in patients with MASLD without fibrosis, assessment every three years with non-invasive methods of fibrosis indices (FIB-4, HFS; NFS) is recommended (LoE: 2; degree of recommendation: weak; degree of consensus: 85.8%).

Recommendation 4.4.2: in patients with significant fibrosis (≥F2) assessment is recommended every year (LoE: 2; degree of recommendation: weak; degree of consensus: 92.5%).

Recommendation 4.4.3: in patients with advanced fibrosis (F3-F4), hepatoportal ultrasound is recommended every six months to screen for HCC and the development of portal hypertension (LoE: 1; degree of recommendation: strong; degree of consensus: 87.5%).

What is the interaction between metabolic dysfunction-associated steatotic liver disease and diabetes: differential or bidirectional?

The increase in the prevalence of MASLD is related to the increase in the prevalence of metabolic syndrome, obesity and T2DM. Among patients with T2DM, the prevalence of MASLD is estimated at 40–70% and the prevalence of steatohepatitis at 22%.⁷⁶ In Spain the prevalence of T2DM in the Spanish population is 13.8%,⁷⁷ which would place the estimated rates of MASLD at around 5.5–9.7%. There is a demonstrated relationship between insulin resistance in people with T2DM and liver fibrosis (HR = 1.53; 95% CI: 1.1–2.2; p = 0.026).⁷⁸ In most studies, patients with T2DM tend to present with more advanced stages of MASLD, particularly advanced fibrosis. A recent meta-analysis showed that DM2 is related to a higher incidence of serious liver events (cirrhosis, complications and death) (HR = 2.25; 95% CI: 1.83–2.76; p < 0.001).⁷⁹ Having T2DM therefore worsens the prognosis of patients with MASLD.

In parallel, MASLD has a negative impact on T2DM, in terms of increased incidence and complications such as cardiovascular events and chronic kidney disease.⁸⁰ Therefore, MASLD can be considered an emerging complication of T2DM. This idea would require early screening and treatment, using different therapeutic tools with beneficial effects on factors such as weight and insulin resistance. Since 2019, the American Diabetes Association has recommended screening for steatohepatitis and fibrosis in patients with prediabetes or T2DM with elevated ALT levels or steatosis detected by ultrasound.⁸¹ Patients without diabetes with MASLD and significant fibrosis show an increased risk of developing T2DM during follow-up.⁸² In addition, MASLD worsens the complications of diabetes, and in turn, diabetes worsens the prognosis of MASLD.

Recommendation 4.5.1: early detection of MASLD is recommended in all individuals with T2DM (LoE: 1; degree of recommendation: strong; degree of consensus: 95.8%).

Recommendation 4.5.2: we recommend monitoring for the development of diabetes in patients with MASLD, as individuals without diabetes with MASLD and significant fibrosis show an increased risk of developing T2DM (LoE: 2; degree of recommendation: weak; degree of consensus: 95.8%).

Recommendation 4.5.3: it is advisable to monitor for the development of hypertension, as normotensive individuals with MASLD and significant fibrosis show an increased risk of developing hypertension (LoE: 2; degree of recommendation: weak; degree of consensus: 81.7%).

What is the relationship between metabolic dysfunction-associated steatotic liver disease and obesity?

Obesity is the most common and best studied risk factor for MASLD. There are studies with biopsies from decades ago which confirmed even back then that there was a prevalence almost 10 times greater of steatohepatitis in individuals with obesity compared to patients of standard weight: 18.5% compared to 2.7%.⁸³ In patients with BMI > 35 kg/m², 80.2% had MASLD, 65.9% steatosis (grade 1–3) and 14.3% steatohepatitis and/or fibrosis.⁸⁴ The risk increases depending on the patient's location on the spectrum between overweight and severe obesity, ranging from 57% of overweight individuals attending outpatient clinics to more than 80% of individuals with morbid obesity. The median prevalence of steatohepatitis in the obese population is 33%, varying from 10% to 56%.⁸⁵ The prevalence of MASLD in obese people defined as metabolically healthy is high, ranging from 29% to 39%. Furthermore, metabolically healthy obese subjects with MASLD have twice the risk of developing metabolic disease.⁸⁶ With the growing obesity epidemic, the incidence of MASLD-related HCC has increased at a rate of 9% annually.⁸⁷ In the paediatric population, a recent meta-analysis has indicated a prevalence of 7.6% in children in general population studies compared to 34.2% in studies based on paediatric obesity clinics.⁸⁸ There is a notably higher prevalence in male children compared to females. In a study of obese children with MASLD and obstructive sleep apnoea, the severity of hypoxaemia was associated with the severity of MASLD, particularly in relation to the stage of fibrosis.⁸⁹

Many patients with advanced steatohepatitis will require liver transplantation. A higher degree of obesity is associated with a higher risk of clinical disease and decompensation while awaiting transplantation.⁹⁰ Likewise, there are also higher rates of post-transplant complications, graft loss and mortality among patients with class III obesity (BMI > 40 kg/m²).⁹¹ Furthermore, the prevalence of obesity and sarcopenia among patients with steatohepatitis and cirrhosis is high; in fact, sarcopenia has consistently been identified as an independent predictor of post-transplant mortality and graft loss.⁹¹

Recommendation 4.6.1: early diagnosis of MASLD is recommended in all people with obesity (LoE: 1; degree of recommendation: strong; degree of consensus: 94.2%).

Recommendation 4.6.2: we recommend assessing nutritional status in all patients with MASLD, especially those on the liver transplant waiting list (LoE: 1; degree of recommendation: strong; degree of consensus: 94.2%).

Recommendation 4.6.3: patients with obesity and MASLD should be assessed for comorbidities such as insulin resistance, polycystic ovary syndrome and obstructive sleep apnoea-hypopnoea syndrome (LoE: 1; degree of recommendation: strong; degree of consensus: 87.5%).

Treatment

What therapeutic goals should be recommended and how should therapeutic measures be selected?

The therapeutic goals in the management of MASLD converge in the improvement of survival and quality of life by preventing the progression of liver disease to cirrhosis and hepatocellular carcinoma,⁹² cardiovascular events⁹³ or the development of extrahepatic cancers.⁶⁷ Regression of fibrosis improves patient prognosis by decreasing the rate of cirrhosis complications.⁹⁴ The therapeutic goal should therefore be to achieve the regression of fibrosis.

In patients in whom fibrosis regression is not possible, long-term intervention should be considered with the aim of:

• •

  Decreasing the rate of hepatocarcinoma development.

• •

  Preventing progression to cirrhosis in non-cirrhotic patients.

• •

  Avoiding decompensation in patients with liver cirrhosis.

Therapeutic measures should be selected based on availability. Typically, treatment should begin with a structured lifestyle intervention based on a Mediterranean diet and physical exercise, along with improved control of metabolic or inflammatory comorbidities.

Recommendation 5.1.1: we recommend that therapeutic goals pursue the regression of fibrosis with the consequent positive impact on prognosis (LoE: 3; degree of recommendation: strong; degree of consensus: 96.6%).

Recommendation 5.1.2: we recommend that a reduction in the rate of hepatocellular carcinoma (HCC) development, early detection and prevention of progression to cirrhosis and liver decompensation be considered as goals with a high impact on patient quality of life and survival (LoE: 4; degree of recommendation: strong; level of consensus: 99.2%).

The role of lifestyle changes in weight loss: how and where to implement them?

Lifestyle changes (low-calorie diet and physical exercise) are one of the basic pillars of treatment for MASLD, as different randomised studies based on liver biopsies have shown that a sustained decrease >10% in initial weight is associated with a remission of steatotic liver disease in >90%, 50% in steatohepatitis and variable in the decrease of fibrosis.^95–97 However, it has also been found that after bariatric surgery these same goals are achieved⁹⁸ for a longer period, such that clear decreases have been reported of 82% in hepatic events and of 70% in the associated cardiovascular risk.⁹⁹

Regarding the macronutrient composition, measures aimed at reducing both de novo lipogenesis and the percentage of intrahepatic triglycerides focus on reducing the content of saturated fats, trans fatty acids and rapidly absorbed carbohydrates and replacing them with unsaturated fats. Prototype diets, such as the DASH diet and in particular the Mediterranean diet, are generally considered to be the most appropriate nutritional pattern to achieve these goals, and are therefore the model of choice in numerous scientific societies.^100–103

Exercise, combined with a low-calorie diet, is the form of intervention that has yielded the most results in terms of improvement in steatosis and remission of steatohepatitis.^104,105 However, as demonstrated in different meta-analyses, exercise contributes independently to the reduction of intrahepatic fat content.¹⁰⁶ The important thing is the regularity and intensity of the exercise performed, with no differences between the practice of aerobic or resistance exercise.¹⁰⁷ Moderate physical activity, 30−60 min, performed at least three times a week, is sufficient to achieve improvement goals in MASLD.¹⁰⁸

Recommendation 5.2.1: lifestyle modification with a low-calorie Mediterranean diet and moderate aerobic physical exercise is recommended with the aim of losing weight (LoE: 1; degree of recommendation: strong; degree of consensus: 93.3%).

Recommendation 5.2.2: we recommend promoting 10% loss of body weight through lifestyle changes, with diet and exercise, as this is accompanied by an improvement in steatotic liver disease, steatohepatitis and fibrosis in patients with MASLD (LoE: 2; degree of recommendation: strong; degree of consensus: 98.3%).

Recommendation 5.2.3: we recommend that the macronutrient content of the diet focus on limiting the intake of ultra-processed products, saturated and trans fats, sugary drinks and alcohol (LoE: 3; degree of recommendation: strong; degree of consensus: 97.5%).

Recommendation 5.2.4: we recommend following a Mediterranean-style diet (LoE: 2; degree of recommendation: strong; degree of consensus: 97.5%).

Recommendation 5.2.5: we recommend doing regular physical exercise, both aerobic and resistance, moderate physical activity, 30−60 min a minimum of 3−5 times a week, as this works together in tandem with a balanced diet to achieve the planned goals of changes in body composition and cardiometabolic and liver health (LoE: 2; degree of recommendation: strong; degree of consensus: 96.6%).

Which hypoglycaemic and lipid-lowering drugs are most appropriate?

In addition to lifestyle changes, when prescribing drug therapy to treat associated hyperglycaemia, it is advisable to select those with liver and/or cardiovascular benefits, as liver and cardiovascular problems are the main causes of death. The ideal drug in patients with T2DM and MASLD would be one that concomitantly resolves insulin resistance/hyperglycaemia and MASLD, in addition to reducing cardiovascular risk.

Pioglitazone is a drug from the thiazolidinediones group that has been shown to induce the resolution of steatohepatitis and improve fibrosis at any stage.¹⁰⁹ In addition, it improves atherogenic dyslipidaemia and reduces cardiovascular events. Among the adverse effects, weight gain should be taken into account, but with a reduction in visceral fat, and the potential risk of heart failure and bone fracture.¹¹⁰ Among GLP-1 receptor agonists (GLP-1RA), liraglutide demonstrated superiority over placebo in the resolution of steatohepatitis,¹¹¹ and semaglutide 0.4 mg/day also improved the resolution of steatohepatitis without worsening fibrosis. In addition, they also have cardiovascular benefits and promote weight loss.¹¹²

SGLT-2 inhibitors also have beneficial effects on weight reduction and cardiorenal benefits, and although they have shown a reduction in steatotic liver disease,^113–115 there is no evidence of benefits regarding steatohepatitis and fibrosis. Other hypoglycaemic drugs have not shown benefit in MASLD.

Patients with T2DM and MASLD have a higher cardiovascular risk, so recommendations should be applied according to standard clinical practice guidelines for cardiovascular prevention. Statins are safe¹¹⁵ and can be prescribed to patients with non-decompensated cirrhosis. Evidence for the use of other lipid-lowering agents in patients with underlying liver disease is very limited, but fibrates, ezetimibe, omega-3 fatty acids and bile acid sequestrants can be used to treat dyslipidaemia in patients with chronic liver disease.

Recommendation 5.3.1: to treat hyperglycaemia, it is advisable to consider the use of drugs with a beneficial effect on MASLD (GLP-1RA, pioglizatone, SGLT-2 inhibitor) (LoE: 3; degree of recommendation: strong; degree of consensus: 86.6%).

Recommendation 5.3.2: it is advisable to consider adding drugs with cardiovascular benefits, such as GLP-1RA, SGLT2 inhibitor and pioglitazone (LoE: 3; degree of recommendation: strong; degree of consensus: 89.1%).

Recommendation 5.3.3: the use of statins is recommended to treat dyslipidaemia associated with the goal of reducing cardiovascular risk (LoE: 3; degree of recommendation: strong; degree of consensus: 98.3%).

Do we have drugs with proven efficacy?

Patients at risk for progression and complications typically have significant fibrosis and steatohepatitis or advanced fibrosis. Therapeutic measures should be selected based on availability, typically starting with a structured lifestyle intervention with a Mediterranean diet and physical exercise, along with improved control of metabolic or inflammatory comorbidities.

However, treatment of MASLD is an unmet need, and many drugs have not been shown to be superior to placebo; we consider drugs that achieve regression of liver fibrosis to be of proven efficacy, as such regression has been associated with a lower rate of complications.⁹⁴ Emricasan, a pan-caspase inhibitor; simtuzumab, a monoclonal antibody against LOL-2; selonsertib, an ASK-1 inhibitor; cenicriviroc, a CCR2/CCR5 inhibitor and elafibranor, a dual PPAR alpha/delta agonist, were shown not to be superior to placebo in randomised clinical trials. Certain molecules used in the management of diabetes or dyslipidaemia, such as metformin or statins, have also been tested with limited success in MASLD. However, their overall impact on disease progression to liver cancer remains unclear.

Cusi et al.¹¹⁶ demonstrated the superiority of pioglitazone over placebo in 101 patients. Pioglitazone was associated with greater resolution of steatohepatitis and improvement in fibrosis and steatotic liver disease, but also caused body weight gain. However, treatment with pioglitazone has been associated with adverse effects, such as increased bone fractures or a possible increased risk of bladder cancer, although these findings have not been validated in recent meta-analyses.¹⁰⁹ In fact, current evidence does not support the association of pioglitazone use with the development of bladder cancer.¹¹⁷ SGLT2 inhibitors demonstrated the ability to reduce fatty infiltration, but they did not improve the stage of fibrosis.¹¹⁸

Favourable results have been published from a one-year phase 3 trial of resmetirom in people with non-cirrhotic steatohepatitis (primarily stage 2 and 3 fibrosis), leading to its approval by the FDA. Resolution of MASH without worsening of fibrosis was achieved in 25.9% of patients in the resmetirom 80 mg group and 29.9% of those in the resmetirom 100 mg group, compared to 9.7% of those in the placebo group (p < 0.001 for both placebo comparisons). Improvement in fibrosis by at least one stage without worsening of the MASLD activity score was achieved in 24.2% of patients in the resmetirom 80 mg group and 25.9% of those in the resmetirom 100 mg group, compared to 14.2% of those in the placebo group (p < 0.001 for both placebo comparisons).¹¹⁹

Semaglutide, at a dose of 2.4 mg/week, showed superiority over placebo in the regression of fibrosis (37% vs 22%) and resolution of steatohepatitis (63% vs 34%); p < 0.001 in both comparisons in the ESSENCE study.

Obeticholic acid demonstrated superiority over placebo in the regression of fibrosis after 72 weeks of treatment. However, this drug was associated with adverse events such as the development of pruritus and alteration of the lipid profile, with elevated LDL and a slight decrease in HDL. By intention to treat, 23.1% of patients who received 25 mg/d of obeticholic acid achieved regression of at least one stage of fibrosis, compared to only 11.9% in the placebo group.¹²⁰ However, this molecule has been withdrawn from the market in the European Union.

Molecules in development which have demonstrated superiority over placebo in phase 2 studies and continue in phase 3 programmes:

• -

  Lanifibranor: demonstrated significant regression of at least one stage of fibrosis in 42% of 83 patients treated with 1,200 mg of lanifibranor daily versus 24% in the placebo group in a phase 2b study. It also achieved resolution of steatohepatitis in 44% compared to a 9% in the placebo group. This pan-PPAR agonist also reduced insulinaemia, basal blood glucose, glycosylated haemoglobin and triglycerides, and increased HDL cholesterol levels, while decreasing liver enzymes.^121,122

• -

  Efruxifermin: a long-acting Fc-FGF21 fusion protein which prevents proteolysis, it has shown great potential to promote fibrosis regression. In a phase 2 trial of 80 patients randomised into four arms, 50 mg/day achieved a one-stage regression of fibrosis in 62% of patients (8/13) and two stages of fibrosis in 38% (5/13), much superior to placebo.¹²³

• -

  Pegozafermin: in 222 patients, it showed regression of at least one stage of fibrosis in 27% compared to 7% of the placebo group, and resolution of steatohepatitis in 37% compared to 2% with placebo.¹²⁴

• -

  Survodutide: in 212 patients, it showed non-significant superiority over placebo in the regression of fibrosis (32−34% vs 22%) and resolution of steatohepatitis (43–62 % vs 14%, p < 0.001) and steatotic liver disease.¹²⁵

• -

  Efinopegdutide: in 145 patients it demonstrated superiority over semaglutide 1.0 mg/week in decreasing hepatic fatty infiltration measured by PDFF.¹²⁶

• -

  Retatrutide (GLP1-GIP-glucagon triagonist): in 98 patients (phase 2a) it showed superiority in reducing liver fat (PDFF-MRI) (–82.4%, versus placebo +0.3%) after 48 weeks of treatment.¹²⁷

• -

  In the phase 2 SYNERGY-NASH trial, which included 190 patients with steatohepatitis and moderate or severe fibrosis, tirzepatide (a dual GIP and GLP-1 agonist) was more effective than placebo at 52 weeks in resolving steatohepatitis without worsening fibrosis, but not in significantly reducing fibrosis by one stage, perhaps because of the small sample size.¹²⁸

Recommendation 5.4.1: we recommend, when available, the use of drugs that promote fibrosis regression such as resmetirom and semaglutide (LoE: 1; degree of recommendation: strong; degree of consensus: 96.7%).

Recommendation 5.4.2: drugs used in the management of comorbidities such as statins, metformin or vitamin E are not recommended for the purpose of improving fibrosis, as they have not demonstrated efficacy in the regression of fibrosis unequivocally (LoE 3; degree of recommendation: strong; degree of consensus: 99.2%).

Recommendation 5.4.3: pioglitazone is recommended for the treatment of MASLD in patients with diabetes without liver cirrhosis, risk of heart failure or grade 2 obesity (LoE: 4; degree of recommendation: strong; degree of consensus: 93.3%).

Multidisciplinary management

How should metabolic dysfunction-associated steatotic liver disease be managed in primary care?

Due to the high prevalence of MASLD, most patients are treated in primary care, so universal access to the main diagnostic and prognostic tools at this level of care is recommended.² The importance of early diagnosis of the disease and providing patients with optimal care, which involves screening populations at the greatest risk of progression and complications, has increased the interest in guidelines or consensus documents on multidisciplinary management proposals. MASLD tends to be asymptomatic or cause nonspecific symptoms, except when diagnosed at an advanced stage; incidental findings on imaging tests are also common. The medical history should include the presence of risk factors for MASLD and other causes of steatosis or liver dysfunction, personal and family history of associated diseases, alcohol and medication intake, and risk of exposure to hepatotropic viruses. The physical examination should include data on blood pressure, weight, height, waist circumference and body mass index and possible detection of signs of advanced liver disease.¹²⁹

These are tasks for MASLD care in primary care:

• -

  Early detection and diagnosis of the disease and the study of other causes of chronic liver disease.

• -

  Prevention and diagnosis of other infectious liver diseases.

• -

  Assessment of fibrosis using non-invasive tests.

• -

  The assessment of cardiovascular and renal risk.

• -

  Early diagnosis and screening for extrahepatic cancers.

• -

  Treatment based on lifestyle modification and control of cardiometabolic risk factors.

Automatic and systematic calculation of non-invasive fibrosis tests in at-risk populations in primary care is recommended to improve stratification and follow-up.¹³⁰

To rule out significant fibrosis the following are recommended:

• -

  Measurement of liver stiffness by transient elastography <8 kPa.

• -

  Patented tests: ELF <9.8.

• -

  Non-patented tests: FIB-4 <1.3 ( <2 if aged ≥ 65) or NFS < −1.455 or HFS < 0.12.

With regard to the age correction of the cut-off point to rule out significant fibrosis with FIB-4, there are new studies that insist on its importance due to the poor performance of this score in the older population, and we have therefore considered the introduction of both values in clinical practice in primary care.¹³¹

Before referring a patient with a positive non-invasive biochemical test for suspected fibrosis, it is recommended to use transient elastography and/or a patented serum test to rule out advanced fibrosis.¹³² A recent Spanish study between primary and hospital care, applying a patient referral algorithm in clinical practice and incorporating the performance of TE in primary care (with the sequence and cut-off points FIB-4 ≥ 1.3 and liver stiffness ≥8 kPa) has shown an improvement in the stratification of at-risk patients and a decrease in the percentage of patients who would be referred by applying only FIB-4.⁴⁴

Recommendation 6.1.1: in all patients with MASLD, a detailed medical history is recommended to rule out comorbidities, as well as other causes of disease such as viral hepatitis or haemochromatosis (LoE: 1; degree of recommendation: strong; degree of consensus: 97.5%).

Recommendation 6.1.2: universal access for primary care physicians to steatosis and fibrosis calculators, abdominal ultrasound, direct laboratory determination of fibrosis indices, and transient elastography is recommended for stratifying the risk of MASLD-fibrosis (LoE: 3; degree of recommendation: strong; degree of consensus: 87.4%).

Recommendation 6.1.3: we recommend referring patients with transient elastography values ≥8 kPa or ELF >9.8 to hepatology to rule out advanced fibrosis and initiate screening for hepatocellular carcinoma and portal hypertension (LoE: 1; degree of recommendation: strong; degree of consensus: 95.8%).

Recommendation 6.1.4: vaccination against hepatitis A and B is recommended for patients with MASLD (LoE: 3; degree of recommendation: weak; degree of consensus: 82.4%).

Recommendation 6.1.5: initial assessment for cardiometabolic risk and extrahepatic cancer is recommended, in order to design a personalised care and follow-up plan according to the risk (LoE: 2; degree of recommendation: strong; degree of consensus: 89.1%).

When to refer to endocrinology/internal medicine and for what?

Patients with MASLD may be referred to endocrinology/internal medicine according to availability and local circuit both from hepatology, in the management of MASLD with advanced fibrosis, and from primary care in the following cases:

• a)

  T2DM with poor metabolic control, despite intensive treatment proposed from primary care.⁴⁵

• b)

  T2DM with obesity (BMI ≥ 35 kg/m²) who may be a candidate for metabolic endoscopy or bariatric surgery.^133,134

• c)

  T2DM with severe chronic complications: diabetic foot, peripheral neuropathy, chronic kidney disease, retinopathy, cardiovascular disease, intermittent claudication, erectile dysfunction.¹³⁵

• d)

  Resistant hypertension.

• e)

  Severe obstructive sleep apnoea (OSA).

• f)

  Severe dyslipidaemia.

• g)

  Acute complications of diabetes: recurrent hypoglycaemia; hyperglycaemia with ketoacidosis; hyperosmolarity.

• h)

  Obesity, without diabetes, with BMI ≥35 kg/m² or ≥30 kg/m², with two or more comorbidities who may benefit from treatment with GLP-1 receptor agonists for weight loss and improvement of MASLD.

Recommendation 6.2.1: we recommend that multidisciplinary referral protocols be agreed on between levels in each health area (LoE: 4; degree of recommendation: weak; degree of consensus: 97.5%).

Recommendation 6.2.2: referral to endocrinology or internal medicine is advised for people with T2DM with poor metabolic control (HbA1c >8.5%) and/or severe complications of diabetes (target organ damage), severe obesity, treatment-resistant hypertension, sleep apnoea/hyponoea syndrome (SAHS) and severe dyslipidaemia, as well as acute complications of diabetes after optimised treatment in primary care (LoE 3; degree of recommendation: strong; degree of consensus: 84.9%).

When to refer to a hepatologist and for what?

Patients with MASLD at risk of progression should be referred to a hepatologist to assess the liver damage properly and to design the most appropriate follow-up and treatment.

In areas outside of hepatology, it is necessary to refer patients with significant or advanced fibrosis. For this purpose, two-step detection can be performed¹³⁶:

• a)

  Use readily available fibrosis biomarkers such as FIB-4 >1.3 or (FIB-4 >2 if aged ≥65 years), HFS >0.12 and NFS > −1.456, and select patients with suspected significant fibrosis.¹³⁷

• b)

  A second step to assess patients at risk for fibrosis is by transient elastography (TE) or 2D shear wave elastography, or by biochemical methods such as ELF or OWLiver.¹³⁸

This 2-circuit, 2-step screening and referral is cost-effective and reduces disease burden by screening patients and reducing healthcare expenditure.^139,140

The main goal of referral will be the correct diagnosis, monitoring and treatment of patients with significant or advanced fibrosis. These patients will benefit from close, personalised follow-up and inclusion in clinical trials. Subsequent follow-up should be multidisciplinary and joint among all healthcare professionals involved. Patients who do not meet fibrosis risk criteria should not be referred to hepatology.¹⁴¹

Recommendation 6.3.1: referral to gastroenterology-hepatology is recommended for all patients at risk of disease progression, i.e., patients with steatohepatitis and significant fibrosis or advanced fibrosis, as well as all patients with advanced chronic liver disease (LoE: 3; degree of recommendation: strong; degree of consensus: 95.8%).

Recommendation 6.3.2: screening of at-risk patients using non-invasive methods in two steps is advised (FIB-4/NFS/HFS + ELF/OWLiver/VCTE), as it is cost-effective, through reducing the disease burden in hepatology units and healthcare expenditure as a result (LoE: 2; degree of recommendation: strong; degree of consensus: 85.7%).

Recommendation 6.3.3: we recommend referring to hepatology for accurate evaluation of liver damage and assessment of the risk of progression, as well as promoting early intervention in complications by optimising treatment (LoE: 3; degree of recommendation: strong; degree of consensus: 95.8%).

How to monitor progress and what parameters should we record?

Patients with MASLD should be monitored in primary care unless they have advanced fibrosis or metabolic comorbidities that are difficult to control.⁴²

Monitoring should include periodic assessment of other comorbidities as well as liver disease.¹¹

The assessment of comorbidities should include:

• a)

  Calculation of fibrosis indices (FIB-4/HFS/NFS) every 2−3 years.

• b)

  Metabolic monitoring every six months through blood tests (fasting blood glucose, HbA1c, kidney function, total cholesterol, HDL-C, LDL-C and triglycerides) to assess carbohydrate metabolism and the presence of atherogenic dyslipidaemia, and urine tests to assess the albumin/creatinine ratio (UACR).

• c)

  Monitoring of high blood pressure and obesity (BMI and waist circumference).

• d)

  Promote smoking cessation and avoiding alcohol consumption.

Recommendation 6.4.1: in cases of low risk of fibrosis, re-assessment using non-invasive markers is recommended every 2−3 years, and in cases of significant fibrosis, annual follow-up is recommended (LoE: 3; degree of recommendation: strong; degree of consensus: 95.8%).

Recommendation 6.4.2: in case of cirrhosis, six-monthly follow-up is recommended to assess the progression of portal hypertension and screen for hepatocellular carcinoma (LoE: 3; degree of recommendation: strong; degree of consensus: 98.3%).

Recommendation 6.4.3: in all cases, screening for and monitoring of comorbidities is recommended, as well as promoting smoking cessation and avoiding alcohol consumption, recommending moderate aerobic physical exercise and a healthy diet, and reinforcing adherence to treatment (LoE: 1; degree of recommendation: strong; degree of consensus: 97.5%).

How to organise the care of patients with metabolic dysfunction-associated steatotic liver disease? Importance and composition of the functional unit in metabolic dysfunction-associated steatotic liver disease

MASLD is a common, progressive and complex chronic lifestyle-related disease associated with numerous metabolic comorbidities and cardiovascular and liver complications. Appropriate management includes prevention, screening and diagnosis of liver disease and comorbidities, as well as treatment to prevent disease progression and comorbidities and their complications, which should be multifactorial and progressive/additive to adapt it to the evolutionary phase of the disease.¹⁴²

In this context, traditional care models, which suffer from poor coordination and communication between healthcare professionals, tend to be unsatisfactory for patients, the professionals and the healthcare system. Among the interventions that have demonstrated the best results in the care of chronic patients, the Chronic Care Model (CCM) is the most used in T2DM, as it includes interventions in the community, the healthcare system and clinical practice,¹⁴³ as well as multidisciplinary clinics (MC),¹⁴⁴ which promote coordinated care by integrating consultations in a clinical space, commonly used in oncology.¹⁴⁵ Information on patients with MASLD is limited,¹⁴⁶ but due to the diverse characteristics and needs of individuals with MASLD, which vary over the course of their disease, we consider that, globally, the CCM is the ideal model to integrate their care at different levels of care. This model allows for the integration of functional units that bring together the various primary care and hospital healthcare professionals involved in the clinical process of patients with MASLD, without the need to share the physical space of the clinic or the centre. Lastly, for patients requiring complex care in a hospital setting, MC in a single clinical space can be a suitable model for providing coordinated care from different healthcare professionals.

The minimum core members should be the primary care physician, the internal medicine specialist, the endocrinologist and the hepatologist, as well as others, including nurses, psychologists and nutritionists. The first three are key for prevention and identifying people at risk for MASLD and their assessment, including estimating fibrosis risk and managing risk factors and associated comorbidities. The hepatologist should be responsible for further assessment of liver disease and management of advanced liver disease. Depending on the needs, available resources and the organisation, other healthcare professionals may form part of these teams. The roles of all healthcare professionals in the management of patients with MASLD and the patient's referring clinician should be clearly defined at all times. Lastly, systematic meetings on clinical and organisational content should be planned.

Recommendation 6.5.1: we recommend that the minimum core members of the multidisciplinary team be the primary care physician and nurse, the internal medicine specialist, the endocrinologist and the gastroenterologist or hepatologist. The first three are key for prevention and identifying people at risk for MASLD and their assessment, including estimating fibrosis risk and managing risk factors and associated comorbidities. The hepatologist should be responsible for further assessment of liver disease and management of advanced liver disease. Depending on the needs, available resources and the organisation, there are other healthcare professionals who can form part of these teams (LoE: 4; degree of recommendation: strong; degree of consensus: 89.9%).

Recommendation 6.5.2: the multidisciplinary approach requires that the roles of all healthcare professionals be explained and the patient's reference clinical representative be identified. Systematic meetings on clinical and organisational content should also be planned (LoE: 4; degree of recommendation: strong; degree of consensus: 96.6%).

Discussion

The level of consensus was considered very high (≥90%) in 48 of the 71 recommendations; in 27 of them the degree of consensus was above 95%. In 21 of the responses, a consensus of 80–89.9 % was obtained and only in two of them was the consensus below 80% (75% in recommendation 2.2.1 and 71% in 3.1.1). In none of the recommendations was the consensus below 70%. The main discrepancies were found in the introduction of new diagnostic technologies, where the added value of a paid method versus free and available methods is not clear. In addition, the role of pioglitazone and its potential beneficial effect versus the risk of adverse events sparked debate. The approval of resmetirom and the positive outcomes produced by semaglutide at a dose of 2.4 mg/week have aroused enthusiasm and a high level of consensus.

The Delphi method offers several advantages when it comes to generating consensus in scientific research. First, it involves individual, anonymous, and structured questionnaires, which reduces group bias and allows participants to engage in more objective reflection. Secondly, the various rounds and iterations allow experts to review and adjust their opinions as the process progresses. However, it should also be noted that this is a lengthy process due to the large number of rounds, as well as the potential difficulties in reaching consensus, especially when dealing with complex, controversial or polarised issues. In the case of this consensus, contact was established with experts from all over the country, with an equal balance in terms of gender (of the responses obtained, 48.8% identified themselves as female and 51.2% as male), and with a wide age range from 30 to 70, although with a particular presence of specialists in the 50−60-year-old age group (36.3%). Regarding medical specialities, the questionnaire was sent to experts from three different areas: Gastroenterology and Hepatology (27.5%), Endocrinology (37.5%) and Internal Medicine and Family Medicine (35%), so the responses were well balanced, as were the characteristics of the participants.

In conclusion, this multidisciplinary consensus lays the foundation for the management of a complex, dynamic, heterogeneous and multisystem disease. A multifaceted view of disease progression mechanisms, diagnostic methods and prevention and treatment options can provide added value in improving the quality of care for patients living with MASLD.

Funding

There has been no funding of any kind for this article.

Acknowledgements

To Javier Pazó for his methodological support in developing the RedCAP for the first round of the Delphi.

To Sara Romero for conducting the second round of Delphi and for correcting the grammar and style of the text.