From Guideline Recommendations to Clinical Practice: Diagnosis and Management of NAFLD/MASLD in Adults

Non-alcoholic fatty liver disease (NAFLD) and its more severe subtype non-alcoholic steatohepatitis (NASH) are liver diseases associated with overnutrition and chronic cardiometabolic risk factors and diseases, such as weight gain, overweight/central obesity, type 2 diabetes, dyslipidaemia, hypertension and atherosclerotic cardiovascular disease, particularly in genetically predisposed individuals.^[1,2] As of July 2023, a new nomenclature has been introduced, Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction Associated Steatohepatitis (MASH) respectively.^[3] NAFLD is diagnosed when a patient has accumulation of excess lipids – steatosis – in >5% of hepatocytes, which is not a result of significant or excessive alcohol consumption or other ‘secondary’ causes (Box 1).^[1–4] It covers a wide spectrum of disease severity, from isolated steatosis to NASH and fibrosis, which can lead to cirrhosis, and hepatocellular carcinoma (HCC).^[2,4] MASLD is defined when steatosis is present in the context of metabolic dysfunction, with at least one out of five criteria present.^[3] The definition is hence slightly different. In contrast to NAFLD, MASLD can be diagnosed concomitantly with other causes of steatosis, most notably alcohol. The small group of patients with NAFLD not meeting any of the MASLD criteria are currently considered as having cryptogenic steatotic liver disease (SLD).

HCV, hepatitis C virus; SLD, steatotic liver disease.

NAFLD/MASLD is the most common liver disorder in Western countries.^[4,5]Few studies have evaluated the incidence, but it is approximately 20–86/1,000 person-years based on elevated liver enzymes and/or ultrasound, varying depending on ethnicity.^[4] In the general population, NAFLD/MASLD has a prevalence of 20–30%, while NASH/MASH has an overall prevalence of 2–3%, and of 10–25% in patients with NAFLD/MASLD.^[1,2,6] Prevalence varies according to the diagnostic method used, as well as age, sex, ethnicity, and comorbidities, mainly the components of the metabolic syndrome, impact on prevalence.^[4,5] The prevalence of NAFLD/MASLD is also steadily increasing, placing a greater burden on healthcare resources.^[1] Furthermore, the epidemic of childhood obesity means that NAFLD/MASLD is increasingly presently in younger people, with up to 38% of obese children having evidence of NAFLD/MASLD.^[1] Approximately 20% of people with NASH/MASH could potentially develop significant liver disease including cirrhosis and its complications, and NASH is one of the top causes of HCC.^[6] The average age of people with NASH/MASH is 40–50 years and with NASH//MASH-associated cirrhosis is 50–60 years.^[1] However, with NAFLD/MASLD developing even in childhood, the age that people develop significant liver disease is likely to decrease, making early diagnosis and management important at all ages.^[1]

The socioeconomic costs of NAFLD/MASLD in Europe are high.^[7] NAFLD/MASLD is asymptomatic in most patients and only detected incidentally when liver blood tests and/or abdominal ultrasound are performed for some other reason, although >80% of patients with NAFLD/MASLD have normal liver blood tests.^[1] Diagnosis of NAFLD requires exclusion of secondary causes and daily alcohol consumption of ≥30 g for men and ≥20 g for women,^[2,4] whereas MASLD can co-exist with these other causes but still needs to be diagnosed in its own right, even if other causes of steatosis are present.^[3] In a given patient with steatosis, all causes of steatosis need hence to be considered and appropriately searched for.^[3]

Advanced age, obesity/overweight, diabetes, and transaminase elevations are associated with an increased risk of progression.^[1,2,6] Liver fibrosis is the most important determinant of liver- and non-liver-related outcomes in patients with NAFLD, including mortality, supporting the need for accurate identification of patients with fibrosis, as well as regular monitoring of fibrosis progression.^[4,8]

The presence and severity of liver fibrosis have historically been assessed and defined by liver histology, hence liver biopsy is the diagnostic gold standard.^[4] In NAFLD, a fibrosis staging system ranging 0-4 (F0-F4) is currently most widely used, with F0 meaning no fibrosis and F4 corresponding to cirrhosis.^[9] F2 or more is termed significant fibrosis, whereas the term advanced fibrosis is used from F3 onwards. As mentioned, fibrosis stage appears to be the histological feature that most strongly predicts patients’ outcomes, both liver- and non-liver related events as well as all-cause mortality, and with a stepwise increase from F2 onwards.^[10] This explains the importance of identifying fibrosis as the target of efforts to timely detect at-risk patients. It is, however, evident that the liver biopsy is not suited for screening or case-finding purposes and belongs to the armamentarium of specialised care and is to be performed only upon specific indications.

Non-invasive tests – such as the fibrosis 4 (FIB4) index, enhanced liver fibrosis (ELF^TM) test, and Fibroscan^® (Box 2) – are increasingly being used to improve the early detection and prognostication of chronic liver diseases across aetiologies.^[11] They can be used in primary care and in non-hepatologic centres like diabetology clinics, mainly to identify patients at risk of having NAFLD/MASLD with some degree of fibrosis due to increased metabolic risk, and also in secondary and tertiary care settings for further confirmation and refinement of the diagnosis, as well as, to some extent, to identify those with worse prognosis (e.g. with “severe” referring mainly to the fibrosis stage with current most popular tests). Their usefulness in monitoring disease progression and predicting response to therapeutic interventions is not without promise but requires further study.^[4] Also, to what extent the data on their accuracy in NAFLD translate into the MASLD patients, requires further study, but as NAFLD and isolated MASLD (so, MASLD without any other cause of steatosis) largely overlap, it is reasonably likely that the performance will be comparable.

Box 2. Non-invasive tests for NAFLD/MASLD

Because NAFLD/MASLD is largely asymptomatic and because optimal timing of treatment depends on accurate staging of fibrosis, screening at the primary care level and in diabetology clinics is critical.^[8] As no licensed treatment is currently available to treat NAFLD/MASLD,^[1,4–8] the main goal of screening is to prevent progression to complications, development of cirrhosis, liver-related mortality, and all-cause mortality by implementing early interventions such as lifestyle modifications to reverse the unfavourable metabolic profile and by managing associated comorbidities (see Boxes 4 and 5).^[2,6,8] In patients who are identified as having cirrhosis, screening for oesophageal varices and surveillance for hepatocellular carcinoma can reduce mortality.^[15]

Early detection and management of NAFLD/MASLD with fibrosis are key to improving patient outcomes, but lack of awareness about the disease and about non-invasive tests among non-hepatologists, particularly primary care clinicians, diabetologists, and endocrinologists, means that it is often overlooked.^[6,16] Indeed, <5% of people with NAFLD/MASLD are aware of their disease compared with 38% of people with viral hepatitis.^[6] Furthermore, most patients are first seen in primary care or endocrine clinics, but it can be difficult for these non-hepatology specialists to identify patients and if diagnosed, to recognise which patients with NAFLD/MASLD or NASH/MASH might benefit from hepatology care and when to refer them, which all can lead to poor outcomes.^[8] Although different medical societies have developed clinical practice guidelines on diagnosis and management of NAFLD,^[1,2,4,6,8] differences in the guidance can be confusing. There is therefore an opportunity to harmonise existing guideline recommendations and develop practical guidance to help primary care physicians and non-hepatology specialists identify and manage adults with NAFLD/MASLD and NASH/MASH, including when to refer to secondary or tertiary care.

This Medscape Expert Guidance Article

An expert group was convened to develop an algorithm to support the diagnosis and management of NAFLD/MASLD and NASH/MASH in adults (this guidance does not cover children with NAFLD/MASLD). The aim was to summarise guideline recommendations and to bridge gaps and inconsistencies in existing guidance by addressing:

• identification of NAFLD/MASLD and NASH/MASH, including diagnostic tools for evaluating the risk of fibrosis

• initial management strategies for NAFLD/MASLD and NASH/MASH

• identification of patients requiring further evaluation and when to refer to specialist care.

Identification and management of patients with NAFLD/MASLD

• Patients with NAFLD/MASLD may be identified through three different routes:^[6]

  • the presence of risk factors for NAFLD/MASLD (Box 3)^[3,6,8]

  • steatotic liver identified on ultrasound (or but more rarely, any other imaging modality) performed for another indication^[6,8]

  • suspicion of steatotic liver disease because of:

    • abnormal liver blood tests outside the usual reference range of the local laboratory: alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyl transferase (GGT)^[6,8]

    • hyperferritinaemia (this often raises the suspicion of haemochromatosis, but it is also a marker of inflammation and liver cell damage and often increased in NAFLD/MASLD, but, in contrast to hemochromatosis, with normal transferrin saturation (TS))

• NAFLD/MASLD patients may have normal liver enzymes, or liver enzymes that are at the high end of the normal range: normal liver enzymes do hence not exclude NAFLD/MASLD, nor NAFLD-cirrhosis.^[17]

• Age >40 years is an important risk factor because the prevalence of metabolic syndrome is higher and so the risk of advanced fibrosis is higher. On the other hand, patients <40 years should not be discounted, as NAFLD may still be present.

BMI, body mass index; HDL, high-density lipoprotein; MASLD, metabolic dysfunction associated steatotic liver disease; NAFLD, non-alcoholic fatty liver disease; T2DM, type diabetes mellitus.

(A) The criteria for the diagnosis of MASLD only require one metabolic criterion to be fulfilled but the expert group recommends a slightly stricter definition in order to avoid overdiagnosis.

• In any case of suspected chronic liver disease: check for alcohol and concomitant alcohol-related liver disease^[1,8] and act accordingly

• Perform ultrasound and screening for HBV/HCV in case of abnormal liver blood tests^[4,8]

  • refer to a hepatology clinic if there are signs of cirrhosis on ultrasound and/or if the patient is HBV/HCV positive and/or if elevated liver tests remain unexplained (besides HBV/HCV, other causes of chronically elevated liver tests need to be excluded)

• Calculate the FIB4 as a first line test to assess the risk of fibrosis (Boxes 2 and 4):

  • FIB4 has a low sensitivity in patients <35 years, so in this case alternative testing should be used or patients should be referred if there is a high index of suspicion

  • other non-invasive tests to assess the fibrosis risk are available, and cut-offs may vary according to different methods (Box 4)

    • ELF^TM test

    • FibroScan^®

    • other validated tests.

ELF^TM, enhanced liver fibrosis test; FIB4, fibrosis 4 test.

• If FIB4 <1.3 (or <2 in patients aged >65 years), the patient is at low risk of advanced fibrosis:

  • recommend lifestyle modifications (Box 5)

  • treat the components of metabolic syndrome and according to the cardiovascular risk assessment (including starting statins if indicated^[1]) (Box 6)

  • reassess FIB4 at 1–3 years (the magnitude of the interval is to be adapted according to risk factors).

• If FIB4 ≥1.3 (or ≥2 if aged >65 years), the patient is at intermediate–high risk of advanced fibrosis:

  • perform second-line non-invasive fibrosis testing (elastography or serum test) according to local practice:

    • if the second line test indicates a low risk for advanced fibrosis (Box 4):

      • recommend lifestyle modifications and implement the other measures mentioned above

    • if the second line test indicates an intermediate or high risk for advanced fibrosis (Box 4):

      • refer to gastroenterology/hepatology for:

        • confirmation of the diagnosis of advanced fibrosis/cirrhosis

        • intensification of the medical management, including, if indicated, a surveillance programme for HCC (ultrasound every 6 months) or screening for portal hypertension according to local practice and BAVENO guidelines^[21]

        • inclusion in a clinical trial can represent an additional therapeutic option

      • management of the metabolic syndrome and cardiovascular risk factors is done in close collaboration with primary care

  • the performance of second line testing as mentioned here can be situated in primary, secondary, or tertiary care, according to local resources, regulations and expertise, as indicated in Figure 1.

• If hepatology assessment does not confirm advanced disease, patients are referred back to primary care for:

  • lifestyle modifications (Box 5)

  • management of components of metabolic syndrome according to the cardiovascular risk assessment (including starting statins if indicated^[1]) (Box 6)

  • reassessment of FIB4 at 1–3 years (the magnitude of the interval is to be adapted according to risk factors).

BMI: body mass index; GLP-1, glucagon like peptide 1; T2DM, type 2 diabetes mellitus.

Figure 1 summarises the expert group’s pathway for the investigation and management of NAFLD/MASLD.

Figure 1. Algorithm for investigation and management of NAFLD/MASLD.

Jemma Lough, Independent Medical Writer, drafted this article, which was reviewed by the members of the expert group.