Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO)

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell’Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l’Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources.

Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.

The present report is a summary of Clinical Practice Guidelines resulting from a cooperative work of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell’Obesità (SIO). Current knowledge on the diagnosis and treatment of non-alcoholic fatty liver disease (NAFLD) is translated into relevant practical recommendations for management following the rules and the methodology suggested in Italy by the Centro Nazionale per l’Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). In this summary, we report the outline of disease burden and the risks associated with disease progression, followed by PICO questions and recommendations. The review of the literature at the basis of individual recommendations is uploaded as supplementary material.

The natural history of nonalcoholic fatty liver disease (NAFLD) has been extensively investigated in the past 20 years. Steatosis is the hallmark of NAFLD and has been identified as an independent risk factor for the full spectrum of liver damage including inflammation, ballooning and fibrosis. The diagnosis of NAFLD requires the exclusion of both secondary causes and of alcohol consumption ≥30 g per day for men and ≥20 g per day for women. Recently, a consensus of experts proposed to overcome the current nomenclature “NAFLD” and adopt for a “positive” definition the acronym Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD) using metabolic dysfunctions as diagnostic criteria independently of the presence of other causes of chronic liver disease. The mean prevalence of NAFLD worldwide is 24.1%, ranging from 13.5% in Africa to 31.8% in Middle East, with differences among studies also related to diagnostic methods, age, gender and ethnicity. Italian studies indicate a prevalence of 22.5–27.0% in the general population, with a 2% prevalence of noninvasively-assessed advanced fibrosis due to NAFLD.

The prevalence increases in patients with metabolic comorbidities and the metabolic syndrome (MetS), defined by the presence of at least three metabolic alterations among elevated waist circumference (≥94 cm in males; ≥80 cm in females in Europids), elevated triglycerides (≥150 mg/dL), reduced HDL-C (≤40 mg/dL in males; ≤50 mg/dL in females), elevated blood pressure (systolic pressure ≥130 mmHg and/or diastolic pressure ≥85 mm or antihypertensive drug treatment) and elevated fasting glucose (≥100 mg/dL antihyperglycemic treatment). NAFLD is observed in 54–90% and 78.8% of cases with obesity or with MetS, respectively. In the Dionysos study, the presence of steatosis was closely associated with obesity and in the Dionysos and Nutrition Liver Study the risk of NAFLD was 9-fold increased by the presence of BMI ≥ 30 kg/m² and 6-fold by abdominal obesity (waist circumference ≥102 cm in males, ≥88 in females), independently of altered liver enzymes. Raised liver enzymes, assumed as surrogate indexes of NAFLD, were reported in 21% of cases with obesity and did not increase systematically with obesity class.

In a more recent analysis of 890 subjects of the community-based ABCD (“Alimentazione, Benessere Cardiovascolare e Diabete”) study, Petta et al. reported a NAFLD prevalence of 48%, with a relative risk for obesity of 4.02 (95% confidence interval, 2.77–5.84), but the various diagnostic tools and/or settings may provide slightly different results.

The prevalence of NAFLD is as high as 70–80% in patients with type 2 diabetes mellitus (T2DM), who are also more likely to have nonalcoholic steatohepatitis (NASH) and cirrhosis, even in the presence of fairly normal serum aminotransferase levels. In Italian patients with diabetes NAFLD is reported in 59.0–73.2%, with about 13%-18% of them experiencing advanced fibrosis. A bidirectional association exists between NAFLD and T2DM, worsening the course of both diseases; the presence of T2DM increases the risk of NAFLD progression to advanced fibrosis and cirrhosis, as well as also of incident hepatocellular carcinoma (HCC), liver-related hospital admissions and liver-related deaths, whereas the presence of NAFLD in T2DM is associated with a reduced probability of achieving good glycemic control, and exacerbates atherogenic dyslipidemia, further increasing the risk of chronic kidney disease and adverse CV outcomes, particularly in the presence of NASH-fibrosis.

The lifetime costs of all NASH patients in the United States in 2017 is estimated at $222.6 billion, and the cost of the advanced NASH population at $95.4 billion. Data from Italian local Health Units, based on administrative data and resources utilization, calculated an average direct cost for NAFLD/NASH progressively increasing from the non-advanced stage, to advanced NAFLD disease, compensated cirrhosis, liver transplant, and hepatocellular carcinoma (HCC), also driven by comorbidities, up to over € 65.000/year. Considering the projections calculated by disease modeling for the next decades, the total costs is likely to become very challenging for the National Health system.

Patients with NAFLD have an increased overall mortality compared to matched control populations. According to a meta-analysis, overall mortality was reported to be 15.4 per 1,000 person-years (range, 11.7–20.3) for patients with NAFLD and 25.6 (range, 6.3–103.8) for the cohort with NASH. The presence of NASH (adjusted hazard ratio_adjHR], 9.16), age (_adjHR, 1.06), and the presence of T2DM (_adjHR, 2.09) increased all-cause and liver-related mortality, after controlling for other variables. Liver-specific mortality was estimated as 0.8 (range, 0.3–1.8) in NAFLD and 11.8 (range, 7.1–19.5) in NASH. Cardiovascular (CV) disease (CVD) remains the most common cause of death, independent of other metabolic comorbidities, driven by the atherogenic profile and widespread CV complications, independently of other known risk factors. Fibrosis stage is the strongest predictor for mortality from CVD and liver-related disease in a cohort of biopsy-proven NAFLD after up to 33 years of follow-up NAFLD is also associated with an approximate 2-fold increased risk of incident T2DM, ranging from a 35% to a 5.5-fold increase, independent of overweight/obesity and other common risk factors. The risk of incident T2DM appears to diminish over time following the improvement or resolution of NAFLD. Patients with NAFLD also have a nearly 40% increase in the long-term risk of incident chronic kidney disease as well as other recognized associations with sleep apnea, osteoporosis, psoriasis and endocrinopathies.

The presence of NASH increases liver-related mortality, but the most important driver of mortality is fibrosis at histology, specifically, zone 3 sinusoidal fibrosis plus periportal fibrosis (stage 2), advanced fibrosis (bridging fibrosis [stage 3] or cirrhosis [stage 4]), associated with the multiple component of MetS. Patients with stage 4 fibrosis (cirrhosis) had a nearly 10-fold risk of liver-related complications, with liver-related events occurring in 8.9 per 100 person-years (95% CI, 6.7–11.7]. The reported annual incidence of hepatic decompensation was 3.3 and 15.6 per 100 person-years among patients with Child Pugh (CP)-A5 and CP-A6 cirrhosis, respectively.

NAFLD is the third-most common cause of HCC in the United States, after hepatitis C and alcohol-related disease, accounting for 14.1% of all cases. The cumulative incidence of NAFLD-associated HCC has been reported to range from 2.4% to 12.8% over a median follow-up period of 3.2–7.2 years, corresponding to 0.44 (range, 0.29–0.66) per 1000 person-years and increasing at a 9% annual rate. Patients with NAFLD fibrosis stages F3 and F4 have an almost 7-fold increased risk of HCC compared to people without liver disease and the risk is >10 folds higher in association with T2DM and obesity, making NAFLD the second leading cause of liver transplantation (LT) due to HCC in U.S and the most rapidly increasing indication. At diagnosis, patients with NAFLD-related HCC are older, have higher prevalence of extrahepatic comorbidities but lower prevalence of cirrhosis (absence of cirrhosis in up to 1/3 of cases), and shorter survival time, being more likely to die from their primary liver cancer than other HCC patients. These conditions may be driven by less systematic surveillance, leading to diagnosis at later stage and less treatment.

Other extra-hepatic cancers are similarly increased, namely cancers of the uterus (IRR=2.3; 95%CI 1.4, 4.1), stomach (IRR=2.3; 95%CI 1.3, 4.1), pancreas (IRR=2.0; 95%CI 1.2, 3.3) and colon (IRR=1.8; 95%CI 1.1, 2.8). The association with cancer risk is stronger in NAFLD than in obesity.

The term ‘lean’ NAFLD refers to patients with a BMI within the ethnic-specific cut-off of normalweight, but frequently extended to the area of overweight (30 kg/m² in Caucasian and 27 kg/m² in Asian subjects). It is conceivable that ‘lean’ NAFLD comprises an heterogeneous NAFLD cohort associated with environmental and genetic factors, as well as differences in fat distribution and body composition, accounting for 5–26% of total NAFLD cases in the Asian population and 7–20% in the Western areas. A recent meta-analysis of 33 observational studies from 14 countries concluded for a global prevalence of NAFLD in lean individuals (BMI ≤ 23 kg/m² for Asian subjects and BMI ≤ 25 kg/m² for non-Asian subjects) of 9.7% (95% CI: 7.7–11.8%), with an upward trend between 1988 and 2017. Their rate of comorbidity is lower compared to obese patients, but higher compared to healthy controls. Data on histological severity are controversial; they can develop the full spectrum of liver disease associated with NASH and similar adverse health outcomes when longitudinally examined

Following the needs of an updated guidance upon clinical management of the Non Alcoholic Fatty Liver Disease, the Scientific Societies whose members are primarily involved in its management (Italian Association for the Study of the Liver – AISF; Italian Society of Diabetology – SID; Italian Society of Obesity – SIO) commissioned to an experts panel the drafting of a new dedicated document to outline the updated clinical practice guidelines. The present document was made according to the rules dictated by the Italian Center for the Cure Excellence (Centro Nazionale per l’Eccellenza delle Cure – CNEC), an institution recently set up by the Italian National Institute of Health (Istituto Superiore di Sanità – ISS) to outline the methodologies needed to provide evidence-based clinical, diagnostic and therapeutic guidelines in Italy. According to these rules, a “multi-societary” and “multi-disciplinary” committee of experts was selected by the abovementioned Scientific Societies. The committee defined the objectives, the key issues and retrieved the relevant evidences by performing a systematic review of literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines’ key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes). The most relevant questions were chosen by voting among the whole committee. The mean agreement among panel members on recommendations was 98.15%, as reported in supplementary Table 1. For each PICO question, a systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase) by performing both a free-text research and by a BOOLEAN research string formulated on purpose (see Appendix 1). The profiles of evidence were developed by applying the GRADE-Evidence to Decision (EtD) frameworks as per CNEC manual indications

In particular, all aspects regarding the questions, the assessment of evidence and the conclusions drawings were discussed between the panel members and voted to obtain a final decision. The GRADEpro GDT online tool was used to develop the questions and make the decisions. The quality of evidence was evaluated by applying the “Quality Assessment of Diagnostic Accuracy Studies version 2” (QUADAS-2) checklist for the diagnostic accuracy questions, the “revised tool for Risk of Bias in randomized trials” (RoB 2) and the “Risk Of Bias in Non-randomized Studies – of Interventions” tool (ROBINS-I) for randomized clinical trials and non-randomized studies where applicable.

The present report is a summary of Clinical Practice Guidelines resulting from a cooperative multi-society work and by using rigorous methodology suggested in Italy by the Centro Nazionale per l’Eccellenza delle cure and Istituto Superiore di Sanità. Lack of awareness for NAFLD and obstacles to apply and implement guidelines could limit their utility.

NAFLD is an emerging liver disease with a growing epidemiological and clinical burden. National guidelines for the management of NAFLD patients are not still available.

The present document is the first effort to provide multi-society national guidelines on NAFLD aimed to a multidisciplinary and shared management of NAFLD patients.

(A) Assessment of disease severity

– In patients with NAFLD non-invasive tests do not have acceptable accuracy for the diagnosis of NASH, and liver biopsy remains the reference standard (B,2).