If obesity and diabetes mellitus represent the pandemic giant worldwide for the next decades, definitely MASLD provides their ominous shadow. The term MASLD (Metabolic Dysfunction-Associated Steatotic Liver) was proposed in 2023 to better define the disease characterized by hepatic steatosis (verified through imaging techniques or liver biopsy) and at least one of the following conditions: obesity, metabolic dysregulation, type 2 diabetes mellitus (T2DM). (1) Metabolic dysregulation means the presence of at least two between the following conditions: waist circumference above 102/88 cm for Caucasian males/females, blood pressure above 130/85 or antihypertensive medication, plasma triglycerides above 150 mg/dl or related medication, HDL cholesterol under 40 mg/dl for men and 50 mg/dl for women, prediabetic condition (fasting plasma glucose between 100–125 mg/dl or 2 h post load between 140–199 mg/dl or glycosylated haemoglobin between 5.7–6.4%), homeostasis model assessment (HOMA) score > 2.5, high-sensitivity C-reactive protein levels above 2 mg/L.(2) The old term NAFLD (Non-Alcoholic Fatty Liver Disease) remains confined to forms of steatosis (more than 5% of hepatocytes) not related to alcohol (less than 20/10 grams per day for males/females), viruses, genetic diseases, or toxic medications. (2, 3) Therefore MASLD does not just represent the new term for NAFLD, but, together with its more aggressive form named MASH (Metabolic dysfunction-Associated Steato-Hepatitis, definition that, in turn, replaces NASH), involves the manifold ensemble of metabolic disorders and is steadily increasing worldwide and will be the main cause of chronic liver diseases in the coming decades: in USA only, the prevalence of MASLD increased from 28.4% in 1999–2002 to 35.8% in 2011–2016. (4, 5) Moreover, compared to the diagnosis by exclusion in NAFLD, MASLD is a diagnosis of inclusion, studies have shown that a portion of the NAFLD population is excluded under the proposed MASLD definition. (6)
A team of the University of Singapore elaborated a meta-analysis and systematic review in over 10 millions of individuals, documenting for the first time that global prevalence and clinical features of MASLD are very impressive: in pooled analysis of over 3,3 millions individuals, the overall prevalence of MASLD was found to be 38.77%, with significant differences in geographical regions: highest in Europe (55.33%), followed by Asia (36.31%) and the lowest in North America (35.99%, 95% CI 30.68–41.66%). (7) In the same work, in a pooled analysis of 4,09 millions patients with MASLD, the mean age of MASLD patients was 51.99 years, with an average BMI and waist circumference of 27.71 kg/m2 and 92.91 cm, respectively; 41.38% suffered from hypertriglyceridemia, 43.72% were hypertensive, and 22.79% (95% CI 19.42–26.55%) were diabetic. In the analysis of MASLD demographics, 27.51% were smokers, and 19.28% had excessive alcohol consumption. A pooled mean of liver function test shows the average AST, ALT, and GGT levels to be 35.08 U/L, 43.71 U/L, and 60.47 U/L, respectively.
In Italy, the Diabetes Barometer Report 2023 documented a self-reported prevalence of diabetes of 3.9 millions (6.6% in general population), with an evident age-correlated gradient, achieving the prevalence of 18,7% in over 65 years subjects. (8) The prevalence of MASLD among diabetic patients in Italy amounts to 67.97%. (9) Therefore, the estimated prevalence of MASLD in Italy, calculated considering the presence of the disease in T2DM population (2,651 millions of T2DM patients present MASLD) and applying the above reported prevalence of 22.79% of T2DM among MASLD population, (7) amounts to approximately 11,6 millions out of a population of 58,85 millions in January 2023 (19,62%), (as shown in Methods).(10)
Thus, MASLD is a multisystem disease presenting an increased risk of developing not only diabetes itself, but also cardiovascular diseases (CVD), renal impairment (CKD), extrahepatic cancers (mainly colon-rectal), not forgetting the obvious liver-related complications heading towards MASH, cirrhosis (compensated, CC, and decompensated, DCC), and hepatocellular carcinoma (HCC).
Not being available data about the incidence of diabetes in MASLD population, the risk of developing T2DM among subjects with MASLD can be estimated starting from the annual incidence of T2DM among Italian population: 350,000 new diagnosis per year.(11) Knowing that the prevalence of MASLD among diabetic patients is 68%, as reported above, we can deduce that about 238,000 new T2DM are diagnosed per year among non-diabetic MASLD subjects, thus determining an annual incidence of 2.66%.
If we consider also the T2DM related events, among MASLD complications the most common, as well as the major cause of death, is CVD, representing advanced liver disease the second item in order of relevance.
A 2013 metanalysis reported several studies demonstrating an increased risk of CVD among patients with NAFLD, (12) but we had to wait for a paper published in 2021 to have an idea about the prevalence of myocardial infarction (MI) and stroke in USA adults, expressed as percentage of 10-year risk, for MASLD compared to non-MASLD subjects. (5) In the above cited work, which analyzed data from 19617 adults aged ≥ 20 years from the cross-sectional US National Health and Nutrition Examinations Survey periods ranging from 1999 to 2016, the estimated 10-year risk of MI and stroke ranged from 10.8 to 13.2% in MASLD subjects and from 6.6 to 7.1% in non-MASLD population; therefore, the highest prevalence presented by MASLD subjects ranges from 5.2 to 6.1% over a 10 years period. Applying these data to Italian population we therefore deduce that in the MASLD individuals, apart T2DM-related complications (included in the computation of its global costs), we can estimate a population presenting IMA or stroke over a 10-year period ranged between 465,000 to 545,000.
Chronic kidney disease (CKD) is another very important and recognized complication of MASLD.(13) In the main institutional document of Italian Ministry of Health about the management of CKD, defined as evaluated glomerular filtration rate (eGFR) < 60 mL/min/mq 1,73 and/or urinary albumin-to-creatinine ratio (ACR) ≥ 3 mg/mmol, the prevalence, based principally on the STUDIO CHARES, is 7,1% (7,5% in men and 6,5% in women), including 2,6% in Stage 3 (eGFR 30–59 mL/min/mq 1,73) and 0,3% in stage 4–5 (eGFR < 30 mL/min/mq 1,73).(14) Considering these epidemiologic data, we can calculate renal impairment in general population amounting to about 4,18 million subjects, including 177,000 affected by stage 4–5 CKD. Another review reported that NAFLD patients presented a higher risk of incident CKD compared with those without NAFLD over a median follow-up of nearly 5 years (HR 1.37, 95% CI 1.20–1.50) (15), so, considering that MASLD individuals present a lower glomerular filtration rate and a greater prevalence of CKD than NAFLD individuals (29,6% vs 25.56%, P < 0,05), (16) even applying the previous and more conservative rate of 1.37 to Italian MASLD population, we can estimate at least 1,13 million subjects with CKD of which 47,600 presenting stage 4–5 CKD. Therefore, excluding MASLD patients with T2DM, which represent two-thirds of all diabetic patients, and considering that T2DM determines about 20% of all cases of CKD, (17) we can deduce about 590,000 not-T2DM MASLD subjects presenting CDK, and 24,600 with stage 4–5 CKD.
Another important epidemiological association presented by MASLD subjects regards the increase in colorectal cancer (CRC) risk. A study starting from a nationwide health screening database including more than 8.9 million participants demonstrated that MASLD, more than NAFLD, was associated with a higher CRC risk, that, after multivariable adjustment for age, sex, household income quartile, residential area, CCI index (Charlson Comorbidity Index, which predicts 10-year survival in patients with multiple comorbidities), aspirin use, nonsteroidal anti-inflammatory drug use, tobacco smoke, exercise frequency, alcohol intake and concomitant liver diseases, was expressed as an HR of 1.16 (95% CI, 1.13–1.18).(18) The study also detected that patients with fatty liver disease and advanced liver fibrosis were at higher CRC risk than those with simple steatosis, suggesting that an adequate intervention on the disease could reduce the overall risk. Considering that the incidence rate detected for individuals without MASLD was 57,5 per 100.000 person-years, the extra incidence attributable to MASLD can be quantified in 9,2 per 100.000 person-years. Applying this to the above defined Italian MASLD population (11,6 million) we can consider an extra incidence of CRC in MASLD subject of about 1067 patients per year.
Last but not least, MASLD presents a higher risk of hepatic events, which incidence is related to the stage of fibrosis detected (F0-F2 versus F3 versus F4) as follows: variceal hemorrhage (0.00 versus 0.06 versus 0.70), ascites (0.04 versus 0.52 versus 1.20), encephalopathy (0.02 versus 0.75 versus 2.39), and hepatocellular carcinoma (HCC) (0.04 versus 0.34 versus 0.14) per 100 persons-year.(19) Considering that the annual incidence of HCC in NAFLD (and moreover MASLD) patients is 0.44 per 1000 person-years (95% CI: 0.29–0.66) whereas for MASH is 5.29 per 1000 person-year and reminding also that approximately 41% (95% CI: 34.69–47.13) of MASH patients present a worsening of fibrosis with an annual progression rate of 0.09% (95% CI: 0.06–0.12), the development of HCC an mortality has been stratified by NAFLD/MASLD or MASH status, as shown in Material and Methods.(20)
Considering the constant growth of MASLD in terms of percentage of population concerned (21), aim of our study is to evaluate the economic impact of MASLD among Italian population from the Italian National Healthcare Service (NHS) perspective.