Willy Theel

The introduction provides an overview of the epidemiology, pathophysiology, and clinical significance of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition now recognized as the most prevalent chronic liver disease worldwide. It outlines how MASLD arises at the intersection of obesity, type 2 diabetes, and metabolic dysfunction, and explains its reclassification from NAFLD to MASLD/MASH to better reflect its metabolic origins.

This part discusses the global variation in disease burden, the critical role of fibrosis and genetic predisposition in determining outcomes, and the growing recognition of MASLD as both a hepatic and systemic metabolic disorder. It also highlights the strong bidirectional link between MASLD and cardiovascular disease, emphasizing the need for integrated approaches to screening and management.

Finally, it considers recent conceptual shifts in defining obesity and their implications for diagnosing and treating MASLD within the broader context of metabolic health.

PART I – MASLD IN SPECIFIC POPULATIONS

This body of work focuses on the epidemiology, pathophysiology, and non-invasive assessment of MASLD/MASH across distinct high-risk populations.

Chapter 1 provides a comprehensive review of the mechanisms leading to steatosis, inflammation, and fibrosis in MASLD/MASH (NAFLD/NASH in the text). It emphasizes the rising global prevalence driven by obesity and type 2 diabetes, the strong association with cardiovascular and liver-related morbidity and mortality, and the urgent need for reliable non-invasive diagnostic tools. Although several blood- and imaging-based tests are available, liver biopsy remains the diagnostic gold standard.

Chapter 2 examines the prevalence and diagnostic accuracy of non-invasive tests (NITs) in a Dutch bariatric surgery cohort. Among 220 patients, MASLD prevalence was 50.6%, while MASH and at-risk MASH were identified in 5.3% and 2.6%, respectively, lower than expected for this high-risk group. The study found that the capped MAF-5 score outperformed FIB-4 and transient elastography for detecting significant fibrosis (≥F2), suggesting it may be a more reliable tool in bariatric populations.

Chapter 3 investigates MASLD and fibrosis in cardiometabolic outpatients, including individuals with and without diabetes. MASLD was present in 39.2% overall and was most common in type 2 diabetes (57%). Fibrosis risk was also highest in T2DM (22.5%), but MASLD and fibrosis were not associated with carotid intima-media thickness, indicating that hepatic and vascular pathology may progress independently. BMI and triglycerides were consistent predictors of MASLD and fibrosis, underscoring the importance of metabolic control and weight reduction.

PART II – MASLD, CARDIOVASCULAR RISK AND METABOLIC ASSOCIATIONS

In part 2 of this thesis, I demonstrate that MASLD and liver fibrosis are common and metabolically driven in diverse outpatient populations, and that non-invasive markers of fibrosis, such as FIB-4, may also reflect cardiovascular vulnerability.

Chapter 4 investigated the prevalence of MASLD and liver fibrosis in an outpatient population and examined their relationship with carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis. In this cohort of 475 individuals, MASLD and significant fibrosis were highly prevalent, affecting 40.2% and 18.9% of patients, respectively. Both conditions were strongly associated with metabolic risk factors, particularly higher body mass index (BMI) and triglyceride levels. Multiple regression analyses confirmed BMI as an independent predictor of both MASLD and fibrosis. Although cIMT correlated positively with age, BMI, and LDL cholesterol, no significant association was observed between cIMT and liver steatosis or fibrosis, indicating that vascular changes may occur independently of hepatic alterations. These findings highlight that MASLD and fibrosis are common in the outpatient setting but that cIMT has limited utility as a marker of liver-related disease burden.

Chapter 5 explored the association between liver fibrosis, estimated using the FIB-4 index, and cardiovascular risk factors in patients with rheumatoid arthritis (RA) participating in the FRANCIS study. Among 326 RA patients without type 2 diabetes or established CVD, 15% had an elevated FIB-4 score (≥1.3), indicating higher fibrosis risk. Patients with elevated FIB-4 displayed increased carotid intima-media thickness (cIMT), higher systolic blood pressure, and elevated levels of apolipoprotein B48 and alkaline phosphatase, as well as reduced leukocyte counts and complement component 3 levels. Medication analyses revealed that statin use was associated with higher FIB-4, while hydroxychloroquine use correlated with lower FIB-4, suggesting possible medication effects on hepatic or metabolic status. Disease activity was not related to FIB-4 levels. These results indicate that even in the absence of diabetes or overt CVD, RA patients with higher FIB-4 scores exhibit greater cardiovascular vulnerability, underscoring the potential value of incorporating non-invasive fibrosis assessment into CV risk stratification in this population.

PART III – INTERVENTIONS AND PROGNOSIS

Part 3 addresses the complex interplay between MASLD, obesity, genetic susceptibility, and cardiovascular outcomes across different clinical and demographic contexts.

Chapter 6 describes the design of a prospective cohort study investigating the long-term hepatic and metabolic effects of bariatric surgery in patients with obesity and MASLD/MASH (NAFLD/NASH in the text). By integrating metabolic, cardiovascular, genomic, proteomic, lipidomic, metabolomic, and microbiome analyses, this study aims to elucidate the mechanisms underlying regression of hepatic steatosis and fibrosis following weight loss surgery. The longitudinal approach, including transient elastography and histological evaluation up to five years postoperatively, seeks to identify predictors of sustained hepatic improvement and metabolic health restoration.

Chapter 7 shifts the focus to the genetic determinants of MASLD/MASH in an elderly Western European population from the PROSPER cohort. Five single nucleotide polymorphisms (SNPs) previously associated with MASLD/MASH were linked to variation in FIB-4 scores, reflecting differences in fibrosis risk. Furthermore, select variants (TRIB1, SLC39A8, and ANPEP) were associated with cardiovascular and mortality outcomes, suggesting that genetic predisposition to hepatic fibrosis may also confer systemic vulnerability. These findings underscore the potential of incorporating genetic risk profiling to refine both hepatic and cardiometabolic disease stratification in aging populations.

Chapter 8 further explores the prognostic relevance of hepatic fibrosis, assessed by FIB-4, in relation to mortality and cardiovascular endpoints within the same elderly cohort. Participants with high FIB-4 scores had increased all-cause mortality, independent of cardiovascular events. Notably, this excess risk was attenuated in those receiving pravastatin, suggesting a possible protective role of statin therapy beyond lipid lowering. This observation supports the concept that hepatic fibrosis serves as a systemic marker of vulnerability that may be modifiable through pharmacologic intervention.

Chapter 9 expands upon these findings by examining the combined impact of obesity and liver fibrosis on cardiovascular risk and the modifying effect of pravastatin. Elderly individuals with both high BMI and high FIB-4 scores demonstrated a markedly increased risk of (non-) fatal stroke in the placebo group, an association that was abolished by pravastatin treatment. In contrast, lean individuals with high FIB-4 exhibited higher all-cause mortality in the absence of statin therapy, a risk that was again mitigated by pravastatin. These results suggest that both metabolic and fibrotic phenotypes influence cardiovascular vulnerability, and that statin therapy may confer differential protective effects depending on body composition and fibrosis status.

Collectively, these chapters reveal that MASLD and liver fibrosis represent systemic expressions of metabolic dysfunction and genetic predisposition that extend beyond the liver. They highlight the potential of integrating omics-based profiling, fibrosis assessment, and cardiometabolic risk evaluation to guide individualized preventive and therapeutic strategies. Moreover, the observed mitigating effect of statin therapy on mortality and stroke risk in high-fibrosis groups underscores its possible role in modulating the hepatic–vascular axis in elderly individuals.