Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder characterized by inflammation, fibrosis, and metabolic dysfunction. In recent years, therapeutic options have expanded significantly. The thyroid hormone receptor-β agonist resmetirom became the first drug approved in Germany in 2025 for non-cirrhotic MASH with moderate to advanced fibrosis. Furthermore, incretin mimetics, originally developed for diabetes and obesity, are being investigated. In a phase 3 study, semaglutide demonstrated significant improvements in hepatic inflammation and fibrosis. Beyond GLP-1 analogs, which act indirectly through metabolic pathways, several liver fibrosis-specific therapies are emerging, including FGF-21 analogs and dual incretin receptor agonists (e.g. survodutide) that directly affect hepatocytes via glucagon receptor signaling. Combination therapies are increasingly being explored to harness synergistic effects and enable individualized treatment. Ongoing phase 3 studies assess long-term efficacy and safety. In parallel, biomarkers are being refined for patient selection and treatment monitoring. The German SLD Registry will collect patient data and clinical outcomes following the implementation of new therapies. This review summarizes recent advances and future perspectives in the pharmacological treatment of MASH. The combination of metabolic and liver-targeted therapies offers substantial promise for personalized medicine.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease and a major hepatic manifestation of metabolic syndrome. It is closely linked to obesity and type 2 diabetes mellitus. While many patients display a steatotic liver, some progress to steatohepatitis, fibrosis, and cirrhosis, increasing the risk of hepatocellular carcinoma (HCC). Current management targets metabolic risk factors. Metabolic and bariatric surgery (MBS) has therefore emerged as both an obesity treatment and a therapeutic option for MASLD. This narrative review summarizes evidence on clinical outcomes, efficacy, and mechanisms. Histology-based studies show MASLD resolution and relevant fibrosis regression after MBS, with durable benefits. Comparative studies indicate superiority over lifestyle intervention and conservative treatment, while direct comparisons with modern drugs (e.g. GLP-1 agonists) remain limited. Mechanistic studies suggest that MASLD remission by MBS is driven through a combination of sustained weight loss and surgery-specific effects on hepatic lipid metabolism, mitochondrial function, glucose metabolism, incretin and bile acid signalling, adipose tissue biology, and the gut-liver axis. Emerging evidence suggests fewer liver-related events and lower HCC incidence, with potential benefits in selected high-risk patients. In conclusion, MBS is not merely a weight loss intervention, but a disease-modifying, multi-system metabolic therapy with direct hepatic effects.

With the introduction of steatotic liver disease (SLD) as an umbrella term and metabolic dysfunction-associated steatotic liver disease (MASLD) as one of its major subcategories, a new diagnostic category was proposed to better reflect the coexistence of metabolic dysfunction and alcohol consumption: MetALD. MetALD identifies individuals with hepatic steatosis and cardiometabolic risk factors whose alcohol intake exceeds MASLD thresholds but remains below the levels typical of alcohol-related liver disease. The prevalence of MetALD in the general population is approximately 4%. Evidence suggests that MetALD is associated with more severe liver-related outcomes and higher all-cause mortality compared to MASLD, although findings are not entirely consistent. Despite these risks, MetALD remains underdiagnosed because alcohol consumption is often self-reported and underestimated due to recall bias, social desirability bias, or stigma. Consequently, managing MetALD requires a multidisciplinary approach addressing both cardiometabolic comorbidities and alcohol-related behavioral factors. MetALD should be viewed not only as a medical condition but also as a disorder with significant behavioral and social dimensions that influence diagnosis, treatment adherence, and long-term outcomes. This review discusses the clinical implications and therapeutic considerations specific to this newly introduced terminology.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major global health challenge, largely driven by the increasing prevalence of obesity and type 2 diabetes mellitus. The disease spectrum ranges from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH) with progressive fibrosis. Advanced fibrosis substantially increases the risk of cirrhosis, hepatocellular carcinoma, and cardiovascular complications, thereby contributing significantly to morbidity and mortality.Although lifestyle modification remains the cornerstone of therapy, pharmacological treatment is gaining importance in patients with progressive disease or high-risk profiles. Advances in the understanding of MASLD pathophysiology have enabled the development of targeted therapies addressing hepatic lipid accumulation, insulin resistance, inflammation, and fibrogenesis. Promising clinical data have been reported for resmetirom, semaglutide, tirzepatide, survodutide, lanifibranor, and fibroblast growth factor-21 analogues including efruxifermin, pegozafermin, and efimosfermin.This review summarises current and emerging diagnostic and therapeutic strategies and provides practical guidance for clinical management. In addition, a structured treatment algorithm for non-cirrhotic MASLD (F0-F3), restricted to therapies currently available in Europe and stratified according to diabetes status and fibrosis stage, is proposed as an evidence-based tool for routine clinical practice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has undergone a major conceptual shift from a steatosis-centred condition to a disease spectrum, in which advanced fibrosis is the major prognostic determinant. It affects up to one-third of the adult population but remains asymptomatic in the majority of patients. Therefore, the efficient identification of at-risk individuals is a central clinical task. Non-invasive tests increasingly complement histological staging and are embedded in sequential diagnostic algorithms. In particular, FIB-4, as a first-line screening tool followed by vibration-controlled transient elastography for liver stiffness assessment, has been adopted by expert recommendations and clinical guidelines.

X-linked hyper IgM-syndrome caused by CD40L deficiency is a rare primary immunodeficiency. Affected male individuals who reach adulthood often develop sclerosing cholangitis. Here, we report the case of a 33-year-old patient with long-standing solitary pre-papillary bile duct stenosis but without further signs of sclerosing cholangitis, who developed distal cholangiocarcinoma. Given the increased risk of malignancy in these patients, this case highlights, that individuals with CD40L deficiency should be screened for the presence of cholangiopathy and be closely monitored for any signs of disease progression, development of hepatobiliary dysplasia or malignancy.