Alessandra Scamporrino

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the hepatic manifestation of systemic metabolic dysfunction and has emerged as one of the leading causes of chronic liver disease worldwide. Its pathogenesis is complex and multifactorial, involving insulin resistance, altered lipid metabolism, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. Beyond these classical mechanisms, growing evidence highlights the central role of modifiable lifestyle-related factors, including chronic positive energy balance, high intake of fructose and saturated fats, ultra-processed foods, physical inactivity, sleep disruption, and environmental exposures such as endocrine-disrupting chemicals and air pollution, which have been associated with the activation of lipogenic and proinflammatory pathways in preclinical and observational studies. Conversely, protective dietary patterns, particularly the Mediterranean diet, together with regular physical activity, exert hepatoprotective metabolic and anti-inflammatory effects. An extensive literature search was conducted across the PubMed, Scopus, Cochrane Library, and Embase databases, covering publications through June 2026. The review was conducted following the SANRA recommendations for narrative reviews. The inclusion criteria encompassed clinical trials, systematic reviews, meta-analyses, and international clinical practice guidelines. This review provides an integrated framework by linking in a single interpretative model the classical pathogenic pathways with emerging dietary, behavioral, and environmental determinants and with systemic interorgan communication networks involving hepatokines, adipokines, and myokines. Understanding MASLD as a multisystemic metabolic disease driven by multiple determinants has critical implications for the development of targeted preventive and therapeutic strategies aimed at reducing its global burden and prevalence.

Background and Aims: Gut‐liver axis has been implicated in the pathophysiology of cirrhosis due to metabolic dysfunction‐associated steatotic liver disease (MASLD), an in vitro model for studying epithelial gut dysfunction in MASLD is lacking. In this study, we aimed to characterise intestinal organoids derived from subjects with MASLD. Materials and Methods: Intestinal organoids were obtained from duodenal samples of individuals with non‐fibrotic MASLD and with MASLD‐cirrhosis. After 7 to 10 days of culture, RNA extraction, transcriptomic analysis and real‐time PCR were performed. Energetic and redox status of organoids were assessed by chromatographic analysis. Results: Microarray analysis showed approximately 600 dysregulated transcripts in organoids isolated from patients with MASLD‐cirrhosis compared to non‐fibrotic MASLD. Bioinformatic analysis indicated that dysregulated transcripts were involved in pathways related to regeneration and pluripotency of stem cells and regulating mitochondrial metabolism and hypoxia. Overall, chromatographic analysis demonstrated that energetic status was remarkably impaired in both differentiated and undifferentiated organoids from cirrhotic patients compared to steatotic subjects. In either undifferentiated or differentiated organoids from cirrhotic subjects, the triphosphate sum, the ATP/ADP and NAD ⁺ /NADH ratios were lower in MASLD‐cirrhosis, indicating a decline in the phosphorylating capacity and a mitochondrial derangement of duodenal cells. In addition, we found lower levels of reduced glutathione, NADPH and UDP‐glucuronic acid in undifferentiated and differentiated cells from cirrhotics indicating impairment of antioxidant defence and of response to xenobiotics. Conclusions: Our study provides a comprehensive view of intestinal epithelial dysfunction in MASLD‐cirrhosis, characterised by a cluster of regenerative and metabolic disturbances.

Background: Bouveret syndrome is a complication of cholelithiasis, characterized by the migration of a large gallstone from the gallbladder to a part of the stomach or intestine through a bilio-enteric fistula. This condition results in a rare form of gallstone ileus, presenting signs and symptoms of gastric outlet obstruction. Methods: This case report aims to present a rare instance of Bouveret syndrome in a 64-year-old woman who presented to our emergency department with recurrent epigastric pain and vomiting for over 2 months. After a CT scan, an esophagogastroscopy was performed following a multidisciplinary discussion. An endoscopic evaluation revealed a large (4 cm) gallstone found in the proximal duodenum using an endoscope. We then inserted the holmium laser fiber system through a standard ERCP catheter, passing it through the endoscope’s working channel. By positioning the holmium laser fiber within the catheter, we stabilized the energy on the gallstone, which was then fragmented into smaller pieces after administering pulse energy. Results: In this case report, we successfully treated Bouveret syndrome using endoscopic laser lithotripsy combined with mechanical lithotripsy, avoiding traditional surgery. Conclusions: The endoscopic approach that combines laser and mechanical lithotripsy appears effective in fragmenting large gallstones into smaller pieces, facilitating their passage through the digestive tract and resolving the obstruction.

Background and Aims: Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase‐associated lipocalin (u‐NGAL), urinary beta‐2‐microglobulin (u‐B2M), urinary osteopontin (u‐OPN), urinary trefoil factor 3 (u‐TFF3) and urinary Cystatin C (u‐Cys). Methods: This is a case‐control study investigating the following urinary biomarkers of tubular damage: u‐NGAL, u‐B2M, u‐OPN, u‐TFF3 and u‐Cys, in patients with mild acute hyperbilirubinemia. Seventy‐four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice. Results: Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u‐NGAL, u‐B2M, u‐OPN, u‐TFF3 and u‐Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u‐NGAL values (OR = 3.8, 95% CI 1.07–13.5, p = .03) and u‐B2M (OR = 9.4, 95% CI 2.3–38.9, p = .0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes. Conclusions: This study demonstrated increased urinary biomarkers of tubular damage (u‐NGAL, u‐B2M, u‐OPN, u‐TFF3, and u‐Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology).

Diabetes mellitus (DM) is a complex and multifactorial disease characterised by high blood glucose. Type 2 Diabetes (T2D), the most frequent clinical condition accounting for about 90% of all DM cases worldwide, is a chronic disease with slow development usually affecting middle-aged or elderly individuals. T2D represents a significant problem of public health today because its incidence is constantly growing among both children and adults. It is also estimated that underdiagnosis prevalence would strongly further increase the real incidence of the disease, with about half of T2D patients being undiagnosed. Therefore, it is important to increase diagnosis accuracy. The current interest in RNA molecules (both protein- and non-protein-coding) as potential biomarkers for diagnosis, prognosis, and treatment lies in the ease and low cost of isolation and quantification with basic molecular biology techniques. In the present study, we analysed the transcriptome in serum samples collected from T2D patients and unaffected individuals to identify potential RNA-based biomarkers. Microarray-based profiling and subsequent validation using Real-Time PCR identified an uncharacterised long non-coding RNA (lncRNA) transcribed from the ASAP1 locus as a potential diagnostic biomarker. ROC curve analysis showed that a molecular signature including the lncRNA and the clinicopathological parameters of T2D patients as well as unaffected individuals showed a better diagnostic performance compared with the glycated haemoglobin test (HbA1c). This result suggests that the application of this biomarker in clinical practice would help to improve the diagnosis, and therefore the clinical management, of T2D patients. The proposed biomarker would be useful in the context of predictive, preventive, and personalised medicine (3PM/PPPM).

Diabetic kidney disease (DKD) is a complication that strongly increases the risk of end-stage kidney disease and cardiovascular events. The identification of novel, highly sensitive, and specific early biomarkers to identify DKD patients and predict kidney function decline is a pivotal aim of translational medicine. In a previous study, after a high-throughput approach, we identified in 69 diabetic patients 5 serum mitochondrial RNAs (MT-ATP6, MT-ATP8, MT-COX3, MT-ND1, and MT-RNR1) progressively downregulated with increasing eGFR stages. Here, we analyzed the protein serum concentrations of three well-validated biomarkers: TNFRI, TNFRII, and KIM-1. The protein biomarkers were gradually upregulated from G1 to G2 and G3 patients. All protein biomarkers correlated with creatinine, eGFR, and BUN. Performing multilogistic analyses, we found that, with respect to single protein biomarkers, the combination between (I) TNFRI or KIM-1 with each RNA transcript and (II) TNFRII with MT-ATP8, MT-ATP6, MT-COX-3, and MT-ND1 determined an outstanding improvement of the diagnostic performance of G3 versus G2 patient identification, reaching values in most cases above 0.9 or even equal to 1. The improvement of AUC values was also evaluated in normoalbuminuric or microalbuminuric patients considered separately. This study proposes a novel, promising multikind marker panel associated with kidney impairment in DKD.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m², absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.

Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is similar to other members of the same drug family, there is still much concern regarding the risk of lactic acidosis. This article aims to highlight the correlation between the use of metformin and the onset of renal damage or lactic acidosis. Metformin-associated lactic acidosis exists; however, it is rare. The appropriate use of the drug, under safe conditions, induces benefits without risks.

Type 2 diabetes and renal damage are strictly linked. The progressive increase in T2D incidence has stimulated the interest in novel biomarkers to improve the diagnostic performance of the commonly utilized markers such as albuminuria and eGFR. Through microarray method, we analyzed the entire transcriptome expressed in 12 serum samples of diabetic patients, six without DKD and six with DKD; the downregulation of the most dysregulated transcripts was validated in a wider cohort of 69 patients by qPCRs. We identified a total of 33 downregulated transcripts. The downregulation of four mitochondrial messenger RNAs (MT-ATP6, MT-ATP8, MT-COX3, MT-ND1) and other two transcripts (seysnoy, skerdo) was validated in patients with eGFR stage G3 versus G2 and G1. The four messenger RNAs correlated with creatinine and eGFR stages, while seysnoy and skerdo were associated with white blood cell values. All transcripts correlated also with Blood Urea Nitrogen. The four mitochondrial messenger RNAs had a high diagnostic performance in G3 versus G2 discrimination, with AUC values above 0.8. The most performant transcript was MT-ATP6, with an AUC of 0.846; sensitivity = 90%, specificity = 76%, p-value = 7.8 × 10⁻⁵. This study led to the identification of a specific molecular signature of DKD, proposing the dosage of RNAs, especially mitochondrial RNAs, as noninvasive biomarkers of diabetes complication.

Intestinal cell dysfunctions involved in obesity and associated diabetes could be correlated with impaired intestinal cell development. To date, the molecular mechanisms underlying these dysfunctions have been poorly investigated because of the lack of a good model for studying obesity. The main aim of this study was to investigate the effects of lipotoxicity on intestinal cell differentiation in small intestinal organoid platforms, which are used to analyze the regulation of cell differentiation. Mouse intestinal organoids were grown in the presence/absence of high palmitate concentrations (0.5 mM) for 48 h to simulate lipotoxicity. Palmitate treatment altered the expression of markers involved in the differentiation of enterocytes and goblet cells in the early (Hes1) and late (Muc2) phases of their development, respectively, and it modified enterocytes and goblet cell numbers. Furthermore, the expression of enteroendocrine cell progenitors (Ngn3) and I cells (CCK) markers was also impaired, as well as CCK-positive cell numbers and CCK secretion. Our data indicate, for the first time, that lipotoxicity simultaneously influences the differentiation of specific intestinal cell types in the gut: enterocytes, goblet cells and CCK cells. Through this study, we identified novel targets associated with molecular mechanisms affected by lipotoxicity that could be important for obesity and diabetes therapy.