Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition

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Dear Colleagues,

The management of gastrointestinal and hepatic diseases is constantly evolving. The progressive understanding of pathogenic mechanisms has improved daily management, representing real translational medicine. For example, understanding the mechanisms underlying HCV virus infection has enabled the development of Direct-Acting Antivirals (DAAs), with a cure rate of 98%. However, patients with advanced liver disease, albeit cured from HCV infection, are still at risk of hepatocellular carcinoma (HCC) development. Therefore, these patients will remain a medical challenge for years to come. New antiviral agents are currently under development for the treatment of chronic delta hepatitis (CHD).

Hopefully, in the near future we will be able to at least control liver disease progression in patients with CHD, the most severe form of chronic viral hepatitis. In the coming decades, NAFLD/NASH will supplant viral hepatitis as the leading cause of chronic liver damage. Efforts are ongoing to identify novel biomarkers and tools for the detection of liver fibrosis and stratify the risk of liver disease progression. Moreover, novel molecules targeting several pathways involved in NAFLD onset and progression are under investigation. The decrease in the prevalence of Helicobacter pylori (H. pylori) infection, the widespread use of proton pump inhibitors, and the relative ease of access to gastroscopies have reduced the incidence of peptic disease and stomach cancer, which was once the main gastrointestinal pathology. In many areas of the world, however, H. pylori infection remains widespread, and there is still room for improvement in eradication strategies. Understanding the inflammatory pathways involved in inflammatory bowel disease has enabled the development of target therapies (anti-TNF, anti-IL12/23, anti-JAK, S1P1 modulators). Increased understanding of the microbiome will lead to applications that will go beyond the confines of the gut, although the COVID-19 pandemic will continue to affect the management of all diseases.

The objective of this Topic is to present the most up-to-date data on the pathogenesis and management of gastrointestinal and hepatological diseases, with a view to an increasingly personalized management of patients.

Dr. Davide Giuseppe Ribaldone
Dr. Gian Paolo Caviglia
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	4.5	7.8	2013	18.2 Days	CHF 2600	Submit
Current Oncology curroncol	3.6	6.1	1994	22.6 Days	CHF 2200	Submit
Diagnostics diagnostics	3.8	6.9	2011	20.4 Days	CHF 2600	Submit
Gastrointestinal Disorders gastrointestdisord	1.9	2.1	2019	19.6 Days	CHF 1400	Submit
Journal of Clinical Medicine jcm	3.3	5.2	2012	16.6 Days	CHF 2600	Submit
Livers livers	2.2	4.1	2021	28 Days	CHF 1200	Submit
Transplantology transplantology	-	1.2	2020	21.1 Days	CHF 1200	Submit

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Published Papers (17 papers)

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Open AccessReview

Immunotherapy for Recurrent Hepatocellular Carcinoma After Liver Transplantation: Current Evidence and Challenges

by Stella Vasileiadou, Stavros Neiros, Filippos F. Karageorgos, Athanasios Kofinas, Ifaistion Palios, Nikolaos Antoniadis, Emmanouil Sinakos and Georgios Tsoulfas

Transplantology 2026, 7(3), 20; https://doi.org/10.3390/transplantology7030020 (registering DOI) - 18 Sep 2026

Abstract

Background/Objectives: Hepatocellular carcinoma (HCC) frequently develops in the set-ting of chronic liver disease, and liver transplantation (LT) represents the most effective curative option for selected patients. Despite advances in patient selection and surveillance, HCC recurrence after LT remains a major cause of post-transplant [...] Read more.

Background/Objectives: Hepatocellular carcinoma (HCC) frequently develops in the set-ting of chronic liver disease, and liver transplantation (LT) represents the most effective curative option for selected patients. Despite advances in patient selection and surveillance, HCC recurrence after LT remains a major cause of post-transplant mortality and is associated with limited therapeutic options. Immune checkpoint inhibitors (ICIs) have transformed the management of advanced HCC in non-transplant populations; however, their role after liver transplantation remains controversial due to safety concerns and the risk of allograft rejection. This narrative review aims to critically evaluate the current evidence on immunotherapy for recurrent HCC after liver transplantation. Methods: A structured narrative review of PubMed/MEDLINE was conducted through 31 May 2026. Primary clinical reports describing ICI treatment for recurrent HCC after LT were selected using predefined eligibility criteria. Results: Twenty-one primary publications were included, consisting predominantly of case reports and small case series, supplemented by three retrospective cohorts. The reports described heterogeneous oncological outcomes, including occasional durable responses, but progressive disease remained common. Allograft rejection was an important safety concern and was sometimes associated with graft failure and death. More favourable outcomes were observed among some recipients treated at longer intervals after LT; however, this pattern remains hypothesis-generating and may reflect selection and survivor bias, tumour biology, graft stability, and differences in maintenance immunosuppression. Conclusions: ICI treatment for recurrent HCC after LT is associated with uncertain oncological benefit and a clinically important risk of allograft rejection. Its use should be restricted to highly selected recipients following multidisciplinary assessment and, whenever possible, within prospective studies or structured registries. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

12 pages, 7560 KB  

Open AccessCase Report

A Pyogenic Liver Abscess Masquerading as Advanced Hepatocellular Carcinoma: Diagnostic Pitfalls of LI-RADS 5 in a Non-Cirrhotic Patient and Vascular Complications of Percutaneous Drainage

by Finly Septianto and Ummi Maimunah

Gastrointest. Disord. 2026, 8(3), 53; https://doi.org/10.3390/gidisord8030053 - 9 Sep 2026

Viewed by 200

Abstract

Background: Liver abscesses represent uncommon yet potentially life-threatening infections of the hepatic parenchyma. Their imaging appearances can vary widely, and—in rare instances—may closely resemble hepatocellular carcinoma (HCC) on multimodality imaging. We report a case of pyogenic liver abscess initially misclassified as advanced HCC [...] Read more.

Background: Liver abscesses represent uncommon yet potentially life-threatening infections of the hepatic parenchyma. Their imaging appearances can vary widely, and—in rare instances—may closely resemble hepatocellular carcinoma (HCC) on multimodality imaging. We report a case of pyogenic liver abscess initially misclassified as advanced HCC based on imaging characteristics meeting LI-RADS 5 criteria. Case Presentation: A 45-year-old male without known cirrhosis, viral hepatitis, or diabetes presented with right upper quadrant pain, abdominal rigidity, nausea, and vomiting. He denied alcohol use, recent dental procedures, and travel to endemic areas. Contrast-enhanced computed tomography and magnetic resonance imaging demonstrated multiple exophytic hepatic masses with arterial-phase hyperenhancement and venous/delayed washout, classified as LI-RADS 5 and initially interpreted as advanced HCC (BCLC stage C). Alpha-fetoprotein (AFP) was not elevated. Hepatitis B surface antigen and anti-HIV were non-reactive. Ultrasound-guided fine-needle aspiration biopsy yielded purulent material; histopathology confirmed chronic suppurative inflammation consistent with an abscess, with negative acid-fast bacilli staining. Cultures were sterile. The patient was treated with doripenem and metronidazole. A post-drainage complication of middle hepatic artery bleeding required urgent transcatheter embolization. The patient was subsequently discharged in stable condition. Discussion: This case illustrates a recognized but uncommon diagnostic pitfall: pyogenic liver abscesses fulfil imaging criteria for HCC. LI-RADS 5 classification carries an estimated false-positive rate of approximately 5%, and its application is technically restricted to patients with established HCC risk factors (e.g., cirrhosis, chronic hepatitis B). In non-cirrhotic patients presenting with fever, leukocytosis, and an atypical or rapidly enlarging hepatic mass, tissue confirmation is essential before committing to an oncological diagnosis. Conclusions: When a hepatic mass displays imaging features fulfilling LI-RADS 5 criteria in a non-cirrhotic patient with clinical signs of infection—including fever, leukocytosis, and elevated inflammatory markers—the possibility of a liver abscess must be actively excluded. Biopsy and percutaneous drainage are essential to avoid misdiagnosis and to enable timely, appropriate treatment. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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Open AccessArticle

The C-Reactive Protein–Triglyceride–Glucose Index as a Biomarker of Metabolic Dysfunction-Associated Steatotic Liver Disease: Results from the Population-Based Italian NUTRI-HEP Cohort

by Gianluigi Casimo, Rossella Donghia, Caterina Bonfiglio, Rossella Tatoli, Giovanni Maria Biancofiore and Gianluigi Giannelli

Biomedicines 2026, 14(8), 1860; https://doi.org/10.3390/biomedicines14081860 - 19 Aug 2026

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Abstract

Background/Objectives: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is rapidly becoming one of the main Non-communicable Chronic Diseases (NCDs) in the global population. It is based on the presence of hepatic steatosis linked to other metabolic alterations. Currently, the gold standard techniques to [...] Read more.

Background/Objectives: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is rapidly becoming one of the main Non-communicable Chronic Diseases (NCDs) in the global population. It is based on the presence of hepatic steatosis linked to other metabolic alterations. Currently, the gold standard techniques to evaluate hepatic steatosis are liver biopsy and hepatic ultrasound examinations (FIBROSCAN^®). However, liver biopsy is an invasive technique and ultrasonic examination is expensive. Therefore, the search for a possible low-cost and non-invasive examination has highlighted the C-reactive protein-triglycerides-glucose index (CTI index) as a possible alternative. This index has already been shown to be associated with cancer survival and with cardiovascular diseases and stroke in previous studies and was found to be predictive for the development of several cardiovascular diseases and stroke incidence. This analysis aimed to investigate the possible association between CTI and MASLD in a southeastern Italian cohort. Methods: This study included 1297 subjects from the NUTRI-HEP project: 629 (48.5%) were affected by MASLD and 668 (51.5%) were not. The CTI index was calculated using the formula proposed by Ruan et al. and was used as both a continuous and a categorical variable. Four logistic regression models were fitted using MASLD as the outcome and the CTI index as the exposure. They were adjusted for several covariates. Results: All logistic regression models indicated a positive association between the CTI index and MASLD development. Focusing on Model 4, using Q1 as a reference, the Odds Ratios were 1.48 (95% C.I. 1.00; 2.17, p = 0.049), 2.06 (95% C.I. 1.38; 3.08, p < 0.001) and 3.62 (95% C.I. 2.32; 5.64, p < 0.001). Conclusions: This study highlights a strong association between MASLD and the CTI index. This association strengthens the role of CTI in predicting the onset and development of MASLD. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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10 pages, 331 KB  

Open AccessArticle

Association Between Diabetes Prevalence and Mortality from Gastrointestinal Cancers in Türkiye: A Longitudinal Ecological Study

by Muammer Bilici, Güray Ceylan and Kadir Yılmaz

J. Clin. Med. 2026, 15(15), 6037; https://doi.org/10.3390/jcm15156037 - 3 Aug 2026

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Abstract

Background/Objectives: This study aimed to analyze the effect of diabetes prevalence on mortality levels from gastrointestinal cancers. Methods: The study utilized mortality data for Türkiye from the World Health Organization (WHO) Mortality Database, covering deaths from stomach, colon and rectum, liver, [...] Read more.

Background/Objectives: This study aimed to analyze the effect of diabetes prevalence on mortality levels from gastrointestinal cancers. Methods: The study utilized mortality data for Türkiye from the World Health Organization (WHO) Mortality Database, covering deaths from stomach, colon and rectum, liver, and pancreas cancers, as well as diabetes prevalence data, between 2009 and 2023. Health expenditure and life expectancy data from the World Bank were used as control variables. Results: Diabetes prevalence was significantly correlated with colon and rectum cancer mortality (r = 0.929; p < 0.01), pancreas cancer mortality (r = 0.978; p < 0.01), life expectancy (r = 0.941; p < 0.01), and health expenditure (r = −0.635; p < 0.01). Correlations of diabetes prevalence with esophagus, stomach, and liver cancer mortality were statistically insignificant (p > 0.05). According to generalized linear model analysis results, there was an effect of diabetes prevalence on colon and rectum cancer mortality (B = 383.108; p < 0.01) and pancreas cancer mortality (B = 330.415; p < 0.01). Effects of diabetes prevalence on esophagus, stomach, and liver cancer mortality were statistically insignificant (p > 0.05). Conclusions: Diabetes prevalence was significantly associated with mortality levels for colon and rectal cancer and pancreatic cancer; however, it did not have a significant effect on mortality levels for esophageal, gastric, and liver cancers. Although there is a close relationship between diabetes and the digestive system, a similar relationship between cancer mortality levels of digestive system organs and diabetes is not valid for every organ. We believe that the effect of diabetes on gastrointestinal cancers has a tissue- or organ-specific mechanism of action rather than a digestive mechanism. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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12 pages, 737 KB  

Open AccessArticle

Real-World Safety and Herpes Zoster Outcomes After Recombinant Zoster Vaccination in Inflammatory Bowel Disease

by Gian Mario Morrone, Sara Sandri, Marta Vernero, Angelo Armandi, Gian Paolo Caviglia and Davide Giuseppe Ribaldone

J. Clin. Med. 2026, 15(13), 5310; https://doi.org/10.3390/jcm15135310 - 7 Jul 2026

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Abstract

Background/Objectives: Patients with inflammatory bowel disease (IBD) are at an increased risk of herpes zoster (HZ), particularly during immunosuppressive treatment. To assess the safety of the recombinant zoster vaccine (RZV, Shingrix^®) and describe HZ occurrence in a real-world IBD cohort, including [...] Read more.

Background/Objectives: Patients with inflammatory bowel disease (IBD) are at an increased risk of herpes zoster (HZ), particularly during immunosuppressive treatment. To assess the safety of the recombinant zoster vaccine (RZV, Shingrix^®) and describe HZ occurrence in a real-world IBD cohort, including patients receiving advanced therapies. Methods: This prospective, single-centre observational study included 114 adults with IBD who were offered RZV; 69 received at least one dose, and 45 declined or postponed vaccination. Follow-up began at the vaccine proposal. For time-to-event analyses, vaccination was modelled as a time-varying exposure beginning 14 days after a documented second dose. IBD clinical relapse was defined by worsening disease-activity indices and/or treatment escalation. Results: During a median follow-up of 17 months (IQR 9–29), 11 patient-reported HZ episodes occurred: 8/69 (11.6%) among patients who received vaccination and 3/45 (6.7%) among those who did not. The time-dependent association between complete vaccination and HZ was not statistically significant (HR 2.51; 95% CI 0.66–9.51; p = 0.18), and adjustment for advanced therapy did not materially change the estimate. Prior HZ was associated with a higher risk of a subsequent reported episode (adjusted HR 6.26; 95% CI 1.80–21.76; p = 0.004). IBD clinical relapse occurred in 4/69 (5.8%) vaccinated and 2/45 (4.4%) unvaccinated patients (p = 1.00). Among 72 patients receiving advanced therapy, HZ occurred in 4/42 vaccinated and 2/30 unvaccinated patients (p = 1.00), while IBD relapse occurred in 3/42 and 1/30, respectively (p = 0.64). No serious vaccine-related adverse events or significant pre-/post-vaccination changes in disease activity were observed. Conclusions: RZV showed a favourable short-term safety profile in patients with IBD, including those receiving advanced therapies. The small number of self-reported HZ events and the non-randomised design preclude conclusions regarding vaccine effectiveness. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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12 pages, 9793 KB  

Open AccessEditor’s ChoiceArticle

Liver Iron Content and Magnetic Resonance: A “Biopsy-Free” Quantification Method and Its Validation

by Lorenzo Cinci, Cosimo Nardi, Martina Legato, Valentina Carrai, Valeria Santini, Ginevra Danti, Simone Busoni, Susanna Pucci, Luca Messerini and Linda Calistri

Livers 2026, 6(4), 60; https://doi.org/10.3390/livers6040060 - 1 Jul 2026

Viewed by 602

Abstract

Background/Objectives: Accurate liver iron content (LIC) quantification and monitoring are crucial for managing patients with hematological disorders. Biopsy-based LIC assessment is invasive and prone to sampling errors. This study aimed to develop a simple and safe method for calibrating MR scanner to accurately [...] Read more.

Background/Objectives: Accurate liver iron content (LIC) quantification and monitoring are crucial for managing patients with hematological disorders. Biopsy-based LIC assessment is invasive and prone to sampling errors. This study aimed to develop a simple and safe method for calibrating MR scanner to accurately measure LIC. Methods: Five certified test objects with increasing aqueous Fe³⁺ solutions were used for R2* relaxometry to create a calibration curve with equation for converting R2* value to iron content (mg/g), using two different MR scanners. Additionally, two sets of test objects (aqueous and gelled solutions to mimic liver tissue) were developed to evaluate the feasibility of using homemade test objects. Our method was compared with two existing methods (Wood et al.’s equation and the Iron Calculator App) in 59 hematological patients, using the certified test object method as reference. We also compared our method with biopsy-based iron quantification (inductively coupled plasma optical emission spectroscopy) in four patients. Results: The equations derived from our homemade test objects were comparable to those from certified test objects across both MRI scanners. The literature methods consistently overestimated LIC compared to our method. For biopsy validation, our method was more accurate in two out of four cases. Conclusions: Our homemade calibration method offers a simple, reliable alternative for LIC quantification. The type of test object (aqueous or gelled) showed no significant difference. While biopsy-based methods remain useful, our MRI-based approach is quicker and avoids the limitations of biopsy sampling. This method, relying on the relationship between iron concentrations and relaxation times, could provide a more comprehensive and accurate assessment of liver iron levels. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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12 pages, 736 KB  

Open AccessArticle

Red Blood Cell Aggregation, Angiogenesis and Hypoxia Biomarkers in Pancreatic Cancer

by Maciej Wiewiora, Dorian Andreade, Christian Heiliger and Konrad Karcz

J. Clin. Med. 2026, 15(11), 4109; https://doi.org/10.3390/jcm15114109 - 26 May 2026

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Abstract

Background/Objectives: This study aimed to investigate the effect of pancreatic ductal adenocarcinoma (PDAC) on the alterations in red blood cell aggregation related to angiogenesis and hypoxia markers. Methods: We studied 31 patients with confirmed PDAC. The aggregation of red blood cells (RBCs) was [...] Read more.

Background/Objectives: This study aimed to investigate the effect of pancreatic ductal adenocarcinoma (PDAC) on the alterations in red blood cell aggregation related to angiogenesis and hypoxia markers. Methods: We studied 31 patients with confirmed PDAC. The aggregation of red blood cells (RBCs) was evaluated using a Laser-assisted Optical Rotational Cell Analyzer (LORCA). Serum vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) levels were measured using ELISA. We estimated the following parameters specific to the aggregation process: the aggregation index (AI), the aggregation half-time (t_1/2), and the threshold shear rate (γ_thr). Results: All measured RBC aggregation parameters among PDAC subjects differed from those in the controls. The AI (p < 0.05) and γ_thr (p < 0.005) were significantly higher in the PDAC group, whereas t_1/2 (p < 0.01) and AMP (p < 0.001) were significantly lower compared to the control group. The levels of VEGF (p < 0.0001) and HIF-1α (p < 0.0001) were significantly higher in the PDAC group than in the control group. There were significant correlations between RBC aggregation parameters and VEGF and HIF-1α. Multivariate analyses further identified t_1/2 (p < 0.01) and γ_thr (p < 0.05) as independent predictors for VEGF. For HIF-1α, t_1/2 (p < 0.05) was confirmed as an independent predictor. Conclusions: The results suggest, but do not demonstrate, a direct pathophysiological link between PDAC-associated hypoxia/angiogenesis and erythrocyte aggregation. Further studies are needed because the relationship linking PDAC to these aggregation indices is unclear. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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21 pages, 5208 KB  

Open AccessEditor’s ChoiceArticle

The MRI Signature of Neuroendocrine Liver Metastases: Toward a Radiologic Identikit

by Alessandro Serafini, Clara Gaetani, Laura Bergamasco, Stefano Cirillo, Teresa Gallo, Marco Gatti, Paolo Fonio and Riccardo Faletti

Livers 2026, 6(3), 41; https://doi.org/10.3390/livers6030041 - 12 May 2026

Viewed by 1285

Abstract

Background: Neuroendocrine neoplasms are frequently diagnosed after the detection of liver metastases, often when the primary tumor remains occult. Accurate non-invasive differentiation of neuroendocrine liver metastases (NELMs) from other focal hepatic lesions is therefore crucial. This study aimed to characterize the magnetic resonance [...] Read more.

Background: Neuroendocrine neoplasms are frequently diagnosed after the detection of liver metastases, often when the primary tumor remains occult. Accurate non-invasive differentiation of neuroendocrine liver metastases (NELMs) from other focal hepatic lesions is therefore crucial. This study aimed to characterize the magnetic resonance imaging (MRI) features of NELMs using hepatocyte-specific contrast agents and to identify a potential radiologic “signature” that may suggest a neuroendocrine origin. Methods: This retrospective study included three cohorts: patients with histologically confirmed NELMs (n = 51; 146 lesions), patients with colorectal cancer liver metastases (n = 18; 46 lesions), and patients with benign hepatic hemangiomas (n = 28; 51 lesions). All subjects underwent standardized liver MRI with Gd-EOB-DTPA. Lesions were evaluated for size, diffusion-weighted imaging characteristics, apparent diffusion coefficient values, arterial-phase enhancement, T2-weighted signal, hepatobiliary-phase appearance, and hemorrhagic components. Statistical analyses included univariate and multivariate testing and receiver operating characteristic curve analysis. Results: NELMs commonly demonstrated arterial hyperenhancement, diffusion restriction, and variable T2 and hepatobiliary-phase signal heterogeneity. Compared with colorectal metastases and hemangiomas, NELMs showed distinctive patterns, particularly higher rates of hepatobiliary-phase heterogeneity and arterial enhancement. Lesion size, ADC metrics, T2 heterogeneity, and hemorrhage were significant discriminators. Conclusions: Hepatocyte-specific MRI enables identification of characteristic imaging features of NELMs. An integrated assessment of morphologic, diffusion, and hepatobiliary-phase findings may facilitate early recognition of neuroendocrine metastases, even when the primary tumor is unknown, improving diagnostic confidence and clinical management. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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17 pages, 782 KB  

Open AccessReview

TIPS in Older Adults: Reserve-Based Risk Stratification and Practical Approach

by Yi He, Yuanyuan Li, Langli Gao and Xiaoze Wang

J. Clin. Med. 2026, 15(8), 2928; https://doi.org/10.3390/jcm15082928 - 12 Apr 2026

Viewed by 808

Abstract

The transjugular intrahepatic portosystemic shunt (TIPS) is a cornerstone intervention for complications of portal hypertension, including variceal bleeding and refractory ascites. As the population with cirrhosis ages, clinicians increasingly face the question of whether and how to perform TIPS safely in older adults. [...] Read more.

The transjugular intrahepatic portosystemic shunt (TIPS) is a cornerstone intervention for complications of portal hypertension, including variceal bleeding and refractory ascites. As the population with cirrhosis ages, clinicians increasingly face the question of whether and how to perform TIPS safely in older adults. We reviewed observational cohorts, registry analyses, and systematic reviews/meta-analyses. Existing evidence does not support chronological age as an absolute contraindication; however, multiple studies suggest that advanced age is associated with higher rates of post-TIPS hepatic encephalopathy (HE), early mortality, and readmissions. These findings underscore the need to shift from a binary “eligible vs. ineligible” paradigm to a structured, actionable framework that addresses modifiable risks and anticipates age-related vulnerabilities. Recent clinical practice guidance emphasizes comprehensive pre-TIPS assessment and vigilant post-procedure care, with specific attention to HE risk factors (e.g., prior HE, hyponatremia, renal dysfunction, sarcopenia) and cardiopulmonary reserve. In this narrative review, we propose an elderly-focused clinical pathway built around a four-domain assessment (Liver–Brain–Body–Heart/Kidney) and a traffic-light risk tiering system to guide patient selection, procedural strategy, follow-up scheduling, and triggered management of HE, cardiac decompensation, and renal dysfunction. This pathway aims to preserve the benefits of portal decompression while reducing preventable complications and improving outcomes that are meaningful to older patients, including functional status and quality of life. This narrative review emphasizes that outcomes after TIPS in older adults are determined not by chronological age alone but by multidomain physiological reserve. The proposed pathway informs patient selection, procedural planning, and early post-discharge monitoring in older adults. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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32 pages, 1455 KB  

Open AccessEditor’s ChoiceReview

The Future of Liver-Targeted Protein Synthesis Inhibition: Current Treatments, Emerging Strategies, and Next-Generation Therapeutics

by Julia Horwacik, Mateusz Maligłówka, Łukasz Bułdak and Bogusław Okopień

Livers 2026, 6(2), 25; https://doi.org/10.3390/livers6020025 - 1 Apr 2026

Viewed by 3225

Abstract

The liver produces the majority of plasma proteins, maintaining the metabolic homeostasis. The dysregulation of liver protein synthesis underlies many systemic conditions. Therefore, there is a great potential in therapies that inhibit the hepatic protein production. This is the mechanism of action of [...] Read more.

The liver produces the majority of plasma proteins, maintaining the metabolic homeostasis. The dysregulation of liver protein synthesis underlies many systemic conditions. Therefore, there is a great potential in therapies that inhibit the hepatic protein production. This is the mechanism of action of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). These therapeutics have undergone rapid development and are revolutionizing the pharmacological landscape of many liver-related diseases (e.g., inclisiran in familial hypercholesterolemia). Furthermore, gene-editing technologies that allow a direct correction of impaired genes in the liver are currently being evaluated. They hold a promise for future advances in treatment, especially of monogenic disorders such as hereditary transthyretin amyloidosis or alpha-1 antitrypsin deficiency. In this review, we describe the most relevant systemic diseases caused by dysfunction of protein synthesis in liver cells, in which significant therapeutic progress has been made over the last decades. Moreover, we present currently available drugs and their mechanisms of action, including six siRNA agents and five ASOs that have been approved to date. Finally, we discuss emerging strategies, focusing on novel RNA-based therapeutics that are the subjects of ongoing clinical trials. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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16 pages, 823 KB  

Open AccessEditor’s ChoiceReview

Intrahepatic Cholangiocarcinoma: Contemporary Approaches to Surgical, Systemic, and Liver-Directed Therapy

by Kizuki Yuza, Miho Akabane and Timothy M. Pawlik

Livers 2026, 6(2), 24; https://doi.org/10.3390/livers6020024 - 27 Mar 2026

Cited by 1 | Viewed by 1858

Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is an uncommon but increasingly recognized primary liver malignancy with a poor prognosis. Although surgical resection offers the only realistic opportunity for cure, recurrence is common and the optimal integration of surgery with systemic and liver-directed therapies continues to [...] Read more.

Background: Intrahepatic cholangiocarcinoma (ICC) is an uncommon but increasingly recognized primary liver malignancy with a poor prognosis. Although surgical resection offers the only realistic opportunity for cure, recurrence is common and the optimal integration of surgery with systemic and liver-directed therapies continues to evolve. Summary: This review summarizes contemporary evidence on the diagnosis and multidisciplinary management of ICC with particular emphasis on surgical, systemic, locoregional, and transplant-based strategies. Cross-sectional imaging plays a central role in staging and assessing resectability including evaluation of vascular invasion and the future liver remnant. Upfront resection is appropriate for selected patients with resectable disease and preserved liver function, with margin-negative resection and lymphadenectomy remaining key oncologic goals. Systemic therapy continues to evolve with cytotoxic chemotherapy forming the backbone of treatment for advanced disease and immunotherapy and targeted agents demonstrating promise in biomarker-defined subgroups. Locoregional modalities such as hepatic arterial infusion therapy and radioembolization may provide disease control in liver-dominant ICC and are increasingly used within a multidisciplinary framework. Liver transplantation remains investigational but may offer favorable outcomes in highly selected early-stage disease. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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Open AccessArticle

Sampling Extension, Chronic Infiltrates, and Eosinophils: Support for the Evaluation of Histological Healing in Inflammatory Bowel Disease with Endoscopic Remission

by Gabriella Canavese, Enrico Costantino Falco and Davide Giuseppe Ribaldone

Diagnostics 2026, 16(5), 739; https://doi.org/10.3390/diagnostics16050739 - 2 Mar 2026

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Abstract

Background/Objectives: Histological healing, primarily assessed by the absence of neutrophils in mucosal biopsies, is increasingly used to evaluate treatment efficacy in inflammatory bowel disease (IBD) and may identify residual inflammation despite endoscopic mucosal healing. We aimed to quantify histological parameters commonly linked to [...] Read more.

Background/Objectives: Histological healing, primarily assessed by the absence of neutrophils in mucosal biopsies, is increasingly used to evaluate treatment efficacy in inflammatory bowel disease (IBD) and may identify residual inflammation despite endoscopic mucosal healing. We aimed to quantify histological parameters commonly linked to active disease in patients with endoscopic healing and to explore their association with neutrophil-defined histologic activity in endoscopically healed mucosa. Methods: We assessed 371 colonoscopies from IBD patients with an endoscopic report of mucosal healing at a reference center. For each procedure, we recorded the number of biopsy samples obtained and histologic features according to ECCO consensus/position statements, including neutrophil infiltration, lymphoplasmacytic infiltrate, eosinophil infiltrate, and mucosal lesions. Results: Histologic activity was found in 21/98 (21.4%) procedures with one to three biopsy samples and in 89/273 (32.6%) procedures with more than three samples (p = 0.04). Neutrophils were absent in 207/212 (97.6%) procedures with normal lymphoplasmacytic infiltrate versus 55/159 (34.6%) with increased lymphoplasmacytic infiltrate (p < 0.00001). Eosinophils were below cut-off values in 122/168 (72.6%) procedures with normal lymphoplasmacytic infiltrate versus 90/203 (44.3%) with increased lymphoplasmacytic infiltrate (p < 0.00001). Eosinophils were below cut-off in 148/168 (88.1%) procedures without neutrophils and in 114/203 (56.2%) with neutrophils in the lamina propria (p < 0.00001). Conclusions: In IBD patients with endoscopic healing, the extent of biopsy sampling is associated with the detection of histologic activity. Lymphoplasmacytic and eosinophil infiltrates are strongly associated with neutrophil presence and are associated with neutrophil-defined activity and may serve as supportive indicators prompting closer pathological assessment in endoscopically healed mucosa. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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14 pages, 1006 KB  

Open AccessArticle

The Predictive Value of TyG-BMI and TG/HDL-C for Metabolic Dysfunction-Associated Steatotic Liver Disease in Obstructive Sleep Apnea: A Single-Center Retrospective Cohort Analysis

by Furong Lv, Tong Li, Fei Zou, Xiuli Chen, Haiying Tang and Jingwei Mao

J. Clin. Med. 2026, 15(5), 1859; https://doi.org/10.3390/jcm15051859 - 28 Feb 2026

Viewed by 855

Abstract

Background/Objectives: This study aimed to evaluate the predictive value of the triglyceride-glucose index with body mass index (TyG-BMI) and the triglyceride-to-high-density lipoprotein-cholesterol (TG/HDL-C) ratio for predicting the occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) in obstructive sleep apnea (OSA). Methods: [...] Read more.

Background/Objectives: This study aimed to evaluate the predictive value of the triglyceride-glucose index with body mass index (TyG-BMI) and the triglyceride-to-high-density lipoprotein-cholesterol (TG/HDL-C) ratio for predicting the occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) in obstructive sleep apnea (OSA). Methods: Data from patients diagnosed with OSA were analyzed in this retrospective cohort study. The participants were stratified into two groups: OSA alone and OSA with MASLD. The clinical characteristics and polysomnography data were collected. TyG-BMI and TG/HDL-C ratios were categorized into tertiles. Logistic regression and receiver operating characteristic (ROC) curve analyses were conducted to identify risk factors and assess their predictive performance for MASLD in OSA. Results: Among the 133 patients with OSA, 104 (78.2%) were diagnosed with MASLD. Multivariate analysis identified alanine aminotransferase (ALT), alkaline phosphatase, and TyG-BMI as independent risk factors for MASLD development in patients with OSA. Both TyG-BMI and TG/HDL-C ratio were significant predictors of MASLD in this patient population. The optimal cut-off values for TyG-BMI and TG/HDL-C ratio were 0.546 (sensitivity, 79.6%; specificity, 75.0%) and 0.539 (sensitivity, 93.2%; specificity, 60.7%), respectively. Combining TyG-BMI with ALT improved the predictive accuracy, yielding a cutoff of 0.696 (sensitivity, 76.7%; specificity, 92.9%). Similarly, the combination of TG/HDL-C ratio with ALT resulted in a cutoff value of 0.728 (sensitivity, 83.5%; specificity, 89.3%). Conclusions: TyG-BMI and the TG/HDL-C ratio are effective predictors of MASLD in patients with OSA. A combined model incorporating these indices with ALT levels demonstrated enhanced predictive accuracy for MASLD in this population. These indices are well-suited for risk stratification in resource-constrained settings facing a rising dual burden of OSA and MASLD. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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10 pages, 2759 KB  

Open AccessCase Report

Steroid-Refractory Cholestatic Immune-Mediated Hepatitis Following Nivolumab Therapy in an Elderly Patient with Metastatic Melanoma: A Rare and Challenging Presentation

by Luis Posado-Dominguez, Jorge Feito-Perez, María Escribano-Iglesias, Miriam Bragado Pascual and Emilio Fonseca Sánchez

Curr. Oncol. 2025, 32(12), 663; https://doi.org/10.3390/curroncol32120663 - 27 Nov 2025

Cited by 3 | Viewed by 935

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, but they may cause a wide range of immune-related adverse events (irAEs). Hepatic toxicity occurs in approximately 1–6% of patients treated with nivolumab and usually presents with a hepatocellular pattern responsive to [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, but they may cause a wide range of immune-related adverse events (irAEs). Hepatic toxicity occurs in approximately 1–6% of patients treated with nivolumab and usually presents with a hepatocellular pattern responsive to corticosteroids. The cholestatic-predominant immune-mediated hepatitis seems to respond poorly to immunosuppression. We describe an 87-year-old man with metastatic melanoma treated with nivolumab who developed steroid-refractory, cholestatic-predominant immune-mediated hepatitis after 18 cycles of therapy. Laboratory tests revealed a mixed but predominantly cholestatic pattern (ALT 585 U/L, GGT 2261 U/L, total bilirubin 2.0 mg/dL). Imaging excluded biliary obstruction or hepatic metastases. Liver biopsy showed acute lobular hepatitis with intracanalicular cholestasis and mild bile duct injury, consistent with immune-mediated, drug-induced injury (Ishak score 5). Mycophenolate mofetil produced only partial biochemical improvement. The patient died one month later from influenza A pneumonia in the context of combined immunosuppressive therapy. This case illustrates a cholestatic-predominant phenotype of nivolumab-induced hepatitis, characterized by poor corticosteroid response and incomplete recovery despite second-line immunosuppression. Recognition of this entity is essential, as early introduction of agents such as mycophenolate may improve outcomes. In elderly and frail patients, however, the risks of intensified immunosuppression must be carefully balanced against infection risk, highlighting the need for individualized management and vigilant monitoring. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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14 pages, 530 KB  

Open AccessArticle

Adiposity and Metabolic Indices in the Diagnosis and Histological Stage Association of Metabolic Dysfunction-Associated Steatotic Liver Disease

by Lorena del Rocio Ibarra-Reynoso, Nemry Rodriguez-Hernandez, Maria-Luisa Lazo-de-la-Vega-Monroy, Juana Rosalba Garcia-Ramirez, Yeniley Ruiz-Noa, Benjamin Jordan-Perez, Serafin Garnelo-Cabañas, Veronica Muñoz-Cornejo and Monica del Carmen Preciado-Puga

J. Clin. Med. 2025, 14(23), 8365; https://doi.org/10.3390/jcm14238365 - 25 Nov 2025

Cited by 3 | Viewed by 1106

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MALSD) is defined as the excessive accumulation of triglycerides in the liver in the presence of at least one cardiometabolic risk factor and liver biopsy remains the diagnostic gold standard. This study aimed to evaluate the diagnostic [...] Read more.

Background: Metabolic dysfunction-associated steatotic liver disease (MALSD) is defined as the excessive accumulation of triglycerides in the liver in the presence of at least one cardiometabolic risk factor and liver biopsy remains the diagnostic gold standard. This study aimed to evaluate the diagnostic performance of adiposity and metabolism related indices for the non-invasive detection of MASLD and the metabolic dysfunction-associated steatohepatitis (MASH). Methods: A cross-sectional study was conducted in 161 Mexican adults undergoing laparoscopic cholecystectomy, during which liver biopsies were obtained for histological evaluation. Indices such as the Hepatic Steatosis Index (HSI), the Triglyceride–Glucose index (TyG), TyG-BMI (TyG adjusted for body mass index), and TyG-WC (TyG adjusted for waist circumference), among others, were calculated. Results: Of the 161 participants, 66 were diagnosed with MASLD, and 50 of them had histological evidence of MASH. All adiposity and metabolic indices evaluated were significantly higher in MASLD patients compared with controls. Logistic regression identified HSI, TyG, TyG-BMI, and TyG-WC as independently associated with MASLD and MASH, with TyG showing the strongest association. Correlation analyses demonstrated that TyG-BMI and TyG-WC were most strongly associated with histological features of MASH. Receiver operating characteristic curve analyses showed that TyG-WC had the highest diagnostic accuracy for MASLD (AUC 0.721, 95% CI 0.641–0.802) and MASH (AUC 0.735, 95% CI 0.648–0.823), while TyG-BMI displayed high sensitivity (0.758 for MASLD; 0.780 for MASH). Conclusions: Triglyceride–glucose-based indices, particularly TyG-WC and TyG-BMI, showed the highest diagnostic performance for detecting MASLD and MASH, suggesting that these indices may serve as practical, non-invasive tools for identifying individuals at risk. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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16 pages, 1463 KB  

Open AccessReview

Macrophages in Autoimmune Liver Diseases: From Immune Homeostasis to Precision-Targeted Therapy

by Tianfu Liu, Yizhe Wang, Yichen Huang, Rui Zhao and Haili Shen

Biomedicines 2025, 13(10), 2520; https://doi.org/10.3390/biomedicines13102520 - 16 Oct 2025

Cited by 3 | Viewed by 2488

Abstract

Autoimmune liver diseases (AILDs) represent a diverse spectrum of chronic inflammatory conditions characterized primarily by compromised hepatic immune tolerance, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Recent evidence positions macrophages as pivotal players in AILDs pathogenesis, attributable [...] Read more.

Autoimmune liver diseases (AILDs) represent a diverse spectrum of chronic inflammatory conditions characterized primarily by compromised hepatic immune tolerance, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Recent evidence positions macrophages as pivotal players in AILDs pathogenesis, attributable to their multifaceted roles in inflammation amplification, immune regulation, and fibrogenesis. In the context of AILDs, macrophages exhibit marked polarization imbalance, increased recruitment of monocytes, and impaired clearance of apoptotic cells. Through complex interactions with T lymphocytes and hepatic stellate cells, macrophages orchestrate a pathological milieu promoting inflammation and fibrosis. Notably, diverse programmed cell death (PCD) modalities—autophagy, necroptosis, pyroptosis, and ferroptosis—not only determine macrophage survival and functional phenotype but also significantly impact cytokine release, phenotypic plasticity, and the trajectory of immunopathological progression. This review synthesizes current understandings of macrophage-driven immunoregulatory mechanisms in AILDs, characterizes the regulatory attributes of various macrophage-related PCD processes, and evaluates their relevance in experimental disease models. Furthermore, we highlight recent advancements in biomarker identification and targeted therapeutic strategies. Comprehensive elucidation of the interplay between macrophage immunological activity and programmed cell death pathways promises to inform novel, personalized therapeutic approaches for patients with AILDs. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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14 pages, 1397 KB  

Open AccessReview

The Emerging Role of CKAP4 in GI Cancer: From Molecular Pathways to Clinical Applications

by Markos Despotidis, Orestis Lyros, Tatiana S. Driva, Panagiotis Sakarellos, René Thieme, Andreas Mamilos, Stratigoula Sakellariou and Dimitrios Schizas

Curr. Oncol. 2025, 32(10), 561; https://doi.org/10.3390/curroncol32100561 - 7 Oct 2025

Viewed by 3171

Abstract

Cytoskeleton-associated protein 4 (CKAP4) has emerged as a critical player in gastrointestinal (GI) cancer progression, diagnosis, and therapy. This comprehensive review synthesizes current knowledge on CKAP4′s multifaceted roles across GI malignancies, providing novel insights into its mechanisms of action and clinical potential. Its [...] Read more.

Cytoskeleton-associated protein 4 (CKAP4) has emerged as a critical player in gastrointestinal (GI) cancer progression, diagnosis, and therapy. This comprehensive review synthesizes current knowledge on CKAP4′s multifaceted roles across GI malignancies, providing novel insights into its mechanisms of action and clinical potential. Its interaction with DKK1 and subsequent activation of the PI3K/AKT pathway underscores its role in promoting tumor growth. This review also highlights novel insights into CKAP4′s mechanisms of action beyond the well-established DKK1-CKAP4 axis, including its interaction with integrin β1 and involvement in angiogenesis through the FMNL2/EGFL6/CKAP4/ERK pathway. CKAP4′s impact on tumor microenvironment and immune evasion is elucidated, offering a new perspective on its contribution to cancer progression. In addition, CKAP4 arises as a promising serum biomarker for early detection and prognosis across multiple GI cancers, emphasizing its potential superiority over traditional markers. The therapeutic potential of targeting CKAP4 is extensively explored, including novel approaches like anti-CKAP4 antibodies and aptamers, and their synergistic effects with existing treatments. By integrating findings from esophageal, gastric, pancreatic, and colorectal cancers, this review provides a unique, comprehensive overview of CKAP4 in GI oncology, underscoring CKAP4′s potential to revolutionize GI cancer diagnosis and treatment and paving the way for future translational research. Full article

(This article belongs to the Topic Advances in Gastrointestinal and Liver Disease: From Physiological Mechanisms to Clinical Practice, 2nd Edition)

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