Harnessing autophagy: A potential breakthrough in digestive disease treatment.

Autophagy, a conserved cellular degradation process, is crucial for various cellular processes such as immune responses, inflammation, metabolic and oxidative stress adaptation, cell proliferation, development, and tissue repair and remodeling. Dysregulation of autophagy is suspected in numerous diseases, including cancer, neurodegenerative diseases, digestive disorders, metabolic syndromes, and infectious and inflammatory diseases. If autophagy is disrupted, for example, this can have serious consequences and lead to chronic inflammation and tissue damage, as occurs in diseases such as Chron's disease and ulcerative colitis. On the other hand, the influence of autophagy on the development and progression of cancer is not clear. Autophagy can both suppress and promote the progression and metastasis of cancer at various stages. From inflammatory bowel diseases to gastrointestinal cancer, researchers are discovering the intricate role of autophagy in maintaining gut health and its potential as a therapeutic target. Researchers should carefully consider the nature and progression of diseases such as cancer when trying to determine whether inhibiting or stimulating autophagy is likely to be beneficial. Multidisciplinary approaches that combine cutting-edge research with clinical expertise are key to unlocking the full therapeutic potential of autophagy in digestive diseases.

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases.

Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.

Components from Curcuma longa (Turmeric) Against Hepatobiliary Diseases Based on Gut-Liver Axis: Pharmacotherapeutic Properties and Potential Clinical Applications.

Turmeric is widely used worldwide, and there are many examples of its use in treating hepatobiliary diseases. The gut-liver axis is a bidirectional relationship between gut microorganisms and the liver that is closely related to the pathogenesis of hepatobiliary diseases. This review systematically summarizes the components of turmeric. It links the studies on turmeric affecting gut microorganisms to its effects on liver and biliary diseases to explain the potential mechanism of turmeric's regulation of the gut-liver axis. Besides, ethnopharmacology, phytochemicals, and clinical adverse events associated with turmeric have been researched. Furthermore, turmeric is a safe agent with good clinical efficacy and without apparent toxicity at a certain amount. By summarizing the influence of turmeric on the liver by regulating the gut-liver axis, especially the gut microbiota, it provides a preclinical basis for using turmeric as a safe and effective therapeutic agent for the prevention and treatment of hepatobiliary diseases based on the gut-liver axis. However, more efforts should be made to exploit its clinical application further.

Relationship between Quality of Life and Oral Health Status of Patients with Chronic Liver Disease

ABSTRACT Objective: To investigate the relationship between the quality of life and work ability related to the oral health status of patients with chronic liver diseases. Material and Methods: The sample size contains all patients referred to the internal ward of Afzalipour and Bahonar hospitals due to chronic liver disease from 2019 to 2020. Patient selection was based on a simple census and a questionnaire that contained characteristics information of the patient, Work Ability Index questionnaire and SF-36 questionnaire were completed by the patients and some information was extracted from medical file. The SF-36 questionnaire assesses the quality of life in two general dimensions (physical health and mental health) with the physical function subscale. DMFT, Gingival index, and Periodontal disease index are used to evaluate the severity and extent of gingivitis and periodontitis. For data analysis, ANOVA, Spearman correlation coefficients were used and the significant level was p<0.05. Results: a total of 108 patients were examined. The mean age of participants was 41.2 ± 4.3 years. The DMFT index in patients was also reported as 22.6 ± 7.35. Also, 32.4% of people described their ability to do work as poor, 21.3% as good, and 7.4% as excellent. Patients with poor or moderate workability reported a higher index of DMFT. Among the participants, 61 and 21 patients had gingivitis and periodontitis, respectively. Mean results of total SF-36 indices were reported at a low level in patients with increased DMFT and gum diseases. Patients with poor or moderate workability had a higher index of DMFT. There was a significant relationship between these two variables (p=0.001). However, they were not significantly associated with periodontitis. Conclusion: There was a significant relationship between the SF-36 index, the ability to work and the type of liver disease.

Magnetic resonance spectroscopy for quantification of liver iron deposition in hereditary hemochromatosis of a Chinese family: Four case reports.

RATIONALE: Hereditary hemochromatosis (HH) is a major cause of liver iron overload. The gold standard for the diagnosis of liver iron overload is the histopathological analysis of a liver sample collected by biopsy. The biopsy procedure is both invasive and painful and carries some risks of complications. The multi-echo single-voxel magnetic resonance spectroscopy (HISTO) technique can be used for noninvasive, quantitative assessment of liver iron overload. PATIENT CONCERNS: We report 4 Chinese Han men, who were relatives. Patient A was admitted with diabetes and presented with thrombocytopenia and skin hyperpigmentation. The other patients had no specific clinical presentation. DIAGNOSES: Patient A was suspected of having iron in the liver on routine magnetic resonance imaging, therefore, further HISTO, laboratory testing, and liver biopsy were performed, which confirmed iron metabolic abnormalities. Furthermore, we identified hepatic iron deposition using HISTO and laboratory testing of his son and 2 brothers. Combined with symptoms, auxiliary examinations, and liver biopsy, HH was considered. INTERVENTIONS: As the 4 patients had no other discomfort other than patient A who had diabetes, patient A was placed on therapy comprising the insulin pump, acarbose, and platelet booster capsule. OUTCOMES: After treatment, the diabetic symptoms of patient A improved. The patient and his relatives were regularly followed-up for HH. LESSONS: HH should be considered when hepatic iron deposition is suspected by routine magnetic resonance, as the HISTO sequence can quantitate liver iron deposition and leads to a promising diagnosis. HISTO is of great value in familial cases, especially in young patients requiring long-term follow-up.

Alterações gastrointestinais causadas pela infecção do Sars-Cov-2 / Gastrointestinal changes caused by infection do Sars-Cov-2 / Cambios gastrointestinales causados por la infección de Sars-Cov-2

A pandemia de COVID-19 se propagou rapidamente pelo mundo, causada pela infecção do novo coronavírus (SARS-CoV-2), que surgiu na China no final de 2019. Apesar da porta de entrada mais comum do agente etiológico ser pelo trato respiratório, evidências demonstram que a doença pode apresentar sintomas extrapulmonares, como os do trato gastrointestinal. Descrever sobre possíveis alterações gastrointestinais ocasionadas em pacientes infectados pelo SARS-CoV-2. Tratou-se de uma revisão bibliográfica, que utilizou artigos científicos disponíveis na íntegra em bases de dados Medical Literature Analysis and Retrieval System Online, Google Acadêmico, Scientific Electronic Library Online, nos meses de abril a outubro de 2021, além de monografias, dissertações, teses e livros. Foram utilizados como descritores as palavras: SARS-CoV-2 e intestino, COVID-19 e intestino, alterações intestinais na COVID-19. Os distúrbios gastrointestinais mais prevalentes são náuseas, vômitos e diarreia e dor abdominal. O papel da microbiota intestinal em influenciar as doenças pulmonares foi bem articulado, devido à existência do eixo intestino-pulmão, a inflamação em um desses órgãos interfere diretamente no perfil inflamatório no outro. Embora ainda não esteja totalmente esclarecido se os sintomas gastrointestinais indicam maior viremia ou um processo fisiopatológico alternativo, observa-se que a presença destes configura um fator de risco para a maior severidade da doença.

The COVID-19 pandemic has spread rapidly around the world, caused by the infection of the new coronavirus (SARS-CoV-2), which emerged in China at the end of 2019. respiratory evidence shows that the disease can present extrapulmonary symptoms, such as those in the gastrointestinal tract. Objective: To describe possible gastrointestinal alterations caused in patients infected by SARS-CoV-2. Methodology: this was a literature review, which used scientific articles available in full in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Academic Google, Scientific Electronic Library Online (SciELO) databases, as well as monographs, dissertations, theses and books. The words used as descriptors were: SARS-CoV-2 and intestine, COVID-19 and intestine, intestinal alterations in COVID-19. Development: The most prevalent gastrointestinal disorders are nausea, vomiting and diarrhea and abdominal pain. The role of the intestinal microbiota in influencing lung diseases was well articulated, due to the existence of the gut- lung axis, inflammation in one of these organs directly interfering with the inflammatory profile in the other. Conclusion: Although it is not yet fully understood whether the gastrointestinal symptoms

La pandemia COVID-19 se ha extendido rápidamente por todo el mundo, causada por la infección del nuevo coronavirus (SARS-CoV-2), que surgió en China a finales de 2019. Las evidencias respiratorias muestran que la enfermedad puede presentar síntomas extrapulmonares, como los del tracto gastrointestinal. Objetivo: Describir las posibles alteraciones gastrointestinales causadas en pacientes infectados por SARS-CoV-2. Metodología: se trató de una revisión bibliográfica, que utilizó artículos científicos disponibles en su totalidad en las bases de datos Medical Literature Analysis and Retrieval System Online (MEDLINE), Academic Google, Scientific Electronic Library Online (SciELO), así como monografías, disertaciones, tesis y libros. Las palabras utilizadas como descriptores fueron: SARS-CoV-2 e intestino, COVID-19 e intestino, alteraciones intestinales en COVID-19. Desarrollo: Las alteraciones gastrointestinales más prevalentes son náuseas, vómitos y diarrea y dolor abdominal. Se articuló bien el papel de la microbiota intestinal en la influencia de las enfermedades pulmonares, debido a la existencia del eje intestino-pulmón, la inflamación en uno de estos órganos interfiere directamente en el perfil inflamatorio del otro. Conclusiones: Aunque aún no se comprenda del todo si los síntomas gastrointestinales indican una mayor viremia o un proceso fisiopatológico alternativo, se observa que su presencia es un factor de riesgo para la mayor gravedad de la enfermedad.

Histopathology of Gastrointestinal Immune-related Adverse Events: A Practical Review for the Practicing Pathologist.

Immune checkpoint inhibitors target checkpoint proteins with the goal of reinvigorating the host immune system and thus restoring antitumor response. With the dramatic increase in the use of checkpoint inhibitors for cancer treatment, surgical pathologists have assumed a major role in predicting the therapeutic efficacy (score based on programmed cell death ligand 1 immunohistochemistry and mismatch repair protein loss) as well as diagnosing the complications associated with these medications. Immune-related adverse events (irAEs) manifest as histologic changes seen in both the upper and lower gastrointestinal tract, and when viewed in isolation, may be morphologically indistinguishable from a wide range of diseases including infections, celiac disease, and inflammatory bowel disease, among others. Evaluation of biopsies from both the upper and lower gastrointestinal tract can aid in the distinction of gastrointestinal irAEs from their mimics. In the liver, the histologic changes of hepatic irAEs overlap with de novo diseases associated with hepatitic and cholangitic patterns of injury. The diagnosis of irAEs requires communication and collaboration from the pathologist, oncologist, and gastroenterologist. This review provides a background framework and illustrates the histologic features and differential diagnosis of gastrointestinal and hepatic irAEs.

Diseases of the digestive system of agoutis (Dasyprocta leporina) raised in captivity in the Brazilian semiarid region / Doenças do sistema digestivo de cutias (Dasyprocta leporina) criadas em cativeiro na região semiárida brasileira

The objective of this study was to describe the clinical and pathological aspects of diseases of the digestive system in agoutis (Dasyprocta leporina Linnaeus, 1758) diagnosed by the "Laboratório de Patologia Veterinária" (Veterinary Pathology Laboratory) of the "Universidade Federal Rural do Semi-Árido" (UFERSA), from January 2018 to February 2020. During the study period, necropsy and a survey of the clinical history of 27 agoutis were performed, 25.93% (7/27) of which were diagnosed with digestive system diseases. The percentages of digestive tract diseases among the diagnosed were: acute carbohydrate overload (11.12%), gastric ulcer (7.41%), gastric volvulus (3.70%), and intestinal volvulus (3.70%). Studies on the occurrence rate of these diseases, as well as the description of their clinical and anatomopathological aspects, may serve as a basis for guiding the appropriate management in the breeding of these animals.

O objetivo deste estudo foi descrever os aspectos clínicos e patológicos das doenças do aparelho digestivo em cutias (Dasyprocta leporina Linnaeus, 1758) diagnosticadas pelo Laboratório de Patologia Veterinária da Universidade Federal Rural do Semiárido (UFERSA), de janeiro 2018 a fevereiro de 2020. Durante o período do estudo, foram realizadas necropsias e levantamento da história clínica de 27 cutias, sendo 25,93% (7/27) diagnosticadas com doenças do aparelho digestivo. Os percentuais de doenças do aparelho digestivo foram: sobrecarga aguda de carboidratos (11,12%), úlcera gástrica (7,41%), vólvulo gástrico (3,70%) e vólvulo intestinal (3,70%). Estudos sobre a taxa de ocorrência dessas doenças, bem como a descrição de seus aspectos clínicos e anatomopatológicos, podem servir de base para orientar o manejo adequado na criação dessa espécie.

Diseases of the digestive system of agoutis (Dasyprocta leporina) raised in captivity in the Brazilian semiarid region / Doenças do sistema digestivo de cutias (Dasyprocta leporina) criadas em cativeiro na região semiárida brasileira

The objective of this study was to describe the clinical and pathological aspects of diseases of the digestive system in agoutis (Dasyprocta leporina Linnaeus, 1758) diagnosed by the "Laboratório de Patologia Veterinária" (Veterinary Pathology Laboratory) of the "Universidade Federal Rural do Semi-Árido" (UFERSA), from January 2018 to February 2020. During the study period, necropsy and a survey of the clinical history of 27 agoutis were performed, 25.93% (7/27) of which were diagnosed with digestive system diseases. The percentages of digestive tract diseases among the diagnosed were: acute carbohydrate overload (11.12%), gastric ulcer (7.41%), gastric volvulus (3.70%), and intestinal volvulus (3.70%). Studies on the occurrence rate of these diseases, as well as the description of their clinical and anatomopathological aspects, may serve as a basis for guiding the appropriate management in the breeding of these animals.(AU)

O objetivo deste estudo foi descrever os aspectos clínicos e patológicos das doenças do aparelho digestivo em cutias (Dasyprocta leporina Linnaeus, 1758) diagnosticadas pelo Laboratório de Patologia Veterinária da Universidade Federal Rural do Semiárido (UFERSA), de janeiro 2018 a fevereiro de 2020. Durante o período do estudo, foram realizadas necropsias e levantamento da história clínica de 27 cutias, sendo 25,93% (7/27) diagnosticadas com doenças do aparelho digestivo. Os percentuais de doenças do aparelho digestivo foram: sobrecarga aguda de carboidratos (11,12%), úlcera gástrica (7,41%), vólvulo gástrico (3,70%) e vólvulo intestinal (3,70%). Estudos sobre a taxa de ocorrência dessas doenças, bem como a descrição de seus aspectos clínicos e anatomopatológicos, podem servir de base para orientar o manejo adequado na criação dessa espécie.(AU)

Relevance of VEGF and CD147 in different SARS-CoV-2 positive digestive tracts characterized by thrombotic damage.

Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS-CoV-2) infection, as an example of a multi-organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS-CoV-2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS-CoV-2 nucleocapsid protein were analyzed deriving from three patients, negative to naso-oro-pharyngeal swab for SARS-CoV-2. These COVID-19-negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS-CoV-2 combined with a panel of SARS-CoV-2 related proteins angiotensin-converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen-G (HLA-G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS-CoV-2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co-localization with SARS-CoV-2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS-CoV-2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.

Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells: Applications in Disease Modeling and Drug Screening.

The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages -hepatocytes and cholangiocytes-and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.

Single-Cell Transcriptome Analysis Uncovers Intratumoral Heterogeneity and Underlying Mechanisms for Drug Resistance in Hepatobiliary Tumor Organoids.

Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single-cell RNA sequencing. HCC272 with high status of epithelia-mesenchymal transition proves broad-spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo-time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta-1 (CTNNB1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak-STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N-Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance.

A RETROSPECTIVE REVIEW OF POST-METAMORPHIC MOUNTAIN CHICKEN FROG (LEPTODACTYLUS FALLAX) NECROPSY FINDINGS FROM EUROPEAN ZOOLOGICAL COLLECTIONS, 1998 TO 2018.

The mountain chicken frog (Leptodactylus fallax) is the largest endemic amphibian species in the Western Hemisphere. Since 1998, this critically endangered species has been maintained as a European Endangered Species Programme, but low breeding success and a high mortality rate threaten the sustainability of the captive frog population. In the current study, we analyzed gross and histopathologic postmortem information from 212 mountain chicken frogs that died in European zoological collections from 1998 to 2018. Thin body condition was the most commonly reported finding across all submissions, observed in 125 frogs. The gastrointestinal and urinary systems were reported to have the highest prevalence of pathologic findings on gross and histopathologic examination. Inflammatory disease was the most frequent diagnosis after histopathologic examination of relevant tissues, with intestinal inflammatory disease (n = 76) followed by tubulointerstitial nephritis (n = 26) being the most commonly reported. Neoplasia was reported in 42 of 212 (19.8%) frogs, all of which were adults. A defined cause of death, or reason for euthanasia, was proposed for 164 of 212 (77.4%) frogs, with inflammatory diseases processes (74 of 212; 34.9%) most commonly implicated. Intestinal adenocarcinoma, seemingly restricted to the colon, caused the deaths of 31 adult frogs. Further investigations to determine factors contributing to the high incidence of inflammatory disease processes and neoplasia are advocated to improve the health and sustainability of the captive mountain chicken frog population.

Pembrolizumab-induced large duct cholangiopathy: Diagnosis and follow.up imaging.

Immune-checkpoint inhibitor mediated hepatobiliary injury is an emerging concern in cancer treatment. Most of these adverse reactions are attributed to nivolumab and are characterized by panlobular hepatitis. Large duct cholangiopathy related to these drugs is extremely rare. We present a case of adenocarcinoma of lung treated with pembrolizumab who developed biochemical and imaging features consistent with cholangiopathy characterized by common bile duct dilatation, wall enhancement, and gallbladder wall edema. On follow-up in the fourth month, the imaging features persisted despite the normalization of liver enzymes. To the best of our knowledge, this is the first description of diagnosis and follow-up imaging of pembrolizumab-related cholangiopathy in imaging literature.

Hepatobiliary Organoids and Their Applications for Studies of Liver Health and Disease: Are We There Yet?

Organoid culture systems have emerged as a frontier technology in liver and biliary research. These three-dimensional (3D) cell cultures derived from pluripotent and adult hepatobiliary cells model organ structure and function. Building on gastrointestinal organoid establishment, hepatobiliary organoid cultures were generated from mouse leucine-rich repeat-containing G-protein-coupled receptor 5-positive liver progenitor cells. Subsequently, 3D hepatobiliary organoid cultures were developed from hepatocytes and cholangiocytes to model human and animal hepatobiliary health and disease. Hepatocyte organoids have been used to study Alagille syndrome, fatty liver disease, Wilson disease, hepatitis B viral infection, and cystic fibrosis. Cholangiocyte organoids have been established to study normal cholangiocyte biology and primary sclerosing cholangitis and to test organoid potential to form bile ducts and gallbladder tissue in vitro. Hepatobiliary cancer organoids, termed tumoroids, have been established from frozen and fresh human tissues and used as a drug-testing platform and for biobanking of cancer samples. CRISPR-based gene modifications and organoid exposure to infectious agents have permitted the generation of organoid models of carcinogenesis. This review summarizes currently available adult cell-derived hepatobiliary organoid models and their applications. Challenges faced by this young technology will be discussed, including the cellular immaturity of organoid-derived hepatocytes, co-culture development to better model complex tissue structure, the imperfection of extracellular matrices, and the absence of standardized protocols and model validation.

Roles of Bile-Derived Exosomes in Hepatobiliary Disease.

Exosomes are vesicles with a diameter of 30-150 nm produced by living cells and secreted into the extracellular matrix. Exosomes mediate cellular communication by carrying active molecules, such as nucleic acids, proteins, and liposomes. Although exosomes are found in various body fluids, little is known about bile-derived exosomes. This review is the first to summarize the methods of bile storage and isolation of biliary exosomes, highlighting the roles of bile-derived exosomes, especially exosomal noncoding RNAs, in physiological and disease states and discussing their potential clinical applications.

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy.

CONTEXT.­: Immune checkpoint inhibitors (CPIs), including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, are being increasingly used for treating many advanced malignancies. However, CPI therapy is also associated with gastrointestinal and hepatobiliary adverse effects. OBJECTIVES.­: To review the adverse effects of CPI therapy on the gastrointestinal tract and hepatobiliary system. To describe histopathologic patterns and discuss differential diagnostic considerations in the diagnosis of CPI injuries. DATA SOURCES.­: Published peer-reviewed literature in the English language and personal experience in the diagnosis of CPI injuries. CONCLUSIONS.­: The pathologic manifestations of CPI therapy-induced gastrointestinal and hepatobiliary injury are broad. The patterns of esophageal CPI injury include lymphocytic inflammation and ulcerative esophagitis, while those of gastric injury include chronic active gastritis, lymphocytic gastritis, focal enhancing gastritis, and periglandular inflammation. The duodenal injury may present as duodenitis with villous blunting and granulomas. We also noticed active colitis, microscopic colitis, chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes in colonic injuries. The reported histologic features of hepatobiliary injuries are panlobular hepatitis, centrilobular necrosis, portal inflammation with bile duct injury, steatosis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. In summary, we discuss the pathologic features and differential diagnosis of CPI therapy-induced gastrointestinal and hepatobiliary injury. Recognition of CPI injury is important to determine the proper management that often includes cessation of CPI therapy, and administration of steroids or other immunosuppressive agents, based on severity of injury.

Clinical profiles and diagnostic challenges in 1158 children with rare hepatobiliary disorders.

BACKGROUND: Diagnosis of rare diseases possesses a great challenge in pediatric hepatology because expert knowledge in the field is extremely insufficient. The study aims to explore new findings and collect diagnostic experience from pediatric rare liver diseases. METHODS: The large-sample case analysis study included pediatric patients who had liver-involved rare diseases. All cases underwent liver biopsy and/or gene sequencing. RESULTS: A total of 1158 pediatric patients were identified. Liver-based genetic diseases were most frequent (737 cases), followed by liver damages involved in extrahepatic or systemic disorders (151 cases) and cryptogenic hepatobilliary abnormalities (123 cases). Of note, diagnoses of 16 patients were re-evaluated according to genetic results combined with clinical pointers. In addition, 101 patients who underwent gene sequencing remained undiagnosed. Of them, 55 had negative genetic findings, 30 harbored mutations that failed to meet their typically pathogenic condition, and 16 had detected variants that were inconsistent with clinical pointers. CONCLUSIONS: As a study involving known largest number of children with rare hepatobiliary disorders, it allows us to accumulate information (especially new findings) on the etiology and diagnosis of these disorders. The results can help to improve the diagnostic quality in the population. IMPACT: Liver-based genetic diseases were most frequent in clinical profiles of pediatric rare liver diseases. Some novel variants in cases with genetic diseases (for example, two variants of c.3638G>T and c.1435G>C in a patient with progressive familial intrahepatic cholestasis type 2) were identified. As a study involving known largest number of pediatric cases with rare hepatobiliary disorders, it allows us to accumulate information on the etiology and diagnosis of these disorders. The study can help to optimize the diagnostic process and significantly improve the diagnostic quality in the field of pediatric hepatology. Given that clinical variability often exists within rare genetic disease entities and not all rare disorders are genetic, clinicians should not over-depend on the genetic results in the diagnosis.

Anatomopathological lesions of infection caused by Platynosomum illiciens (Braun, 1901) in Neotropical primates kept in captivity.

This study described the hepatobiliary anatomopathological lesions associated with trematode Platynosomum illiciens parasitism in Neotropical primates kept in captivity. In the evaluated organs, we observed portal fibrosis, biliary epithelial hyperplasia, and inflammatory reaction with a predominance of lymphocytes and plasmocytes, and in some cases infiltration of eosinophils and neutrophils.

Liver injury with COVID-19 based on gastrointestinal symptoms and pneumonia severity.

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.