Search Results (120)

Hypothermia-related deaths present significant diagnostic challenges due to non-specific and often inconsistent autopsy findings. This study investigated the histological and immunohistochemical alterations associated with primary and secondary hypothermia in an experimental Rattus norvegicus model, focusing on the effects of benzodiazepine and alcohol ingestion. Twenty-one male rats were divided into three groups: control (K), benzodiazepine-treated (B), and alcohol-treated (A). After two weeks of substance administration, hypothermia was induced and multiple organ samples were analyzed. Histologically, renal tissue showed hydropic and vacuolar degeneration, congestion, and acute tubular injury across all groups, with no significant differences in E-cadherin expression. Lung samples revealed congestion, emphysema, and hemorrhage, with more pronounced vascular congestion in the alcohol and benzodiazepine groups. Cardiac tissue exhibited vacuolar degeneration and protein denaturation, particularly in substance-exposed animals. The spleen showed preserved architecture but increased erythrocyte infiltration and significantly elevated myeloperoxidase (MPO)-positive granulocytes in the intoxicated groups. Liver samples demonstrated congestion, focal necrosis, and subcapsular hemorrhage, especially in the alcohol group. Immunohistochemical analysis revealed statistically significant differences in MPO expression in both lung and spleen tissues, with the highest levels observed in the benzodiazepine group. Similarly, CK7 and CK20 expression in the gastroesophageal junction was significantly elevated in both alcohol- and benzodiazepine-treated animals compared to the controls. In contrast, E-cadherin expression in the kidney did not differ significantly among the groups. These findings suggest that specific histological and immunohistochemical patterns, particularly involving pulmonary, cardiac, hepatic, and splenic tissues, may help differentiate primary hypothermia from substance-related secondary hypothermia. The study underscores the value of integrating toxicological, histological, and molecular analyses to enhance the forensic assessment of hypothermia-related fatalities. Future research should aim to validate these markers in human autopsy series and explore additional molecular indicators to refine diagnostic accuracy in forensic pathology. Full article

Hyaloserositis, also known as the icing sugar phenomenon, may be commonly observed during autopsies; however, it is not a well-documented topic with varying nomenclature and etiology, which can be generally defined as an organ being covered with a shiny, fibrous hyaline membrane. In our work, we present the case of a 71-year-old female patient with alcohol-induced liver cirrhosis and subsequent ascites and recurrent peritonitis. During the autopsy, a cirrhotic liver and an enlarged spleen were observed, both exhibiting features consistent with hyaloserositis, accompanied by acute fibrinopurulent peritonitis. Histological examination revealed the classical manifestation of hyaloserositis, further proven by Crossmon staining. The cause of death was concluded as hepatic encephalopathy. During our literature review, a total of seven cases were found. It must be emphasized that no publication describing hyaloserositis from the perspective of a pathologist was discovered. Regarding etiology, abdominal presentations were most commonly caused by serohepatic tuberculosis, while pleural manifestation was observed following trauma. Hyaloserositis may prove to be a diagnostic difficulty in imaging findings, as it can mimic malignancy; therefore, a scientific synthesis is necessary. Full article

Background and Objectives: Alcoholic hepatitis (AH) is a growing public health concern with its rising incidence and its contribution to nearly half of all cirrhosis-related deaths in the United States. In this systematic review, we aimed to comprehensively evaluate the current evidence and trials on the use of anti-interleukin-1 (anti-IL-1) drugs in patients with AH, assessing their efficacy and adverse events compared to routinely prescribed drugs like corticosteroids. Materials and Methods: A comprehensive literature search was conducted across five databases to identify randomized controlled trials (RCTs) evaluating the role of anti-IL-1 agents like canakinumab and anakinra among patients diagnosed with AH. Data was extracted and pooled in the form of mean and standard deviation for continuous variables and event and total for dichotomous variables. Results: Three RCTs were included for quantitative synthesis, encompassing 307 patients. Using canakinumab, 58% of patients showed improvement in histology. Prednisolone was associated with higher 90-day survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14–0.83, p = 0.018) and transplant-free survival. Overall, a higher incidence of acute kidney injury and new-onset cardiac disorders was noted in the anti-IL-1 arm when compared to placebo. Conclusions: This study concludes the lack of efficacy of anti-IL-1 agents in causing improvement in patient outcomes when compared to standard therapies. A higher incidence of adverse events was also noted in the anti-IL-1 arm. These results emphasize the need for future clinical trials to evaluate the use of anti-IL-1 agents in AH objectively. Full article

This study investigates the recombinant Tarim red deer hepatocyte growth factor (HGF) in a mouse model to develop an HGF/c-Met-based regenerative therapy for alcoholic liver disease. We constructed a recombinant HGF fusion protein and expressed and purified it in Escherichia coli. The recombinant protein was administered via intravenous injection to treat mice with alcoholic liver disease induced by chronic alcohol feeding followed by acute alcohol gavage (NIAAA model). The therapeutic effects were evaluated based on liver tissue histology and biochemical indicators. The recombinant Tarim red deer HGF protein successfully reduced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in mice, increased serum albumin (ALB) levels, decreased hepatic steatosis and triglyceride (TG) levels, lowered hepatic malondialdehyde (MDA) levels, and increased the levels of the antioxidants glutathione (GSH) and superoxide dismutase (SOD) in the liver. Additionally, it enhanced the proliferation capacity of liver cells, thereby promoting liver regeneration. In conclusion, our study demonstrates that recombinant Tarim red deer HGF effectively reduces liver damage in a mouse model of alcoholic liver disease. Full article

The global burden of liver diseases continues to rise, encompassing diverse pathologies such as viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In recent years, TNFR1-associated death domain protein (TRADD), a pivotal adaptor molecule in the TNF signaling pathway, has been found to play a dual regulatory role in the pathogenesis of liver diseases. Through its death domain, TRADD binds to TNFR1 and dynamically recruits downstream factors (e.g., TRAF2, RIPK1, FADD) to form Complex I or IIa, thereby activating pro-survival or pro-apoptotic signals that dictate hepatocyte fate and modulate the inflammatory microenvironment. This review systematically summarizes the molecular structure and functional networks of TRADD, along with its mechanistic roles in liver diseases: in HCC, TRADD expression correlates with tumor differentiation and is regulated by miRNA targeting; in ALD and MASLD, TRADD-mediated apoptosis is closely linked to fibrotic progression; and in acute liver injury, TRADD signaling is modulated by factors such as HO-1 to mitigate damage. Furthermore, TRADD inhibitors and antisense oligonucleotides demonstrate therapeutic potential. This review highlights the clinical translational value of TRADD as a diagnostic, therapeutic, and prognostic biomarker for liver diseases, providing a theoretical foundation for future precision medicine strategies. Full article

Bone fracture activates the immune system and induces inflammation crucial for fracture healing but may also affect trauma-distant organs like the liver. Acute alcohol intoxication (AAI) dysregulates immune responses and affects organ damage post-trauma. However, the bone–liver axis and alcohol’s role in this process remain poorly understood. This study explores liver inflammation and damage following fracture, with and without prior AAI. Twenty-four male C57BL/6J mice were randomly assigned to four groups (n = 6) and received either NaCl (control) or 35% ethanol via gavage. Mice underwent femur osteotomy with external fixation or sham surgery. After 24 h, liver damage was assessed using hematoxylin–eosin and activated caspase-3 staining. Liver inflammation was evaluated through CXCL1 and polymorphonuclear leukocyte (PMNL) immunostaining, cytokine gene and protein expression analyses, and immune cell profiling in the liver via flow cytometry. Western blotting assessed NF-κB and Wnt signaling. Neither fracture alone nor with AAI caused significant liver damage. However, fracture significantly increased PMNL infiltration and altered monocyte populations, effects that were amplified by AAI. The hepatic neutrophil-to-monocyte ratio significantly decreased after fracture and was absent in the fracture AAI group. CXCL1 increased post-fracture, while MCP-1 and IL-10 decreased significantly, with AAI further significantly amplifying these changes. Wnt1 and Wnt3a levels increased significantly after fracture and were further strongly elevated by AAI. AAI completely abolished fracture-induced significant β-catenin reduction and significantly increased its phosphorylation, effects that potentially involve an AAI-induced β-catenin stabilization as well as its increased degradation. NF-κB activation was significantly decreased, while A20 expression significantly increased after fracture and AAI. Fracture influences the inflammatory liver response and signaling pathways, effects which were further modulated by AAI. Full article

This study investigated the hepatoprotective mechanisms of Volvariella volvacea fruiting body polypeptide (VVFP, 1–3 kDa) against acute alcohol-induced liver injury using multi-omics approaches. Male ICR mice pretreated with VVFP (100–400 mg/kg) showed significantly prolonged alcohol tolerance latency (p < 0.05) and accelerated sobriety recovery compared to controls. Integrated transcriptomics and metabolomics revealed VVFP’s dual regulatory effects: (1) transcriptional regulation of 36 endoplasmic reticulum stress genes (e.g., ERP57, Derl) through protein processing pathways (KEGG:04141), and (2) metabolic modulation of 23 hepatic metabolites, particularly phosphatidylcholines and organic acids, via amino acid biosynthesis and glycerophospholipid metabolism. Cross-omics analysis identified eight coregulated genes (Got1, Arg2, Srm, etc.) interacting with key metabolites (4-guanidinobutyric acid, GABA) through linoleic acid metabolism. These findings demonstrate VVFP’s therapeutic potential as a functional food ingredient by highlighting its ability to simultaneously target hepatic stress responses and metabolic homeostasis during alcohol detoxification. Full article

Hepatitis E virus (HEV), the causative agent of hepatitis E, is the leading cause of acute viral hepatitis worldwide; under immunosuppression, infection can lead to chronic liver disease. Furthermore, extrahepatic manifestations, particularly renal manifestations, are frequently associated with infection. This is important considering the global burden of chronic kidney disease (CKD). However, the study of chronic hepatitis E has been limited to liver disease, and its definition with respect to renal disease is still incomplete. Recently, through a protocol aimed at identifying HEV seroprevalence in a cohort of patients on hemodialysis, we incidentally identified HEV RNA in a patient with a history of alcoholism, diabetes mellitus, and essential systemic hypertension. In this study, we aimed to follow up this case to characterize hepatitis E in the context of CKD. Notably, we identified the development of chronic HEV genotype 3 infection without seroconversion or evidence of liver damage. Moreover, apparent immunocompetence was identified in the patient. Considering that HEV is still neglected in numerous countries and that it is not included in the differential diagnosis of kidney disease, our findings support the need to consider HEV infection in patients with renal disease, even in the absence of liver deterioration. Full article

Non-alcoholic fatty liver disease (NAFLD) has been associated with depression and inadequate response to antidepressants. While ketamine has demonstrated efficacy in treating depression, its impact on pre-existing liver injury and depression remains unclear. This study aimed to evaluate the effects of ketamine treatment in a murine model of depression and liver damage, considering age-related differences. Young and aged male C57BL/6N mice were submitted to chronic unpredictable mild stress (CUMS) and methionine–choline-deficient (MCD) diet to induce depressive-like behavior and NAFLD. Behavioral testing (sucrose preference test, open field test, novel object recognition test, Crawley’s sociability test) were used to assess ketamine’s (50 mg/kg) effect on behavior. Hepatic ultrasonography was utilized to evaluate liver status. The cortical and hippocampal NeuN+, GFAP+, and Iba1+ signals were quantified for each animal. Ketamine administration proved effective in relieving anhedonia and anxiety-like behavior, regardless of liver damage. Although ketamine treatment did not improve memory in animals with liver damage, it enhanced sociability, particularly in aged subjects. The acute administration of ketamine did not affect the severity of liver injury, but seems to affect astrogliosis and neuronal loss. Although animal models of depression only replicate certain clinical features of the condition, they remain valuable for evaluating the complex and varied effects of ketamine. By applying such models, we could demonstrate ketamine’s therapeutic versatility, and also indicate that responses to the treatment may differ across different age groups. Full article

Background and Objectives: Fatty Liver Disease is a major health problem worldwide. We can distinguish liver steatosis as non-associated or associated with chronic/acute alcohol consumption. These two entities share similar stages ranging from hepatic fat storage (namely, steatosis) to inflammation, necrosis, and fibrosis until hepatocellular carcinoma (HCC). Over time, “Metabolic Associated Fatty Liver Disease” (MAFLD) has replaced nonalcoholic fatty liver disease (NAFLD) nomenclature and has included cardiometabolic criteria in these patients definition. Thus, obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia are MAFLD features and are of the metabolic syndrome. Importantly, there is not a specific treatment for MAFLD, but there are therapeutic strategies that act on metabolic dysfunction related to MAFLD. They can reduce the progression of liver fibrosis and its complications. Materials and Methods: For all these reasons, we conducted a narrative review of the literature, and we focused on metabolic dysfunction related to MAFLD, with a special regard for cholesterol metabolism. Results: MAFLD is a recently redefined condition that better describes the metabolism derangement responsible for fatty liver disease. This distinguishes MAFLD from NAFLD. In fact, the diagnostic criteria for MAFLD require the presence of liver steatosis together with at least one of the following: obesity, T2DM, or evidence of metabolic disorder such as hypertriglyceridemia, low high-density lipoprotein cholesterol, or hypertension. As a result, MAFLD is closely linked to an increased cardiometabolic risk. Current therapeutic approaches can be used to reduce this risk, focusing on lifestyle interventions and pharmacological strategies. Several treatments in patients diagnosed with MAFLD are mainly cholesterol-lowering remedies. Among these, Pro-protein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9i) show the most promising efficacy profile but data on liver fibrosis are lacking. Agonists of GLP-1 receptor, Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have a “ multi-hit “ action allowing their use also in diabetic patients with MAFLD. Conclusions: Lifestyle modifications, some nutraceuticals, statins, incretins, and PCSK9i have changed the natural course and significantly improved the cardiometabolic outcomes of MAFLD. Emerging cholesterol-lowering drugs, such as Bempedoic acid, can overcome low compliance to statins’ use and their controversial effect on liver fibrosis. Finally, medications targeting insulin resistance allow for strategic interventions of the convoluted pathophysiology of MAFLD in multiple steps, with the potential to reduce liver steatosis, inflammation, and necrosis and, sometimes even to reverse liver fibrosis. Full article

Liver health is integral to overall human well-being and the pathogenesis of various diseases. In recent years, kynurenine and its derivatives have gradually been recognized for their involvement in various pathophysiological processes, especially in the regulation of liver diseases, such as acute liver injury, non-alcoholic fatty liver disease, cirrhosis, and liver cancer. Kynurenine and its derivatives are derived from tryptophan, which is broken down by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), converting the essential amino acid tryptophan into kynurenine (KYN) and other downstream metabolites, such as kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and quinolinic acid (QA). In liver diseases, kynurenine and its derivatives can promote the activity of the transcription factor aryl hydrocarbon receptor (AhR), suppress T cell activity for immune modulation, inhibit the activation of inflammatory signaling pathways, such as NF-κB for anti-inflammatory effects, and inhibit the activation of hepatic stellate cells to slow down fibrosis progression. Additionally, kynurenine and other downstream metabolites can influence the progression of liver diseases by modulating the gut microbiota. Therefore, in this review, we summarize and explore the mechanisms by which kynurenine and its derivatives regulate liver diseases to help develop new diagnostic or prognostic biomarkers and effective therapies targeting the kynurenine pathway for liver disease treatment. Full article

Alpha-Glutathione-S-transferase (alphaGST) is a liver enzyme whose serum levels increase with the worsening of fibrosis in alcoholic and viral chronic hepatitis. Its usefulness in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) remains unexplored. From January 2016 to December 2017, 200 patients with MASLD and 30 controls were enrolled. AlphaGST serum levels were measured. Variables related to advanced fibrosis (AF) were selected via Principal Component Analysis (PCA), and the best cut-off (BCO) was estimated using ROC analysis. Liver stiffness measurement (LSM), NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and BMI-AST/ALT Ratio-Diabetes (BARD) scores were determined. The first acute cardiovascular events (ACE) in ACE-naïve subjects were recorded over five years. A validation cohort of 60 MASLD patients was enrolled from January 2018 to May 2019 and followed for five years. AlphaGST levels increased with fibrosis stage (p < 0.0001) in both cohorts, showing high accuracy in predicting AF (TrC: AUC 0.89, VlC: AUC 0.89). PCA-selected variables were HbA1c, HDL, and alphaGST, forming the “FLAME” model. FLAME showed superior predictive performance for AF and ACEs compared to other models and scores. FLAME represents a novel tool that accurately predicts AF and ACEs in MASLD. Full article

Background and Objective: Drug-induced liver injury (DILI) is increasingly becoming a cause of acute hepatitis. The study evaluated the role of liver-specific microRNAs (miRNAs) and keratin-18 (K-18) markers M30 (apoptosis) and M65 (necrosis) as biomarkers of acute hepatitis. Methods: Sixty-eight patients were sub-grouped as DILI, HBV- and alcohol-related acute hepatitis. Five healthy controls were included. The expression of plasma miR-21-5p, miR-34a-5p and miR-122-5p was evaluated by RT-qPCR analysis using healthy volunteers as reference. M30 and M65 were determined with ELISA kits. Results: All markers were significantly higher in the acute liver disease patients compared to controls. In DILI, miRNA levels positively correlated with M30, M65 and ALT. miR-122-5p had the highest AUC of 0.73, sensitivity of 76.2 and specificity of 72.2 in identifying DILI from other groups. Patients with hepatocellular-pattern DILI showed higher miR-122-5p and miR-21-5p compared to patients with cholestatic or mixed pattern. A new score to discriminate DILI versus other causes of acute hepatitis was developed using the identified risk factors as follows: 0.012 × miR-34a-5p + 0.012 × miR-122-5p − 0.001 × M30 + 2.642 × 1 (if mixed pattern) + 0.014 × 1 (if hepatocellular pattern) + 1.887. The AUC of the score was 0.86, with a sensitivity and specificity of 81%, better than the values of the single markers. Conclusions: Liver-specific miRNAs and K-18 could be promising serum biomarkers of DILI, especially when used in combination. Full article

Background/Objectives: Probiotics have great potential in improving acute alcohol intoxication. The aim of this study was to investigate the mitigating effect and mechanism of action of Weizmannia coagulans BC99 on acute alcohol intoxication (AAI) in SD rats. Methods: BC99 was divided into different doses administered by gavage to rats, and a rat model of acute alcohol intoxication was established by multiple gavages of excess alcohol. Results: Our study demonstrated that W. coagulans BC99 intervention significantly prolonged the latency period of intoxication; significantly attenuated alcohol-induced lipid elevation, liver injury, hepatic inflammation, and intestinal barrier damage; and lowered plasma endotoxin (LPS) levels in rats. In addition, W. coagulans BC99 could effectively restore the balance of intestinal flora, increase the abundance of Lachnospiraceae_NK4A136, Prevotellaceae_NK3B31, Parabacteroides, and Ralstonia, and thus increase the content of intestinal short-chain fatty acids (SCFAs), especially butyric acid. Moreover, we demonstrated through sodium butyrate validation experiments that butyrate could attenuate intestinal barrier damage and reduce the diffusion of LPS, thereby reducing liver inflammation. Conclusions: In conclusion, W. coagulans BC99 ameliorates acute alcohol intoxication in rats by increasing the abundance of butyrate-producing genera and thereby increasing butyrate abundance to alleviate intestinal barrier injury. Full article

Background/Objectives: Alcohol can directly damage the liver, causing steatosis, steatohepatitis, cirrhosis, and hepatocellular cancer. The aim of this study was to examine 28-day survival in hospitalized patients with alcohol-related liver disease (ALD) cirrhosis, as well as to develop and validate a new survival prediction model. Methods: A total of 145 patients with ALD cirrhosis were included; 107 were diagnosed with acute decompensation (AD) and 38 with acute-on-chronic liver failure (ACLF). The new liver mortality inpatients (LIV-IN) score was calculated using the following variables: hepatic encephalopathy (HE), hepatorenal syndrome (HRS), ascites, systemic inflammatory response syndrome (SIRS), community-acquired infection (CAI), and fibrinogen. The diagnostic accuracy of the LIV-IN score was tested, along with the model for end-stage liver disease (MELD), model for end-stage liver disease-sodium (MELD-Na), albumin-bilirubin (ALBI), neutrophil-to-lymphocyte ratio (NLR), chronic liver failure consortium-C acute decompensation (CLIF-C AD), and chronic liver failure consortium-acute-on-chronic liver failure (CLIF-C ACLF). Results: Lethal outcome occurred in 46 (31.7%) patients. The mortality rate was higher in the ACLF group (n = 22, 57.9%) compared to the AD group (n = 24, 22.4%) (p < 0.01). The highest predictive power for short-term mortality was observed for the LIV-IN score (AUC 73.4%, p < 0.01). In patients with AD, the diagnostic accuracy of the CLIF-C AD score was better than for the LIV-IN score (AUC 0.699; p = 0.004, AUC 0.686; p = 0.007, respectively). In patients with ACLF, only the LIV-IN score had statistically significant discriminative power in predicting 28-day survival. Conclusions: The liver mortality inpatients prognostic score is a new, reliable prognostic model in predicting 28-day mortality. Full article