Livers

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally. The impact of statins on liver fibrosis severity in MASLD individuals remains uncertain, despite their known cardiovascular benefits. Methods: A cross-sectional study was performed utilizing the National Health and Nutrition Examination Survey (NHANES) database from 2017 to 2018. MASLD was defined by hepatic steatosis (controlled attenuation parameter [CAP] score ≥ 288 dB/m) without other etiologies. Using inverse probability treatment weighting to minimize confounding, we examined the association between statin use and MASLD outcomes, including at-risk steatohepatitis (FibroScan-aspartate aminotransferase [AST] [FAST] score ≥ 0.67), significant and advanced fibrosis (liver stiffness measurement [LSM] ≥ 8.8 kilopascals [kPa] and ≥ 11.7 kPa), and advanced fibrosis (AGILE 3+ score ≥ 0.68). Results: Of 1283 MASLD patients, 376 were prescribed statins within the past 30 days. After adjustment for confounders, statin use was significantly associated with reduced risks of at-risk steatohepatitis, significant fibrosis, and high AGILE 3+ scores, with odds ratios (ORs) of 0.29 (95% CI: 0.01 to 0.87), 0.54 (95% CI: 0.31 to 0.95), and 0.41 (95% CI: 0.22 to 0.75), respectively. However, a subgroup analysis showed this effect persisted only with lipophilic statins. Conclusions: Statin use was associated with reduced steatohepatitis and fibrosis in patients with MASLD, supported by robust causal inference and vibration-controlled transient elastography-derived scores. Full article

Background: Unlike other chronic liver disorders, in primary biliary cholangitis (PBC), systemic oxidative stress (SOS) worsens along with liver disease progression status (DPS), influencing muscle metabolism, muscle quantity (MQ), and itch pathways. Synergistically, cholestasis contributes to reduced vitamin D absorption, with a negative impact on MM and SOS. Despite this evidence, the prevalence of sarcopenia in PBC, and the SOS-MQ relationship comparing PBC with other CLDs, has never been investigated. Moreover, the relationship between vitamin D and MQ-SOS, and the correlation between SOS and pruritus severity, remains unexplored in PBC. Methods: A total of 40 MASLD, 52 chronic HBV infections, 50 chronic HCV infections, and 41 ursodeoxycholic acid/antioxidant-naïve PBC patients were enrolled. Biochemical, nutritional, and liver stiffness (LSM) data were collected, and sarcopenia was assessed after a normalizing 3-month dietetic–physical exercise regimen. The d-ROMs/BAP tests evaluated SOS. The validated “PBC-40 questionnaire” estimated pruritus and quality of life (QoL). Results: Unlike other CLDs, in PBC patients, sarcopenia was more prevalent in initial mild fibrosis (PBC: 57.10% vs. MASLD: 30.76%, HBV: 22.60%, HCV: 20.70%, all p < 0.0001), and SOS significantly correlated with MQ (dROMs-ASM/h², p: 0.0002; BAP-ASM/h²: p: 0.0092). PBC patients presented lower vitamin D levels and a significant correlation of these with SOS and MQ (all p < 0.0001). SOS also correlated with pruritus severity (dROMs, R: 0.835; BAP, R: −0.775, p < 0.0001). QoL impairment was significantly more represented in PBC individuals with sarcopenia, SOS imbalance, and relevant pruritus (p: 0.0228). Conclusions: In PBC, SOS correlates with MQ impairment and pruritus severity, configuring two independent relationships simultaneously impacting QoL. Full article

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors. Full article

Long regarded as illicit substances with no clinical value, N-dimethylated tryptamines—such as N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine—have been found to produce naturally in a wide variety of species, including humans. Known for their psychoactive effects through serotonin receptors (5-HTRs), N-dimethylated tryptamines are currently being reinvestigated clinically for their long-term benefits in mental disorders. Endogenous tryptamine is methylated by indolethylamine-N-methyltransferase (INMT), which can then serve as an agonist to pro-survival pathways, such as sigma non-opioid intracellular receptor 1 (SIGMAR1) signaling. Fibrogenic diseases, like metabolic-associated fatty liver disease (MAFLD), steatohepatitis (MASH), and chronic kidney disease (CKD) have shown changes in INMT and SIGMAR1 activity in the progression of disease pathogenesis. At the cellular level, endothelial cells and fibroblasts have been found to express INMT in various tissues; however, little is known about tryptamines in endothelial injury and fibrosis. In this review, I will give an overview of the biochemistry, molecular biology, and current evidence of INMT’s role in hepatic fibrogenesis. I will also discuss current pre-clinical and clinical findings of N-methylated tryptamines and highlight new and upcoming therapeutic strategies that may be adapted for mitigating fibrogenic diseases. Finally, I will mention recent findings for mutualistic gut bacteria influencing endogenous tryptamine signaling and metabolism. Full article

The liver is a common site for metastatic disease. In select patients with isolated liver metastases, surgical resection improves survival and may be potentially curative in patients with favorable “tumor biology”. However, when surgical resection is not feasible, liver-directed therapies (LDTs) can also improve outcomes, including survival, in the appropriate clinical situations. LDTs, including hepatic artery infusion, radioembolization, radiation, and ablation techniques, such as thermal ablation and histotripsy, offer local control and potential systemic effects, including the abscopal effect. The abscopal effect occurs when nontargeted, nontreated tumors regress following localized therapy to other tumors. Preclinical and clinical studies suggest that antigen-induced upregulation of key immune regulators plays a central role in this process. Unfortunately, clinical reports of the abscopal effect following LDT are exceedingly rare. However, histotripsy, a noninvasive, nonionizing, and nonthermal ablation technique, may induce an abscopal effect more frequently and robustly than other LDTs. Histotripsy enhances tumor immunogenicity through precise acoustic cavitation that better preserves the local tissue architecture while increasing antigen release, resulting in a robust local and systemic immune response. Ongoing trials are investigating these immunogenic mechanisms and the ability to generate an abscopal effect more reliably with adjuncts such as checkpoint inhibitors. This work has significant implications regarding the management of patients with liver metastasis. Full article

Background/Objectives: The approval of direct-acting antiviral (DAA) therapy for hepatitis C (HCV) resulted in a highly effective oral treatment for patients. The primary objective of this study was to identify reasons that patients were not treated versus why patients were treated. Identifying potential reasons for the failure to treat can provide a pathway to interventions using evidence-based data. Methods: The electronic medical records in an urban predominately African American (AA) population were searched for all patients with HCV seen at least once in a Gastroenterology or Infectious Disease clinic in 2019. Data collected included demographics, treatment visits, laboratory data, insurance and ZIP codes for median income. Results: Of the 441 patients who were not yet treated at the first 2019 visit, only 43% were treated by July 2020. Insurance and median income were not factors in failure to treat. Patients with an average of four visits were more likely to be treated than those with two or less, suggesting that failure to follow up was a significant factor for patient treatment (42% vs. 8% p < 0.0001). Confirmation of viral infection at first visit was an important factor with respect to treatment (treated 38% vs. not treated 25% p < 0.02). Conclusions: Significant numbers of our patients (57%) failed to be treated after at least one clinic visit. The two critical factors were PCR confirmation prior to the initial visit and the requirement for multiple visits before the initiation of treatment. Since the degree of fibrosis had no impact on treatment, initiating treatment immediately after confirming infection with HCV should improve patient treatment rates and outcomes. Full article

Infection of hepatitis B (HBV) patients with hepatitis D (HDV) can cause the most severe form of viral hepatitis, leading to liver fibrosis, liver failure, and hepatocellular carcinoma. HDV relies on simultaneous infection with HBV for the generation of infectious viral particles. The innate immune response, which is weakly induced in HBV infection, becomes strongly activated upon HDV co-infection. In HBV/HDV co-infection, the immune system comprises a cell-intrinsic strong IFN response, which leads to the induction of interferon-stimulated genes (ISGs), the local activation of liver-resident innate immune cells, and additional immune cell recruitment from the blood. Efficient innate immune responses are indispensable for successful viral control and spontaneous viral clearance. Despite this fact, innate immune cell activation can also contribute to adaptive immune cell inhibition and accelerate liver damage in HBV/HDV infection. While the intrinsic IFN response in HDV-infected cells is well characterized, far less is known about the cellular innate immune cell compartment. In this review, we summarize HBV/HDV replication characteristics and decipher the role of innate immune cell subsets in the anti-viral response in HBV/HDV infections. We further review the impact of epigenetic and metabolic changes in infected heptatocytes on the innate anti-viral response. Moreover, we discuss the potential of exploiting the innate immune response for improving vaccination strategies and treatment options, which is also discussed in this review. Full article

Background: Pediatric hepatitis B virus (HBV) serostatus remains variably characterized, hardly determined at times, or documented as part of national monitoring of the Extended Programs for Immunization (EPI). Methods: We cross-sectionally characterized the seroprevalence of HBV vaccine and/or infection status among 501 and 288 children <5 and 15–17 years old, respectively, in Kawempe Division, Kampala, Uganda, between May and August 2023. These children received HBV vaccination under the Uganda National Extended Program on Immunizations (UNEPI). Samples were qualitatively screened for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb or anti-HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb or anti-HBe), and for hepatitis B core antibody (HBcAb or anti-HBc) using three different HBV Combo test rapid immunochromatographic diagnostic tests: Nova, Fastep, and Beright. Results: The seroprevalence of HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc was 1.52%, 27.75%, 0.88%, 0.63%, and 0.76%, respectively, for the combined study age groups. The HBsAg seroprevalence of 2.78% was almost 3.5-fold higher among adolescents when compared to the 0.8% observed in the under-5-year-olds. The qualitative seroprevalence of anti-HBs was 33.1% and 18.4% in the under-5 and among the 15–17-year-old study groups, respectively. Conclusions: The proportion of qualitatively detectable anti-HBs in both groups of vaccinated children is low and probably indicates reduced seroprotection. Consequently, a large proportion of children who received the hepatitis B vaccine under UNEPI may be at risk of HBV infection, especially adolescents. A booster dose of the Hepatitis B Vaccine may be required for adolescents. Full article

Hepatic steatosis is considered the hepatic manifestation of metabolic disorders. Its global prevalence is a growing public health concern, estimated to affect over 30% of the population. Steatosis is strictly linked to metabolic dysfunction, leading to the revised terminology of MASLD (metabolic dysfunction-associated steatotic liver disease). The disease often progresses in conjunction with metabolic syndrome components, significantly increasing cardiovascular and overall mortality risks. The interplay between sex hormones and metabolic dysfunction is crucial, with male hypogonadism and female hyperandrogenism exacerbating the risk and severity of hepatic steatosis. In men, testosterone deficiency is associated with increased visceral adiposity and insulin resistance, creating a vicious cycle of metabolic deterioration. Conversely, in women, hyperandrogenism, particularly in conditions like polycystic ovary syndrome, may lead to severe metabolic disturbances, including hepatic steatosis. Estrogen deficiency also contributes to central adiposity and metabolic syndrome. The aim of this paper is to discuss this complex sex-dimorphic relationship. Full article

Background: Creating a model for acute liver failure in animal models is essential for research on liver regeneration and cancer. Current surgical techniques allow for a maximum of 80% partial hepatectomy in rats, with low survival rates due to poor inflow control. The common resection technique involves ligation at the liver lobe neck, causing peri-operative blood loss and postoperative blood loss. Methods: A 90% partial hepatectomy was performed on 5 rats using a bile duct-saving portal ligation technique, involving two hilum dissections for bile duct preservation. The first dissection controlled the blood supply to the median and left lateral lobes, and the second to the right inferior and superior lobes. Before closing, all rats were given 5 mL of 10% dextrose intraperitoneally and had access to ClearH₂O DietGel Recovery and 20% dextrose. Weight and behavior were closely monitored for seven days post-operatively. Results: This method resulted in 100% survival, with a 3.1% increase in liver mass and 12.3% increase in liver-to-body mass ratio. Conclusions: This technique is the first bile duct-saving portal ligation for rodent models of acute liver failure, with long-term survival and complete hepatic regeneration. Our procedure offers a viable 90% hepatectomy model for research with improved survival and regeneration outcomes. Full article

Background/Objectives: Efforts to preoperatively risk stratify and optimize patients before liver resection allow for improvements in postoperative outcomes, with hypoalbuminemia being increasingly researched as a surrogate for nutrition, overall health and functional status. Given the paucity of studies examining the relationship between hypoalbuminemia and liver resection, this study aims to determine the impact of hypoalbuminemia on outcomes following liver resections using a large multicenter database. Methods: The American College of Surgeons–National Surgical Quality Improvement Program (2017–2021) database was used to extract the data of patients who underwent a hepatic resection. Two cohorts were defined; those with hypoalbuminemia (HA; <3.0 g/L) and those with normal albumin levels (≥3.0 g/L). Both baseline characteristics and 30-day postoperative complication rates were compared between the two cohorts. Multivariable logistic regression models were used to assess the independent effect of HA on various outcomes. Area under curve–receiver operating characteristic (AUC-ROC) curves were used to identify optimal albumin thresholds for both serious complications and mortality. Results: We evaluated 26,394 patients who underwent liver resections, with 1347 (5.1%) having preoperative HA. The HA patients were older (62.3 vs. 59.8; p < 0.001) and more likely to be of an ASA class ≥ 4 (13.0% vs. 6.5%; p < 0.001). The patients with HA had significantly more complications such as an increased length of stay, readmission, reoperation, sepsis, surgical site infection, bile leak, and need for transfusion. After controlling for demographics and comorbidities, HA remained a significant independent predictor associated with both 30-day serious complication rates (aOR 2.93 [CI 95% 2.36–3.65, p < 0.001]) and mortality (aOR 2.15 [CI 95% 1.38–3.36, p = 0.001]). The optimal cut-off for albumin with respect to predicting serious complications was 4.0 g/dL (sensitivity 59.1%, specificity 56.8%, AUC-ROC 0.61) and 3.8 g/dL (sensitivity 56.6%, specificity 68.3%, AUC-ROC 0.67) for mortality. Conclusions: In this large, retrospective database analysis, preoperative HA was significantly associated with 30-day morbidity and mortality rates following hepatic resection. Preoperative albumin may serve as a useful marker for risk stratification in conjunction with pre-existing calculators. Future studies evaluating the risk mitigation impact of nutrition and exercise prehabilitation in these patients and its capacity to modify hypoalbuminemia would be beneficial. Full article

The primary objective of modern medicine is to extend human life expectancy. Currently, the majority of hospital patients across various clinical settings are elderly or advanced-age individuals, often with multiple comorbidities and age-related alterations in peripheral tissues. One such alteration is sarcopenia, a progressive decline in muscle mass, strength, and function, which significantly increases the risk of disability and mortality in older adults. Sarcopenia is associated with numerous adverse outcomes, and its underlying mechanisms are the subject of ongoing research. This narrative review discusses the epidemiology, pathophysiology, and diagnostic criteria for sarcopenia. It also examines the connections between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting potential treatment approaches for the coexistence of these two pathologies. Full article

Intestinal mucus serves as the first line barrier within the mucosa to protect against microbiota attack due to its water-repellent properties, which are the result of the high abundance of phosphatidylcholine bound to mucins. A deficiency of mucus phosphatidylcholine predisposes it to mucosal inflammation by the attack of commensal microbiota, as it is intrinsically low in ulcerative colitis. However, for precipitation of an acute inflammatory episode, mucus phosphatidylcholine has to fall below the critical level required for mucosal protection. Bacterial ectophospholipase could be a candidate for further thinning of the mucus phosphatidylcholine shield as shown, for example, with the ectophospholipase containing Helicobacter pylori bacterium. Despite supporting evidence for this mechanism in the intestine, the responsible ectophospholipase-carrying bacteria species are still to be defined. Applying phosphatidylcholine to the lumen can serve to fill up empty mucin-binding sites in ulcerative colitis as well as provide a substrate for the ectophospholipase-carrying bacteria preventing their attacks on the mucus phosphatidylcholine layer. Evidence supporting this concept comes from clinical trials in humans with ulcerative colitis as well as from colitis mouse models where phosphatidylcholine was substituted in the lumen. An alternative strategy could involve adding non-absorbable phospholipase inhibitors to the intestinal lumen, which has been shown to be effective in a mouse model of ulcerative colitis. Bacterial phospholipase should be considered a pathogenetic factor of the intestinal microbiota and therapeutic strategies should be developed to prevent their hyperactivity for clinical improvement of intestinal inflammation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area. Full article

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant global health issue. The condition is closely linked to metabolic dysfunctions such as obesity and type 2 diabetes. The gut–liver axis, a bidirectional communication pathway between the liver and the gut, plays a crucial role in the pathogenesis of NAFLD. This review delves into the mechanisms underlying the gut–liver axis, exploring the influence of gut microbiota, intestinal permeability, and inflammatory pathways. This review also explores the potential therapeutic strategies centered on modulating gut microbiota such as fecal microbiota transplantation; phage therapy; and the use of specific probiotics, prebiotics, and postbiotics in managing NAFLD. By understanding these interactions, we can better comprehend the development and advancement of NAFLD and identify potential therapeutic targets. Full article

Liver transplantation is the most effective treatment for end-stage liver disease. Despite improvements in surgical techniques, transplant rejection remains a significant concern. The liver is considered an immune-privileged organ due to its unique microenvironment and complex interactions among various cell types. Alloimmune responses mediated by T cells and antigen-presenting cells (APCs) play crucial roles in transplant rejection. The liver’s dual blood supply and unique composition of its sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs) contribute to its immune privilege. Alloantigen recognition by T cells occurs through direct, indirect, and semidirect pathways, leading to acute cellular rejection (ACR) and chronic rejection. ACR is a T cell-mediated process that typically occurs within the first few weeks to months after transplantation. Chronic rejection, on the other hand, is a gradual process characterized by progressive fibrosis and graft dysfunction, often leading to graft loss. Acute antibody-mediated rejection (AMR) is less common following surgery compared to other solid organ transplants due to the liver’s unique anatomy and immune privilege. However, when it does occur, AMR can be aggressive and lead to rapid graft dysfunction. Despite improvements in immunosuppression, rejection remains a challenge, particularly chronic rejection. Understanding the mechanisms of rejection and immune tolerance, including the roles of regulatory T cells (Tregs) and hepatic dendritic cells (DCs), is crucial for improving transplant outcomes. Strategies to induce immune tolerance, such as modulating DC function or promoting Treg activity, hold promise for reducing rejection and improving long-term graft survival. This review focuses on the liver’s unique predisposition to rejection and tolerance, highlighting the roles of individual cell types in these processes. Continued research into the mechanisms of alloimmune responses and immune tolerance in liver transplantation is essential for developing more effective therapies and improving long-term outcomes for patients with end-stage liver disease. Full article

Cell-death-inducing DNA fragmentation factor-alpha (DFFA)-like effector b (CIDEB) was first identified as an apoptosis-inducing protein. Further research revealed a pivotal role in lipid metabolism, regulating very-low-density lipoprotein (VLDL), lipid droplets (LD), sterol response element-binding protein (SREBP), and chylomicrons. Recent studies have uncovered that rare germline variants in CIDEB protect against liver diseases, including MAFLD, cirrhosis, and viral hepatitis. Furthermore, CIDEB influences steps of the hepatitis C virus (HCV) replication cycle. This review summarizes the current knowledge about CIDEB’s roles in apoptosis, lipid metabolism, and viral hepatitis, and highlights its critical role in liver diseases. Full article

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant primary hepatic cancer that affects mainly adolescents and young adults without underlying liver disease. Its biology remains unknown, but it is pathologically distinct from traditional HCC. Therapeutic strategies are not well defined and, as chemotherapies seem to have limited efficacy, surgical resection remains the only effective treatment. Here we report on a case of a metastatic FL-HCC in an 18-year-old man successfully treated with aggressive intra-thoracic bilateral lung metastasectomy following primary tumour resection and adjuvant chemotherapy. Survival time after initial hepatectomy is 39 months, with no recurrence of disease to date. Aggressive surgical resection and redo surgery should be considered until more effective multimodality therapies are identified. Multidisciplinary team discussion and involvement of medical and surgical specialties are essential in managing these rare entities. Full article

Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Genotype 1 (HDV-1) is by far the most prevalent in Europe and globally, while HDV-5 predominates in Western Africa. Data about HDV seroprevalence in Portugal are scarce and genotyping studies have not been performed yet. We aimed to assess the seroprevalence and genotypes of HDV in a large cohort of HBsAg-positive patients followed in our Hepatology Unit between 2012 and 2022. The anti-HDV-positive patients were subjected to a cross-sectional analysis, including blood sample collection for HDV RNA testing and genotype determination. In the cohort of HBsAg-positive patients, 57.5% (480/835) were born in African countries and 665/835 (79.6%) had been screened for anti-HDV antibodies. The HDV seroprevalence obtained was 6.5% (43/665). Twenty-one patients (age 41.2 ± 9.9 years; 57.1% male) were included in further molecular analyses. HDV RNA was positive in 8/21 (38.0%) and classified as HDV-5 in 7 patients (6 from Guinea-Bissau and 1 from Cape Verde) and HDV-1 in 1 patient (from Ukraine). In the largest and most comprehensive study performed in Portugal regarding HDV epidemiology to date, seroprevalence and genotype distribution of HDV (with predominance of HDV-5) were strongly influenced by immigration, notably from African countries. Full article