Livers

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

Acetaminophen (APAP) overdose can induce hepatocyte necrosis and acute liver failure in experimental rodents and humans. APAP is mainly metabolized via hepatic cytochrome P450 enzymes to generate the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which forms acetaminophen protein adducts (APAP-adducts) and damages mitochondria, triggering necrosis. APAP-adducts and damaged mitochondria can be selectively removed by autophagy. Increasing evidence implies that the activation of autophagy may be beneficial for APAP-induced liver injury (AILI). In this minireview, we briefly summarize recent progress on autophagy, in particular, the pharmacological targeting of SQSTM1/p62 and TFEB in AILI. Full article

The preS1 region of the large hepatitis B virus (HBV) surface protein is a crucial component in HBV infection; however, its impact on the development of hepatocellular carcinoma (HCC) remains unknown. This study investigated the relationship between serum preS1 levels and hepatocarcinogenesis in patients with chronic hepatitis B (CHB). The preS1 levels were measured in 531 patients with CHB without a history of HCC. Among the patients, 293 HBV carriers who had never received nucleotide/nucleoside analog (NA) therapy had their preS1 levels measured at their first visit (non-NA group), and 238 patients who had received NA therapy had their preS1 levels measured at the start of NA administration (NA group). The two groups had no significant differences in hepatitis B surface antigen (HBsAg) levels; however, the NA group’s preS1/HBsAg ratio was significantly higher. The preS1/HBsAg ratio was significantly different between patients with CHB not meeting the NA treatment criteria and patients with chronic hepatitis and cirrhosis who were eligible for NA treatment. The predictors of HCC development were analyzed, and the preS1/HBsAg ratio was identified in both groups. The preS1/HBsAg ratio could predict hepatocarcinogenesis in patients with CHB with or without NA administration. Full article

To clarify the risk factors for the aggravation of esophagogastric varices (EGVs) after hepatitis C virus (HCV) eradication with direct-acting antiviral (DAA) therapy, we enrolled 167 consecutive patients with HCV-related compensated cirrhosis who achieved a sustained virological response (SVR) after DAA therapy. During a median of 69 months, EGVs were aggravated in 42 (25%) patients despite SVR. The cumulative 1-, 3-, 5-, and 10-year aggravated EGV rates were 7%, 23%, 25%, and 27%, respectively. Multivariate analysis identified a platelet count < 11.0 × 10⁴/μL, LSM ≥ 18.0 kPa, total bile acid ≥ 33.0 μmol/L, and a diameter of left gastric vein (LGV) ≥ 5.0 mm at HCV eradication as independent risk factors for EGV aggravation post-SVR. In groups that met all of these risks, the cumulative EGV aggravation rates at 1, 3, and 5 years were 27%, 87%, and 91%, respectively. However, none of the patients who had only one or none of the risk factors experienced EGV aggravation. Platelet count, LSM, total bile acid, and diameter of LGV at HCV eradication were associated with aggravated EGV post-SVR. EGVs tend to worsen as two or more of these risk factors increase. Full article

Overdose of acetaminophen (APAP) produces fulminant hepatic necrosis. The underlying mechanism of APAP hepatotoxicity involves mitochondrial dysfunction, including mitochondrial oxidant stress and the onset of mitochondrial permeability transition (MPT). Reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity, and iron is a critical catalyst for ROS formation. This review summarizes the role of mitochondrial ROS formation in APAP hepatotoxicity and further focuses on the role of iron. Normally, hepatocytes take up Fe³⁺-transferrin bound to transferrin receptors via endocytosis. Concentrated into lysosomes, the controlled release of iron is required for the mitochondrial biosynthesis of heme and non-heme iron-sulfur clusters. After APAP overdose, the toxic metabolite, NAPQI, damages lysosomes, causing excess iron release and the mitochondrial uptake of Fe²⁺ by the mitochondrial calcium uniporter (MCU). NAPQI also inhibits mitochondrial respiration to promote ROS formation, including H₂O₂, with which Fe²⁺ reacts to form highly reactive •OH through the Fenton reaction. •OH, in turn, causes lipid peroxidation, the formation of toxic aldehydes, induction of the MPT, and ultimately, cell death. Fe²⁺ also facilitates protein nitration. Targeting pathways of mitochondrial iron movement and consequent iron-dependent mitochondrial ROS formation is a promising strategy to intervene against APAP hepatotoxicity in a clinical setting. Full article

Segmental or lobar liver atrophy is a common but not well-understood clinical condition. Hepatic atrophy can be classified into hepatic atrophy secondary to other pathologies and primary segmental hepatic atrophy, which is a benign intrahepatic lesion (pseudotumor) not associated with any other pathology. The pathophysiological mechanisms underlying atrophy can be divided into three main situations: obstruction of biliary outflow, obstruction of the systemic venous outflow, and obstruction of incoming portal venous flow. For what may concern secondary hepatic atrophy, there are many pathologies that could underlie this condition, ranging from benign to intrahepatic malignancies, with particular reference to particularly hepatocellular carcinoma and biliary duct carcinoma. An accurate and prompt differential diagnosis between the various forms and causes of atrophy is important for early identification and adequate treatment of underlying pathologies. A comprehensive review of the literature on the etiology and the radiological and histological characteristics of different types of hepatic atrophy is currently unavailable. Therefore, the aim of this review is to summarize the primary and secondary causes of segmental or lobar liver atrophy (excluding forms involving the entire liver parenchyma) and to provide practical tools for clinical and radiological differential diagnosis. Full article

Background: As transgender people initiate gender-affirming hormone therapy (GAHT), they are exposed to exogenous sex hormones that have effects that have not yet been fully studied. While exogenous estrogen is associated with a risk of venous thrombosis, the full impact of estrogen on the liver is unknown. Conversely, the erroneous attribution of risks from GAHT presents a barrier to treatment for some patients. We present a case of obliterative portal venopathy (OPV) and possible DILI occurring after the initiation of estrogen in a transgender woman. Case presentation: A 28-year-old transgender woman on GAHT was referred to hepatology for liver enzyme elevations. She did not have any notable comorbid conditions, family history, or psychosocial history. Lab and imaging workup were unremarkable, and the patient underwent liver biopsy. The patient’s biopsy results showed OPV. The patient continued GAHT at a lower dose and liver enzyme elevations resolved. Conclusions: OPV is a vascular disease that falls under the category of porto-sinusoidal vascular disorder. Patients with this condition can present with or without overt clinical signs of portal hypertension. Porto-sinusoidal vascular disorder is rare and given the timing and possible dose dependence, it might be reasonable to consider that the observed OPV was influenced by the exogenous estrogen administered in an association not previously reported. Alternatively, the patient’s continued estrogen treatment without ill effect could suggest that the events were not connected and that the fear of harm could have served as a barrier to the patient receiving indicated care. Full article

Cacti are renowned for their resilience in arid environments and have been utilized as a valuable food source in various cultures for centuries. The potential effects of cactus (Cactaceae) consumption on liver health have garnered significant scientific interest in recent years. This review aimed to consolidate and analyze existing research findings regarding the relationship between cactus-derived compounds and their influence on liver function and health. Various cactus species, particularly Opuntia spp., are rich reservoirs of antioxidants, polyphenols, flavonoids, and betalains. In vitro and in vivo studies with animal models have shown that bioactive constituents of cactus exhibit anti-inflammatory, antioxidative, and antifibrotic properties, which potentially mitigate liver damage induced by oxidative stress, inflammation, and hepatotoxic agents. Understanding their mechanisms of action and conducting rigorous clinical studies with administration of cactus will ascertain their role in preventing and treating liver ailments, offering novel avenues in nutrition, hepatology, and natural medicine. Full article

Background: The risk of hepatocarcinoma in HCV cirrhotic patient responders after treatment with DAAs decrease, but HCC still occurs. A correlation between specific miRNAs and the development of hepatocarcinoma have been highlighted. Aim: To investigate miRNA expression in HCV-infected cirrhotic patients treated with DAAs, regarding whether or not they developed HCC at follow-up. Methods: A total of 73 outpatients with HCV-related cirrhosis treated with DAAs were enrolled, 28 of which had HCC. Samples were collected at the start and at the end of treatment. In the screening phase, 172 miRNAs were analyzed at baseline. Differentially expressed miRNAs were validated in the entire cohort. Results: In the validation phase, at baseline and in patients treated for 12 weeks, miR-28-5p was confirmed to be more highly expressed in the HCC group compared to the non-HCC group. In all of the patients treated for 12 weeks, at end of the treatment we found a significant downregulation in miR-132-3p, miR-133b-3p, miR-221-3p and miR-324-3p. In the HCC group, miR-28-5p was significantly downregulated after DAA therapy as well as in HCC patients treated for 24 weeks. Conclusion: In the HCC group, miR28-5p was differently expressed both at baseline and at the end of therapy with DAAs. This difference in expression should suggest its involvement in HCC development. Full article

Hepatorenal syndrome (HRS) is a unique form of renal dysfunction that results from circulatory hemodynamic dysfunction in advanced liver disease. We aimed to determine longitudinal trends in both all-cause and cause-specific readmissions for HRS in the United States. Using the National Readmission Database (2010–2018), we identified adult HRS patients during index admission via ICD codes. Fisher’s exact test and Cox regression analysis were used to compare proportions and compute adjusted p-values, respectively. Regression models were adjusted for gender, age, the Charlson comorbidity index, median household income, and hospital factors. A total of 169,522 HRS patients were included in the analysis (overall mean age 58.97 years). The incidence of HRS hospitalization increased from 5.30% in 2010 to 5.84% in 2018 (p < 0.01). Over the same duration, all-cause readmission at 30 days showed an overall increasing trend from 19.81% to 19.99% (trend p < 0.01). HRS-specific readmission at 30 days following an index hospitalization ranged from 13.60 to 15.98, with an overall increasing trend in the study period (2010–2018). While cirrhosis, hepatic failure, and infection were uniformly the three most common causes of readmission throughout the study period, cirrhosis and infection showed an upward trend. Rising readmissions, especially with hepatic failure and infection, in HRS patients signal a need for national strategies to manage and prevent HRS towards reducing its healthcare burden. Full article

The clearance of peripheral beta amyloid (Aβ) is a potential target for the treatment of Alzheimer’s disease (AD). The liver has been implicated in the elimination of Aβ from the peripheral circulation. Here, the single-pass uptake of Aβ40 in perfused livers from young and old rats (6 to 10 rats per group) was investigated with the multiple indicator dilution technique. Aβ40 had volumes of distribution between those of the vascular marker Evans Blue and the extracellular marker sucrose. The hepatic extraction of Aβ40 was negligible, explained in part by the small permeability surface area products consistent with a high endothelial barrier to liver uptake. There were no substantial effects of age on any of these results. In vitro experiments with isolated hepatocytes and liver sinusoidal endothelial cells showed only very small amounts of Aβ uptake consistent with low intrinsic clearance. These results indicate that the hepatic clearance of Aβ is capacity-limited, explained by the low-permeability surface area products and hepatocyte uptake. However, this does not preclude an effect of aging in longer-term in vivo studies where age-related changes in liver blood flow and protein binding influence liver clearance. Full article

Autoimmune hepatitis (AIH) is a varied inflammatory chronic liver disease. AIH’s prevalence varies and has increased recently. Diagnosis involves the discovery of histologic features following liver biopsy and serologic testing. Clinical features vary, and up to 40% of patients may be asymptomatic. Evaluating thiopurine methyltransferase (TMPM) activity before treatment is crucial for an optimal response. The primary treatment goal is biochemical remission, normalized serum IgG, and liver enzymes. Induction therapy typically involves azathioprine and corticosteroids. Close monitoring of liver function tests and serum immunoglobulin levels is essential. Medications can be tapered after achieving biochemical remission. Liver transplantation may be required for refractory disease or cirrhosis. Further therapeutic approaches are needed, particularly for non-responders to first-line treatments. Full article

Many metabolic processes at the molecular level support both viral attack strategies and human defenses during COVID-19. This knowledge is of vital importance in the design of antiviral drugs. In this study, we extracted 18 articles (2021–2023) from PubMed reporting the discovery of hub nodes specific for the liver during COVID-19, identifying 142 hub nodes. They are highly connected proteins from which to obtain deep functional information on viral strategies when used as functional seeds. Therefore, we evaluated the functional and structural significance of each of them to endorse their reliable use as seeds. After filtering, the remaining 111 hubs were used to obtain by STRING an enriched interactome of 1111 nodes (13,494 interactions). It shows the viral strategy in the liver is to attack the entire cytoplasmic translational system, including ribosomes, to take control of protein biosynthesis. We used the SARS2-Human Proteome Interaction Database (33,791 interactions), designed by us with BioGRID data to implement a reverse engineering process that identified human proteins actively interacting with viral proteins. The results show 57% of human liver proteins are directly involved in COVID-19, a strong impairment of the ribosome and spliceosome, an antiviral defense mechanism against cellular stress of the p53 system, and, surprisingly, a viral capacity for multiple protein attacks against single human proteins that reveal underlying evolutionary–topological molecular mechanisms. Viral behavior over time suggests different molecular strategies for different organs. Full article

Oxidative stress and inflammation play a central role in the progression of nonalcoholic steatohepatitis (NASH), which can lead to liver cirrhosis. Barley bran has potential bioactivities due to its high content of functional substances, such as anthocyanins, with anti-inflammatory and anti-oxidative properties. Here, we investigated whether barley bran polyphenol-rich extracts (BP) can prevent NASH in Sprague–Dawley rats fed a high-fat and high-cholesterol diet including 1.25% or 2.5% cholesterol for 9 weeks. In the rat model of NASH with advanced hepatic fibrosis, BP prevented NASH development by ameliorating the histopathological findings of lobular inflammation. The BP also tended to attenuate serum aspartate aminotransferase level in this model. In the rat model of NASH with mild-to-moderate hepatic fibrosis, BP tended to attenuate the serum levels of transaminases. BP-dose-dependent effects were revealed for several parameters, including monocyte chemoattractant protein-1, transforming growth factor-β, and manganese superoxide dismutase gene expressions in the liver. These results suggest that BP may prevent NASH development or progression, presumably due to its anti-inflammatory and anti-oxidative properties. Full article

Non-invasive tests (NITs) are a potential alternative to screening oesophagogastroduodenoscopy (OGD) for ruling out high-risk varices (HRVs) in patients with compensated advanced chronic liver disease (cACLD). This retrospective study aimed to externally validate and compare various NITs in a multi-centre Australian cohort. Patients with cACLD were enrolled between January 2013 and December 2022. Liver stiffness measurements (LSMs), clinicopathological data, and OGD results were collected. A total of 210 patients were included. The median age was 57 years and 65.7% were male. The main aetiology of cACLD was hepatitis C (41.9%), and 91.9% of patients were Child–Pugh A. HRV prevalence was 12.4%. The Baveno VI criteria (B6C) was the only NIT that could safely reduce the need for OGDs across all aetiologies of cACLD, with a negative predictive value of 98.6 and spared OGD in 33.8%. The FIB-4 would have avoided the most OGDs (71%); however, the HRV miss rate was 6%. The results suggest that the B6C is the best performing NIT in our cohort and reliably excludes HRVs in cACLD patients, regardless of aetiology. This study confirms that the Baveno VI criteria can be applied in an Australian, mixed aetiology cohort to avoid unnecessary screening OGD. Full article