Livers, Volume 3, Issue 2 (June 2023) – 11 articles

Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity. However, little is known about the underlying pathophysiology. The leading hypothesis is that TKIs are converted by cytochrome P450 3A4 (CYP3A4) to reactive metabolites that damage proteins. Indeed, there is strong evidence for this bioactivation of TKIs in in vitro reactions. However, the actual toxic effects are underexplored. Here, we measured the cytotoxicity of several TKIs in primary mouse hepatocytes, HepaRG cells and HepG2 cells with and without CYP3A4 modulation. To our surprise, the data indicate that CYP3A4 increases resistance to sorafenib and lapatinib hepatotoxicity. The results have implications for the mechanism of toxicity of these drugs in patients and underline the importance of selecting an appropriate experimental model. Full article

Liver regeneration is a compensatory response to tissue injury and loss. It is known that liver regeneration plays a crucial role in recovery following acetaminophen (APAP)-induced hepatotoxicity, which is the major cause of acute liver failure (ALF) in the US. Regeneration increases proportional to the extent of liver injury upon APAP overdose, ultimately leading to regression of injury and spontaneous recovery in most cases. However, severe APAP overdose results in impaired liver regeneration and unchecked progression of liver injury, leading to failed recovery and mortality. Inter-communication between various cell types in the liver is important for effective regenerative response following APAP hepatotoxicity. Various non-parenchymal cells such macrophages, stellate cells, and endothelial cells produce mediators crucial for proliferation of hepatocytes. Liver regeneration is orchestrated by synchronized actions of several proliferative signaling pathways involving numerous kinases, nuclear receptors, transcription factors, transcriptional co-activators, which are activated by cytokines, growth factors, and endobiotics. Overt activation of anti-proliferative signaling pathways causes cell-cycle arrest and impaired liver regeneration after severe APAP overdose. Stimulating liver regeneration by activating proliferating signaling and suppressing anti-proliferative signaling in liver can prove to be important in developing novel therapeutics for APAP-induced ALF. Full article

The activation of hepatic stellate cells (HSCs) is the key event of hepatic fibrosis. Furthermore, activated HSCs also play an important role in the progression of hepatocellular cancer (HCC). Bone morphogenetic protein 14 (BMP14) is a member of the TGF-β/BMP superfamily. So far, most studies have analyzed BMP14 in the context of bone and cartilage formation and homeostasis. The aim of this study was to assess the expression and function of BMP14 in liver fibrosis and HCC. The BMP14 expression increased during the in vitro activation of primary human HSCs and also in mouse models of liver fibrosis. In human HCC, as well as non-tumorous liver tissues, there was a significant correlation between the expression of BMP14 and alpha-smooth-muscle actin (α-SMA), an established marker for HSC activation. RNAi-mediated BMP14 suppression in activated HSCs resulted in the reduced expression of the transcription factors inhibitor of differentiation 1 (ID1) and ID2, known targets of BMP signaling. Interestingly, α-SMA and collagen expression was also reduced in BMP14-depleted cells, while treatment with recombinant BMP14 induced ID1, ID2, α-SMA and collagen expression. In human HCC cell lines, treatment with recombinant BMP14 induced proliferation, migratory activity and colony formation. In summary, our data indicate activated HSCs as a major cellular source of enhanced BMP14 expression in fibrotic liver disease and HCC, and show that BMP14 exhibits pro-fibrogenic as well as pro-tumorigenic effects. Future analyses will reveal the potential of this soluble growth factor as a therapeutic target or prognostic marker for the progression of fibrosis and HCC in patients with chronic liver disease. Full article

Around 118.5 million blood donations are collected annually to save precious lives. The donated blood may also be associated with blood-borne infections. With around 247 million population, Pakistan is an endemic country for viral hepatitis, and there is a high risk of having asymptomatic blood donors among healthy donors. Viral hepatitis is 2.5% prevalent in the general population, and blood donation and its screening have become grave health concerns for Pakistani health authorities. Asymptomatic viral hepatitis needs screening to rule out subliminally diseased individuals, as recommended by the World Health Organization. Knowing the prevalence of the transfusion transmissible infectious (TTIs) agents in healthy blood donors helps assess the disease burden in any population, boosts treatment rates, and precludes dreaded complications in the affected people. The objective of the current study was to determine the prevalence and trends of significant TTIs among blood donors visiting the Armed Forces Institute of Transfusion (AFIT), Rawalpindi, Pakistan. A total of 15,405 blood donors were screened for HBV, HCV, HIV, malaria, and syphilis during this cross-sectional descriptive study. Most donors had an O-positive blood group; AB-negative donors were only 0.7%. Out of the study population, we reported 1.06% HBV, 0.54% HCV, 0.19% HIV, and 0.31% syphilis-positive asymptomatic blood donors. However, no blood donor was found positive for malaria. The Punjab province was reported as the most burdened for TTIs, and youngsters aged 18–27 years were mainly positive, indicating the need to conduct national-level awareness campaigns about TTIs. The stakeholders need to strengthen the blood collection guidelines, and effective performance should be strictly monitored through internal and external audits considering the aim of reaching non-infectious blood products. Full article

The excessive consumption of diets rich in sugar and fat is associated with metabolic manifestations involving adipose tissue and the liver. Bergamot, due to its antioxidant and anti-inflammatory properties, has been used to treat metabolic disorders. This work aimed to verify the effect of Bergamot leaves extract (BLE) on the crosstalk in the adipose tissue–liver axis of obese rats. For 20 weeks, Wistar rats were distributed into two groups: control (Control) and high sugar–fat (HSF) diet groups. Afterwards, the animals were redistributed into three groups for 10 weeks: control diet + vehicle (Control, n = 08), HSF + vehicle (HSF, n = 08), and HSF + BLE (HSF + BLE, n = 08). The BLE was carried out daily by gavage (50 mg/kg). The HSF group presented obesity, hyperglycemia, hypertriglyceridemia, insulin resistance, hepatic microvesicular steatosis, higher inflammation and oxidative stress in the liver and adipose tissue. In comparison to the HSF group, HSF + BLE animals showed protection by reducing the triglyceride levels, insulin resistance, inflammation and oxidative stress in hepatic and adipose tissues. BLE acted on the inflammation and oxidative stress in the adipose tissue–liver axis in obese rats when compared to the HSF group, which may have reflected on the improvement of insulin resistance and dyslipidemia. Full article

The peritoneum represents a confined microenvironment that has an emerging role as a distinct immunological compartment. In health, this niche is mainly populated by a heterogenous group of macrophages and T lymphocytes but also Natural Killer cells and B lymphocytes. Together they are crucial for immunological surveillance, clearance of infection and resolution of inflammation. Development of ascites is a defining feature of decompensated liver cirrhosis, and spontaneous bacterial peritonitis is the most frequent bacterial infection occurring in this patient group. Recent studies of ascitic fluid have revealed quantitative, phenotypic and functional differences in both innate and adaptive immune cells compared to the healthy state. This review summarises current knowledge of these alterations and explores how the peritoneum in chronic liver disease is simultaneously an immunologically compromised site and yet capable of provoking an intense inflammatory response. A better understanding of this might enable identification of new therapeutic targets aimed to rebalance the peritoneal immunity and reduce the reliance on antimicrobials in an era of increasing antimicrobial resistance. Full article

Chronic hepatitis B remains a major public health concern and a leading cause of morbidity and mortality worldwide, specifically through its causative role in chronic liver disease and hepatocellular carcinoma. Worldwide, it affects up to 292 million people. In this paper, we review the historic discovery of the hepatitis B virus and chronicle the significant advances in our understanding of the virus and its interactions with the human host to cause disease. We also overview advancements in therapies for hepatitis B virus and the current absence of curative therapies and highlight on-going therapeutic efforts in search of curative therapies to control transmission and eradicate hepatitis B virus. Full article

Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells responsible for energy-intensive metabolic function, such as hepatocytes. Extensive research over the last decades have identified compromised mitochondrial function as a central feature in the pathophysiology of liver injury induced by an acetaminophen (APAP) overdose, the most common cause of acute liver failure in the United States. While hepatocyte mitochondrial oxidative and nitrosative stress coupled with induction of the mitochondrial permeability transition are well recognized after an APAP overdose, recent studies have revealed additional details about the organelle’s role in APAP pathophysiology. This concise review highlights these new advances, which establish the central role of the mitochondria in APAP pathophysiology, and places them in the context of earlier information in the literature. Adaptive alterations in mitochondrial morphology as well as the role of cellular iron in mitochondrial dysfunction and the organelle’s importance in liver recovery after APAP-induced injury will be discussed. Full article

According to studies, the liver’s ability to perform its physiological functions in the body determines the diet of patients with liver diseases. Malnutrition results from the liver’s inability to metabolize nutrients as a result of chronic liver dysfunctions. Objectives: Reviewing the data about diets and dietary supplements that manage liver dysfunctions nutritionally. Results: Malnutrition is particularly prevalent in cirrhosis patients, according to clinical studies. Because malnutrition has a significant negative impact on morbidity, mortality, and quality of life, it is crucial to evaluate all cirrhosis patients, regardless of etiology or severity. A term of supplemental enteral nutrition may be suggested for patients who do not achieve their nutritional objectives. A detailed nutritional and exercise assessment will enable the development of an individualized treatment plan that includes dietary and exercise plans. The dietary treatment should outline daily calorie targets with a focus on high-quality protein and address any vitamin and micronutrient deficiencies, with a diet high in those nutrients or supplements. Conclusions: While there is evidence to support the use of particular restricted dietary plans and dietary supplements to manage liver diseases, these findings should be regarded as preliminary until they are confirmed in larger randomized controlled clinical trials. Full article

More than 90% of all liver malignancies are hepatocellular carcinomas (HCCs), for which chemotherapy and immunotherapy are the ideal therapeutic choices. Hepatocellular carcinoma is descended from other liver diseases, such as viral hepatitis, alcoholism, and metabolic syndrome. Normal cells and tissues may suffer damage from common forms of chemotherapy. In contrast to systemic chemotherapy, localized chemotherapy can reduce side effects by delivering a steady stream of chemotherapeutic drugs directly to the tumor site. This highlights the significance of controlled-release biodegradable hydrogels as drug delivery methods for chemotherapeutics. This review discusses using hydrogels as drug delivery systems for HCC and covers thermosensitive, pH-sensitive, photosensitive, dual-sensitive, and glutathione-responsive hydrogels. Compared to conventional systemic chemotherapy, hydrogel-based drug delivery methods are more effective in treating cancer. Full article