The Mechanisms and Physiological Consequences of Diurnal Hepatic Cell Size Fluctuations: A Brief Review.

Liver size in mammals fluctuates throughout the day and correlates with changes in hepatocyte size. However, the role of these daily changes in liver and hepatocyte size and the underlying molecular mechanisms remain largely unknown. In this review, we highlight the view that hepatocyte size, and thus, overall organ size, is subject to regulation by the circadian clock and feeding/fasting cycles. To that end, we provide an overview of the current literature dealing with this phenomenon and elaborate the role of feeding and nutrients in this process. We will discuss the role of hepatic protein content and synthesis, which are both subject to diurnal regulation, in daily hepatocyte and liver size fluctuations. Although there is evidence that changes in hepatocyte and liver size are associated with daily variations in macromolecule content, there is also evidence that these changes in size may be actively regulated by modifications of the cells' osmotic environment. Future research will need to examine the intriguing possibility that hepatocyte and liver size fluctuations may be required for normal liver function and to reveal the underlying molecular mechanisms behind this process.

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease. As well, cells in a SASP state secrete a multitude of inflammatory and pro-fibrogenic factors that modulate the microenvironment. Cellular SASP and the associated, secreted factors have been implicated in the progression of liver diseases, such as cholestatic injury that target the biliary epithelial cells (i.e., cholangiocytes) lining the bile ducts. Indeed, cholangiocyte senescence/SASP is proposed to be a driver of disease phenotypes in a variety of liver injuries. Within this review, we will discuss the impact of cholangiocyte senescence and SASP in the pathogenesis of cholestatic disorders.

Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development

Liver development is a highly complex process that is regulated by the orchestrated interplay of epigenetic regulators, transcription factors, and microRNAs (miRNAs). Owing to the lack of global in vivo targets of all miRNAs during liver development, the mechanisms underlying the dynamic control of hepatocyte differentiation by miRNAs remain elusive. Here, using Argonaute (Ago) high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse liver at different developmental stages, we characterized massive Ago-binding RNAs and obtained a genome-wide map of liver miRNA-mRNA interactions. The dynamic changes of five clusters of miRNAs and their potential targets were identified to be differentially involved at specific stages, a dozen of high abundant miRNAs and their epigenetic regulation by super-enhancer were found during liver development. Remarkably, miR-122, a liver-specific and most abundant miRNA in newborn and adult livers, was found by its targetome and pathway reporter analyses to regulate the Hippo pathway, which is crucial for liver size control and homeostasis. Mechanistically, we further demonstrated that miR-122 negatively regulates the outcomes of the Hippo pathway transcription factor TEAD by directly targeting a number of hippo pathway regulators, including the coactivator TAZ and a key factor of the phosphatase complex PPP1CC, which contributes to the dephosphorylation of YAP, another coactivator downstream of the Hippo pathway. This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner. As the Hippo pathway plays important roles in cell proliferation and liver pathological processes like inflammation, fibrosis, and hepatocellular carcinoma (HCC), our study could also provide a new insight into the function of miR-122 in liver pathology.

Pregnancy and weaning regulate human maternal liver size and function

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women’s livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.

PBPK modelling of dexamethasone in patients with COVID-19 and liver disease

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35% - 60%) and the plasma concentrations increased (170% - 400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

Kaposiform hemangioendothelioma/Kasabach–Merritt syndrome. Сlinical and laboratory characteristics. Analysis of clinical cases

Kaposiform hemangioendothelioma (KHE) is a rare, usually congenital vascular tumor. It resembles Kaposi sarcoma histologically, but etiologically it is not associated with herpes simplex virus type 8. KHE refers to tumors of intermediate malignancy degree. The most severe complication is the addition of thrombocytopenia and consumption coagulopathy, i.e. development of the Kasabach–Merritt syndrome/phenomenon (KMS), which determines the high mortality rate (up to 30%) in this histological variant. The frequency of occurrence of KMS is unknown. Over Patients with KHE/KMS have clear clinical and laboratory characteristics, which in most cases allow make to diagnose without histological confirmation. Over 7-year follow-up period 32 patients with KHE were registered in our center; in 90.6% of cases it was complicated by the development of KMS. The study was approved by the Independent Ethics Committee and Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. In the most of patients the tumor was detected from birth (84%), in half of the cases (52%) hematological complications were diagnosed simultaneously with the detection of the tumor. Сommon local complications include joint contractures, destruction of bone tissue, and invasion of neighboring organs. The half of the patients had changes in the heart function: from minor cardiac pathology to congenital defects. In addition, there were clinical and instrumental changes associated with volume overload: an increase in liver size, myocardial hypertrophy. Despite the presence of clear clinical and laboratory characteristics of KMS, some cases require differential diagnosis with other vascular anomalies accompanied by thrombocytopenia and consumption coagulopathy – with congenital hemangiomas (rapidly involuting congenital hemangioma), multifocal lymphangioendotheliomatosis with thrombocytopenia, kaposiform lymphangiomatosis, venous malformations. The parents of the patients agreed to use the information, including photos of children, in scientific research and publications.

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

Estimation of Ghanaian Adult Liver dimensions and body parameters

Despite refinements in surgical techniques for liver transplantation, liver size disparity remains one of the most common problems in patients. The general aim of this study is to estimate the size of liver volume and length of the liver in the midclavicular section and also estimate body parameters such as BMI, BSA, and BSI. The height and weight of patients going for abdominal CT were measured. The BSA, BSI and BMI were then calculated and compared to other measurements. Using MeVisLab software each patient liver volume was measured from their CT images.

Fetal Liver Size, Hepatic Artery Doppler Study in Late Intra Uterine Growth Restriction

Background: Intrauterine growth restriction (IUGR) is a condition in which the fetus does not reach its growth potential. It is well known that a fetus affected with late IUGR has smaller abdominal size. The aim of the study is to evaluate the fetal liver size, fetal hepatic artery blood flow and other fetal vascular Doppler indices in cases of late IUGR. Methods: This observational analytical, cross-sectional study was carried out on 100 pregnant women at or above 32 weeks. Participants were divided into two groups: Group 1 (study group): 50 pregnant women as study group who were affected with IUGR. Group 2 (control group): 50 normally pregnant women as control group. Results: There was no statistically significant correlation between fetal weight and liver length. There was a positive highly statistically significant correlation between symphysial fundal height and the estimated fetal weight by ultrasound in cases of IUGR. There was a statistically significant decrease in the liver size in IUGR compared to the normal group. There was a statistically significant reduced hepatic arterial Doppler indices. Conclusions: Reduced liver size and hepatic arterial Doppler indices (PI, RI) can be valid diagnostic methods in IUGR. SFH, in fetuses suffering from IUGR when compared to normal cases, was correlated with EFW.