Normothermic machine perfusion of explanted livers: Exploratory study of an alternative translational model for end-stage liver disease.

Background: Normothermic machine perfusion (NMP) is a technique for donor liver preservation and assessment in transplantation. NMP has gained momentum recently by enabling safer use of higher risk organs via organ viability assessment. It also offers a platform for investigating ex vivo organ biology.

NOTCH1 drives tumor plasticity and metastasis in hepatocellular carcinoma.

Liver cancer, the third leading cause of cancer-related mortality worldwide, has two main subtypes: hepatocellular carcinoma (HCC), accounting most of the cases, and cholangiocarcinoma (CAA). NOTCH pathway regulates the intrahepatic development of bile ducts, which are lined with cholangiocytes, but it can also be upregulated in 1/3 of HCCs. To better understand the role of NOTCH in HCC, we developed a novel mouse model driven by activated NOTCH1 intracellular domain (NICD1) and MYC overexpression in hepatocytes.

Shwachman-Diamond syndrome mimicking mitochondrial hepatopathy.

Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by multiorgan dysfunction primarily involving the bone marrow and exocrine pancreas. Frequently overlooked is the hepatic dysfunction seen in early childhood which tends to improve by adulthood.

von Meyenburg complexes are more frequently associated with cholangiocarcinoma.

Aim: There is some evidence that von Meyenburg complexes (VMCs) can progress to cholangiocarcinoma (CC). This study aimed to evaluate the prevalence of VMCs in CC cases.

Methods: All hepatic resections and explants with intra-hepatic CC (I-CC) and hilar-CC (H-CC) from 1985 to 2020 were studied.

Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

Background And Aims: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease.

Approach And Results: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022.

Erythrophagocytosis is not a reproducible finding in liver biopsies, and is not associated with clinical diagnosis of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH.

Profiling of mouse and human liver diseases identifies targets for therapeutic treatment of autoimmune hepatitis.

Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and non-alcoholic steatohepatitis (NASH) are chronic liver diseases (CLDs) of distinct etiologies that represent a public health risk with limited therapeutic options. A common feature among CLDs is an aggressive T cell response resulting in destruction of liver tissue and fibrosis. Here, we assessed the presence and nature of T cell inflammation in late-stage human AIH, PSC and NASH and examined whether targeting the T cell response can improve disease pathology in a mouse model (Traf6ΔTEC) of spontaneous AIH.

Systemic Disease and the Liver Part 2: Pregnancy-Related Liver Injury, Sepsis/Critical Illness, Hypoxia, Psoriasis, Scleroderma/Sjogren's Syndrome, Sarcoidosis, Common Variable Immune Deficiency, Cystic Fibrosis, Inflammatory Bowel Disease, and Hematologic Disorders.

The liver is involved in many multisystem diseases and commonly may manifest with abnormal liver chemistry tests. The liver test perturbations may be multifactorial in nature, however, as patients are receiving many different medications and can also have intrinsic liver disease that may be exacerbated by the systemic disorder. Some disorders have typical histologic findings that can be diagnosed on liver biopsy, whereas others will show a more nonspecific histology.

Systemic Disease and the Liver-Part 1: Systemic Lupus Erythematosus, Celiac Disease, Rheumatoid Arthritis, and COVID-19.

The development of liver dysfunction in patients having various systemic diseases is common and has a broad differential diagnosis, at times being the initial manifestation of the disorder. Liver injury associated with systemic lupus erythematosus is heterogeneous and may present with nonspecific histology. Differentiating autoimmune hepatitis from lupus hepatitis is challenging on histologic grounds alone.

Histologic and Clinical Outcomes of Patients Developing Post-Liver Transplant Plasma Cell-Rich Rejection.

Objectives: Plasma cell-rich rejection (PCCR), also known as "plasma cell hepatitis" or "de novo autoimmune hepatitis," is a cause of allograft dysfunction occurring post-liver transplantation (LT). Patients often develop allograft failure and may require repeat LT. PCRR may fall within the spectrum of different histologies associated with antibody-mediated rejection (AMR), which is associated with donor-specific antibodies (DSAs) and positive complement component C4 (C4d) immunostaining.

An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis.

Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH.

Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.

Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis.

Identification and clinical significance of nodular regenerative hyperplasia in primary sclerosing cholangitis.

Background And Aim: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts. PSC is frequently associated with inflammatory bowel disease (IBD). Nodular regenerative hyperplasia (NRH) can occur in IBD with the use or even in the absence of thiopurine treatment.

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation.

Neoadjuvant clinical trials provide a window of opportunity for cancer drug discovery.

Window-of-opportunity trials, during which patients receive short-duration pre-surgical therapies, provide a platform for understanding the therapies’ mechanisms of action, but will require a paradigm shift in trial design, specimen collection and analysis.

Tumor Size, Not Small Vessel Invasion, Predicts Survival in Patients With Hepatocellular Carcinoma.

Objectives: The 8th edition American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) has been criticized for failing to stratify patients. We aimed to reassess and modify the tumor staging criteria for HCC.

Methods: Three independent study cohorts were collected and analyzed.