Seminars in Liver Disease

The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults...

The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system...

Patients with cirrhosis frequently require admission to the intensive care unit as complications arise in the course of their disease. These admissions are associated with high short- and long-term morbidity and mortality. Thus, understanding and characterizing complications and unique needs of patients with cirrhosis and acute-on-chronic liver failure helps providers identify appropriate level of care and evidence-based treatments. While there is no widely accepted critical care admission criteria for patients with cirrhosis, the presence of organ failure and primary or nosocomial infections are associated with particularly high in-hospital mortality...

Growth hormone (GH) and downstream insulin-like growth factor 1 (IGF1) signaling mediate growth and metabolism. GH deficiency causes short stature or dwarfism, and excess GH causes acromegaly. Although the association of GH/IGF1 signaling with liver diseases has been suggested previously, current studies are controversial and the functional roles of GH/IGF1 signaling are still undefined. GH supplementation therapy showed promising therapeutic effects in some patients, such as non-alcoholic fatty liver disease, but inhibition of GH signaling may be beneficial for other liver diseases, such as hepatocellular carcinoma...

Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria...

Complications of cirrhotic portal hypertension (PHTN) in children are broad and include clinical manifestations ranging from variceal hemorrhage, hepatic encephalopathy (HE), ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS) to less common conditions such as hepatopulmonary syndrome, portopulmonary hypertension, and cirrhotic cardiomyopathy. The approaches to the diagnosis and management of these complications have become standard of practice in adults with cirrhosis with many guidance statements available...

Cases of alcohol-associated liver disease (ALD) are increasing at a steady rate in the United States with more patients presenting with alcohol-associated hepatitis and alcohol-associated cirrhosis. While alcohol use has increased across many demographic groups, women are suffering from a greater increase in alcohol use disorder (AUD), and are at a greater risk of ALD due to pathophysiological differences which include absorption of alcohol, first pass metabolism, and hormonal differences. Differences across race have also been found with Native Americans and Hispanics suffering from some of the largest increases in ALD rates...

The burden for hepatocellular carcinoma (HCC) attributed to nonalcoholic fatty liver disease (NAFLD) continues to grow in parallel with rising global trends in obesity. The risk of HCC is elevated among patients with NAFLD-related cirrhosis to a level that justifies surveillance based on cost-effectiveness argument. The quality of current evidence for HCC surveillance in all patients with chronic liver disease is poor, and even lower in those with NAFLD. For a lack of more precise risk-stratification tools, current approaches to defining a target population in noncirrhotic NAFLD are limited to noninvasive tests for liver fibrosis, as a proxy for liver-related morbidity and mortality...

Biliary epithelium (i.e., cholangiocytes) is a heterogeneous population of epithelial cells in the liver, which line small and large bile ducts and have individual responses and functions dependent on size and location in the biliary tract. We discuss the recent findings showing that the intrahepatic biliary tree is heterogeneous regarding (1) morphology and function, (2) hormone expression and signaling (3), response to injury, and (4) roles in liver regeneration. This review overviews the significant characteristics and differences of the small and large cholangiocytes...

Viral hepatitis is a leading cause of liver morbidity and mortality globally. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. In vitro models of viral hepatitis circumvent the high costs and ethical considerations of animal models, which also translate poorly to studying the human-specific hepatitis viruses. However, significant challenges are associated with modeling long-term infection in vitro. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection, but standard two-dimensional (2D) models are limited because they fail to mimic the architecture and cellular microenvironment of the liver, and cannot maintain a differentiated hepatocyte phenotype over extended periods...

Diet could be both culprit and solution of NAFLD. Dietary modifications have been associated with histological features improvement in NAFLD. The Western diet was related to a greater risk of disease progression while the Mediterranean diet (MD) could promote regression of histological lesions. Modifications in the nutrient composition seems to have lesser impact on NAFLD than dietary modifications. An intrinsic interaction between nutrients in the diet support a specific effect not seen when added separately...

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases are both highly prevalent conditions around the world, and emerging data have shown an association between them. This review found several longitudinal and cross-sectional studies showing that NAFLD was associated with coronary artery disease, cardiac remodeling, aortic valve remodeling, mitral annulus valve calcifications, diabetic cardiomyopathy, diastolic cardiac dysfunction, arrhythmias, and stroke. Although the specific underlying mechanisms are not clear, many hypotheses have been suggested, including that metabolic syndrome might act as an upstream metabolic defect, leading to end-organ manifestations in both the heart and liver...

Early palliative and supportive care referral is the standard of care for many malignancies. This paradigm results in improvements in patients' symptoms and quality of life and decreases the costs of medical care and unnecessary procedures. Leading oncology guidelines have recommended the integration of early referral to palliative and supportive services to care pathways for advanced malignancies. Currently, early referral to palliative care within the hepatocellular carcinoma (HCC) population is not utilized, with gastroenterology guidelines recommending referral of patients with Barcelona Clinic Liver Cancer stage D to these services...

Acute kidney injury (AKI) is a frequent complication in patients with cirrhosis that is associated with poor outcomes and decreased survival. The definition of AKI in cirrhosis is currently based on changes of serum creatinine levels with respect to baseline values. Differential diagnosis of the causes of AKI is of major relevance, considering that some causes of AKI, such as hepatorenal syndrome, have specific treatment options and different prognosis. Prediction of kidney function recovery and patients' survival is also crucial in this patient population to guide clinical decisions...

Obesity is strongly associated with nonalcoholic fatty liver disease as well as advanced forms of the disease such as nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. While lifestyle and diet modifications have been the cornerstone of treatment for NASH thus far, they are only effective for less than half of the patients. New endoscopic bariatric therapies (EBTs) have already proved to be safe and effective for the treatment of obesity and type 2 diabetes mellitus, and may provide an intermediate, less invasive, cost-effective option for patients with NASH...

Liver cancer, mainly hepatocellular carcinoma (HCC), remains a major cause of cancer-related death worldwide. With the global epidemic of obesity, the major HCC etiologies have been dynamically shifting from viral to metabolic liver diseases. This change has made HCC prevention difficult with increasingly elusive at-risk populations as rational target for preventive interventions. Besides ongoing efforts to reduce obesity and metabolic disorders, chemoprevention in patients who already have metabolic liver diseases may have a significant impact on the poor HCC prognosis...

Despite the rising prevalence of nonalcoholic fatty liver disease (NAFLD), the underlying disease pathophysiology remains unclear. There is a great need for an efficient and reliable "human" in vitro model to study NAFLD and the progression to nonalcoholic steatohepatitis (NASH), which will soon become the leading indication for liver transplantation. Here, we review the recent developments in the use of three-dimensional (3D) liver organoids as a model to study NAFLD and NASH pathophysiology and possible treatments...

Although the underlying cause may vary across countries and demographic groups, liver disease is a major cause of morbidity and mortality globally. Orthotopic liver transplantation is the only definitive treatment for liver failure but is limited by the lack of donor livers. The development of drugs that prevent the progression of liver disease and the generation of alternative liver constructs for transplantation could help alleviate the burden of liver disease. Bioengineered livers containing human induced pluripotent stem cell (iPSC)-derived liver cells are being utilized to study liver disease and to identify and test potential therapeutics...

The burden of nonalcoholic fatty liver disease (NAFLD) is rising globally. Cardiovascular disease is the leading cause of death in patients with NAFLD. Nearly half of individuals with NAFLD have coronary heart disease, and more than a third have carotid artery atherosclerosis. Individuals with NAFLD are at a substantially higher risk of fatal and nonfatal cardiovascular events. NAFLD and cardiovascular disease share multiple common disease mechanisms, such as systemic inflammation, insulin resistance, genetic risk variants, and gut microbial dysbiosis...

The excessive accumulation of extracellular matrix proteins results in fibrosis-a condition implicated in several diseased conditions, such as non-alcoholic steatohepatitis, viral hepatitis, and autoimmune hepatitis. Despite its prevalence, direct and effective treatments for fibrosis are lacking, warranting the development of better therapeutic strategies. Accumulating evidence has shown that liver fibrosis-a condition previously considered irreversible-is reversible in specific conditions. Immune cells residing in or infiltrating the liver, e...