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BACKGROUND: Although most patients with autoimmune hepatitis (AIH) respond to treatment with prednisone and/or azathioprine, some patients are intolerant or refractory to standard therapy. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and has demonstrated efficacy in other autoimmune conditions.

Purpose: Alcohol consumption is a strong risk factor for both cirrhosis and esophageal squamous cell carcinoma (ESCC). Few studies have been conducted on the treatment of ESCC in patients with cirrhosis. This study aimed to analyze the clinical outcomes of ESCC in patients with cirrhosis. Materials and methods: Medical records of patients with esophageal cancer between January 2009 and December 2023 were retrospectively reviewed. A total of 479 patients with ESCC were included and divided into cirrhotic (n = 69) and non-cirrhotic (n = 410) groups. Clinical outcomes and survival according to treatment were compared between these groups. Results: The cirrhotic group was younger (median age 64 years vs. 69 years, p = 0.022) and had a higher proportion of male (97.1 % vs. 88.3 %, p = 0.042) than the non-cirrhotic group. Patients with cirrhosis were less likely to undergo surgery (31.9 % vs. 47.8 %, p = 0.015) and were more likely to receive no active cancer treatment (26.1 % vs. 13.7 %, p = 0.010). Overall survival was lower in the cirrhotic group (hazard ratio [HR], 1.41; 95 % confidence interval [CI], 1.01–1.99; p = 0.045), however, no difference was found between Child-Pugh class A patients and those in the non-cirrhotic group (HR, 1.04 [95 % CI, 0.69–1.56]; p = 0.864). Postoperative mortality was significantly higher in cirrhotic group (27.3 % vs. 8.7 %, p = 0.011). Upon performing concurrent chemoradiotherapy (CRT), the clinical complete response rate (84.2 % vs. 43.3 %, p = 0.004) was better in the cirrhotic group. CRT yielded better overall survival for patients with cancer in the resectable stages in the cirrhotic group compared to surgery (HR, 0.19 [95 % CI, 0.42–0.84]; p = 0.029]. Conclusions: In patient with ESCC and cirrhosis, chemoradiotherapy may be a better treatment option than surgery.

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (

BACKGROUND: Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported.

BACKGROUND: Surveys originating from universities appear to have higher response rates than those from commercial sources. In light of the growing scrutiny placed on physician-industry relations, the present study aimed to determine the impact of the pharmaceutical industry versus university sponsorship on response to a postal survey completed by Canadian hepatitis C virus (HCV) care providers.

Chronic hepatitis B (CHB) is a dynamic disease that may be affected by immune changes in pregnancy. Guidelines suggest consideration of nucleos/tide analogs (NA), i.e., tenofovir, (TDF) in highly viremic mothers to reduce vertical transmission risk. HBV variability affects CHB outcome, but little is known about HBV genetic changes in pregnancy due to immune or NA selection.To evaluate HBV diversity in NA treated or untreated pregnant vs. post-partum CHB carriers.In plasma collected from 21 mothers (7 matching pre/post-partum), HBV serological tests, genotype and viral load were assayed. The HBV pre-surface (S) /S overlapping polymerase (P) (N = 20), pre-core (C) /C (N = 11) and/or full genome PCR amplicons (N = 3) underwent clonal sequence analysis.The median age was 31 y, 71% Asian, 68% genotype B or C, 33% HBV eAg+, 5 received TDF (median HBV DNA 8.5 log IU/ml). In untreated mothers, median antepartum vs. post-partum ALT was 21 vs. 24 U/L and HBV DNA was 2.7 vs. 2.4 log(10) IU/ml. ALT and/or HBV DNA flares occurred during pregnant and/or post-partum period in 47% (10/21). Clonal sequencing antepartum showed the presence of minor "a determinant" and/or vaccine escape mutants (VEM) but drug resistant variants were infrequent. Analysis of pregnant vs. post-partum samples showed different HBV variants and viral diversity.Differences in immune and/or by NA selective pressures during pregnancy may affect HBV evolution during pregnancy. The presence of minor VEM warrant infant follow-up.

Variceal bleeding is a severe complication of cirrhosis leading to significant morbidity and mortality. Treatment of acute variceal bleeding has improved dramatically since the era of the mechanical balloon tamponade. These advances include endoscopic band ligation or sclerotherapy, and vasoactive pharmacological options such as somatostatin, octreotide, vasopressin and terlipressin. Evidence from a multitude of clinical trials and meta-analyses comparing endoscopic and pharmacological treatments suggests near equivalence in efficacy for initial hemostasis, mortality and rate of rebleeding. This raises the question of whether on-call gastroenterologists should be performing emergency endoscopic treatment in the middle of the night or start pharmacological treatment and delay endoscopy until optimal patient and working conditions the next morning. The present review analyzes the available comparative data between endoscopic and pharmacological treatment options. Although the literature cannot yet definitively answer the question posed, the authors suggest that delaying endoscopic treatment until the next morning may be the most reasonable practical approach.

BACKGROUND: Acute esophageal variceal bleeding (EVB) is a major cause of morbidity and mortality in patients with liver cirrhosis. Guidelines have been published in 1997; however, variability in the acute management and prevention of EVB rebleeding may occur.

OBJECTIVE: To survey gastroenterologists in British Columbia and Alberta with regard to awareness of chronic hepatitis C virus (HCV) management and practice patterns among physicians who treat and do not treat HCV-infected patients.

Reactivation of hepatitis B virus (HBV) is a recognized complication of bone marrow transplantation (BMT). Lamivudine is a nucleoside analogue with potent antiviral activity that has been used in the prophylaxis of HBV reactivation in at-risk BMT recipients. Currently, no data exist regarding the safety of nucleoside analogue withdrawal in these patients. A 32-year-old BMT recipient with hepatitis B e antigen (HBeAg)-negative, chronic HBV who developed a serious flare of hepatic inflammation due to a rebound in viral replication within 12 weeks of discontinuing lamivudine therapy is described. The patient remained HBeAg-negative despite high level viremia, suggesting the emergence of a mutant viral strain. The patient's acute hepatitis resolved promptly with the reinstitution of lamivudine therapy. Further studies are necessary to define the safety and efficacy of nucleoside analogues in the prevention of HBV reactivation in at-risk BMT recipients. Clinicians should consider the risk of inducing serious flares of hepatic inflammation due to abrupt nucleoside analogue withdrawal in these patients.

Persistent hyperkinetic circulation after liver transplantation has been described in humans, but similar changes have not been well characterized in the rat model. This study aimed to investigate the hemodynamics of the systemic and splanchnic circulations in both arterialized and nonarterialized hepatic allografts. Orthotopic liver transplantation was performed in four groups of Sprague-Dawley rats. Group A comprised sham-operated rats with hepatic artery ligation that did not receive transplants; group B comprised rats that received transplants without arterialization; group C comprised sham-operated rats with intact hepatic artery that did not receive transplants; and group D comprised rats that received transplants with arterialization. Blood flow measurements were performed three weeks after the surgical procedure, using the radioactive microsphere method. The results showed that rats that received transplants exhibited a significantly higher cardiac index and lower systemic vascular resistance than the control rats. Splanchnic hyperemia was also present with increased mesenteric blood flow. However, there was no difference in hemodynamics between rats that received arterialized transplants and those that received nonarterialized transplants. Arterial collateral vessels from adjacent tissues were observed in the nonarterialized grafts; this was confirmed histologically. It is concluded that rats that undergo orthotopic liver transplantation exhibit hyperdynamic circulation, regardless of the arterial reconstruction procedure, possibly due to extensive collateral formation in the hepatosplanchnic circulation.

The circadian regulatory network is organized in a hierarchical fashion, with a central oscillator in the suprachiasmatic nuclei (SCN) orchestrating circadian oscillations in peripheral tissues. The nature of the relationship between central and peripheral oscillators, however, is poorly understood. We used the tetOFF expression system to specifically restore Clock function in the brains of Clock(Δ19) mice, which have compromised circadian clocks. Rescued mice showed normal locomotor rhythms in constant darkness, with activity period lengths approximating wildtype controls. We used microarray analysis to assess whether brain-specific rescue of circadian rhythmicity was sufficient to restore circadian transcriptional output in the liver. Compared to Clock mutants, Clock-rescue mice showed significantly larger numbers of cycling transcripts with appropriate phase and period lengths, including many components of the core circadian oscillator. This indicates that the SCN oscillator overcomes local circadian defects and signals directly to the molecular clock. Interestingly, the vast majority of core clock genes in liver were responsive to Clock expression in the SCN, suggesting that core clock genes in peripheral tissues are intrinsically sensitive to SCN cues. Nevertheless, most circadian output in the liver was absent or severely low-amplitude in Clock-rescue animals, demonstrating that the majority of peripheral transcriptional rhythms depend on a fully functional local circadian oscillator. We identified several new system-driven rhythmic genes in the liver, including Alas1 and Mfsd2. Finally, we show that 12-hour transcriptional rhythms (i.e., circadian "harmonics") are disrupted by Clock loss-of-function. Brain-specific rescue of Clock converted 12-hour rhythms into 24-hour rhythms, suggesting that signaling via the central circadian oscillator is required to generate one of the two daily peaks of expression. Based on these data, we conclude that 12-hour rhythms are driven by interactions between central and peripheral circadian oscillators.

The correct treatment of portal hypertension associated with myeloproliferative disorders remains uncertain. Splenectomy has been advocated by some to eliminate the forward flow component of the portal hypertension and thus reduce portal pressure. The authors describe three recent cases of myeloproliferative disorder in whom splenectomy failed to achieve any significant amelioration of portal hypertension, with in-depth hemodynamic studies in one patient. Based on these experiences, the authors suggest that splenectomy is not the optimum treatment of the portal hypertension associated with myeloproliferative disorders.

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease worldwide. Famciclovir is a nucleoside analogue with potent antiviral activity that appears promising in the management of patients with HBV infection. No data exist regarding the safety of nucleoside analogue withdrawal in patients treated for HBV cirrhosis. The authors describe a 41-year-old man with compensated HBV cirrhosis who developed fatal hepatic decompensation due to a rebound in viral replication within six weeks of discontinuing famciclovir therapy. Although several mutations in the HBV DNA polymerase gene have been documented, none has been associated with famciclovir resistance or adverse clinical outcomes. Clinicians should consider the risk of inducing serious flares in hepatic inflammation as a result of abrupt nucleoside analogue withdrawal. Until further data are available regarding the safety of withdrawal of these agents, indefinite treatment may be required in patients with established cirrhosis.

The role of the autonomic nervous system in circulatory regulation of the splanchnic organs (stomach, small intestine, colon, liver, pancreas and spleen) is reviewed. In general, the sympathetic nervous system is primarily involved in vasoconstriction, while the parasympathetic contributes to vasodilation. Vasoconstriction in the splanchnic circulation appears to be mediated by alpha-2 receptors and vasodilation by activation of primary afferent nerves with subsequent release of vasodilatory peptides, or by stimulation of beta-adrenergic receptors. As well, an important function of the autonomic nervous system is to provide a mechanism by which splanchnic vascular reserve can be mobilized during stress to maintain overall cardiovascular homeostasis.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.

Summary: Cirrhotic cardiomyopathy (CCM) is defined as systolic or diastolic dysfunction in the absence of prior heart disease or another identifiable cause in patients with cirrhosis, in whom it is an important determinant of outcome. Its underlying pathogenic/pathophysiological mechanisms are rooted in two distinct pathways: 1) factors associated with portal hypertension, hyperdynamic circulation, gut bacterial/endotoxin translocation and the resultant inflammatory phenotype; 2) hepatocellular insufficiency with altered synthesis or metabolism of substances such as proteins, lipids, carbohydrates, bile acids and hormones. Different criteria have been proposed to diagnose CCM; the first in 2005 by the World Congress of Gastroenterology, and more recently in 2019 by the Cirrhotic Cardiomyopathy Consortium. These criteria mainly utilised echocardiographic evaluation, with the latter refining the evaluation of diastolic function and integrating global longitudinal strain into the evaluation of systolic function, an important addition since the haemodynamic changes that occur in advanced cirrhosis may lead to overestimation of systolic function by left ventricular ejection fraction. Advances in cardiac imaging, such as cardiac magnetic resonance imaging and the incorporation of an exercise challenge, may help further refine the diagnosis of CCM. Over recent years, CCM has been shown to contribute to increased mortality and morbidity after major interventions, such as liver transplantation and transjugular intrahepatic portosystemic shunt insertion, and to play a pathophysiologic role in the genesis of hepatorenal syndrome. In this review, we discuss the pathogenesis/pathophysiology of CCM, its clinical implications, and the role of cardiac imaging modalities including MRI. We also compare diagnostic criteria and review the potential diagnostic role of electrocardiographic QT prolongation. At present, no definitive medical therapy exists, but some promising potential treatment strategies for CCM are reviewed.

Acute coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) is rare. The few previously reported cases all describe acute HBV followed by acute HCV, leading to HBV clearance but chronic HCV. This is the first reported case of acute concurrent infection and spontaneous clearance of both HBV and HCV.

The paradox of dilutional hyponatremia, as described by Ovid two millennia ago, continues to apply to patients with advanced cirrhosis today: they have unremitting thirst despite vastly increased total body water. Hyponatremia of less than 130 mmol/L occurs in 30% of cirrhotic patients (1), and is mainly due to the reduced capacity of their kidneys to excrete free water.

Approximately 30% to 70% of patients with cirrhosis have QT interval prolongation. In patients without cirrhosis, QT prolongation is associated with an increased risk of ventricular arrhythmias, such as torsade de pointes (TdP). In cirrhotic patients, there is likely a significant association between the corrected QT (QTc) interval and the severity of liver disease, and possibly with increased mortality. We present a stepwise overview of the pathophysiology and management of acquired long QT syndrome in cirrhosis. The QT interval is mainly determined by ventricular repolarization. To compare the QT interval in time it should be corrected for heart rate (QTc), preferably by the Fridericia method. A QTc interval >450 ms in males and >470 ms in females is considered prolonged. The pathophysiological mechanism remains incompletely understood, but may include metabolic, autonomic or hormonal imbalances, cirrhotic heart failure and/or genetic predisposition. Additional external risk factors for QTc prolongation include medication (IKr blockade and altered cytochrome P450 activity), bradycardia, electrolyte abnormalities, underlying cardiomyopathy and acute illness. In patients with cirrhosis, multiple hits and cardiac-hepatic interactions are often required to sufficiently erode the repolarization reserve before long QT syndrome and TdP can occur. While some risk factors are unavoidable, overall risk can be mitigated by electrocardiogram monitoring and avoiding drug interactions and electrolyte and acidbase disturbances. In cirrhotic patients with prolonged QTc interval, a joint effort by cardiologists and hepatologists may be useful and significantly improve the clinical course and outcome.

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.