Abstract
Background
Transjugular intrahepatic portosystemic shunt (TIPS) is a well-validated treatment option for clinically significant portal hypertension (CSPH) in the context of liver cirrhosis. ...Its high efficacy and safety in the management of treatment-refractory ascites and variceal bleeding have been extensively proven. Contraindications for TIPS include severe right heart failure, hepatic encephalopathy, and sepsis. However, the role of liver malignancy in TIPS is debatable. Mostly, primary liver malignancies such as hepatocellular carcinoma (HCC) emerge from advanced liver diseases. Coexisting portal hypertension in HCC often results in limited treatment options and a poor prognosis.
Summary
Previous studies have shown that TIPS implantation in patients with HCC is technically feasible and is usually not associated with major adverse events. Furthermore, TIPS may help in bridging the time to liver transplantation in early HCC and allow for locoregional treatment in advanced HCC. However, several studies suggest that seeding tumour cells to the lungs by TIPS placement might worsen the prognosis.
Conclusions
TIPS placement in patients with coexisting liver malignancy remains a case-by-case decision, and there is no profound evidence allowing general recommendations. This review aims to provide a state-of-the-art overview of the potential risks and benefits of TIPS placement in patients with liver malignancies.
Key points
Nitric oxide (NO) is an important inhibitory neurotransmitter in the gastrointestinal tract. Oesophageal achalasia may result from impairment of nitrergic relaxation.
Smooth muscle cells ...(SMCs) have been accepted to be the major targets for neuronal NO to mediate relaxation. However, besides SMCs, the receptor for NO, NO‐sensitive guanylyl cyclase (NO‐GC), has been shown in interstitial cells of Cajal (ICC).
Using cell‐specific knockout mice, this study shows that NO‐GC in SMC and ICC modulates lower oesophagus sphincter tone in vitro and in vivo.
More importantly, NO‐GC in ICC possesses a dominant role in mediating swallowing‐induced relaxation. Lack of functional nitrergic signalling, thus, results in deficits in relaxation of the lower oesophagus sphincter as seen in achalasic patients.
Oesophageal achalasia is a disease known to result from reduced relaxation of the lower oesophageal sphincter (LES). Nitric oxide (NO) is one of the main inhibitory transmitters. NO‐sensitive guanylyl cyclase (NO‐GC) acts as the key target of NO and, by the generation of cGMP, mediates nitrergic relaxation in the LES. To date, the exact mechanism of nitrergic LES relaxation is still insufficiently elucidated. To clarify the role of NO‐GC in LES relaxation, we used cell‐specific knockout (KO) mouse lines for NO‐GC. These include mice lacking NO‐GC in smooth muscle cells (SMC‐GCKO), in interstitial cells of Cajal (ICC‐GCKO) and in both SMC/ICC (SMC/ICC‐GCKO). We applied oesophageal manometry to study the functionality of LES in vivo. Isometric force studies were performed to monitor LES responsiveness to exogenous NO and electric field stimulation of intrinsic nerves in vitro. Cell‐specific expression/deletion of NO‐GC was monitored by immunohistochemistry. Swallowing‐induced LES relaxation is strongly reduced by deletion of NO‐GC in ICC. Basal LES tone is affected by NO‐GC deletion in either SMC or ICC. Lack of NO‐GC in both cells leads to a complete interruption of NO‐induced relaxation and, therefore, to an achalasia‐like phenotype similar to that seen in global GCKO mice. Our data indicate that regulation of basal LES tone is based on a dual mechanism mediated by NO‐GC in SMC and ICC whereas swallow‐induced LES relaxation is mainly regulated by nitrergic mechanisms in ICC.
Endoscopic therapy of early malignant alterations can be difficult and cumbersome. Our research study group took advantage of new methods for rapid prototyping (i. e. 3D printing) to design and test ...an overtube system with two manipulator arms at the tip. Both arms can be steered independently from each other by a dedicated user platform.
This animal study involved a randomized evaluation of the new overtube device for endoscopic submucosal dissection (ESD) compared with a conventionally performed ESD. In total, 12 ESDs in six pigs were performed. Six ESDs were performed in the stomach and six in the colon. Size (in cm(2)) of resected specimens, the time needed to perform endoscopic resection, and adverse events were assessed.
The overtube-assisted ESD was faster and therefore more effective than the conventional ESD technique (0.45 ± 0.24 cm(2)/min vs. 0.22 ± 0.11 cm(2)/min; P = 0.029). Only one adverse effect was recorded in the conventional group.
The overtube-assisted ESD was feasible in an animal model. ESD can be performed more quickly and potentially more effectively with the newly designed overtube device compared with the conventional ESD technique.
Background. Assessment of hepatic venous pressure gradient (HVPG) is the most reliable, though invasive method for evaluation of portal hypertension. Non-invasive, elastography-based techniques are ...well established in diagnosis, but not in monitoring of portal hypertension. The aim of our prospective study was to determine the value of acoustic radiation force impulse (ARFI) elastography technique of the liver and spleen in diagnosis and monitoring of portal hypertension. Methods. We prospectively assessed portal hypertension by HVPG and corresponding elastography of the liver and spleen in 31 patients with liver cirrhosis and an indication for primary prophylaxis by non-cardio selective beta-blockers. Investigations were performed at baseline and a follow-up visit after 6-8 weeks. To address the known large variability of values for spleen elastography, well-defined corresponding areas in the spleen were used for baseline and follow-up elastography. Sensitivity, specificity, and AUC-ROC values for both spleen and liver elastography monitoring of portal hypertension were calculated. Results. Liver but not spleen elastography significantly correlated with HVPG results and was suitable for initial evaluation of portal hypertension. However, changes in HVPG results did not show any correlation with alterations of ARFI values from baseline to follow-up visits both for liver and spleen elastography. Spleen stiffness results were not homogeneous across the whole organ differing significantly between the upper, hilar, and bottom placed investigation areas. Conclusions. In this prospective study ARFI-based assessment of liver elastography showed itself suitable for initial assessment but not for monitoring of portal hypertension. Spleen elastography was not appropriate for both, evaluation and monitoring of portal hypertension. A possible explanation for this new data that are in some contrast to previously published results is the degree of portal hypertension in our study, a comparatively short follow-up period, and well-defined investigation areas for spleen elastography in repetitive ARFI investigations. This trial is registered with NCT03315767.
Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral ...hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon.
In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D.
Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events.
In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment.
Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.
Display omitted
•114 patients were treated with bulevirtide under real-world conditions, including 50 with signs of significant portal hypertension.•A virologic response was observed in 87/114 patients, with 25 patients achieving HDV-RNA negativity.•ALT levels improved regardless of virologic response status.•In a small subgroup of patients with decompensated liver disease, bulevirtide treatment appeared to be safe.
Heat shock protein (Hsp) 72 is a molecular chaperone which is upregulated in response to a variety of stress situations and has a general cytoprotective function. Increased Hsp72 levels were ...implicated in protection from acute pancreatitis; a hypothesis which was not tested in a transgenic mouse model yet.
To analyze the role of Hsp72 during acute pancreatitis, well-characterized transgenic animals overexpressing rat Hsp72 (Hsp72 mice) under the control of the ß-actin promoter were subjected to caerulein- and L-arginine-induced acute pancreatitis. The severity of experimental pancreatitis was determined via serum lipase levels, morphometric evaluation and quantification of pancreatic edema/inflammation.
Hsp72 mice displayed ∼100-times Hsp72 overexpression, but no changes in the remaining chaperones. Robust Hsp72 signal was observed in pancreatic acini, but not in islets or ductal cells. In both models, elevated Hsp72 did not protect from development of acute pancreatitis and the pancreatitis-associated lung injury, but accelerated recovery from caerulein-induced tissue injury (lower lipase levels, edema, inflammation and necrosis 36 h after caerulein administration). The observed protective function of Hsp72 in caerulein-induced pancreatitis is likely due to an attenuated NF-κB signalling.
Hsp72 overexpression accelerates the recovery from acute pancreatitis and may represent a potential treatment strategy.
Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf‐3 (DKK3) is identified as novel factor for organ regeneration using combined ...transcription‐factor‐induced reprogramming and RNA‐interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three‐germ‐layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3‐null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5+ liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical‐Wnt‐signaling in Dkk3‐null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog‐signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical‐Wnt‐, and Hedgehog‐signaling.
Re‐activation of embryonic pathways is a hallmark of tissue repair after injury. During somatic reprogramming similar molecular patterns are re‐activated, thus providing an excellent platform to identify relevant factors in tissue repair. Here, Dickkopf‐3 (DKK3) is identified as key player of gastrointestinal tissue regeneration and repair via a DKK3‐mediated interplay of canonical Wnt‐ and Hedgehog‐signaling.
Enteric glia cells (EGC) play an important role in the maintenance of intestinal mucosa integrity. During the course of acute Crohn's disease (CD), mucosal EGC progressively undergo apoptosis, though ...the mechanisms are largely unknown. We investigated the role of Glial-derived neurotrophic factor (GDNF) in the regulation of EGC apoptosis.
GDNF expression and EGC apoptosis were determined by immunofluorescence using specimen from CD patients. In primary rat EGC cultures, GDNF receptors were assessed by western blot and indirect immunofluorescence microscopy. Apoptosis in cultured EGC was induced by TNF-α and IFN-γ, and the influence of GDNF on apoptosis was measured upon addition of GDNF or neutralizing anti-GDNF antibody.
Increased GDNF expression and Caspase 3/7 activities were detected in in specimen of CD patients but not in healthy controls. Moreover, inactivation of GDNF sensitized in EGC cell to IFN-γ/TNF-α induced apoptosis.
This study proposes the existence of an autocrine anti-apoptotic loop in EGC cells which is operative in Crohn's disease and dependent of GDNF. Alterations in this novel EGC self-protecting mechanism could lead to a higher susceptibility towards apoptosis and thus contribute to disruption of the mucosal integrity and severity of inflammation in CD.
Background & Aims Lsc/p115 originally was described as hematopoietic Ras homologous protein guanine exchange factor (Rho-GEF) regulating leukocyte migration, adhesion, and marginal zone B-cell ...homeostasis. Here we investigate the expression pattern of lsc/p115 in the gastrointestinal tract and the consequences of lsc/p115 deficiency in lsc/p115-knockout mice. Methods The phenotype of lsc/p115-deficient mice was analyzed in vivo with small-animal computed tomography scans and esophageal manometry. The morphology and myenteric plexus were evaluated with immunohistochemistry, morphometry, Western blot analyses, and quantitative reverse-transcription polymerase chain reaction. Results lsc/p115 is expressed in the gastrointestinal tract, sparing the segment of the small intestine. Immunohistochemical staining detects lsc/p115 in the muscle layer and the glial fibrillary acidic protein–positive glia in the esophagus. Esophageal manometry uncovers a severe motor dysfunction in lsc/p115-deficient mice. This achalasia-like phenotype is characterized by disturbed peristalsis, hypertension of the lower esophageal sphincter, and impaired relaxation of the lower esophageal sphincter. Lsc/p115-deficient mice develop a progressive dilatation of the esophagus and decrease of the muscle layer. The muscle cell differentiation is not altered in lsc/p115-deficient mice. However, the density of inhibitory and excitatory neurons and glia cells in the myenteric plexus and the muscle layer are reduced in morphometric analyses. This reduced number of glia cells is accompanied by reduced expression of the neurotrophic nerve growth factor. Conclusions lsc/p115 deficiency results in impaired neuronal innervation and in motor dysfunction recapitulating several aspects of esophageal achalasia. Reduced expression of nerve growth factor and a reduced number of glia cells most likely contribute to this phenotype.
Hepatitis E virus (HEV) infection is the most common form of viral hepatitis and is reported to cause neurological manifestation in up to 30% of diagnosed infections. We evaluated the medical reports ...of all patients (
n
= 29,994) who were discharged from the Department of Neurology of Ulm University between 01.01.2015 and 30.09.2022 to detect neurological manifestations of HEV
.
In addition, we retrospectively analyzed the serum samples of
n
= 99 patients representing different neurological diseases possibly related to HEV for anti-HEV-IgM and anti-HEV-IgG. At the time of discharge from hospital, the etiology of neurological symptoms in these patients was unclear. Overall, five cases of extrahepatic neurological manifestation of HEV (defined as anti-HEV-IgM and HEV-IgG positive) could be detected. An increase of both, anti-IgM- and anti-IgG-serum levels was significantly more common in neuralgic amyotrophy/plexus neuritis/radiculitis than in AIDP/CIDP (
P
= 0.01), meningitis/encephalitis (
P
= 0.02), idiopathic peripheral facial paralysis (
P
= 0.02) and tension headache (
P
= 0.02). In 15% (
n
= 15 out of 99) of retrospectively analyzed serum samples, conspicuous positive anti-HEV-IgG levels were detected. This finding was most common in AIDP/CIDP. In conclusion, results of this study indicate neurological manifestation of HEV to be a rare but still underestimated course of disease, occurring at any age and gender. Therefore, testing for HEV should be considered in patients with neurological symptoms of unknown origin, especially in those with neuralgic amyotrophy/plexus neuritis.
PDF
