Introduction: Standardization of diagnostic criteria of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) variant syndrome (AIH-PBC VS) has not been achieved so far and evidence-based ...recommendations for monitoring and treatment of the disease are still lacking. Our study aimed to assess the prevalence, biochemical, and serological features, as well as the clinical course, of VS. Methods: We performed a retrospective study including all patients with VS between 1999 and 2020 in four German centers. Data on demographic parameters, biochemical and serological tests, treatment, and outcome were collected. Results: Of 90 patients (3.1%) meeting Paris criteria for VS diagnosis, 65.6% showed AIH and PBC histological features, while biochemical Paris criteria were observed comparatively rarely. Further antibodies, which were not part of the diagnostic criteria of VS, were found in a subgroup of patients with available data (ACA: 30.0%; anti-CENP-A: 25.0%; anti-CENP-B: 33.3%; anti-SP100: 21.4%). Biochemical response was more frequently observed in patients treated with a combined therapy of ursodeoxycholic acid (UDCA) and immunosuppression (IS). Liver cirrhosis was detected in 31 patients (34.4%) and 25 patients (27.8%) developed clinical manifestations of portal hypertension. Conclusions: Biochemical Paris criteria of VS were rarely detected, thus implying that these cut-off values should be redefined. Regarding pharmacological treatment, combined therapy of UDCA and IS appeared to be more effective than monotherapy with UDCA.
Increasing evidence reveals a close and reciprocal link between acute-on-chronic liver failure (ACLF) and immunodysfunction.
A literature search in PubMed and abstract databases of relevant ...congresses was performed.
Important characteristics of liver cirrhosis like tissue hypoxia, cell death, or bacterial translocation maintain a state of chronic inflammation. Precipitating events of ACLF such as infections or alcoholic hepatitis are capable of strongly augmenting cirrhosis-associated systemic inflammation to grades sufficient to induce ACLF-defining organ failures. Chronic systemic inflammation, however, is causally linked to profound immunosuppression. As a consequence, patients with liver cirrhosis and in particular with ACLF are at high risk for severe infections. Promising strategies to ameliorate immunodysfunction, like albumin substitution, administration of recombinant interleukin-22 or granulocyte colony-stimulating factor, antibiotic prophylaxis, or anticoagulation, are under development and offer the chance to specifically prevent and treat ACLF.
A better understanding of the immunopathology of ACLF will likely translate into the implementation of specific therapeutic modalities to prevent and overcome ACLF.
Objective
Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. ...thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis.
Design
Human liver tissue was obtained from explanted livers following transplantation. TRα‐deficient (TRα‐KO) and wild‐type (WT) mice were fed a control or a profibrogenic methionine‐choline deficient (MCD) diet. Liver tissue was assessed by qRT‐PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor‐specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT‐PCR.
Results
TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ‐induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα‐KO enhanced MCD diet‐induced liver fibrogenesis.
Conclusion
These observations indicate that TH action in non‐parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH–TR axis may be a valuable target for future therapy of liver fibrosis.
The proper management of patients being treated with platelet aggregation inhibitors or anticoagulant drugs is a common clinical problem for both elective and emergency procedures in gastroenterology ...and visceral surgery. The essential matters that must be kept in mind in this situation are the hemorrhagic risk of the procedure, the indication for anticoagulation, and the pharmacology of anticoagulant drugs and platelet aggregation inhibitors.
This review is based on publications retrieved by a selective search in PubMed and on the guidelines of the relevant specialist societies.
Nearly all procedures in gastroenterology and visceral surgery can be performed under monotherapy with acetyl - salicylic acid. Other platelet aggregation inhibitors, such as clopidogrel or prasugrel, or anticoagulant drugs generally do not need to paused before diagnostic endoscopic procedures with a low risk of bleeding (<1.5%), but they must be paused before procedures in gastroenterology and visceral surgery where the risk of bleeding is high (≥ 1.5%). Bridging with heparin is reserved for patients with a very high risk of thromboembolism ( ≥ 5%).
Knowledge of the current recommendations on the management of anticoagulants before gastroenterological and visceral surgical procedures gives the clinician a well-founded means of dealing with this complex and common clinical situation.
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. A growing number of local and systemic therapies are available, and ...accurate staging is critical for management decisions. We assessed the impact of neovasculature imaging by
Ga-PSMA-11 PET/CT on disease staging, prognostic groups, and management of patients with HCC compared with staging with CT.
Forty patients who received imaging with
Ga-PSMA-11 PET/CT for HCC staging between September 2018 and September 2019 were retrospectively included. Management before and after PET scanning was assessed by standardized surveys. The presence of HCC was evaluated by 3 masked readers on a per-patient and per-region basis for PET/CT (PET criteria) and multiphase contrast-enhanced CT (CT criteria) in separate sessions. Lesions were validated by follow-up imaging or histopathology, and progression-free survival was recorded. Endpoints were detection rate and positive predictive value for
Ga-PSMA-11 PET versus CT, interreader reproducibility, and changes in stage, prognostic groups, and management plans.
Median age was 65 y (range, 37-81 y), and median Child-Pugh score was 5 (range, 5-9). Most patients were treatment-naïve (27/40, 67.5%). The sensitivity of PET versus CT to identify liver lesions for patients with lesion validation was 31 of 32 (97%) for both modalities, whereas it was 6 of 6 (100%) versus 4 of 6 (67%), respectively, for extrahepatic lesions. PET and CT each had a positive predictive value of 100% at the liver level. PET versus CT stage was congruent in 30 of 40 (75%) patients; upstaging was seen in 8 of 40 patients (20%), whereas 2 of 40 (5%) had downstaging by PET. Intended management changed in 19 of 40 patients (47.5%); 9 of 19 of these patients were found to have detectable distant metastases (47.4%) and assigned stage 4 disease, most of whom were shifted to systemic therapy (8/9, 89%). Two patients underwent
Lu-PSMA-617 radioligand therapy. Median progression-free survival was 5.2 mo for the entire cohort; 5.3 mo for PET M0, and 4.7 mo for PET M1 patients, respectively.
Ga-PSMA-11 PET demonstrated higher accuracy than CT in the detection of HCC metastases and was associated with a management change in about half the patient cohort.
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. A growing number of local and systemic therapies are available, and ...accurate staging is critical for management decisions. We assessed the impact of neovasculature imaging by 68Ga-PSMA-11 PET/CT on disease staging, prognostic groups, and management of patients with HCC compared with staging with CT. Methods: Forty patients who received imaging with 68Ga-PSMA-11 PET/CT for HCC staging between September 2018 and September 2019 were retrospectively included. Management before and after PET scanning was assessed by standardized surveys. The presence of HCC was evaluated by 3 masked readers on a per-patient and per-region basis for PET/CT (PET criteria) and multiphase contrast-enhanced CT (CT criteria) in separate sessions. Lesions were validated by follow-up imaging or histopathology, and progression-free survival was recorded. Endpoints were detection rate and positive predictive value for 68Ga-PSMA-11 PET versus CT, interreader reproducibility, and changes in stage, prognostic groups, and management plans. Results: Median age was 65 y (range, 37–81 y), and median Child–Pugh score was 5 (range, 5–9). Most patients were treatment-naïve (27/40, 67.5%). The sensitivity of PET versus CT to identify liver lesions for patients with lesion validation was 31 of 32 (97%) for both modalities, whereas it was 6 of 6 (100%) versus 4 of 6 (67%), respectively, for extrahepatic lesions. PET and CT each had a positive predictive value of 100% at the liver level. PET versus CT stage was congruent in 30 of 40 (75%) patients; upstaging was seen in 8 of 40 patients (20%), whereas 2 of 40 (5%) had downstaging by PET. Intended management changed in 19 of 40 patients (47.5%); 9 of 19 of these patients were found to have detectable distant metastases (47.4%) and assigned stage 4 disease, most of whom were shifted to systemic therapy (8/9, 89%). Two patients underwent 177Lu-PSMA-617 radioligand therapy. Median progression-free survival was 5.2 mo for the entire cohort; 5.3 mo for PET M0, and 4.7 mo for PET M1 patients, respectively. Conclusion: 68Ga-PSMA-11 PET demonstrated higher accuracy than CT in the detection of HCC metastases and was associated with a management change in about half the patient cohort.
Direct acting antivirals (DAA) have revolutionized the treatment of hepatitis C virus (HCV). Sustained virological response rates of nearly 100% have become common in the general population. However, ...physicians face the growing problem of managing HCV in patients with the complications of cirrhosis, eg hepatic decompensation or hepatocellular carcinoma (HCC). Safety and efficacy remain a clinical challenge in these difficult‐to‐treat patients. This review focuses on the current state of knowledge and treatment regimens in patients with decompensated cirrhosis as well as the potential risk of the development of HCC following DAA therapy.
As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent ...injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design.
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Abstract
OBJECTIVES
Severe mitral regurgitation (MR) and tricuspid regurgitation (TR) aggravate haemodynamic stress leading to congestive heart failure with impaired hepatic function, also known as ...cardiohepatic syndrome (CHS). Current perioperative risk calculators do not sufficiently consider CHS and serum liver function parameters lack sensitivity to diagnose CHS. Indocyanine green and its elimination (measured by the LIMON® test) represent a dynamic and non-invasive test which correlates with the hepatic function. Nevertheless, its utility in the setting of transcatheter valve repair/replacement (TVR) to predict CHS and outcome remains unknown.
METHODS
We analysed liver function and outcomes of patients undergoing TVR for MR or TR between August 2020 and May 2021 at the Munich University Hospital.
RESULTS
Out of a total of 44 patients treated at the University Hospital of Munich, 21 (48%) were treated for severe MR, 20 (46%) for severe TR and 3 (7%) for both diseases. Procedural success defined as MR/TR ≤2+ was 94% among MR patients and 92% among TR patients. While classical serum liver function parameters did not change after TVR, there was a significant improvement in liver function as assessed by the LIMON® test (P ≤ 0.001). Patients with baseline indocyanine green plasma disappearance rate <12.95%/min showed significantly increased 1-year mortality (hazard ratio: 1.54, 95% confidence interval: 1.05–2.25, P = 0.027) and lower New York Hear Association class improvement (P = 0.05).
CONCLUSIONS
Especially in the context of the recently stressed importance of a careful patient selection prior to the interdisciplinary treatment of valvular heart disease, the LIMON® test may provide further real-time information on the patients’ cardiohepatic injury and prognosis.
For cardiac surgeons and cardiologists, transcatheter technologies have evolved to a core element for the treatment of atrio-ventricular valvular heart disease, especially in patients with increased surgical risk 1–4.
The hepatitis C virus (HCV) NS3‐4A protease is not only an essential component of the viral replication complex and a prime target for antiviral intervention but also a key player in the persistence ...and pathogenesis of HCV. It cleaves and thereby inactivates two crucial adaptor proteins in viral RNA sensing and innate immunity, mitochondrial antiviral signaling protein (MAVS) and TRIF, a phosphatase involved in growth factor signaling, T‐cell protein tyrosine phosphatase (TC‐PTP), and the E3 ubiquitin ligase component UV‐damaged DNA‐binding protein 1 (DDB1). Here we explored quantitative proteomics to identify novel cellular substrates of the NS3‐4A protease. Cell lines inducibly expressing the NS3‐4A protease were analyzed by stable isotopic labeling using amino acids in cell culture (SILAC) coupled with protein separation and mass spectrometry. This approach identified the membrane‐associated peroxidase GPx8 as a bona fide cellular substrate of the HCV NS3‐4A protease. Cleavage by NS3‐4A occurs at Cys 11, removing the cytosolic tip of GPx8, and was observed in different experimental systems as well as in liver biopsies from patients with chronic HCV. Overexpression and RNA silencing studies revealed that GPx8 is involved in viral particle production but not in HCV entry or RNA replication. Conclusion: We provide proof‐of‐concept for the use of quantitative proteomics to identify cellular substrates of a viral protease and describe GPx8 as a novel proviral host factor targeted by the HCV NS3‐4A protease. (Hepatology 2014;59:423–433)
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