The Role of Sex in Acute and Chronic Liver Damage Sayaf, Katia; Gabbia, Daniela; Russo, Francesco Paolo ...
International journal of molecular sciences,
09/2022, Volume:
23, Issue:
18
Journal Article
Peer reviewed
Open access
Acute and chronic hepatic damages are caused by xenobiotics or different diseases affecting the liver, characterized by different etiologies and pathological features. It has been demonstrated ...extensively that liver damage progresses differently in men and women, and some chronic liver diseases show a more favorable prognosis in women than in men. This review aims to update the most recent advances in the comprehension of the molecular basis of the sex difference observed in both acute and chronic liver damage. With this purpose, we report experimental studies on animal models and clinical observations investigating both acute liver failure, e.g., drug-induced liver injury (DILI), and chronic liver diseases, e.g., viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), autoimmune liver diseases, and hepatocellular carcinoma (HCC).
Cardiac implantable electronic devices (CIED) are a heterogeneous group of medical devices with increasingly sophisticated diagnostic capabilities, which could be exploited in forensic ...investigations. However, current guidelines are lacking clear recommendations on the topic. The first aim of this systematic review is to provide an updated assessment of the role of postmortem CIED interrogation, and to give practical recommendations, which can be used in daily practice. Secondly, the authors aim to determine the rates of postmortem CIED interrogation and autopsy investigations, the type of final rhythm detected close to death (with a focus on the significance of documented arrhythmias), as well as the role of postmortem CIED interrogation in the determination of final cause/time of death, and any potentially fatal device malfunctions.
A systematic search in MEDLINE and Scopus aiming to identify reports concerning postmortem human CIED interrogation was performed, including a systematic screening of reference lists. Case reports, letters to the editors, commentaries, review articles or guidelines were excluded, along with studies related to cardiac devices other than CIED. All data were pooled and analyzed using fixed-effects meta-analysis models, and the I2 statistic was used to assess heterogeneity.
A total of 25 articles were included in the systematic review, enrolling 3194 decedent CIED carriers. Ten studies (40%) had a 100% autopsy rate, whereas in further 6 studies autopsy findings were variably reported; CIED interrogation was available from 22 studies (88%), and it was never performed prior to autopsy. The overall rate of successful postmortem CIED interrogation was 89%, with high heterogeneity among studies, mainly due to device deactivation/battery discharge. Twenty-four percent of CIED carriers experienced sudden cardiac death (SCD), whereas non-sudden cardiac and non-cardiac death (NSCD, NCD) were reported in 37% and 30% of decedents, respectively. Ventricular tachyarrhythmias were recorded in 34% of overall successfully interrogated CIED, and in 62% of decedents who experienced a SCD; of all ventricular tachyarrhythmias recorded, 40% was found in NSCD or NCD. A clear interpretation of the etiological role of recorded arrhythmias in the causation of death required integration with autopsy findings. Overall, potentially fatal device malfunctions were detected in 12% of cases.
Postmortem CIED interrogation is a valuable tool for the determination of the cause of death, and may complement autopsy. Forensic pathologists need to know the potential utility, pitfalls, and limitations of this diagnostic examination to make this tool as much reliable as possible.
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•Postmortem CIED interrogation could be an important tool in forensic medicine.•It complements autopsy in the determination of the cause, timing, and mode of death.•The interpretation of stored arrhythmias’ role in causing death may be challenging.•CIED analysis may unveil unsuspected, potentially lethal device malfunctions.•A closer cooperation of forensic pathologists and electrophysiologists is needed.
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a ...major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.
It is common knowledge that cancer patients are more prone to develop venous thromboembolic complications (VTE). It is therefore not surprising that patients with hepatocellular carcinoma (HCC) ...present with a significant risk of VTE, with the portal vein being the most frequent site (PVT). However, patients with HCC are peculiar as both cancer and liver cirrhosis are conditions that can perturb the hemostatic balance towards a prothrombotic state. Because HCC-related hypercoagulability is not clarified at all, the aim of the present review is to summarize the currently available knowledge on epidemiology and pathogenesis of non-malignant thrombotic complications in patients with liver cirrhosis and HCC. They are at increased risk to develop both PVT and non-splanchnic VTE, indicating that both local and systemic factors can foster the development of site-specific thrombosis. Recent studies have suggested multiple and often interrelated mechanisms through which HCC can tip the hemostatic balance of liver cirrhosis towards hypercoagulability. Described mechanisms include increased fibrinogen concentration/polymerization, thrombocytosis, and release of tissue factor-expressing extracellular vesicles. Currently, there are no specific guidelines on the use of thromboprophylaxis in this unique population. There is the urgent need of prospective studies assessing which patients have the highest prothrombotic profile and would therefore benefit from early thromboprophylaxis.
The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data ...assessed HCC recurrence risk following DAA administration.
We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.
Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I
=74.6%) and 5.7 (2.5 to 15.3, I
=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).
Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver ...carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the "primum movens" of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.
Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for ...PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT.
We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models.
While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio aHR 0.41; 95% CI 0.28–0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13–0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22–0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49–0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28–3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death.
Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality.
Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We performed the largest international study of transplanted patients with primary biliary cholangitis to date. Preventive administration of ursodeoxycholic acid after liver transplantation was associated with reduced risk of disease recurrence, graft loss, liver-related and all-cause mortality. A regimen combining cyclosporine and preventive ursodeoxycholic acid was associated with the best outcomes.
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•Preventive UDCA after liver transplantation for PBC is associated with a reduced risk of disease recurrence.•This parallels a reduction in the long-term risk of graft loss, liver-related death and all-cause death.•Exposure to cyclosporine rather than to tacrolimus added to the protective effect of UDCA.
Liver transplantation (LT) is the only curative treatment for various liver diseases, including acute liver failure, end-stage liver disease, and selected unresectable liver malignancies. Combination ...antiretroviral therapy has improved outcomes for people living with HIV (PLWH), transforming the status of acquired immune deficiency syndrome from a fatal disease to a chronic and manageable condition. These powerful antiviral therapies have not only increased the number of HIV+ enlisted patients by improving their survival but also made the use of HIV+ organs a viable option. In this review, we summarise current knowledge on the peculiarities of liver transplantation in PLWH. In particular, we focus on the indications, contraindications, specific considerations for treatment, and outcomes of LT in PLWH. Finally, we present available preliminary data on the use of HIV+ liver allografts.
To evaluate waiting list (WL) registration and liver transplantation (LT) rates in patients with hepatitis C virus (HCV)-related cirrhosis since the introduction of direct-acting antivirals (DAAs).
...All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectively-updated database; patients with HCV-related cirrhosis were divided by indication for LT dec-HCV
HCV/ hepatocellular carcinoma (HCC) and into two interval times (2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated.
One thousand one hundred and ninty-four male (M)/female (F): 925/269 patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration (490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction (from 43.3% in 2006-2013 to 37.2% in 2014-2017,
= 0.05), especially amongst dec-HCV (from 24.2% in 2006-2013 to 15.9% in 2014-2017,
= 0.007). Even HCV remained the most common indication to LT over time (289/666, 43.4%), there was a trend towards a decrease after DAAs introduction (from 46.3% in 2006-2013 to 39% in 2014-2017,
= 0.06). HCV patients (M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival (log-rank test
= 0.02) and delisting rate (
= 0.002) than untreated HCV patients.
Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis.
Treatment of hepatitis C (HCV) has been revolutionized with the introduction of direct-acting antivirals (DAAs). Patients can be treated at more advanced stages of liver disease, with a growing ...number of cirrhotic patients achieving sustained virological response (SVR). Long-term outcomes for cured patients and the optimal follow-up care of patients after SVR are yet to be defined, because most studies on cirrhotic patients cured with DAAs have a short follow-up period. There are many open questions related to patient management after viral eradication with DAAs, such as which could be the most reliable non-invasive tool to predict liver-related complications, or to what extent viral eradication reduces the risk of liver disease progression in the long term. Growing evidence supports the personalization of follow-up care based on individual risk. The aim of this narrative review is to analyze the impact of viral eradication with DAAs on clinically significant portal hypertension, hepatocellular carcinoma, and extrahepatic manifestations, as well as to summarize indications for optimal follow-up care of HCV patients treated with DAAs.
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