Challenges in COVID-19 drug treatment in patients with advanced liver diseases:A hepatology perspective

The global incidence of coronavirus disease 2019(COVID-19)continues to increase despite health care efforts.The disease is caused by coronavirus 2 with high transmission and mortality rates.Little is known about the management of COVID-19 in advanced liver disease.The aim of work was to propose a plan for management of this drastic disease in case of this specific population with review of medications that could be suitable for advanced liver disease.All the guidelines and medications available for treatment of COVID-19 were reviewed with selection of the less toxic medications that could be used in advanced liver disease.Drugs suitable to manage COVID-19 in patients with liver disease might include remdesivir intravenously,nitazoxanide+sofosbuvir,ivermectin,tocilizumab,convalescent plasma,and low molecular weight heparin in certain situations.Advanced liver disease is associated with portal hypertension and splenomegaly with reduction of blood elements and immune dysfunction and impaired T cell function.Thus,when confronted by cytokine storm as an immune response to COVID-19,there may be an increase in the mortality rate of these patients.Through this review,a plan to treat COVID-19 in this special group of patients with advanced cirrhosis is proposed.

Liver cell cancer surveillance practice in Nigeria:Pitfalls and future prospects

Hepatocellular carcinoma(HCC)is a disease of public health concern in Nigeria,with chronic hepatitis B and C infections contributing most to the disease burden.Despite the increasing incidence of HCC,surveillance practices for early diagnosis and possible cure are not deeply rooted in the country.This article aims to review the current status of HCC surveillance in Nigeria,stressing the encounters,breaches,and potential prospects.Several factors,such as limited tools for screening and diagnostics,insufficient infrastructure,and low cognizance among the doctors,and the general public affect the surveillance practices for HCC in Nigeria.Moreover,the lack of standardized guidelines and protocols for HCC surveillance further intensifies the suboptimal diagnosis and treatment.Nevertheless,there are opportunities for refining surveillance practices in the country.This would be achieved through boosted public health sensitization campaigns,integrating HCC screening into routine clinical services,and leveraging technological developments for early detection and monitoring.Furthermore,collaboration between government agencies,healthcare providers,and international organizations can facilitate the development of comprehensive HCC surveillance programs person-alized to the Nigerian setting.Thus,HCC surveillance practice faces substantial challenges.By addressing the drawbacks and leveraging prospects,Nigeria can improve HCC surveillance,with subsequent improved outcomes for individuals at risk of developing the disease.

Rectal neuroendocrine tumors:Current advances in management,treatment,and surveillance

Rectal neuroendocrine neoplasms(r-NENs)are considered among the most frequent digestive NENs,together with small bowel NENs.Their incidence has increased over the past few years,and this is probably due to the widespread use of endoscopic screening for colorectal cancer and the advanced endoscopic procedures available nowadays.According to the current European Neuroendocrine Tumor Society(ENETS)guidelines,well-differentiated r-NENs smaller than 10 mm should be endoscopically removed in view of their low risk of local and distant invasion.R-NENs larger than 20 mm are candidates for surgical resection because of their high risk of distant spreading and the involvement of the muscularis propria.There is an area of uncertainty regarding tumors between 10 and 20 mm,in which the metastatic risk is intermediate and the endoscopic treatment can be challenging.Once removed,the indications for surveillance are scarce and poorly codified by international guidelines,therefore in this paper,a possible algorithm is proposed.

Noninvasive scores for the prediction of esophageal varices and risk stratification in patients with cirrhosis

The primary purpose of variceal screening in patients with cirrhosis is to detect gastroesophageal varices at high risk of hemorrhage and implement preventative intervention(s).It was previously recommended that all patients with cirrhosis undergo initial and periodic longitudinal variceal screening via upper endoscopy.However,there has been growing interest and methods to identify patients with cirrhosis who may not have clinically significant portal hypertension and therefore be unlikely to have varices requiring intervention or benefit from upper endoscopy.Because the population of patients with compensated advanced chronic liver disease continues to grow,it is neither beneficial nor cost-effective to perform endoscopic variceal screening in all patients.Therefore,there is ongoing research into the development of methods to non-invasively risk stratify patients with cirrhosis for the presence of high-risk esophageal varices and effectively limit the population that undergoes endoscopic variceal screening.This is particularly important and timely in light of increasing healthcare reform and barriers to healthcare.In this review,we discuss and compare,with respect to test characteristics and clinical applicability,the available methods used to noninvasively predict the presence of esophageal varices.

Compensated liver cirrhosis:Natural course and disease-modifying strategies

Compensated liver cirrhosis(CLC)is defined as cirrhosis with one or more decompensating events,such as ascites,variceal haemorrhage,or hepatic encephalopathy.Patients with CLC are largely asymptomatic with preserved hepatic function.The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors.The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis,as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years.Furthermore,early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition.With the advent of effective non-invasive tools for detecting hepatic fibrosis,more and more patients with CLC are currently being recognised.This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or,at the very least,prevent its progression.There are numerous emerging approaches for preventing or delaying decompensation in CLC patients.A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression,and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension.Additionally,address-ing various cofactors(such as obesity,diabetes,dyslipidaemia,and alcoholism)and precipitating factors(such as infection,viral hepatitis,and hepatotoxic drugs)that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC.However,high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these diseasemodifying techniques for CLC patients.This article discussed the natural history of CLC,risk factors for its progression,and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.

Role of taxanes in pancreatic cancer

Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.

Factors influencing the failure of interferon-free therapy for chronic hepatitis C:Data from the Polish EpiTer-2 cohort study

BACKGROUND The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C,making it highly effective and safe for patients.However,few researchers have analyzed the factors causing therapy failure in some patients.AIM To analyze factors influencing the failure of direct antiviral drugs in the large,multicenter EpiTer-2 cohort in a real-world setting.METHODS The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020.Data collected from the online EpiTer-2 database included the following:hepatitis C virus(HCV)genotype,stage of fibrosis,hematology and liver function parameters,Child-Turcotte-Pugh and Model for End-stage Liver Disease scores,prior antiviral therapy,concomitant diseases,and drugs used in relation to hepatitis B virus(HBV)and/or human immunodeficiency virus(HIV)coinfections.Adverse events observed during the treatment and follow-up period were reported.Both standard and machine learning methods were used for statistical analysis.RESULTS During analysis,12614 patients with chronic hepatitis C were registered,of which 11938(mean age:52 years)had available sustained virologic response(SVR)data[11629(97%)achieved SVR and 309(3%)did not].Most patients(78.1%)were infected with HCV genotype 1b.Liver cirrhosis was diagnosed in 2974 patients,while advanced fibrosis(F3)was diagnosed in 1717 patients.We included patients with features of hepatic failure at baseline[ascites in 142(1.2%)and encephalopathy in 68(0.6%)patients].The most important host factors negatively influencing treatment efficacy were liver cirrhosis,clinical and laboratory features of liver failure,history of hepatocellular carcinoma,and higher body mass index.Among viral factors,genotype 3 and viral load also exerted an influence on treatment efficacy.Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex,which was not confirmed by the multivariate analysis using the machine learning algorithm(random forest).Coinfection with HBV(including patients with on-treatment reactivation of HBV infection)or HIV,extrahepatic manifestations,and renal failure did not significantly affect the treatment efficacy.CONCLUSION In patients with advanced liver disease,individualized therapy(testing for resistance-associated variants and response-guided treatment)should be considered to maximize the chance of achieving SVR.

Pulmonary complications of portal hypertension:The overlooked decompensation

The systemic nature of cirrhosis and portal hypertension has long been recognized,and the amount of data characterizing the interplay between each system is becoming ever so complex.Lung involvement was among the first described associated entities in cirrhosis,with reports dating back to the late nineteenth century.However,it appears that throughout the years,interest in the pulmonary complications of portal hypertension has generally faded,especially in contrast to other decompensating events,as expertise in this field has primarily been concentrated in highly experienced tertiary care facilities and liver transplantation centers.Despite affecting up to 10%-15%of patients with advanced liver disease and having a proven prognostic impact,hepato-pulmonary syndrome,porto-pulmonary hypertension,and hepatic hydrothorax are frequently misdiagnosed,mistreated,or misinterpreted.This lack of precision might adversely impact patient care,referral to expert centers,and,ultimately,liver disease-related mortality and successful transplantation odds.The present minireview aims to increase awareness of the pulmonary complications of chronic liver disease by providing a brief overview of each of the three entities.The paper focuses on the essential theoretical aspects,addressing the most critical knowledge gaps on the one hand and,on the other hand,critically discussing one key issue for each complication.

Advanced Chronic Obstructive Pulmonary Disease： Innovative and Integrated Management Approaches

Chronic obstructive pulmonary disease （COPD） is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. By the year 2020, COPD will be the third leading cause of mortality and the fifth leading cause of disability worldwide, In a population based study conducted at multiple international sites, approximately 10% of participants 40 years of age or older were found to have airflow obstruction of at least moderate severity according to spirometric criteria. In China, the overall prevalence of COPD in individuals 40 years of age or older was 8.2%.m COPD is a slowly progressive respiratory disease, which, although preventable and treatable, is not curable. The final years for patients with advanced COPD are characterized by progressive functional decline, frequent exacerbations, poor quality of life, increasing dependency on informal caregivers and on the health care system. According to the literature, 5-year survival from diagnosis is estimated to be 78% in men and 72% in women with mild disease, but only 30% in men and 24% in women with advanced COPD.

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

Neuroendocrine tumors(NETs)represent a spectrum of rare neoplasms arising in different organism sites.Depending on the site of onset,they also can be distinguished using lab exams(secreting vs.nonsecreting),clinical symptoms(functioning vs.nonfunctioning),behavioral,morphological characteristics(tumor cells’architectural growth patterns,mitotic and Ki-67 index,presence of necrosis),and grade of cellular differentiation.The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic(GEP)and bronchopulmonary(BP)neuroendocrine neoplasms.The scientific literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases,selecting principal and more recent research articles,clinical trials,and updated guidelines.Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs.The pathogenesis of NETs has been the subject of increased interest in recent years.Many driver mutations pathway genes have been identified as important factors in the carcinogenesis process and,therefore,as potential targets for new anticancer therapies.Activating mutations have been shown in epidermal growth factor receptor,stem cell factor receptor,platelet-derived growth factor receptor,vascular endothelial growth factor,basic-fibroblastic growth factor,transforming growth factor,insulin-like growth factor-1,and their receptors.Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this field such as everolimus.New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials.

PRELIMINARY RESULTS OF VALIDATION OF A NEW PATIENT-REPORTED OUTCOME INSTRUMENT FOR ADVANCED CHRONIC KIDNEY DISEASE

The uremic symptoms of advanced chronic kidney disease(CKD)can severely impair physical function,psychological health and social life.Some patients,especially for the older,chose conservative kidney management(CKM)and Traditional Chinese medicine(TCM)but not dialysis in this stage.To measure the patients-reported outcome(PRO)from these people,Advanced Chronic Kidney

Noncontrast-enhanced MRI-based Noninvasive Score for Portal Hypertension(CHESS1802):An International Multicenter Study

Background and Aims:This study aimed to determine the performance of the non-invasive score using noncontrastenhanced MRI(CHESS-DIS score)for detecting portal hy-pertension in cirrhosis.Methods:In this international multicenter,diagnostic study(ClinicalTrials.gov,NCT03766880),patients with cirrhosis who had hepatic venous pressure gradient(HVPG)measurement and noncontrast-enhanced MRI were prospectively recruited from four university hospitals in China(n=4)and Turkey(n=1)between December 2018 and April 2019.A cohort of patients was retrospectively recruited from a university hospital in Italy between March 2015 and November 2017.After segmentation of the liver on fat-suppressed T1-weighted MRI maps,CHESS-DIS score was calculated automatically by an in-house developed code based on the quantification of liver surface nodularity.Results:A total of 149 patients were included,of which 124 were from four Chinese hospitals(training cohort)and 25 were from two international hospitals(validation cohort).A positive correlation between CHESS-DIS score and HVPG was found with the correlation coefficients of 0.36(p<0.0001)and 0.55(p<0.01)for the training and validation cohorts,respectively.The area under the receiver operating characteristic curve of CHESS-DIS score in detection of clinically significant portal hypertension(CSPH)was 0.81 and 0.9 in the training and validation cohorts,respectively.The intra-class correlation coefficients for assessing the inter-and intra-observer agreement were 0.846 and 0.841,respectively.Conclusions:A non-invasive score using noncontrast-enhanced MRI was developed and proved to be significantly correlated with invasive HVPG.Besides,this score could be used to detect CSPH in patients with cirrhosis.

Diagnosis of cirrhosis and portal hypertension:imaging,non-invasive markers of fibrosis and liver biopsy

The concept of‘cirrhosis’is evolving and it is now clear that compensated and decompensated cirrhosis are completely different in terms of prognosis.Furthermore,the term‘advanced chronic liver disease(ACLD)’better reflects the continuum of histological changes occurring in the liver,which continue to progress even after cirrhosis has developed,and might regress after removing the etiological factor causing the liver disease.In compensated ACLD,portal hypertension marks the progression to a stage with higher risk of clinical complication and requires an appropriate evaluation and treatment.Invasive tests to diagnose cirrhosis(liver biopsy)and portal hypertension(hepatic venous pressure gradient measurement and endoscopy)remain of crucial importance in several difficult clinical scenarios,but their need can be reduced by using different non-invasive tests in standard cases.Among non-invasive tests,the accepted use,major limitations and major benefits of serum markers of fibrosis,elastography and imaging methods are summarized in the present review.