Comprehensive approach to esophageal variceal bleeding:From prevention to treatment

Esophageal variceal bleeding is a severe complication often associated with portal hypertension,commonly due to liver cirrhosis.Prevention and treatment of this condition are critical for patient outcomes.Preventive strategies focus on reducing portal hypertension to prevent varices from developing or enlarging.Primary prophylaxis involves the use of non-selective beta-blockers,such as propranolol or nadolol,which lower portal pressure by decreasing cardiac output and thereby reducing blood flow to the varices.Endoscopic variceal ligation(EVL)may also be employed as primary prophylaxis to prevent initial bleeding episodes.Once bleeding occurs,immediate treatment is essential.Initial management includes hemodynamic stabilization followed by pharmacological therapy with vasoactive drugs such as octreotide or terlipressin to control bleeding.Endoscopic intervention is the cornerstone of treatment,with techniques such as EVL or sclerotherapy applied to directly manage the bleeding varices.In cases where bleeding is refractory to endoscopic treatment,transjugular intrahepatic portosystemic shunt may be considered to effectively reduce portal pressure.Long-term management after an acute bleeding episode involves secondary prophylaxis using betablockers and repeated EVL sessions to prevent rebleeding,complemented by monitoring and managing liver function to address the underlying disease.In light of new scientific evidence,including the findings of the study by Peng et al,this editorial aims to review available strategies for the prevention and treatment of esophageal varices.

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

In the Western world, nonalcoholic fatty liver disease(NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstratedby several epidemiological, familial, and twin studies and case series, and likely reflects the wide interindividual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148 M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167 K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous casecontrol studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.

Staging systems of hepatocellular carcinoma:A review of literature

Hepatocellular carcinoma(HCC)is a major health problem with a high incidence and mortality all over the world.Natural history of HCC is severe and extremely variable,and prognostic factors influencing outcomes are incompletely defined.Over time,many staging and scoring systems have been proposed for the classification and prognosis of patients with HCC.Currently,the non-ideal predictive performance of existing prognostic systems is secondary to their inherent limitations,as well as to a non-universal reproducibility and transportability of the results in different populations.New serological and histological markers are still under evaluation with promising results,but they require further evaluation and external validation.The aim of this review is to highlight the main tools for assessing the prognosis of HCC and the main concerns,pitfalls and warnings regarding its staging systems currently in use.

Natural history of untreatable hepatocellular carcinoma:A retrospective cohort study

AIM: To investigate the clinical course of untreatable hepatocellular carcinoma (HCC) identified at any stage and to identify factors associated with mortality. METHODS: From January 1999 to December 2010, 320 out of 825 consecutive patients with a diagnosis of HCC and not appropriate for curative or palliative treatments were followed and managed with supportive therapy. Cirrhosis was diagnosed by histological or clinical features and liver function was evaluated according to Child-Pugh score. The diagnosis of HCC was performed by Ultra-Sound guided biopsy or by multiphasic contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging. Data were collected for each patient including all clinical, laboratory and imaging variables necessary for the outcome prediction staging systems considered. HCC staging was performed according Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program scores. Follow-up time was defined as the number of months from the diagnosis of HCC to death. Prognostic baseline variables were analyzed by multivariate Cox analysis to identify the independent predictors of survival. RESULTS: Seventy-five per cent of patients had hepatitis C. Ascites was present in 169 patients (53%), while hepatic encephalopathy was present in 49 patients (15%). The Child-Pugh score was class A in 105 patients (33%), class B in 142 patients (44%), and class C in 73 patients (23%). One hundred patients (31%) had macroscopic vascular invasion and/or extra-hepatic spread of the tumor. A single lesion > 10 cm was observed in 34 patients (11%), while multinodular HCC was present in 189 patients (59%). Thirty nine patients (12%) were BCLC early (A) stage, 55 (17%) were BCLC intermediate (B) stage, 124 (39%) were BCLC advanced (C) stage, and 102 (32%) were end-stage BCLC (D). At the time of this analysis (July 2011), 28 (9%) patients were still alive. Six (2%) patients who were lost during follow-up were censored at the last visit. The overall median survival was 6.8 mo, and the 1-year survival was 32%. The 1-year survival according to BCLC classes was 100%, 79%, 12% and 0%, for BCLC A, B, C and D, respectively. There was a significant difference in survival between each BCLC class. The median survival of patients of BCLC stages A, B, C and D was 33, 17.4, 6.9, and 1.8 mo, respectively (P < 0.05 for comparison between stages). The median survival of Child-Pugh A, B and C classes were 9.8 mo (range 6.4-13), 6.1 (range 4.9-7.3), and 3.7 (range 1.5-6), respectively (P < 0.05 for comparison between stages). By univariate analysis, the variables significantly associated to an increased liklihood of mortality were Eastern Cooperative Oncology Group performance status (PS), presence of ascites, low level of albumin, elevated level of bilirubin, international normalized ratio (INR) and Log-[(α fetoprotein (AFP)]. At multivariate analysis, mortality was independently predicted by bad PS (P < 0.0001), high INR values (P = 0.0001) and elevated Log-(AFP) levels (P = 0.009). CONCLUSION: This study confirms the heterogeneous behavior of untreated HCC. BCLC staging remains an important prognostic guide and may be important in decision-making for palliative treatment.

Factors affecting the quality of bowel preparation for colonoscopy in hard-to-prepare patients:Evidence from the literature

Adequate bowel cleansing is critical for a high-quality colonoscopy because it affects diagnostic accuracy and adenoma detection.Nevertheless,almost a quarter of procedures are still carried out with suboptimal preparation,resulting in longer procedure times,higher risk of complications,and higher likelihood of missing lesions.Current guidelines recommend high-volume or low-volume polyethylene glycol(PEG)/non-PEG-based split-dose regimens.In patients who have had insufficient bowel cleansing,the colonoscopy should be repeated the same day or the next day with additional bowel cleansing as a salvage option.A strategy that includes a prolonged low-fiber diet,a split preparation regimen,and a colonoscopy within 5 h of the end of preparation may increase cleansing success rates in the elderly.Furthermore,even though no specific product is specifically recommended in the other cases for difficult-to-prepare patients,clinical evidence suggests that 1-L PEG plus ascorbic acid preparation are associated with higher cleansing success in hospitalized and inflammatory bowel disease patients.Patients with severe renal insufficiency(creatinine clearance<30 mL/min)should be prepared with isotonic high volume PEG solutions.Few data on cirrhotic patients are currently available,and no trials have been conducted in this population.An accurate characterization of procedural and patient variables may lead to a more personalized approach to bowel preparation,especially in patients undergoing resection of left colon lesions,where intestinal preparation has a poor outcome.The purpose of this review was to summarize the evidence on the risk factors influencing the quality of bowel cleansing in difficult-to-prepare patients,as well as strategies to improve colonoscopy preparation in these patients.

Second line systemic therapies for hepatocellular carcinoma: Reasons for the failure

Hepatocellular carcinoma(HCC) is the main cause of death in patients with cirrhosis, with an increasing incidence worldwide. Sorafenib is the choice therapy for advanced HCC. Over time several randomized phase Ⅲ trials have been performed testing sunitinib, brivanib, linifanib and other molecules in head-tohead comparison with Sorafenib as first-line treatment for advanced-stage HCC, but none of these has so far been registered in this setting. Moreover, another feared vacuum arises from the absence of molecules registered as second-line therapy for patients who have failed Sorafenib, representing an urgent unmet medical need. To date all molecules tested as second-line therapies for advanced hepatocellular carcinoma, failed to demonstrate an increased survival compared to placebo. What are the possible reasons for the failure? What we should expect in the near future?

Imaging appearance of treated hepatocellular carcinoma

Surgical resection and imaging guided treatments play a crucial role in the management of hepatocellular carcinoma(HCC).Although the primary end point of treatment of HCC is survival,radiological response could be a surrogate end point of survival,and has a key role in HCC decision-making process.However,radiological assessment of HCC treatment efficacy is often controversial.There are few doubts on the evaluation of surgical resection;in fact,all known tumor sites should be removed.However,an unenhancing partial linear peripheral halo,in most cases,surrounding a fluid collection reducing in size during follow-up is demonstrated in successfully resected tumor with bipolar radiofrequency electrosurgical device.Efficacy assessment of locoregional therapies is more controversial and differs between percutaneous ablation(e.g.,radiofrequency ablation and percutaneous ethanol injection)and transarterial treatments(e.g.,conventional transarterial chemoembolization,transarterial chemoembolization with drug eluting beads and radioembolization).Finally,a different approach should be used for new systemic agent that,though not reducing tumor mass,could have a benefit on survival by delaying tumor progression and death.The purpose of this brief article is to review HCC imaging appearance after treatment.

clinical course and prognostic factors of hepatorenal syndrome:a retrospective single-center cohort study

AIM: To investigate clinical and biochemical features of hepatorenal syndrome(HRS), to assess short and long- term survival evaluating potential predictors of early mortality. METHODS: Sixty-two patients with liver cirrhosis and renal failure, defined as a serum creatinine value > 1.5 mg/dL on at least two measurements within 48 h, admitted to our tertiary referral Unit from 2001 to 201, were retrospectively reviewed. Among them, 33 patients(53.2%) fulfilled the revised criteria of the International Ascites Club for the diagnosis of HRS. Twenty-eight patients were treated with combinations of terlipressin and albumin, two with dopamine and al- bumin, and three with albumin alone. No patients were suitable for liver transplantation. Complete response was defined as normalization of creatinine levels to less than 1.5 mg/dL, partial response as a decrease of at least 50% but not to less than 1.5 mg/dL, no response as no reduction in creatinine or a decrease of less 50% compared to pre-treatment values. All of the patients were followed up for at least 1 year until January 2013. RESULTS: HRS type 1 was diagnosed in 15 patients(45.5%). Hepatitis C virus infection was the primary etiology(69.6%), followed by alcohol(15.2%), and cryptogenesis(15.2%). Complete response to therapy was obtained in only 3 cases(9.1%) and partial re- sponse in 7 patients(21.2%). Median survival was 30 d(range: 10-274) without significant differences be- tween type 1 and type 2 HRS. By univariate analysis, Child-Pugh class C(P = 0.009), presence of hepatocel- lular carcinoma(P = 0.04), low serum sodium(P = 0.02), high bilirubin values(P = 0.009) and high Model for End-stage Liver Disease(MELD) score(P = 0.03) were predictive factors of 30-d mortality. By multivari- ate analysis, only serum sodium < 132 mEq/L(OR = 31.39; P = 0.02) and MELD score > 27(OR = 18.72; P = 0.01) were independently associated with a survival of less than one month. CONCLUSION: HRS still has a poor prognosis, even when vasoactive drug therapies are extensively used.

Effectiveness of very low-volume preparation for colonoscopy:A prospective, multicenter observational study

BACKGROUND The effectiveness of colonoscopy strictly depends on adequate bowel cleansing.Recently,a 1 L polyethylene glycol plus ascorbate(PEG-ASC)solution(Plenvu;Norgine,Harefield,United Kingdom)has been introduced on the evidence of three phase-3 randomized controlled trials,but it had never been tested in the real-life.AIM To assess the effectiveness and tolerability of the 1 L preparation compared to 4 L and 2 L-PEG solutions in a real-life setting.METHODS All patients undergoing a screening or diagnostic colonoscopy after a 4,2 or 1 L PEG preparation,were consecutively enrolled in 5 Italian centers from September 2018 to February 2019.The primary endpoints of the study were the assessment of bowel cleansing success and high-quality cleansing of the right colon.The secondary endpoints were the evaluation of tolerability,adherence and safety of the different bowel preparations.Bowel cleansing was assessed through the Boston Bowel Preparation Scale.Adherence was defined as consumption of at least 75%of each dose,while tolerability was evaluated through a semiquantitative scale.Safety was systematically monitored through adverse events reporting.RESULTS Overall,1289 met the inclusion criteria and were enrolled in the study.Of these,490 patients performed a 4 L-PEG preparation(Selgesse^■),566 a 2 L-PEG cleansing(Moviprep^■or Clensia^■)and 233 a 1 L-PEG preparation(Plenvu^■).Bowel cleansing by Boston Bowel Preparation Scale was 6.5±1.5 overall and 6.3±1.5,6.2±1.5,7.3±1.5(P<0.001)in the subgroups of 4 L,2 L and 1 L-PEG preparation,respectively.Cleansing success was achieved in 72.4%,74.1%and 90.1%(P<0.001),while a high-quality cleansing of the right colon in 15.9%,12.0%and 41.4%(P<0.001)for 4 L,2 L and 1 L-PEG preparation groups,respectively.The 1 L preparation was the most tolerated compared to the 2 and 4 L-PEG solutions in the absence of serious adverse events within any of the three groups.Multiple regression models confirmed 1 L PEG-ASC preparation as an independent predictor of overall cleansing success,high-quality cleansing of the right colon and of tolerability.CONCLUSION This study supports the effectiveness and tolerability of 1 L PEG-ASC,also showing it is an independent predictor of overall cleansing success,high-quality cleansing of the right colon and of tolerability.

Use of artificial intelligence in improving adenoma detection rate during colonoscopy:Might both endoscopists and pathologists be further helped

Colonoscopy remains the standard strategy for screening for colorectal cancer around the world due to its efficacy in both detecting adenomatous or precancerous lesions and the capacity to remove them intra-procedurally.Computeraided detection and diagnosis(CAD),thanks to the brand new developed innovations of artificial intelligence,and especially deep-learning techniques,leads to a promising solution to human biases in performance by guarantying decision support during colonoscopy.The application of CAD on real-time colonoscopy helps increasing the adenoma detection rate,and therefore contributes to reduce the incidence of interval cancers improving the effectiveness of colonoscopy screening on critical outcome such as colorectal cancer related mortality.Furthermore,a significant reduction in costs is also expected.In addition,the assistance of the machine will lead to a reduction of the examination time and therefore an optimization of the endoscopic schedule.The aim of this opinion review is to analyze the clinical applications of CAD and artificial intelligence in colonoscopy,as it is reported in literature,addressing evidence,limitations,and future prospects.

Management of antiplatelet or anticoagulant therapy in endoscopy: A review of literature

Endoscopic procedures hold a basal risk of bleeding that depends on the type of procedure and patients’comorbidities.Moreover,they are often performed in patients taking antiplatelet and anticoagulants agents,increasing the potential risk of intraprocedural and delayed bleeding.Even if the interruption of antithrombotic therapies is undoubtful effective in reducing the risk of bleeding,the thromboembolic risk that follows their suspension should not be underestimated.Therefore,it is fundamental for each endoscopist to be aware of the bleeding risk for every procedure,in order to measure the risk-benefit ratio for each patient.Moreover,knowledge of the proper management of antithrombotic agents before endoscopy,as well as the adequate timing for their resumption is essential.This review aims to analyze current evidence from literature assessing,for each procedure,the basal risk of bleeding and the risk of bleeding in patients taking antithrombotic therapy,as well as to review the recommendation of American society for gastrointestinal endoscopy,European society of gastrointestinal endoscopy,British society of gastroenterology,Asian pacific association of gastroenterology and Asian pacific society for digestive endoscopy guidelines for the management of antithrombotic agents in urgent and elective endoscopic procedures.

Gastrointestinal tract injuries after thermal ablative therapies for hepatocellular carcinoma:A case report and review of the literature

BACKGROUND Radiofrequency ablation(RFA)and microwave ablation(MWA)represent the standard of care for patients with early hepatocellular carcinoma(HCC)who are unfit for surgery.The incidence of reported adverse events is low,ranging from 2.4%to 13.1%for RFA and from 2.6%to 7.5%for MWA.Gastrointestinal tract(GIT)injury is even more infrequent(0.11%),but usually requires surgery with an unfavourable prognosis.Due to its low incidence and the retrospective nature of the studies,the literature reporting this feared complication is heterogeneous and in many cases lacks information on tumour characteristics,comorbidities and treatment approaches.CASE SUMMARY A 77-year-old man who had undergone extended right hepatectomy for HCC was diagnosed with early disease recurrence with a small nodule compatible with HCC in the Sg4b segment of the liver with a subcapsular location.He was treated with percutaneous RFA and a few week later he was urgently admitted to the Surgery ward for abdominal pain and fever.A subcutaneous abscess was diagnosed and treated by percutaneous drainage.A fistulous tract was then documented by the passage of contrast material from the gastric antrum to the abdominal wall.The oesophagogastroduodenoscopy confirmed a circular wall defect at the lesser curvature of gastric antrum, leading directly to the purulentabdominal collection. An over-the-scope clip (OTSC) was used to successfullyclose the defectCONCLUSIONThis is the first reported case of RFA-related GIT injury to have been successfullytreated with an OTSC, which highlights the role of this endoscopic treatment forthe management of this complication.

Surveillance strategies for precancerous gastric conditions after Helicobacter pylori eradication:There is still need for a tailored approach

Prevailing evidence declares that Helicobacter pylori (H. pylori) eradication therapycould shift precancerous gastric conditions (PGC) and positively confines gastriccancer (GC) risk during long-term endoscopic follow-up. Nonetheless, there is ayet unsolved controversy regarding the best-individualized surveillance strategiesfollowing H. pylori eradication, based on malignant risk stratification. This lastdispute is due to the uncertainty of contemporary evidence and the role of H.pylori inflammatory changes in underestimating PGC at the index endoscopy.However, the current state of the art suggests that it is reasonable that highqualityendoscopy with histological assessment for the most accurate diagnosis ofPGC may be delayed in selected high-risk patients without alarm signs formalignancy, following the eradication of H. pylori. Notwithstanding, these aspectsneed to be further examined in the next future to establish and optimize the mostbeneficial and cost-effective strategies for recognizing and managing H. pyloripositivepatients with PGC in the short- and long-term follow-up. Accordingly,additional studies are yet required to sharpen the hazard stratification of patientswith the greatest chance of GC evolution, also recognizing the evolving racial,ethnic, immigration factors and the necessity of novel biomarkers to limit GCdevelopment or accomplish a diagnosis of malignancy at an early stage.

Hepatocellular carcinoma and synchronous liver metastases from colorectal cancer in cirrhosis:A case report

A 68-year-old Caucasian man with hepatitis C virus- related cirrhosis was admitted to our Unit in February 2010 for a diagnostic evaluation of three centimetric hypoechoic focal liver lesions detected by regular sur- veillance ultrasound. The subsequent computer tomog- raphy(CT) led to a diagnosis of unifocal hepatocellular carcinoma(HCC) in Ⅵ hepatic segment, defined the other two nodules in the Ⅵ and Ⅶ segment as sus- pected metastases, and showed a luminal narrowing with marked segmental circumferential thickening of the hepatic flexure of the colon. Colonoscopy detected an ulcerated, bleeding and stricturing lesion at the hepatic flexure, which was subsequently defined as ad- enocarcinoma with a moderate degree of differentiation at histological examination. Finally, ultrasound-guided liver biopsy of the three focal liver lesions confirmed the diagnosis of HCC for the nodule in the Ⅵ segment, and characterized the other two lesions as metastases from colorectal cancer. The patient underwent laparo- tomic right hemicolectomy with removal of thirty-nine regional lymph nodes(three of them tested positive for metastasis at histological examination), and simulta- neous laparotomic radio-frequency ablation of both nodule of HCC and metastases. The option of adju- vant chemotherapy was excluded because of the post- surgical onset of ascites. Abdomen CT and positron emission tomography/CT scans performed after 1, 6 and 12 mo highlighted a complete response to treat- ments without any radiotracer accumulation. After 18 mo, the patient died due to progressive liver failure. Our experience emphasizes the potential coexistence of two different neoplasms in a cirrhotic liver and the complexity in the proper diagnosis and management of the two tumours.

New endoscopy advances to refine adenoma detection rate for colorectal cancer screening:None is the winner

Colorectal cancer(CRC) is the third most common cancer in males and second in females, and globally the fourth cause for cancer death worldwide. Oncological screening of CRC has a major role in the management of the disease and it is mostly performed by colonoscopy. Anyway, effectiveness of endoscopic screening for CRC strictly depends on adequate detection and removal of potentially precancerous lesions, and accuracy of colonoscopy in detection of adenomas is still suboptimal. For this reason, several technological advances have been implemented in order to improve the diagnostic sensitivity of colonoscopy in adenoma detection. Among these:(1) Visual technologies such as chromoendoscopy and narrow band imaging;(2) optical innovation as high definition endoscopy, full-spectrum endoscopy or Third Eye Retroscope; and(3) mechanical advances as Cap assisted colonoscopy, Endocuff, Endoring and G-Eye endoscope. All these technologies advances have been tested over time by clinical studies with mixed results. Which of them is more likely to be successful in the next future?

Emerging artificial intelligence applications in gastroenterology: A review of the literature

Artificial intelligence(AI)allows machines to provide disruptive value in several industries and applications.Applications of AI techniques,specifically machine learning and more recently deep learning,are arising in gastroenterology.Computer-aided diagnosis for upper gastrointestinal endoscopy has growing attention for automated and accurate identification of dysplasia in Barrett’s esophagus,as well as for the detection of early gastric cancers(GCs),therefore preventing esophageal and gastric malignancies.Besides,convoluted neural network technology can accurately assess Helicobacter pylori(H.pylori)infection during standard endoscopy without the need for biopsies,thus,reducing gastric cancer risk.AI can potentially be applied during colonoscopy to automatically discover colorectal polyps and differentiate between neoplastic and nonneoplastic ones,with the possible ability to improve adenoma detection rate,which changes broadly among endoscopists performing screening colonoscopies.In addition,AI permits to establish the feasibility of curative endoscopic resection of large colonic lesions based on the pit pattern characteristics.The aim of this review is to analyze current evidence from the literature,supporting recent technologies of AI both in upper and lower gastrointestinal diseases,including Barrett's esophagus,GC,H.pylori infection,colonic polyps and colon cancer.

Primary biliary cirrhosis and hereditary hemorrhagic telangiectasia: When two rare diseases coexist

Primary biliary cirrhosis is a slowly progressive cholestatic autoimmune liver disease that mainly affects middle-aged women with an estimated prevalence ranging from 6.7 to 402 cases per million. Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber disease, is an autosomal dominant disorder characterized by angiodysplastic lesions (telangiectases and arteriovenous malformations) that can affect many organs, including liver, with a prevalence of 1-2 cases per 10000. We describe the coexistence, for the first time to our knowledge, of these two rare diseases in a 50-year old Caucasian woman. In this setting, the relevance of an accurate medical history, the role of liver histology and the characterization of liver involvement through dynamic imaging techniques can be emphasized.

Progressive multi-organ expression of immunoglobulin G4-related disease: A case report

A 63-year-old Caucasian man presented with a cholestatic syndrome, renal failure and arthralgias. A laboratory examination revealed high immunoglobulin G (IgG) and IgG4 levels (5.95 g/L; normal range: 0.08-1.4 g/L), pointing to a diagnosis of systemic IgG4-related disease, with definite radiological evidence of biliary and pancreatic expression, and plausible renal, articular, salivary and lacrimal glands involvement. Due to the rarity of the condition, there are currently no random control trials to point to the optimal therapeutic approach. The patient has been on steroid therapy with the subsequent introduction of azathioprine, with a complete resolution of all symptoms, a rapid reduction to normalization of all blood tests, and a complete regression of the radiological picture. Our experience underlines the complexity of IgG4-related disease and its variable and sometimes progressive presentation, while pointing out the need for a careful and complete assessment for possible multi-organ involvement.

Incidence of hepatocellular carcinoma after HCV eradication:assessing the risk

Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related death and the first cause of death in patients with cirrhosis.An increasing incidence worldwide and poor prognosis are reported despite the application of screening protocols and potentially radical therapies(1).