Autoimmune hepatitis and eosinophilia:A rare case report

BACKGROUND Autoimmune hepatitis consists of a chronic liver disease whose etiology is unknown.It is comprised of relevant immunological aspects and of immunemediated liver injury.Eosinophilia may be a considerable feature,particularly happening in male patients.CASE SUMMARY We report here a Crohn´s disease patient presenting with de novo hypergammaglobulinemia,circulating autoantibodies and elevated transaminase levels.He also had significant peripheral eosinophilia and elevated immunoglobulin E levels at diagnosis.The pathology findings from liver biopsy were compatible with autoimmune hepatitis with eosinophilic infiltration.CONCLUSION This is the first report of autoimmune hepatitis with exuberant eosinophilic infiltration in the liver and bone marrow,described in a patient with Crohn’s disease.

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy:A single center report of 8 cases

This article describes cases of anti-tumor necrosis factor(TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis(AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.

Endoscopic mucosal resection and endoscopic submucosal dissection in the treatment of sporadic nonampullary duodenal adenomatous polyps

Although uncommon, sporadic nonampullary duodenal adenomas have a growing detection due to the widespread of endoscopy. Endoscopic therapy is being increasingly used for these lesions, since surgery, considered the standard treatment, carries significant morbidity and mortality. However, the knowledge about its risks and benefits is limited, which contributes to the current absence of standardized recommendations. This review aims to discuss the efficacy and safety of endoscopic mucosal resection(EMR) and endoscopic submucosal dissection(ESD) in the treatment of these lesions. A literature review was performed, using the Pubmed database with the query: "(duodenum or duodenal)(endoscopy or endoscopic) adenoma resection", in the human species and in English. Of the 189 retrieved articles, and after reading their abstracts, 19 were selected due to their scientific interest. The analysis of their references, led to the inclusion of 23 more articles for their relevance in this subject. The increased use of EMR in the duodenum has shown good results with complete resection rates exceeding 80% and low complication risk(delayed bleeding in less than 12% of the procedures). Although rarely used in the duodenum, ESD achieves close to 100% complete resection rates, but is associated with perforation and bleeding risk in up to one third of the cases. Even though literature is insufficient to draw definitive conclusions, studies suggest that EMR and ESD are valid options for the treatment of nonampullary adenomas. Thus, strategies to improve these techniques, and consequently increase the effectiveness and safety of the resection of these lesions, should be developed.

Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding:A systematic review

BACKGROUND Anemia is considered a public health issue and is often caused by iron deficiency.Iron-deficiency anemia(IDA)often originates from blood loss from lesions in the gastrointestinal tract in men and postmenopausal women,and its prevalence among patients with gastrointestinal bleeding has been estimated to be 61%.However,few guidelines regarding the appropriate investigation of patients with IDA due to gastrointestinal bleeding have been published.AIM To review current evidence and guidelines concerning IDA management in gastrointestinal bleeding patients to develop recommendations for its diagnosis and therapy.METHODS Five gastroenterology experts formed the Digestive Bleeding and Anemia Workgroup and conducted a systematic literature search in PubMed and professional association websites.MEDLINE(via PubMed)searches combined medical subject headings(MeSH)terms and the keywords“gastrointestinal bleeding”with“iron-deficiency anemia”and“diagnosis”or“treatment”or“management”or“prognosis”or“prevalence”or“safety”or“iron”or“transfusion”or“quality of life”,or other terms to identify relevant articles reporting the management of IDA in patients over the age of 18 years with gastrointestinal bleeding;retrieved studies were published in English between January 2003 and April 2019.Worldwide professional association websites were searched for clinical practice guidelines.Reference lists from guidelines were reviewed to identify additional relevant articles.The recommendations were developed by consensus during two meetings and were supported by the published literature identified during the systematic search.RESULTS From 494 Literature citations found during the initial literature search,17 original articles,one meta-analysis,and 13 clinical practice guidelines were analyzed.Based on the published evidence and clinical experience,the workgroup developed the following ten recommendations for the management of IDA in patients with gastrointestinal bleeding:(1)Evaluation of hemoglobin and iron status;(2)Laboratory testing;(3)Target treatment population identification;(4)Indications for erythrocyte transfusion;(5)Treatment targets for erythrocyte transfusion;(6)Indications for intravenous iron;(7)Dosages;(8)Monitoring;(9)Indications for intravenous ferric carboxymaltose treatment;and(10)Treatment targets and monitoring of patients.The workgroup also proposed a summary algorithm for the diagnosis and treatment of IDA in patients with acute or chronic gastrointestinal bleeding,which should be implemented during the hospital stay and follow-up visits after patient discharge.CONCLUSION These recommendations may serve as a starting point for clinicians to better diagnose and treat IDA in patients with gastrointestinal bleeding,which ultimately may improve health outcomes in these patients.

Capsule enteroscopy is useful for the therapeutic management of Crohn's disease

AIM: To analyze therapeutic changes in Crohn's disease(CD) patients following video capsule endoscopy(VCE) and to assess the usefulness of Lewis score and the Patency Capsule.METHODS: Patency Capsule was performed in every patient that had indication for VCE, and those with negative patency did not undergo VCE. Patients with established CD that underwent VCE between January 2011 and February 2014 were selected for this study; those with suspected CD were excluded, independent of VCE results, since our purpose was to address differences in therapeutic regimen in CD patients before and after VCE. Patients with inconclusive VCE were also excluded. Patients had to be free of non-steroidal anti-inflammatories for at least 1 mo. Those patients who met these criteria were allocated into one of three groups: Staging group(asymptomatic CD patients that underwent VCE for staging of CD), Flare group(patients with active CD), or Post-op group(CD patients evaluated for post-operative recurrence). Lewis score was calculated for every VCE procedure. Statisticalanalysis was performed to address the impact of VCE findings on the therapeutic management of CD patients and to evaluate the utility of the Lewis score.RESULTS: From a total of 542 VCEs, 135 were performed in patients with CD. Patency capsule excluded nearly 25% of the patients who were supposed to undergo VCE. No videocapsule retention during VCE was reported. From these 135 patients, 29 were excluded because CD diagnosis was not established at the time of VCE. Therefore, a total of 106 patients were included in the final analysis. From these, the majority were in the Staging group(n = 73, 69%), and the remaining were in the Flare(n = 23, 22%) or Post-op(n = 10, 9%) group. Median time between diagnosis and VCE was 5.5 years. Overall, VCE determined changes in the treatment of 40% of patients: only 21% remained free of immunosuppressors after VCE compared to 44% before VCE(P < 0.001). The differences in therapy before and after VCE achieved statistical significance in the Staging and Flare groups. In addition, patients were significantly different when stratified regarding time since diagnosis to the date of VCE. A higher Lewis score was associated with therapeutic modifications(P < 0.0001); where a score higher than 1354 was related to 90% probability of changing therapy [area under the receiver operative characteristic(AUROC) 0.80(95%CI: 0.69-0.88)]. CONCLUSION: VCE significantly changed the therapeutic management of CD patients, even in those with long-term disease. Systematic use of Patency capsule allowed for no videocapsule retention.

Fecal marker levels as predictors of need for endoscopic balloon dilation in Crohn's disease patients with anastomotic strictures

AIM To evaluate the accuracy and best cut-off value of fecal calprotectin(FC) and fecal lactoferrin(FL) to predict disease recurrence in asymptomatic patients presenting with anastomotic strictures. METHODS This was a longitudinal single tertiary center study based on prospectively collected data(recorded in a clinical database created for this purpose) performed between March 2010 and November 2014. Crohn's disease(CD) patients with anastomotic stricture who submitted to postoperative endoscopic evaluation were included. Stools were collected on the day before bowel cleaning for FC and FL. Endoscopic balloon dilation(EBD) was performed if the patient presented an anastomotic stricture not traversed by the colonoscope, regardless of patients' symptoms. Successful dilation was defined as passage of the colonoscope through the dilated stricture into the neotermimal ileum.Postoperative recurrence was defined as a modified Rutgeerts score of ≥ i2 b. RESULTS In a total of 178 patients who underwent colonoscopy, 58 presented an anastomotic stricture, 86% were asymptomatic, and 48(54% male; median age of 46.5 years) were successfully dilated. Immediate success rate was 92% and no complications were recorded. FC and FL levels correlated significantly with endoscopic recurrence(P < 0.001) with an optimal cut-off value of 90.85 μg/g(sensitivity of 95.5%, specificity of 69.2%, positive predictive value(PPV) of 72.4%, negative predictive value(NPV) of 94.7% and accuracy of 81%] for FC and of 5.6 μg/g(sensitivity of 77.3%, specificity of 69.2%, PPV of 68%, NPV of 78.4% and accuracy of 72.9%) for FL.CONCLUSION Fecal markers are good predictors of CD endoscopic recurrence in patients with asymptomatic anastomotic stricture. FC and FL may guide the need for EBD in this context.

Management of autoimmune hepatitis:Focus on pharmacologic treatments beyond corticosteroids

In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use butit can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers.

Not all liver tumors are alike—an accidentally discovered primary hepatic leiomyosarcoma:A case report

BACKGROUND Primary hepatic leiomyosarcoma is a very rare entity that originates from smooth muscle.Preoperative diagnosis requires a high degree of suspicion due to atypical clinical presentation and non-specific imaging features.CASE SUMMARY We report the case of a 42-year-old man,with no relevant past medical history,accidentally diagnosed with a nodular liver lesion on a routine abdominal ultrasound.Liver function tests and hematology parameters as well as tumor markers were normal.A contrast-enhanced abdominal computed tomography scan revealed a heterogenous hepatic lesion measuring 40 mm 30 mm,adjacent to the left branch of the portal vein and the round ligament.Due to the unclear diagnosis,the patient underwent surgical resection.Histopathological and immunohistochemical examinations confirmed complete(R0)resection of a hepatic leiomyosarcoma.The patient remains without any signs of tumor recurrence for more than 2 years.CONCLUSION We report a rare case of accidentally diagnosed primary hepatic leiomyosarcoma originating from the portal vein or the round ligament.Although this tumor has aggressive metastatic potential,a tumor-free resection margin is essential to improve survival.

HIPPOCRATES®project:A proof of concept of a collaborative program for hepatitis C virus micro-elimination in a prison setting

BACKGROUND In the last few years we have witnessed a revolution in the treatment of hepatitis C virus(HCV)infection.With the introduction of direct-acting antiviral agents(DAAs),sustained virological response(SVR)is achieved in more than 95%of the patients.The focus is now being turned to the global targets set by the World Health Organization,with the aim of achieving HCV elimination by 2030.Prison inmates constitute one of the high-risk groups,and receive treatment less frequently due to several barriers in access to health care.AIM To describe the management and follow-up of a cohort of HCV monoinfected patients treated with DAA in the prison setting,where tertial referral liver center specialists locally provide,on-site assessment and treatment for the prisoners.METHODS A prospective observational study was conducted from April 2017 to March 2020,which included all HCV monoinfected prison inmates in the largest Northern Portugal prison.Demographic,clinical,and laboratory data,as well as transient elastography measurements,were collected onsite by the medical team and prospectively recorded.Patients were treated with DAA according to international guidelines.The primary endpoint was SVR at post-treatment week 12.RESULTS There were 98 monoinfected HCV male inmates(mean age,42.7±8.6 years)included in the analysis.Injecting drugs or tattooing were reported in 74.5%,with 38.8%of the latter being done in prison.Alcohol consumption of more than 30 g/d was referred in 69.4%.The most prevalent genotype was 1a(54.1%),followed by 3(27.6%),4(9.2%)and 1b(6.1%).Pretreatment fibrosis degree was mild-tomoderate(F0-F2)in 77.6%and severe in 22.4%(F3-F4).Treatment regimens chosen were:45.9%elbasvir/grazoprevir,29.6%sofosbuvir/velpatasvir,and 12.2%sofosbuvir/ledispavir and glecaprevir/pibrentasvir.No major adverse events were observed.SVR at post-treatment week 12 was 99%.CONCLUSION In a population considered to be both hard-to-access and a cornerstone for HCV elimination,the onsite evaluation and treatment of HCV-infected prisoners,achieved an exceptional highly effective success rate.This type of collaborative program should be considered to be expanded,to support hepatitis C elimination efforts.

Liver and COVID-19:From care of patients with liver diseases to liver injury

The global pandemic of coronavirus disease 2019(COVID-19)changed dramatically all priorities on medical society and created several challenges for clinicians caring for patients with liver diseases.We performed a comprehensive review about how COVID-19 can affect the liver,the influence of liver diseases on the risk of developing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and COVID-19 severity and also some strategies to overcome all the challenges clinicians have to face in the management of patients with liver diseases in a period of time when all the focus turned on COVID-19.We analyze the relationship between COVID-19 and non-alcoholic fatty liver disease,alcoholic liver disease,viral hepatitis,autoimmune liver disease,cirrhosis,hepatocellular carcinoma and liver transplantation,as well as the approach to SARS-CoV-2 vaccination.

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities

BACKGROUND Individuals within specific risk groups for pancreatic ductal adenocarcinoma(PDAC)[mucinous cystic lesions(MCLs),hereditary risk(HR),and new-late onset diabetes mellitus(NLOD)]represent an opportunity for early cancer detection.Endoscopic ultrasound(EUS)is a premium image modality for PDAC screening and precursor lesion characterization.While no specific biomarker is currently clinically available for this purpose,glypican-1(GPC1)is overexpressed in the circulating exosomes(crExos)of patients with PDAC compared with healthy subjects or those harboring benign pancreatic diseases.AIM To evaluate the capacity of GPC1+crExos to identify individuals at higher risk within these specific groups,all characterized by EUS.METHODS This cross-sectional study with a prospective unicentric cohort included 88 subjects:40 patients with MCL,20 individuals with HR,and 20 patients with NLOD.A control group(CG)was submitted to EUS for other reasons than pancreatic pathology,with normal pancreas and absence of hereditary risk factors(n=8).The inclusion period was between October 2016 and January 2019,and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João,Porto,Portugal.All patients provided written informed consent.EUS and blood tests for quantification of GPC1+crExos by flow cytometry and carbohydrate antigen 19-9(CA 19-9)levels by ELISA were performed in all subjects.EUS-guided tissue acquisition was done whenever necessary.For statistical analysis,SPSS®27.0(IBM Corp.,Armonk,NY,United States)version was used.All graphs were created using GraphPad Prism 7.00(GraphPad Software,San Diego,CA,United States).RESULTS Half of MCLs harbored worrisome features(WF)or high-risk stigmata(HRS).Pancreatic abnormalities were detected by EUS in 10.0%and 35.0%in HR and NLOD individuals,respectively,all considered non-malignant and“harmless.”Median levels of GPC1+crExos were statistically different:MCL[99.4%,interquartile range(IQR):94.9%-99.8%],HR(82.0%,IQR:28.9%-98.2%),NLOD(12.6%,IQR:5.2%-63.4%),and CG(16.2%,IQR:6.6%-20.1%)(P<0.0001).Median levels of CA 19-9 were within the normal range in all groups(standard clinical cut-off of 37 U/mL).Within HR,individuals with a positive history of cancer had higher median levels of GPC1+crExos(97.9%;IQR:61.7%-99.5%),compared to those without(59.7%;IQR:26.3%-96.4%),despite no statistical significance(P=0.21).Pancreatic cysts with WF/HRS were statistically associated with higher median levels of GPC1+crExos(99.6%;IQR:97.6%-99.8%)compared to those without(96.5%;IQR:81.3%-99.5%)(P=0.011),presenting an area under the receiver operating characteristic curve value of 0.723(sensitivity 75.0%and specificity 67.7%,using a cutoff of 98.5%;P=0.012).CONCLUSION GPC1+crExos may act as biomarker to support the diagnosis and stratification of PDAC precursor lesions,and in signaling individuals with genetic predisposition in the absence of EUS abnormalities.

Endoscopic balloon dilation of crohn's disease stricturessafety,efficacy and clinical impact

AIM To evaluate the incidence of anastomotic strictures after intestinal resection in Crohn's disease(CD), demonstrate long-term efficacy and safety of endoscopic balloon dilation(EBD) in CD strictures and its impact on the diagnosis of subclinical postoperative endoscopic recurrence. METHODS Retrospective single tertiary center study based on prospectively collected data between 2010 and 2015including anastomotic and non-anastomotic strictures. RESULTS29% of 162 CD patients included developed an anastomotic stricture. 43 patients with anastomotic strictures and 37 with non-anastomotic strictures underwent EBD; technical success was 97.7% and 100%, respectively, however, 63% and 41% needed repeat dilation during the 4.4-year follow-up. Longer periods between surgery and index colonoscopy and higher lactoferrin levels were associated with the presence of stricture after surgery. Calprotectin levels > 83.35 μg/g and current or past history of smoking were associated with a shorter time until need for dilation(HR = 3.877, 95%CI: 1.480-10.152 and HR = 3.041, 95%CI: 1.213-7.627). Anastomotic strictures had a greater need for repeat dilation(63% vs 41%, P = 0.047). No differences were found between asymptomatic and symptomatic cohorts. Disease recurrence diagnosis was only possible after EBD in a third of patients. CONCLUSION EBD is an effective and safe alternative to surgery, with a good short and long-term outcome, postponing or even avoiding further surgery. EBD may allow to diagnose disease recurrence in patients with no clinical signs/biomarkers of disease activity.

Discontinuation of antiviral therapy in chronic hepatitis B patients

Nucleos(t)ide analogs(NUC)are the first-line therapy for patients with chronic hepatitis B(CHB)recommended by most current guidelines.NUC therapy decreases progression of liver disease,reduces the risk of liver-related complications,and improves the quality of life of patients with CHB.Although indefinite or long-term NUC therapy is usually recommended,this strategy raises several concerns,such as side-effects,adherence,costs,and patient willingness to stop therapy.Recent data showed the feasibility,efficacy,and safety of stopping antiviral therapy in carefully selected CHB patients,leading to its incorporation in international guidelines.Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen(HBsAg)loss compared to patients who continue on therapy.Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines.For hepatitis B e antigen(HBeAg)-positive patients,durable HBeAg seroconversion is considered an acceptable treatment endpoint.For HBeAg-negative patients,some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years,while others consider HBsAg loss as the only acceptable endpoint.CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner.No reliable predictor of relapse has been consistently identified to date,although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.

Liver manifestations and complications in inflammatory bowel disease:A review

Hepatobiliary manifestations are common in inflammatory bowel disease(IBD),with 30%of patients presenting abnormal liver tests and 5%developing chronic liver disease.They range from asymptomatic elevated liver tests to lifethreatening disease and usually follow an independent course from IBD.The pathogenesis of liver manifestations or complications and IBD can be closely related by sharing a common auto-immune background(in primary sclerosing cholangitis,IgG4-related cholangitis,and autoimmune hepatitis),intestinal inflammation(in portal vein thrombosis and granulomatous hepatitis),metabolic impairment(in non-alcoholic fatty liver disease or cholelithiasis),or drug toxicity(in drug induced liver injury or hepatitis B virus infection reactivation).Their evaluation should prompt a full diagnostic workup to identify and readily treat all complications,improving management and outcome.

Gastroenterology,hepatology and movies:A holistic insight

The Project "Movies and Health in Night talks" took place in Braga and Porto,northern Portugal,in the last 3 years.This Project demonstrated how medical knowledge may surround and integrate a cosmopolitan and holistic approach,so that we as doctors and the general public,are able to become much closer and much more prone to understand the vital cycles of our society.

Lot to give,got to live-the restless minds of the“Liver on Tour”project

The Liver on Tour was a special project devoted to increase the public awareness on Liver Health and Liver Diseases that the Portuguese Association for the Study of Liver Diseases launched throughout the country in 2010.

Conscience imperative of providing information and knowledge in hepatology:The Portuguese approach

The last 25 years have been a thrilling time for the Portuguese hepatologists. Our national meetings have been providing the forum for the exchange of scientific ideas and the presentation of clinical research in clinical Hepatology, a growing world of knowledge in medical care. Bridging the gaps between technology and clinical daily practice, the latest development and the almost humble bedside care, has been a challenge for the increasing numbers of doctors devoted to the diagnostic and treatment of liver disease. We have been trying to be very persuasive among the Portuguese medical community in demonstrating that cultural vectors may influence the origin and pattern of liver disease among us. Viral hepatitis and alcoholic liver disease are paradigms of this assumption. Chronic liver disease is responsible for 3% of the deaths in Portugal, which accounts for the top ten causes of death in our country. The recognition by public health authorities of this fact along with the national net of hepatology outpatient consultation in public hospitals, has brought liver diseases under the lights of doctors concerns and an increased public awareness of its dimension.