Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

A computer-aided detection system in the everyday setting of diagnostic, screening and surveillance colonoscopy: an international, randomized trial.

BACKGROUND AND STUDY AIM: Computer-aided detection (CADe) has been developed to improve detection during colonoscopy. After initial reports of high efficacy, there has been an increasing recognition of variability in the effectiveness of CADe systems. The aim of this study was to evaluate a CADe system (PENTAX Medical, Tokyo, Japan) in a varied colonoscopy population. PATIENTS AND METHODS: A multicenter, randomized trial was conducted at 7 hospitals (both university and non-university) in Europe and Canada. Participants referred for diagnostic, non-iFOBT screening, or surveillance colonoscopy were randomized (1:1) to undergo CADe-assisted or conventional colonoscopy (CC) by experienced endoscopists. Participants with insufficient bowel preparation were excluded from the analysis. Primary outcome was adenoma detection rate (ADR). Secondary outcomes included adenomas per colonoscopy (APC) and sessile serrated lesions per colonoscopy (SSLPC). RESULTS: In total, 581 participants were enrolled, of which 497 were included in the final analysis: 250 in the CADe-arm and 247 in the CC-arm. Surveillance was the indication in 202/497 (40.6%) colonoscopies, diagnostic in 199/497 (40.0%), and non-iFOBT screening in 96/497 (19.3%). Overall, ADR (38.4% vs. 37.7%; p=0.43) and APC (0.66 vs. 0.66; p=0.97) were similar between CADe and CC. SSLPC was increased (0.30 vs. 0.19; p=0.049) in the CADe-arm vs. CC. CONCLUSIONS: In this study conducted by experienced endoscopists, CADe did not result in a statistically significant increase in ADR. However, the ADR of our control group substantially surpassed our sample size assumptions, increasing the risk of an underpowered trial. (Trialsearch.who.int:NL9135).

[Green endoscopy - strategy for more sustainablility in endoscopy]. / Green Endoscopy ­ Strategien für mehr Nachhaltigkeit in der Endoskopie.

Climate protection, ecology and CO2 neutrality have been discussed intensively and increasingly in society for years. This is also becoming increasingly important in hospitals and other medical facilities. The health care sector is responsible for 5.6% of all CO2 emissions in Germany, particularly due to high energy consumption and a daily waste production of 6kg per patient. The following article summarizes the options for endoscopy to contribute to ecological sustainability, with a special focus on measures that can be easily implemented today.

Angled-tip vs. straight-tip guidewire in ERCP: a randomized, multicenter study.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is the mainstay for interventional treatment of biliopancreatic diseases, and guidewires are decisive for successful treatment. METHODS: A randomized, multicenter, open-label study was conducted in patients in whom a guidewire was required in ERCP. Success rate and duration of the investigation were evaluated by randomly applying hydrophilic guidewires with a straight tip (ST) or an angled tip (AT) configuration, with normal (type NF) or enhanced (type EF) flexibility. Randomization was stratified by indication, i.e., stricture of the intra-hepatic bile ducts, stricture of the extrahepatic bile ducts, obstruction by bile duct stones, or interventions involving the pancreas. Cross-over was allowed if the initially allocated guidewire did not result in treatment success. RESULTS: Four hundred fifty-three patients were included, and 422 were finally analyzed. In 363 procedures (86%), the initially allocated wirés use resulted in treatment success. The success rate for using a guidewire with an angled tip configuration was 87.5 vs. 79.9% in a straight tip configuration (p = 0.049), and in negotiating an intrahepatic stricture the success rate was 90.7 vs. 69.1%, respectively (p = 0.008). No significant differences were observed in other indications. Procedural duration time did not differ in between the treatment groups. CONCLUSION: ERCP guidewires with an angled tip were more frequently successful when compared to straight tipped wires and most successful in treating intrahepatic strictures. Guidewires with standard vs. enhanced tip flexibility showed equal success rates in all indications.

Recurrence rates after endoscopic resection of large colorectal polyps: A systematic review and meta-analysis.

BACKGROUND: Complete polyp resection is the main goal of endoscopic removal of large colonic polyps. Resection techniques have evolved in recent years and endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR) with margin ablation, cold snare polypectomy (CSP), cold EMR, and underwater EMR have been introduced. Yet, efficacy of these techniques with regard to local recurrence rates (LRRs) vs traditional hot snare polypectomy and standard EMR remains unclear. AIM: To analyze LRR of large colonic polyps in a systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, EBM Reviews, and CINAHL were searched for prospective studies reporting LRR or incomplete resection rate (IRR) after colonic polypectomy of polyps ≥ 10 mm, published between January 2011 and July 2021. Primary outcome was LRR for polyps ≥ 10 mm. RESULTS: Six thousand nine hundred and twenty-eight publications were identified, of which 34 prospective studies were included. LRR for polyps ≥ 10 mm at up to 12 mo' follow-up was 11.0% (95%CI, 7.1%-14.8%; 15 studies; 4904 polyps). ESD (1.7%; 95%CI, 0%-3.4%; 3 studies, 221 polyps) and endoscopic mucosal resection with margin ablation (3.3%; 95%CI, 2.2%-4.5%; 2 studies, 947 polyps) significantly reduced LRR vs standard EMR without (15.2%; 95%CI, 12.5%-18.0%; 4 studies, 650 polyps) or with unsystematic margin ablation (16.5%; 95%CI, 15.2%-17.8%; 6 studies, 3031 polyps). CONCLUSION: LRR is significantly lower after ESD or EMR with routine margin ablation; thus, these techniques should be considered standard for endoscopic removal of large colorectal polyps. Other techniques, such as CSP, cold EMR, and underwater EMR require further evaluation in prospective studies before their routine implementation in clinical practice can be recommended.

Reducing the environmental footprint of gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) Position Statement.

Climate change and the destruction of ecosystems by human activities are among the greatest challenges of the 21st century and require urgent action. Health care activities significantly contribute to the emission of greenhouse gases and waste production, with gastrointestinal (GI) endoscopy being one of the largest contributors. This Position Statement aims to raise awareness of the ecological footprint of GI endoscopy and provides guidance to reduce its environmental impact. The European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) outline suggestions and recommendations for health care providers, patients, governments, and industry. MAIN STATEMENTS 1: GI endoscopy is a resource-intensive activity with a significant yet poorly assessed environmental impact. 2: ESGE-ESGENA recommend adopting immediate actions to reduce the environmental impact of GI endoscopy. 3: ESGE-ESGENA recommend adherence to guidelines and implementation of audit strategies on the appropriateness of GI endoscopy to avoid the environmental impact of unnecessary procedures. 4: ESGE-ESGENA recommend the embedding of reduce, reuse, and recycle programs in the GI endoscopy unit. 5: ESGE-ESGENA suggest that there is an urgent need to reassess and reduce the environmental and economic impact of single-use GI endoscopic devices. 6: ESGE-ESGENA suggest against routine use of single-use GI endoscopes. However, their use could be considered in highly selected patients on a case-by-case basis. 7: ESGE-ESGENA recommend inclusion of sustainability in the training curricula of GI endoscopy and as a quality domain. 8: ESGE-ESGENA recommend conducting high quality research to quantify and minimize the environmental impact of GI endoscopy. 9: ESGE-ESGENA recommend that GI endoscopy companies assess, disclose, and audit the environmental impact of their value chain. 10:  ESGE-ESGENA recommend that GI endoscopy should become a net-zero greenhouse gas emissions practice by 2050.

Liver Injury in COVID-19 Patients with Drugs as Causatives: A Systematic Review of 996 DILI Cases Published 2020/2021 Based on RUCAM as Causality Assessment Method.

Patients with coronavirus disease 19 (COVID-19) commonly show abnormalities of liver tests (LTs) of undetermined cause. Considering drugs as tentative culprits, the current systematic review searched for published COVID-19 cases with suspected drug-induced liver injury (DILI) and established diagnosis using the diagnostic algorithm of RUCAM (Roussel Uclaf Causality Assessment Method). Data worldwide on DILI cases assessed by RUCAM in COVID-19 patients were sparse. A total of 6/200 reports with initially suspected 996 DILI cases in COVID-19 patients and using all RUCAM-based DILI cases allowed for a clear description of clinical features of RUCAM-based DILI cases among COVID-19 patients: (1) The updated RUCAM published in 2016 was equally often used as the original RUCAM of 1993, with both identifying DILI and other liver diseases as confounders; (2) RUCAM also worked well in patients treated with up to 18 drugs and provided for most DILI cases a probable or highly probable causality level for drugs; (3) DILI was preferentially caused by antiviral drugs given empirically due to their known therapeutic efficacy in other virus infections; (4) hepatocellular injury was more often reported than cholestatic or mixed injury; (5) maximum LT values were found for alanine aminotransferase (ALT) 1.541 U/L and aspartate aminotransferase (AST) 1.076 U/L; (6) the ALT/AST ratio was variable and ranged from 0.4 to 1.4; (7) the mean or median age of the COVID-19 patients with DILI ranged from 54.3 to 56 years; (8) the ratio of males to females was 1.8-3.4:1; (9) outcome was favorable for most patients, likely due to careful selection of the drugs and quick cessation of drug treatment with emerging DILI, but it was fatal in 19 patients; (10) countries reporting RUCAM-based DILI cases in COVID-19 patients included China, India, Japan, Montenegro, and Spain; (11) robust estimation of the percentage contribution of RUCAM-based DILI for the increased LTs in COVID-19 patients is outside of the current scope. In conclusion, RUCAM-based DILI with its clinical characteristics in COVID-19 patients and its classification as a confounding variable is now well defined, requiring a new correct description of COVID-19 features by removing DILI characteristics as confounders.

[Single-use products in endoscopy-from consumables to single-use scopes]. / Einmalprodukte in der Endoskopie ­ vom Zubehör bis zu den "single-use scopes": Die Zukunft?

Clinically relevant infections triggered by the use of flexible endoscopes and respective consumables have become the focus of clinical and scientific interest in the literature. Endoscopy-associated infections can be assigned to one of two groups: (i) endogenous infections are triggered by the spread of the patient's own local flora and (ii) exogenous infections result from transmission of contaminated material or endoscopes. The number of reported infectious complications in flexible endoscopy is low but likely underestimated due to inadequate surveillance strategies and lack of clinical symptoms. To prevent exogenous infections, single-use endoscopes were brought to the market. Single-use bronchoscope have been part of routine clinical care for years, while single-use duodenoscopes have only recently been approved. The increased patient safety and economic costs were clearly evaluated for the single-use bronchoscopes, but this still needs to be studied for single-use duodenoscopes. The use of single-use endoscopes-at first glance-represents an additional financial burden on the healthcare system. However, in addition to the material costs of disposable endoscopes, the costs that are avoided by them (e.g., prolonged hospitalization, intensive care treatment, and follow-up interventions) must also be included in the overall calculation.

Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview.

Herbal products including herbal medicines are worldwide used in large amounts for treating minor ailments and for disease prevention. However, efficacy of most herbal products has rarely been well documented through randomized controlled trials in line with evidence-based medicine concepts, which could be used to estimate the benefit/risk ratio. Instead, much better documented are adverse reactions such as liver injury associated with the consumption of some herbal products, so called herb-induced liver injury (HILI), which represents a clinical challenge. In order to establish HILI as valid diagnosis, the use of a diagnostic algorithms such as Roussel Uclaf Causality Assessment Method (RUCAM) is widely recommended, although physicians in some countries are reluctant to use RUCAM for their HILI cases. This review on worldwide HILI and RUCAM, developed as part of the artificial intelligence ideas, reveals that China is the leading country with 24 publications on HILI cases that were all assessed for causality using RUCAM, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 4 reports. The total number of assessed HILI cases is 12,068 worldwide derived from 80 publications but in each report HILI case numbers were variable in a range from 1 up to 6,971. This figure compares with 46,266 cases of drug-induced liver injury (DILI) published worldwide from 2014 to early 2019 also assessed for causality by RUCAM. The original version of RUCAM was validated and established in 1993 and updated in 2016 that should be used in future HILI cases. RUCAM is an objective, structured, and validated method, specifically designed for liver injury. It is a scoring system including case data elements to be assessed and scored individually to provide a final score in five causality gradings. Among the 11,404/12,068 HILI (94.5%) cases assessable for evaluation, causality gradings were highly probable in 4.2%, probable in 15.5%, possible in 70.3%, and unlikely or excluded in 10.0%. To improve the future reporting of RUCAM based HILI cases, recommendations include the strict adherence to instructions outlined in the updated RUCAM and, in particular, to follow prospective data collection on the cases to ensure completeness of case data. In conclusion, RUCAM can well be used to assess causality in suspected HILI cases, and additional efforts are now required to increase the quality of the reported cases.

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support.

Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.

Is obesity rather than the dietary supplement used for weight reduction the cause of liver injury?

Acute liver injury has been attributed to dietary supplements (DS) used for weight loss, but their causal role was much questioned, and obesity as an alternative cause of the liver injury remained unclear. A comprehensive search of the Medline database was conducted with terms that included "DS," "liver injury," "obesity," "obesity-related liver diseases," and "nonalcoholic steatohepatitis." For each term, we focused on the first 50 publications. We undertook a manual search to identify additional reports. Underlying liver diseases and other health issues are common in patients taking DS for weight reduction. These include obesity or morbid obesity, as well as complex metabolic disorders complicated by excess morbidity and mortality due to associated liver diseases. Among these are nonalcoholic fatty liver disease with potential progression to nonalcoholic steatohepatitis and cirrhosis, often classified as cryptogenic with a rare risk of hepatocellular carcinoma. With the exception of hepatocellular carcinoma, these obesity-related liver diseases were observed to varying degrees in patients, and some even required a liver transplant. This raises the question whether the liver injury that occurred in these patients is due to DS consumed for weight loss or to the underlying obesity-related liver diseases. This analysis showed that, in many instances, the causal role of obesity has been neglected. Obesity-associated liver diseases should be considered as differential diagnosis of liver injury in obese patients using DS.

Drug Induced Liver Injury: Can Biomarkers Assist RUCAM in Causality Assessment?

Drug induced liver injury (DILI) is a potentially serious adverse reaction in a few susceptible individuals under therapy by various drugs. Health care professionals facing DILI are confronted with a wealth of drug-unrelated liver diseases with high incidence and prevalence rates, which can confound the DILI diagnosis. Searching for alternative causes is a key element of RUCAM (Roussel Uclaf Causality Assessment Method) to assess rigorously causality in suspected DILI cases. Diagnostic biomarkers as blood tests would be a great help to clinicians, regulators, and pharmaceutical industry would be more comfortable if, in addition to RUCAM, causality of DILI can be confirmed. High specificity and sensitivity are required for any diagnostic biomarker. Although some risk factors are available to evaluate liver safety of drugs in patients, no valid diagnostic or prognostic biomarker exists currently for idiosyncratic DILI when a liver injury occurred. Identifying a biomarker in idiosyncratic DILI requires detailed knowledge of cellular and biochemical disturbances leading to apoptosis or cell necrosis and causing leakage of specific products in blood. As idiosyncratic DILI is typically a human disease and hardly reproducible in animals, pathogenetic events and resulting possible biomarkers remain largely undisclosed. Potential new diagnostic biomarkers should be evaluated in patients with DILI and RUCAM-based established causality. In conclusion, causality assessment in cases of suspected idiosyncratic DILI is still best achieved using RUCAM since specific biomarkers as diagnostic blood tests that could enhance RUCAM results are not yet available.

Suspected Liver Injury and the Dilemma of Causality.

For causality assessment in cases of suspected liver injury, RUCAM provides objective and transparent results and should be the preferred tool rather than the DILIN method, which is based on subjective opinion.

The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges.

In 2013, physicians at the Honolulu Queen's Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS's and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be "probable" for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC's questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions.

[How to do: Colonoscopy]. / Ileo-Koloskopie.

Colonscopy is the examination of choice for the diagnostic of colorectal disease. Since 2002 it is part of the prevention programm for colorectalcancer in Germany. If you are aware of a few contraindications like acute bowel inflammation or respiratory insufficiency, the diagnostic colonoscopy is a safe procedure. Besides the experience of the examiner the bowel preparation is essential for the quality of the examination. If there are no contraindications the examination should be performed under sedation. To reach the coecum the beginner often needs to exercise patience but with sufficent anatomic background and some technically maneuver it can be done in most cases. The inspection of the mucosa at the withdrawal of the endoscope needs conscientiousness and enough time for an optimal result for the patient.