Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis.

INTRODUCTION: Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson's disease (WD) and yet reports in the literature are limited. The aim of our study was to systematically assess the data according to early neurological deteriorations in WD, its outcome and risk factors. METHODS: Using PRISMA guidelines, a systematic review of available data on early neurological deteriorations was performed by searching the PubMed database and reference lists. Random effects meta-analytic models summarized cases of neurological deterioration by disease phenotype. RESULTS: Across the 32 included articles, 217 cases of early neurological deterioration occurred in 1512 WD patients (frequency 14.3%), most commonly in patients with neurological WD (21.8%; 167/763), rarely in hepatic disease (1.3%; 5/377), and with no cases among asymptomatic individuals. Most neurological deterioration occurred in patients treated with d-penicillamine (70.5%; 153/217), trientine (14.2%; 31/217) or zinc salts (6.9%; 15/217); the data did not allow to determine if that reflects how often treatments were chosen as first line therapy or if the risk of deterioration differed with therapy. Symptoms completely resolved in 24.2% of patients (31/128), resolved partially in 27.3% (35/128), did not improve in 39.8% (51/128), with 11 patients lost to follow-up. CONCLUSIONS: Given its occurrence in up to 21.8% of patients with neurological WD in this meta-analysis of small studies, there is a need for further investigations to distinguish the natural time course of WD from treatment-related early deterioration and to develop a standard definition for treatment-induced effects.

Endoscopic ultrasound-guided drainage of peripancreatic fluid collections: What impacts treatment duration?

BACKGROUND: Peripancreatic fluid collections (PFCs) are complications resulting from acute or chronic pancreatitis and require treatment in certain clinical conditions. The present study aimed to identify the factors influencing the duration of endoscopic ultrasound (EUS)-guided drainage of symptomatic pancreatic pseudocysts (PPCs), walled-off necrosis (WON), and acute necrotic collections (ANCs). METHODS: This was a retrospective cohort study of 68 patients with PFCs who underwent EUS-guided drainage. The timing and duration of EUS-guided drainage of various PFCs (ANC, WON, and PPCs) were compared, and the factors influencing the duration of endoscopic treatment were identified. RESULTS: The mean time to first EUS-guided PFC drainage since the acute pancreatitis episode was 372.0, 505.0, and 18.7 days for WON, PPC, and ANC, respectively, and the mean duration of treatment was 90, 60, and 63 days, respectively. A disconnected pancreatic duct, a history of percutaneous drainage, and an infected PFC were identified as factors influencing the treatment duration. A positive correlation was observed between the treatment duration and patients' age. Patients with a disconnected pancreatic duct had to undergo more procedures. In patients with PPC, clinically successful drainage was more frequently achieved after a single procedure without the need for repeated procedures than in those with WON (90% vs. 59%, P = 0.01). CONCLUSIONS: Patients with a history of percutaneous drainage, disconnected pancreatic duct, or PFC infection may require longer endoscopic treatment.

Genetic Variants in Matrix Metalloproteinases MMP3 (rs3025058) and MMP9 (rs3918242) Associated with Colonic Diverticulosis.

Background and Objectives: Diverticulosis affects a significant portion of the elderly population, with age and lifestyle being established risk factors. Additionally, genetic predisposition is gaining recognition as a contributing factor. This pilot study sought to explore the frequency of genetic variants in matrix metalloproteinases (MMPs) 3, 9, and 12 in a population of colonic diverticulosis patients. Materials and Methods: The study encompassed 134 participants: 59 diagnosed with colon diverticulosis during colonoscopy and 75 healthy controls. The cases and controls were meticulously matched in terms of age and gender. We assessed the distribution of genetic variants MMP3 rs3025058, MMP9 rs3918242, and MMP12 rs2276109 using the polymerase chain reaction-restriction fragments length polymorphism technique. Results: The MMP9 rs3918242 allele T was notably more frequent in individuals with diverticulosis when compared with the control group (p < 0.03). Furthermore, it was associated with dominant (OR = 2.62; 95% CI: 1.24-5.56; p < 0.01) and co-dominant (OR = 2.10; 95% CI: 1.06-4.13; p < 0.03) genetic models. The MMP3 rs3025058 5A/5A genotype was nearly twice as frequent in patients with diverticulosis, while the 6A/6A genotype was only half as common in this group. Conversely, no significant correlation was established between MMP12 rs2276109 and colonic diverticulosis. Conclusions: Our study offers the first insight into a potential connection between genetic variants in MMPs and colon diverticulosis. Specifically, allele T of MMP9 rs3918242 and allele 5A of MMP3 rs3025058 appear to be linked to this condition. These findings indirectly suggest a role for extracellular matrix proteins in the pathogenesis of diverticulosis.

Serotonin Metabolism and Serotonin Receptors Expression Are Altered in Colon Diverticulosis.

Background and Objectives: Diverticulosis is frequently accompanied by altered bowel habits. The biogenic amines within colonic mucosa control bowel motility, and in particular, alterations in serotonin signaling may play a role in colon diverticulosis. The aim of the study was to assess the concentration of biogenic amines and serotonin receptor expression in the colonic mucosa in patients with diverticulosis and healthy controls. Materials and Methods: This prospective, comparative study included 59 individuals: 35 with sigmoid diverticulosis and 24 healthy controls. The study was held at the Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Poland. Mucosal samples were taken from the right and left colon during a colonoscopy in all patients. Concentrations of norepinephrine, 3-methoxy-4-hydroxyphenylglycol, dopamine, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid were measured with high-performance liquid chromatography. Expressions of human 5-hydroxytryptamine receptor 3A, 5-hydroxytryptamine receptor 4, 5-hydroxytryptamine receptor 7, solute carrier family 6 member 4 (SERT) for serotonin, as well as the neuroglia activation markers glial fibrillary acidic protein, S100 calcium-binding protein B, and proteolipid protein 1, were assessed with polymerase chain reaction. Results: The median age and sex distribution were comparable in both study groups (median 69 y vs. 52 y; p < 0.455 and males/females in cases 11/17 vs. 18/19 in controls; p < 0.309). In diverticulosis patients, there was a higher concentration of serotonin in the left affected colon compared to the right healthy part of the colon (median 8239 pg/mg vs. 6326 pg/mL; p < 0.01). The SERT expression was lower in the affected left segment compared to the right colon (median 0.88 vs. 1.36; p < 0.01). There was a higher colonic mucosa concentration of serotonin (median 8239 pg/mg vs. 6000 pg/mL; p < 0.02) and 5-hydroxyindoleacetic acid/serotonin ratio (median 0.27 vs. 0.47; p < 0.01) in diverticulosis patients compared to controls in the left side of the colon. Conclusions: The concentration of serotonin in the mucosa of the colon segment affected by diverticula is higher than in the healthy segment in the same individuals and higher than in healthy controls. These results underline serotonin signaling in colon diverticulosis pathophysiology.

Serum Neurofilament Light Chain as a Biomarker of Brain Injury in Wilson's Disease: Clinical and Neuroradiological Correlations.

BACKGROUND: Clinical scales and neuroimaging are used to monitor nervous system injury in Wilson's disease, while data on serum markers are scarce. OBJECTIVE: To investigate whether serum concentrations of neurofilament light chain (sNfL) correlate with brain injury in Wilson's disease patients. METHODS: In 61 treatment-naïve patients, the Unified Wilson's Disease Rating Scale and a validated semiquantitative brain magnetic resonance imaging scale were compared with concentrations of sNfL. RESULTS: Concentrations of sNfL were significantly higher in patients with neurological disease compared with patients presenting with other forms (39.7 ± 73.4 pg/mL vs. 13.3 ± 9.2 pg/mL; P < 0.01). Moreover, the sNfL concentration positively correlated with neurological severity scores and with acute and chronic brain damage based on the neuroimaging scale. CONCLUSIONS: Neurofilament light chain concentrations may be used as a marker of brain injury in Wilson's disease, in addition to the clinical and neuroimaging disease severity scales. © 2022 International Parkinson and Movement Disorder Society.

Antiplatelet drugs and liver fibrosis.

Liver fibrosis results from an imbalance between extracellular matrix formation and degradation. The background of liver fibrosis is chronic inflammation and subsequent microcirculation disturbance including microthrombosis. Platelets actively participate in liver fibrosis not only as a part of the clotting system but also by releasing granules containing important mediators. In fact, platelets may play a dual role in the pathophysiology of liver fibrosis as they are able to stimulate regeneration as well as aggravate the destruction of the liver. Recent studies revealed that antiplatelet therapy correlates with inhibition of liver fibrosis. However, liver impairment is associated with extensive coagulation disorders thus the safety of antiplatelet therapy is an area for detailed exploration. In this review, the role of platelets in liver fibrosis and accompanying hemostatic disorders are discussed. Additionally, results of animal and human studies on antiplatelet drugs in liver disorders and their potential therapeutic utility are presented.

Effect of homeostatic iron regulator protein gene mutation on Wilson's disease clinical manifestation: original data and literature review.

OBJECTIVE: Wilson's disease (WD) is a hereditary disorder of copper metabolism. The metabolic pathways of copper and iron are interrelated. Our goal was to determine the frequency of the two most common mutations in the coding region of the human iron homeostatic protein gene (HFE) in Europe: C282Y (rs1800562) and H63D (rs1799945) in WD patients, as well as to analyze their relation with WD phenotypic traits. MATERIAL AND METHODS: HFE mutations were studied by PCR RFLP method in 445 WD patients and 102 controls. All patients met the diagnostic criteria of WD 8th International Conference on Wilson Disease and Menkes Disease. RESULTS: HFE C282Y heterozygotes, both women and men, showed WD symptoms earlier than patients with wild-type HFE genotype. HFE 63HD heterozygous men presented symptoms later than HFE 63HH homozygotes, but HFE 63HD women manifested symptoms later than those with HFE 63HH genotype. CONCLUSIONS: HFE genotype seems to be one of the factors modifying Wilson's disease phenotype.

Identification of information about adverse drug reactions in local medical journals using MEDLINE and Embase versus manual full text review.

INTRODUCTION: Collecting information about drugs in clinical practice is essential for ongoing riskbenefit analysis of the drug use. Medical literature is an important source of new information on drug safety, in particular for the signal assessment. A signal is an information about a new potentially causal association, or a new aspect of a known association (e.g. change in frequency or severity of the reaction) between a drug and an adverse event (AE). AIM OF THE STUDY: To verify the effectiveness of the identification of adverse drug reaction (ADR) reports published in the local medical literature using MEDLINE and Embase, versus manual full text review of journals. MATERIAL AND METHODS: The study was performed for 20 randomly selected drugs and 84 Polish medical journals and covers a review of 1,576 individual journal issues with 20,146 articles. Retrospective analysis of literature reports collected during manual full text review was performed and compared to the outcome of database search. RESULTS: ADRs for analyzed drugs were identified only in 17 out of 84 journals, as a result of which 66 reports were analyzed. The majority of reports (55%) were found in local non-indexed journals. Three reports originated from journals indexed in MEDLINE and 9 reports from journals indexed in Embase were not found in these databases because databases do not fully cover conference abstracts and journal supplements. Moreover, while using databases for ADR report search there is a risk of missing up to 30% of ADR reports. The average gap between article publication date and database entry was 119 days. CONCLUSIONS: We verified that the effectiveness of the identification of ADR reports published in the local medical literature is more accurate based on manual full text review than by searching in bibliographic databases.

Toxic milk mice models of Wilson's disease.

Wilson's disease (WD) is a rare genetic disorder inherited as an autosomal recessive trait. The signs and symptoms of this disease are related to dysfunctional ATP7B protein which leads to copper accumulation and cellular damage. The organs that are most commonly affected by WD are the liver and brain. The dysfunctional ATP7B homolog has previously been identified in many different species, including two naturally occurring murine models called toxic milk mice. The aim of this paper was to compare the toxic milk mouse described by Rauch (tx) to that from Jackson Laboratory (txJ) through a review of studies on these two groups of mice. The two mice strains differ in the type of carried mutation and the phenotype of the disease. The data of the studies showed that the tx mice developed mild chronic hepatitis but suffered severe organ destruction with faster progression to full-liver cirrhosis. No changes were noted in the neurological and behavioral status of this strain despite the described toxic accumulation of copper and neuronal destruction in their brain. On the other hand, though the Jackson toxic milk mice (txJ) also presented chronic hepatitis, the condition was a bit milder with slower progression to end-stage disease. Moreover, hepatocyte suitable to perform neurobehavioral research as their phenotype characterized by tremors and locomotor disabilities better corresponds with the cliniconeurological picture of the humans.

Iron metabolism is disturbed and anti-copper treatment improves but does not normalize iron metabolism in Wilson's disease.

Wilson's disease (WD) is a rare hereditary disorder of copper metabolism. Some data suggest that iron metabolism is disturbed in WD and this may affect the course of the disease. The current study aimed to determine whether anti-copper treatment could affect iron metabolism in WD. One hundred thirty-eight WD patients and 102 controls were examined. Serum ceruloplasmin and copper were measured by colorimetric enzyme assay or atomic adsorption spectroscopy, respectively. Routine and non-routine parameters of iron metabolism were measured by standard laboratory methods or enzyme immunoassay, respectively. WD patients, both newly diagnosed and treated, had less serum copper and ceruloplasmin than controls (90.0, 63.0, 22.0 mg/dL, respectively, p < 0.001); in the treated patients blood copper and ceruloplasmin were lower than in untreated patients (p < 0.001). Untreated patients (n = 39) had a higher median blood iron (126.0 vs 103.5 ug/dL, p < 0.05), ferritin (158.9 vs 47.5 ng/mL, p < 0.001), hepcidin (32, 6 vs 12.1 ng/mL, p < 0.001) and sTfR (0.8 vs. 0.7 ug/mL, p < 0.001) and lower blood transferrin (2.4 vs. 2.7 g/L, p < 0.001), TIBC (303.0 vs 338.0 ug/dL, p < 0.001), hemoglobin (13.1 vs 13.9 g/dL, p < 0.01) and RBC (4.3 vs. 4.6, p < 0.002) than controls. Treated patients (n = 99) had a significantly lower median iron (88.0 vs. 126.0 ug/dL, p < 0.001), ferritin (77.0 vs. 158.9 ng/mL, p < 0.005) and hepcidin (16.7 vs. 32.6 ng/mL, p < 001) and higher transferrin (2.8 vs. 2.4 g/L, p < 0.005), TIBC (336.0 vs 303.0 ug/dL, p < 0.001), RBC (4.8 vs. 4.3 M/L, p < 0.001) and hemoglobin (14.4 vs. 13.1 g/dL, p < 0.001) than untreated; the median iron (p < 0.005) was lower, and ferritin (p < 0.005), RBC (p < 0.005) and hepcidin (p < 0.002) were higher in them than in the control group. Changes in copper metabolism are accompanied by changes in iron metabolism in WD. Anti-copper treatment improves but does not normalize iron metabolism.

Eosinophilic esophagitis: an interdisciplinary clinical problem.

Eosinophilic esophagitis is a newly described entity of increasing incidence. Previously thought to be a variation of gastroesophageal reflux disease, now it becomes well known among gastroenterologists, allergologists, paediatricians and pathologists. Aetiology of the disease is strongly correlated with atopic and allergic disorders but exact pathogenesis and cellular mechanisms of inflammatory process in the esophagus are still unknown. Diagnostic criteria have been described but diagnostic tools are still in the research and improvement phase. Clinical manifestation varies considerably between age groups, which causes a delay in the course of diagnosis due to improperly recognized symptoms. Since eosinophilic esophagitis is a chronic disease without a tendency to be self-limiting, delayed diagnosis may lead to complications associated with oesophageal tissue remodelling. Some forms of treatment are approved and of great therapeutical value, nevertheless clinical trials of new medications provide new possibilities. Therefore, many questions regarding eosinophilic esophagitis arise and are still unanswered.

Gastropathy in patients with Wilson disease.

Background: Gastrointestinal symptoms are common in patients with Wilson disease (WD) and may be related to the disease itself or to adverse drug reactions (ADRs).Aim: To investigate gastroscopy findings in patients with WD and to analyze the risk of gastropathy in the context of different manifestations and treatments of WD as well as Helicobacter pylori infection status.Methods: This cross-sectional study included patients diagnosed or monitored for WD between 2007 and 2017. All enrolled patients were examined with gastroscopy and checked for infection with a urease test. Based on predominant manifestations, WD was classified as pre-symptomatic, hepatic (only liver symptoms) or neurological. Patients were divided into three treatment groups: untreated, treated with d-penicillamine (DPA) or zinc sulfate therapy.Results: Of 115 patients, 58 were male and the median age was 30 years. Gastropathy was observed in 65.2% of all patients. Factors that increased the risk of gastropathy were zinc sulfate (odds ratio [OR] = 3.01; 95% confidence interval [CI]: 1.12-8.09, p = .03), H. pylori infection (OR = 2.96; 95%CI: 1.34-6.56, p = .01) and neurological manifestations (OR = 2.55; 95%CI: 1.16-5.60, p = .02). In total, 9.6% of patients had gastric or duodenal ulcers and 29.6% had esophageal varices but no difference was seen by treatment status. In multivariate analysis, zinc sulfate remained associated with higher risk of gastropathy compared with no treatment (OR = 4.57; 95%CI: 1.21-17.19; p = .03) and DPA (OR = 6.28; 95%CI: 1.43-27.56; p = .01).Conclusions: Our results show that gastropathy in WD may be influenced by the treatment used.KeypointsIn a retrospective study of 115 patients with Wilson's disease, gastric injury was frequent.Patients receiving zinc sulfate had increased gastropathy risk compared with those receiving no treatment or d-penicillamine.

Treatment with D-penicillamine or zinc sulphate affects copper metabolism and improves but not normalizes antioxidant capacity parameters in Wilson disease.

Copper accumulation in tissues due to a biallelic pathogenic mutation of the gene: ATP7B results in a clinical phenotype known as Wilson disease (WD). Aberrations in copper homeostasis can create favourable conditions for superoxide-yielding redox cycling and oxidative tissue damage. Drugs used in WD treatment aim to remove accumulated copper and normalise the free copper concentration in the blood. In the current study the effect of decoppering treatment on copper metabolism and systemic antioxidant capacity parameters was analyzed. Treatment naïve WD patients (TNWD) (n = 33), those treated with anti-copper drugs (TWD) (n = 99), and healthy controls (n = 99) were studied. Both TNWD and TWD patients characterised with decreased copper metabolism parameters, as well as decreased total antioxidant potential (AOP), glutathione (GSH) level, activity of catalase, glutathione peroxidase (GPx), and S-transferase glutathione, compared to controls. TWD patients had significantly lower copper metabolism parameters, higher total AOP and higher levels of GSH than TWD individuals; however, no difference was observed between these two patient groups with respect to the rest of the antioxidant capacity parameters. Patients who had undergone treatment with D-penicillamine or zinc sulphate did not differ with respect to copper metabolism or antioxidant capacity parameters, with the exception of GPx that was lower in D-penicillamine treated individuals. These data suggest that anti-copper treatment affects copper metabolism as well as improves, but does not normalize, natural antioxidant capacity in patients with WD. We propose to undertake studies aimed to evaluate the usefulness of antioxidants as well as selenium as a supplemental therapy in WD.

Neurochemical and behavioral characteristics of toxic milk mice: an animal model of Wilson's disease.

Toxic milk mice have an inherited defect of copper metabolism. Hepatic phenotype of the toxic milk mice is similar to clinical findings in humans suffering from Wilson's disease (WND). In the present study, neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of WND. Mice aged 2 and 12 months were used in the experiment. The mice were tested according to rotarod and footprint protocols. Monoamine content in brain structures was measured by high performance liquid chromatography. In order to detect neuronal loss, expression of enzymes specific for dopaminergic [tyrosine hydroxylase (TH)], noradrenergic (dopamine beta-hydroxylase) and serotoninergic [tryptophan hydroxylase (TPH)] neurons was analyzed by Western blot. The 12-month-old toxic milk mice demonstrated impaired locomotor performance in behavioral tests. Motor deficits were accompanied by increased copper and serotonin content in different brain regions and slight decrease in dopamine concentration in the striatum. The expression of TH, dopamine beta-hydroxylase and TPH in the various brain structures did not differ between toxic milk mice and control animals. Despite differences in brain pathology between humans and rodents, further exploration of neuronal injury in toxic milk mice is warranted to broaden the understanding of neuropathology in WND.

Intestinal expression of metal transporters in Wilson's disease.

In Wilson's disease (WND), biallelic ATP7B gene mutation is responsible for pathological copper accumulation in the liver, brain and other organs. It has been proposed that copper transporter 1 (CTR1) and the divalent metal transporter 1 (DMT1) translocate copper across the human intestinal epithelium, while Cu-ATPases: ATP7A and ATP7B serve as copper efflux pumps. In this study, we investigated the expression of CTR1, DMT1 and ATP7A in the intestines of both WND patients and healthy controls to examine whether any adaptive mechanisms to systemic copper overload function in the enterocytes. Duodenal biopsy samples were taken from 108 patients with Wilson's disease and from 90 controls. CTR1, DMT1, ATP7A and ATP7B expression was assessed by polymerase chain reaction and Western blot. Duodenal CTR1 mRNA and protein expression was decreased in WND patients in comparison to control subjects, while ATP7A mRNA and protein production was increased. The variable expression of copper transporters may serve as a defense mechanism against systemic copper overload resulting from functional impairment of ATP7B.

Endoscopic Treatment of Malignant Hilar Biliary Obstruction.

Stent implantation is an effective approach for palliative treatment of Bismuth-Corlette type III-IV malignant hilar biliary obstructions (MHBOs). In this article, we reviewed the currently used access methods for biliary stent placement (percutaneous transhepatic biliary drainage, endoscopic biliary drainage, endosonography guided biliary drainage), the available stent types (plastic stent, self-expanding metallic stent, full cover self-expanding metallic stent, radioactive self-expanding metallic stent), major approaches (unilateral, bilateral) and deployment methods (stent-in-stent, stent-by-stent). Finally, this review gives an outlook on perspectives of development in stenting and other palliative methods in MHBO.

Elastography of the Liver in Wilson's Disease.

Staging of liver fibrosis is of special significance in Wilson's disease as it determines the patient's prognosis and treatment. Histopathological examination is a standard method for fibrosis assessment; however, non-invasive methods like transient elastography and share wave elastography are believed to be reliable and repetitive and are expected to replace liver biopsy in Wilson's disease. This article presents a short description of available elastography techniques and the results of the most recent studies on elastography of the liver in patients with Wilson's disease.

Wilson's Disease-Genetic Puzzles with Diagnostic Implications.

(1) Introduction: Wilson's disease (WND) is an autosomal recessive disorder of copper metabolism. The WND gene is ATP7B, located on chromosome 13. WND is characterized by high clinical variability, which causes diagnostic difficulties. (2) Methods: The PubMed, Science Direct, and Wiley Online Library medical databases were reviewed using the following phrases: "Wilson's disease", "ATP7B genotype", "genotype-phenotype", "epigenetics", "genetic modifiers", and their combinations. Publications presenting the results of experimental and clinical studies, as well as review papers, were selected, which concerned: (i) the diversity of genetic strategies and tests used in WND diagnosis; (ii) the difficulties of genetic diagnosis, including uncertainty as to the pathogenicity of variants; (iii) genetic counseling; (iv) phenotypic effects of ATP7B variants in patients with WND and in heterozygous carriers (HzcWND); (v) genetic and epigenetics factors modifying the clinical picture of the disease. (3) Results and conclusions: The genetic diagnosis of WND is carried out using a variety of strategies and tests. Due to the large number of known variants in the ATP7B gene (>900), the usefulness of genetic tests in routine diagnostics is still relatively small and even analyses performed using the most advanced technologies, including next-generation sequencing, require additional tests, including biochemical evidence of abnormal copper metabolism, to confirm the diagnosis of WND. Pseudodominant inheritance, the presence of three various pathogenic variants in the same patient, genotypes indicating the possibility of segmental uniparental disomy, have been reported. Genotype-phenotype relationships in WND are complex. The ATP7B genotype, to some extent, determines the clinical picture of the disease, but other genetic and epigenetic modifiers are also relevant.