A comparison of different symptomatic reflux esophagitis treatments: A real-world study.

BACKGROUND: Proton pump inhibitors (PPIs) are currently the reference drugs for gastroesophageal reflux disease (GERD), but symptoms often recur after their withdrawal. Moreover, whether prokinetics or barrier drugs used alongside PPIs are more effective remains under debate. OBJECTIVES: The aim of the study was to assess the efficacy of different therapeutic approaches to GERD treatment. MATERIAL AND METHODS: We enrolled 211 grade A reflux esophagitis patients who consented to participate in this non-randomized, open-label trial. The study consisted of 6 sequentially administered medical treatments for GERD, lasting 2 months, with a 3-week washout period between each drug schedule: Group A: PPI (esomeprazole 40 mg/day before breakfast); Group B: mucosal protective drugs (a combination of hyaluronic acid, chondroitin sulfate and poloxamer 407, or a combination of hyaluronic acid, chondroitin sulfate and aluminum, 3 times daily after a meal); Group C: prokinetics (levosulpiride 25 mg or domperidone 10 mg, 3 times daily before a meal); Group D: barrier drug (alginate 3 times daily after a meal); Group E: PPI (esomeprazole 40 mg/day before breakfast) and mucosal protective drugs (a combination of hyaluronic acid, chondroitin sulfate and poloxamer 407, or a combination of hyaluronic acid, chondroitin sulfate and aluminum, before sleep); Group F: PPI (esomeprazole 40 mg/day before breakfast) and prokinetics (levosulpiride 25 mg or domperidone 10 mg before lunch and dinner). Symptoms were evaluated using the visual analogue scale (VAS) and global symptomatic score (GSS), as follows: heartburn: 0-3; retrosternal chest pain: 0-3; regurgitation: 0-3. RESULTS: All but 2 treatments (groups C and D) significantly improved VAS and GSS, with group E showing the most significant GSS improvement. Group C had the highest number of dropouts due to treatment failure and reported more side effects. CONCLUSION: Using PPIs and mucosal protective drugs resulted in significant symptom alleviation. However, the administration of prokinetics caused higher dropouts due to treatment failure.

PPIs and gastric cancer: any causal relationship?

Hydrochloric acid is crucial in gastric physiology. In 1978 cimetidine, the first H2 antagonist of histamine receptors on the gastric parietal cell was introduced into therapy, inducing acid. Lasting the years, several studies focused on the potential relationship between inducing hypo-achlorhydria and risk of developing gastric cancer. In 1988 omeprazole, the first proton pump inhibitor, entered therapy. In 1996, Kuipers underlined the danger of progression of chronic atrophic gastritis in subjects taking PPIs. In 2018, one paper from Korea and an another on from Sweden suggested a possible relationship between long-term PPI therapy and the development of gastric cancer. Over the years, several articles, meta-analyzes and population based  focused on relationship between long-term of PPI use and the onset of gastric cancer, with conflicting results. As reported, the presence of bias in the collection of cases, in particular concerning the evaluation of the H.p. status and presence of atrophic gastritis and intestinal metaplasia in subjects treated with PPI, can lead to noticeable errors in the results and conclusions, as demonstrated in the literature by exhaustive methodological studies of pharmacoepidemiology. A possible bias in the collection of case histories is due to the fact that PPIs are often administered to dyspeptic patients, among which there are patients already carriers of gastric neoplasia: the so-called inverse causality.  Literature data, amended by methodological bias (sampling errors, lack of comparative assessment of Hp status and atrophic gastritis) NOT support a causal relationship between long-term PPIs therapy and the onset of gastric cancer.

Appropriateness of Proton Pump Inhibitor Prescription Evaluated by Using Serological Markers.

Inappropriate prescription of proton pump inhibitors (PPI) has been widely reported, often lacking initial exclusion of Helicobacter pylori (HP) infection and evaluation of gastric functional status. The aim of this study was to evaluate the utility of gastric functional tests to define the acid output, as well as HP status, in order to better direct PPI therapy prescription. Dyspeptic patients without alarm symptoms from a primary care population were evaluated. For each patient, serum Pepsinogen I (PGI) and II (PGII), gastrin 17 (G17) and anti-HP IgG antibodies (Biohit, Oyj, Finland) were determined. For each subject, data were collected regarding symptoms, past medical history of HP infection, and PPI use. Therapeutic response to PPIs was determined according to PGI and G17 values, where G17 > 7 in the presence of elevated PGI and absence of chronic atrophic gastritis (CAG) was considered an adequate response. Among 2583 dyspeptic patients, 1015/2583 (39.3%) were on PPI therapy for at least 3 months before serum sampling, and were therefore included in the study. Active HP infection and CAG were diagnosed in 206 (20.2%) and 37 (3.6%) patients, respectively. Overall, an adequate therapeutic response to PPIs was observed in 34.9%, reaching 66.7% at the highest dose. However, 41.1% and 20.4% of patients showed low (G17 1-7) or absent (G17 < 1) response to PPI, regardless of the dosage used. According to gastric functional response, most patients currently on PPI maintenance therapy lack a proper indication for continuing this medication, either because acid output is absent (as in CAG) or because gastrin levels fail to rise, indicating absence of gastric acid negative feedback. Lastly, HP eradication is warranted in all patients, and gastric function testing ensures this pathogen is sought for and adequately treated prior to initiating long-term PPI therapy.

Improvement of Symptoms in Patients Affected by Chronic Atrophic Gastritis Using L-Cysteine (Acetium®).

BACKGROUND: Chronic atrophic gastritis (CAG) alone is a precancerous condition for gastric cancer. Achlorhydria plays an important role in the formation of a class I carcinogen, acetaldehyde. L-cysteine has been claimed to bind acetaldehyde covalently. Symptoms are present in 55% of CAG patients, of whom 70% have upper gastrointestinal complaints. The aim of this study was to investigate the properties of L-cysteine in the modification of symptom patterns in CAG patients. METHODS: Consecutive patients with histological diagnosis of CAG (OLGA ≥1 with gastric corpus involvement) were evaluated with serological determination of gastric function, clinical assessment of symptoms using the visual analog score (VAS) and the global symptomatic score (GSS), and considered for therapy with L-cysteine, 300 mg daily. Data regarding symptoms were collected at enrollment and after 3, 6, 12, 18, and 24 months, with an ultimate follow-up of 2 years. RESULTS: A total of 330 patients with CAG were divided in group 1 (77 patients treated with L-cysteine) and group 2 (50 patients who received no specific treatment - control group). A statistically significant improvement in the VAS score (7.8 at baseline vs. 4.5 after 24 months; p < 0.01) was observed in patients treated with L-cysteine, while no significant changes in symptom pattern/intensity were recorded in the 2-year follow-up of untreated patients with CAG. CONCLUSIONS: Long-term treatment with L-cysteine provides symptom improvement in CAG patients and might be proposed as maintenance therapy in such patients.

Burning mouth syndrome and Reflux Disease: relationship and clinical implications.

BACKGROUND AND AIM: An association between reflux and burning mouth syndrome (BMS) has been proposed. Aims of this study were: 1) to investigate the frequency of BMS in a sample of GERD patients; 2) to measure G17, in a sample of BMS patients; 3) to assess the efficacy of different therapeutical schedules for GERD in BMS patients. METHODS: We divided the study in 3 main steps. In step one, we analyzed 500 consecutive GERD patients' type and frequency of extraesophageal manifestations including BMS. In step two, we collected 124 consecutive BMS patients' symptoms and  G17.  In step three, we evaluate the efficacy of 3 different drugs on BMS. RESULTS: In step one, 204 patients complained heartburn; 31 globus pharyngeus; 52 chronic cough; 54 pharyngitis; 31 postnasal drip; 56 burning mouth symptoms; 34 noncardiac chest pain; 17 asthma and 21 sleep apnea. In step two, 29 patients had G17 ≤ 1 pg/L; 64 patients between 1 and 3; and 31 patients ≥ 3. In step three, 49 patients reported slight benefit with PPI, 75 no benefit. 61 patients reported slight benefit with sodium alginate and sodium bicarbonate, 63 no benefit. 23 reported an almost complete remission with HYCHSA, 26 slight benefit, 33 no benefit. CONCLUSIONS: Prevalence of BMS in GERD patients was similar to that reported for chronic chough and pharyngitis. Low levels of G17 were found in the majority of BMS patients. Finally, we observed a greater benefit from barrier drugs therapy than from PPI therapy in BMS patients. (www.actabiomedica.it).

Recovery of gastric function in patients affected by chronic atrophic gastritis using l-cysteine (Acetium®): one year survey in comparison with a control group.

BACKGROUND AND AIM: Chronic Atrophic Gastritis (CAG) is a precancerous condition for gastric cancer (GC) as single risk factor, being a consequence of a previous Helicobacter pylori (Hp) infection or based on autoimmune mechanisms. Achlorhydria plays an important role towards the formation of a class I carcinogen, acetaldehyde, after food intake. L-cysteine has been claimed to be able to bind in a covalent way acetaldehyde when administered at means. METHODS: In this study we enrolled two CAG groups of patients, one treated whit 300 mg/daily of L-cysteine for one year, the other one untreated. We assessed gastric function lasting the one year follow-up by using non invasive surrogates, i.e. Pepsinogen I (PGI) and gastrin 17 (G17). RESULTS: In the group of 77 CAG on therapy we found a statistically significative increase in PGI values and a decrease in G17 levels, in comparison with unchanged values in control group. CONCLUSIONS: L-cysteine seems able to provide a recovery in gastric function when administered in CAG patients and could be proposed as a possible therapy in such patients.

Barrett's esophagus: results from an Italian cohort with tight endoscopic surveillance.

BACKGROUND AND AIM: Barrett's Esophagus represents a condition that predisposes to the development of esophageal adenocarcinoma. The aim of the present study was to analyze the demographic and clinical characteristics of patients with BE, to establish the presence of risk factors for this condition, and to determine the frequency of dysplastic lesions as well as the evolution towards adenocarcinoma under tight endoscopic control. METHODS: In this study, we retrospectively collected and analyzed data from a cohort of patients with Barrett's Esophagus identified through endoscopic records of ULSS7 in Northern Italy, who underwent upper esophagogastroduodenoscopy over a 10-year period from July 2008 to December 2020. RESULTS: A total of 264 patients were identified as having BE and included in the study. Mean follow-up was 6.7 years (range: 3 months-13 years). Demographic characteristics of the study population included mean age of 62.7 years (range 33-90 years), with 62.5% of the study population being aged 60 or older, and a male predominance. Females were significantly older than males (65.7 years, range 37-90 vs 61.9 years, range 33-87, p=0.043, respectively). CONCLUSIONS: The present study confirms the importance of tight endoscopic control in the management of BE, favoring early detection of BE degeneration towards high-grade dysplasia or adenocarcinoma. In a subset of patients with high-risk factors including male sex, cigarette smoking and heavy alcohol intake, it may be worthwhile to consider endoscopic control over time in order to detect the development of BE.

Pepsinogen II in gastritis and Helicobacter pylori infection.

BACKGROUND AND AIM: In the gastric mucosa, pepsinogen II (PgII) is produced/secreted by glands in the mucus-secreting antral and cardia compartments, but also by the chief cells and the oxyntic glands. Increasing PgII serum levels are associated with the whole spectrum of gastric inflammatory diseases, including gastritis induced by Helicobacter pylori (H. pylori). This review critically addresses the clinical value of PgII serology for assessing gastric mucosal inflammation, and as a marker of H. pylori status, in both H. pylori-positive patients and after eradication therapy. RESULTS: A search in PubMed/Scopus records yielded 39 out of 1190 published scientific studies meeting the selection criteria for this study. In the studies considered, PgII levels were significantly associated with non-atrophic gastric inflammatory lesions (p-values: 0.025-0.0001). H. pylori-positive patients had significantly higher PgII levels than H. pylori-negative individuals (p-values: 0.o5-0.0001). While a significant drop in serum PgII levels is consistently reported in H. pylori-eradicated patients (p-values: from 0.05 to 0.0001), inconsistencies in the related negative and positive predictive values significantly lower the clinical reliability of PgII testing by comparison with other available non-invasive tests. CONCLUSIONS: PgII serology may provide clinically useful information on gastric inflammatory diseases, particularly if they are non-atrophic. PgII serology is inconsistent, however, for the purposes of distinguishing patients whose H. pylori eradication therapy is successful from those who remain infected.

Comparison of performances of infliximab biosimilars CT-P13 versus SB2 in the treatment of inflammatory bowel diseases: a real-life multicenter, observational study in Italy.

BACKGROUND: To compare the performances of Infliximab (IFX) biosimilar CT-P13 and SB2 in the treatment of Inflammatory Bowel Diseases (IBD) outpatients in Italy. RESEARCH DESIGN AND METHODS: Three hundred and eighty IBD outpatients were retrospectively evaluated. The primary endpoint was to compare the two IFX biosimilars in terms of reaching and maintenance of remission at any timepoint. RESULTS: 197 patients with Ulcerative Colitis (UC) and 183 patients with Crohn's Disease (CD) treated with CT-P13 or SB2 and having a median (IQR) follow-up of 12 (6-36) months were compared: 230 (60.5%) were naïve to anti-TNFα, 20 (5.26%) were switched from IFX originator or from IFX CT-P13 to IFX SB2. Clinical remission was achieved in 133 (67.5%) UC patients and in 164 (89.6%) CD patients (p < 0.000), with no differences between CT-P13 and SB2 in the rate of remission in UC (p = 0.667) and CD (p = 0.286). Clinical response, steroid-free remission, rate of surgery, mucosal healing (MH) in UC, switching from IFX originator or from other biosimilar, and safety were similar. Higher MH rate was obtained in CD patients treated with CT-P13 (p = 0.004). CONCLUSION: This first comparative study found that both IFX biosimilars CT-P13 and SB2 are effective and safe in managing IBD outpatients.

Low Levels of Gastrin 17 are Related with Endoscopic Findings of Esophagitis and Typical Symptoms of GERD.

BACKGROUND AND AIMS: In clinical practice, most patients with symptoms suggestive of gastroesophageal reflux disease (GERD) undergo esophago-gastro-duodenoscopy (EGD), despite its low sensitivity in detecting reflux stigmata. Gastrin 17 (G-17) has been proposed to be related with GERD, due to the negative feedback between acid secretion and this hormone. We assessed the clinical usefulness of fasting G-17 serum determination for a non-invasive diagnosis of GERD in patients with typical symptoms. METHODS: We consecutively enrolled patients complaining of typical GERD symptoms in two different settings: a single referral center and a primary care setting. Control groups consisted of dyspeptic patients. All subjects underwent assessment of serum levels of G-17 and EGD. RESULTS: At the academic hospital, 100 GERD patients (n=89 with erosive esophagitis and 11 with Barrett's esophagus) had statistically significant low levels of G-17 as compared with 184 dyspeptic patients (1.7±1.2 pg/L vs 8.9±5.7 pg/L p<0.0001). Similarly, in the primary care setting, 163 GERD patients had statistically significant low levels of G-17 as compared with 132 dyspeptic patients (0.5±0.2 pg/L vs. 4.0±2.6 pg/L, p<0.0001). Moreover, in the primary care setting, no statistically significant differences were found for G-17 levels between patients with erosive and non-erosive reflux pattern (0.4±0.2 vs 0.7±0.3; p=0.08). In primary care, the accuracy of G-17 less than 1 pg/L to diagnose non-invasively GERD was 94.3%. CONCLUSIONS: Low levels of G-17 were detected in patients with erosive esophagitis and Barrett's esophagus in a referral center and in patients with typical GERD symptoms in a sample of patients from a primary care setting.

Functional Dyspesia.

Dyspepsia is a functional GI disorder consisting in a wide range of symptoms. The main diagnostic challenge has been whether to perform an EGD or an abdominal US in order not to miss organic lesions, but to avoid unnecessary and sometimes invasive tests. Pepsinogen serology has been proposed as an useful non-invasive test to explore the status of the gastric mucosa, suggesting this strategy as an adequate approach in management of dyspepsia. In a primary care setting, 266 dyspeptic patients were investigated to establish the proper diagnosis. The workup included upper GI endoscopy with biopsies, a structured questionnaire including type and severity of symptoms, serological determination of serum pepsinogens, gastrin 17 and IgG against Hp. Inclusion criteria were dyspeptic symptoms (epigastric pain, nausea and/or vomiting, post prandial fullness, early satiation) lasting more than 1 year and the association between symptoms and food ingestion.. Helicobacter pylori infection was present in 114 subjects, characterized by high levels of pepsinogen II and IgG against Hp. Twenty subjects were classified according with the diagnosis of chronic body atrophic gastritis. Nausea and post prandial fullness were the most frequent symptoms (48% and 41%, respectively) in the studied population, followed by epigastric pain and early satiation (37% and 26% respectively). A diagnosis of normality by serological diagnosis was found in half of patients experiencing epigastric pain and in about 60% of subjects with the three other symptoms (nausea, post prandial fullness, and early satiation). In conclusion, this experience confirms the clinical usefulness of serology in dyspepsia, contributing to correctly diagnosing CAG and H.p. infection in such patients and providing a good correlation with the clinical picture.

A prediction model for successful anticoagulation in cirrhotic portal vein thrombosis.

BACKGROUND AND OBJECTIVE: Portal vein thrombosis (PVT) is a common complication in cirrhosis, and when complete, it increases morbidity and mortality in liver transplant candidates. The aim of the study was to assess the hemostatic status, as well as clinical characteristics of thrombus and patients, as predictors of therapeutic efficacy of anticoagulation for the treatment of PVT in cirrhotics. PATIENTS AND METHODS: Patients with cirrhosis consecutively treated for PVT with enoxaparin were enrolled. All patients underwent evaluation of coagulation status and thrombophilia screening. Thrombus characteristics and extension were evaluated at baseline and during follow-up. Anticoagulation was continued until recanalization or up to 12 months. Variables correlated with the response to anticoagulation were used to create a predictive score that was validated in an external multicenter cohort. RESULTS: A total of 65 patients were included and had partial PVT in most cases (72%). Treatment with enoxaparin resulted in an overall response rate of 66% (43/65) after a median time of 4.4 months and 76% (33/43) within the first 6 months. At multivariate analysis, efficacy of anticoagulation correlated with the severity of liver disease, complete verus partial PVT, age of the thrombus, and time interval from treatment start (<6 months). The areas under the curve of the statistical model for predicting the response to anticoagulation were 0.84 and 0.76 for the training (n=65) and validation (n=60) cohorts, respectively. CONCLUSION: Early diagnosis and early treatment are key factors for the successful management of PVT in cirrhosis, so that screening of PVT and prompt start of anticoagulant treatment should be mandatory.

Epidemiology and risk factors of pancreatic cancer.

The most frequent pancreatic cancer is pancreatic adenocarcinoma. It has high and early locally and distant invasiveness; this is the reason why it often shows little sign or symptoms in early stage and poor prognosis after the diagnosis, frequently in advanced stage. Although it is possible to detect this tumor in early stage because of its neoplastic precursor (PanINs). Epidemiological data shows that pancreatic cancer is not very common but obvious it is one of the most neoplastic death-cause in the world. The trend of incidence is quite increasing through years, proportionally to the increase of risk factors. About risk factors, it is not easy to detect in all the cases but it is known the role of some of that: there are hereditary risk factors, such as genetic pattern like HBOC, HNPCC, FAP, PJS, FAMMM, HP and CF and environmental ones (modifiable) such as smoke, alcohol consumption, chronic pancreatitis, obesity and diabetes mellitus. This narrative review aims to analyze the epidemiological data of pancreatic cancer and associated risk factors.

Clinical manifestations of chronic atrophic gastritis.

Although the actual prevalence of chronic atrophic gastritis is unknown and it is probable that this entity goes largely underdiagnosed, patients in whom diagnosis is established usually present advanced stages of disease. Destruction of parietal cells, either autoimmune-driven or as a consequence of Helicobacter pylori infection, determines reduction or abolition of acid secretion. Hypo/achloridia causes an increase in serum gastrin levels, with an increased risk of the development of neuroendocrine tumors. Microcytic, hypochromic anemia frequently precedes the development of megaloblastic, vitamin B12-associated anemia. Moreover, vitamin B12 deficiency,may cause elevation of homocysteine, with an increase in the cardiovascular risk, and may be associated with neurological manifestations, mainly characterized by spinal cord demyelination and atrophy, with ensuing sensory-motor abnormalities. Gastrointestinal manifestations seem to be associated with non-acid reflux and tend to be non-specific.

Autoimmune diseases in autoimmune atrophic gastritis.

Autoimmune diseases, characterized by an alteration of the immune system which results in a loss of tolerance to self antigens often coexist in the same patient. Autoimmune atrophic gastritis, characterized by the development of antibodies agains parietal cells and against intrinsic factor, leads to mucosal destruction that affects primarily the corpus and fundus of the stomach. Autoimmune atrophic gastritis is frequently found in association with thyroid disease, including Hashimoto's thyroiditis, and with type 1 diabetes mellitus, Other autoimmune conditions that have been described in association with autoimmune atrophic gastritis are Addison's disease, chronic spontaneous urticaria, myasthenia gravis, vitiligo, and perioral cutaneous autoimmune conditions, especially erosive oral lichen planus. Interestingly, however, celiac disease, another frequent autoimmune condition, seems to play a protective role for autoimmune atrophic gastritis. The elevated prevalence of autoimmune disease clustering should prompt the clinicial to exclude concomitant autoimmune conditions upon diagnosis of any autoimmune disease.

Long-Term Outcome of Splanchnic Vein Thrombosis in Cirrhosis.

INTRODUCTION: Little is known about the long-term outcome of cirrhotic patients with splanchnic vein thrombosis (SVT). This prospective cohort study aimed to describe the clinical presentation, bleeding incidence, thrombotic events, and mortality in patients with SVT associated with cirrhosis. METHODS: Among 604 consecutive patients with SVT enrolled over 2 years, 149 had cirrhosis. Major bleeding, thrombotic events, and all-cause mortality were recorded during a 2-year follow-up. In a subgroup, the degree of recanalization with or without anticoagulation therapy, and the correlation between clinical events and liver disease severity were also investigated. RESULTS: The most common thrombosis sites were the portal (88%) and mesenteric veins (34%). At presentation, 50% of patients were asymptomatic. Anticoagulation was administered to 92/149 patients for a median of 6.5 months. Vessel recanalization was documented in 47/98 patients with a radiological follow-up. Anticoagulation was associated with a 3.33-fold higher of recanalization rate, and a lower recurrent thrombosis rate, while patients with and without anticoagulation experienced a similar rate of major bleeding episodes. Mortality rates were 6.8 per 100 patient-years for patients with thrombosis completely or partially resolving during the follow-up, and 15.4 per 100 patient-years for those with stable or progressing thrombosis. An impact of SVT on survival was only apparent in patients with more advanced liver disease (Child-Pugh B-C). CONCLUSIONS: Patients with SVT and cirrhosis have a substantial long-term risk of recurrent thrombotic events, which is reduced by anticoagulation therapy without any increase in bleeding risk. Anticoagulation can improve the likelihood of vessel recanalization, and is associated with a lower risk of death for decompensated patients.

Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma.

BACKGROUND: Cirrhotic patients with hepatocellular carcinoma (HCC) exhibit hypercoagulability. AIM: We investigated whether thromboelastometry can detect hypercoagulability in these patients and the association with portal vein thrombosis (PVT). METHODS: At baseline, cirrhotic patients with and without HCC underwent thromboelastometry. PVT onset was recorded over a 12-month follow-up period. RESULTS: Seventy-six patients (41 with and 35 without HCC) were included. Vital tumor volume (VTV) was >5cm3 in 18 patients. Fibrinogen was higher in HCC patients with VTV>5cm3 as compared to those with VTV≤5cm3 and those without HCC. Mean platelet count was significantly increased in HCC patients compared with non-HCC. At baseline thromboelastometry, HCC patients showed shorter CTF and higher MCF than non-HCC. PVT incidence was 24,4% and 11.4% in patients with (10/41) and without (4/35) HCC, respectively. Among HCC, 50% of PVT occurred in Child A patients. In HCC, FIBTEM MCF>25mm was associated with a 5-fold increased PVT risk [RR: 4.8 (2-11.3); p=0.0001]. Cox multivariate analysis confirmed HCC and increased MCF (FIBTEM) to be independently associated with increased PVT risk. CONCLUSIONS: Hypercoagulability in HCC which can be detected by thromboelastometry is associated with increased risk of PVT even in Child A patients. The clinical implication of these findings deserves further investigation.

Wilson's disease: A review of what we have learned.

Wilson's disease (WD), which results from the defective ATP7B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.

Neoplastic disease after liver transplantation: Focus on de novo neoplasms.

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.