Objective: To determine the incidence, distribution, and prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) over the last 30 years and analyze changes over time.
Methods: All ...patients diagnosed with GEP-NETs in Iceland from 1985 to 2014 were identified through the Icelandic Cancer Registry and pathology laboratory records. Relevant clinical information was obtained from medical records. In order to assess trends, the study period was divided into two periods, 1985-1999 and 2000-2014.
Results: A total of 364 patients with GEP-NETs were identified. Overall, 18 patients diagnosed at autopsy or with primary tumors of an unknown site were excluded, leaving 346 patients with 351 primary tumors for final analysis. The overall mean annual incidence 1985-2014 was 3.65/100,000, 3.39/100,000 during 1985-1999 and 3.85/100,000 during 2000-2014 (p = NS). The most common primary tumor site was the appendix (32%), followed by the jejunum/ileum (24%) and stomach (17%). In all, 18% of patients presented with distant metastases at the time of diagnosis, most noticeably patients with primary tumors of the colon (47%), pancreas (46%) and jejunum/ileum (39%). The most favorable 5-year survival was observed for tumors of the appendix (94%) and rectum (88%) and the least favorable for tumors of the pancreas (31%), colon (47%) and jejunum/ileum (66%). There were no statistically significant changes in incidence, staging or survival between the two time periods.
Conclusions: In this population-based study, the incidence of GEP-NETs has not changed significantly over the last decades. The incidence of metastatic disease has remained stable and overall prognosis has not improved in recent years.
Introduction: PSC is a rare liver disease that leads frequently to cirrhosis and need for liver transplantation. No medical treatment is of proven value. Liver transplantation is the only curative ...therapy available. There is a big medical need to find medical therapy that can alter the natural history of the disease.
Areas covered: The authors highlight advances in PSC, based on recent literature retrieved from PubMed until September 2020 regarding both medical and endoscopic biliary therapy.
Future possibilities for treatment of PSC are discussed.
Expert opinion: Biliary endoscopy is the cornerstone in the treatment of dominant strictures. Single-user peroral cholangioscopy is an emerging modality. Balloon dilatation therapy is the treatment of choice of dominant strictures. The most promising medical therapies showing efficacy in phase II trials are nor-Ursodeoxycholic acid, obethicolic acid, the non-steroidal FXR agonist Cilofexor and Aldafermin, a synthetic analogue of FGF-19. Antibiotics, particularly vancomycin have shown potential benefits, particularly in children but phase III studies are lacking. In observational studies of effects of biological therapy in patients with IBD/PSC adalimumab was associated with reduction in ALP. Results of liver transplantation are favorable but recurrence can be of clinical relevance particularly in patients transplanted before the age of 40.
drug-induced liver injury (DILI) is a common cause of acute liver injury and can lead to death from acute liver failure or require liver transplantation. Although the total burden of liver injury is ...high, the frequency of DILI caused by specific agents is often low. As the liver injury is by per definition
, the prediction of which patients will develop liver injury from specific drugs is currently a very difficult challenge.
The current paper highlights the most important studies on prediction of DILI published in 2019-2023, including studies on genetic, metabolomic, and demographic risk factors, concomitant medication, and the role of comorbid liver diseases. Risk stratification using demographic, metabolomic, and multigenetic risk factors is discussed.
Great advances have been made in identifying genetic risk factors for DILI. Combining these risk factors with demographic information and other biomarkers into multigenetic risk models might become highly useful in risk stratifying patients exposed to DILI. However, a more detailed mapping of genetic risk factors is needed. Results of these studies need to be validated in the selected ethnic groups before applicability and cost-effectiveness can be determined.
Secondary sclerosing cholangitis (SSC) is a term used for a group of chronic cholestatic disease affecting the intra- and/or extrahepatic biliary tree with inflammation and progressive stricture ...formation, which can lead to biliary cirrhosis. A newly recognized form of SSC is secondary sclerosing cholangitis in critically ill patients (SSC-CIP). Pathogenesis is believed to involve ischemic injury of intrahepatic bile ducts associated with prolonged hypotension, vasopressors administration, and/or mechanical ventilation in patients treated in the intensive care unit (ICU). Patients diagnosed with SSC-CIP have no prior history of liver disease and no known pathologic process or injury responsible for bile duct obstruction prior to ICU treatment. Reasons leading to ICU treatment are many including multitrauma, burn injury, cardiac surgery, severe pneumonia, other infections, or bleeding after abdominal surgery. Patients have in common prolonged ICU admission. SSC-CIP is associated with rapid progression to liver cirrhosis and poor survival with limited treatment options except a liver transplantation. Transplant-free survival is around 17-40 months, which is lower than in other SSC patients. During the initial stages of the disease, the clinical symptoms and biochemical profile are not specific and easily missed. Biliary casts formation may be considered pathognomonic for SSC-CIP since most patients have them in early stages of the disease. Increased awareness and early detection of the disease and its complications is considered to be crucial to improve the poor prognosis.
Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is ...unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI.
A search was performed in PubMed, searching for the terms: "corticosteroids" and "drug-induced liver injury". Observation studies were included, but case reports excluded.
A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33-50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33-100% (mean 72%).
The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI.
OBJECTIVE:The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines.
BACKGROUND:Azathioprine (Aza) and 6-mercaptopurine (6-MP) can ...cause liver injury, but no large series exist.
METHODS:Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed.
RESULTS:Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset.
CONCLUSIONS:Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.
Gastrin elevation secondary to proton pump inhibitor (PPI) therapy is well documented. Recent studies have demonstrated a sex-related difference where females on PPIs have significantly higher ...baseline gastrin levels than males. The aim of the study was to analyse the pharmacokinetics of esomeprazole and short-term effect on serum gastrin levels and evaluate potential sex-related difference.
Healthy volunteers received 40 mg of esomeprazole daily for five days. After the 1st and 5th dose blood samples for fasting gastrin and pharmacokinetic analysis were collected at scheduled time-points for eight hours. Esomeprazole was analysed by liquid chromatography and gastrin concentrations were measured using radioimmunoassay.
A total of 30 volunteers were enrolled. Females had higher median baseline gastrin (pM) than males 12 (IQR 10-15) vs. 7 (IQR 4-11) (p = .03). In the study cohort, median gastrin levels rose from 10 (IQR 6-14) to 15 (IQR 13-20) (p = .0002). The serum levels for esomeprazole increased by an average of 299.8 ng/mL (p < .001) from day 1 to day 5. Comparison of the esomeprazole pharmacokinetic parameters between males and females revealed no significant sex-related differences. No significant correlation was found between the AUC and the gastrin level on day 5 (p = .15).
In healthy volunteers, serum gastrin increased significantly after a four-day PPI-therapy. There was also a significant increase in serum esomeprazole from day 1 to day 5. The increase in gastrin and esomeprazole concentration was not related to sex and no significant sex-related difference was found in terms of pharmacokinetic parameters. European Clinical Trial Database (2015-002230-41).
Background & Aims
No multi‐national prospective study of drug‐induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and ...short‐term outcomes of the cases and controls is reported.
Methods
Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016–2021. DILI cases or non‐DILI acute liver injury controls following causality assessment were enrolled.
Results
Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre‐existing liver disease. DILI cases and non‐DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin‐clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug‐induced autoimmune‐like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver‐related death), and another six received liver transplantation.
Conclusions
In this first multi‐national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.
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