Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study.

BACKGROUND: There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. METHODS: We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. RESULTS: There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1-8.4). CONCLUSIONS: This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).

Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.

Liver Complications Following Treatment of Hematologic Malignancy With Anti-CD22-Calicheamicin (Inotuzumab Ozogamicin).

Treatment of hematological malignancy with antibody-drug conjugates (ADCs) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells, but may also injure hepatic sinusoids (sinusoidal obstruction syndrome; SOS). We studied patients who received an anti-CD22/calicheamicin conjugate (inotuzumab ozogamicin; InO) to gain insight into mechanisms of sinusoidal injury, given that there are no CD22+ cells in the normal liver, but nonspecific uptake of ADCs by liver sinusoidal endothelial cells (LSECs). Six hundred thirty-eight patients (307 with acute lymphocytic leukemia [ALL], 311 with non-Hodgkin's lymphoma [NHL]) were randomized to either InO or standard chemotherapy (controls). While blinded to treatment assignment, we reviewed all cases with hepatobiliary complications to adjudicate the causes. Frequency of SOS among patients who received InO was 5 of 328 (1.5%), compared to no cases among 310 control patients. Drug-induced liver injury (DILI) developed in 26 (7.9%) InO recipients and 3 (1%) controls. Intrahepatic cholestasis (IHC) was observed in 4.9% of InO recipients and in 5.5% of controls. Subsequent to the randomization study, 113 patients with ALL underwent allogeneic hematopoietic cell transplantation (HCT); frequency of SOS in those previously exposed to InO was 21 of 79 (27%) versus 3 of 34 (9%) in controls. An exploratory multivariate model identified a past history of liver disease and thrombocytopenia before conditioning therapy as dominant risk factors for SOS after transplant. Conclusion: Frequencies of SOS and DILI after inotuzumab ozogamicin treatment were 1.5% and 7.9%, respectively, compared to none and 1% among controls who received standard chemotherapy. These data suggest that ADCs that do not target antigens present in the normal liver have a relatively low frequency of SOS, but a relatively high frequency of DILI.

Clinical and histopathologic features of fluoroquinolone-induced liver injury.

BACKGROUND & AIMS: Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features. METHODS: We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods. RESULTS: Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23-80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1-39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase. CONCLUSIONS: Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur.

Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.

Long-term quality of life improvement in subjects with healed erosive esophagitis: treatment with lansoprazole.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a chronic symptomatic condition and may be associated with erosive esophagitis (EE). Considerable data on the long-term maintenance of healing of EE are available, but data on long-term GERD symptom prevention and patient quality of life (QOL) are limited. AIMS: To investigate QOL in subjects with healed EE who received 12 months of double-blind maintenance treatment with lansoprazole or ranitidine, followed by long-term open-label lansoprazole therapy to prevent recurrence of EE. METHODS: Subjects with healed EE received 12 months of double-blind maintenance treatment with lansoprazole 15 mg once daily or ranitidine 150 mg twice daily, followed by dose-titrated, open-label lansoprazole therapy for up to 82 months. RESULTS: During double-blind treatment (n = 206), lansoprazole-treated patients showed significantly (P

Lansoprazole for long-term maintenance therapy of erosive esophagitis: double-blind comparison with ranitidine.

In a study evaluating the efficacy and safety of lansoprazole to prevent the relapse of erosive esophagitis (EE), 206 of 241 patients (85%) healed after open-label treatment with lansoprazole 30 mg once daily for 8 weeks and received double-blind maintenance treatment with lansoprazole 15 mg once daily or ranitidine 150 mg twice daily for up to 1 year. At 1 year, 67% of lansoprazole-treated and 13% of ranitidine-treated patients remained healed (P<0.001). Lansoprazole-treated patients experienced significantly greater symptom relief (P<0.001), and, if asymptomatic at entry into the maintenance phase, remained asymptomatic for significantly longer than ranitidine-treated patients (P<0.001). Symptom status correlated with healing (P=0.001), supporting the symptom-directed management of EE. Both treatments were well tolerated and no unexpected events occurred. Daily therapy with lansoprazole to prevent the relapse of EE is effective, well tolerated, and superior to ranitidine in the maintenance of healing and symptom relief.

Long-term efficacy of lansoprazole in preventing relapse of erosive reflux esophagitis.

In a phase III study of lansoprazole treatment, patients with healed or unhealed erosive esophagitis entered a titrated open-label treatment period and received lansoprazole for

Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis.

BACKGROUND: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.

Recurrent pneumonia from severe nonacid reflux: a case report and discussion.

The role of acid in the pathophysiology of gastroesophageal reflux disease (GERD) is extensively studied and well accepted. The role of nonacid reflux is poorly understood and its diagnosis is elusive. It has been postulated that the nonacid component of refluxate may play a significant role in causing esophageal mucosal damage and extra esophageal manifestations of GERD. We report a patient with severe nonacid reflux causing recurrent pneumonias and choking episodes resulting in serious morbidity and extensive utilization of health care resources. The diagnosis was established by combined intraluminal pH-impedance testing. Medical management with prokinetic agents and proton pump inhibitors failed. The patient's symptoms were ultimately controlled by a permanent jejunostomy. This patient illustrates the combined challenges in the diagnosis and treatment of nonacid reflux, particularly as it relates to larnyngopharyngeal and pulmonary manifestations.

Therapeutic choices in reflux disease: defining the criteria for selecting a proton pump inhibitor.

Gastroesophageal reflux disease (GERD) is among the most common disorders of the gastrointestinal tract, with symptoms affecting a substantial proportion of the US population on a daily basis. Heartburn and related symptoms arise from a number of pathophysiologic mechanisms, including dilated intercellular spaces, increased duration of acid reflux, greater proximal extent of reflux, and esophageal sensitivity. Chronic reflux may result in serious complications, such as esophageal erosions or ulceration, stricture, and Barrett esophagus. The goals of GERD therapy are to relieve patients' symptoms and prevent complications. Proton pump inhibitors (PPIs) represent the most effective treatment option for GERD, relieving symptoms, healing erosions, and maintaining a healed mucosa. Differences in the pharmacokinetics and pharmacodynamics among the PPIs may result in differences in intragastric pH holding time as well as the onset of symptom relief. Lansoprazole and esomeprazole produce similar degrees and onset of symptom relief, with both providing greater symptom relief as compared with omeprazole. Although manufactured as capsules containing enteric-coated granules, lansoprazole, omeprazole, and esomeprazole maintain their high level of pharmacologic efficacy when the capsule contents are emptied into soft foods or various liquids. Lansoprazole and pantoprazole also are manufactured as intravenous formulations, and lansoprazole is available as strawberry-flavored granules for oral suspension and as an orally disintegrating tablet. These alternative routes of administration are particularly beneficial in the management of acid-related disorders in infants, children, the elderly, and patients of all ages who have difficulty swallowing or are unable to swallow intact capsules or tablets and those in the critical care setting.

Lansoprazole for maintenance of remission of erosive oesophagitis.

Gastro-oesophageal reflux disease, which is experienced daily by a significant proportion of individuals, may result in serious sequelae such as erosive oesophagitis. Short-term treatment with acid antisecretory therapy (a proton pump inhibitor or a histamine H(2) receptor antagonist) is highly effective in healing the erosive oesophagitis lesion. However, numerous studies confirm that unless maintenance therapy is initiated virtually all patients will experience oesophagitis relapse within 1 year, as well as an increasing severity of oesophagitis and risk for complications such as Barrett's oesophagus and adenocarcinoma. Studies evaluating the efficacy of proton pump inhibitor and H(2) antagonist maintenance therapy have found that only the proton pump inhibitors significantly reduce the incidence of oesophagitis relapse. Pharmacoeconomic studies have also confirmed that proton pump inhibitor maintenance therapy is cost effective, by virtue of the ability of these agents to reduce the incidence of relapse as well as prolong the time to relapse and increase the number of weeks per year that patients are without symptoms. Lansoprazole, a member of the proton pump inhibitor class of agents, has been extensively studied in the treatment of patients with a variety of acid-related disorders. Among those with erosive oesophagitis, maintenance therapy with lansoprazole 15 or 30mg once daily is highly effective in preventing relapse. Studies have documented that lansoprazole 15 and 30mg once daily for six months prevents oesophagitis relapse in up to 81 and 93% of patients, respectively, with comparable percentages of patients remaining in remission after 1 year of treatment. These high rates of remission have also been observed in studies of patients with lesions that were difficult to heal at baseline (resistant to healing with at least 3 months of H(2) antagonist therapy). Moreover, lansoprazole produces high remission rates regardless of the grade of erosive oesophagitis before acute healing. Among symptomatic patients with heartburn, lansoprazole provides rapid and effective relief of daytime and night-time heartburn and prevents relapse of symptoms. Lansoprazole has a wide margin of safety and is well tolerated when administered as monotherapy in short- and long-term clinical trials. Taken together these data suggest that proton pump inhibitor therapy represents the preferred and ideal long-term management strategy for the patient with erosive oesophagitis. Lansoprazole is a well-established member of this class of agents and, as such, has an extensive body of literature that supports its safety, tolerability and clinical efficacy in preventing relapse in these patients.

Gastroesophageal reflux in children: pathogenesis, prevalence, diagnosis, and role of proton pump inhibitors in treatment.

A substantial percentage of infants, children and adolescents experience gastroesophageal reflux disease (GERD) and its accompanying symptoms, as well as disease complications. The diagnosis of GERD in children is made based upon the child's history, and data derived primarily from pH monitoring tests and endoscopy. In those children with confirmed reflux disease, the options for management parallel those recommended in adult patients, with the first step consisting of lifestyle changes. Surgical procedures may also be performed; however, these are rarely recommended prior to an adequate course of pharmacologic therapy, and appropriate case selection is important. Among the current pharmacotherapeutic options available in the US, the prokinetic agents and the acid-inhibitory agents (histamine-2 receptor antagonists, proton pump inhibitors) are the most widely used. The clinical utility of the prokinetic agents has been limited by the recent withdrawal of cisapride from the US marketplace and the potential for irreversible central nervous system complications with metoclopramide. Numerous clinical studies performed in adults, and several studies involving children, have demonstrated that the proton pump inhibitors are more effective than the histamine-2 receptor antagonists in the relief of GERD symptoms and healing of erosive esophagitis. In children, omeprazole and lansoprazole may be administered as the intact oral capsule, or in those who are unable or unwilling to swallow, the granule contents of the capsule may be mixed with soft foods (e.g. apple sauce) or fruit drinks/liquid dietary supplements prior to oral administration with no detrimental effects on pharmacokinetics, bioavailability, or pharmacodynamics. Studies performed with omeprazole and lansoprazole in children have shown pharmacokinetic parameters that closely resemble those observed in adults. In over a decade of use in adults, the proton pump inhibitor class of agents has been found to have a good safety profile. Studies involving children have also shown these agents to be well tolerated. In numerous drug-drug interaction studies performed with these two proton pump inhibitors, relatively few clinically significant interactions have been observed.

Motion - All patients with GERD should be offered once in a lifetime endoscopy: arguments against the motion.

The evidence for the recommendation that patients with gastroesophageal reflux disease (GERD) be offered once in a lifetime endoscopy is weak and is not supported by any clinical trials. GERD is a very prevalent condition, yet only 10% of patients with GERD have Barrett's esophagus (BE). Esophageal adenocarcinoma (EAC) is a rare condition and is uncommon even among patients with BE. A decision analysis found that surveillance of BE patients is performed because of inflated estimates of the rate of progression from BE to EAC. Dysplasia more often regresses to more benign histological findings than to cancer, and transient dysplasia can also lead to a high rate of unnecessary endoscopy. Even though practice guidelines about endoscopic surveillance have been published, there is no consensus among gastroenterologists about appropriate protocols, and many physicians are more aggressive than the guidelines. It has not been proved that surveillance saves lives, in part because BE rarely leads to death from EAC. The favourable results from some specialized centres may not be widely applicable. The recommendation for 'once in a lifetime' endoscopy for GERD patients is premature.

Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work.

BACKGROUND: Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans. OBJECTIVE: (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase). DATA SOURCES AND EXTRACTION: (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase. DATA SYNTHESIS: After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF. CONCLUSIONS: This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD), the major hepatic manifestation of type 2 diabetes mellitus, is the most common liver disease in the US. Thiazolidinediones, a commonly used drug class for the treatment of type 2 diabetes, have emerged as a potentially useful treatment for NAFLD. There are, however, lingering concerns about their potential toxicity as well as emerging concerns about how to monitor for and assess hepatotoxicity. We conducted a randomized, long-term, double-blind, hepatic safety study at 171 centres in the US in which 2097 patients with type 2 diabetes received either pioglitazone or glibenclamide (glyburide). METHODS: Patients were randomized to receive either pioglitazone (15-45 mg once daily) or glibenclamide (5-15 mg once daily) for 3 years. The primary objective was to evaluate drug-induced liver injury manifested by liver enzyme elevations, measured every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint was a confirmed ALT greater than three times the upper limit of normal (>3 x ULN) with a secondary endpoint of 8 x ULN. MAIN RESULTS: The intent-to-treat population included 1051 pioglitazone-treated and 1046 glibenclamide-treated patients; of these, 411 pioglitazone patients and 413 glibenclamide patients completed the study. The incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617). Analyses of the secondary endpoints revealed no ALT >8 x ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 x ULN + total bilirubin 2 x ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 x ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p < or = 0.05) fewer cases of ALT >1.5 x ULN, aspartate aminotransferase >1.5 x ULN and gamma-glutamyl transpeptidase >1.5 x ULN were seen with pioglitazone compared with glibenclamide. No case of hepatic dysfunction or hepatic failure was reported in either treatment group; two cases of hepatic cirrhosis with glibenclamide were reported. CONCLUSION: This study demonstrates an hepatic safety profile of pioglitazone similar to that of glibenclamide in long-term use in patients with poorly controlled type 2 diabetes. Trial registration number (clinicaltrials.gov): NCT00494312.

Use of pH-impedance testing to evaluate patients with suspected extraesophageal manifestations of gastroesophageal reflux disease.

GOALS: To report the use of pH-impedance testing in evaluating patients with suspected gastroesophageal reflux disease (GERD) with atypical symptoms. BACKGROUND: Although the role of acid reflux in causing atypical GERD symptoms is generally accepted, the role, if any, of nonacid reflux is controversial, largely because until recently it has not been possible to detect nonacid reflux. The advent of intraluminal combined pH impedance testing (MII-pH), to detect nonacid reflux has heightened interest in its possible contribution to atypical symptoms. STUDY: Fifty consecutive patients referred for MII-pH testing to evaluate the cause of atypical symptoms presumed due to GERD were evaluated. The symptoms were either refractory to acid inhibition therapy or so atypical that further work up was desired by the referring physician. Patients underwent MII-pH testing to determine whether reflux was present, and, if so, if it was due to acid, nonacid, or gas. RESULTS: Only 16%, 22%, and 2% patients were found to have symptoms due to acid reflux, nonacid reflux, or both, respectively. Ten percent of these patients had gas reflux. MII-pH testing was useful in redirecting the management of patients who did not have reflux as the cause of their symptoms. CONCLUSIONS: MII-pH testing is useful in determining whether gastroesophageal reflux is present in patients with atypical symptoms that have not responded to proton pump inhibitor therapy. It also distinguishes between reflux due to acid, nonacid, and gas, with consequences for management.

Advancing patient care: integrating new data.

Physicians involved in the management of patients with chronic hepatitis B infection are frequently faced with complex clinical issues concerning the diagnosis, investigation, and treatment of patients. Guidelines exist within the literature that help with decision making; however, in practice individual nuances are often encountered necessitating decisions that go beyond the current guidelines. Following presentation of the available data, a panel of expert hepatologists and gastroenterologists sought to identify and solve challenges that are faced by clinicians in the daily management of patients with chronic hepatitis B infection. The following summary provides an overview of the outcome of these discussions. Because of the complexities of clinical management, the recommendations reflect the opinion of the majority; however, many recommendations were not unanimous. Furthermore, the recommendations that follow are limited to adult patients; the treatment of children was not discussed. A number of issues were identified, and statements concerning possible management strategies that could be applied were developed.