Search

Since the early trials in viral hepatitis, more and more new drugs are being tested for use in various liver diseases. Since drug hepatotoxicity is a major cause of drugs under investigation not making it to market, the assessment of drug-induced liver injury in clinical trials of new drugs is crucial. This review will focus on the systems that are used to assess drug-induced liver injury in clinical trials and will discuss how some of these criteria are inappropriate or inaccurate in this function together with suggestions for improvement., Competing Interests: None., (Thieme. All rights reserved.)

OBJECTIVE. This systematic review presents evidence-based consensus statements as reported by a multidisciplinary expert panel (six abdominal radiologists, four hepatobiliary surgeons, and two hepatologists) regarding the use of gadoxetic acid for liver MRI. CONCULSION. Although this review highlights the incremental diagnostic value of hepatobiliary phase imaging with gadoxetic acid-enhanced liver MRI in multiple clinical scenarios, there remains a need for further impact studies for some clinical applications, such as hepatocellular carcinoma in cirrhosis.

Objective: To determine the outcome of small arterial phase-enhancing nodules, 10-20 mm, seen on serial triphasic liver CT scans in a hepatocellular cancer-screening population., Methods: Of 58 patients referred for triphasic liver CT, 20 (18 men, 2 women) with 32 nodules formed the study group. Each patient in the study group had at least two CT scans, a minimum of 3 months follow-up, at least one nodule measuring 10-20 mm, no prior diagnosis of hepatocellular carcinoma, and no nodule greater than 20 mm typical of hepatocellular carcinoma at the time of the first CT. Serial CT scans were reviewed by an abdominal imaging radiologist who classified the nodules as stable, decreasing, or increasing in size., Results: A mean of six CT studies (range 2-10) were performed for each patient with a mean follow-up of 25 months (range 4-47 months). Of 32 nodules, 14 (44%) were stable, 9 (28%) decreased, and 9 (28%) increased in size. Nodules that increased in size were treated as hepatocellular carcinoma: six were hepatocellular carcinoma, two were biopsy negative but showed recurrent tumor after radiofrequency ablation, and one was a high-grade dysplastic nodule. Mean doubling time for these nine nodules was 5.7 months (range 2.3-10.8 months)., Conclusions: Most small (10-20 mm) arterial phase-enhancing nodules seen on triphasic liver CT are not hepatocellular carcinoma. Serial CT is useful to guide management in these patients. Growth of small arterial phase-enhancing nodules can be used as an indicator that the nodule should be treated as hepatocellular carcinoma.

The advent and efficacy of surveillance for hepatocellular carcinoma (HCC) has necessitated the refinement of assessing who is at risk for this cancer. Initially, risk was assessed for all individuals with hepatitis B and all those with cirrhosis. However, the majority of these individuals do not develop HCC so that providing surveillance for all is a waste of resources. There are now many different scores that have been developed that allow better identification of who is at risk and who is not. Specific models have been developed for hepatitis B before and on treatment, for hepatitis C before and after treatment, and for cirrhosis in general. There are also models for assessing risk in the general population. Some models can only be applied to patients coming from the population in which the score was developed (e.g., hepatitis B). Others are more generalizable. Many lack external validation. With some exceptions, the models do not attempt to assess the score at which surveillance should start. Overall, the models provide some useful guidance as to who does not need to undergo surveillance, but the long-term performance and how changes in risk score correlate with changes in HCC risk has not been completely assessed. [ABSTRACT FROM AUTHOR]

The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches. [ABSTRACT FROM AUTHOR]

The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC. [ABSTRACT FROM AUTHOR]

Background & Aims: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. Methods: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). Results: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was −5.11 log10 copies/mL for entecavir-treated patients and −0.48 log10 copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. Conclusions: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile. [Copyright &y& Elsevier]

Chronic hepatitis B infection presents a number of challenges to clinicians. There are additional considerations when defining management strategies for individuals with advanced liver disease, or coinfection, or those at high risk of developing hepatocellular carcinoma (HCC). Treatment of decompensated cirrhosis is particularly important. Evidence suggests that suppression of viral replication through nucleos(t)ide analog therapy leads to longer time to transplantation, improved liver function, and improved survival times. The use of interferon in patients with decompensated hepatitis B is associated with serious complications and is currently contraindicated for these patients by the AASLD Practice Guidelines. Hepatitis B coinfection is often associated with more extensive disease. In patients with HBV/HCV coinfection, one disease is usually dominant and consequently should be the focus of therapy. HIV/HBV coinfection increases the risk of progressive liver disease. Therapeutic agents active against both viruses should be utilized at the correct dose to limit the development of resistance. Agents specific for HBV, e.g., entecavir, enable hepatitis to be treated while avoiding the risk of HIV resistance developing. Dual infection with HBV and HDV is particularly challenging. Nucleos(t)ide analogs are ineffective in treating HDV infection, and there is limited data concerning the efficacy of interferon in this setting. The association between chronic hepatitis B infection and hepatocellular carcinoma (HCC) is well established. In patients at high risk of HCC, screening regimes may be effective. Furthermore, there is an increasing body of evidence indicating that effective suppression of viral replication may be associated with a reduced risk of HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The American Association for the Study of Liver Diseases (AASLD) guidelines on the management of hepatocellular carcinoma (HCC) includes an algorithm to assist in the diagnosis of small liver nodules found on surveillance. The algorithm was developed on the basis of expert opinion. The two authors of the guidelines have since validated the algorithm. In this issue, the first external validation of the diagnostic algorithm is presented. [ABSTRACT FROM AUTHOR]

Background/Aims: Low hepatic n −6 and n −3 polyunsaturated fatty acid (PUFA) may contribute to steatosis and steatohepatitis and can be affected by diet and oxidative stress. Methods: Seventy-three patients referred for elevated liver enzymes and suspected NAFLD were assessed. Nutritional assessment, hepatic FA composition and oxidative stress were compared between these groups: simple steatosis (SS, n =18), steatohepatitis (NASH, n =38) and minimal findings on liver biopsy (MF, n =17). Results: Patients with NASH had higher: BMI, central obesity, body fat, insulin resistance, dyslipidemia and lower physical activity compared to the other groups. They also had relatively lower hepatic n −3 and n −6 PUFA, a decrease in the ratio of metabolites to essential FA precursors for both n −6 and n −3 FA (eicosapentaenoic+docosahexaenoic/linolenic and arachidonic/linoleic acid ratios) and higher liver lipid peroxides with lower antioxidant power, when compared to MF. Overall, there was no significant difference between SS and NASH in FA composition. Self-reported dietary intake and red blood cell FA composition were similar among the three groups. Conclusions: NASH patients have more metabolic abnormalities. This is associated with higher oxidative stress and lower n −3 and n −6 PUFA in the liver in the absence of any differences in dietary FA composition. [Copyright &y& Elsevier]

Background: Very few quality indicators of care exist for surgical procedures. These may be used to both score the quality of care received, and as a method of improving the quality of care delivered (quality improvement initiatives). Materials and Methods: The goal of this study was to develop a set of evidence-based quality indicators by expert consensus for patients undergoing hepatic resection of colorectal metastases to the liver. A Delphi approach was used to develop a set of evidence-based quality indicators for patients undergoing hepatic resection of colorectal metastases to liver. A panel of experts was formed through nomination by members of the Canadian Hepatopancreaticobiliary Society (CHPBS). The Delphi process consisted of three iterations of questionnaires. During each round, the panel members were asked to score the potential indicators and suggest any new indicators. Results: A list of 70 potential indicators was generated from the literature, of which 27 achieved consensus for inclusion in the final list of quality indicators. After consolidating similar or redundant indicators, the final list had 18 quality indicators. All of the indicators in the final list were from our original literature search. Conclusions: This Delphi process has used the best available evidence, along with a consensus methodology employing the opinion of experts in the field, to identify 18 quality indicators for patients undergoing hepatic resection for metastatic colorectal cancer. These indicators will provide a means for benchmarking quality of care among surgeons, institutions, and health regions. [Copyright &y& Elsevier]