Amit G. Singal

Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis

Background  A majority of studies investigating the accuracy of ultrasound for detecting hepatocellular carcinoma (HCC) do not reflect how this test is used for surveillance vs. diagnosis.

A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus.

BACKGROUND & AIMS The incidences of decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices), hepatocellular carcinoma (HCC), and liver-related mortality among patients infected with hepatitis C virus (HCV) who achieve a sustained viral response (SVR), compared with patients who fail treatment (treatment failure), are unclear. We performed a meta-analysis to quantify the incidences of these outcomes. METHODS This meta-analysis included observational cohort studies that followed HCV treatment failure patients; data were collected regarding the incidence of decompensated cirrhosis, HCC, or liver-related mortality and stratified by SVR status. Two investigators independently extracted data on patient populations, study methods, and results by using standardized forms. The agreement between investigators in data extraction was greater than 95%. Data analysis was performed separately for studies that enrolled only HCV patients with advanced fibrosis. RESULTS We identified 26 appropriate studies for meta-analysis. Among treatment failure patients with advanced fibrosis, rates of liver-related mortality (2.73%/year; 95% confidence interval [CI], 1.38-4.080), HCC (3.22%/year, 95% CI, 2.02-4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61-4.22) were substantial. Patients with SVR are significantly less likely than patients who experienced treatment failure to develop liver-related mortality (relative risk [RR], 0.23; 95% CI, 0.10-0.52), HCC (RR, 0.21; 95% CI, 0.16-0.27), or hepatic decompensation (RR, 0.16; 95% CI, 0.04-0.59). CONCLUSIONS HCV patients with advanced fibrosis who do not undergo an SVR have substantial liver-related morbidity and mortality. Achieving SVR is associated with substantially lower liver-related morbidity and mortality.

A Primer on Effectiveness and Efficacy Trials

Although efficacy and effectiveness studies are both important when evaluating interventions, they serve distinct purposes and have different study designs. Unfortunately, the distinction between these two types of trials is often poorly understood. In this primer, we highlight several differences between these two types of trials including study design, patient populations, intervention design, data analysis, and result reporting.

The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: A meta-analysis

Objectives:The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease.Methods:We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model.Results:Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20–1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12–1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27–2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96–1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed.Conclusions:PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.

Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice

The epidemiology of hepatocellular carcinoma (HCC) is characterized by dynamic temporal trends, several major established (i.e., HCV, HBV, alcohol) and emerging (i.e., diabetes, obesity, NAFLD) risk factors. Epidemiologic studies and clinical trials have identified additional demographic, clinical, pharmacological, genetic and life style factors that further affect or modify the likelihood of HCC and can be used in clinical practice to identify at-risk patients (i.e., risk stratification or prognostic algorithms) that can be targeted for prevention and early detection programs. These studies have also paved the way toward several well established preventive measures including HBV vaccination, HBV treatment, HCV treatment and HCC surveillance, and potential chemoprevention using statins, metformin or coffee. However, the effectiveness of HCC prevention in clinical practice and at the population level has lagged behind due to patient, provider, system, and societal factors. The Quality in the Continuum of Cancer Care model provides a framework for evaluating the HCC prevention processes, including potential failures that create a gap between efficacy and effectiveness.

Meta‐analysis: insulin sensitizers for the treatment of non‐alcoholic steatohepatitis

Aliment Pharmacol Ther 2010; 32: 1211–1221

Systematic review with network meta‐analysis: the efficacy of anti‐tumour necrosis factor‐alpha agents for the treatment of ulcerative colitis

Antibodies against tumour necrosis factor‐alpha (anti‐TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown.

Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease

Anti‐tumour necrosis factor‐alpha agents (anti‐TNF) are effective therapies for the treatment of Crohns disease (CD), but their comparative efficacy is unknown.

Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study

Objective To determine the frequency of prescriptions for short term use of oral corticosteroids, and adverse events (sepsis, venous thromboembolism, fractures) associated with their use. Design Retrospective cohort study and self controlled case series. Setting Nationwide dataset of private insurance claims. Participants Adults aged 18 to 64 years who were continuously enrolled from 2012 to 2014. Main outcome measures Rates of short term use of oral corticosteroids defined as less than 30 days duration. Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation. Results Of 1 548 945 adults, 327 452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P<0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001). Conclusion One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.

Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy The HELP Randomized Clinical Trial

IMPORTANCE Hepatic encephalopathy (HE) is a common cause of hospitalization in patients with cirrhosis. Pharmacologic treatment for acute (overt) HE has remained the same for decades. OBJECTIVE To compare polyethylene glycol 3350-electrolyte solution (PEG) and lactulose treatments in patients with cirrhosis admitted to the hospital for HE. We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose. DESIGN, SETTING, AND PARTICIPANTS The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE. INTERVENTIONS Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization. MAIN OUTCOMES AND MEASURES The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay. RESULTS A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related. CONCLUSIONS AND RELEVANCE PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01283152.