Drug-Induced Liver Injury

Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of “English language” and “humans” and custom date range of “January 1, 2000.” The authors also manually searched bibliographies from key references and included seminal references before the year 2000.     

Comparative Efficacy of Biologic Therapy in Biologic-Naïve Patients With Crohn Disease: A Systematic Review and Network Meta-analysis

ObjectiveTo study the comparative efficacy of biologic therapy in the management of biologic-naïve patients with Crohn disease (CD).Patients and MethodsWe conducted a systematic review of randomized controlled trials published from January 1, 1985, through September 30, 2013, comparing biologic agents (infliximab [IFX], adalimumab [ADA], certolizumab pegol, natalizumab, vedolizumab, and ustekinumab) with each other or placebo for inducing and maintaining clinical remission in adults with moderate to severe CD. To increase comparability across trials, we focused on a subset of biologic-naïve patients for the induction end point and on responders to induction therapy for the maintenance end point. We followed a Bayesian network meta-analysis approach.ResultsWe identified 17 randomized controlled trials of good methodological quality comparing 6 biologic agents with placebo, with no direct comparison of biologic agents. In network meta-analysis, we observed that IFX (relative risk [RR], 6.11; 95% credible interval [CrI], 2.49-18.29) and ADA (RR, 2.98; 95% CrI, 1.12-8.18), but not certolizumab pegol (RR, 1.48; 95% CrI, 0.76-2.93), natalizumab (RR, 1.36; 95% CrI, 0.69-2.86), vedolizumab (RR, 1.40; 95% CrI, 0.63-3.28), and ustekinumab (RR, 0.61; 95% CrI, 0.15-2.49), were more likely to induce remission than placebo. Similar results were observed for maintenance of remission. Infliximab had the highest probability of being ranked as the most efficacious agent for induction (86%) and ADA for maintenance of remission (48%).ConclusionOn the basis of network meta-analysis, IFX may be most efficacious agent for inducing remission in CD in biologic-naïve patients. In the absence of head-to-head treatment comparison, the confidence in these estimates is low. Future comparative efficacy studies are warranted.     

Physical Activity Promotion in the Health Care System

Physical activity (PA) and exercise training (ET) have great potential in the prevention, management, and rehabilitation of a variety of diseases, but this potential has not been fully realized in clinical practice. The health care system (HCS) could do much more to support patients in increasing their PA and ET. However, counseling on ET is not used widely by the HCS owing partly to attitudes but mainly to practical obstacles. Extensive searches of MEDLINE, the Cochrane Library, the Database of Abstracts of Reviews of Effects, and ScienceDirect for literature published between January 1, 2000, and January 31, 2013, provided data to assess the critical characteristics of ET counseling. The evidence reveals that especially brief ET counseling is an efficient, effective, and cost-effective means to increase PA and ET and to bring considerable clinical benefits to various patient groups. Furthermore, it can be practiced as part of the routine work of the HCS. However, there is a need and feasible means to increase the use and improve the quality of ET counseling. To include PA and ET promotion as important means of comprehensive health care and disease management, a fundamental change is needed. Because exercise is medicine, it should be seen and dealt with in the same ways as pharmaceuticals and other medical interventions regarding the basic and continuing education and training of health care personnel and processes to assess its needs and to prescribe and deliver it, to reimburse the services related to it, and to fund research on its efficacy, effectiveness, feasibility, and interactions and comparability with other preventive, therapeutic, and rehabilitative modalities. This change requires credible, strong, and skillful advocacy inside the medical community and the HCS.     

Safety and Efficacy of Extracorporeal Shock Wave Myocardial Revascularization Therapy for Refractory Angina Pectoris

ObjectiveTo assess the safety and efficacy of extracorporeal shockwave myocardial revascularization (ESMR) therapy in treating patients with refractory angina pectoris.Patients and MethodsA single-arm multicenter prospective trial to assess safety and efficacy of the ESMR therapy in patients with refractory angina (class III/IV angina) was performed. Screening exercise treadmill tests and pharmacological single-photon emission computed tomography (SPECT) were performed for all patients to assess exercise capacity and ischemic burden. Patients were treated with 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy end points were exercise capacity by using treadmill test as well as ischemic burden on pharmacological SPECT at 4 months after the last ESMR treatment. Safety measures included electrocardiography, echocardiography, troponin, creatine kinase, and brain natriuretic peptide testing, and pain questionnaires.ResultsFifteen patients with medically refractory angina and no revascularization options were enrolled. There was a statistically significant mean increase of 122.3±156.9 seconds (38% increase compared with baseline; P=.01) in exercise treadmill time from baseline (319.8±157.2 seconds) to last follow-up after the ESMR treatment (422.1±183.3 seconds). There was no improvement in the summed stress perfusion scores after pharmacologically induced stress SPECT at 4 months after the last ESMR treatment in comparison to that at screening; however, SPECT summed stress score revealed that untreated areas had greater progression in ischemic burden vs treated areas (3.69±6.2 vs 0.31±4.5; P=.03). There was no significant change in the mean summed echo score from baseline to posttreatment (0.4±5.1; P=.70). The ESMR therapy was performed safely without any adverse events in electrocardiography, echocardiography, troponins, creatine kinase, or brain natriuretic peptide. Pain during the ESMR treatment was minimal (a score of 0.5±1.2 to 1.1±1.2 out of 10).ConclusionIn this multicenter feasibility study, ESMR seems to be a safe and efficacious treatment for patients with refractory angina pectoris. However, larger sham-controlled trials will be required to confirm these findings.     

Prognostic Value of Exercise Capacity in Patients With Coronary Artery Disease: The FIT (Henry Ford ExercIse Testing) Project

ObjectiveTo examine the prognostic value of exercise capacity in patients with nonrevascularized and revascularized coronary artery disease (CAD) seen in routine clinical practice.Patients and MethodsWe analyzed 9852 adults with known CAD (mean ± SD age, 61±12 years; 69% men [n=6836], 31% black race [n=3005]) from The Henry Ford ExercIse Testing (FIT) Project, a retrospective cohort study of patients who underwent physician-referred stress testing at a single health care system between January 1, 1991, and May 31, 2009. Patients were categorized by revascularization status (nonrevascularized, percutaneous coronary intervention [PCI], or coronary artery bypass graft [CABG] surgery) and by metabolic equivalents (METs) achieved on stress testing. Using Cox regression models, hazard ratios for mortality, myocardial infarction (MI), and downstream revascularizations were calculated after adjusting for potential confounders, including cardiac risk factors, pertinent medications, and stress testing indication.ResultsThere were 3824 all-cause deaths during median follow-up of 11.5 years. In addition, 1880 MIs, and 1930 revascularizations were ascertained. Each 1-MET increment in exercise capacity was associated with a hazard ratio (95% CI) of 0.87 (0.85-0.89), 0.87 (0.85-0.90), and 0.86 (0.84-0.89) for mortality; 0.98 (0.96-1.01), 0.88 (0.84-0.92), and 0.93 (0.90-0.97) for MI; and 0.94 (0.92-0.96), 0.91 (0.88-0.95), and 0.96 (0.92-0.99) for downstream revascularizations in the nonrevascularized, PCI, and CABG groups, respectively. In each MET category, the nonrevascularized group had similar mortality risk as and higher MI and downstream revascularization risk than the PCI and CABG surgery groups (P<.05).ConclusionExercise capacity was a strong predictor of mortality, MI, and downstream revascularizations in this cohort. Furthermore, patients with similar exercise capacities had an equivalent mortality risk, irrespective of baseline revascularization status.     

Liver Renewal: Detecting Misrepair and Optimizing Regeneration

Cirrhosis and liver cancer, the main causes of liver-related morbidity and mortality, result from defective repair of liver injury. This article summarizes rapidly evolving knowledge about liver myofibroblasts and progenitors, the 2 key cell types that interact to orchestrate effective repair, because deregulation of these cells is likely to be central to the pathogenesis of both cirrhosis and liver cancer. We focus on cirrhosis pathogenesis because cirrhosis is the main risk factor for primary liver cancer. Emerging evidence suggests that the defective repair process has certain characteristics that might be exploited for biomarker development. Recent findings in preclinical models also indicate that the newly identified cellular and molecular targets are amenable to therapeutic manipulation. Thus, recent advances in our understanding about key cell types and fundamental mechanisms that regulate liver regeneration have opened new avenues to improve the outcomes of liver injury.Trial Registrationclinicaltrials.gov Identifier: NCT01899859     

Evaluation and Management of Patients With Heart Disease and Cancer: Cardio-Oncology

The care for patients with cancer has advanced greatly over the past decades. A combination of earlier cancer diagnosis and greater use of traditional and new systemic treatments has decreased cancer-related mortality. Effective cancer therapies, however, can result in short- and long-term comorbidities that can decrease the net clinical gain by affecting quality of life and survival. In particular, cardiovascular complications of cancer treatments can have a profound effect on the health of patients with cancer and are more common among those with recognized or unrecognized underlying cardiovascular diseases. A new discipline termed cardio-oncology has thus evolved to address the cardiovascular needs of patients with cancer and optimize their care in a multidisciplinary approach. This review provides a brief introduction and background on this emerging field and then focuses on its practical aspects including cardiovascular risk assessment and prevention before cancer treatment, cardiovascular surveillance and therapy during cancer treatment, and cardiovascular monitoring and management after cancer therapy. The content of this review is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.     

A Summary and Critical Assessment of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Filling the Gaps

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines has recently released the new cholesterol treatment guideline. This update was based on a systematic review of the evidence and replaces the previous guidelines from 2002 that were widely accepted and implemented in clinical practice. The new cholesterol treatment guideline emphasizes matching the intensity of statin treatment to the level of atherosclerotic cardiovascular disease (ASCVD) risk and replaces the old paradigm of pursuing low-density lipoprotein cholesterol targets. The new guideline also emphasizes the primacy of the evidence base for statin therapy for ASCVD risk reduction and lists several patient groups that will not benefit from statin treatment despite their high cardiovascular risk, such as those with heart failure (New York Heart Association class II-IV) and patients undergoing hemodialysis. The guideline has been received with mixed reviews and significant controversy. Because of the evidence-based nature of the guideline, there is room for several questions and uncertainties on when and how to use lipid-lowering therapy in clinical practice. The goal of the Mayo Clinic Task Force in the assessment, interpretation, and expansion of the ACC/AHA cholesterol treatment guideline is to address gaps in information and some of the controversial aspects of the newly released cholesterol management guideline using additional sources of evidence and expert opinion as needed to guide clinicians on key aspects of ASCVD risk reduction.     

Ulcerative Colitis: Epidemiology,Diagnosis, and Management

Ulcerative colitis is a chronic idiopathic inflammatory bowel disease characterized by continuous mucosal inflammation that starts in the rectum and extends proximally. Typical presenting symptoms include bloody diarrhea, abdominal pain, urgency, and tenesmus. In some cases, extraintestinal manifestations may be present as well. In the right clinical setting, the diagnosis of ulcerative colitis is based primarily on endoscopy, which typically reveals evidence of continuous colonic inflammation, with confirmatory biopsy specimens having signs of chronic colitis. The goals of therapy are to induce and maintain remission, decrease the risk of complications, and improve quality of life. Treatment is determined on the basis of the severity of symptoms and is classically a step-up approach. 5-Aminosalycilates are the mainstay of treatment for mild to moderate disease. Patients with failed 5-aminosalycilate therapy or who present with more moderate to severe disease are typically treated with corticosteroids followed by transition to a steroid-sparing agent with a thiopurine, anti–tumor necrosis factor agent, or adhesion molecule inhibitor. Despite medical therapies, approximately 15% of patients still require proctocolectomy. In addition, given the potential risks of complications from the disease itself and the medications used to treat the disease, primary care physicians play a key role in optimizing the preventive care to reduce the risk of complications.     

Association of Coronary Artery Calcification With Hepatic Steatosis in Asymptomatic Individuals

ObjectiveTo determine the association of coronary artery calcification with hepatic steatosis in asymptomatic volunteers.Patients and MethodsThe study group comprised 400 asymptomatic volunteers, enrolled from April 1, 2011, to September 30, 2012, without known coronary artery disease who were self-referred for screening noncontrast computed tomography to determine coronary calcium score (CCS). Computed tomographic images were used to determine the presence of hepatic steatosis. An a priori model was created to predict a CCS of 100 Agatston units (AU) or higher on the basis of Framingham risk factors, diabetes mellitus, and metabolic syndrome. Hepatic steatosis was then added to this model. Computation of the odds ratio (OR) for hepatic steatosis predicting a CCS of 100 AU or higher was performed. Finally, the OR for a CCS of 100 AU or higher being associated with hepatic steatosis was calculated.ResultsWhen hepatic steatosis was added to traditional coronary risk factors, it was independently associated with a CCS of 100 AU or higher (OR, 2.85). This was greater than the OR of Framingham factors, diabetes mellitus, or metabolic syndrome. A CCS of 100 AU or higher was independently associated with an increased risk for hepatic steatosis (OR, 2.4). This OR was higher than traditional hepatic steatosis risk factors or metabolic syndrome.ConclusionHepatic steatosis is a strong independent predictor of a CCS of 100 AU or higher in asymptomatic patients. It is associated with an increased risk of coronary artery disease beyond that expected from traditional coronary risk factors and/or metabolic syndrome. Additional studies are needed to clarify the role of hepatic steatosis as a possible independent risk factor for the development of coronary artery disease.     

Comparative Effectiveness of Telaprevir-Based Triple Therapy in Patients With Chronic Hepatitis C

ObjectiveTo examine the effectiveness and tolerability of triple therapy with pegylated interferon (p-IFN), ribavirin (RBV), and telaprevir in patients with chronic hepatitis C receiving treatment in an academic practice setting and in a more clinically diverse population compared with patients receiving treatment in phase 3 trials.Patients and MethodsA prospective database of all patients with viral hepatitis undergoing antiviral therapy from January 1, 2006, to July 1, 2012, was queried to identify treatment-naive and -experienced patients with chronic hepatitis C receiving dual and triple therapies. On-treatment response categories included rapid virologic response, extended rapid virologic response, early virologic response, and sustained virologic response. These patients were compared with matched controls, namely, patients who underwent dual therapy with p-IFN and RBV. Matching was performed for age, cirrhosis status, and prior treatment.ResultsThere were 55 patients who received triple therapy and met the eligibility criteria, consisting of treatment-naive (n=35) and -experienced patients (n=20: those with relapse, 9; those with nonresponse, 9; and those who terminated the treatment early, 2). Rapid virologic response was achieved in 41% of the patients, extended rapid virologic response in 41%, and early virologic response in 75%. Sustained virologic response was observed in 51% (18/35) of treatment-naive patients, 67% (6/9) of the patients with prior nonresponse, and 56% (5/9) of those with prior relapse. Corresponding results after dual therapy were 37% (23/62), 11% (2/18), and 27% (3/11), respectively. The mean decrease in the hemoglobin level at weeks 4, 8, and 24 of triple therapy was 2.8, 3.8, and 3.2 mg/dL compared with 2.4, 2.6, and 2.4 mg/dL with dual therapy (to convert mg/dL to mmol/L, multiply values by 0.0259).ConclusionTelaprevir-based triple therapy in clinical practice is considerably more effective than dual therapy with p-IFN and RBV despite the significant degree of anemia that complicated therapy, requiring RBV dose reduction and erythropoietin support.     

Hemoglobin A1c in Nondiabetic Patients: An Independent Predictor of Coronary Artery Disease and Its Severity

ObjectiveTo examine the association between hemoglobin A_1c (HbA_1c) and the presence, severity, and complexity of angiographically proven coronary artery disease (CAD) in nondiabetic patients.Patients and MethodsWe performed a single-center, observational, cross-sectional study of 1141 consecutive nondiabetic patients who underwent coronary angiography from January 1, 2011, through December 31, 2011. The study population was divided into 4 interquartiles according to HbA_1c levels (<5.5%, 5.5%-5.7%, 5.8%-6.1%, and >6.1%).ResultsPatients with higher HbA_1c levels tended to be older, overweight, and hypertensive, had higher blood glucose levels, and had lower glomerular filtration rates. Higher HbA_1c levels were associated in a graded fashion with the presence of CAD, disease severity (higher number of diseased vessels and presence of left main and/or triple vessel disease), and disease complexity (higher SYNTAX score, higher number of patients in intermediate or high SYNTAX tertiles, coronary calcium, and chronic total occlusions). After adjustment for major conventional cardiovascular risk factors, compared with patients with HbA_1c levels less than 5.5%, the odds ratios of occurrence of CAD in the HbA_1c quartiles of 5.5% to 5.7%, 5.8% to 6.1%, and greater than 6.1% were 1.8 (95% CI, 1.2-2.7), 3.5 (95% CI, 2.3-5.3), and 4.9 (95% CI, 3.0-8.1), respectively.ConclusionThe HbA_1c level has a linear incremental association with CAD in nondiabetic individuals. The HbA_1c level is also independently correlated with disease severity and higher SYNTAX scores. Thus, HbA_1c measurement could be used to improve cardiovascular risk assessment in nondiabetic individuals.     

Influence of Early Surgical Treatment on the Prognosis of Left-Sided Infective Endocarditis: A Multicenter Cohort Study

ObjectiveTo analyze the influence of early valve operation on mortality in patients with left-sided infective endocarditis (IE).Patients and MethodsA multicenter cohort study was carried out between 1990 and 2010. Data from consecutive patients with definite IE and possible left-sided IE were collected. Propensity score matching and adjustment for survivor bias were used to control for confounders. The primary outcome was in-hospital mortality.ResultsA total of 1019 patients with a mean age of 61 years (interquartile range, 47-71 years) were included. Early surgical treatment was performed in 417 episodes (40.9%). By propensity score, we matched 316 episodes: 158 who underwent early surgical treatment and 158 who did not (medical treatment group). In-hospital mortality and late mortality were lower in the surgically treated group (26.6% vs 41.8%; absolute risk reduction [ARR], −15.2%; P=.004 and 29.7% vs 46.2%; ARR, −16.5%; P=.002, respectively). Operation was independently associated with a lower risk of in-hospital mortality (odds ratio, 0.42; 95% CI, 0.22-0.79; P=.007). Operation was associated with reduced mortality in patients with paravalvular complications (ARR, −40.5%), severe heart failure (ARR, −32%), and native valve endocarditis (ARR, −17.8%).ConclusionThis study supports the benefit of surgical treatment in patients with left-sided IE carried out during the initial phase of hospitalization, especially in patients with moderate or severe heart failure and paravalvular extension of infection.     

Prostate Cancer Ki-67 (MIB-1) Expression,Perineural Invasion,and Gleason Score as Biopsy-Based Predictors of Prostate Cancer Mortality: The Mayo Model

ObjectiveTo determine the role of cellular proliferation and other biopsy-based features in the prediction of prostate cancer mortality.Patients and MethodsBetween 1993 and 2012, our institution has performed quantitation of prostate cancer DNA ploidy and Ki-67 (MIB-1) on most prostate cancer needle biopsy specimens. The outcomes of 451 consecutive patients with biopsy-proven cancer treated by radical prostatectomy between January 24, 1995, and December 29, 1998, without neoadjuvant hormonal therapy were assessed. Clinical and biopsy information obtained before radical prostatectomy was placed in multivariate Cox proportional hazards regression models to predict local or systemic progression and cancer-specific death. Predictive ability was evaluated using a concordance index.ResultsWith a median follow-up of 12.9 years, 46 patients experienced local or systemic progression, and 18 patients died of prostate cancer. On multivariate analysis, the biopsy features of Ki-67 expression, perineural invasion, and Gleason score were associated with local or systemic progression. Ki-67 expression, perineural invasion, and Gleason score were associated with cancer-specific death with a concordance index of 0.892. After adjusting for perineural invasion and Gleason score, each 1% increase in Ki-67 expression was associated with a 12% increased risk of cancer-specific death (P<.001). Ki-67 expression alone was a strong predictor of cancer-specific outcomes and improved the predictive ability of currently used algorithms.ConclusionThis study documents that long-term prostate cancer outcomes are best estimated with a combination of Gleason score, perineural invasion, and Ki-67 expression. Given its low cost, rapid assessment, and strong predictive power, we believe that adding Ki-67 expression to perineural invasion and Gleason score at biopsy should be considered a standard by which all new biomarkers are compared before introducing them into clinical practice.     

Alcohol and Cardiovascular Health: The Dose Makes the Poison…or the Remedy

Habitual light to moderate alcohol intake (up to 1 drink per day for women and 1 or 2 drinks per day for men) is associated with decreased risks for total mortality, coronary artery disease, diabetes mellitus, congestive heart failure, and stroke. However, higher levels of alcohol consumption are associated with increased cardiovascular risk. Indeed, behind only smoking and obesity, excessive alcohol consumption is the third leading cause of premature death in the United States. Heavy alcohol use (1) is one of the most common causes of reversible hypertension, (2) accounts for about one-third of all cases of nonischemic dilated cardiomyopathy, (3) is a frequent cause of atrial fibrillation, and (4) markedly increases risks of stroke—both ischemic and hemorrhagic. The risk-to-benefit ratio of drinking appears higher in younger individuals, who also have higher rates of excessive or binge drinking and more frequently have adverse consequences of acute intoxication (for example, accidents, violence, and social strife). In fact, among males aged 15 to 59 years, alcohol abuse is the leading risk factor for premature death. Of the various drinking patterns, daily low- to moderate-dose alcohol intake, ideally red wine before or during the evening meal, is associated with the strongest reduction in adverse cardiovascular outcomes. Health care professionals should not recommend alcohol to nondrinkers because of the paucity of randomized outcome data and the potential for problem drinking even among individuals at apparently low risk. The findings in this review were based on a literature search of PubMed for the 15-year period 1997 through 2012 using the search terms alcohol, ethanol, cardiovascular disease, coronary artery disease, heart failure, hypertension, stroke, and mortality. Studies were considered if they were deemed to be of high quality, objective, and methodologically sound.