Safety of fibrates in cholestatic liver diseases.

BACKGROUND AND AIM: Off-label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases. METHODS: A systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed. Electronic databases were searched up to December 2019 for published studies evaluating treatment outcomes associated to fibrates for these 2 diseases. RESULTS: A total of 37 studies were identified, including 31 for PBC and 6 for PSC, with a total of 1107 unique patients treated with fibrates ± ursodeoxycholic acid (UDCA). Most studies evaluated fenofibrate and bezafibrate, and only 1 study evaluated pemafibrate. There were no studies evaluating gemfibrozil or clofibrate. The most commonly reported adverse events (AEs) were gastrointestinal and musculoskeletal. Elevations of aminotransferases and serum creatinine were reported more commonly in patients treated with UDCA plus fibrates versus UDCA monotherapy. CONCLUSIONS: Fibrates appear to be safe and well tolerated in patients with PBC, with a low frequency of AEs. There are scarce data about the safety of these agents for treatment of PSC.

Novel targeted therapies for the management of liver fibrosis.

Introduction: Prolonged liver injury results in tissue damage and replacement by extracellular matrix and fibrosis. Cirrhosis represents a leading cause of mortality worldwide and imposes a major financial burden on health-care systems. Fortunately, fibrogenesis has proven to be reversible if halted early, encouraging the development of novel anti-fibrotic agents that may accelerate histological restoration. Preclinical data have elucidated numerous potential therapeutic targets and many anti-fibrotic agents are currently at various stages of clinical research.Areas covered: The present review summarizes recent clinical data regarding anti-fibrotic drugs including monoclonal antibodies, targeted conjugates, and small molecule agents.Expert opinion: Although undeniable progress has been made in the development of anti-fibrotic agents in recent years, most data currently available are derived from preclinical and early clinical studies. The efficacy and safety of these agents will need to be corroborated by larger clinical trials, some of which are ongoing with results expected in the upcoming years. Combination therapy with agents targeting different pathways of fibrogenesis will also be of great interest for the future and will need to be explored in clinical trials.

Bacterial Infection in Patients with Cirrhosis: Don't Get Bugged to Death.

Bacterial infection remains a leading cause of mortality and morbidity for patients with cirrhosis, with hospitalization, alterations in the intestinal microbiota, and therapeutic drugs all implicated in its development. Bacterial infections also remain the most common precipitant of acute-on-chronic liver failure, with infection occurring as a direct consequence of the progression of this syndrome. Furthermore, recent epidemiological analyses have demonstrated that infections due to multidrug-resistant bacteria are occurring with increasing frequency in patients with cirrhosis. Despite significant advances in the understanding of the pathophysiological processes triggered by an infection in patients with cirrhosis, a demonstrable survival benefit for the sickest patients who require ICU admission has not yet occurred. Early diagnosis of infection and appropriate antimicrobial treatment is essential to ensuring optimal outcomes for these patients. This review provides an evidence-based analysis of both the current strategies for prevention and the recommended management of common bacterial infections in patients with cirrhosis.

Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients.

Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single-center treatment protocol of patients with HCV genotype 1 infection who received a 12-week combination regimen of sofosbuvir and simeprevir. Sixty-one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9-8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%-97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%-100%), whereas SVR12 was 89% (95% CI, 74%-95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3-F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%-86%); P = 0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12-week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse.

Current diagnosis and management of post-transjugular intrahepatic portosystemic shunt refractory hepatic encephalopathy.

Transjugular intrahepatic portosystemic shunt has evolved into an important option for management of complications of portal hypertension. The use of polytetrafluoroethylene covered stents enhances shunt patency. Hepatic encephalopathy (HE) remains a significant problem after TIPS placement. The approach to management of patients with refractory hepatic encephalopathy typically requires collaboration between different specialties. Patient selection for TIPS requires careful evaluation of risk factors for HE. TIPS procedure-related technical factors like stent size, attention to portosystemic pressure gradient reduction and use of adjunctive variceal embolization maybe important. Conservative medical therapy in combination with endovascular therapies often results in resolution or substantial reduction of symptoms. Liver transplantation is, however, the ultimate treatment.

Viral hepatitis in the elderly.

As life expectancy continues to rise, elderly adults represent a rapidly growing proportion of the population. The likelihood of complications of acute and chronic liver disease and overall mortality are higher in elderly populations. Several physiological changes associated with aging, greater prevalence of co-morbid conditions, and cumulative exposure to hepatotropic viruses and environmental hepatotoxins may contribute to worse outcomes of viral hepatitis in the elderly. Although pharmacotherapy for hepatitis B and C continues to evolve, the efficacy, tolerability, and side effects of these agents have not been studied extensively in elderly adults. Immunization against hepatitis A and B in naïve elderly adults is an important public health intervention that needs to be revised and broadened.

Chronic Kidney Disease After Liver Transplantation.

Improved survival after liver transplantation has led to an aging cohort of recipients at risk of renal dysfunction. The etiology of renal dysfunction is typically multifactorial; calcineurin inhibitors nephrotoxicity, pretransplant renal dysfunction, and perioperative acute kidney injury are important risk factors. Metabolic complications such as hypertension, diabetes mellitus, and metabolic-associated fatty liver disease also contribute to the development of renal disease. Most LT recipients will eventually develop some degree of renal dysfunction. Criteria to select candidates for simultaneous liver and kidney transplantation have been established. Both delayed introduction of CNIs and renal-sparing immunosuppressive regimens may reduce progression of renal dysfunction.

Chronic liver disease in the Hispanic population of the United States.

Chronic liver disease is a major cause of morbidity and mortality among Hispanic people living in the United States. Environmental, genetic, and behavioral factors, as well as socioeconomic and health care disparities among this ethnic group have emerged as important public health concerns. We review the epidemiology, natural history, and response to therapy of chronic liver disease in Hispanic patients. The review covers nonalcoholic fatty liver disease, viral hepatitis B and C, coinfection of viral hepatitis with human immunodeficiency virus, alcoholic cirrhosis, hepatocellular carcinoma, autoimmune hepatitis, and primary biliary cirrhosis. For most of these disorders, the Hispanic population has a higher incidence and more aggressive pattern of disease and overall worse treatment outcomes than in the non-Hispanic white population. Clinicians should be aware of these differences in caring for Hispanic patients with chronic liver disease.

Should ribavirin be used to treat hepatitis C in dialysis patients?

Hepatitis C virus infection adversely affects outcomes in patients with chronic kidney disease undergoing maintenance dialysis. Pegylated interferon and ribavirin, the standard-of-care treatment in patients with intact renal function, is associated with severe side effects, toxicity, and high dropout rates in this population. Ribavirin has an important role in maintaining antiviral response following completion of therapy and increases sustained viral response (SVR) rates. However, the use of ribavirin in dialysis patients has been limited by the high frequency of severe hemolytic anemia and is currently reserved for study protocols and highly selected candidates treated at experienced centers. Encouraging data from small trials have shown a significant increase in SVR rates with the use of different dosing regimens of ribavirin in addition to interferon-based therapy and aggressive erythroid-stimulating agent support in dialysis patients. Use of ribavirin in selected dialysis patients, particularly renal transplant candidates, by experienced clinicians is appropriate.

Keeping Patients with End-Stage Liver Disease Alive While Awaiting Transplant: Management of Complications of Portal Hypertension.

Complications of portal hypertension such as gastroesophageal variceal hemorrhage, ascites, and spontaneous bacterial peritonitis, as well as pulmonary complications, are often responsible for diminished quality of life, excess morbidity and mortality, increased health care resource use and expenditure, and dropout from the liver transplant (LT) waiting list. Therefore, the care of LT candidates on the waiting list must be centered on anticipation and prompt intervention for these complications.

The Evolving Role of Advanced Endoscopic Techniques in Hepatology.

The role of advanced endoscopy in the field of hepatology has evolved rapidly over the last decade. Several novel diagnostic and therapeutic interventions can now be accomplished endoscopically both easily and safely in patients with liver disease; these include endoscopic ultrasound (EUS)-guided liver biopsy, EUS-guided measurement of the portal pressure gradient, EUS-guided therapy for gastric varices, and EUS elastography. This article highlights advances in endoscopic tools and techniques that can be applied in the field of hepatology.

Advances in the Management of Renal Dysfunction in Patients With Cirrhosis.

Renal dysfunction frequently develops in patients with advanced liver disease. Renal dysfunction in this setting is associated with adverse outcomes and an unfavorable prognosis. Hepatorenal syndrome (HRS), defined as worsening renal function in patients with advanced cirrhosis that can present either acutely (<3 months) or more indolently in the absence of other etiologies, remains a common cause of acute kidney injury. If reversal is not promptly achieved, rapid decline to mortality is common. Volume expansion and vasoconstrictors are the mainstays of therapy. Terlipressin, a vasopressin analogue licensed in several countries but not in the United States, is currently used for the treatment of HRS. Timely liver transplantation remains the only effective therapeutic option for a large group of patients with persistent renal dysfunction despite pharmacotherapy. In patients with underlying chronic renal dysfunction, simultaneous liver-kidney transplantation should be considered. The aim of this article is to present an overview of renal dysfunction in patients with cirrhosis, including diagnosis and management.

Diagnosis and management of renal dysfunction in patients with cirrhosis.

Introduction: Renal dysfunction commonly occurs in patients with cirrhosis and is typically associated with poor prognosis. Several pathophysiologic mechanisms are responsible for renal disease in these patients, prompt identification permits individualized management.Areas covered: Pathophysiology, evaluation and differential diagnosis, management and prognosis of renal disease in patients with cirrhosis. Special focus on management of hepatorenal syndrome and indications for simultaneous liver-kidney transplantation.Literature search methodology: a detailed literature search was performed using PubMed without date restrictions. Published guidelines and position papers were also used and cross-referenced to identify additional studies.Expert opinion: The prognostic significance of renal dysfunction in patients with cirrhosis is highlighted by the inclusion of serum creatinine in the model for end-stage liver disease (MELD). Both acute and chronic renal dysfunction result in increased mortality in patients with cirrhosis, although there are marked differences related to the etiology of renal disease. Early recognition and prompt intervention determined by the most likely etiology are key in the management of these patients. Simultaneous liver-kidney transplantation improves patient survival compared to isolated liver transplantation in patients with cirrhosis and persistent renal impairment; however, selection of candidates must be judicious and individualized due to the ongoing shortage of donor kidneys.

Evaluation of the diagnostic and therapeutic utility of retrograde through-the-scope balloon enteroscopy and single-balloon enteroscopy.

BACKGROUND: Retrograde single balloon enteroscopy (SBE) is a minimally invasive procedure which is less frequently performed compared with antegrade SBE. There are few studies on the retrograde through-the-scope enteroscopy (TTSE), a novel technique for evaluation of the small bowel. AIM: To compare the clinical utility and safety of retrograde TTSE with retrograde SBE. METHODS: Clinical data and complications of retrograde TTSE (2014-2018) and retrograde SBE (2011-2018) performed in a community hospital were reviewed and presented as mean ± SD or frequency (%) and compared using proper statistical tests. Technical success was defined as insertion of the enteroscope > 20 cm beyond ileocecal valve. RESULTS: Data obtained from 54 retrograde SBE in 49 patients and 27 retrograde TTSE in 26 patients were studied. The most common indication for retrograde enteroscopy was iron deficiency anemia (41 patients) followed by gastrointestinal bleeding (37 patients), and chronic diarrhea (7 patients). The duration of retrograde SBE procedure (91.9 ± 34.2 min) was significantly longer compared with retrograde TTSE (70.5 ± 30.7 min) (P = 0.04). Technical success was comparable in TTSE [23/27 (85.2%)] and SBE [41/54 (75.9%) (P = 0.33)]. The mean depth of insertion beyond the ileocecal valve in retrograde SBE (92.5 ± 70.0 cm) tended to be longer compared with retrograde TTSE (64.6 ± 49.0 cm) (P = 0.08). No complication was observed in this study. CONCLUSION: Both retrograde TTSE and retrograde SBE are feasible and safe. Retrograde TTSE takes a shorter time and has a comparable technical success with SBE. TTSE has a lower capacity of small bowel insertion.