Hepatic Medicine : Evidence and Research最新文献

Among the various risky complications of liver cirrhosis, refractory ascites is associated with poor survival of cirrhotics and persistently worsens their quality of life (QOL). Major clinical guidelines worldwide define refractory ascites as ascites that cannot be managed by medical therapy either because of a lack of response to maximum doses of diuretics or because patients develop complications related to diuretic therapy that preclude the use of an effective dose of diuretics. Due to the difficulty in receiving a liver transplantation (LT), the ultimate solution for refractory ascites, most cirrhotic patients have selected the palliative therapy such as repeated serial paracentesis, transjugular intrahepatic portosystemic shunt, or peritoneovenous shunt to improve their QOL. During the past several decades, new interventions and methodologies, such as indwelling peritoneal catheter, peritoneal-urinary drainage, and cell-free and concentrated ascites reinfusion therapy, have been introduced. In addition, new medical treatments with vasoconstrictors or vasopressin V2 receptor antagonists have been proposed. Both the benefits and risks of these old and new modalities have been extensively studied in relation to the pathophysiological changes in ascites formation. Although the best solution for refractory ascites is to eliminate hepatic failure either by LT or by causal treatment, the selection of the best palliative therapy for individual patients is of utmost importance, aiming at achieving the longest possible, comfortable life. This review briefly summarizes the changing landscape of variable treatment modalities for cirrhotic patients with refractory ascites, aiming at clarifying their possibilities and limitations. Evolving issues with regard to the impact of gut-derived systemic and local infection on the clinical course of cirrhotic patients have paved the way for the development of a new gut microbiome-based therapeutics. Thus, it should be further investigated whether the early therapeutic approach to gut dysbiosis provides a better solution for the management of cirrhotic ascites.

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic disease characterized by destruction of small- and medium-sized intrahepatic bile ducts. It is no longer a rare disease, since many new asymptomatic cases are incidentally identified. Liver biopsy is diagnostically critical but not always feasible or practical to be performed. Many potential, noninvasive, markers have been proposed to replace liver biopsy and further provide the assessment of disease severity and ultimate prognosis. In this review, we evaluated serum biomarkers proposed for diagnosis, extent of fibrosis, disease prognosis and attempts for early prediction of treatment response. Older biochemical and immunological markers are presented along with recent reports including the role of microRNAs and promising results based on proteomics and metabolomics.

Chronic hepatitis C virus (HCV) infection impacts approximately 71 million people and approximately 400,000 deaths are attributed to HCV-related liver disease annually worldwide. Mainstay of treatment for over 25 years has been pegylated interferon until the advent of protease inhibitors, which has led to all-oral HCV treatment regimens that have changed the outlook of hepatitis C treatment. Grazoprevir/elbasvir provides high rates of efficacy and tolerability and is an all-oral once daily treatment option for HCV infection. Efficacy of grazoprevir/elbasvir has been proven in patients with cirrhosis, patients who have previously failed treatment with peginterferon and ribavirin (RBV), patients with end-stage renal disease and patients with HIV co-infection. Data have shown a high barrier to resistance despite the presence of resistance-associated substitutions. Grazoprevir/elbasvir represents a very promising regimen for treatment of HCV infection. This review provides a summary of pharmacology, efficacy, and safety of grazoprevir/elbasvir for the treatment of HCV infection.

Background/purpose: Dipeptidyl peptidase 4 (DPP-4) expression is directly associated with hepatic lipogenesis and liver injury in nonalcoholic steatohepatitis (NASH). This study has been designed to elucidate the histological improvement of NASH with the DPP-4 inhibitor sitagliptin.

Materials and methods: In this open-label randomized control trial, paired liver biopsy was taken from 40 NASH patients. Sitagliptin 100 mg was given once daily to the SL group and no sitagliptin was given to the L group for 1 year. Patients from both groups were encouraged to exercise moderately and advised to avoid saturated fat, excessive sugar, soft drinks, fast food, and refined carbohydrates to reduce weight.

Results: Steatosis improved in the SL group (from 2.3±0.6 to 1.2±0.8; P=0.000) and the L group (from 2.1±0.6 to 1.6±0.9; P=0.008), ballooning decreased from 1.8±0.6 to 1.3±06 (P=0.002) in the SL group, but not in the L group. Nonalcoholic fatty liver disease activity score (NAS) attenuated in both groups: the SL group (from 5.8±0.9 to 3.9±1.4; P=0.000) and the L group (from 5.3±0.6 to 4.6±1.2; P=0.009). NAS improvement was much higher in the SL group (1.9±1.4) than in the L group (0.7±1.1) (P=0.006), with NAS improving by ≥2 in 13 patients from the SL group and five patients from the L group (P=0.01). Improvement was irrespective of diabetes. Regression analysis explored that sitagliptin had odds of 6.38 and weight reduction had odds of 4.51 for NAS reduction.

Conclusion: Sitagliptin 100 mg once daily for 1 year ameliorates NAS by improving steatosis and ballooning, irrespective of diabetes. Sitagliptin has stronger efficacy than that of weight reduction.

In the past years, what has always been considered undisputed true in liver fibrosis staging has been challenged. Diagnostic performance of histological evaluation has proven to be significantly influenced by sample- and observer-related variabilities. Differentiation between lower levels of fibrosis remains difficult for many, if not all, test modalities, including liver biopsy but, perhaps, such a distinction is not indispensable in light of current therapeutic approaches. Biomarkers and elastography offer, nonetheless, high predictive values for advanced fibrosis and cirrhosis and correlate well with liver-related outcomes. Necroinflammation, steatosis, and hemodynamic changes may significantly interfere with elastography-based techniques, and longitudinal follow-up strategies must be tailored in light of these findings. Knowledge of different test modalities and diagnostic performance indicators can allow for better clinical decision-making and resource allocation.

Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. HE is observed in acute liver failure, liver bypass procedures, for example, shunt surgry and transjugular intrahepatic portosystemic shunt, and cirrhosis. These are classified as Type A, B and C HE, respectively. HE can also be classified according to whether its presence is overt or covert. The pathogenesis is linked with ammonia and glutamine production, and treatment is based on mechanisms to reduce the formation and/or removal of these compounds. There is no specific diagnostic test for HE, and diagnosis is based on clinical suspicion, excluding other causes and use of clinical tests that may support its diagnosis. Many tests are used in trials and experimentally, but have not yet gained universal acceptance. This review focuses on the definitions, pathogenesis and treatment of HE. Consideration will be given to existing treatment, including avoidance of precipitating factors and novel therapies such as prebiotics, probiotics, antibiotics, laxatives, branched-chain amino acids, shunt embolization and the importance of considering liver transplant in appropriate cases.

Background: The combination of sofosbuvir (SOF) with ribavirin (RBV) or daclatasvir (DCV) or simeprevir (SIM) for the treatment of patients infected by chronic hepatitis C (CHC) have led to significantly increased rates of sustained virological response (SVR). However, there is only limited data regarding factors associated with treatment failure in a "real-life" cohort.

Patients and methods: Consecutive treatment-naive and treatment-experienced patients F3-F4 were treated with SOF-based interferon-free therapy in our hospital from November 2013 to July 2015. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after cessation of therapy (SVR12).

Results: A total of 167 treatment-naive and 207 treatment-experienced patients were treated and followed up for 2 years (n=383). Overall, 71% were men; among them, 54% had cirrhosis and the median age was 53 years. SVR12 was achieved by 82% of the patients receiving SOF+RBV, 92% receiving SOF+DCV, and 79% receiving SOF+SIM. Metavir F4 and albumin serum were found as independent risk factors associated with treatment failure in groups receiving SOF+RBV (p=0.008 and p=0.001), SOF+DCV (p=0.038 and p=0.043), and SOF+SIM±RBV (p=0.014 and p=0.017), respectively. The most common adverse events were fatigue, nausea, headache, and anemia. Three patients discontinued the treatment due to an adverse event.

Conclusion: These findings suggest that 12-week SOF-based regimen plus RBV or DCV or SIM is an efficacious and well-tolerated treatment in CHC patients with fibrosis stage F3-F4. Patients, who display risk factors for cirrhosis, should be referred to an experienced viral hepatitis center.

A single-nucleotide polymorphism occurring in the sequence of the human patatin-like phospholipase domain-containing 3 gene (PNPLA3), known as I148M variant, is one of the best characterized and deeply investigated variants in several clinical scenarios, because of its tight correlation with increased risk for developing hepatic steatosis and more aggressive part of the disease spectrum, such as nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis. Further, the I148M variant is positively associated with alcoholic liver diseases, chronic hepatitis C-related cirrhosis and hepatocellular carcinoma. The native gene encodes for a protein that has not yet a fully defined role in liver lipid metabolism and, according to recent observations, seems to be divergently regulated among distinct liver cells type, such as hepatic stellate cells. Therefore, the aim of this review is to collect the latest data regarding PNPLA3 expression in human liver and to analyze the impact of its genetic variant in human hepatic pathologies. Moreover, a description of the current biochemical and metabolic data pertaining to PNPLA3 function in both animal models and in vitro studies is summarized to allow a better understanding of the relevant pathophysiological role of this enzyme in the progression of hepatic diseases.

Background: Liver fibrosis is the most important prognostic factor in chronic hepatitis C virus (HCV) patients, and Egypt shows the highest worldwide HCV prevalence with genotype-4 pre-dominance. The aim of this study was to investigate the degree of liver stiffness measurement (LSM) improvement after successful HCV eradication.

Patients and methods: The study included 84 chronic HCV Egyptian patients, and was conducted at Qena University Hospital from November 1, 2015 till October 31, 2016. LSM was obtained by FibroScan® before starting direct acting antiviral (DAA) treatment and after achieving sustained virologic response-24 (SVR-24). Based on baseline LSM, patients were stratified into F0-F1, F2, F3 and F4 groups (METAVIR). LSM and laboratory data after achieving SVR-24 was compared with that before starting therapy in each fibrosis group (F0-F4), p-value <0.05 was statistically significant.

Results: Following DAA treatment, 80 patients achieved SVR-24; of these, 50 were males (62.5%), mean age: 54.2±7.6 years, and mean body mass index: 28.6±2.2 kg/m². Mean baseline LSM dropped from 15.6±10.8 to 12.1±8.7 kPa post-SVR; the maximum change of -5.8 occurred in F4 versus -2.79, -1.28 and +0.08 in F3, F2 and F0-F1 respectively (p<0.0001). At baseline, 41 patients were in the F4 group; only 16 (39%) regressed to non-cirrhotic range (<12.5 kPa), while 25 (61%) were still cirrhotic despite achieving SVR-24 (p<0.0001). Patients who achieved LSM improvement (n=64) have had significantly higher baseline aspartate transferase (AST) and alanine transaminase (ALT). Also, those patients showed significant improvement in AST, AST/platelets ratio index (APRI) and fibrosis-4 index (Fib-4) after achieving SVR; 91% showed AST improvement (p=0.01) and APRI improvement (p=0.01) and 81% showed Fib-4 improvement (p=0.04). Females, diabetics, patients with S3 steatosis and patients older than 50 years showed less LSM improvements than their counterparts. Baseline LSM ≥9 kPa, bilirubin ≥1 mg/dl, ALT ≥36 U/L and AST ≥31 U/L were significant predictors for LSM improvement.

Conclusion: Successful HCV genotype-4 eradication results in significant LSM improvement; the best improvement occurs in F4 patients. But as the majority of cirrhotics are still at risk for liver decompensation and hepatocellular carcinoma development despite achieving SVR-24, early detection and treatment are highly recommended.

Purpose: Hepatic encephalopathy (HE) is associated with a reduced survival, an increased risk of hospitalization for recurrences, and a reduced health-related quality of life. The purpose of the present economic analysis was to evaluate the impact on the Italian National Health Service (INHS) expenditure of the treatment with rifaximin 550 mg twice daily (Tixteller^®/Tixtar^®) for the reduction of the recurrences of overt HE, with respect to the current treatment approach.

Patients and methods: Costs associated with patients treated with rifaximin 550 mg twice daily were estimated considering the reduction in hospitalizations for HE recurrences revealed by registrative clinical trial (-50%) applied to the hospitalization rate (42.5%) emerging from an Italian observational real-world study; costs associated with patients not treated with rifaximin were estimated based on the hospitalization rate, resulting from the same Italian observational study. Sensitivity analyses considering possible different discount levels to INHS structures for rifaximin were performed. The INHS perspective for a period of 3 years was considered.

Results: The treatment with rifaximin 550 mg twice daily, although increasing drug costs, is associated with a reduction in hospitalizations for HE recurrences that leads to an overall reduction of total costs charged to INHS, which could be estimated, based on the forecasted uptake of the treatment, at about €130,000 in the first year, reaching ~€260,000 in the third year. Considering a possible discount for rifaximin 550 mg to INHS structure of 20%, the total saving at the third year accounts for ~€3,000,000. Moreover, a relevant reduction in the number of hospitalizations and bed days is associated with rifaximin treatment.

Conclusion: The treatment with rifaximin 550 mg twice daily, even if associated with an increase in drug expenditure, results in a reduction in total health care costs charged to INHS due to a reduction in hospitalizations for HE recurrences.