Andrea Lisotti

Endoscopic ultrasound-guided treatments: Are we getting evidence based - a systematic review

The continued need to develop less invasive alternatives to surgical and radiologic interventions has driven the development of endoscopic ultrasound (EUS)-guided treatments. These include EUS-guided drainage of pancreatic fluid collections, EUS-guided necrosectomy, EUS-guided cholangiography and biliary drainage, EUS-guided pancreatography and pancreatic duct drainage, EUS-guided gallbladder drainage, EUS-guided drainage of abdominal and pelvic fluid collections, EUS-guided celiac plexus block and celiac plexus neurolysis, EUS-guided pancreatic cyst ablation, EUS-guided vascular interventions, EUS-guided delivery of antitumoral agents and EUS-guided fiducial placement and brachytherapy. However these procedures are technically challenging and require expertise in both EUS and interventional endoscopy, such as endoscopic retrograde cholangiopancreatography and gastrointestinal stenting. We undertook a systematic review to record the entire body of literature accumulated over the past 2 decades on EUS-guided interventions with the objective of performing a critical appraisal of published articles, based on the classification of studies according to levels of evidence, in order to assess the scientific progress made in this field.

Spleen stiffness measurement can predict clinical complications in compensated HCV-related cirrhosis: A prospective study

BACKGROUND & AIMS Hepatic venous pressure gradient (HVPG) measurement represents the best predictor of clinical decompensation (CD) in cirrhotic patients. Recently data show that measurement of spleen stiffness (SS) has an excellent correlation with HVPG levels. Aim of the present prospective study was to assess SS predictive value for CD compared to HVPG, liver stiffness (LS), and other non-invasive tests for portal hypertension in a cohort of patients with HCV-related compensated cirrhosis. METHODS From an initial cohort of 124 patients, 92 underwent baseline LS, SS, HVPG measurements and upper gastrointestinal endoscopy at enrolment and then followed-up for 2 years or until the occurrence of the first CD. Univariate and multivariate logistic regression models were used for determining judgement criteria associated parameters. Accuracy of predictive factors was evaluated using c statistic. The final model was internally validated using the bootstrap method. RESULTS During follow-up, 30 out 92 (32.6%) patients developed CD. At univariate analysis varices at enrolment, all non-invasive parameters, HVPG, and model for end-stage liver disease (MELD) resulted clinical predictors of CD. At multivariate analysis only SS (p=0.0001) and MELD (p=0.014) resulted as predictive factors. A decision algorithm based on the results of a predictive model was proposed to detect patients with low risk of decompensation. CONCLUSIONS This study shows that in compensated cirrhotic patients a SS and MELD predictive model represents an accurate predictor of CD with accuracy at least equivalent to that of HVPG. If confirmed by further studies, SS and MELD could represent valid alternatives to HVPG as prognostic indicator of CD in HCV-related cirrhosis.

Indocyanine green retention test as a noninvasive marker of portal hypertension and esophageal varices in compensated liver cirrhosis

Noninvasive markers would be useful for the assessment of portal hypertension (PH) and esophageal varices (EV) in patients with cirrhosis. The aim of our study was to evaluate the performance of the indocyanine green (ICG) retention test as a noninvasive marker of PH and EV, measured against the gold standards (hepatic venous pressure gradient [HVPG] measurement and upper endoscopy). We prospectively enrolled patients with compensated cirrhosis referral to our unit. All patients underwent laboratory tests, abdominal ultrasound, upper gastrointestinal endoscopy, HVPG measurement, and the ICG 15‐minute retention (ICG‐r15) test. We evaluated the sensitivity and specificity of the ICG retention test and other noninvasive tools for the diagnosis of PH and EV. Ninety‐six consecutive Child‐Pugh A patients (67 male and 29 female; 60.3 ± 11.8 years of age) were enrolled. Seventy‐four patients had clinically significant portal hypertension (CSPH), of whom 59 had severe portal hypertension (SPH). ICG‐r15 and Lok index were independently related to the presence of both CSPH and SPH, whereas ICG‐r15 and INR were related to EV. ICG‐r15 values (<6.7% and <6.9%, respectively) were able to rule out the presence of CSPH and SPH (LR− 0.15 and 0.14); ICG‐r15 <10% provided a 97.8% sensitivity (LR− 0.042) for the exclusion of EV and a 100% sensitivity (LR− 0.0) for large EV. Conclusion: The ICG‐r15 test is an effective tool for assessment of PH in patients with compensated cirrhosis. Although this would not replace endoscopy, the ICG‐r15 appears able to identify patients with advanced liver disease in which endoscopy is mandatory as well as rule out the presence of EV in patients with compensated cirrhosis. (Hepatology 2014;59:643–650)

Berberine and its metabolites: relationship between physicochemical properties and plasma levels after administration to human subjects.

Berberine (1) is an alkaloid used widely in the treatment of several diseases. However, its physicochemical properties, pharmacokinetics, and metabolism remain unclear, and conflicting data have been reported. In this study, the main physicochemical properties of 1 and its metabolites were evaluated, including lipophilicity, solubility, pKa, and albumin binding. A sensitive HPLC-ESIMS/MS method was developed and validated to identify 1 and its main metabolites in human plasma. This method was used to quantify their levels in the plasma of healthy volunteers and hypercholesterolemic patients following a single dose and chronic administration, respectively. In both cases, berberrubine (2) was found to be the main metabolite. Surprisingly, 2 is more lipophilic than 1, which suggests that this compound tautomerizes to a highly conjugated, electroneutral quinoid structure. This was confirmed by NMR studies. These results indicate that the higher plasma concentration of 2 was a consequence of a more efficient intestinal absorption, suggesting that berberrubine is potentially more pharmacologically active than berberine.

Contrast Harmonic-Endoscopic Ultrasound Is Useful to Identify Neoplastic Features of Pancreatic Cysts (With Videos).

Objectives To evaluate the potential role of contrast harmonic endoscopic ultrasound (CH-EUS) in the differential diagnosis of pancreatic cysts and detection of malignancy. Methods Patients who underwent CH-EUS for evaluation of cyst wall, septae, and solid components of pancreatic cysts were included. The findings were compared to fine needle aspiration and surgery. Results Seventy-six patients were included. Serous and mucinous cysts were both hyperenhanced (86% and 89%, respectively; P = ns), whereas pseudocysts were hypoenhanced in 90% of the cases (P = 0.000004 vs serous cysts and P = 0.000005 vs mucinous cysts). Patients showing hyperenhanced solid components were finally diagnosed with malignancy (2 malignant intraductal papillary mucinous neoplasms, 2 cystic neuroendocrine tumors), in contrast to the patients with nonenhanced solid components who resulted to have either benign cysts with internal mucus clots (n = 10) or pseudocysts with internal debris (n = 8). Conclusions CH-EUS allowed differentiation between pseudocysts and other pancreatic cysts but not mucinous versus serous cysts. Malignant vegetations inside pancreatic cystic lesions were clearly shown by CH-EUS as solid components with features of hyperenhancement, directing EUS-fine needle aspiration of potential neoplastic areas and avoiding puncture of debris and mucus plugs.

The clinical impact of ultrasound contrast agents in EUS: a systematic review according to the levels of evidence

BACKGROUND AND AIMS The use of contrast-harmonic EUS (CH-EUS) in routine clinical practice is increasing rapidly but is not yet standardized. We present the levels of evidence (LEs) found in the literature to put its clinical outcomes in the appropriate perspective. METHODS We conducted a systematic review of the available English-language articles. The LEs were stratified according to the Oxford Centre for Evidence-Based Medicine guidelines. RESULTS Overall, 210 articles were included and presented according to different pathologic conditions. For pancreatic solid neoplasms, the pooled sensitivity and specificity in the diagnosis of pancreatic carcinoma were very high (LE 1); quantitative analysis and guidance of FNA were reported as investigational research (LE 2-3). For pancreatic cystic lesions, the identification of neoplastic solid components as hyperenhanced lesions represented a promising application of CH-EUS (LE 2). For lymph nodes, CH-EUS increased the diagnostic yield of B-mode EUS for the detection of malignancy (LE 2). For submucosal tumors, CH-EUS seemed useful for differential diagnosis and risk stratification (LE 2-3). For other applications, differential diagnosis of gallbladder and vascular abnormalities by CH-EUS were reported (LE 2-3). CONCLUSIONS The LEs of CH-EUS in the literature have evolved from the initial descriptive studies to multicenter and prospective trials, and even meta-analyses. The differential diagnosis between benign and malignant lesions is the main field of application of CH-EUS. With regard to pancreatic solid neoplasms, the concomitant use of both CH-EUS and EUS-FNA may have additive value in increasing the overall accuracy by overcoming the false-negative results associated with each individual technique. Other applications are promising but still investigational.

The Pharmacological Management of Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy is the most common liver disease occurring in the second half of pregnancy, characterized by pruritus and elevated serum bile acids often coupled to abnormal liver tests. Maternal prognosis is favourable with a complete symptom resolution after delivery, while preterm deliveries, fetal respiratory distress and stillbirths may occur. The goal of the pharmacological treatment of the disease is to improve maternal symptoms and biochemical alterations and, most importantly, to reduce fetal adverse events.The present manuscript will review the current knowledge on the pharmacological treatment of intrahepatic cholestasis of pregnancy.

High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy.

Background Ursodeoxycholic acid (UDCA) administration in intrahepatic cholestasis of pregnancy (ICP) induces bile acids (BA) efflux from the foetal compartment, but the molecular basis of this transplacental transport is only partially defined. Aim To determine if placental breast cancer resistance protein (BCRP), able to transport BA, is regulated by UDCA in ICP. Methods 32 pregnant women with ICP (14 untreated, 34.9±5.17 years; 18 treated with UDCA - 25 mg/Kg/day, 32.7±4.62 years,) and 12 healthy controls (33.4±3.32 years) agreed to participate in the study. Placentas were obtained at delivery and processed for membrane extraction. BCRP protein expression was evaluated by immunoblotting techniques and chemiluminescence quantified with a luminograph measuring emitted photons; mRNA expression with real time PCR. Statistical differences between groups were evaluated by ANOVA with Dunn’s Multiple Comparison test. Results BCRP was expressed only on the apical membrane of the syncytiotrophoblast. A significant difference was observed among the three groups both for mRNA (ANOVA, p = 0.0074) and protein (ANOVA, p<0.0001) expression. BCRP expression was similar in controls and in the untreated ICP group. UDCA induced a significant increase in placental BCRP mRNA and protein expression compared to controls (350.7±106.3 vs 100±18.68% of controls, p<0.05 and 397.8±56.02 vs 100±11.44% of controls, p<0.001, respectively) and untreated ICP (90.29±17.59% of controls, p<0.05 and 155.0±13.87%, p<0.01). Conclusion Our results confirm that BCRP is expressed only on the apical membrane of the syncytiotrophoblast and show that ICP treatment with high dose UDCA significantly upregulates placental BCRP expression favouring BA efflux from the foetal compartment.

Relationship between indocyanine green retention test, decompensation and survival in patients with Child-Pugh A cirrhosis and portal hypertension.

Indocyanine green retention test (ICG‐r15) is a non‐invasive marker of functional hepatic reserve. Among patients with compensated cirrhosis, ICG‐r15 correlates to the degree of portal hypertension (PH); however, its prognostic relationship with the occurrence of decompensation events still requires clarification.

Palliative care in patients with liver cirrhosis: it is the time to deal with the burden

We read, with great interest, Dr Gola et al s1 manuscript entitled “Economic analysis of costs for patients with end stage liver disease over the last year of life”, in which the authors clearly demonstrated the increased economic burden of end stage liver disease (ESLD) on health systems. This original article should not be considered only a mere analysis of costs related to ESLD but also as a starting point for future directions in this field. Liver cirrhosis is the common result of different injuries to liver tissue, leading to necroinflammation and neofibrogenesis. The prognosis of patients with chronic liver disease varies widely, depending on the presence of portal hypertension, the clinical stage, the removal of the underlying pathogenetic noxa (ie, alcohol, hepatitis C virus) or the occurrence of decompensation and other clinical events (ie, infections, kidney injury). Quality of life results reduced in almost all patients with cirrhosis because of an impairment in all the three areas of health-related QoL (HRQOL), namely, physical, psychological and social; despite these evidences, the assessment of HRQOL is frequently a marginal issue in the clinical evaluation of the patient with cirrhosis. The stage of the disease, age (older), gender (female) and cultural and socioeconomic issues significantly influence patients’ QoL. …