An overview of recent treatment options for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic hepatic dysfunction characterized by inflammatory and tissue-degenerative strictures of the biliary tree, leading to cirrhosis and cholangiocarcinoma. The pathophysiological mechanisms involve immune-mediated responses. Numerous treatment modalities targeting the inflammatory aspects have been suggested, but a consensus on the best treatment option is lacking. This study aims to review the most up-to-date treatment options for PSC.

Detection of Helicobacter Pylori in Nasal Polyps: An Epidemiological Study.

Many studies have described the detection of Helicobacter pylori (HP) in the nasal polyps; however, although gastroesophageal reflux has been associated with chronic rhinosinusitis and nasal polyps development, the role of HP remains unclear. Our aim was to describe the prevalence of HP detection in nasal polyps and its association with gastric HP infection and gastroesophageal reflux dsease (GERD). The prospective study involved 36 patients with nasal polyps, who underwent to endoscopic surgery removal of nasal polyps. Before surgical procedure all patients were tested for gastric HP infection by 13 C-urea breath test, while tissue samples from nasal polyps were tested for HP detection, using rapid urease test (CLO test) and histological examination with Giemsa stain. All patients were asked about GERD-related symptoms. HP in nasal polyps was detected in 9 out of 36 patients (25%) using histological examination with Giemsa stain, while the detection rate of HP was 30.5% (11/36) using CLO test. Furthermore, 28 out of 36 patients (77.7%) had gastric HP infection. All patients with HP colonization in nasal polyps had gastric HP infection and all patients with HP in nasal polyps reported symptoms related to GERD. HP was detected in approximately one out of three patients in nasal polyps, while all patients with HP detection in nasal polyps had concurrently gastric HP infection and reported GERD-related symptoms, suggesting a gastro-nasal route of HP.

Conversion of Propranolol to Carvedilol Improves Renal Perfusion and Outcome in Patients With Cirrhosis and Ascites.

BACKGROUND: In recent years, concerns have been raised on the potential adverse effects of nonselective beta-blockers, and particularly carvedilol, on renal perfusion and survival in decompensated cirrhosis with ascites. We investigated the long-term impact of converting propranolol to carvedilol on systemic hemodynamics and renal function, and on the outcome of patients with stable cirrhosis and grade II/III nonrefractory ascites. PATIENTS AND METHODS: Ninety-six patients treated with propranolol for esophageal varices' bleeding prophylaxis were prospectively evaluated. These patients were randomized in a 2:1 ratio to switch to carvedilol at 12.5 mg/d (CARVE group; n=64) or continue propranolol (PROPRA group; n=32). Systemic vascular resistance, vasoactive factors, glomerular filtration rate, and renal blood flow were evaluated at baseline before switching to carvedilol and after 6 and 12 months. Further decompensation and survival were evaluated at 2 years. RESULTS: During a 12-month follow-up, carvedilol induced an ongoing improvement of systemic vascular resistance (1372±34 vs. 1254±33 dynes/c/cm5; P=0.02) along with significant decreases in plasma renin activity (4.05±0.66 vs. 6.57±0.98 ng/mL/h; P=0.01) and serum noradrenaline (76.7±8.2 vs. 101.9±10.5 pg/mL; P=0.03) and significant improvement of glomerular filtration rate (87.3±2.7 vs. 78.7±2.3 mL/min; P=0.03) and renal blood flow (703±17 vs. 631±12 mL/min; P=0.03); no significant effects were noted in the PROPRA group. The 2-year occurrence of further decompensation was significantly lower in the CARVE group than in the PROPRA group (10.5% vs. 35.9%; P=0.003); survival at 2 years was significantly higher in the CARVE group (86% vs. 64.1%; P=0.01, respectively). CONCLUSION: Carvedilol at the dose of 12.5 mg/d should be the nonselective beta-blocker treatment of choice in patients with cirrhosis and nonrefractory ascites, as it improves renal perfusion and outcome.

Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study.

BACKGROUND: Hepatobiliary and pancreatic manifestations have been reported in patients with Crohn's disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used. METHODS: Data were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center. RESULTS: Our study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated. CONCLUSION: In our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.

Systemic hemodynamic response to terlipressin predicts development of hepatorenal syndrome and survival in advanced cirrhosis.

BACKGROUND: The aim of this study was to predict the occurrence of hepatorenal syndrome (HRS) and death in patients with advanced cirrhosis and ascites. PATIENTS AND METHODS: We retrospectively evaluated 2-year data of 78 patients with cirrhosis and ascites (Child-Pugh B/C: 45/43). The mean arterial pressure (MAP) and cardiac output (CO) were measured in all patients just before administration of 2 mg of terlipressin and 30 min later. Systemic vascular resistance (SVR) was calculated as MAP/CO. ΔMAP, and ΔCO, and ΔSVR were defined as the percentage change of MAP, CO, and SVR, respectively, after terlipressin injection. Plasma renin activity (PRA) and plasma aldosterone were evaluated at baseline. Two multivariate models were used: one excluding (model 1) and one including (model 2) the Model of End-stage Liver Disease score. RESULTS: Higher ΔSVR, Model of End-stage Liver Disease score, and PRA were related independently to the severity of cirrhosis. Independent predictors of HRS at 12 and 24 months were ΔSVR (models 1/2: P=0.008/0.01 and 0.01/0.02, respectively), ΔCO (models 1/2: P=0.01/0.03 and 0.03/0.04, respectively), and PRA (models 1/2: P=0.04 and model 1: P=0.04, respectively). ΔSVR at 12 and 24 months (models 1/2: P=0.005/0.01 and 0.01/0.03, respectively) and ΔCO at 24 months (models 1/2: P=0.02/0.01, respectively) were related independently to survival. Patient groups with significantly higher probability of HRS and mortality were identified by certain cutoffs of ΔSVR (20.6 and 22.8%, respectively) and ΔCO (-10.6 and -11.8%, respectively). ΔSVR and ΔCO independently predicted survival in patients with the most advanced cirrhosis and infection-related survival. CONCLUSION: An increase in SVR by at least 20% and a decrease in CO at least 10% in response to terlipressin could predict HRS and mortality in patients with advanced cirrhosis.

von Willebrand factor and procoagulant imbalance predict outcome in patients with cirrhosis and thrombocytopenia.

BACKGROUND & AIMS: Several lines of evidence suggest that the hemostatic disorders of cirrhosis may have a significant clinical impact. We investigated the independent predictive value of components of the hemostatic system on the occurrence of ascites, variceal bleeding (VB), and survival. METHODS: One hundred and two patients with thrombocytopenia (Child-Pugh class A/B/C: 34/34/34) were enrolled. Platelet counts, factors (F) II, V, VII, and VIII, antithrombin, protein C (PC), FVIII-to-PC ratio as an index of procoagulant imbalance, von Willebrand factor antigen (vWF-Ag), and model for end-stage liver disease (MELD) were evaluated. Two multivariate analyses were performed: one excluding (model 1) and one including MELD (model 2). RESULTS: Higher vWF-Ag levels and FVIII-to-PC ratios were the most prominent hemostatic disorders in patients with cirrhosis. Increased levels of vWF-Ag and FVIII, and higher FVIII-to-PC ratios independently predicted the presence of ascites and varices at baseline. Independent predictors of ascites and VB during follow-up were vWF-Ag (model 1/2: p=0.001/p=0.009 and p=0.008/p=0.01, respectively) and FVIII-to-PC ratio (model 1/2: p=0.003/p=0.02 and p=0.01/p=0.03, respectively). vWF-Ag (model 1/2: p=0.007/p=0.002), FVIII-to-PC ratio (model 1/2: p=0.001/p=0.01), and MELD (p=0.02) independently predicted mortality. Patient groups with significantly higher probability of new-onset ascites, VB, and mortality were identified by certain cut-offs of vWF-Ag (213%, 466%, and 321%, respectively) and FVIII-to-PC ratio (1.99, 3.29, and 2.36, respectively). vWF-Ag and FVIII-to-PC ratio equaled MELD in mortality prediction. CONCLUSIONS: Advanced cirrhosis is characterized by increased thrombotic potential. vWF-Ag and FVIII-to-PC ratio independently predict new-onset ascites, VB, and mortality. Targeting hypercoagulability could improve the outcome of patients with cirrhosis. LAY SUMMARY: Higher von Willebrand factor antigen (vWF-Ag) levels and factor VIII-to-protein C (FVIII-to-PC) ratio are the prominent hemostatic disorders in patients with cirrhosis. vWF-Ag and FVIII-to-PC ratio independently predict new-onset ascites, variceal bleeding, and mortality in these patients.

von Willebrand factor antigen as a therapeutic target of portal hypertension in cirrhosis.

Increased thrombotic potential within the liver sinusoids due to local endothelial production of von Willebrand factor antigen macromolecules could represent an additional therapeutic target of portal hypertension in patients with cirrhosis. In this case, anti-inflammatory and antithrombotic drugs could modulate portal pressure by preventing the formation of intrahepatic platelet-induced microthrombi.

Thrombin generation measured as thrombin-antithrombin complexes predicts clinical outcomes in patients with cirrhosis.

AIM: Hypercoagulability has been detected in patients with cirrhosis yet its clinical significance remains unclear. We investigated the association of hypercoagulability with clinical outcomes in patients with cirrhosis. METHODS: Thrombin-antithrombin (TAT) complexes as thrombin generation (TG) marker, D-dimer, antithrombin (AT), protein C, protein S, international normalized ratio (INR), activated partial thromboplastin time, fibrinogen, Child-Pugh class and Model for End-Stage Liver Disease (MELD) were evaluated. Two different multivariate analyses were performed: one not including MELD (model 1) and one including MELD and excluding INR (model 2). RESULTS: Eighty-one patients (Child-Pugh class A/B/C: 27/27/27) and 40 healthy subjects were enrolled. Only ΤΑΤ and AT were independently associated with increasing liver disease severity. Increased TAT levels and MELD score were significantly associated with ascites and varices at baseline. Independent predictors of follow-up events were: TAT and MELD score for new-onset ascites; TAT and AT for variceal bleeding (VB); TAT and AT for portal vein thrombosis (PVT); and TAT and MELD for mortality. TAT equaled MELD in mortality prediction at 12 and 18 months. TAT cut-offs at 5.35, 14.6, 13.5 and 9.25 ng/mL identified patient groups with significantly higher probability of new-onset ascites, VB, PVT and mortality, respectively. CONCLUSION: Increased TG is strongly correlated with portal hypertension-related complications, PVT and mortality in patients with cirrhosis. Measuring TG by TAT could enable risk stratification and institution of preventive strategies to improve clinical outcomes.

Pancreatitis potentially associated drugs as a risk factor for post-endoscopic retrograde cholangiopancreatography pancreatitis: a prospective cohort study.

OBJECTIVES: The aim of this study was to assess the role of known risk factors and specifically evaluate the role of pancreatitis potentially associated drugs as potential risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS: This was a prospective, single-center cohort study conducted in a tertiary university hospital. All eligible ERCP procedures within a 16-month period were evaluated, and all interventions, patient characteristics, and medications used were documented. The association of potential risk factor with PEP was investigated with univariable analyses. Those statistically significant were entered in a multivariable regression model. RESULTS: Three hundred eighteen ERCP procedures were studied. Post-ERCP pancreatitis occurred in 28 patients (8.8%). Twenty-three potential risk factors were studied in univariable analyses, and 3 of them were found to be nominally statistically significant. These 3 factors were independently associated with PEP in the multivariable model and included the use of pancreatitis potentially associated drugs, belonging to Badalov classes I or II, during the last month before ERCP (odds ratio [OR], 4.39; 95% confidence interval [CI], 1.70-5.47; P = 0.003), more than 1 guide-wire insertions in the pancreatic duct (OR, 5.00; 95% CI, 1.97-12.81; P = 0.001) and bile duct stone extraction (OR, 0.12; CI, 0.05-0.32; P < 0.001). CONCLUSIONS: Pancreatitis potentially associated drugs used before ERCP seem to increase the risk for PEP.

Scintigraphic evaluation of intrapulmonary shunt in normoxemic cirrhotic patients and effects of terlipressin.

AIM: The magnitude of intrapulmonary shunt (IPS) in cirrhotic patients without hypoxemia remains undefined. We evaluated the severity and clinical correlations of IPS in normoxemic cirrhotics, and possible IPS alterations after terlipressin treatment. METHODS: Fifteen patients with alcoholic cirrhosis without hypoxemia were studied at baseline and after the administration of 2 mg of terlipressin. The IPS fraction was evaluated by lung perfusion scan after the i.v. injection of technetium-99m-labeled macroaggregated albumin ((99m) Tc-MAA) and calculation of brain uptake (positive value ≥6%). Cardiac output (CO), pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were evaluated by Doppler echocardiography. Mean arterial pressure (MAP) was measured and the ratio MAP/CO was calculated as an index of systemic vascular resistance (SVR). Portal vein velocity (PVV) and portal venous flow (PVF) were also assessed by Doppler ultrasonography. RESULTS: Three patients (20%) had an IPS fraction of more than 6%. A significant inverse correlation with platelet count (P = 0.001) and a direct correlation with Child-Pugh score (P = 0.06), PVV (P = 0.07) and PVF (P = 0.07) were noted. IPS fractions decreased significantly after terlipressin administration (P = 0.00001); the IPS fraction fell below 6% in all three patients with positive baseline values. Terlipressin treatment induced a significant decrease in CO (P = 0.003) and significant increases in MAP (P = 0.0003), SVR (P = 0.0003), SPAP (P = 0.001) and PVR (P = 0.01). CONCLUSION: IPS fractions detected by (99m) Tc-MAA lung scan were inversely correlated with platelet count and directly with liver disease severity, and found abnormal in 20% of normoxemic cirrhotic patients. Terlipressin reduced significantly the magnitude of the shunt.

Effects of terlipressin and somatostatin on liver and thorax blood volumes in patients with cirrhosis.

BACKGROUND: Variceal bleeding in cirrhosis can cause liver ischaemia and deteriorate the hyperdynamic state; thus, the effects of vasoconstrictor therapy on liver blood volume (LBV) and thorax blood volume (ThBV) are important. AIM: To evaluate and compare the effects of terlipressin and somatostatin on LBV and ThBV in stable patients with cirrhosis and portal hypertension. METHODS: Twenty patients were studied (Child-Pugh class A/B/C: 5/8/7). The radioactivities in the liver region (LRR) and the thorax region (ThRR) by single-head gamma camera technique, as indicators of LBV and ThBV, respectively, and systemic haemodynamics were measured at baseline and after intravenous infusion of 2 mg of terlipressin (n=10) or somatostatin 250 mg/h after an initial bolus of 250 mg (n=10). RESULTS: LRR and ThRR decreased significantly with increasing severity of cirrhosis. Thirty minutes after terlipressin infusion, LRR and ThRR increased by 7.8 ± 4.4% (NS) and 14 ± 5.3% (P=0.01) compared with baseline values; the increase in ThRR was significantly related to the increase in LRR (r=0.682, P=0.03). In contrast, somatostatin reduced LRR and ThRR by 13.3 ± 6.5% (P=0.07) and 1 ± 4% (NS) respectively. LRR and ThRR increased significantly in the terlipressin group compared with the somatostatin group (P=0.01 and P=0.02 respectively). Terlipressin reduced cardiac output and heart rate (both P=0.01) and increased the mean arterial pressure (MAP) and systemic vascular resistance (P=0.009 and P=0.002 respectively); MAP decreased after somatostatin infusion (P=0.03). CONCLUSIONS: Terlipressin, but not somatostatin, maintains LBV, increases ThBV and improves the hyperdynamic state in cirrhosis. These effects can be beneficial in variceal bleeding, particularly in patients with advanced liver disease.

Effects of terlipressin on water excretion after oral water load test in nonazotemic cirrhotic patients with ascites without hyponatremia.

OBJECTIVE: Impaired water excretion is a major prognostic factor in decompensated cirrhotic patients. We investigated if terlipressin improves water excretion after a water load test in nonazotemic cirrhotic patients with ascites without hyponatremia. METHODS: Fifteen patients (Child-Pugh B/C: 6/9) were studied after an oral water intake of 20 ml/kg within 40 min and water excretion over 5 h was measured at baseline: day 1, and after a bolus infusion (2 mg) of terlipressin: day 3. Mean arterial pressure (MAP) before and after water loading on day 1, and MAP, cardiac output (CO), and systemic vascular resistance (SVR) before and 1 h after terlipressin infusion on day 3, were evaluated. The 5-h creatinine clearance (ClCre), diuresis, and sodium excretion were also evaluated in each study day. RESULTS: The water load excreted on day 1 was significantly correlated with Child-Pugh score, ClCre, sodium excretion, and SVR. The water load excreted and diuresis increased significantly after terlipressin infusion in the 12 patients that completed the study (48.3±3.3% vs. 39.5±4.9%; p=0.001 and 2.51±0.21 vs. 2.06±0.29 ml/min; p=0.001, respectively); significant increases in ClCre and sodium excretion, a significant decrease in CO and significant increases in MAP and SVR were also noted. The changes in the percentage of water load excreted were significantly correlated with the changes in SVR and ClCre. CONCLUSIONS: Terlipressin increases water excretion during a water load test in nonazotemic cirrhotic patients without hyponatremia, suggesting that the administration of arterial vasoconstrictors could influence the prognosis of these patients.

Steatosis and steatohepatitis in postmortem material from Northwestern Greece.

AIM: To determine the prevalence of steatosis and steatohepatitis in a series of autopsies in Northwestern Greece. METHODS: Liver biopsy material from a total of 600 autopsies performed over a period of 2 years (2006-2008) to define the cause of death was subjected to histological examination. Patient demographic data were also collected. Tissue sections were stained with different dyes for the evaluation of liver architecture, degree of fibrosis and other pathological conditions when necessary. RESULTS: Satisfactory tissue samples for histological evaluation were available in 498 cases (341 male, 157 female) with a mean age of 64.51 +/- 17.78 years. In total, 144 (28.9%) had normal liver histology, 156 (31.3%) had evidence of steatosis, and 198 (39.8%) had typical histological findings of steatohepatitis. The most common causes of death were ischemic heart disease with or without myocardial infarction (43.4%), and traffic accidents (13.4%). CONCLUSION: A high prevalence of steatosis and steatohepatitis was detected in postmortem biopsies from Northwestern Greece. Since both diseases can have serious clinical consequences, they should be considered as an important threat to the health of the general population in Greece.

Thrombosis and recanalization of straight sinus.

We describe a case of a 14-year-old boy who presented to the emergency department with nausea, vomiting, headache, and mental status changes. Noncontrast computed tomography scan of the brain in the emergency department revealed bilateral thalamic and striatocapsular infarcts. The patient was diagnosed with possible thrombosis of the thalamostriate veins, which was confirmed with urgent magnetic resonance venography (MRV). Magnetic resonance venography revealed that the thrombosis was extended to the straight sinus and the internal cerebral veins. Thrombosis of the straight sinus in children results in a rare stroke with inconsistent clinical manifestations, depending on collateral venous circulation of the thrombosed sinus. The diagnosis is quite difficult, especially when symptoms are nonspecific and variable. Timely diagnosis, based on the decision of performing emergency magnetic resonance imaging and MRV, followed by the administration of anticoagulation therapy may reverse this condition as in our patient who made an excellent recovery.

Baseline cholesterol is associated with the response to antiviral therapy in chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) partially interacts with low-density lipoprotein (LDL) receptors, suggesting a role for lipids in regulating HCV clearance. Our aim was to study if baseline lipids can discriminate responders from non-responders among patients with HCV infection. METHODS: A total of 109 HCV patients were studied. Laboratory measurements included serum lipids, aminotransferases and viral load, as well as HCV genotype determinations. RESULTS: Responders (n = 53) had significantly higher serum baseline levels of total cholesterol, LDL cholesterol and apolipoprotein B compared to non-responders (n = 56). Multivariate logistic regression analysis showed that a 10 mg/dL increase in total cholesterol was associated with 3.02 higher odds of responding to treatment (95% CI 1.74-5.32, P < 0.001), while a 10 mg/dL increase in apolipoprotein B levels was associated with 1.81 higher odds of responding to treatment (95% CI 1.37-2.54, P < 0.001), after adjustment for age, sex, body mass index (BMI), smoking habits, baseline viral load, liver histology and administration of pegylated interferon. An inverse association between BMI and response to treatment was also evident (adjusted odds ratio 0.73, 95% CI 0.55-0.96; P = 0.03). CONCLUSION: Baseline serum total cholesterol levels and BMI could be helpful in discriminating responders to antiviral therapy among patients with HCV infection.