Transarterial therapies for hepatocellular carcinoma.

Transarterial therapies for hepatocellular carcinoma are considered palliative and should be offered to patients with intermediate stage multinodular disease without extra-hepatic metastases and sufficient liver reserve. They mainly include transarterial chemoembolisation and transarterial embolisation. While transarterial therapy is now a validated treatment for unresectable HCC, there is still a lack of conclusive evidence as to which type and schedule is the optimal procedure. This is mainly due to the lack of standardisation. Combining local therapies or intra-arterial therapies with systemic targeted therapies might prove more effective strategies in the future. In the present article, we review transarterial therapies and critically comment on their indications, complications and outcomes.

Treatment of portal vein thrombosis in cirrhosis: a multicenter real life cοhort study.

BACKGROUND: Portal vein thrombosis (PVT) is a common complication of cirrhosis and can be a cause or consequence of liver disease progression. It is unclear whether PVT treatment is affecting clinical outcomes in cirrhotics. METHODS: This is a multicenter study of cirrhotics with PVT, initially retrospectively and thereafter prospectively registered in a data base. We studied the impact of PVT treatment on this population for efficacy, safety and the impact on survival. In survival analysis Mantel-Cox and Wilcoxon-Breslow-Gehan tests were used. A P value of <0.05, was considered significant. For statistical computations the STATA 12.1 was used. RESULTS: Seventy-six patients were included (76% decompensated, median MELD score 12 and Child-Pugh score 7), 47% with concomitant HCC. Fifty-one patients with PVT were treated with Vitamin-K antagonists or Low-Molecular-Weight Heparin. Patients were followed up for at least 6 months after PVT diagnosis, or until death or transplantation. PV patency after 6 months was not statistically different between patients receiving or not anticoagulation (complete-partial recanalization 27.4% of treated vs. 20% of untreated, P=0.21). Median survival was statistically worse between patients treated with anticoagulation than those untreated (10 vs. 15 months, P=0.036). Less portal hypertensive bleeding and less decompensation rates were found in treated cirrhotics vs. untreated (45.8% vs. 54.2%, P=0.003 and 78% vs. 80.9%, P=0.78, respectively). Patients with HCC had worse survival when treated vs. untreated (P=0.047). CONCLUSIONS: In our cohort of cirrhotics with PVT, treatment was feasible with acceptable side effects, but without meaningful clinical benefits.

Critical illness-related corticosteroid insufficiency in patients with cirrhosis and variceal bleeding.

BACKGROUND & AIMS: Relative adrenal insufficiency (AI) occurs in patients with cirrhosis with sepsis, but not with variceal bleeding. We evaluated adrenal function in cirrhotic patients with and without bleeding. METHODS: Twenty cirrhotic patients with variceal bleeding were evaluated using the short synacthen test (SST) and 10 using the low-dose synacthen test (LDSST) followed by SST. The control group included 60 stable cirrhotic patients, assessed by LDSST (n = 50) or SST (n = 10), and 14 healthy volunteers. AI was diagnosed using SST, based on peak cortisol levels ≤ 18 µg/dL in nonstressed patients or Δmax <9 µg/dL or a total cortisol level <10 µg/dL in stressed patients with variceal bleeding-the current criteria for critical illness-related corticosteroid insufficiency. Using LDSST, diagnosis was based on peak concentrations of cortisol ≤ 18 µg/dL in nonstressed patients and <25 µg/dL (or Δmax <9 µg/dL) in patients with variceal bleeding. We evaluated patients with levels of serum albumin >2.5 g/dL, to indirectly assess cortisol binding. RESULTS: All healthy volunteers had normal results from LDSSTs and SSTs. Patients with variceal bleeding had higher median baseline concentrations of cortisol (15.4 µg/dL) than stable cirrhotic patients (8.7 µg/dL, P = .001) or healthy volunteers (10.1 µg/dL, P = .01). Patients with variceal bleeding had higher median peak concentrations of cortisol than stable cirrhotic patients (SST results of 32.7 vs 21 µg/dL, P = .001; LDSST results of 9.3 vs 8.1 µg/dL; nonsignificant), with no differences in Δmax in either test. These differences were greater with variceal bleeding than in stable cirrhotic patients with AI. Subanalysis of patients with albumin levels >2.5 g/dL did not change these differences. CONCLUSIONS: Cirrhotic patients with variceal bleeding have AI. Despite higher baseline concentrations of serum cortisol and subnormal Δmax values, they did not have adequate responses to stress, and therefore had critical illness-related corticosteroid insufficiency.

Primary prevention of variceal hemorrhage.

Variceal hemorrhage is one of the leading causes of death in patients with cirrhosis, with the 6-week mortality after each episode ranging from 15% to 20%. The two main strategies for primary prevention of variceal bleeding in patients with cirrhosis and varices are the administration of nonselective ß-blockers or the obliteration of varices with use of endoscopic band ligation. In this review, we present and critically review the latest data on primary prevention of variceal hemorrhage. We advocate that nonselective ß-blockers should be the first line therapy, and band ligation should be offered only in cases of intolerance or side effects. We also explore potential future therapies based on preliminary experimental and clinical data.

A comparison of kaolin-activated versus nonkaolin-activated thromboelastography in native and citrated blood.

Thromboelastography can be performed with native or citrated blood (a surrogate to native blood in healthy controls, surgical and cirrhotic patients). Activators such as kaolin are increasingly used to reduce the time to trace generation. To compare kaolin-activated thromboelastography with nonkaolin-activated thromboelastography of native and citrated blood in patients with liver disease, patients undergoing treatment with warfarin or low-molecular weight heparin and healthy volunteers. We studied thromboelastography parameters in 21 healthy volunteers (group 1) and 50 patients, including 20 patients with liver cirrhosis with a nonbiliary aetiology (group 2), 10 patients with primary biliary cirrhosis or primary sclerosing cholangitis (group 3), 10 patients on warfarin treatment (group 4) and 10 patients with enoxaparin prophylaxis (group 5). Thromboelastography was performed using four methods: native blood (kaolin-activated and nonkaolin-activated) and citrated blood (kaolin-activated and nonkaolin-activated). For all thromboelastography parameters, correlation was poor (Spearman correlation coefficient < 0.70) between nonkaolin-activated and kaolin-activated thromboelastography, for both citrated and native blood. In healthy volunteers, in patients with liver disease and in those receiving anticoagulant treatment, there was a poor correlation between nonkaolin-activated and kaolin-activated thromboelastography. Kaolin-activated thromboelastography needs further validation before routine clinical use in these settings, and the specific methodology must be considered in comparing published studies.

Prevention of the development of varices and first portal hypertensive bleeding episode.

Variceal bleeding is a serious complication in patients with cirrhosis. Although bleeding related mortality rates have fallen recently, it continues to be amongst the leading causes of death. Cirrhotics should be screened for varices at diagnosis. Data on preventing formation/growth of oesophageal varices (pre-primary prophylaxis) are conflicting, with insufficient evidence to use beta-blockers. In order to prevent first bleeding, there is strong evidence in patients with medium/large size oesophageal varices that either non-selective beta-blockers or banding ligation can be used. Banding is superior with respect to bleeding but mortality is similar. Non-selective beta-blockers should remain first line treatment being effective, cheap and without serious complications. In contrast banding ligation is more expensive, requires specialised staff, cannot prevent bleeding from portal hypertensive gastropathy and can cause iatrogenic bleeding. Patients with small varices, particularly if they have progressive liver disease also benefit from beta-blockers, but fewer studies confirm this therapeutic approach.

Male hepatitis C patients' sexual functioning and its determinants.

OBJECTIVE: The aim of the study was to detect sexual impairment in male hepatitis C virus patients and determine its associations. PATIENTS AND METHODS: A total of 61 male hepatitis C virus patients were enrolled in this cross-sectional study. Sexual functioning was assessed using the International Index of Erectile Function. Health-related quality of life (HRQOL) was evaluated using the Greek version of the Short Form 36 Health Survey, and the presence and severity of anxiety and depression were assessed using the Greek version of the Hospital Anxiety and Depression Scale. RESULTS: Noncirrhotic patients showed clinically significant dysfunction, mainly in intercourse (59.6%) and overall satisfaction (57.4%). Erectile functioning and desire were correlated with depression (r=-0.520, P=0.000 and r=-0.473, P=0.000), anxiety (r=-0.443, P=0.000 and r=-0.428, P=0.001), physical (r=0.427, P=0.001 and r=0.329, P=0.012), and mental (r=0.379, P=0.003 and r=0.432, P=0.001) HRQOL, platelet count (r=-0.357, P=0.012 and r=0.366, P=0.010), and international normalized ratio (INR) levels (r=-0.373, P=0.013 and r=-0.440, P=0.003). Erection was also correlated with albumin levels (r=0.310, P=0.032). Orgasmic functioning was associated significantly with platelet count (r=0.322, P=0.024) and INR levels (r=-0.425, P=0.004). Intercourse satisfaction was significantly related to depression (r=-0.435, P=0.001) and anxiety (r=-0.335, P=0.008) levels, physical (r=0.374, P=0.004) and mental (r=0.300, P=0.022) HRQOL, platelet count (r=0.333, P=0.020), and INR levels (r=-0.373, P=0.013), and overall satisfaction was significantly correlated with depressive (r=-0.435, P=0.001) and anxiety (r=-0.278, P=0.033) symptoms, mental HRQOL (r=0.340, P=0.010), platelet count (r=0.316, P=0.029), and INR levels (r=-0.332, P=0.030). CONCLUSION: Hepatitis C is accompanied by poor sexual functioning even in the absence of cirrhosis and different correlations emerge for distinct subdomains of male sexuality.

The effects of unfractionated heparin, low molecular weight heparin and danaparoid on the thromboelastogram (TEG): an in-vitro comparison of standard and heparinase-modified TEGs with conventional coagulation assays.

To investigate the effects of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and danaparoid (DPD) added to whole blood in vitro on standard and heparinase-modified thromboelastogram (TEG) parameters compared with conventional assays of coagulation. The effects of UFH, LMWH and DPD on standard TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-activated factor X (anti-FXa) activity, at concentrations of these anticoagulants ranging from 0.025 to 1 U/ml. In the second part of the study, the effects of very low concentrations (0.005-0.05 U/ml) of UFH, LMWH and DPD on the difference between standard and heparinase-modified TEG parameters were compared with the prothrombin time, activated partial thromboplastin time, thrombin time and anti-FXa activity. Standard TEG parameters were outside the reference range at lower concentrations of UFH, LMWH and DPD than most conventional coagulation assays were able to detect. Only anti-FXa activity was more sensitive to the presence of these anticoagulants than the standard TEG alone. The lowest concentration of UFH, LMWH and DPD used in this study (0.005 U/ml) caused significant differences between the standard and heparinase-modified alpha-angles of the TEG. In addition, the difference between standard and heparinase-modified TEG parameters distinguished between low concentrations (0.005-0.05 U/ml) of UFH with greater sensitivity than anti-FXa activity, but were less sensitive to LMWH and DPD. The standard TEG is more sensitive to UFH, LMWH and DPD than most conventional coagulation tests, with the exception of anti-FXa activity. Calculation of the difference between standard and heparinase-modified TEG parameters greatly increases the sensitivity of the assay for the effects of these anticoagulants, and is more sensitive to very low quantities of UFH than anti-FXa activity.

Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications.

The intestinal lumen is a host place for a wide range of microbiota and sets a unique interplay between local immune system, inflammatory cells and intestinal epithelium, forming a physical barrier against microbial invaders and toxins. Bacterial translocation is the migration of viable or nonviable microorganisms or their pathogen-associated molecular patterns, such as lipopolysaccharide, from the gut lumen to the mesenteric lymph nodes, systemic circulation and other normally sterile extraintestinal sites. A series of studies have shown that translocation of bacteria and their products across the intestinal barrier is a commonplace in patients with liver disease. The deterioration of intestinal barrier integrity and the consulting increased intestinal permeability in cirrhotic patients play a pivotal pathophysiological role in the development of severe complications as high rate of infections, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding, progression of liver injury and hepatocellular carcinoma. Nevertheless, the exact cellular and molecular mechanisms implicated in the phenomenon of microbial translocation in liver cirrhosis have not been fully elucidated yet.

Higher free serum cortisol is associated with worse survival in acute variceal bleeding because of cirrhosis: a prospective study.

BACKGROUND AND AIMS: Critical illness-related corticosteroid insufficiency has been reported in acute variceal bleeding (AVB). In cirrhosis, free serum cortisol (FC) is considered optimal to assess adrenal function. Salivary cortisol (SC) is considered a surrogate for FC. We evaluated FC and its prognostic role in AVB. METHODS: Total serum cortisol, SC, cortisol-binding globulin, and FC (Coolens' formula) were evaluated in AVB (n=38) and in stable cirrhosis (CC) (n=31). A Cox proportional hazards model was evaluated for 6-week survival. RESULTS: In AVB, the median FC and SC levels were higher with worse liver dysfunction [Child-Pugh (CP) A/B/C: 1.59/2.62/3.26 µg/dl, P=0.019; CPA/B/C: 0.48/0.897/1.81 µg/ml, P<0.001, respectively]. In AVB compared with CC, median total serum cortisol: 24.3 versus 11.6 µg/dl (P<0.001), SC: 0.86 versus 0.407 µg/ml (P<0.001); FC 2.4 versus 0.57 µg/dl (P<0.001). In AVB, 5-day rebleeding was 10.5%, and 6-week and total mortality were 21.1 and 23.7%, respectively. Independent associations with 6-week mortality in AVB were FC at least 3.2 µg/dl (P<0.001), hepatocellular carcinoma (P<0.001), CPC (P<0.001), and early rebleeding (P<0.001). Among patients with normal cortisol-binding globulin (n=14) and albumin (n=31), the factors were hepatocellular carcinoma (P=0.003), CP (P=0.003), and FC (P=0.036). SC was also found to be an independent predictor of 6-week mortality (P<0.001). Area under the curve of FC for predicting 6-week mortality was 0.79. CONCLUSION: Higher FC is present in cirrhosis with AVB compared with CC and is associated independently with bleeding-related mortality. However, whether high FC solely indicates the severity of illness or whether there is significant adrenal insufficiency cannot be discerned.

Surgical repair of umbilical hernias in cirrhosis with ascites.

The most common complications of umbilical hernias in patients with cirrhosis and ascites include leakage, ulceration, rupture and incarceration. If such a complication is present, there is a high mortality rate after surgical repair. Elective repair is the most effective choice, as it prevents complications with a lower mortality. However, the control of ascites before and/or after repair is mandatory but may not always be possible with diuretics and paracentesis. Portal decompression by transjugular intrahepatic portosystemic shunt (TIPS) with better control of ascites may allow these patients to undergo surgery. Patients with cirrhosis and umbilical hernias should be referred for consideration of an elective surgical repair with mesh, preferably after optimal management of ascites. There should be a low threshold for placement of a TIPS to facilitate surgery and reduce the chance of severe recurrence of ascites. If surgery is contraindicated, a TIPS must be considered for control of ascites.

Terlipressin therapy for renal failure in cirrhosis.

OBJECTIVES: Renal failure is common in cirrhosis frequently due to hepatorenal syndrome (HRS). Terlipressin and albumin improve renal function with a trend to prolong survival in HRS, but prognostic factors with therapy have been poorly studied. METHODS: Forty-five cirrhotics seen consecutively in a single centre with renal failure defined as oliguria/anuria and/or rising creatinine and no response to volume loading, without intrinsic renal disease, sepsis, gastrointestinal bleeding [median Child-Pugh score 12(8-14)/Model for End-Stage Liver Disease 29(10-40)], had intravenous terlipressin and albumin and were audited retrospectively classified into three groups: group 1 HRS type 1 (15), group 2 HRS type 2 (11) and group 3(19): not fulfilling HRS 1 or 2 criteria. Baseline median creatinine was 1.7 (0.9-5.46) mg/dl and 30 (67%) had creatinine greater than 1.5 mg/dl. All 45 patients had initial colloid/albumin and 31 continued terlipressin (2-4 mg/day) for a median 8 (2-76) days. RESULTS: Improvement in serum creatinine occurred in 23 (51%) [(1.3 mg/dl (0.6-3.9)] compared with baseline [1.7 mg/dl (0.92-3.75)] (P<0.001). In the multivariate analysis a greater reduction in creatinine between baseline and day 4 (95% confidence interval, odds ratio: 0.25) was associated with improved survival at 6 weeks. CONCLUSION: Albumin and terlipressin improve renal failure in the absence of sepsis in cirrhosis independently of whether HRS criteria are fulfilled or not. Improvement at 4 days of therapy is associated with better survival. Randomized studies are needed for oliguria and rising creatinine in cirrhotics even if HRS criteria are not fulfilled.

Predictors of early rebleeding and mortality after acute variceal hemorrhage in patients with cirrhosis.

Despite improvements over the past 20 years in patient survival following episodes of acute variceal hemorrhage (AVH) secondary to cirrhosis, AVH is still associated with a high rate of mortality. The ability to predict which patients are at high risk of death, or which are not likely to respond to standard therapy at admission to hospital is important, as it enables the immediate initiation of vasoactive drugs, early endoscopic intervention and prophylactic antibiotics. This commentary discusses a study that attempts to predict early rebleeding and mortality after AVH in patients with cirrhosis using the Model for End-stage Liver Disease. In this study, the model was a significant predictor of mortality; however, several defects in the study's design limit the conclusions that can be drawn from it. The model described in this study is neither more useful, nor more accurate, than those previously published for the prediction of rebleeding and mortality in patients with AVH.

TIPS for refractory ascites: a single-centre experience.

PURPOSE: Transjugular intrahepatic portosystemic shunt (TIPS) has been reported superior to large-volume paracentesis for refractory ascites, but post-TIPS encephalopathy is a major complication. We intended to assess the outcome of limited diameter TIPS on ascites control, mortality, and encephalopathy in patients with refractory ascites at our centre. METHODS: TIPS was successfully performed on 56 patients. Initial stent dilatation was to 6 mm, if there was a reduction in portal pressure gradient (PPG) >25%, further dilatation was not proposed. RESULTS: Either complete or partial response was obtained in 58%, 81%, 83%, and 93% of patients at 1, 3, 6, and 12 months, respectively. Mortality was 10%, 29%, 37%, and 50% at 1, 3, 6, and 12 months, respectively. In 27 patients (48%), a new episode of encephalopathy developed, but only 6 (22%) were grade III or IV and 23 (85%) responded quickly to treatment. CONCLUSIONS: The results of our study confirm the efficacy of TIPS for refractory ascites. The use of narrow-diameter dilatation without aiming at lowering the PPG below a certain threshold might simplify the procedure and the follow-up for these patients.

Hepatic venous pressure gradient to assess fibrosis and its progression after liver transplantation for HCV cirrhosis.

Progression of fibrosis following recurrent hepatitis C virus (HCV) infection is frequent after liver transplantation (LT). Histology remains the gold standard to assess fibrosis, but the value of hepatic venous pressure gradient (HVPG) is being explored. We evaluated patients with recurrent HCV infection after LT to assess whether HVPG correlates with liver histology, particularly fibrosis. A total of 90 consecutive patients underwent 170 HVPG measurements concomitant with transjugular liver biopsy (TJB), with 31.5 (range, 6-156) months of follow up. Median biopsy length was 22 mm and total portal tract count was 12 (complete 6, partial 6). Median HVPG was 4 mmHg: 38% of patients > or =6 mmHg (portal hypertension, PHT), 13% > or =10 mmHg. HVPG correlated with Ishak stage (r = 0.73, P < 0.001) for mild (0-3) and severe fibrosis (4-6), and grade score (r = 0.47, P < 0.001), but neither correlated with interval from LT nor biopsy length. HVPG was > or =10 mmHg in 15 patients: 12 had stage 5 or 6, and 3 severe portal expansion. HVPG was repeated in 49, between 7 and 60 months with weak correlation to fibrosis score (r = 0.30, P = 0.045). A total of 12 patients with HVPG > or =6 mmHg had fibrosis score < or =3, while 8 patients had normal HVPG but fibrosis stage > or =4. These discrepancies were mostly associated with specific histological features such as perisinusoidal fibrosis rather than errors in measuring HVPG. In 29 with HVPG <6 mmHg at 1 yr, none decompensated compared to 4 of 13 (31%) with PHT. In conclusion, HVPG correlates with fibrosis and its progression, due to recurrent HCV infection, assessed in TJB.

Sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis.

Immunosuppression is a main determinant for the increased Hepatitis C Virus (HCV) replication after liver transplantation and the accelerated course of recurrent HCV liver disease. We present two patients both with diabetes, renal dysfunction with proteinuria converted to sirolimus therapy, who cleared serum HCV RNA without antiviral treatment. This is a potentially important observation that should stimulate study into factors that may help viral clearance from blood.

Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation.

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.