Dimitrios Samonakis

Infection, coagulation, and variceal bleeding in cirrhosis

Bacterial infections in cirrhotic patients are common. There is a predisposition to intestinal bacterial overgrowth, intestinal dysmotility, and increased intestinal permeability, all leading to an increase in bacterial translocation. Bacterial translocation is the probable mechanism for some of the most common infections in cirrhosis, such as spontaneous bacterial peritonitis, but is also the source of bacterial byproducts such as endotoxin which can cause an increase in portal pressure, impairment of liver function, and worsening of haemostasis. The effects of bacterial infection and bacterial products on portal and systemic haemodynamics in cirrhosis and clinical data on infection, from both retrospective and prospective studies of variceal bleeding and other settings, demonstrate the importance of infection in pathophysiological mechanisms in cirrhosis. This has been followed by recent clinical evidence that antibiotic therapy reverses systemic vasodilation and prevents early variceal rebleeding. In cirrhotic patients there is an increased susceptibility to bacterial infection, related to the degree of liver dysfunction1 leading to several abnormalities of defence mechanisms, all of which increase the susceptibility to infection, including deficiency of bactericidal and opsonic activities, impaired monocyte function, depressed phagocytic activity of the reticuloendothelial system (RES), defective chemotaxis, and low levels of complement in serum. A particularly important role is played by the reduced RES activity, due to the presence of extrahepatic and intrahepatic shunts through sinusoids without Kupffer cells, reduced number of Kupffer cells, and impaired Kupffer cell function. Thus cirrhotics with impaired RES phagocytic activity (as assessed by elimination of 99 m technetium-sulphur colloid) develop acute bacterial infections more frequently than cirrhotics with normal RES phagocytic activity.2 Both community and hospital acquired bacterial infections are frequently diagnosed in cirrhotics, most frequently spontaneous bacterial peritonitis (SBP), urinary tract infections, pneumonia, and skin infections.3 Their incidence rises with worsening liver function.3 Importantly, half of …

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.

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 ≥ 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. (Liver Transpl 2005;11:386–395.)

Transjugular liver biopsy: how good is it for accurate histological interpretation?

Background: A transjugular liver biopsy (TJLB) specimen is often smaller or more fragmented than a percutaneous liver biopsy (PLB) specimen. Recently, for PLB, the minimum requirements to evaluate chronic hepatitis have been set at 20–25 mm length and ⩾11 complete portal tracts. Aim: To evaluate and compare length of TJLB and PLB specimens, portal tract number, fragmentation and adequacy for histopathological diagnosis and staging. Patients and methods: 326 consecutive TJLB specimens in 274 patients (109 who had undergone a transplantation), always using three passes (19-G Tru-cut) and 40 consecutive PLB specimens (15-G Menghini). Results: No technical failures occurred with the TJLB, and histological diagnosis was possible in 98.5%. The median (range) number of fragments was 5 (1–13) and the median total length was 22 (3–46) mm, with 65% of specimens ⩾20 mm and 36% ⩾25 mm; 60% of TJLB specimens were ⩾28 mm long had ⩾11 complete portal tracts. No difference in complete portal tract number or biopsy length was found between PLB and TJLB specimens. Conclusion: A TJLB specimen with three passes is adequate for histological diagnosis, with 89% of specimens being either ⩾15 mm or having ⩾6 complete portal tracts. Although adequate sampling remains a limitation for staging and grading of chronic hepatitis, TJLB is comparable to PLB in this respect.

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 ≥6 mmHg (portal hypertension, PHT), 13% ≥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 ≥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 ≥6 mmHg had fibrosis score ≤3, while 8 patients had normal HVPG but fibrosis stage ≥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. Liver Transpl 13:1305–1311, 2007.

Immunosuppression and HCV recurrence after liver transplantation

HCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens. From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency. There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6 months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed.

Liver transplantation and hepatitis C virus: systematic review of antiviral therapy.

Antiviral therapy for recurrent hepatitis C after liver transplantation is increasingly used. This systematic review presents both viral and histological response in three areas: pretransplant (5 studies/180 patients), preemptive therapy soon after transplant (10 studies/417 patients), and therapy for established disease (75 studies/2027 patients). There were only 16 randomized studies (543 patients). Significant dose reductions and drug stoppage rates occurred. The data on histological improvement and risk of rejection are conflicting. Even the best antiviral therapy (pegylated interferon/ribavirin) is neither easily used nor reasonably effective. The best strategy will be pretransplant treatment, most likely with newer agents.

Exploring the bidirectional interactions between human cytomegalovirus and hepatitis C virus replication after liver transplantation

Recurrence of Hepatitis C (HCV) post‐liver transplantation (LT) is universal and its course is more aggressive than in immunocompetent individuals. Human cytomegalovirus (CMV) infection is a common post‐LT infection and has immunomodulatory effects that could adversely affect the outcome of HCV. To date, the effect of HCV replication on the dynamics of CMV have not been investigated. From 2000 to 2004, a cohort of 69 HCV‐infected liver transplant recipients and 188 HCV‐negative liver transplant recipients (NON‐HCV cohort) were monitored for CMV infection twice weekly by CMV polymerase chain reaction (PCR) with preemptive therapy initiated after 2 consecutive positive results. None of the patients received CMV prophylaxis. A subset of 18 HCV‐infected patients had their HCV viral load monitored regularly post‐LT by quantitative PCR. CMV DNAemia (>200 genomes/mL blood) did not influence the level of HCV replication within 150 days posttransplantation or the stage of liver fibrosis in liver biopsies at 1 yr post‐LT. There were no differences in the incidence of CMV DNAemia or replication dynamics in the HCV cohort compared to the NON‐HCV cohort. In conclusion, short term CMV viremia does not enhance the replication of HCV after LT, while HCV replication does not alter the replication dynamics of CMV. Liver Transpl 13:130–135, 2007.

Endogenous heparinoids in acute variceal bleeding

The risk of variceal bleeding in cirrhotics is associated with increasing liver dysfunction, larger varices, endoscopic red signs, and higher portal pressure. However, why bleeding occurs unpredictably and infrequently in individual patients is unknown. Bacterial infections occur in 35–66% of cirrhotics presenting with gastrointestinal bleeding.1 We proposed a possible pathophysiological basis linking infection and variceal bleeding via endotoxin induced endothelin release and subsequent portal pressure rise, combined with impaired platelet aggregation due to endotoxin induced nitric oxide and prostacyclin.2 Infected cirrhotics demonstrate a heparin effect using heparinase I modified thromboelastography (TEG) and have anti-Xa activity.3,4 Now we show similar findings in two cirrhotics during the course of acute variceal bleeding. Patient 1 was male, 66 years old (Child-Pugh grade C), and patient 2 was female, 42 years old …

Transjugular liver biopsy in patients with diffuse liver disease: comparison of three cores with one or two cores for accurate histological interpretation

Background: Transjugular liver biopsy (TJLB) can be performed to obtain more than two cores safely. This advantage has not been evaluated in terms of diagnostic accuracy or grading/staging evaluation.