Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B.

Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20,000 IU/mL vs. ≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg-negative patients in four groups: Group I (n = 55): HBV DNA ≥20,000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20,000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20,000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20,000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut-off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I-IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut-off 20,000 vs. 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088-0.868; P = 0.0276) and milder (A0-1) necroinflammatory grade (OR, 0.135; CI: 0.063-0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20,000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51% vs. 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg-negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut-offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.

Systematic review: tuberculous peritonitis--presenting features, diagnostic strategies and treatment.

The peritoneum is one of the most common extrapulmonary sites of tuberculous infection. Peritoneal tuberculosis remains a significant problem in parts of the world where tuberculosis is prevalent. Increasing population migration, usage of more potent immunosuppressant therapy and the acquired immunodeficiency syndrome epidemic has contributed to a resurgence of this disease in regions where it had previously been largely controlled. Tuberculous peritonitis frequently complicates patients with underlying end-stage renal or liver disease that further adds to the diagnostic difficulty. The diagnosis of this disease, however, remains a challenge because of its insidious nature, the variability of its presentation and the limitations of available diagnostic tests. A high index of suspicion is needed whenever confronted with unexplained ascites, particularly in high-risk patients. Based on a systematic review of the literature, we recommend: tuberculous peritonitis should be considered in the differential diagnosis of all patients presenting with unexplained lymphocytic ascites and those with a serum-ascites albumin gradient (SAAG) of <11 g/L; culture growth of Mycobacterium of the ascitic fluid or peritoneal biopsy as the gold standard test; further studies to determine the role of polymerase chain reaction, ascitic adenosine deaminase and the BACTEC radiometric system for acceleration of mycobacterial identification as means of improving the diagnostic yield; increasing utilization of ultrasound and computerized tomographic scan for the diagnosis and as a guidance to obtain peritoneal biopsies; low threshold for diagnostic laparoscopy; treatment for 6 months with the first-line antituberculous drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) in uncomplicated cases.

Indocyanine green clearance reflects reperfusion injury following liver transplantation and is an early predictor of graft function.

BACKGROUND/AIMS: Primary graft dysfunction is difficult to predict. We have previously shown that indocyanine green clearance measured at 24 h following orthotopic liver transplantation predicts graft survival and outcome. We prospectively evaluated the use of indocyanine green clearance (with a cut-off value of 200 ml/min) as a marker of graft function following orthotopic liver transplantation and investigated its relationship with the markers of reperfusion injury during orthotopic liver transplantation. METHODS: In all patients indocyanine green clearance was measured at 24 h. Repeated blood samples were taken before, during the anhepatic and reperfusion phase and up to 12 h following orthotopic liver transplantation to measure the levels of neutrophil elastase and reactive oxygen intermediates. All patients studied had normal hepatic arterial pulse on Doppler-ultrasound post orthotopic liver transplantation. RESULTS: All patients with indocyanine green clearance >200 ml/min recovered following orthotopic liver transplantation and remained well up to 3 months of follow up. Four patients had an indocyanine green clearance <200 ml/min; three were re-transplanted for graft failure within 3 days of the transplant, while one survived after prolonged intensive support and hospitalization. Indocyanine green clearance significantly correlated with reactive oxygen intermediates production and neutrophil elastase during orthotopic liver transplantation (r=-0.61, p<0.002 and r=-0.66, p<0.0009, respectively). Indocyanine green clearance was also significantly correlated with alanine aminotransferase and prothrombin time at 24 h post-transplantation (r=-0.35, p<0.02 and r=-0.4, p<0.0077, respectively). CONCLUSION: Indocyanine green reflects the degree of reperfusion injury and is a good early marker of primary graft function. Indocyanine green clearance over 200 ml/min is associated with favorable outcome.

Influence of cyclic guanosine monophosphate changes on hemodynamics after reperfusion in liver transplantation.

Orthotopic liver transplantation (OLT) is often associated with hemodynamic instability upon reperfusion, recognized as postreperfusion syndrome. Changes in vascular tone due to humoral factors released upon reperfusion of the graft have been suggested as a possible mechanism. In this study, we looked at the perioperative changes in cyclic guanosine monophosphate (cGMP), a mediator of vascular smooth muscle relaxation, and investigated its relationship with hemodynamic parameters. cGMP was measured in the plasma of 14 patients undergoing OLT by radioimmunoassay serially at the preanhepatic and anhepatic phases, and after reperfusion at 30, 60, and 120 min. Hemodynamic data recorded were systemic and pulmonary arterial pressures, cardiac output, and pulmonary and systemic vascular resistance. cGMP decreased markedly after reperfusion from a baseline level of 5.33+/-0.7 ng/ml to 1.63+/-0.5 ng/ml (P<0.01). Pulmonary arterial pressure increased from 17+/-1.21 mmHg to 23.5+/-1.9 mmHg (P<0.05), and pulmonary vascular resistance increased from 62.8 +/-12.9 dynes/sec/cm5 to 135+/-42.7 dynes/sec/cm5 (P<0.01). Changes in cardiac output and systemic vascular resistance were not significant. The changes in cGMP correlated with pulmonary arterial pressure (r=0.74, P=0.005) and pulmonary vascular resistance (r=0.7, P=0.01). These data confirm the occurrence of hemodynamic changes during OLT, and provide evidence to suggest that the reduction in cGMP after reperfusion may mediate the vascular changes.

Graft dysfunction following liver transplantation: role of free radicals.

BACKGROUND/AIMS: Following orthotopic liver transplantation primary graft non-function occurs in about 10% of patients, and survival depends on early retransplantation. The aetiology has yet to be defined, but reperfusion injury as a result of free radical production has been considered as a possible mechanism. In this study we looked for evidence of free radical generation intraoperatively and assessed the relationship between free radical production and graft function. METHODS/RESULTS: Twenty-one patients (M:F 10:11, mean age; 53 +/- 3.8 years) who underwent liver transplantation for end-stage liver disease were studied. Free radical activity increased significantly following reperfusion, as shown by: (i) the diene conjugated method, where the percentage molar ratio increased from a baseline of 10.87 +/- 0.78% to 24.42 +/- 7.8% (p < 0.01), and (ii) by electron paramagnetic resonance, where a more than a twofold rise in radical concentration was detected (p < 0.05). The increase in free radical activity detected by the diene conjugated method was significantly higher in patients with poor outcome as compared with those who had uneventful recovery (p < 0.01). CONCLUSION: Free radical activity is increased following reperfusion of liver graft during transplantation, and the magnitude of the rise is related to the severity of graft dysfunction.

Neutrophil elastase: a determinant of endothelial damage and reperfusion injury after liver transplantation?

Reperfusion injury has been implicated in the development of primary graft dysfunction (PGD) after liver transplantation. Neutrophil migration and activation may be involved in the pathogenesis of this injury. We studied neutrophil activation and its role in the etiology of PGD by measuring neutrophil elastase by radioimmunoassay, in serial blood samples of 19 patients before, during, and for 24 hr after transplantation. In a subgroup of patients, we also measured soluble thrombomodulin at the same time points as a marker of endothelial damage. The pretransplant elastase level was significantly raised (40.13+/-4.84 ng/ml, mean+/-SEM) compared with levels of healthy controls (18.7+/-5.6 ng/ml, P<0.05). A marked increase in elastase activity followed reperfusion, with a peak at 2 hr (370+/-50.5 ng/ml, P<0.01). Thereafter, there was a decline, but elastase remained elevated at 24 hr (186+/-60.94 ng/ml). The mean increase in neutrophil elastase after reperfusion correlated significantly with markers of graft function (P<0.05) and with the mean rise in soluble thrombomodulin (P=0.042), which increased from a pretransplant level of 81.2+/-11.32 to 186+/-50.4 ng/ml, 6 hr after reperfusion (P<0.05). The results of this study indicate that marked neutrophil activation and endothelial cell damage occurs after graft reperfusion during orthotopic liver transplantation, and the degree of activation correlates with markers of graft function, which may suggest a role in the etiology of PGD.