Mini-microabscess syndrome in liver transplant recipients

Cytomegalovirus (CMV) is a significant cause of morbidity in immunosuppressed patients. It is characterized in the liver by parenchymal microabscesses, usually containing CMV-infected cells. However, not all hepatic microabscesses are due to CMV infection. In 1992, we described ''mini'' microabscess (MMA) syndrome, a distinct clinical syndrome that occurs in transplanted livers. This report analyzes the clinical and laboratory features of 57 cases of MMA syndrome occurring in 52 patients and compares these with 19 biopsy-proven cases of CMV infection. The diagnosis of MMA syndrome can only be made histologically. The microabscesses are smaller and more numerous than in CMV infection, and there are no viral inclusions present. CMV DNA could not be detected in liver biopsy specimens with MMAs by using ''nested'' polymerase chain reaction (PCR), indicating that MMA syndrome is not caused by CMV infection. The pattern of liver enzyme and bilirubin elevation is predominantly hepatocellular, with transaminase levels elevated, on average, six to eight times the upper limit of normal. The clinical features of MMA syndrome are that it predominantly affects female (40 of 52 patients) orthotopic liver transplant (OLT) recipients of all ages (range, 11 months to 66.9 years). MMA syndrome is unrelated to the indication for initial OLT and tends to occur later after transplantation than CMV infection (median, 91 days post-OLT vs. 32 days for CMV hepatitis). Although the etiology of MMA syndrome is not clear, it does not appear to adversely affect graft or patient survival.

Real-time and Doppler US after pediatric segmental liver transplantation

Background Accurate diagnosis of portal vein (PV) stenosis by real-time and color Doppler US (CD-US) after segmental liver transplantation in children can decrease morbidity by avoiding unnecessary biopsy, PV hypertension, thrombosis and loss of the graft. Objective To evaluate CD-US parameters for the prediction of PV stenosis after segmental liver transplantation in children. Materials and methods We retrospectively reviewed 61 CD-US examinations measuring the diameter at the PV anastomosis, velocities at the anastomosis (PV1) and in the segment proximal to the anastomosis (PV2), and the PV1/PV2 velocity ratio. The study group comprised patients with stenosis confirmed by angiography and the control group comprised patients with a good clinical outcome. Results PV stenosis was seen in 12 CD-US examinations. The mean PV diameter was smaller in the study group (2.6 mm versus 5.7 mm) and a PV diameter of < 3.5 mm was highly predictive of stenosis (sensitivity 100%, specificity 91.8%). Conclusion A PV diameter of < 3.5 mm is a highly predictive CD-US parameter for the detection of hemodynamically significant stenosis on angiography.

Durable Complete Responses in Metastatic Colorectal Cancer Treated with Chemotherapy Alone

Background/Purpose: The median survival for patients with metastatic colorectal cancer (mCRC) has progressively increased over the past decades. Since the introduction of 5-fluorouracil (5-FU)-based chemotherapy, followed by hepatic resection of metastases, and more recently the adoption of newer chemotherapeutic regimens associated with targeted therapy, the gains are getting more substantial. Despite the recognition of the potential for long-term survival after surgical resection of metastatic disease, long-term survival data to determine the potential curative role of chemotherapy alone is lacking. Methods: We performed a retrospective review of 2751 patients who presented with mCRC at The MD Anderson Cancer Center from 1990 through 2003. Patients alive at 5 years who achieved complete response with chemotherapy and were not submitted to any surgical or interventional procedures directed to the metastatic sites were included in the analysis. Results: The 5-year overall survival rate for all patients with mCRC during this period was 10.8%. Among these long-term survivors, 2.2% achieved a sustained complete response after chemotherapy (all 6 with fluoropyrimidines and 2 with irinotecan) as the only treatment modality and were without evidence of disease until the last follow-up visit (median of 10.3 years). This number corresponds to 0.24% (6 of 2541) of all patients with mCRC included in this review. Conclusion: Cure with chemotherapy alone is possible for a very small number of patients with metastatic colorectal cancer. Improved therapies are increasing complete response rates, but the impact of modern chemotherapy on durable complete responses will require additional follow up.

Amino acids change liver growth factors gene expression in malnourished rats

Background: Glutamine and proline are metabolized in the liver and may collaborate on its regeneration. Parenteral nutrition (PN) containing either glutamine or proline was given to partially hepatectomized rats. The total RNA content and growth factor gene expression in hepatic remnants was measured, to determine the effects of these amino acid supplementation on the expression of growth factors during liver regeneration. Methods: Wistar rats nourished (HN) and malnourished (HM) were hepatectomized and divided in two groups: 20 receiving PN enriched with Alanyl-Glutamine (HN-Gln and HM-Gln) and 20 PN enriched with proline+alanine (HN-Pro and HM-Pro). The control groups comprised 7 nourished (CN) and 7 malnourished (CM) rats that didn`t undergo surgery. Growth factor and thymidine kinase mRNA levels were measured by RT-PCR. Results: In nourished rats, total hepatic RNA levels were lower in the HN-Gln and HN-Pro groups (0.75 and 0.63 mu g/mg tissue, respectively) than in control group (1.67 mu g/mg tissue) (P<0.05). In malnourished rats, total hepatic RNA content was higher in the HM-Pro group than FIN-Pro, HM-Gln, and CM (3.18 vs. 0.63, 0.93 and 1.10 mu g/mg, respectively; P<0.05). Hepatocyte growth factor mRNA was more abundant in the HM-Gln group when compared to CM (031 vs. 0.23 arbitrary units) and also in HM-Pro in relation to HM-Gln, HN-Pro, and CM (0.46 vs. 033 and 0.23, respectively, P<0.05). Conclusions: Proline or glutamine supplementation in malnourished rats improves total RNA content in the remnant hepatic tissue. Amino acids administration increased HGF gene expression after partial hepatectomy in malnourished rats, with a greater effect of proline than glutamine.

Midterm and long-term results of percutaneous endovascular treatment of venous outflow obstruction after pediatric liver transplantation

PURPOSE: To evaluate retrospectively the midterm and long-term results of percutaneous endovascular treatment of venous outflow obstruction after pediatric liver transplantation. MATERIALS AND METHODS: During a 9-year period, 18 children with obstruction of a hepatic vein (HV) or inferior vena cava (IVC) anastomosis underwent percutaneous transluminal angioplasty (PTA) with balloon dilation or stent placement in case of PTA failure after liver transplantation. Patients` body weights ranged from 7.7 kg to 42.6 kg (mean, 18.8 kg +/- 9). Potential predictors of patency were compared between balloon dilation and stent placement groups. RESULTS: Forty-two procedures were performed (range, 1-11 per patient; mean, 2). Technical and initial clinical success were achieved in all cases. Major complications included one case of pulmonary artery stent embolization and one case of hemothorax. Three children (25%) with HV obstruction were treated with PTA and nine (75%) were treated with stent placement. Three children with IVC obstruction (75%) were treated with PTA and one (25%) was treated with a stent. There were two children with simultaneous obstruction at the HV and IVC; one was treated with PTA and the other with a stent. Cases of isolated HV stenosis have a higher probability of patency with balloon-expandable stent treatment compared with balloon dilation (P < .05). Follow-up time ranged from 7 days to 9 years (mean, 42 months +/- 31), and the primary assisted patency rate was 100% when stent placement was performed among the first three procedures. CONCLUSIONS: In cases of venous outflow obstruction resulting from HV and/or IVC lesions after pediatric liver transplantation, percutaneous endovascular treatment with balloon dilation or stent placement is a safe and effective alternative treatment that results in long-term patency.

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC(3) program

Background & Aims: EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods: Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results: Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2 = 0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p <= 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p <= 0.001): genotype 2/3 (odds ratio = 2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions: FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Molecular Characterization, Distribution, and Dynamics of Hepatitis C Virus Genotypes in Blood Donors in Colombia

Hepatitis C virus (HCV) is a frequent cause of acute and chronic hepatitis and a leading cause for cirrhosis of the liver and hepatocellular carcinoma. HCV is classified in six major genotypes and more than 70 subtypes. In Colombian blood banks, serum samples were tested for anti-HCV antibodies using a third-generation ELISA. The aim of this study was to characterize the viral sequences in plasma of 184 volunteer blood donors who attended the ""Banco Nacional de Sangre de la Cruz Roja Colombiana,`` Bogota, Colombia. Three different HCV genomic regions were amplified by nested PCR. The first of these was a segment of 180 bp of the 5`UTR region to confirm the previous diagnosis by ELISA. From those that were positive to the 5`UTR region, two further segments were amplified for genotyping and subtyping by phylogenetic analysis: a segment of 380 bp from the NS5B region; and a segment of 391 bp from the E1 region. The distribution of HCV subtypes was: 1b (82.8%), 1a (5.7%), 2a (5.7%), 2b (2.8%), and 3a (2.8%). By applying Bayesian Markov chain Monte Carlo simulation, it was estimated that HCV-1b was introduced into Bogota around 1950. Also, this subtype spread at an exponential rate between about 1970 to about 1990, after which transmission of HCV was reduced by anti-HCV testing of this population. Among Colombian blood donors, HCV genotype 1b is the most frequent genotype, especially in large urban conglomerates such as Bogota, as is the case in other South American countries. J. Med. Virol. 82: 1889-1898, 2010. (C) 2010 Wiley-Liss, Inc.

Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma

Aims We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. Methods A bolus of injectate containing [Cr-51] labelled red blood cells, [C-14]-sucrose and [H-3]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [Cr-51] or beta [C-14 and H-3] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). Results The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. Conclusions The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.

Impulse-response studies on tracer doses of [C-14]lignocaine and its multiple metabolites in the perfused rat liver

The outflow-concentration-time profiles for lignocaine (lidocaine) and its metabolites have been measured after bolus impulse administration of [C-14]lignocaine into the perfused rat liver. Livers from female Sprague-Dawley rats were perfused in a once-through fashion with red-blood-cell-free Krebs-Henseleit buffer containing 0 or 2% bovine serum albumin. Perfusate flow rates of 20 and 30 mL min(-1) were used and both normal and retrograde flow directions were employed. Significant amounts of metabolite were detected in the effluent perfusate soon after lignocaine injection. The early appearance of metabolite contributed to bimodal outflow profiles observed for total C-14 radioactivity. The lignocaine outflow profiles were well characterized by the two-compartment dispersion model, with efflux rate << influx rate. The profiles for lignocaine metabolites were also characterized in terms of a simplified two-compartment dispersion model. Lignocaine was found to be extensively metabolized under the experimental conditions with the hepatic availability ranging between 0.09 and 0.18. Generally lignocaine and metabolite availability showed no significant change with alterations in perfusate flow rate from 20 to 30 mt min(-1) or protein content from 0 to 2%. A significant increase in lignocaine availability occurred when 1200 mu M unlabelled lignocaine was added to the perfusate. Solute mean transit times generally decreased with increasing flow rate and with increasing perfusate protein content. The results confirm that lignocaine pharmacokinetics in the liver closely follow the predictions of the well-stirred model. The increase in lignocaine availability when 1200 mu M unlabelled lignocaine was added to the perfusate is consistent with saturation of the hydroxylation metabolic pathways of lignocaine metabolism.

Timing-dependent protection of hypertonic saline solution administration in experimental liver ischemia/reperfusion injury

Background. Diving liver ischemia, the decrease in mitochondrial energy causes cellular damage that is aggravated after reperfusion. This injury can trigger a systemic inflammatory syndrome, also producing remote organ damage. Several substances have been employed to decrease this inflammatory response during liver transplantation, liver resections, and hypovolemic shock. The aim of this study was to evaluate the effects of hypertonic saline solution and the best timing of administration to prevent organ injury during experimental liver ischemia/reperfusion. Methods. Rats underwent 1 hr of warm liver ischemia followed by reperfusion. Eighty-four rats Were allocated into 6 groups: sham group, control of ischemia group) (C), pre-ischemia treated NaCl 0.9% (ISS) and NaCl 7.5% (HTS) groups, pre-repefusion ISS, and HTS groups. Blood and tissue samples were collected 4 hr after reperfusion. Results. HTS showed beneficial effects in prevention of live ischemia/reperfusion injury. HTS groups developed increases in AST and ALT levels that were significantly less than ISS groups; however, the HTS pre-reperfusion group showed levels significantly less than the HTS pre-ischemia group. No differences in IL-6 and IL-10 levels, were observed. A significant decrease in mitochondrial dysfunction as well as hepatic edema was observed in the HTS pre-reperfusion group. Pulmonary vascular permeability Was significantly less in the pre-reperfusion HTS group compared to the ISS group. No differences in myeloperoxidase activity were observed. The liver histologic score was significantly less in the pre-reperfusion HTS group compared to the pre-ischemia I-ITS group. Conclusion. HTS ameliorated local and systemic injuries in experimental liver ischemia/reperfusion. Infusion of HTS in the pre-reperfusion period may be an important adjunct to accomplish the best results. (Surgery 2010;147:415-23.)

Propranolol reduces variceal pressure and wall tension in schistosomiasis presinusoidal portal hypertension

Background and Aim: Although prophylaxis with beta-blockers has been shown to decrease variceal pressure and wall tension in cirrhotic patients, this has not been demonstrated in non-cirrhotic portal hypertension caused by Schistosoma mansoni infection. Methods: Thirteen patients without history of previous gastrointestinal bleeding were included. All of them had high-risk esophageal varices at endoscopy. An endoscopic gauge and a high-frequency endoscopic ultrasonography miniprobe were used to assess transmural variceal pressure and wall tension before and after achieving beta-blockade with propranolol. Results: Baseline variceal pressure decreased from 13.3 +/- 3.5 to 8.2 +/- 2.0 mmHg (P < 0.0001) and wall tension from 500.2 +/- 279.8 to 274.0 +/- 108.3 mg.mm-1. The overall effect of propranolol on decreasing variceal pressure and wall tension expressed in percentage change in relation to baseline values was 35.7 +/- 18.4% and 35.9 +/- 26.7%, respectively (P = 0.9993). Conclusion: Propranolol significantly reduced variceal pressure and wall tension in schistosomiasis.

A Prospective Study of Conventional and Expanded Coagulation Indices in Predicting Ulcer Bleeding After Variceal Band Ligation

BACKGROUND & AIMS: There is controversy over whether coagulation status predicts bleeding caused by ulceration after esophageal varices band ligation (EVL). METHODS: EVL was performed for primary (n = 45) or secondary (n = 105) prophylaxis in 150 patients with cirrhosis (Child A, n = 74, 49%; Child B, n = 42, 28%; Child C, n = 34, 23%). International normalized ratio (INR) and platelet counts were assessed in all. In 92 patients, levels of factor V, fibrinogen, D-dimer, protein C and protein S, von Willebrand factor, and thromboelastography (TEG) were assessed. Platelet count < 50 x 10(3)/mm(3) and INR > 1.5 were considered high-risk cutoff for bleeding. Conversely, platelet count >= 50 x 10(3)/mm(3) with INR <= 1.5 were safe cutoffs. RESULTS: Overall, 11 patients (7.3%) had post-EVL ulcer bleeding. Bleeding occurred in S patients with Child A/B (4.3%) and 6 patients with Child C (17%) (P = .0174 for Child A/B versus Child C). Eight patients with bleeding were among the 110 below the cutoff for INR and platelet count, whereas only 3 of the patients with bleeding were among the 40 patients with purported high-risk values (P = 1.0). Among the 92 patients with expanded coagulation tests, bleeding occurred in S. There was no difference in any of the coagulation parameters, including overall TEG patterns, between patients who did and did nor bleed. CONCLUSIONS: Post-EVL ulcer bleeding was associated with Child C status but not with conventional or expanded coagulation indices in cirrhotic patients without renal failure or infection undergoing elective EVL. These results call into question the common use of prophylactic procoagulants in the elective setting.

Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon alfa/Ribavirin Therapy

Background & Aims: Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. Methods: This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 mu g/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator`s request. Results: Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (<= 600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. Conclusions: Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

Follow-up of Pregnant Women With Autoimmune Hepatitis The Disease Behavior Along With Maternal and Fetal Outcomes

Goals: To assess maternal and fetal outcomes and clinical management of pregnancy in patients with autoimmune hepatitis (AIH). Background: There is a paucity of information about maternal and fetal outcomes, and AIH activity during pregnancy and in the postpartum period. There is no consensus about the administration of azathioprine during pregnancy and breastfeeding. Study: Retrospective analysis of 54 pregnancies (3 still in progress) in 39 AIH patients. Results: The median age at conception was 24 years, and 68.4% of women had liver cirrhosis. Before conception and in early pregnancy, azathioprine and prednisone were administered in 48.1%, but treatment regimen vas usually changed further to 20 mg/d prednisone and 20.4%, were off treatment. There were 36 livebirths, and fetal loss rates were 29.4% (13 miscarriages, 1 stillbirth, and 1 ectopic pregnancy). Preterm birth rate was 11.8%. In 2 cases, there was acute fetal distress; and in 2 others congenital malformations (3.9%). The rate of serious maternal complication was 7.8%, with no deaths. There were no flares in 41.2% pregnancies, but aminotransferase elevations occurred in 54.9%, 31.4% of which were true AIH relapses, only registered in the postpartum period. Conclusions: Despite the high fetal miscarriage rate, pregnancy in AIH was safe. Patients needed careful monitoring, especially in the postpartum period because of relapses. There was no evidence of a cause and effect relationship among azathioprine administration and premature births and congenital abnormalities, but more studies are necessary. Higher doses of prednisone may be an alternative option for those who prefer azathioprine withdrawal during pregnancy.

CFTR Polymorphisms in Patients with Alcoholic Chronic Pancreatitis

Introduction: Pancreas susceptibility to alcohol is variable and only 5-10% of chronic alcohol abusers develop chronic pancreatitis; the role of genetic factors in this process is unknown. The CFTR gene encodes a protein that acts on epithelial cells and plays a key role in normal exocrine pancreatic function. Methods: This study investigated the frequency of polymorphisms in intron 8 of the CFTR gene in patients with alcoholic chronic pancreatitis. Three groups of patients were studied: group A-68 adult alcoholics with a diagnosis of chronic pancreatitis; group B-68 adult alcoholics without pancreatic disease or liver cirrhosis and group C-104 healthy nonalcoholic adults. Results: T5/T7 genotype was more frequent in group A (11.8%) than in group B (2.9%) (p = 0.0481), and there was no statistical difference when groups A and C (5.8%) were compared (p = 0.1317). The haplotype combination (TG) 10-T7/(TG) 11-T7 was more frequent in groups B (23.5%) and C (20.2%) than in group A (7.3%) (p = 0.0080 and 0.0162). Conclusion: There are differences when these three groups are compared and individuals with T5/T7 genotype might have a greater risk of developing chronic pancreatitis when they become chronic alcoholics. Copyright (C) 2008 S. Karger AG, Basel and IAP