There are over 9000 liver transplants in the United States per year, with acute cellular rejection (ACR) being a prevalent early post-transplant complication (20%-40%) treated using corticosteroids. Ischemia-reperfusion injury (IRI), another early post-transplant pathology, has similar laboratory results but typically resolves without therapy. ACR confirmation requires invasive liver biopsy, bearing risks like hemorrhage and pneumothorax. Attenuation Measuring Ultrasound Shearwave Elastography (AMUSE) assesses shear wave velocity (c) and attenuation (α) without rheological models and have shown potential for noninvasive tissue characterization.

We analyzed 58 transplanted livers suspected for ACR by comparing AMUSE measurements to biopsy findings. Thirteen patients underwent longitudinal tracking from ACR diagnosis on day 7 to therapy initiation and repeat biopsy on day 14. Statistical methods and support vector machine (SVM) were used for performance analysis.

AMUSE measurements at 100, 200, and 300 Hz showed statistical significance (p < 0.001) for ACR presence, with 200 Hz exhibiting the highest Spearman correlation coefficients for c and α (0.68 and -0.83). High c (> 2.2 m/s) and low α (< 130 Np/m) at 200 Hz correlated with ACR diagnostic, while low c and high α indicated no ACR. Combining c and α into a single biomarker α/c improved patient differentiation, yielding an F1-score of 0.97. SVM was used to evaluate AMUSE ACR staging capabilities using all available frequencies, reaching 0.95 F1-score for categorical classification, with an AUROC of 0.99. When evaluating the presence of ACR the SVM reached 0.99 F1-score, with 1.00 sensitivity/recall.

These findings support the use of AMUSE potential for detection and staging of liver ACR.

Percutaneous liver biopsy has proven to be a valuable tool in the workup of pediatric acute liver failure and the management of post-transplant rejection. However, consensus regarding pre-procedure laboratory values and post-procedure monitoring is lacking.

To characterize the incidence of complications, procedural time, and specimen adequacy for percutaneous liver biopsy in the pediatric patient.

Retrospective review of percutaneous liver biopsies at a single institution was performed for a 5-year span. Procedural notes and anesthesia records were sampled for patient weight and procedural factors across a continuous 6-month period, as well as for the subgroup of patients under 24 months of age. A representative continuous subset of pathology reports comprising 376 patients were reviewed for estimation of specimen adequacy.

Eight hundred and sixty-seven ultrasound-guided percutaneous liver biopsies were performed in a 5-year period, 450 of which were in the post-transplant setting with about a 3:1 ratio of split: whole liver transplant. Patient ages ranged from 1 month to 21 years old, with weight ranging from 2.7 to 125 kg. Of the 376 pathology reports available, none were found to be inadequate for evaluation. Two major complications occurred, both of which were biliary leaks in the setting split-liver transplant. There were no incidences of post-procedure hemorrhage. Of the sample reviewed, mean "skin-to-skin" procedure time was under 8.5 min (median of 7 min). Solely among transplant patients, biopsies for split livers averaged 9.2 min, biopsies for whole livers averaged 6.2 min (two-tailed independent t test, p = 0.0426).

Ultrasound guided percutaneous liver biopsy is fast, useful, and safe in pediatric patients on an outpatient basis with same day discharge.

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Acute rejection (AR) and recurrent hepatitis C virus (R-HCV) are significant complications in liver allograft recipients. Noninvasive diagnosis of intragraft pathologies may improve their management.

We performed small RNA sequencing and microRNA (miRNA) microarray profiling of RNA from sera matched to liver allograft biopsies from patients with nonimmune, nonviral (NINV) native liver disease. Absolute levels of informative miRNAs in 91 sera matched to 91 liver allograft biopsies were quantified using customized real-time quantitative PCR (RT-qPCR) assays: 30 biopsy-matched sera from 26 unique NINV patients and 61 biopsy-matched sera from 41 unique R-HCV patients. The association between biopsy diagnosis and miRNA abundance was analyzed by logistic regression and calculating the area under the receiver operating characteristic curve.

Nine miRNAs-miR-22, miR-34a, miR-122, miR-148a, miR-192, miR-193b, miR-194, miR-210, and miR-885-5p-were identified by both sRNA-seq and TLDA to be associated with NINV-AR. Logistic regression analysis of absolute levels of miRNAs and goodness-of-fit of predictors identified a linear combination of miR-34a + miR-210 (P < 0.0001) as the best statistical model and miR-122 + miR-210 (P < 0.0001) as the best model that included miR-122. A different linear combination of miR-34a + miR-210 (P < 0.0001) was the best model for discriminating NINV-AR from R-HCV with intragraft inflammation, and miR-34a + miR-122 (P < 0.0001) was the best model for discriminating NINV-AR from R-HCV with intragraft fibrosis.

Circulating levels of miRNAs, quantified using customized RT-qPCR assays, may offer a rapid and noninvasive means of diagnosing AR in human liver allografts and for discriminating AR from intragraft inflammation or fibrosis due to R-HCV.

Complications associated with ultrasonographically guided percutaneous transhepatic liver biopsy (PTLB) after liver transplantation (LT) have been rarely reported, and there is no consensus about its safety. We retrospectively reviewed the safety and outcomes of PTLB after pediatric LT.

Between January 2008 and December 2019, 8/1122 (0.71%) pediatric patients who underwent ultrasonographically guided PTLB after LT developed complications. The median age at PTLB was 7.8 years (range 0.1-17.9). Grafts included left lobe/left lateral segment in 1050 patients and others in 72. PTLB was performed using local anesthesia±sedation in 1028 patients and general anesthesia in 94.

Complications after PTLB included acute cholangitis in 3 patients, sepsis in 2, respiratory failure due to over-sedation in 1, subcapsular hematoma in 1, and intrahepatic arterioportal fistula in 1. The incidence of complications of PTLB in patients with biopsy alone and those with simultaneous interventions was 0.49% and 3.19%, respectively (p = .023). Patients who developed acute cholangitis, respiratory failure, subcapsular hematoma, and arterioportal fistula improved with non-operative management. Of two patients with sepsis, one underwent PTLB and percutaneous transhepatic portal vein balloon dilatation and developed fever and seizures the following day. Sepsis was treated with antibiotic therapy. Another patient who underwent PTLB and exchange of percutaneous transhepatic biliary drainage catheter developed fever and impaired consciousness immediately. Sepsis was treated with antibiotic therapy, mechanical ventilation, and continuous hemofiltration.

Percutaneous transhepatic liver biopsy after pediatric LT is safe. However, combining liver biopsy with simultaneous procedures for vascular and biliary complications is associated with an increased risk of complications.

Acute cellular rejection (ACR) after liver transplantation (LT) goes along with allograft dysfunction, which is diagnosed by liver biopsy and concomitant histological analysis, representing the gold standard in clinical practice. Yet, liver biopsies are invasive, costly, time-intensive and require expert knowledge. Herein we present substantial evidence that blood plasma residing peripheral liver-derived extracellular particles (EP) could be employed to diagnose ACR non-invasively. In vitro experiments showed organ-specific EP release from primary human hepatocytes under immunological stress. Secondly, analysis of consecutive LT patients (n=11) revealed significant heightened EP concentrations days before ACR. By conducting a diagnostic accuracy study (n = 69, DRKS00011631), we explored the viability of using EP as a liquid biopsy for diagnosing ACR following LT. Consequently, novel EP populations in samples were identified using visualization of t-distributed stochastic neighbor embedding (viSNE) and self-organizing maps (FlowSOM) algorithms. As a result, the ASGR1⁺CD130⁺Annexin V⁺ EP subpopulation exhibited the highest accuracy for predicting ACR (area under the curve: 0.80, 95% confidence interval [CI], 0.70-0.90), with diagnostic sensitivity and specificity of 100% (95% CI, 81.67-100.0%) and 68.5% (95% CI, 55.3-79.3%), respectively. In summary, this new EP subpopulation presented the highest diagnostic accuracy for detecting ACR in LT patients.

Percutaneous liver biopsy is a relatively safe procedure with low complication rates. Infections following liver biopsy are uncommon and can lead to a poor outcome. There are limited data on liver biopsy-related infections among liver transplant (LT) recipients. Also, there is a paucity of data regarding the use of prophylactic antibiotics in LT patients undergoing percutaneous liver biopsy. We report a case of systemic sepsis following percutaneous liver biopsy in a LT recipient with choledochojejunal anastomosis. This was followed by severe rejection and deterioration of liver function and recurrence of primary sclerosing cholangitis (PSC) to the extent that he has been listed for retransplantation. This case report emphasizes the potential risk of sepsis in LT recipients with bilioenteric anastomosis undergoing percutaneous liver biopsy. This increased risk may warrant periprocedural broad spectrum antibiotic prophylaxis, in this subgroup of patients.

Liver biopsy is required when clinically important information about the diagnosis, prognosis or management of a patient cannot be obtained by safer means, or for research purposes. There are several approaches to liver biopsy but predominantly percutaneous or transvenous approaches are used. A wide choice of needles is available and the approach and type of needle used will depend on the clinical state of the patient and local expertise but, for non-lesional biopsies, a 16-gauge needle is recommended. Many patients with liver disease will have abnormal laboratory coagulation tests or receive anticoagulation or antiplatelet medication. A greater understanding of the changes in haemostasis in liver disease allows for a more rational, evidence-based approach to peri-biopsy management. Overall, liver biopsy is safe but there is a small morbidity and a very small mortality so patients must be fully counselled. The specimen must be of sufficient size for histopathological interpretation. Communication with the histopathologist, with access to relevant clinical information and the results of other investigations, is essential for the generation of a clinically useful report.

Although liver biopsy is the gold standard for assessing allograft health, its attendant risk has deterred its use in routine monitoring of stable liver transplant recipients during long-term follow-up. We utilized prospectively collected data on adverse events from 2 clinical trials of immunosuppression withdrawal to quantify the risk of liver biopsy in pediatric liver transplant recipients. The trials included 451 liver biopsies in 179 children. No biopsies led to bleeding requiring transfusion or intervention, suggesting a clinically significant bleeding risk of <0.8%. Complications were reported in 5.5% of biopsies (95% CI 3.6%-8.1%): 5.8% (21/363) of protocol biopsies and 4.5% (4/88) of for-cause biopsies (P = .80). Mild complications occurred in 1.8% of biopsies, moderate in 1.8%, and severe in 2.0%. The majority of complications (89%) resolved within 1 week. Six of 9 (67%) severe complications were related to biliary issues; 5 were episodes of cholangitis. Biopsy-related cholangitis occurred only in children with underlying biliary strictures. Overall, biopsy-related complications were infrequent and resolved quickly. Severe complications were rare, with occult biliary stricture as the dominant driver. Our study provides evidence for clinicians who are considering the risk vs benefit of surveillance liver biopsies in pediatric liver transplant recipients.

Adult liver recipients (ALR) differ from the general population with pyogenic liver abscess (PLA) as they exhibit: reconstructed biliary anatomy, recurrent hospitalizations, poor clinical condition and are subjected to immunosuppression. The aim of this study was to identify risk factors associated with PLA in ALR and to analyze the management experience of these patients.

Between 1996 and 2016, 879 adult patients underwent liver transplantation (LT), 26 of whom developed PLA. Patients and controls were matched according to the time from transplant to abscess in a 1 to 5 relation. A logistic regression model was performed to establish PLA risk factors considering clusters for matched cases and controls. Risk factors were identified and a multivariate regression analysis performed.

Patients with post-LT PLA were more likely to have lower BMI (p = 0.006), renal failure (p = 0.031) and to have undergone retransplantation (p = 0.002). A history of hepatic artery thrombosis (p = 0.010), the presence of Roux en-Y hepatojejunostomy (p < 0.001) and longer organ ischemia time (p = 0.009) were independent predictors for the development of post-LT PLA. Five-year survival was 49% (95%CI 28-67%) and 89% (95%CI 78%-94%) for post-LT PLA and no post-LT PLA, respectively (p < 0.001).

history of hepatic artery thrombosis, the presence of hepatojejunostomy and a longer ischemia time represent independent predictors for the development of post-LT PLA. There was a significantly poorer survival in patients who developed post-LT PLA compared with those who did not.

To determine the incidence of major adverse events related to a large volume of image-guided liver biopsies performed at our institution over a 12-year period and to identify risk factors for major bleeding events.

A retrospective analysis of an internally maintained biopsy registry was performed. The analysis revealed that 6613 image-guided liver biopsies were performed in 5987 adult patients between December 7, 2001, and December 31, 2013. Liver biopsies were performed using real-time ultrasound guidance and a spring-loaded biopsy device, with rare exceptions. Adverse events considered major and included in this study were hematoma, infection, pneumothorax, hemothorax, and death. Using data from the biopsy registry, we evaluated statistically significant risk factors (P<.05) for hematoma related to image-guided liver biopsy, including coagulation status, biopsy technique, and medications.

A total of 49 acute and delayed major adverse events (0.7%) occurred after 6613 liver biopsy events. The incidence of hematoma requiring transfusion and/or angiographic intervention was 0.5% (34 of 6613). The incidence of infection was 0.1% (8 of 6613), and that of hemothorax was 0.06% (4 of 6613). No patient (0%) incurred a pneumothorax after biopsy. Three patients (0.05%) died within 30 days of liver biopsy, 1 being directly related to biopsy. Thirty-eight of 46 major adverse events (83%) presented acutely (within 24 hours). More than 2 biopsy passes, platelets 50,000/μL or less, and female sex were statistically significant risk factors for postbiopsy hemorrhage.

Image-guided liver biopsy performed by subspecialized interventionalists at a tertiary medical center is safe when the platelet count is greater than 50,000/μL. With appreciation of specific risk factors, safety outcomes of this procedure can be optimized in both general and specialized centers.

While Roux-en-Y hepaticojejunostomy (RYH) is the common anastomotic technique for liver transplantation (LT) in patients with primary sclerosing cholangitis (PSC), duct-to-duct (DD) reconstruction may be used if the recipient common bile duct is normal. There are conflicting observational data on the rate of success of DD reconstruction versus RYH, in PSC.

The aim of this study was to assess the safety and efficacy of DD anastomosis, compared to RYH reconstruction, among adults transplanted for PSC.

All adult patients, who underwent primary LT for PSC between 1990 and 2012, were evaluated, according to type of biliary reconstruction. Recipient and graft survival, postoperative medical and surgical complications, and postoperative resource utilization rates were compared between the two groups.

Totally, 73 patients fulfilled the inclusion criteria. Of them, 58 had RYH and 15 had DD reconstruction. A total of 53 subjects (73%) were male, with the mean age ± standard deviation at LT of 43.3 ± 14.4 years. Rates of recipient mortality, graft failure, biliary complications, acute cellular rejection, and reoperation were similar in both groups. Postoperative cholangiography was used more frequently in patients with DD reconstruction (33.3% vs. 8.6%, P = 0.026).

In selected recipients with PSC, DD reconstruction is a safe and efficacious technique, with long-term clinical outcomes comparable to RYH.

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

The purpose of this study is to provide an overview of bacterial biliary tract infections in liver transplant recipients with a focus on pathogenesis and conservative treatment strategies.

The development of interventional endoscopic and radiologic interventions has improved the outcome of conservative treatments for bile tract strictures and bilomas. However, recent data show an important rise of infections with multidrug-resistant (MDR) pathogens in liver transplant recipients.

Both recurrent cholangitis and infected bilomas are bacterial biliary tract infections in liver transplant recipients responsible for significant morbidity and graft loss, which require a multidisciplinary approach. Risk factors for biliary tract strictures and bilomas formation have recently been identified. With the improved outcome of a conservative management including prolonged and/or recurrent antibiotic treatments, the risk of selecting resistant pathogens is increased. There is an urgent need to develop new strategies to reduce the risk of secondary infections by MDR isolates in liver transplant recipients.

Data from published studies regarding risk factors for liver biopsy (LB)-related infectious complications in liver transplant recipients are inconsistent. We carried out a retrospective cohort study analyzing consecutive LBs for orthotopic liver transplant patients at a tertiary hospital (2001-2011): there were 667 LB procedures (575 percutaneous procedures and 92 transjugular procedures) in 286 liver transplant recipients. There were 20 complications in 19 patients (overall incidence = 3.0%): 10 were infectious complications (8 cases of bacteremia and 2 cases of peritonitis). The causal microorganisms were mainly Pseudomonas aeruginosa (4 patients) and Enterobacteriaceae (4 patients). All complications occurred with biopsies performed in patients hospitalized for more than 48 hours (381 biopsies for 201 patients); hence, only this group was included in the risk factor analysis. The variables associated with the development of infectious complications after LB were the presence of impaired biliary drainage at the time of biopsy (40% versus 15.1%, P = 0.03) and low albumin levels (2.4 versus 3.1 g/dL, P = 0.01). In conclusion, according to our experience, infectious complications secondary to LB in liver transplant recipients are related to hospitalization at the time of biopsy, particularly in the presence of impaired biliary drainage and low albumin levels.

Although an LDLT can successfully treat biliary atresia (BA), some patients develop liver fibrosis or inflammation. To study the incidence and risk factors associated with these complications, we performed serial protocol biopsies. Twenty-four patients with BA who received a pediatric LDLT underwent protocol biopsies. All patients received standard tacrolimus-based immunosuppression and steroids. The last available biopsies were assessed. The mean age at the time of transplant was 4.8yr and the follow-up period ranged from 1.2 to 12.3yr. The GRWR ranged from 0.8% to 4.5%. The mean time from transplantation to the latest biopsy was 4.7yr. No complications occurred with the biopsy protocol. The last available biopsies for 13 (54%) and 4 (17%) patients indicated grade 1 and grade 2 portal fibrosis, respectively, and 14 patients (54%) had inflammation. No ductopenia was detected. A younger age at LDLT was significantly correlated with graft fibrosis (p=0.036). These results indicate that biopsy-proven fibrosis can be detected in patients with BA after LDLT, even in the context of normal liver function blood tests. Therefore, a serial biopsy is a safe and effective follow-up procedure for pediatric LDLT.

Arterioportal shunts (APS) are well-known critical complications after liver transplantation (OLT). The aims of this study were to assess the frequency and causes of APS after OLT and to analyze APS patients with poor outcomes.

We evaluated 1415 OLT recipients retrospectively investigating APS cases.

APS were detected in at least 9 patients (0.6%). All patients with APS had a history of posttransplant invasive procedures; percutaneous transhepatic cholangio drainage (n = 6) or needle biopsy (LNB; n = 3). Two patients with poor outcomes showed proximal APS caused by LNBs. The other 7 patients with distal APSs, showed stable conditions. Imaging findings in the 2 proximal APS patients revealed drastic changes in graft hemodynamics. Although they finally underwent re-OLT, their outcomes were poor, owing to fatal complications associated with advanced collaterals.

We concluded that even careful LNBs can cause APS at unexpected points. Earlier, more aggressive treatments are required, especially for proximal APS patients.

The aim of this study was to evaluate the infectious complications after living donor liver transplantation (LDLT) in children. We enrolled 95 children (38 boys and 57 girls) who underwent LDLT from 1994 to 2004. The median age was 22 months (range, 6 months to 15 yr). We retrospectively investigated the proven episodes of bacterial, viral, and fungal infection. There occurred 150 infections in 67 (70%) of 95 patients (1.49 infections/patient); 74 in 43 patients were bacterial, 2 in 2 were fungal, and 74 in 42 were viral. The most common sites of bacterial infection were the bloodstream (33%) and abdomen (25%). Most of the bacterial infections occurred within the first month after LDLT. Bacterial and fungal infections did not result in any deaths. The most common causes of viral infection were Epstein-Barr virus in 37 patients and cytomegalovirus in 18. Seven of the 14 deaths after LDLT were associated with viral infection. Our study suggests that infection is one of the important causes of morbidity and mortality after LDLT. Especially careful monitoring and management of viral infections is crucial for improving the outcome of LDLT in children.

To elucidate the role of Doppler hepatic hemodynamic parameters as surrogate markers of acute rejection (AR) after live donor liver transplantation (LDLT), serial Doppler measurements were prospectively performed during the first 2 weeks after LDLT to compare the longitudinal hepatic hemodynamic changes between patients with histologically proven AR and patients without histologically proven AR. Forty-six patients that had undergone adult-to-adult LDLT using a right lobe graft were enrolled in this study. The portal venous maximum velocity (PVV; cm/second), portal venous flow volume, hepatic arterial peak systolic velocity, hepatic arterial pulsatility index, hepatic venous maximum velocity, hepatic venous pulsatility index, and splenic arterial pulsatility index were measured. Fourteen patients were diagnosed by biopsy to have clinically relevant AR. Markedly increased PVV was seen soon after surgery and gradually decreased in both patients with clinically relevant AR and patients without clinically relevant AR. This serial change of decreasing PVV was significantly greater in patients with clinically relevant AR (P < 0.0001). After postoperative day 6, the PVV in patients with clinically relevant AR was significantly lower than that in patients without clinically relevant AR (PVV on postoperative day 6: 35.6 +/- 21.3 versus 58.3 +/- 27.1 cm/second, respectively, P = 0.0080). A PVV cutoff value of 20.2 cm/second demonstrated the best accuracy for predicting clinically relevant AR. The sensitivity and specificity for predicting clinically relevant AR were 92.9% and 87.1%, respectively. The area under the curve was 0.94. In conclusion, serial Doppler measurement of hepatic parameters in LDLT is useful for the diagnosis of clinically relevant AR. Clinically relevant AR should therefore be suspected when a marked unexpected decrease in the PVV is observed.

A Roux-en-Y hepaticojejunostomy (HJ) is usually performed during live donor liver transplantation (LDLT) when a duct-to-duct reconstruction is not possible. However, direct anastomosis of the bile duct to the duodenum (hepaticoduodenostomy [HD]) is an alternative technique for biliary repair that has been previously used for conventional biliary surgery and at our center for cadaveric liver transplant. We provide the first evidence that HD is an alternative technique for biliary reconstruction in LDLT.

We performed a total of 71 LDLT between 2002 and 2008. An end-to-end anastomosis was used in 30 patients. Forty-one patients had a biliary enteric anastomosis in which seven were reconstructed with an HD. Accessory ducts were fashioned into a common duct or implanted into the duodenum separately.

There were no patient deaths or retransplants in a follow-up period that ranged from 90 to 771 days after surgery. One patient was diagnosed with cholangitis that responded to intravenous antibiotics and removal of the stent by endoscopy.

This preliminary case series suggests that that HD is a feasible alternative to HJ biliary anastomosis when a duct-to-duct anastomosis cannot be performed. HD offers the possible advantage of simple postoperative access to the biliary system by endoscopy and avoids complications caused by HJ bowel anastomosis.

The utility of protocol liver allograft biopsies remains controversial, particularly in patients with normal liver function tests (LFTs). However, histologic evaluation of these biopsies provides an opportunity to examine the types and severity of liver diseases that can occur in livers with normal clinical and biochemical function. We studied 165 protocol allograft biopsies taken from 100 liver transplant patients at the time of normal LFTs and normal clinical function at 3 to 8 months (n=36), 1 year (n=52), 2 to 3 years (n=54), and 4 to 5 years (n=23). Biopsies were classified as normal, minimal changes (eg, nonaggressive portal or lobular mononuclear inflammation, steatosis <10%), fatty liver disease, recurrent primary liver disease, and transplant-related disease (portal-based rejection or central venulitis, an inflammatory pattern that encompasses perivenular hepatocyte dropout, mononuclear inflammation, pigment-laden macrophages, and variable zone 3 fibrosis). Among these 100 patients, a total of 394 protocol biopsies were performed, and 165 (42%) were taken at the time of normal LFTs and normal clinical function. One hundred twenty-one (73%) were normal or showed minimal/nonspecific changes. Forty-four (27%) showed histologic abnormalities that included fatty liver disease (n=19, nonalcoholic in 18 cases; 13 with mild steatosis, 6 with moderate steatosis, 7 with grade 1/3 steatohepatitic activity, and 2 with stage 1/4 steatohepatitic fibrosis), recurrent primary biliary cirrhosis (n=9; all stage 1/4), recurrent hepatitis C infection (n=6; grade 0/4 in 1, grade 1/4 in 5, stage 0/4 in 4, stage 1/4 in 1, and stage 2/4 in 1), recurrent sarcoidosis (n=1), Ito cell hyperplasia (n=4; marked in 2 and mild in 2), central venulitis (n=10; 5 with mild zone 3 fibrosis or central vein obliteration and 1 with central-portal bridging fibrosis), and mild acute portal rejection (n=2). We judged the histologic changes to be of clinical significance in 19 (11.5%) cases. These results indicate that even at the time of normal clinical and laboratory function, a significant fraction of protocol allograft biopsies harbor histologic (27%) and clinically significant (11.5%) abnormalities. These most commonly include fatty liver disease, low-grade/low-stage recurrent hepatitis C and primary biliary cirrhosis, and central venulitis (including some cases with subsequent fibrosis progression). The data support performance of protocol biopsies to assess allograft status, and provide insight into the types and severity of liver diseases that can smolder in transplanted (and by extension, probably also in native) livers with apparent normal function.

Protocol liver allograft biopsies are liver biopsies carried out at specific time points according to predetermined guidelines, rather than in response to specific indications such as change in the patient's clinical status or biochemical tests. Use of protocol liver allograft biopsy has been declining over the last decade: an informal survey of 35 transplant units showed that whereas 65% of units undertake protocol biopsies for those grafted for Hepatitis C virus infection, only 25% do so for patients grafted for other indications. In this overview, we consider the arguments against and those in favor of liver biopsies in adult liver allograft recipients. Arguments against the use of protocol liver biopsies are that they biopsies put the patient are associated with a small risk of morbidity and mortality, are expensive, do not provide useful information and do not alter clinical practice. The estimated rate of major complications is 0.6% and the estimated mortality rate 0.02%. However, the argument in favor of protocol biopsies is that even when standard liver tests are normal, there is on-going inflammation in the graft which, if immunosuppression is not altered, will lead to progressive fibrosis, cirrhosis and even graft loss. Conversely, normal liver histology may allow for reduction in the immunosuppression and so lower the risk of the complications associated with immunosuppression. Currently available diagnostic techniques are not yet sufficiently sensitive or specific to provide an accurate reflection of the state of the graft and the presence or absence of graft damage. We conclude that, while there are no clear data showing that protocol liver allograft biopsies are cost effective and lead to improved patient and graft outcome, such biopsies still have a role in the management of the liver transplant recipient.

To investigate the correlation between systemic hemodynamics and splanchnic circulation in recipients with cirrhosis undergoing living-donor liver transplantation (LDLT), and to clarify how systemic hemodynamics impact on local graft circulation after LDLT.

Systemic hemodynamics, indocyanine green (ICG) elimination rate (K ICG) and splanchnic circulation were simultaneously and non-invasively investigated by pulse dye densitometry (PDD) and ultrasound. Accurate estimators of optimal systemic hyperdynamics after LDLT [i.e., balance of cardiac output (CO) to blood volume (BV) and mean transit time (MTT), defined as the time required for half the administered ICG to pass through an attached PDD sensor in the first circulation] were also measured. Thirty recipients with cirrhosis were divided into two groups based on clinical outcomes corresponding to postoperative graft function.

Cirrhotic systemic hyperdynamics characterized by high CO, expanded BV and low total peripheral resistance (TPR) were observed before LDLT. TPR reflecting cirrhotic vascular alterations was slowly restored after LDLT in both groups. Although no significant temporal differences in TPR were detected between the two groups, CO/BV and MTT differed significantly. Recipients with good outcomes showed persistent cirrhotic systemic hyperdynamics after LDLT, whereas recipients with poor outcomes presented with unstable cirrhotic systemic hyperdynamics and severely decreased K ICG. Systemic hyperdynamic disorders after LDLT impacted on portal venous flow but not hepatic arterial flow.

We conclude that subtle systemic hyperdynamics disorders impact on splanchnic circulation, and that an imbalance between CO and BV decreases portal venous flow, which results in critical outcomes.

Liver biopsy is a common study performed after hepatic transplantation. Most centers routinely perform a biopsy 1 week after surgery to evaluate for the possibility of acute rejection. Subsequent biopsies are based on clinical symptoms and routine hepatic function laboratory testing. We report the clinical presentation and treatment of a biliary-venous fistula resulting in sepsis and bilhemia (elevated serum bilirubin levels caused by a biliary-venous fistula) in a 2(1/2)-year-old patient 4 months after partial left lateral segment living related liver transplantation. This case is unusual in that the fistula is the reversal of the more common venous-biliary fistula. The fistula developed after a percutaneous liver biopsy was performed.

Reliable monitoring enabling evaluation of graft function is crucial after living-donor liver transplantation (LDLT). A method to identify poor graft function at an early postoperative period would allow opportune intensive clinical management to bring about further improvements in LDLT outcomes. This study assessed the reliability of the indocyanine green (ICG) elimination rate constant (K(ICG)) value as an estimator of graft function and determined the actual temporal changes of K(ICG) after LDLT. K(ICG) values were measured using a noninvasive method in 30 adult recipients up to 28 days after LDLT. The receptor index (LHL15) based on liver scintigraphy, and graft parenchymal damage score based on histopathological findings were evaluated after LDLT and correlated well with simultaneous K(ICG). Thus, K(ICG) measured by noninvasive method was confirmed as accurately evaluating graft function. Changes of K(ICG) after LDLT in recipients with good graft function were maintained, after some falls in the early periods, and had a significant difference compared with those for recipients without good graft function; moreover, there were already significant differences in K(ICG) 24 hours after LDLT. Mean transit time reflecting systemic hemodynamics revealed that recipients without good outcomes fell into an unstable systemic hemodynamic state, and effective hepatic blood flow has a large influence on liver regeneration after LDLT. In conclusion, we suggested that K(ICG) values can predict clinical outcomes at the early postoperative period after LDLT by sharply reflecting the influence of systemic dynamics on splanchnic circulation.

Bilomas, infected hepatic fluid collections, are a frequent complication of liver transplantation. We report a case-control cohort study to determine the incidence and microbiologic profile of bilomas and risk factors for biloma formation in 492 patients undergoing liver transplantation from 1994 to 2001. Fifty-seven patients (11.5%) developed one or more bilomas; 95% in the first year post-transplantation. The most common initial infecting pathogens were enterococci (37%), one-half resistant to vancomycin (VRE); coagulase-negative staphylococci (26%); and Candida species (26%). Infection by coagulase-negative staphylococci was strongly associated with the presence of a T-tube (OR 9.60, p=0.02). In stepwise logistic regression multivariable analyses, hepatic artery thrombosis (OR 90.9, p<0.0001), hepatic artery stenosis (OR 13.2, p<0.0001) and Roux-en-Y choledochojejunostomy (OR 5.8, p=0.03) were independent risk factors for biloma formation; ursodeoxycholic acid use was highly protective (OR 0.1, p=0.002). Strategies to prevent biloma formation must focus on measures to prevent hepatic artery thrombosis and colonization of liver transplant patients by multiresistant nosocomial pathogens. T-tube drainage post-transplantation bears reassessment. The protective effect of ursodeoxycholic acid found in this study warrants confirmation in a prospective multicenter, randomized trial.

Infections following solid-organ transplants are a major cause of morbidity and mortality. Few studies have reported the complications of hepatic abscesses.

This investigation consisted of a retrospective chart review of all solid-organ transplant recipients from 1990 to 2000. Criteria for diagnosis included parenchymal hepatic lesions, positive cultures from liver aspirates or blood cultures, or both, and a compatible clinical presentation.

Of 2,175 recipients of all organ transplants (heart, lung, kidney, liver, pancreas), we identified 12 patients who had experienced 14 episodes of hepatic abscess, all in liver transplant recipients. Median time from transplant to hepatic abscess was 386 days (range 25-4,198). The most common predisposing factor was hepatic artery thrombosis (HAT), which occurred in eight patients, and was diagnosed at an average of 249 days (range 33-3,215) after transplantation. Clinical presentation of hepatic abscess was similar to that described in non-immunosuppressed patients. All but one patient showed hypoalbuminemia (<3.5 g/dL); those with HAT also had significantly elevated lactate dehydrogenase. Liver aspirates grew gram-positive aerobic bacteria (50% of isolates), gram-negative aerobic bacteria (30%), and anaerobes and yeasts (10% each). Patients received an average of 6 weeks of intravenous antibiotic therapy. Catheter drainage was successful in 70% of cases; and five patients required retransplantation. Altogether, five of the patients died, yielding a mortality rate of 42%.

Hepatic abscess, a rare complication after liver transplantation, was frequently associated with hepatic artery thrombosis. Mortality was higher than in patients who had not undergone transplantation. Prolonged antibiotic therapy, drainage, and even retransplantation may be required to improve the outcome in these patients.

Protocol biopsy results in the first few weeks after liver transplantation sometimes display histologic features of acute cellular rejection (ACR), even in the absence of significant clinical or biochemical dysfunction. At present there is no clear consensus about the need to treat such cases with adjuvant immunosuppression. This systematic review describes, from the available evidence, the natural history of untreated histologic ACR in the absence of biochemical graft dysfunction. An electronic search of the Medline, Embase, and Cochrane Library databases was performed to select studies that reported protocol liver biopsies in the early posttransplant period from 1983 to 2000. Studies that identified patients with ACR on protocol biopsy who were not treated with adjuvant immunosuppression formed the basis of the study group. Data from individual studies were extracted using standardized pro forma and pooled for descriptive analysis. The search identified 3431 studies, of which 516 were cited in full. Of these, 15 studies met all of the inclusion criteria. These 15 studies reported on 1566 patients who had protocol biopsies performed in the early posttransplant period, of which 1048 (67%) had histologic evidence of ACR. Three hundred and thirty one (32%) patients with histologic ACR on protocol biopsy had no associated biochemical graft dysfunction. Without treatment, only 14% of these patients subsequently developed biochemical graft dysfunction requiring adjuvant immunosuppression. Steroid-resistant rejection and chronic rejection both had a prevalence of 4% in patients with untreated histologic ACR and no biochemical graft dysfunction. Withholding adjuvant immunosuppression from patients with histologic ACR and no biochemical graft dysfunction seems to be safe, as long as graft function is carefully monitored. The rationale for performing protocol biopsies in the absence of biochemical graft dysfunction is questionable.

To conduct a descriptive study with an analysis of risk factors for early infection in liver transplant patients, and to determine the resistance of the bacteria involved.

The study included 149 liver transplant recipients. All cases of infection occurring 0-90 days after transplantation were considered early infection. Pre-, intra- and postoperative variables were analyzed, and isolated microorganisms were studied. Selective bowel decontamination with quinolones, and perioperative and antifungal prophylaxis were carried out in all patients.

The incidence of infection was 73.1%: bacterial (49.7%), viral (35.5%), fungal (10.1%) and mixed (4.5%). In the first postoperative month the most frequent infections were bacterial and in the second and third months, viral (p = 0.001). Multivariate analysis of risk factors identified the following: days of parenteral nutrition, duration of surgery > 5 hours, rejection and CMV seronegative status. Among 1278 cultures, the following microorganisms were isolated: 77.9% gram-positive cocci (GP) and 19% aerobic gram-negative bacilli (GNB). Sensitivity of Staphylococcus to vancomycin was 99.6-100% and to teicoplanin 97.9-100%. VAN resistance was observed in 1.2% of E. faecalis and 4.5% of E. faecium. Among S. aureus strains, 68.7% were MRSA. The resistance rate of GNB to quinolones was 38.8%.

Incidence of infection was higher the first 30 days after transplantation, with bacterial infection predominating. Duration of surgery > 5 hours was the most important risk factor for acquiring bacterial infection. GP were the most frequently isolated bacteria. Empirical treatment of early bacterial infection should include vancomycin or teicoplanin. Selective bowel decontamination resulted in a low incidence of GNB infections, among which there was 38.8% resistance to quinolones.

Percutaneous liver biopsy is an essential diagnostic tool utilized in the management of patients with liver disease. This procedure is generally performed by a physician and has a small but well-defined complication rate. We report on the complication rate and efficiency of ultrasound-assisted percutaneous liver biopsy performed by an experienced physician assistant.

One thousand eighty-six consecutive outpatient liver biopsies (847 hepatic allografts and 239 native livers) were performed at a single center by a physician assistant between June, 1996 and June, 2000. Patients with hepatic mass lesions, unusual hepatic anatomy, and uncorrectable coagulopathy (international normalized ratio > 1.7, platelet count < 50 x 10(9)/L) were excluded. Bedside ultrasonography was used to determine the optimal site for the liver biopsy. Liver biopsies were performed with a 15-gauge Jamshidi aspiration biopsy needle. Patients were observed for 3 h after biopsy, followed by dismissal with subsequent contact in 24 h to assess outcome and complications.

Adequate tissue was obtained in 1084 cases (99.8%), with a mean tissue length of 3.2 cm. After the procedure, narcotic analgesia was necessary in 116 (10%) of the patients undergoing liver biopsies. The overall complication rate requiring hospitalization was 0.6%. Major complications requiring intervention occurred in four patients (0.4%). There were no deaths resulting from liver biopsies.

We conclude that outpatient percutaneous liver biopsy can be safely and effectively performed by a trained physician assistant.

In addition to the net state of immunosuppression, the risk of infection after transplantation is largely determined by the transplant recipient's epidemiologic exposures. Potential sources of infection in the transplant recipient include the environment and the recipient's endogenous flora. This article presents aspects of prevention of infection after solid-organ transplantation such as avoidance of epidemiologic exposures, antibacterial prophylaxis, prophylaxis for tuberculin-positive transplant recipients, and prophylaxis against infections with Pneumocystis carinii and Toxoplasma gondii.

The diagnosis of acute rejection in liver transplantation usually needs hepatic biopsy, but hepatic biopsy sometimes involves severe complications. We analyzed biliary bilirubin fraction after living related liver transplantation by using high performance liquid chromatography (HPLC) and investigated availability for the early diagnosis of acute rejection retrospectively. Nine children with liver cirrhosis due to biliary atresia were included in this study, who underwent living related liver transplantation at The Second Department of Surgery, Tohoku University School of Medicine. Bile was collected daily from a biliary canulae inserted into the hepatic duct of the graft under aseptic and without exposure to the light. We measured the proportion of bilirubin diglucuronide (BDG), bilirubin monoglucuronide (BMG) and unconjugated bilirubin (UCB) of bile pigments in the bile by HPLC. In three of four patients with acute rejection, BDG + BMG (= Bc) was above 85% and BDG/Bc ratio was below 0.6 at the time of hepatic biopsy. After rejection therapy, BDG/Bc ratio increased in their bile. The remaining one case with acute rejection as well as bile duct injury due to arterial thrombosis of S2, Bc was below 85%, and BDG/Bc ratio was below 0.6. In four of the other five patients who had several severe complications, i.e., arterial or portal vein thrombosis, bile stasis due to cholangitis and sepsis due to necrotizing myofascitis, Bc was below 85% and BDG/Bc ratio was below 0.6. We concluded that analysis of biliary bilirubin fraction after liver transplantation could be reliable as a noninvasive maker and valuable for the early diagnosis of acute rejection.

Solid-organ transplantation is a therapeutic option for many human diseases. Infections are a major complication of solid-organ transplantation. All candidates should undergo a thorough infectious-disease screening prior to transplantation. There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur posttransplantation. Most infections during the first month are related to surgical complications. Opportunistic infections typically occur from the second to the sixth month. During the late posttransplant period (beyond 6 months), transplantation recipients suffer from the same infections seen in the general community. Opportunistic bacterial infections seen in transplant recipients include those caused by Legionella spp., Nocardia spp., Salmonella spp., and Listeria monocytogenes. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections, caused by both yeasts and mycelial fungi, are associated with the highest mortality rates. Mycobacterial, pneumocystis, and parasitic diseases may also occur.

Harvest injury in liver transplantation adversely affects both allograft function and subsequent acute rejection. The aim of this study was to use receiver-operating characteristic (ROC) analysis to determine the strength of histological features in time-zero liver allograft biopsies as predictors of subsequent acute rejection episodes or primary allograft failure. The study population consisted of 38 patients who underwent orthotopic liver transplantation between 1989 and 1992. Time-zero biopsies and all subsequent biopsies were retrospectively reviewed. The following time-zero histological features were graded: hepatocyte swelling, centrilobular necrosis, centrilobular hemorrhage, neutrophilic infiltrate, cholestasis, and number of apoptotic cells. Eleven transplants showed primary graft nonfunction; 15 experienced one or more episodes of moderate to severe acute rejection; 4 experienced only mild rejection episodes; and 8 showed no rejection over long follow-up periods. ROC analysis showed that the presence of hepatocyte swelling in the time-zero biopsy is a significant predictor of subsequent moderate to severe rejection. Apoptotic cells, centrilobular hemorrhage, hepatocyte swelling, and centrilobular necrosis were all significant predictors of primary graft failure. No histological feature was predictive of subsequent mild rejection. In conclusion, certain histological features serve as markers for adverse outcomes in the liver transplant population. Patients who show apoptotic cells, centrilobular hemorrhage and necrosis, or hepatocyte swelling in their time-zero biopsy should be monitored carefully for signs of graft failure and rejection.

To analyze the clinical characteristics of and identify specific risk factors for enterococcal bacteremia following liver transplantation, we performed a study in 405 consecutive liver transplantation recipients prophylaxed with a selective bowel decontamination regimen. Seventy enterococcal bacteremias in 52 patients were identified. Enterococcus faecalis (50) outnumbered Enterococcus faecium isolates (18), and 49% of enterococcal bacteremias were polymicrobial. Biliary tree complications were present in 34% of enterococcal bacteremias. Of the 15 deaths (29%) among the patients with enterococcal bacteremia, 4 were directly associated with enterococcal bacteremia. In a multivariate analysis, Roux-en-Y choledochojejunostomy (P=0.005), a cytomegalovirus-seropositive donor (P=0.013), prolonged transplantation time (P=0.02), and biliary stricturing (P=0.016) were identified as significant risk factors. Other risk factors identified in a univariate analysis included primary sclerosing cholangitis (P=0.009) and symptomatic cytomegalovirus infection (P=0.008). Enterococcal bacteremia is a frequent infectious complication in liver transplantation recipients receiving selective bowel decontamination. Its association with cytomegalovirus and biliary tree abnormalities suggest specific areas for prophylactic intervention.

This study aimed to determine whether there is an increased infectious risk following liver biopsy in liver transplant patients with choledochojejunostomy.

We evaluated the incidence of liver-biopsy-related sepsis in a consecutive series of 27 patients who underwent choledochojejunostomy, either during the transplant procedure (17 patients) or later following biliary complications (10 patients). We evaluated another 138 patients as a control group who had orthotopic liver transplantation during the same period and underwent duct-to-duct anastomosis. All liver biopsies had routine, prior ultrasound evaluation to detect dilated biliary ducts.

In the 27 patients who underwent choledochojejunostomy, 96 liver biopsies were performed: the sepsis rate was 3.12% per biopsy (n = 96) or 7.4% per patient (n = 27). However, despite a normal ultrasound, subsequent ERCP demonstrated biliary obstruction in one patient. Thus the rate of sepsis was 2.1% per biopsy or 3.7 per patient. In the control group 338 liver biopsies were performed: the sepsis rate was 1.5% per biopsy (n = 338) or 2.9% per patient (n = 138). The difference was not significant. All septic episodes had positive blood cultures for a single enteric microorganism, and all responded to antibiotics

Our data do not suggest that liver-transplanted patients with choledochojejunostomy are more at risk of sepsis following liver biopsy, providing there is no "occult" biliary obstruction; therefore, they do not require prophylactic antibiotics as has been suggested by other authors.

Conventional percutaneous liver biopsy in the early postoperative period, within 30 days, following liver transplantation may be impossible due to coagulopathy and/or ascites. The use of transjugular liver graft biopsy (TJLB) in this setting is an attractive alternative in that a tissue diagnosis can be obtained despite the relative contraindications for percutaneous biopsy during this period. During the early posttransplant period, 124 TJLBs were performed in 105 liver patients, the majority (89%) of whom had standard liver transplantation without preservation of the native inferior vena cava; the others (11%) had the native inferior vena cava intact. The technical success rate was 87%, with adequate specimen for definitive diagnosis in most instances (86%), which included both rejection (61%) and nonrejection (39%) diagnoses on final histopathology. The biopsy diagnosis influenced clinical management in the majority of cases (65%), with decisions made to perform retransplantation (3%), to influence initiation of antirejection therapy (59%), and to institute antiviral therapy (3%). There was no morbidity or mortality associated with TJLB and it is feasible, safe, and effective in the early period after liver transplantation.

Although liver biopsy is a very useful procedure used frequently in the diagnosis and management of liver dysfunction occurring after orthotopic liver transplantation, complications can occur with its use. An unusual complication of arterioportal fistula is reported here. Based upon this small series of an unusual event and the knowledge that the posttransplant liver may be more hypervascular than prior to OLTx and that it is uniquely susceptible to hepatic infarction and abscess formation, any attempt at fistula closure should be considered carefully prior to initiating the therapy (15). Unless a serious complication occurs [such as a transient biliary obstruction due to hemobilia as occurred in case 2, portal hypertension as also occurred in case 2, or systemic sepsis or other symptoms develop related directly to the fistula], simple observation may be the best choice of action. Should therapy be required, hepatic arterial embolization should be reserved for adults with intrahepatic fistulas. Primary surgical closure of intrahepatic fistula should be reserved for cases of extrahepatic fistula.