Outcomes of liver transplantation for acute fatty liver disease of pregnancy

Acute fatty liver of pregnancy (AFLP) often resolves after pregnancy delivery but can progress to acute liver failure necessitating liver transplantation. We performed a retrospective review of the national Scientific Registry of Transplant Recipients (SRTR) data to identify all women in the United States undergoing liver transplantation (LT) for acute liver failure (ALF) from AFLP from 1991 to 2015, and compared to outcomes in women of childbearing age undergoing transplant for ALF from acetaminophen and ALF from other etiologies. Women with AFLP were likely to be on life support at time of LT and had high rates of renal dysfunction (median Cr 2.1, IQR 1.2‐2.3), and hyperbilirubinemia (median bilirubin 17.1, IQR 11.0, 19.9). Although their early and late LT survival outcomes were comparable to the other indications for LT, cumulative 5‐year graft survival was numerically lower among AFLP patients (54%, 95% CI, 27‐76) compared to APAP (70%, 95% CI, 63‐77) and “Other ALF” (76%, 95% CI, 72‐80) groups. In conclusion, although AFLP is a rare indication for LT, AFLP patients were as sick or sicker than other women of childbearing age undergoing LT for ALF. Worsened graft survival may be related to higher rates of rejection in the AFLP group.     

Adult Living Donor Liver Transplantation for Acute‐on‐Chronic Liver Failure in High–Model for End‐Stage Liver Disease Score Patients

The large volume of adult living donor liver transplantations (ALDLTs) at our center affords a unique opportunity to examine the impact of acute‐on‐chronic liver failure (ACLF) among high–Model for End‐Stage Liver Disease MELD score patients. From February 1998 to March 2010, 1958 cirrhotic recipients were analyzed to study the relationship between MELD scores and ALDLT outcomes. A total of 327 high‐MELD score recipients were categorized into ACLF and non‐ACLF groups, and their outcomes were compared. The 5‐year graft and patient survival in the high‐MELD group were 75.2% and 76.4%, respectively, which were significantly worse than the low and intermediate MELD groups. The presence of ACLF associated with higher MELD scores appeared to be the dominant factor responsible for the inferior results of patients with MELD score of 30–34 points. The 5‐year graft survivals in the ACLF group was 70.5% and in the non‐ACLF group it was 81.0% (p = 0.035). Therefore, ALDLT should be performed as soon as possible in high‐MELD score patients prior to ACLF development. Moreover, ACLF patients should be separately categorized when analyzing the outcomes of ALDLT. ALDLT for ACLF patients should not be discouraged because favorable outcomes can be expected through timely ALDLT and comprehensive management.     

Liver transplantation for hepatitis C virus (HCV) non‐viremic recipients with HCV viremic donors

In the context of organ shortage, the opioid epidemic, and effective direct‐acting antiviral (DAA) therapy for hepatitis C virus (HCV), more HCV‐infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor‐derived HCV in previously non‐viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor‐derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing. Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non‐viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12 weeks posttreatment with DAA‐based regimens, with a median time from transplant to treatment initiation of 43 days (IQR 20–59). There have been no instances of graft loss or death, with median follow‐up of 380 days (IQR 263–434) posttransplant. Transplantation of HCV‐viremic livers into non‐viremic recipients results in acceptable short‐term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation.     

Ex Vivo Liver Resection and Autotransplantation for End‐Stage Alveolar Echinococcosis: A Case Series

The role of autotransplantation in end‐stage hepatic alveolar echinococcosis (AE) is unclear. We aimed to present our 15‐case experience and propose selection criteria for autotransplantation. All patients were considered to have unresectable hepatic AE by conventional resection due to critical invasion to retrohepatic vena cava, hepatocaval region along with three hepatic veins, and the tertiary portal and arterial branches. All patients successfully underwent ex vivo extended right hepatectomy and autotransplantation without intraoperative mortality. The median autograft weight was 706 g (380–1000 g); operative time was 15.5 hours (11.5–20.5 hours); and anhepatic time was 283.8 minutes (180–435 min). Postoperative hospital stay was 32.3 days (12–60 days). Postoperative complication Clavien–Dindo grade IIIa or higher occurred in three patients including one death that occurred 12 days after the surgery due to acute liver failure. One patient was lost to follow‐up after the sixth month. Thirteen patients were followed for a median of 21.6 months with no relapse. This is the largest reported series of patients with end‐stage hepatic AE treated with liver autotransplantation. The technique requires neither organ donor nor postoperative immunosuppressant. The early postoperative mortality was low with acceptable morbidity. Preoperative precise assessment and strict patient selection are of utmost importance.     

Liver transplant for hepatocellular carcinoma in the United States: Evolving trends over the last three decades

Hepatitis C virus infection has been the most common etiology in HCC‐related liver transplantation (LT). Since 2014, direct‐acting antivirals (DAAs) have dramatically improved HCV cure. We aimed to study the changing pattern of etiologies and impact in outcome in HCC‐related LT according to HCV treatment‐era through retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) database (1987‐2017). A total of 27 855 HCC‐related liver transplants were performed (median age 59 years, 77% male). In the DAA era (2014‐2017) there has been a 14.6% decrease in LT for HCV‐related HCC; however, HCV remains the most common etiology in 50% of cases. In the same era, there has been a 50% increase in LT for NAFLD‐related HCC. Overall survival was significantly worse for HCV‐related HCC compared to NAFLD‐related HCC during pre‐DAA era (2002‐2013; P = .031), but these differences disappeared in the DAA era. In addition, HCV patients had a significant improvement in survival when comparing the DAA era with IFN era (P < .001). Independent predictors of survival were significantly different in the pre‐DAA era (HCV, AFP, diabetes) than in the DAA era (tumor size). HCV‐related HCC continues to be the main indication for LT in the DAA era, but patients’ survival has significantly improved and is comparable to that of NAFLD‐related HCC.     

Improving the Diagnostic Criteria for Primary Liver Graft Nonfunction in Adults Utilizing Standard and Transportable Laboratory Parameters: An Outcome‐Based Analysis

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single‐center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000–2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty‐two patients (3.7%) had 2‐week graft failure. Transplant albumin, day‐1 aspartate aminotransferase (AST), day‐1 lactate, day‐3 bilirubin, day‐3 international normalized ratio (INR), and day‐7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)‐(0.0972*TxAlbumin)‐4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889–0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634–0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789–0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624–0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post‐LT days only (AUROC of 0.818, 0.776–0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).     

Left Lobe Auxiliary Liver Transplantation for End‐stage Hepatitis B Liver Cirrhosis

Auxiliary liver transplantation (ALT) for hepatitis B virus (HBV)‐related liver cirrhosis previously showed poor results, because the native liver was a significant source of HBV recurrence and the graft could be rapidly destroyed by HBV infection in an immunosuppressive condition. Four patients with HBV‐related liver cirrhosis were unable to undergo orthotopic liver transplantation because the only available grafts of left lobe were too small. Under entecavir‐based anti‐HBV treatment, they underwent ALT in which the recipient left liver was removed and the small left lobe graft was implanted in the corresponding space. The mean graft weight/recipient weight was 0.49% (range, 0.38%–0.55%). One year after transplantation, the graft sizes were increased to 273% and the remnant livers were decreased to 44%. Serum HBV DNA was persistently undetectable. Periodic graft biopsy showed no signs of tissue injury and negative immunostaining for hepatitis B surface antigen and hepatitis B core antigen. After a mean follow‐up period of 21 months, all patients live well with normal graft function. Our study suggests that ALT for HBV‐related liver cirrhosis is feasible under entecavir‐based anti‐HBV treatment. Successful application of small left livers in end‐stage liver cirrhosis may significantly increase the pool of left liver grafts for adult patients.     

Combined Liver–Kidney Transplantation for Primary Hyperoxaluria Type 2: A Case Report

Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver‐specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44‐year‐old man with PH2, frequent stone events, and end‐stage renal disease; he received a combined liver/kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate, and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow‐up at 13 months suggests that correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.     

Observations on the ex situ perfusion of livers for transplantation

Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH < 7.4) from those that did not (pH > 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25‐50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid‐base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.     

Living donor liver transplantation for biliary atresia: An analysis of 2085 cases in the registry of the Japanese Liver Transplantation Society

Biliary atresia (BA) is the most common indication for liver transplantation (LT) in pediatric population. This study analyzed the comprehensive factors that might influence the outcomes of patients with BA who undergo living donor LT by evaluating the largest cohort with the longest follow‐up in the world. Between November 1989 and December 2015, 2,085 BA patients underwent LDLT in Japan. There were 763 male and 1,322 female recipients with a mean age of 5.9 years and body weight of 18.6 kg. The 1‐, 5‐, 10‐, 15‐, and 20‐year graft survival rates for the BA patients undergoing LDLT were 90.5%, 90.4%, 84.6%, 82.0%, and 79.9%, respectively. The donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were found to be significant predictors of the overall graft survival. Adolescent age (12 to <18 years) was associated with a significantly worse long‐term graft survival rate than younger or older ages. We conclude that LDLT for BA is a safe and effective treatment modality that does not compromise living donors. The optimum timing for LT is crucial for a successful outcome, and early referral to transplantation center can improve the short‐term outcomes of LT for BA. Further investigation of the major cause of death in liver transplanted recipients with BA in the long‐term is essential, especially among adolescents     

Evidence for a rebalanced hemostatic system in pediatric liver transplantation: A prospective cohort study

In adults with end‐stage liver disease concurrent changes in pro‐ and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017‐October 2018). Routine hemostasis tests, thrombomodulin‐modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age‐matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end‐stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin‐dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis.     

Meta-analysis and meta-regression of outcomes for adult living donor liver transplantation versus deceased donor liver transplantation

Prior single center or registry studies have shown that living donor liver transplantation (LDLT) decreases waitlist mortality and offers superior patient survival over deceased donor liver transplantation (DDLT). The aim of this study was to compare outcomes for adult LDLT and DDLT via systematic review. A meta-analysis was conducted to examine patient survival and graft survival, MELD, waiting time, technical complications, and postoperative infections. Out of 8600 abstracts, 19 international studies comparing adult LDLT and DDLT published between 1/2005 and 12/2017 were included. U.S. outcomes were analyzed using registry data. Overall, 4571 LDLT and 66,826 DDLT patients were examined. LDLT was associated with lower mortality at 1, 3, and 5 years posttransplant (5-year HR 0.87 [95% CI 0.81–0.93], p < .0001), similar graft survival, lower MELD at transplant (p < .04), shorter waiting time (p < .0001), and lower risk of rejection (p = .02), with a higher risk of biliary complications (OR 2.14, p < .0001). No differences were observed in rates of hepatic artery thrombosis. In meta-regression analysis, MELD difference was significantly associated with posttransplant survival (R² 0.56, p = .02). In conclusion, LDLT is associated with improved patient survival, less waiting time, and lower MELD at LT, despite posing a higher risk of biliary complications that did not affect survival posttransplant.     

Toward a Better Liver Graft Allocation That Accounts for Candidates With and Without Hepatocellular Carcinoma

In some countries where the Model for End‐Stage Liver Disease (MELD) score is used for graft allocation, selected patients with hepatocellular carcinoma (HCC) receive a fixed number of exception points at listing, and increasing priority on the list by accruing additional exception points at regular time intervals. This system originally aimed at balancing the risks of HCC patients of developing contraindications and of non‐HCC patients of dying before transplantation, is not ideal because it appears to offer an advantage to HCC patients, regardless of tumor characteristics and response to loco‐regional treatment. Scores modulated by HCC characteristics have been proposed. They are based on a more refined estimate of the risk of pretransplant drop‐out or of the posttransplant transplant benefit expressed as the life‐years gained for each graft. This review describes the newly proposed systems, and discusses their advantages and drawbacks. We believe that the current exception points allocation should be revised and that drop‐out‐equivalent or transplant benefit‐equivalent models should be studied further. As with all policy changes, these should be done under close monitoring that allows subsequent revisions.     

Living‐donor liver transplantation for liver hemorrhaging due to peliosis hepatis in X‐linked myotubular myopathy: Two cases and a literature review

X‐linked myotubular myopathy (MTM) (OMIM 310400) is a severe neuromuscular disorder caused by mutations in the myotubularin (MTM1) gene. Liver hemorrhaging due to peliosis hepatis (PH) is a fatal complication. We herein report 2 successful cases of living‐donor liver transplantation (LDLT) for MTM patients due to liver hemorrhaging caused by PH and review previous reports. A boy who was 9 years and 4 months old initially underwent left lateral segmentectomy due to massive hepatic and intraperitoneal hemorrhaging. As bleeding from the remnant liver continued after hepatectomy, this patient emergently underwent LDLT using a left lateral segment graft from his father. Another boy who was 1 year and 7 months old underwent transcatheter arterial embolization due to hepatic hemorrhaging and was referred to our hospital for LDLT using a left lateral segment graft from his father. The pathological findings in both cases showed sinusoidal dilatation with degenerative changes in reticular fiber and hematoma in the explanted liver, which were consistent with PH associated with MTM. LT should be considered as a treatment option for patients with episodes of hepatic hemorrhaging due to MTM in order to protect against fatal bleeding.     

Novel techniques and preliminary results of ex vivo liver resection and autotransplantation for end‐stage hepatic alveolar echinococcosis: A study of 31 cases

Ex vivo liver resection combined with autotransplantation is a recently introduced approach to cure end‐stage hepatic alveolar echinococcosis (HAE), which is considered unresectable by conventional radical resection due to echinococcal dissemination into the crucial intrahepatic conduits and adjacent structures. This article aims discuss the manipulation details and propose reasonable indications for this promising technique. All patients successfully underwent liver autotransplantation with no intraoperative mortality. The median weight of the autografts was 636 g (360‐1300 g), the median operation time was 12.5 hours (9.4‐19.5 hours), and the median anhepatic phase was 309 minutes (180‐ 460 minutes). Intraoperative blood loss averaged 1800 mL (1200‐6000 mL). Postoperative complications occurred in 13 patients during hospitalization; 5 patients experienced postoperative complications classified as Clavien‐Dindo grade III or higher, and 2 patients died of intraabdominal bleeding and acute cerebral hemorrhage, respectively. Twenty‐nine patients were followed for a median of 14.0 months (3‐42 months), and no HAE recurrence was detected. The technique requires neither an organ donor nor any postoperative immunosuppressant, and the success of the treatment relies on meticulous preoperative assessments and precise surgical manipulation.     

The Diagnostic Conundrum and Liver Transplantation Outcome for Combined Hepatocellular‐Cholangiocarcinoma

Combined hepatocellular‐cholangiocarcinoma (cHCC‐CC) is a rare primary liver malignancy with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) histological features. It is almost impossible to obtain an accurate, preoperative noninvasive diagnosis of cHCC‐CC with tumor markers or cross‐sectional abdominal imaging due to the mixed histological features. Despite these difficulties, accurate cHCC‐CC diagnosis remains an important goal with prognostic significance. In our study, we retrospectively reviewed the tumor markers: AFP and CA 19‐9, and cross‐sectional liver imaging, in light of liver explant findings, to identify and characterize cHCC‐CC features followed by liver transplantation (LT) outcome analysis. The results from this 12 patient cohort failed to identify characteristic features for cHCC‐CC. None of the imaging features helped to identify the cHCC‐CC tumor and they mimicked either HCC or CC, depending on the degree of glandular differentiation expressed histologically. In our cHCC‐CC LT recipients, the 1‐, 3‐ and 5‐year cumulative survival probabilities were 79%, 66% and 16%, respectively with a 5‐year survival comparable to or better than LT for intrahepatic CC but poorer than LT for HCC following the Milan criteria. Conceivably explained by its cholangiocarcinoma component the LT outcome for this rare and hard to diagnose tumor appears poor.     

Successful living donor liver transplantation for liver failure due to maternal T cell engraftment following cord blood transplantation in X-linked severe combined immunodeficiency disease: Case report

Maternal T cells from perinatal transplacental passage have been identified in up to 40% of patients with severe combined immunodeficiency (SCID). Although engrafted maternal T cells sometimes injure newborn tissue, liver failure due to maternal T cells has not been reported. We rescued a boy with X-linked SCID who developed liver failure due to engrafted maternal T cell invasion following living donor liver transplantation (LDLT) following unrelated umbilical cord blood transplantation (UCBT). After developing respiratory failure 3 weeks postpartum, he was diagnosed with X-linked SCID. Pathological findings showed maternal T cells engrafted in his liver and hepatic fibrosis gradually progressed. He underwent UCBT at 6 months, but hepatic function did not recover and liver failure progressed. Therefore, he underwent LDLT using an S2 monosegment graft at age 1.3 years. The patient had a leak at the Roux-en-Y anastomosis, which was repaired. Despite occasional episodes of pneumonia and otitis media, he is generally doing well 6 years after LDLT with continued immunosuppression agents. In conclusion, the combination of hematopoietic stem cell transplantation (HSCT) and liver transplantation may be efficacious, and HSCT should precede liver transplantation for children with X-linked SCID and liver failure.