Subclinical biliary strictures as a cause of long-term allograft dysfunction in children who underwent liver transplantation

We aimed to evaluate the role of liver biopsy to predict subclinical biliary strictures (BS) and assess the impact of BS on long-term allograft dysfunction following liver transplantation in children (LT). We reviewed all liver biopsies performed from 2012-2018. Percutaneous transhepatic cholangiography (PTC) was performed in patients presenting cholangiolar proliferation on cytokeratin-7 stained sections. We performed 271 biopsies in 161 children (86% with a left lateral segment); 44/161 (27%) presented with diffuse or multifocal cholangiolar proliferation. Among them, a tight BS was confirmed in 38/44 (86%, 24% of total) and it was managed by balloon dilatation. Cholangiolar proliferation showed a positive predictive value (PPV) for BS of 86.4%. Levels of alkaline phosphatase >325 IU/L predicted BS (P = .007). Dilatation of intrahepatic bile ducts on ultrasound was found only in 44% of patients with BS. Following a median follow-up of 9.2 years, only 15/38 (39%) patients resolved the BS. In conclusion subclinical BS is very common and probably underdiagnosed in these patients. Histological evidence of cholangiolar proliferation detectable by cytokeratin-7 immunostain should be preferred to liver function tests and ultrasound to suspect BS. BS in this setting should be regarded as a main cause of long-term allograft dysfunction.     

Outcomes following liver transplantation in young infants: Data from the SPLIT registry

Liver transplantation (LT) in young patients is being performed with greater frequency. We hypothesized that objective analysis of pre-, intra-, and postoperative events would help understand contributors to successful outcomes and guide transplant decision processes. We queried SPLIT registry for pediatric transplants between 2011 and 2018. Outcomes were compared for age groups: 0-<3, 3-<6, 6-<12 months, and 1-<3 years (Groups A, B, C, D respectively) and by weight categories: <5, 5-10, >10 kg; 1033 patients were available for analysis. Cholestatic disease and fulminant failure were highest in group A and those <5 kg; and biliary atresia in group C (72.8%). Group A had significantly higher life support dependence (34.6%; P < .001), listing as United Network for Organ Sharing status 1a/1b (70.4%; P < .001), and shortest wait times (P < .001). The median (interquartile range) for international normalized ratio and bilirubin were highest in group A (3.0 [2.1-3.9] and 16.7 [6.8-29.7] mg/dL) and those <5 kg (2.6 [1.8-3.4] and 13.5 [3.0-28.4] mg/dL). A pediatric end -stage liver disease score ≥40, postoperative hospital stays, rejection, and nonanastomotic biliary strictures were highest in group A with lowest survival at 93.1%. Infants 0 to <3 months and those <5 kg need more intensive care with lower survival and higher complications. Importantly, potential LT before reaching status 1a/1b and aggressive postoperative management may positively influence their outcomes.     

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.     

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.     

Sinusoidal obstruction syndrome as a manifestation of acute antibody-mediated rejection after liver transplantation

Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.     

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.     

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.     

Heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration: A new technique to enhance liver transplantation

We describe a patient with liver metastases from colorectal cancer treated with chemotherapy and hepatic resection, who developed unresectable multifocal liver recurrence and who received liver transplantation using a novel planned technique: heterotopic transplantation of segment 2-3 in the splenic fossa with splenectomy and delayed hepatectomy after regeneration of the transplanted graft. We transplanted a segmental liver graft after in-situ splitting without any impact on the waiting list, as it was previously rejected for pediatric and adult transplantation. The volume of the graft was insufficient to provide liver function to the recipient, so we performed this novel operation. The graft was anastomosed to the splenic vessels after splenectomy, and the native liver portal flow was modulated to enhance graft regeneration, leaving the native recipient liver intact. The volume of the graft doubled during the next 2 weeks and the native liver was removed. After 8 months, the patient lives with a functioning liver in the splenic fossa and without abdominal tumor recurrence. This is the first case reported of a segmental graft transplanted replacing the spleen and modulating the portal flow to favor graft growth, with delayed native hepatectomy.     

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.     

Erythropoietic protoporphyria in an adult with sequential liver and hematopoietic stem cell transplantation: A case report

Erythropoietic protoporphyria (EPP) is a rare inherited disorder of the heme biosynthesis pathway resulting in the accumulation of protoporphyrins in the blood, erythrocytes, and other tissues. Because of a gene mutation in the FECH gene, ferrochelatase, the enzyme involved in the final step of heme synthesis, is deficient in these patients. Although the major symptom of this disorder is photosensitivity, rarely, it can cause progressive liver disease requiring liver transplantation (LT). However, LT is not curative and only bone marrow transplantation (BMT) can correct the underlying enzymatic defect. Because liver disease results from accumulation of protoporphyrin in the liver, LT without hematopoietic stem cell transplantation leaves the new liver at risk for similar EPP‐related damage. A handful of pediatric patients undergoing sequential LT and stem cell transplantation have been described in the literature; however, to date none has been described in detail in adults. We report a case of an adult male with EPP and liver failure who successfully underwent a sequential liver and hematopoietic stem cell transplantation (HSCT).     

Outcomes of en bloc simultaneous liver‐kidney transplantation compared to the traditional technique

Simultaneous liver‐kidney transplantation (SLKT) is indicated for patients with end‐stage liver disease (ESLD) and concurrent renal insufficiency. En bloc SLKT is an alternative to traditional separate implantations, but studies comparing the two techniques are limited. The en bloc technique maintains renal outflow via donor infrahepatic vena cava and inflow via anastomosis of donor renal artery to donor splenic artery. Comparison of recipients of en bloc (n = 17) vs traditional (n = 17) SLKT between 2013 and 2017 was performed. Recipient demographics and comorbidities were similar. More recipients of traditional SLKT were dialysis dependent (82.4% vs 41.2%, P = .01) with lower baseline pretransplant eGFR (14 vs 18, P = .01). En bloc SLKT was associated with shorter kidney cold ischemia time (341 vs 533 minutes, P < .01) and operative time (374 vs 511 minutes, P < .01). Two en bloc patients underwent reoperation for kidney allograft inflow issues due to kinking and renal steal. Early kidney allograft dysfunction (23.5% in both groups), 1‐year kidney graft survival (88.2% vs 82.4%, P = 1.0), and posttransplantation eGFR were similar between groups. In our experience, the en bloc SLKT technique is safe and feasible, with comparable outcomes to the traditional method.     

Angiotensin II type I receptor agonistic autoantibodies are associated with poor allograft survival in liver retransplantation

Angiotensin II type I receptor (AT1R) agonistic autoantibodies (AT1R‐AA) are detrimental to kidney transplantation. Early studies suggested a similar negative effect in primary liver transplantation. Here, we studied AT1R‐AA in a retrospective cohort of 94 patients who received a second liver transplant to determine their prevalence and effects. The concentrations of preformed AT1R‐AA before transplantation were higher (P = .019) in the 48 patients who lost their liver grafts than in the 46 patients whose grafts survived. About half (48/94, 51.1%) of the patients were positive for AT1R‐AA >17 U/mL before the second liver transplantation. In 22 (23.4%) patients, strong positive AT1R‐AA (defined as >40 U/mL) were detected, of whom 16 (72.7%) patients lost their grafts. Based on Kaplan‐Meier analysis, patients with strong positive AT1R‐AA had significantly worse graft survival than those with AT1R‐AA <40 U/mL (P = .035). In multivariate Cox models that included confounders such as sex and age, either AT1R‐AA >40 U/mL (HR = 1.999 [1.085‐3.682], P = .026) or increased concentrations of AT1R‐AA (HR = 1.003 [1.001‐1.006] per incremental U/mL, P = .019) were significantly associated with elevated risk for graft loss. In conclusion, our data indicate that there is a high prevalence of AT1R‐AA in candidates for second liver transplantation and that their presence is associated with inferior long‐term outcomes of the second graft.     

Outcomes of status 1 liver transplantation for Budd-Chiari Syndrome with fulminant hepatic failure

There is a paucity of data on the outcome of liver transplantation (LT) in Budd-Chiari Syndrome (BCS) patients who are listed as status 1. The objective of our study was to determine patient or graft survival following LT in status 1 BCS patients. We utilized United Network for Organ Sharing (UNOS) database to identify all adult patients (> 18 years of age) listed as status 1 with a primary diagnosis of BCS in the United States from 1998 to 2018, and analyzed their outcomes and compared it to non-status 1 BCS patients. Four hundred and forty-six patients with BCS underwent LT between 1998 and 2018, and of these 55 (12.3%) were listed as status 1. There was no difference in long-term post-liver transplant or “intention-to-treat” survival from the time of listing to death or the last day of follow-up between status 1 and non-status 1 groups. Graft and patient survival at 5 years for status 1 patients were 75% and 82%, respectively. Cox regression analysis showed that patients listed as status 1 (aHR: 0.45, p < .02) were associated with a better survival. BCS patients listed as status 1 have excellent survival following emergency LT.     

Trends in deceased donor liver enzymes prior to transplant: The impact on graft selection and outcomes

We sought to characterize the trend in alanine aminotransferase elevations prior to transplant and the impact on the pattern of enzyme elevations on organ utilization and graft function. We performed a retrospective cohort study of UNOS data on all deceased donors between 2007 and 2016. Serum alanine aminotransferase (ALT) was categorized into six study groups with peak ALT < 499, 500‐749, 750‐999, 1000‐1999, 2000‐2999, and >3000 IU/L. The change from peak ALT to terminal ALT prior to transplant was categorized as no change/increasing at time transplant, 0.1‐9.9%, 10‐24.9%, 25‐49.9%, 50‐74.9% and >75% change. In multivariable models evaluating liver utilization, the interaction between peak ALT and percent change in ALT was most pronounced at the highest peak ALT levels, where liver utilization varied markedly as a function of percentage drop from peak to terminal ALT. There was no increased risk of graft failure based on peak ALT. Markers of ischemic liver injury and recovery are significantly associated with liver utilization, yet among transplanted livers they were not associated with graft outcomes and may represent an area to expand the donor pool.     

Discovery and validation of a novel blood‐based molecular biomarker of rejection following liver transplantation

Noninvasive biomarker profiles of acute rejection (AR) could affect the management of liver transplant (LT) recipients. Peripheral blood was collected following LT for discovery (Northwestern University [NU]) and validation (National Institute of Allergy and Infectious Diseases Clinical Trials in Organ Transplantation [CTOT]‐14 study). Blood gene profiling was paired with biopsies showing AR or ADNR (acute dysfunction no rejection) as well as stable graft function samples (Transplant eXcellent—TX). CTOT‐14 subjects had serial collections prior to AR, ADNR, TX, and after AR treatment. NU cohort gene expression (46 AR, 45 TX) was analyzed using random forest models to generate a classifier training set (36 gene probe) distinguishing AR vs TX (area under the curve 0.92). The algorithm and threshold were locked and tested on the CTOT‐14 validation cohort (14 AR, 50 TX), yielding an accuracy of 0.77, sensitivity 0.57, specificity 0.82, positive predictive value (PPV) 0.47, and negative predictive value (NPV) 0.87 for AR vs TX. The probability score line slopes were positive preceding AR, and negative preceding TX and non‐AR (TX + ADNR) (P ≤ .001) and following AR treatment. In conclusion, we have developed a blood biomarker diagnostic for AR that can be detected prior to AR‐associated graft injury as well a normal graft function (non‐AR). Further studies are needed to evaluate its utility in precision‐guided immunosuppression optimization following LT.     

Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient

Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies.     

Sex‐based disparities in delisting for being “too sick” for liver transplantation

Women with cirrhosis awaiting liver transplantation (LT) experience higher rates of waitlist mortality than men; it is unknown whether practices surrounding delisting for being “too sick” for LT contribute to this disparity beyond death alone. We conducted an analysis of patients listed for LT in the United Network for Organ Sharing/Organ Procurement and Transplantation Network not receiving exception points from May 1, 2007 to July 1, 2014 with a primary outcome of delisting with removal codes of “too sick” or “medically unsuitable.” A total of 44 388 patients were included; 4458 were delisted for being “too sick” for LT. Delisting was more frequent in women (11% vs 9%, P < .001). Compared to delisted men, delisted women differed in age (58 vs 57), non–hepatitis C virus listing diagnoses (69% vs 56%), hepatic encephalopathy (36% vs 31%), height (161.9 vs 177.0 cm), private insurance (47% vs 52%), and Karnofsky performance status (60 vs 70) (P < .001 for all). There were no differences in Model for End‐Stage Liver Disease including serum sodium and Child Pugh Scores. A competing risk analysis demonstrated that female sex was independently associated with a 10% (confidence interval 2%‐18%) higher risk of delisting when accounting for rates of death and transplantation and adjusting for confounders. This study demonstrates a significant disparity in delisting practices by sex, highlighting the need for better assessments of sickness, particularly in women.     

Transcatheter aortic valve replacement (TAVR) as bridge therapy restoring eligibility for liver transplantation in cirrhotic patients

Severe aortic stenosis is a widespread valve disease, constituting a contraindication to organ transplantation due to cardiovascular morbidity and projected mortality. Mortality after conventional surgical aortic valve replacement in cirrhotic patients depends upon the Child–Pugh class. In the past few years, transcatheter aortic valve replacement has progressively become the treatment of choice for high‐risk patients with severe aortic stenosis. Here, we report the cases of 3 cirrhotic patients who became eligible for liver transplantation after successful transcatheter aortic valve replacement as bridge therapy.     

Multidisciplinary approach to cardiac and pulmonary vascular disease risk assessment in liver transplantation: An evaluation of the evidence and consensus recommendations

Liver transplant (LT) candidates today are older, have greater medical severity of illness, and have more cardiovascular comorbidities than ever before. In addition, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Cirrhotic cardiomyopathy, a condition characterized by increased cardiac output and a reduced ventricular response to stress, is present in up to 30% of patients with cirrhosis, thus challenging perioperative management. Current noninvasive tests that assess for subclinical coronary and myocardial disease have low sensitivity, and altered hemodynamics during the LT surgery can unmask latent cardiovascular disease either intraoperatively or in the immediate postoperative period. Therefore, this review, assembled by a group of multidisciplinary experts in the field and endorsed by the American Society of Transplantation Liver and Intestine and Thoracic and Critical Care Communities of Practice, provides a critical assessment of the diagnosis of cardiac and pulmonary vascular disease and interventions aimed at managing these conditions in LT candidates. Key points and practice‐based recommendations for the diagnosis and management of cardiac and pulmonary vascular disease in this population are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.