Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3) is a rare inherited liver disease caused by a mutation in the ABCB4 gene, leading to dysfunction of multidrug resistance protein 3 (MDR3). The earlier the onset of PFIC3 in children is, the more severe the prognosis. The diagnosis of PFIC3 is typically based on clinical symptoms, laboratory tests, and imaging assessments, with final confirmation requiring genetic testing. The aim of this study was to investigate the associations between genetic mutations in PFIC3 and clinical features, molecular genetics, and liver histopathology to improve early recognition and understanding of this disease. By analysing the data of three children with PFIC3 who underwent parental liver transplantation, we were able to gain a deeper understanding of the complexity and diversity of the disease. With respect to molecular genetics, we identified five mutation sites in the ABCB4 gene, including three newly discovered mutations. Immunohistochemical analysis revealed reduced expression of the MDR3 protein in child 1 and no expression in child 2 or child 3, revealing an intrinsic link between the ABCB4 gene and the MDR3 protein. Histopathologically, all three patients presented with significant portal vein fibrosis or cholestatic liver cirrhosis. In conclusion, this study emphasizes the importance of molecular genetic and pathological evaluation of patients with PFIC3 mutations and elucidates the impact of these three mutations on the course of the disease in children, for whom early symptomatic treatment and early preparation for liver transplantation are options worth considering.

Post-transplant lymphoproliferative disease (PTLD) is a rare but serious complication of liver transplantation (LT) with morbidity and mortality. The risk factors for PTLD in adults are ill-defined. This study aimed to assess the risk factors for PTLD after LT in adults. All adult LT recipients between 1986 and 2016 from 2 centers in the Netherlands were included, with follow-up until 2020. PTLD was diagnosed according to the World Health Organization (WHO) classification. Potential risk factors for PTLD were assessed using multivariate Cox regression analysis. A total of 1281 patients were included, of whom 29 (2.3%) developed PTLD. Results show that independent risk factors for PTLD after LT in adults were no Epstein-Barr virus load monitoring strategy, primary sclerosing cholangitis as an indication for LT, era (historic era linked to more intense long-term immunosuppression), and Epstein-Barr virus-seronegative recipient. No other independent risk factors were identified in this study. Of the 207 patients with primary sclerosing cholangitis as an indication for LT, 13 (6.3%) developed PTLD versus 16 out of 1074 (1.5%) patients with other underlying liver diseases (log-rank p <0.001). The yearly PTLD incidence was higher in the first year than in the later years after LT (2.4%/y vs. 0.6%/y) for primary sclerosing cholangitis, but not for other indications (0.16%/y). In Epstein-Barr virus-seronegative recipients PTLD occurred earlier after LT, while in 97% of seropositive recipients it could occur very late after LT.

The most prevalent malignancy that complicates both adult and pediatric solid organ transplantation is post-transplant lymphoproliferative disorder (PTLD). This study aimed to analyze the clinical and pathological characteristics, treatments, and outcomes of Epstein-Barr virus (EBV) DNAemia and PTLD in pediatric liver transplant recipients. A retrospective chart review was performed on 112 patients less than 18 years of age who underwent isolated orthotopic liver transplantation (OLT) between 2010 and 2022 at Ege University Children's Hospital. Data gathered for 1-year post-OLT included age at OLT, EBV, immunoglobulin (Ig)M/IgG status of the donor and recipient, indication for OLT, induction regimen, all immunosuppression levels, date and result of EBV polymerase chain reaction testing, rejection episodes documented by liver biopsy, and the development of PTLD. Forty-nine patients (43.75%) developed EBV DNAemia (median interval from surgery: 2 months, min-max: 2-36), of which 43 (87.8%) grafts came from living donors, and 6 (12.2%) came from deceased donors. Nine (18.4%) patients died during follow-up, and eight (16.3%) developed PTLD. Of these 8 patients; five patients developed EBV-related disease, one child developed hemophagocytic lymphohistiocytosis, one developed aplastic anemia, and one child developed B cell lymphoma. When PTLD patients and without-PTLD patients were compared, pediatric intensive care unit hospitalization, abnormal bone marrow biopsy findings, lymphadenopathy, age at diagnosis of EBV DNAemia, EBV viral load, tacrolimus (FK 506) pre-infection, were higher and tacrolimus 1-month levels were lower in patients with PTLD (p < 0.05). In logistic regression analysis, we showed that the age at diagnosis of EBV DNAemia was significantly higher in children with PTLD (p = 0.045; OR: 1.389; 95% CI: 1.007-1.914). PTLD is a rare but severe complication associated with EBV after OLT. This study demonstrated that PTLD is associated with older age, higher tacrolimus blood levels before EBV DNAemia, and higher peak EBV viral load at 1 month of EBV DNAemia.

We aimed to summarize the cancer risk among patients with indication of group I pharmaceuticals as stated in monographs presented by the International Agency for Research on Cancer working groups. Following the PRISMA guidelines, a comprehensive literature search was conducted using the PubMed database. Pharmaceuticals with few studies on cancer risk were identified in systematic reviews; those with two or more studies were subjected to meta-analysis. For the meta-analysis, a random-effects model was used to calculate the summary relative risks (SRRs) and 95% confidence intervals (95% CIs). Heterogeneity across studies was presented using the Higgins I square value from Cochran's Q test. Among the 12 group I pharmaceuticals selected, three involved a single study [etoposide, thiotepa, and mustargen + oncovin + procarbazine + prednisone (MOPP)], seven had two or more studies [busulfan, cyclosporine, azathioprine, cyclophosphamide, methoxsalen + ultraviolet (UV) radiation therapy, melphalan, and chlorambucil], and two did not have any studies [etoposide + bleomycin + cisplatin and treosulfan]. Cyclosporine and azathioprine reported increased skin cancer risk (SRR = 1.32, 95% CI 1.07-1.62; SRR = 1.56, 95% CI 1.25-1.93) compared to non-use. Cyclophosphamide increased bladder and hematologic cancer risk (SRR = 2.87, 95% CI 1.32-6.23; SRR = 2.43, 95% CI 1.65-3.58). Busulfan increased hematologic cancer risk (SRR = 6.71, 95% CI 2.49-18.08); melphalan was associated with hematologic cancer (SRR = 4.43, 95% CI 1.30-15.15). In the systematic review, methoxsalen + UV and MOPP were associated with an increased risk of skin and lung cancer, respectively. Our results can enhance persistent surveillance of group I pharmaceutical use, establish novel clinical strategies for patients with indications, and provide evidence for re-categorizing current group I pharmaceuticals into other groups.

To evaluate response rates and survival in adults developing post-transplant lymphoproliferative disorder (PTLD) following liver transplantation.

Patients were identified retrospectively and data collected through local liver and haematology electronic databases and pharmacy records.

Forty-five patients were identified. The median age at first transplant and at development of PTLD was 48 and 54 years, respectively, with the median time from transplant to PTLD diagnosis of 56 months. The majority of cases (76%) were monomorphic B-cell lymphomas, and 36% of tumours were EBV positive. Treatment involved reduction in immune-suppression (RIS) in 30 (67%) with RIS the only treatment in 3. Ten (22%) patients were treated with rituximab alone, 13 (29%) with chemotherapy alone and 14 (31%) patients were treated with rituximab and chemotherapy. Twenty-six (58%) patients achieved a complete response (CR). At a median follow-up of 27 months, the median overall survival (OS) was 50 months. Response and OS were not associated with clinical factors or the use of rituximab.

Outcomes reported in this study are favourable and comparable to those reported previously. The addition of rituximab did not appear to have improved outcomes in this series, although a significant proportion of patients were able to avoid chemotherapy.

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is associated with chronic inflammatory disorders. We present an indolent pancolonic MALT lymphoma occurring in a 39-year-old female with history of autoimmune hepatitis requiring liver transplant in 1997 and ulcerative colitis diagnosed in 2004. Random biopsies from a grossly unremarkable surveillance colonoscopy in 2015 revealed a dense monomorphic plasmacytoid infiltrate causing expansion of lamina propria without significant crypt infiltration or destruction. These cells were positive for CD79a and CD138 and showed lambda restriction; however, CD20, CD43, CD56, HHV8, and EBER were negative. A similar pancolonic infiltrate was identified in all prior colorectal biopsies from 2010 and 2012 upon retrospective review. Subsequent computed tomography of the abdomen revealed no bowel wall thickening nor enlarged lymph nodes. Bone marrow revealed involvement consistent with stage IV disease. Biopsies from 2010 and 2015 demonstrated clonal immunoglobulin gene rearrangement. MYD88 mutation was not detected. The overall features were indicative of MALT lymphoma. Although low-grade B-cell lymphomas are not considered part of the post-transplant lymphoproliferative disorder spectrum, such cases have been reported, and are typically EBV-negative. Patient underwent treatment with pentostatin for her MALT lymphoma reaching a sustained remission despite additional immunosuppression for resurgent hepatic dysfunction. To our knowledge, this is the first reported case of EBV-negative pancolonic MALT lymphoma with plasmacytic differentiation post liver transplant presenting in an indolent, asymptomatic fashion with persistence for greater than five years successfully managed without compromising the patient's liver transplant.

Autoimmune hepatitis (AIH) fulfills the generally accepted contemporary criteria of an autoimmune liver disease: the presence of autoantibodies and autoreactive T cells, a female gender bias, association with other autoimmune diseases, response to immunosuppressive therapy and strong associations with the major histocompatibility complex HLA loci. It occurs worldwide in both children and adults and is marked by both etiopathogenic and clinical heterogeneity, differing from the other putative autoimmune liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), albeit occasionally presenting with overlapping features of PBC or PSC. Although diagnostic criteria have been established and validated, there are still major issues to be clarified due to its variability, such as autoantibody-negative AIH, drug-induced AIH, AIH sharing features with PBC or PSC, and post-transplant de novo AIH. In view of the diverse presentations and courses, including classical chronic onset, acute and acute severe onset, cirrhosis and decompensated cirrhosis, individualized management of patients is indicated. Each patient should receive a personalized analysis of the benefits and side effect risks of drugs. Herein we describe a comprehensive review of the clinical phenotypes of AIH underscoring its clinical heterogeneity.

Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients.

Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population.

A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81).

A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.

At the time of transplantation, a recipient's serum is tested against the prospective donor's lymphocytes to identify specific reactivity and to look for a donor-specific crossmatch (CXM). Here, we investigated the relationship between the pretransplantation lymphocytotoxic CXM results and the long-term outcome of liver transplantation at a single center.

From October 1998 to April 2011, medical records, laboratory data, and pretransplantation lymphocytotoxic CXM results were collected from 1133 consecutive liver transplant recipients.

We performed liver transplantations on 80 (7.1%) patients after a true-positive CXM (t+CXM). The t+CXM group exhibited higher initial aminotransferase levels immediately after transplantation compared with a negative CXM group. However, no significant differences in rejection, biliary or vascular complications, viral disease recurrence, or de novo malignancies were found. Although overall graft and patient survival did not differ between the groups, liver-specific graft survival was inferior in the t+CXM group. It was also found that, in 42 (3.7%) recipients, initially positive results converted to final negative results after the elimination of immunoglobulin M autoantibodies. We defined this subpopulation as a false-positive CXM. Significantly decreased posttransplantation aminotransferase levels with a higher incidence of de novo malignancies were observed in this group compared with negative controls.

Our findings demonstrate that t+CXM transplants show increased aspartate aminotransferase and alanine aminotransferase peak immediately after transplantation, which influences liver-specific graft outcomes. Additionally, the presence of circulating immunoglobulin M autoantibodies against recipients' own antigens may be protective in liver grafts. However, this may be a predisposing factor for de novo malignancies.

Hepatocellular carcinoma and extrahepatic malignancies can complicate the course of autoimmune hepatitis, and these occurrences may increase in frequency as the survival of patients with cirrhosis is extended and the prospect of new nonstandard immune-modifying intervention is realized. The frequency of hepatocellular carcinoma in patients with autoimmune hepatitis and cirrhosis is 1-9 %, and annual occurrence in patients with cirrhosis is 1.1-1.9 %. The standardized incidence ratio for hepatocellular carcinoma in autoimmune hepatitis is 23.3 (95 % confidence interval (CI) 7.5-54.3) in Sweden, and the standardized mortality ratio for hepatobiliary cancer is 42.3 (95 % CI 20.3-77.9) in New Zealand. The principal risk factor is long-standing cirrhosis, and patients at risk are characterized mainly by cirrhosis for ≥ 10 years, manifestations of portal hypertension, persistent liver inflammation, and immunosuppressive therapy for ≥ 3 years. Multiple molecular disturbances, including the accumulation of senescent hepatocytes because of telomere shortening, step-wise accumulation of chromosomal injuries, and aberrations in transcription factors and genes, may contribute to the risk. Extraheptic malignancies of diverse cell types occur in 5 % in an unpredictable fashion. The standardized incidence ratio is 2.7 (95 % CI 1.8-3.9) in New Zealand, and non-melanoma skin cancers are most common. Outcomes are related to the nature and stage of the tumor at diagnosis. Surveillance recommendations have not been promulgated, but hepatic ultrasonography every six months in patients with cirrhosis is a consideration. Routine health screening measures for other malignancies should be applied diligently.

Complications after liver transplantation are major factors that determine the prognosis of patients. In this study, we aimed at investigating an important though less frequently occurring complication, post-transplant lymphoproliferative disorders (PTLD), in a single institution after liver transplantation.

15 cases with a diagnosis of PTLD in post-liver transplant patients were retrieved from our archive and the clinicopathological features reviewed.

The overall incidence of PTLD was 2.3% (n=15/658), and the incidence was much higher in the paediatric than the adult age groups, being 11.1% (9/81) and 1% (6/577), respectively. The median time of presentation was 16 months after transplantation (occurrence time ranging from 2 to 87 months after transplantation). Lymph nodes, gastrointestinal tract and graft liver were the commonest sites of involvement. 11 cases were classified as monomorphic PTLD according to WHO classification and the majority (n=10/11) of them were of B cell differentiation. 12 of the total 15 PTLD cases showed a positive result for Epstein-Barr virus-encoded RNAs with in situ hybridisation. Eight patients were alive at the time of review, and two of them suffered from recurrence of the PTLD. Among the seven patients who died, six succumbed within 1 year from the diagnosis of PTLD.

Despite its relative rarity as a complication for liver transplantation, PTLD imposes significant effects on the morbidity, mortality and treatment implications in postliver transplant patients. The clinicopathological data would hopefully provide better insight into the surveillance and management for susceptible patients.

Liver transplantation is a life-saving therapy for patients with end-stage liver disease, acute liver failure, and liver tumors. Over the past 4 decades, improvements in surgical techniques, peritransplant intensive care, and immunosuppressive regimens have resulted in significant improvements in short-term survival. Focus has now shifted to addressing long-term complications and improving quality of life in liver recipients. These include adverse effects of immunosuppression; recurrence of the primary liver disease; and management of diabetes, hypertension, dyslipidemia, obesity, metabolic syndrome, cardiovascular disease, renal dysfunction, osteoporosis, and de novo malignancy. Issues such as posttransplant depression, employment, sexual function, fertility, and pregnancy must not be overlooked, as they have a direct impact on the liver recipient's quality of life. This review summarizes the latest data in long-term outcome after liver transplantation.

Hepatitis C virus infection has a 10.5% frequency in liver transplant posttransplant lymphoproliferative disorders. Studies have suggested that hepatitis C virus infection plays a role in developing posttransplant lymphoproliferative disorders. Pooling data of posttransplant lymphoproliferative disorders developing in liver recipients from the literature, we analyzed and compared characteristics, behavior, and prognoses of posttransplant lymphoproliferative disorders arising in hepatitis C virus-positive versus negative liver graft recipients.

We conducted a search for the available data though PubMed and Google Scholar for reports of posttransplant lymphoproliferative disorders and hepatitis C virus infection in liver transplant recipients. Overall, 29 studies were found and their data are included in the analyses.

Overall, data of 212 liver transplant patients were included. Sixty-three percent were male. No difference was found between hepatitis C virus-positive liver transplant patients with posttransplant lymphoproliferative disorders compared to their hepatitis C virus-negative counterparts regarding sex, time from transplant to lymphoma development, lymphoma cell type, remission, mortality rate, multiorgan involvement, disseminated posttransplant lymphoproliferative disorders, and histopathologic evaluations (P > .1 for all). Hepatitis C virus-positive liver transplant recipients representing posttransplant lymphoproliferative disorders who were concomitantly positive for Epstein-Barr virus were significantly more likely to develop lymphomas in the early posttransplant period (26 [67%] vs 16 [40%]; P = .024) and to complicate liver (19 [63%] vs 8 [30%]; P = .017) than hepatitis C virus-/Epstein-Barr virus+ patients.

Hepatitis C virus infection alone has no significant effect on lymphoproliferative disorders after liver transplant; but when combined with Epstein-Barr virus infection, it represents some significant different presentations of the disease. However, no survival effect was found for hepatitis C virus with or without simultaneous Epstein-Barr virus infection, in the posttransplant lymphoproliferative disorders setting. Future prospective studies are needed for confirming our results.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication after adult orthotopic liver transplantation (AOLT). Besides EBV and immunosuppression, relatively little is known about the pretransplant clinical parameters associated with the risk of PTLD, and the benefit of using EBV surveillance to predict EBV-associated disease in AOLT patients is uncertain. The aims of this single-center study were to monitor EBV viral loads (VLs) in AOLT patients and to investigate any associations with age, sex, cytomegalovirus (CMV) serostatus, posttransplant times, and indications for transplantation. 1275 blood samples that were collected from 197 AOLT patients 1 day to more than 15 years after transplantation were investigated with quantitative polymerase chain reaction for EBV and CMV DNA. Seventy-two percent of the patients had EBV DNAemia less than 100 days after transplantation without clinical manifestations. No association was observed between the EBV copy numbers and the time since transplantation. EBV DNAemia was weakly associated with male sex but was not associated with age, CMV serostatus, or indications for AOLT. The highest EBV VL levels were observed in patients who presented with congenital liver diseases, whereas patients with viral hepatitis maintained high EBV VLs after transplantation. None of the patients developed PTLD during the study period; however, 3 patients presented with EBV-associated diseases. In conclusion, EBV DNAemia is common in AOLT patients, and routine EBV surveillance has limited value for predicting EBV-associated morbidity or mortality.

Despite contemporary immunosuppressive regimens, posttransplant lymphoproliferative disease (PTLD) remains a major complication after liver transplantation. This review highlights advances in the understanding of the pathophysiology, diagnosis, and management of PTLD in liver transplant recipients.

The spectrum of PTLD after liver transplant ranges from polymorphic lymphoproliferation to high-grade monoclonal lymphoma and is usually related to outgrowth of lymphocytes infected with Epstein-Barr virus (EBV). Risk factors for PTLD include EBV-seronegativity of the recipient, young age, intensity of immunosuppression, and the first year posttransplant. Measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD although the specificity for PTLD is only about 50% (specificity for EBV is ∼100%). In patients diagnosed with PTLD, management options include reduction of immunosuppression, rituximab, combination chemotherapy, and adoptive immunotherapy. Outcomes have improved because rituximab has been incorporated into treatment regimens, and immunotherapy approaches show promise.

PTLD is a significant complication after liver transplantation, particularly in children. Advances in early detection approaches have aided in the diagnosis and management of PTLD, but further research to identify better predictive biomarkers is needed to improve risk-based treatment strategies.

Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr virus (EBV)-infected B-cells, whereas EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver disease, or alcoholic liver cirrhosis contribute to an increased risk for PTLD. Therapeutic regimens include reduction of immunosuppression, the anti-CD20 antibody rituximab, and chemotherapy, as well as new approaches using interferon-α and anti-interleukin-6 antibodies. Despite the different therapeutic regimens, mortality from PTLD remains high. Therefore, it is of major importance to identify patients at risk at an early stage of the disease. In this review, risk factors for PTLD development after liver transplantation, clinical presentation, diagnosis, and therapy are discussed.

Based on very limited data, it has been recently suggested that hepatitis B virus infection can play significant roles in post transplantation lymphoproliferative disorders. In the current study pooling data of PTLD in HBV positive liver recipients gathered from the existing literature, we sought to analyze and compare characteristics, behavior and prognosis of PTLD arising in HBV positive liver graft recipients.

A comprehensive search for the available data though PubMed and Google Scholar for reports of PTLD and HBV infection in liver recipients was conducted. Data of 18 different studies were pooled and analyzed.

Liver recipients with HBV positive-PTLD were comparable to their HBV negative counterparts in gender, age at transplantation, time from transplantation to PTLD development, lymphoma cell type, histopathology of lesions, remission episodes, mortality rate, multi-organ involvement, and disseminated PTLD (p > 0.1 for all). HBV positive PTLD patients were significantly less likely to complicate spleen (0 vs. 23%, respectively; p = 0.015). Survival of the two patient groups were comparable (p = 0.8).

HBV infection has no significant impact on inducing some distinct types of PTLD and represents no survival effect in PTLD setting. Future prospective studies are needed for confirming our findings.