Maternity After Orthotopic Liver Transplantation: Can the Use of Biological Fertility Indicators Help? Our Own Experience and Literature-based Recommendations.

Over the last 5 decades, the fulfillment of maternity wishes in solid organ transplanted women has become a reality. Despite pregnancy contraindication in transplanted women during the early post-transplant period, such a condition can be overcome after 12 months if patients show a good clinical evolution and do not present other general pre-conceptional findings. This article presents the case report of a young female liver transplanted patient that used symptothermal method as a reliable family planning method. After her gestational contraindication was lifted, observation of biological fertility indicators and fertility-guided sexual intercourse helped her fulfill her maternity wish and conceive and carry out a healthy offspring. Based on this case and on the available bibliographic evidence, this paper reviews the potential implications of the use of this kind of approach as a safe and effective alternative to assisted reproduction technology in the management of potential infertility problems in the young female transplanted population, a population which according to literature has higher rates of unsuccessful parenthood and might also be more vulnerable to iatrogenicity of ovarian hyperstimulation process and to multiple pregnancy.

Pediatric Liver Transplantation: Then and Now.

This paper reviews the past 50 years of liver transplantation in children from the perspective of patient demographics, perioperative patient management, surgical techniques, immunosuppression and patient outcomes.

Sequential transplantation and implications for clinical management: OLT followed by HCT and consequent RT in a pediatric patient.

We report a case of a pediatric patient who required three separate transplants: OLT at the age 5, HCT at age 13 (8 years post-OLT), and cadaveric RT at age 15 (10 years post-OLT). The child initially presented with fulminant liver failure without known cause, ultimately undergoing OLT from his mother. He then developed SAA, for which he required HCT. Unfortunately, he developed ESRD secondary to prolonged CNI exposure, for which he underwent cadaveric RT. These processes then resulted in 7 years largely free from complications, during which a multi-disciplinary team monitored the patient for complications. Regrettably, at the age of 21 he developed poorly differentiated mucinous adenocarcinoma of the colon which ultimately led to his demise. While there are case reports of patients requiring two sequential transplants, there is a paucity of reports of successfully completing three separate organ transplants in the same patient. Our case demonstrates progression of a pediatric patient through OLT, HCT, and RT with discussion of notable clinical implications. Secondarily, this case highlights the importance of coordination of care amongst various subspecialties to facilitate tandem transplantations and manage the complications of these processes. As pediatric patients have improved survival rates and may require multiple transplants, it remains important to highlight the feasibility as well as the complications of the tandem transplant process.

Assessment of the hepatocytic differentiation ability of human skin-derived ABCB5+ stem cells.

The continuously decreasing willingness for liver donation aggravates treatment of end-stage liver diseases requiring organ transplantation as the only curative strategy. Cell therapy approaches using human hepatocytes or stem cell-derived hepatocyte-like cells may be a therapeutic option out of this dilemma. ABCB5-positive mesenchymal stromal cells from human skin featured promising potential to treat immune-mediated diseases. Since most of chronic liver diseases involve exaggerating immune mechanisms, it was the aim to demonstrate in this study, whether ABCB5+ stem cells may serve as a resource to generate hepatocytic cells for application in liver cell transplantation. Using an established single-step protocol, which had been successfully applied to differentiate mesenchymal stromal cells into the hepatocytic lineage, ABCB5+ skin-derived stem cells did not gain significant characteristics of hepatocytes. Yet, upon culture in hepatocytic differentiation medium, ABCB5+ stem cells secreted immunomodulatory and anti-fibrotic factors as well as proteins, which may prompt hepatic morphogenesis besides others. Hepatic transplantation of ABCB5+ stem cells, which had been prior cultured in hepatocytic differentiation medium, did not cause any obvious deterioration of liver architecture suggesting their safe application. Thus, human ABCB5+ skin-derived stem cells secreted putative hepatotropic factors after culture in hepatocytic differentiation medium.

Liver transplantation for neonatal-onset citrullinemia.

Citrullinemia or ASS deficiency in its classical form presents in the neonatal period with poor feeding, hyperammonemia, encephalopathy, seizures, and if untreated can be fatal. Despite advances in medical therapy, neurocognitive outcomes remain suboptimal. LT has emerged as a potential management option. A retrospective single-center review identified 7 children with a median age of 1.1 years (range, 0.6-5.8) at referral. Five children presented clinically, and 2 were treated prospectively from birth due to positive family history. All patients received standard medical and dietary therapy prior to LT. The indications for LT were frequent metabolic decompensations in 4, elective in 2, and ALF in 1. The median age at LT was 2.4 years (range, 1.3-6.5). Five patients received 6 left lateral segment grafts, one a live unrelated donor left lateral segment as an APOLT graft, and one a cadaveric whole liver graft as APOLT. One child required retransplantation due to hepatic artery thrombosis. Graft and patient survival were 86% and 100%, respectively. Median follow-up is 3.1 years (range, 0.1-4.1), and the median age at follow-up is 5.5 years (range, 4.0-9.8). There have been no metabolic decompensations in 6 children, while 1 patient (with APOLT) developed asymptomatic hyperammonemia with no clinical or histological signs of liver injury, requiring additional medical therapy. Our medium-term experience following LT in citrullinemia is favorable, demonstrating a positive transformation of the clinical phenotype.

Hangzhou criteria are more accurate than Milan criteria in predicting long-term survival after liver transplantation for HCC in Germany.

BACKGROUND: Milan criteria are used for patient selection in liver transplantation for hepatocellular carcinoma (HCC). Hangzhou criteria have been shown in China to enable access to liver transplantation for more patients when compared to Milan criteria without negative effects on long-term survival. The purpose of this study was to evaluate the Hangzhou criteria in a German cohort. METHODS: One hundred fifty-nine patients transplanted for HCC between 1975 and 2010 were investigated. Patients were categorized into four groups depending on the fulfillment of Milan and Hangzhou criteria. General and tumor baseline characteristics were compared. Overall and tumor-free survival rates were investigated with the Kaplan-Meier analysis. RESULTS: One-, 3-, 5-, and 10-year survival rates for patients fulfilling Milan criteria (n = 68) were 89.7, 83.7, 75.8, and 62.1%, respectively, versus 89.8, 82.2, 75.2, and 62.6% for patients fulfilling Hangzhou criteria (n = 109) (p = 0.833). When comparing patients exceeding Milan or Hangzhou criteria, survival rates were 75.3, 53.2, 48.1, and 41.1% versus 63.3, 31.4, 26.9, and 22.1%, respectively (p = 0.019). The comparison of tumor-free survival rates in patients fulfilling Milan or Hangzhou criteria was statistically not significant (p = 0.785), whereas the comparison of the groups exceeding the criteria showed significantly worse survival for patients outside Hangzhou criteria (p = 0.007). The proportion of patients fulfilling Hangzhou criteria (68.6%) was significantly larger as compared to the proportion fulfilling Milan criteria (42.8%) (p < 0.001). CONCLUSION: Hangzhou criteria are more accurate in predicting long-term survival after liver transplantation for HCC in Germany. Deployment of the Hangzhou criteria for patient selection could enlarge the pool of transplantable patients.

Patients' Age Rather Than Model of End-Stage Liver Disease Score Predicts Survival After Liver Transplantation.

BACKGROUND: The model of end-stage liver disease (MELD) score is the standard tool for prioritizing patients awaiting liver transplantation. There is currently no definite high cutoff score reflecting disease severity that might exclude patients from transplantation. Furthermore, the age limit that used to disqualify patients from eligibility to transplantation was recently withdrawn in several countries. AIMS: The aims of this study were to assess the effects of MELD score and age at time of transplantation on patients' short- and long-term survival. METHODS: We conducted a retrospective single-center study on a cohort of patients transplanted for the first time due to non-fulminant liver failure. RESULTS: Four hundred and seventeen patients (mean age 50.2 years, 63% males) who underwent liver transplantation for the first time were included. Both higher patients' and donors' age were significantly associated with increased long-term mortality (p = 0.007, 95% CI 1.006-1.038 for patient age, p = 0.02, 95% CI 1.002-1.023 for donor age). Patients' age remained significantly associated with survival at 1 year post-transplantation, as well. We found no association between higher MELD score at transplantation and long-term mortality (p = 0.189, 95% CI 0.99-1.051) irrespective of patients' age. Specifically, when patients were divided according to their MELD score at transplantation (MELD < 15, MELD 15-25 and MELD > 25), no significant differences in long-term survival were detected between these three subgroups. Results did not differ significantly in a subgroup analysis of patients without hepatocellular carcinoma at the time of transplantation. CONCLUSIONS: Patients' and donors' age rather than patients' MELD score at transplantation determine survival following liver transplantation.

Plasminogen Deficiency: A Case Report and Review.

Plasminogen deficiency, a rare disorder characterized by impaired fibrinolysis, frequently results in ligneous conjunctivitis. In this report, we report a case of a Saudi girl manifesting both conjunctivitis and hydrocephalus. Her initial symptoms at 1 month of age were recurring eye redness, which was inaccurately diagnosed as simple conjunctivitis. Surgical intervention for her ocular lesions revealed underlying membrane deposition. She later exhibited signs of increased intracranial pressure, resulting in a hydrocephalus diagnosis and subsequent surgery. Genetic analysis confirmed the presence of plasminogen deficiency. Clinical evaluations highlighted ligneous conjunctivitis, variations in visual acuity, and facial acne. Laboratory assessments demonstrated diminished plasminogen levels. The therapeutic approach encompassed plasminogen replacement, administered intravenously (1000 units, thrice weekly) and as eye drops, with the potential addition of fresh frozen plasma. Notably, this replacement therapy led to a significant reduction in hospital admissions and the severity of her conjunctivitis. Given the challenges in procuring consistent plasminogen supplies, the viability of hepatic transplantation is currently under investigation.

A systematic review and meta-analysis on the impact of pre-existing and new-onset atrial fibrillation on outcomes before and after liver transplantation.

BACKGROUND AND AIMS: Atrial Fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia. It is associated with significant morbidity and mortality, as it is a major risk factor for cerebral vascular accidents (CVA). Our aim was to determine the prevalence of pre-existing and new-onset AF among patients undergoing liver transplantation (LT) and its impact on post-transplant outcomes. METHODS: Medline and Embase were searched. Single-arm analysis was conducted using the generalized linear mixed model to determine the prevalence of pre-existing and new-onset AF. Logistic regression was performed to analyze risk factors. Comparative meta-analysis in odds ratio was conducted for binary outcomes. RESULTS: Twenty articles were included, with 17 studies on pre-existing AF, and 7 including data on new-onset AF post-LT. The prevalence of pre-existing AF was 3.3% (CI 2.3-4.7) (14 studies, 45,070 patients) in pooled analysis. Significantly higher prevalence of pre-existing AF patients from North America was noted when compared to Europe (4.5%, CI 3.4-5.8 vs 1.5%, CI 0.8-2.7; p = 0.001). Body mass index (BMI), history of hypertension, diabetes, coronary artery disease (CAD), and cerebrovascular accidents (CVA) were risk factors for pre-existing AF. Pre-existing AF was significantly associated with major adverse cardiac or cerebrovascular events (MACCE) postoperatively (OR 8.02, 95%CI 5.40-11.90, p < 0.001). New-onset AF post-LT had an incidence of 6.8% (CI 4.9-9.3), and was associated with increased risk of mortality (OR 2.31, 95% CI 1.76-3.02, p < 0.001) and graft failure (OR 2.98, CI 1.99-4.47, p < 0.001). CONCLUSION: AF is relatively more common among patients undergoing LT compared to the general non-transplant population. Additionally, it is associated with adverse outcomes including MACCE, thus warranting clinical attention. Thorough cardiac assessment, and close surveillance of post-operative AF may be clinically prudent.

Acute severe hepatitis in adult-onset Still's disease: case report and comprehensive review of a life-threatening manifestation.

Acute severe hepatitis is a rare complication of adult-onset Still's disease (AOSD). This condition is poorly characterized. We performed a review of the medical literature to describe clinical, biological, pathological, and treatment characteristics from AOSD patients with acute severe hepatitis. Their characteristics were compared with AOSD patients without severe hepatitis. Twenty-one cases were collected including a new case reported here. Patients with severe hepatitis were mostly young adults with a median age of 28 years (range: 20 to 55 years). Overall, patients with severe hepatitis had less arthritis, macular rash, sore throat, lymphadenopathy, or splenomegaly than patients without severe hepatitis. Cytopenia was more frequent in case of severe hepatitis. Most patients were treated with steroids, and the use of biotherapies has increased over the last decade. Despite treatment, 49% of patients required liver transplantation and 24% died. Key Points • Acute severe hepatitis in adult-onset Still's disease (AOSD) is associated with liver transplantation and/or death in, respectively, 43% and 24% of cases. • Severe hepatitis is the inaugural manifestation of AOSD in half of cases. Diagnosis is difficult when extra-hepatic clinical manifestations are lacking. • The mechanism of hepatic necrosis in AOSD with severe hepatitis is unknown. Liver biopsy is not specific and should not delay treatment initiation.

Reusing hepatic grafts in Korea: a case report.

The shortage of donor organs has compelled transplant centers to use organs from non-standard donors. The Korean Network for Organ Sharing data showed that there were 5,804 potential recipients on the waiting list, and only 1,579 patients underwent liver transplant in 2019. Reuse of a graft that has been transplanted previously to other recipients could be an option in this situation. However, given the susceptibility of hepatic grafts to ischemic damage, their reuse must be considered extremely carefully. In this retrospective, observational study, we investigated the outcomes of six cases of hepatic graft reuse in Korea since the year 2000, from information gathered from patient medical records from ten transplant centers. Only three of the six reused hepatic grafts functioned well. Among the three successful transplants, two had minimal ischemic damage owing to a longer interval between the first and second transplants, and because they were obtained from living donors. Two of the five cadaveric transplants were successful. The outcome of reusing hepatic grafts in Korea has not been ideal. However, in patients with limited choices, it can be carefully considered, provided the graft is thoroughly checked for ischemic damage and the recipient status is ascertained.

Post-transplant malignancies in alcoholic liver disease.

Post-transplant malignancy is emerging as an important cause of mortality in patients with cirrhosis undergoing liver transplant (LT). However, establishing the exact relationship between the two needs further evaluation. It has been observed that approximately 30% deaths after 10 years of hepatic transplantation occur due to de novo malignancies. Various known risk factors include immunosuppression, age of patient, alcoholic liver disease (ALD) or primary sclerosing cholangitis, smoking, and oncogenic viral infections. There is scanty literature on the post-transplant malignancy risk in patients with alcoholic cirrhosis. The current evidence suggests a particularly increased risk of oropharyngeal and lung cancers in patients transplanted for ALD. Abstinence from alcohol, smoking and other tobacco-containing products along with optimization of immunosuppression are paramount for decreasing the risk of post-transplant malignancies.

Assessment of Renal Function in Post-Liver Transplant HCV-Positive Patients Treated with Direct Acting Antivirals.

PURPOSE: Direct acting antiviral agents (DAAs) have greatly improved the clearance of hepatitis C virus (HCV) infection. The effect of DAAs on renal function in post-liver transplant HCV-positive patients remains questionable, especially considering the possibility of drug interactions between immunosuppressants and DAAs. PATIENTS AND METHODS: A retrospective observational study included 84 post-liver transplant patients with HCV infection. Patients were divided into two groups: group I received sofosbuvir plus ribavirin for 24 weeks, group II received sofosbuvir plus daclatasvir for 12 weeks. Laboratory data and eGFR were determined before, at the end, and 6 months after completion of treatment. RESULTS: The treatment was well tolerated with 100% sustained virologic response (SVR 12). There was no statistically significant difference between the two groups regarding clinical and laboratory data before treatment. Mean eGFR significantly reduced from 87.36 mL/min to 76.16 mL/min in group I (P=0.001). However, within 6 months after treatment, mean eGFR recovered to 81.51 mL/min, which was not significant when compared to baseline eGFR (P=0.09). Mean eGFR in group II showed non-significant change. There were no significant changes in immunosuppressive drug levels and eGFR in either group of patients, who received either ciclosporin or tacrolimus before and at the end of treatment. CONCLUSION: DDAs in post-liver transplant patients with HCV infection were well tolerated and associated with stable renal function. Moreover, sofosbuvir plus daclatasvir regimen showed relatively better renal safety compared to sofosbuvir plus ribavirin.

A Retrospective Cohort Study of Risk Factors for Surgical Site Infection Following Liver Transplantation.

BACKGROUND: Surgical site infection is an important complication in the postoperative period among liver transplant recipients. However, little is known about the risk factors in this patient group. Therefore, the objective of this study was to analyze the incidence and risk factors for surgical site infections among adult liver transplant recipients. METHODS: Medical records of adult liver transplant recipients from January 1, 2009, to December 31, 2015, were analyzed in this retrospective cohort study. RESULTS: We enrolled 156 recipients' medical records. Forty-two (26.9%) cases of surgical site infections were identified. The main isolated microorganisms were methicillin-resistant Staphylococcus species, extended spectrum ß-lactamase-producing Klebsiella species, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii, and vancomycin-susceptible Enterococcus faecalis. We found that long operative times (≥487 minutes) and differences in body mass index between donor and recipient (≥1.3 kg/m2) increased the risk for surgical site infections by approximately 5 times (odds ratio [OR], 5.5; 95% confidence interval [CI], 2.5-11.8), and capillary glycemia ≥175 mg/dL in the first 96 postoperative hours increased the risk by approximately 3 times (OR, 2.97; 95% CI, 1.43-6.17). CONCLUSIONS: There was a high incidence of surgical site infections among the studied population and that some risk factors identified differ from those reported in the scientific literature.

Very late hepatic arterial thrombosis manifesting as central biliary necrosis: A rare presentation.

Hepatic artery thrombosis should always be considered on a liver graft recipient with mild and nonspecific symptoms, even after a decade of the transplantation.

Risk factors for development of surgical site infections among liver transplantation recipients: An integrative literature review.

BACKGROUND: Surgical site infection (SSI) is an important complication in the postoperative period of recipients of liver transplantation. The purpose of this integrative literature review is to summarize the knowledge available about the risk factors contributing to the development SSI among adults undergoing liver transplantation. METHODS: We reviewed the Medical Literature Analysis and Retrieval System Online/PubMed, the Cumulative Index to Nursing and Allied Health Literature, the Latin American and Caribbean Health Sciences Literature, Scopus, and Web of Science databases. RESULTS: Two hundred sixteen articles were identified and the final sample of 9 articles was analyzed in full length. The SSI rate found in the investigations ranged between 9.6% and 35.5%. Risk factors for SSI were grouped into categories related to the preoperative period, such as Model for End-Stage Renal Disease score > 35 and ventilated support on day of transplant; to the intraoperative period activity, such as transfusion of packed red blood cells, extended surgical time, hyperglycemia >200 mg/dL, use of vasopressor drugs, and ascites flow >1 L; and to the donor/recipient relationship, such as age differences >10 years, ratio of donor liver mass to recipient body mass < 0.01. Additionally, centers that annually perform <50 transplants appear to have higher rates of SSI. CONCLUSIONS: Few studies have addressed the subject of SSI in relation to liver transplantation in the scientific literature. Risk factors for SSI in patients who underwent liver transplantation vary between institutions.

Rupture of Sinus of Valsalva Aneurysm into Left Atrium in a Patient who is a Candidate for Hepatic Transplantation.

Sinus of valsalva aneurysm (SVA) is a rare cardiac disease. The most common complication of SVA is rupture into the right atrium or right ventricle. Rupture into the left chambers is very rare. Patients with ruptured SVA are likely to die of heart failure or endocarditis. We present a 29-year-old man who was hospitalized for hepatic transplantation with rupture of SVA. Transthoracic echocardiography and transesophageal echocardiography showed rupture of a noncoronary SVA into the left atrium. Mitral valve infective endocarditis developed and surgery was planned for the patient, but the patient died due to multiple organ dysfunction syndrome.

Transplante hepático: variação dos níveis sanguíneos de tacrolimo e desfechos de sobrevida, rejeição e óbito / Liver transplantation: tacrolimus blood levels variation and survival, rejection and death outcomes

ABSTRACT BACKGROUND: Immunosuppressive drugs have important role in transplant of solid grafts, it aim avoid episodes of acute and chronic rejection and improving graft survival and patient survival. In Brazil, in 2016, liver transplantation was the third most frequent, with 1,880 transplants performed, of which 150 in Rio Grande do Sul. Several studies evaluated the association between variability in blood levels of immunosuppressive tacrolimus and late acute cellular graft rejection. OBJECTIVE: To investigate the association of tacrolimus blood levels with clinical outcomes late acute cellular rejection, death, patient survival and graft survival in patients undergoing liver transplantation. METHODS: This is a retrospective longitudinal study including patients submitted to adult liver transplantation by the Liver Transplantation Group in the Santa Casa de Misericórdia Hospital of Porto Alegre, from January 2006 to January 2013, and who used tacrolimus as immunosuppressive therapy. RESULTS: Of the 127 patients included in the study, the majority were male (70.1%), 52-60 years old (33.9%) at the transplant. The most frequent causes of liver transplantation in this series were hepatitis C virus and hepatocellular carcinoma (24.4%) and alcohol (15.7%). Thirteen patients had late acute cellular rejection (10.2%); of these, three had two episodes. Regarding severity classification, seven patients had mild late acute cellular rejection. The mean time of rejection after liver transplantation was 14 months (ranging from 8 to 33 months). Overall survival was 8.98 years. Regarding tacrolimus blood levels, 52 patients with a variation ≥2 standard deviations were identified. Of these patients, eight had rejection; however, the association was not significant (P=0.146). A significant association was found between variation ≥2 standard deviations in tacrolimus blood levels and death (P=0.023) and survival (P=0.019). Regarding 5-year follow-up of graft survival, being two standard deviations above increases by 2.26 times the risk of transplanted graft loss, and for each unit of increase of standard deviation of tacrolimus blood levels there is a two-fold increase in the risk of graft loss in 5 years. CONCLUSION: Increased risk of graft loss associated with increased standard deviations of tacrolimus blood levels may indicate the need for more rigorous and prospective monitoring of tacrolimus blood levels.

RESUMO CONTEXTO: Os imunossupressores desempenham importante papel no transplante de órgãos sólidos, com o objetivo de evitar a rejeição aguda e crônica, aumentando o tempo de sobrevida do órgão e do paciente. No Brasil, em 2016, o transplante de fígado foi o 3° mais frequente, com um número de 1.880 transplantes, sendo 150 realizados no Rio Grande do Sul. OBJETIVO: Investigar a associação da variação dos níveis sanguíneos de tacrolimo com os desfechos clínicos, rejeição celular aguda tardia, óbito, sobrevida de paciente e enxerto em pacientes submetidos ao transplante hepático. MÉTODOS: Trata-se de um estudo longitudinal retrospectivo, no qual foram incluídos os pacientes submetidos ao transplante hepático adulto pelo grupo de transplante hepático na Irmandade Santa Casa de Misericórdia de Porto Alegre, no período de janeiro de 2006 a janeiro de 2013, e que fizeram o uso de tacrolimo como terapia imunossupressora. RESULTADOS: Dos 127 pacientes incluídos no estudo, a maioria era do gênero masculino (70,1%), caucasiana (86,4%), com idade entre 52 e 60 anos (33,9%). As associações de causas mais frequentes para transplante hepático foram vírus da hepatite C, carcinoma hepatocelular (24,4%) e álcool (15,7%). Um total de treze pacientes apresentaram rejeição celular aguda tardia (10,2%); destes, três tiveram dois episódios. O tempo médio de rejeição após o transplante hepático foi de 14 meses, variando de 8 a 33 meses. A sobrevida global foi de 8,98 anos. Em relação aos níveis sanguíneos de tacrolimo, foram identificados 52 pacientes com uma variação maior ou igual a dois desvios-padrão. Destes pacientes, oito tiveram rejeição, contudo, a associação não foi significativa (P=0,146). Foi encontrada uma associação significativa entre a variação maior ou igual a dois desvios-padrão nos níveis sanguíneos de tacrolimo com óbito (P=0,023) e sobrevida (P=0,019). Em relação ao acompanhamento de sobrevida do enxerto em cinco anos, estar dois desvios-padrão acima aumenta em 2,26 vezes o risco de perda do enxerto transplantado, e a cada unidade de aumento de desvio-padrão dos níveis sanguíneos de tacrolimo há um aumento de duas vezes no risco de perda do enxerto transplantado em 5 anos. CONCLUSÃO: O aumento do risco da perda do enxerto associado ao aumento da variação dos níveis sanguíneos de tacrolimo pode indicar a necessidade do acompanhamento mais rigoroso e prospectivo dos níveis sanguíneos de tacrolimo.