Outflow reconstruction with arterial patch in domino liver transplantation: a new technical option

Domino liver transplantation (LT), using livers from familial amyloidotic polyneuropathy (FAP) patients, is a well described technique useful to expand donor pool. One of the main difficulties of this type of LT arises from the necessity to share the vascular pedicles between the graft and the donor. The most important challenge resides in restoring a proper hepatic venous outflow in the FAP-liver recipient. This is specially challenging when using the piggy-back technique, because the hepatic stumps may be too short. To overcome this issue, surgeons explored several techniques using different types of venous grafts. We describe a new technical option by using an arterial graft from the deceased donor. By using both iliac arteries a long graft is created and sutured as needed to the hepatic vein stump. We describe herein this new technique employed in a domino liver recipient who underwent retransplantation for ischemic cholangitis. The procedure was performed using the piggy-back technique; the venous stump of the FAP liver was reconstructed with the arterial graft. The patient had uneventful postoperative and mid-term hepatic function, and anastomosis was patent 24 months after LT.     

How important is donor age in liver transplantation?

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation(LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.     

Transient hyperglycemia during liver transplantation does not affect the early graft function

Background and rationale for the study. Hyperglycemia after graft reperfusion is a consistent finding in liver transplantation (LT) that remains poorly studied. We aim to describe its appearance in LT recipients of different types of grafts and its relation to the graft function.Material & methods. 436 LT recipients of donors after brain death (DBD), donors after cardiac death (DCD), and familial amyloidotic polyneuropathy (FAP) donors were reviewed. Serum glucose was measured at baseline, during the anhepatic phase, after graft reperfusion, and at the end of surgery. Early graft dysfunction (EAD) was assessed by Olthoff criteria. Caspase-3, IFN-γ, IL1β, and IL6 gene expression were measured in liver biopsy.Results. The highest increase in glucose levels after reperfusion was observed in FAP LT recipients and the lowest in DCD LT recipients. Glucose level during the anhepatic phase was the only modifiable predictive variable of hyperglycemia after reperfusion. No relation was found between hyperglycemia after reperfusion and EAD. However, recipients with the highest glucose levels after reperfusion tended to achieve the best glucose control at the end of surgery and those who were unable to control the glucose value after reperfusion showed EAD more frequently. The highest levels of caspase-3 were found in recipients with the lowest glucose values after reperfusion. In conclusion, glucose levels increased after graft reperfusion to a different extent according to the donor type. Contrary to general belief, transient hyperglycemia after reperfusion does not appear to impact negatively on the liver graft function and could even be suggested as a marker of graft quality.     

Living donor liver transplantation

The introduction of living donor liver transplantation (LDLT) has been one of the most remarkable steps in the field of liver transplantation (LT). First introduced for children in 1989, its adoption for adults has followed only 10 years later. As the demand for LT continues to increase, LDLT provides life-saving therapy for many patients who would otherwise die awaiting a cadaveric organ. In recent years, LDLT has been shown to be a clinically safe addition to deceased donor liver transplantation (DDLT) and has been able to significantly extend the scarce donor pool. As long as the donor shortage continues to increase, LDLT will play an important role in the future of LT.     

The critical role of therapeutic plasma exchange in ABO-incompatible liver transplantation

BackgroundThe shortage of donor liver restricts liver transplantation (LT). Nowadays, donor liver with ABO blood group incompatibility between donor and recipient has become an option to expand the source of donor liver. Although it is now possible to perform ABO-incompatible (ABO-I) LT, antibody-mediated rejection (AMR) has been recognized as the primary cause of desperate outcomes after ABO-I LT. Anti-A/B antibody is the trigger of immune response to ABO-I LT graft injury. Therapeutic plasma exchange (TPE) can quickly reduce the titer of plasma antibodies and effectively inhibit humoral immunity.Data sourcesWe searched PubMed and CNKI databases using search terms “therapeutic plasma exchange”, “ABO-incompatible liver transplantation”, “ABO-I LT”, “liver transplantation”, “LT”, “antibody-mediated rejection”, and “AMR”. Additional publications were identified by a manual search of references from key articles. The relevant publications published before September 30, 2020 were included in this review.ResultsDifferent centers have made different attempts on whether to use TPE, when to use TPE and how often to use TPE. However, the control standard of lectin revision level is always controversial, the target titer varies significantly from center to center, and the standard target titer has not yet been established. TPE has several schemes to reduce antibody titers, but there is a lack of clinical trials that provide standardized procedures.ConclusionsTPE is essential for ABO-I LT. Hence, further research and clinical trials should be conducted to determine the best regimen for TPE to remove ABO antibodies and prevent AMR.     

Living-donor liver transplantation in Budd-Chiari syndrome with inferior vena cava complete thrombosis: A case report and review of the literature

BACKGROUND Budd-Chiari syndrome(BCS) is a challenging indication for liver transplantation(LT) due to a combination of massive liver,increased bleeding,retroperitoneal fibrosis and frequently presents with stenosis of the inferior vena cava(IVC).Occasionally,it may be totally thrombosed,increasing the complexity of the procedure,as it should also be resected.The challenge is even greater when performing living-donor LT as the graft does not contain the retrohepatic IVC;thus,it may be necessary to reconstruct it.CASE SUMMARY A 35-year-old male patient with liver cirrhosis due to BCS and hepatocellular carcinoma beyond the Milan criteria underwent living-donor LT with IVC reconstruction.It was necessary to remove the IVC as its retrohepatic portion was completely thrombosed,up to almost the right atrium.A right-lobe graft was retrieved from his sister,with outflow reconstruction including the right hepatic vein and the branches of segment V and VIII to the middle hepatic vein.Owing to massive subcutaneous collaterals in the abdominal wall,venovenous bypass was implemented before incising the skin.The right atrium was reached via a transdiaphragramatic approach.Hepatectomy was performed en bloc with the retrohepatic vena cava.It was reconstructed with an infra-hepatic vena cava graft obtained from a deceased donor.The patient remains well on outpatient clinic follow-up 25 mo after the procedure,under an anticoagulation protocol with warfarin.CONCLUSION Living-donor LT in BCS with IVC thrombosis is feasible using a meticulous surgical technique and tailored strategies.     

Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors

Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.     

Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection

The recurrence of liver fibrosis after liver transplantation (LT) for hepatitis C virus (HCV) infection is responsible for graft loss and patient mortality. Although the contribution of the immune system to fibrosis recurrence is anticipated, systematic studies evaluating immune parameters as predictive markers of allograft fibrosis are lacking. The infiltration of immune cells into the graft is governed by chemokines. Here we assessed the predictive value of serum levels of chemokines [chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and chemokine (C-C motif) ligand 2 (CCL2)] with respect to fibrosis recurrence after LT in 90 HCV-infected organ recipients. Chemokines were determined within the first and third years after LT and were correlated with histological fibrosis progression in protocol biopsy samples at 1, 3, 5, and 7 years (median follow-up = 3 years). The association of chemokines with fibrosis progression was assessed by univariate and multivariate analyses and by Cox regression analysis. The results for the analyzed chemokines showed that CXCL10 levels in the first year after LT were strongly associated with early fibrosis recurrence (P = 0.005) independently of risk confounders (including the donor age, HCV viral load, HCV genotype, acute rejection, and inflammatory activity). As assessed by Cox regression analysis, a CXCL10 serum level ≤ 140 pg/mL was significantly predictive of the absence of F2 fibrosis (P = 0.001), whereas a level ≤ 220 pg/mL early after LT predicted the absence of F3 fibrosis during follow-up (P = 0.035). CONCLUSION: CXCL10 is an independent biomarker of the recurrence of significant fibrosis after LT for HCV infection. These results might guide patients' care after transplantation and help us to select optimal candidates for antiviral therapy post-LT.     

Rescue policy for discarded liver grafts: a single-centre experience of transplanting livers 'that nobody wants'

Background

There is a worldwide need to expand the donor liver pool. We report a consecutive series of elective candidates for liver transplantation (LT) who received ‘livers that nobody wants’ (LNWs) in Argentina.

Methods

Between 2006 and 2009, outcomes for patients who received LNWs were analysed and compared with outcomes for a control group. To be defined as an LNW, an organ is required to fulfil two criteria. Firstly, each liver must be officially offered and refused more than 30 times; secondly, the liver must be refused by at least 50% of the LT programmes in our country before our programme can accept it. Principal endpoints were primary graft non-function (PNF), mortality, and graft and patient survival.

Results

We transplanted 26 LNWs that had been discarded by a median of 12 centres. A total of 2666 reasons for refusal had been registered. These included poor donor status (n = 1980), followed by LT centre (n = 398) or recipient (n = 288) conditions. Incidences of PNF (3.8% vs. 4.0%), in-hospital mortality (3.8% vs. 8.0%), 1-year patient (84% vs. 84%) and graft (84% vs. 80%) survival were equal in the LNW and control groups.

Conclusions

Transplantable livers are unnecessarily discarded by the transplant community. External and internal supervision of the activity of each LT programme is urgently needed to guarantee high standards of excellence.     

Interventional radiology in living donor liver transplant

The shortage of deceased donor liver grafts led to the use of living donor liver transplant (LDLT). Patients who undergo LDLT have a higher risk of complications than those who undergo deceased donor liver transplantation (LT). Interventional radiology has acquired a key role in every LT program by treating the majority of vascular and non-vascular post-transplant complications, improving graft and patient survival and avoiding, in the majority of cases, surgical revision and/or re-transplant. The aim of this paper is to review indications, diagnostic modalities, technical considerations, achievements and potential complications of interventional radiology procedures after LDLT.     

Management of Hepatitis C Before and After Liver Transplantation in the Era of Rapidly Evolving Therapeutic Advances

Management of hepatitis C (HCV) in liver transplantation (LT) population presents unique challenges. Suboptimal graft survival in HCV+ LT recipients is attributable to universal HCV recurrence following LT. Although eradication of HCV prior to LT is ideal for the prevention of HCV recurrence it is often limited by adverse events, particularly in patients with advanced cirrhosis. Antiviral therapy in LT candidates needs careful monitoring, and prophylaxis with HCV antibodies is ineffective. Early antiviral therapy after LT has been investigated, but no clear benefit has been demonstrated. Protocol liver biopsy is generally recommended in HCV+ LT recipients, and antiviral therapy can be considered in those with severe/progressive HCV recurrence. Sustained virological response (SVR) can be achieved in approximately 30% of LT recipients with pegylated interferon/ribavirin (PEG-IFN/RBV) with survival benefit, but adverse effects are common. Favorable patient characteristics for response to therapy include non-1 genotype, previously untreated, low baseline HCV-RNA, and donor IL28B genotype CC. Direct acting antiviral (DAA)-based triple therapy is associated with higher rates of SVR, but with similar or slightly higher rates of side effects, and immunosuppressive regimens need to be closely monitored and adjusted during the treatment period. Notably, the safety and efficacy of HCV treatment are very likely to improve with newer generation DAA. The benefit of immunosuppressive strategy on the natural history HCV recurrence has not been well elucidated. Based upon available evidence, cyclosporine A (CSA), mycophenolate mofetil (MMF), and sirolimus appear to have a neutral or small beneficial impact on HCV recurrence. Donor interleukin 28 B (IL28B) polymorphisms appear to impact the course and treatment outcomes in recurrent HCV. Retransplantation should be considered for patients with reasonable survival probability.     

Asymptomatic transmission of Treponema pallidum (syphilis) through deceased donor liver transplantation

A 55‐year‐old woman underwent liver transplantation (LT) with a graft from a deceased donor. Mandatory pre‐donation investigations showed positive syphilis serology that was available only after the transplant, with high Treponema pallidum particle agglutination assay titer compatible with donor syphilis infection. Despite the institution of appropriate post‐exposure prophylaxis, the recipient demonstrated latent seroconversion; however, liver graft function improved without evidence of syphilitic hepatitis or other manifestations of the disease. Through this first reported case of asymptomatic transmission of syphilis following LT, we highlight the investigations and treatment strategies for donor‐derived syphilis in liver transplant recipients. This report supplements the existing limited evidence on safe use of infected grafts from syphilitic donors through appropriate post‐exposure prophylaxis.     

Pediatric liver transplantation: a North American perspective

Liver transplantation (LT) is an important component in the therapeutic armamentarium of managing end-stage liver disease. In North American children, biliary atresia remains the most common indication for LT compared to hepatitis C in adults, while hepatoblastoma is the most common liver tumor requiring LT, versus Hepatocellular carcinoma in adults. Rejection, lymphoproliferative disease, renal insufficiency, metabolic syndrome, recurrent disease, ‘de novo’ autoimmune hepatitis and malignancy require careful surveillance and prompt action in adults and children after LT. In children, specific attention to EBV viremia, growth, development, adherence and transition to the adult services is also required. Antibody mediated rejection and screening for donor specific antibodies is becoming important in managing liver graft dysfunction. Biomarkers to identify and predict tolerance are being developed. Machine perfusion and stem cells (iPS) to synthesize organs are generating interest and are a focus for research.     

Interventional radiology procedures in adult patients who underwent liver transplantation

Interventional radiology has acquired a key role in every liver transplantation （LT） program by treating the majority of vascular and non-vascular post-transplant complications, improving graft and patient survival and avoiding, in the majority of cases, surgical revision and/or re-transplantation. The aim of this paper is to review indications, technical consideration, results achievable and potential complications of interventional radiology procedures after deceased donor LT and living related adult LT.     

Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions

Milan criteria are currently the benchmark related to liver transplantation(LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria(yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of "Metroticket" and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.     

Small-for-size syndrome in liver transplantation: Definition,pathophysiology and management

BackgroundSince the first success in an adult patient, living donor liver transplantation (LDLT) has become an universally used procedure. Small-for-size syndrome (SFSS) is a well-known complication after partial LT, especially in cases of adult-to-adult LDLT. The definition of SFSS slightly varies among transplant physicians. The use of a partial liver graft has risks of SFSS development. Persistent portal vein (PV) hypertension and PV hyper-perfusion after LT were identified as the main factors. Hence, various approaches were explored to modulate PV flow and decrease PV pressure in order to alleviate this syndrome. Herein, the definition, clinical symptoms, pathophysiology, basic research, as well as preventive and treatment strategies for SFSS are reviewed based on an extensive review of the literature and on our own experiences.Data sourcesThe articles were collected through PubMed using search terms “liver transplantation”, “living donor liver transplantation”, “living liver donation”, “partial graft”, “small-for-size graft”, “small-for-size syndrome”, “graft volume”, “remnant liver”, “standard liver volume”, “graft to recipient body weight ratio”, “sarcopenia”, “porcine”, “swine”, and “rat”. English publications published before March 31, 2020 were included in this review.ResultsMany transplant surgeons performed PV flow modulation, including portocaval shunt, splenic artery ligation and splenectomy. With these techniques, patient outcome has been improved even when using a "small" graft. Other factors, such as preoperative recipients’ nutritional and skeletal muscle status, graft congestion, and donor factors, were also identified as risk factors which all have been addressed using various strategies.ConclusionsThe surgical approach controlling PV flow and pressure could help to prevent SFSS especially in severely ill recipients. In the absence of efficacious medications to resolve SFSS, conservative treatments, including aggressive fluid balance correction for massive ascites, anti-microbiological therapy to prevent or control sepsis and intensive nutritional therapy, are all required if SFSS could not be prevented.     

Pringle's manoeuvre in living donors

The safety of the donor is paramount in living donor liver transplantation. The most important risk to the donor during hepatectomy is bleeding, and the inflow occlusion technique (Pringle's manoeuvre) has been reported to decrease bleeding without inducing liver injury in liver surgery. However, most transplant centres are doing donor hepatectomies without this technique for fear that it would result in ischaemic injury to the graft. We have done 46 living donor hepatectomies with Pringle's manoeuvre without any negative outcome on the quality of the graft. Surgeons should not hesitate to apply this technique in living donor hepatectomy.     

De novo acute hepatitis B infection in a previously vaccinated liver transplant recipient due to a strain of HBV with a Met 133 Thr mutation in the “a” determinant

Abstract: De novo HBV infection post‐liver transplantation (LT) from an anti‐HBc seropositive donor rarely presents as acute failure. We report a 42‐year‐old Caucasian female, HBsAg and anti‐HBc seronegative, with primary biliary cirrhosis who received an allograft from a HBsAg negative, anti‐HBc seropositive donor. The patient, previously vaccinated years pre‐LT, was re‐vaccinated against HBV and 1 year post‐LT had an anti‐HBs titre of 256 IU/l. Two years post‐LT, elevated serum aminotransferases and worsening liver function with an INR of 2.0 developed. The HBsAg became positive, anti‐HBs undetectable and serum HBV‐DNA >2000 pg/ml by hybridisation assay. Liver biopsy revealed significant ballooning degeneration, piecemeal necrosis and positive immunostaining for HBsAg. Progressive liver failure developed followed by sepsis and terminal multi‐organ failure. Subsequent analysis of the predominant HBV strain revealed mutations in the “a” determinant: Met 133 Thr (codon change ATG to ACG) and Asn 131 Thr. Conclusion: Acute de novo HBV infection from an anti‐HBc sero‐positive donor may occur long after LT despite protective anti‐HBs titres post‐vaccination secondary to the emergence of “a” determinant mutated strains of HBV.     

Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver

Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of the existence of hematopoietic stem/progenitor cells (HSPCs) in the liver. We characterized the blood chimerism in a large cohort of 249 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.43%, of which 11.11% was among short-term (1 day to 6 months) and 3.77% was among long-term (6 months to 8 years) LT patients. Hematopoietic Lin(-) CD34(+) CD38(-) CD90(+) populations have been demonstrated to generate long-term lymphomyeloid grafts in transplantations. In human adult livers, we detected Lin(-) CD34(+) CD38(-) CD90(+) populations accounting for 0.03% ± 0.017% of the total single liver cells and for 0.05% ± 0.012% of CD45(+) liver cells. Both Lin(-) CD34(+) and Lin(-) CD45(+) liver cells, from extensively perfused human liver grafts, were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, Lin(-) CD45(+) or CD45(+) liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of the presence of putative HSPC populations in the adult human liver, where the liver is a good ectopic niche. The discovery of the existence of HSPCs in the adult liver have implications for the understanding of extramarrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation, and de novo cancer recurrence in LT patients. Conclusion: The human adult liver contains a small population of HSPCs. In LT patients, there are two types of chimerisms: transient chimerism, resulting from mature leucocytes, and long-term chimerism, derived from putative HSPCs in the liver graft. (HEPATOLOGY 2012).     

Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Platelets are anucleate fragments mainly involved in hemostasis and thrombosis, and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation, angiogenesis, regeneration and ischemia/reperfusion injury (I/R injury), which are involved in the physiological and pathological processes during living donor liver transplantation (LDLT). LDLT is sometimes associated with impaired regeneration and severe I/R injury, leading to postoperative complications and decreased patient survival. Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT. Although it is not fully understood whether thrombocytopenia is the cause or result, increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies. Based on rodent experiments, previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy. However, the role of platelets in LDLT is controversial, as platelets are supposed to aggravate I/R injury in the liver. Recently, a rat model of partial liver transplantation (LT) was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation. It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT. Clinical strategies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist and platelet transfusion, may improve graft regeneration and survival after LDLT.