Recent trends and new developments in liver transplantation.

Liver transplantation (LT) has been an established treatment for end-staged liver disease for acute, chronic, metabolic diseases and liver cancer. Advanced surgical techniques, refined indications and contraindications for LT, improvements of donor selection, prognostic scorings system and immunosuppressive regimens have contributed to the improved outcomes of liver transplantation. The etiologies of cirrhosis have been shifting from viral hepatitis to metabolic associated fatty liver disease. New indications include peripheral or mass forming bile duct cancer, metastases from bowel cancers or neuroendocrine tumors. Resection and partial liver segments 2-3 transplantation with delayed total hepatectomy has been performed to the limited cases, which was the explored technique of auxiliary partial orthotopic LT. Minimally invasive donor hepatectomy (laparoscopic or robotic) has been increasingly done. In this review are described the recent pressing topics in LT.

A novel scoring system to predict short-term mortality after living donor liver transplantation for acute liver failure.

Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.

The First Successful Living Donor Liver Transplantation for Acute-on-Chronic Liver Failure Caused by Severe Acute Necrotizing Pancreatitis: A Case Report.

Liver transplantation (LT) is the only life-saving option when acute-on-chronic liver failure (ACLF) does not improve with conservative therapy. Acute pancreatitis (AP) can cause chronic liver disease progression to ACLF. However, deceased donor LT for patients with AP has had mixed results, and no consensus has been established regarding the indication for LT. We report the first successful living donor LT (LDLT) for ACLF caused by severe AP. The 38-year-old patient with alcoholic liver disease was transferred to our institute with worsening refractory ascites. During the pretransplant workup, she developed severe acute necrotizing pancreatitis, resulting in grade 3 ACLF. The patient's clinical course was further complicated by high levels of donor-specific antibodies and immune thrombocytopenia. The AP gradually improved after intensive care combined with artificial liver support. The patient successfully underwent urgent LDLT with upfront splenectomy and desensitization therapy, including plasm exchange, high-dose intravenous immunoglobulin, and anti-thymocyte globulin. No infection or recurrence of AP was observed postoperatively. We conclude that LDLT is a feasible option for ACLF patients caused by severe AP if a deceased donor is not readily available.

Reappraisal of anatomical liver resection for hepatoblastoma in children.

Background: The principle of hepatoblastoma (HB) treatment is complete resection. The removal of tumor-bearing section(s) or hemiliver is widely accepted. However, neither the standardized anterior approach for right hepatectomy nor parenchymal sparing anatomical liver resection has been described for HB. Methods: We retrospectively reviewed the clinical course of two pediatric HB patients who underwent extended right hepatectomy using the anterior approach with the liver hanging maneuver and one who underwent parenchymal sparing anatomical liver resection of S4 apical+S8 ventral/dorsal+S7. The critical aspects of surgical techniques are described in detail. Results: In all three patients, R0 resection was achieved without complications and are currently alive without recurrence after an average follow-up of 23 months. Intraoperative cardiac hemodynamics were stable, even in a trisomy 18 patient with cardiac disease. Conclusions: Our findings suggest that these innovative techniques established in adults are safe and feasible for HB in children. These techniques also allow optimal anatomical liver resection to accomplish curative surgery while maintaining the functional reserve of the remnant liver.

Hepatic venous outflow obstruction after adult living donor liver transplantation.

Hepatic venous outflow obstruction (HVOO) is a rare but critical vascular complication after adult living donor liver transplantation. We categorized HVOOs according to their morphology (anastomotic stenosis, kinking, and intrahepatic stenosis) and onset (early-onset < 3 mo vs. late-onset ≥ 3 mo). Overall, 16/324 (4.9%) patients developed HVOO between 2000 and 2020. Fifteen patients underwent interventional radiology. Of the 16 hepatic venous anastomoses within these 15 patients, 12 were anastomotic stenosis, 2 were kinking, and 2 were intrahepatic stenoses. All of the kinking and intrahepatic stenoses required stent placement, but most of the anastomotic stenoses (11/12, 92%) were successfully managed with balloon angioplasty, which avoided stent placement. Graft survival tended to be worse for patients with late-onset HVOO than early-onset HVOO (40% vs. 69.3% at 5 y, p = 0.162) despite successful interventional radiology. In conclusion, repeat balloon angioplasty can be considered for simple anastomotic stenosis, but stent placement is recommended for kinking or intrahepatic stenosis. Close follow-up is recommended in patients with late-onset HVOO even after successful treatment.

Elevated Alfa-Fetoprotein and Des-Gamma-Carboxy Prothrombin Levels Predict Poor Outcomes After Liver Transplantation for Hepatocellular Carcinoma Beyond the Japan Criteria.

AIM: The Japan criteria (Milan criteria + 5-5-500 rule) was established recently to select cirrhotic patients with hepatocellular carcinoma for liver transplantation. We evaluated factors associated with poor prognosis after liver transplantation and investigated whether a further extension of the criteria would be worthwhile. METHODS: We retrospectively analyzed 86 patients who underwent liver transplantation for hepatocellular carcinoma at Kumamoto University Hospital since 2004; 69 patients (80.2%) met the Japan criteria (the JCIN group), and 17 patients (19.8%) did not (the JCOUT group). RESULTS: The 5-year cancer-specific survival rates of the JCIN group (92.2%) were significantly better than that of the JCOUT group (39.2%; P < .001). In univariable analysis, alfa-fetoprotein and des-gamma-carboxy prothrombin were significant independent factors associated with cancer-specific survival rates. According to the receiver operating characteristic curves, the cutoff values of alfa-fetoprotein and des-gamma-carboxy prothrombin that predicted hepatocellular carcinoma recurrence after liver transplantation were 756 ng/mL and 1976 mAU/mL, respectively. The JCOUT group was divided into 2 subgroups according to alfa-fetoprotein and des-gamma-carboxy prothrombin: low risk (alfa-fetoprotein level <756 ng/mL and des-gamma-carboxy prothrombin level <1976 mAU/mL) and high risk (alfa-fetoprotein level ≥756 ng/mL and/or des-gamma-carboxy prothrombin level ≥1976 mAU/mL). The 5-year cancer-specific survival rate in the low-risk group (67.5%) was significantly better than that in the high-risk group (0%; P < .001). CONCLUSIONS: Alfa-fetoprotein levels of <756 ng/mL and des-gamma-carboxy prothrombin levels of <1976 mAU/mL may help identify cirrhotic patients with hepatocellular carcinoma who do not meet the Japan criteria but still benefit from liver transplantation.

Recent advances in surgical strategies and liver transplantation for hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although the development of treatment strategies with advances in chemotherapy has greatly improved the prognosis of HB, surgical resection and liver transplantation still play a vital role in the treatment of HB. In recent years, technological innovations have led to the development of new surgical approaches for HB. In this review, we describe the latest research on the surgical management of HB, including new imaging technologies, minimally invasive approaches, and the application of associating liver partition portal vein ligation for staged hepatectomy. We also discuss the current role of liver transplantation, use of ante-situm or ex-situ liver resection with auto-transplantation, and management of metastatic HB.

Massive duodenal ulcer bleeding due to the ruptured hepatic artery pseudoaneurysm after living donor liver transplantation.

BACKGROUND: The rupture of a hepatic artery pseudoaneurysm (HAP) is a rare but lethal complication after living donor liver transplantation (LDLT) and often manifests as acute gastrointestinal bleeding. CASE PRESENTATION: This report describes three patients who experienced HAP after LDLT. These patients initially presented with active bleeding of a duodenal ulcer (DU) in the duodenal bulb, followed by diagnosis of the ruptured HAP by angiography. None of the patients had evidence of an active intra-abdominal infection or bile leakage preceding the rupture of HAP. All patients were initially treated by transcatheter arterial coil embolization (TAE). In all cases, TAE was successful for hemostasis but resulted in complete obstruction of the arterial inflow to the graft. Arterial revascularization by surgical reconstruction using the autologous arterial graft in one case and re-LDLT in another one was successfully performed. The other one succumbed to sepsis caused by later liver abscesses. CONCLUSION: This is the first detailed case series of massive DU bleeding as a warning signal of ruptured HAP after LDLT. HAP should be included in the differential diagnosis when an LDLT recipient presents with gastrointestinal bleeding.

Liver transplantation for patients with hepatocellular carcinoma: Its current status and advances.

Liver transplantation is one of the best treatment options for selected patients with hepatocellular carcinoma (HCC). The Milan criteria (a single tumor with a maximum size of 5 cm or two or three tumors with a maximum size of 3 cm without evidence of vascular or extrahepatic involvement or metastasis) are one of the most common criteria to select patients with HCC for transplantation, though they are considered too restrictive. A moderate expansion of the criteria has been found to yield comparable recurrence-free survival rates. HCC will recur in approximately 10% of patients, and mostly within the first 2 years after transplantation. The preoperative level of alpha-fetoprotein, macrovascular invasion, tumor size, and tumor number are prognostic factors for recurrence. Recurrence of HCC after transplantation results in a poor prognosis.

Surgical Outcomes of Domino Liver Transplantation Using Grafts From Living Donors With Familial Amyloid Polyneuropathy.

Domino liver transplantation (DLT) using grafts from donors with familial amyloid polyneuropathy is an acceptable procedure for expanding the donor pool. The vascular and biliary reconstructions in living donor DLT (LDDLT) are technically demanding, and data on the short-term and long-term surgical outcomes of domino donors and recipients in LDDLT are limited. In this study, we identified 25 domino recipients from our liver transplantation program (1999-2018), analyzed the vascular and biliary reconstructions performed, and evaluated the surgical outcomes, including graft survival. Piggyback technique was adopted in all 25 domino donors. The only surgical complication in domino donors was hepatic vein (HV) stenosis with an incidence rate of 4%. In 22 domino recipients, right HV and middle/left HV were reconstructed separately. A total of 10 recipients had 2 arteries anastomosed, and 18 underwent duct-to-duct biliary anastomosis. HV stenosis and biliary stricture had incidence rates of 8% and 24%, respectively, in the recipients, but none of them developed hepatic artery thrombosis. The 1-year and 5-year graft survival rates were 100% each in the domino donors, and 84.0% and 67.3% in the domino recipients, respectively. In conclusion, LDDLT has acceptable outcomes without increasing the operative risk in donors despite the demanding surgical technique involved.

Intellectual development of patients with biliary atresia who underwent living donor liver transplantation in infancy.

BACKGROUND: The impact of pediatric liver transplantation on intellectual development has yet to be determined. We investigated the intellectual outcomes of school-aged patients after living donor liver transplantation for biliary atresia in infancy. METHODS: The Wechsler Intelligence Scale for Children-fourth edition test was administered to 20 patients who survived [Formula: see text] 5 years after living donor liver transplantation. Borderline full scale intelligence quotient was defined as ≤ 85. Pre-, peri-, and postoperative data were compared between patients with > 85 and ≤ 85 to identify predictive factors of borderline performance. RESULTS: The one-sample t test demonstrated that the mean full scale intelligence quotient of patients after transplantation for biliary atresia was significantly lower than that of the general population (91.8 vs. 100.0, p = 0.026) and 7 (35%) were classified as intellectual borderline functioning. Multivariable logistic regression models were unable to identify any factors predictive of full scale intelligence quotients of ≤ 85. CONCLUSION: This is the first study to indicate that the mean full scale intelligence quotient among school-aged patients who underwent living donor liver transplantation for biliary atresia in infancy is significantly lower than that of the general population.

Budd-Chiari syndrome: consensus guidance of the Asian Pacific Association for the study of the liver (APASL).

Budd Chiari syndrome (BCS) is a diverse disease with regard to the site of obstruction, the predisposing thrombophilic disorders and clinical presentation across the Asia-Pacific region. The hepatic vein ostial stenosis and short segment thrombosis are common in some parts of Asia-Pacific region, while membranous obstruction of the vena cava is common in some and complete thrombosis of hepatic veins in others. Prevalence of myeloproliferative neoplasms and other thrombophilic disorders in BCS varies from region to region and with different sites of obstruction. This heterogeneity also raises several issues and dilemmas in evaluation and approach to management of a patient with BCS. The opportunity to recanalize hepatic vein in patients with hepatic vein ostial stenosis or inferior vena cava stenting or pasty among those membranous obstruction of the vena cava is a unique opportunity in the Asia-Pacific region to restore hepatic outflow closely mimicking physiology. In order to address these issues arising out of the diversity as well as the unique features in the region, the Asia Pacific Association for Study of Liver has formulated these guidelines for clinicians.

Hungry Bone Syndrome After Living Donor Liver Transplant for Biliary Atresia.

Hungry bone syndrome is a rare but potentially lethal complication that is characterized by rapid, severe, long-lasting hypocalcemia and hypophosphatemia secondary to increased bone metabolism. We present a case of hungry bone syndrome after living donor liver transplant for biliary atresia. Following a failed Kasai procedure for biliary atresia, a 5-month-old boy underwent living donor liver transplant with reduced left lateral lobe from his father. Despite the oral administration of alfacalcidol, the patient exhibited severe craniotabes before the surgery. He developed severe hypocalcemia and hypophosphatemia im-mediately after liver transplant and required supplementation of calcium and phosphorus for 1 month thereafter. After serum levels of calcium and phosphate had normalized, there was a rapid increase in the serum bone-type alkaline phosphatase level, and the craniotabes subsided remarkably. To our knowledge, this is the world's first reported case of hungry bone syndrome after liver transplant for cholestatic cirrhosis. It underscores the importance of strict nutritional and electrolyte management in the perioperative period. A prompt diagnosis and correction of hungry bone syndrome are imperative to prevent the associated significant morbidity and mortality.

Surgical treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and cirrhosis is a risk factor for HCC. Resection is indicated for those unilobar tumors without vascular invasion and metastases in the liver and preserved liver function. Small HCC (< 2 cm) without microvascular invasion is associated with a 5-year recurrence rate as high as 50% to 60%, whereas liver transplantation is indicated for those within the Milan criteria (solitary tumor ≤ 5 cm or two or three nodules ≤ 3 cm) who have decompensated cirrhosis. The 1-, 3-, and 5-year survival rates of living donor liver transplantation for HCC are 85%, 75%, and 70%, respectively. This review summarizes the scientific evidence supporting the clinical practice recommendations for patients with HCC, and it discusses surgical treatment of HCC.

In vivo dynamics and adaptation of HTLV-1-infected clones under different clinical conditions.

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression.

Impact of Donor Age on the Outcome of Living-donor Liver Transplantation: Special Consideration to the Feasibility of Using Elderly Donors.

BACKGROUND: The use of elderly donors (≥60 y) in living-donor liver transplantation (LDLT) remains controversial. In this study, we aimed to determine the safety of surgery for elderly donors and the impact of donor age on LDLT outcomes. METHODS: We, retrospectively, reviewed 470 cases of LDLT at Kumamoto University Hospital from December 1998 to March 2017. RESULTS: Donors were divided into 5 groups according to age: 20-29 (n = 109), 30-39 (n = 157), 40-49 (n = 87), 50-59 (n = 81), and ≥60 (n = 36). At our institution, elderly donor candidates required additional preoperative work-up. There were no significant differences in the incidence of postoperative complications and duration of postoperative hospital stay among the 5 donor groups. Regardless of graft type, elderly donors were comparable to younger donor groups (<30 y) in postoperative recovery of liver function. Risk-adjusted overall survival rates of recipients among donor groups were not significantly different. Additionally, donor age was not significantly associated with 6-month graft survival of adult and pediatric recipients. CONCLUSIONS: Elderly candidates ≥60 years of age can safely be selected as LDLT donors after meticulous preoperative work-up.

Portal Vein Complications After Adult Living Donor Liver Transplantation: Time of Onset and Deformity Patterns Affect Long-Term Outcomes.

Portal vein complications (PVCs) after adult living donor liver transplantation (LDLT) are potentially lethal. We categorized PVCs by the time of onset (early versus late, <1 month versus ≥1 month, respectively) and deformity patterns (portal vein stenosis [PVS], portal vein thrombosis [PVT], and portal vein occlusion [PVO]) to establish optimal treatment strategies. Overall, 35/322 (10.9%) recipients developed PVCs between 2000 and 2019. Pretransplant PVT (odds ratio [OR], 15.20; 95% confidence interval [CI], 3.70-62.40; P < 0.001) was the only independent risk factor for PVS. In contrast, male sex (OR, 5.57; 95% CI, 1.71-18.20; P = 0.004), pretransplant PVT (OR, 4.79; 95% CI, 1.64-14.00; P = 0.004), and splenectomy (OR, 3.24; 95% CI, 1.23-8.57; P = 0.018) were independent risk factors for PVT. PVS was successfully treated with interventional radiology regardless of its time of onset. On the other hand, late PVT and PVO had significantly lower treatment success rates (2/15, 13%) compared with those that occurred in the early period (10/11, 91%) despite aggressive intervention (P < 0.001). Deformity patterns had a significant impact on the 5-year cumulative incidence of graft loss as a result of PVC (PVO + Yerdel grades 2-4 PVT group [n = 16], 41% versus PVS + Yerdel grade 1 PVT group [n = 19], 0%; P = 0.02). In conclusion, late grades 2 to 4 PVT and PVO are refractory to treatment and associated with poor prognoses, whereas PVS has a good prognosis regardless of time of onset. A tailored approach according to the time of onset and deformity patterns of PVC is essential.

Asymptomatic hepatic artery dissection early after living-donor liver transplantation with simultaneous splenectomy: two case reports.

BACKGROUND: Hepatic artery dissection after liver transplantation is an uncommon morbidity. The onset mechanism and management for this disorder remain unclear. The present report describes the cases of two patients with hepatic artery dissection after living-donor liver transplantation (LDLT) with simultaneous splenectomy and provides new insight into the onset mechanism of this disorder. CASE PRESENTATION: CASE 1: A 51-year-old man with liver cirrhosis caused by hepatitis B virus underwent LDLT with a right lobe graft and splenectomy simultaneously. The recipient's right hepatic artery had partial dissection at the anastomosis site; therefore, his left hepatic artery was anastomosed. Contrast-enhanced computed tomography (CT) on postoperative day (POD) 27 showed dissection from his celiac artery to his left hepatic artery with bleeding in the false lumen. There was a risk of rupture of the false lumen; therefore, emergency interventional radiology and coil embolization of the false lumen were performed. The patient was doing well at 6 months after LDLT. CASE 2: A 58-year-old woman with liver cirrhosis caused by primary biliary cholangitis underwent LDLT with a left lobe graft and splenectomy simultaneously. Her hepatic artery had a dissection that extended from her left hepatic artery to the proper hepatic artery. The gastroduodenal artery was anastomosed. Contrast-enhanced CT on POD 8 revealed dissection from the celiac artery to the common hepatic artery as well as a pseudoaneurysm at the celiac artery. We managed the patient with conservative treatment and performed daily follow-ups with Doppler ultrasonography examination and serial contrast-enhanced CT. At the time of writing this report, the patient was doing well at 34 months after LDLT. CONCLUSIONS: Patients who have an intimal dissection at the anastomosis site and/or simultaneous splenectomy are at a higher risk of hepatic artery dissection. Most patients with asymptomatic hepatic artery dissections can be treated conservatively. Blood flow in the intrahepatic artery should be checked frequently using Doppler ultrasonography or contrast-enhanced CT soon after diagnosis.