Liver transplantation for a giant mesenchymal hamartoma of the liver in an adult: Case report and review of the literature

Mesenchymal hamartomas of the liver(MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography(CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm × 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen includedintraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg(dry weight) and measured 41 cm × 32 cm × 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months after transplantation, the patient remains well and is fulfilling all normal activities. Adult giant MHL is extremely rare. Symptoms, physical signs, laboratory results, and radiographic imaging are nonspecific and inconclusive. Surgical excision of the lesion is imperative to make a definite diagnosis and as a cure. Liver transplantation should be considered as an option in the treatment of a non-resectable MHL.

The potential of genetically-engineered pigs in providing an alternative source of organs and cells for transplantation

There is a critical shortage of organs, cells, and corneas from deceased human donors worldwide. There are also shortages of human blood for transfusion. A potential solution to all of these problems is the transplantation of organs, cells, and corneas from a readily available animal species, such as the pig, and the transfusion of red blood cells from pigs into humans. However, to achieve these ends, major immunologic and other barriers have to be overcome. Considerable progress has been made in this respect by the genetic modification of pigs to protect their tissues from the primate immune response and to correct several molecular incompatibilities that exist between pig and primate. These have included knockout of genes responsible for the expression of major antigenic targets for primate natural anti-pig antibodies, insertion of human complement- and coagulation-regulatory transgenes, and knockdown of swine leukocyte antigens that stimulate the primate＇s adaptive immune response. As a result of these manipulations, the administration of novel immunosuppressive agents, and other innovations, pig hearts have now functioned in baboons for 6-8 months, pig islets have maintained normoglycemia in diabetic monkeys for 〉 1 year, and pig corneas have maintained transparency for several months. Clinical trials of pig islet trans- plantation are already in progress. Future developments will involve further genetic manipulations of the organ- source pig, with most of the genes that are likely to be beneficial already identified.

Acute antibody-mediated rejection after intestinal transplantation

AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection(ABMR) after intestinal transplantation(ITx).METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody(DSA), acute tissue damage, C4 d deposition, and allograft dysfunction.RESULTS Acute ABMR was identified in 18(10.3%) out of 175 intestinal allografts with an average occurrence of 10 d(range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class Ⅰand/or Ⅱ antigens with a detectable DSA. A positive cross-match was seen in 14(77.8%) cases and twelve of 18 patients(66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4 d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibodyas a significant independent risk factor. Despite initial improvement after therapy, eleven recipients(61.1%) lost transplant secondary to rejection. Of those, 9(50%) underwent graft removal and 4(22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo(range, 13.3-76.4), 8(44.4%) recipients died.CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes.

Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease

在胆汁的树上的 Basic 和翻译创伤愈合研究在皮和胃肠道上在类似的研究后面显著地落后。这是至少对为学习的胆道的容易的存取的缺乏部分可归因。但是临床的关联，对胆汁的上皮的房间(BEC ) 的更多的兴趣 BEC 文化的病理生理学，和普遍可获得性是颠倒这个趋势的因素。在额外肝的胆汁的树上，徒劳的创伤愈合，结疤，苛评开发紧迫发出。在损害的最小的 intra 肝的胆汁管任何一个， BEC 增长或繁的回答能贡献肝疾病。在大、小的胆汁管的慢性炎和坚持的创伤愈合反应经常导致肝癌症。当他们适用于胆道，依赖于表明小径的 IL-6/gp130/STAT3 的细胞的过程的重要性，未答复的问题，和未来方向，愈合的创伤的一般概念被讨论。

A comparison of three methods of decellularization of pig corneas to reduce immunogenicity

·AIM: To investigate whether decellularization using different techniques can reduce immunogenicity of the cornea, and to explore the decellularized cornea as a scaffold for cultured corneal endothelial cells(CECs).Transplantation of decellularized porcine corneas increases graft transparency and survival for longer periods compared with fresh grafts.·METHODS: Six-month-old wild-type pig corneas were cut into 100-200 μm thickness, and then decellularized by three different methods: 1) 0.1% sodium dodecyl sulfate(SDS); 2) hypoxic nitrogen(N2); and 3) hypertonic NaCl. Thickness and transparency were assessed visually. Fresh and decellularized corneas were stained with hematoxylin/eosin(H&E), and for the presence of galactose-α1,3-galactose(Gal) and N-glycolylneuraminic acid(NeuGc, a nonGal antigen). Also, a human IgM/IgG binding assay was performed. Cultured porcine CECs were seeded on the surface of the decellularized cornea and examined after H&E staining.· RESULTS: All three methods of decellularization reduced the number of keratocytes in the stromal tissue by 】80% while the collagen structure remained preserved. No remaining nuclei stained positive for Gal or NeuGc, and expression of these oligosaccharides on collagen was also greatly decreased compared to expression on fresh corneas. Human IgM/IgG binding to decellularized corneal tissue was considerably reduced compared to fresh corneal tissue. The cultured CECs formed a confluent monolayer on the surface of decellularized tissue.· CONCLUSION: Though incomplete, the significant reduction in the cellular component of the decellularized cornea should be associated with a significantly reduced in vivo immune response compared to fresh corneas.

Role of the IL-33-ST2 axis in sepsis

Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33(IL-33) is a recently described member of the IL-1 family that is widely expressed in cells of barrier tissues. Upon tissue damage, IL-33 is released as an alarmin and activates various types of cells of both the innate and adaptive immune system through binding to the ST2/IL-1 receptor accessory protein complex. IL-33 has apparent pleiotropic functions in many disease models, with its actions strongly shaped by the local microenvironment. Recent studies have established a role for the IL-33-ST2 axis in the initiation and perpetuation of inflammation during endotoxemia, but its roles in sepsis appear to be organism and model dependent. In this review, we focus on the recent advances in understanding the role of the IL-33/ST2 axis in sepsis.

Bioartificial liver assist devices in support of patients with liver failure

Bioartificial liver assist devices (BALs) offer anopportunity for critical care physicians and transplantsurgeons to stabilize patients prior to orthotopic livertransplantation. Such devices may also act as a bridgeto transplant, providing liver support to patientsawaiting transplant, or as support for patients post liv-ing-related donor transplant. Four BAL devices thatrely on hepatocytes cultured in hollow fiber membranecartridges (Circe Biomedical HepatAssist (r), VitagenELADTM, Gerlach BELS, and Excorp Medical BLSS)are currently in various stages of clinical evalua-tion. Comparison of the four devices shows that severalunique approaches based upon the same overall systemarchitecture are possible. Preliminary results of theExcorp Medical BLSS Phase I safety evaluation at theUniversity of Pittsburgh, after treating four patients(F, 41, acetominophen-induced, two support periods;M, 50, Wilson's disease, one support period; F, 53, a-cute alcoholic hepatitis, two support periods; F, 24,chemotherapy-induced, one support period) are pre-sented. All patients presented with hypoglycemia andtransient hypotension at the start of extracorporealperfusion. Hypoglycemia was treated by IV dextroseand the transient hypotension responded positively toIV fluid bolus. Heparin anticoagulation was used onlyin the second patient. No serious or adverse eventswere noted in the four patients. Moderate biochemicalresponse to support was noted in all patients. Morecomplete characterization of the safety of the BLSSrequires completion of the Phase I safety evaluation.

D-galactosamine based canine acute liver failure model

Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that re- moves many of the artifacts evidenced in prior canine models is presented. Methods: Six male hounds, 24-30 kg, under isoflu- rane anesthesia, were administered 1.5 g/kg D- galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pres- sure, extradural intracranial pressure (ICP), pul- monary artery pressure, and end-tidal CO_2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure>80 mmHg for 20 minutes despite maximal fluids and 20 μg·kg^(-1)·min^(-1) dopamine infusion. Results: The mean survival time was 43.7±4.6 hours (mean±SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/L), bilirubin (0.25 to 1.30 mg/dl), ammonia (19. 8 to 85. 3 μmol/L), and coagulopathy (pro- thrombin time from 8.7 to 46 s). Increased lability and elevations in intracranial pressures were ob- served. All animals were refractory to maintenance of cerebral perfusion pressure even with only mode- rately elevated intracranial pressure. Severe neuro- logic obtundation, seen in 2 of 6 animals, was associ- ated with elevations of ICP above 50 mmHg. Post- mortem liver histology showed evidence of massive hepatic necrosis. Postmortem blood and ascites mi- crobial growth was consistent with possible transloca- tion of intestinal microbes. Conclusions: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.

Surgical closure of large splenorenal shunt may accelerate recovery from hepato-pulmonary syndrome in liver transplant patients

Dear editor,Hepatopulmonary syndrome(HPS)is not uncommon in the setting of liver disease,especially in liver cirrhosis patients.The prevalence of HPS in liver cirrhosis patients varies from 4%to 47%.[1-3]About the definition of HPS,it is a pulmonary vascular disorder with evidence of intrapulmonary arterial venous shunt.[4]Pulmonary dyspnea and polycythemia are common presentations of HPS.Dyspnea,cyanosis and clubbed fingers were present in most of all cases.Spider nevi is another common clinical feature of patients with HPS.

肝脏移植术后的外科并发症

目的 探讨肝移植术后外科并发症的防治。方法 根据美国匹兹堡大学医疗中心Starzl移植研究所的经验 ,介绍与外科操作技术有关的术后常见并发症的防治方法。结果与结论 术后腹腔出血、肝动脉血栓形成、门静脉血栓形成、胆漏、胆道梗阻、胃肠道穿孔、胃肠道出血等是与外科技术操作有关的外科并发症。对肝脏移植术后异常情况的快速诊断和及时处理 ,是减少外科并发症的发生率和死亡率的重要措施。

肝移植供肝获取的现代方法与实践

目的 :介绍目前美国供肝切取的现代方法。方法 :3 0例供体 ,17例 ( 5 6.7% )因脑血管意外 ,13例 ( 4 3 .3 % )因外伤致脑死亡。 19例血流动力学相对稳定 ,11例 ( 3 6.7% )需用 2～ 3种升压药维持血压。先探测有无变异供肝动脉 ,游离肝周韧带及切断胆总管后 ,自腹主动脉插管灌注UW液 2 0 0 0ml。 3 0例中 ,2 8例切取供肝后再行门静脉插管灌注UW液 10 0 0ml;2例于术中行腹主动脉、门静脉双插管 ,分别灌注UW液 2 0 0 0ml、10 0 0ml。修整供肝时注意变异的供肝动脉 ,并予以重建。结果 :3 0例供肝中 ,2 8例用于受体 ,其中 1例移植后肝原发性无功能、1例移植后肝功能不良 ,均行两次肝移植 ,1例于移植后 18h大出血死亡 ;余 2 5例移植后如期恢复。结论 :美国获取供肝的条件趋于放宽 ,供肝切取的方法趋于快速 ,简捷。

肝移植术肝动脉栓塞的原因及血管重建的方式

目的分析肝移植术中和术后肝动脉栓塞(hepatic artery thrombosis,HAT)的原因,并探讨不同血管重建方式的效果. 方法回顾性总结Pittssburgh大学器官移植中心和南京大学附属鼓楼医院共21例肝移植术中、术后HAT,其中12例(57.1%) 施行了肝动脉重建术(hepatic artery reconstruction, HAR).HAR方法有直接吻合(4例)、供体肝动脉-受体腹主动脉架桥术(aortohepatic interposition graft,AHIG)(6例)、髂动脉架桥术(interposition graft,IG)(2例). 结果肝动脉血流重建成功率为58.3%(7/12);其余5例平均3.8(3～6)d内再次发生HAT.成人HAR成功率为62.5%(5/8),儿童为50.0%(2/4).HAR结果与HAT发生时间、 HAT原因和HAR方式无明显相关性 (P>0.05). 结论肝移植术HAT可能原因有机械因素、受体肝动脉细小、供体肝动脉感染、供体DIC等,尽量减少或避免上述危险因素是最好的预防方法.肝移植术HAT时HAR方式包括直接吻合、AHIG、IG等,成功取决于能否及时获得诊断.有趋势表明机械因素所致HAT,HAR方式采用直接吻合和AHIG有较好的临床结果.

晚期移植肝功能不全的原因

总结复习晚期移植肝功能不全各方面的相关文献 ,综合分析肝移植术后晚期移植肝功能不全的原因。结果显示晚期移植肝功能不全是比较常见的远期并发症 ,其病因主要包括有排异、胆道或血管并发症、原发病的复发、感染、以及其他原因等。随着肝移植存活率的不断提高 ,晚期移植肝功能不全将日益受到重视。

转基因猪对异种移植的影响研究

对于器官衰竭的患者来说,器官移植是最好的治疗手段。尽管在过去的50年做了很大的努力,但这个问题仍未完全解决,事实上还有很多新的问题。纵观20世纪,有人尝试用动物器官作为临床移植器官的来源[1-2]。这些动物一般为非人类灵长动物（nonhuman primates,NHPs）。通过一些使用NHPs作为供者的实验发现,

Vitamin B-reath easier:vitamin B6 derivatives reduce IL-33 to limit lung inflammation

It has been known for some time that low PLP blood levels are common in asthmatic patients,and supplementation with vitamin B6 may reduce the severity of asthma symptoms[12].In the current study,a comparison of PLP levels in the plasma of asthmatic patients(n=52)and healthy controls(n=58)confirmed lower PLP concentrations in asthmatic patients,which correlated with reduced lung function and increased circulating eosinophils,suggestive of increased type 2 inflammation.Using several mouse models of acute lung inflammation,they confirmed that systemic or local administration of PLP reduced lung inflammation and eosinophil density,suggesting that PLP concentration may be directly controlling immune responses that lead to the development of allergic airway disease.ILC2s constitutively express ST2,and IL-33 profoundly promotes ILC2 expansion and secretion of IL-5 and IL-13 to mediate allergic reactions and support host defenses against parasitic worms.PLP reduces the number of type 2 innate lymphoid cells(ILC2s)and their expression of IL-5 and IL-13.Conversely,diet-induced vitamin B6 deficiency in mice increased papain-induced lung inflammation,including increasing the proportion of IL5+and IL-13+ILC2s.The authors revealed that PLP treatment decreased IL-33 levels in the bronchoalveolar lavage fluid(BALF)and lung and targeting IL-33 with an antibody during papain-induced lung inflammation did not reduce inflammation beyond that of PLP treatment alone.An important clue to the regulation of IL-33 was that PLP treatment did not modify IL-33 mRNA levels.Instead,pyridoxal(PL)treatment of a human alveolar basal epithelial cell line(A549)stably expressing full-length IL-33 with a hemagglutinin(HA)tag established that PL exposure potently decreased intracellular IL-33 protein levels.The researchers used this cell line to explore the underlying mechanisms and verified that PL conversion to PLP by pyridoxal kinase(PDXK)controlled the stability of IL-33.Consistent with these data,the IL-33 concentration and papain-induced lung inflammation were augmented significantly in PDXK-deficient mice.The author’s use of degradative pathway inhibitors and truncated IL-33 constructs pinpointed a mechanism involving protective ubiquitylation of the IL-33 N-terminal domain that is inhibited by vitamin B6.A comprehensive database search for proteome-wide known and predicted ubiquitin ligase/deubiquitinase-substrate interactions showed that mouse double minute 2 homolog(MDM2)was a likely E3 ubiquitin ligase interacting with IL-33.Recent studies have shown that MDM2,while best known for its regulation of p53,mediates the ubiquitination and stability of numerous nuclear proteins,including Foxp3,HDACs,and STATs[13,14,15].In the current work,MDM2 interacted with IL-33 via a RING domain to facilitate IL-33 stability via ubiquitination of lysines to control IL-33 homeostasis,and this ubiquitination could be inhibited by vitamin B6(Fig.2).It will be important for future studies to establish how precisely PLP suppresses the functional interactions between IL-33 and MDM2.

Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling

Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

96例肝移植后胆道并发症的诊断和处理经验

目的研究肝移植后胆道并发症的诊断和处理及分析相关因素.方法回顾性研究Pittsburgh移植中心96例肝移植病人.结果 94例(97次移植) 存活2天以上的病人,92例为端端+T管的胆道吻合.随访时间为5.8月(0. 3-10.2).分析发现92例病人中8例有胆道并发症(8.5%):T管拔除时胆漏2例,术后早期胆漏2例,胆漏和狭窄2例,狭窄2例.75%胆道并发症有诱因,诱因:肝动脉狭窄2例,其中1 例合并严重排斥反应;肝动脉血栓3例;供-受体胆管直径不匹配1例.冷缺血时间无显著性差异.5例有肝动脉血栓和/或狭窄>50%行再移植,另3例无肝动脉血栓和/或狭窄<50%经皮穿刺和内窥镜+支架或行气囊扩张.所有病人均获得良好疗效.结论肝移植术后胆道并发症发生率为8.5%α胆-胆端端吻合+T管),胆道狭窄晚于胆漏,肝动脉栓塞和/或狭窄是最重要的相关因素;无肝动脉栓塞和/或狭窄,则无需手术治疗,若有肝动脉栓塞和/或狭窄,应尽早作再次肝移植.

不同比例缩小体积肝移植的大动物研究

目的研究不同比例缩小体积肝移植的结果,确定猪能耐受的最小体积的肝移植。方法远系繁殖猪70头分为原位全肝移植作为对照组和3组不同比例缩小体积原位肝移植(按照缩小体积的移植肝占受体切除肝脏重量的百分比;1组:60%;2组:30%;3组:20%);实验采用原位经典肝移植方式(静脉转流)。术后第3天和第5天取肝标本。结果对照组和3组不同比例缩小体积肝移植的移植物与受体肝脏重量百分比(GIWRW)分别为87·4%±8·3%、59·9%±5·2%、33·6%±4·9%和22·1%±3·4%;移植物与受体体重百分比(GIWBW)分别2·4%±0·4%、1·43%±0·17%、0·81%±0·09%和0·53%±0·06%。对照组、1组和2组存活率达100%;3组存活率仅为53%。4个组的动物处死后肝脏移植物重量均有显著的增加。结论安全的缩小体积肝移植,应以移植物与受体肝脏重量百分比不小于33%,同时移植肝与受体重量百分比不小于0·8%为限。