Recovery of graft steatosis and protein-losing enteropathy after biliary diversion in a PFIC 1 liver transplanted child

PFIC 1 is a genetic disorder characterized by hepatic and gastrointestinal disease, often requiring LT during childhood. Extrahepatic symptoms, such as diarrhea and malabsorption, do not improve or may be aggravated after LT, as graft steatosis or steatohepatitis as consequences of the interaction between transplanted liver and native bowel. We describe a patient with PFIC 1 who presented with cholestasis in infancy, who developed intractable pruritus and liver fibrosis. The child underwent living donor LT at 3.6 yr of age, and he early developed severe refractory diarrhea, secondary malabsorption with protein-losing enteropathy, and an early fatty liver disease trough graft steatohepatitis. As the response to cholestyramine was unsatisfactory, we decided to perform an EBD by using the jejunal loop used for the cholangiojejunostomy. Diarrhea resolved rapidly after surgery. He remained well after six months following biliary diversion, with normal stool output and no protein loss. We documented a dramatic improvement of graft steatosis at histology as well as normalization of liver function test. EBD can be considered a valuable treatment option to avoid organ disfunction and loss in PFIC 1 transplanted patients who develop graft steatohepatitis.     

Factors predicting persistent thrombocytopenia after living donor liver transplantation in pediatric patients

Thrombocytopenia is common after LT for pediatric end-stage liver diseases. Seventy-six pediatric patients (≤15 yr old) who underwent LDLT were evaluated for the incidence and predictive factors of post-transplant thrombocytopenia (PLT <100, 000/mm(3) ). The prevalence of thrombocytopenia at two wk and at 12 months post-transplant was 22/76 (28.9%) and 11/62 (17.7%), respectively. Thrombocytopenia at two wk after LDLT was significantly associated with age at transplant, preoperative PLT, GRWR, acute rejection, and CMV infection in univariate analysis. Moreover, preoperative PLT, GRWR, and acute rejection had a strong correlation in multivariate analysis. Thrombocytopenia at 12 months after LDLT was associated only with preoperative PLT. We also demonstrated that vascular complications caused thrombocytopenia and that successful treatment recovered the PLT. These results showed that, in addition to considering the preoperative PLT, post-operative monitoring of platelets is very helpful for the early detection of adverse events related to the graft liver in pediatric liver transplant patients.     

小儿肝移植13例经验回顾

目的 总结小儿肝脏移植13例的经验及教训.方法 从2001年9月至2007年8月对13例终末期肝病患儿实施了肝移植术,其中先天性胆道闭锁7例,先大性肝纤维化3例,肝豆状核变性1例,Caroli病1例.肝脏血管内皮肉瘤1例,年龄5个月至12岁.供体及受体在门诊进行367个月随访并收集数据,对受体存活期与手术方式、术者经验、患儿年龄及原发病、家庭经济状况、父母教育背景等因素的关系进行分析.结果 本组13例患儿全部顺利完成肝移植手术.不同手术方式的结果 :亲体肝移植4例,供体随访6～59个月,均无并发症,健康生活;4例受体,1例于手术后15个月死于急性坏死性肠炎.另外3例无并发症健康生活,其中1例手术后25个月免疫耐受.尸体肝移植9例,目前存活4例,已死亡4例;另外1例手术后14个月因慢性排斥反应行二次肝脏移植手术.不同手术时间的结果 :2001年1月至2003年1I)月间手术6例.已死亡5例,2年生存率为33.3%;2004年4月至2007年4月间开展手术7例,已死亡1例.存活6例,2年牛存率为57.1%.结论肝移植是治疗小儿终末期肝病的有效方法 ,随着经验的积累,手术并发症和病死率有大幅度降低的趋势.医生和护理人员的经验,患儿的病情,家庭的经济实力,家庭主要成员的心理承受力、挽救孩子生命的动机、坚定程度和毅力,医护人员和家长的密切配合是影响肝移植预后的因素.     

Biliary drainage as treatment for allograft steatosis following liver transplantation for PFIC‐1 disease: A single‐center experience

Development of macrovesicular steatosis post–LT in patients with PFIC‐1 is increasingly being observed, with the etiology not fully understood. We highlight successful and effective EBD for reversal of allograft steatosis in 2 patients with PFIC‐1 disease and discuss our experience with internal biliary diversion in this patient population.     

Liver transplantation in a child with liver failure due to chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor

Englert C, Ganschow R. Liver transplantation in a child with liver failure due to chronic graft‐versus‐host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor. Abstract: We report a case of a six‐yr‐old boy who developed chronic GVHD of the liver, intestines, and skin following allogeneic hematopoietic SCT. The boy received an allogeneic hematopoietic stem cell transplant at the age of two yr because of early recurrence of ALL. Chimerism analysis showed complete chimerism. In the following year, he developed GVHD despite adequate immunosuppressive therapy. Liver biopsy showed liver GVHD resulting in liver cirrhosis by the age of five yr. LTx was performed with a left liver lobe from the unrelated donor from whom the stem cells had been taken. Immunosuppressive therapy consisted of low‐dose steroids and low‐dose cyclosporine. The postoperative course was uneventful. Graft function was excellent, and we performed protocol biopsies at seven days and three wk as well as three, six, and nine months after transplantation; none of these showed any signs of rejection or GVHD. Immunosuppressive therapy was discontinued nine months after LTx. Three yr after transplantation, the boy is in good condition with normal graft function. To our knowledge, this is the first report on LTx following allogeneic hematopoietic SCT from the same unrelated living donor.     

活体肝移植治疗Ⅰ型酪氨酸血症的疗效

目的 探讨活体肝移植治疗Ⅰ型酪氨酸血症(HT Ⅰ)的手术疗效和预后.方法 2013年7月至2015年5月,4例确诊为HT Ⅰ的患儿(3男1女)在我中心接受了活体肝移植手术,手术指征均为肝硬化失代偿及AFP过高.患儿术前Child分级:B级3例,C级1例.患儿中位手术年龄4.4岁(1.9～5.9岁),供体均为患儿父母.患儿术后中位随访时间17个月(9～24个月).结果 4例活体肝移植手术供、受体均手术顺利,术后恢复良好.患儿术后酪氨酸代谢恢复正常,异常代谢产物琥珀酰丙酮(SA)、琥珀酰乙酰乙酸(SAA)、延胡索酰乙酰乙酸(FAA)和马来酰乙酰乙酸(MAA)的血清水平下降到测不出水平,肝功能和AFP在随访期间都维持正常.术后电解质水平恢复正常,肾功能维持稳定.所有患儿术后均表现出追长趋势.并发症方面,1例患儿出现EBV病毒感染和急性排斥反应,1例患儿术后存在乳糜漏和反复腹水,1例患儿出院后6个月感染手足口病病毒,均得以治愈.结论 活体肝移植是治疗HTⅠ的有效方式,术后患儿的代谢异常、肝肾功能和AFP水平均恢复正常,其术后生存率令人满意,但长期随访应注意肾功能的检测.     

Towards minimizing immunosuppression in pediatric liver transplant recipients

Abstract:  Immunosuppression regimens after liver transplantation focus mainly on preventing rejection and subsequent graft loss. However, in children, morbidity and mortality rates from infections exceed those from rejection after transplant, and immunosuppression can hinder growth, renal function, and graft tolerance. We hypothesized that early steroid withdrawal, with a primary aim of TAC monotherapy would yield no penalty in terms of rejection and graft loss, while reducing risks of infection and maximizing growth. We prospectively evaluated 64 consecutive pediatric liver transplant recipients. One yr patient/graft survival was 93/90%, respectively. At one yr post-transplant, 75.4% of patients were on TAC monotherapy. No deaths or graft losses were caused by infection. Sixty-one percent of patients had at least one episode of rejection, most within three months following transplant and 3.8% were treated for chronic rejection. One non-compliant adolescent died from chronic rejection. CMV, EBV, and lymphoproliferative disease rates were 3.1%, 5.3%, 1.8%, respectively. Pretransplant and one yr post-transplant glomerular filtration rates were unchanged. One yr improved catch-up growth was observed. We conclude that immunosuppression minimization after pediatric liver transplant yields no serious complications from rejection, and might confer advantages with respect to infection, renal function, growth, and is deserving of wider application and study.     

Liver graft volumetric changes after living donor liver transplantation with segment 2 graft for small infants

Urahashi T, Mizuta K, Sanada Y, Wakiya T, Yasuda Y, Kawarasaki H. Liver graft volumetric changes after living donor liver transplantation with segment 2 graft for small infants. Abstract: LT for small infants weighing <5 kg with liver failure might require innovative techniques for size reduction and transplantation of small grafts to avoid large‐for‐size graft, but little is known about post‐transplant graft volumetric changes. Five of 172 children who underwent LDLT received monosegment or reduced monosegment grafts using a modified Couinaud’s segment II (S2) graft for LDLT. Serial CT was used to evaluate the changes in the GV and other factors before LDLT and one and three months after LDLT. The shape of these grafts was classified into an OL type and an LL type. The GV increased in all patients one month after LDLT, whereas the GV decreased three months after LDLT in OL in comparison with one month after LDLT. The GRWR of the OL type has tended to decrease at three months, whereas the LL type showed a continuous increase with time, but finally they had adapted graft size for their body size. In conclusion, the volume of S2 grafts after LDLT had unique changes toward the ideal volume for the child weight when they received the appropriate liver volume.     

Optimizing hepatic venous outflow reconstruction for hepatic vein stenosis with indwelling stent in living donor liver retransplantation

The patient was a boy of 7 years and 5 months of age, who underwent LDLT for acute liver failure at 10 months of age. HV stent placement was performed 8 months after LDLT because of intractable HV stenosis. At 7 years of age, his liver function deteriorated due to chronic rejection. The patient therefore underwent living donor liver retransplantation from his father. The HV was transected with the stent in situ. The IVC was resected due to stenosis. The pericardial cavity was opened and detached around the IVC to elongate the IVC. The divided ends of the IVC were joined by suturing to the posterior wall of the IVC. A new triangular orifice was made by adding an incision on the anterior wall of the IVC. The graft HV was then anastomosed to the new orifice with continuous sutures in the posterior wall and interrupted sutures in the anterior wall using 5‐0 non‐absorbable sutures. Doppler ultrasound showed a triphasic waveform. We successfully performed HV reconstruction without a vascular graft. This is a feasible procedure for overcoming HV stenosis in LDLT patients with an indwelling stent.     

Living donor liver transplantation for acute liver failure in infants: the impact of unknown etiology

Abstract:  Infants with ALF occasionally have the most urgent need for a liver transplant. In urgent situations for liver transplantation, LDLT has been advocated. Between July 1995 and April 2004, medical records of 15 infants undergoing LDLT for ALF of unknown etiology were reviewed and their outcomes were compared with infants undergoing LDLT for other liver diseases. They received LLS (n = 9), MS (n = 3), and RMS (n = 3) grafts. Eight technical complications occurred, with a similar incidence for LDLT and the other liver diseases. On the other hand, the liver biopsies after LDLT showed a significantly higher incidence of ACR with centrilobular injuries. Ten patients died after primary LDLT because of refractory rejection (n = 6), rotavirus infection (n = 2), chronic rejection (n = 1), and surgical complications (n = 1). With a median follow-up of 7.0 months, five-yr graft and patient survival rates were 17.8% and 26.7%, respectively. In conclusion, the outcome of LDLT for ALF in infants, especially cases with unknown etiology, was unsatisfactory and refractory rejection often led to liver failure. From our observation the centrilobular changes were characteristics of ACR in infantile LDLT for cryptogenic ALF.     

Total internal biliary diversion during liver transplantation for type 1 progressive familial intrahepatic cholestasis: a novel approach

LT for PFIC type 1 is often complicated by postoperative diarrhea and recurrent graft steatosis. A 26‐month‐old female child with cholestatic jaundice, pruritus, diarrhea, and growth retardation revealed total bilirubin 9.1 mg/dL, gamma‐glutamyl transpeptidase 64 IU/L, and TBA 295.8 μmol/L. Genetic analysis confirmed ATP8B1 defects. A LT (segment 2, 3 graft) from the heterozygous father was performed. Biliary diversion was performed by a 35‐cm jejunum conduit between the graft hepatic duct and the mid‐transverse colon. Stools became pigmented immediately. Follow‐up at 138 days revealed resolution of jaundice and pruritus and soft‐to‐hard stools (6–8 daily). Radioisotope hepato‐biliary scintigraphy (days 26, 68, and 139) confirmed unobstructed bile drainage into the colon (t_1/2 34, 27, and 19 minutes, respectively). Contrast meal follow‐through at day 62 confirmed the absence of any colo‐jejuno‐hepatic reflux. At 140 days, contrast follow‐through via the biliary stent revealed patent jejuno‐colonic anastomosis and satisfactory transit. Graft biopsy at LT, 138 days, and 9 months follow‐up revealed comparable grades of macrovesicular steatosis (<20%). TIBD during LT may be a clinically effective stoma‐free biliary diversion and may prevent recurrent graft steatosis following LT for PFIC type 1.     

Successful autologous peripheral blood stem cell transplantation with a double-conditioning regimen for recurrent hepatoblastoma after liver transplantation

Abstract:  A four-yr-old boy developed a solitary metastasis nine months after living-related liver transplantation for unresectable hepatoblastoma. After resection of the metastatic lesion, he received an auto-PBSCT with a double-conditioning regimen consisting of melphalan and thiotepa. Auto-PBSCT could be safely performed without any serious regimen-related toxicity or infection. However, transient cessation of tacrolimus during myelosuppression resulted in graft rejection of the liver just after hematological engraftment, but rejection was resolved by tacrolimus and methylprednisolone. The patient is alive and free from disease two yr after auto-PBSCT without any signs of graft rejection. High-dose chemotherapy using this conditioning regimen may be feasible for recurrent hepatoblastoma after liver transplantation in terms of safety and anti-tumor activity.     

Therapeutic Interventions in Progressive Familial Intrahepatic Cholestasis: Experience from a Tertiary Care Centre in North India

Medical therapy has limited value in managing symptoms of progressive familial intrahepatic cholestasis (PFIC). Liver transplantation (LT) is the only definite therapy for progressive liver failure and intractable pruritis. In recent years, biliary diversion (BD) has also shown therapeutic promise. This study was designed to review the experience of management and outcome of seven PFIC patients. Two children each had type II and III and three had type I/II PFIC, respectively. Medical treatment was successful in only one. Decompensated cirrhosis had already set in four children. They underwent a living related LT. There was one post transplant mortality. Remaining all children had a normal graft function at a mean follow-up of 50 months. One patient of PFIC type I/II received internal and another of PFIC type II received external BD. Both patients were asymptomatic at follow-up of 19 and 23 months respectively. Nontransplant surgical options should be offered to noncirrhotic children with PFIC.     

Budd–Chiari syndrome in children and outcome after liver transplant

Gomes AC, Rubino G, Pinto C, Cipriano A, Furtado E, Gonçalves I. Budd–Chiari syndrome in children and outcome after liver transplant. Abstract: BCS is a rare form of portal hypertension in children. The authors describe two cases of BCS with differing presentations. Case 1: Previously healthy four‐yr‐old girl. BCS was diagnosed during the course of an episode of acute gastroenteritis with dehydration. Despite conservative therapy for two months, the condition was progressive resulting in liver failure leading ultimately to LT. Molecular studies showed that she was heterozygous for the Factor (F) V Leiden. At follow‐up, six yr post‐LT (two yr without anticoagulation therapy), no thromboembolic/bleeding events were apparent. Case 2: Three‐yr‐old boy with IgA deficiency and liver disease. Following a febrile episode, he developed fulminant liver failure requiring urgent LT from a living donor (father). Molecular studies disclosed MTHFR C677T homozygosity and FV Leiden heterozygosity. The father was homozygous for the MTHFR mutation. Three months post‐LT, persistent graft dysfunction was associated with stenosis of the IVC, which improved upon stent placement. He received dipyridamole and aspirin for five yr, after which time dipyridamole was discontinued. Evidence is sparse on the follow‐up of BCS cases with liver transplant. The authors discuss their findings, particularly the need for long‐term anticoagulation.     

Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience

Heffron TG, Pillen T, Smallwood G, Rodriguez J, Sekar S, Henry S, Vos M, Casper K, Gupta NA, Fasola CG, Romero R. Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience.
Pediatr Transplantation 2010:14:228–232. © 2009 John Wiley & Sons A/S. Abstract: Children transplanted for ALF urgently require an optimal graft and have lower post‐transplant survival compared with children transplanted for chronic liver disease. Over 10 yr, 33 consecutive children transplanted for ALF were followed. Demographics, encephalopathy, intubation, dialysis, laboratory values, graft type ABOI, XL (GRWR > 5%), DDSLT, LDLT and WLT were evaluated. Complications and survival were determined. ALF accounted for 33/201 (16.4%) of transplants during this period. Twelve of 33 received ABOI, five XL grafts, 18 DDSLT, and three LDLT. Waiting time pretransplant was 2.1 days. One‐ and three‐yr patient survival in the ALF group was 93.4% and 88.9%, and graft survivals were 86.4% and 77.7%. Median follow‐up was 1452 days. ABOI one‐ and three yr patient and graft survival in the ALF was 91.6% and 78.6%. No difference in graft or patient survival was noted in the ALF and chronic liver disease group or the ABOI and the ABO compatible group. A combination of ABO incompatible donor livers, XL grafts, DDSLT, LDLT and WLT led to a short wait time and subsequent graft and patient survival comparable to patients with non‐acute disease.     

Recanalization of post‐transplant late‐onset long segmental portal vein thrombosis with bidirectional transhepatic and transmesenteric approach

PV complications are the most frequent vascular complications in pediatric LT. We have experienced a case with chronic postoperative PVT that necessitates combined transhepatic and transmesenteric approach and have confirmed mid‐term patency. An eight‐yr‐old boy had successful LDLT with a left lateral segment graft at the age of two months for HBV‐related acute liver failure. Seven years after transplantation, the patient suddenly showed a melena with hypovolemic shock. Doppler ultrasound and CT revealed intrahepatic bile duct dilatation and main PVT with collateral formation at hepatic hilus and mesenterium of the Roux‐en‐Y jejunal loop. Urgent splenic artery embolization was performed to control the bleeding and was temporarily effective. Therefore, recanalization of PVO was attempted. Because of long segmental PVO and steep angle between the intrahepatic PV and the portal trunk, bidirectional transhepatic and transmesenteric approach was selected and resulted in deploying three metallic stents necessitating additional infusion thrombolytic therapy. The patient is now followed as an outpatient with patent stents for two yr since the procedure. For the rescue of these patients, recanalization of obstructed PV trunk with bidirectional approach would be feasible with better graft survival and less invasiveness than conventional surgical interventions.     

Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a severe cholestatic liver disease of early life often requiring liver transplantation. Organ shortage leads to consider living-related liver transplantation. Because of possible partial metabolic defect in heterozygotes, the use of familial donors might be questionable. We therefore evaluated the safety of this procedure, for both donors and recipients. We compared a series of seven parental-children pairs, having participated in the living related liver transplant program for PFIC between 1994 and 2001, with that of a series of seven parental-children pairs, performed for biliary atresia (BA) during the same period. No primary graft dysfunction was observed. There was no difference in the course of transaminases, gamma-glutamyl transpeptidase and bilirubin levels after transplantation in both donor and recipient series. Thirteen recipients and 14 donors are alive and well 3-10 yr post-surgery. One PFIC recipient died nine months post-orthotopic liver transplantation from sepsis. We conclude that PFIC heterozygote status of the donor does not increase the risk of liver dysfunction in either recipients or donors, with a similar course compared with BA recipients and donors.     

Sequential liver-kidney transplantation in a boy with congenital hepatic fibrosis and nephronophthisis from a living donor

Udagawa T, Kamei K, Ogura M, Tsutsumi A, Noda S, Kasahara M, Fukuda A, Sakamoto S, Shigeta S, Tanaka H, Kuroda T, Matsuoka K, Nakazawa A, Nagai T, Uemura O, Ito S. Sequential liver–kidney transplantation in a boy with congenital hepatic fibrosis and nephronophthisis from a living donor.
Pediatr Transplantation 2011. © 2011 John Wiley & Sons A/S. Abstract: A five‐yr‐old boy developed chronic liver failure and ESKD because of CHF and juvenile NPHP. He underwent sequential liver and kidney transplantation with a compatible blood type from his father, at five yr, seven months and five yr, 11 months old, respectively. Because the patient was not in ESKD, we initially performed LDLT because of significant portal hypertension. Even after LDLT, his ascites was not ameliorated, and he needed continuous drainage of ascites and daily albumin and gamma globulin infusion. Thereafter, he progressed to ESKD and needed hemodialysis for one month before LDKT. CDC crossmatch for donor B cells in the warm test, FCXM for B cell IgG, and flow PRA for donor class II were positive before LDKT. After pretreatment of three courses of plasma exchange and intravenous gamma globulin, LDKT was performed. Two weeks after LDKT, AIHA concomitant with autoimmune thrombocytopenia, also called Evans syndrome, occurred because of passenger lymphocytes from the donor; however, the patient was successfully treated with intravenous methylprednisolone. Eighteen months have passed since LDKT, and liver and kidney function in both the recipient and donor are normal.     

Bowel obstruction due to diaphragmatic hernia in an elder child after pediatric liver transplantation

A 10-yr-old boy with end-stage liver cirrhosis due to Wilson's disease received a living donor liver transplantation (LDLT) at our institution. The donor was his father and the graft was a left lateral segment. The liver transplantation procedure and the postoperative course were uneventful. Two months after the procedure, he developed a first episode of bowel obstruction that was treated with conservative therapy. During a second episode of bowel obstruction, he also presented respiratory distress. A plain chest X-ray revealed the presence of small intestine loops in the right thoracic cavity and bowel obstruction due to diaphragmatic hernia was diagnosed. Repair of the diaphragmatic hernia was performed and the patient has been doing well after the surgery. Diaphragmatic hernia after LDLT is rare but should be recognized as a possible complication when a left lobe or a left lateral segment graft is used.     

Liver transplantation for hereditary tyrosinemia type I: analysis of the UNOS database

Patients with HT-1 can develop progressive liver disease and have a high incidence of HCC. LT is indicated in patients with fulminant liver failure, HCC or decompensated chronic liver disease refractory to NTBC. To determine the need for LT and outcomes after LT in children with HT-1. Children with HT-1 who had LT between 10/1987 and 5/2008 were identified from the UNOS database. Of 11,467 children in the UNOS database, 125 (1.1%) required LT secondary to HT-1. Mean age at LT was two and half yr (s.d. ± 3.6 yr). Mean age at LT during the first 10 yr of the study (1.82, s.d. ± 2.86 yr) was significantly lower than in the last decade (3.70, s.d. ± 4.42 yr), p = 0.01. Nearly half of the patients (58, 46.4%) were transplanted between 1988 and 1992. Overall, one- and five-yr patient survival was 90.4% and 90.4%, respectively. LT is a valuable option for children with HT-1 with fulminant liver failure or when medical treatment fails. The rate of LT for children with HT-1 has decreased and age at transplant increased over the last decade most probably reflecting the effect of early diagnosis and treatment with NTBC.